1 Drug Product Development in the Pharmaceutical Industry G u r vi n d e r S i n gh R ek h i L e o n Sh a r ge l
I. INT...
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1 Drug Product Development in the Pharmaceutical Industry G u r vi n d e r S i n gh R ek h i L e o n Sh a r ge l
I. INTRODUCTION A. Ac t i ve p h a r ma c eu t i ca l i ng r e d ie n t ( AP I ) 1 . A d ru g su b s ta n ce i s th e A P I o r c om po n en t th at p r od uc es ph a rm ac o lo gic a l a c ti vi t y. 2 . Th e A P I m a y b e p r o du c e d b y c h e m i ca l s y n t he s is , r e co v e r y f r om a na tu r a l p r o du c t, en z y m a t ic re ac ti o n , r ec om b in an t D N A tec h no l og y , fe r m e n ta t io n , o r a c om b in a ti o n o f t he s e p roc es s es . F u rt h e r p u ri fi c at io n of t he A P I m a y b e n ee d e d b e f o re it c a n b e u s e d i n a d r ug pr o du c t. 3 . A new c he m ic a l e n ti ty ( N C E ) i s a d ru g s ub s tan c e wi t h u nk no wn c li ni c al , t o xi c o l og ic , p h y s i c al , a nd c h em ic a l p r op e r ti es . I n a d di t io n , t he U . S . F oo d a n d D ru g A d m in is t ra t io n (F D A ) c on s id e rs an N C E a s a n AP I t ha t ha s n ot be e n a ppr o ve d fo r m a rk e ti n g i n t he U ni t ed S t a t es . 4 . Th e id e n ti t y, s t r e n g th , q ua l i t y, a n d p u r i t y o f a d ru g s ub s ta nc e d e pe nd o n p r o pe r c o n tr o l o f t h e m an u f ac tu r i ng an d s y n th e tic p ro ce s s . B . D r u g p r od u c t 1 . A d r u g p r od uc t i s t h e f i n i s he d d o sa g e f o r m (e . g . , ca ps u le , ta bl e t, in j ec t ab l e ) t h a t c on t ai ns th e A PI , gen e r al l y in as s o c i a ti on wi t h o th e r e xc i p i en ts , or in er t i n g re d ie n ts . 2 . Th e e xc i pi en t s i n t he d r u g p r od uc t m a y af f ec t t h e fu nc t io na l it y a nd pe r fo r m an ce o f t he dr u g p r od uc t , i nc lu d in g m o di fi ca t io n o f th e r a t e o f d r ug s u bs t an c e re l ea s e, i m p ro vi ng d ru g s t ab il i t y , a n d m as k i ng t he dr u g t as t e . 3 . D i ff e re n t a p p r oa c he s a r e ge ne r a ll y us e d t o p ro d uc e d r ug p ro d uc ts th a t c on t ai n N C E s , p ro du c t l in e e xt e n s i on s , ge n e ri c d r ug pr o du c ts , a n d s p ec i al t y d ru g p r o du c ts . C . N ew d r u g p r o du c t d eve l o p m en t D r u g p ro du c ts c on t ai n ing N C E a re de ve l op e d s eq u e nt i a l l y i n th e f o ll o wi ng p ha s e s . 1 . P r ec l i ni c al . A ni m a l ph a r m a c o lo g y a nd to xi c o lo g y d at a a r e o b ta i n e d t o d e te r m i n e t h e s a fe t y an d e f f ic ac y of t h e d ru g . Be c a us e l i tt l e i s k no wn a b ou t t h e h um a n an d t h e t h e r ap eu t ic / to xi c o l og ic po t e nt i al , m an y d r ug p ro du c ts wi l l n o t r ea c h t he m a r k et p la c e . N o a t te m p t i s m ad e t o de v e l o p a f i na l f o rm ul a ti on d u ri ng t he pr ec l in ic a l st a g e. N o n c l in i ca l st u d ie s a r e n o nh um a n s tu di es t ha t m a y co n ti nu e at an y s tag e of r e s ea r ch to ob t ai n a d di tio n al in f o rm a ti on c o nc e rni n g t h e p ha r m a c o lo g y a nd t o xi c o l og y o f t h e d r ug . 2 . P ha s e I a . A n I n ve s t ig a t io n al New D r ug ( I N D ) a pp l ic at io n fo r hu m a n t e st i ng i s su b m i t te d to t h e F D A. C li n ic al te s t i ng t a k e s p la c e af t e r t he I ND a p pl ic a ti o n is s u bm it t ed . P.2
b . H e al t h y v ol u nt e e rs a re us e d i n p ha se I c li ni c a l s t ud ie s t o d e te r m i n e d rug t o l er a nc e a nd t o xi c it y . c . Fo r or a l d r ug ad m i ni s tr a t io n , a s im p le ha r d g ela t i n ca ps u le fo r m u l at i on c o nt a in in g t h e A PI is us ua ll y u s e d fo r I N D s t ud i es . d . To xi c o l o gi c s t u di es — in c lu di n g a cu t e, c h r on ic , s u bc h ro ni c , a nd m u ta g en i c i t y — a nd o t h e r su c h s t u di es in v a ri o us an im al s p ec i es a r e p l an n ed du r in g th is ph as e . 3 . P ha s e I I a . A l im i te d n um b e r o f pa t i en ts wi t h th e d is e as e o r c o n di t io n f o r wh ic h t he d r ug wa s d e ve l op ed a re t re a te d un d e r c lo s e s u pe r v i s i on . b . D os e - re s p o ns e s tu d ies , bi oa va i la bi l it y , a nd pha r m a c ok in e ti cs a r e p e r for m e d t o d e t e rm in e t h e o pt im um do s ag e re gi m e n fo r t re a tin g th e d is e as e. c . S af e t y i s m ea s u r ed b y a t t em pt i ng to de t e rm in e t h e t h e r ap e u ti c i n d ex (r a t io o f t o xi c d os e t o e f f ec ti v e do s e ). d . A dr u g f o rm ul a ti o n h av i n g go o d p h ys ic o -c h em ic a l s ta bi l it y i s d e vel op e d. e . C h ro n ic to xi c i t y s t u di es a re s t a r te d i n t wo s pe c i e s ; su c h s t ud i es n o rm a lly l a s t m o r e t ha n 2 y e a rs ' du r a ti o n . 4 . P ha s e I I I a . La r g e- s c a le , m u l ti c ent e r c l in i ca l s t u d ie s a r e p e r f or m e d wi t h t h e f in a l d o s a g e f o r m d e vel o pe d i n p ha s e I I . Th es e s tu d ie s a r e d on e to de t e rm in e t h e s af et y a n d e f f ic ac y o f t h e d ru g p r o du c t i n a l a r ge pa t ie n t p op u la t io n wh o ha v e th e d is e as e o r c o nd i ti on f o r wh i c h t he dr u g wa s d e v e lo p ed . b . S id e e f f ec ts ar e m on i to r e d . I n a l a r ge po pu l at io n , n e w t o xi c e f fe c t s m ay o c cu r t h a t we r e n o t e v i de n t i n p r e v i ou s c li ni c a l tr i al s. 5 . S ub m i s s io n o f a N ew D r u g Ap p l i c a ti o n ( N D A) . A n N D A i s s ub m i t te d t o t h e F D A f o r r e vie w a n d a p pr o v a l a f t e r t he c o m p le t io n o f c li n ic al t ri a ls th a t s h o w t o t h e s a ti s fa c t i on of t he m e di c a l c om m u n it y t h at t he dru g p ro du c t is e ff ec t i v e by a l l p a r am e te r s a nd is re as on a bl y s af e a s d em o ns t rat e d b y a ni m a l a n d h um an s tu di es . 6 . P ha s e I V a . A f te r th e N D A i s s u bm i t t ed , a n d b e fo r e a pp r o va l to m a rk e t t h e p r od uc t i s o b ta i ne d f r o m t he F D A , m an u fa c t ur i n g s ca l e -u p ac ti v i t ie s o c c u r . S c al e -u p i s t he inc r e as e i n t h e b a tc h s i z e f r om th e c l i ni c a l b a tc h , s u bm is s i o n b a tc h , o r b o th to t he fu ll- s c a l e p r o du c ti on ba t c h s i z e , us i ng th e fi ni sh e d, m a r k e te d p ro du c t. b . Th e d ru g p r od uc t m a y b e i m p r o v e d as a r es u lt o f eq u ip m e n t, r eg u la t or y , s up pl y , o r m a r ke t d em a nd s . c . A dd it i on a l c l i ni c a l s tud i es m a y be p er f o rm ed in s p ec i al po p ul a ti on s , s uc h a s t h e e l de r l y, pe di a t ri c , an d ren a l -i m p a ir e d, t o o bt a in i n f o rm a ti o n o n t he ef f ic ac y o f t he d r u g i n t h es e s u b je c t s . d . A dd i ti o na l c li ni c a l s t ud i es m a y be p er f o rm ed to d e t e rm i ne if th e d r u g c a n be us ed f o r a n e w o r a d di t io n al l ab e li n g i nd ic a ti o ns . 7 . P ha s e V a . A f te r th e F D A g ra n ts m a rk e t a pp r o v a l o f t he dr u g , p r od u ct de ve l op m e nt m a y c o nt i nu e . b . Th e d r ug f o rm u l at i o n m a y be m o di f ie d s li gh t l y a s a re s ul t o f d a ta ob t ain e d d u r in g th e m an u fa c t u ri n g s c a le - u p a nd v a li da t io n p r o c e ss es .
c . C ha n ge s i n d ru g f o rm u l a ti o n s ho ul d al wa y s b e wi t h in th e s ca le - u p an d po st a p p ro va l c ha n ge ( S U P AC ) g u id el i ne s . D . P r o d uc t l in e e x t en s io n s a r e d os a ge fo r m s in wh i c h th e p h ys i ca l f o rm o r s t r en g th , b u t n o t t he us e o r in di c at io n , o f th e p r od u ct ch a ng es . P ro du c t l in e e xt e n s i on is u s ua ll y p e rfo r m ed du r in g p h as e I I I, IV , o r V. 1 . D e vel o pi n g a t r a ns de rm a l p at ch wh e n on l y ta b le t s h a ve b e en a v ai la b le , f o r e xa m p l e :
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P r o g es t er o ne
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N i c ot i ne
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E s t r ad io l
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N i t r o gl y c e ri n
2 . Ad d i t i o na l s t r e ng t h s— a s l o ng as th es e s t re ng t hs a re wi t h in t he to t al d a il y d os e , f o r e xa m pl e :
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I b u p ro f en
P.3
3 . C o n t ro l l ed - r e le a se or m o d i fi e d - re l ea s e d os ag e fo r m s wh e n o nl y a n im m e d ia t e r e l ea se do s a g e f o rm is av a i l ab l e. Th i s is an on g oi n g p r oj ec t fo r al l b r an d c om p an i es ; a lm os t e v e r y N C E h as o r wi l l e ven t ual l y h a ve a m od i fi e d -r e le as e d os a ge f o r m o f t h e im m e d ia t e- r el e as e p r od uc t . E . B i o l og i c p r o du c t s 1 . A b i ol o gi c p ro d uc t i s an y v i r u s , se r um , to xi n , an t i to xi n , va c c i ne , b l oo d , b l oo d c om p on e nt o r d e ri v a t i v e, a l le r ge n ic p r o du c t , o r an a lo g ou s p r od uc t ap pl ic a b le t o t he p r e ve n ti on , t re a tm en t , o r c u re of di s e a s e s o r i nj u ri e s . 2 . B io l og ic pr o du c t s a r e a s ub s e t o f d r ug p ro d uc ts , di s t i ng ui sh e d b y t he i r m a nu f ac tu r i ng p ro c e s s es ( b io l og ic v s . c h e m i c a l ). I n ge n e ra l , t he te r m d r ugs in cl u de s b i ol o gi c p r od uc ts . 3 . B i ol o g ic l ic e ns e a p pli c a t io n ( B L A) . B io lo g ic p r o du c ts a r e a p pr o v e d fo r m a rk e ti n g u nd e r t h e p rov i s i on s o f t h e P u bl ic H eal t h Se r vi ce ( P H S ) A c t. F . G e n e ri c d r u g p ro d uct s 1 . A f te r pa t e nt ex p i r a ti on o f t h e A P I a n d / o r b r and d r ug pr o du c t, a g en e ric d ru g p r o du c t m a y b e m ar k et ed . A g e ne r ic d ru g p r od uc t i s t he r ap e ut ic a ll y e qu i va l en t to t h e b r a nd na m e d ru g p r od u c t an d c o nt ai n s t he s am e a m o u nt o f t he d ru g in t he s a m e t yp e o f d os ag e f o rm ( e. g. , t ab le t , l i qu id , i n je c ta ble ) . 2 . A g e ne r ic d ru g p r od uc t m us t b e b i oe q u i va le n t ( i . e. , ha v e th e s am e r a te a nd e xt e n t o f d r u g a bs or p ti on ) t o t he b ra n d d r ug pr od u c t . Th e re f o re , a g en e ric d ru g p r o du c t is e xp e c te d t o g iv e t h e s am e c l i ni c a l r e s po n s e ( C ha p te r 7 ). Th es e s t ud ie s a r e no rm a ll y p e rf o rm e d wi t h h e al t h y h u m a n v ol un t e e rs . 3 . S om e g en e r ic p r od u c ts a re no t a b so r be d ; f o r so m e o th e rs bi o eq ui va l enc e i s n o t a g o o d m a r k e r . Un d e r t ho s e c o n di t io ns , c o m pa r a t ive c l i n ic a l t r i a ls or s t u di e s wi t h
p h a r ma c o d yn a m i c e nd p o i n ts a re c o ns id e r ed to m ea su r e th e e qu i v a le nce o f t wo p r o du c ts . I n ha la t io n p r od u c t s a n d n on ab s o r b ed d r u g p r od uc t s f al l i n to thi s c a te go r y. 4 . Th e ge ne r ic d ru g p r odu c t m a y d i ff e r fr om t he br a n d p r od uc t i n ph ys i c a l a p p ea r a nc e (i . e. , s i z e , c o l o r, s h a pe ) o r in th e am o u n t a nd t y pe o f e xc i p ien t s u s e d i n t h e fo rm u la t io n . 5 . A g e ne r ic d ru g p r od uc t m a y n o t d if f e r i n b ot h th e qu al i ta t i ve a n d t he qua n t it a ti v e c om p os it i on s f o r l iq u id s , i n je c t a bl es , s em is ol i ds , t r a ns d er m al p a tc h es , i nha l a ti on p r o du c ts , a nd op h th a lm ic p ro d uc ts , u n le ss a d equ a t e s a f e t y s t ud ie s h a v e b e en p e r f or m e d . 6 . B ef o r e a g e ne r ic dr u g p r o du c t is m a rk e te d , t h e m a nu f ac tu r e r m us t s ub m i t an Ab b r e vi a t e d N ew D r u g Ap p l i c a t i on ( AN D A) t o t h e F D A f o r a pp r o v a l. B ec a us e p r e cl in ic a l s a f e t y a n d e f fi c ac y s t u di es ha v e al r ead y b e en pe r f o rm ed fo r the N D A a p p ro ve d b r a nd p ro du c t, h um a n b io e qu i v al e nc e st u d ie s, in s te ad o f cl i ni c al t r ia ls , a r e ge ne r a ll y r eq u i re d f or t h e A N D A . Th e c he m i s tr y, m an u f ac tu r in g , a nd co n t r ol s r e q ui r em e nt s f o r t h e g ene r i c d ru g p r o du c t a re s im i l a r to th os e fo r th e b r an d na m e d r u g p r od uc t . G . S p e ci a l t y d r u g p r o d u c t s a r e e xi s t i ng pr o du ct s de v e lo p ed as a n e w de l i ve r y s ys t em o r fo r a n e w t h e ra p e ut ic in di c at io n . Th e sa f e t y an d e f fi c a c y of t he d r u g p r o du c t we r e es t ab l is hed i n t he in i ti al N D A - ap p ro v e d do sa g e f o rm . F o r exa m p l e , th e n i t ro g l yc e r in t ra ns d e rm al d e li v e r y s y s t em ( pa tc h ) wa s d e v e lo p ed af t e r e xp e r i en c e wi t h n i t ro g l yc e ri n s u bl in gu a l t a bl e ts .
II. PRODUCT DEVELOPMENT. F o r ea ch d ru g , v a r i ou s s t u d ie s a r e r eq u i re d t o d ev e l o p a s a fe , ef f ec t i v e, an d s t ab l e d o sa g e f o rm . A. N e w c he m ic a l e n ti t i es 1 . P r e fo r m u la t i on is th e c ha r ac t e ri z a t io n o f th e p h ys ic al an d c he m i c a l p ro p e r ti es of t h e a c ti v e dr u g s ub s t a nc e a nd do sa g e f o rm . Th e t h e r ap eu t ic in di c a t io n o f t h e d r u g a n d t h e r o ut e o f ad m i ni s tr a t io n di ct a te th e t y pe of d r u g p ro d uc t o r dr u g d eli v e r y s ys t em (e . g. , im m e di a te r e l ea s e , c o nt r ol l ed r el eas e , s up p os it o r y , p a r en t era l , t r a ns d er m al ) th a t n ee ds t o be de v e l op e d. a . P r ef o rm u la ti o n a c t i v i tie s a r e u su a ll y p e rf o rm ed d u ri n g t h e p re cl i ni c a l s ta g e . H o we ve r , t h es e a c ti v i ti es m a y c o n ti n ue in t o p ha se s I a nd II . b . Th e fo l lo wi n g i n fo r m a ti o n i s o bt a in ed d ur i ng p re f o rm u la ti o n . P.4
( 1 ) P h ys i c a l , i nc lu di n g pa r t ic le si ze an d s ha p e, cr y s t a ll in i t y, p o l ym o r ph is m , de ns i t y, s u r fa ce a re a , h y g r os c o pic i t y (a b il i t y to ta k e up and r e ta i n m o is t u re ) , a n d po wd e r flow ( 2 ) S o lu b i li t y, i n c lu di n g i n t ri ns ic di s s o lu ti o n , p H s o lu bi l it y p r o f i le , a n d g en e r al s o lu bi l it y c ha r ac t er is t ic s i n v a ri o us s o l v en ts ( 3 ) C h em i ca l , i nc lu d in g s u r fa c e en e r g y , p H s t ab il i t y p ro f il e , p K a, te m p e r at u r e s t ab i li t y ( d r y o r un d er v ar i o us hu m i di t y c o n di t io ns ) , a nd e xc i pi e nt in t e ra c t io n s
( 4 ) An a l yt i c a l m e t ho d s d e v e l op m e n t, in cl u di ng de ve l o pm en t o f a s t a bi li t y i n di ca t in g m e th o d ( m e as u r es b o th th e A P I a nd th e re l at e d su b s t a nc es ) , a nd c l ea n ing m e t ho ds 2 . F o rm u la t i o n d e ve lo pm e n t i s a c on t in u in g p r oc es s . I ni t ia l d r ug f o rm ul at i o ns a r e d e ve l op ed f or ea r l y c l in ic a l s tu di es . W he n t he s ub m iss i on of an N D A is co n s i d er e d, t h e m an u fa c tu r e r a t te m pt s to de v e l op th e fi na l (m a r k et e d) d os ag e f o rm . Th e do se of t h e d r u g a nd th e ro u te of a dm i ni s t r a ti o n a re im po rt a n t i n d e te rm i ni ng t he m o di f ic at i on s n ee d ed . a . I nj e c ta b le ( 1 ) A fi na l i n je c t a bl e d r ug p r od uc t i s u s u al l y de vel o p e d i n th e p r ec li n ic al ph a s e . ( 2 ) Ma j o r c o nc e rn s i nc lud e th e s t ab il i t y of th e d ru g in s o lu t io n a n d t he s te r i li t y o f t he p r o du c t. ( 3 ) B ec au s e f e w e xc i p ien t s a r e a ll o we d in in je c ta b le p ro d uc ts , th e f o rm ula t o r m us t c h oo se a f in a l p r od uc t ea r l y in t he de v e l op m e n t p r o c e ss . ( 4 ) I f t he f o rm ul at i on is c h a n ge d , b io a vai l ab il i t y s tu d ie s a r e n o t r eq u i re d f or i n t ra ve n ou s s ol u ti on in j ec t io ns be c au se th e p r o du c t i s i nj ec t ed di r ec tl y i nt o t he b o d y. ( 5 ) F or m u l at i on c h an g es m a y re q ui r e a cu t e t o xi c it y s t ud i es . b . T op i ca l ( fo r l oc a l a pp l i c at i o n ). In c l u de s a n tib a c t e r ia ls , a n ti f un g al s, c o r ti co s te r oi ds , a n d l oc al a ne s t h et ic s . ( 1 ) Th e fi n al d o s a ge f orm f or a t o pi c a l d r ug p ro du c t i s us u al l y de v e lo p ed d u r in g p h as e I s t u di es be c a us e a n y m a j o r f o rm ul a ti on c ha n g es m a y re q ui r e f u r the r c l in ic a l t r i al s . ( 2 ) Th e re l ea s e of t he d ru g f ro m t he m a t ri x i s m ea s u re d i n v it r o wi t h va r i ou s d i f fu si o n c e l l m o d el s . ( 3 ) S ig n if ic a nt p ro bl em s e n c o u nt e re d wi t h l oc a ll y a c ti n g t op ic a l d r ug pr o duc t s i n cl ud e l oc a l i r ri t a ti on , s k i n s e n is ti z a t io n a n d s y s t e m i c d r ug ab s o r p ti o n. c . To p i ca l (f o r s ys t e m i c d r u g a b s o rp t i o n) . In c l ud e s d r ug de li ve r y t h ro u gh t he s k in ( t r a ns de r m a l ) , m u c o u s m e m b ra ne s (i nt r a na s a l ) , an d r ec ta l m uc os a . ( 1 ) A pr o to t y p e f o rm u la tio n is d e ve lo p ed fo r ph ase I . ( 2 ) A fi na l to pi c a l d r u g pr o d uc t i s d e v el o pe d d u rin g p h as e I I I a f t er t he a va i la b le t e ch n ol o g y a n d d es i re d s y s t em ic l e ve ls a r e c on s i d e re d . d. Oral ( 1 ) P r ot o t y pe do s ag e f o rm s a r e o f te n d e v e lo pe d d u r in g th e p r e cl i n ic a l ph a s e t o e n su r e t h at t he dr u g is op t im a ll y a v a il ab l e a nd tha t t he pr o du c t di s s o l ves i n th e g a st r o in t es ti n al t ra c t . ( 2 ) I n t he ea r l y s t ag es o f p r o du ct de ve l op m e n t, ha r d g el a t in ca p su l e d os a g e f o rm s a r e of t en de v e l op ed f o r p h a se I c li ni c a l tr i al s. I f t h e d r u g sh o ws e ff ic ac y , t h e s am e d r u g f o rm ul a ti o n m a y b e u s ed in ph as e I I s t ud i es . ( 3 ) Fi n al p ro d uc t d e v el op m en t b e gi ns wh e n th e dr u g pr o c e ed s d u ri n g p has e II an d b e f o re in it i at i ng ph as e III c li ni c a l s t ud ie s . 3 . M a r k et e d P ro d uc t . Co n s i d er a ti o ns i n th e d e ve l op m en t o f a f in al do s ag e fo r m i n cl ud e th e f o ll o wi n g : a . C ol o r , s ha pe , s i z e , t as t e , v i s c os i t y , s en si ti vi t y , sk i n f ee l , a nd ph y s ic al a p p ea r an c e o f t he do s a ge f o rm b . S i ze a nd s h a pe of th e p ac k a g e o r c on t ai n e r
c . P ro d uc ti o n e qu i pm en t d . P r od uc t io n s i te e . C ou n t r y of o ri gi n i n wh i c h th e d r u g is to b e m an u f ac tu r e d f . C o un t r y in wh i c h t he dr u g wi l l b e m ar ke t e d B . P r o d uc t l in e e x t en s io n s a r e g e ne r al l y de f in ed as d ru g p r o du ct s c on t ai n in g a n N D A - a p p ro v e d d r u g i n a d i f fe r e nt do s a g e s tr e ng th o r i n a di f fe r e nt do s a ge f o rm ( e . g ., m o di f ie d re l ea s e , o r a l l iq ui d ) . 1 . O r a l p r o d uc t li n e e x te n s io n s a . Th e s im p le s t do s a g e fo r m t o d e v e lo p i s a di f fer e n t d os a ge s t r en g th of a d r ug in a t a b le t o r c a ps ul e . O n l y bi o eq u i v al e nc e s tu di es a re n ee d ed . P.5
b . A mo d i fi e d - re l ea s e do s ag e f o rm is m o re di f f ic u l t t o d e ve lo p wh e n o nl y a n i m m e di a te - r el e as e d os ag e fo r m e xi s t s . C li n ic al tr i a ls a r e n o rm a ll y r eq u i re d . c . C on si d er a ti o ns i n d e ve l op i ng th e s e do sa ge f o rm s a r e s i m i l a r t o t ho s e fo r t he fi n al d r u g p r od uc t (s ee I I. A . 3 ). d . M a r k e ti n g h as a r ol e i n th e c ho ic e o f th e d os ag e fo r m . e . B ec au s e t he o ri gi n al b r a nd d ru g p r o du c t in f o rm a ti o n co n t ri b ut es t o t he b o d y o f k n o wl e dg e a b ou t t h e d r ug , no p re f o rm ul a ti on is ne e d ed . Al l o t he r fa c t o rs c o ns id e re d f o r th e o r i gi na l p r o du c t ar e s i m i la r . If t he re l at i on b e t we e n in vi t r o di ss ol ut i o n a nd i n vi vo b i oa v a il a bi li t y is k n o wn , th e i n no v a t or c an p r og r e s s t o a fi ni s h e d d o s a g e f o r m r e la t i v el y q ui c k l y . f . R e g ul a t o r y a p p r o va l is ba s e d on th e f o ll o wi n g: ( 1 ) A na l y t ic al an d m an u fa c tu r i ng c o nt r ol s ( 2 ) S t ab il i t y i n fo r m a t io n ( 3 ) B io a v a il ab i li t y an d b io e q ui v a le nc e s t ud ie s ( 4 ) C li n ic al t ri al s (i n t h e c as e o f m o di f ie d - re le a se d os a ge fo r m s ) g . A ne w t h e r ap eu t ic in dic a ti o n f o r a d r u g r e qu i res ne w e f f i c ac y s t u d i e s a n d a ne w N D A. 2 . L iq u i d p r o du c t l i n e ex t e n si o ns a . I f t he c u r r en t m a rk e ted p r od uc t i s a l i qu i d p re pa r a ti o n , t he n t h e s am e fa c to r s a s f o r th e s ol i d o r al do s a ge f o rm s a r e c on s i de r e d ( s e e I I. B . 1. a , b , c , d , e , f an d g ). b . I f t h e m a r k e t ed p ro duc t is a s o li d o r al do s a g e f o r m a nd th e p r o du ct li ne e xt e n si o n i s a li q ui d , p ro d uc t d e v e lo p m e n t m u s t p r oc ee d wi th c a u ti o n b ec au se t he rat e an d e xt e n t o f a bs o r pt i on fo r li q ui d a n d s ol id do s a g e fo r m s m a y n ot be th e s am e . c . R eg u l at o r y a p p r o va l r e q ui r es ( 1 ) A na l y t ic al an d m an u fa c tu r i ng c o nt r ol s ( 2 ) S t ab il i t y i n fo r m a t io n ( 3 ) B io a v a il ab i li t y an d b io e q ui v a le nc e s t ud ie s ( 4 ) S a fe t y s t u di es (e . g ., d e p en di n g o n t he d ru g s u b st a nc e , lo c al i r r i ta t io n) ( 5 ) C li n ic al t ri al s , i f t h e ra t e a n d e xt e n t of d ru g ab s o rp t io n a r e d r as ti ca l l y a l t er e d f r o m t he o ri g in al do s a g e f o r m C . C o m b in a t io n p r o d uct s a re m a de u p o f t wo o r m o re r eg ul a te d c om p one n ts ( e. g . , d r u g /d e v ic e , b io lo g ic /d e vi c e, d ru g /b i ol og ic , or d ru g / d e vic e/ b io l og ic ) th a t a re
p h ys ic al l y , c h em i c al l y , or o t he r wi s e c om bi n ed o r m i xe d a nd p ro du c ed as a si n gl e e n t it y. 1 . Th e se m a y be t wo o r m o r e s e p a ra t e p ro d uc ts p a ck ag e d t og e th e r i n a s i n gl e p a ck ag e o r as a un i t a nd m a y be c om p os ed o f d ru g an d d e vic e p r o du c t s , d e v i c e an d b i ol o gi c p r od uc ts , or bi o lo g ic an d d r ug p ro d uc ts . 2 . A n e xa m pl e i s a n i nha l a ti on s t e r oi d ( e .g . , b ec l o m e t ha so n e i nh al a ti o n a e r os ol ) in wh i c h th e de v i c e c om p on e n t is im po r t an t fo r d e liv e r y o f t he s t e ro i d.
III. PREAPPROVAL INSPECTIONS (PAIs) A. Th e m a n uf ac t u ri n g f ac i li t y is i ns p ec t ed b y th e F D A a f te r an N D A , a bb r evi a t e d a n t ib io t ic dr u g a pp l ic at i on ( A A D A ) , o r A N D A i s s ub m it t ed an d b e fo r e t h e ap p li c a t io n i s a p p ro v e d . B . A P A I m a y al s o be in it i a te d i f a m a jo r ch an g e is r ep o r te d i n a s u pp l em en t a l a p pl ic a ti o n t o a n N D A, AA D A , o r A N D A . C . D u r in g th e PA I , t h e FD A i n v es t ig a to r : 1 . P e r fo r m s a ge ne r a l c u r r e nt go o d m an u fa c t u rin g p ra c t ic e (c G MP ) i n s pe c ti o n r e l at i ng s p ec i fi c a ll y t o t he d r ug pr o du c t in t e nd ed f o r th e m a rk e t 2 . R e vi ew s t h e d e v el opm e nt r ep o r t t o v er i f y th a t t h e d r ug p ro du c t h as e no u g h s u pp o r ti ng do c um en t at i on t o e ns u re a v al id a te d pr o d uc t a n d a ra t io n al e f or t h e m a nu f ac tu r i ng di r ec ti o ns 3 . C o ns u l ts th e c h em is tr y , m an u f ac tu r in g , a nd c o n t r ol ( C MC ) s ec t io n o f th e N D A , A A D A , o r A N D A a nd de te r m in es th e c ap a bi li t y o f t h e m an u fa c t u r er t o p rod u c e th e d r u g p r od uc t as d es c ri b ed P.6
4 . V e r if i es t he t ra c e a bi lit y o f th e i n fo r m a t io n s ubm i tt e d i n t he C MC s e c ti on t o t h e o r i gi n al l a bo r a to r y n ot e bo o k s , e le c t ro ni c i n fo rm a ti o n , a nd ba tc h re c o r ds 5 . V e r if i es a nd en s u r es t h a t al l th e q u al it y s y s tem s a r e i n p la ce to m a n ufa c tu r e t h e p r o du c t s o it r e ta in s t h e i d en t i t y , s t re ng t h , q ua li t y, a nd pu r i t y o f th e d r u g pr o d uc t t h a t we r e a pp r o v e d b y t he c e n te r . 6 . R ec o mm e n ds ap p ro v a l fo r th e m an u fa c tu r e o f t h e d r ug p ro du c t b as ed o n th e s t a tu s o f t h e i ns pe c t i on
IV. SCALE-UP AND POSTAPPROVAL CHANGES (SUPACs) A. P u r p o s e . Th es e g ui de l in es a re in t en d ed to r ed u c e th e n u m b e r o f m anu f ac t u ri n g c h an g es th a t r eq u i re pr e- a p p ro va l b y t h e F D A . Th e gu id e li n es a r e p u bl ish e d b y t he F D A o n t h e I nt e r ne t (h t tp: / / ww w. f d a . g o v / c de r /g u ida n c e / in d e x. h t m ) . B . F u nc t i o n. Th es e g u ide l in es p ro v i d e r ec om m e nd a t io ns to s p on s o r s o f ND A s , A A D A s , a n d A N D A s d u rin g th e p os t ap p r o v al pe r io d wh e n 1 . Ma k i ng s l ig h t c ha ng e s i n t h e a m o un t of th e e xc i p i en t to ai d i n t h e p r oce s s i ng of t h e p r o du c t du r in g s c a l e-u p 2 . C ha n gi n g t he s it e o f m a nu f ac tu r e
3 . S ca l i ng u p ( in c re as i ng ) o r s ca l i ng d ow n ( d ec r e a s i ng ) th e b a tc h s i ze of t h e f o r m u l at io n 4 . C ha n gi n g t he m a nu f ac t u r in g p ro c es s o r eq u i pm e n t C . Th e F D A m us t b e n o tif i e d a bo u t a p r o po se d c ha n g e t o a d r u g p r od uc t th r o ug h d i f fe r e nt r eg u l a to r y d o c u m e n ta t i on , d e pe n di ng o n th e t y pe of c h an g e p ro p os e d. 1 . An n u a l re p o r t . C h an ge s th a t a re u nl ik el y t o h av e a n y d et ec t ab l e e ff ec t o n f o r m u l at io n qu al i t y a n d pe r f o rm an c e ca n b e i ns t itu t e d wi t h o ut ap p r o v al b y t h e F D A a n d re po r t ed an n ua ll y . Exa m p l e s o f t h es e c h a ng es in c l u de : a . C o mp l ia n ce wi t h an of f i c i al c o m p en d iu m b . L ab e l d es c r i p ti o n o f t h e d r u g p ro d uc t o r ho w i t is s u pp li e d ( n ot in v o l vin g do s a g e s t r en g th o r d os ag e f o rm ) c . D el e ti on o f a n i n g re d ie n t th a t a f fe c t s o n l y t h e c o lo r of th e p r o du c t d . E xt e n s io n o f th e e x pi ra t i o n d a te ba s e d o n fu ll s h el f -l i fe da t a o b ta in e d fr o m a p r o t oc ol ap p ro v e d i n th e a p pl ic a ti on e . C o n ta i ne r an d c l o su re s ys t e m f o r t he d ru g p ro d uc t (e xc e p t a ch a ng e in c o nt a in e r s i z e f o r n on s o li d do s a g e f o rm s ) ba se d o n eq ui v a l en c y to t he app r o ve d s ys t em u n de r a p r ot oc o l a p p ro v e d i n th e a pp l ic at io n o r p ub li s h e d i n a n o f fic i al c om p en d iu m f . A d di t io n o r d e le t io n o f a n a l t e r na t e a na l yt i c a l m e t h od 2 . C h an g es be i n g e f fe ct e d ( C B E ) s u p pl e me n t . C h a n ge s t ha t pr o ba b l y wo u ld no t h a ve an y d e te c t a bl e e f fec t bu t re qu i r e so m e v a li da t i on ef f o rt s r e qu i re s p ec i fi c d o cu m e n ta t io n , d ep e nd in g on th e c ha n ge . A s upp l em e n t is s ub m i t t ed , a nd t he c h an g e c a n b e i m p l em ent e d wi t ho u t p r e v io us ap pr o v a l ( C B E -0 ) b y th e F DA o r , i n s om e c as es , th e F D A has 30 da y s to r e v ie w t h e c h a n ge ( C B E -3 0 ) . F D A m a y r e j ec t t h is su pp l em en t . E xa m ple s o f re a s o ns fo r s u bm it ti n g a s u pp l em en t i nc l ud e a . Ad d i t i o n o f a new s pe c i f ic a t io n o r te s t m e t ho d o r c h a ng es in m e th o ds , fa ci li t ie s , o r co n t ro ls b . L ab e l c ha n g e t o a dd o r s t r e ng t he n a c o nt r a ind i c a t io n , wa r n i ng , pr e c au t i on , o r a d ve r s e r ea c t i on c . Us e o f a d i f fe r e n t f a ci l i t y t o m an u fa c tu r e t he d r u g s ub s t a nc e a nd d ru g p r o du c t ( t h e m an u fa c tu r in g p r oc e s s in t he ne w f a c i l it y d oe s n o t d i ff e r m at e ri a ll y f ro m th a t i n t h e fo rm e r f a c i li t y , an d th e ne w f a c il it y h as r ec eiv e d a s a ti s f ac t o r y c G MP i ns p ec ti o n wi t h i n th e p r e v i ou s 2 y ear s c o v e r in g t h at m a nu f act u r in g pr oc e s s ) 3 . P r e -a p p r o va l s u pp l em e n t . C h an g es th a t c o u ld h a v e a s ig n if ic a nt e ff ec t on f o r m u l at io n qu al i t y a n d pe r f o rm an c e r eq u i re s p ec if i c d oc um en t a ti on . Th is s u pp l em en t m us t b e a p pr o v e d be f o re th e p r op o se d c h a n g e is in i ti a te d . Ap p r op r i at e e xa m p l es fo r p re - ap p r o va l s u pp le m en t a r e : a . A dd i ti o n o r d el e ti o n o f a n in g r ed i e nt b . R e la xa t i o n o f t h e l im its f or a s p ec i f ic a t io n P.7
c . Es t ab li s hm en t o f a n ew r eg u l a to r y a n a l yt i c a l m e t h od d . D e le t io n o f a sp e ci f i ca t i o n o r re g ul a to r y a na l yt i c a l m e th od
e . C ha n ge in th e m e th o d o f ma n u fa c tu r e of th e dr u g pr o du c t, in cl ud i ng cha n gi n g o r r e l a xi n g a n i n - pr oc e s s c o n t r ol f . E xt e n s io n o f th e e x pi r a t i o n d a te o f t he d ru g p ro d uc t b a s e d o n d a ta ob ta i ne d u n d er a n e w o r re v i s ed s t a b il i t y t e s t in g p r o to c o l th a t wa s b e en ap p ro ve d in t he a p pl ic a ti o n D . W hen an y c h a ng e t o a d r ug pr o du c t is p ro po s e d , th e m an u fa ct u r er m us t s h o w t h a t t h e r es ul t an t d ru g p ro d uc t i s b i oe q u i va le n t an d t he r a pe u t ic a l l y e q u i va l e n t to t h e o r i gi na l a p pr o v e d d ru g p ro du c t ( s ee C ha p te r 7 ) . 1 . A m i n o r c h an g e is a c h an g e t ha t h a s m i ni m al p o te n ti a l t o h a v e a n a d ve r s e e ff e c t o n th e i d en t it y , s t r e ng t h, q u al i t y, p u ri t y , or po t enc y o f t h e p r od uc t a s t h e y m a y r e l at e to th e s a fe t y o r e f fe c ti v e n es s o f t he p ro d uc t . I f t h e p ro p os ed ch an ge is c o ns id e re d m in o r b y t h e F D A , bi o eq u i val en c e m ay b e de m o n s t r a te d b y com p a ra t i v e d i ss ol u ti on p ro f il es f or t he o ri g in a l a nd ne w f o r m u l a t io ns . 2 . A m a j o r c ha n g e is one t ha t ha s s u bs t an t ia l p ot e n ti a l t o h a v e a n a d v e rs e e f fe c t o n th e i d en t it y , s t r e ng t h, q u al i t y , p u ri t y, or po t enc y o f a p ro d uc t a s t he y m a y r el a te t o t he s a fe t y o r e f fe c ti v en e s s o f th e p r o du ct . If t he p r op os ed c h a ng e i s c on s id e re d m a jo r b y t h e F D A , b i oe qu i v a le n c e m us t be de m on s t ra t ed b y an in vi v o b i oe q ui v a l en c e s t ud y c om p a ri ng t he or i gi n al a n d n e w f o r m u l at i on s.
V. GOOD MANUFACTURING PRACTICES (GMPs) a r e re g ul a ti o ns d e v e lo ped b y t he F D A. G MP s a r e m i ni m u m r e qu i re m e n ts th a t th e i n du s t r y m us t m ee t wh e n m an u fa c tu r in g , p r oc es sin g , p ac k i n g, o r h ol d in g hu m an an d ve t e r i na r y d ru gs . Th es e r e g ul a ti o ns , a ls o k no wn a s c G M P s, es t ab li s h c ri te r i a f o r p e r so nn e l, f ac il i ti es , a n d m an u fa c tu r in g p r oc es s es t o e ns u re th a t t he f in is h e d d r ug p r o du c t h as th e c o rr ec t id e n ti t y , s t r en g th , q u al i t y, a nd pu r i t y c h ar ac t e ri st ic s . A. G o o d Ma n u f a c t u ri n g P r a c ti c e s a r e d esc r i be d in t he C o de of Fe d e ra l Re g ul a ti o ns ( C F R ) , t it l e 2 1, s e c t io n s 2 1 0 a n d 2 11 . B . Q u a l i t y c o n t r o l ( Q C ) i s th e g r ou p wi t hi n t h e m a n u fa ct u r e r t ha t i s r es p on s ib le f o r e s ta b li sh in g pr oc e s s a n d p r o du ct sp ec i fi c a t io ns . 1 . S pe c i fi c a ti o n s a re t he c ri t e ri a t o wh ic h a d ru g p r o du c t s h ou l d c o n fo r m t o be c o ns id e re d h a v i ng ac c e pt a b le qu al i t y fo r it s i nt e nd e d u s e . 2 . Th e Q C un i t t e st s th e p r o du c t an d ve ri f ie s t hat t h e s p ec i fi ca t io ns a re m e t . Q C t e s ti ng in c l u de s t he ac ce p t a nc e o r r ej e c ti o n o f t h e i nc om i ng r a w m a t e ria l s, p a ck ag i ng c om p on e nt s , d r u g p r od uc t s , wa t e r s ys t e m , a nd en vi r on m e n ta l c o nd i ti on s ( e . g ., he a ti n g, v e n ti la t ion , ai r - c o nd i ti o ni ng , ai r qu a li t y , m i cr o bi al lo a d ) t ha t e xi s t d u r in g th e m an u fa c t u ri n g p r oc es s . C . Q u a l i t y a s s u r a n ce (Q A) i s t h e g r ou p wi t hi n th e m a nu f ac t ur e r t h at de te r m in es t h a t t h e s y s t em s a nd f ac i l it i es ar e a d eq u at e a n d th a t th e wr i t te n p r oc ed u re s a r e f o l lo we d t o e ns u re th a t th e fi n is he d d r ug p ro d uc t m ee t s t he ap p li c a bl e s pe c if ic a ti o ns f o r qu a li t y . P.8
STUDY QUESTIONS
D i r e c t i on s : E a c h s t a te m e n t i n t h is s ec t io n c an be c o r r ec t l y c om pl e te d b y o n e o r m o r e o f th e s ug g es t ed ph r a s e s . C ho o s e th e c o r re c t an s we r , A - E: 1 . H ea l t h y h u m a n vo l u nt e e r s a r e us e d i n d r u g d e ve l o pm e n t f o r I . p ha s e I te s t in g af t e r th e su b m is s io n of a n i nve s t i g a t io n al n ew d r u g ( I N D ) a p p l ic a t io n . I I . ge n e r ic d r ug de ve l op m e n t f o r a n ab b r e vi a te d new d r u g a p pl i ca t i on ( AN D A) s u b mi s si o n . I I I . ph a se II I te s t in g ju st b e f o re t he s ub m is s ion o f a n ew d r u g a p p li c at i o n ( N D A) . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a nd I I a r e c o r r ec t D i f II an d II I ar e c o r re c t E i f I, I I, an d I I I a r e c o r re c t V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . T h e r eq u i r e d i n f o rm a t io n c o n t ai n ed i n a new d r ug a p pl i ca t i on ( N D A) t h at i s no t in c l ud e d i n th e a b b r e vi a te d new d r u g ap p l i ca t i on ( AN D A) c o n s i s t s o f I . p r ec l i ni c al a ni m al t oxi c i t y s t u d i e s . I I . cl i n ic a l e f f ic a c y s t u d i e s . I I I . hu ma n sa f e t y a n d t o l e r a nc e s t u di e s. A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a nd I I a r e c o r r ec t D i f II an d II I ar e c o r re c t E i f I, I I, an d I I I a r e c o r re c t V i e w A n s we r 2 . T h e a n sw e r i s E [s e e] . 3 . A p r o d u c t l in e e x te n s io n c o n ta i n s t h e new d r u g a p pl i ca t i on ( N D A) a p p r o ve d d r ug i n a n ew I . d os a ge f o rm . I I . do s ag e st r e n gt h . I I I . th e r a pe u t ic in d i ca t io n . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a nd I I a r e c o r r ec t D i f II an d II I ar e c o r re c t E i f I, I I, an d I I I a r e c o r re c t V i e w A n s we r 3 . T h e a n sw e r i s C [ se e] . D i r e c ti o ns : E a c h s ta t em e nt in th is s ec t io n c a n b e c o r r ec t l y c om p le t ed b y on e o f th e s u gg es t ed ph r as es . C hoo s e t he b e s t a ns we r . 4 . T he r eg u l at i o ns de ve l o p e d b y t h e U . S . F o o d a n d D r u g Ad m i n i st r a t i on ( F D A) f o r t h e p h a rm a ce u t ic a l i n d u st r y f o r m e e t i ng t he m in i m um r eq u i r em e n ts i n th e m a n u fa c tu r i n g , p r o ce ss i n g , p ac k in g , o r h o ld in g o f h u ma n a n d ve te r in a r y d r u g s a r e kn ow n as ( A ) g oo d m an u fa c tu r in g p r a c t ic es ( G MP s ) . ( B ) q ua l it y a s s ur a nc e ( Q A ) . ( C ) q u al it y c on t r ol ( Q C ) .
( D ) p r e -a p pr o v a l i ns pe c tio n ( P A I) . ( E ) sc a le - up an d p os t - app r o v a l c ha ng e s ( S U P A Cs ) . V i e w A n s we r 4 . T h e a n sw e r i s A [ se e] . 5 . T h e u ni t w i t h i n t h e p h a r ma c eu t i ca l m a n uf ac t u r e r th a t e n su r e s th at t h e fi n is h e d d os a ge fo r m h as m e t al l th e s p ec i f ic a t ion s f o r i t s i n t en d ed u se i s t he ( A ) a na l y t ic al m e t ho ds un i t . ( B ) m ar k e t in g a n d s al es u n i t. ( C ) p r e -a p pr o v a l i ns pe c tio n ( P A I) un i t . ( D ) q u al it y a s s u ra nc e ( QA ) u ni t . ( E ) q ua l it y c on t ro l ( Q C ) u n i t. V i e w A n s we r 5 . T h e a n sw e r i s E [s e e] . 6 . M a n u fac t u r e r s m a y m a k e a c ha n g e i n t h e f o r mu l a ti o n a f t e r m a r ke t ap p r o va l . I f t he c h an g e i n th e fo r m u la ti o n is c o n si d e r ed a m i no r c han g e , th e m a nu f ac t u r e r n e e ds t o re p o r t t h e c han g e to t he FDA only in the ( A ) a nn u al r ep o rt . ( B ) p r e -a pp r o v a l s u p pl em e nt . ( C ) i n v es t ig a ti o na l n e w dr u g ( I N D ) s u bm is s i o n. ( D ) c ha n ge s b ei ng e ff ec te d s u pp l em en t , 3 0 d a y s ( C B E - 3 0 ) . ( E ) n o r e po r t i s r e qu i re d f o r a m i n o r ch a ng e . V i e w A n s we r 6 . T h e a n sw e r i s A [ se e] . P . 9
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C (I , II) [ s e e I. C . 2 .b ; I . F .2 ] . P h a se I t es t in g i s t he f irs t s e t o f h um a n st u di es p e r f or m e d d u r in g n e w d ru g d e ve l op m e n t. P ha s e I s tu d ie s e s t a bl is h t h e t ol e ra n c e an d t o xi c i t y of t he d r u g i n h u m a ns . Bi o eq ui v a l en c e s t ud i es fo r g e ne r ic d ru g d e v e l op m e n t a re m o st o ft e n p e r f or m e d i n h e al t h y h um a n v o l un t ee r s . Th e se st u d ie s es t ab l is h t he bi o eq u i v al e nc e o f t he ge ne r ic d ru g p r odu c t a ga i ns t t h e b r an d d ru g p ro du c t. P ha se I II t es t i n g e nt a il s l a r ge - sc al e , m u l ti c e n te r c l in ic al st u di es pe r f or m ed i n p at i en ts wi t h th e d is e a s e o r c o nd i ti on t o b e t r ea t ed . P h a s e I II s t ud i es d e t er m in e th e s a fe t y an d e f f ic ac y o f t he d r u g i n a l a r ge pa t ie n t po p ul a ti o n. 2 . T he an sw e r is E ( I , II, a nd I II ) [s e e I . C .5 ; I. F .6 ] . Th e d e v e lo pm e nt of a n ew d r u g r e qu i re s e xt e n s i ve t o xi c i t y a n d e f fi c a c y t es t in g i n a n im al s a n d h um an s . Th e N D A d oc um en ts al l s t ud i es pe r f or m e d on th e d ru g . Th e A N D A i s u s e d f o r g e ne r ic d ru g p r o du c t s u bm is sio n s . Th e ge ne r ic d ru g p ro d uc t i s s im i la r to th e o r ig i na l b ra n d d r ug p ro d uc t t h at has al r e ad y b ee n m a rk et e d. B e c a us e t h e e f fi c ac y , s a fe t y , an d t o xi c i t y o f t hi s d r ug p ro du c t h a ve b e en s t ud i ed an d d o cu m e n te d , f u r th e r s tud i es of t hi s n at u re a re un n ec es s a r y . 3 . T he an sw e r is C (I , II) [ s e e I. D ] . P r o d uc t l in e e xt e n s i on s a r e de v e lo p ed af t e r f u r the r s t u di es wi t h th e o r ig i na l N D A a p p ro ve d d r u g p r od uc t . F r o m t he s e s t u di es , th e m a nu f ac tu r e r m a y d e v e lo p a n e w d o sa g e f o rm (e . g. , c o nt ro l le d - re l ea se p ro d uc t ) o r a ne w d o s ag e s t re n gt h . A n e w t h e r ap eu t ic in di c a t io n req u i re s a n N D A.
4 . T he an sw e r is A [ s ee V ] . Q u a l it y c on t r ol an d q ua l it y a s s u r an c e fo l lo w G MP r e g ul a ti on s t o e ns u r e t ha t t he f i n is he d p r od uc t m e et s al l ap pl ic a bl e s pe ci f ic at i on s fo r q u al i t y . Th e F D A m a y i n sp ec t a m a n uf ac t u ri ng s i te ( P A I ) b ef o r e t he d rug a pp li c a t io n i s a p pr o ved . I n a d di t io n , t h e F D A m us t be n ot i fi e d a bo u t a n y p r op o s e d c ha n ge s t o a n a pp r o v e d d r ug p r o du c t. 5 . T he an sw e r is E [ s e e V . B ] . Th e Q C u n it pe r f o rm s t he a pp r op r i at e t es t s o n t he d os ag e f o rm . P A I is per f o r m e d b y F D A c om pl ia nc e i ns p ec to r s , wh o e xa m i ne t he pha r m ac e u t ic al m a nu f ac tu re r a nd r e v i e w t h e p r oc e du r es an d r ec or d s f o r m a n uf ac tu r i ng t he fi ni s he d d os age f o rm b e f o re th e a dm i ni s t r a ti on g r a nt s m ar k e t ap p ro v a l . Th e a na l y t ic al de ve l op m e n t u n it d e ve l op s t he an a l y ti c a l m e th o ds u s ed in te s t i ng t h e d r u g p ro d uc t . 6 . T he an sw e r is A [ s ee I V . C . 1] . A l l c h an ge s i n t h e f o rm ula t i on m us t be re p o rt e d to t he F D A . A m i no r c h ang e is a c h an g e t ha t h a s m i ni m al p o te n ti a l t o h a v e a n a d ve r s e e ff e c t on th e i d en t ity , s t r en g th , q u al i t y , p u ri t y , o r p ot e nc y o f t he p ro du c t a s t he y m a y re la t e t o th e p r o du c t 's s a fe t y o r e f fe c ti v e n es s. C h an ge s t h at a re u nl ik el y t o h a v e a n y de t ec t ab l e e f f ec t o n f o rm u la t io n q ual i t y an d p e r fo r m a nc e c an b e i ns t it u t ed wi t h ou t a pp r o v a l b y t h e F D A a nd ne ed on l y to b e r e po r te d i n th e a n nu a l r e po r t .
2 Pharmaceutical Calculations and Statistics R i c c a r do L . B o n i
I. FUNDAMENTALS OF MEASUREMENT AND CALCULATION. Th e p h a rm ac is t i s o ft e n re q ui r e d t o p e rf o rm o r e va l ua t e a v a r ie t y of c a lc ul a ti on s i n h is o r h er p r ac t ic e. Ma n y o f t he s e c a lc ul a ti on s i n v o l ve t he u s e o f d i re c t o r i n v e rs e p r o po r t io ns . D im e ns i o na l ( o r u n it ) an a l ys i s a n d a p p r o xi m at i o n c a n be us e fu l i n s ol v i n g t he se p ro b le m s . In di m e ns io n al a n al ys is , d im e ns io ns ( o r u n i ts ) a r e i nc lu d ed wi t h e a ch nu m b e r u se d i n t h e c a lc ul a ti on . U ni ts c o m m o n to t he nu m e r a to r a n d d e n om in a to r m a y be c a nc el e d a nd th e re m a i ni n g u ni t s p r o vid e t h e u ni ts f or t he fi n al an s we r . I n a p p ro xi m a t io n , e ac h n um b e r us e d i n t he c a lc ul at i o n is r ou n de d t o a s i ng le s i gn i fi ca n t d ig i t. Fa c to r s c om m o n to th e n um e r at or a n d d en om in a to r m a y be c a nc el e d a nd th e a ns we r t o th is ap p ro xi m a t io n s ho u l d be r ea so n ab l y c l os e t o t he fi n al e xa c t a ns we r . A. R a t i o a n d p r o po r t i o n 1 . R a t io . Th e r e la t i v e m a g ni t ud e of t wo li k e qu an t i ti es is a r a ti o , wh i c h is e xp r e s s ed as a f r ac ti o n. C e r t a in ba si c p r in c i pl es a p pl y t o th e r a ti o , a s t hey d o to al l f r ac t io ns . a . W he n t h e t wo t e rm s of a ra t io a re m u lt i pl ie d o r d i v i de d b y t he s a m e n u m b e r , t he v a lu e o f th e r a t io is u nc h an g ed .
b . Two r a t i os wi t h th e s am e v al u e a r e e qu i v al e nt . E q u i val en t ra t io s h a ve e q u al c r os s p r od uc ts and e qu al r ec ip r oc a ls . F o r e xa m p l e :
and 1 × 6 = 3 × 2 = 6 I f t wo r a ti os a re eq u al , th e n t h ei r re c i p r oc al s a r e e q ua l :
2 . P r o po r t i o n. Th e e xp re s s i on of t he eq u al it y o f t wo r a t i os i s a p ro po r t io n. Th e p r o du c t of t he e xt r em es is eq ua l to th e p r o du c t o f t h e m ea ns fo r an y p r o po r t io n . F u rt h e rm o re , t h e n um e ra t o r o f t h e o ne f r ac ti o n e qu a ls t h e p r o du c t o f i ts de n om in a to r a nd th e o t he r f ra c t i on ( i . e ., on e m is s i ng t er m c a n a l wa ys b e f o un d g i v en t he o th e r t h r ee te r m s ) . Mo s t ph a rm ac eu t ic al c a lc ul a ti on s c an be pe r fo r m ed b y u s e o f p ro p o rt io n . a . P r o pe r r a t io s . S om e p h a rm ac is ts us e p r op e r ra t i os (i n wh ic h s im il a r u n i ts a r e u s e d i n t h e n um e r at o r a nd d en om in a tor o f e ac h ra t io ) in th e ir p r o po r t io n c al c u l at i on s . S e v e r a l e xa m p le s f o ll o w. ( 1 ) I f 2 40 m L of a c o u gh s y r u p c on t ai ns 48 0 m g of d e xt r o m et h or p ha n h yd r o b ro m i d e, t he n wh a t m as s o f d r ug is c o nt ai ne d i n a c h i ld ' s d os e , 1 t e as p oo n fu l (5 m L ) o f s y r u p ?
P.11
( 2 ) I f a c hi l d 's do s e ( 5 m L ) o f a c ou g h s yr u p c o n ta i ns 10 m g o f d e xt r o m e th o r ph an h y d rob r o m i de , wh a t m as s o f dr u g i s c on t ai n ed in 24 0 mL?
( 3 ) I f t he am o un t o f d e xt r o m et h or p ha n h y d r o br o m i d e i n 2 40 m L of c o ug h s yr u p i s 4 80 m g , wh a t wo u ld be t he vo lu m e r eq uir e d fo r a c h i ld ' s d os e o f 1 0 mg?
( 4 ) H o w m an y m il li g ra m s o f de xt r o m e th o rp h an bas e (m ol e c u la r we i gh t = 2 7 1 .4 ) ar e e q ui v a l en t t o 1 0 m g o f de xt r o m e th o rp ha n h y d ro b ro m i d e ( m o le cu la r we i g ht = 3 52 .3 ) ?
b . M i x ed r a t io s . S om e ph a r m a c i st s u s e m i xe d r at i os ( in wh i c h di ss im il a r u n i ts a r e u s e d i n t h e n um e r at o r a nd d en om in a tor o f e ac h ra t io ) in th e ir p r o po r t io n c al c u l at i on s . S u c h c o m p u ta t io n s g en er a l l y g i v e c o r re c t a ns we r s , p r o vi di n g t he c o nd i ti o ns i n wh i c h m i xe d r a ti os c an n o t b e us e d a r e kn o wn . A l a t er e xa m p le s h o ws m i xe d r at i os l e ad in g to fa il ur e in t he c as e of di lu t io n, wh e n i n v e rs e p r op o r ti o ns a re r eq ui r e d. Fo r i n ve rs e p r op o r t i on s , s i m i l a r u n i ts m us t b e u s e d i n the n um e ra t or a nd de no m in a t o r o f e ac h r a ti o . F o l lo wi n g i s a n e xa m p l e o f a m i xe d ra t io c a lc ul a tio n us in g t h e p r e v io us p r o bl em .
Th e s a me an sw e r i s o b ta i ne d i n th is e xa m pl e whe t h e r we u s e p ro p e r r a tio s , wi t h s im il a r u ni t s i n n um e r a t or an d d e no m i n at o r , o r m i xe d r a t io s . Th is is no t t h e c as e wh e n d ea li n g w i t h i n v e rs e p r op o r ti o ns . 3 . I n ve r se p r op o r t i on . Th e m os t c om m o n e xa m p l e o f t h e n ee d fo r i n ve rs e p r o po r t io n f o r t h e p ha r m a c is t i s t he ca s e of d il u ti o n . W he re as in th e p r e vi ou s e xa m p l es o f p ro p o r ti on t he re l at i on s h i ps i n vo l ve d d i re c t p r o po r t io n , t he c a s e of di l u ti on c a ll s f o r a n i n v e rs e p r op o rt i on ( i. e ., as vo l u m e in c re as es , c o nc en t r a ti o n d ec re a s e s) . Th e n ec es s i t y o f u si ng in ve rs e p r o po r t io ns fo r di l ut i on pr o b le m s is s ho wn i n th is e xa m p l e . I f 1 20 m L of a 1 0 % s t o c k s o lu t i on i s d i lu t ed t o 2 4 0 m L, w h a t i s th e fi na l c o n ce n t r a ti o n ? U s i n g i nv e r s e p r o po r ti o n,
A s e xp e c te d , t he fi n al c on c en t r at i on is o n e h al f t he o ri g in a l co nc e nt r a ti o n b e ca us e th e v ol um e i s do u bl e d. H o we v e r , if t he p h a rm ac is t a t t em pt s t o us e d i r ec t p r op o r ti o n a nd neg l ec ts t o es t im a te an app r o p ri a te an s we r , th e
r e s ul ti n g c al c u la t io n wo ul d pr o v i de an an s we r o f 2 0 % , wh i c h is t wi c e t he a c tu a l co n c e n tr a ti o n.
P.12
L i ke wi s e , t h e p ha rm a c i s t u s i n g m i xe d r a t io s f ai ls i n th is c a se .
and
B . Al i q u o t . A p ha r m a c i s t r e q ui r es th e a li q uo t m e th o d o f m ea s ur em e nt wh e n t h e s e ns i t i vi t y ( t h e s m all e s t qu a nt i t y th a t c an be m e as u re d wi t h t he r e q ui r e d ac c u r ac y a nd p re c is io n ) o f t h e m e a s u r ing d e v ic e is no t g re a t e n o ug h f o r t h e r e qu i re d m e as u re m e n t. A li q uo t c al c ul a ti on s c an be us ed fo r m e as u re m e n t o f s ol id s or l iq u id s, al l o wi n g t he pha r m ac is t t o re al i z e th e r e q ui r e d p re c i s i o n t h ro ug h a p r oc ess o f m e as u r in g a m u l ti p le of th e de si re d a m ou n t f ol l o we d b y d il u tio n an d f i na ll y s el ec t io n a n d m ea s u r em e nt of an a l iq u ot pa r t th a t c o n ta i ns t h e d es i re d a m o u nt o f m a t e ri a l. Th i s e xa m p le p r o bl em in v o l v es we i g hin g b y th e a li q uo t m e th od, u s i ng a p r es cr i pt i on b a la n ce . A p r es c ri p ti on ba l an c e ha s a s e ns i ti v i t y r eq u ir em e n t o f 6 m g . H o w wo u l d yo u we i g h 1 0 m g o f d r ug wi t h a n a cc u ra c y o f ± 5% , us in g a s u i ta bl e d i lu en t ? 1 . Fi r s t, c a lc ul a te th e l ea s t we ig h ab l e q ua n ti t y fo r t he ba l an c e wi t h a s e ns it i v i t y re q ui r em e nt of 6 m g , as s um in g ± 5 % ac c u r ac y i s r e qu i re d .
2 . N o w i t i s o b v io us t ha t a n al iq u ot ca lc ul a ti o n is r e q ui r e d b ec au s e 10 m g o f d r u g i s r eq u i re d , wh e r e as t he le as t we i gh a bl e q ua n t it y i s 1 20 m g t o a c hi eve t h e re q ui r ed pe r c e n ta g e o f e r ro r . Us in g t h e l ea s t we i g h a bl e q u an t it y m et ho d o f al i qu o t m e as u r em en t , u s e t he s m al le s t q ua n ti t y we i g h a bl e o n t h e b al an ce a t ea ch s t e p t o p r es e r v e m a te r i al s . a . W ei gh 12 × 1 0 m g = 12 0 m g o f dr u g. b . D il u t e t he 12 0 m g o f dr u g ( fr om s t e p a ) wi t h a s u it a bl e d il u en t b y g e om e t ri c a l d il u ti o n t o ac h ie v e a m i xt u r e t h at wi l l p r o v i de 10 m g o f dr u g in e a ch 12 0 -m g a li q uo t . The am o un t o f di lu e nt t o be us e d c an be de t er m i n ed t h r o ug h p r o p o r ti o n .
c . W eig h 12 0 m g ( 1 /1 2 ) o f t he to t al m i xt u r e , wh i ch wi l l c o nt a in th e re q ui r ed 1 0 m g o f dr u g.
II. SYSTEMS OF MEASURE. Th e p h a rm ac is t m us t b e f a m i l ia r wi t h th r e e s ys t e m s of m e as u re : th e m e t ri c s ys t e m a n d t wo c om m o n s y s te m s of m e as u re ( the a vo i r d up o i s a nd a p o t he c a ri e s' s y s t em s ). Th e p r im a r y s ys te m o f m e as u re in ph a rm ac y a nd m e di ci n e is th e m e tr ic s ys t em . Mo s t s tu d en t s f in d i t e a s i es t t o c o n v er t m e as u re m e n ts i n th e c om m o n s ys te m s to m e t ri c u n i ts . A t ab le o f c o n ve rs io n e q ui va l en t s is p ro v i de d an d s h ou l d b e m e m o r i ze d b y t h e p ha r m a c i s t (s e e A p p en d i x A ) . Th e m e t ri c s y s t em , b ec a us e o f i ts un i v e r s a l a cc ep t an c e an d b r o ad us e , wi l l no t b e rev i e we d h e r e. A. Ap o t h e c a r ie s ' s ys t e m o f fl u i d m ea s u re . Th e a p ot h ec a ri es ' s ys t em of f l u id m e as u re is s um m a ri z e d in A pp en d i x A . B . Ap o t h e c a r ie s ' s ys t e m f o r m e as u r i ng w e i gh t. Th e a po t he c a r ie s ' s ys te m f o r m e as u ri ng we i g h t i nc l u de s u ni t s o f g r ai ns , s c ru p le s , d r am s , ou nc es , an d p o u nd s ( s e e Ap p en di x A ) . C . Avo i r d u p o i s s ys t e m o f m ea s u ri n g w ei g h t. Th e a voi r du p oi s ( A V ) s ys t em o f m e as u ri ng we ig h t i nc l ud es th e g r a in , ou n c e , a n d p ou n d. Th e g r a in is a u ni t c om m o n w i t h t h e a po t he c a r i es ' s ys t e m a nd al l o ws fo r ea s y c o n ve rs io n b e t we e n t he s y s t em s . Th e a v o i r du po is po u nd , h o we v e r , P.13
i s 1 6 A V o un c e s i n c on t ra s t t o t h e a po t he ca r i es ' p o u nd , wh ic h i s 1 2 a p o th ec a ri es ' o un c e s (s ee A p pe nd i x A ) . D . C o n ve r s i on eq u i va l en t s . Se e Ap p en di x A .
III. REDUCING AND ENLARGING FORMULAS. Th e p h a rm ac is t i s o ft e n re q ui r e d t o r e du c e o r e nla r g e a re c i p e. P r ob l em s o f t h is t yp e a re s o l v e d t h rou g h p r op o r ti o n, o r b y m ul t i pl ic a ti on o r d i v is io n b y t h e a p p ro p ri a te fa c to r to o b t ai n t h e r e qu i re d a m ou n t o f ea ch in g re d ie n t t ha t wi l l g i ve t h e d es i re d t o tal m a s s or v o l um e o f t he fo r m ul a . F o rm ul as c a n b e p r o vi de d i n a m o u nt s o r in p a rt s . A. F o r m u l a s t h at i nd i cat e p a r ts . W hen de a li ng wi t h f o rm u la s t h at s p ec ify p a r ts , p a r ts b y we i gh t wil l re q ui r e t h e d et e rm in a ti o n of we i g ht s o f i n g re d ie n ts , wh e re as pa rt s b y v ol um e wa r r a nt th e c al cu l at i on of v o lu m e s of i n g re d ie n ts . A l wa y s f in d t h e to t al nu m b e r o f p a r ts i n di c a t ed in th e fo rm u la , a n d e q ua t e t ha t to t al wi th t he t ot a l m a ss or vo lum e o f th e d es i re d fo r m u la i n o r d e r t o s et up a p r op o r ti o n . S uc h a p ro p or t io n wil l al lo w c a lc ul a ti o n o f t h e
m as s o r v o lu m e of ea c h i n g re d ie n t i n u ni ts c o m m o n to t he to t al m as s o r vo l u m e . W h a t q u a nt i t ie s sh o ul d b e us e d t o p r e p a re 10 0 g o f c am p h o ra t e d p a r a ch l o r o ph e no l ?
Rx
parachlorophenol
7 parts
camphor
13 parts
7 parts + 13 parts = 20 parts total
B . F o r m ul a s t h at i nd i cat e q ua n t i ti e s. Th e pr e vio u s p r esc r i pt i on fo r c o ld c r e am p r o v i de s a 1 0 0 g q u a nt i t y. W h a t m a ss o f e ac h in g re d i en t i s r e qu i r e d t o p ro vi d e 1 p o u nd ( AV ) o f c r e a m?
Rx
white wax
12.5 g
mineral oil
60.0 g
lanolin
2.5 g
sodium borate
1.0 g
rose water 1 lb = 454 g
24.0 g
12.5 g × 4.54
=
56.8 g of white wax
60.0 g × 4.54
=
272 g of mineral oil
2.5 g × 4.54
=
11.4 g of lanolin
1.0 g × 4.54
=
4.54 of sodium borate
24.0 g × 4.54
=
109 g of rose water
IV. CALCULATING DOSES. C a l cu l at i on of do s e s g ene r a ll y c an be pe r fo r m e d wi t h d im e ns io n al an al ys is . P r o b l e ms en c o un t e re d in t he ph a rm ac y i nc lu d e c a lc ul a ti on o f t he nu m b er o f d o se s, q ua n ti ti es in a d os e o r to t al m a ss / vol um e , a m o u nt o f ac t i v e o r i n ac t i ve i ng r ed i en ts , an d s i z e o f d os e . Ca lc ul a ti on o f c h il d r e n' s d o se s i s c om m o n l y p e r fo r m e d b y t h e p h a rm ac is t . D os a ge is op t im al l y c a lc ul a te d b y u s in g t h e c h i ld ' s b o d y we i gh t o r m a s s an d t h e a pp r o p ri a te do se in m i ll ig r am s p e r k i l og r am (m g /k g ). W ith ou t t h es e da t a , t h e f ol lo wi n g f or m u la s b a se d o n a n a d ul t d os e c a n b e u s e d . A. F r i e d ' s r ul e fo r i n fa nt s
P.14
B . C l a r k 's r u le
C . C h i l d' s do s ag e b a sed o n b o d y s u r f a c e a r ea ( B S A )
D . Y o u ng ' s ru l e f o r ch i ld r e n ≥ 2 ye a r s o l d
E . C o n s ta n t ra t e i n t r a ve n o us i n fu s io n s . S om e d r u gs ar e ad m i ni s te r ed i n t ra ve n ou s l y a t a c o ns ta n t ( z e ro - o rd e r ) r a te b y u s in g a c o nt i nu o us - dr i p i n f us io n s et o r a c o ns ta nt - r a t e i nf us i on pu m p . The f lo w r a t e ( v ol um e p e r u n i t t im e ) r e qu i re d c an be c a lc u la t ed f ro m t h e v o lu m e t o b e a dm in is t e re d a n d t h e d u ra t io n o f t h e in f us i on . Th e r a te o f d r ug a dm i ni st r a ti o n c a n b e c a lc ul a te d f r om th e c o nc e n t r at i on of d ru g i n t h e in f us e d s ol ut i on an d t h e f l o w r a t e o f t h e i nf us i on s e t o r p u m p . Co n v e rs i on f a c t o rs m a y be r eq u i re d t o o b t ai n t h e f in a l a ns we r in t he c o r r ec t u ni t s ( d ro ps pe r m i nu t e o r m il li l it e rs p e r ho u r ). A va n co m y c i n s ol u ti o n c o n t ai ni n g 1 00 0 m g o f v an c om y c in h y dr o c h lo r id e d i lu t ed t o 2 50 m L wi t h D5W is to be in f us ed at a c o ns ta n t ra t e wi t h a c o nt i nu o us -d r i p i nt r a v e no u s i nf us i on s e t t h at de l iv e r s 25 d ro ps / m L . W h a t f l ow r a t e ( d r o ps / mi n ) sh o u l d b e u s ed t o i n f use a l l 2 50 m L o f t he va n c o m yc i n h yd r o c h l o ri d e so l u ti o n i n 2 h r ?
V. PERCENTAGE, RATIO STRENGTH, AND OTHER CONCENTRATION EXPRESSIONS A. P e r c e n t a ge w e ig h t in vo l u m e (w / v) 1 . D e f in i t io n . Pe r c e n ta ge , in d ic at i ng pa r ts pe r hu n d re d , i s a n im p or t an t m e an s o f e xp r e s s i n g c o nc e nt r a ti o n i n p ha rm a c y pr a c ti ce . Pe r c e n ta g e w/ v i n di ca t es th e n um b e r o f g r a m s o f a c o ns t it u en t pe r 1 00 m L o f s ol u ti o n o r l i qu i d f o rm ul a ti o n. Th e ph a r m a c i st m a y b e r eq u i re d to pe r f o rm th r e e t yp e s o f ca lc ul a ti o ns : d e te r m i ne t he w e i gh t of ac ti v e ing r e di e nt in a c er t ai n vo l u m e wh e n g i v e n t he pe r c en t ag e s t re n gt h , d et er m i ne th e p e r ce n t ag e w /v wh e n t h e we ig h t o f s ub s ta n c e an d vol um e o f l i qu id f o rm ul a ti o n a re k n o wn , a n d d e te r m i ne t he vo l um e of li q ui d m i xt u r e wh en t he pe r ce n ta g e s tr e ng th a n d a m o u nt of s u bs t an c e a r e k n o wn . 2 . T ol u ba l sa m s yr u p . T o l u b al s a m t i nc tu r e c on ta i ns 20 % w/ v t o lu ba ls am . W h a t i s th e pe r c en t a ge c o nc e n t ra t i o n o f to l u ba l s am i n t h e s yr u p ?
tolu balsam tincture
50 mL
magnesium carbonate
10 g
sucrose
820 g
purified water, qs ad
1000 mL
a . Fi r s t, de t e rm in e wh a t t h e a m o u nt o f t ol u b a ls am is i n th e 5 0 m L q ua n ti ty o f ti n ct u re us e d f o r t he s y r u p . Th e n, b y p ro po r t ion , c a lc ul a te t he c o nc en t r at i on of t ol u b als am in t he s yr u p .
I n an s we r i ng th is on e q ue s ti o n, t he fi r s t t wo t y p es o f p ro b le m s l is t ed a bov e h a ve be e n s o l v e d, wh i l e e xh i b i t in g t wo m e th o ds of s ol v i ng pe r c e n ta g e p r o bl em s —n am e l y , b y d im e n si o na l an a l ys i s a n d p r o p o r t io n . b . F o r a n e xa m p le of th e t h i r d t yp e o f p e rc en t age w/ v p r o b le m , d et e rm ine wh a t v o l u m e of s y r u p c ou l d b e p r ep a r ed if we h ad o nl y 8 g o f m a g ne si um c a r bo na t e . U s e p ro p o rt i on t o f in d th e t o ta l v ol um e o f s y r u p t h at ca n b e m a de us in g o n l y 8 g o f m a gn es i um P.15
c a r bo na t e . I f we ha v e 8 g o f m ag ne si um ca r bo n at e in 10 0 0 m L o f s o l ut i on, t h e n, ac c o r di n g t o t h e r ec i pe , 8 0 0 m L o f s o l ut i on c a n b e p r ep a re d u si n g a ll 8 g o f th e d r ug .
B . P e r c en t a ge vo l um e in vo l u m e ( v/ v) . P e r ce n ta g e v/ v in di ca t es th e n u m b e r o f m il li l it e rs of a c on s ti t ue n t i n 1 00 m L o f l i qu id f or m u l at i on . Th e p e r ce n ta ge s t r e ng t h o f m i xt u r e s o f l iq u id s i n l iqu i ds is i n di c a t ed b y p e rc e n t v/ v, wh i c h in d ic at es t he p a r ts b y v o lu m e of a s ubs t an c e in 10 0 p a r ts of the l i qu i d p r ep a ra t io n . Th e th r e e t yp e s o f p ro b le m s th a t a r e e nc o un t e re d i n vo l ve c al c u l at i ng pe r ce n t a ge s t re n g th , c a lc ula t i ng vo l um e of i ng r e d ie n t ,
a n d c al c u l at i ng vo l um e o f t h e l i qu i d p r e pa r a t i on . U si n g t he sa m e to l u b a ls am s y r u p fo rm u la f rom ea r li e r , we ' l l n o w wo r k a pe r c e n t v / v p r o bl em . W h a t i s th e pe r c en t a ge s t r e ng t h v/ v o f t he t olu b a ls am t i nc t u r e i n the s yr u p p r e p a r a t i on ? B y p r o po r t io n , we c a n so l ve t h e p r ob l em i n o n e s t e p.
C . P e r c en t a ge w e ig h t in w e i g ht (w /w ) . Pe r c e n ta g e w/ w i n d ic a te s t he n u m b e r o f g r am s o f a c on s ti t ue n t p e r 1 00 g o f f o rm u la t io n ( s ol id o r l iq ui d ). S o l u ti on o f p ro b le m s i n vo l v i ng pe r ce n ta g e w/ w i s s t ra i gh t fo r wa r d wh e n the t o t al m a s s o f th e m i xt u r e i s a v a il a bl e o r wh e n t h e t o t al m as s c an be d e t e rm in ed f ro m t h e a v a il a bl e d a ta . In c a lc ul a ti o ns si m i la r to t ho s e fo r p e r ce n ta ge w/ v a n d v / v , t h e p h a rm ac is t m ig h t n ee d to s o l v e s e v e ra l t yp es o f p r o bl em s , i nc lu di n g d et er m i na ti o n o f t h e we i g h t of a c o ns ti t ue n t , t he to t al we i g h t of a m i xt u r e , o r th e pe r c e n ta g e w/ w. 1 . H ow ma n y g r a m s o f d r u g su b s ta n ce sh o u ld b e us e d to p re p a r e 2 40 g o f a 5 % w /w s o l u ti o n i n w a te r ? a . Th e fi r s t s t ep in an y pe r c en t ag e w/ w p r o b le m is t o a tt em p t i de n ti f ic a ti on o f t he to t al m as s o f th e m i xt u r e . In th is p ro bl e m , t h e t o ta l m as s is , o b vi o us l y , p r o v id e d ( 24 0 g ) . b . Th e p ro bl em c a n b e ea s il y s o l v e d t h ro u gh d ime n s io n a l a na l ys i s .
2 . W he n t h e t ot a l m a s s of t h e m i xt u r e is un a v a il ab l e o r c a nn o t b e d e t e rm in ed , an ex t r a s t ep is r eq u i re d i n t h e c a lc ul a t io ns . Be c a us e i t i s u s ua ll y i m p os s i b le to k no w h o w m u c h v o l um e is d i s p l a c ed b y a s o li d m a te r i al , t h e p ha r m a c i s t i s u n ab le t o p r ep a re a sp e c i f ie d v ol um e o f a s o lu t io n g i v e n t he pe r c en t a ge w/ w. H ow m u c h d r u g s ho u l d b e ad d e d t o 3 0 m L o f w a t e r t o m ak e a 10 % w /w s o l u t io n ? Th e v o lu m e o f wa t e r t h at is d is p la c e d b y t h e d r ug is un kn o wn , s o t h e fi na l v ol um e i s u nk nown . L i ke wi s e , e v e n th oug h th e m as s o f s ol ve n t is k n o wn ( 30 m L × 1 g /m L = 3 0 g ) , i t i s n ot k n o wn ho w m u c h d ru g i s n e ed ed , s o th e t o ta l m as s is un k no wn . Th e wa t e r r e pr es e nt s 10 0% - 1 0 % = 90 % o f t h e to t al m i xt u r e . Th en , b y p r o po r ti o n, t he m as s o f d ru g t o b e u s ed c a n be i d en t i fi ed .
Th e c o mm o n e r r o r th a t m a n y s t ud e nt s m a k e i n so l vi ng p ro b le m s o f th is t yp e is to as s u m e th a t 30 g i s t h e t ot a l m a ss of th e m i xt u r e . So l v i ng th e p r o bl em wi t h th a t a s s um p t i on gi ve s t he f ol lo wi n g i n c o r r ec t a ns we r .
D . R a t i o s t r en g t h . S ol i d o r li qu i d f o rm ul a ti o ns t ha t co n ta in lo w c o nc en t r at i on s o f a c t i v e i n g re d ie n ts wi l l o f te n h av e c on c en t ra t io n e xp r e s s e d i n r a ti o s t r e n gt h . Ra t io s t r en g th , a s t h e n am e im p l ie s , is t he e xp r e s s io n o f c o nc en t r at i on b y m ea n s o f a r a ti o . Th e n um er a to r a n d d en om i na t or o f t he r a t io in d ic at e gr am s ( g ) o r m i ll i li t er s (m L) o f a s ol i d o r l i qu id c o ns t it u en t in t h e to t al m as s ( g ) o r v o lu m e ( m L ) of a s ol id o r l iq u id p re p a ra t io n . B ec a us e p e r c en t a ge s t re n g th is P.16
e ss e nt i al l y a r a ti o o f p a rt s pe r h u nd r e d, c o n ve rs io n be t we e n ra t io s t r en g th a n d p e rc en t a ge s t r en g th i s e as il y a cc om pl is h ed b y p r o po r ti o n. 1 . E xp r e ss 0 .1 % w / v as a r a t i o s t r en g t h. a . R a ti o s t re n gt hs a re b y c on v e n ti o n e xp r e s s e d i n r e d uc ed fo r m , s o in s e t ti ng up ou r p ro p or t io n t o s o l v e f o r r a ti o s t re n gth , us e t h e n um e ra l 1 i n t h e n um e r at o r o f th e r i ght h a nd r at i o as sh o wn :
b . Li k e wi s e , c on v e r s i o n fr o m ra t io s t r en g th to pe rc e nt a ge s t r en g th b y p r o po r t io n i s e as y , as s ee n in th e fo ll o wi n g e xa m p l e . K e ep in m i nd th e d e f in i ti on o f p er c en t ag e s t r en g th ( pa r ts pe r hu n dre d ) wh e n s et t in g u p th e p r o po r t io n . 2 . E xp r e ss 1 :2 5 00 as a p e r c en t a ge s t re n g th .
E . O t h e r c o n ce n t r at i o n e x p r es s io n s 1 . M o l a r it y ( M) i s t h e e xp r e s s io n o f t h e n um be r of m ol es of s o lu t e d is s o l ve d p e r l i te r o f s o l ut io n . I t i s c a lc ul a te d b y d i vid i ng the m o l es o f s o lu t e b y t he vo l u m e of s o lu t io n i n l i ter s .
2 . N o r ma l i t y. A c o n v e n ie n t wa y o f d e al in g wi t h ac i ds , b as es , a n d e l ec t r ol y t es in v o l v es t he u s e o f e qu i v a le n ts . O ne e q ui v a l en t of an ac id is +
t h e q u an t it y o f t h at ac i d t h a t s up pl i es o r do n at es 1 m o l e o f H i on s . O n e -
e q ui va l en t of a b as e is th e qu a nt i t y th a t f u rn is h es 1 m ol e o f O H i on s. O ne e q ui va l en t of ac id r ea c t s wi t h 1 eq ui va l en t o f ba se . E qu i v a le n t we i g h t c a n b e c a lc ul a te d f o r a t om s o r m o l ec ul es .
Th e n o r m al i t y ( N ) o f a s o l u ti on is th e n um b e r o f g r a m - e qu i va le n t we i g h ts ( e q ui va l en ts ) of s o lu t e pe r li t e r o f s ol u ti on . N o rm a l i t y i s a na l og ou s t o m o la r it y ; h o we v e r , i t is de f i ne d i n t e rm s o f e qu i v al e n ts ra t he r th a n m o l es .
3 . M o l al i t y ( m ) i s t he m ol e s o f s ol u te di ss ol v e d pe r k i lo g r am o f s o l v en t . Mo l a l i t y is c a lc ul a te d b y d i v i di n g t he nu m be r o f m o l es of s o lu t e b y t he n u m b e r o f k il o gr am s o f s o l v e n t. Mo l a l it y o f fe r s a n a d v a nt a ge o v e r m o l a ri t y b e ca us e i t i s b as e d o n s o l v e n t we i g h t a nd a voi ds p r o bl em s as so c i a te d wi th vo l u m e e xp a ns i on o r c o nt r a c t i on o wi n g t o t h e a ddi t i on of s o lu t es .
4 . M o l e f r a c ti o n ( X) i s th e r at i o o f t he nu m b e r o f m ol es o f o ne c om p on e nt t o t he to t al m o le s o f a m ixt u r e o r s o l ut i on .
VI. DILUTION AND CONCENTRATION. I f t he am ou n t o f d r ug r em a in s c o n s t a nt in a d il u ti o n o r c o nc en t r at io n , t h en a n y ch a ng e i n t h e m as s o r v o l um e o f a m i xt u r e is i n v e rs e l y p r o po r ti o na l t o t h e c on c en t ra t io n . A. D i l u t i o n a n d c o nc e n tr a t i o n p r o b le m s c an be s o l ve d b y: 1 . I n ver s e p ro p o rt i on (a s m en t io n ed ea r li e r ) 2 . Th e eq ua t io n q u an t it y 1 × c o nc en t r at i on 1 = qu an t i t y 2 × c o nc en t r a ti on 2 3 . D e te r m i ni n g t he am oun t o f ac t i v e i ng r ed i en t p re s en t i n th e i ni t ia l m i xt u re a n d , wi t h t he as s um p ti o n t h a t t he in i ti al qu a nt i t y d o es no t c h an ge , c a lc ul a ti ng o f t he f in al c o n c e n t ra t io n o f t h e n e w to t a l m a s s o r v o l um e P.17
4 . Al l i g a t io n m e di a l . A m e th o d f o r c al c u la t in g t he a v e r ag e c on c e n t ra t io n o f a m i xt u r e o f t wo o r m o r e s ub s ta nc es 5 . Al l i g a t io n a l t e rn a t e. A m et h od f or ca lc ul a ti n g t h e n um b e r o f p a rt s o f two o r m o r e c om po n en ts o f k n o wn c on ce n t ra t io n t o be m i xe d wh e n t h e f in al d e si r ed c o nc e nt r a ti on is k n o wn B . D i l u t io n of a lc o ho l s a n d a c i ds
1 . D i lu t i o n o f a l co h o ls . W hen a lc oh ol an d wa t e r a r e m i xe d , a c on t ra c ti on o f vo lu m e oc c u r s . As a re s ul t , t h e f in al vo l um e o f s ol u ti o n ca n no t b e d e t e rm in ed ac c u r a te l y . N o r c a n th e v ol um e o f wa t e r n e ed ed t o d il u te to a c e r ta i n p er c en t ag e v / v be i de n ti f ie d . A c c o rd in g l y , p e rc e nt a ge w/ w i s o f te n u s ed fo r s o lu t io ns o f a lc o h ol . 2 . Th e pe r c en t a ge s t re ng t h o f co nc e nt r a te d a c i ds is e xp r e ss ed as p e r ce n ta ge w/ w. Th e c o nc e nt r a ti o n o f d il u te d a c i ds is e xp r e ss ed as p e r ce n ta ge w/ v . D e t e rm in i ng t he vo lu m e of co nc e n t r at e d ac i d t o b e u s e d i n p r e pa r i ng a d il ut e d a c i d r e q ui r es th e s p ec if ic g rav i t y o f th e c o nc en t ra t e d a c id . C . D i l u t io n a n d c o nc e n tr a t i o n o f l iq u id s a n d s ol i d s . D i lu t io n a n d c o nc en t r at i on p ro bl em s a r e of t en ea si l y s o l v ed by i d e nt i f y in g th e a m o un t o f d r u g i n v ol v e d fo ll o we d by u s e o f a n a p p ro p ri a te p r o po r t io n . 1 . H ow ma n y m i l l i l i t e r s o f a 1 :5 0 s t oc k s o lu t i on o f ep h ed r i n e s ul f a te s h o u ld be u se d i n co mp o u n di n g th e fo l l ow in g p r e sc r i p t io n ?
Rx
ephedrine sulfate
0.25%
rose water, ad
30 mL
2 . H ow ma n y m i l l i l i t e r s o f a 1 5 % w / v c o n ce n t r at e o f b e nz a lk o ni u m c h l o r id e s h o ul d be us ed i n p r e p a ri n g 3 0 0 m L of a s to c k s ol u t i on su c h t h a t 15 m L d i l u te d to 1 L w i l l yi e l d a 1 : 5 00 0 sol u t i o n? a . Fi r s t, de t e rm in e t h e am o un t o f dr u g i n 1 L o f a 1 : 50 0 0 s o l ut i on .
b . N o w, b ec a us e 1 5 m L o f t he s t oc k s o l ut i on is be i ng di l ut e d t o 1 L, a s toc k s o lu t io n i s n ee d ed in wh ic h 1 5 m L c on t ai n 0 . 2 g of d r ug . Th e a m o un t of d r u g r e qu i re d to m ak e 30 0 m L o f th e s t oc k s o lu t io n is fo un d b y p r op o r ti on .
c . Fi n al l y , t o d e te r m i n e th e am ou n t o f 1 5% c o nc en t r a te r eq ui r e d,
3 . W he n t h e r el a ti v e am o u n t o f c om po n en ts m u st b e d e te rm i ne d f o r p r e pa r a ti o n o f a m i xt u r e o f a d es i re d c on c e n t ra t ion , t he pr o bl em is m os t e a si l y s o l v ed us in g a l li ga t i on al t er n a te . H ow m a n y g r a m s o f 2. 5% h yd r o c o r t i s o ne c re am s ho u l d b e m i xe d w i th 3 6 0 g o f 0 .2 5 % c r e a m to m ak e a 1 % h yd r o c o r t i s o n e c r ea m ?
Th e r e la t i v e a m o u nt s o f th e 2. 5 % a nd 1% c r e am s a r e 1 t o 2 , r e sp ec t i v el y. B y p r o p or t io n , t h e m a s s o f 2 .5 % c re a m t o us e c an b e d et e rm i ne d . I f 2 par t s o f 0 .2 5 % c r e a m is r ep r es e n t ed b y 3 6 0 g , t he n th e t o ta l m a ss ( 3 p a r ts ) i s r e p r e se n t ed b y w h a t ma s s ?
P.18
W ith t he t ot a l m a s s k n own , t h e am ou n t o f 2 . 5% c r e am c an be id e nt i fi e d. I f 3 p a r ts r ep r es en t th e t o t al m as s o f 5 4 0 g , t h en 1 p ar t r e pr e s e n ts t h e m as s of 2 . 5 % c re am (x g = 18 0 g) .
VII. ELECTROLYTE SOLUTIONS. E l e ct r ol y t e s o lu t io ns c o nt a i n s p ec i es (e l ec t ro l yt es ) th a t d is so c i a te in t o i on s . Th e m i l li e qu i va l e n t ( m Eq ) is th e u n it us ed t o e xp r e s s t he c o nc en t r at i on of
e l ec t r ol y t es in s o lu t io n . Ta b l e 2- 1 e xh i bi t s so m e p h ys io l og ic al l y im po r t an t i o ns an d t h ei r pr o pe r t ie s . A. M i l l i eq u i va l en t s . Th e m il li e qu i v a le n t is t he am o u n t, in m i ll ig r am s , o f a s o lu t e e qu a l t o 1 /1 0 00 of i t s g ra m -e q ui va le n t we ig h t . Co n v e rs io n o f c o nc en t r at i on s i n t he f orm o f m i ll i eq ui va l en t to co n c e n t ra t io ns in pe r c e n ta g e s t r en g th , m il l ig r am s p er m i ll il i te r s ( m g /m L ) o r an y o t he r te r m s , b e gi ns wi t h c a lc ul a ti on o f t he nu m b er o f m il l ie qu i va le n ts o f dru g . Th e f ol l o wi n g e xa m p l es de m o ns t r at e th e c om p ut a ti o n o f m il li eq u i v a l e nt s a n d m a n ip ul a ti o n o f da t a f r om Ta b le 2- 1 to p e r fo r m t he r eq ui r e d ca lc u la t io ns fo r p re pa r i ng e l ec t r ol y t e s ol u ti o ns . W h a t i s th e co n ce n t r a tio n , in p e rc e n t w / v, o f a s o l u ti o n c o nt a i ni n g 2 m E q o f p ot a ss i um c hl o ri d e pe r mi l l il i t e r ? C a l cu l at i on s i n v ol v i ng m il l ie q ui va le n ts a re ea s i l y s o l ved if t he pr a c t i ti on e r f o l lo ws a p r e de f in ed p roc e du r e t o d e te r m i n e t he m i l l ie q ui v a le n t we i gh t . Th i s i n vo l ves th r e e s te ps . 1 . Fi n d t he m o le c ul a r we i g h t ( m o l wt ) .
Atomic wt K
=
39
Atomic wt Cl
=
35.5
39 + 35.5 = 74.5 g
=
mol wt of KCl
2 . C al cu l at e th e e q ui v a len t we i g ht ( E q wt ) o f K C l.
3 . D e te r m i ne t he m il l ie qu i v a le n t we i gh t , wh i c h i s o f th e e q ui va le n t we ig h t. m E q wt = 7 4 .5 g / 10 0 0 = 0 . 7 4 5 g o r 74 . 5 m g
Table 2-1. Valences, Atomic Weights, and Milliequivalent Weights of Selected Ions
Formula
Valence
Atomic/Formula Weight
Milliequivalent Weight (mg)
Aluminum
A+++
3
27
9
Ammonium
NH4+
1
18
18
Calcium
Ca++
2
40
20
Ferric
Fe+++
3
56
18.7
Ferrous
Fe++
2
56
28
Lithium
Li+
1
7
7
Magnesium
Mg++
2
24
12
Bicarbonate
HCO3-
1
61
61
Carbonate
CO3-
1
60
30
Chloride
Cl-
1
35.5
35.5
Citrate
C6H5O7---
3
189
63
Gluconate
C6H11O7-
1
195
195
Lactate
C3H5O3-
1
89
89
Phosphate
H2PO4-
1
97
97
Sulfate
SO4--
2
96
48
Potassium
K+
1
29
39
Ion
Sodium
Na+
1
23
23
Acetate
C2H3O2-
1
59
59
P.19
N o w t h a t we k no w t h e m il l ie q ui va le n t we i gh t , we c a n ca lc u la t e b y d i m e ns i on al an a l ys is and p r op o rt i on th e c o nc en tr a t i o n i n p e rc e nt a ge in a f o u r th s t ep . 4 . 0 .0 74 5 g / m Eq × 2 m Eq = 0 . 1 49 g o f d r ug
+
H ow m a n y m i l l i e q u i va len t s o f N a w o ul d be con t a i ne d in a 1 5 -m L vo l u m e of t he f o ll ow i n g b u f f e r?
Na2HPO4·7H2O
180 g
NaH2PO4·H2O
480 g
Purified water
ad
1000 mL
F o r ea ch s a lt , th e m as s (a n d m il li e qu i val e nt s ) m us t be fo u nd in a 1 5 -m L d o se .
B . M i ll i os m ol e s ( m O s mo l ) . O s m ot ic p re s s u re is d i r ec tl y p r op o r ti o na l t o th e t o t al nu m b e r o f p a r ti c l es i n s ol u ti o n. Th e m il l io sm o le is th e u ni t of m e as u r e f o r osm o ti c c on c e n t ra t ion . F or no n el ec t r ol y t es , 1 m il li m ol e r e p re s e n ts 1 m i ll io sm ol e . Ho we v e r , f or e le c t ro l yt es , t h e t ot a l nu m be r of pa r t ic le s i n s o lu t io n i s d et e rm i ne d by t h e nu m b e r o f p a r ti c l es p r o du ce d i n s ol u ti on and i n f lu en ce d b y t h e d eg r e e o f di s s oc ia t io n . A s s um ing c o m p l et e d is s oc ia ti o n, 1 m i ll im ol e o f K Cl r ep r es en t s 2 m i ll io s m ol es o f t ota l pa r ti c l e s , 1 m i l li m o le o f C a C l 2 re p r es en ts 3 m il li os m o l es o f to t al pa r t ic le s , e t c . Th e i d ea l o s m ol a r c o nc en t r at i on c a n b e c alc u la t ed wi t h th e f o ll o wi ng e qu a ti o n.
Th e p h a rm ac is t s ho ul d re c og n i z e t he di f fe r e nc e b e t we e n id e al os m o la r c o nc en t r at i on an d a c t ual o s m ol a ri t y. As th e c o nce n t r at i on of s o lu t e i n c re as es , i n te r ac t io n b et we e n d is so l ved pa r t ic les in c re as es , re s ul ti n g i n a r e d uc t io n o f t h e a c t u al os m o l a r va l ue s . C . I s o to n ic s ol u t io n s . An i s ot o n ic s o lu t io n i s o ne t ha t ha s t he s a m e o sm o ti c p r es s u r e a s b ody f l u id s . I so s mo t i c f lu i ds a re fl u id s wi t h t he s am e o sm o ti c p r es s u r e . S ol u tio n s t o b e a dm in is t e re d to p at i en ts s h ou l d b e
i s os m o ti c wi t h b od y f lu i ds . A h yp o t o n i c s o lu t io n is on e wi t h a lo we r o s m oti c p r e ss u re th a n b od y f lu i ds , wh e r ea s a h yp e r t o n i c s ol u ti o n h as a n o s m o ti c p r e ss u re th a t is g re a te r th a n b o d y f l ui ds . 1 . P r e pa r a t io n of i so t on i c so l u ti o ns . C ol li g at i ve p r op e rt i es , i nc lu d in g f r e e zi ng po in t de p re s s ion , a re r ep r es en t a ti v e of th e nu m b e r o f p a r ti c l es in s o lu t io n a n d c o ns i de r ed i n pr e pa r a ti o n o f is o to n ic s ol u ti o ns . a . W he n 1 g m o l wt o f a ny n o n el ec t r ol y t e i s d is s o lve d i n 1 00 0 g of wa t e r , t h e fr e e z in g p o in t o f th e s o lu t io n i s d ep r es s e d b y 1 . 8 6 ° C. B y p ro p o rt i on , t he we i g h t of an y n o ne le c tr ol y t e ne e de d t o m ak e t h e s o l u t io n i so t on ic wi t h b od y f l u id c a n b e c a lc u la t ed . P.20
b . B o ri c a c i d ( H 3 B O 3 ) h as a m ol wt o f 6 1 .8 g. Th us 61 . 8 g of H 3 B O 3 i n 1 000 g o f wa t e r s h o ul d p r od uc e a fr e e zin g p o in t o f 1 . 86 ° C . Th e r ef o r e, k n o wi n g t h a t t h e f r ee z i ng p oi nt de p r es s i on o f b od y f lu i ds i s -0 . 52 ° C ,
a n d 1 7 .3 g o f H 3 B O 3 in 10 0 0 g of wa t e r pr o v i de s a s o l ut i on th a t i s i so t o n ic . c . Th e d e gr e e o f d is s o c ia t i on of el ec t r ol yt es m u s t b e t ak e n i nt o a c c ou n t in s uc h c al c ul a ti on s . F o r e xa m pl e , N a C l i s a pp r o xi m a t e l y 8 0 % d is s o c i at e d i n we a k s ol u ti on s , y i e ld in g 1 8 0 p a r ti cl es in s o lu t io n f o r ea ch 10 0 m ol ec u le s o f N a C l . Th e re f o re ,
i n di ca t in g th a t 9 .0 9 g o f N a C l in 10 0 0 g o f wa t e r ( 0 . 9 % w/ v ) s h o ul d m a k e a s o lu t io n i s o t on ic . L ac k i ng a n y i n fo r m a t io n o n t h e d e g re e o f di s s oc ia t io n o f a n el ec t r ol y t e , t he f ol lo w i n g d i ss o ci a t io n va l ue s ( i ) m a y be us ed . ( 1 ) S ub s ta nc es th a t d is s o c ia t e i nt o t wo io ns : 1 . 8 ( 2 ) S ub s ta nc es th a t d is s o c ia t e i nt o th r ee io ns : 2 .6 ( 3 ) S ub s ta nc es th a t d is s o c ia t e i nt o fo u r i on s : 3 .4 ( 4 ) S ub s ta nc es th a t d is s o c ia t e i nt o fi ve i o ns : 4 . 2 2 . S o di u m c h lo r i de e qui va l e n t s. Th e ph a rm ac is t wi l l of t e n b e r eq u i re d to p r e pa r e a n i s o t on ic s o lu ti o n b y a dd i ng an ap p ro p ri a t e am o un t o f an o th e r s u bs ta n c e (d r u g o r i ne r t e l ec t r ol y t e o r no ne l ec t ro l y t e ) . C o ns id e ri n g t ha t i s ot o ni c f lu i ds c on t ai n the e qu i v al e n t o f 0 .9 % N aC l , t he qu es t io n a r is es , H o w m u c h o f t h e a dd ed in g r ed i en t i s r e qu i re d to m ak e th e s ol u ti on is o to nic ? A c o mm o n m e th o d f o r c o m pu t in g t h e am o un t o f a d d ed i n g re di e n t t o us e f o r r e a ch in g i s o t on ic i t y in v o lv e s t he us e o f s o di u m ch l o r i de e qu i va l en t s . a . D e f in i t io n . Th e s o d ium c h lo r i de eq ui va l en t rep r e s e n ts th e a m o u n t of N a C l t ha t i s e qu i v a le n t to t he am ou n t o f p a r ti cu lar d r ug in qu es t io n . F o r
e ve r y s ub s ta nc e , t he r e is on e q u an t it y t h at s h ou ld h a ve a c o ns ta n t t on ic e f f ec t wh e n d is s o l v ed in 1 0 0 0 g o f wa t e r . Th i s is 1 g m ol wt o f th e s u bs ta n c e di v i de d b y i ts d i s s oc ia t io n val u e ( i ). b . E xa m p le s ( 1 ) C o ns id e ri n g H 3 B O 3 , fr o m t h e l as t s ec ti o n, 17 .3 g o f H 3 B O 3 is eq u i val en t t o 0 .5 2 g of N a Cl in t on ic i t y . Th e re f or e , t h e r e la tive q u an t it y o f Na C l th a t is e q ui va l en t to H 3 B O 3 i n to n ic i t y e f f ec ts i s d e te r m in e d a s f ol l o ws :
A p p l yin g th is m e th o d t o a t r o pi ne s u l fa t e, r ec al l th a t th e m ol ec ul a r we i gh t o f N a C l an d th e m ol ec ul a r we i g h t of a tr o pi n e s u l fa te a r e 5 8. 5 a n d 6 95 g, r e s pe c t i v e l y , a nd t he i r i v a l u es a re 1. 8 a n d 2 .6 , re s pe c t i ve l y. Ca lc u la t e t he m as s o f Na C l re p r es en t ed b y 1 g of a tr o pi n e s u l fa t e ( Ta bl e 2 - 2 ).
Table 2-2. Sodium Chloride (NaCl) Equivalents Substance
NaCl Equivalent
Atropine sulfate (H2O)
0.12
Boric acid
0.52
Chlorobutanol
0.24
Dextrose (anhydrous)
0.18
Ephedrine hydrochloride
0.29
Phenacaine hydrochloride
0.20
Potassium chloride
0.78
P.21
( 2 ) A n e xa m p le o f t he p ra c ti c a l u s e o f s o d iu m ch lo r i de eq u i v al en t s is se en i n th e f o ll o wi n g p r ob l em .
H ow m a n y g r a m s o f b o ri c ac i d s h ou l d b e us e d i n c om p ou n d in g th e f o l l ow i ng p r es c r ip t i o n?
Rx
phenacaine hydrochloride
1%
chlorobutanol
0.5%
boric acid
qs
purified water, ad
60.0 mL
make isotonic solution Th e p r es c ri p ti on c a ll s f o r 0 . 3 g of c h lo r ob u t an ol an d 0. 6 g o f p he na c ai ne . H o w m u c h b o ri c ac i d is re q ui r e d t o p r ep a re t hi s pr e s c r ip t io n ? Th e qu e st ion i s b es t an s we r e d in f ou r s t ep s . ( a ) Fi n d t h e m a s s of s o diu m c hl o r id e r e p re se n te d b y a l l i ng r ed i en ts .
0.20 × 0.6
=
0.120 g
of sodium chloride represented by phenacaine hydrochloride
0.24 × 0.3
=
0.072 g
of sodium chloride represented by chlorobutanol
0.192 g
of sodium chloride represented by the two active ingredients
( b ) F in d t h e m a s s of s o di u m c h l o ri de r eq ui r e d t o p r e pa r e a n e q ua l v ol um e o f is o to ni c s ol u ti on .
( c ) C al c ul at e , b y s u b t ra c t i o n, th e am ou n t o f N a C l r e q ui r ed to m a k e th e s o lu t io n i s o t on ic .
0.540 g NaCl required for isotonicity 0.192 g NaCl represented by ingredients 0.348 g NaCl required to make isotonic solution
( d ) B ec a us e t he p re s c r ipt i o n c a l ls fo r b o r ic a c i d to b e us e d, on e l a s t s t ep i s r e q ui r e d.
VIII. STATISTICS A. I n t r o d u c t io n . S t a ti s t ic s c an be us ed t o d es c r ib e an d c om pa r e d a ta d i st r ib u ti o ns . Su c h f r eq ue n c y d i s t r i b u t i o ns a re c o ns t ru c te d b y cl as si f yi ng i n di vi d ua l o bs e r v a ti o ns in t o c a te go r i es c o r re sp o nd i ng t o f i xe d nu m e r ic i n t er va l s a nd pl o tt i ng th e n um b e r o f o bs e r vat i on s i n ea ch s u ch c a te g or y ( i . e ., i n te r va l f r eq u en c y) v e r s us th e c at e go r y d es c ri p to r ( e. g ., t he in t er v al m e an o r r an g e ). B ec au s e o f r a nd om e r ro rs , r ep ea t e d o bs e r vat i on s o r m e as u re m e n ts (o f th e s am e v al u e ) a re n ot id en t ic a l . Th es e o bs e r v a ti on s h a ve a n o r ma l di s t r ib u ti o n . No r m a l l y d is t r ib u te d d a ta a re de sc r ib e d b y a b e l l -s h a pe d ( Ga u ss i a n) c u r ve wi t h a m a xi m u m , µ ( p o p ul a t io n me a n) , c o r re s po nd i ng to t he c e nt r a l t e nd e nc y o f t he po pu l a ti on an d a s p r ea d c h a ra ct e ri z e d b y t h e p op u l a t io n s t a nd a r d d e via t i o n ( σ ) . S ta t is ti cs de r ive d f r o m a s a mp l e o r s u bs et o f a p op ul a ti o n c a n b e us e d as es t im at es o f t he p o p ul at i on pa r am e te r s . B . F r e q ue n c y d i s t r i b u t io n 1 . E s ti m a te s o f po p u la ti o n me a n. Th e p o pu l at i on m e a n, µ , i s t h e b es t e s ti m a t e o f t h e t r ue v a lue . a . T he sa m pl e m e an . For a fi n it e n um b e r o f o bs er v a t i o ns , t he a ri t hm e ti c a ve r a ge o r m ea n ( [ X w ith b a r a bo ve ] ) i s t he be s t e s ti m a t e o f t he t r ue v a lu e , µ.
wh e r e Σ x i i s th e s um o f a l l ( n ) o bs e r v a ti o ns .
P.22
( 1 ) Ac c u r a c y i s t h e d eg re e to wh i c h a m ea s u r e d v a l u e (X o r [ X w it h b a r a b ov e ] ) a g re es wi t h th e “t r u e ” v al ue ( µ ) . ( 2 ) E r r o r (o r bi as ) is th e d i ff e r en ce be t we e n a m e a su r ed v a lu e ( X o r [X wi t h b a r ab ov e ] ) a nd th e “t r ue” v a l u e ( µ ) . b . M e d ia n . Th e m e d ia n is t he m i dm os t v al ue o f a d a ta di s tr i bu t io n . W hen a l l t h e val u es a r e a r r an g ed i n in c r e as in g (o r de c re asi n g ) o r de r , t h e m e d ia n i s t h e m id d le v a lu e f o r a n od d nu m be r o f ob se r va t ion s . F o r a n e ve n nu m b e r o f o b se r va t io ns , th e m ed ian is t he ar i th m e t ic m e an o f t he t wo m i dd l e va l ue s . F o r a n o r ma l d i s t r ib u t ion , t h e m ed i an eq u a ls t he m ea n . Th e m e di a n i s l e ss a f f ec te d b y “ o ut l ie r s ” o r b y a s k e we d d is t r ib ut i o n. c . M o de . Th e m od e i s t he m o s t f r eq u en tl y o cc u r rin g v a lu e (o r v al u es ) i n a f r e q ue nc y d is t ri b ut io n . Th e m o de is u s ef ul f o r n on - n o rm al di s t r i bu t io ns , e s pe ci a ll y t ho s e th a t a r e b i m od a l. 2 . E s ti m a te s o f va r i ab i li t y. F o r a n in f i ni t e n um be r o f o bs e r vat i on s , t he 2
p o p u la t i on va r i a nc e ( σ ) c an be us ed t o d es c r i be t he v a r ia b il it y o r “ s p re a d ” o f o bs e r v a ti on s i n a da t a d is t ri b ut i on . Fo r a fi n i te nu m b e r o f 2
o b se r v a t io ns , th e s am p le va r i a n ce (s ) c an be us e d t o d es c ri be t he va r i a bi l it y o r s p re a d o f ob s e r v at i on s i n a d a ta di s t r i bu t io n . 2
a . S am p le va r i a nc e (s ) i s e s ti m a t ed b y
wh e r e [ X w i th ba r a b ov e ] i s t h e m e a n a nd ( n - 1) is t he nu m b e r o f d e gr e es o f f re e do m ( d f ). b . R a ng e . F o r a v e r y s m a l l n um be r o f o bs er va t ion s , t h e r a n ge ( w ) c an be u s ed to de s c r ib e th e v a ria b il i t y in th e d a ta se t : w = | Xlar gest - Xsmal l est| c . Th e s t a nd a r d d e vi a t io n ( s o r S D) , on e o f th e m os t c om m o n l y e n co u nt e re d es ti m a t es of v a r i ab il i t y, i s e qu a l t o th e s q ua r e ro o t o f t he va r i a nc e .
or
d . P r e ci s io n ( re p r od uc ibi l it y ) i s t he de g r ee to wh ic h re p li ca t e m e as u re m e n ts “m ad e i n e xa c t l y t h e sa m e wa y” a g r e e wi t h e ac h o th e r . P r e c i si o n i s o f te n e xp r e s s e d a s t h e r e l at i ve s tan d a r d d e vi a t io n ( R S D or %RSD):
3 . Th e st a n da r d d e vi a t io n o f th e m ea n (s m ) , o r s t an d a rd e rr o r o f th e m ea n ( S E M) , i s a n es t im a te of t h e va r i ab i l it y o r e r r o r in t h e m ea n o b t ai ne d fr om n o bs e r v at i on s . I t is o ft en us e d t o e s t a bl is h c on f id e nc e i n te r va ls fo r d e sc r ib in g th e m ea n o f a d a ta s e t o r wh e n c om par i n g t h e m e a ns o f t wo dat a s e ts .
P.23
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 30 : E a c h qu e st io n , st a t em en t , o r in co m p le t e s t a te m e n t i n t hi s s ec ti o n c an be co r r ec tl y a ns we r e d o r c o m p l et e d b y o ne o f t h e s ug g es t ed an s we r s or p h ra s e s . C h oo s e t he be s t an s we r . 1 . I f a vi t am i n s o l ut i o n c o n t ai n s 0 . 5 m g o f f l u or i d e io n in ea c h m i ll i l i te r , t h e n h ow ma n y m i l l i g r am s o f f l uo r i d e i o n w o u ld b e p r o vi d e d b y a d r o p p e r t h a t d e li ve r s 0.6 m L ? (A) 0.3 mg (B) 0.1 mg (C) 1 mg ( D ) 0 . 83 m g V i e w A n s we r 1 . T h e a n sw e r i s A [ se e] . 2 . How ma n y c h l o r am p he n ic o l c a ps ul e s , e ac h co n t ai n i ng 250 m g , a re ne e de d t o p r o vi d e 25 m g pe r kg pe r d a y f o r 7 d a ys f o r a p e r s o n w e i gh i n g 2 00 l b? ( A ) 9 0 c ap s u le s ( B ) 6 4 c ap s u le s ( C ) 1 3 c ap s u l es ( D ) 2 5 c ap s u l es
V i e w A n s we r 2 . T h e a n sw e r i s B [ se e] . 3 . I f 3. 1 7 k g o f a d ru g is u s e d t o m a ke 50 , 00 0 tab l e t s, h ow m a n y m i l l i g ra m s w il l 30 ta b l et s c o n t ai n ? (A) 1.9 mg ( B ) 1 90 0 m g ( C ) 0 . 00 1 9 m g (D) 3.2 mg V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . 4 . A c ap su l e co n t ai n s 1 /8 g r o f e ph e d r in e s u l fa t e , ¼ g r o f t h eo p h yl l i n e , a n d g r o f p h en o ba r b i ta l . W h a t i s th e t ot a l m as s o f t h e a c ti ve i n g re d ie n ts i n m i l li g r am s ? (A) 20 mg (B) 8 mg (C) 28 mg (D) 4 mg V i e w A n s we r 4 . T h e a n sw e r i s C [ se e] . 5 . I f 1 f l uid o u nc e o f a c o ug h s yr u p c o n t a i ns 10 g r o f s o d iu m c i t r a te , h ow ma n y m i l l i g r am s a r e c o n t ai n ed i n 1 0 m L? ( A ) 6 50 m g (B) 65 mg (C) 217 mg (D) 20 mg V i e w A n s we r 5 . T h e a n sw e r i s C [ se e] . 6 . How ma n y c a p s u l es , e a ch c o n t ai n i ng ¼ g r o f ph en o b a r bi t a l, ca n be ma nu f a c t u re d if a b o t t le c o n t ai n i ng 2 a vo i r d u poi s o un c es o f p he n o ba r bi t a l is a va il a bl e ? ( A ) 7 71 c a ps ul e s ( B ) 3 50 c a ps ul e s ( C ) 3 5 00 c a ps ul es ( D ) 1 2 50 c a ps ul es V i e w A n s we r 6 . T h e a n sw e r i s C [ se e] . 7 . Us i n g th e f o rm u l a f o r c a l am i ne l o ti o n, d e te r mi n e t he am o un t o f c al am i n e ( i n g r a ms ) n e c es s a r y t o p r e p a r e 24 0 m L of l o ti o n .
Calamine
80 g
Zinc oxide
80 g
Glycerin
20 mL
Bentonite magma
250 mL
Calcium hydroxide topical solution
sufficient quantity to make 1000 mL
( A ) 1 9 .2 g ( B ) 1 40 g (C) 100 g (D) 24 g V i e w A n s we r 7 . T h e a n sw e r i s A [ se e] . 8 . F r o m th e f o ll ow i ng f o r m u la , ca l cu l a te t he a m o un t o f w h i t e w ax r eq u i r e d t o m a ke 1 l b o f c o l d c r e am . De t e r mi n e t h e ma s s i n g r a ms .
Cetyl esters wax
12.5 parts
White wax
12.0 parts
Mineral oil
56.0 parts
Sodium borate
0.5 parts
Purified water
19.0 parts
( A ) 5 6 .7 5 g ( B ) 2 54 . 24 g ( C ) 5 4 .4 8 g ( D ) 8 6 .2 6 g V i e w A n s we r 8 . T h e a n sw e r i s C [ se e] . 9 . How ma n y g r a m s o f a s pi r i n s h o u ld be u se d to p r epa r e 1 .2 55 k g o f th e p ow d e r ?
ASA
6 parts
Phenacetin
3 parts
Caffeine
1 part
( A ) 1 25 g ( B ) 7 50 g (C) 175 g (D) 360 g V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . P . 24
1 0 . A s o lu t i o n c on t a in s 1 . 25 m g o f a d r u g pe r m i l l il i t e r . At w h a t r a t e s h o u ld t he s o l u t io n b e in f u se d (d ro p s /m i n ) i f t he d r ug is t o b e a dm i n is t e r ed a t a r a t e of 80 m g / h r? ( 1 m L = 3 0 d r o ps ) ( A ) 6 4 d r op s / m i n ( B ) 1 . 06 dr o ps /m in ( C ) 3 2 d r op s /m in ( D ) 2 0 d r op s /m in V i e w A n s we r 1 0 . T he a nsw e r i s C [ se e] . 1 1. T he re c o mm e nd e d m ai n t en an c e d o s e o f am i no p h yl l i n e f o r c h il d r e n i s 1 . 0 m g / k g/ h r b y i n j e c t i o n . I f 10 m L o f a 25 m g /m L s o lu t i o n o f a m ino p h yl l i n e i s a dd e d t o a 1 0 0 -m L b o t t le f o r d ex t ro s e , w ha t s h o u ld be t he r a te o f de l i ve r y i n m L / h r f o r a 40 - l b c h i ld ? ( A ) 2 . 30 m L /h r ( B ) 8 . 00 m L /h r ( C ) 1 8 .9 m L /h r ( D ) 1 8 .2 m L /h r V i e w A n s we r 1 1 . T he a nsw e r i s B [ se e] . 1 2. F o r ch i l d r en , st r e p t om yc i n i s t o b e ad m i ni s te r e d a t a d os e o f 3 0 m g / k g o f b o d y w e ig h t d a i l y i n d i vi d e d d o s es e ve r y 6 - 1 2 h r . Th e d r y p ow d e r is d is s ol ve d b y a d d in g w a te r f o r i n je c ti o n , U S P i n a n a mo u n t t o yi e l d t h e de s i r ed co n ce n t r a tio n as i nd i ca t e d i n th e fo l l ow i ng t a b l e ( f o r a 1 -g vi a l ) .
Approximate Concentration (mg/mL)
Volume (mL)
200
4.2
250
3.2
400
1.8
R e c o ns t i t u ti n g a t t he low e st p os s ib l e c o nc e n t ra t i o n , w h a t vo lu m e ( i n m L ) w ou l d b e w i t hd r aw n t o o b ta i n o n e da y' s d o s e f o r a 5 0- l b c hi l d? (A) 3.4 mL ( B ) 2 2 .7 3 m L ( C ) 2 . 50 m L ( D ) 2 . 27 m L V i e w A n s we r 1 2 . T he a nsw e r i s A [ se e] . 1 3. T he a tr o p i n e s u lf a t e i s a va i l a b le on l y i n t h e for m o f 1 / 1 50 gr t ab l e ts . H ow m a n y a t r o p i n e s ul fa t e ta b l et s w o ul d yo u u s e t o co m po u n d th e fo l l ow in g p res c r i p t io n ?
Atropine sulfate
1/200 gr
Codeine phosphate
1/4 gr
Aspirin
5 gr
d.t.d.
#24 capsules
Sig:
1 capsule p.r.n.
( A ) 3 ta bl e ts ( B ) 6 ta bl e ts ( C ) 1 2 t a bl e ts ( D ) 1 8 t a bl e ts V i e w A n s we r 1 3 . T he a nsw e r i s D [ se e] . 1 4. I n 2 5.0 m L o f a so l u ti o n fo r i n j e ct i o n, t he r e a re 4. 00 m g o f t h e d r u g . I f th e d o s e t o be ad m in i s te r ed t o a p a t i en t is 20 0 µ g, w h a t q u a n ti t y ( i n m L ) o f t hi s s o l u t io n s h o ul d be us ed ? ( A ) 1 . 25 m L
( B ) 1 25 m L ( C ) 1 2 .0 m L ( D ) N o n e o f t h e a bo v e V i e w A n s we r 1 4 . T he a nsw e r i s A [ se e] . 1 5. H ow m a n y m i l l i g r a m s o f p a p a ve r i ne w i l l t h e p a tie n t r ec e i ve e a ch d a y?
Rx
papaverine
1.0 g
hydrochloride aqua
30.0 mL
syrup tolu, qs ad
90.0 mL
Sig:
1 teaspoon t.i.d.
(A) 56 mg (B) 5.6 mg (C) 166 mg (D) 2.5 mg V i e w A n s we r 1 5 . T he a nsw e r i s C [ se e] . 1 6. C o ns id e r i n g t h e f o l low i n g f o r m u la , how m an y g r a m s o f s od i u m b r o mi d e s h o u ld be u se d i n f il l i ng t h i s p r e s c r ip t i on ?
Rx
sodium bromide
1.2 g
syrup tolu
2.0 mL
syrup wild cherry, qs ad
5.0 mL
d.t.d.
#24
(A) 1.2 g ( B ) 1 20 0 g ( C ) 2 8 .8 g (D) 220 g
V i e w A n s we r 1 6 . T he a nsw e r i s C [ se e] . 1 7. H ow m a n y m i l l i l i t e r s o f a 7 .5% s t o c k s ol u t i on o f K M n O 4 s h ou l d b e u s ed t o o b ta i n t he KM n O ne e de d ? KMnO4, qs D i s t i l le d w a te r , a d 1 0 00 S i g : 2 t e as p oo n s d i l ut ed t o 50 0 m L yi e l d a 1 :50 0 0 s o l ut i o n ( A ) 2 67 m L ( B ) 1 33 m L ( C ) 2 6 .7 m L ( D ) 1 3 .3 m L V i e w A n s we r 1 7 . T he a nsw e r i s B [ se e] . 1 8. T he fo r m u l a f o r R in g e r 's s o l u t io n fo l l ow s. H ow m u c h s o di u m c h lo r i de is n ee d ed t o m ak e 12 0 m L ?
Rx
sodium chloride
8.60 g
potassium chloride
0.30 g
calcium chloride
0.33 g
water for injection, qs ad
1000 mL
( A ) 1 20 g ( B ) 1 . 03 g ( C ) 0 . 12 g (D) 103 g V i e w A n s we r 1 8 . T he a nsw e r i s B [ se e] . P . 25
1 9 . H ow m a n y g r a m s o f t a l c s h ou l d b e a d de d to 1 lb o f a pow d e r c o n ta i n i ng 20 g o f z i nc u nd e c yl e n a t e p e r 10 0 g t o re d uc e t he c o nc e n t ra t i o n o f z i nc u n d ec yl e n a t e t o 3 %? ( A ) 3 02 6 .7 g ( B ) 2 57 2 .7 g (C) 17 g (D) 257 g V i e w A n s we r 1 9 . T he a nsw e r i s B [ se e] . 2 0. H ow m a n y m i l l i l i t e r s o f a 0 .9% a q u eo u s s o lu t i o n c an be m ad e f ro m 2 0 .0 g o f so d i u m c hl o r i de ? ( A ) 2 22 2 m L ( B ) 1 00 m L (C) 222 mL (D) 122 mL
V i e w A n s we r 2 0 . T he a nsw e r i s A [ se e] . 2 1. T he b lo o d o f a re c kl e ss d r i ver c o n t ai n s 0 . 1 % a l c o h o l . E x p r e ss t he co n ce n t r a ti o n o f a lc o h ol i n p a r ts p e r m i l l io n . ( A ) 1 00 pp m ( B ) 1 00 0 p pm ( C ) 1 pp m ( D ) 2 5 0 p pm V i e w A n s we r 2 1 . T he a nsw e r i s B [ se e] . 2 2. S yr u p i s an 85 % w / v so l u t io n o f s u c r os e in w a t e r. I t h a s a d en s i t y o f 1 . 3 1 3 g /m L . H ow ma n y m i l l i l i t e r s o f w a t e r s h o u ld be u se d to ma ke 1 25 m L of s yr u p ? ( A ) 1 06 . 25 m L ( B ) 1 64 . 1 m L ( C ) 5 7 .9 m L ( D ) 2 5 .0 m L V i e w A n s we r 2 2 . T he a nsw e r i s C [ se e] . 2 3. H ow m a n y g r a m s o f b e n ze t h on i um ch l o r i de s h o u ld be u se d i n p re pa r i n g 5 ga l . o f a 0 .0 2 5 % w / v s o l u t io n ? ( A ) 1 89 . 25 g ( B ) 1 8 .9 g ( C ) 4 . 73 g (D) 35 g V i e w A n s we r 2 3 . T he a nsw e r i s C [ se e] . 2 4. H ow m a n y g r a m s o f me n t h ol s h o u ld be u se d to p r epa r e t h is p re s c ri p t i on ?
Rx
menthol
0.8%
alcohol, qs ad
60.0 mL
( A ) 0 . 48 g (B) 0.8 g (C) 4.8 g ( D ) 1 . 48 g V i e w A n s we r 2 4 . T he a nsw e r i s A [ se e] . 2 5. H ow m a n y m i l l i l i t e r s o f a 1 :1 5 0 0 s o l u t io n c a n b e m a de by d i s s o l vi n g 4 .8 g o f c et yl p yr i d i n i u m c h lo r i d e in w a t e r ? ( A ) 7 20 0 m L (B) 7.2 mL
(C) 48 mL (D) 4.8 mL V i e w A n s we r 2 5 . T he a nsw e r i s A [ se e] . 2 6. T he ma n u f ac t u r e r s pe c i f ie s th a t o n e D om e bo r o t ab l e t d is s o l ve d i n 1 p in t o f w a te r m ak e s a m o d if i e d B ur ow 's s o l u t io n a p p r ox i ma t e l y e q u i va le n t to a 1 :4 0 di lu t i o n . H ow ma n y t a b l e ts s ho u l d b e us e d i n p re p a r in g ½ g a l o f a 1 :1 0 di l u t io n ? ( A ) 1 6 t a bl et s ( B ) 1 89 t ab le t s ( C ) 1 2 t a bl e ts ( D ) 4 5 t a bl e ts V i e w A n s we r 2 6 . T he a nsw e r i s A [ se e] . 2 7. H ow m a n y m i l l i o s m ol e s o f c a l ci u m c h lo r i d e ( C a C l 2 · 2 H 2 O - m o l w t = 14 7 ) ar e r e p r es e n te d i n 14 7 m L o f a 1 0 % w / v ca l ci u m c h lo r id e so l u t io n ? ( A ) 1 00 m Os m o l ( B ) 2 00 m Os m o l ( C ) 3 0 0 m Os m o l (D) 3 mOsmol V i e w A n s we r 2 7 . T he a nsw e r i s C [ se e] . 2 8. H ow m a n y g r a m s o f b o r ic aci d s h o u ld be u se d i n co mp o u n di n g th e fo l l ow in g p r e sc r i p t io n ? P h e n ac a in e H C l 1 . 0 % ( N a C l e q = 0. 1 7) C h l o r o b u ta n ol 0 .5 % ( N a C l e q = 0 .1 8 ) B o r i c ac i d , q s ( N a C l e q = 0 .5 2 ) P u r i f i e d H 2 O , ad 30 m L M a ke is o t o ni c s o l ut i o n S i g : 1 d r o p i n e a ch e ye ( A ) 0 . 37 g ( B ) 0 . 74 g ( C ) 0 . 27 g ( D ) 0 . 47 g V i e w A n s we r 2 8 . T he a nsw e r i s A [ se e] . 2 9. A p h ar m a c is t p re p a r es 1 g al o f K C l s o l ut i o n b y m i x i n g 5 6 5 g o f K C l ( va l en c e = 1 ) i n a n a p p ro p r i at e veh i c l e. +
H ow m a n y m i l l i e q u i va len t s o f K a r e i n 1 5 m L of t h i s s o lu t i on ? (a t o mi c w ei g h ts : K = 30 ; C l = 35 . 5 ) ( A ) 7 . 5 m Eq ( B ) 1 0 m Eq (C) 20 mEq (D) 30 mEq ( E ) 4 0 m Eq V i e w A n s we r 2 9 . T he a nsw e r i s D [ se e] . P . 26
3 0 . A va n c o m yc i n s o l u ti o n co n t ai n i ng 10 0 0 m g o f va n c om yc i n h yd r o c h l o r i de d i l u t ed t o 2 50 m L w i th D 5W i s t o b e in f u se d a t a c on s ta n t r at e w i th an i n f us i on p u m p i n 2 h r. W ha t is th e r a te o f d r u g a d mi n ist r a t i o n? ( A ) 2 . 08 m g /m in
( B ) 8 . 33 m g /m in ( C ) 4 . 17 m g /m in ( D ) 1 6 .7 m g /m in ( E ) 5 . 21 m g /m in V i e w A n s we r 3 0 . T he a nsw e r i s B [ se e] . F o r q u es ti o n s 3 1 -3 4 : F i v e i b up r o fe n t a b le ts we r e as s a y e d f o r d r u g c o n te n t , a nd th e f ol l o wi n g r es u lt s we r e o b tai n ed b y h i gh - p r es s u r e li q ui d c h rom a to g r ap h y ( H P L C ) a na lys i s : 1 98 . 2 m g , 19 9 .7 m g , 20 2 .5 m g , 2 01 . 3 m g, 19 6 .4 m g . 3 1 . W h a t i s th e m e an i bu p r o f e n c on t e n t? ( A ) 1 96 . 9 m g ( B ) 2 00 . 2 m g ( C ) 1 9 9. 6 m g ( D ) 2 4 9. 5 m g ( E ) 2 02 . 5 m g V i e w A n s we r 3 1 . T he a nsw e r i s C [ se e] . 3 2. W ha t i s t he s ta n da r d de vi a t io n o f i b up r o f en c on t e nt i n t h e a n a l yz e d t a b le t s ? ( A ) 2 . 17 m g ( B ) 3 . 35 m g ( C ) 2 . 42 m g ( D ) 3 . 00 m g ( E ) - 2 .1 7 m g V i e w A n s we r 3 2 . T he a nsw e r i s C [ se e] . 3 3. W ha t i s t he p e rc e n t r e la t i ve s t a n da r d de vi a t i on ( %R S D ) f o r t h is ib u p r o fe n ta b l e t a na l ys i s ? ( A ) 1 . 69 % ( B ) 1 . 21 % ( C ) 8 . 25 % ( D ) 3 . 35 % ( E ) 1 . 50 % V i e w A n s we r 3 3 . T he a nsw e r i s B [ se e V I I I. B . 4] .34 . W ha t is t he s ta n da r d d e vi a t i o n o f th e m e an dr u g c on t e n t o f th i s s amp l e ? ( A ) 0 . 48 0 m g ( B ) 0 . 60 5 m g ( C ) 1 . 21 m g ( D ) 1 . 08 m g ( E ) 0 . 82 5 m g V i e w A n s we r 3 4 . T he a nsw e r i s D [ se e V I I I. C] . P . 27
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is A [ s ee I . A . 2] . 2 . T he an sw e r is B [ s ee I I ] . 3 . T he an sw e r is B [ s ee I I ] . 4 . T he an sw e r is C [ s ee I I ] . 5 . T he an sw e r is C [ s ee I . A . 2] .
6 . T he an sw e r is C [ s ee I I ] . 7 . T he an sw e r is A [ s ee I I I ] . 8 . T he an sw e r is C [ s ee I I ; II I . A ]. Th e f o rm u la te l ls th e p har m ac is t th a t wh i t e wa x ( W .W .) r e p re s e n ts 12 pa rt s ou t o f t h e to t al 10 0 p a rt s i n t h e p r es c ri p ti on . W ha t we w i s h t o d e te rm i ne is th e m a s s o f wh i t e wa x r e q u i re d t o p re p a re 45 4 g ( 1 l b ) o f t h e r e c i p e. Th is ca n b e e as il y s ol v e d b y p r o po r ti o n:
9 . T he an sw e r is B [ s ee I I I . A] . 1 0 . Th e a n sw e r i s C [ s ee I V . E ]. 1 1 . Th e a n sw e r i s B [ s ee I I ; I V ] . 1 2 . Th e a n sw e r i s A [ s ee I V ] . 1 3 . Th e a n sw e r i s D [ s ee I I ; I I I. B ] . 1 4 . Th e a n sw e r i s A [ s ee I . A .2 ; I I ] . D i m en si o na l a na l y s i s i s o f t en us e fu l f o r c al c u l at in g do s e s . C o ns id e ri n g t ha t 4 m g o f t h e d r u g is p re s e n t i n e ac h 2 5 m L o f s ol u ti o n, we c an ea si l y c a lc ul a te t he n u m b e r o f m i ll il i te r s t o b e u s e d t o gi v e a d os e o f 0. 2 00 m g (2 0 0 µg ) . Al wa y s i nc l ud e u n i ts i n yo u r ca lc u la t io ns .
1 5 . Th e a n sw e r i s C [ s ee I I I. B ] . 1 6 . Th e a n sw e r i s C [ s ee I I I. B ] . 1 7 . Th e a n sw e r i s B [ s ee V . A ; V I ] . F i r st , de t er m i n e t he m a s s o f d ru g i n th e f i na l d il ut e d s ol u ti o n.
N o w, i f 0 .1 g o f d r ug is pr e s en t i n 5 0 0 m L o f 1 :5 00 0 s o lu t io n , 2 te as po o n fu l s ( 1 0 m L ) o f th e p r es c r i pt i on c o n t ai ns th e s am e a m o u nt o f d r ug ( 0. 1 g) be f o re di l u ti on . F r o m t hi s , t he am ou n t o f d r u g i n 1 00 0 m L ( t he to ta l v o lu m e ) of th e p r es c rip t i on c a n b e de t e rm in ed :
F i n al l y , t o o b ta i n t he c o rr e c t am o un t of d ru g t o f or m u la t e t he p re s c r ip ti o n ( 1 0 g) , we a r e to us e a 7. 5 % s t oc k s o lu t io n . R e c a ll i ng th e de f i ni t io n o f p e rc e nt a ge s tr e n g th w/ v:
P.28
1 8 . Th e a n sw e r i s B [ s ee I I I. B ] . 1 9 . Th e a n sw e r i s B [ s ee V . C ; VI . C ] . 2 0 . Th e a n sw e r i s A [ s ee I . A .2 ; V. A ] . U s i ng di m e ns i on al an a l ys is
2 1 . Th e a n sw e r i s B [ s ee V . D . 1] . 2 2 . Th e a n sw e r i s C [ s ee I . A ; V . A .1 ] . U s i ng th e de ns i t y , t he we i gh t of 12 5 m L o f s yr u p c a n b e c al cu la t ed : 1 2 5 m L × 1. 3 13 g /m L = 16 4 . 12 5 g U s i ng p ro p or t io n a n d t he s uc r os e c on ce n t ra t io n in w/ v, t h e we i gh t of su c ro s e i n 1 25 m L o f s y r u p c an be c a lc u l a te d :
F i n al l y , t h e we i g h t o f wat e r in 12 5 m L o f s yr u p c an b e ca lc u la t ed : 1 6 4 .1 2 5 g - 1 06 . 25 g = 57 . 8 75 g wh i c h ha s a v o lu m e of 57 . 9 m L . 2 3 . Th e a n sw e r i s C [ s ee I ; I I ; V] . 2 4 . Th e a n sw e r i s A [ s ee I ; V] . 2 5 . Th e a n sw e r i s A [ s ee I ; V] . Th e p r o bl em i s e as i l y s olv e d b y p ro p o rt i on . Th e qu e st i on to be an s we r e d is , If 1 g of d r u g i s p re s en t i n 1 5 00 m L o f s o lu t io n , wh a t vo lum e c an be m a d e wi t h 4. 8 g o f d r u g?
2 6 . Th e a n sw e r i s A [ s ee I ; V] . 2 7 . Th e a n sw e r i s C [ s ee V I I . B] . R e c al l in g t h e e xp r e s s i on f o r i d ea l o sm ol a r c on c en t r a ti o n:
2 8 . Th e a n sw e r i s A [ s ee V I I . C] . 2 9 . Th e a n sw e r i s D [ s ee V I I . A] . 3 0 . Th e a n sw e r i s B [ s ee I V . E ]. U s i ng di m e ns i on al an a y ls is :
3 1 . Th e a n sw e r i s C [ s ee V I I I. B . 1] . Th e m ea n i s c al c u la t ed d i r ec tl y f r om th e eq ua t ion :
P.29
3 2 . Th e a n sw e r i s C [ s ee V I I I. B . 3] . Th e s t an da r d d e v i at i on c a n be c a lc ul a te d wi t h t he m o s t co m m on l y us e d eq u a ti on :
3 3 . Th e a n sw e r i s B [ s ee V I I I. B . 4] .
3 4 . Th e a n sw e r i s D [ s ee V I I I. C ] .
3 Pharmaceutical Principles and Drug Dosage Forms L aw re n ce H . B lo c k
I. INTRODUCTION. P h a r m a c e u ti c a l p r in c i pl es a re th e u n de r l y in g ph y s ic oc h em ic al p ri nc ip l es t h a t a ll o w a d ru g t o be i nc o r po r at e d i nt o a p ha rm a c eu t ic al d os a ge f o rm ( e . g ., so lu t io n , c ap s u l e) . Th e s e p r in ci p le s a pp l y wh e t h e r th e d r u g is e xt e m p o r an e ou s l y c o m po u n de d b y t he ph a rm ac is t or m a n uf ac t u re d f o r c om m e r c i a l d is t ri bu t io n a s a d r u g p r o du c t . A. Th e f i n is h ed do s ag e f o r m c o n ta in s t h e ac t i ve d r u g i ng r ed i en t i n a ss o ci at i on wi t h no nd r u g ( u s u a ll y i ne r t ) i ng r ed i ent s (e x ci p i en t s ) t h at m ak e u p th e ve h ic l e, o r f o r mul a t i o n m at r i x . B . Th e d r u g d e li ve r y s ys t e m c on c e p t, wh i c h h as e vo l ve d si n ce th e 1 9 60 s , i s a m o r e h ol is t ic c on c ept . I t e m b r ac es no t o n l y th e d ru g ( o r p r o dr u g ) a nd i t s f o rm ul a ti o n m a t r i x, b ut a ls o t h e d y n am ic i n te r ac t io ns am on g th e d r ug , its f o r m u l at io n m a t ri x, i t s c on t a in e r , a nd th e p h y si o log i c m i l ie u x o f th e pa ti e n t. Th e s e d y n a m i c in t e ra c tio n s a r e t he s u bj ec t of b io p h a r ma ce u t ic s (s ee C h a p te r 4 ).
II. INTERMOLECULAR FORCES OF ATTRACTION A. I n t r o d u c t io n . Th e a pp l ic a ti on o f p ha r m a c e u tic a l p ri n c i pl es t o d ru g d o sa g e f o rm s is il lu s t r a te d wh e n d r u g d os ag e f o rm s a r e c a te g o r iz ed a cc o r di ng t o t he i r p h ys i c a l s t a te , de g r ee o f h e te r o g e ne i t y, a n d c h em i ca l c o m po s i ti o n . Th e us u al r e l e v an t s t at e s o f m a t t e r a r e g a se s , l i qu i d s, an d s o l i ds . In t er m o l ec ul a r f or c es o f a tt r ac t io n a r e wea k es t i n g as es an d s t r on g es t i n s ol id s . C o n ve r s io ns f ro m o ne ph y s ic a l s t a te to an o th e r c an i n vo l ve s im pl y o v e rc om in g in t e rm ol ec ul a r f o rc es o f a tt r ac t io n b y a dd i ng e n e rg y ( h ea t ) . Ch em ic a l c om p os it i on c a n h a ve a d r a m a t ic e f fe c t o n p h ys ic oc he m i c a l p r o pe r tie s a n d b eh a vi o r. Fo r th is r e as o n, it is ne ce s s a r y to d i st i ng ui s h b et we e n po lym e r s , o r m ac r o mo l ec ul e s , a nd m o r e c on ve n ti on a l ( i . e ., sm al le r ) m o le c u le s , o r mi c r om o l ec u le s . B . I n t e rm o le c u la r f o rc es o f a t t r a ct i o n. B ec au s e a t om s v a r y i n t he i r e l ec t r on eg a ti v i t y , el ec t r on s h a r in g b e t we e n d if f e re n t a t om s is li ke l y to be u n e qu al . Th is as y m m e t ric el ec t r on di s t r i bu t io n c au s es a s h i ft in t he o v er a ll e l ec t r on c l ou d i n t h e m o le c ul e . A s a re s u l t , t he m o l ec ul e te n ds t o b e ha ve a s a d i po l e ( i .e . , a s i f i t h ad a p os i ti v e an d a ne g a tive p o le ) . Th e d ip ol e a ss o ci at e d wi t h e ac h c ov a l e n t b on d h as a c or r es p o n d i ng d ip o le m om e nt ( µ ) d e fi n ed as t h e p r od uc t of th e d is t a nc e o f c ha rg e s e pa r a ti on ( d ) a nd the c h a rg e ( q ) : µ = q × d Th e m ol ec u la r di po l e m om e nt m a y b e vi e we d as th e vec t o r s um o f th e i n di vi d ua l b o nd m om e nt s .
1 . N o np o l a r m o l ec ul es th a t h a v e pe r f ec t s ym m e t r y ( e . g . , c a rb on t e t r ac hl o ri d e ) h a v e d ip ole m o m e n ts of z e r o ( F ig ur e 3 -1 ) . 2 . P o la r m o le c u l es a r e as ym m e t r i c a nd ha v e non z e r o di po l e m o m e n ts . 3 . W he n d i po l a r m ol ec u le s a p p ro ac h o n e a no t he r c lo s e en o ug h — “p os i ti v e t o po si t i v e ” o r “n e ga ti v e t o ne g at i v e ” —s o t h at t hei r el ec t r on c l ou ds i n t er p en e t ra t e, i n te r m ole c u la r r e pu l s i ve fo r c es a r is e . W hen th es e d ip o la r m o le cu l es a p pr o ac h o ne a n o th e r s o t ha t th e p os i ti v e P.31 p o le o f o ne is c lo s e t o t he n eg a ti v e po l e o f t he o th e r , m ol ec u la r a t t r a c ti on o cc u rs ( d ip o le d i po l e i n te r a c t io n ) . W hen th e i d en t ic a ll y ch a r ge d p ol es o f t h e t wo m o le c u l es a r e c lo s e r, r e pu l si o n o c c u rs .
Figure 3-1. The carbon tetrachloride molecule.
C . T yp e s o f i nt e r m ol e cu l a r f o rc e s o f a t t r a ct i on i nc lu d e t he f ol lo wi n g : 1 . N on p ol a r m ol ec ul e s do n ot ha v e pe r m a n en t d ip o le s . H o we v e r , t he i n st a nt a ne o us e l ec t ro n di s t ri bu t io n i n a m o le c u l e c a n b e a s ym m e t r ic . Th e r e s ul t an t t r a ns ie n t d ip ol e m om en t c a n i nd uc e a dip o le in an ad j ac en t m o le cu l e. Th is i nd u ce d d i p o le - i nd u ce d di p o le in t e r a c ti o n ( L o nd o n d i s pe r s i on f o r ce ) , wi t h a f o rc e o f 0 . 5 -1 k ca l /m ol, i s s u f fi ci e nt t o f ac il i ta t e o r d e r i n a m ol ec u la r ar r ay . Th e s e re la t i v el y we a k e l ec t r os ta t ic fo r c e s a r e r e s po ns ib l e f o r t he li q ue fa c ti o n o f n on p ol a r g as es . 2 . Th e t ra ns ie n t d ip o le in d uc e d b y a p e rm an e nt d i po l e , o r d i po l e -i n d uc ed d i p o le i nt e r ac t i o n ( D e bye i n d u c t i o n f o r ce ) , i s a s tr o ng e r i n te r ac t io n , wi t h a f o rc e o f 1 - 3 k c a l/ m o l . 3 . P e rm a ne n t di p o le in te r a c t io n s ( K e es o m o r i en t a t i on f o rc e s ), wi t h a f o r ce of 1 -7 k c al /m o l, tog e t he r wi t h De b y e an d Lo n d on fo r ce s , c o ns t it u te va n d e r Wa a ls f o rc e s. C o l l ec ti v e l y , th e y a re re s p o ns i bl e f o r t h e m o r e s u bs ta n ti v e s t r uc t u re and m o l ec ul a r o r de r in g fo un d in li qu i ds . 4 . H yd r o g e n b on d s . B ec a us e t h e y a r e sm a ll and h a ve a l a r ge el ec t r os tat i c f i e ld , h y d r o ge n a t om s c an a pp r oa ch hi g hl y e le c t ro n e ga ti ve a to m s (e . g ., f l u or i ne , o xy g e n , n i t ro gen , c h lo r i ne , s ul f u r) an d i n t e r ac t e le c t r os t a ti c a ll y to f o r m a h y d r o ge n b o nd . De p e nd in g o n th e e le c tr o ne g a ti v i t y o f t he se c o nd
a t om an d th e m ol ec ul a r e n v i r on m e n t i n wh ic h h y d r o ge n b o nd i ng oc c u rs , h yd r o ge n b o nd en e r g y va r i es f ro m a pp r o xi m a te l y 1 t o 8 k c a l/ m ol . 5 . I on - i on , io n - d ip o le , an d i on - i n du c ed d ip o le fo r c e s. P o si t i ve - ne g a t i ve i o n in t e r ac t i on s i n th e s o l id s t a te in vo l v e fo rc e s o f 10 0 - 20 0 kc a l/ m o l . I o nic i n t er a ct i on s a re r ed uc e d c o ns id e ra b l y i n l i qu id s ys t em s i n t he p re se nc e o f o t h e r e le c t r ol y t e s . I on - d ip o l e i n te r ac ti o n , o r d i p ol e i nd u c ti o n b y a n i o n , c a n a ls o a f fe c t m o le c u l ar a g gr e ga t io n , o r o r d er i ng , in a s y s te m .
III. STATES OF MATTER A. G a s e s . Mo l e c u le s i n th e ga s e o us s t at e c an be p ic t u re d a s m o v in g a lo ng s t r ai g ht pa t hs , i n a ll di r ec t io ns an d a t hi gh ve lo c it i es ( e. g . , m e a n ve l oc it y f o r H 2 O v a po r : 5 87 m / s ec ; fo r O 2 : 4 40 m / s e c ), unt i l t h e y c o ll id e wi t h o t he r m o le cu l es . A s a re s ul t o f t h es e r a nd om c o ll is i on s, m ol ec u la r ve lo ci t ie s a nd p a t hs c h an ge , an d t h e m o l ec ul e s c o n ti n ue to c o ll id e wi t h o t he r m o le c u l es a n d wi t h t he bo u nd a ri e s o f t he s y s t em (e . g. , th e wa l l s of a c on t ai ne r ho l di n g t h e g as ) . Th is p ro c e s s , re p e at e d i nc es s a nt l y , is re s po ns i bl e f o r t h e p r e s su r e e xh i bi t ed wi t h in t he c o n fi ne s o f th e s y s t e m . 1 . Th e i n te r r el a ti o n a m on g vo l um e ( V ), p r es s u re ( P ) , a n d t he ab s o lu t e t e m p e ra t u r e ( T ) i s g i v en b y t h e i de a l g a s l aw , wh i ch is th e e qu a ti o n o f s t a te fo r an id ea l g a s : PV = nRT P V = ( g/ M) R T wh e r e n is th e n um be r o f m ol es o f g as — eq ui v a l en t t o t he nu m b e r o f g r am s ( g ) o f g as d i v i de d b y t he m ol ec u la r we i gh t of t he g a s ( M) — a n d R is th e m o l a r g a s c on s t an t ( 0. 08 2 0 5 L a tm / m o le de g ) . 2 . P ha r m a c e u ti c a l g as es i nc l ud e t h e a ne s t he t i c g a s es ( e. g ., ni t r ou s o xi d e , h a lo t ha n e ). C o mp r e ss ed g as e s i nc lu d e o xy g e n ( f o r th e ra p y ) , ni t ro g en , an d c a r bo n d io xi d e . L iq u e fi ab l e ga s es , i nc lu d in g c e rta i n h a lo h yd r o c a r b o n s a n d h yd r o c a r b o n s , a re u s ed as pr o pe ll a nt s i n ae r o s o l p r o du c t s ( p r e s su r i z e d p a ck a g in g) , as a re co m p r es se d g as es , s uc h a s n i t ro us o xi de , n i t ro g en , an d c ar b on di oxi d e . E t h yl en e o xi d e is a g as us e d t o s te r il i z e o r d i si n fe ct he a t -l a bi le ob j ec t s . 3 . I n g en e ra l , as t he te m p e r a tu r e o f a s u bs ta n ce in c r ea se s , i ts h e a t c o n t en t , o r en t h al p y, i n c r e as es a s we ll . a . S ub s ta nc es c a n u nd e rg o a c h a ng e o f s t at e , o r p h as e c ha n ge , fr om t he s o li d t o t h e l iq u id s t at e (m e l t in g ) o r f ro m t h e li q ui d to th e ga se ou s s ta t e ( va p o r i z at i o n ). b . V o la t i le l iq u i ds (e . g ., e t he r , h a lo t ha n e, m e th ox y f l u r a n e) a re us ed as i n ha l at i on an es t he t ic s . Am y l ni t r it e i s a vo la ti l e l iq u id t ha t i s i nh a le d f o r i ts va s o di l at in g ef f ec t i n a c u t e a n gi n a. c . S ub l im a t io n oc c u rs wh e n a s o li d i s h ea t ed di re c tl y t o t h e g as eo us , o r va p o r , s t at e wi t ho u t p as s i ng th r o ug h t h e l iq ui d s ta t e (e . g. , c am p ho r , i o di n e ). Ic e s ub l im es a t p r e s s u re s b el o w P.32
3 t o r r. Th e p r oc es s o f f re e z e - d r yi n g , o r l yo p h i l i z a t io n , i s a fo r m o f v a c uu m d r y i n g i n wh ic h wa t e r is r e m o v ed b y s ub l im at i on f r o m t he f ro z e n pr o du c t. I t i s a n e sp e c i al l y us ef u l p ro c es s f o r d r y in g a q ue o us s o lu t io ns o r d is pe r s i o ns o f he a t - o r o xy g e n - s e ns iti v e d r ug s a nd bi ol o gi c a ls ( e . g. , pr o te i ns , p e pt id e s ) . d . Th e r e v er s e p ro c e s s (i . e ., di r ec t t ra ns i ti on f rom t he va po r s t at e to th e s o li d s ta t e ) is al s o r e fe r re d to as s u bl im a ti on , bu t t h e p r ef e r re d te r m is d e p os i t i on . So m e f or m s o f s u lf u r a nd c o ll o id al sil i c o n d io xi d e a r e p r ep a red i n th is wa y . 4 . Th e i n te r m o l ec ul a r f o rc es o f a t tr ac t io n i n g as es a re vi r tu a ll y n on e xi s t en t a t r oo m t em p er a tu r e . G as es di s p l a y l i t tl e o r n o o rd e r in g . B . L i q ui d s. Th e in t er m o le c ul a r f o rc es of a tt r ac t ion i n l iq ui ds ( va n de r W a a ls f o rc e s ) a r e s u f fi c i e n t t o im p os e s om e o r de r i ng , or r eg u la r a r r a ng em e nt , am on g t h e m ol ec u le s. H yd r o g e n bo n d i ng in c re as es t he l i ke li h oo d o f c oh e s i on in l i qu i ds a n d f u r th e r a f fe c ts t he i r p h y si co c h em ic al b e h a vio r . Ho we v e r , t he s e f o rc es ar e m uc h we ak er t h an co va l e n t o r i o n ic f o r ce s . Th e r e fo r e, li q ui ds t en d t o d is p la y sh o r t -ra n g e r a th e r t ha n l o ng - r an g e o r d e r. H y p o th e ti c a l l y , a lth o u gh m o le cu le s o f a li qu i d wo u ld te n d t o a g g re g at e i n l oc a li z e d c lu s te r s , n o d ef i ne d s t ru c tu r i ng wo u l d b e e v i de n t. 1 . S u r fa c e a n d i n te r f a cia l t en s i on a . Mo l e c u l es i n th e b ul k p h as e o f a li q ui d a r e s urr o u nd e d b y o th e r m o le cu l es o f th e s am e k in d ( Fi gu r e 3 - 2 A ) . Mo l e c ul e s a t t h e s u r f ac e o f a l i qu i d a r e n ot c o m p le t el y s u r ro un d ed b y li k e m o lec u le s ( F ig u re 3 -2 B ) . As a r e s ul t , m o l ec ul es at o r ne a r th e s u rf ac e o f a l iq uid e xp e r i en c e a n e t i n wa rd p u ll f ro m m ol ec ul e s i n t he i nt e ri o r o f th e l iq u id . Be c au s e o f t hi s n et in wa r d i n t er m ol ec ul a r a t t ra c t i on, t h e li q ui d s u rf ac e te nd s t o s p on t an eo u s l y c o nt r ac t . Th us l i qu id s t en d to as su m e a sp h e ri cal s h a pe ( i. e ., a v ol um e wi t h t h e m in im um s u r fa c e a rea ) . Th is c o n fi gu r a ti o n h as t he le as t f r e e e ne r g y . b . A n y e xp a ns i on of th e s u r fa c e in c re as es t he f ree e ne r g y of t he s y s t em . Th u s s u r fa ce f r ee e ne r gy c a n b e d e fi n ed b y th e wo r k r e q ui r ed to in c re as e t h e s u rf a c e ar e a A o f t he l i qu id b y 1 a r ea un it . Thi s v al u e is e xp r e s s ed as t h e n um b e r o f m i l li - N e wt o n s ( m N ) n ee d ed to e xp a n d a 1 -m 2 s u r f ac e b y 1 u n i t: wo r k = γ × ∆ A wh e r e ∆ A is th e i n c r e as e i n s u rf ac e a r e a a nd γ is t h e s u r f ac e te n si o n , o r -1
s u r f a ce f r ee en e r g y, i n m N m —e q ui va l en t t o ce n t im et e r -g r am - s e co n d -1
( C G S ) u n it s o f d y n es c m . A t 2 0° C . wa t e r h as a s u r fa ce t en si on o f 7 2 m N -1
-1
m , wh e r e as n- oc t an o l ha s a s u r f ac e t en si o n o f 27 m N m . Th us m o r e wo r k m us t be e xp e n de d t o e x p a n d t he s u r fa c e o f wa t er t h an to e xp a n d t h e s u r fa ce o f n -o c ta n ol (i . e., t o p r oc ee d f ro m a g i ven vo l um e o f b ul k l iq u id to t h e c o r re s p o nd in g v ol um e o f s m a ll dr o pl e ts ) . c . A t t he b ou n da r y, o r i n t e r f a ce , b e t we e n t wo im m i sc ib l e l iq ui ds t ha t a re i n c o nt ac t wi t h o n e a no t he r, t h e c o r r es po n di n g i n te rf a c i al t en s io n (i . e ., f re e e n e rg y, o r wo r k r e qu i re d t o e xp a nd t he in t e rf ac i al a r e a) r ef l ec ts th e e xt e n t o f t he i n t er m o l ec ul a r f o rc es o f a t tr ac t io n a n d r e pu l s i on a t t he in t e rf ac e .
W hen t he in t e rf ac e i s b et we e n t wo l i qu id s , su bs ta n t ia l m ol ec ul a r i n te r ac t io n o cc u rs ac r os s t he in t e rf ac e b e t we e n t h e t wo p ha s e s . Th is i n te r ac t io n P.33
r e d uc es th e i m b a la nc e in f o rc es of at t r ac ti o n wi t h i n e ac h p h as e. Th e i n t er f ac i al te ns i on be t we e n n -o c t a no l a nd wa t e r is r ed uc e d t o 8 . 5 m N m from 72 mN m
-1
-1
(γ ai r / wa t e r ) . Th is re d uc ti o n i nd ica t es , in pa r t , t he
i n t er f ac i al i n te r ac t io n b et we e n n - oc ta n ol an d wa te r .
Figure 3-2. A. Molecules in the bulk phase. B. Molecules at the surface of a liquid.
Figure 3-3. Liquid flow.
2 . Th e fl o w o f a li q ui d a c r o s s a s ol id s u r fa ce c a n b e e xa m in e d i n t e rm s o f t h e ve l oc i t y, o r r a t e of m o v em e nt , of t he li qu i d re l a ti v e to t he s u r fa c e a c r oss wh i c h i t f lo ws . M o r e i n s i gh t c a n b e g ai ned b y vi s u al i zi ng th e fl o w o f l i qu i d as in v o l v i ng th e m o v e m en t o f nu m e r ou s p ar a l l e l l a ye rs of li q ui d b e t we e n a n u p pe r , m o v ab l e p la t e a nd a l o we r , fi x e d pl a te ( Fi gu r e 3 - 3 ) . Th e a p pl ic a ti o n o f a c o ns ta n t f o rc e (F ) t o t he up p er pla t e c au s es b o th th is pl a te a n d t h e u pp e rm os t l a y e r o f li q ui d i n c on t ac t wi t h i t t o m o v e wi t h a v el oc i t y ∆ y / ∆ x . Th e i n te r ac t io n be t we e n t he fi xe d b o tt om p l a te an d t h e l iq ui d l a y e r c l os es t t o i t p r e v e nt s t h e m o v em en t of t he bo t to m l a y e r o f l i qu id . Th e
ve l o c i t y ( v ) o f t h e r em ain i ng la ye r s o f l i qu id be twe e n t h e t wo p l at es is p r o po r t io n al to th e i r di s ta n c e f ro m t h e im m o va b le p la t e ( i .e . , ∆y / ∆x ) . Th e ve l o c i t y g r a d i e n t l ea ds t o de f o rm at i on of t he li qu i d wi t h t im e . Th i s d e f o rm at i on is t h e r a t e of s h ea r , dv /d x , o r D. N ew t o n d ef i ne d f l o w i n t e rm s o f t he ra t io o f t he fo r c e F a pp l ie d t o a pl a te of a re a A — sh e a r s t r es s (τ ) — d i vi de d b y t h e v e l oc it y gr a d ie n t ( D ) in d uc ed b y τ :
or
Th e p r o po r ti o na li t y c o ns ta n t η is th e c oe f fi ci e nt o f vi s c o s it y. I t i n di c a t es t h e re si s t a nc e t o f l o w o f a d ja c en t l a y e rs of fl u id . Th e r e c i p ro c a l o f η is -2
-1
f l u i d i t y. U n i t s of v is c os ity i n t he C G S s ys t em a r e d y n es c m s , o r p o is e . -2
-1
I n t he S I s y s t em , th e u n it s ar e N e wt o ns m s , wh i ch c o r re s po nd s t o 1 0 p o is e . Th e v i s c os it y o f wa t e r a t 2 0 ° C i s a pp r o xi m a t e l y 0 . 01 po is e , o r 1 -2
-1
c e nt i po is e (c ps ) , wh i c h c o r r es p on ds t o 1 m N m s . a . S ub s ta nc es th a t f l o w in ac c o r d an ce wi t h th e eq u a ti on in I II . B . 2 ( N e wt on ' s l a w) a r e k n o wn as N ew to n i a n s ub s t an c es . L i qu id s th a t c o ns is t of s im p le m o le cu l es a n d d il u te di s p e r s i on s t e nd to be N ew t o n i an . Fo r a N e wt o n ia n f l u id , a pl o t o f s he a r s t res s a s a fu nc t io n o f s he a r r a t e ( a fl ow cu r ve o r r h e o g r am ) y i el ds a s tr a ig h t l i ne wi t h a sl op e o f η ( F i gu r e 3 - 4, C u rv e 1 ) . b . N o n - New to n ia n su b st a n c es do no t o b e y Ne w t o n ' s e qu a ti o n o f f lo w. Th e s e s ub s ta nc es t en d to e xh i b i t s he a r - de p en d en t o r ti m e- d e pe n de n t vi s c o s i t y. I n e i t he r c as e, v i s c os i t y i s m o re ap t l y t e r m e d a p pa r e n t vi s c o s i t y b e c a us e N e wto n ' s l a w i s n o t s t r ic t l y o be ye d . H et e ro g en e ou s l i qu i ds a n d s ol id s a r e m os t li k e l y no n - Ne wt o n i an . ( 1 ) S he a r - de p e nd e n t vi s c o si t y i n v o l v e s e i th e r an i nc r ea s e in ap pa r e nt vi s co si t y ( i .e . , s h ea r t hic k e ni n g , o r d i l at a nc y) ( F i g ur e 3 - 4 , Cu r ve 3) o r a d e c re as e i n a p pa r en t v is c os i t y (i . e ., sh e a r t h i nn in g , o r p se u do - p la s t ic i ty) ( F i gu r e 3 - 4 , C u rv e 2 ) wi t h a n i nc r ea se in th e ra t e o f s h ea r . Sh ea r th ic k en in g i s d is p la y e d b y s us pe ns io n s t ha t ha v e a h ig h s ol id s c on t e nt of s m al l , d e f lo cc ul a te d p a r ti c l es . S h e a r t hi n ni n g is di sp l a ye d b y p o l ym e r P.34 o r m a c ro m o le c ul e s ol u tio n s . P l as t ic , or B i n gh am b o d y, b e h a vi o r ( F ig u re 3 4 , C u rv e 4 ) i s e xe m p li f ied b y f lo cc ul a te d p a r ti cl es in c o nc e n t r a te d s us p en s i o ns th a t s h o w no a pp a re n t r e sp on s e t o lo w- l e v e l s t r es s . F lo w b e gi n s o nl y a ft e r a li m i t in g y i el d s t re s s ( yi e l d va l u e ) i s e xc e e d ed .
Figure 3-4. Non-Newtonian flow curves.
( 2 ) T im e - de p en d en t vi sc o s i t y ( a ) Th e y i el d v al ue o f p la s t i c s ys t em s m a y b e tim e d e pe n de n t ( i .e . , m a y d e p en d o n t h e t im e s c a le i n v ol v e d i n t h e a pp li c at i o n o f f o rc e ). T hi x o t r opi c s ys t em s di s p l a y s h ea r - thi n ni n g b eh a v i or b ut do no t im m e di a te l y r ec o v e r t h e ir hi g he r ap p ar e nt v i s c os i t y wh e n t h e r a te o f sh e a r i s l o we r ed . In a t h i xo t r o p ic s y s te m , s t r uc t u r al r ec o ve r y is re la t i v ely s l o w c om pa r e d wi t h s t r uc t ur a l b r ea k d o wn . ( b ) T h ix o t r op y o c c u rs wi t h h e te r o ge ne o us s y s t em s t h at in v o l v e a t hr e e d i m e ns i on al s t r uc t u re or n e t wo r k . W hen s uc h a s ys t em is a t re s t, it ap p ea rs t o ha ve a r e la t i v el y r i gi d c o ns is te n c y . U n de r s h ear , t he s t r uc t u re br e ak s d o wn a n d f lu i di t y in c re as e s (i . e. , ge l - so l tr a ns f orm a ti o n ). ( c ) R h eo p ex y ( n e g a t i ve t h i x ot r o p y, o r a n t i t h i xo t r o p y) o c c ur s wh e n t he a p p ar e nt v i s c os it y o f t h e s y s te m c on t in ue s t o i nc re a s e wi t h c o nt i nu ed a p pl ic a ti o n o f s he a r u p to s o m e eq u il ib r i um val u e a t a gi v e n s h ea r ra t e . Th e s e s y s te m s di s p la y a s o l - ge l t r a ns fo r m a t io n . O n e e xp l a na t io n fo r a n t it h i xo t r o pi c b eh a v io r is t ha t c on t in u ed s h ea r inc r e as es th e f r eq u en c y of p a r ti c l e or m a c ro m o le c u le i nt e r ac ti o ns a n d l ea ds t o in c re as e d s tr uc t u re in t h e s ys te m . C . S o l i ds . I n te r m o l ec ul ar f o rc es o f a tt r ac t io n a r e s t ro n ge r in s o li ds th a n in l i qu i ds o r ga s e s . Mo l e c ula r a r ra n ge m e n ts i n s ol i ds m a y b e ch a r ac te r i ze d a s e i t he r c r y s ta l li ne o r am or p h ou s . 1 . C r ys t a l l i n e s o li d s h av e t h e f o ll o wi n g a t tr i bu t es : a . Fi xe d m o l ec u la r o r der ( i . e. , m o le cu le s o c c up y s e t p os it i on s i n a s pe c i fi c array) b . A di st i nc t m el ti n g p oi nt c . An i s o t r op i ci t y ( i . e . , th e i r p r op e r ti es ar e n o t t he sa m e in al l d i re c ti on s ) , wi t h t h e e xc e p t io n o f c ubi c c r y s ta ls 2 . Am o r p h o us so l i ds hav e t h e f o ll o wi n g a t tr i bu t es : a . R an d om l y ar r a ng ed m o l ec ul e s wi t h th e s h or t - ra n g e o rd e r t y p i c a l o f l i qu i ds b . N o m el t in g p o in ts
c . Is o t r o pi c i t y ( i . e . , p rop e r ti e s a re t he s am e i n al l di r ec ti o ns ) P.35
d . L ess th e rm o d y na m i c s t a b il i t y t h an th e c o r re sp on d in g c r y s ta l li ne so li d a nd t h e r ef o re m o r e a p t t o e xh i bi t c h em ic al an d p h y sic a l i ns ta b il i t y, i nc r ea s e d d i ss ol u ti on r a te , e tc . 3 . P o l ym o r p h i s m i s t h e c o nd i ti on wh e r e in s u bs t an c es c a n e xi s t i n m o re t h a n o ne c r y s t al li n e f o rm . Th e s e p o l ym o r p h s h a ve d if f e re n t m o l ec ul a r a r r a ng em e nt s o r c r y s ta l la t t ic e s t ru ct u r es . A s a r es u lt , th e d i ff e r en t p o l ym o r ph s o f a d ru g s oli d c a n h a v e d if f e re n t p r op e r ti e s. Fo r e xa m pl e , t he m e lt i ng po in t , s ol u bi li t y , d i s s ol u ti on r a te , d e ns it y , a n d s ta bi l it y c an di f fe r c o ns id e ra b l y a m on g t h e p o l y m o r ph ic f or m s of a dr u g . Ma n y d r ug s e xh i b i t p o l ym o r ph ic be h a v io r . Fa t t y ( t ri g l yc e r id e ) e xc i p ien t s ( e .g . , th eo b r om a o il , c oc o a b u tt e r ) a r e r ec o gni z e d fo r th e i r p ol ym or p hic be h a vio r . 4 . Th e i n c o r po r a ti on o f s o l v e n t m o l ec ul es in t o t he c r ys ta l l a tt ic e o f a so li d r e s ul ts in a m o l ec ul a r a dd u c t k n o wn as a s o l va te o r h yd r a t e ( t h e l a t te r t e r m is us e d wh e n wa t e r i s t h e s o l v e nt ) . In ge ne ra l , s ol va t es or h y d ra t es e xh i b i t di f fe r e nt s o lu bi l it ie s a n d d is s o lu t io n ra t e s t h a n t he i r u n so l va te d /a n h y d ro us c ou n t e rp a rt s . 5 . M e l t in g po i n t a n d h ea t o f fu s io n . Th e m e l ti ng p oi n t o f a s o li d i s t he t e m p e r at u re a t wh i c h t h e s ol i d is t ra ns f o rm ed t o a l i qu id . W he n 1 g of a s o li d i s h ea t ed an d m el ts , t h e h ea t a bs o r be d i n t he p r oc es s is re f e r re d t o a s t h e la t en t he a t o f f us i on . D . P h a se di a g r am s a n d p h a se eq u i li b r i a. A ph as e d ia g r am r ep r es en t s th e s t a te s o f m at t e r ( i .e . , s oli d , l i qu id , an d g as ) th a t e xi s t a s t em pe r a tu r e a n d p r e ss u re ar e v a ri e d ( F igu r e 3- 5 ) . Th e da t a P.36
a r r a y s s ep a ra t in g th e p ha s es i n Fi gu r e 3 - 5 d el i nea t e th e t em p er a t ur es and p r e ss u re s a t wh i c h t h e ph a s e s c an c o e xi s t . Th u s g a s ( o r vap o r ) a nd li q ui d c o e xi s t a lo n g “ c u r v e ” B C, s ol id an d l i qu id c o e xi s t a l on g “c ur v e ” A B , a nd s o li d a nd g as (o r v a po r ) c o e xi s t a lo n g “ c u r v e ” D B. D e pe n di n g o n t he ch ang e i n te m p e r at u re an d p r es s u r e, e va po r a t i on o r c on d e ns a t io n oc c u r a l on g c u r ve B C , f u si o n o r m e lt i n g al on g c u r v e A B , and s ub l i ma t i on o r d e p os i t i on al o ng c u r v e D B . Th e t h re e “ c ur v e s ” in t e rs ec t at po i nt B . O n l y a t t h is un i qu e t em p e ra t ur e a n d p r es s u r e , k n o wn a s t h e t r ip l e p o in t , d o a l l t h r e e p ha s e s e xi s t in equ i li b ri u m . ( Th e t r i pl e p oin t f or wa t e r is 0 . 01 ° C and 6 . 0 4 × 10
-3
a tm . ) C o nt i nu i ng al o ng cu r v e B C , t o h i gh e r te m p e ra t u re s a nd
p r e ss u re s , on e u l ti m a t ely r e a c h es po i nt C , k no w n as t he c ri t i ca l po i n t, a b o ve wh ic h th e re is n o d i s t i nc ti o n b et we e n t he l iq u id an d th e g as ph as es. S u b st a nc es th a t e xi s t abo v e t hi s c ri t ic al po i nt a re k no wn a s s u pe r c r i t ic a l f l u i d s. S up e rc r it ic a l f lu id s s uc h a s c ar b on di o xi d e ( c ri t i c al po in t , 3 0 .9 8 ° C a n d 7 3 .8 at m ) o f te n e xh i b i t m a rk ed l y al t e re d p h ys ic oc h em ic al p ro p er t ie s ( e . g ., de ns i t y , d i ff u s i v i t y , o r s o lu b il it y c ha r ac t e ri s ti cs ) th a t r e nd e r t h em
u s ef u l as s o l v e nt s a nd pr o c es s i ng ai ds in th e p r od u c t i on of ph a rm ac e ut ic a l s a n d d r ug de l i v e r y s y s tem s .
Figure 3-5. Phase diagram for CO2 showing the variation of the state of matter as pressure and temperature are varied. The solid state exists in the region ABD; the liquid state, in the region ABC; and the gas state, in the region to the right of curve CD. B corresponds to the triple point, the pressure and temperature at which all three phases coexist. C corresponds to the critical point, the pressure and temperature above which the liquid and gas phases are indistinguishable.
IV. PHYSICOCHEMICAL BEHAVIOR A. H o m o g e ne o u s s ys t e m s 1 . A s o l u ti o n i s a h om og e n eo us s y s t em i n wh ic h a s ol u t e is m o le c u l ar l y d i sp e rs ed , o r di s s o l v ed , i n a s ol ve n t . Th e s ol v e nt i s t he p re do m i n an t s p ec ie s . S a tu r a t ed s ol ut i o n s a r e s o l ut i on s t ha t , a t a g i ven t em pe r a tu r e a n d p r es s u r e , c o n ta i n t he m a xi m u m a m o u nt of s ol u t e t ha t c a n b e a cc o m m od a te d b y t he s ol v e n t . I f th e s at u r at i on , or s ol u bi li t y, li m i t i s e xc e e d e d, a f r ac t io n o f th e s o lu t e ca n s e pa r at e fro m th e s ol u ti on an d e xi s t i n eq ui l ib r iu m wi t h i t. a . S o lu t es c a n b e g as es , l iq u id s, o r s o l id s , an d no n el e c t r ol y t e s o r e l ec t r ol y t es . ( 1 ) N o ne l ec t r o l yt e s a r e s u bs ta n c e s t ha t do n ot fo r m i on s wh e n d is s o l v ed i n wa t e r . E xa m p l es ar e es t r ad i ol , g l yc e r in , ur e a, a n d s uc r os e. Th e i r a q u eo us s o lu t io ns do not c on du c t e le c t r ic c u r r en t. ( 2 ) E l ec t r o l yt e s a r e s u bs t an c e s t h at d o f o r m i on s in so lu t io n . E xa m p l es a r e s o di um c h lo r id e , h y dr o c hl o ri c ac i d, an d a t r op in e . As a r es ul t , t h ei r a q u eo us s o lu t io ns c o nd uc t el ec t ri c c u rr e nt . El e ct ro l y t es a re c h a ra c t e r i z ed a s s t r o n g o r w ea k . S t r on g el ec t r ol y t es ( e. g . , s o di u m c h l o ri de , h y dr o c h lo r ic a c id ) ar e c o m pl e te l y i o n i z ed in wa t e r a t al l co nc e nt r a ti o ns . W eak e l ec t r ol y t es ( e. g . , as p ir in , a tr o pi n e) a re pa r t i a ll y i o n iz e d in wa t e r . b . Th e co l l ig a t i ve p r o pe r t i e s o f a s ol u t io n de pe n d o n t h e t o ta l n u mb e r o f i o n i c a nd n on i o ni c s o l ut e m ol e cu l es i n t h e s o lu t i o n . Th e se p ro p er t ie s d e p en d o n i on i z a ti o n b ut a r e i n d ep e nd e n t o f o t he r c he m ic a l p r o p e r ti e s o f t h e so l u te . 2 . C o ll i g at i ve p r o pe r t i es i nc lu de t he fo l lo wi n g : a . L ow e ri n g o f va p o r p re s s u re . Th e p a r t ia l va po r p r e ss u r e o f e ac h vo l a t il e c om po n en t i n a s o l u ti on is eq ua l to th e p ro d uc t o f th e m ol f ra c ti on
o f t he c om p on e nt in th e s o lu t io n a n d t he va po r pr e s s u r e o f t he pu r e c om p on e nt . Th is is Ra o ul t ' s law :
wh e r e p A is th e p a r ti a l v a p o r p r es s u r e a bo ve a so l u ti on in wh i c h t he m o l f r a ct i on of t he s o lu t e A is x A a n d is th e va p o r p re s s u re o f t he pu r e c om p on e nt A . Th e v a p o r p r es s u r e i s t he p re s s u re a t wh i c h an eq ui l ib r iu m i s e s ta b li sh e d b et we e n th e m o le c u l es o f A i n t h e li qu i d s ta t e a nd t he m o le cu l es o f A i n t h e g as e ou s ( va p o r) st a te in a c l os ed , e v a c ua t ed c o nt a in e r . Th e v a po r p res s u r e i s t em p er a tu r e d e pe n d en t , b ut in d ep e nd en t o f t he am ou n t o f l iq u id an d v a po r . Ra o ul t ' s l a w ho l ds fo r id e al s o lu ti o ns of n o n el ec t ro l y t es . F o r a b in a r y s o l u t i o n ( i .e . , a s o lu t i on of co m p on e nt B in c om p on e nt A )
Th e l o we r i ng o f t he v a por p r es s u r e o f t h e s ol ut i on r el a ti v e t o t he va p or p r e ss u re of th e p u r e s o l ve n t i s p r op o r ti on a l t o t h e n um b e r o f m ol ec ul es o f s o lu t e i n t he s o lu t io n . The ac t ua l l o we r i ng o f t he va p o r pr e s s ur e b y t h e s o lu t e, ∆ p A , i s g i v en b y
b . E l e va ti o n o f t he b oi l in g p oi n t . Th e b o il i n g po i n t i s t h e t em pe r a tu r e at wh i c h th e v a po r P.37
p r e ss u re of a l iq ui d e q ual s a n e xt e r n a l p r es s u r e of 7 60 m m Hg . A s ol u ti o n o f a n on v o l at i le s o lu t e ha s a hi g he r bo il i ng po in t t h a n a p u r e s o l v e nt b e ca us e th e s ol u te lo we r s t he v a po r pr es s ur e o f th e s o l ven t . Th e am o un t o f e l e va ti on o f t he bo i li ng po i n t ( ∆ T b ) d ep e nd s o n t he co nc e n tr a ti o n o f t h e s o lu t e:
wh e r e K b is th e m ol al bo il i ng po i nt el e v a ti o n c o n s t a n t , R is th e m ol a r g as c o ns ta n t , T i s a bs o lu t e te m pe r a tu r e ( d eg r ee s K) , M 1 i s t he m o le c u l a r we i g h t o f t he s o lu t e, m is th e m o l al i t y of th e s ol u ti o n, and ∆ H v a p i s t he m o la l e n t ha lp y o f v ap o r i z at i on o f t he s o l v en t . c . D ep r e ss i o n o f th e f ree z i ng po i n t . Th e f r ee z ing p o in t , o r m e lt i ng po i nt, o f a p u re c o m p ou n d is t he t em pe r a tu r e a t wh ic h th e s o li d a n d t he li qu i d p h as es a re in eq ui l ib r ium un d e r a p r es s u r e o f 1 a t m o sp h e re ( at m ). Th e f r e e zi ng po in t of a s ol ut io n is th e t em p er a t ur e a t wh i c h th e s o li d p ha s e o f t h e p u r e s o l v e nt an d th e l i qu id ph as e o f th e s ol u ti o n a r e i n e qu i li b ri um u n d er a p r es s u r e o f 1 atm . Th e a m o u nt of d ep r es s i on of t he f re e zin g po in t ( ∆ T f ) de p en ds on th e m ol a li t y o f t he s o lu t io n :
wh e r e K f is th e m ol al f r ee z i n g p oi n t c on s t a n t a nd ∆ H f u s i o n i s t he m o la l h e at o f f us io n . d . O s mo t i c p r e ss u r e. Os m o si s i s t h e p ro c e s s by wh i c h s o l v e nt m o le cu l es p a ss th r ou g h a s em ip e rm e ab l e m e m b r an e (a ba rr i e r th r ou g h wh i c h o nl y s o l ven t m ol ec u le s m a y pa s s ) f ro m a re g io n o f d i lu t e s ol u ti o n t o o ne o f m or e c o nc en t r at e d s o l ut i on . So l v e n t m o l ec ul es t ra ns f er b ec a us e o f t h e i ne qu a lit y i n c h em ic al po t en t ia l o n t h e t wo s i de s o f t h e m em b r an e . S ol v e n t m ol ec u le s i n a co nc e nt r a te d s ol u ti on h a v e a l o we r ch e m i ca l p o t en t ia l t h an s o l ven t m o le cu l es i n a m o r e d il ut e s o lu t io n . ( 1 ) O s mo t i c p r e ss u r e is t h e p r e ss u r e t h at m us t b e ap pl i ed to t he s o lu t ion t o p re ve n t t h e f lo w o f pur e s o l v e nt in t o t he c o nc en t r a te d s ol u ti o n. ( 2 ) S ol ve n t m ol ec ul es m o v e f r om a r eg i on wh e r e t h e ir e sc a pi n g t e nd e ncy i s h ig h to on e wh e r e t hei r es c ap i n g t e nd e nc y i s l ow . Th e p r es e nc e o f d i ss ol ve d s ol u te lo we r s th e es c a pi n g t en d en c y o f t h e s ol v e n t i n p ro p o rt i on t o t he s o lu t e c o nc e nt r a tio n . ( 3 ) Th e va n ' t H o f f e q ua ti o n de f in es th e o s m o ti c p r e ss u re π as a f u nc ti o n o f t h e n um b e r o f m ol es of s o l u te n 2 in th e s ol u ti o n of v o l um e V: πV = n2RT 3 . E le c t r o l yt e s o l u t i on s a n d i o n ic eq u i li b r i a a . Ac i d - b as e e q ui l i b r ia ( 1 ) A cc or d in g t o th e Ar r h e n i us di s so c ia t i o n t h eo r y, a n a c i d i s a +
s u bs ta n c e th a t l ib e ra t es H i n aq ue o us s o lu ti o n . A b a se is a su bs t an c e t ha t -
l i be r a te s h y d r o xy l i o ns (O H ) i n a qu e ou s s ol u ti on. Th i s d e fi ni t io n a p pl ie s o n l y un d er aq u eo us c o nd i t io ns . ( 2 ) Th e Low r y- B r ø n s t e d t h e o r y i s a m o r e p o we r fu l c o nc ep t th a t a pp li es to a q u eo us an d n o na qu e ous s ys t em s . I t is m o st com m o n l y u se d fo r p h a rm ac e ut ic al an d bi olo g ic s y s t em s b ec au s e the s e s ys t em s a r e p r im a ri ly a q u eo us . ( a ) A cc or d in g t o th is de f in i t io n , a n a ci d i s a s u bs ta n ce (c h a rg ed o r u n ch a rg e d ) t ha t i s c ap a bl e of do n at i ng a p r ot o n. A b a se is a su bs t an c e ( c h ar g ed o r u nc ha r g ed ) th a t i s c ap ab l e o f a c c ep t in g a p r ot o n f r om a n a c i d. -
Th e d is s o c i a ti o n o f a n ac i d ( H A ) al wa y s p r od uc es a b as e (A ) a c c o rd i ng to t h e fo ll o wi n g f o rm u la : +
HA ↔ H + A
-
( b ) H A an d A a re a c on ju g a t e a ci d - ba s e p a i r ( an ac i d a nd a b as e t h at e xi s t i n e qu i li b ri um an d d i f fe r in s t r uc tu r e b y a pro t o n ). Th e p r o to n o f an a c id do es no t e xi s t f r ee in s o l ut i on , b u t c om bi ne s wi t h t h e s o l v e nt . In wa t e r , +
t h is h yd r a t e d p r o t o n i s a h yd r o n i u m io n ( H 3 O ). ( c ) Th e re l at i v e s t r e n gt hs o f a c i ds an d b as es a re d e te r m i n ed b y t h ei r a b il i t y to do n at e o r ac c ep t p ro t on s . F o r e xa m p le , i n wa t e r, H C l d o na t es a p r o t on m o re r ea d il y t ha n d o es a c et ic ac id . Th us H C l i s a s t ro n ge r ac id . Ac i d s t r en g th is a ls o de t er m i ne d b y th e a f fi n it y o f t h e s o l v en t fo r p r o to ns . Fo r
e xa m p l e , H C l m a y di s s oc i at e c om pl e te l y in li q ui d a m m on i a, bu t on l y v e r y s l ig h tl y i n g la c i al ac e ti c a c id . Th us H C l is a s t ro ng ac i d i n l iq ui d a m m on i a a n d a we a k a c i d i n g la c ia l ac et ic ac id . P.38
( 3 ) Th e Lew i s th e o r y e x t e n ds th e a c i d -b as e c o nc e pt t o r ea c ti o ns t h at do n o t i n vo l v e p r ot o ns . I t d ef i n es a n a c i d as a m ol ecu l e o r i o n t h at acc e p ts an e l ec t r on pa i r f r om a n o the r a to m a nd a b as e as a s ub s ta nc e t h at do n at e s a n e l ec t r on pa i r t o b e s ha r ed wi t h an o th e r a t om . +
b . H c on c en t r a t io n v alu e s a r e v e r y s m a ll . Th ere f o r e, th e y a re e xp r e ss ed i n ex p on e n ti a l n o t at i o n a s p H . Th e p H i s t he lo ga r i th m o f th e r e ci p ro ca l o f +
t h e H c on c e n t ra t io n
+
+
wh e r e [ H ] is th e m ol a r c o n c e n t ra t io n o f H . B ec au s e t he lo g a ri t hm o f a r e c ip r oc al eq u al s t he neg a t i ve l og a r i th m o f th e n u m b e r , t hi s e qu a ti o n m a y b e r e wr i t te n a s : +
p H = -l o g [ H ] or +
[ H ] = 10
-pH +
Th u s t he p H v a l ue m a y be d ef i ne d a s t he ne g a ti v e l og a ri t hm of th e [ H ] +
-6
va l u e . F o r e xa m p le , i f the H c o nc e nt r a ti o n o f a s o l u ti on is 5 × 1 0 , th e pH va l u e m a y b e c a lc ul a te d a s fo ll o ws :
pH
=
-log (5 × 10-6)
log 5
=
0.699
log 10-6
=
-6.0
pH
=
-(-6 + 0.699)
=
-(-5.301)
=
5.301 +
c . As p H d ec r ea s e s , H c o n ce n t r a ti o n i n c re a ses e xp o ne n t ia l l y. W he n th e +
p H d ec r ea s e s f r om 6 t o 5 , t he H c o nc en t r at io n in c r ea s e s f r om 10
-6
-5
to 10 ,
o r 1 0 t im es i t s o ri g in a l v a l ue . W he n t he p H f a ll s fr o m 5 to 4 .7 , t h e H c o nc en t r at i on in c re as es f r o m 1 × 1 0
-5
+
-5
t o 2 × 1 0 , o r do u bl e i ts in i ti al va lue .
d . D i ss o ci a t io n co n s tan t s . Io n iz a ti o n i s t he com p le t e s e p a ra t io n o f t h e i o ns in a c r y s t al la t t ic e wh e n t h e sa l t i s d is s o l v ed . D i s s oc i a ti o n is t he s e pa r a ti on o f i on s i n s o lu t i on wh e n t h e i on s a r e a s s o c i at e d b y i nt e ri o ni c a t t r ac ti o n. ( 1 ) F or w e ak el e c t ro l yt e s , di s s oc ia t io n i s a re v e rs i bl e p r oc es s. Th e e q ui l ib r iu m o f t h is p r oc es s c an be e xp r e s s ed b y th e la w o f m a ss a c ti on . Th i s la w s t a te s t h at th e ra t e o f th e c he m i c a l re ac ti o n i s p r op o rt i on al t o t he p r o du c t o f t h e c o nc e nt r at i o n o f t h e r ea c ti ng su bs ta n c e s, e ac h r ai s e d to a p o we r o f th e n um be r o f m o le s o f t h e s u bs t an c e in s o l ut i on . ( 2 ) F or w e ak ac i ds , di s s o c ia t io n i n wa t e r is e xp r e ss e d a s: +
HA ↔ H + A
-
Th e d yn am ic eq u il ib r i um b e t we e n t h e s i m u l ta n eou s fo r wa r d an d re v e r se r e a ct i on s is in d ic at e d b y t h e a r r o ws . B y t h e l a w of m as s ac t io n , r a t e o f fo r wa r d r ea c t i on = K 1 [ H A ] +
-
r a t e o f re v e r s e r ea c t i on = K 2 [ H ] [ A ] A t e qu i li b ri um , t h e f o r wa r d a nd re v e r se r at e s a re e q u al . Th e re f or e , +
-
K1[HA] = K2[H ][A ] Th u s t he e qu i l ib r i um e xp r e s si o n fo r t he d is s oci a t i o n o f a w e ak ac i d is wr i t t e n as :
wh e r e K a r ep r es e nt s t h e a c id di s s oc ia t io n c on s tan t . Fo r a we a k a c i d , t h e a c i d d i ss o ci a t io n co n s ta n t is c on v e n ti o na l l y e xp r e s s e d as p K a , wh i c h is -5
l o g K a . Fo r e xa m p l e, t he K a o f a c e t ic a c i d a t 25 ° C i s 1 . 75 × 1 0 . Th e p K a is c a lc ul a te d a s f ol l o ws : P.39
pKa
=
-log (1.75 × 10-5)
log 1.75
=
0.243
log 10-5
=
-5
pH
=
-(-5 + 0.243)
=
-(-4.757)
=
4.76
( 3 ) F or w e ak ba s es , di s s oc i at i on m a y al s o b e e xp r e ss ed wi t h th e K a e xp r e s s io n f o r t h e c o nj ug a t e a c id o f t h e b a se . Th i s ac i d is f or m e d wh e n a p r o t on re a c t s wi t h t he bas e . F o r a ba se th a t d oe s n o t c on t ai n a h yd ro xy l g r o up , +
+
BH ↔ H + B Th e d i s so c ia t i on co n s ta n t fo r th is r ea c ti on is exp r e s s e d as :
H o we ve r , a b as e d i ss o ci a t i o n c on s t an t i s t r a di tio n al l y de f in e d f o r a we ak b a se wi t h th is e xp r e s s ion : -
B + H2O ↔ OH + BH
+
wh e r e K b r ep r es en t s t he d i s s oc ia t io n c on s ta n t o f a we a k ba s e . Th is d i s so c i at i o n c on s t an t c a n be e xp r e s s ed as p K b , a s f o ll o ws : p K b = - l og K b ( 4 ) C e r t ai n c o mp o u nd s ( a c id s o r b as es ) c a n ac ce p t o r do n at e m o re th a n o n e p r o to n . C o ns eq u en t ly , t h e y ha ve m o re t ha n o n e di s so c ia t i on c o n s ta n t . e . H e nd e r so n - H as s el b al c h eq u a ti o ns de s c r ib e th e r el a ti on be t we e n th e i o ni ze d a n d t h e u ni on i z ed s p ec i es of a we a k el ec t r o l y t e. ( 1 ) F or w e ak ac i ds , th e H e n d e rs on - H as s e lb a lc h e q u at io n i s o b ta i ne d f r o m t h e e q ui li b r iu m r el a ti o n de s c r i be d i n I V . A .3 d . (2 ) :
( 2 ) S im il a rl y , t he H en d e rs o n - Ha s s el b al c h eq u at ion f o r w e a k b as e s is as f o l lo ws :
+
wh e r e B is th e u n io n i z ed we a k b as e a nd B H i s th e p ro t on a te d b as e . f . Th e d eg r e e o f io n iz a ti o n ( α ) , t he f ra c ti on o f a we a k e le c tr o l yte t ha t i s i o ni ze d i n s ol u ti o n, is c a lc u la t ed f ro m t he f ol lo wi n g e qu a ti o n:
wh e r e [ I ] a n d [ U ] re p re s en t t he c o nc en t r at i on s o f t h e i o ni z e d a n d u ni on i zed s p ec ie s , r es pe c ti v e l y . The d eg r ee o f i on i za ti on dep e n ds s ol e l y o n t h e p H of t h e s ol u ti o n a nd th e p K a o f t he we a k e le c t r o l yte . W h e n p H = p K a , t h e H e n d e rs on - H as s e lb a lc h e q u at io n s a re , fo r a we a k ac i d an d a we a k b as e , r e s pe c t i v e l y :
t h us
P.40
t h us
I n e ff ec t , wh e n t he p H o f t h e s ol u ti on is nu m e r ic al l y e qu i val e nt t o t he p K a o f t h e we a k e le c t r ol y t e , whe t h e r a we ak ba s e o r a we a k a c i d , [ I ] = [ U] an d th e d e g re e o f io ni z a t io n α = 0 . 5 (i . e. , 50 % o f t h e s ol ut e is i o ni ze d ) . g . S o lu b i li t y o f a w e a k e l e c t ro l yt e v a r i e s as a fu n ct i on of p H . ( 1 ) F or a w ea k a c id , th e t o t al s ol u bi l it y C s is gi v e n b y th e e xp r e s si on : -
Cs = [HA] + [A ] wh e r e [ H A ] is t h e i nt r i ns ic s o lu b il i t y o f th e u n io niz e d we a k ac id an d i s -
-
d e n ot e d as C 0 , wh e r e as [ A ] i s t h e c o nc e nt r a ti o n o f it s a ni o n . B ec a us e [ A ] c a n b e e xp r e s s e d i n t e rm s o f C 0 a nd th e d is s o c ia t i on c o ns ta n t K a ,
Th u s t he so l u bi l i t y o f a w e ak ac i d i n c re a se s w it h i n c re a si n g p H ( i. e ., wi t h a n i nc r e as in g d e gr ee o f i on i z a ti o n, as th e a ni o n i s m o r e p o la r a n d t h e r ef o re m o r e wa t e r s o lu b le t ha n t h e u ni o ni z e d we a k a ci d ). ( 2 ) S im il a rl y , f o r w e ak ba s e s,
Th u s t he so l u bi l i t y d e c r e a s es w i t h i nc r e as i n g p H b ec a us e m o r e o f th e we a k b as e i s i n t he un p ro t o na t ed fo r m . Th i s f o rm i s l es s p ol a r a nd th e r ef or e l e ss wa t e r s ol ub l e. h . B u f fe r s an d b u f f e r ca p a ci t y ( 1 ) A bu f f e r i s a m i xt u r e o f s a lt wi t h a c i d or ba s e t h a t r es is ts ch an g es i n p H wh e n s m a ll qu a nt i ti es of a c id o r b as e a r e a dd ed . A b u ff e r c an be a c o m bi n a ti o n o f a we a k a c id an d i ts c o nj u ga t e ba s e ( s a l t ) o r a c om b in a tio n o f a we ak ba s e an d i t s c o n ju g at e ac id (s al t ) . Ho we v e r , bu f fe r so lu t io ns a re m o r e c om m on l y p r e p a re d f ro m we ak ac id s a nd t h e ir sa l ts . Th e y a r e n o t o r d in a ri l y p re p a re d f r om we a k b as es an d t h ei r s a lt s be c a us e we ak ba s es a r e of t en un s ta bl e a n d v o l a ti le . ( a ) F or a w ea k a c id an d i t s s a l t, t he fo l lo wi n g bu f f e r e qu a ti o n is s a ti s fa c t o r y fo r c a lc ul a tio n s wi t h a p H of 4 -1 0 . I t i s i m p o r ta n t i n t he p r e pa r a ti o n o f b uf f e re d ph a r m a ce u ti c a l s ol u ti on s :
( b ) F o r a w ea k b a se and i t s s a lt , th e b u f fe r e q ua t i on is s im il a r b u t a ls o d e p en ds on th e d is s o c i a ti o n c on st a nt o f wa t e r ( pK w ) . Th e e q u at i on b e co m e s :
( 2 ) B u f fe r a ct i o n is t he r e s is ta nc e to a ch a ng e in p H . ( 3 ) B u f fe r c ap a ci t y i s t he a bi li t y o f a b u f fe r s o lu ti o n t o re s i st c h a ng es in p H . Th e sm a ll e r th e p H c h a ng e c a us ed b y a d di t io n of a g i ven am ou n t o f a c id o r b as e, t he g re a t er t h e bu f f e r c a pa c i t y o f t h e s ol u ti o n. ( a ) B u ff e r c ap ac i t y i s t h e n um b e r o f g r am e q ui v a le n ts o f a n ac i d o r b as e t h a t c ha ng e s t he p H o f 1 L o f b uf f e r s o l ut i on b y 1 u n it . ( b ) B u ff e r c ap ac i t y i s a f fe c te d b y t h e c o n c e n tr a tio n of t he bu f fe r c o ns ti t ue n ts . A h ig h er c on c en t r at i on pr o v i de s a gre a t e r ac i d o r b as e r e s er ve . B uf f e r c a p ac it y ( β ) i s r el a te d to to t al c o nc e nt r a ti o n ( C ) as fo ll o ws : P.41
wh e r e C r e p re s e n ts th e m o la r c o nc en t r at i on s o f th e ac id an d t h e s al t .
( c ) Th u s b uf f e r c a p ac it y d e p en ds on th e val u e o f t h e ra t io of t he s a lt to t he a c id fo r m . I t i nc r ea s e s as t he ra t io ap p r oa c h es un i t y . Ma xi m u m bu f f er c a pa ci t y oc c u r s wh e n p H = p K a , an d i s r e p re s e n te d b y β = 0 .5 76 C . B . H e t e r og e ne o u s ( d is pe r s e ) s ys t e m s 1 . I n t ro d uc t i o n a . A s u s pe n si o n i s a t w o - p ha s e s ys t em th a t i s co m po s e d o f a s o li d m a ter i a l d i sp e rs ed in an oi l y o r aq u e ou s li q ui d . Th e pa r t icl e s i ze o f th e d is p er s ed s o li d i s us u al l y > 0 . 5 µ m . b . A n e m ul s io n i s a he te r o ge n eo us s ys t em th a t c o ns is ts of a t l ea s t on e i m m is ci b le li qu i d t ha t i s in t im a te l y di s p e rs e d i n a n o t he r in th e f o rm of d r o pl e ts . Th e d r op le t di am e te r us ua l l y e xc e e d s 0 .1 µ m . E m u ls i on s a r e i n h e r en t l y u n s t a b l e b e c a u s e th e d r o pl e ts o f th e d i s p e rs ed li q ui d t e nd to c o al es ce t o f o rm l a rg e d ro p le t s u nt i l a ll of th e d isp e r s e d d r op l et s h a v e c o al es ce d . Th e t hi r d c om p on e nt of t he s y s t em is an em u l si f yi n g a g e nt . Th i s ag e nt p re v e n ts c o ale s c e nc e a nd m a in t ai ns th e i n t eg r it y o f th e i n di vi d ua l d r op l et s . 2 . D i sp e r si o n s t a bi l i t y. I n an i de a l d i sp e r si o n , th e di s p e rs ed p ar t ic le s do n o t i n te r ac t . Th e p ar t ic les a re un i fo r m i n s i z e an d u n de r go no ch a ng e i n p o si t io n o t he r th a n t he ra n d om m o v em en t th a t r es u lt s f r om B ro wn i a n m o ti o n. I n c o n t ra s t , in a r e a l di s pe r s i on , th e p a rt i c l es a re no t u n if o rm l y s i z e d ( i .e . , t h e y a r e n o t m o n o di s pe r s e ). Th e p a rt i c l es a re s u bj ec t to p a r ti c ul a te ag g re g at i on , o r c l um p in g , a nd th e d is p e r s i on be co m es m o re h e t e ro ge n eo us wi t h ti m e. Th e r a t e o f s e t tl i n g ( se p a r a ti n g , o r c re a mi n g ) o f t h e d is p e rs ed ph as e i n th e di s p e rs io n m ed i um i s a f un c ti on o f t he pa r t ic le s i z e , d is pe r s i o n p ha s e v is c o s i t y , an d d i f fe r en c e in d en s i t y be t we e n th e d i sp e rs ed ph a s e an d t h e d is p e rs io n m ed iu m , i n ac co r d an c e wi t h S to k es ' s l aw :
wh e r e d is th e p a rt ic l e d ia m et e r , g i s t h e ac c e l e rat i o n o wi n g t o g r a v i t y , η is t h e vis c o s i t y o f t he di s p er s i on m e di um , a n d ( ρ 1 - ρ 2 ) is t h e d if f e re nc e b e t we e n th e d en s i t y o f th e pa r t ic le s ( ρ 1 ) an d th e d e ns i t y o f th e d is p e rs io n m e di um ( ρ 2 ) . Al t ho ug h St o k e s ' s la w wa s d e r i v e d t o de t e rm in e t h e s et t li ng, o r se d im en t at i on , o f n o nin t e r ac ti n g s p h e ri c a l p a rt i c l es , i t a ls o p r o v id e s g u id a nc e f o r d e te r m i ni n g t h e s ta b il i za ti on o f di s pe r s io n : a . P a r ti c le s iz e s h o ul d be as sm a l l as po ss ib l e. S m a ll e r p a rt ic l es y ie l d s l o we r s e di m e n ta t io n , o r f l ot a ti o n, r a te s . b . H i g h p a r ti c u la t e ( d isp e r s ed p ha s e) c on c en t ra t i o ns in c re as e t h e r a te o f p a r ti c l e - pa r t ic le c o ll is io ns an d i n te r ac t io n . A s a re s ul t , p a rt ic l e a gg r eg a ti on o cc u rs , an d i ns t ab il i t y i nc r e as es a s t h e a gg r eg a te s b e ha v e as la r ge r p a r ti c l e s . In t he c as e o f li q ui d - li qu i d d is pe r s i on s , p a r ti c l e - pa r t ic le c o ll is io ns c a n l ea d t o c oa l es c e nc e ( i . e ., la r g er pa r t ic le s ) a nd d ec r ea s e di sp e rs io n s t ab i li t y. c . Avo i d a n ce o f p a r t ic le - p a r t ic l e i n te r a c ti o n s
( 1 ) A gg r e ga t io n c an be pr e v e n t ed if th e p a r ti c l es h a v e a s i m i l a r e le c t r ic al c h a rg e . P a r ti c l es in an aq u e ou s s y s t em al wa ys ha ve so m e el e ct r ic al c h a rg e b e ca us e o f io n iz a t io n o f c he m i ca l g r o up s o n t he p a r ti c l e s u r fa ce o r a d s o r pt i o n o f c ha r ge d m o le c u l es o r io ns at t he i n t er f ac e . I f t h e a ds o rb ed s p ec ie s is a n i on i c s u r fa c t a nt ( e. g . , s o d iu m l au ry l s ul f a te ) , t h e c h a r ge a ss o ci at e d wi t h t he s u r fac t an t io n ( e .g . , l a ur y l su lf a t e a ni o n ) wi l l a cc u m u la t e a t t h e i nt e r fac e . Ho we ve r , i f a re l at i ve l y n on - s u r f ac e- a c t i v e e l ec t r ol y t e i s a ds o rb e d, th e s i gn of t he c h a rg e o f t h e a ds o r be d i on is le s s r e a di l y p re di c te d . ( 2 ) Th e ma g ni t u de o f t he c ha r g e i s t he di f fe r e nce i n e le ct r ic al p ot e nt ia l b e t we e n th e c ha r ge d s u rf a c e o f t he pa r t ic le an d th e bu lk of t he di s p e rs io n m e di um . Th is m a gn i tu de i s a pp r o xi m a te d b y t h e e l e c t ro k i ne t ic , or z e t a , p o t e n ti a l ( ζ ) . Th e z e ta po t e nt i al is m ea s u r e d f r om t he fi xe d , a vi dl y b ou nd l a ye r s o f i on s a nd s o l v ent m ol ec ul es on t he pa r ti cl e s u r fa c e . W hen ζ is h i gh ( e . g ., ≥ 25 m V ) , i n te r p ar ti c ul a te r ep u l si ve f o r ce s e xc e e d th e a t t ra ct i v e f o r ce s . A s a re s u l t, t he di s pe r s i on is de f l oc c ul a te d an d re l at i v el y s ta b le to c o ll is io n a n d s ub s e qu e nt a g g re ga t io n ( fl o cc u la t io n ) . W hen ζ is s o l o w t ha t i n t er p a rt ic u la t e a t t r ac t i ve f o r ce s p r e do m i na t e , l oo s e p a rt ic l e a gg r eg a te s , o r f l oc s , f o rm (i . e. , f lo cc u l a ti o n o c c u rs ) . d . D e ns i t y c a n b e m an i pu l a te d t o d ec r e as e t he ra t e o f di s p e rs io n i n st a bi li t y . Th e s e tt l in g P.42
r a t e d ec r e as es a s ( ρ 1 - ρ 2 ) a pp r oa ch e s z e r o . H o we ve r , th e d e ns i t y o f th e d i sp e rs io n m ed i um u s ua ll y c an n ot be al t e re d s u ff ic i en t l y to ha l t t he s e t tl ing ( o r f lo t at i on ) p r oc es s . I n t h e d is p e rs ed ph as e , t he d e ns it y o f s ol i d p ar t ic les i s n o t r e ad il y a l te r ed ; al te r i ng t he de ns i t y o f l i qu id p a rt ic l es wo u ld r eq ui r e t h e a d di t io n o f a m i s c ib le l iq ui d o f hi gh e r (o r l o we r ) de ns i t y . Al t e ri ng t he c om p os it i on of s u s p e ns io n s is al so p ro b le m a t ic be c a u se m o st s o li d p a r ti c l e s a re de n s e r th an t h e d is pe r s i o n m e d iu m . A d d i ti v e s o f h ig h er ( o r l o we r ) d en s i t y m i g ht al t er t h e b io p ha rm a ce u ti c a l c h a ra c t e ri s ti c s o f th e f o r m u l at io n (e . g ., r at e o f d r u g r el e as e, r es id e nc e t i m e a t t he s i te o f a d m i ni s t ra ti o n , o r a bs o rpt i o n) . e . Th e se d im e n ta t i on , or f l o t at i o n, r a te is in v e rs e l y p r o po r ti o na l t o th e vi s c o s i t y. A n i n c r e as e in t he vi s c os i t y o f t h e d is p e r si o n m e di u m d e c re as es th e ra t e o f s ett l i ng , o r fl o ta t io n . H o we v e r , al t ho u gh th e ra t e o f d e st a bi li z a t io n c a n b e s lo we d b y a n i nc r ea se in v i s c os i t y , i t c a nn o t b e h a l te d . 3 . E mu l s io n s t a bi l i t y. C o a l es c en c e oc c ur s i n em u ls io n s ys te m s wh e n t he l i qu i d p a rt ic l es o f th e d is p e r s e d p ha s e m e r ge t o fo r m l a rg e r p a r ti cl es . C o a l esc e nc e is la r g el y pr e v e n t ed b y th e i n t e r fa ci a l f il m o f s u r fa ct a nt a r o un d th e d r op l et s . Th is f ilm p re v e n ts di r ec t c on t ac t of th e l i qu i d p ha se o f t h e d r o pl e ts . C o al es c e n c e o f d r op l et s i n o il in wa te r ( o / w) em u ls io ns is a ls o i n hi b it e d b y t he el e c t ro st a t i c re p u ls i on o f s i m i lar l y c ha r ge d pa r ti c l es . C r e a m i ng is th e re ve r s ib l e s e pa r at i on of a l a y e r o f em ul s i fi e d p a rt ic l es .
B e c au se m i xi n g o r s h ak in g m a y be s u f fi ci e nt t o re c on s t i tu t e t h e em u ls io n s ys t em , c r ea m i ng is no t n e c e s s a ri l y un ac c e p ta b le . H o we v e r , c ra c ki n g , or i r r e ve r s i b le p ha s e s ep ar a t i o n , is ne v e r ac c e p tab l e . P h as e i n ve r s i on , or e m ul si o n- t y p e r e v e rs a l, in v o l v e s t h e r e ve rs io n o f a n em ul si o n f r om a n o / w t o a wa t e r in oi l ( w/ o ) fo rm , or v i ce v e rs a . P h as e in ve r s io n c an c h an g e t he c o ns is te n c y o r te xt u r e o f t h e e m u ls io n o r c a us e fu r t h er de t e ri o ra t io n i n i t s s t ab i li t y .
V. CHEMICAL KINETICS AND DRUG STABILITY A. I n t r o d u c t io n . Th e s tab i l i t y o f t h e ac t i ve co mp o n e nt o f a d r u g is a m a jo r c r i te r io n i n t h e r a tio n al de s i g n a nd e val u at i o n of d ru g d os a ge fo r m s. P r o b le m s wi t h s t a bi l i t y c a n d et e rm i ne wh e t he r a g i v e n f o rm ul a ti o n is a cc e pt e d o r re j ec te d . 1 . E xt e n s i v e c h em ic a l d eg r a da t io n o f th e a c ti v e i ng r e di e nt ca n c au s e s u b s ta n t ia l lo s s o f ac t i ve i ng r ed i en t fr om t he dos a ge fo r m . 2 . C he m i c al d e g ra d at i on c an p ro d uc e a to x ic p ro d u c t t h at ha s u nd es i r ab l e s i de ef f ec ts . 3 . I ns ta b il it y o f th e d r ug p r o du c t c a n c au s e d ec r ea s e d b i oa va i l ab i l i t y. A s a r e s ul t , t he t he r ap e ut ic e ff i c a c y of t he do sa ge f o rm m a y b e su bs t an t ia l l y r e d uc ed . B . R a t es a nd o r de r s of r e a c t io n s 1 . Th e r a te o f a re a c ti on , o r d eg r a da t io n r a te , is t h e v el oc i t y wi t h wh ic h th e r e a ct i on oc c u rs . Th is r ate is e xp r e ss ed as d C/ d t ( t h e c ha n ge in c o nc en t r at i on , o r C , wi t hi n a g i v en ti m e in t e r val , o r d t ). a . R ea c ti o n r a te s d ep e nd o n c e r t ai n c on d it i on s (e . g . , r e ac t a nt c o n ce n t r a ti o n , t em p e r at u r e , p H, p r es e nc e o f so l ve n t s o r a dd i t i ve s ). R a d i at i on an d c at a l y ti c ag e n ts (e . g. , po l y va l en t ca t i on s ) a ls o h a ve a n e f f ec t . b . Th e ef f ec t i v e s tu d y of r e ac t io n ra t es i n th e b od y r e q ui r es ap pl ic a ti o n of p h a r ma c ok i n et i c p r i n cip l e s ( s e e C ha p te r 6 ) . 2 . Th e o rd e r o f a re a c tio n is th e wa y i n wh ic h t he co nc e n tr a ti o n o f t h e d ru g o r r ea c ta n t i n a c he m i c a l r e ac t io n a f fe c ts th e r a t e. Th e r a te of a r e ac ti o n, d C / d t , is p ro p or t io n al to t h e c on c en t ra t io n to th e n t h p o we r , wh e r e n is the o r d e r o f t h e r e ac ti o n— t ha t is ,
Th e s t ud y o f r e ac ti o n o rd e r s is a c ru c i a l as p ec t o f ph a rm ac ok i ne t ic s ( s ee C h a p te r 6 ). U s u al l y , ph ar m a c eu t i ca l de g r ad a t ion c an be t re a te d a s a z e r o - o rd e r , fi r s t - o rd e r , o r h i gh e r - o rd e r r ea c t ion . Th e fi r s t t wo a r e s um m a r i z e d as f ol lo ws . a . I n a z e r o- o r d e r re a ct io n , th e ra t e is in d e pe nd e n t o f t he c on c en t r a t io n o f t h e r e ac t a n ts (i . e ., dC / d t
0
C ) (s e e C h ap t e r 6 ) . O th e r f a ct o rs , s uc h a s
a b so r p ti on o f l ig h t in c e rt a i n p ho t oc he m i c a l re ac ti o ns , d e te r m i n e t he r at e . P.43
Figure 3-6. Concentration (C) versus time (t) for a zero-order reaction. The slope of the line equals -k0. The slope of the line is not equal to the rate constant because it includes the minus sign.
( 1 ) A z e r o -o r d e r re a c ti on c an be e xp r e s s ed as : C = -k0t + C0 wh e r e C is t he d ru g c on c e n t r at i on , k 0 i s t he ze r o -o r d e r r a te co ns t an t i n u n i ts o f c o nc en t r at i on / tim e , t is th e t im e , a nd C 0 i s t h e in i ti a l c o nc e n tr a tio n . ( 2 ) W hen t h is e q ua t io n is pl o t te d wi t h C on t he ve r t ic al a xi s ( or d in a te ) a g ai n st t o n t h e h o ri z o n ta l a xi s (a bs ci ss a ), t he slo p e of t he l in e is eq u a l t o - k 0 ( F ig u re 3 -6 ) . Th e n e g at i v e s ig n i n di c a t es th a t th e s lo pe is d e c re as in g . b . I n a fi r s t - o r de r r ea c t io n , th e ra t e de p en d s o n t h e fi r s t pow e r o f t h e c o n ce n t r a ti o n o f a s in gl e r e ac t an t ( i. e ., d C /d t
1
C ).
( 1 ) I n a f i rs t - o rd e r r e ac tio n , d ru g c o n ce n t r at i o n d e c r ea s es ex p on e n ti a l ly w i t h t i me , i n a c c o rd a nc e wi t h t he eq ua t io n C = C0e
-k t 1
wh e r e C is t he c o nc en t r at i o n o f t h e r ea c ti ng m a t er i a l, C 0 i s t h e i ni ti a l c o nc en t r at i on , k 1 i s t he fi r s t -o r de r r at e c on s ta n t in u ni ts o f r ec ip r oc a l t im e, a n d t is ti m e . A p lo t o f the l og a ri t hm of c o nc en t r ati o n a ga i ns t t im e p r o du ces a s tr a ig h t l in e wi t h a s lop e of -k / 2 .3 0 3 ( Fi g u re 3 -7 ) . ( 2 ) Th e ha l f - li f e (t 1 / 2 ) o f a r e ac ti o n is th e ti m e req u i re d fo r th e c o nc en t r at i on of a d r ug to d ec r ea s e b y o n e h al f . F o r a f i rs t -o r de r r ea ct i on, h a l f- l if e i s e xp r e s s e d b y :
( 3 ) Th e t im e re q u i re d for a d r u g t o d e g r ad e t o 90 % of it s o r ig i na l c o nc en t r at i on ( t 9 0 % ) is als o i m p o r ta n t. Th i s t im e re p r es en t s a re as o na bl e l i m i t o f d e g ra da t io n fo r th e ac ti ve in g r ed ie n ts . The t 9 0 % c an be ca lc ul a te d as:
( a ) B ec au s e k 1 = 0 .6 9 3 / t ½ ( b ) Th e n
P.44
Figure 3-7. Logarithm of concentration (log C) versus time (t) for a first-order reaction. The slope of the line equals -k/2.303.
( 4 ) B o th t ½ an d t 9 0 % a re c o n ce n t r a ti o n i n de p e nd e n t . Th us , f o r t ½ , i t t ak e s t h e s am e a m o u nt of t im e t o re d uc e t h e c o nc e nt r at i o n o f t h e d ru g fr om 1 00 m M t o 5 0 m M a s it do es f r o m 5 0 m M t o 25 m M. C . F a ct o r s th a t a f f ec t re a c t io n r at e s. F ac to r s ot h e r t h an c o nc en t r at i on c a n a f f ec t t h e r e ac ti o n r a te an d s t ab i li t y o f a d r ug . The s e f ac t o rs i nc l ud e t e m p e r at u re , th e p r es e nc e o f a so l v e nt , p H, an d t h e p r es e nc e o f a dd i ti ves . 1 . T em pe r a t u r e. A n i n c re a s e i n t e mp e r a tu r e c au s es a n i n c r e as e i n r e a ct i on ra t e , as e xp r e s s e d in th e e q ua t io n f i rs t s u g g es te d b y A r r h en iu s : k = Ae
-Ea/RT
or
wh e r e k i s t h e s p ec i fi c re a c t i on r at e c on s ta n t, A i s a c o ns t an t k no wn a s th e f r e q ue nc y f ac t or , E a is th e en e rg y o f a c ti v a t io n , R i s t h e m o l a r g as c on s ta n t ( 1 . 9 87 c a l/ d eg r ee × m ol e) , a nd T i s t he ab so l ut e te m pe r a tu r e. a . Th e co n s ta n ts A an d E a a re o bt ai n ed b y de t erm i ni ng k a t s e ve ra l t e m p e r at u re s a n d t he n pl o t ti n g l og k ag a in st 1 /T . Th e s lo pe o f t he r es ul t in g l i ne eq u al s - E a / (2 . 30 3 × R ) . Th e in t e rc ep t on th e v e r t i c a l a xi s e qu a ls l o g A . b . Th e ac ti v a t io n e n e rg y ( E a ) is th e a m o u nt of ene r g y r eq u i re d t o p u t t h e m o le cu l es i n a n a c t i va ted s t a te . Mo l ec u le s m u s t b e ac ti v a t ed t o r e ac t. A s
t e m p e ra t u r e i nc r e as e s , m o re m o le c u l es a r e a c t iv a t e d , a nd t he r ea c t io n r a t e i nc r e as es . 2 . P r es e nc e of s ol ve n t . Ma n y d o s a ge fo r m s re qu i r e t h e in c or p o ra t io n o f a wa t e r - m is c i b le s o l v en t —f o r e xa m pl e , l o w m ol ec ula r we i g h t a lc oh ol s , su c h a s th e p ol y e t h y le n e g l y c o l s ( P E G s ) —t o s t ab il i ze t h e d r u g. a . A c h an ge in t he s o l ven t s ys t em al t e r s t he t ra ns i ti o n s ta t e a nd th e a c t i vi t y c o e f f i c ie n ts o f t h e re ac t an t m ol e cu le s . It c an al so c a us e s im u lt a ne o us c ha n ge s i n p h y s i c o c he m i c a l p a ra m e t e rs , s uc h a s p K a , su r f ac e t e ns i on , a n d v i s c os i t y . Th e s e c h an g es in d i r ec t l y a f f ec t t he r ea c t io n r a te. b . I n so m e c a s e s , a dd i t io n a l re a c ti o n p a thw a ys a r e g e ne r at e d. F o r e xa m p l e , wi t h a n in c re as i n g c on ce n t ra t io n o f e t han o l i n a n a qu e ou s s o lu t io n , as p i ri n d eg r a des b y an e xt r a r ou t e a nd fo r m s th e et h y l e st e r o f a c et yl sa l ic y l ic a c i d . Ho we v e r , a c ha n g e i n s o l ven t c an a ls o s t a bi l iz e the drug. P.45
3 . C h an g e i n p H . Th e m a g ni t ud e of th e ra t e o f a h y d r o l yt ic re ac t io n +
-
c a ta l yze d b y H a n d O H c an v a r y co ns i de r ab l y wi t h p H . +
-
a . H ca t a l ys i s p r e do m in a t es a t low e r p H , wh e re a s O H ca t a l ys i s o p e rat e s a t h ig h e r p H . A t i n te r me d i a te p H , t he r at e m a y b e p H i n de p e nd e n t o r m a y +
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b e c a ta l y z e d b y b o t h H a n d O H . R a te c o ns t an ts i n t h e i nt e rm e di a te p H r a n ge a re t y pi c al l y l es s th a n t h os e a t h ig h e r o r l owe r p H . b . To d et e rm i ne th e e f f ec t o f p H o n d e g ra d a ti on k i ne t i cs , d ec om p os it i on +
i s m ea s u r e d a t s e v e ra l H c o nc en t r at io n s. Th e p H o f o p ti m um st a b il i t y c a n b e de t e rm in ed b y pl o tt i ng t he lo g a ri t hm o f th e r a te c o ns t a nt (k ) as a f u nc t io n o f p H ( F ig u re 3 -8 ) . Th e po i n t o f in f l ec t io n o f t he pl o t is t he p H o f o p t im um s t ab il i t y . Th is va l ue is us ef u l i n t he de v e l op m en t o f a s t a bl e d r ug f o r m u l at io n . 4 . P r es e nc e of a dd i t i ves a . B u f fe r s al t s m us t b e a d d ed to m a n y dr u g so l ut i o ns to m a in t ai n t h e f o r m u l at io n at op t im um pH . Th e s e sa l ts ca n a f f ect t h e ra t e o f de g r a da t i on , p r i m a r il y as a r e s u lt o f s a l t i nc r e as in g t h e i on ic st r e n gt h . ( 1 ) I nc r ea s i ng s a l t c o nc en t r a ti o ns , p a rt ic u la r l y f rom po l y e le c t r o l y te s ( e .g . , c i t ra t e, ph os p ha t e ), c a n s u b s ta n t ia l l y a f f e c t t h e m a gn i t u de o f p K a . I n t hi s wa y, t h e y c h an ge t he ra te c o ns t a nt . ( 2 ) B u ff e r s al ts c a n a ls o p r o m o te d r u g d eg r a da t io n t h ro ug h g e ne r al ac id o r b as e c a t al y s is . b . Th e ad d i t io n o f su r f ac t a n ts m a y ac c e l e ra t e or d ec e le r at e d r u g d e g ra d at i on . ( 1 ) Ac c e l e ra t i on o f d e gr a d a t io n is c om m o n a nd i s c au s e d b y m i ce l la r c a ta l ysi s . ( 2 ) S t ab i l iz a ti o n o f a d ru g t h ro ug h th e a dd i ti o n o f a s ur f ac t an t i s l es s c om m o n .
c . C om p le x i ng ag e n ts c a n im p ro v e dr u g s ta b il it y. A r om a ti c e s t e rs ( e. g ., b e n zoc a in e , p r oc ai ne , tet r a c a i ne ) in c r ea s e i n h al f - l i f e i n t he p re s e nc e o f c a f fe in e . Thi s i nc r ea s ed s t ab i li t y ap p ea r s t o r es u l t f r om th e f o rm a ti o n o f a l e ss re ac t i v e c om pl e x b et we e n t h e a ro m a t ic es te r a n d t he c a f fe i ne . D . M od e s o f ph a r ma c eut i c a l d e g ra d a ti o n. Th e d e c o m p os i ti o n o f a c t i v e i n g re d ie n ts i n a do s a g e fo r m o c c u rs th r ou g h s e v e r a l p a t h wa ys (e . g. , h yd r o l ys i s , o xi d a ti o n, pho t o l ys is ; s e e C h ap t e r 1 2, I I . A ) . 1 . H yd r o l ys i s i s t he m o s t c om m o n t yp e o f d e g ra da t i on be c a us e m an y m e di ci n al c om p ou nd s a re es t e rs , a m i d es , o r l ac ta m s . +
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a . H an d O H a r e t h e m o s t c om m o n c a t al y s ts o f h yd r o l y t ic d e g ra da t io n i n s o lu t io n . b . E s te r s u s ua ll y u nd e r go h y d r ol y t ic r ea c t i on s t ha t c a us e d r ug in s ta bi l it y . B e c au se es t er s a r e r a pid l y d eg r ad e d i n a qu e ou s s ol u ti o n, f or m u l at o rs a re r e l uc t an t t o i nc o r po r a te d r u gs th a t h a v e e s t e r f un c ti o na l g r ou ps in t o l iq u id d o sa g e f o rm s .
Figure 3-8. Semilogarithmic plot of the rate constant (k) versus pH. This plot is used to determine the pH of optimum stability.
P.46
2 . O x i da t i on is u s u a ll y m e di a te d t h r ou gh r ea c ti on wi t h a tm os ph e ri c o xyg e n u n d er am bi e nt c o n di ti o ns ( au t o -o xi d a t io n ) . a . Me d i c i n al c om p ou n ds t h a t u nd e r go au t o -o xi d a ti o n a t ro om te m p e r at u r e a r e af f ec te d b y o x yg e n d i s so l ve d in t he s ol ve nt a n d i n t he he a d sp ac e o f t h e ir p ac k a ge s . Th e s e c o m po u nd s sh o ul d b e p ack e d i n a n i n e r t a t m o sp h e re ( e. g . , ni t r oge n ) to e xc l ud e a i r f r om th e i r c on t ai ne r s. b . Mo s t o xi d a ti o n r e ac ti on s i n v o l ve a f re e r ad i ca l m e ch a ni s m a nd a c h ain r e a c t io n . F r e e r ad ic a ls te n d t o ta k e el ec t r on s f r om o th e r c om po un ds . ( 1 ) An t i o x id a n ts in t he fo r m ul a ti on r ea ct wi t h th e f r e e r a di ca ls b y p r o vi di ng e l ec t r on s a nd ea s i l y a v ail a bl e h yd r o ge n a t om s . In t h is wa y , t h e y p r e v e nt th e p r o pa g at i on of c h ai n re ac t io ns .
( 2 ) C o mm o nl y u s e d a n ti o x i da n t s in cl u de as co rb i c ac i d, bu t y l a te d h yd r o xya n i s o le ( B H A ), bu t y l a te d h y d r o xy t o l u e ne ( B H T) , p r o p y l g al l at e , s o di um bi s u l fi t e, s o di um s u lf i te , a n d t h e t oc op h e ro l s . 3 . P h ot o l ys i s i s th e de gr a d a ti on o f d ru g m ol ec u le s b y n o rm al su nl i gh t o r r o o m li g ht . a . Mo l e c u l es m a y ab s o r b t h e p r op e r wa v e l en g th of l ig h t a nd ac q u i re s u f f i ci e n t e ne r g y t o u nd e r g o re a c ti o n . U su a ll y, p h ot o l y ti c d eg r a da t io n o cc u rs on e xp o s ur e to lig h t o f wa v e l e ng t hs < 400 nm . b . A n a m be r g la ss b o tt le o r a n o p a qu e c o n ta i ne r a c t s a s a b a r ri e r t o t hi s l i gh t , t h e re b y p re v e n ti ng o r r et a rd i ng ph o to l ys i s . F o r e xa m pl e , s od iu m n i t ro p r us s i de in aq u eo us s ol u ti o n h as a s h el f li f e o f on l y 4 h r i f e xp o s e d t o n o r m a l r o om l i gh t . W hen p r o te c t e d f r om li gh t , t h e s ol u ti o n is st a bl e f o r a t l e as t 1 y e a r. E . D e t e rm i n at i o n o f s h el f l i fe . Th e s he l f l if e o f a d r u g p re p a ra t io n i s t he a m ou n t o f t im e t h at t he p r o du c t ca n b e s t o re d b ef o r e i t b ec om e s u nf i t f o r u s e, t hr o ug h e i th e r c he m i c al de co m p os i ti o n o r p hy s i ca l d e te r i or a ti o n. 1 . S t o ra g e t e mp e r a tu r e a f f ec ts s h el f l i fe . It is gen e r al l y un d e rs to o d t o b e a m bi e nt te m p e r at u r e u nle s s s p ec i al s t o ra ge c o n di t i o n s a r e s p ec i fi e d. 2 . I n g en e r a l, a p r e pa r at i o n is co n s id e r ed f i t f or u s e i f i t va r i e s f r o m th e n o m i na l c o nc e n t ra t i o n o r d o se b y n o m o r e t h an 1 0 %, p r o vi d e d t h at t he d e co m p os i ti o n p ro d uc ts a r e no t m o re to xi c o r h a rm f ul t ha n t h e o ri g in al m a te r i al . 3 . S he l f - l if e te s t in g a i ds in de t e rm in i ng th e s ta nd a r d s he l f li f e o f a f o r m u l at io n . a . Sa m p l es a r e s t o re d a t 3 - 5 ° C a n d a t r oo m t em p er a tu r e (2 02 5 ° C ) . Th e s a m p l es ar e t h e n a na l yz e d a t v a ri o us i n te r va ls to de t e rm in e th e r a t e o f d ec o mp o s it i o n. S h e l f li f e i s c a lc u la t ed f ro m th is ra t e . b . B ec a us e s t o r ag e t im e a t th es e t e m p e ra t u re s ca n r es ul t i n a n e xt e n d e d t e s ti ng ti m e, ac c el e r a ted t e s ti n g i s c o n du ct e d as we l l , wi t h a ra n ge of h i gh e r te m p e ra t u re s . Th e r a t e c o ns t an t s o b ta i ne d f ro m t he s e s a m p l es ar e u s ed to p re d ic t s he l f li f e a t am bi e nt o r r e f ri ge r a ti on t em pe r a tu r es . T e m pe r a t u re - a cc e le r a t ed s t ab i l i t y t e s t i n g is n o t u se f ul if t em pe r a tu r e c h an g es a r e a c c om pa n ied b y c h a ng es in th e re act i o n m e c h a ni s m o r b y p h ys ic al c h an g es i n th e s y s t em (e . g. , c h an g e f r om t he s o li d t o t h e l iq ui d p h as e ) . c . S ta b i li t y a t r o o m te mp e r a t u re c a n b e p r ed ic te d f ro m a cc el e ra t ed te s tin g d a t a b y t he A r rh e ni us equ a t io n :
wh e r e k T 2 an d k T 1 a re the r a te c o ns t an ts at t he ab s ol u te te m p e r at u r es T 2 a n d T 1 , re s p ec t i v el y ; R is t he m o la r g a s co ns t an t; a nd E a is t he en e rg y o f a c ti va t io n . d . A l te r na t i v el y , an e xp r e s s i on of co nc e nt r a ti on c a n b e p lo t te d a s a li ne ar f u nc t io n o f ti m e . R at e c on s ta n ts (k ) fo r de g ra d at io n at se v e r al t em pe r at u re s a r e ob t ai ne d . Th e l og a ri th m o f th e ra t e co ns t an t (l o g k ) i s p lo t te d a g ai ns t
t h e re ci p ro c al o f ab s o l ute t em pe r a tu r e (1 / T ) t o ob t a in , b y e xt r a p o la t io n , th e r a t e c on s ta n t f o r d eg r ada t i on at r oo m t em pe r a tu re ( F ig u re 3 -9 ) . e . Th e le n g th o f t i me t ha t t h e d r u g w i l l m a in t a in i t s re q ui r e d p o t en c y c a n a ls o b e p r ed ic t ed b y c al c u l at i on of t he t 9 0 % ( se e V . B. 2 .b . ( 3 ) ). Th is m e th o d a pp li e s t o c h e m ic a l r e ac ti o ns wi t h a c t i v a ti o n e ne r g ie s o f 1 0 -3 0 k ca l /m ol , th e m ag n it u de o f t he ac ti v a t io n e n e rg y fo r m a n y ph a rm ac e ut ic a l d e g ra d at i on s t ha t oc c u r in s o l ut i on . P.47
Figure 3-9. Semilogarithmic plot of the rate constant (k) versus the reciprocal of absolute temperature (1/T), showing the temperature dependency of degradation rates.
VI. DRUG DOSAGE FORMS AND DELIVERY SYSTEMS A. O r a l s o l u t io n s. Th e U n i t e d St a t es P ha r m aco p e ia ( U S P ) 3 1 / Na t i o nal F o r m u la r y ( N F) 26 c a t eg o r i z es o ra l so l u ti o n s as “ li qu i d p r ep a ra t io ns , i n t en de d fo r or a l a dm in is t r a t io n , t ha t c o nt a in on e o r m o r e s ub s t a nc es wi t h o r wi t h o ut fl a v o r in g , s we e t e ni ng , o r co l or i ng ag en t s d is so l ve d in wa t e r o r c os o l ven t - wa t e r m i xt u r e s . ” O r a l s ol u ti on s c an c o nt a i n c e r t ai n p o l yol s ( e .g ., s o r bi t ol , g l y c e r in ) to in h ib i t c r y s ta ll i za ti o n a nd to m o di f y so lu b il i t y, t as t e, m o ut h fe el , an d o t he r v eh i c l e p r op e r ti es . Th e y c an b e “ f o rm ul a te d f o r d i rec t o r a l a dm in is t r at i on to t he p at i en t o r th e y m a y b e d i s p e ns ed in a m o r e c o nc en t r at e d f o rm th a t m us t be di lu t ed p ri o r t o a d m i ni s t ra ti o n .” D r u gs in s o l u t io n a r e m o re ho m og e n eo us an d e as i er t o s wa l l o w t h a n d r u gs i n s ol id f o r m . F or d ru gs t ha t h a ve a s lo w d i s s o lu ti o n r a te, o ns e t o f a c t i on an d b i oa va i la b il it y a r e a ls o im p r o v ed . Ho we ve r , d r ugs i n s o lu t io n a r e b u lk ie r d o sa g e f o rm s , de g ra d e m o r e r ap i dl y , an d a r e m o r e l i k e l y to in t e ra c t wi t h c o ns ti t ue n ts th a n t ho s e in s o l id fo r m . 1 . Wa t e r i s t h e m os t com m o nl y u s e d ve h i cl e for d r ug s o lu t io ns . Th e U SP r e c og ni z e s s e v en t y p es o f wa t e r fo r th e p r ep a r at io n of do s a g e f o rm s :
a . P u r i fi e d w a t e r U S P is wa t e r o b ta in e d b y di s ti lla t i on , i o n e xc h a ng e , r e v e r s e os m o s i s , o r o t her s ui t ab l e t r ea tm e nt . It c a n n ot c o nt a in m o r e t ha n 1 0 pa r ts pe r m i ll io n (p pm ) o f to t al s o li d a nd s h ou l d h a ve a p H b et we e n 5 a n d 7 . Pu r i fi ed wa t e r is u s ed in p re s c r ip ti o ns and f in is h ed m a nu f ac tu r e d p r o du c ts e xc e p t pa r en t e ra l an d o p ht h al m i c p ro d uc t s . b . W at e r f o r i n je c t io n US P i s wa t e r ob t ai n ed b y d i st i ll a ti on o r b y r e ve rs e o sm o si s . I t c o n fo r m s to th e s t an d a rd s o f p u ri f ie d wa t e r b u t i s al s o f r ee of p yr o g en . W at e r f o r i nj ec ti o n i s us e d as a s ol v e n t f o r th e p r e pa r a ti on o f p a r en t e ra l s ol u ti o ns . c . S te r i l e w a t e r fo r i nj ec t i o n U SP is wa t e r fo r i nj e ct i on th a t i s s t e r il i z ed a n d p ac k a g ed in s i ng le -d o s e c o n ta in e rs of t y p e I a n d I I g l as s . Th es e c o nt a in e rs do no t e xc e e d a c ap a c i t y of 1 L . Th e li m it a ti o ns f o r to t al s o li ds d e p en d o n t h e s i z e o f t he c o n ta i ne r . d . B a ct e r i os t a t ic w a te r f o r i n je c t io n U S P i s s te ri l e wa t e r f o r i nj ec t io n t h at c o nt a in s o ne o r m o r e s uit a b le an t im ic r ob ia l a g en ts . It is al s o pa c k ag e d i n s i ng le - o r m u l ti p le - do s e c o nt a in e rs of t y p e I o r I I g l as s . Th e s e c o nt a in e rs d o n o t e xc e e d th e c ap ac i t y o f 30 m L . e . S t e ri l e w at e r f o r i n hal a t i o n U S P is wa t e r t h at i s p u ri f ie d b y d is t il la t io n o r b y r e v e rs e os m o s i s (i .e . , wa t e r f o r i nj e c t i on ) an d r en de r e d s te r il e . I t c o nt a in s n o a nt im ic r o bi al a g en ts , e xc e pt wh e n us e d in hu m i di f ie r s o r s im ila r d e vi ce s. Th i s t y p e o f wa te r s h o ul d n o t b e us e d f or p a re n te r a l a dm in is t ra t io n o r f o r o th e r s te r il e do s a ge f o rm s . f . S t e r il e w a te r f o r i r r i ga t i o n U SP is wa t e r fo r i nj e c t i on th a t i s s t e r il i zed a n d s ui t ab l y pa c k ag e d. It c on t ai ns no an t im ic r ob ia l ag en t s o r o t he r ad d ed s u bs ta n c e . P.48
g . S t e r il e p u r i f ie d w a ter U S P i s p u ri fi e d wa t e r st e r il i ze d a nd s u i ta bl y p a ck ag e d. I t c o n ta i ns n o a n ti m i c ro bi a l a ge n t. I t i s n o t i nt e nd e d f o r u s e i n p a r en t e ra ls . 2 . O r a l d r u g s o l ut i o ns in c lu d e s yr u p s a nd e li x i rs as we l l a s o t he r le s s wi d e l y p r es c ri be d c la s s ic ( g a le n i ca l ) f o rm ul a ti o ns, s uc h as a r om a t ic w a te r s , ti n c tu r e s, f l ui de x t r a ct s , a nd s pi r i t s. a . S yr u p s a r e t r a di ti o na ll y p e r or a l so l ut i on s t ha t c o nt a in hi g h c o nc en t r at i on s o f s uc r os e o r o t he r s u ga r s . Th r o ug h c om m o n us ag e , t he t e r m s y r up ha s a ls o c om e t o i nc lu d e a n y o t he r li qu i d d os a ge fo r m p r ep a red i n a s we e t , v i s c ou s v eh ic l e , i nc l ud in g p e r or a l s us p e ns i on s. ( 1 ) S yr u p N F ( s i mp l e s yr u p ) is a co nc e nt r a te d o r n e a rl y s a t u ra t ed aq u eo us s o lu t io n o f s ug a r (8 5% ; 6 5 % w/ w) . ( 2 ) S yr u ps ha v e a l ow so l ve n t ca p ac i t y f o r w a te r - s o lu b l e d r u gs be c a us e t h e h yd r o ge n b o nd in g b et we e n s uc ro s e a nd wa t e r i s v er y s t ro n g. Fo r t hi s r e a so n , i t c a n be di f fi c u l t o r im po s s ib l e t o d iss o l ve a d r u g i n a s yr u p. O f t en , t h e d r u g is be s t di s s o l v ed i n a s m a ll qu a nt i t y of wa t e r , a nd t he fl a v o ri n g s yr u p i s a dd e d.
( 3 ) Th e su c r os e c o n ce nt r a t i o n o f s yr u p p la y s a c r uc i al ro l e i n t he co n tr ol o f m i cr o bi al g ro wt h . D i lut e s u c ro s e s o lu t io ns a re e xc e l l e nt m e di a f o r m ic r o or g an is m s . As th e c o nc en t r at i on of s u c ro s e a p p ro ac he s s at u r at i on , th e s yr u p b ec om e s s e l f -p r es e r v i n g ( i .e . , re qu i r es n o a d di t io n al p re s e r v a t i v e) . H o we ve r , a s a t u ra t ed s o lu t i on is u n de s i r ab l e b ec a u s e te m p e r at u r e f l uc t ua t io ns m a y c a us e c r y s t a ll i za ti o n. S yr u p N F i s a s e l fp r es e r ved s o lu t io n wi t h a m i ni m a l te nd e nc y t o un d e rg o c r y st a ll i z a ti on . b . E l ix i r s a r e t r ad i ti o na lly p e r o ra l s ol u ti o ns th a t c o n t ai n a lc o ho l a s a c os o l ven t . Ma n y p e ro r al s o lu t io ns a re no t d es c ri be d as e l i xi r s b u t c on t ai n a l co h ol . ( 1 ) To b e c o ns i de r ed an e l i xi r , t he s o lu t io n m u st c o n t ai n al c oh o l . Tr a d i t io n al l y , th e a lc oh o l c on t en t of el i xi r s ha s v ar i e d f r om 5% to 40 % . Mo s t e l i xi r s b e c o m e tu r bi d wh e n m o de r a te l y di lu t ed b y a q ue o us l i qu id s . E li xi r s a r e no t t h e p r ef e r re d v ehi c le fo r s a lt s b ec a us e a lc o h ol ac c e n tu a te s s al in e t a s te . Sa l ts a ls o h a v e l im i te d s ol u bi li t y i n a lc oh ol . Th e r ef o r e, th e a lc o ho l ic c o nt e nt o f s a l t -c on t ai n ing e li xi r s m u s t be lo w. ( 2 ) Ar o m a t i c e l ix i r N F, p r e pa r e d i n p ar t f ro m s y ru p , c on t ai ns ap p r o xi m ate l y 2 2 % a lc o ho l. Th e li m i t ed u s e f ul n es s o f t hi s e li xi r a s a s o l v e nt fo r d ru gs wa s o f f se t b y t h e d e v el op m en t o f i so - a lc o h ol i c e l ix ir . I t i s a c om b in a ti o n o f l ow -a l co h o li c e l i xi r , an e l i xi r wi t h lo w a l c oh ol ic c o nt e nt ( 8% - 1 0% al c o h o l) , a n d h i g h -a l co h ol i c e l ix ir , a n e li xi r wi t h h i gh al c oh o li c c on t en t (7 3 %- 7 8% a l co h ol ) . Mi xi n g a pp r o pr ia t e v ol um es o f t he t wo el i xi r s p ro v i d es a n a lc o ho li c c o nt e nt s u f fi c i e nt t o di s s o l v e th e d r u gs . B . M is c el l a ne o us so l u t io n s 1 . Ar o m a t i c w a t e rs a re c l ea r , s a t u ra t e d a qu e o us s o lu t i on s o f vo l a t il e o i l s o r ot h er a ro m a t ic or v o l a ti l e s u bs t an ce s . A r om a ti c wa t e rs m a y be us ed a s p l ea s a n tl y f la v o r e d v eh i c l es fo r a wa t e r - s o l ub le d r ug or as an aq u eo us p h as e i n a n e m u ls i on or s us p en s i o n. I f a l a r ge am o u n t o f wa t e r -s ol u bl e dr u g i s a d de d t o a n a r om a ti c wa t e r , t h en an in s o lu b le l a y e r m a y f or m a t t h e t op . Th i s “s a lt i n g o u t” is a c o m pe t it i v e p r oc es s . Th e m o le cu l es o f wa t e r -s ol u bl e d r u gs ha v e m o r e a tt r ac t io n fo r th e s ol ve n t m ol ec u l es of wa t e r th a n t he “ oi l ” m o le cu l es . Th e as s o c i a te d wa t e r m ol ec u le s a r e p u ll e d a wa y f r o m t he oi l m o le cu l es , wh i c h a r e n o l o ng e r h e ld in s o lu t io n . A r o m at ic wa t e rs s h ou l d b e s t o re d i n t i gh t , l ig h t - re s is t an t bo t tl es t o r ed uc e vo l a ti li z a t io n a n d d e g ra d at i on f ro m s un li g ht . A r om a ti c wa t e r s a r e us u al l y p re pa r e d b y on e of t h e fo ll o wi n g m et h od s : a . D i s ti l la t i o n is a u ni v er s a l m e t ho d b u t is n ot p ra c ti ca l o r ec on om ic a l f o r m os t pr o du c ts . I t i s t h e on l y m e t ho d , h o we v e r , fo r p r e pa r in g s t ro n g r os e wa t e r a n d o r an ge f lo we r wa t e r . b . W ith t h e s o lu t i on me th o d , t h e v o l a ti le , o r a rom a ti c , su bs t an c e is a d m i xe d wi t h wa t e r , wi t h o r wi t h ou t th e u s e of a d i s p e rs an t ( e. g ., t al c) . 2 . S p i ri t s , o r e s se n ce s , a r e al c o ho l ic o r h yd ro al c o h ol ic s o lu t io n s o f vo l at i le s u bs ta n c e s , th a t c on t ai n 5 0 % -9 0% al c o h ol . Th is h i g h a l co h o li c c o n te n t m a in t ai ns th e wa t e r -i ns ol u bl e v ol a ti l e o il s i n so l u t i o n. I f wa t e r is ad de d to a s p i ri t , t he oi ls s e pa r a te . S o m e sp i ri t s a r e m ed i cin a l (e . g ., a ro m a t ic
a m m o ni a s pi r i t) . Ma n y s p i r it s (e . g. , c om p ou nd o ra n g e s p i ri t , c om po u nd c a r da m o m s p i ri t ) ar e u s ed as f la v o r in g a g en ts . Spi r i ts s h ou l d b e st o r ed in t i g ht co n ta in e rs to r ed uc e l os s b y e v ap o ra t io n . 3 . T in c t u re s a r e a lc o ho lic o r h y d r oa lc o ho li c s ol u ti o ns of ch em i c al s o r s o lu bl e c o ns ti t ue n ts of ve g e ta bl e dr u gs . Al t ho ugh t in c tu r es v a r y in dr u g c o nc en t r at i on ( ≤ 5 0 % ), th o s e p re pa r e d f r om p o ten t d ru gs a re us ua ll y 1 0 % i n s t r en g th ( i. e ., 1 00 m L o f t h e ti nc t ur e h a s t he ac ti vi t y o f 1 0 g of t he d ru g ). Ti n c t u re s a r e us u al l y c on s id e re d s t ab le . Th e a lc o h o l c o n te n t o f t h e o f fi cia l t i nc t u re s v a r i es fr om 1 7% t o 2 1% f or op i um ti nc tu r e U S P a n d f r om 7 4 % to 8 0 % f o r c om po u nd be n zo i n t i nc tu r e U S P. Mo s t tin c tu r es a re p re pa r e d b y a n e x t r a ct i o n p r o ce ss o f P.49 m ac e r at i on or p er c o l at i on . Th e s e le c t i on of a s o lve n t , o r m en s tr u um , i s b a se d o n t h e s ol ub i li t y of t h e ac t i v e a nd in e r t c o ns t i tu en t s o f t h e c ru de d r u gs . Ag i ng c a n c a us e p r e c i pi t a ti on o f t he in ac t iv e c on s ti t ue n ts o f t i nc t u re s . G l y c er i n m a y be a dd e d t o t he h yd ro a lc oh o li c s ol v e n t t o i nc r ea se t h e s ol u bi li t y o f t h e ac t i ve c o ns t i tu en t an d re du ce p r ec i pi t at io n on s t o ra ge. Ti n c t u re s m u s t b e t ig h tl y s t op pe r e d a nd k e pt f rom e xc e s s i ve t em p er a tu r es . B e c au se m a n y of th e i r c o n s t i tu e nt s u nd e r go a p ho t oc h em ic al c h an g e wh e n e xp o s e d to l i gh t , t i nc tu r es m u s t be s t o re d i n l i gh t -r e s is ta n t c on t ai ne r s . 4 . F lu i de x t r ac t s a r e l iq ui d e xt r a ct s o f v eg e ta b le d r u gs th a t c on t ai n a lc oho l a s a so l v e nt , p r es e r v a ti v e , o r b ot h . F l ui de xt r a c t s a r e pr e pa r ed b y p e r co la t io n s o t h at ea c h m i ll il i te r c o nt a in s t he t her a p eu t ic c o ns ti t ue n ts of 1 g o f t h e s t a nd a r d d ru g . B e c au s e of t he i r h ig h d ru g c o nt e nt , fl u id e xt r a c ts a r e s om e ti m e s re f er r e d t o a s “ 1 0 0% ti nc t u re s . ” Fl u id ext r a c t s of po t en t d ru gs ar e u s ua ll y 1 0 t im es as c o nc e n t r at e d, o r p ot e nt , as t he co r r es p on di n g t in c tu r e. F o r e xa m pl e , t he us u al do s e o f t i nc tu r e b el l ad o nna is 0 .6 m L ; t he e q ui va l en t do s e of th e m o r e po t en t f l ui d e xt r a ct is 0 . 06 m L . Ma n y f l u id e xt r a c ts a r e c on s i d er e d to o p o te n t f o r s el f -a dm i ni s t r a ti on b y pa t ie n ts , s o th e y a re al m o s t ne v e r p r es c ri be d . I n a d di t io n , m a n y fl ui d e xt r a c ts a r e s im p l y to o b i tt e r . To d a y , m os t fl u id e xt r a c ts a r e m o d i fi ed b y ei t he r fl a v o ri ng o r s we e te n in g a g en ts . 5 . N as a l , o p ht h a lm i c, ot i c , a n d p a r en t e r al so l ut i o n s a r e c l as si f ie d s e pa r a te l y be c a us e o f the i r s p ec if ic us e a nd m e th o d o f p r e pa r at i on . 6 . M o u t hw as h es ar e s olu t i on s t ha t ar e u s ed to c le a ns e t h e m ou t h o r t r ea t d i se as es o f t he o ra l m uc o u s m e m b r a ne . Th e y of te n c o nt a in al co h ol or g l yc e ri n t o a i d i n di s s o l v in g th e v ol a ti l e i ng r ed i e n ts . Mo u t h wa s he s a r e m o re o f t en us ed c o s m et ic a ll y th a n t h e ra pe u ti c a l l y. 7 . As t r i n g en t s a r e l oc al ly a p p li ed so l ut io n s t ha t p r e ci pi t a te pr o te i n. Th e y r e d uc e c el l p e rm ea b il i t y wi t h o u t c a us in g i nj u r y . As t r in g en ts c a us e c o n s t ri c t i on , wi t h wr i nk li n g a nd bl a nc hi n g o f t h e s k i n . Be ca us e a s t r i ng en ts r e d u ce se c r e t io n s, t he y c an be us e d as an t ip e rs p i r an t s .
a . Al u m i n um ac e ta t e a nd a l um i nu m s u ba c e ta t e s o l u ti o ns a re us ed as we t d r e ss in gs in c o nt ac t de rm a ti t is . Th e p r ec ip i ta ti o n i s m i n im i z ed b y th e a d di t io n o f bo r ic ac id . b . C a lc i um h yd r o x i d e so l u t i on is a m i ld s t r in g en t t ha t i s us e d i n l ot i on s a s a r e ac ta n t a nd an al k a l i ze r . 8 . An t i b a c te r i al t o pi c al s o l u t io n s ( e .g . , b en za lko n iu m c hl o ri d e, st r on g i o di n e, po v i d on e io di n e ) k i ll ba c t e ri a wh e n a pp l ied t o t h e s k in o r m u co u s m em b r an e i n t h e p r op e r s t r en g th an d u n de r ap p ro p r ia t e c on di t io ns . C . S u s pe n si o ns 1 . L o ti o ns , m a gm a s ( i .e. , s u s p e ns io ns of f in el y d i v i de d m a te r ia l i n a s m a l l a m ou n t o f wa t e r) , an d mi x t u r es a re al l s us pe ns io n s t ha t ha v e ha d o f fi c i al f o r m u l as f o r s om e t im e (e . g . , c a l am in e l o ti on U SP , k ao li n m i xt u r e wi t h p e ct i n N F ) . O ff ic i al fo r m u l as a re gi v e n i n t h e U SP / N F . a . A c o m pl e te f o r mu l a a n d a de t a il e d m e th o d o f p r e pa r a t io n a r e a va i la b le fo r s o m e of f ic ia l s us p en s i o ns . F o r o t her s , o n l y th e c o nc e n t ra t io n o f t he ac ti v e in g re d ie n ts i s g i v e n, an d th e m an u fac t u re r ha s c o n si de r a bl e l a t it u de in th e f o rm u la t ion . b . S om e d r ug s a r e p ac k a g e d in a d r y f o r m t o c i rc um ve n t t h e i ns ta b il i t y of a q u eo us di s p e rs io ns . W a t e r i s a dd e d a t t h e t im e o f di s p en s i n g t o r e c on s t i tu t e t h e s u s p e ns i o n . 2 . P u r po s es o f s us p e nsi o n a . S us t a in i n g e f fe c t . F or a s u s t ai n ed - r el e as e p re p a ra t io n , a s us p en si o n n e ce ss it a t es d r ug di s s olu t i on be f o re ab s o r p ti on . b . S t ab i l i t y. D r u g d e g rad a t io n i n s us pe ns i on or s o li d d os a ge fo r m s o cc ur s m uc h m o re s l o wl y t h an de g r ad a ti o n i n s o l ut i on for m . c . Ta s te . A d r ug wi t h an u n pl e as an t ta st e c a n b e c o n v e rt e d i nt o a n i n so lu b le fo r m a nd t he n p r e pa r e d as a s us pe ns i on . d . B a si c s o l ub i l it y. W he n s u it a bl e s ol ve n ts ar e n o t a va i la bl e , t h e s us p en s i o n p r o v id es an a l t er n a ti ve . F o r e xa m p l e, o n l y wa t e r c an be us ed a s a so l ve nt f or o ph t ha lm ic p r e pa r a ti o ns b ec a us e o f t h e p os si b il i t y o f c o rn e al d a m a g e. O p ht h al m i c s u s p e ns i on s p ro vi d e a n a lt er n a ti v e t o o ph t ha lm ic s o lu t io ns . 3 . S us p e nd i n g a ge n t s in c lu d e h y d ro p hi li c c ol l oid s , c la y s , a nd a f e w o t h er a g e nt s. S om e a r e a ls o us e d as em u l si f yi n g a g en t s (s e e V I . D .3 ) . a . H yd r o p h i l i c c o ll o i ds ( i . e ., h yd r o c o l l o i d s ) i nc r e a s e th e v is co s i t y o f wa t e r b y b in d in g wa t e r m o le c u l es , t hu s l im i ti ng th e i r m ob il i t y , o r fl ui d it y. V i sc os i t y is p r op o r ti o na l t o t he c o nc en t r at i on of th e h yd ro c o ll o id . Th es e a g e nt s s u pp o r t th e g row t h o f mi c r o o rg a n is ms a n d re qu i r e a p r es e r va tive . Th e y a r e m o s t l y an i o ni c, wi t h t he e xc e p ti on o f m e t h yl c el l ul os e P.50
( n e u tr a l ) a nd c h it os a n ( c a t i on ic ) . Th us th e a ni o nic h yd ro c o l lo id s a r e i n co m p a ti bl e wi t h q u at e rn a r y a nt i ba c t e ri a l a ge n ts a n d o th e r p os i ti ve l y c h a rg ed d ru gs . C hi t os an i s i nc om pa t ib l e wi t h ne ga t i ve l y c ha r g ed d ru gs and e xc i p i e nt s . Mo s t h y d ro c ol l oi ds a re i ns o lu b l e i n al c o h ol i c s o lu t i on s .
( 1 ) Ac a c i a is us ua l l y u s ed as a 3 5% di s p e rs i on in wa t e r ( m u ci l ag e ) . I ts vi s co si t y is g re a te s t b etwe e n p H 5 a nd p H 9 . Ac a c ia is s us c e p ti bl e to m ic r o bi al de c o m p os i ti o n. ( 2 ) T r ag a ca n t h is us ua l ly u s ed as a 6 % d is pe r s io n in wa t e r (m uc il a ge ) . O n e a d va n ta g e o f t r ag ac a nt h o v e r ac ac i a is t ha t l es s is ne e de d . A ls o , t r a g ac an t h d oe s n ot c o n ta i n t h e o xi d a s e th a t i s p re s en t i n a ca c i a . Th is o xi d a s e c a ta l y z e s t he dec om p os it i on of o rg a ni c ch e m i c a ls . Th e vis c os i t y o f t r a g ac an t h is g re a te s t a t p H 5 . ( 3 ) M e t h yl c e l l u l o se is a p ol y m e r t ha t i s n o ni on ic an d s t ab le t o h ea t a n d l i gh t . I t is a v a i la bl e i n s ev e r a l v is c o si t y g ra d es . Be c au s e it is s o lu bl e i n c ol d wa t e r , b u t n ot in ho t wa te r , di s p e rs io n s a re p re pa r e d b y a dd in g m e th y l c e ll ul os e to bo il i ng wa t e r a n d t he n c oo l in g t h e p re p a ra t io n u n ti l t h e m at e ri a l d i ss ol ve s . ( 4 ) C a r bo x ym e t h yl c e l l ul o s e i s a n a ni on ic m a t er ia l th a t is so l ub le in wa t er . P r o l on g ed e xp o s u r e t o he a t c au s es l os s o f vis c os i t y . b . C l a ys ( e . g . , be n to ni t e, V e eg um ) a re s i li c a t es th a t a r e a n io ni c i n a qu e ou s d i sp e rs io ns . Th e y a re s t ro n gl y h y d r a te d a n d e xh i b i t th i xo t r o p y ( t h e p r o pe r t y o f f o rm in g a ge l- l ik e s t r uc tu r e o n s ta n di ng a nd be c o m i n g f lu i d o n a g i ta t io n ). ( 1 ) Th e of f ic ia l f o rm of be n t o ni t e i s t h e 5 % m a gm a . ( 2 ) V ee g um is h y d ra t ed t o a g r ea t e r d eg r ee t ha n b e nt o ni t e. Th u s i t is m or e vi s co u s a t t he s a m e c o nc e nt r a ti o n. c . O t he r a ge n t s i nc lu de a g a r , c h o nd r us (c a r ra g ee n a n) , ge la t in , pe c t i n, an d g e la t in i z e d s ta r c h . Th ei r u s e is li m i t ed b y th e ir s us c e p ti b il i t y to ba ct e ri a l a t t ac k, t he i r i nc om pa t ib ili t i es , a nd t he i r co s t. Xa nt h a n g um i s u se d i n m any m o de r n s us pe ns i on fo r m u l a ti on s b ec a us e o f i ts c o s ol ve n t c om pa t ib il i t y, i ts s t ab i li t y, an d i ts s o lu t io n' s h ig h v is c o s i t y r el a ti v e t o c o nc e nt r a ti on . 4 . P r e pa r a t io n a . S o li d s a r e w et t e d i n it i a l l y t o s e p a ra t e i nd i vidu a l p a r ti c l es an d c oa t the m wi t h a la y e r of di s pe rs i on m e d iu m . W ett in g i s acc om p li sh e d b y l e vi ga t i on ( i . e ., ad d it i on of a s ui t abl e no ns ol v e n t , o r l e vi g a ti n g ag e n t, t o t he s o li d m a te r i al , f o ll o we d b y b l en d in g to fo r m a p a s t e ) , us i ng a g la s s m o r ta r a n d p e st l e o r a n o i nt m e n t s l ab . A s u r f ac t a n t c a n a ls o b e u s e d . b . S u sp e nd i n g a ge n t s ar e t he n a d de d a s d r y powd e r a l on g wi t h t h e ac t i ve i n g re d ie n t. Fo r be s t r es ul t s , t he s u s p en d in g a g ent i s a dd ed in t he fo r m o f i t s a q ue o us d is p e rs i o n. ( 1 ) Th e aq ue o us di s p e rs io n is a d de d t o th e s ol id (o r t he le vi g at e d s o l id ) b y g e o me t r i c d i lu t i o n. ( 2 ) Th e pr e pa r a ti on is b ro u g ht to t he de s i r ed v o lum e b y s ti r r in g i n t h e a p p ro p r ia t e v e h ic le . D . E m u ls i on s 1 . P u r po s es o f e mu l s ion s a . I nc r e as e d d r u g s o lub i l i t y. Ma n y d r u g s h a v e l i m i t ed aq ue o us s o lu bi l ity b u t h a ve m a xi m um s o lu bi l it y i n t h e o il ph as e o f an em u ls io n . D r u g
p a r ti t io n in g f r om t he oi l p h as e t o th e wa t e r p ha s e ca n m ai n ta i n o r e n ha nc e a c ti vi t y. b . I nc r e as e d d r u g s t ab il i t y. Ma n y d r u g s a r e m o re s ta bl e wh e n i n co r po r a te d i n to an em ul s io n r a t he r th an an aq ue o u s s o lu t io n . c . P r ol o n ge d d ru g a c t i on . I nc o rp o ra t io n o f a d rug i nt o a n e m u ls i on c a n p r o lo n g b io a v ai l ab i li t y , as wi t h c e r ta i n in t r am us c u l a r i n je ct i on p re pa r a ti o ns . d . I mp r o ve d ta s t e. D r ugs wi t h an un pl e as an t ta ste a r e m o r e p al a ta b le and t h us m o r e c on v e ni e nt l y a d m i ni s te r ed in em ul si o n f o rm . e . I mp r o ve d a p p ea r a nce . O i l y m a te r ia ls in t en d ed f o r t op ic a l a pp li c at io n a r e m o r e a pp ea l in g i n a n e m u l s i f ie d f o rm . 2 . P ha s es o f e mu l s io n s. Mo s t e m u ls io ns a re c on s id e re d tw o -p h as e s ys t e m s . a . Th e li q u id d r op l e t is k n o wn as th e d i s pe r s ed , i n t e r na l , o r d i s co n t i nu o us p ha s e. Th e ot h e r li q ui d i s k no wn a s th e d i sp e r s io n m e d iu m , e x te r n a l p ha se , o r c o nt i n uo u s p h as e . b . I n p ha r m a c e u ti c a l a p pl i c a t io ns , o n e p ha s e is us u al l y an aq u e ou s s o l u t io n . Th e o th e r p has e i s u s u al l y l ip i d o r oi ly. Th e l i pi ds r an ge f r om ve g e t ab l e o r h y d r oc a rb on o il s t o s em is ol id h yd roc a r bo ns an d wa xe s . E m u ls io ns a re us ua ll y de s c r i be d i n t e rm s o f wa te r a nd oi l. O i l is t he li pi d, o r n o n aq ue o us , p h as e, r ega r d le s s of it s c om po s i t ion . P.51
( 1 ) I f wa t e r is th e i n t e r na l p ha s e, th e e m u ls i on is cl as s i f ie d a s w / o . ( 2 ) I f wa t e r is th e e x t e rna l p ha s e, th e e m u ls i on is cl as s i f ie d a s o /w . c . Th e t yp e o f e m ul s i on f o rm e d is p ri m a r il y d e ter m i ne d b y t he r e la t i ve p h a se vo l u me s a nd t he e m u ls i f yi n g a g e n t us ed. ( 1 ) F or an id e al em ul s i on , t he m a xi m um c o nc en tr a t io n of in t e rn al ph as e is 7 4 % (i .e . , th eo r e ti c a ll y , a n o/ w e m ul si o n c an be p r e pa r e d c o n ta i ni ng ≤ 74% o i l ). ( 2 ) Th e c h oi c e of an em u l s i f y i ng ag e nt is m o re im p o rt a nt th a n t h e r el a ti v e p h as e v ol um es in de t e rm i n in g th e f i na l e m u ls io n ty p e . Mo s t ag e nt s p r e f er e nt i al l y fo r m o ne ty p e o f e m u ls io n o r t he oth e r i f th e p h as e v o l um e p e r m i ts . 3 . E mu l s if yi n g a g e n ts . A n y c om po u nd t ha t l o we r s th e i n te r f ac ia l t e ns io n a n d f o rm s a fi lm at th e in t e r fa c e c a n p o te n ti al l y fu n c t i on as a n e m ul s i f y ing a g e nt . Th e e f fe c t i v e ne s s o f th e e m u ls i f yin g a g en t d e pe n ds o n i ts ch em ic a l s t r uc t ur e , c on c e n t ra t io n , s ol u bi li t y, p H , p h ys ic a l p r o pe r t ie s , an d e l ec t r os ta t ic e f f ec t . T r u e e m ul s i f yi n g a g e n t s ( p rim a r y ag e nt s ) c an fo r m a n d s ta b il i z e e m u ls i on s b y t h em s e l v es . S ta b i li z er s ( a u xi l ia r y a ge n ts ) d o n o t f o r m ac c ep t ab le em ul s i on s wh e n u s e d a lo n e, bu t a ss i s t p r im a r y ag en t s i n s t ab i li zi ng t he p ro du c t ( e. g . , i nc r ea se v i s c os it y) . E m u ls if y i n g a ge n ts a r e e i t he r na t u r al o r s yn t h e t i c . a . N a tu r a l e m ul s i f yi n g a g e n ts :
( 1 ) Ac a c i a f o rm s a g oo d, s ta b le em ul si on o f l o w v i s co s i t y. I t t en ds t o c rea m e a si l y, i s a c i di c , a nd is s t a b le at a p H r an ge o f 2 -1 0 . L ik e o t he r gu m s , i t i s n e g at i vel y c ha r g ed , d e hy d r a t es ea si l y , an d u su all y r e q ui r es a p re s e r va t i ve . I t is in co m p a ti bl e wi t h Pe r u v i an ba ls am , bi sm ut h s al t s , an d c a rb o na t es . ( 2 ) T r ag a ca n t h f o rm s a s t ab l e em u ls io n t h at is co a r s e r th a n ac ac i a e m ul si o n. I t is an i on ic , is di f fi c ul t t o h y d r a te , and is us ed m a in l y f or i ts e f f ec ts on v i s c os it y . L es s t ha n o f t h e a m o un t us ed f o r ac a ci a is n ee de d . ( 3 ) Ag a r is a n a ni on ic gum t ha t i s p r im ar i l y u s e d to i nc r ea s e vis c o si t y. I ts s t ab i li t y is af f ec te d b y he a t in g , d eh y d r a ti on , an d d es t r uc ti o n o f c ha r ge . I t i s a l so s us c ep t ib le to m i c rob i al de g r ad a ti on . ( 4 ) P ec t i n i s a q u as i- em u l s i f ie r th a t is us ed in t he sa m e p ro p o rt i on as t r a g ac an t h. ( 5 ) G e la t i n p r o v id es go od em u ls io n s ta b il i za ti on in a c on c en t ra t io n o f 0. 5% 1 . 0 %. I t m a y b e a ni o ni c o r c a t io n ic , d ep e nd in g on i ts i s oe le c tr ic po i nt . Ty p e A g e la t in ( +) , pr e pa r ed f ro m a n a ci d - t re a te d p r ecu r s or , is u se d i n a c i d ic m e di a . Ty p e B g el at i n ( - ), p r ep a re d fr o m a n a lk al i- t r e a te d p r ec u rs o r, is us e d i n ba si c m e d ia . ( 6 ) M e t h yl c e l l u l o se is n o ni o ni c a nd in d uc es vis c os i t y . I t is u s e d a s a p r i m a r y em ul s i f ie r wi t h m i ne r al oi l a n d c o d l i ve r o i l , a nd y i el ds an o/ w e m ul si o n. I t is us ua l l y u s e d in 2% c o nc en t r at i on . ( 7 ) C a r bo x ym e t h yl c e l l ul o s e i s a ni on ic an d i s u s u a ll y u s e d t o i nc r e as e vi s co si t y . I t t ol e r at es al c o h ol up t o 4 0% , fo rm s a b a si c s o l ut i on , a n d p r e ci pi t a te s i n t he p re s en c e o f f r ee ac i ds . b . S yn t h e t i c e m u ls i f yi n g a ge n t s a r e a ni o ni c , c at i o ni c , o r n on i on ic . A l t h ou gh t he s e s u r fa c ta nt s ar e a m ph ip h il ic m o le cu l e s , th ei r li po p hi li c a n d h yd r o ph i li c r e gi on s a r e s e l do m i n ve rs e e qu a ls of e a c h ot h e r: S om e s u r fa c ta n t m o l ec ul es te nd t o b e p r ed om i na n tl y l ipo p hi l ic , wh e re as o th e rs a r e pr e do m i n an t l y h y d r op h il ic . Th is im ba l an c e is r e f le c te d i n t h e h yd r o ph i li c -l ip o ph il ic ba la n c e ( H L B ) s c al e : Th e lar g e r th e HL B v a lu e , t he m o r e h y d r op hi l ic t h e m ole c ul e . Ta b l e 3 - 1 li s ts H LB va l u es fo r s u r fa c t a nt s a n d t h ei r c o r re s p o nd i ng u s es .
Table 3-1. Hydrophilic-Lipophilic Balance (HLB)
HLB Value RangeSurfactant Application 0-3
Antifoaming agents
4-6
Water-in-oil emulsifying agents
7-9
Wetting agents
8-18
Oil-in-water emulsifying agents
13-15
Detergents
10-18
Solubilizing agents
P.52
( 1 ) An i o n i c s y n th e ti c a ge n ts in cl u de su l f u r ic ac id e s te r s (e . g. , s o di um l a u r yl s ul f at e ) , s ul f o n ic a c i d d e r i va t i ve s ( e .g . , di o c t y l s o di um s u lf os uc c i n a te ) , a nd s oap s . So a ps ar e fo r e xt e r n a l us e. Th e y h a v e a h i gh p H a nd a re , th e re f o re , s e n s i t i v e t o t h e a dd i ti on of a c i ds an d e le c t ro l yt es . ( a ) Al k a l i s o ap s a r e h y dr o p hi l ic a n d f o rm a n o / w e m ul s i o n. ( b ) M e t a ll i c s oa p s a r e wa t e r i ns o lu bl e a n d f o rm a w/ o em u ls io n . ( c ) M o n o va le n t s o a ps fo r m a n o / w e m ul s i on . ( d ) P o l yva l e n t s oa p s f or m a w/ o e m u ls i on . ( 2 ) C a t io n ic s y nt h et ic ag e n ts (e . g. , be n z a lk on ium c h lo r i de ) a r e u se d a s s u r fa ce - ac t i v e a ge n ts in 1 % c o nc en t r at i on . Th e y a r e i n c o m p a ti bl e wi t h s o ap s. ( 3 ) N o ni o n ic s y nt h et ic ag e n ts a r e re si st a nt t o t he a dd i ti on o f ac i ds a n d e l ec t r ol y t es . ( a ) Th e so r b i ta n es t e rs k n o wn as S pa n s a r e h y dr o p ho b ic i n n a tu r e a n d f o r m w/ o e m u ls i on s . Th ey h a v e lo w h y d r o p hi l ic -l ip o p hi li c b al a nc e v a l ue s (1 9 ) ( Ta b le 3 -2 ) . ( b ) Th e po l ys o r b a t e s k no wn a s Tw ee n s a re h y d ro p hi l ic a n d t en d to fo r m o / w e m ul s i o ns . Th e y m ay f o r m c om pl e xe s wi t h ph e n ol i c c om p ou nd s . Th ey h a ve hi g h h y d r op hi l ic -l i po p hi l ic b a la nc e v al u es (11 - 2 0 ). 4 . P r e pa r a t io n . Va r io us m e th o ds a r e u se d to p rep a r e e m u ls io ns , de p en din g o n th e t y pe of em ul s i f y i ng a ge n t. a . C la ss ic al , ac ac ia - s t a bi l i z ed em ul s i o ns a r e p r ep a r e d b y on e o f th e f o l lo wi n g fo u r m et h od s :
( 1 ) W et g um ( E ng l is h ) m e t h od . A p r im a r y e m u ls i on of fi xe d o i l, wa t e r , an d a c ac ia ( in a 4 :2 : 1 r a ti o ) is p re p ar e d a s f ol lo ws : ( a ) Two p a r t s o f wa t e r a re a dd e d a ll a t on c e to one p a rt of ac ac i a. Th e m i xt u r e is tr i tu r a te d u n ti l a s m oo t h m u c i l ag e i s f or m e d. ( b ) O i l is ad d ed in s m al l i n c re m e n ts (1 - 5 m L) , wi th c o n ti n uo us t ri t u ra t io n , u n t il th e p r im a r y em ul s i on is f or m e d . ( c ) Th e m i xt u r e ( an o/ w e m ul s i o n) is t ri t ur a te d for a n ot h er 5 m in . ( d ) Th e o/ w m i xt u r e c a n t h e n b e b r ou gh t to vo lu m e wi t h wa t e r an d m i xe d to a c hi e v e h om o ge n ei t y . ( 2 ) D r y g u m ( c o nt i n en ta l ) me t h od . A p r im a r y em u ls io n o f th e f i xe d o il , wa t e r , a nd ac ac ia ( in a 4: 2 : 1 r a ti o ) i s p r ep a re d a s f o ll o ws :
Table 3-2. Commonly Used Surfactants and Their Hydrophilic-Lipophilic Balance (HLB) Values Agent
HLB Value
Sorbitan trioleate (Span 85, Arlacel 85)
1.8
Sorbitan tristearate (Span 65)
2.1
Propylene glycol monostearate (pure)
3.4
Sorbitan sesquioleate (Arlacel C)
3.7
Sorbitan monooleate (Span 80y)
4.3
Sorbitan monostearate (Arlacel 60)
4.7
Sorbitan monopalmitate (Span 40, Arlacel 40)
6.7
Sorbitan monolaurate (Span 20, Arlacel 20)
8.6
Glyceryl monostearate (Aldo 28, Tegin)
5.5
Gelatin
9.8
Triethanolamine oleate (Trolamine)
12.0
Polyoxyethylene alkyl phenol (Igepal CA-630)
12.8
Tragacanth
13.2
Polyoxyethylene sorbitan monolaurate (Tween 21)
13.3
Polyoxyethylene castor oil (Atlas G-1794)
13.3
Polyoxyethylene sorbitan monooleate (Tween 80)
15.0
Polyoxyethylene sorbitan monopalmitate (Tween 40)
15.6
Polyoxyethylene sorbitan monolaurate (Tween 20)
16.7
Polyoxyethylene lauryl ether (Brij 35)
16.9
Sodium oleate
18
Sodium lauryl sulfate
40
P.53
( a ) O i l is ad d ed to t he ac a c ia , a n d t he m i xt u r e is tr i t u ra t ed un t il th e po wd er i s d is t r ib u te d u n if o rm l y th r o ug h ou t th e o il . W at e r i s a d de d a ll a t o nc e, f o l lo we d b y r ap id t ri t u ra ti o n t o f o rm t he pr im a r y em u ls io n . ( b ) A n y r em ai ni n g wa t e r a n d o t he r in g re d ie n ts a re a dd e d t o f in is h th e p r o du c t. ( i ) E l ec t r o l yt e s i n h i g h c o n ce n t r a ti o n t e nd to cra c k an em ul s i o n . Th e y s h ou l d b e a dd ed la s t a nd i n as di l ut e a f or m a s po s s i bl e . ( i i ) Al c o h ol i c s o lu t i o ns t e n d t o d eh yd r a te an d p re c ip i ta t e h y d r oc ol lo i ds . Th e y s h ou l d b e a dd e d i n a s d il u te a c on c e n t ra t ion a s po ss i bl e. ( 3 ) B o t t le me t h od ( a v a ri a t io n o f t h e d r y gu m m eth o d u s e d f o r v ol a ti l e o il s ) . O i l is ad de d to th e a c a c ia i n a b o t tl e. Th e r at io o f o i l, wa t e r , a nd ac ac i a s h ou l d b e 3 :2 : 1 o r 2 : 1 : 1. Th e lo w v i s c os i t y o f th e vo l a ti l e o il re q ui r es a h i gh e r p r o po r ti o n o f a c ac i a. ( 4 ) N a sc e nt s oa p m e t hod . A s o ap is fo rm e d b y m i xi n g r el at i ve l y eq ua l vo l u m e s o f a n o il an d a n a q ue o us s ol u ti o n t ha t c o n t ai ns a su f f ic ie n t am ou n t o f al ka l i. Th e s o ap ac ts a s a n e m u ls i f yin g a g en t .
( a ) Th i s m e t ho d i s u s e d to f o rm a n o / w o r a w/ o em u ls io n , d ep e nd in g o n th e s o ap fo r m e d . F o r e xa m p le , ol i v e o i l, wh i c h co n ta in s o l ei c ac i d, is m i xe d wi t h l i m e wa t e r d u ri n g t he p rep a r a ti on o f ca l am in e l o tio n to ca lc iu m o le a te , an e m ul si f y i ng ag e nt . ( b ) A 50 : 50 r at i o o f o il to wa t e r e ns u re s s uf f ic ie n t e m u ls i on , p r o v i de d t h at t h e o i l c o n ta i ns a n a d equ a t e am o un t o f f re e f a t t y a c i d . Ol i v e o i l us u al l y d o es . C ot t on s e e d o il , p ea n u t o il , a n d s o m e o th e r v e g e t ab l e o il s d o n ot . ( c ) Th e ad di t io n o f an ac i d de s t r o ys t h e em u ls if y in g s o ap an d c au se s t h e e m ul si o n t o s e p a ra t e. b . E m u ls io ns s t a bi li z e d b y s y n t he t ic e m u ls i f y in g a g e n t s a r e r e ad il y p r e pa r e d b y a t wo - p h as e p r oc e du r e : ( 1 ) O i l- m i s c i bl e i ng r ed i en t s a nd wa t e r - m i sc ib le ing r e d i e nt s a r e s ep a ra t el y a d m i xe d , us i ng he a t i f ne c es s a r y t o e ns u re li qu ef a c ti on an d e as e of m i xi n g o f ea ch ph a s e . ( a ) H ig h m el t in g p o in t o i l- m is c i b le i n g re di e nt s (e .g . , wa xe s ) a r e m el t ed b e f o re lo we r m el ti n g p oin t in g r ed ie n ts (e . g ., oi ls ) a r e a d de d . ( 2 ) Th e t wo ph as e s a re h e a te d t o 7 0 ° - 80 ° a n d t he n c om b in e d wi t h st i r ri ng u n t il th e re s u l ta n t em u ls io n ha s c oo le d . ( a ) I n g en e ra l , h ea t - la bi le o r v ol a ti le in g r ed ie n ts s h ou l d n ot be in c o r po r a te d i n th e s ep a r at e p h as es bu t in th e re s u l ta n t e m u ls io n af t e r i t h as c o ol e d t o a b o ut 40 ° C . o r le s s . ( 3 ) F ur t he r m e c h an ic a l pr o c es s i ng of t he em ul s i on b y a h an d h o m o ge n i zer , i m m e rs i on bl en d e r, o r o th e r eq ui pm e nt m a y b e w a r r a n t e d t o i m p r o v e t h e h o m o g en ei t y a nd s t ab i li ty o f t he p ro d uc t. 5 . I nc o r p o ra t i on o f m e di c i n al ag e n ts . Me d ic i na l a g en ts ca n b e i n co r po r a te d i n to an em ul s io n e i th e r d u ri ng o r a f te r i ts fo rm a ti o n. a . Ad d i t i o n o f a d r ug du r i n g e m u ls i on f o r ma t io n . It is be s t t o i nc or p o ra t e a d r ug in t o a v eh ic l e d ur in g em ul s i o n f o rm at i on , wh e n i t c a n b e i n co r po r a te d i n m ol ec u lar f o rm . So l ub le d ru gs s ho u l d be di s s o l v ed in th e a p p ro p r ia t e p ha s e ( e. g ., d r u gs th a t a r e s o l ub l e in t h e e xt e r n a l p ha s e o f t he e m ul si o n s h o ul d b e a dd ed as a s ol u ti on t o t he p rim a r y em ul si o n) . b . Ad d i t i o n o f a d r u g t o a p r e fo r m ed em u ls i o n c a n p r es en t s om e d i f fi cu l t y , d e pe nd i ng on th e t y pe o f em u ls io n a n d t h e n a tu r e o f th e e m ul si f ie r ( Ta bl e 3 - 3 ) . ( 1 ) Ad d i t i o n o f o l ea g i no u s m a t e ri a l s t o a w / o e m u ls i o n p re s en ts no p r o bl em be c a u s e of th e m is c i b il i t y o f th e a d di ti v e wi t h t h e e xt e r n a l p ha se . H o we ve r , a d d i ti o n o f ole a g in o u s m at e r i al s to an o /w em u ls i o n c a n b e d i f fi cu l t a f te r em ul s i on f or m a ti o n. ( a ) O cc as i on al l y , a s m al l a m o u nt o f o il y m a t e ri al is ad d ed if e xc e ss e m ul si f ie r wa s u s e d i n the o ri g in a l f o rm at i on . ( b ) A s m a l l am o un t o f an o i l- s o l ub l e d ru g c a n b e a d d ed i f it is d is s ol v e d in a ve r y s m al l q ua n ti t y o f o il wi t h g eo m e t r ic di lu t io n te c hn i qu es . ( 2 ) Ad d i t i o n o f w a te r o r a n aq u eo u s m a te r i al t o a w / o e m ul s io n is e xt r e m e l y di f fi c u l t , u nl es s en o ug h e m u ls i fi e r h as b e e n in c or p o ra t ed in t o th e e m ul si o n. H o we v e r , ad d it i o n o f a qu e ou s m a t e ria l s to a n o /w e m u ls i on
u s ua ll y p r es en t s n o p r obl e m s i f th e a d de d m at e ria l do es no t i n te r ac t wi t h t h e e m u ls i f y in g a g en t . Po t e nt i al in t er a ct io n s s h ou l d b e e xp e c t ed wi t h c a ti o ni c c o m p o un ds an d s a lt s o f we ak ba s es . ( 3 ) Ad d i t i o n o f s m al l qua n t i t ie s o f al c o ho l ic s ol u t i o ns t o a n o /w e m u ls i o n is po s s ib l e i f th e s o lu t e is c o m p a ti bl e or d is p er s i b le in th e a q u eo us ph as e o f th e em u ls io n . I f P.54
a c ac ia o r a no t he r gu m is u s e d a s t h e em u ls if yi n g a g e nt , th e a lc oh o li c s o lu t io n s ho u ld be di lu t ed wi t h wa t e r be f or e i t is a d d ed . Ta bl e 3 - 3 l is ts s om e c om m e r c i al em ul s io n ba s e s a nd t he i r g en e ra l c o m p os it i on .
Table 3-3. Selected Commercial Emulsion Bases: Emulsion Type and Emulsifier Used Commercial Base
Emulsion TypeEmulsifier Type
Allercreme skin lotion
o/w
Triethanolamine stearate
Almay emulsion base
o/w
Fatty acid glycol esters
Cetaphil
o/w
Sodium lauryl sulfate
Dermovan
o/w
Fatty acid amides
Eucerin
w/o
Wool wax alcohol
HEB base
o/w
Sodium lauryl sulfate
Keri lotion
o/w
Nonionic emulsifiers
Lubriderm
o/w
Triethanolamine stearate
Neobase
o/w
Polyhydric alcohol esters
Neutrogena lotion
o/w
Triethanolamine lactate
Nivea cream
w/o
Wool wax alcohols
pHorsix
o/w
Polyoxyethylene emulsifiers
Polysorb hydrate
w/o
Sodium sesquioleate
Velvachol
o/w
Sodium lauryl sulfate
o/w, oil in water; w/o, water in oil.
( 4 ) Ad d i t i o n o f c r ys t a l l i n e d r ug s to a w /o em u ls i o n o c c u rs m o re ea si l y i f t h e d r u gs a r e d is s o l v e d o r di s pe rs e d i n a s m a ll qu a n ti t y o f o il b e f or e th e y a r e ad de d . E . O i n t me n t s 1 . I n t ro d uc t i o n. O i n tm en t s a re se m is o li d p re p ar a t i o ns i n te n de d fo r e x t e r na l us e . Th e y a r e e a s i l y s p r ea d . Mo d i f yi n g t h e fo rm u la t io n c on t r ol s t h e ir pl a s t ic v is c o s i t y . O in t m e n ts a re t ypi c a ll y u s ed as : a . E mo l l ie n t s t o m ak e th e s k i n m o re pl i ab le b . P r o t ec t i ve ba r r i e r s to p r e v en t h a rm f ul s u bs t an c es f ro m co m i n g i n c o nt ac t wi t h th e s k i n c . V eh i cl e s i n wh i c h t o in c o rp o ra t e m ed ic a ti on 2 . O i n tm e n t b as e s a . O l ea g i no u s b as e s a re a nh y d r ou s a n d i ns ol ubl e in wa t e r . Th e y c an n ot a b so r b o r c o nt a in wa t e r a n d a r e n o t wa s h ab l e i n wa t e r . ( 1 ) P e t ro l a t um i s a go o d b as e fo r o i l -i ns ol u bl e i ng r e di e nt s . I t f o rm s a n o cc l us i ve f il m o n t h e s k in , ab s o r bs < 5 % wa t e r un d e r n o rm al c o nd i ti o ns , a n d d o es n o t b ec om e r an c id . W a x c a n b e i nc o r po r a t ed to s t i ff e n t he ba s e . ( 2 ) S yn t h e t i c e s t e rs a re u s e d a s c on s t i tu e nt s o f o l ea g in o us b as es . Th es e e s te r s i nc lu d e g l yc e r y l m o n os t ea r a te , i so p r op y l m yr i s t at e , i s o p ro p yl p a lm i ta t e, bu t y l s t ea r a te , a n d b ut y l pa lm i ta t e . L ong - c ha in al c o h ol s ( e .g . , c e t yl a lc oh o l, s t e a r y l al c o h ol , P E G ) c an al s o b e u s ed . ( 3 ) L an o l in de r i va t i ve s a r e of t en us ed in t op ic al a n d c os m e ti c p r e pa r a ti o ns . E xa m p l es a r e l a no l in oi l a nd h yd rog e n at e d l an ol i n. b . Ab s o r p t i on b as es a re a nh y d r ou s a n d wa t e r in s ol u bl e. Th e r e fo r e, t hey a r e no t wa s h a bl e i n wa t er , a lt h ou g h t he y c an ab so r b wa t e r . Th e s e ba s es p e r m i t wa t e r -s ol ub l e m ed i c a m e n ts to be in cl ud e d t h r ou g h p ri o r s ol u ti o n an d u p t ak e a s t he in t e rn al pha s e. ( 1 ) W oo l fa t ( an h y d ro us l a no l in ) c o nt a in s a h i gh p e r c e n ta ge o f ch o le s t e r ol a s we l l as es t e rs a n d a lc o h ol t ha t c on t ai n fa t t y ac i d s. I t a bs o rb s t wi c e i ts we i g h t in wa t e r a n d m e l ts be t we e n 36 ° C an d 4 2 °C .
( 2 ) H yd r o p h i l i c p e t r ol a tu m is a wh i t e p e t ro la t um c om bi n ed wi t h 8% b e es wa x, 3 % s t ea r y l al c o h ol , an d 3 % c ho l es te r ol. Th e s e c o m p o ne n ts a r e a d d ed to a w/ o e m u ls i fi er . P r e pa r ed fo r m s i n c l ude A q ua ph o r , wh ic h u s e s wo o l a lc o ho l t o re nd e r wh i t e p et r ol a t um e m u ls i fi ab l e . A q ua ph o r i s s up e ri or i n it s a bi li t y t o a bs o rb wa t e r . c . Em u l si o n b a se s m a y b e w/ o em ul si o ns , wh ic h a r e wa t e r i ns ol u bl e a n d a r e no t wa s h a bl e i n wa t er . Th e se em ul si o ns c a n a b s o r b wa t e r b ec au se of t h e ir a qu eo us in t e rn a l ph a s e . Em ul s i o n b as es m a y a l s o b e o / w e m ul si o ns , wh i c h a re wa t e r i ns o lu ble b ut wa s h ab le in wa t e r . Th e y c a n a bs o rb wa t e r in t h e ir a qu eo us e xt e r n al ph a s e . P.55
( 1 ) H yd r o u s w oo l fa t (l an o li n ) i s a w/ o em ul s i o n t h a t c on t ai ns a p p ro xi m a t el y 2 5% wa t er . I t a c t s a s a n e m o ll i en t a n d oc cl u si ve fi lm on the s ki n , e f fe c ti v e l y pr e v e nt in g ep id e rm a l wa t e r lo s s . ( 2 ) C o ld c r ea m i s a w/ o e m ul s i o n t ha t i s p r ep a red b y m e l ti ng wh i t e wa x, s p e rm ac et i , a nd e xp r e s s e d al m o n d oi l to ge t he r ; a d di n g a ho t a q ue ou s s o lu t io n o f s od i um b o r ate ; an d s t ir r i ng un t il th e m i xt u r e is c o ol . ( a ) Th e us e o f m i n e ra l o il r a th e r t h an al m o nd oi l m ak e s a m o re s t ab l e co ld c r e am . H o we v e r , c o l d c re a m p r ep a re d wi t h a lm on d oi l m ak es a be t t e r e m ol li e nt ba s e . ( b ) Th i s o in tm e nt s h ou l d b e fr es h l y p r e pa r ed . ( 3 ) H yd r o p h i l i c o i n tm e nt i s a n o / w e m u ls i on th a t u s e s s od i um l a ur y l s u lf a te as an em ul s i f y i ng a g en t . I t a b s o r bs 3 0 % -50 % w/ w wi t h o u t l os in g i ts c o ns is te n c y . I t i s r e ad il y m is c i bl e wi t h wa t e r a nd i s re m o v e d fr om t he s k i n e a si l y. ( 4 ) V an i s hi n g c r e am is a n o/ w e m ul s i o n t h at c o nt a i ns a la r g e p er c e n t ag e o f wa t e r a s we ll as hu m e c ta n t (e . g. , gl y c e ri n , p ro p yl e ne gl y c ol ) t ha t re t ar d s m o is tu r e l os s . A n e xc e s s o f s t ea r ic ac id in th e fo rm u la he lp s f o rm a t hi n f i lm wh e n th e wa t e r e v a po r a t es . ( 5 ) O t h e r e m ul s io n ba se s in c l ud e D er m o van , a h y p o a ll e rg e ni c , g re as el es s e m ul si o n b as e, an d Un i ba s e, a n on g r ea s y e m ul sio n ba s e th a t a bs o rb s a p p ro xi m a t el y 3 0% o f i ts we i g h t i n wa t e r a nd ha s a p H c lo s e to t ha t o f th e s ki n . d . W at e r - so l u bl e ba se s m a y be an h yd r ou s o r m ay c o n ta in s o m e wa t e r . Th e y a r e wa s ha b le in wa t e r an d a bs o r b wa t e r to th e po in t of s o lu b il i t y . ( 1 ) P E G o in t me n t i s a ble n d o f wa t e r -s ol u bl e p oly e t h yl e ne gl yc ol s t h at for m a se m i s o l id ba s e . Th is ba s e c a n s o lu bi l i z e wa t e r -s o lu bl e d r u gs a n d s om e wa t e r - i n s o lu b le dr u gs . I t i s c om pa t ib l e wi t h a wi de r a ng e o f d r ug s . ( a ) Th i s b as e c o n ta i ns 40 % P E G 33 50 an d 6 0 % P E G 4 0 0 . I t i s p re p a re d b y t h e fu si on m e t ho d (s ee V I . E . 3 .b ) . ( b ) O n l y a s m al l a m o u nt o f li q ui d ( < 5% ) c an be in c o rp o ra t ed wi t h ou t lo ss o f vi s co si t y . Th i s b as e c a n b e m a de s t i ff e r b y i nc r eas i ng th e a m o u nt o f P E G 3 3 5 0 t o 6 0% .
( c ) I f 6 % t o 2 5% o f a n aq u e ou s s o l ut i on is t o b e i n c o r po r a te d , 5 g o f t he 4 0 g o f P E G 3 35 0 c an be r ep l ac e d wi t h an eq u al am o u n t o f s te a r y l a lc o ho l . ( 2 ) P r o p yl e n e g l yc o l a nd p r o p yl e n e g l yc o l - e t h an o l fo r m a c le a r g e l wh e n m i xe d wi t h 2% h y d ro xy p r o p y l c e ll ul os e . Th is b as e i s a po pu l a r d er m a t ol o gic ve h i cl e . 3 . I nc o r p o ra t i on o f m e di c i n al ag e n ts . Me d ic i na l s ub s ta nc es m a y b e i n co r po r a te d i n to an oi n tm e nt ba se b y le vi g a t i on o r b y th e fu s io n m e t hod . I n so l ub le s u bs t an c e s s ho u ld be r ed uc e d t o t h e f in e s t po ss i bl e f o rm an d l e vi ga t ed b ef o re in c o r p ora t i on wi t h a s m al l a m o unt o f c om pa t ib l e l e vig a ti ng a g e nt o r wi t h t he ba s e its e lf . a . L e vi ga t i on . Th e s ub s ta n c e is i nc o r po r a te d i n to t h e o in t m e n t b y l e vi ga t io n o n a n oi nt m e nt s la b . ( 1 ) A s t ai nl e s s -s t ee l s pat u l a wi t h a l on g , b r oa d , fl e xi b l e b l ad e s ho u ld be u s ed . If th e s u bs ta nc e m a y i n te r ac t wi t h a m e ta l s p at u la ( e. g ., wh e n i n co r po r a ti n g i od in e a n d m e rc u ri c s al ts ) , th en a ha r d ru b be r s p at u la c a n be u s ed . ( 2 ) I ns ol ub l e s u b s t a nc es s ho u ld be po wd e r e d f i ne l y i n a m o rt a r a n d m i xe d wi t h a n e q ua l q u an t it y o f b as e u n ti l a sm oo t h, g ri t- f r e e m i xt u r e i s o bt a in e d. Th e r e st o f t he ba s e is ad d e d in in c re m e n ts . ( 3 ) Le vi g at i on of po wd e r s in t o a s m a l l p or t io n o f b a se is fa ci li t a te d b y t he u s e o f a m e lt e d b as e o r a s m al l q u an t it y o f c om pa t i bl e l e v ig a ti o n a id ( e. g ., m i ne r al oi l , g l yc e r in ) . ( 4 ) W ate r -s ol u bl e s al ts ar e in c or p o ra t ed b y d is s o lv i n g th em in t he s m a l le s t p o ss ib l e am o un t o f wa t er a n d i nc or p o ra t in g t h e aq u e ou s s o l ut i on di r ec tl y i n t o a c om pa t ib l e b as e. ( a ) U su a ll y , o rg an ic s o l ve n ts ( e. g . , e th e r , c h l o ro fo r m , a lc oh o l) a re no t use d t o di ss ol v e t he d ru g b ec a u s e th e d r u g m a y c r y s ta l li z e as th e s ol ve n t e va p o ra t es . ( b ) S ol v e n ts a re us ed as l e v i ga t in g a id s o nl y i f t he s o l id wi l l b ec om e a fi ne p o wd e r a ft e r t h e s ol v e n t e v a p o ra t es . b . F us i o n m et h o d. Th i s m e th o d is us e d wh e n th e b as e c o nt ai n s s o li d s t hat h a ve hi g he r m el t in g p o int s (e . g ., wa xe s , c e t y l a lc o h ol , gl y c e r y l m o no st e a ra t e ). Th is m e th o d i s a ls o us e fu l fo r s o li d m e di c a m e n ts , wh ic h ar e r e a di l y s o lu b le in th e m el t e d b as e. ( 1 ) Th e oi l p ha s e s h ou l d b e m e lt e d s e p a ra t el y , s ta r t in g wi t h m at e r ia ls th a t h a ve th e h i gh es t m el t in g p o in t . A l l o th e r o il - s o l ub l e in g re d ie n ts a r e a d de d i n d e c re as in g o r d e r o f m e l tin g po in t . ( 2 ) Th e in g re d ie n ts i n t he wa t e r ph as e a r e c om bin e d a n d h ea t ed s e pa r a tel y t o a t em p er a tu r e th a t is e q u al to o r s e v e r al d eg re e s a bo v e t ha t o f th e m e lt e d o il ph as e . P.56
( 3 ) Th e t wo ph as e s a re c o m bi n ed . I f a w/ o s y s te m i s d es i re d , t he n th e h o t a q u eo us ph as e i s i nc o rpo r a t ed in t o t he ho t o i l p ha s e wi t h a gi ta t io n . I f a n
o / w s ys t em is p r e fe r r ed , t h e n t he ho t oi l p ha s e is i n c o r po r a te d i n to th e h o t a q u eo us ph as e . ( 4 ) V ol a ti l e m a t e ri al s ( e .g . , m e nt h ol , c am ph o r , i od i ne , al c o h ol , p e r fu m e s ) a r e ad de d a f t er t he m e lte d m i xt u r e c o ol s t o 4 0 ° C o r le ss . F . S u pp o s it o r i es 1 . I n t ro d uc t i o n. A s up po s it o r y is a s ol i d o r se mi s o l id ma s s i n te n de d t o b e i ns e r t ed in t o a b od y o r i f i ce (i . e ., r ec tu m , v ag i na , u re t hr a ) . A f t er i t is i n se r t ed , a s u pp os i to r y ei t h er m e l ts a t bo d y te m pe r a t ur e o r di ss ol v e s ( o r d i sp e rs es ) i n t o t he aq u eo u s s e c re t io ns o f t he bod y c a vi t y. a . S up p os it o ri e s a re o ft en us e d f o r l oc al ef f ec ts (e . g . , r el i ef o f h em or r h oi ds o r in f ec t io n ) . b . W hen u s e d re c t a ll y , s u p p os it o ri es c a n p r o vid e s ys te m i c m ed ic a ti on . The a b so r p ti on o f a d r u g f r om a s up po s i t o r y th r ou g h t h e re c t a l m u c os a i nt o t he c i rc u la ti o n i n v ol v e s t wo s t ep s : ( 1 ) Th e dr u g is r el e as ed f r o m a v e hi c l e a nd pa r t it io n s / d if f us es th r o ug h t h e m uc o sa . ( 2 ) Th e dr u g is t r an s p o rte d th r o ug h t h e v e i ns o r lym p h v es s e ls in t o s ys t em ic fl ui ds o r t is s u es . Th e f i rs t - pa s s e f f ec t is a voi d ed be ca us e th e r e c ta l vei ns “ b y pa s s ” th e l i v e r . c . R ec ta l s up p os it o r ie s ar e us e fu l wh e n o r al ad m in i s t r a ti o n is in a pp r op r ia te , a s wi t h i n fa n ts , d eb i li t ate d o r c o m a t os e p a ti en t s, a n d p at i en ts wh o h a ve n a us e a, v o m i ti n g, o r g as t r o in t es t in al di s tu r ba nc es . S om e d ru g s ca n c au s e d i st u r ba nc es of t he ga s t ro i n te s t i na l t r ac t . 2 . T yp e s o f s u pp o s it o r ie s a . R ec t a l s u pp o si t o r i es a r e u s u a ll y c yli n dr ic a l an d ta p e re d t o a po i nt , f o r m i n g a b u ll et - l ik e s h ap e . As th e re c t um c o n tr ac t s , a s up po s i t o r y of th is s h ap e m o v es in wa r d r at he r t ha n o u t wa r d . S u pp osi t o ri es f o r a du l ts we i gh a p p ro xi m a t el y 2 g. S up po s it o ri e s f o r i nf a nt s a nd c h il d re n a r e sm a ll e r . b . V a gi n al s up p os i t o r ies a r e o v a l a nd t ypi c a l l y we i g h a pp r o xi m a te l y 5 g . D r u g s a dm in is t e re d b y th i s r o ut e a r e i n te nd e d t o h a v e a lo c a l e f f ec t , b ut s ys t em ic a bs o r pt i on c a n o c c u r . A n ti s e p ti cs , c on t ra c ep t i v e a ge n ts , a n d d rug s u s ed to t re a t t r ic h om on al, m on il i al , o r ba ct e ri a l i nf e c ti on s a r e o f te n f o r m u l at e d as v a gi n al s up p os i to r ie s . c . U r e th r a l s u pp o s it o r ie s a re t y pi c a l l y l o ng an d t a pe r e d. Th e y a re a p p ro xi m a t el y 6 0 m m lo ng a nd 4 -5 m m i n d ia m e t er . Th e y a r e a dm in is t e re d f o r a l oc al ef f ec t a n d a r e m os t o f te n us ed fo r an t i- i n fe c ti v e ag e nt s . A l p r os ta d il , o r p ro s t a gl an d in E 1 (P G E 1 ) , wh e n u s e d to t re a t e r ec t il e d ys f un c ti o n, is a v a i la bl e f o r u re t hr a l i ns e rt i on in th e fo r m o f a m ic r o pe ll e t, o r m i c ro s u p po s i t or y , t ha t i s o nl y 3 - 6 m m lo ng an d 1 . 4 m m in di am e te r . 3 . S u pp o si t o r y b a s e s a . C r i t e ri a fo r s a ti s fa c to r y s u p p o s i t o r y b a s e s . S u p po s i t o r y b as es s h oul d ( 1 ) R em a in fi r m a t r o om t e m p e r at u re t o a ll o w i nse r t io n . Th e s u p po si t o r y s h ou l d n ot s o f te n < 30 ° C t o a v oi d m el ti n g d u ri n g s t o ra g e. ( 2 ) H a ve a na r r o w, o r s ha r p , m el t in g ra ng e
( 3 ) Yi e l d a c le a r m el t j us t b el o w b o d y te m p e ra t u re o r d is so l ve ra pi d l y i n th e c a vi t y fl u id ( 4 ) B e i ne r t a n d c o m p a tib l e wi t h a v a ri e t y of d ru gs ( 5 ) B e n on i r ri t at i ng an d n o ns e ns it i z i ng ( 6 ) H a ve we t t in g a nd em u l s i f y i ng p ro pe r t ie s ( 7 ) H a ve a n a c i d v al u e of < 0. 2 , a s a po ni f ic a ti on v a l u e o f 2 0 0 -2 45 , an d a n i o di n e v a l ue of < 7 if t he b as e i s f a tt y b . S e le c ti n g a su p p os i to r y b a s e . L ip id - wa t e r s ol u bi l it y m us t b e c on si de re d b e ca us e o f i t s r e la ti o n t o t h e d r ug - r el e as e r a te . ( 1 ) I f a n o il - s o lu b le d ru g i s i nc o r po r at e d i nt o a n o il y b as e , t h en th e ra t e o f a b so r p ti on is s om e wh a t le s s t ha n t h at ac hi e ve d w i t h a wa t e r -s o lu bl e b a se . Th e l i pi d -s ol u bl e d r ug ten d s t o r e m a in di s s ol ve d in t he oi l y po o l f r om th e s u pp os i to r y . I t is le s s li k e l y t o e sc ap e i n to th e m u c ou s s ec re t io n s f r om wh i c h it is ul t im at el y a bs o r b ed . ( 2 ) C o n v er s el y , a wa t e r -s o lu bl e d r u g t en ds t o p as s m o re ra p id l y f ro m t he o i l p h as e t o th e a q ue ou s p ha s e. Th e r ef o r e, if r ap i d on s et o f ac t io n i s d es i re d , t h e wa t e r -s ol u bl e d r ug s h o ul d b e i n co r po r a te d i nt o t he oi l y ba se . c . B as e s t h at me l t i nc l ud e co c oa b ut t e r , o t he r co m b i na t i on s o f f a ts and w a xe s , W i te p so l ba s es , a n d W ec o be e ba se s ( Ta b le 3 -4 ) . ( 1 ) C o co a b u t t e r ( t he o br o m a o il ) i s t h e m o s t wi d e l y us e d s up po si t o r y b a se . I t is fi r m a nd s o li d u p t o a t em pe r a tu r e o f 3 2 ° C , at wh i c h p oi n t i t b e gi ns to s o f te n . A t 3 4 - 35 ° C , i t m el t s t o p r od uc e a t hi n , b lan d , o i l y l i qu id . P.57
Table 3-4. Composition, Melting Range, and Congealing Range of Selected Bases That Melt Base
Composition
Melting Congealing Range (°C) Range (°C)
Cocoa butter
Mixed triglycerides of oleic, palmitic, and stearic acids
34-35
28 or less
Cotmar
Partially hydrogenated cottonseed oil
34-75
—
33-36
32-33
37-39
36-37
Dehydag Base I Base
Hydrogenated fatty alcohols and esters
II Base III
9 ranges
9 ranges
Wecobee R
Glycerides of saturated fatty acids C12-C18
33-35
31-32
Wecobee SS
Triglycerides derived from coconut oil
40-43
33-35
32-33
29-32
H-15
33-35
32-34
H-85
42-44
36-38
Witepsol H-12
Triglycerides of saturated fatty acids C12-C18, with varied portions of the corresponding partial glycerides
( a ) C oc o a b ut t e r is a g ood b as e f o r a r ec t a l s up po s i t o r y, b u t i t i s l es s t han i d ea l fo r a v a g in al o r u r et h r al s u p po s i t or y . ( b ) A m i xt u r e of t ri g l yc e ri d es , c oc o a b ut t e r e xh i b it s po l y m o r ph is m . D e p e nd in g o n th e f us i on t e m p e ra t u re , i t c a n c r ys t a l li ze in t o a n y o n e o f f ou r c r ys t al fo r m s . ( c ) M a j o r l i mi t a t io n s o f c o c oa b ut t e r . Be c a us e o f t he fo ll o wi n g l im i ta t ion s , m a n y c om bi n a ti on s o f f at s an d wa xe s a r e us e d as s u bs t it u te s ( Ta b l e 3 - 4): ( i ) An i n a bi l i t y t o a b s o rb a q ue o us so l u t io n s. Th e ad di t io n o f no ni o ni c s u r fa c ta n ts t o th e b as e am e li o ra t es th is p ro bl em to s o m e e xt e n t . Ho we v e r , t h e re su l ta n t s up po s i t o rie s h a v e po o r s ta bi l it y a nd m a y t u r n r an c i d ra p id l y. ( i i ) T he low e r i n g o f th e m e l t in g po i n t p r o d uc e d b y c e r t a i n d r ug s (e . g. , c h lo r al h y d ra t e ). ( 2 ) W i te p so l b as e s c o n ta i n n a tu r al sa t ur a te d fa t ty a c id c h ai n s b et we e n C1 2 a n d C1 8 . L au r ic ac id is th e m a jo r c om p on e nt . Al l 1 2 ba s e s o f t h is s e ri es ar e c o lo r le ss an d a lm os t o d or l e s s . Th e d ru g - re l ea se c h a ra ct e ri s ti c s o f W it ep so l H 1 5 a re s im i la r to th os e o f c o c o a b u tt e r . ( a ) U nl ik e c oc o a b ut t e r, W itep s o l b as es do no t exh i b i t p ol ym o rp hi s m wh en h e a te d a n d c o o le d . ( b ) Th e in t e r v al be t we e n s o ft e ni ng an d m el t in g tem p e ra t ur e s is v e r y s m al l. B e c au se W it ep s o l b as e s s ol i di f y r ap id l y in t he m o l d , l ub r ic at i on of t he m ol d i s n o t n ec es s a r y .
( 3 ) W ec o be e b as es a re d e r i v ed f ro m c oc on u t o il . Th e i r ac ti o n is si m i la r to t h a t o f W ite ps o l b as es . In c o rp o ra t io n o f g l y c er y l m o no s t e a ra t e a nd p r o p yle n e g l yc o l m o n os te a r a te m ak es t he s e ba s e s e m u ls i fi a bl e . d . B a se s th a t d i ss o l ve in c lu d e P E G po l ym e r s wi th a m ol ec u la r we i gh t of 4 0 0 -6 0 00 . ( 1 ) A t ro om te m p e r at u re , P E G 4 0 0 is a l iq ui d , PEG 1 0 0 0 is a s e m i s ol id , P E G 1 5 00 an d 1 6 00 a re f a i rl y f i rm s em is o li ds , a nd P E G 3 35 0 a nd 60 0 0 a re f i r m wa x- l i k e s o l id s . ( 2 ) Th e s e ba s e s a r e wa t e r s o l ub le , bu t t h e d is s o lu t i on p ro c e ss i s ver y s low. I n t he re c tu m a nd v a gi n a, wh e r e t he am ou n t o f f lui d is v e r y s m a ll , th e y d i ss ol ve v e r y s l o wl y , b ut t h e y s o f te n a nd s p r ea d . ( 3 ) P E G s c om pl e x wi t h s e v e r a l d r ug s a nd a ff ec t dr u g re l ea se an d a b so r p ti on . ( 4 ) Mi xt u r e s o f P E G p o l ym e rs in va r yi ng p ro po r t ion s p r o v i de a b as e o f d i f fe r e nt p ro pe r t ie s ( Ta b le 3 - 5) . 4 . P r e pa r a t io n . Su pp os it o r ie s a r e p r ep a r ed b y t he f ol l o wi ng t h re e m et h ods : a . H a nd - r o l li n g i n v ol v e s m ol d in g t h e s u p po si t o r y wi t h t h e f in g er s a f te r a p l as t ic m as s is f or m e d . ( 1 ) A fi ne l y po wd e r e d d ru g is m i xe d wi t h th e g r a te d ba s e in a m o r t a r a nd p e st l e, us in g l e v i ga t io n a n d g e om et r ic di lu t io n tec h ni q ue s . A s m a ll qu a nt it y o f fi xe d o i l m a y b e a d ded t o f ac il i ta t e p r ep a r at i on . P.58
Table 3-5. Mixtures of Polyethylene Glycol (PEG) Bases Providing Satisfactory Room Temperature Stability and Dissolution Characteristics Base Comments 1
2
Provides a good general-purpose, watersoluble suppository
Provides a good general-purpose base that is slightly softer than base 1 and dissolves
Proportion Components (%) PEG 6000
50
PEG 1540
30
PEG 400
20
PEG 4000
60
more rapidly
3
Has a higher melting point than the other bases, which is usually sufficient to compensate for the melting-point lowering effect of such drugs as chloral hydrate and camphor
PEG 1500
30
PEG 400
10
PEG 6000
30
PEG 1540
70
( 2 ) Th e un i fo rm l y m i xe d s em i pl as t ic m as s is k n e ad e d f u r th e r , r ol l ed in t o a c yl i nd e r , a nd di v i de d i n to t he r eq u is it e n um b er of s up po s i t o ri es . Ea c h s m a l l c yl i nd e r i s r ol l ed b y h a nd u nt i l a s up p os it o r y sh ap e is fa s h io n ed . b . C o mp r e ss i o n is ge n er a l l y u s ed wh e n c oc oa bu t t e r is us ed as a b as e . ( 1 ) A un if o rm m i xt u r e o f d r u g a nd ba s e is p re pa re d as fo r th e h a nd - r ol li ng m e th o d. ( 2 ) Th e m i xt u r e is p l ac ed i n to a s up po s i t o r y c om pr e s s i on de v i c e . P re s s u re i s a p pl ie d , a nd t he m i xt u r e is fo r c e d i n to lu b ri c a te d c om p r es s i on m o ld c a vi ti es . Th e m ol d i s t hen c o o le d a n d t he s u pp os i t o ri es ej e ct e d. ( 3 ) Th i s p ro c ed u re ge n era l l y pr o du c e s a 2 -g s u ppo s it o r y. H o we ve r , a la r ge vo l u m e of t he ac ti v e in g re d ie n ts c a n a f fe c t t he am o un t o f c oc o a b ut t e r r e q ui r e d f o r a n i nd i v id u al f o rm ul a . ( a ) Th e am ou n t o f c oc oa b u t te r n e ed e d is de t e rm i n ed b y c a lc ul a ti n g t he t o t al am ou n t o f a c t i v e i ng r e di e nt t o b e us e d, di vid i ng t hi s n um be r b y th e c oc o a b u tt e r d en s i t y f ac to r ( Ta b le 3 -6 ) , a n d s u b t ra c ti n g t he r es ul t in g n u m b e r f r om th e to t al am o un t o f c oc o a b ut t e r r eq u i re d fo r th e d es i re d n u m b e r o f s up p os it o r ie s . ( b ) F o r e xa m p le , s up p os e 1 2 s u p po si t o ri es , e ac h c on t ai n in g 3 0 0 m g as pi ri n , a r e re q ui r ed . E ac h m o l d c a v i t y ha s a 2 - g c ap ac i t y. F o r 1 3 s up po si t o ri es ( c a lc ul a te d t o p r o v id e one e xt r a ) , 3 .9 g as p ir i n ( 13 × 0 . 3 g = 3 . 9 g ) i s r e q ui r e d. Th is nu m b e r i s d i v i de d b y t he de n s i t y fa c to r of as pi r i n ( 1 .1 ) ( Tab l e 3 - 6 ) . Th us 3 . 9 g of as pi r in r e pl ac es 3. 5 5 g o f c oc o a bu t te r . Th e t o ta l a m ou n t o f c oc oa bu t te r ne e d ed fo r 13 s u pp os i to r ie s o f 2 g e ac h e q ua ls 26 g . Th e am ou n t o f c oc oa b u t te r r eq ui r e d is 26 g - 3 . 5 5 g , o r 2 2 .4 5 g. c . Th e fu s io n me t h od is t h e p r in c i p al wa y t h a t s u p p os it o ri es a re m a de c om m e r c i a ll y . Th is m e t ho d is u s e d p r im a ri l y f or su p p os it o ri es t ha t c on t ai n c oc o a b u tt e r , P E G , an d g l y c e ri ng e la t in P.59
b a se s. Mo l d s m ad e o f a lu m in um , b r as s , o r n ic k e l- c o pp e r a ll o ys a r e us e d a n d c an m a k e 6- 5 0 s up po s it o ri e s a t o ne ti m e .
Table 3-6. Cocoa Butter Density Factors of Drugs Commonly Used in Suppositories Drug
Cocoa Butter Density Factor Drug
Cocoa Butter Density Factor
Aloin
1.3
Dimenhydrinate
1.3
Aminophylline
1.1
Diphenhydramine hydrochloride
1.3
Aminopyrine
1.3
Gallic acid
2.0
Aspirin
1.1
Morphine hydrochloride
1.6
Barbital sodium
1.2
Pentobarbital
1.2
Belladonna extract
1.3
Phenobarbital sodium
1.2
Bismuth subgallate
2.7
Salicylic acid
1.3
Chloral hydrate
1.3
Secobarbital sodium
1.2
Codeine phosphate
1.1
Tannic acid
1.6
Digitalis leaf
1.6
( 1 ) Th e ca p ac i t y o f t h e m o l ds is de t e rm i n ed b y m e lt i ng a s u f fi c i e n t q u a nt i t y o f ba s e o v e r a s t e am ba t h , p ou r in g i t i n to t he m o ld s , a nd al lo wi n g i t to co n ge al . Th e “b la nk ” s up p os it o ri e s a re t ri m m e d , re m o ve d , a nd we i g h e d . O n c e th e we i gh t is k n o wn , th e d r ug - c on t a in in g s u pp os i to r ie s a re p r e pa r e d.
( a ) To p re p a re s u pp os i tor i e s , th e d r u g is r ed uc e d t o a f in e p o wd e r . A sm all a m ou n t o f g r at e d c oc oa b u t te r is l i qu e fi ed in a s ui t a bl e c on t ai ne r pl ac e d in a wa t e r ba t h a t 3 3 ° C o r le s s . ( b ) Th e fi n el y p o wd e r ed d r u g i s m i xe d wi t h m el t ed c o c o a bu t te r wi t h c o nt i nu o us s ti r r in g . ( c ) Th e re m a i nd e r o f th e g r a te d c oc oa bu t t er is ad d e d wi t h st i r ri ng . Th e t e m p e r at u re is m a in t ai ned a t o r b e lo w 3 3 ° C . Th e l i qu i d sh o ul d a p pe a r c r e am y r at h e r t ha n c le a r. ( d ) Th e m o ld is v e r y l i ght l y l ub r ic a te d wi t h m i n e ra l oi l , a nd th e c r ea m y m e l t i s p o u re d i n to th e m ol d at r o om te m p e ra t u re . Th e m e lt is po u re d c o nt i nu o us l y t o a v o i d l a ye r i ng . ( e ) A f te r th e s up p os it o rie s c on g ea l , t he y a r e p lac e d i n a re f r ig e ra t o r t o h a r de n . Af t e r 3 0 m i n , t hey a r e r em o v ed f ro m t h e re f r ig e r at o r , t r im m e d, a nd u n m o l de d . ( 2 ) Th e fu s i o n p ro c es s s h o ul d b e us ed c a r ef ul l y wi t h t h e r m ol a bi l e d r u gs a n d i n s ol u bl e pow d e r s. ( a ) I ns ol ub l e p o wd e rs in t h e m el t m a y se t tl e o r fl oa t du r i ng po u ri n g, d e p en di n g o n t he i r d e ns it y . Th e y m a y al so c o ll ec t a t on e e nd o f t he s u pp os i to r y b ef o r e t he m e l t c on g ea ls , a n d c au se a n on u ni f or m d r ug d i st r ib u ti o n. ( b ) H a r d c r ys t al l in e m at er i a ls (e . g ., io di n e, m e r b ro m i n ) c a n b e i nc o rp o ra t ed b y d is so l v i ng th e c r y s ta ls in a m in im um vo lu m e of s ui t ab le so l ven t be f o re t h e y a re in c o r p or a te d i n to t he ba se . ( c ) V eg e ta b le e xt r a c ts c a n be in c o r po r a te d b y m o i s t e ni ng wi t h a f e w d r ops o f al co h ol an d l e v i ga ti n g wi t h a s m a l l am o un t o f m e lt e d c o co a bu t te r . G . P ow d e r s 1 . I n t ro d uc t i o n. A p h a rm ac e ut ic a l p o wd e r i s a m i xt u r e of f in el y d i v id e d d r u gs or c h em ic a ls i n d ry f o r m . Th e po wd e r m a y b e us ed in t e rn al l y o r e xt e r n a l l y . a . Ad va n t a g es o f p o wd er s ( 1 ) Fl e xi b i li t y o f c om po un d in g ( 2 ) G o od c h em ic al s t a bi lit y ( 3 ) R a pi d d is pe r s i o n o f in g r ed i en ts be c au s e of the s m al l p a r ti cl e s i z e b . D i sa d va n t ag e s o f p owd e r s ( 1 ) Ti m e- c o n s u m i ng p re pa r a ti o n ( 2 ) I na cc u ra c y o f do s e ( 3 ) U ns u it a bi li t y f or m a ny u n p le as a nt - t as ti n g, h yg r o s c op ic , a n d d el iq u es c e n t d r u gs c . M i l li n g i s t he m e c h an ic a l p r oc ess o f r ed u c i ng th e pa r t ic le s i ze o f s ol i ds ( c o mm i n u ti o n ) b ef o r e m i xi n g wi t h o th e r c om po n en t s , f u rt h e r p ro c e ss i ng , o r i n co r po r a ti o n i nt o a fi n al p r o du ct ( Ta b le s 3 - 7 a nd 3 - 8 ) . Th e pa r t ic le s i z e of a p o wd e r i s r e la t ed to the p r op o rt i on of t he po wd e r t ha t c an p as s th r o ug h t h e o p en i ng of s t an d a rd s i e v es o f v a r io us di m e nsi o n s in a sp ec i fi e d am o un t o f ti m e. M i c r om e r i ti c s is t he s t ud y o f p a r ti c l es .
Table 3-7. United States Pharmacopeia Standards for Powders of Animal and Vegetable Drugs Type of Powder
Sieve Size All Particles Sieve Size Percentage of Pass Through Particles Pass Through
Very coarse (#8)
#20 sieve
20% through a #60 sieve
Coarse (#20)
#20 sieve
40% through a #60 sieve
Moderately coarse (#40)
#40 sieve
40% through a #80 sieve
Fine (#60)
#60 sieve
40% through a #100 sieve
Very fine (#80)
#80 sieve
No limit
P.60
Table 3-8. United States Pharmacopeia Standards for Powders of Chemicals Type of Powder
Sieve Size All Particles Sieve Size Percentage of Pass Through Particles Pass Through
Coarse (#20)
#20 sieve
60% through a #40 sieve
Moderately coarse (#40)
#40 sieve
60% through a #60 sieve
Fine (#80)
#80 sieve
No limit
Very fine (#120)
#120 sieve
No limit
( 1 ) Ad va n t a g e s o f m i l li ng ( a ) I nc r ea s e s t he s u r fa c e a r ea , wh ic h m a y in c rea s e t he di s s ol u ti o n r a te a s we l l a s b io a v a il ab i li t y ( e.g . , gr is e of u l vin ) ( b ) I nc r ea s e s e xt r a c t io n , o r le ac h in g , f r om a n im al g l an ds ( e. g ., li v e r , p a nc r ea s ) a nd f ro m c r ude v e g et a bl e e xt r a c t s ( c ) F ac il it a te s d r y i ng o f we t m a s s es b y i nc r ea s ing t he s u r fa c e a re a a n d r e d uc in g th e d is t an c e tha t m o is t ur e m us t tr a v e l to r e ac h t he ou t e r su r f ac e .
Mi c r o n i z a t io n a nd s u bs eq u e nt d r y in g , i n t u rn , i nc r e a s e s t ab i li t y as occ l ude d s o l ven t i s r e m o v e d . ( d ) Im p r o v es m i xi n g , o r b l en d in g , o f s e ve ra l s ol id i ng r ed i en ts i f t he y a r e r e d uc ed t o a pp r o xi m a te ly t h e s am e s i z e ; a ls o m in i m i ze s s e g r eg a ti on a nd p r o vi de s g r ea t e r d os e u ni f o rm i t y ( e ) P e rm it s u ni f o rm d is t r ib u t io n o f c ol o r in g a ge n ts i n a r t if ic i al l y c o lo r ed s o li d p ha r m a c e u ti c a ls ( f ) I m p r o v es th e fu nc t io n o f l u b ri ca n ts u s ed to c oa t t he s u r fa c e of t he g r a nu l at i on o r p o wd e r i n c om p r ess e d t ab l et s a n d c a p s ul es ( g ) Im p r o v es th e t e xt u r e , a p pe a ra nc e , a n d p h ys ic a l s t ab i li t y of oi n tm en t s , c r e am s , an d p as t es ( 2 ) D i sa d va n t ag e s o f m il l in g ( a ) C a n c h a ng e t h e p ol y m o r ph ic fo r m o f t h e ac t i ve i ng r ed i en t , r e nd e ri n g i t l e ss a c ti v e ( b ) C a n d eg r ad e th e d r ug as a r e s u lt o f h ea t b u ild u p , o xi d a t io n , o r a d so r p ti on o f u n wa n te d m o is tu r e b ec a us e o f i nc re a s e d s u rf ac e a r e a ( c ) D ec r ea s es t h e b ul k de n s i t y o f t he ac t i v e c o m po u n d a nd e xc i pi en t s , c a us in g f l o w p r ob l em s an d s e g re ga t io n . ( d ) D ec r e as es th e p a rt ic le s i z e o f t he r a w m at e ri al s a n d m a y c r ea t e p r o bl em s wi t h s ta t ic c ha rg e , wh ic h m a y ca us e p a rt i c l e a g g re ga t io n a n d d e c re as e t h e d is s o lu t io n r a t e ( e ) I nc r ea s e s s u r f ac e a re a , wh ic h m a y p ro m o t e ai r ad s or p ti o n a nd in h ib it we t t a b i li t y ( 3 ) C o mm i nu t i o n t ec h n iq u e s. O n a la r g e sc al e , v a r i o us m i ll s a nd p u l ve ri z e r s ( e .g . , ro t ar y c u t te r , h am m e r , ro ll e r , f lu i d e ne r g y m i ll ) a re us ed d u r in g m an u fa c tu r in g . O n a s m a ll s c al e , t he ph a rm ac is t us ua ll y u se s o ne o f t h e fo ll o wi n g c om m i nu t ion t ec hn i qu es : ( a ) T r i tu r a t i on . Th e s ubs t an c e is r ed uc ed t o s m a l l p a rt ic l es b y r u bb i ng it i n a m o r t a r wi t h a p es t le . Tr i t u ra t io n a ls o d es c ri b es t h e p r oc es s b y wh i c h f ine p o wd e r s a r e i n ti m a t el y m i xe d i n a m o rt a r . ( b ) P u l ve r iz a t io n b y i n t e r ve n t i o n . S u bs ta nc es ar e r ed uc e d a nd s u bd i v i de d wi t h a n a d di t io n al m a te r ia l (i . e ., so l ven t ) th a t is ea s il y r em o ve d a f te r p u l ve ri z a t io n . Thi s t ec h ni q ue is of t en us ed wi t h gu m m y s ub s t a nc es th a t r e a gg l om e ra t e o r re s i s t g r i nd i ng . F o r e xa m p l e, c a m ph o r i s r ea d il y r e du ced a f t e r a s m a ll am ou n t o f al c oh ol o r o t he r v ol a ti l e s o l v e n t is ad d ed . Th e s o l ven t i s t h en pe r m i t te d t o e v ap o ra t e . ( c ) L e vi ga t i on . Th e p a r tic l e s i z e o f t he su bs t an c e i s r e du c e d b y a dd i ng a s u it a bl e n o ns ol v e n t ( le v ig a t in g a g en t ) t o f o rm a pa s te . Th e p as t e i s t he n r u b be d i n a m o r ta r an d pe s tl e o r us in g a n o i nt m en t s l ab an d s pa t ul a . Th is m e th o d is o ft e n us e d t o p r e v e n t a g r i tt y f e el wh en s o l id s a r e i nc or p o ra t ed i n t o d e rm at o lo gi c o r o p hth a lm ic oi n tm en ts an d s us p e n si o ns . Mi n e ra l o il is a c om m o n l e v i ga t in g a g en t. 2 . M i x in g pow d e r s. P o wd e r s a re m i xe d , o r b l en de d , b y t h e f ol l o wi ng f i v e m e th o ds :
a . S pa t u la t i o n. A s pa t ula is us ed t o b le nd sm al l a m ou n ts o f po wd e r s o n a s h ee t o f pa pe r o r a p i ll til e . ( 1 ) Th i s m e t ho d i s n o t s ui t a bl e f o r l a rg e q u an t it i es o f p o wd e rs o r f o r p o wd e r s t h at c o n ta in p ote n t s ub s ta nc es be c a us e h o m o g en eo u s bl e nd i ng m a y no t oc c u r . P.61
( 2 ) Th i s m e t ho d i s p a rt ic u l a rl y u se f ul fo r s o li d s ub s ta nc e s t ha t l i qu e f y o r f o r m e u te c t ic mi x t u re s ( i . e ., m i xt u r e s t h at m e l t a t a l o we r te m pe r at u r e th a n a n y o f t h ei r i n g re di e nt s ) wh e n i n c lo se , pr o lo n ge d c on t ac t wi t h o ne an o th er b e ca us e l i tt l e c o m p r es s io n o r c o m p ac t io n re su l ts . ( a ) Th e s e s u bs ta n c e s i nc l ud e p h en ol , c am p ho r , m e nt h ol , th y m ol , a sp i ri n , p h e n yls al ic y l a te , a n d p he n ac e ti n . ( b ) To d im in is h c on t ac t , p o wd e r s p r ep a r ed f ro m th e s e s u bs t an c e s a r e c om m o n l y m i xe d wi t h an i n er t di lu e nt ( e. g . , l ig h t m a gn es i um o xi d e o r m a gn es i um c a rb o na t e, k a o li n , s ta r ch , b e nt o ni t e ). ( c ) S il ic ic ac id ( ap p ro xi m a t e l y 2 0 % ) p re v e n ts eu t exi a wi t h a s pi r i n, p h e n yls al ic y l a te , a n d o the r t r ou bl es om e c om p ou nd s . b . T r i tu r a t i on is u s ed bot h t o c o m m in u te an d to m i x p o wd e r s . ( 1 ) I f co m m i nu ti o n is d es i r e d, a p o rc el a in o r ce r am ic m o r ta r wi t h a r ou g h i n ne r su r fa c e is p re f er r ed t o a gl as s m o r t a r wi t h a s m oo t h wo r k i ng s u r f ac e . ( 2 ) A gl as s m o r t a r is p ref e r a bl e f o r c he m i ca ls th at s ta i n a p o rc el a in o r c e r am ic s u rf ac e as we l l a s fo r s im pl e a d m i xt u r e o f su bs t an c e s wi t h o u t s p ec ia l n e ed fo r c om m i nu t i on . A g la s s m o r ta r c lea n s m o r e re a di l y af t e r us e . c . G e om e t r ic di l u t io n i s u s e d wh e n p o te n t su bs ta n c e s m us t b e m i xe d wi t h a l ar g e a m o un t of di l ue nt . ( 1 ) Th e po t en t d r u g a nd a n ap p ro xi m a t el y e q ua l v o l u m e of di l ue n t a r e p l ac e d in a m o rt a r a nd th o r ou g hl y m i xe d b y t r i tu ra t i on . ( 2 ) A s ec o nd po r ti o n o f di l ue n t , e qu al in v o lu m e to t he po wd e r m i xt u r e i n t h e m o rt a r , is a dd ed , and t r it u r at i on i s re pe a te d . Th e p r oc es s i s co n ti n ued ; e q u al v ol u m e s o f d il u en t a r e a d de d t o t h e p o wd er m i xt u r e i n t h e m o r t a r un t i l a l l o f t h e d il u en t i s i nc o rp o r a te d . d . S i f ti n g . P o wd e r s a r e m i xe d b y pa s s i ng th em th r o ug h s i ft e rs s im i la r to t h os e u s ed to s i f t f lo u r . Th i s p ro ce s s re s ul ts in a l i gh t , f lu f f y p ro d uc t. U s u al l y , i t is n o t a c c ep t ab l e f o r i nc o rp o r at i ng po te n t d r u gs i n to a d il u en t b a se . e . T um b li n g i s t he p ro c es s o f m i xi n g p o wd e r s i n a l ar g e c on t ai ne r r ot a te d b y a m o t o ri z e d p r oc es s . Th e s e b l en d er s a r e wi del y u se d i n i n du s t r y , as a re l a r ge - vo l um e p o wd e r m i xe r s t h at us e m ot o r i z ed bla d e s to bl e nd th e p o wd er i n a l ar g e m i xi n g v e s s e l. 3 . U se a nd pa c ka g i ng of p ow d e rs . D ep e nd in g on t he i r i n te n de d u se , p o wd e r s a r e p ac k a g ed an d di s p e ns ed b y p h a rm ac is t s a s bu lk po wd e r s o r d i vi de d p o wd e r s .
a . B ul k p o wd e rs a re di s pe n s e d b y t h e p ha rm a c i s t i n b u lk c on t ai n e rs . A p e r f o r a te d , o r si f t e r , c an is us e d f o r e xt e r n a l d us t in g , a nd an ae r o s ol c o n t ai n e r i s us e d f o r s pr a y i n g o n to s ki n . A w i d e- m o u t he d g l as s ja r p e r m i ts ea s y re m o v a l of a s p o on f ul of po wd e r . ( 1 ) P o wd e rs c o m m on l y di s pe ns e d i n b ul k f o rm ( a ) An t a c i d a nd l ax a t i ve p ow de r s ar e us ed b y m i xi n g th e d i r ec te d a m ou n t o f po wd e r ( us u al l y ap p roxi m a t e l y 1 t e as po o n) in a p o rt i on of li qu i d, wh i c h t h e p a ti e nt t he n d r in k s . ( b ) D o uc h e p ow d e rs a re d is s o l v ed in wa r m wa te r a nd ap pl i ed va gi n al l y . ( c ) M e d ic a te d an d no nm e d ic a t ed pow d e r s f o r e x t e r na l us e a r e us u al l y d i sp e ns ed in a s i f te r f or c o n v en i en t a p pl ic a ti on to t he s k in . ( d ) D e n ti f r i ce s , o r de n ta l c le a ns i ng p ow de r s , a r e us ed fo r o ra l h y g ie ne . ( e ) P o wd e rs f or t he ea r , n o s e, t h r oa t , to o t h s ock e t s , o r va gi n a a r e a d m i ni s te r ed wi t h an in s u f f la t o r, o r p o wd e r b l o wer . ( 2 ) N o np o t en t su b s ta n ce s a re us ua ll y d is pe n se d i n b u lk p o wd e r fo r m . Th o s e i n te n de d f o r e xt e r n a l u s e s h ou l d b e cl e ar l y l a be le d . ( 3 ) H yg r o s c o p i c, de l i que s c en t , o r vo l a ti l e p o wde r s s ho u ld be pa c k ed in g l as s j a rs ra t he r th a n p as t eb o a rd c o nt a in e rs . Am b e r or g re e n g la s s s ho u ld b e us ed if ne e de d t o pr ev e n t de c om po s i t io n o f l igh t - s e ns i ti v e c o m p on e nt s . A l l p o wd e r s s ho ul d b e s to r e d i n t ig h tl y c lo se d c on t a in e rs . b . D i vi d e d p ow de r s ar e d i s p e ns ed in in di v i d ua l do s es , u s u a ll y in f ol d e d p a p e rs ( i. e . , c h a r tu l ae ) . Th e y m a y a ls o b e d is pe ns e d i n m e t al f oi l, sm al l h e a t -s ea le d o r r es ea l ab le p l as t ic b ag s , o r o t he r c o nt a in e rs . ( 1 ) A f te r th e i n gr e di e nt s a r e we i gh e d, c o m m in u ted , an d m i xe d , th e p o wd er s m us t be ac c u r at e l y d i vi de d in t o t he p re s c r ib e d nu m be r of do se s . ( 2 ) D e pe nd i ng on th e p o te n c y o f th e d r u g s u bs t anc e , t h e p ha r m a ci s t d e ci d es wh e th e r t o w e igh e ac h p o rt i on s e pa r a te ly b e f o re pa c k ag i ng o r t o a p p ro xi m a t e p o r ti on s b y t h e bl o ck - a nd - d i vi de me t h o d. P.62
( 3 ) P ow de r p ap e r s c an b e of an y c on ve n ie n t s i ze t ha t fi ts t he re q ui r ed d o se . Fo u r b as ic t y pe s ar e us e d: ( a ) V eg e t ab l e p a r ch m ent i s a th in , s em i op aq u e, m o is tu r e - re s i s ta n t p ap e r. ( b ) W hi t e b o n d is an opa q u e p ap e r t ha t ha s n o m o is tu r e - re s i s ta n t p r o pe r t ie s . ( c ) G l as s i ne is a gl a z e d, t r a ns pa r e nt , m oi s tu r e - res is t an t pa pe r . ( d ) W ax e d p ap e r is a t ran s pa r en t wa t e r p ro o f p ape r . ( 4 ) H yg r os c o p ic a n d v o l at i l e d ru g s a re be s t p r ot ec t ed wi t h wa xe d p a p e r t ha t i s d o ub le wr a p p ed an d c o v e r e d wi t h a b o nd pa p er t o i m p r o ve t h e a p p ea r an c e . Pa r c h m e n t a n d g la s s i ne pa pe r s a r e o f li m i t ed us e f o r t h es e d r u gs . 4 . S pe c ia l p r ob l em s . V ol a t il e s ub s t a nc es , e u te ct ic m i xt u r e s , l iq ui ds , an d h yg r o sc op ic o r d el iq u es c e n t s ub s ta nc es p re se n t p r o b l em s wh e n t he y a r e m i xe d i nt o p o wd e r s t ha t r e q ui r e s pe c i a l t r ea tm e nt.
a . V o la t i le su b s ta n ce s (e . g . , c a m p h o r, m e nt h ol , e ss e nt i al oi ls ) c a n b e l ost b y vo l a ti l i z at i on af t e r t hey a r e in c o r p or a te d i n to po wd e r s . Th is pr o c e s s i s p r e ve n te d o r re t a rd e d b y t h e u s e of he a t -s ea l ed p l as t ic b a gs o r b y do ub le wr a p p i n g wi t h wa xe d o r g l as s i n e p ap e r i ns id e whi t e b o nd pa p er . b . L iq u i ds a re in c o r po r at e d i n to di v i d ed po wd e r s i n s m a ll am o u n ts . ( 1 ) Ma g n e s i um c a rb o na te , s t a rc h , o r l ac t os e c an b e ad d ed to in c re as e t h e a b so r ba b il i t y o f th e p o wd e r s b y in c re as i ng th e s u r f ac e a r e a. ( 2 ) W hen t h e li q ui d i s a s o l v en t fo r a n on vo la t il e h e a t -s ta b le c om p ou n d, it i s e va p o ra t ed g en tl y i n a wa t e r b a th . So m e f lu id e xt r a c ts an d t i nc tu r es a re t r e a te d i n t h is wa y . c . H yg r o s c o p i c an d de l iq u e sc e n t s ub s t an c es tha t be c o m e m o is t b ec a us e o f an a ff i ni t y fo r m o is tu re i n t he ai r c a n b e p r ep ar e d as d i v i de d p o wd e r s b y a d di n g i ne r t d i lu en t s . D ou b le wr a p p in g i s d es i ra ble f o r f u rt h e r p r ot ec t io n . d . E u te c t ic mi x t u re s H . C a p su l es 1 . I n t ro d uc t i o n. C ap s u le s a r e s ol i d d os ag e f o rm s in wh i ch o ne or m o r e m e di ci n al o r in e r t s u bs t an c es (a s p o wd e r , c om pac t , b e ad s, o r g r an ul a ti o n) a r e en cl os ed wi t h i n a s m a l l g el a ti n s he l l. G e la t in c a ps ul es m a y b e h a rd or s o f t. Mo s t c a ps ul es a re in t e nd e d t o b e s wa l lo we d wh o l e , b u t o c c as io n al l y , t h e c on t en t s a r e r em o v ed f r om th e g el a ti n s he l l an d us ed as a p re m e a su re d d o se . 2 . H a r d g e la t i n c ap s ul es a . P r e pa r a t io n of f i ll e d h a r d ca p su l es in cl u de s p r e pa r i ng th e f o rm u la t ion , s e le ct i ng th e a p p ro p ri a te c ap s u l e, f il li n g t he c a ps u l e s he ll s , a nd c l ea n in g a n d p ol is h in g t h e f il l ed c a p s u l es . ( 1 ) E m p t y ha r d c ap s u l e s h el ls a re m a nu f ac tu r e d f r o m a m i xt u r e of ge l at in, c o lo r an t s , an d s om e ti m es an op a ci f yin g a g en t (e .g . , ti t an iu m d io xi d e ) . The U S P a ls o p e rm i ts th e a dd i t io n o f 0 . 15 % s ul f u r d io xi d e t o p r e ve nt d e co m p os i ti o n o f g el a ti n d u ri n g m an u fa ct u r e. ( 2 ) G e la t in U S P i s o b ta ine d b y p a r ti a l h yd ro l y s i s o f c o ll a ge n o b ta i ne d f r om t h e s ki n , wh i t e c on n ec ti v e t is s u e , a nd bo n es o f an i m a ls . Ty p e s A an d B ar e o b t ai ne d b y a c i d a n d a lk a l i p r oc es si ng , re s pe ct i ve l y . ( 3 ) C a ps ul e s he ll s a r e c a s t b y d ip pi n g co l d m e t all i c m o l ds o r pi ns in t o g e la t in so lu t io ns t ha t a r e m ai n ta i ne d a t a un i fo r m t e m p e r at u re a nd an e xa ct d e g re e o f fl u id it y . ( a ) V a ri a ti on in t he v is c os i t y of th e g e la t in s o lu t ion i nc r ea s e s o r d ec r e as es t h e th ic k n es s o f t h e c a ps u l e wa ll . ( b ) A f te r th e p i ns a r e wi th d r a wn f r om t h e g el a ti n s o lu t io n , t he y a r e r o ta t ed wh i l e b ei ng d ri ed in k i ln s . A s t r o ng bl as t o f fi l te r ed a ir wi t h c o nt r o ll ed h u m i di t y is f or c e d th r ou gh t he k i ln s . E ac h c ap s u le is t he n m ec ha ni c al l y s t r ip p ed , t r im m e d , a nd joi n ed . b . S t o r ag e . H a r d c a p s u le s s ho u ld be st o re d i n tig h t l y c lo s e d g l as s c o nt a in e rs an d p r o te c t e d f r om du s t a nd e xt r e m e s o f hu m i d it y a nd t e m p e r at u re .
( 1 ) Th e s e c a ps ul es c o n ta i n 1 2% - 1 6% wa t e r , var y i n g wi t h s to r ag e c o nd i ti on s . W hen h um i dit y i s l o w, t h e c a ps u le s be c om e b r it t le . W hen h u m i di t y is hi g h, t he c a ps u le s b ec om e f l acc i d a nd s h a pe l ess . ( 2 ) S t or a ge at hi g h t em pe r a t ur es al s o a ff ec t s t he q u al i t y o f ha r d g el a ti n c a ps ul es . c . S iz es . H ar d c a ps ul es a r e a v ai la b le in a v a r i et y o f s i z es . P.63
( 1 ) E m p t y c a ps ul es a re n u m be r e d f r om 00 0 , wh ic h i s t h e l ar g es t s i ze t hat c a n b e s wa l lo we d , t o 5 , th e s m a l le st s i ze . Th e a pp r o xi m a t e ca p ac it y o f c a ps ul es r an g es f r om 600 t o 3 0 m g f o r c a ps u le s fr o m 0 0 0 t o 5 , re sp ec t i v ely . Th e c ap ac i t y v a r ie s b ec au s e o f v a r yin g d en s i t ie s o f po wd e r e d d r ug m a te r i al s a nd th e d e gr e e o f pr es s ur e u s e d to fi l l th e c a ps ul es . ( 2 ) La r g e c a ps u le s a r e av a i l ab l e f o r ve t e r i na r y m e d ic i ne . ( 3 ) S e le c ti n g c a ps u le s . C a p s u l e s i z e sh ou l d b e c h os en c a r ef u ll y. A p r o pe r l y fi l le d c ap s u l e s h o ul d h a v e it s b od y f il l ed wi t h t he dr u g m i xt u r e an d i t s c ap fu l l y e xt e n d e d d own t h e b od y. Th e c a p is m e an t to en cl os e t h e p o wd e r , no t to re t ai n a dd i t io na l p o wd e r . Ty p i c a lly , h a r d g el a ti n c ap s u l es a r e u s ed to en c ap s u la t e b e twe e n 6 5 m g a nd 1 g of po wd e r e d m a te r ia l , i nc lu di n g t h e d r u g a nd an y d il ue n ts ne e de d . ( a ) I f t he d ru g d os e i s i na d e qu a te to fi l l t he c a ps u l e , a d i lu en t (e . g ., l a ct os e ) i s a dd e d. ( b ) I f t h e am o un t o f dr u g n e ed e d f o r a u su a l d os e i s t o o la r g e t o p la c e in a s i ng le c a ps u le , t wo o r m o r e c a ps ul es m a y b e r equ i r ed . ( c ) Lu b r ic an ts s u c h as m a g n es iu m s t e a ra t e ( f r equ e n tl y , 1% ) a re ad de d to f a ci l it a te th e fl o w o f th e p o wd e r wh e n an au t om ati c c ap su l e -f i ll in g m ac hi ne i s u se d . ( d ) W ett in g a g en ts ( e. g . , s od i um l a u r yl s u l fa t e ) m a y b e a d de d t o c a ps ul e f o r m u l at io n s t o e nh a nc e d r u g d is so lu t io n . d . F il l i ng ca p s ul e s. W he t h e r o n a l a rg e - o r a s m a l l -p r od u ct io n s ca l e, th e c a p is f ir s t s e p a ra t ed f rom t he bo d y of t he c a ps ule b ef o r e f il li n g t he c a ps ul e b o d y wi t h th e f o rm u la t ion a nd th e n r e at t ac hi n g th e c a p. A u to m a t ed an d s em i au t om at e d c ap s u le - fi l li n g e qu ip m e n t f i ll th e ca p s u l e b od ie s wi t h t he f o r m u l at io n b y g r a v i t y fi ll, t am p in g , o r a s c re w- f e ed ( i .e . , a ug e r ) m ec h an is m . E xt e m p o ra ne o us l y c o m p ou n de d c aps u le s a r e us u al l y fi l le d by t h e p u nc h m et h od . ( 1 ) Th e po wd e r is pl ac ed o n p a pe r an d f l at t en e d wi t h a s p a tu la so th a t t he l a ye r of po wd e r is no m or e t ha n a p pr o xi m a t el y o ne t hi r d t h e l en g th of t he c a ps ul e . Th e pa p e r is hel d in th e l e ft ha n d. Th e bo d y o f t h e ca ps u le is h e ld i n th e ri gh t ha n d a nd re pe a t ed l y p re s s ed in t o t he p o wd e r u nt il t he c a ps ul e i s fi ll e d. Th e c ap is r ep lac e d a nd th e c a ps ul e we ig h e d. ( 2 ) G r a n ul a r m a te r ia l tha t do es no t le nd i ts el f we l l t o t h e p un ch m e t ho d c a n b e po u re d i n to ea c h c a ps u le f ro m t he po wd e r p ap e r o n wh i c h it wa s we i g h e d .
( 3 ) C r ys t a l l i n e m at e ri a ls , e s p ec ia l l y th os e t h at c o n si st o f a m as s o f f i l am en t -l ik e c r y s ta ls ( e.g . , qu in i ne s a lt s ) wi l l no t f i t i n to a c a ps u le ea s i l y u n le ss th e y a re po wd e r ed . ( 4 ) A f te r th e y a re fi l le d , c a ps ul es m u st be cl ea n ed a nd po li s he d . ( a ) O n a sm a l l s ca l e, c ap s ul es a re c l ea n ed i n di v id u al l y o r i n sm a ll n u m b er s b y r u b bi ng t he m o n a c lea n ga u ze o r c l ot h . ( b ) O n a l a r ge sc a le , m a n y c a p su le - f il li n g m a c h in e s h a ve a c l ea ni n g va c u um th a t r em o v es any e xt r a n e o us m a t e ri al as t h e c ap s u le s l ea ve t he m ac h in e . 3 . S o f t g el a t i n c ap s ul es a . P r e pa r a t io n ( 1 ) S o ft ge la t in c a ps u le s a r e p r ep a r ed f ro m g el a tin s h e ll s. G l y c e r i n o r a p o l yh y d ri c a lc oh o l ( e .g . , s o r bi t ol ) i s a dd e d t o t h ese s h e ll s t o m ak e t he m e l as t ic o r pl as t ic - li k e . ( 2 ) Th e s e s h el ls c o nt a in p r e s e r va ti v e s (e . g. , m e thy l a n d p r op yl pa r ab e ns , s o r bi c ac i d) t o p r e v en t th e g ro wt h o f f u ng i . b . U s es . So f t g el a ti n s hel l s a re o bl on g , e ll i pt ic al , o r sp h er ic a l. Th e y a r e u s ed to c o n ta in li q ui ds , s us p en si o ns , p as t es , d r y p o wd e r s , o r p el l et s. ( 1 ) D r ug s t h at a re c om m e r c ia ll y p r ep a re d i n s o ft c a ps ul es in c l u de d e m e cl oc y c li n e h y d r oc hlo r i de ( D ec lo m yc i n , L ed er l e ) , c hl o ra l h y d r a te , d i go xi n ( L a no xi c a ps , G laxo S m i t h K li n e ), v i t am in A, a nd v i t am in E . ( 2 ) S o ft ge la t in c a ps u le s a r e u s u a ll y p re p a re d b y t h e p l at e p r oc es s o r b y t h e ro t a r y o r r ec ip r oc a ti ng d ie p ro ce s s . 4 . U n i fo r m i t y a n d d i s i nte g r a t io n a . Th e un i f o rm i t y o f d o s a g e f o rm s c an be de m o ns t r at e d b y ei t h er we i g ht va r i a ti o n o r c on t en t un i fo r m it y m e t ho d s. Th e o f f ic i al c om p en d ia s h ou ld be c o ns ul t ed fo r de t ai ls o f th e s e p ro ce d ur es . b . D i si n t eg r a t i on te s ts a r e no t u s u a ll y r eq u i re d f o r c a ps ul es un l es s t he y h a ve be e n t r ea t ed to r es i s t s ol u ti on in ga s tr ic f lu id ( e nt e ri c c oa t ed ) . I n th is c as e , t h e y m us t m ee t the r e qu i re m e n ts fo r di s i n te g r a ti on o f e nt e ri c -c oa t ed t a b le ts . P.64
I . T AB L E T S 1 . I n t ro d uc t i o n a . Th e o ra l r ou t e i s t h e m os t im po r ta n t m et h od fo r a dm in is t er i ng d ru gs for s ys t em ic e f f ec t . O r a l d r ug s c an b e gi v e n as s ol i ds o r l iq ui d s . ( 1 ) Ad va n t a g e s o f s o l id d o sa g e fo r m s ( a ) A cc ur a t e d os ag e ( b ) E as y s hi pp i ng an d ha n dl i ng ( c ) Le ss s h el f s pa c e n eed e d p e r d os e t h an fo r li qu i d ( d ) N o p r es e r v a ti o n r eq ui r e m e n ts ( e ) N o t as t e -m as k i ng p rob l em ( f ) G e n er a ll y m o r e s t ab le t ha n l i qu id s , wi t h lo n ge r e xp i r a ti o n d at es
( 2 ) Ad va n t a g e s o f l i q uid d o sa g e f o r ms ( a ) F or s o m e d ru gs ( e. g ., a ds o rb e nt s , a nt ac i ds ) , g r e a te r e f f ec ti v e n es s t han s o li d f o rm ( b ) U se f ul f or pa t ie n ts wh o ha v e t ro u bl e s wa l l o win g s o li d d os a ge fo r m s b . T ab l e ts a re th e m o s t c o m mo n l y u s e d s o l id do s a ge f o rm . ( 1 ) Ad va n t a g e s ( a ) P r ec is io n a n d l o w c on t e nt v a r ia b il it y o f th e un i t d os e ( b ) L o w m a n uf ac t u ri n g c o s t ( c ) E as y t o p ac k a ge a nd s hi p ( d ) S im pl e to id en t i f y ( e ) E as y t o s wa l lo w ( f ) A p p ro p ri a te fo r s p ec ia l - r el ea s e f o rm s ( g ) B es t s ui t ed t o l ar g e -s c a l e p r od uc t io n ( h ) Mo s t s t a bl e o f a l l o ral d os ag e f o rm s ( i ) E s s en t ia ll y t am p e rp r oo f ( 2 ) D i sa d va n t ag e s ( a ) S om e d r ug s r es is t c om p r es s i on in t o t ab l et s . ( b ) S om e d r ug s ( i .e . , t h os e wi t h p o or we t t i ng , s low d i s s ol ut i on p ro p er t ie s , i n t er m ed ia t e t o l a rg e d os e s , o p ti m u m a bs o rp t io n h i g h in t he ga s t r o in t es ti na l t r a ct , or a n y c om bi n at i on o f th es e f e a tu r es ) m a y b e di f fi cu l t t o f o rm u la t e to p r o vi de ad e qu a te bi o a v ai l ab i li t y . ( c ) S om e d r ug s ( e .g . , t ho s e wi t h a n o bj ec ti o na b le t as t e o r o d or , th os e s e ns it i v e to o xy g e n o r a tm os p he r ic m o is tu r e ) r e qu i r e e nc ap s u l at i on o r e n t r ap m e n t b ef o r e c o m pr e s s i on . Th es e d r ug s a r e m o re ap p ro p r ia t e i n c a ps ul e f o rm . 2 . T ab l e t d es i gn a nd f or m u l a ti o n a . C h a ra c te r i s t ic s o f i de a l ta b le t s ( 1 ) F re e o f de f ec ts (e . g ., c hi ps , c r ac k s , d is co l or a ti o n , co n ta m i n at i on ) ( 2 ) S t ro n g e no u gh to wi t h s ta n d t he m e c h a ni c a l s tr e s s es o f p ro d uc ti o n ( 3 ) C h em ic al l y an d p h y s ic a ll y s ta bl e o v e r ti m e ( 4 ) C a pa bl e o f re l ea s i n g m e di c i n al a g en t s i n a p re d ic t ab le a nd re p r od uc ibl e m a nn e r b . T ab l e t e xc i p ie n ts . Tab l e ts a r e m an u fa c tu r ed by w e t g r a n ul a t io n , d r y g r a n u la t i on , or d i re c t co m p r es s i on . R eg a rd l ess o f th e m et h od of m a nu f ac tu r e , t a bl e ts f o r o r a l i ng es t io n u su a ll y c on t a in e xc i pi e nt s, wh i c h ar e c om p on e nt s a dd e d t o t he ac t i v e i ng r e di en t s t ha t h a v e s p ec ia l f u nc ti o ns ( Ta b l e 3 - 9 ) . ( 1 ) D i l ue n ts a re fi l le r s de s ig n ed to m a k e up th e re q ui r e d b ul k o f t h e t ab l et wh e n t h e d r ug do s a g e am o un t i s i na d eq u at e . D i lu e n ts m a y al so im p ro v e c o he si o n, pe r m i t d i re c t c o m p re ss io n , o r p r om o te f l o w. ( a ) C o mm o n d i lu e n ts inc l ud e k ao li n , l ac t os e, m an n i to l , s t a rc h , m ic r oc r y s ta l li ne c e ll u lo s e , po wd e r e d s ug a r , a nd c a l c iu m p ho s p h at e . ( b ) S e le c t io n o f t he d ilu e n t i s b as ed on t he e xp e r i en ce o f t he m a nu f ac tu r e r a s we l l as o n th e c os t o f th e d il u en t a n d i ts c om p at i bi li t y wi t h t h e o t he r ta b le t i n g re di en t s . F o r e xa m p le , c al c i um sa l ts c an n ot be us e d a s
f i ll e rs f or t et r ac y c li n e p ro d uc ts b ec au s e c a lc iu m i n t er f e re s wi t h t he a b so r p ti on o f t et r ac y c li ne f r om th e g as t r oi n te st i na l t ra ct . ( 2 ) B i nd e r s a n d a d he s ive s a r e a dd e d i n e it h e r d r y o r li qu i d f o rm to p r o m o t e g ra n ul a ti o n o r to p r om ot e c oh es i v e c om p a ct s d u ri n g d ir e c t c om p r es s i on . ( a ) C o mm o n b i nd i n g a ge n t s i nc lu d e a 10 % -2 0 % a q ue o us p r e pa r at i on of c o r ns ta r c h , a 25 % - 50 % s o l u ti on o f g lu c o se , m ol ass es , v a r io us na t ur a l g um s ( e . g ., ac ac ia ) , c e ll ul os e d e r i v a ti v e s ( e .g . , m et h y lc e ll ul os e , c a r bo xy m e t h y l c el lu l os e, m ic r oc r y s ta l li ne P.65
c e ll ul os e ) , g el a ti ns , an d p o v i d on e . Th e na t u ra l g um s a r e va r i ab le in c om p os it i on an d a r e u s ua l l y c o nt am i na t ed wi t h ba c te r i a.
Table 3-9. Some Common Tablet Excipients Diluents Calcium phosphate dihydrate NF (dibasic) Calcium sulfate dihydrate NF Cellulose NF (microcrystalline) Cellulose derivatives Dextrose Lactose USP Lactose USP (anhydrous) Lactose USP (spray dried) Mannitol USP Starches (directly compressible)
Starches (hydrolyzed) Sorbitol Sucrose USP (powder) Sucrose-based materials Binders and adhesives Acacia Cellulose derivatives Gelatin Glucose Povidone (PVP) Sodium alginate and alginate derivatives Sorbitol Starch (paste) Starch (pregelatinized) Tragacanth Disintegrants Alginates
Cellulose Cellulose derivatives Clays Crospovidone (cross-linked PVP) Starch Starch derivatives Lubricants PEGs Stearic acid Stearic acid salts Stearic acid derivatives Surfactants Talc Waxes Glidants Cornstarch Silica derivatives
Talc Colors, flavors, and sweeteners FD&C and D&C dyes and lakes Flavors available in two forms (spray dried, oil) Artificial sweeteners Natural sweetener D&C, drugs and cosmetics; FD&C, food, drugs, and cosmetics; NF, National Formulary; PEG, polyethylene glycol; PVP, polyvinylpyrrolidone (more commonly, povidone); USP, United States Pharmacopeia. ( b ) I f t h e d ru g s u bs ta nc e i s a d v e rs el y a f fe c t e d b y a n a q ue o us b i nd e r, a n o n a qu e ou s bi n de r c a n b e u s e d o r t he bi nd e r c a n be ad d ed dr y . Th e b i nd i ng ac ti o n is us u al l y m o r e e ff e c t i ve wh e n t he b i nd e r i s m i xe d i n l i qu i d form. ( c ) Th e am o un t of bi n der o r ad he si ve us e d d ep en d s o n t he e xp e r i en ce of t h e m an u fa c tu r e r as we l l a s o n t h e o th e r t a bl e t i ng r e di e nt s . O ve r we t t i n g u s ua ll y p r od uc e s g ra n ule s th a t a re t oo ha r d t o a ll o w p r o pe r t ab le t in g . U n d e r we t t in g u s u a ll y p r od u c e s t a bl et s t h at a re too s o f t a n d t en d to c r um ble . ( 3 ) D i si n t eg r a n ts a re add e d t o ta bl e t f o rm ul a ti o ns t o f ac il i ta t e d i si n te g ra t io n wh e n t he ta b le t c o nt ac t s wa t e r in th e ga s t r o in t es ti n al t ra ct . D i s in t eg r an t s f un c ti on b y d r a wi n g wa t e r i nt o t h e ta b le t , s we l l in g , a nd c a us in g t h e t ab l et t o b u rs t . ( a ) Ta b le t di s i nt e g ra t io n m a y be c ri ti c al to th e s ub s eq u en t d is s o l ut i on of th e d r u g a nd t o s a t is f ac to r y d r u g b io a va il ab i li t y . ( b ) C o mm o n d i si n t eg r an t s in c l ud e c o rn s ta r c h an d po t at o s t a rc h; s t a rc h d e r i va ti v e s ( e .g . , s od iu m s t ar c h gl yc o la t e) ; c e ll ulo s e d e ri v a t i v es (e . g. , s o di um c a r bo xy m e t h y l c el l ul os e , c r os c a rm el l os e s o d iu m ) ; c l a y s ( e .g . , V E E G U M, b e n to n it e ) ; a nd c a t io n e xc h a n ge r es in s . ( c ) Th e to t al am o un t o f d i s i n te g r an t is n o t a l ways a dd e d t o t h e d r ug d i lu e nt m i xt u r e . A p o r ti on c a n b e a d de d , wi t h t he l u br ic a n t, to t he pr e pa r ed g r a nu l at i on of t he dr u g. Th i s ap p r oa ch c a us es dou b l e di si n te g r at i on of t he t a b le t . Th e p or t io n o f di s i n t eg r an t th a t is ad d ed la s t c au se s t he t ab le t to b r e ak in t o s m al l p i ec es , o r c h u nk s . Th e p o r ti on th a t i s a dd e d f i rs t b r ea ks t h e p i ec es o f ta b le t i n to f i n e p a rt ic le s .
( 4 ) L ub r i c an t s , a n ti a dhe r e n t s, an d gl i da n t s h av e o ve r l ap pi n g f un c ti on . ( a ) L ub r i c an t s r e du c e t he f r ic ti o n t ha t occ u rs be twe e n t h e wa ll s o f t h e t a b le t a n d t he wa l ls o f t he d ie c a vi t y wh e n t h e t abl e t i s e je c te d . Ta l c , m a gn es i um s t ea r at e , a nd c a lc i um s t ea r a te ar e c o m m o nl y us e d . P.66
( b ) An t i a d he r e n ts r ed uc e s ti c k in g , o r a d he s i on , o f t he ta b le t g r an u la t io n o r p o wd e r t o t he f ac es o f the p un c h es o r t he di e wa ll s . ( c ) G l i da n t s p ro m ot e t he f lo w o f t he t ab le t g r a nu l a ti on o r p o wd e r b y r e d uc in g fr ic t io n a m o n g p a r ti c l e s. ( 5 ) C o lo r s an d d ye s d i s g u is e o f f -c ol o r d r ug s , p ro vi d e p r od uc t i d en t i fi ca t io n , a nd pr o duc e a m o r e a es t he t ic al l y a p p ea li n g p ro d uc t . F o od, d r u g , a n d c os m e ti c d ye s a r e a pp li e d as s o lu t io ns . La k es ar e d y e s t h at h a ve be e n a bs o rb ed on a h y d r ou s o xi d e . L ak e s a r e t y pi ca l l y u s e d a s d r y p o wd e r s . ( 6 ) F la vo r i n g a g en t s a re us u al l y li m i t ed to c h e wa b le t ab le t s o r t a bl e ts tha t a r e i n t en de d to di s s ol v e i n th e m ou t h . ( a ) W ate r -s ol u bl e f l a v or s u s u a ll y h a v e p oo r s t ab i li t y. F o r t hi s r e as on , fl a vo r o i ls or d r y po wd e r s a r e ty p i c al l y us ed . ( b ) F la v o r oi ls m a y be ad d e d t o t ab l et g ra n ul a ti on s i n s ol ve n ts , d is p e rs ed o n c l a ys a nd ot h er ad s orb e n ts , o r e m ul s i fi e d i n aq u e ou s g ra n ul a ti n g a ge nt s . U s u al l y , th e m a xi m um am o un t o f oi l t h at c a n b e a d d ed to a g r an ul a ti o n wi t h o u t a f f ec ti n g i ts ta ble t c h a ra c te r is ti cs is 0 . 5% - 0 . 75 % . ( 7 ) Ar t i f i c i al sw ee t e ne rs , li k e fl a vo rs , ar e t y pi c al l y us e d o nl y wi t h c h e wa b le ta b le ts o r t ab le t s t h at a re in t en d ed to d i s s ol v e in th e m ou t h . ( a ) S om e sw e e tn e ss m ay c o m e f ro m t he di l ue n t (e . g . , m a n ni t ol , l ac t os e ). O t h e r ag en t s ( e .g . , s ac c h a r in , as pa r ta m e) m a y a ls o b e a d de d . ( b ) S ac c ha r i n h a s a n u np l ea s an t a f te r t as t e. ( c ) As p a r t am e i s n o t s tab l e i n t h e p r es en ce of m o i s t u r e a nd he a t. ( 8 ) Ad s o r b e nt s (e . g ., m a g n es iu m o xi d e , m ag n es i u m c a r b on a te , b e nt o ni t e, s i li co n d io xi d e ) h ol d q uan t i ti es of f lu id in an ap p ar e n tl y d r y s ta t e. 3 . T ab l e t t yp e s a n d c las s e s. Ta b le ts a re c l as s i fi e d a c c o rd in g to th e ir r ou t e o f ad m i n is t ra t io n , d r ug de l i v e r y s ys t em , a nd f or m a n d m e t ho d o f m a nu f ac tu r e ( Ta bl e 3 - 10) . a . T ab l e ts f o r o r a l i n ges t i o n a r e d es ig n ed to be s wa l l o we d i n ta c t, wi t h th e e xc e p t i on of c h e wa b le t ab l e ts . Ta bl et s m a y be c oa t e d f o r a n um b e r o f r e a so ns : to m as k t h e t as t e , c o lo r , o r o d o r o f t h e d r u g ; t o c o n t ro l d r u g r e l ea se ; to p ro t ec t t h e d ru g f ro m t he ac id e n vir o nm e nt o f t he s t om ac h ; t o i n co r po r a te an o th e r d r ug a n d p r o vid e s eq u en ti a l re l ea s e o r a v o id i n co m p a ti bi l it y ; o r t o i m pr o v e a pp ea r a nc e. ( 1 ) C o mp r e ss e d t a bl e t s a r e f o rm e d b y c o m p r es s i o n a nd h a v e n o sp ec i al c o at i ng . Th e y ar e m a de fr o m p o wd e r ed , c r ys ta l li ne , o r g r an ul a r m at e r ia ls , a l on e o r in c o m b in a ti o n wi t h e xc i p i en t s s u ch as b i n d e rs , di s i n te g ra n ts , d i lu e nt s , a nd c o lo r an t s .
( 2 ) M u l t ip l e c o mp r e ss ed t a b le t s a r e l a y er e d o r c om p r ess i on - c o a te d . ( a ) L a ye r e d t a b l e ts ar e p r e pa r e d b y co m p r es si ng a ta bl e t g r an u la ti o n a r o un d a p re v i o us l y c om p r e s s ed g ra nu l at i on . Th e o p e ra t io n i s r ep e at e d t o p r o du c e m u l ti pl e l a y e rs . ( b ) C o mp r e ss i o n -c o at ed , o r d r y- c o a t e d , t ab l e ts a r e p re p a re d b y f ee d ing p r e vi ou s l y c om p re s s ed ta b le t s i nt o a s p ec ia l ta ble t i ng m ac h in e . Th i s m ac h in e c om p re s s es an o u t e r s h e ll ar o un d t h e t ab l e ts . Thi s p r oc es s a pp l ie s a t hi n ne r , m o re un i fo rm c o at i ng th a n s u g a r co a tin g , a n d i t c an be us ed s a fe l y wi t h d ru gs th a t a re s e ns i ti v e t o m o is t u re . Th i s p ro ce s s c a n b e us ed t o se pa r a te in c o m p a ti b le m a te r ia ls , to P.67
p r o du c e r ep e at - ac t io n o r p r ol o ng e d -a c t i on pr o du c t s or t o p r od uc e t a bl e ts wi t h a m u l ti la y e r e d a pp ea r a nc e .
Table 3-10. Tablet Types and Classes Tablets for oral ingestion Compressed Multiple compressed Layered Compression coated Repeat-action Delayed action and enteric coated Sugar coated and chocolate coated Film coated Air suspension coated Chewable
Tablets used in the oral cavity Buccal Sublingual Troches, lozenges, and dental cones Tablets used to prepare solutions Effervescent Dispensing Hypodermic Triturates ( 3 ) R e pe a t -a c t io n ta b le ts a r e l a y er e d o r c om p res s i o n -c oa t ed ta b le ts in wh i c h th e ou t er la y e r o r s h el l r a pi d l y d is i nt e gr a t e s in t he s t om ac h ( e .g . , R e p e ta bs , Sc h er i ng ; E xt e n t ab s , W ye th ) . Th e c om p o n en ts of t he in ne r la y er o r in n e r t ab l et a re in s o l ub l e i n g as t ri c m ed i a b ut s o lu bl e i n i n te s ti na l m ed ia . ( 4 ) D e la ye d - a c t i o n a nd e n t e r ic - c oa t e d t a bl e ts d e la y t h e r e le as e o f a d ru g f r o m a d o s a ge f or m . Th is de l a y i s i n te nd e d t o p re v e n t d e s t r uc t io n o f t h e d r u g b y g as t ri c j ui c e s , t o p r e v e nt i rr i ta t io n o f th e s t om ac h l in i ng b y th e d r u g , o r t o p r om o te ab s or p t io n , wh ic h i s b e tt e r i n t h e i n te s ti ne t ha n i n t h e s t om ac h . ( a ) E n te r i c -c o a te d ta bl et s ar e c o at e d a nd re m ai n i n ta c t in t he s t om ac h , bu t yi e l d t h ei r i n g re di e nt s i n t h e i n te s ti ne s ( e .g . , Ec o tr i n , Gl a xo S m i th K l in e ). E n t e ri c -c oa t ed t ab le t s a re a fo rm o f d el a y e d- ac t ion t ab l et . H o we ve r , n o t a ll d e la ye d - ac ti o n t ab l et s a re e nt e r ic o r ar e i n te n de d t o pr o du ce an en t e ri c e f f ec t . ( b ) A ge n ts us ed t o c o a t th e s e ta b le ts in c l u de fa t s, f a tt y a ci ds , wa xe s , s h el la c , a nd c e ll ul o s e ac e t a te ph t ha l at e . ( 5 ) S u ga r - c oa t ed an d ch o c o la t e -c o a te d ta b le t s a r e c om p re s s ed t ab le t s t h a t a r e c o a t ed fo r v a ri ou s re as o ns . Th e co a ti n g m a y be ad d ed t o p ro t ec t t h e d r u g f r om a i r a n d h um i di t y , to p ro vi de a b a r rie r t o a d r u g 's ob je c ti o nab l e t a s te or s m el l , o r t o i m p ro v e t he ap p ea r a nc e o f t he t ab l et .
( a ) Ta b le t s m a y b e c oa t ed wi t h a c ol o re d o r an unc o lo r ed s u ga r . Th e p r o ce s s i nc l ud es se a l co a t i ng ( wa t e r p ro o fi n g) , s u b co a t in g , s yr u p c o a ti n g ( f o r s m o o th i ng an d c ol o rin g ) , a n d p o li s hi n g . Th es e s t ep s t ak e p la c e in a s e r ie s o f m ec ha ni c a l l y op e r a te d c oa t in g p an s . ( b ) D i sa d va n t ag e s o f s ug a r -c o at e d t a bl et s i nc l ude t he ti m e a nd e xp e r ti s e r e q ui r e d f o r t he p ro c e s s a n d t h e i nc r ea s e in ta b let s i z e a nd we i g ht . Su g a rc o at e d t ab l et s m a y b e 50 % la r ge r an d h e a v ie r tha n th e o r i gi na l t a bl e ts . ( c ) C h oc ol a te -c o a te d t a bl e ts a re r ar e to d a y . ( 6 ) F il m - co a te d ta b l et s a r e c om p r es s e d t ab l et s th a t a r e c oa t ed wi t h a t hin l a ye r of a wa t e r - i ns ol ub le o r wa t e r -s ol ub l e p ol ym e r ( e .g . , h yd r o xyp r o p y l m e th y l c e l lu lo s e, et h y lc e ll u lo s e , po v i d on e , P E G ) . ( a ) Th e fi lm is u s u a ll y c ol o r ed . It is m o re du r a bl e , l es s b ul k y , a n d l es s t im e c o ns um in g t o ap pl y t h an s ug a r c oa t in g . A l th o ug h t h e f il m t y p ic a ll y i nc r eas es t a b le t we i gh t b y o nl y 2 %- 3 % , i t i nc r e as es fo rm u lat i o n e ff ic i en c y , re s i s t a nc e t o ch ip p in g , a nd ou t pu t . ( b ) F il m - c oa ti n g s ol u ti ons us ua l l y c o nt ai n a f il m fo r m er , an al lo y i n g s u bs ta n c e , a pl as t ic i z e r, a s u r fa c ta n t, op ac i fi e rs , s we e t e ne rs , fl a vo rs , c o lo r s , gl os s a n ts , a n d a v o l a t il e s ol v e n t. ( c ) Th e v o la t il e s ol v e n ts u s ed in th es e s ol u ti o ns a r e e xp e ns i v e a n d p o t en t ia ll y t o xi c wh e n re le a s e d i n to th e a t m o s p h er e . S pe c i f ic al l y fo r m u la t ed a q u eo u s d i sp e r s io n s o f p o l ym e rs ( e. g . , e th yl ce l lu l os e ) a r e n o w a va il a bl e a s a l te r n at i v es t o o rg a nic s o l v en t - ba s e d c o at in g s o lu t io ns . ( 7 ) Ai r s u s pe n si o n -c o a te d t ab l e ts a re fe d i n to a v e r t ic a l c yli n de r an d s u pp o r te d b y a c ol um n of a i r t ha t en t er s f r om th e b o t to m o f t he c y li nd e r . A s t h e c oa t in g s ol u ti o n e nt er s th e s ys te m , i t is r ap i dly a p p li ed t o t he s us p en d ed , ro t at i ng s o lid s (W u r s te r p r oc e ss ) . Ro u n di ng co a ts c an be a p pl i ed in < 1 hr wh e n bla s ts of wa r m ai r a r e re lea s ed in th e c ha m be r . ( 8 ) C h e wa bl e ta bl e ts di s in t e g ra t e sm oo t hl y a nd r ap i dl y wh e n c h e we d o r a l lo we d t o d is s o l v e i n t he m o u th . Th es e ta bl e ts c o n t ai n s pe c i a ll y c o l or e d a n d f l a v o re d m an ni t ol and y i e ld a c re am y b as e . ( a ) C h e wa bl e ta bl e ts a re e s p ec i al l y us ef u l i n f o rm u la t io ns fo r c h il d re n . ( b ) Th e y a r e c o m m on l y us e d f o r m ul ti vi t am in t ab le t s a nd a re us ed f or so m e a n t ac id s a nd an t ib i ot ic s . b . Ta b le t s us e d i n t he o ra l c a v i t y ar e a l lo we d t o d i s s ol v e in th e m ou t h . ( 1 ) B uc c a l a nd s u bl i ng u al t ab l et s a ll o w a bs o r pt i on t h ro u gh th e o r al m u c o s a a f t e r t he y d is s o l v e i n t h e b uc c a l p o uc h ( b uc c a l t ab l e ts ) o r be lo w t h e to n gue ( s u bl in g ua l t a bl e ts ) . Th es e fo rm s a r e u se f ul fo r dr u g s t ha t a r e d es t r o y ed b y g a st r ic ju ic e o r po o rl y a bs o r be d f r om th e i n te s ti nal t r ac t . E xa m p l es i nc l ud e s u bl in g ua l n i t ro gl y c e ri n ta b le t s , wh i c h di s s o l v e p ro m pt l y t o g i v e r ap i d d r ug e f f ec ts , an d b uc c a l p r oge s te r o ne ta b le ts , wh i c h d i s s ol v e s l o wl y . P.68
( 2 ) Tr o c h e s , lo z e n ge s , an d de n ta l c on es di s s ol v e s lo wl y i n t he m o ut h a n d p r o vi de p ri m a r il y l oc al e ff e c ts .
c . Ta b le ts us ed t o p re p ar e s o l ut i on s a re di s s ol ve d i n wa t e r be f o re a d m i ni s t ra ti o n . ( 1 ) E f fe r v e s c en t ta bl e ts a r e pr e pa r ed b y c o m p r es s i ng g ra nu l a r e ff e r ves cen t s a lt s o r o t he r m a t er i al s (e . g . , c i t r ic a c i d , t a r ta r ic a c id , s od i um b ic a r bo n ate ) t h a t r e le as e c a rb o n d io xi d e ga s wh e n t he y c o m e in t o c on t ac t wi t h wa t e r. C o m m e rc i al al k a li n i z in g a n al g es ic ta b le ts a re of te n m a de to e ff e r v es c e t o e n co u ra g e r a pi d d is s o l uti o n a nd a bs or p ti o n ( e .g . , A l ka - S el t z e r , Ba y e r ) . ( 2 ) O t he r ta b le t s us e d t o p r e pa r e s ol ut i on s i nc lu de d i s pe ns i ng ta b le ts , h yp o d er m i c t a bl e ts , a nd t a b le t t r i tu r a te s . 4 . P r oc es s i ng p ro bl e m s a . C ap p in g i s t he p ar t ia l o r c o m p l et e s ep a r at i on of t h e t op o r b ot t om c r o wn f r o m t he m a in bo d y o f t he t ab l et . La m i na t io n i s s e p a ra t io n o f a t ab l et in t o t wo o r m or e d is t in c t l a y er s . Th es e p r ob l em s a re u s ua ll y c au s e d b y e n t r ap m e n t o f a i r d u ri ng p r o c e s s in g . b . P ic ki ng is re m o v al of th e s u r fa c e m a t er i al of a t a b le t b y a pu nc h . S t ic kin g i s a d he s i o n o f t ab l et m a te r i al to a d ie wa l l . Th es e p r o bl em s a re c a us e d b y e xc e s s i v e m o is t u re o r t he i nc lu si on o f s u bs t a nc es wi t h lo w m e lt i ng t e m p e r at u re s i n t h e f o rm u l a ti on . c . Mo t t l in g i s u ne q ua l c ol o r d is t r ib u ti o n, wi t h l i gh t o r da r k a r ea s s ta nd i ng o u t o n a n o t he r wi s e u n ifo r m s u rf ac e . Th is p r ob l em oc c u r s wh e n a d r ug ha s a d if f e re n t c o l o r t ha n t h e t a bl e t e xc i p ie n ts or wh e n a d r u g h as c ol o r ed d e g ra d at i on p ro du c ts . Co l o ra n ts s o l v e t he p ro b lem b u t c a n c re a te ot h e r p r o bl em s . 5 . Ta b le t e v a l ua t io n a n d c o nt r o l a . Th e ge ne r a l a pp ea r a nc e o f ta b le ts is an i m p o r ta n t fa c t o r i n c on s u m e r a cc e pt a nc e . I t a ls o a ll o ws m o ni t o ri n g o f l ot - t o -l o t u n i fo r m i t y , ta bl e t -t o - ta b le t u n i fo r m i t y , a n d e le m e n ts o f th e m an u fa c tu r in g p ro c es s . Th e a p pe a ra n c e o f t h e ta bl e t i nc lu d es v is ua l i d en t it y a nd o v e ra l l a pp e a r an c e . Th e a p pe a ra nc e o f t he ta b le t i s c o n t ro l led b y m e as u re m e n t o f a t tr i b ut e s s u c h as s i z e , s hap e , c o lo r , o d or , ta s te , s u rf ac e , t e xt u r e , p h ys ic a l f la ws , c on s i s t e nc y, an d l e gi b il i t y o f m a rk in gs . b . H a rd n es s a nd r es is tan c e t o f r ia b il i t y a r e n ec es sa r y f o r t a bl e ts t o wi t h s t an d th e m ec ha n ic al s h oc k s of m a nu f ac t u re , p ac ka g in g , a nd sh ip p in g, a n d t o e ns u r e c o ns u m e r a c c e pt a nc e . H a r dn es s i nv o l v e s b o t h t ab le t d i si n te g ra t io n a n d d r ug d i s s ol u ti on . C e rt a in ta b le t s t h at a re in t en d ed to d i ss ol ve s l o wl y a r e m a de h a rd . O th e r t a bl e ts th at a r e i nt e nd e d t o d is s o l ve r a p id l y a re m a de s o f t. F ri a bi l it y i s t he te n de nc y of t h e t ab l et to cr u m b le . ( 1 ) Ta b le t ha r dn es s t es te r s m ea s u r e t h e d eg r e e o f f or c e r eq u ir e d t o b r eak a t a b le t . ( 2 ) F ri a bi la t o rs de t er m i ne f r ia bi l it y b y a ll o wi n g t he t ab l et t o r ol l a n d f al l wi t h i n a r o ta t in g t um b li ng a pp a ra t us . Th e t a bl et s a r e we i gh ed b ef o re an d a f t e r a s pe c i f ie d n u m b e r o f r ot a ti o ns , a nd t he we ig h t l os s i s d et e rm in e d . ( a ) R es is t an c e t o we i g h t l o ss i n di ca t es th e a bi l it y o f t he ta b le t t o wi t hs t an d a b r as io n d u r in g h an d li n g, p ac k a gi n g, an d s h ip pi ng . C om p re s s e d t ab l et s th a t l o se < 0 . 5% - 1% of t he i r we i g h t a re us ua ll y c on s id e r ed ac c e p ta b le .
( b ) S om e c he wa b l e t a bl et s an d m os t e f fe r ve s c en t t a bl e ts ar e h i gh l y f ri a ble a n d re qu i r e s p ec i al un i t p a c k ag i ng . c . Ta b le ts a re r ou ti n el y we i g h e d t o e ns u r e t ha t th e y c o n t ai n t he p ro p e r a m ou n t o f d r ug . ( 1 ) Th e U S P d e fi n es a we i gh t v a r ia ti o n s ta n da r d t o wh i ch t ab le t s m u s t c o nf o rm . ( 2 ) Th e s e s t an d a rd s a ppl y t o ta bl e ts th a t c on t ai n 5 0 m g o r m o r e o f d r ug s u bs ta n c e wh e n t h e d r ug s ub s ta nc e i s 5 0% o r m or e ( b y we i g ht ) of th e d o sa g e f o rm u n it . d . C o nt e nt un i fo r m i t y is e v a l u at e d t o e ns u re th a t e ac h ta bl e t c on t ai ns th e d e si r ed am ou n t o f d r u g s u b s t a nc e , wi t h li t tl e v a ria t i on am on g c on t en t s wi t h i n a b at c h . Th e U S P d e f in es c o nt e nt u ni fo r m i ty t e s ts fo r ta b le ts t ha t c o nt a in 50 m g o r le s s of d r u g s ub st a nc e. e . D is in t eg r a ti o n is e v al ua t e d t o e ns u re t ha t t h e dr u g s u bs ta nc e i s f u ll y a va i la b le fo r di s s ol u ti o n a n d a bs o rp t io n fr o m t he g a st r o in t es ti n al t ra ct . ( 1 ) A ll U S P ta bl e ts m us t p a s s a n of f ic ia l d is in t eg ra t i on te s t t ha t i s c o nd uc t ed in v i t ro wi t h s p e c i al eq u ip m e n t . ( a ) D is in t eg r a ti o n t im es fo r u nc oa t ed U S P t a bl e ts a r e a s l o w a s 2 m in ( n i t ro g l yc e r in ) to 5 m i n (a s pi r in ) . Mo s t h a ve a m axi m u m di si n te g r at i on ti m e o f le s s th a n 3 0 m i n . ( b ) B uc c a l t a bl e ts m us t d i s i n te g ra t e wi t hi n 4 hr . ( c ) E n te r ic -c o at e d t ab l ets m u s t sh o w n o e v i d en ce o f d is in t eg r a ti o n a ft e r 1 h r in si m u la t e d g as t ri c f lu i d . I n si m ul at e d i nt e st i na l fl u id , t h e y s h ou ld d i si n te g ra t e i n 2 hr pl us t h e ti m e s p ec if i ed . P.69
( 2 ) D is s o l ut io n re q ui r em e n ts in t he U S P h a ve rep l ac e d e ar l ie r di si nt e g ra ti o n r e q ui r em e nt s f o r m an y dr u g s . f . D is s ol u ti on c h a ra c t e r is t ic s a r e t es te d to de t e rm i ne d ru g a bs o rp t io n a nd p h ys io l og ic a v ai la b il i t y . ( 1 ) Th e U S P g i v es s t a nda r d s f o r t ab l et di s s ol u ti on . ( 2 ) A n i nc r ea s e d e m p h as i s o n te st i ng ta b le t d is sol u t io n a nd de t e rm in i ng d r u g b io a v a il ab i li t y ha s in c r ea s e d t h e us e o f s o ph i s t ic a te d te s t i ng s y s t em s . J . A e ro s o l p r od uc t s 1 . I nt r od uc t io n . Ae r os ol p r o du c ts , o r a e r os ol s , a re p r es s u ri z e d do s a g e f o r m s . Th e y a r e d es i gn ed t o d el i v e r d r ug s ys t em ic a ll y o r t o pi c a ll y wi t h t he a i d o f a li q ue f ie d o r p r o pe l le d g as ( p ro p el la n t ). Ae r o s o l p r od uc t s co ns is t o f a p r ess u ri z a b le c o n ta in er ( t i n- p la t ed s t ee l , a lu m in u m , gl as s , o r p la s ti c ); a va l v e t ha t al lo ws t h e p r es s u r i z e d p r od uc t t o be exp e l l e d f ro m t he c o n ta ine r ( e i th e r c on t in u ou s l y o r i nt e r m i t te n tl y ) wh e n t he ac t u a to r is p r es se d ; a nd a d i p t u be th a t c on v e y s the f o rm ul a ti o n f r om t h e bo t t om of th e c o nt ai n e r t o t h e val v e as s e m b l y . Ae ro s ol s a r e p r ep a re d b y s pe c ia l m et h od s ( c o l d f il li ng , p r e ss u re fi ll i ng ) be c a us e o f th e g as e ou s c o m po ne n ts .
2 . S y s te m i c o r p u lm on a ry d r u g d e li v e r y is p ro v i de d b y a e r os ol d ru g d el i ve r y s ys t em s , o r m e t e re d d os e i nh al e rs ( MD I s ) . Th e s e d e v ic es al l o w a dr u g t o b e i n ha l ed as a f in e m is t o f d r u g o r d r u g -c on t ai ni n g p a r ti c l e s . MD I s u se s p ec i a l m e te r i ng v a l v es to re g ula t e th e a m o un t of f or m u la t i on an d d r ug t ha t i s d i sp e ns ed wi t h e ac h d o s e ( i .e . , e ac h a c t u at i on of t h e c on t ai ne r ) . Ae r os ol p r o du c ts a r e u s e d fo r top i c a l d r ug de l i v e r y. Th e fo r m ul a ti on s r a ng e f r om s o lu t io ns to di s p e rs i on s . Me t e r i n g val v e s m a y a lso b e us e d wi t h t op ic a l a e r os ol p ro d uc ts to r eg ula t e th e a m o un t of d ru g ap p li e d p e r a pp li c a t io n . 3 . P r op el l an ts us e d i n ae r o s o l p r od uc t s a . C om p re s s e d g as es i nc l ud e c a rb on di o xi d e , n i tr o g en , an d n i tr o us o xi d e. A e r o so l p r od uc t s t ha t c on t a in c om p r es s e d g as ten d to lo se p re s s u re o v e r t i m e as th e p r od u c t is d is p en s e d . Th e d ro p i n p re s s u r e r e fl ec ts t he e xp a n s i on of th e he ad s p a c e in th e c on t ai n e r ( i .e . , i n cr e as e i n t he v o l um e t h a t t h e g as c an oc c u p y ) a s f o rm ul a ti o n is wi t h d ra wn f o r us e . F o r t hi s r e a so n , h ig he r in i ti al p res s u r es a re t ypi c al l y u s ed wi t h c om p re s s ed ga s b a se d s y s te m s th a n wi t h l i qu e fi ab l e g as - ba s e d f or m u la ti o ns . b . Li q ue f ia b le ga s e s i nc lu d e s at u r at e d h yd r oc a rbo n s ( n -b u t an e , is o bu t an e, p r o pa n e ); c h lo r o fl uo r oc ar b o ns ( C F Cs ) , i nc lu d in g t e t r af l uo r od ic h lo r oe t ha ne ( p r o pe ll a nt 1 14 ) , d ic hl o ro d i fl uo r om e th a ne ( pr o pel l a n t 12 ) , a n d t r i c h lo r o fl u o ro m e t ha ne (p r o pe l la n t 1 1 ); di m e t h yl e t h e r; an d h yd r o f lu o ro c a r b on s , s u c h as 1 ,1 , 1, 2 - fl uo r o et h ane ( p ro p el la n t 1 3 4a ) a n d 1 , 1 d i f lu o ro e th a ne ( pr o pe ll an t 15 2 a ). Th e n e ga t i v e ef f e c t of ol d e r C F C s o n a t m o s p h e ri c o z o ne an d th e po t en t ia l f o r g lo b al wa r m in g l ed t o t he wo r l d wi d e r e du c t i on in CF C p r od uc t io n u n de r th e Mo n t r e a l P ro t oc ol . Th is p l an ca ll e d f o r a ge ne r a l b a n o n C F C p ro d uc ti o n i n in du s t ri al i z e d co u nt r i es b y J an u a r y 1 9 96 . As a re s ul t , t h e us e o f C F Cs in p h a rm ac eu t ic al p ro du c ts i s b e in g p h as ed ou t . Te m p o ra r y e xe m p ti o ns f o r C F C s in MD I s wi l l e ve n t ua ll y l a ps e ( in 20 08 ) as s t a bl e, s a f e, an d ef f e c t i v e a l te r na t i ve f o r m u l at io n s a re de v e l ope d wi t h m o re ac c e p ta bl e p r o pe ll a nt s ( e .g . , h yd r o f lu o ro c a r b on s ) . 4 . A d van t ag es o f a e ro s o l p r o du ct s i nc lu d e t he c on v e n i en c e of pu s h - b ut t on d i sp e ns in g o f m ed ic a ti o n a n d t he st a bi li t y a ff o r ded b y a c lo se d , p r ess u r i ze d c o nt a in e r t h at m i ni m i z e s t h e l ik el i ho od o f t am pe r in g an d p r o te ct s t h e c o nt e nt s f r om li gh t , m oi s t u r e , a i r ( o xy g e n ) , an d m i c r ob ia l c on t am in a ti o n. A e r o so l f o rm ul a ti o ns a n d p ac k a g in g c om po n en t s (v a l v e s , a ct u at o rs ) pe r m i t a wi d e r an ge o f p r od uc ts t o be di s p en se d as s p rays , f oa m s , o r s em is o li ds . 5 . Th e pr i nc ip al di s a d v an t a ge of ae r os o l p r od uc ts is en v i r on m e n ta l (e . g. , d i sp os a l o f p r es s u r i z ed p a c k ag es , ve nt i ng of p rop e l l a nt s t o th e a t m o s p h e re ) . K . C o n t ro ll e d -r e le as e d os a ge fo r m s 1 . I nt r od uc t io n . Co n t ro ll ed - r e le as e d os a ge fo r m s a r e al s o k n o wn as d e la ye d - r el ea s e , s us t ai ne d - ac t io n , p ro l on g ed - ac tio n , s us t ai ne d - r el ea se , p r o lo n ge d - re l ea s e , t im e d- r e l ea s e , s lo w- r e l e as e , ext e n d e d - ac t io n , a nd e xt e n d e d - re l ea s e fo r m s . Th e y a r e de si g ne d t o re le a s e d ru g s ub s t a nc e s l o wl y t o p r o v id e p r o lo nge d ac ti o n i n t he bo d y .
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2 . A d van t ag es o f c o n t ro lle d - r el e as e f o rm s a . F e we r pr o bl em s wi t h p a t ie n t c o m p l ia nc e b . U se o f le s s to t al d ru g c . Fe we r l oc a l o r s y s te m ic s i de e ff ec t s d . Mi n i m a l d r u g ac c u m u la t i on wi t h l o ng - t er m d os a g e e . F e we r pr o bl em s wi t h p o t en t ia t io n o r l o ss o f d ru g ac ti vi t y wi t h lo n g -t e rm use f . I m p r o v ed t re a tm en t ef fi c ie nc y g . Mo r e r a pi d c on t r ol of th e pa t ie n t 's c o nd i ti o n h . Le ss fl uc t ua t io n i n d r ug l e v el i . Im p r o v ed bi oa v a i la b il ity f o r s o m e d ru gs j . Im p r o v ed ab il i t y to p rov i d e s p ec ia l e f fe c ts (e . g., m or n in g re li e f o f a r t hr i ti s b y b e dt im e d o s i ng ) k . R ed u c e d c os t 3 . S us t ai ne d - re l ea s e fo rm s c an be g ro up e d a c c or d i ng t o t he i r p h a rm ac e ut ic al m e c h a nis m . a . C oa t e d b ea ds or g ra nu l es ( e. g ., S pa ns u le s, G la xo S m i t h K li ne ; Se q ue ls , W ye th ) p r o du c e a b lo o d l e v e l p r o fi le s im i la r to tha t ob t ai n ed wi t h m ul t ip l e d o si n g. ( 1 ) A s o lu ti o n o f t h e d r ug s u bs t a nc e i n a n o na que o us s o l ven t (e . g ., al c o ho l ) i s c oa t ed on t o s m a ll , i n er t b ea ds , o r g ra n ul es , m a d e o f a co m b in a ti o n o f s u ga r an d s ta r c h . W hen t h e d r u g d os e is la r g e, th e s t a rt i ng g ra nu l es m a y b e c om p os ed o f t he d ru g i t s e lf . ( 2 ) S om e o f t h e g r an ul e s a r e l e ft un co a te d to p rov i d e im m e di a te r el ea se o f t h e d r u g. ( 3 ) C o at s o f a li pi d m a ter i a l ( e .g . , b e es wa x) o r a c e ll ul os ic m a t e ri al ( e. g . , e t h ylc e ll ul os e ) a r e a p pl ie d to t he re m a i ni n g g ra nu l es . So m e g ra n ul es r e c ei ve fe w c o a ts , a nd s o m e r ec e i ve m a n y. Th e va r i o us c o at i ng th ic k n es s es p r o du c e a s us ta i ne d - re l ea s e e f fe ct . b . Mi c r o en c a p s u la t io n i s a p ro c e ss b y wh ic h s ol id s , l iq u id s , o r g as es ar e e n ca se d i n m ic r os c o pi c c a ps ul es . Th in c o a ti ng s o f a “ wa l l ” m a te r ia l a r e f o r m e d a r ou n d t h e s u bs ta n c e to be en c ap s u la t ed. ( 1 ) C o ac er v a t io n i s t h e m os t c om m o n m e th o d o f m ic r o en c a ps u la ti o n. I t o cc u rs wh e n a h y d r op hi l ic s u bs t an ce is a d de d to a c o l lo id a l d r ug di sp e rs io n a n d c au s e s l a y e ri n g a nd t h e f o rm a ti on o f m i c ro c ap s ul es . ( 2 ) Fi lm - f o rm in g s ub s ta nc es t ha t a r e u s e d a s t h e c o at i ng m a te r i al i n cl ud e a va r i e t y of na t u ra l a n d s yn t h et ic po l ym e r s . Th e se m a te r i al s in c l u de s h el l ac s , wa xe s , g e la t in , s ta r c h es , c el l ul os e a c e t at e p h th a la t e , a nd e th y l c e ll u lo s e . A f t e r t h e c oa t in g m at e ri al d is s o l v es , a ll o f t he d rug i ns id e t h e m i c ro c a ps u le i s i m m ed i at e l y a v a i la bl e f o r di s s ol u ti o n a nd ab s o rp t i on . Th e t hi ck n es s o f th e wa l l c an v a r y f ro m 1 to 20 0 m m , d ep en d in g o n t he am o un t o f c o at i ng m a te r i al u s ed (3 % - 30 % o f t ot al we i g h t) .
c . Ma t r i x t a b l et s u s e in s o l ub l e p la s t ic s (e . g. , p o ly e t h yl e ne , p o l yv i n y l a c et a te , po l y m e t ha c r y la te ) , h y d ro p hi li c p ol y m e rs ( e . g ., m e t h y lc el lu l os e, h yd r o xyp r o p y l m et h y lc e llu l os e ) , o r f a tt y c om po u nd s (e . g. , va r io us wa xe s , g l yc e r y l t r is te a r at e ) . E xa m p le s i nc lu d e G r a du m e t ( A b b ot t ) an d Do s p a n ( A ve n t is ) . ( 1 ) Th e m os t c om m o n m e t h od of p re p ar a ti o n is m i xi n g of t he dr u g wi t h th e m a t ri x m a t e ri a l f ol lo we d b y c om p re s s io n o f th e m a t e ri a l i nt o ta bl e ts . ( 2 ) Th e pr im a r y do s e , or t h e p o r ti o n o f t he d ru g to b e re l ea s e d i m m ed ia t ely , i s p l ac ed on th e ta bl e t as a l a y e r, o r c oa t . Th e r es t of th e d o s e is re le as ed s l o wl y f r om th e m at r i x. d . O sm o ti c s y s t e m s i nc lu d e t h e O r o s s y s t em ( A lz a ) , wh i c h i s a n o ra l o sm o ti c p um p c om po s e d o f a c o r e t a bl e t a nd a s e m ip e rm ea b le c o at i ng tha t h a s a s m a ll ho l e ( 0 .4 m m in di am e te r ) fo r dr u g exi t . Th e h o le is p ro du ce d b y a l as e r b ea m . E xa m p le s i n c l ud e G lu co t r ol XL ( gl ip i z i de e xt e n d ed - r el ea s e t a b le ts , P fi z e r ) a n d P r oc a r d ia XL ( n if e di pi n e e xt e n d e d- r e le as e t a bl e ts , P f i ze r ) . ( 1 ) Th i s s y s t em r eq ui r es o n l y osm o ti c p r es su r e t o b e e f f ec ti v e . It is e ss e nt i al l y in d ep en d en t o f p H c ha n ge s i n t he en v i r o nm en t . ( 2 ) Th e dr u g - re le as e ra te c a n b e c h an ge d b y c han g in g th e t a bl e t su r f ac e a r e a , t he na t u re of t he m e m b ra ne , or t he di am e ter o f th e d r ug - r el e as e a p e r tu r e. e . I on - e xc h an g e r es i ns c a n be c om p le xe d wi t h d ru g s b y p as s a ge of a c a ti o ni c d r ug s o lu t io n t h ro u g h a c ol um n t h at c o n ta i ns th e re si n . Th e d ru g i s c om p le xe d t o th e re s i n by r e p l ac em en t o f h y dr o ge n at om s . E xa m p l es i n cl ud e Io n am i n c a ps ul es ( C el l te c h ; re s i n c om pl exe s o f p he n te r m i ne ) an d t h e Pe n nk in e ti c s y s t em (C e l l te c h ) , wh ic h i nc o r po ra t es a p ol ym e r b a r ri e r c o at i ng an d b e ad te c h n ol o g y in ad di t io n to th e i on - e xc h a n ge m ec h an is m . P.71
( 1 ) A f te r th e c om po n en ts a r e c om pl e xe d , t he re s in - d r ug c o m p le x i s wa s h ed a n d t a bl e te d , e nc ap s u l ate d , o r s u sp en d ed in an aq u e ou s ve h ic le . ( 2 ) R el e as e o f d r ug f r om t h e c om pl e x d e p en ds on t h e i on ic en v i r o nm en t wi t h i n th e g as t r oi n te s ti na l t ra c t an d o n th e p r op er t i es of t he re s i n . Us ua l ly , r e l ea se is gr e at e r i n t h e h i gh l y ac id ic s t om a ch tha n in th e l es s a c i di c sm al l i n t es ti n e. f . C o m p le x f o r m a ti on is u s ed fo r c e r ta i n d r ug s ub s ta nc e s t ha t c om bi n e c h em ic al l y wi t h o t h er age n ts . Fo r e xa m pl e , h y d r ox y p r o p y l - β - c y c l o de xt r i n f o r m s a c h em ic a l c o m p l ex t h a t c an be on l y sl o wl y s ol u bl e f r om bo d y fl u id s , d e p en di n g o n t he p H o f th e en v i r on m e n t . Ta n n ic a c id (i . e ., t an na t es ) c om p le xe s wi t h t he am ino g r ou ps of we a k b as es d i s s ol ve at a s lo w r a t e i n t h e g as t r oi n te s ti na l t r ac t, t h er e b y p r o v i di ng f o r a p r o lo n ge d re le as e o f dr ug . E xa m p l e s o f t h e l at t e r i nc l ud e b r om ph e ni r am in e ta n n at e ( Br o v e x, A t h l on ) a n d c hl o rp h en i ra m i n e/ p he n y l e ph r in e t a nn a te s ( Ry n a t a n, W alla c e ) . P.72
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 28 : E a c h o f t he qu es t i o ns , s ta t em en t s , o r i n co m p l et e s ta t em e nt s i n t h is s ec t io n c an be c o r re c tl y a ns we r e d or c om p le t ed b y on e o f t h e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r . 1 . W hi c h s u bs t an c e i s c l a ss i f ie d a s a w e ak e le c t r o l yt e ? ( A ) g lu c o s e ( B ) u r ea ( C ) e p he d ri n e ( D ) s od i um c hl o ri d e ( E ) s uc ro s e V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . T h e p H va l u e is ca l cu l a te d m a t h em a ti c al l y a s t h e ( A ) l og of t he h y d ro xy l i o n ( O H - ) co nc e nt r a ti on . -
( B ) n eg a ti v e lo g o f th e OH c o n c e n tr a ti o n. +
( C ) l og o f t he h y d ro g en io n ( H ) c on c en t ra t io n . +
( D ) n e ga ti v e l og of th e H c o nc en t r at io n . +
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( E ) r a ti o o f H / O H c on c en t r a ti o n. V i e w A n s we r 2 . T h e a n sw e r i s D [ se e] . 3 . W h ic h p r o p e r t y i s c l a ss i f ie d a s c o l li g a ti ve ? ( A ) s ol ub i li t y of a s ol u te ( B ) o s m ot ic p re s s u re +
( C ) h y d r og e n i on ( H ) c on c en t r at i on ( D ) d is s o c i a ti o n o f a s olu t e ( E ) m i s c i bi li t y o f t he li q ui d s V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . 4 . T h e c o ll i g a t i ve p r o pe r t i e s o f a s o l u ti o n a r e re l a ted t o t he ( A ) p H of th e s o lu ti o n. ( B ) n um be r of io ns in t he s ol u ti o n. ( C ) t o ta l n um b e r o f s ol ute p a rt ic l es i n t h e so l ut i on . ( D ) n um b er o f u ni on i z e d m o le cu l es i n t h e s o l ut i on. ( E ) p K a o f t h e s o l ut i on . V i e w A n s we r 4 . T h e a n sw e r i s C [ se e] . 5 . T h e p H o f a b u f fe r s ys t e m c a n b e ca l cu l a te d w i th t h e ( A ) N o y e s -W hit n e y e q ua ti o n . ( B ) H e nd e rs o n - Ha s s el b al c h e qu a ti o n. ( C ) Mi c h a e li s- Me n t e n e qu a t io n . ( D ) Yo u n g e q ua t io n . ( E ) S t ok es eq u at i on . V i e w A n s we r 5 . T h e a n sw e r i s B [ se e] . 6 . W h ic h m e c ha n is m i s m o s t o f t e n re s po n s ib l e f o r ch e m ic a l d e g ra d a ti o n ? ( A ) r ac em i z a ti o n
( B ) p ho t ol y s is ( C ) h y d r ol y s is ( D ) d ec a rb o xy l a t i o n ( E ) o xi d a t io n V i e w A n s we r 6 . T h e a n sw e r i s C [ se e] . 7 . W h ic h e q u a ti o n i s u s ed t o p r e d i ct t h e s ta b i li t y o f a d r u g p r o du c t a t r o om t e m pe r a t u re f r om e x p e ri m en t s a t ac c el e ra t e d te m pe r a t u re s ? ( A ) S t ok es eq u at i on ( B ) Yo u n g e q ua t io n ( C ) A r r h en iu s e q ua t io n ( D ) Mi c h a e li s- Me n t e n e qu a t io n ( E ) H i xs o n - C r o we l l e qu at i o n V i e w A n s we r 7 . T h e a n sw e r i s C [ se e] . k kk 8 . B a se d o n t h e r e la t i o n b e tw e e n t h e d eg r e e o f io n i z a t i on a nd t he so l u bi l i t y o f a w e ak ac i d , t h e d r u g as p i r in ( p K a 3 .4 9 ) w i l l b e m os t so l u bl e a t ( A ) p H 1. 0 ( B ) p H 2. 0 ( C ) p H 3. 0 ( D ) p H 4. 0 ( E ) p H 6. 0 V i e w A n s we r 8 . T h e a n sw e r i s E [s e e] . 9 . W h ic h s o l u t io n i s us e d a s a n as t r i n ge n t ? ( A ) s t ro ng io d in e s ol u ti on U S P ( B ) a lu m i n um a c e t a te top i c a l s ol u ti on U S P ( C ) a c e t ic a c i d N F ( D ) a r om a ti c am m o n ia s p i r it U S P ( E ) b en z a lk o ni um c h lo r ide s o l ut i on N F V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . 1 0. T he pa r t i c le s iz e o f th e d i s pe r s e d s ol i d i n a s us p e ns i o n i s u s ua l l y g r e a t e r t ha n (A) 0.5 µm (B) 0.4 µm (C) 0.3 µm (D) 0.2 µm (E) 0.1 µm V i e w A n s we r 1 0 . T he a nsw e r i s A [ se e] . 1 1. I n t h e e x t em p o ra n eo u s p r e p a r at i o n o f a s us p en s i o n, le vi g a t i on i s u sed t o ( A ) r e du c e th e z e ta po t en t i al . ( B ) a v o id ba c te r ia l g r o wt h . ( C ) r e du c e pa r t ic le s i z e . ( D ) e n ha nc e v is c os i t y . ( E ) r e du c e v i s c os it y . V i e w A n s we r 1 1 . T he a nsw e r i s C [ se e] . 1 2. W hi c h c o mp o u nd i s a n a t u r al em u l si f yi n g a g en t ? (A) acacia ( B ) l ac t os e
( C ) p ol y s o rb a te 2 0 ( D ) p ol y s o rb a te 8 0 ( E ) s or b it a n m o n op a lm ita t e V i e w A n s we r 1 2 . T he a nsw e r i s A [ se e] . A c ac i a ,P .7 3
1 3 . Va n is h i ng c r ea m i s a n o in t me n t th a t m a y b e c la s si f i ed as ( A ) a wa t e r -s ol u bl e b as e. ( B ) a n o le a gi no u s b as e. ( C ) a n a bs o rp t io n b a s e . ( D ) a n e m u ls i on ba s e . ( E ) a n o le ic ba s e . V i e w A n s we r 1 3 . T he a nsw e r i s D [ se e] . 1 4. R e ct al s u pp o si t o r i es i n t e nd e d f o r ad u l t u s e u s u al l y w ei g h a p p ro x im a t e l y ( A ) 1 g. ( B ) 2 g. ( C ) 3 g. ( D ) 4 g. ( E ) 5 g. V i e w A n s we r 1 4 . T he a nsw e r i s B [ se e] . 1 5. I n t h e f u s i on me t h od o f m a k in g c o c oa bu t t e r s up p o s it o r i es , w h ic h s u bs t a n ce is mo s t l i ke l y t o b e us e d to lu b r i ca t e the m ol d ? ( A ) m i n e ra l o il ( B ) p r op y l e ne gl y c ol ( C ) c et y l al c o h ol ( D ) s te a r ic a c i d ( E ) m ag ne s i um s i li c a t e V i e w A n s we r 1 5 . T he a nsw e r i s A [ se e] . 1 6. A ve r y f i n e p ow de r e d c h e mi c al i s d e fi n ed as o n e th a t ( A ) c om pl e te l y pa s s es thr o u gh a # 80 s i e v e . ( B ) c om pl e te l y pa s s es thr o u gh a # 12 0 s ie v e . ( C ) c om pl e te l y pa s s es thr o u gh a # 20 si e ve . ( D ) p as s e s t h ro u gh a # 60 si e ve a n d n ot m o r e t h an 4 0% th r o ug h a #100 sieve. ( E ) p as s e s t h ro u gh a # 40 s i e v e a n d n ot m o r e t h an 6 0% th r o ug h a # 6 0 s ie v e . V i e w A n s we r 1 6 . T he a nsw e r i s B [ se e] . 1 7. W hi c h t e c hn i q ue is t yp i c a l l y u s e d t o mi l l ca m p ho r ? ( A ) t r it u r at i on ( B ) l e v ig a ti o n ( C ) p ul v e r i z a ti o n b y in t e rv e n t i on ( D ) g e om et r ic di lu t io n ( E ) a t t ri ti o n
V i e w A n s we r 1 7 . T he a nsw e r i s C [ se e] . 1 8. T he d is p e ns i n g p h a r ma c is t us u a ll y b l e n d s po t e nt p ow de r s w i th a la r g e a mo u n t o f d i l u en t b y ( A ) s pa t ul a ti on . ( B ) s i f t in g . ( C ) t r i tu r a ti on . ( D ) g e om et r ic di lu t io n . ( E ) l e v ig a ti o n. V i e w A n s we r 1 8 . T he a nsw e r i s D [ se e] . 1 9. W hi c h t yp e o f p a p e r b e s t p r o t ec t s a d i vi de d h yg r o s c o p i c p ow d e r? ( A ) wa xe d p a pe r ( B ) g la s s in e ( C ) wh i t e bo n d ( D ) b lu e b o nd ( E ) v e g e ta bl e p a rc hm e nt V i e w A n s we r 1 9 . T he a nsw e r i s A [ se e] . 2 0. W hi c h c a ps u l e s iz e h as t h e sm a ll e s t c ap a ci t y? (A) 5 (B) 4 (C) 1 (D) 0 ( E ) 0 00 V i e w A n s we r 2 0 . T he a nsw e r i s A [ se e] . 2 1. T he sh e l l s o f s o f t g e l a ti n ca p su l es ma y b e m ad e e l as t i c o r p la s tic - l i ke b y t h e a d d i t io n of ( A ) s or b it o l. ( B ) p o v id o ne . ( C ) p ol y e t h y l en e g l y c o l (P E G ) . ( D ) l ac t os e. ( E ) h y d r o xy p r o p y l m e t h y lc e ll ul os e . V i e w A n s we r 2 1 . T he a nsw e r i s A [ se ea n d] .2 2 . T he U n i te d S ta t e s P h a r m ac o pe i a ( U S P ) con t e n t u n i fo r m i t y t e s t f o r t a b l et s is us e d t o e n s u re w h i ch q ua l i t y? ( A ) b io e qu i v al e nc y ( B ) d is s o lu t io n ( C ) p o te nc y ( D ) p u ri t y ( E ) t o xi c i t y V i e w A n s we r 2 2 . T he a nsw e r i s C [ se e] . 2 3. Al l o f t h e f ol l ow i ng s t a t em e n ts ab o u t c he mi c a l d e g ra d a ti o n a r e t rue e xc e p t ( A ) a s t em pe r a tu r e i nc r ea s es , d e gr a da t io n d ec r ea s es . ( B ) m os t d r ug s d eg r ad e b y a f ir s t- o r de r pr o ce s s . ( C ) c he m i c a l d e gr a da t ion m a y p r od uc e a t o xi c p ro d uc t . ( D ) c he m i c a l d e gr a da t ion m a y r e s u l t in a l os s o f a c ti v e in g r ed ie n ts . ( E ) c he m i c a l d eg r a da t ion m a y a f fe c t t he th e r ap eu t ic ac t i v it y o f a drug.
V i e w A n s we r 2 3 . T he a nsw e r i s A [ se ea n d] .k A e
-Ea/RT
k A E a RT 2 4. Al l
o f t h e f o l low i n g s t a te me n t s c o nc e r n in g z e r o -or d e r d eg r a d at i o n a r e t r u e e x c ep t ( A ) i ts r at e i s i nd e pe nd en t o f t he c o nc en t r at i on . ( B ) a pl ot o f c o nc e nt r a ti on ve r s u s t im e yie l ds a str a i gh t l i ne on r e c ti li n ea r pa p er . ( C ) i ts ha l f -l i fe is a c h ang i ng pa r am e te r . ( D ) i ts c o nc e nt r a ti on r em a i ns un c h a ng ed wi t h r esp e c t t o t im e. ( E ) t h e s l o pe of a p lo t o f c on c e n t ra t io n ve rs us tim e y ie l ds a r at e c o ns ta n t . V i e w A n s we r 2 4 . T he a nsw e r i s D [ se e] . C t P . 74
2 5 . Al l o f t h e f o l low i n g s t a t em e n ts ab o u t f i r s t -o r d e r de g r a da t i on a r e t r u e ex c ep t ( A ) i ts r at e i s d ep e nd en t o n th e c on c en t ra t io n . ( B ) i ts ha l f- l if e i s a c h ang i ng pa r am e te r . ( C ) a pl o t o f t h e l og a ri t hm o f c o nc e nt r a ti o n v e r sus t im e y i e ld s a s t r ai g ht li ne . ( D ) i ts t 9 0 % is in d ep e nd en t o f t he c o nc en t r at i on . ( E ) a pl ot o f t he lo g a ri thm o f co nc e nt r a ti o n v e r s us t im e a ll o ws th e r a t e c on s ta n t t o b e d et e rm i ne d . V i e w A n s we r 2 5 . T he a nsw e r i s B [ se e] . t k t2 6 . A sa t i s fa c t o r y s u p p os i t o r y b a s e m us t m e e t a l l o f th e fo l l ow ing c r i t e ri a e x ce p t ( A ) i t s ho ul d h a v e a n ar ro w m e l ti n g r a ng e . ( B ) i t s ho ul d b e no ni r r it at i n g a nd no ns e ns it i z i ng . ( C ) i t s ho u ld di s s ol v e o r d i s i n te g ra t e r a pi dl y i n t he b od y c a v it y. ( D ) i t s ho u ld m e lt < 3 0 ° C. ( E ) i t s ho ul d b e i n e rt . V i e w A n s we r 2 6 . T he a nsw e r i s D [ se e] . 2 7. C o co a b u t t e r ( t h e o b ro m a o i l ) e xh i b its a l l o f th e fo l l ow in g p ro p e r t ie s ex ce p t ( A ) i t m el ts a t t em pe r a tur e s b e t we e n 3 3 ° C a nd 35 ° C . ( B ) i t i s a m i xt u r e o f gl y c e r i de s . ( C ) i t i s a p o l y m o r ph . ( D ) i t i s u s e f ul i n fo r m u lat i n g r ec t al s u pp os i to r ie s . ( E ) i t i s s o l ub le in wa t e r . V i e w A n s we r 2 7 . T he a nsw e r i s E [s e e] . T he o b r oma c ac a o. 2 8. U n i t e d St a t es P ha r m aco p e ia ( U S P ) te s ts t o e ns u r e th e qu a li t y o f d r u g p r o d u c ts in t ab l e t f o r m i n c lu d e a l l o f th e fo l l ow i ng e xc ep t ( A ) d is in t eg r a ti on . ( B ) d is s o lu t io n . ( C ) h a rd n es s a nd f ri ab i li ty. ( D ) c on t en t u n if o rm i t y . ( E ) we i g h t v a ri at i on .
V i e w A n s we r 2 8 . T he a nsw e r i s C [ se e] . D i r e c ti o ns f o r qu e s ti o ns 2 9 - 42 : Th e q u es ti o ns and i nc om pl e te s t a te m e n ts i n t h is s ec t io n c an be c o r re c tl y a ns we r e d o r c om p le t ed b y on e o r m o re o f th e s ug g es te d a ns we r s . C h o os e th e a ns we r , A- E . 2 9 . Fo r m s o f w a te r t ha t a r e su i t ab l e f o r us e i n p a r e n te r a l p r e pa r a t i on s i n c l ud e I . p u r if i e d w a t e r U S P. I I . w a te r f o r in j ec t i on US P . I I I . s t e r i le w a te r f o r i n je c t i on U S P . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 9 . T he a nsw e r i s D [ se e] . 3 0. T he pa r t i c le s in an i de a l s u s pe n si o n s h o ul d s a t is f y w h ic h of t he f o ll ow in g c r i te r i a? I . T he i r si z e s ho u l d b e u n i f o r m. I I . Th e y s h o u l d b e s t a t io n a r y o r m o ve r a n do m ly. I I I . Th e y s h o u l d r e ma i n d i s c re t e . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 0 . T he a nsw e r i s E [s e e] . 3 1. T he se d i me n t a ti o n o f p a r t i c le s i n a s us p en s io n ca n be mi n i mi z e d b y I . a dd i n g s od i u m b en z oa t e . I I . i nc r e as i ng t he vi s c os i t y o f t h e su s pe n s io n . I I I . r ed u ci n g t h e p a r t ic le s iz e o f t he ac t i ve in g re d i en t . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 1 . T he a nsw e r i s D [ se e] . 3 2. I ng r ed i e n ts t ha t ma y b e u s e d a s s u sp e nd i n g a ge n t s i n c lu d e I . m et h yl c e l l u l os e . I I . ac a ci a . I I I . ta l c. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t
V i e w A n s we r 3 2 . T he a nsw e r i s C [ se e] . 3 3. M e c ha n i sm s th a t a r e t h o u g ht t o p r o vi d e s t a bl e em u l si f i ca t i on s i n c lud e t he I . f o r ma t i on o f i n t e r fa c ia l f i lm . I I . l ow e ri n g o f in t e r f ac ia l t en s i on . I I I . p re s en c e o f c h a rg e o n t he i on s . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 3 . T he a nsw e r i s E [s e e] . 3 4. N o ni on i c su r f a ce - ac t i ve a g e n ts us e d a s s yn t h e t i c em u l si f i e rs i nc l ud e I . t r a ga c an t h . I I . so d i um la u r yl s u l f a te . I I I . s o r b i ta n e s t e rs ( S pan s ) . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 4 . T he a nsw e r i s B [ se e] . 3 5. Ad va n t a g e s o f s ys t e m i c d r u g ad m i ni s t r at i o n b y r e c t a l s u pp o si t o r ie s inc l u de I . a vo i da n ce o f f i r s t -p as s e ff e c ts . I I . su i t ab i l i t y w h en t he o r a l r o ut e is no t f ea s ib le . I I I . p re d ic t a bl e d ru g r ele a s e a nd a bs o r p ti o n . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 5 . T he a nsw e r i s C [ se ea n d] .3 6 . T ru e s ta t em e n ts a b o u t t h e m i ll i n g o f p ow d e rs i nc l ud e I . a fi n e p a r t ic l e s iz e i s e s se n t ia l if t he l ub r i c an t i s t o f un c t io n p r o p e r l y. I I . an i nc r e as e d s u r fa c e a r e a m a y e n h a n c e th e d i s so l u t io n r at e . I I I . m i l li n g m a y c a u s e de g r a da t i o n o f th e r mo l ab i l e d r u g s. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 6 . T he a nsw e r i s E [s e e] . P . 75
3 7 . Su b s ta n ce s u s ed t o i n s ul a t e p ow de r c om po n e n ts t ha t l iq u e f y w h en m i x ed i nc l ud e I . t a lc . I I . ka o l in . I I I . li g h t m ag n es i um o xid e . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 7 . T he a nsw e r i s D [ se e] . 3 8. A c e ra m i c m o r ta r ma y b e p r ef e r a bl e to a g l ass m o r ta r w h e n I . a vo la t i le o il i s a dd e d t o a p ow d e r m ix t u r e . I I . co l o r ed su b s ta n ce s ( d ye s ) a r e m ix e d i n t o a p ow d e r . I I I . c o mm i n ut i o n i s d e sir e d i n a d di t i on t o m i xi ng . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 8 . T he a nsw e r i s B [ se e] . 3 9. D i vi de d p ow de r s m a y b e d is p en s ed i n I . i nd i vi d u al - d os e pa cke t s . I I . a b u lk co n t ai n e r . I I I . a p e r fo r a t ed , s i f t e r -t yp e c o n t a i ne r . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 3 9 . T he a nsw e r i s A [ se ea n d] .4 0 . T ru e s ta t em e n ts a b o u t t h e f u nc t i o n o f ex c i p ie n ts u se d i n ta b l et f o r m u la t i on s i n c lu d e I . b in d e r s p r o mo t e g r a nu l a t i on du r i n g t h e w et g r a n u la t i on p r oc e ss . I I . g li d an t s h e l p p r om o te t h e f l ow of t he t ab l e t g r a n u la t i on d u r in g m a n u fa c tu r e . I I I . lu b r ic a n ts h el p th e p a t i en t sw al l ow th e ta bl e t s . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 0 . T he a nsw e r i s C [ se e] . 4 1. W hi c h m a nu f a c tu r i n g va r i a b l e s w o u ld b e l i kel y t o a f f e c t th e di s so l u ti o n o f a p r e d ni s o ne t a b l e t i n t h e b o d y? I . t h e a mo u n t a nd t yp e o f b i nd e r a d d ed
I I . t he am o un t an d t yp e o f d is i n te g r an t ad d e d I I I . th e fo r c e o f co m p res s i on u se d d u r i n g t a ble t i n g A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 1 . T he a nsw e r i s E [s e e V I .2 . b . (3 )] .4 2 . Ag e n ts t ha t m a y b e u s ed t o c o a t e nt e r i c - co a te d ta b l et s in cl u d e I . h yd r o x yp r o p yl m e t h yl c e l lu l os e . I I . ca r b ox ym e t h yl c e l l u l o s e . I I I . c e l lu l os e a c e ta t e p ht h a l a te . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 2 . T he a nsw e r i s B [ se e] . D i r e c ti o ns f o r qu e s ti o ns 4 3 - 46 : E a c h o f t h e f ol l owi n g t a bl e t -p r oc es si ng pr o b le m s c a n b e t he r es ult o f o n e t h e f ol l o wi n g r ea s o ns . Th e p r oc es si n g p ro b lem s m a y b e u se d m o re t ha n o n ce o r n ot a t al l . Ch o os e t he b es t a ns we r , A- E . 4 3 . Pi c ki n g A e xc e s s i v e m o is t ur e i n t h e g r a nu la t io n B e n t ra pm e nt o f a ir C t a bl e t f r ia b il i t y D d e g ra d ed dr u g E t a bl e t h a rd ne s s V i e w A n s we r 4 3 . T he a nsw e r i s A [ se e] . 4 4. M o t t l in g A e xc e s s i v e m o is t ur e i n t h e g r a nu la t io n B e n t ra pm e nt o f a ir C t a bl e t f r ia b il i t y D d e g ra d ed dr u g E t a bl e t h a rd ne s s V i e w A n s we r 4 4 . T he a nsw e r i s D [ se e] . 4 5. C a pp in g A e xc e s s i v e m o is t ur e i n t h e g r a nu la t io n B e n t ra pm e nt o f a ir C t a bl e t f r ia b il i t y D d e g ra d ed dr u g E t a bl e t h a rd ne s s V i e w A n s we r 4 5 . T he a nsw e r i s B [ se e] . 4 6. S t ic k in g A e xc e s s i v e m o is t ur e i n t h e g r a nu la t io n B e n t ra pm e nt o f a ir C t a bl e t f r ia b il i t y D d e g ra d ed dr u g E t a bl e t h a rd ne s s
V i e w A n s we r 4 6 . T he a nsw e r i s A [ se e] . D i r e c ti o ns f o r qu e s ti o ns 4 7 - 49 : E a c h o f t h e f ol l owi n g p r oc es s e s c an be de sc r i be d b y o ne of t he f o l lo wi n g c om m i n ut i on pro c ed u re s . Th e p ro c e s s es m a y b e us e d m o r e th an o n ce o r n ot a t al l . Ch o os e t he b es t a ns we r , A- E . 4 7 . R ub b i ng o r g r i n di ng a su b s ta nc e in a m o r ta r t h a t h as a ro u g h i n ne r s u r f a ce A t r i t u r a ti o n B s p at ul a ti o n C l e v i ga t io n D p u l v e ri z a t io n b y i nt e r ve n t io n E t um b li n g V i e w A n s we r 4 7 . T he a nsw e r i s A [ se e] . 4 8. R e du ci n g an d s u b d i vi di n g a su b s ta n ce b y a d d i n g a n e a si l y r e m o ve d s o l ve n t A t r i t u r a ti o n B s p at ul a ti o n C l e vi ga t io n D p u l ve ri z a t io n b y i nt e r ve n t io n E t um b li n g V i e w A n s we r 4 8 . T he a nsw e r i s D [ se e] . 4 9. Ad d i ng a su i t ab l e a ge n t to f or m a p as t e a n d t h e n r u b bin g o r g ri n d in g th e pa s te i n a mo r t a r A t r i t u r a ti o n B s p at ul a ti o n C l e vi ga t io n D p u l ve ri z a t io n b y i nt e r ve n t io n E t um b li n g V i e w A n s we r 4 9 . T he a nsw e r i s C [ se e] . P . 76
D i r e c t i on s fo r q ue s t io ns 5 0 -5 3 : E ac h o f th e fo llo wi n g c o n t ro ll e d -r e le as e d os a ge f o r m s i s re p re s e n te d b y o n e o f th e f o ll o wi n g d r ug p r o du c t s . Th e do s a g e f or m s m a y b e us ed m o r e t ha n o nc e o r n ot at al l . Ch oo s e t he b e s t a ns we r , A- E . 5 0 . Io n am i n c ap s u le s A m a t r i x f o r m ul a ti on s B i o n -e xc h a n ge re s i n c om p le x C d r u g c o m p l e xe s D o sm o ti c s y s t em E c oa t ed be a ds o r g ra n ul e s V i e w A n s we r 5 0 . T he a nsw e r i s B [ se e] . 5 1. T ho r az i n e S p an s ul e c a ps u l es A m a t r i x f o r m ul a ti on s B i o n -e xc h a n ge re s i n c om p le x C d r u g c o m p l e xe s D o s m o ti c s y s t em E c oa t ed be a ds o r g ra n ul e s V i e w A n s we r 5 1 . T he a nsw e r i s E [s e e] . 5 2. R yn a t a n pe d i a t ri c s u sp e ns i on A m a t r i x f o r m ul a ti on s
B i o n -e xc h a n ge re s i n c om p le x C d r u g c o m p l e xe s D o sm o ti c s y s t em E c oa t ed be a ds o r g ra n ul e s V i e w A n s we r 5 2 . T he a nsw e r i s C [ se e] . 5 3. P r o car d i a X L A m a t r i x f o r m ul a ti on s B i o n -e xc h a n ge re s i n c om p le x C d r u g c o m p l e xe s D o sm o ti c s y s t em E c oa t ed be a ds o r g ra n ul e s V i e w A n s we r 5 3 . T he a nsw e r i s D [ se e] . P . 77
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C [ s ee I V . A . 1. a ; I V . A .3 . d] . G l u c os e, u re a , a nd s u c ro s e a r e n on el e c t r ol y t e s . S o d iu m c hl o ri d e is a s t ron g e l ec t r ol y t e . E l ec t ro l y t es a r e s u bs ta nc e s t ha t fo rm i o ns wh e n d is s o l v ed in wa t e r . Th u s t he y c a n c on d uc t an e le c t r ic c u r r en t t h r ou gh t he s o lu t io n . I o ns a r e p a r ti c l e s t h a t b ea r el ec t r ic al c h a rg e s : C a ti o ns a r e p os i ti v el y c ha r g ed , a n d a ni on s ar e n e g at i vel y c ha r g ed . St r on g el ec t r ol yt es a re c om pl e t el y i on i z ed in wa t e r at a l l c o nc en t r at i on s . W eak e le c t ro l y t es (e . g ., ep h ed r in e ) ar e o n l y p a r ti a ll y i oni z e d at m os t c o nc en t r at i on s . B ec a us e n on e le ct r o l y te s d o n o t f o rm io ns wh e n i n s o l u ti on , t h e y a re no nc o nd uc t o rs . 2 . T he an sw e r is D [ s ee I V . A . 3. b ]. Th e p H is a m e as u r e o f th e ac id i t y , o r h yd r o ge n io n c o nc en t r at i on , o f an a q u eo us +
s o lu t io n . Th e p H i s t he lo g a ri t hm of th e re c i p r oc a l of th e h y dr o ge n i o n ( H ) c o nc en t r at i on e xp r e s s ed i n m ol es pe r li t er . B ec au s e t he lo g a ri t hm o f a r ec i p ro c a l e q u al s t he ne g at i v e l o gar i t hm of t he nu m b e r , t he p H is t he ne g at i v e l o ga r it h m o f t h e +
H c o nc en t r at i on . A p H of 7 . 0 in d ic a te s n eu t r al it y. A s th e p H de c re as es , the ac i di t y i n c re as es . Th e p H of a rte r i al bl o od is 7 . 35 - 7 .4 5 ; o f u ri n e, 4. 8 - 7. 5 ; o f g as tr i c j ui c e , a p p ro xi m a t el y 1 . 4; an d of c er e b ro s p i na l f lu i d, 7 .35 - 7 . 40 . Th e co n c e p t o f pH wa s i n t ro d uc ed b y S ör e ns en in t he ea r l y 19 0 0s . A lk a lin i t y is th e n e ga t i ve l og a ri t hm o f -
[ O H ] an d i s i n v e rs el y r e la t e d t o a ci di t y. 3 . T he an sw e r is B [ s ee I V . A . 2. d ]. O s m ot ic p re s s u re is an exa m p l e of a c ol li g at i v e pr o p e rt y . Th e os m o t ic p r es s u r e i s t h e m ag n it u de of p re s s u re n ee d ed to s t o p os m o s is ac r os s a s em ip e rm e ab le m em b r an e b e t we e n a s olu t i on an d a pu r e s ol ve n t. Th e c ol li g at i v e p r op e r ti es o f a s o lu t io n d e pe nd on t he to t a l n um be r of di s s oc ia te d an d u n di s s oc ia t ed s o lu t e p a r ti c l e s . Th es e p r o pe r t ie s a r e i n de pe n de n t o f t he s i z e o f t he so lu t e . O t he r c o ll ig a ti v e p ro p e rt ie s o f s o lu t es a r e re d uc ti o n i n th e va po r p re s s u re of th e s ol u ti o n, e l e va ti on o f i ts bo il i ng po i n t, an d d e p re s s io n o f i ts f re e z i ng po i nt . 4 . T he an sw e r is C [ s ee I V . A . 1. b ]. Th e c ol l ig a ti v e pr o pe r t ies o f a s ol u ti o n a re r el a te d t o t h e t ot a l n um be r of s o lu t e p a r ti c l e s t ha t i t c o nt a in s . E xa m p l es o f c o l li ga t i v e p r o pe r t ie s a r e t he os m o ti c
p r e ss u re , l o we r i ng of t he v a p o r p r es su r e , e le v a t ion o f t h e b oi li n g p oi n t, and d e p re ss io n o f th e fr e e z ing , o r m e l ti n g, po i nt . 5 . T he an sw e r is B [ s ee I V . A . 3. e ]. Th e H e n de r s o n - H as s e lba l c h eq u at i on fo r a we a k a c i d a n d i ts s a lt is a s f ol l o ws :
wh e r e p K a i s t he ne g a ti v e l og of t he di s s oc ia t io n c o ns ta n t o f a we a k a ci d a n d [ s al t ] /[ ac i d] is th e ra t io of t h e m o l ar c o nc e nt r a ti on o f s a lt an d a ci d u s e d to p r e pa r e a b u f fe r . 6 . T he an sw e r is C [ s ee V . D . 1 ]. A l t h ou gh al l o f th e m ec ha n is m s l is t ed ca n b e re sp o ns i bl e, t he c h em ic al de g r ad a ti o n o f m e di c i n al c om p ou n ds , p a r ti c u l ar l y es t er s i n l iqu i d f o rm ul a ti o ns , i s us u al l y ca us e d b y h yd r o l ys is . Fo r th is r ea s on , d r u gs th a t h a ve es t e r fu nc t io n al g ro up s a r e f o r m u l at e d i n d r y fo r m wh e n e v er po s s i bl e . O xi d a t i o n i s a no t he r c om m o n m o de of d e g ra d at i on an d i s m i n im i z e d b y in c l u di n g a nt i oxi d a n t s (e . g. , as c o r bi c ac i d ) in d ru g f o r m u l at io n s . P ho t ol y s is i s re d uc ed b y p ac k ag in g s us c ep ti b le p ro d uc ts i n am b e r o r o p a qu e c on t ai ne r s . D ec ar b o xy l a t i o n , wh i c h is t he r e m o v al of C O O H g r ou ps, a f fe c t s c om p ou n ds th a t i nc lu de c a r bo xyl i c ac i d. R ac em i za t i o n ne u t ra li ze s t h e e ff ec t s o f a n o p t ic al l y ac ti v e c o m p o und b y c o n v e r ti ng ha l f o f i ts m o le c u l es i n to t he i r m ir r o r - im ag e c o nf i gu r a ti on . As a r es u lt , t he de xt r o r o t a to r y a nd l e v o r o ta t or y f o rm s c an cel e ac h o t h e r o ut . Th is t y pe o f de g r ad a ti o n a f fe c t s o nl y dr u g s t ha t a r e c ha r ac t e ri z e d b y o p t ic al is om e ri s m . 7 . T he an sw e r is C [ s ee V . E . 3 .d ] . Te s t i ng o f a d r ug f or m ula t i on to de t e rm in e i ts s he l f l i fe c a n b e a c c el e ra t ed b y a p pl yi n g t h e A r r he ni u s eq u a ti on t o d at a o b ta i ne d a t hi gh e r t em p e ra t u re s . Th e m e th o d i n v ol v e s d e te rm in i ng t he r at e c on s ta n t ( k) va l u es f o r th e d eg r a da ti o n o f a d r u g a t v a ri ou s e le v a t e d t e m p e r at u re s . Th e lo g o f k is p l ot t ed ag a in s t th e r e c ip r oc al o f t he ab s o lu t e t em p e ra tu r e , a n d t he k v a l ue fo r d e g ra d at i on at r oo m t em p e r a tu r e is o b t ai ne d b y e xt r a p o la t ion . P.78
8 . T he an sw e r is E [ s e e I V . A . 3. g ]. Th e s ol u bi li t y o f a we a k a c id v a r ie s as a f u nc ti o n o f p H. B ec au s e p H a n d p K a ( th e d i ss oc ia t io n c on s ta n t) a re r el a t ed , s ol u bi li t y is als o re l at e d t o t he d eg r ee o f i o ni za t io n . As pi r in is a we a k ac i d t ha t is c om pl e tel y i o ni z e d a t a p H t h at is 2 un i ts g r e a te r th an i ts p K a . Th er e f o re , it is m os t s ol u bl e a t p H 6 .0 . 9 . T he an sw e r is B [ s ee V I . B . 7] . A l u m i nu m a c e t at e a n d a lu m in um s u ba c e t a te s o lu ti o ns a re as t ri ng e nt s t h at a r e u s e d a s a n ti p e rs pi r an t s a nd as we t d r es s i ng s f o r c on ta c t d e rm a ti ti s . S t r on g i od i ne s o lu t io n a n d b en z a lk on i um c h lo r i de ar e to pi ca l a nt i b ac te r i al s ol u ti o ns . Ac et i c a ci d i s a d d ed to p ro du c ts a s a n a c id i fi e r. A r om at ic am m on i a s pi r it is a r es p ir a to r y s t im ul a nt . 1 0 . Th e a n sw e r i s A [ s ee I V . B .1 . a] .
A s us pe ns i on is a t wo - ph a s e s y s t em th a t c o n si s ts o f a f i ne l y po wd e r e d s o l id d i sp e rs ed in a l iq u id v e hi c le . Th e p a rt ic l e s i z e o f t h e s us p en de d s ol i d s h ou l d b e a s s m a l l as po s s ib l e t o m in im i z e s ed im e nt a ti o n, bu t i t is u s ua ll y > 0. 5 µm . 1 1 . Th e a n sw e r i s C [ s ee V I . E .3 . a] . L e vi g at io n i s t h e p r oc es s o f bl en d in g a n d g ri n di ng a su bs t an c e to s e p ar a te t h e p a r ti c l e s , r ed uc e t h ei r s iz e , a nd f or m a pa st e . L ev i g a t io n i s p e rf o rm ed b y a d di n g a s m a l l am o un t o f s u it a bl e l e v i ga t in g a ge n t (e . g. , gl y c e r in ) to th e s ol i d a nd b l en d in g t h e m i xt u r e wi t h a m o r ta r a n d p es tl e . 1 2 . Th e a n sw e r i s A [ s ee V I . D .3 ] . A c ac i a, o r g um a r a bi c , is t h e e xu d a t e o b ta in e d f ro m th e s te m s an d b r an c h e s o f va r i o us s p ec ie s o f Ac ac ia , a wo o d y p l an t n a ti ve to A f r ic a. Ac a c i a i s a n a tu r a l e m ul si f y i ng ag e nt th a t p ro v i d es a s ta bl e e m ul s i on o f l o w v i s co s i t y . Em u ls io n s a r e d r o pl e ts of on e o r m o r e im m i s c ib l e l iq ui ds di sp e rs e d i n a no t he r li qu i d. Em u l s i on s a r e i n he r e nt l y un s t a bl e : t h e d r o pl e ts t e nd t o co a le sc e i n to la r g er an d l a r ge r d ro ps . Th e p u r po s e of an em ul s i f y i n g a ge n t is t o k e e p t he d r op le t s d is pe r s e d a nd p r e v e nt t h em f ro m c oa l es c i ng . Po l y s o rb a te 20 , p o l ys o r bat e 80 , an d s o rb it a n m on op a lm i ta t e a r e al so em ul s i f ie rs , bu t a r e s y n t he t ic , n o t n at u r al , s u bs t an c e s . 1 3 . Th e a n sw e r i s D [ s ee V I . E .2 ] . O i n t m e n ts a r e t y p i c a ll y us e d as em ol l ie n ts to s o f te n th e s k i n , as p ro t ec ti v e b a rr i e rs , o r as ve hi c l es f or m e di c a t i on . A v a r i et y o f o i nt m e n t b as e s a re a v ai l ab le . V a n is hi n g c r e am , a n e m u ls io n t y pe o f oi nt m en t b as e , is a n o i l -i n - wa t e r e m u ls io n th at c on t ai ns a h ig h p e rc en t ag e o f wa te r . S te a ri c a c i d i s us e d to c re a te a t hi n fi lm on the sk in wh e n t h e wa t e r e v a po r ate s . 1 4 . Th e a n sw e r i s B [ s ee V I . F. 2 .a ] . B y c o n v en t io n , a r ec ta l s u p p os it o r y fo r an ad u lt we i gh s a p pr o xi m a te l y 2 g . S u p po si t o ri es f or in f an t s a n d c h i ld r en a re s m al le r. V a gi n al s u pp os i to r ie s typ i c al l y we i g h a pp r o xi m a te l y 5 g . R e c ta l s up p os it o ri es a re u s u a ll y sh a pe d l ik e a n el o ng a te d b u ll e t ( c y li n d ri c a l a nd t ap e r ed a t o ne en d ) . V ag i na l s u pp os i to r ie s a r e u sua l l y o v oi d . 1 5 . Th e a n sw e r i s A [ s ee V I . F. 4 .c ] . I n t he fu s i o n m e t ho d o f m ak i ng s u pp os i to r ie s , m o l ds m a de of al um i nu m , b r a s s , o r n i ck el - co pp e r a l lo y s a r e u s ed . Fi ne l y po wd e r e d dr u g m i xe d wi t h m e l te d c oc o a b ut t e r i s p o u re d i n to a m o l d t hat i s lu b r ic at e d v e r y l ig h tly wi t h m i ne r al oi l . 1 6 . Th e a n sw e r i s B [ s ee V I . G ; Ta bl e 3 - 8] . Th e U S P d e fi ne s a v e r y f i n e c h em ic a l p o wd e r a s o n e t h at c o m p le t el y p as s e s t h r o ug h a s t an d a rd #1 20 s ie v e , wh i c h ha s 1 25 - µm op e ni n gs . Th e U S P c la s s i fi c a t io n f o r po wd e r e d v eg e ta bl e a n d a ni m al d r u gs d i f fe rs f r o m t ha t fo r po wd e r e d ch e m i ca ls . To b e cl as s i f ie d a s v e r y f i n e, po wd e r e d veg e ta b le a nd an im al d ru gs m u st p as s c om p le t el y t h ro u gh a # 80 s i e v e , wh ic h h as 18 0 - µm op e ni n gs . 1 7 . Th e a n sw e r i s C [ s ee V I . G .1 . c . ( 3 . (b ) ] . P u l ve r i z at i on b y i n te r v e nt i o n is th e m il l in g t ec h ni q u e t h at is us ed fo r d ru g s u bs ta n c e s t ha t ar e g um m y a nd t en d t o re a gg lo m e r a t e o r r e si st g ri nd i ng (e . g . , c am p ho r , i o di ne ) . In th is s en s e , in t er v e n t io n i s t he a dd i ti on o f a s m a ll am o u n t o f m a te r i al th a t a id s m i l li ng a n d c a n b e re m o v e d e as i l y a f t er pu l v e r i z at i on is c om pl e te . F o r e xa m pl e , c am ph o r c a n be r ed uc e d r ea d il y i f a s m al l a m o u nt o f v o l at i le so l ve nt ( e . g ., al c o h ol ) is a d de d . Th e s ol v e n t i s t he n a l lo we d to e vap o r at e .
P.79
1 8 . Th e a n sw e r i s D [ s ee V I . G .2 . c] . Th e p h a rm ac is t u s e s g eo m et r ic di lu t io n to m i x p o t e nt s u bs t an ce s wi t h a la r g e a m ou n t o f d il u en t . Th e po t e nt d ru g a n d a n e qu al a m ou n t o f d il u en t a r e f i rs t m i xe d i n a m o r t a r b y t ri t u ra t io n . A v o l um e o f di lu e nt eq u al t o t he m i xt u r e in th e m o rt a r is a d d ed , a n d t he m i x i s aga i n t r i tu r a te d . Th e p ro ced u r e i s r ep e at e d, a nd eac h ti m e , d i lu e nt eq u al in v o lu m e to t he m i xt u r e t he n i n t h e m o rt a r i s a dd e d, un t il all o f t he d i lu e nt is in c o r po r a te d . 1 9 . Th e a n sw e r i s A [ s ee V I . G .3 . b . (4 ) ] . H yg r o s c o pi c a nd v o la t il e d r u gs a r e b es t p r o te c ted b y wa xe d p a p e r , wh i c h i s wa t e r p r o o f. Th e p ac k et m a y be do u bl e - wr a p pe d wi t h a bo n d p ap e r t o i m pr o ve t he a p p ea r an c e o f t he c om p le t e d p o wd e r . 2 0 . Th e a n sw e r i s A [ s ee V I . H .2 .c . ( 1 )] . H a r d c a ps ul es a re nu m be r e d f r om 00 0 (l a rg es t ) to 5 (s m a ll es t ) . Th e i r a p pr o xi m a t e c a pa ci t y r an g es fr o m 6 00 t o 3 0 m g; ho we v e r , t h e c ap ac i t y of t he c a ps ul e d e p en ds o n th e d e ns it y o f th e c ont e n ts . 2 1 . Th e a n sw e r i s A [ s ee V I . H .3 . a a nd b] . Th e s he l ls o f s o ft ge l at i n c ap s u l es ar e p l as ti ci ze d b y t h e a dd i ti on o f a p o l yh yd r i c a l co h ol (p o l y ol ) , s uc h a s g l y c e r i n o r s o rb it o l. A n a n t if u ng al p re s e r v a t i ve ca n al so be a d d ed . Bo t h h a rd an d s of t g el at i n c ap su le s c an be f il l ed wi t h a po wd e r o r a n o th e r d r y s ub s ta nc e . S o ft ge l ati n c a ps ul es a re al s o us efu l do sa g e f o rm s f or f lu ids o r s em is o li ds . 2 2 . Th e a n sw e r i s C [ s ee V I . H .4 . a] . A c on t en t un i fo rm i t y te s t i s a te st o f p ot e nc y. To e n s u r e t h at ea ch t ab le t o r ca ps u le c o nt a in s t he in t en d ed am o un t o f dr u g s ub s t a nc e, t h e U S P p ro v i de s t wo t e s ts : we i gh t va r i a ti o n a nd c o n te n t u nif o r m i t y . Th e c on t en t un i fo r m it y t es t c an be us e d fo r a n y d o sa g e u ni t , b ut is r eq uir e d fo r c o at e d t ab l et s , f or t a bl e ts i n wh ic h th e a c ti ve i n g re d ie n t m a k e s u p < 50 % of t he ta b le t , f o r s us p e ns i on s i n s i n gl e -u n it c o n t ai ne r s o r i n s o f t c a ps u le s , an d fo r m a n y s ol i ds th a t co n ta i n a d d ed s u bs ta nc e s. Th e we i g h t va r i a ti o n t es t c a n b e us ed f o r l iq ui d - fi ll e d s of t c ap s ul es , fo r a n y d os ag e fo r m u n it t h a t c on t ai ns at le as t 50 m g o f a s i n gl e d r ug if t he d r ug m ak es up a t l ea s t 5 0 % o f t h e b u lk , f o r s ol id s t h at d o no t c on t ai n a d de d s ub s ta nc e s, an d f o r f r e e ze- d r i ed s o lu t io ns . 2 3 . Th e a n sw e r i s A [ s ee V . A a n d V . B ] . Th e r e ac t io n v el oc i t y , o r d e g ra d at i on r at e , o f a pha r m ac eu t ic al pr o du c t is a f f ec t ed b y s e ve ra l fa c t o rs , i nc l ud i ng t em pe r a tu r e, so l ve nt s , a n d li g h t. Th e d e g ra da t i on r at e i n c re as es t wo t o t h re e t im es wi t h ea c h 10 ° in c rea s e i n t em pe r a tu r e . Th e e f f ec t o f t e m p e r at u re o n r ea c ti on r a t e i s g i ven b y th e Ar r he n iu s e q ua t io n : k = Ae
-Ea/RT
wh e r e k i s t h e r ea c ti o n ra t e c on s ta n t, A i s t h e f r eq u e nc y f ac to r , Ea is th e e n e rg y o f a c ti va t io n , R is t he ga s c o n s t a nt , an d T is th e a bs o l u te te m p e r at u re . 2 4 . Th e a n sw e r i s D [ s ee V . B .2 . a ].
I n ze r o -o r de r de g ra d at i on , t he c o nc en t r at i on of a d r u g d ec r ea se s o ve r t im e . H o we ve r , t h e c ha n ge of c o nc en t r at i on wi t h re sp ec t to ti m e is un c h a ng ed . I n t he e q u at io n :
t h e fa ct th a t d C / dt is ne ga t i v e s ig n if i es th a t t he co n c e n t ra t io n i s d ec r ea s in g . H o we ve r , t h e v el oc i t y o f t h e c on c en t ra t io n c ha n ge is c o ns t an t . 2 5 . Th e a n sw e r i s B [ s ee V . B .2 . b .( 2 ) ]. Th e h a lf - li f e ( t 1 / 2 ) is th e t i m e r eq ui r e d f o r t he co nc e nt r a ti o n o f a d r u g t o de c r ea s e b y o n e h al f . F o r a f ir s t- o r der d e gr a da t io n :
B e c au se bo t h k a n d 0 .6 93 a r e c o ns t an t s , t 1 / 2 i s a c o ns ta n t . P.80
2 6 . Th e a n sw e r i s D [ s ee V I . F. 3 ]. A s a ti sf ac t o r y s up p os it o ry b a s e sh o ul d r em a in fi rm a t r oo m t em p e ra t ur e . P r e f e ra b l y , i t sh ou l d n ot m e l t < 3 0 ° C t o a v oi d p r em at u r e s o f te n in g d u r in g s to r a ge an d i ns e r ti o n. I t sh o ul d a ls o b e i ne r t , no n s e ns i ti z i n g, no n ir r i ta t in g , a n d c o m pa ti b le wi t h a v a r i et y o f d r u gs . Mo r e o v e r , i t s ho uld m e l t j us t b el o w b o d y tem p e ra t ur e a n d s ho ul d d is s o l v e o r d i si n te g ra t e r a pi dl y i n t he f lu i d o f t he b od y c a v i t y i n to wh i c h i t is in se r t ed . 2 7 . Th e a n sw e r i s E [s ee V I . F. 3 .c . (1 ) ] . C o c oa bu t t er is a f at t ha t i s o b ta in e d f r om th e s eed o f T h eo b ro m a ca c a o . C h e m i ca l l y , i t i s a m i xt u re o f s te a ri n , p al m i t in , and o th e r g l y ce r id e s t ha t ar e i n so lu b le in wa t e r a n d f re e l y s o lu bl e i n e t h er an d c hl o r of o rm . De p en d in g o n th e f u si o n t em pe r a tu r e , c o c oa b ut t e r c a n c r y s ta l li z e in t o a n y on e o f fo u r c r ys ta l fo r m s . C o c oa bu t t er is a g oo d ba s e f o r r ec t al s u pp o si to r ie s , a l th ou g h i t i s l ess tha n id ea l f o r va gi n al or u re t h ra l s up p os i to r ie s . 2 8 . Th e a n sw e r i s C [ s ee V I . I. 5 ]. To s a t is f y th e U S P s ta nda r d s , ta b le ts a re r eq u ir ed t o p as s o ne of t wo t es ts . A we i g h t v a r ia t io n t es t i s us e d i f t h e ac t i v e i ng r e di en t m a k e s u p t he bu lk o f th e ta b le t . A c on t en t un i fo rm i t y te s t i s u s e d i f t h e t ab l et is co a t ed o r i f t he ac t i v e i ngr e d ie n t m ak e s u p < 5 0 % o f t h e bu l k o f t h e t ab l et . Ma n y t ab l e ts fo r o r a l a dm in is t ra ti o n a r e r e q ui r e d t o m e e t a di s i n te g r a ti on t es t. D is i nt e gr a ti o n t im es a re s p ec if i ed in t he i n di vi d ua l m on o gr a ph s . A d is s o l ut i on te s t m a y be r e qu i re d i ns t ea d i f th e a c ti ve c om p on e nt o f t he ta b le t h a s l im it e d wa t e r so lu b il it y . H a r d ne ss a n d f r ia b il ity wo u l d a f f ec t t h e d is in t eg r a ti on a n d d is s o l ut i on ra t es , b ut h a rd n es s an d fr i ab il i t y t e s ts a r e i n - ho us e q u al i t y c on t r ol te s ts , n o t o f fi ci al U S P te s t s . 2 9 . Th e a n sw e r i s D ( I I , I I I ) [s ee V I . A. 1 ]. W ate r f o r i nj ec t io n U S P is wa t e r th a t h as be en pur i f ie d b y d is t il la t io n o r b y r e v e r s e o sm o si s . Th is wa t e r i s us e d t o p r ep a r e p ar e nt e r al s o l ut i on s t ha t ar e s u bj ec t to fi n al
s t e ri li za t io n . F o r p a re n ter a l s ol u ti o ns th a t a r e p r ep a r ed as ep t ic al l y an d n ot s u bs eq u en t l y s t er i li z e d , s t e ri le wa t e r fo r in je c ti on U S P is us e d. S te r il e wa te r f o r i n je c ti on U S P is wa t e r f or i nj ec t io n U S P t h at ha s b e e n st e r il i zed an d s ui t ab l y p a ck ag e d. Th i s wa t e r m ee t s t h e U S P r eq ui r em e nts f or st e ri l it y . B ac t e ri os ta t ic wa t e r f o r in je c ti on U S P is s t er il e wa t e r f o r i n je ct i on U SP t h at c o n ta i ns o n e o r m o r e a n t im ic r ob ia l a g en ts . It c a n be us ed in pa r en t e ra l s ol u ti o ns i f th e a n ti m i c ro b ia l a d di t i ves a re c om p at i bl e wi t h t h e o th e r i ng r e di ent s in th e s ol u ti o n, bu t i t c a nn o t b e u s ed in ne wb o r n s . P u ri fie d wa t e r U S P i s n ot us ed i n p a re n te r al p re pa r a tio n s. 3 0 . Th e a n sw e r i s E ( I , II , I I I) [s e e I V . B .2 ] . A n i de al s u s p e ns io n wo ul d ha v e pa r t ic le s o f u ni f or m s i z e , m in im al s e di m en t a ti o n, a n d n o i n te r ac t io n b e t wee n pa r t ic le s. A lt h ou g h t he s e i de al c ri t er i a a r e r a re l y m e t , t h e y ca n b e a p pr o xi m a ted b y k e e pi ng th e pa r ti cl e s i z e a s sm al l a s p os si ble , t he d e ns i ti es of t he s o li d a nd t he di sp e rs i on m e di um a s s im il a r as po s s i bl e, an d th e d i sp e rs io n m ed i um a s v is c o u s as po s s ib l e. 3 1 . Th e a n sw e r i s D ( I I , I I I ) [s ee I V . B. 2 ]. A s S to k es ' s l a w i nd ic a tes , th e s ed im e nt a ti o n r a te o f a su s p e ns io n i s sl o we d b y r e d uc in g i t s d en s i t y , re du c in g t h e si ze o f t he s u sp e n de d p a rt ic l es , o r i n c re a s i n g i ts vi s co si t y b y in c o r p o ra ti ng a th ic k e ni n g a ge n t. S od i um be n z o at e i s a n a n tif u n ga l a g e nt an d wo u ld no t re du c e t he se di m en t at io n rat e o f a s us pe ns i on . 3 2 . Th e a n sw e r i s C ( I , II ) [ s e e VI . C . 3] . A c ac i a a nd m e th y l c el lu l os e a r e c om m o n s us pe n din g ag e nt s. A ca c i a i s a na t u r al p r o du c t, an d m e th y l c e ll ul o s e is a s y nt h et ic po l y m e r . B y in c re as i ng th e vis c os i t y of t h e l i qu id , th es e a g en ts e n a bl e p a rt ic l es to re m a in s u sp e nd e d f o r a l o ng e r p e ri o d . 3 3 . Th e a n sw e r i s E ( I , II , I I I) [s e e V I . D .3 ] . E m u ls if y i n g a ge n ts p r o v id e a m e ch a ni c a l b a r ri e r to c o a le s c en c e . Th e y al s o r e du ce t h e n a tu r a l t en d en c y o f th e d ro pl e ts in th e i n te r na l ph as e (o il o r wa t e r ) of t h e e m ul si o n t o c o a le s c e . Th r e e m ec h an is m s a p pe a r t o be in v o l v e d. S om e e m u l s i f ie rs p r o m o t e s ta bi l it y b y f o rm i n g s t ro n g, pl i ab le in t e rfa c ia l f i lm s a ro u nd th e d ro p le t s . E m u ls if y i n g a ge n ts a ls o r e d uc e i n te r fa c i a l t en s i on . Fi n al l y , i o ns (f r om t he e m u ls i fi e r ) i n th e i n te r f ac ia l f i lm c an l e ad to ch a rg e re p ul s i o n t h a t ca us es d ro p le ts t o r e p el on e a n o th e r , t he r eb y p r e v e nti n g c oa le s c e nc e. 3 4 . Th e a n sw e r i s B ( I I I) [ s e e V I. D . 3 ]. A l l o f th e s ub s ta nc es li s te d a re em ul si f y i ng ag en ts , bu t o n l y s o rb i ta n e s t e rs a re n o ni o ni c s y n th e ti c a ge n ts . Tr a ga c an t h, li ke ac ac ia , is a n at u ra l e m u ls i f y ing a ge n t. S o d iu m l au r y l s u lf a te is a n an io n ic s u r fa c t a nt . Sor b i ta n es te r s ( k n o wn co l lo q ui a ll y a s Sp a ns b e c a us e o f t h ei r t r ad e n am es ) ar e h y d ro p h ob ic an d f o rm wa t e r -in - o il e m ul si o ns . Th e po l y s or ba t es ( k n o wn c o ll o qu i al l y a s Twe e n s ) a r e a ls o n oni o ni c , s yn t he t ic s o r bi t an de r i v at i v e s . H o we ve r , t he y a r e h yd r o ph i li c a nd th e r ef o re f o rm oi l i n - wa t e r e m ul s i on s . S o diu m l a u r y l su l fa t e, as an a l k a li s o ap , is a ls o h yd r op h il ic an d t h us f or m s oi l -i n - wa t e r em u ls io ns . P.81
3 5 . Th e a n sw e r i s C ( I , II ) [ s e e VI . F .1 an d 2 ] .
R e c t al s u pp os i to r ie s a r e u s ef u l f o r d el i v e ri n g s y ste m ic m ed ic a ti o n u nd e r c e r t ai n c i rc um s ta nc es . Ab s o r p tio n of a d r ug f ro m a re c tal s u p po s i t o r y i n v o l v es re le a s e of t h e d r u g f r om th e s up pos i to r y v e h ic le , d i f fu s i on th r o ug h th e r e c t al m u co s a , an d t r a ns p or t to t he c i rc ul a tio n th r o ug h t h e r ec t al ve in s . Th e r ec t al ve in s b ypa ss t he l i ve r , s o t hi s r o ut e a v oi ds r ap i d h ep a ti c d eg r ad a ti o n of ce r ta i n d r ug s ( f i rs t- p a ss e f f ec t ) . Th e r ec ta l ro u te i s a ls o u s e f ul wh e n a d rug c a n no t b e g i v e n o r al l y ( e . g ., b e c a us e o f v om i ti n g) . H owe v e r , t h e e xt e n t o f d r ug r e le a s e an d a bs o rp t io n is va r i a bl e . I t d e pe n ds o n th e p ro pe r t ie s o f t h e d r ug, t h e su p po s i t o r y b as e , an d th e e n vi r on m e n t i n t h e r ec t um . 3 6 . Th e a n sw e r i s E ( I , II , I I I) [s e e V I . G .1 . c] . Mi l l i n g i s t h e p ro c e s s of m ec h an ic a ll y r ed u c i ng t he p a rt ic l e s i z e of s o li ds b e f o re t h e y a re fo r m u l at e d i nt o a f in a l p ro d uc t . To wo r k e f f ec t i v el y, a l ub r ic an t m u s t c oa t t h e s u rf a c e of th e g r a nu la t i on o r p o wd e r . H e nc e fi n e p a r ti c l e si ze is es s e nt i a l. D e c r ea s i n g t he pa r t ic le s i z e i nc r ea s e s t he su r f ac e a r ea an d c an en h an c e t h e d i ss ol u ti on r a te . Th e rm ola b il e d r u gs m a y un d er g o d e g ra da t io n b ec a us e o f t h e b u il d up of he a t d u ri n g m il l in g . 3 7 . Th e a n sw e r i s D ( I I , I I I ) [s ee V I . G .2 . a. ( 2 ) ]. S o m e so l id s u bs ta n c e s (e . g . , as p ir i n, ph e n y ls al icy l a t e , p he n ac et i n, t h ym ol , c am p ho r ) l i qu e f y or f or m e u te c ti c m i xt u r e s wh e n in c l os e , p r ol o ng ed c o n tac t wi t h o n e a n ot h er . Th es e s ub s t a nc es a re be s t i ns ul a ted b y t he ad di t io n o f li gh t m a gn es i um o xi d e o r m agn e s i um c a r bo n at e . O t h e r i n er t di lu e nt s t h at c a n be us e d a r e k a ol in , s t a rc h, a nd be n ton i t e. 3 8 . Th e a n sw e r i s B ( I I I) [ s e e V I. G . 2 .b ] . W hen p o wd e rs a re m i xe d , if c o m m in u ti o n is es pec i al l y im po r ta n t , a p o rc e la i n o r c e r am ic m o rt a r t h at ha s a r o ug h i nn e r s u rf ac e i s p r e f er r e d o ve r t h e s m o oth wo r k i ng s u r fa ce o f a g l as s m o r ta r. B e c a us e a gl as s m o r t a r c le a ns m o re ea si l y a ft e r u s e , it is p r e f er r e d f o r c h em ic a ls th a t m a y s t ai n a po r ce l ain o r c e ra m i c m o r t a r as we l l a s f o r s im p le m i xi n g of s u bs t anc es t ha t d o n o t r e qu i re c o m m i nu t io n . 3 9 . Th e a n sw e r i s A ( I ) [ s ee V I . G .3 . a a nd b] . P o wd e r s fo r o ra l u s e c a n b e d is p en s e d b y t h e p ha r m ac is t i n b ul k f o rm or d i vi de d i n t o p r em ea s u r ed do s e s ( d i v i de d p o wd e r s ). D i v ide d p o wd e r s a r e t r a di ti o na l l y d i sp e ns ed in fo l de d p ape r p ac k e ts (c h ar t ul a e ) m a d e o f p a rc hm e nt , bo nd p a p er , g l as si n e, o r wa xe d p a p er . H o we ve r , i nd i v id u al dos es c a n b e p ac ka g ed in m e ta l fo il o r sm al l p la s ti c b ag s i f th e po wd e r n ee ds g re a te r p r o te ct i on f ro m h um id i t y o r e va p o ra t io n . 4 0 . Th e a n sw e r i s C ( I , II ) [ s e e VI . I .2 . b] . Ta b l e ts f or o ra l i n ge s t i on us u al l y c o nt a in e xc i pi en t s t h at a re ad d ed to th e f o r m u l at io n fo r th e ir s p ec i al fu nc t io ns . Bi n de r s an d ad h es i v es a r e a d de d t o p ro m o t e g r a nu l at i on o r c o m p ac t ion . D il u en ts a re fi l le r s t ha t a r e a dd e d t o m ak e u p th e r e q ui r e d t ab l et bu lk . Th ey c a n a ls o a id in t he m an u f ac tu r i ng pr o c e ss . Di sin t e g ra n ts a i d i n t a bl e t d is in t eg r at i on i n g as t ro i nt es t in a l f l u ids . Lu b ri c a n ts , a n ti a dh e ren t s , a nd g l id a nt s a id in r ed uc i ng fr i c ti on o r a dh es i on be t we e n p a r ti cl es or be t we e n t a bl e t a nd d i e . F o r e xa m p le , l u b ri c an t s a r e u se d i n t h e m a n uf a c tu r e o f t a bl e ts to re d uc e fr ic t io n wh e n t h e t a bl et is ej ec t ed f r om th e d ie ca v i t y. Lub r i c a n ts a r e u su a ll y h y d ro p h ob ic s u bs ta n c e s t ha t c a n a ff ec t th e d is so l ut i on ra t e o f t h e a c t i v e i n gr e di e nt .
4 1 . Th e a n sw e r i s E ( I , II , I I I) [s e e V I .2 . b . (3 ) ] . D i s in t eg r an t s a r e a dd ed t o t ab le t fo r m u la t io ns t o f a ci l it a te di s i n te g ra t io n in g a st r o in t es ti n al fl ui d s . Di s in t eg r a ti on o f t he ta b l et i n t he b od y is c r i ti ca l t o i t s d i ss ol u ti on a nd s u bs eq ue n t a bs o r pt i on an d b io a va i la b il i t y . Th e bi n de r an d t h e c om p r es s i on fo r c e us ed d u r in g ta bl e t m an u fa ct u rin g af f ec t t h e h a rd n es s of t h e t a b le t a s we ll as ta b le t di s in t eg r a ti on an d d r u g d i s s o l ut i on . 4 2 . Th e a n sw e r i s B ( I I I) [ s e e V I. I .3 . a .( 4 ) ] . A n e nt e ri c -c oa t ed t ab le t h a s a c o at in g th a t r em a in s i n ta c t i n t he s t om ac h , b u t d i ss ol ve s i n t he in t es t in es t o y i e ld th e t a bl e t i ng re d ie n ts th e r e. E nt e r ic c oa t i ng s i n cl ud e v a ri o us fa ts , fa t ty a c id s , wa xe s , an d s he ll a c s . Ce ll u lo s e ac e ta t e ph t h al a te r e m ai ns in t ac t i n t he s t om ac h b e c a us e i t d is so l ve s o n l y wh e n t h e p H > 6 . O t h e r e n t e ri c- c o a ti n g m at e ri a ls i nc l ud e p o vi do ne ( po l y v in y l p y r r o li d on e ), po l y vi n yl ac e ta t e p h t ha la t e , a nd h y d ro xy p r o p y l m e th y l c e l lu lo s e p hth a l a t e . 4 3 . Th e a n sw e r i s A [ s ee V I . I. 4 ]. 4 4 . Th e a n sw e r i s D [ s ee V I . I. 4 ]. 4 5 . Th e a n sw e r i s B [ s ee V I . I. 4 ]. P.82
4 6 . Th e a n sw e r i s A [ s ee V I . I. 4 ]. S t i ck in g i s a dh es i on of ta b le t m a te r i al to a d ie wa l l . I t m a y b e c au s ed b y e xc e s s i ve m o is tu r e o r b y th e u s e of i n gr e di e nt s t h at ha v e low m e l t in g te m p e ra t u re s. Mo t t l i n g i s u n e ve n c o l or di s t ri bu t io n. I t i s m os t o f te n c au se d b y p o o r m i xi n g o f t h e t abl e t g r a nu l at i on bu t m a y al s o o c c u r wh en a d e gr a de d d r u g p r od uc es a c ol o re d m e ta b ol i te . Ca p pi n g is s e p a ra t io n o f th e t o p o r bo t t om c r o wn o f a ta bl e t fr o m t h e m a in bo d y . C ap pi n g im p li e s t ha t c om p r ess e d p o wd e r i s n o t co h es i v e . R e as o ns fo r c a pp i ng i n c l ud e e xc e s s i v e f o rc e o f c om p re s s io n , u s e o f i ns u ff ic i en t b i nd e r, wo r n t a b le t t o ol i ng eq ui pm e nt , a n d e nt r a pm en t o f ai r du r i ng p ro ce s s in g . P ic ki ng is a d h er e nc e o f t a bl e t s u r fa c e m a t e ri a l t o a p u nc h . I t c a n b e c au s e d b y a g ra n ul a ti o n t h a t i s t oo da m p , b y a s c r a t c h e d p un c h , b y s ta t ic c h a rg es on th e p o wd e r , a n d p a r ti c ul a rl y b y t he us e o f a pu nc h ti p t h at is e n g ra ve d o r em b oss e d . 4 7 . Th e a n sw e r i s A [ s ee V I . G .1 . c; V I . G .2 ] . 4 8 . Th e a n sw e r i s D [ s ee V I . G .1 . c; V I . G .2 ] . 4 9 . Th e a n sw e r i s C [ s ee V I . G .1 . c; V I . G .2 ] . C o m m i nu t io n i s t he p ro c e s s o f r e du ci ng t he pa r tic l e s i z e o f a p o wd e r to in c r ea s e it s f i n en es s . S e v e ra l c om m in u t io n t ec h ni q ue s a re s ui t a b l e f o r sm a ll - s c al e u s e i n a p h a rm ac y . Tr i t u ra t io n i s u s ed bo t h t o c om m i nu t e a n d t o m i x d r y p o wd e r s . I f c om m i n ut i on is d es i r ed , t h e s ub s ta nc e i s r u bb e d i n a m o r t a r t ha t h a s a rou g h i nn e r s u r fa ce . Pu l v e r i z at i on b y i n te r v e n ti o n is of t en us ed f o r s u b s t a nc es th a t t end t o a g gl o m e r at e o r r es is t g r in d in g . A s m al l a m o u nt o f e as i l y re m o v e d (e . g. , v ol a t il e ) s o l ven t i s a dd e d. A f te r th e s u bs t an c e is p u l v er i ze d , th e s ol v e n t is al l o wed t o e va p o ra t e o r i s o t he r wi s e r em o v e d. Le v i g at i on is o f t en us ed to p re p ar e pa s te s o r o i n tm en ts . Th e p o wd e r is r ed uc e d b y ad d in g a s u i t ab le no n s o l v en t (l e v i ga t i ng ag e nt ) t o f or m a pa s t e a n d t he n e i th e r ru bb i ng th e p as t e i n a m o r ta r wi t h a p es tl e o r r u b bi n g i t o n a n o in t m e nt s la b wi t h a s pa t ul a . S pa t u la t io n a nd t um bl in g a re
t e ch n iq u es t h at a re us ed t o m i x o r b le nd po wd e r s , n o t t o r e du ce th em . S pa t u la t io n i s b l en di n g s m al l a m o u n ts o f p o wd e rs b y s t ir r i ng th e m wi t h a s pa t ul a o n a s h ee t o f p a p er o r a p i ll ti l e. Tu m bl i ng is bl en d in g l a rg e a m o u n ts o f po wd e r in a l a rge r o ta t in g c o nt a in e r . 5 0 . Th e a n sw e r i s B [ s ee V I . K .3 . e] . 5 1 . Th e a n sw e r i s E [s ee V I . K .3 . a] . 5 2 . Th e a n sw e r i s C [ s ee V I . K .3 . f] . 5 3 . Th e a n sw e r i s D [ s ee V I . K .3 . d] . C o n t r ol le d - re l ea s e do s ag e fo r m s ar e d es i gn e d t o r e l e a se a d ru g s lo wl y f o r p r o lo n ge d a c t i on in th e bo d y . A v a ri e t y of ph a rm ac e ut ic a l m e c h a ni s m s a re u s e d to p r o vi de t he c o nt r ol l ed r el e as e . I on - e xc h a ng e re s in s m a y be c om p le xe d t o d r u gs b y p a ss in g a c a ti o ni c d r ug s o l u ti on t hr o ug h a co lu m n t h a t c o n ta i ns th e r es i n. Th e d r u g i s c om pl e xe d t o t h e r es in b y r ep l ac em en t o f h y d ro g e n a to m s . Re l ea se of d r u g f r om t h e c om pl e x d e p en ds on t h e i o ni c e n vi ro nm en t wi th i n t h e g as t ro i nt es t in a l tr a c t a nd o n th e p r o pe r ti es o f t he re s in . Co a t ed be ad s ( e . g., Th o r a z i ne S pa ns u le c ap s ul es ) or g r a nu l es p r o du c e bl o od le v e l s s i m i l a r t o t ho s e o bt a i ne d wi t h m u l ti p le do s in g . Th e va r i o us c o at i ng th ic k n es s es p ro d uc e a s us t ai n ed- r e l ea s e ef f ec t . Ma t r i x d e v i c es m a y us e in s ol u bl e p la s ti c s , h yd r oph i li c p ol ym e rs , o r fa t t y c om p ou n ds . Th es e c o m po n e nt s a r e m i xe d wi t h t he d r ug an d c om p re s s ed in t o a t a b le t . Th e p ri m a r y d os e, o r th e p o rt i on of t he d ru g to be r el e as ed im m e di a t el y , is p l ac e d o n t he ta b le t a s a l a y e r o r c o at . Th e re m a in d e r o f t h e d os e i s r el e as e d s l o wl y f r o m t he m a t ri x. R e l a t i v el y i ns o lu bl e ta nn a t e- am in e c om p le xe s p r o v id e f or a p r o lo n ge d g as t r oi n te s t i na l ab s o r p ti on ph as e a n d s us t ai n ed s ys t em ic c o nc e n t r at i on s o f t he we a k b as es . Os m o t ic s ys t em s em p lo y os m o t ic p re s s u re to co n t ro l th e r el ea s e o f t he ac ti v e in g re d ie n t fr o m t h e f o rm ul a ti o n. O sm o ti c t a bl e t f o rm ul a ti on s p r o vi de a s em i pe r m e ab l e m e m br a ne as a c oa t in g t h at su r r ou n ds th e o s m o ti c a ll y a ct iv e c o re . Th e c oa t in g a l lo ws wa t e r t o di f fu se in t o t he c o r e b u t d o es n o t a ll o w d r u g to d if f us e o u t . A s wa t e r f lo ws i n to th e ta b le t , t h e d ru g d is s olv e s . Th e l as e r -d r il l ed ho le i n t he c o at i ng al lo ws t h e d r ug s o l u ti on wi t h in t he ta b le t to f lo w t o t he ou t si de a t a r a t e t ha t i s e q ui va le n t t o th e r a te o f wa t e r fl o w i n to th e ta bl e t . Th e os m o t ic p r es s u re g r ad ie n t a n d a ze r o -o r de r dr u g - rel e as e ra t e wi l l be m a in t ai n ed as lo n g as e xc e s s os m o t ic al l y a c ti ve so lu t e ( e . g. , e l ec tr o l y t e ) r em a in s i n t he t ab l e t c o r e .
4 Biopharmaceutics and Drug Delivery Systems L aw re n ce H . B lo c k
I. INTRODUCTION A. B i o p h a r m ac e u ti c s is t h e s tu d y o f t he r el a ti on o f th e p h ys i c a l a n d c h em ic a l p r o pe r t ie s o f a d ru g t o i ts bi o a v ai la b il i t y , p ha r m ac ok i ne t ics , an d p h ar m a c o d yn am ic a n d t o xi c o lo g ic e f fe c ts . 1 . A d ru g p ro d u ct is th e f i ni s h e d d os ag e f o rm ( e.g . , ta bl e t , c a p su le , s ol u tio n ) th a t c o nt a in s t he ac t i v e d r ug i n g re d ie n t i n as s o c i a ti o n wi t h n on d r ug ( us ua ll y i na c ti v e ) i n g re d ie n ts (e x ci p ie n t s ) t h a t m ak e u p t he ve h i cle , o r f o r m ul a t io n m a t r ix. 2 . Th e ph r as e d r ug de li v e r y s y s te m i s o ft e n us e d i n te r c h a ng ea b l y wi t h t he t e rm s d r u g p r od uc t or do s a g e fo r m . H o we ve r , a d r u g de l i ve r y s ys t e m i s a m o re c om p r eh e ns i v e c o nc e pt , wh i c h in cl u de s t he d ru g fo r m ul a ti on an d th e d yn am ic i n t er a ct i on s am o ng th e dr u g , i ts f or m u l at i on m a t rix, i t s co n t ai ne r , a n d t he p a t ie n t. 3 . B i oa va i l ab i l i t y i s a m e a s u r em e nt of t he ra t e an d e xt e n t ( a m o un t ) o f s y s t em ic a b so r p ti on o f t he t he r ape u t ic al l y ac ti v e d ru g . B . P h a r ma c ok i ne t i cs is t h e s t ud y o f t h e t im e c o ur s e o f d r u g m o ve m e n t i n t h e b o d y d u r in g a bs o r pt i on , d is t r ib u t io n , a nd el im in a ti o n (e xc r e t i o n a nd bi o tr a ns f orm a ti o n ). C . P h a r ma c od yn a m i c s is t he s t ud y o f t h e r e la t ion o f t h e d ru g c o nc en t ra t io n o r a m ou n t a t t h e s i t e o f a c t io n ( re ce p t or ) an d i ts ph ar m ac o lo gi c r e sp on s e as a f un c ti on o f ti m e.
II. DRUG TRANSPORT AND ABSORPTION A. T r a n s p o r t o f d r ug mo l e cu l e s a c ro s s c el l mem b r a ne s . D ru g a bs o rp t io n r eq ui r es t h e d r u g t o b e t r an s p o r ted ac r os s va ri ou s c el l m em b r an es . D ru g m ol ec u les m a y e n t e r t he bl o od s t r e am an d be t ra ns p o rt e d t o t he t i s s ue s a n d o rg a ns o f the b od y . D r u g m o le c u l es m a y c r os s a dd i ti o na l m em b ra ne s t o en t er ce ll s . D r u g m o le c ul es m a y a l so c r os s a n i n tr ac e ll ula r m e m b r an e , s uc h a s t he n uc le a r m em b ra ne o r e n d op la s m ic re t ic ul um , to r e ac h t he si t e o f ac t io n. F ig u r e 4 - 1 d em on s t r a tes so m e of t h e k e y t ra ns p or t p ro c e s s es in v o l ve d i n d r ug ab so r p ti o n .
Figure 4-1. The key drug transport processes in intestinal epithelial cells. 1, Transcellular passive (diffusion and partitioning); 2, paracellular transport (diffusion and convection); 3, carriermediated transport; 4, P-glycoproteinmediated efflux. [Modified from Brayden DJ, Pharm News 4(1);1997:11-15.]
P.84
1 . G e ne r a l p r i n ci p le s a . A c e l l m em b r an e i s a s em ip e rm e ab le s t r uc t u re c o m p o s e d p r im a ri l y of l i pi ds an d p r o t ei ns . b . D r ug s m a y b e t ra ns por t e d b y p as s i ve di f f u si on , p a r ti t i on i n g, ca r r i e r -m e d ia t e d t r a n s po r t , pa r a ce l l ul a r t r a n s po r t , o r ve s i cu l a r t r a n s po r t . c . Us u al l y , p ro t e in s , d r ug s b ou n d t o p r ot e i ns , an d ma c r om o le c u le s d o n o t e as i l y c r os s c el l m em br a ne s . d . N o n po l a r l i p id - s ol u bl e d r ug s tr a v e rs e c e ll m e m b ra ne s m o re ea si l y tha n do i o n i c o r p o l a r w a t e r -s o lu b l e d r u g s. e . L ow m o le c ul a r w e ig ht d r u g s d if f us e a cr o s s a c e ll m em b r an e m or e ea si l y t ha n d o h ig h m o le c u la r w e igh t d r u gs . 2 . P as s i ve d i f f us i o n a nd p a r t i ti o ni n g a . W i th i n t h e c yt o p l a s m o r in in t e r s ti t i al f l ui d , m os t dr u gs un de r g o t r ans p o rt b y s im p le di f fu s i o n. b . F ic k 's l aw o f di f f u si on . S i mp l e p as s i ve di f f us i o n i n v ol ve s t h e t r an s fer o f d r u gs f r o m a n a r ea of hi g h c o nc e nt r a ti o n ( C 1 ) t o a n a r ea o f l o we r c o nc en t r a ti on ( C 2 ) a cc o r di ng t o F ic k 's la w o f d if f us io n :
wh e r e d Q / d t is t he ra t e of d r ug di f fu si o n, D is th e d i f fu si o n c o e f fi ci en t fo r th e d ru g , A i s t he s u r f ac e a r ea of th e pl an e ac ro s s wh i ch t ra n s f e r o c c u rs , h is th e t hi ck n es s o f t h e re g io n t h ro u gh wh i c h d i ff u s i on oc cu r s, an d ( C 1 - C 2 ) i s t he di f fe r e nc e b e t we e n t h e d r u g c o nc e nt r a ti o n in a r ea 1 a nd ar e a 2 , re s p e c t i v e l y . c . P ass i v e d r u g t r an s p o rt a c r o s s c el l m em b ra n es i n v o l v es th e s uc c e s s i ve p a r t i t i on i ng o f a s ol u te b e t we e n a q ue o us a n d l ipi d ph as es as we l l a s d i f fu s i o n wi t h i n th e re s p ec t i v e p has es . Mo d i f y i ng Fi c k ' s l a w o f di f fu s i o n t o ac c om m od a t e t he p a r ti t io n in g o f d r u g g i v es t h e f ol l o wi n g:
Th e r a t e o f d r ug di f fu s i on , d Q /d t , n o w r e f le ct s i ts d i re c t d ep e nd en c e o n K, t h e oi l to wa t e r p a r ti t io n c oe f fi c i e nt o f t h e d r ug , a s we ll as o n A a n d ( C 1 - C 2 ) . d . I on i z a t i on o f a w ea k e l e c t ro l yt e i s a f f ec te d by t h e p H o f t h e m e d iu m in wh i c h t h e d r u g is di s s ol v e d a s we l l a s b y t he p K a of t he d r u g. Th e n o ni o ni ze d s pe c ie s is m o r e li p id s o lu b le th a n th e io ni ze d s p ec ie s, an d it p a rt i ti o ns m o re r ea di l y a c r os s c e ll m em b r an es . 3 . C a r r ie r - m ed i a te d t ran s p o r t a . Ac t i ve t r a n sp o r t o f the d r ug ac r os s a m em br an e is a c a r r ie r -m e di a te d p r o ce s s t h a t h as th e fo ll o wi n g c ha r a c t e ri s ti c s . ( 1 ) Th e dr u g m o v es a g ain s t a c o nc en t r at i on gr a die n t . ( 2 ) Th e pr o c e s s re q ui r es e n e rg y.
( 3 ) Th e c a r ri e r m a y b e s e l ec t i v e f o r c e r t ai n t y pe s o f dr u gs th a t r es em b le n a t u ra l s u bs t ra t es or m e t ab ol i tes t ha t a r e n o rm al l y ac t i ve l y t r an sp o r te d . ( 4 ) Th e c a r ri e r s y s te m m a y b e s a tu r a te d a t a hi gh d r ug c o nc en t r at i on . ( 5 ) Th e pr o c e s s m a y be c om p et i ti ve ( i. e . , d ru g s wi t h s im il a r s t ru c tu r es m a y c om p et e f o r th e s am e c a rr i e r) . b . F ac i l it a t ed d if f u si o n i s a ls o a ca r r ie r -m e di a ted t r an s p o r t s y st em . H o we v e r , f a ci l it a te d d i ff us i on oc c ur s wi t h (i . e. , in th e d i re c ti o n o f ) a c o nc en t r at i on gr a d ie n t a n d d o es n o t r e qu i re ene r g y . 4 . P a ra c el l u la r t r a ns p or t . D r u g t r an sp o r t a c r o s s t i gh t (n a r ro w) j u nc t io ns b e t we e n c e ll s o r t r a ns en d ot h el ia l c h an n el s o f c el ls i s k no wn as p a ra c el l u la r t r an sp o r t . It i n vo l ves bo t h d if f us io n an d th e c o n ve c ti ve ( b ul k ) f l o w o f wa t e r a nd ac co m p a n y i ng wa t e r - s o lu bl e d r u g m o l ec u le s t h ro u gh th e p a r ac el l ul a r c ha n ne ls . 5 . V es i cu l a r t ra n sp o r t is t he pr o c e s s o f en gu l fi ng p a rt ic l es o r di ss ol v e d m a te r i al s b y a ce ll . Ve s i c ul a r t r an s p o r t i s t he on l y t r an s p o rt m ec ha n is m t ha t d o es n ot r e qu i re a d r ug to be in an aq u eou s s ol u ti o n t o b e a bs o rbe d . Pi n o c yt o s i s a n d p ha g o c yt o s i s a r e fo r m s o f v es ic u la r t ra n s p o r t. a . P i no c yt o s i s i s t h e e ng u l fm en t o f s m a l l s o l ut e o r f lu id v o lu m es . P.85
b . P h ag o c yt o s i s i s t he e n g ul fm e nt of la r g er pa r ti c le s, o r m a c ro m o l ec ul es , g en e r al l y b y m ac r op h ag es . c . E nd o c yt o s i s a n d e xoc yt o s i s a r e t h e m o v e m en t o f m a c ro m o l ec ul es in to a nd ou t o f t he c e ll , re s p ec t i v el y . 6 . O t h e r t r a n sp o r t m e ch a n is m s : t r a ns p o r te r pr o t e i ns . V ar i ou s t r a ns po r t e r p r o t e i ns ( e. g ., P - gl yc o p r o t e i n ) a r e em b ed d ed in t h e l ip i d b il a y e r o f c el l m em b r an es i n ta n de m i n α - h el ic a l t ra n s m em b ra n e r eg i on s o r d om a in s . Th e se p ro t ei ns a re a d e no s i ne t ri p ho s p h at e - ( A TP ; e n e rg y ) d ep e nd e nt “ p u m ps , ” wh ic h c an fa ci l it a t e t he e f f lu x o f d r ug m o le c ul es f r o m t he c e ll . B ec au s e the s e t r an sm em b ra n e e f fl ux p u m p s a r e of t en fo u nd in c o nj un c ti o n wi t h m e t ab ol i z i ng e n z y m e s s u ch as c yt o c h r o m e P4 5 0 3 A4 , t h ei r ne t ef f ec t i s to s u bs t a nt ia l l y re d uc e i nt r a c e ll u la r d ru g c on c e n t ra t i on s. Th u s t he y d et e rm i ne , t o a l ar g e e xt e n t , th e p h arm ac o ki ne t ic d is p os i ti on a n d c i rc u la ti n g p la s m a c on c en t r a ti o ns o f d r u gs (e . g. , c y c lo s po r in , n i fe d ip in e , d i go xi n ) t h a t a r e s u b s t r a te s f o r t he s e p r ot e in s . B . R o u t es o f d r u g a dm in i s t r a ti o n 1 . P a re n t e ra l ad m in i s t ra t i o n a . I n t ra ve n o us b ol u s i nj e c t io n . Th e d r ug is i nj ec t ed di r ec t l y i n to t he bl oo d s t r e am , d i st r ib u t es t h r ou gh o u t t he b od y , an d a c ts ra p id l y . A n y s id e e f fe ct s , i nc lu din g an i n t en se ph a rm ac ol o gi c re s po ns e , a na p h y la xi s , o r o ve r t to xi c i t y, al s o oc c ur r a pi d l y . b . I n t ra - a r t e ri a l i n je c t ion . Th e d ru g i s i nj ec t ed in t o a s p ec i fi c a r te r y t o ac h ie v e a h i gh d ru g c on c en t ra t io n in a s pe ci f ic ti s s ue be f o re d r ug di s t r ib u ti o n oc c urs t h r o ug ho u t t h e b od y . I nt ra - a r te r i al i n je c t i on is u s ed f o r d ia g no s t ic ag e nt s an d o cc a si on a ll y f o r c h em o the r a p y . c . In t r a ve n o us in f u si o n. Th e d ru g i s g i v en in t r av e n o us l y a t a c on s ta n t inp u t ra t e. C o n s ta n tr a te in t r a v en o us in f us io n m ai n ta i ns a r el a t i v el y c o ns t an t pl as m a d r u g
c o nc en t r at i on on c e th e in f us i on r at e i s a pp r o xi m a t e l y e q ua l t o th e d r ug ' s e l im in a ti o n r a t e f r om th e bo d y (i . e ., o n c e s t e ad y st a t e is r eac h ed ) . d . I n t ra m us c ul a r in j ec t io n . Th e d r u g is in je c te d d e e p in t o a s ke l et a l m u s c l e. Th e r a t e o f a bs o r pt i on de p end s o n th e v as c u la r i t y o f th e m us c l e s i te , th e l ip i d s o lu bi l it y o f t he dr u g, an d th e f o rm u l a ti on m a t ri x. e . S u bc u ta n e ou s i n j ec t io n . Th e d r u g is in je c te d b e n ea t h t he s k i n . Be c a us e th e s u bc ut a ne o us re g io n i s le s s v a sc ul a r t h an m us c le t i s su es , d r u g a bs o rp ti on is le ss r a p id . Th e f ac t o rs th a t a ff e c t a bs o rp ti o n f r om in t ra m us c u la r de p ot s a ls o af f e c t s u bc ut a ne o us a b s o r pt i on. f . M is ce l l an e ou s pa r e n te r a l r ou t e s ( 1 ) I n t ra - a r t ic u la r i nj e c ti o n . Th e d r ug is i n je ct e d i n to a j oi n t. ( 2 ) I n t ra d e rm a l ( i n t r ac ut a n e ou s ) i n j ec t i on . Th e d r u g is in je c te d i n to th e d e rm is ( i . e ., t he v as c u l a r r eg i on o f th e s ki n b el o w t h e e pi d e rm is ) . ( 3 ) I n t ra t h ec a l i n je c ti o n. Th e d ru g i s i nj ec t ed in to t he sp in a l f lu i d. 2 . E n te r a l a d mi n is t r a t ion a . B u cc a l a nd s ub l i ng ua l a dm i ni s t r a ti o n. A ta bl e t o r lo z e n ge is p l ac ed u n d er t he t o n gu e (s u bl i n gu a l ) o r in c o n ta c t wi t h t he m uc osa l ( bu c ca l ) s u rf ac e o f the c h e ek . Th i s t yp e o f a dm in is t r at io n al lo ws a no n po la r , l i pi d - s o lu b le dr u g t o b e a bs o r b ed a c r oss t he ep i th el i al li nin g of t he m o ut h . A f t er buc ca l o r s u bl i ng ua l a dm i nis t r at i on , t h e d r u g is ab s o r b ed di re c tl y i n to th e s ys te m i c c ir c u la ti o n , b y p as s i ng th e l i ve r a n d a n y f i rs t -p as s e f fe c ts . b . P e r o ra l ( o ra l ) d r u g ad m i n is t r a t io n . Th e d ru g i s a dm in is t e re d o r al l y , is s wa l l o we d , a n d u nd e rg oe s a bs o r pt i on f ro m t he ga s t ro i nt es t in a l t r ac t t h rou g h t h e m es e nt e r ic c i rc ul a ti o n t o t h e h ep a ti c p o rt a l v e i n i n t o th e l i ve r a nd th e n t o t h e s ys t em ic c i rc ul a ti o n. Th e p e r or a l r o ut e i s t he m o s t c om m o n r o ut e o f a dm i ni s t ra t io n . ( 1 ) Th e pe r o ra l r o ut e i s th e m os t c o n ven i en t a n d t h e s a fe s t r ou t e. ( 2 ) D is a d v an t ag es of t his r ou t e i nc lu d e t he f ol lowi n g . ( a ) Th e dr u g m a y n o t b e a b s o r be d f ro m t he ga s tro i n te s t i na l t r ac t c on s i s ten t l y o r c om p le t el y . ( b ) Th e d ru g m a y b e d i ge s te d b y g as t r oi n te st i na l e n zy m es o r d ec om po s ed b y t he a c id p H o f t h e s to m a c h . ( c ) Th e dr u g m a y i r r it a te m uc os al ep i th e li al c e ll s o r c o m p l e x wi t h t h e c o n te n ts o f t he g a st r o in t es ti n al t ra c t . ( d ) S om e d r ug s m a y b e in c om pl e te l y ab s o r b ed bec a us e o f f i rs t - pa s s e f f ec ts o r p r e s ys t em ic el im in a ti o n (e . g . , t he d ru g i s m e t ab o li z e d b y th e l i v e r b ef o r e s y s t e m i c a b so r p ti on oc c u r s ). ( e ) Th e ab s o r p ti on r at e m a y be e r ra t ic b ec a us e o f de l a yed ga s t r ic em p t yi n g o r c h an g es i n i n te s t i na l m oti l it y . P.86
( 3 ) Mo s t d ru gs a re xe n ob i o t i cs or ex o g en o us m o l ec ul e s a nd , c on se q ue nt l y , a re a b so r be d f ro m t he ga s tro i n te s t i na l t r ac t b y p a ss ive d i f f u si o n a n d p a r ti t io n i n g. C a r r i e r - m ed i a te d t ra n sp o r t , pa r a ce l l ul a r t ra n sp o r t , an d ve si c ul a r t r ans p o r t p l a y s m a l le r , b u t c ri t ic al , ro l es , pa r ti cu l a rl y f o r e nd o ge n o us m ol ec u le s .
( 4 ) D r ug m o le c u l es a r e ab s o rb ed t h ro ug h ou t th e g a s t r o i n t es ti n al t ra ct ; but t h e d u o d en a l r e g io n , wh ic h h a s a l a r ge s u r fa ce a re a b ec a us e o f t h e vi l l i an d m ic r o vi ll i, i s th e p r im a r y a bs o r pt i on s i te . Th e l a rg e b lo o d s up p l y p ro vi de d b y t h e m es e nt e r ic ve s s el s al l o ws th e d r u g to b e a bs o rb e d m o r e e f fi c i e n tl y ( se e I I . A .2 ) . ( 5 ) Al t e r e d ga s t r ic em pt yi n g a f f e c t s a r r i v al of th e d ru g i n t h e d uo de n um f o r s ys t em ic a bs o r pt i on . G as t r i c e m p t yi n g t i m e i s af f e ct e d b y f oo d c on t en t , e m ot i on al s t a te , a n d d r ug s t ha t a l te r g as t ro in t es t in al t ra c t m o ti l it y ( e .g . , a n ti c h o li ner g i cs , n a r co t ic a n al ge s i c s , p r ok i n e ti c a ge n ts ) . ( 6 ) N o rm al in t es t in al m o ti l it y f r om pe r i s ta l s is b rin g s t he d ru g i n c on t ac t wi t h t h e i n t es ti n al ep i th el i al c e ll s . A s u f fi c i e nt pe r i od of co n t ac t ( r es i de nc e t im e ) is ne e de d t o p e r m i t d r ug ab s or p ti o n ac r os s t h e c e l l m e m b r a nes f ro m t h e m u c o s al to the s e r os a l s u r fa ce . ( 7 ) S om e d r ug s , s u c h as c i me t i d in e a n d a ce t am in o p h en , wh e n g i ven in an i m m e di a te - r el e as e p er o ra l do sa g e f o rm t o fa s t e d s u bj ec ts p ro d uc e a s y s t em ic d ru g c o nc en t r at i on ti m e wi t h two p e a k s . Th is do u b le - pe a k p h en o me n o n is a tt r ib u t ed to va r i a bi l it y i n s to m a c h em p t y i n g, v a r ia b le in t es ti n a l m o t il i t y , a nd en t e ro h epa t ic c yc li n g. c . R ec t a l a dm i n is t r a ti on . Th e d ru g i n s ol u ti on (e n em a ) o r s u pp os i to r y f or m is p l ac e d in t he r ec tu m . D ru g di f fu si o n f r om th e s olu t i on o r r el e as e f r om th e s u pp os i to r y l ea ds to ab s o r p ti o n a c r o ss t h e m u c os a l s u r f ac e o f t h e r ec t um . D r u g a b so r be d i n th e l o we r t wo t hi r ds of t he r ec tu m e nt e r s t he s ys t em ic c i rc u lat i o n d i r ec tl y, b y p as s i ng t he liv e r a n d a n y fi rs t - pa s s eff e c ts . 3 . R es p i r a to r y t r a c t a dm i n is t r a t i on a . I n t ra n as a l a dm i n is t ra t i o n . Th e d ru g c on t ai ned i n a s ol u ti o n o r s us pe ns i on is a d m i ni s te r ed t o t he na s al m u c o sa , ei t he r a s a s p ra y o r as dr o ps . Th e m e d ic a ti o n m a y be us e d f o r l oc al (e .g . , na s a l d ec on g es t an ts , i n t ra n as al s t e ro id s ) o r s ys t e m i c e f f ec ts . b . P u lm o na r y i n h a l a t i on . Th e d ru g , as li q ui d o r s o li d p a r ti cl es , i s i nh al ed p e ro r al l y ( wi t h a ne b ul i z e r o r a m et e r e d- d os e a e ro so l ) i n to t h e p u lm on a r y t re e . I n ge n e ra l , p a r t i c le s > 60 µ m a r e p ri m a ri l y d e po s i t ed in th e tr a c h ea . Pa r t i c le s > 20 µm d o n ot r e a ch th e b r o nc hi ol es , an d pa r t i c le s < 0. 6 µ m a re n ot de p os it e d a nd a re e x h al e d . P a r t ic le s b e t we e n 2 a n d 6 µ m c a n r ea c h t he al ve o l a r du c t s, al t ho u gh on ly p a r t ic le s o f 1 -2 µ m a r e re t a in e d in t h e a l ve o li . 4 . T r an s de r m al a nd t opi c a l a d mi n is t r a t io n a . T r an s de r m al ( pe r c u ta n e ou s ) d r u g a bs or p ti o n i s t h e pl a ce m e n t o f t h e d r u g ( i n a l o t io n , o in tm e nt , c r ea m , p a s t e , o r p a tc h ) o n t h e sk i n s u r f ac e f o r s y s te m i c a b so r p ti on . A n oc c l us i v e d r es s i n g o r f i lm i m p r o ves s ys t em ic d ru g a bs o rp t io n f ro m t h e s ki n . S m a ll li p id - s o lub l e m ol ec ul e s , s u c h as ni t r og l y c er i n, ni co t in e , sc o p ol a m i ne , c l on id i ne , fe n ta n y l , a nd s t e ro i ds (e . g. , 17 - β - es t ra d io l , t es t os t er o ne ) , a r e r e a di l y a b so r be d f ro m t he s k i n . b . D r ug s (e . g. , a n ti b ac t er i a ls , l oc al an e st h et ic age n ts ) a re ap pl i ed t op i ca ll y t o t h e s ki n fo r a lo c a l e f f ec t . 5 . Mi s c el la n eo us r ou t es o f d ru g a dm i ni s t r a ti on inc l ud e o p h th a lm i c , o t ic , u r e t h r a l, a n d va gi n a l a dm in is t ra t io n . Th es e r o ut e s o f a dm in i st r a ti o n a re ge n e ra ll y u s ed fo r l o ca l t h e ra pe u ti c a c t i v i t y. H o we ve r , so m e s ys t em ic d ru g a bs o r pt i on m a y oc c u r .
C . L o ca l d ru g ac t i vi t y v e r s us s ys t e m i c d ru g abs o r p t i on . Th e r o ut e of a d m i ni s t ra ti o n , a bs or p ti on s i t e , a nd bi oa v a i la bi l ity o f t he d ru g f r om th e d os a ge fo r m a r e m a jo r fa c t o rs in th e d e s i g n o f a d r u g p r od uc t. 1 . D r ug s i n te nd e d f o r l oc a l a c t i vi t y, s u c h as to pi c al an t ib io t ic s , an t i -i n fec t i v es , a n t if u ng al ag e n ts , a nd loc a l a ne st h et ic s a r e f o rm u l a te d i n d os a ge fo r m s th a t m i ni m i ze s y s t em ic a bs o rp t i on . Th e c on c e n t ra ti o n o f t he se dr u gs at th e a pp l ic a ti on s i te a ff ec t s t he i r a c t i v i t y . 2 . W he n s ys t e m i c a b so r p t i o n i s d es i re d , t he bi oa va i la b il i t y o f th e d r ug f ro m th e d o sa g e f o rm a t th e a bs or p t io n s i te m us t be c o ns id e r ed ( e. g . , a d r u g g i ven i n t ra ve n ou s l y i s 1 00 % b io a v a il a bl e b ec a us e a ll of t h e d r ug is p l ac ed di r ec tl y i n to th e s ys t em ic c i rc ul a ti o n) . The am o un t , o r d o s e , o f d ru g in th e d os a ge fo r m i s b a se d o n t h e e xt e n t o f d r ug ab s o rp t i on an d t h e d es i re d s ys t em ic dr u g c on c e n t ra ti on . Th e t y pe o f do sa g e f o rm (e . g ., im m e di a te r el ea s e , c o nt r ol le d r el ea s e ) af f ec ts t he ra t e o f dr u g a b so r p ti on . P.87
III. BIOPHARMACEUTIC PRINCIPLES A. P h ys i c o c h em i ca l p rop e r t i es 1 . D r u g d i ss o l ut i o n. F or m os t d r u gs wi t h l im it e d wa t e r s ol u bi li t y, th e ra t e a t wh i c h t h e s ol i d d r ug en t er s i n to s o l ut i on (i . e ., t he ra t e o f di s s ol u ti o n ) is of t en t he r a te l i m i ti n g s te p i n b i oa v a il ab i li t y . Th e N o ye s - W h i t ne y e q u a t i on de sc ri b es the d if f us io n c o nt r o ll ed r at e o f dr u g d is s o l ut i on ( d m /d t ; i . e. , the ch a ng e i n t h e am o un t o f d ru g i n s o lu t io n wi t h r es p ec t t o ti m e ):
wh e r e D is t he di f fu s i o n c o ef f ic ie n t o f t h e s ol ut e , A i s t he su r f ac e a r ea of th e s o li d u n d er g oi n g di s s o lu t io n , δ is t he th ic k n es s o f th e d i f fu s i o n l a y e r, C s i s t h e c o nc en t r at i on of t he s o l va t e a t s a tu r a ti on , an d C b i s t h e co nc e nt r a ti o n o f th e d ru g i n t h e b u lk s ol u ti o n p ha s e a t ti m e t . 2 . D r u g s o lu b i li t y i n a s a t u r at e d so l ut i on (s e e Ch a p te r 3, I V ) is a s ta t ic ( e q ui l ib r iu m ) p ro p e rt y . Th e di s s ol u ti o n r a te of a dr u g i s a d y na m i c p r op e r ty r e l a te d t o t he ra t e o f a bs o r pt i on . 3 . P a r ti c le s iz e a nd su r fa c e a r e a a r e i n v er s el y re l a te d . A s s ol id d ru g p a rt i c l e s i ze d e c re as es , p a r ti c l e s u rf ac e a r e a i nc r ea se s . a . A s d es c r ib e d b y t he No y e s -W hi tn e y eq u at i on , th e di s s ol u ti o n r a te is d i re c tl y p r o po r t io n al to th e s u r fac e a r e a. A n i nc r ea s e in su r f ac e a r e a al l o ws fo r m o r e c o nt ac t be t we e n th e s ol id d r ug pa r ti c l es an d th e s o l v en t , r e s u lt i ng in a f as t e r d i ss ol u ti on r a te (s ee I I I.A . 1 ) . b . W ith c e rt a in h yd r o p h o b i c d r u g s, e xc e s s i v e pa r t ic le s i z e r ed uc t io n d oe s n o t a l wa ys i nc r ea s e t he di s s o l u ti on r at e . Sm al l p a rt icl e s t en d to re a gg r e ga t e in t o l a r ge r p a r ti c l e s t o r e du c e th e h ig h s u r fa c e f re e e n e rg y pr o d uc ed b y pa r t ic le s i z e r e d uc t io n .
c . To p re v e n t t he f or m a t io n of ag g r eg a te s , sm al l d r u g p a rt ic l es a r e m ol ec u l a rl y d i sp e rs ed in po l y e th y l e ne g l yc o l ( P E G ) , p o l yv i n y lp y r r o l id o ne ( P V P; po v i d on e ) , d e xt r o s e , o r o t he r ag e nts . Fo r e xa m pl e , a m ol ec u l a r d is pe r s i o n o f g r is eo fu l vi n i n a wa t e r - s o lu bl e c a r ri e r s uc h as P E G 40 0 0 ( e .g . , G ris - P E G ) en h an c e s i ts di s s o lu t io n a n d b io a v a il a bi li t y . 4 . P a r ti t i o n c oe f f i ci e n t a n d e x t en t o f i o ni za t i on a . Th e pa r t i t io n co e f fi c ie n t of a d r ug is th e ra ti o o f th e s ol u bi li t y o f t he dr u g , a t e q ui l ib r iu m , in a n o na que o us s o l v en t (e . g ., n -o c ta n ol ) t o t ha t i n a n a q ue ou s s ol ve n t ( e . g ., wa t e r ; p H 7 .4 bu f fe r s o l ut i on ) . H y d ro ph i li c d r u gs wi t h h i gh e r wa t e r s o lu bi l it y h a ve a f as t e r d is s o lu t io n r a t e t ha n d o h y d r o ph o bic o r l ip o ph il ic d ru gs , wh ic h h a ve p o o r wa t e r s o l ub il i t y . b . E x te n t o f i on i z a t i on . D r u g s t ha t ar e we a k e le c t r o l yt es (a c i ds o r b as es ) e xi s t i n b o t h a n i on i z e d f o rm a n d a no n io ni ze d fo r m i n s o lu t i on . Th e e xt e n t of io n i za t i on d e p en ds on th e p K a o f the we a k el ec t ro l y t e a nd th e p H o f t h e so l ut i on . The i on i z ed f o r m is m o r e p ol a r , a nd th e r e fo r e m o r e wa t e r s olu b le , th a n t he no n io ni z e d f o rm . Th e H e n d e r so n - H as s el b al c h e q ua t i o n d es c r i be s t he r e l at i on be t we e n th e i on ize d a nd t h e n o ni o ni z e d f o rm s o f a d r ug as a f un ct i on of pH a n d p K a . W hen t h e p H o f t he m e di um eq u al s t he p K a of t h e d ru g , 5 0% o f t he d ru g in s o lu t io n i s n on io n i ze d an d 5 0 % i s i on i z ed , as c an be s h o wn f r om th e fo ll o wi n g eq u at i on s : ( 1 ) F o r w ea k a ci d s :
( 2 ) F o r w ea k b as e s :
5 . S al t f o rm a t io n a . Th e c h oi c e of s a lt f o rm f or a d r ug de p en ds on t h e d es i re d p h y s i c a l , c he m ic al , o r p h a rm ac ol o gi c p r op e r ti es . C e rt a in s a lt s a r e d es ig n e d t o p r o vid e s lo we r di s s o lu t io n , s l o we r bi oa v a i la b il it y , a nd l on ge r du r a ti o n o f ac t i o n . O th e r s al t s a re s e le ct e d fo r g r e a te r s t ab il i t y , l es s l oc a l ir r i ta t io n a t th e a bs o rpt i o n si t e, o r l es s s ys t em ic t o xi c it y. ( 1 ) S om e s ol ub l e s a l t f o rm s a r e l es s s t a bl e t h an th e no ni o ni z e d fo rm . Fo r e xa m p l e , s o di um as pi r in is le s s s ta b le t ha n a s p i ri n i n t h e ac i d f o rm . ( 2 ) A s o li d d os ag e fo rm c o nt a in in g bu f fe r in g a g en t s m a y b e fo rm u la t ed wi t h t h e f r ee a c id fo r m o f t h e d r ug (e .g . , bu f fe r ed as pi r i n) . P.88
( a ) Th e bu f fe r in g a g en t fo r m s an al k a l in e m ed iu m i n t h e g as t ro i nt es t in a l t ra c t , a nd t h e d r u g d is s o l v es i n s i tu . ( b ) Th e di s s ol v e d s al t for m of t he dr u g d if f us es in t o th e b ul k f l ui d o f t h e g a st r o in t es ti n al t ra c t , fo rm s a fi n e p re c i p it a te t ha t r e di ss o l v es ra p id l y , a n d b ec om e s a va i la b le fo r ab s o r p ti o n. b . E f f e r ve sc e n t g r an u l es o r ta b le t s c on t ai ni n g th e ac id d ru g i n a dd i ti o n to s o d iu m b i ca r bo n at e , t a r ta r ic ac id , c i t ri c a c i d , o r o t he r i ng r e di e nt s a r e a dd e d t o wa t e r j us t b e f o re or a l a dm in is t r at i on . Th e e xc es s s od iu m b ic a r bo na t e f o rm s a n a lk ali n e
s o lu t io n i n wh ic h t h e d r ug d is s o l v es . Ca r b on di o xi d e i s a ls o f o rm ed b y th e d e co m p os i ti o n o f c ar b oni c a c i d . c . Fo r we a k l y a c i di c d r ugs , po t as s i um a n d s o d iu m s al t s a re m o r e s ol ub l e th a n d i va le n t c at i on s a lt s ( e . g. , c a lc i um , m a g ne si um ) o r t r i v al en t c a ti o n sa l ts (e . g . , a l um in um ) . d . F o r we a k b as e s, c om m o n wa t e r - s o l ub le s a l ts in c lu d e t he h yd ro c h l or i de, s ul f at e , c i t ra t e, an d g l uc on a te s al t s . Th e es to l at e , n ap s y la t e , a nd s t e a ra t e s a l ts ar e le s s wa t e r s ol u bl e . 6 . P o l ym o r p h i s m i s t h e a b il i t y of a d r ug to e xi s t i n m o r e t ha n o n e c r ys t al li n e f o rm . a . D i ff e re n t p ol y m o rp hs h a v e di f fe r e nt ph y s ic al pr o p e rt i es , i nc lu d in g m el t in g po in t a n d d is s o l ut i on ra t e . b . Am o r p h o us , o r n on c rys t a l l i n e , f o rm s o f a d rug h a ve f as t e r d is s o lu t io n r a t es t h a n d o c r y s t a ll in e f o rm s . 7 . C h i ra l i t y i s t h e a b il i t y o f a d ru g to e xi s t a s o p ti c a l l y a c t i ve s t e r eo i s om e r s o r e n a n ti o me r s . I n di v i du a l e n a nt io m er s m a y n o t h ave t h e s am e p ha r m a c o k in e t ic a n d p h a rm ac o d y na m i c ac t i v ity . B e c au s e m os t c h ir a l dr u g s a re us e d as r ac em ic m i xt u r e s , t h e re su l ts o f s t ud i es wi th s u c h m i xt u r e s m a y be m is l ea di n g b ec au s e t he d r u g i s a ss u m e d t o b e ha v e as a s i ng le en t i t y . F o r e xa m p le , ib u p ro f en e xi s ts as t he R - an d S - e n an t io m e r s ; on l y t he S - e n an t io m e r is p h a rm ac o l og ic a ll y ac t i v e . W hen th e r a c em ic m i xt u r e o f ib up ro f e n is t ak en o ra ll y , t he R - e n a nt io m er un d e rg oe s p r e s ys t em ic in v e r s i on in t h e g u t t o t h e S - e na n ti om e r . B ec a us e t h e r a te an d e xt e n t o f i n ve r si on a re s i te s p ec i fic an d fo r m u la t io n d e pe nd e n t, ib u p ro f en ac ti v i t y m a y va r y c o ns id e ra b l y . 8 . H yd r a t e s . D r ug s m a y e xi s t i n a h yd r a t e d , o r so l va t e d , f o r m o r as a n an h yd r o u s m o l ec u le . D is s o lu t io n rat e s d i ff e r f o r h y d r a te d a nd a nh y d r ou s f o rm s . F o r e xa m p l e , t h e a n h y d ro us fo r m o f am p ic il li n d is s o l v es f as te r a n d is m o r e r a pi dl y a bs o r b ed t ha n t h e h yd r a te d fo rm . 9 . C o mp l ex f o rm a t io n . A c o mp l ex is a sp ec i es fo r m ed b y th e r e v e rs i bl e o r i r r e ve rs i bl e a s s oc ia t io n o f t wo o r m o re in t er a c t ing m o l ec ul es o r i on s . C h el a t e s a re c om p le xe s t h at t y pi c a l l y i n v o l v e a r in g -l ik e s t ru c tu r e fo r m e d b y t he in t e rac t io n b e t we e n a pa r t ia l r i ng of a t om s a nd a m e t al . Ma n y b i o lo gi c a l l y i m p o r ta n t m o le cu l es ( e . g ., he m o g lo b in , i ns u lin , c y an oc o ba la m i n ) a r e c h e l a te s. D r ug s s uc h a s t e t r ac yc li ne f o r m ch e la t es wi t h d i v a len t ( e. g . , C a
++
, Mg
++
) a n d t r i v a le n t ( e .g . , Al
+++
, Bi
+++
) m e ta l
i o ns . Ma n y d r ug s a ds o rb s t ro n gl y o n c ha rc o al o r c l a y (e . g. , k a ol in , be n to ni t e ) p a r ti c l e s b y fo r m i n g c o m p l e xe s . D ru g c om pl e xe s wi t h p r o te i ns , s uc h as alb u m i n o r α 1 - a c id gl y c op r o te in , of te n oc c u r . a . C om pl e x f o r m at i on us u a ll y a l te r s t he ph ys ic al a n d c he m i c a l c ha r ac t e ri st i c s of th e d r u g . F o r e xa m p le : ( 1 ) Th e c h el a te of te t r ac y c l i ne wi t h c al c i um is le s s wa t e r s o lu bl e a n d is poo r l y a b so r be d . ( 2 ) Th e op h y l li ne c o m p l exe d wi t h e th y l e ne di am i ne t o f o rm am in op h y l li n e is m o r e wa t e r s ol u bl e a n d is us ed f o r p a re n te r al an d re c ta l ad m i ni s tr a ti o n. ( 3 ) C yc lo d e xt r i ns a re us e d to f or m c om pl e xe s wi t h m a n y d ru gs t o i nc re a se t he i r wa t e r s ol u bi li t y .
b . L ar g e d r ug c om p le xe s , s uc h as d ru g -p r o te i n com p le xe s , do n ot c r os s c el l m em b r an es ea s i l y . Th es e c o m p l e xe s m us t d is s oci a t e t o f r ee t he dr u g f o r a b s o r p ti on a t t he ab s o r p ti on s i t e o r t o pe r m i t tr a ns po r t a c ro s s ce ll m e m b r an es o r g lom e r ul a r f i l t ra t io n b e fo r e t h e d ru g i s e xc r e t e d in t o t h e u r ine . B . D r u g p r od u c t a nd d el i ve r y s ys t e m f o r m u l at io n 1 . G e ne r a l c o ns i de r a t i on s a . D es i g n o f th e a p p r o pr i a t e do s ag e fo r m o r del i ve r y s ys t e m d e p en ds o n th e ( 1 ) P h ys i c a l a nd c h em ic a l pr o pe r t ie s o f t h e d r ug ( 2 ) D os e o f th e d r ug ( 3 ) R o ut e o f a dm i ni s t r a tio n ( 4 ) Ty p e o f d r ug de li v e r y s y s te m d es i re d ( 5 ) D es i re d th e ra p eu t ic ef f e c t ( 6 ) P h ys i ol o gi c r e le as e of t h e d ru g fr o m t he de li v e r y s y s te m ( 7 ) B io a v a il ab i li t y o f t he d r u g a t t h e a bs o rp t io n s it e ( 8 ) P ha r m a c o k i n et ic s a nd p ha r m a co d y n am ics o f th e d ru g P.89
b . B i oa va i l a bi l i t y. Th e m o r e c o m p l ic at e d t he f orm u la t io n o f t h e f in is h ed d r u g p r o du c t ( e .g . , c on t ro l le d -r e l ea s e t ab le t , e n te r ic - c o a t ed ta b le t , t r an s de rm al p at c h ) , t h e g r e at e r t h e p ot e nt i al f o r a b io a va il ab i li t y p ro ble m . F o r e xa m p le , th e r ele a s e o f a d r u g f r om a p e ro r al do s ag e fo r m a nd it s s ub s e q ue n t b i oa v a il a bi li t y d ep e nd o n a s uc c ess i on of r at e p r oc es s e s (F ig u r e 4 - 2) . Th es e p r oc es s e s m a y i nc l ud e th e f o l lo wi n g : ( 1 ) At t r i t i o n , d i si n t eg r at i o n , o r di s ag g r e ga t i on o f t he dr u g p r od uc t ( 2 ) D i ss o l ut i o n o f t h e d ru g in an aq u eo us en v i r on m en t ( 3 ) C o n ve c ti o n a nd d i ffu s i o n o f t h e d ru g m ol ecu l es to t he ab so r bi n g su rf a c e ( 4 ) Ab s o r p t i on of t he d ru g ac r os s c e ll m e m b r an es in t o t h e s ys t em ic c i rc u la t i on c . Th e ra t e - li m i ti n g s t ep i n t he bi o a vai l ab il i t y o f a d ru g f r om a d r ug p ro du c t i s t he s l o we s t s t e p i n a s e ri es o f k i ne t ic pr oc e ss es . ( 1 ) F or m o s t c o n v e nt io na l s o li d d r ug p ro d uc ts (e. g . , c ap s u l es , t a bl e ts ) , th e d i ss ol u ti on r a te is t h e s lo we s t , o r r a te - li m i t in g , s t e p fo r b i oa va i la bi l it y. ( 2 ) F or a c on t r ol le d - o r s u s ta i ne d - re l ea se d ru g p ro d uc t , t h e r el e as e o f t h e d r u g f r om t h e d e li v e r y s y s t em is the r a te - li m i t in g s te p . 2 . S o lu t i on s a r e h om o ge n e ou s m i xt u r e s o f on e o r m o r e s ol u te s d i s pe r s ed m o le cu l ar l y in a d is s o l v in g m e di um (s o l ven t ) . a . C om p ar e d wi t h o th e r o r a l a nd pe r o ra l d r u g f o rm u la t io ns , a d ru g d is s o l ve d in an a q u eo us s o lu t io n i s i n t he m o s t b io a vai l ab l e a nd c o ns is te n t f o rm . Be c a u se t he d ru g i s a l re a d y in P.90
s o lu t io n , n o d is s o lu t io n s t e p i s n ec es s a r y b ef o r e s y s t em ic a bs o r pt i on oc c u r s . P e r o r al dr u g s ol u ti on s a re o f te n u s e d a s t he r ef e re n ce p re pa r a ti o n f o r so l id p e ro r al f o r m u l at io n s .
Figure 4-2. The processes involved in drug release from peroral dosage forms. GI, gastrointestinal.
b . A dr u g d is s o l v ed in a h y d r o al co h ol ic s o lu t io n (e . g . , el i xi r ) a ls o h as go od b i oa va i la b il it y . A lc o ho l ai d s d r ug s o lu bi l it y . H o we ve r , wh e n t he dr u g i s di lu t e d b y g a st r o in t es ti n al t ra c t fl u id a nd ot h e r g ut co n te n ts ( e . g. , fo o d) , it m a y f o rm a fi n el y d i vi de d p r ec i pi t at e i n t h e l um e n o f t h e g as t ro in t es t i n al t ra ct . Be c au se of t he e xt e n s i v e di s p e rs io n a n d l a rg e s u r fa c e a re a o f s uc h fi ne l y di v i d ed p re ci pi ta t es , r e d is so lu t io n a n d s u b s e qu e n t a bs o rp t io n o c c u r r ap i d l y. c . A visc o us dr u g s ol ut i on ( e .g . , s yr u p) m a y i nt e r fe r e wi t h d i lu ti o n a nd m i x i n g wi t h g a st r o in t es ti n al t ra c t c o nt e n ts . Th e s ol ut i on de c rea s es th e g as t r ic e m p t y i ng r a te an d t h e ra t e o f t r a ns fe r of d ru g s o lu t io n t o th e d uo d en a l r e gi o n, wh e r e a bs o r pt i o n is m os t ef f ic ie n t. 3 . S us p e ns i on s a r e d is pe r s io ns of fi n el y d i vid e d s o li d p a r ti c l es of a d r ug in a l i qu id m e di um in wh i c h th e dr ug is no t re a di l y s o lu b le . Th e l i qu id m e di um o f a su s pe ns i on c om p r is es a s a t u ra t ed s o l u ti on o f t he d ru g i n e qu i l i b ri u m wi t h th e s ol i d dr u g . a . Th e bi oa v a i la bi l it y o f th e d ru g f r om s us p en si o ns m a y b e s i m i l ar t o t ha t o f a s o lu t io n b ec a us e t he fi ne l y d i v id ed p ar t ic le s a r e d i sp e rs ed an d pr o v i de a l a r ge s u r fa ce a re a f o r ra pi d d is s o l ut i on . O n t he o th e r ha n d , a s lo w d i ss o lu ti o n ra t e d e c re as es th e a b s o r pt i on r a te . b . S u sp e nd i n g a ge n t s ar e o ft e n h yd r op hi l ic c ol l oi d s ( e .g . , c el lu l os e d e ri va t i v es , a c ac ia , xa n t h an gu m ) add e d t o s us p en s i on s t o i nc r e as e v i s c os i t y , i nh i bi t a g gl o m e r at i on , a n d d ec re a s e th e ra t e a t wh ic h pa r t i c le s s et t le . H ig hl y vi sc o us s us p en s i o ns m a y p ro lo ng g as t ri c e m p t y i ng ti m e , s l o w d r ug di ss ol u ti o n, and d e c re as e t h e a bs o rp t io n r a t e . 4 . C a ps u le s a r e s ol id d os a ge fo r m s wi t h h a r d o r s o f t g el a ti n s he ll s t h at c o n t ai n d r u gs , u s u a ll y a dm i xe d wi t h e xc i p i en t s. C oa t i n g t h e c ap su le s h el l o r t he d r u g p a r ti c l e s wi t h i n t he c a ps u l e c an af f ec t b i oa v a il a bi l it y. a . H a r d g e la t i n c ap s ul es a r e us u al l y fi ll e d wi t h a p o wd e r b le n d t h at c o nta i ns th e d r u g . Ty p i c al l y , th e p o wd e r bl en d i s s im pl e r a nd l e ss c om p ac te d t h an t he b l en d i n a c om p r es s e d t ab l et . A ft e r i n ge s t i on , th e g el a ti n s of t e ns , s we l ls , an d b eg i ns t o d i ss ol ve in th e g as t r oi n te s ti n al t ra ct . E nc ap s u la te d d ru gs a re re l ea s e d rap i dl y a nd d i sp e rs ed ea s i l y , an d b ioa v a i la b il i t y i s g oo d . Ha r d g e la t in c a ps ul es a re th e p r e fe r r ed d o sa g e f o rm fo r e a r l y c lin i c a l t r ia ls o f n e w d r ug s .
b . S o f t g e la t i n c ap s ul es m a y c on t ai n a no n aq ue o us s o lu t io n , a p o wd e r , o r a d r ug s us p en s i o n. Th e v e hi c l e m a y be wa t e r m is c i b le ( e. g . , P E G ). Th e c a r di ac glyc o si d e d i go xi n , d is p er s e d i n a wa t e r -m is ci bl e veh ic l e ( L an o xi c a ps ) , h as be t t e r b i oa va i la b il it y t h an a c om p r es s e d t ab l et f or m u l ati o n ( L an o xi n ) . H o we ve r , a s o f t g e la t in ca ps u le th a t c o n ta i ns th e d r u g d is s o l ved in a h yd r o p h o b i c v eh ic l e ( e . g. , ve g e t ab l e o il ) m a y ha v e p o o re r bi o a vai la b il i t y t h an a c om p re s s ed t ab le t for m u la ti o n o f t he dr u g. c . Ag i n g a n d s t o ra g e c on d i t i on s c an a ff ec t th e m o is tu r e c on t en t of th e ge l a ti n c om p on e nt o f t he c a ps ule s h e ll an d t h e b io a v a il ab i l i t y o f t he d ru g . ( 1 ) A t l o w m oi s t u r e l e v els , th e c ap s u l e sh e ll be com es b ri t tl e a n d is ea s i l y r u p t ur e d. ( 2 ) A t h ig h m oi s tu r e l e v el s , t h e c a ps u le s h el l b ec o m es m oi s t, so f t, an d d is t o rt e d. Mo i s t u r e m a y be t ra ns f e rr e d to th e c a ps ul e c on t en t s , p ar t ic ul a r l y i f th e c on t e nt s a r e h yg r o sc op ic . 5 . C o mp r e ss e d t a bl e t s a r e s o li d d os ag e fo r m s in wh i c h h ig h p r es su r e i s u s ed to c om p r es s a p o wd e r b l end o r g r an u la t io n t h at co nt a i n s th e d r ug an d o t he r i n g re d ie n ts , o r e xc i p i en ts , in t o a s ol i d m a ss . a . E xc i p ie n ts , in c l ud i ng d i lu e nt s (f il l e rs ) , b in de r s , d is in t eg r a n t s, lu b r ic an ts , g l id a nt s , s u r f ac t an ts , d y e , an d fl a v o ri n g a ge n ts , h a ve th e fo ll o wi n g p r op er t i es . ( 1 ) Th e y p e rm i t th e e f fi c ie n t m an u fa c tu r e o f c om pr e s s e d t ab l et s . ( 2 ) Th e y a ff e c t th e p h y s ic a l a nd c h em ic al ch a ra c te r i s t ic s o f t h e d r ug . ( 3 ) Th e y a ff e c t bi o a v ai lab i li t y . Th e h i gh e r t h e r a tio o f e xc i p ie n t t o a c ti v e dr u g , t h e g r e a te r th e l ik el i ho o d t ha t t he e xc i pi en t s a f fe c t bi o a vai l ab il i t y . b . E xa m p le s ( 1 ) D i si n t eg r a n ts ( e. g . , s t a rc h , c ro s c a rm el lo s e , s o di um s t a rc h g l y c o la t e ) v a r y i n a c ti o n, de p en d in g o n t h ei r c o nc e nt r a ti on , th e m e th o d b y wh i c h t h e y a r e m ixe d wi t h t h e p o wd e r fo r m u l at i on or g r an u la t io n , a nd th e d eg r e e o f t a bl e t c o m pa ct i on . A l t h ou gh t ab le t di s i n te g ra t i on is u su a ll y n ot a p r o b l em be c a us e i t o f t en occ u rs m o r e r a p id l y t ha n d r ug di s s ol ut i o n, it is ne ce s s a r y fo r di s s o lu t io n i n i m m ed ia t e - re l ea s e f o r m u l at io n s . In a bi li t y t o d i s i n te g ra t e m a y i n te r f e re wi t h bi o a v ai l ab il i t y . P.91
( 2 ) L ub r i c an t s a r e us u all y h y d r o ph ob ic , wa t e r -i ns o lu bl e s u bs ta nc e s s u ch a s s te a ri c a c id , m ag n es iu m s te a ra te , h y d ro g en a te d v eg e ta bl e oi l , a nd ta lc . Th e y m ay r e d uc e we t t i n g o f th e s u rf ac e of t h e s ol i d d r ug pa r ti cl es , s l o wi n g t he di s s ol u ti o n an d b i oa va i la b il it y r a t es o f the d r ug . W ate r - s o lu b le lub r i c a n ts , s uc h as L -l e uc in e , d o n o t i n t er f e re wi t h di s s ol u ti on o r bi o a v ai la b il it y. ( 3 ) G l i da n t s ( e .g . , c ol lo id a l s il ic on di o xi d e ) im pro v e t he f lo w p r o pe r t ie s of a dr y p o wd e r bl e nd be f o re it is c om p re ss ed . R at h e r t han p os in g a po t en t ia l p r obl e m wi t h b i oa va i la b il it y , g li da n ts m a y r ed uc e ta bl e t -t o - ta bl e t v a ri a bi li t y an d i m p r o ve p r od uc t e f f ic ac y . ( 4 ) S u r fa c t an t s e n ha nc e d r u g d iss o lu t io n r a te s an d bi oa v a i la b il it y b y r e du c in g i n t er f ac i al te ns i on at th e b o un d ar y b e t we e n s o l id d r u g a nd li qu i d a nd b y im p r o v in g t h e we t t ab il i t y (c o nt ac t ) o f s o li d d r u g p ar t ic le s b y t h e s ol v e n t.
c . C oa t e d c om p r es s ed ta b l e ts ha v e a s ug a r c oat , a f i lm c oa t , o r an en t e ri c c oa t wi t h t h e f o ll o wi n g p r op e rt i es : ( 1 ) I t p r ot ec t s t he d ru g f ro m m oi s tu r e, li g ht , an d ai r . ( 2 ) I t m a s k s t h e t as te o r o d o r o f t h e d r ug . ( 3 ) I t im p r o v es th e a pp ea r a nc e o f t h e t a bl e t. ( 4 ) I t m a y a f fe c t t he r el ea s e r a te of t he d ru g . d . I n a dd i ti on , en t e r ic co a t i ng s m in im i z e c o nt ac t b e t we e n t he d ru g a nd th e ga st r ic r e g io n b y r e s i s t in g d is s ol u t io n o r a t t ri t io n a n d p r ev e n t i ng c o nt a c t be t we e n t h e u n d er l yi ng d ru g a nd t he g a s t r ic c o n te n ts o r ga s t r ic m u c o sa . So m e en t e ri c c o at i ng s m i ni m i ze ga s t r ic c o n ta c t b e c a us e th e y ar e i ns o lub l e a t a c i d ic p H s . O t h e r c o at i ng s r e s is t a t tr i ti o n a nd r em ain wh o l e l o ng en ou g h f o r t h e ta bl e t t o l e a v e t he ga s t ri c a r e a . B y r es is t in g d is s o lu t i on o r a tt r i ti on , en t e ri c c oa t in gs m a y d ec r ea se b i oa va i la b il it y . E n te r ic c o a t in gs a re us ed to ( 1 ) Mi n i m i z e i r ri ta t io n o f t h e g as t r ic m uc os a b y t he d r ug ( 2 ) P r e v en t i n ac ti v a t io n o r d eg r ad a ti o n o f t he d rug i n t he s t om ac h ( 3 ) D el a y r el e as e o f t h e d r u g u n ti l t h e t ab le t r ea ch e s t he s m al l i n te s t i ne , wh e r e c o nd i ti on s f o r a bs o r pt i on m a y be op t im al 6 . M o d i fi e d - re l ea s e d o sa g e fo r m s a r e d r ug pr o du c ts th a t a lt e r th e r a te or t im i ng of d r u g r e le as e . B ec a us e m o d i fi ed - r el e as e d os ag e fo r m s a re m o r e co m p l e x t h a n c o n ven t io n al im m e di a te -r e l ea s e do s a g e f o rm s , m o r e s t r in ge n t q ua l it y c on tr o l a n d b i oa va i la b il it y t es t s a r e re q ui r e d. D o se du m p in g , o r th e a b r up t , u nc on t r ol le d r e l ea se o f a l a rg e a m o u nt o f d r ug , is a p ro bl em . a . E x te n de d - r el e as e d os a g e f o r ms in cl u de co n tr o l l e d - re l ea s e, s us t ai ne d - a ct i o n, a n d l o n g -a c ti n g d r u g de l i ve r y s ys t e m s . Th es e d e li ve r y s y s te m s a l lo w a t l ea s t a t wo f o l d re d uc ti o n i n d os in g f re q ue nc y co m pa r ed wi t h c on v e n t io na l i m m edi a t er e l ea se f or m u l at i on s . ( 1 ) Th e e xt e n de d , s l o w r e l ea s e o f c o n t ro l le d - re lea s e d r ug p ro du c ts p r o duc es a r e l at i ve l y fl a t, s u s t a in ed p l as m a d ru g c on c e n t ra t io n th a t a v o id s t o xi c i t y ( fro m h i gh d r u g c on c e n t ra t io ns ) o r la c k o f e f fi c a c y (f r om lo w d r u g co nc e nt r a ti o ns ) . ( 2 ) E xt e n d ed - r el e as e d os a ge fo r m s pr o v i de an im m e d ia t e ( i ni ti a l ) r el e ase o f t h e d r u g , f ol lo we d b y a s lo we r s u s ta in e d r el e as e . b . D e la ye d - r e l e a se do sa g e fo r m s r e le as e a c t i ve d r ug at a t im e o t he r tha n i m m e di a te l y af t e r a dm in is t r at i on at a d es i re d s i te i n t h e g as t ro i nt es t in a l t ra c t . F o r e xa m p l e , a n e nt e r ic -c o ate d d ru g p r od uc t do es not a l l o w f o r d is so l ut i on in t h e a c i d e n vi r on m e n t o f t h e s to m a c h b ut , ra t h er , in th e l es s a c i di c e n vi ro nm e nt o f t h e s m a ll i n t es ti n e. 7 . T r an s de r m al d r u g d el i ve r y s ys t e m s , o r p a t ch e s , a r e c o n t ro l le d - re le as e d e v ic e s t h a t c on t ai n t h e d r ug fo r s y s t em ic a bs o r pt i on af t er t o pi c a l a p pl ic a ti on to t he s k in s u r fa ce . Tr a ns de r m a l d ru g de li v e r y s ys te m s a r e a va i la b le fo r a n um be r of d r u gs ( n i t ro g l yc e r in , n ic o ti n e, s c o po l am in e , c l o ni di n e, fen t a n y l, 17 - β - es t r ad io l , an d t e s to st e r on e ). A lt h ou g h th e fo r m u l at i on m a t ri ce s o f t he se de li ve r y s y s te m s di f f er s om e wh a t , t h e y al l d if f e r f r om c o n ve nt i on al t op ic a l fo r m u la t io n s in t he fo l lo wi n g wa ys : a . Th e y h a v e a n im p e rm e a bl e oc c lu s i ve b a ck i ng f i l m t ha t p r e v e nt s i ns en s ib le wa t e r l os s f r om th e s k i n b e n ea t h t he pa t c h . Th is f i lm c a us es in c re as ed h yd r a ti o n
a n d sk i n t em p er a tu r e u nd e r th e p a tc h a nd en h anc e d p e rm ea t io n o f th e sk i n b y th e drug. b . Th e fo r m u l at io n m a t rix o f t h e pa t c h m a in t ai ns t h e d r u g c o nc e nt r a ti o n gr a d ie n t wi t h i n th e d e v ic e a f t e r ap p li c a t io n s o t h at d ru g de l i ve r y to th e i n te r f ac e be t we e n t he p a tc h a n d t he s k in is s us t a i ne d . A s a re su l t , d ru g p a r ti t io n in g a n d d if f us io n i n to th e s ki n p e rs is t , a n d s y s t em ic ab s o r p ti o n is m a in t ai ne d th r o ug ho u t t h e d os in g i n te r v a l . c . Tr a ns d er m a l d r u g d el iv e r y s y s t em s a re k e p t i n p l ac e o n t he s k in s u r fa ce b y an a d h es i ve l a ye r , e n s u ri ng d r ug c o nt ac t wi t h t h e s k i n a nd c o nt i nu e d d ru g de l i v e r y . 8 . T a rg e t ed ( si t e -s p ec i fi c ) d r ug de l i ve r y s ys t e m s a re dr u g c ar r i er s ys te m s t ha t p l ac e t h e d r ug at o r n ea r t h e r ec e pt o r s i te . E xa m p l es in cl ud e m ac r om ol e c u l a r d r ug c a r ri e rs ( p ro t ei n d r ug P.92
c a r ri e rs ) , p a r ti c u l at e d r ug d el i v e r y s y s t em s ( e. g . , l i po s o m e s , na n op a r ti cl es ) , a n d m o no cl o na l a n ti bo d ie s . W ith t a rg e te d d r u g d el i ve r y , t he d ru g m a y be de liv e r e d to a . Th e c a pi ll a r y be d o f th e ac ti v e s i t e b . A s p ec ia l t y p e o f c e ll ( e . g ., t um or c e ll s ) b u t n ot t o n o rm al c e ll s c . A s pe c i f ic o r g an o r t is s u e b y co m p l e xi n g wi t h a c a r r ie r th a t re c o gn i z e s t h e t a rg e t 9 . I ns e r t s, im p l an t s , a nd d e vi ce s a r e u s e d to c o n t r ol dr u g d el i ve r y fo r lo c al i z e d o r s ys t em ic d r u g e ff e c t s . Th e d ru g i s im p re g na t ed in t o a bi o de g ra d ab l e o r n o n bi od e g ra da b le m a te r ia l an d i s r el e as ed s l o wl y. Th e in s er t s , im pl a nt s, an d d e vi ce s a r e i ns e rt e d i nt o a v a r ie t y o f c a vi t ie s ( e .g. , v a g in a , b ucc a l c a v i t y ) o r t iss u es ( e . g ., sk in ) . F o r e xa m p l e, t h e le u p ro li d e a ce t at e im p la n t, V ia d ur , is i ns e r te d be n ea t h t h e s ki n o f t h e u pp e r a rm . It p ro vi d es p a ll ia t i v e tr e a tm e nt of ad v a n ce d p ro s ta t e c a nc e r f o r 1 y ea r . P.93
STUDY QUESTIONS D i r e c t i on s : E a c h qu es t io n , s t at em e nt , or in co m pl e t e s ta t em en t i n t h is s ec t io n c an b e c o r re c tl y a ns we r e d o r c om pl e te d b y o n e o f t h e s ug g es t ed an s we r s o r ph r a se s . C h o os e th e b e st an s we r . 1 . W hi c h s t a te me n t be st d e sc r i b es bi o a va i la b ili t y? ( A ) r e la t io n b e t we e n t he p h y s ic al an d t h e c he m i c a l pr o pe r t ie s o f a dr u g an d it s s ys t em ic a bs o r pt i on ( B ) m ea s u r em en t of th e r a t e a n d am o un t o f th e rap e u ti c a ll y a c t i ve d r u g t ha t r ea ch es t h e s ys te m i c c ir c ul at i on ( C ) m o vem en t of th e d r ug i nt o b o d y ti ss ue s o v e r t i m e ( D ) d is so l ut io n of th e d r ug i n t he ga s tr o in t es ti n al t r a c t ( E ) a m o un t of d ru g d es t ro y e d b y th e l i v e r b e fo r e s y s t em ic a bs o r pt i on f rom t he g a st r o in t es ti n al t ra c t oc c u r s V i e w A n s we r 1 . T h e a n sw e r i s B [ se e] . 2 . T h e r ou t e o f d r u g a dm i n is t r a ti o n t h a t gi ve s t he mo s t ra pi d o ns e t o f t he ph a r mac o l o gi c e f f ec t is ( A ) i nt r am us c u l a r i nj ec t io n .
( B ) i nt r a v e no us in j ec ti o n. ( C ) i n tr a de r m a l i nj ec t io n . ( D ) p e ro r a l a dm in is t ra t ion . ( E ) s ub c u t an e ou s i nj ec tio n . V i e w A n s we r 2 . T h e a n sw e r i s B [ se e] . 3 . T h e r ou t e o f d r u g a dm i n is t r a ti o n t h a t p ro vi d e s c o mp l e te ( 1 0 0 %) b i o a va i l a b il i t y i s ( A ) i nt r am us c u l a r i nj ec t io n . ( B ) i nt r a v e no us in j ec ti o n. ( C ) i n tr a de r m a l i nj ec t io n . ( D ) p e ro r a l a dm in is t ra t ion . ( E ) s ub c u t an e ou s i nj ec tio n . V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . 4 . Af t e r pe r o r a l a d mi n i st r a t i on , d r u g s g e ne r a l l y a r e a b s o r b e d b es t f r om t he ( A ) b uc c a l c a v it y . ( B ) s to m a c h . ( C ) d u od en um . ( D ) i le um . ( E ) r ec t um . V i e w A n s we r 4 . T h e a n sw e r i s C [ se e] . 5 . T h e c ha r a c t e ri s t ic s o f an ac t ive t r a n s po r t p r oc e ss i nc l ud e a ll o f t h e f o l low i n g e x c ep t f o r w h i c h o ne ? ( A ) A c ti v e t ra ns p or t m o ve s d r u g m o l ec ul es ag a ins t a c o nc e nt r a ti o n g ra d ien t . ( B ) A c ti v e t ra ns p or t fo l lows F i c k ' s l a w o f di f fu s i on . ( C ) A c ti v e t ra ns p o rt is a c a r ri e r -m e di at e d t r an s p or t s y st em . ( D ) A c ti v e t ra ns p o rt r eq ui r e s e ne r g y . ( E ) A c ti v e t ra ns p or t of d ru g m o le cu l es m a y be s a tu r a t ed at hi g h d ru g c o nc en t r at i on s . V i e w A n s we r 5 . T h e a n sw e r i s B [ se ea n d] .6 . T h e p a ss a ge o f d r u g m o l ec u le s f r om a r e g ion o f hi g h d r u g c o nc e n tr a t i o n to a r e g io n of l ow d r ug c o n ce n t r a ti o n i s k n ow n a s ( A ) a ct i v e t r a ns po r t . ( B ) b io a v a il ab i li t y . ( C ) b io p ha r m a c e u ti c s . ( D ) s im pl e d i ff us i on . ( E ) p in oc y t o s i s . V i e w A n s we r 6 . T h e a n sw e r i s D [ se e] . 7 . W h ic h e q u a ti o n d e sc r i be s th e r a t e o f d r u g d i ss o lu t i o n f r om a ta b le t ? ( A ) F ic k 's la w ( B ) H e nd e rs o n - Ha s s el b al c h e qu a ti o n ( C ) L a w o f m as s a c t i on ( D ) Mi c h a e li s - Me n t e n e qu a t io n ( E ) N o y e s -W hit n e y e q ua ti o n V i e w A n s we r 7 . T h e a n sw e r i s E [s e e] . 8 . W h ic h c o n d it i o n u s ua l l y i n c r e a s e s t h e r a te o f d r u g d i ss o lut i o n f r om a t a bl e t ? ( A ) i nc r ea s e in th e p a r ti c l e s i z e o f th e d r ug ( B ) d ec r ea s e in th e s u r fac e a r e a o f t h e d ru g
( C ) u se of t he f re e a c i d o r f r ee ba se fo r m o f t h e d r u g ( D ) u se of t he io ni z e d , or s al t , f o rm of t he dr u g ( E ) u se of s u ga r c o at i ng a r o un d th e t a bl e t V i e w A n s we r 8 . T h e a n sw e r i s D [ se ea n d] .9 . Dos e du m p in g is a p r o bl em i n t h e f o rm u la t i o n o f ( A ) c om pr e s s ed ta b le ts . ( B ) m od if i ed - r el e as e d r ug p r od uc ts . ( C ) h a rd ge l at i n c a ps u les . ( D ) s of t ge la t in c a ps ul e s . ( E ) s up po s i t o ri es . V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . 1 0. T he ra t e - l im i t in g s t e p i n th e b i o a va i la b i li t y o f a l i pid - s o lu b l e d r u g f o r mu l at e d as an i mm ed i a te - r e le a s e c o m p re s se d ta b le t i s t he r a t e o f ( A ) d is in t eg r a ti on o f t he t a b le t a n d r e le as e o f t h e d r u g. ( B ) d is s o lu t io n o f th e d r ug . ( C ) t r a ns po r t o f th e d r ug m ol ec u le s ac r os s t h e i nte s ti n al m uc os a l c el ls . ( D ) b lo o d f lo w t o t he ga s t r o in t es t in al t r ac t. ( E ) b io t r an s f o rm a ti o n, o r m e ta bo l ism , of th e d r u g b y t h e l i ve r b ef o r e s y st em ic a b so r p ti on oc c u r s . V i e w A n s we r 1 0 . T he a nsw e r i s B [ se e] . P . 94
1 1 . Th e e x te n t of i on i z at i o n o f a w ea k e l ec t r o l yt e d r u g d ep e n ds on t he ( A ) p H of th e m e di a a nd p K a of t he d ru g . ( B ) o il to wa t e r pa r ti t io n c o ef f ic ie n t o f t h e d r ug . ( C ) p a r ti c l e s i z e a nd s u r fa c e a r ea of t he dr u g. ( D ) N o y e s -W hit n e y e q uat i o n f o r t he d ru g . ( E ) p ol ym o rp h ic f o rm o f th e d ru g . V i e w A n s we r 1 1 . T he a nsw e r i s A [ se e] . 1 2. T he ra t e o f d r u g b i oa va i l ab i li t y i s mo s t r ap i d w h e n t h e d r u g is f o r mu l a te d a s a ( A ) c on t ro l le d - re l ea s e pro d uc t . ( B ) h a rd ge l at in c a ps u le . ( C ) c om p re s s ed ta b le t . ( D ) s ol u ti on . ( E ) s us pe ns io n . V i e w A n s we r 1 2 . T he a nsw e r i s D [ se e] . 1 3. T he am o u n t o f d ru g t ha t a t r a n s de r m al p at c h ( i . e. , t r a n sd e r ma l d r ug de l i ve r y s ys t e m ) d e l i ve r s w it h i n a 2 4h r p e r i od de p e nd s o n th e ( A ) p a tc h c o m p os i ti o n, wh i c h in cl ud e s a n oc c l us i ve b ac k i ng an d a n a d he s iv e f i lm i n c o nt ac t wi t h th e s k i n. ( B ) a f fi ni t y o f t h e d ru g for t h e f o rm ul a ti o n m a t r i x r e l a ti ve to it s a f fi n it y f o r th e s t r at um c o r ne um . ( C ) r a t e o f d r ug pa r ti t io ni n g a nd / o r d i ff us i on th r ou g h t h e p at c h t o t he sk in s u rf a c e . ( D ) s u rf ac e a r e a o f t he pa t c h . ( E ) A l l o f t h e a bo v e
V i e w A n s we r 1 3 . T he a nsw e r i s E [s e e] . P . 95
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee I . A . 3] . B i o a vai l ab il i t y is t h e m ea s u re m e n t o f t h e r a te and e xt e n t (a m ou n t) o f t he ra p e ut ic al l y a c ti ve d ru g t h a t r ea c h e s t h e s y s te m i c c ir c ul at i on . Th e r e la t io n o f th e p h ys ic a l a nd t h e c he m i c a l p r o pe r ti e s o f a d r ug to i ts s y s te m i c a b s o r p ti on ( i. e . , b io a vai la b il i t y ) i s k n o wn as it s b io p ha r m a c e u t ic s . Th e m o v em en t of a d ru g i n to bo d y ti ss u es i s a n a s pe ct o f p ha r m a c o k i n eti c s , wh i c h is th e s tu d y o f d r u g m o v e m e n t i n t h e bo d y o v e r t i m e . Th e d is s o l ut io n of a d r ug in th e g as t r oi n te st i n al t ra ct is a p h ys ic oc he m ic al p r o ce s s th a t a ff e c t s b io av a i l ab i li t y . Si g ni f ic an t d es t r uc ti o n o f a d ru g b y t he l i v er b e f o re it is s y s te m i c a l l y a b s o r be d (k no wn a s t h e f i r st - p as s e ff ec t b e ca us e i t o c c u rs d u r in g th e f i rs t p as s a g e o f t he dr u g t h ro u gh th e l iv e r ) d ec r ea se s b i oa v a il ab i li t y . 2 . T he an sw e r is B [ s ee I I . B .1 . a] . W hen t he ac t i v e f o rm o f t h e d r u g is gi ve n i n t ra ven o us l y, i t en t er s t h e s y ste m ic c i rc u la ti o n d i re c t l y . Th e d r u g i s d el i ve re d ra pi d l y t o al l t is s ue s, in c l u di ng th e d ru g r e c ep t or s i t es . F o r a ll o th e r ro u te s o f d r u g a dm ini s t ra t io n , e xc e p t i n t ra - a rte r i al i n je c ti on , th e d r u g m u s t b e s y s t em ic al l y ab s o r b ed b ef o r e i t is di s tr i bu t ed t o t he dr u g r e c ep t or s i t es . F o r t h is re a s o n , t he on s et of ph a rm ac o lo g ic e f fe c ts i s s lo we r . I f t he d r u g i s a p r od r u g t ha t m u s t b e c on ve r t ed to an ac t i v e d r ug , o r a l a dm in is t ra t i on , n o t i n t ra ve n ou s i nj ec t io n , m a y n o t p r o vid e th e m os t ra p id on s et of ac t i v it y i f co n v e r s i on t o t he ac ti v e f or m t ak es p l ac e i n t h e g as t ro i nt es t in a l t r ac t o r li v e r . 3 . T he an sw e r is B [ s ee I I . C .2 ] . W hen a d r u g is gi v e n b y i n t ra v e n ou s i nj ec t io n , t he e nt i r e d os e e nt e rs th e s ys t em ic c i rc u la ti o n . W ith o t he r r ou t es o f a dm in is t ra t io n , t he d r ug m a y be lo s t b ef o re i t r e a ch es th e s y s te m i c c irc u la t io n . F o r e xa m p le , wi t h f i rs t - pa s s ef f ec ts , a po r t io n of a n o ra ll y a dm in is t e re d d ru g is e l im in a te d , us u al l y t h r o ug h d eg r a da t io n b y li ve r e n zym e s , be f o re th e d r ug r e ac he s i ts re c e p t or si te s . 4 . T he an sw e r is C [ s ee I I . B .2 . b. ( 4 ) ]. D r u g s g i v en o ra ll y a r e w e l l a bs o rb e d f r om th e d uo d e nu m . Th e d u od e nu m h a s a l a r ge s u r fa ce a re a b ec a us e o f t h e p r es e nc e o f vil li an d m ic r o vi ll i. I n a dd i ti on , bec a us e t h e d u o de nu m i s we l l pe r f us e d b y th e m es en t e ri c b loo d v es s el s , a c o n ce n tr a tio n g r a di e nt is m a in t ai ne d be t we e n t he l u m e n o f t h e d u o de nu m a nd t he bl oo d. 5 . T he an sw e r is B [ s ee I I . A .2 an d 3 ] . F i ck ' s l a w o f d i ff u s i on des c ri b es p as s i ve di f f us io n o f dr u g m o l ec ul es m o vin g f ro m a h i gh co nc e nt r a ti on t o a lo w c o n c e n tr a ti o n. Th i s pr o c es s is no t s a tu r ab l e an d do es n o t re q ui r e e ne r g y . 6 . T he an sw e r is D [ s ee I I . A .2 ] . Th e t r a ns po r t o f a d ru g ac r os s a c e ll m em b ra n e by p a s s i v e d i ff us i on fo l lows F i c k ' s l a w o f di f f us io n : Th e d rug m o v e s wi t h a c o nc en t ra t i on g ra di e nt ( i. e . , f r om a n a r e a o f h i gh co nc e nt r a ti on t o a n a r e a o f l o w c on c e n t ra t ion ) . In c o n t ra s t , d r u gs th at a r e a c ti ve l y t ra n s p o rt e d m o v e a ga in s t a c on c en t ra t ion g r ad ie n t . 7 . T he an sw e r is E [ s e e I I I . A. 1 ] .
Th e N o ye s -W hi tn e y eq uat i o n d esc r i be s t he r at e at wh i c h a s o li d d r ug di s s o l v e s. F i ck ' s l a w i s s i m i l ar t o t he N o y e s -W hit ne y e qu a ti on i n t ha t bo t h e qu a ti on s d e s c r ib e d r u g m o v em en t c au s ed by a c on c e n t ra t io n g r ad i en t . Fi c k ' s l a w g en e r al l y re f e rs to p a ss i ve d if f us io n , o r pa s s i v e tr a ns po r t , o f d r ug s . Th e l a w o f m as s a c t i on de sc r i be s t h e ra t e o f a c h em ic al r ea c ti o n, t he Mi c h ae li s - Me n t e n e qu a ti o n i n v ol ve s en z ym e k i ne t ics , an d t h e H e nd e rs o n - Ha s s el b al c h eq u at ion g i v es th e p H of a b u ff er s ol u ti o n. 8 . T he an sw e r is D [ s ee I I I . A. 1 a n d 3 ] . Th e i o ni z e d , o r s al t , f o rm o f a d r ug ha s a c h a rge a nd is g e ne r al l y m o r e wa t e r s o lu bl e a n d , t he r e fo r e, di s s o l v es m o re r ap i dl y t han t he no n io ni ze d ( fr e e ac i d o r f r e e b a se ) fo r m o f t h e d ru g . Th e di s s ol u ti o n r a te is d i re c tl y p r op o r ti on a l t o t h e s u r fa ce a r e a a nd in v e r s e l y p ro p or t i on a l t o t h e p a rt ic l e s i z e . A n i nc r ea s e in th e p a rt i c l e s i z e o r a d ec r e as e i n t he s u r fa c e a r ea s l o ws th e d is sol u t io n r a te . 9 . T he an sw e r is B [ s ee I I I . B. 6 ] . A m od i fi e d- r e le as e , o r c o n t r ol le d - re l ea se , d r u g pr o d uc t c on t ai ns t wo o r m o r e c o n ven t io n al do s e s o f t he d r ug . An ab r up t re l ea se o f t h e d ru g , k no wn a s d o se d u m p i ng , m a y c a us e i nt oxi c a t i o n. P.96
1 0 . Th e a n sw e r i s B [ s ee I I I. B . 1. c ]. F o r li pi d -s o lu bl e d r u gs , th e r at e o f d is s ol ut i on is th e s l o we s t ( i .e . , r a te - li m it i n g) st e p i n dr u g a bs o rp t io n a n d th u s i n b io a v a il ab i li t y. The d is in t eg r a ti on r at e o f an i m m e di a te - r el e as e o r c on v e n t io n al c om p re s s e d ta b le t is u s u a ll y m o r e ra pi d th a n t he r a t e o f d r u g d is s o lu t io n . B e c au s e th e c el l m em b ra n e i s a l i po p ro t ei n s t ru c t u r e , t r a ns p or t of a l ip i d- s o l ubl e dr u g a c r o s s t h e c el l m e m b ra ne is us ua ll y r a pi d. 1 1 . Th e a n sw e r i s A [ s ee I I I. A . 4. b ] . Th e e xt e n t o f i on i z a ti o n o f a we ak el ec t r ol y t e i s d e sc r ib ed b y th e H en de rs o n H a s se lb a lc h e qu a ti o n, wh i c h r el a te s t he p H o f t he s o l ut i on to t he p K a of th e d ru g . 1 2 . Th e a n sw e r i s D [ s ee I I I. B . 2. a ] . B e c au se a d r ug in s o lu t io n is a l r ea d y di s s ol v e d , n o di s s ol u ti o n is ne e de d b e fo r e a b so r p ti on . C on s e q ue n tly , c om p a re d wi t h o th e r dr u g fo r m u la t io ns , a d r ug i n s o lu t io n h a s a h i gh r at e o f bi oa v ai l ab i li t y . A d r ug in aq u eo u s s ol u ti o n h as th e h ig he s t b i oa va i la b il it y r a t e a nd is o ft e n us e d as t he r ef e re n c e p re pa r a ti o n f o r o the r f o r m u l at io n s . D r ug s i n hy d r o a lc oh o li c s o l ut i on ( e. g . , e li xi r s ) a ls o h a v e g oo d b i oa va i la b il it y . Th e r at e o f d ru g b i oa v a il a bi li t y f r om a h a rd ge l at i n c a ps u le, c om p r es s e d t ab l et , or s us p en s i o n m a y b e e qu a l to t ha t of a s ol ut i on if an o p t im al f o r m u l at io n i s m an u fa c t ur e d an d t h e d ru g i s i nh e re n t l y ra p id l y ab s o r be d . 1 3 . Th e a n sw e r i s E [s ee I I I. B . 7] . D r u g de li v e r y f r om a t r ans d e rm al dr u g d el i ve r y s y s t em de pe n ds on al l o f th e fa c to r s c i te d — th a t is , on th e p r es e nc e o f a n o cc lu s i v e bac k i n g ( t o m ai nt a in s ki n hy d r a t i on a n d e le v a t e s k i n t em p era t u r e s l i gh tl y) a nd an adh e s i v e fi lm t o m a i nt ai n co n t ac t o f t h e fo rm u la t io n m at r i x wi t h t he s ki n t o en ab l e d r ug t r an sf e r fr om t he pa tc h i n to th e s ki n . I f th e d r ug ' s a f f in i ty f o r t he fo r m u l at io n m a tr i x i s g r ea t er t ha n i ts a ff in i t y f or t he s t r at um c o r ne um , th e d ru g ' s e s c ap i ng te n de nc y fr o m t h e p at c h wi l l b e re du c ed , m i ni m i zi ng t he gr a di e nt fo r d ru g tr a ns f er in t o t h e s k i n . Th e m i c ro vi sc os it y o f t he
f o r m u l at io n m a t ri x, t h e pr e s en c e of a m em br a ne b e t we e n th e d r ug r es e r vo i r i n th e p a tc h a n d t he s k in s u r fac e , a nd in t e ra c ti on o f t he d r ug wi t h t h e f o rm ul a tio n m a t ri x a f f ec t t h e r a te an d e xt e n t o f d i ff us i on an d /o r pa r tit i o ni ng o f t he d ru g t h r oug h th e p a tc h to th e s k i n s ur f ac e. F in a ll y, t he e xt e n t o f d ru g de li ve r y f r om th e p a tch is d i r ec tl y p r op o r ti o na l t o th e s u r fa c e a re a o f th e pa t c h in co n ta c t wi t h th e s k i n s u r fa ce .
5 Extemporaneous Prescription Compounding L o yd V . Al l e n J r .
I. INTRODUCTION A. D e f i n i t i o ns 1 . C o mp o u nd i ng vs man u f a c tu r i n g 2 . I t is im po r t an t , b u t o f te n t im es d i f fi c u lt , to di s tin g ui s h b et we e n c om p oun d in g a n d m a nu f ac tu r i ng . 3 . C o mp o u nd i ng ha s b ee n de f in e d b y th e N at i ona l As so c i a ti o n o f B o a rd s o f P h a r m a c y a s t h e p re p a ra t i on , m i xi n g , a s s em bl ing , pa c k a gi ng , o r la b el in g o f a d ru g o r d e vic e ( i ) a s t he r es ult o f a p ra c t i ti o ne r ' s p r es c r i pt io n dr u g o r de r o r in it i a ti v e b a se d o n t h e p ha r m a c i s t/ p a ti e nt / p re sc r ib e r r e la t io n s h i p in t he c o u rs e o f pr o f es s i o na l p r a ct ic e o r (i i ) f o r th e p ur p o s e of , a s a n i nc i de n t to r es e ar c h, te ac h in g , o r c h em ic al a n al ys is an d n o t f o r s al e o r di s p e ns in g . C om p ou nd i n g al s o in cl u de s t h e p re p a ra t io n o f d ru gs an d d e v ic es in a n t ic ip a ti on o f p r esc r ip t io n d ru g o r de r s b as ed on r o u ti n e, r e g ul a rl y o bs e r v e d p at t er n s . 4 . M a n u fa c tu r i n g h as be e n d e fi n ed as t h e p r od uc t io n , p r ep a ra t io n , p r op ag a t io n , c o n ve rs io n o r pr o c e s s ing o f a dr u g o r d e v ic e , e i th e r di r ec tl y o r i n di r ec t l y , b y e xt r a c t i on f ro m s ub s t a nc e s o f na t ur a l o r ig in o r i nd e p en de n tl y b y m e a ns o f c he m i ca l o r bi o lo g ic al s y n t he s i s , an d in c l ud e s a n y p ac ka g in g o r r ep a ck ag in g o f th e s u bs ta n c e (s ) o r l ab el i ng o r r el a be li n g o f i ts c o n ta i n e r, a nd th e p r om o ti on a n d m a rk e ti n g o f s uc h d ru g s o r d e v ic es . Ma n u fa c t u ri ng a ls o i nc lu d es t h e p r epa r a ti o n a n d p r om o ti on o f c o m m er c i al l y a va i la b le pr o du c ts f r om bu lk c o m p o un ds for r e sa le b y p h a rm ac ie s , p ra c ti ti on e r s , o r o th e r p e rs o ns . 5 . Th e pu r po s e o f p ha rm a c eu t ic al c om p ou n di ng is t o p re p a re an in di vi d ual i z e d d r ug t r e a tm en t fo r a p at ie n t ba s ed on an o rd e r f r om a d u l y li c e ns e d p re sc r ib e r . Th e f u n da m e n ta l d i ff e r en c e be t we e n c o m p ou n di n g a nd m a n u f ac t u ri n g is t he exi s t e n c e o f a p ha r m a c i s t / p re s c r ib e r /p a t ie n t r el a ti o ns hi p t h a t c o nt r o ls t h e c om po un d ing o f t h e d r u g p r ep a ra t io n . Co m p ou n d ed dr u gs ar e n o t f o r re s al e b u t, r at h e r, a re per s o na l a n d re sp on s i v e t o t he pat i e nt ' s i m m ed i at e n e ed s . Th e y a r e p r e pa r ed an d a d m i ni s te r ed b y th e p a tie n t , c ar e gi ve r o r p at i en t 's he a lt hc a r e p r of es s i o nal s , wh ic h a l lo ws f o r t h e m on it o r in g o f pa ti e n t o ut co m e s . O n t h e o t he r h a nd , dr u g m a nu f ac tu r e rs p ro d uc e ba t c h es c o ns is t in g o f te ns o r hu n dr e ds of th o us and s o f d o sa g e u ni ts , s uc h a s t ab l e ts o r c a ps ul es , fo r re s a l e , us i ng m a n y p e rs o nne l an d l a r ge - sc al e m an u fa c tu r ing e qu ip m en t . Th e se p ro du c ts a re di s t r ib u te d th r ou g h t h e n o r m a l c ha nn e ls o f in t ers t a te c om m e r c e t o in d i v id u al s u nk n o wn to t he c om p an y . Ma n u f a c tu r e rs a re no t req u i re d to , a n d d o n ot , p ro v i d e o v e r si gh t of in d i vid u al p a t ie n ts . I t i s a ls o a c c ept a b le an d ro u ti ne p ra c t ic e f o r p ha r m a ci st s t o c om p o u nd fo r “ o f f ic e us e ” th os e p r ep a ra t i on s t ha t ar e n o t c om m e r c ia ll y a va il a bl e . Th e s e p r e pa r a ti o ns a r e “F o r O ffi c e U s e O n l y ” a n d a r e n ot f o r r es a le o r t o b e g i v en t o t h e p a t ie n ts to ta k e ho m e ; the y a r e t o b e ad m i ni s te r ed a t t h e o ff ic e . 6 . Th e U ni t ed S ta t es Pha r m a c op ei a ( U S P ) us es th e te r m p r ep a ra t io n to ref e r to c om p ou n de d p r es c ri pt i on s a n d t he t e rm p r od u ct s t o re f e r t o m an u fa c t u r ed p h a rm ac e ut ic al s . A ls o , fo r s t a bi li t y p u rp os es , c om p ou n de d p r ep a r at io n s a r e
a ss i gn e d a “b e y o nd - us e ” d a te an d m an u fa c tu r ed p r o du c ts a r e a ss ig n ed an “ e xp i r a t i on da t e. ” B . R e g u la t i on 1 . C u r r e nt g oo d m a n uf ac t u r i n g p r ac t i ce s (c G M P s ) a re t he s t an d a rd s o f p r a c t ic e u s ed in th e p h a rm ac eu t ic a l i nd us t r y an d a r e re gul a t ed b y th e F o od an d D ru g A d m in is t ra t io n (F D A ) . P.98
2 . G o o d c om p o un d in g p r a c t ic e s ( G C P s ) a r e the s ta nd a r ds o f pr a c t ic e de t a il ed in t h e U S P , c h a pt e r < 1 07 5> . C om m u n it y p ha r m a ci st s m us t c om p l y wi t h s ta te b oa r d o f p h a rm ac y l a ws , re gu l at i on s , a nd gu i de li n es to ens u r e a q u al i t y p r ep a r at i on , wh i c h i n cl ud e s us i ng pr o pe r m a t e ri a ls , we i gh in g e q ui pm e nt , do cu m e n te d t ec h ni q ue s , a nd d i sp e ns in g a nd s t o r ag e in s t ru c ti on s . 3 . L eg a l c on s i de r a t io n s a . E xt e m p or a ne o us c om p o u nd in g b y t h e p ha r m ac is t or a p r es c r i pt i on o rde r f r om a l i ce ns e d p ra c ti t io ne r , a s wi t h t h e d is pe n si ng o f an y o t he r p re s c r ip t io n , is c o nt r o ll ed b y t h e s ta t e b oa r ds o f ph a r m a c y . b . Th e le ga l ri s k (l i ab il i ty ) o f c o m p o un di n g is no g r e a te r th an t he ri s k of f il l in g a p r e sc ri p ti o n f o r a m a nu fa c tu r e d p r od uc t b ec a us e t h e p ha r m a c i s t m u s t e ns u r e t ha t t h e c o r re c t d ru g , d os e , an d di r ec t io ns ar e p r o v i ded . Th e ph a rm ac is t i s a lso r e s po ns ib l e f o r p r ep a ri ng a q u al i t y p h a rm ac eu t ica l pr e pa r a ti o n, p ro vi di n g p r o pe r i n st r uc t io ns r eg a rd i ng it s s t or a ge , a n d a d vis in g the p at i en t o f an y a d v e rs e e f f ec ts . 4 . F oo d a n d D r ug Ad m in i s t r a ti o n . Th e F D A h as d e ve lo p ed a li s t o f p r epa r a ti o ns t h a t s ho ul d n o t b e e xt e m p o r an e ou sl y c om po un d ed . Th i s li s t wa s d e vel op ed p ri m ar i l y f r o m co m m e rc ia l p r o du c ts t ha t h a v e b e en r em o ved f r om th e m a rk et o wi n g t o s a f et y a n d /o r ef f ic ac y c o nc e r ns . Th i s i s a l e ng t h y l is t and m u s t b e r e ad c a re f ul l y b e c a us e , i n s om e c as es , o n l y c e r ta i n d os a ge fo r m s o f a s pe c if ic d ru g a r e i nc lu d ed o n th e l is t a n d o t he r s a r e n ot . Th e li s t i s t oo e xt e n s i v e to inc l ud e h e re bu t c a n b e acc es s ed at w w w. f d a . g o v / c d e r /p ha r m c om p /p c wd . t xt . C . S t a b il i t y a n d q u a l i t y c o n t r o l o f c o mp o u nd e d p r e p a ra t i on s 1 . B e yo n d - u s e d a te s . Th e as s i gn m e n t o f a be yon d - us e d a te is o n e o f t he m o s t d i f fi cu l t t as k s re q ui r ed o f a c o m p ou n di n g p ha r m a ci s t . C h ap t e rs < 7 95 > a n d < 7 9 7> of t h e U S P p r o v id e g u id el i ne s fo r th is ta sk . Ch a pt e r < 7 9 5> in vo l ves no ns t e ri le p r e pa r a ti o ns , a nd c h ap t er < 7 97 > i n vo l ves s t e ri le p r e pa r a ti o ns . F o r n on s ter i l e p r e pa r a ti o ns , c ur r e nt U SP c r it e ri a fo r no na q ue o us l i q ui ds an d s ol id f o rm ul a t io ns ( fo r wh i c h a m an u fa c t u r ed dru g p ro du c t is t he s o ur c e o f ac t i ve i ng r ed i en ts ) in c l u de a b e yo n d- u s e da t e n ot la t er t h an 25 % o f th e t im e rem a in in g u n ti l th e p r od uc t' s e xp i r a t i on da t e o r 6 m o nt h s , wh i c he ve r is e a rl i e r. W hen a U SP o r Na t io na l F o r m u l ar y ( N F ) s u bs ta nc e is t he s o ur c e o f ac t i ve i n g re d ie n t, t he be yo nd - us e d a te is n o t l a te r th a n 6 m on t hs . F o r wa t e r -c o nt a in in g fo rm u la t io ns ( pr e pa r ed f r om i n g re d ie n ts i n s ol i d f o rm ), t h e b e y on d -u s e da t e i s n o t l a te r th a n 1 4 d a y s wh e n s t o re d a t c ol d te m p e ra t ur e s . F o r a ll ot h e r f o rm ul at i o ns , t h e b e yon d -u s e dat e is no t l a t er t ha n t h e i nt e nd e d du r a ti o n o f t h e ra p y o r 3 0 d a y s , wh ic h e ve r is ea r li er . Th e se
b e yo n d- u s e da t es m a y be e xc e e de d wh e n t h er e is su pp o r ti n g v a l id s ci e nt if i c s t ab i li t y in f o rm at i on th a t i s d i re c tl y a pp li c ab le t o th e s p ec if ic p re p a ra ti o n . F o r s t e ri l e p re p a ra t io ns , i f a s te r il i t y te s t i ng p ro g ra m i s n o t i n pl a ce , t h e f ol l o wi n g c a n b e u s e d p r o v id e d t he p r ep a ra t io n i s p r op e rl y p a c k a g ed an d s t or e d . L o w- R i s k L e v el C om p oun d e d S t e ri le P r ep a ra t io ns : N ot m o r e t ha n 48 ho u rs a t c o nt r o ll ed r oo m t em p er at u r e , n ot m o r e t h an 14 da ys a t a c ol d te m p e ra t u re ( r e f r ig e ra t o r ) a nd fo r 45 d a y s f ro ze n a t -2 0 ° C o r c o ld e r . Me d i u m - R is k L e v el C om p o u nd ed S t er i le P re p a rat i o ns : No t m o re th a n 3 0 h o u rs at c o nt r o ll ed r oo m t em p er at u r e , n ot m o r e t h an 9 d ays a t c ol d te m p e ra t u re ( re f r ig e r at o r ) a n d f o r 4 5 d a y s f r o z e n at - 2 0 ° C o r c ol d er . H i g h - Ri s k Le v e l Co m p o un d e d S t e ri le P r ep a ra t io ns : N o t m o r e t ha n 24 ho u rs a t c o nt r o ll ed r oo m t em p er at u r e , n ot m o r e t h an 3 d ays a t c ol d te m p e ra t u re ( re f r ig e r at o r ) a n d f o r 4 5 d a y s f r o z e n at - 2 0 ° C o r c ol d er . I f a s te r i li t y te s ti ng p ro g ra m i s i n p la c e , th e b e y on d - us e d a te s f o r n on s te ri l e p r e pa r a ti o ns a p pl y . As in n o ns te r i le c om p ou n di ng, t h es e b e y on d -u s e d at es f or s t e ri le c o m p o un di n g m a y b e e xc e e d ed wh e n th e re is s u pp o r ti n g v a l id s c i en t i fi c s t ab i li t y in f o rm at i on th a t i s d i re c tl y a pp li c ab le t o th e s p ec if ic p re p a ra ti o n . 2 . Q u a li t y c o n t r o l . Q ua li t y c on t ro l i s b ec om in g on e of t he fa s te st g ro wi n g a s p ec t s o f ph a rm ac y c om po u nd ing . P ha r m a c i s t s a r e b ec om i ng m o r e i n v ol ve d i n t he f in a l t e s ti ng o f c o m p o un d ed pr e p a ra t io ns o r a r e s e n din g th em t o co n t ra c t la b or a t o ri es f or t e s ti ng . Fo r e xa m pl e , t he f o ll o wi n g q u al it y c on t r ol t e s t s c an be c o ns id e re d f o r th e r e s pe c t i v e c om po u nd e d d o s a g e f o rm s : P.99
a . O i n tm e n ts , c r e am s , a n d ge l s. Th e o re t ic al we i gh t c om p a re d t o a c tu al we i g h t , p H , s p ec if ic g ra v i t y , ac ti v e dr u g as s a y , ph y s ic al ob s er va t i o ns (c ol o r , c l a ri t y , te xt u r e s u r fa ce , te xt u r e - s pa t ul a s p r ea d , a pp e ar a nc e, f ee l) , a nd r he ol o gi ca l p r op e rt i es . b . H a r d g e la t i n c ap s u les . W ei gh t o ve r a ll , a ve r ag e we i g ht , i n di v i d ua l we ig h t va r i a ti o n , di s s o lu t io n o f c a ps ul e s he l l, di s i n te g ra t i o n o f c ap su le c o n te n ts , a c ti v e d r u g a ss a y , p h y s i c a l a p pe a r an c e ( c o lo r , u n if o rm i ty , e xt e n t o f f i ll , l oc ke d ) , a n d p h ys ic al s t a bi li t y ( di s c olo r a ti o n , c h a ng es in ap p ea r a nc e ). c . S pe c ia l ha r d g e la t i n c a p su l es . W eig h t o ve r all , a ve ra g e we i g h t, in d i vid u al we i g h t va r i a ti o n , di s s o lu t io n o f c a ps ul e s he l l, di s i n te g ra t i o n o f c ap su le c o n te n ts , a c ti v e d r u g a ss a y , p h y s i c a l a p pe a r an c e ( c o lo r , u n if o rm i ty o f a pp ea r a nc e, un i fo r m i t y o f e xt e n t o f f i ll , c lo s u r es ) , a n d p h y s i c a l s t ab il i t y (d is c o l o ra t io n o r o t he r c h ang e s ). d . S u pp o s it o r i es , t r oc he s , lo l l ip o ps , an d s t i cks . W ei gh t , s pe c i f ic g r a vi ty , a c ti v e d r u g a ss a y , p h y s i c a l o bs e r v a t i on s ( c o l or , c l ar i t y , t e xt u r e o f s u rf ac e , a pp ea r a nc e , f e e l) , m e lt i ng te s t, di s s olu t i on te s t, ph y s ic al s t a bil i t y. e . O r a l a n d t o p ic a l l i qu id s . W eig h t t o v ol um e , pH , s pe c i f ic g r a vi t y , a c t i ve d r ug a ss a y, gl o bu le s i z e ra n ge , r he o lo gi ca l p r o pe r ti es/ p o u ra bi l it y , p h ys ic a l o bs e r va t i on s ( c o lo r , c la r it y ) , a nd ph y s i c al s t ab i li t y ( di s c ol o ra t io n , fo r ei g n m a t e ri al s , g as f o r m a t io n , m o l d g r o wt h ) .
f . P a r en t e r al p r ep a r a ti on s . W eig h t o r vol u m e , pH , s pe c i f ic g r a v i t y, o sm ol a li t y , a ss a y, ph y s ic al ob s e r v a ti o ns (c o lo r , c la r it y ) , p ar t ic u la t e m a t t er , s t e ri li t y, an d p yr o g en ic i t y . 3 . Q u a li t y c o n t r o l te s t in g . P ha rm a c i s t s h a ve t he o pt i on of do i ng te s ti ng i n - ho us e o r o u ts o u rc in g i t t o l a bo r a to r i es . a . I n -h o us e te s t in g c an i n c l ud e m e as ur em e n ts s u c h as we i g h t, v o lu m e , pH , s pe c i f ic g r a vi t y, o s m o la li t y , ph y s ic a l o bs e r v at i on s, st e ri l i ty a n d e n do t o xi n s . b . O u t - so u r ce d t es t i ng c a n i nc lu d e st e r il i t y, e ndo t o xi n s , p o te nc y , an d d i s s o lu t io n . c . Te s t re s ul t s s ho u ld be k e p t o n f i le wi t h t h e c om p ou n di ng r ec o rd s f o r th e i n di vi d ua l c om po u nd e d pr e p a ra t io ns .
II. REQUIREMENTS FOR COMPOUNDING A. S o u r c e s fo r c he m ic al s a nd d r ug s . P h a rm ac is t s c a n o b ta i n s m al l q u an t i ti es of t h e a p p ro p ri a te c h em ic als o r d r ug s f r om wh o le s a le r s o r c h em ic al s u pp l y ho u s e s . Th e s e s up p li e rs th e n m ay a l s o s e r v e as c om po u nd i ng c o ns u lt a nt s t o t h e p h a rm ac is ts t o a id i n ens u r in g t h ei r p r o du c t ' s p ur i t y a nd qu a li t y . B . E q u ip m en t . Th e c o rre c t e qu i pm en t i s i m p o rt an t wh e n c om p ou nd i ng . Ma n y s ta t e b o a rd s o f p h a rm ac y ha v e a re q ui r ed m i ni m u m l is t o f e q ui pm en t fo r c om p ou n di n g p r e sc ri p ti o ns . Su gg e s t e d e q ui pm e nt , wh i ch v a ri es a c c o rd i ng to t he am ou n t o f m a te r i al n e ed e d a nd th e t y p e o f c o m p o un d ed pr es c ri p ti o n ( e .g . , p a re n te r al ) , i n cl ud e s t he fo l lo wi n g : 1 . E le ct r o ni c b al an c e a nd / o r c la ss A p r es c r i pt i on b a l a nc e 2 . H o t p la t e 3 . Ma g n e ti c s ti r r e r 4 . E le ct r ic m i xe r 5 . S pe ci a l c o n ta i ne r s f o r p ac k a g in g (e . g. , ap pl ic at o r ti p b o t tl es , i ns u ff l at o rs ) 6 . G r a du a te d c y l in de r s f ro m 1 0 m L t o 1 0 00 m L 7 . G l ass , W ed g wo o d, and p o rc el ai n m o rt a rs an d p e s t l es o f v a ri o us s i z es 8 . F un ne ls o f v a r io u s s i z e s 9 . S pa t ul as o f v a r io us s iz e s , in c l ud i ng s e ve r al pla s ti c s pa t ul as 1 0 . W eig h in g a nd f il t er pa p e rs 1 1 . St i r ri n g r o ds (g l as s ) 1 2 . O in tm e nt / pi l l t il e 1 3 . Ca p s u le - f il li n g m a c h in e 1 4 . O in tm e nt - f il li n g m a c h i ne 1 5 . Au t oc la v e 1 6 . L am i na r fl o w c le a n be n c h 1 7 . Sp ec i al s u pp os i to r y , t r o c h e a n d m e d ic at i on - s ti ck m o ld s P.100
1 8 . Re c or d -k e ep in g s y s te m (c om po u nd in g l o g b oo k ) 1 9 . G la s s b e ak e rs f ro m 5 0 m L to 10 00 m L C . L o ca t i on o f c o mp o un d i n g a r ea . Ma n y p h a rm a c ie s ac t i vel y i n v ol ve d in c om p ou n di ng ha v e d ed ic a t e d a s ep a r at e a r e a i n th e p h a rm ac y t o t h is p r oc e s s . Th e
i d ea l l oc a ti o n is a wa y f r om he a vy f o ot t ra f f ic a n d is ne a r a s i nk wh e r e t h ere is s u f fi ci en t s p ac e t o wo r k a n d s to r e a l l c h em ic a ls an d eq ui p m e n t. Fo r c o m po u n di ng o f s t e ri le p re p a ra t io ns , a lam i na r ai r - fl o w h o od (m in i m a l ) a nd a c l e an ro o m ar e cu r r en t p r a ct ic e , o r i s o l at i on ba rr i e r te c h no l og y e qu i pm en t . D . S o u r ce s o f i n fo r m a tio n 1 . Li b r ar y a t a c o ll e ge of p h a rm ac y 2 . R e fe r e nc e s a . A ll e n J r L V . T he A r t , S c i en c e an d T ec h no l og y o f Ph a r m ac e ut ic a l C o mp o u nd in g . 3 r d ed . W as h in g to n , D C : A m e ri c a n Ph a rm ac eu t ic a l As s o ci a ti o n, 20 0 8. b . A no n . Re m i n gt o n: Th e S c ie nc e a n d P r ac t ic e o f P h a r m ac y . 2 1s t e d. P hi la d el p hi a : L i pp i nc ot t W ill i am s & W ilk i ns ; 2 00 6 . c . Sm i th A , H e c k el m a n PE , O ' N e i l M, B u da v a r i S, e ds . Me r c k I nd e x . 13 t h e d . W hite h ou s e S ta t io n , N J : Me r c k & C o , 2 00 1 . d . T he U S P Ph a r m ac is ts ' P h a r m ac o pe ia . 2n d Ed iti o n Ro c k v i ll e , MD : U . S . P h a r m a c o pe i al C on v e n tio n , In c . , 2 0 08 . e . A ll e n L V J r , P o po v i c h N G , A n se l H C . A ns e l 's Ph a r m a c e u ti ca l Do s a g e Fo r m s an d D r u g D el iv e ry Sy s te m s . 9 t h Ed i ti o n Me d i a , P A: Lip p in c ot t W ill ia m s & W ilk in s , 2 00 8 . 3 . J ou r n al s a . I nt e rn a ti o na l J ou r na l o f P ha r m a ce u ti c a l Co mpo u n di ng b . U . S . P h a r m ac is t c . P ha r m ac y T i m es d . Li p pi nc o tt ' s H os pi t al P h a r m a cy e . A m e r ic an J o u rn al o f He a l th - Sy s te m P h a r m ac is ts 4 . Ma n u f ac t u re rs ' d r ug pr o d uc t i n fo r m a t io n i ns e r ts ; c om p ou n di ng sp ec ia l ty s u pp l ie r s 5 . We b si t e s a . C om p ou nd i ng To d a y : w w w. C o m p o u nd in g To d a y. c om b . I nt e r na t io na l J ou r n al o f P ha r m a ce u ti c a l Co mpo u n di ng : ww w. i j p c .c om c . P ad do c k La b or a to r i es , I n c . : ww w. p a d d oc kl a bs .c om
III. COMPOUNDING OF SOLUTIONS A. D e f i n i t i o n. U S P 3 0 de f i ne s s o lu t i on s a s l iq u id p r ep a ra t io ns th a t c on ta i n o ne o r m o r e ch em ic a l s u bs t an c e s d is s o l ve d ( i .e . , m ol ec u l a rl y d is pe r s e d ) i n a s u it a b le s o l ven t o r m i xt u r e o f m u tu a ll y m is c i bl e s ol ve n ts . A l t h ou gh t he un i fo rm i t y o f t he d o sa g e i n a s ol u ti o n c a n b e a s s um e d, th e s t ab il i ty, p H , so lu b il i t y o f th e d ru g o r c h em ic al s , t as te ( fo r o ra l s ol u ti o ns ) , a nd pa ck ag in g ne e d t o b e c on s i de r ed . B . T yp e s o f so l u t io n s 1 . S t e ri l e p a r en t e r al a nd o p h th a lm i c s o lu t i on s r e q ui r e s p e ci al c o ns id e ra t i on fo r t h e ir p re p a ra t io n ( s e e XI ) . 2 . N o ns t e r il e s o l u ti o ns i n c l ud e o r a l, t op ic al , a n d o t ic s o lu t io ns . C . P r e p a ra t i on o f s o lu t io n s . So lu t io ns a re th e ea s ie st o f t he do s a g e f o rm s t o c om p ou n d e xt e m po r a ne ou s l y , a s l on g a s a fe w g en e r al r ul es a re fo l lo we d . 1 . E ac h d r ug o r c h em ic a l i s d is so l ved in t he s o l v en t in wh i c h i t is m o s t s o lu b le . Th us t h e s ol u bi li t y c h a r ac te r is t i c s of ea c h d ru g o r c h em ic a l m u s t b e k n o wn .
2 . I f a n a lc oh o li c s o l ut i on o f a po o rl y wa t e r - s o l ubl e dr u g i s us e d, th e aq ueo u s s o lu t io n i s a dd e d t o t he a l c o h ol ic s ol u ti o n t o m ain t a in as h i gh an al co h ol c o nc en t r at i on as p os s i b le . P.101
3 . Th e s a lt fo r m o f t h e d ru g — no t th e f r e e -a c i d o r b a s e fo r m , wh i c h b ot h ha v e p oo r s o lu bi l it y— i s u s e d . 4 . Fl a v o r in g o r s we e t e nin g ag e nt s a r e p r ep a re d a h e ad of ti m e . 5 . W he n a dd i ng a s a l t t o a s y r up , d is s o l v e t h e s al t in a f e w m il li l it e rs of wa t e r f i rs t ; t h e n a dd th e s y r u p t o v olu m e. 6 . Th e pr o pe r v e hi c l e (e .g . , s y r u p , e li xi r , a r om a tic wa t e r , p u ri f ie d wa t e r ) m us t be s e le ct e d. D . E x am p l es 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Triamcinolone acetonide
100 mg
Menthol
50 mg
Ethanol
10 mL
Propylene glycol
30 mL
Glycerin
20 mL
Sorbitol 70% solution, qs
100 mL
Sodium saccharin
100 mg
Sodium metabisulfite
20 mg
Disodium EDTA
100 mg
Purified water
5 mL
b . C o mp o u nd i n g p r o ced u r e . Tr i am c i no lo n e a c et o n id e 0 . 1% m o ut h wa s h s o lu t io n i s p r e pa r e d b y di s s ol v i n g th e t ri am c i n ol on e a c e t on id e an d m en t ho l i n t h e e th a n ol . Ad d t h e p r o p y le ne gl y c ol , gl y c e r in , a n d a bo u t 1 0 m L of t h e 7 0% s o rb i to l a n d m ix we l l .
D i s so l v e t h e s o d iu m s a c c h a ri n , so d iu m m e t ab is u lf i t e , an d di s o di um E D TA i n th e p u r if i ed wa t e r . Ad d t h e aq u e ou s s o l ut i on to th e dru g m i xt u r e an d m i x we l l . A d d s u f fi ci en t 70 % s or b it o l s o l u ti on t o v o l um e a nd m ix we l l . H ow m u c h o f th e t ri a mc i n o lo n e b as e is p re s en t i n th i s p r e sc r i p ti o n ? Th e m o le cu l ar we i g ht o f t r iam c i n ol o ne i s 3 9 4. 4 a n d th a t o f t ri am c i no l on e a ce to n id e i s 4 3 4 .5 .
2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Potassium chloride
1 mEq/mL
Preserved flavored, oral vehicle, qs
100 mL
b . C a lc u la t i o ns . Th e m ol e c u la r we i g ht o f p ot as s iu m c hl o r id e i s 7 4. 5 ( K = 3 9 ; Cl = 3 5 . 5 ). O n e m i ll i eq u i v al ent ( m Eq ) we i g hs 7 4 .5 m g . 1 0 0 m L × 74 . 5 m g /m L = 7 4 5 0 m g o r 7 .4 5 g o f K Cl r eq u i re d W h a t i s th e m o l a r c o nce n t r a t io n of t h is p re s c ri p t i o n? 7 . 4 5 g p e r 1 0 0 m L o r 7 4.5 g p e r 1 0 00 m L 1 m o l e o f K C l we i gh t s 7 4. 5 g I t is a 1 m ol a r s ol u ti o n c . C om p o un d i ng p r oc ed u r e . Th e s ol ub i li t y of po t as s i um c h lo r i de is 1 g i n 2. 8 m L wa t e r . Th e r e fo r e , d is s o l ve t he 7 .4 5 g K C l i n 2 1 m L o f p u ri f ie d wa t e r. A dd s u f fi ci en t p r e se r ve d f l a v or e d o r al ve h ic le t o vo l um e a nd m i x we l l . 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Salicylic acid
2%
Lactic acid
6 mL
Flexible collodion, ad
30 mL
b . C o mp o u nd i n g p r o ced u r e . Ph a rm ac is ts m u st u s e c a u ti o n wh e n p re p a ri n g t h is p r e sc ri p ti o n b ec au s e f lexi b l e c ol lo d io n i s e xt r e m e l y f la m m ab l e. A 1 - o z . ap p li c a t o r t i p b o tt l e is c a li b r at e d, us i ng et h an o l, wh i ch is pou r e d o u t a nd an y r em a in in g al c o h ol a l lo we d t o P.102
e va p o ra t e , r es u lt in g i n a d r y b ot t le . S al ic y l ic ac i d ( 0 . 6 g ) i s a dd e d d ir e c t l y i n to th e b o t tl e , t o wh ic h i s a dd e d t h e 6 m L o f l ac t ic ac id . Th e b o t tl e is a gi ta t e d o r a g la s s s t i r ri ng r od is u s e d to dis s o l v e th e s al ic yl ic ac id . F l e xi b l e c o l lo di o n is ad de d up to t h e c al i b ra t ed 30 -m L m ar k on th e a p pl ic a to r - ti p bo t t le . 4 . E xa m pl e 4 a . M e d ic a t io n o rd e r
Iodine
2%
Sodium iodide
2.4%
Alcohol, qs
30 mL
b . C o mp o u nd i n g p r o ced u r e . I o di n e ( 0 .6 g ) a nd s o di um io di d e ( 0 .7 2 g ) ar e d i ss ol ve d i n t h e a lc oh o l, a n d t h e f in a l so l ut i on is p l ac e d in a n am b er bo t t le . A r u b b e r o r p l as t ic s pa t ul a is us ed be c a us e i o d ine i s c o r r os i ve .
IV. COMPOUNDING OF SUSPENSIONS
A. D e f i n i t i o n. S us p en s io n s a r e d e fi n ed b y U S P 3 0 as l i qu id p re p a ra t io ns t h a t c o ns is t o f s ol i d p a rt ic le s d is p e rs ed th r o ug ho u t a l i qu i d p ha s e in wh i c h t he p a r ti cl es a r e no t s ol u bl e . B . G e n e r al ch a r ac t e r is ti c s 1 . S om e s us pe ns i on s s ho u ld c o n ta i n a n a nt im ic ro b ia l a g en t a s a p re se r v a t i v e . 2 . P a rt ic l es s e tt l e i n s u s p e ns i on s e v e n wh e n a s u s pe n di ng ag e nt is ad ded ; t hu s s us p en s i o ns m us t b e we ll s h ak e n b ef o r e us e to en s u re th e d is t r ib u ti on o f p a r ti cl e s f o r a u ni f o rm d os e . 3 . Ti g ht c o n ta i ne rs a re ne c es s a r y t o e ns u re th e s t a b il i t y o f th e f i na l p r ep ar a t io n . 4 . P r in c i pl es t o k e e p i n m i nd wh e n c om po u nd i ng i nc l ud e t h e f ol l o wi n g: a . I ns ol ub l e p o wd e rs s h ou l d b e sm a ll an d u ni f o rm i n s i z e t o d ec r e as e se t tli n g . b . Th e s us p en s i o n s h o uld b e v i sc o us . c . To p ic al s us p en s i o ns s h o ul d h a v e a s m oo t h , im p a lp a bl e t e xt u r e . d . O r a l s u s p e ns io ns s h ou l d h a v e a pl e as an t o d o r a n d t as t e. C . F o r ma t i o n o f s u sp e ns i o ns . S us pe ns i on s a re e a s y to c om p ou n d; ho we v e r , p h ys ic al s t a bi li t y a ft e r c o m po u nd in g th e f i na l p r ep a r a ti on is pr o bl em a ti c . Th e f o l lo wi n g s t ep s m a y m in im i z e s t ab il i t y pr o bl em s . 1 . Th e pa r ti c l e s i z e o f a l l p o wd e r s us e d i n t he f o rm u la t io n s ho ul d be re d uc e d. 2 . A th ic k e ni n g ( s u s pe ndi n g ) a ge n t m a y b e u se d to i nc r ea se v is c o s i t y . C om m o n t h ic ke n in g a g en ts in c l u de a lg in ic ac id , be n to ni t e , V E E G U M, m e t h y l ce ll u los e , a nd t r a g ac an t h. 3 . A l e vi ga t in g a g en t m ay a i d i n t h e i ni t ia l d is p ers i on of in s o l ub le p ar t ic les . C om m o n l e vi ga t in g a g en t s i nc lu de g l y c e r i n, p ro p y le n e g l y co l , a lc o ho l , s yr up s , a nd wa t e r . 4 . Fl a v o r in g a g en ts an d p r e s e r v a ti v e s s ho u ld be s e le c t e d a nd ad d ed if t he p r e pa r a ti o n is in t en d ed fo r o ra l u s e . C om m o n p r es e r va ti v e s i nc lu d e m e t h yl p a ra b en , p r o p ylp a r ab en , be n z o ic a c id , a n d s o d iu m b en z o at e . Fl a vo ri n g a ge n ts m a y b e a n y f l a v o r ed s y r u p o r fl a v o r c o nc en t r at e ( Ta bl e 5 - 1 ). 5 . Th e s o ur c e o f t he ac t iv e i n g re di e nt s ( e .g . , b u lk p o wd e r s v e r su s t a bl e ts o r c a ps ul es ) m us t be c o ns id e r ed ; if c om m er c i a l d os a g e f o rm s a r e us e d, t he i n ac t i ve i n g re d ie n ts m us t b e c ons i de r ed an d o n l y i m m ed ia t e - re l ea s e ta b le ts o r c ap s ul es s h ou l d b e us e d a nd no t m o di f ie d r e le as e . D . P r e p a ra t i on o f s u spe n s io n s 1 . Th e i n s o lu b le po wd e rs a re t ri t u ra t ed to a f i ne p o wd e r . 2 . A s m a ll po r t io n o f l i qui d is u s e d a s a le vi ga t in g a g en t , a nd t he po wd e r s a r e t r i t u ra t ed un t il a s m oo t h p a s t e i s f o rm e d. 3 . Th e v e hi c l e c on t ai ni ng t he s u sp e nd in g a g en t is ad d ed in di v i d ed po r ti on s . A hi g h s p ee d m i xe r g r ea t l y i nc re a s e s t h e di s pe rs i on . P.103
Table 5-1. Selected Flavor Applications
Drug Category
Preferred Flavors
Antibiotics
Cherry, maple, pineapple, orange, raspberry, bananapineapple, banana-vanilla, butterscotch-maple, coconut custard, strawberry, vanilla, lemon custard, cherry custard, fruit-cinnamon
Antihistamines
Apricot, black currant, cherry, cinnamon, custard, grape, honey, lime, loganberry, peach-orange, peachrum, raspberry, root beer, wild cherry
Barbiturates
Banana-pineapple, banana-vanilla, black currant, cinnamonpeppermint, grenadine-strawberry, lime, orange, peach-orange, root beer
Decongestants and expectorants
Anise, apricot, black currant, butterscotch, cherry, coconut custard, custard mint-strawberry, grenadinepeach, strawberry, lemon, coriander, orange-peach, pineapple, raspberry, strawberry, tangerine
Electrolyte solutions
Cherry, grape, lemon-lime, raspberry, wild cherry, black currant, grenadine-strawberry, lime, Port wine, Sherry wine, root beer, wild strawberry
4 . Th e pr e pa r a ti on is br ou g h t t o t h e r eq u i re d vol um e u s i n g t he v e hi c l e . 5 . Th e fi na l m i xt u r e i s t ra n s f e r re d to a “ t ig h t ” b ott l e f o r d is p en s i n g t o t he p a t ie n t. 6 . A ll s us p en s i o ns a r e d is p en s e d wi t h a “s h ak e we l l ” l ab el . 7 . S us pe ns i on s a r e n ot fil t e re d . 8 . Th e wa t e r -s ol u bl e i ng re d ie n ts , i nc l ud in g fl a vo rin g ag e nt s, a re m i xe d i n th e ve h i cl e b e fo r e m i xi n g wi th t he in s o l ub le in g r ed ie nt s . E . E x am p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Propranolol HCI
4 mg/mL
Disp
30 mL
Sig:
1 mL p.o. t.i.d.
b . C a lc u la t i o ns . P ro p ran o lo l H C l: 4 m g / m L × 3 0 m L = 1 20 m g . P r o pr a no lo l H C l is a va i la b le as a p o wd e r o r i n i m m ed i at e - re l ea se and e xt e n d ed - r el e as e ( l on g- a c ti n g) d o sa g e f o rm s . O nl y t h e p o wd e r o r t h e im m e d ia t e- r e l ea s e ta b le ts a re us ed f o r c om p ou n di ng p re s c r ip t ion s ; t h er e fo r e , s om e co m b i na t io n o f p ro p ra n ol ol HC l t ab l et s t h a t yie ld s 1 20 m g ac ti v e d r u g ( e .g . , 3 × 4 0 m g t ab l e ts ) m a y be us ed . c . C om p o un d i ng p r oc ed u r e . Th e p r op r an o lo l t ab l e ts a r e re du c ed to a f in e po wd e r i n a m o r t a r. Th e p o wd e r o r t he c o m m i n u te d t a bl e ts a re le v i g at e d t o a s m oo t h p as t e , u s in g a 2% m e th y l c el lu l os e s ol u ti o n. To t hi s m i xt u r e , a b ou t 1 0 m L o f a s ui t a bl e f l a v o ri n g a ge n t i s a dd ed . Th e m i xt u r e i s t r an sf e r re d to a c al ib r a te d c on t ain e r an d b r o ug h t t o t h e f in a l v o l um e wi t h p u ri f ie d wa t e r o r s ui t ab l e s u s p e nd i ng v e hi c le . A “ s h ak e we l l ” l a be l i s a t tac h ed to t he p re sc ri p ti o n c o nt a in e r . 2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Zinc oxide
10
Ppt sulfur
10
Bentonite
3.6
Purified water, ad
90 mL
Sig:
Apply t.i.d.
b . C o mp o u nd i n g p r o ced u r e . Th e p o wd e rs a re re d uc e d t o a fi ne un i fo r m m i xt u r e in a m o r t a r. Th e p o wd e r s ar e m i xe d t o fo r m a sm o o th p as te us in g wa t e r a n d t r a ns f e r re d t o P.104
a ca l ib r a te d b o tt l e. Th e fi n al v o lu m e is at t ai n ed wi t h p u ri f ie d wa t e r . A “s h ak e we l l ” l a be l i s a t ta c h e d t o t h e pr e s c r ip t io n c o nt ai n e r. 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Rifampin suspension
20 mg/mL
Disp
120 mL
Sig:
u.d.
b . C a lc u la t i o ns . Ri f am pin : 20 m g /m L × 12 0 m L = 2 4 0 0 m g . Ri f am pi n i s a v a i la b le in 1 5 0 -m g a nd 30 0 -m g c aps u le s . H e nc e, 8 c ap s u les c o n ta in i ng 30 0 m g o f rif a m p i n i n e a ch c a ps ul e o r 16 c a ps u l es c o nt a in i ng 15 0 m g o f r i f am p in pe r c a ps ul e ar e n ee de d . c . C om p o un d i ng p r oc ed u r e . Th e c on t en ts of t he a pp r op r i at e n um b e r o f r i f am pi n c a ps ul es a re em pt i ed in to a m o rt a r a n d co m m in u te d wi t h a pe s tl e . Th i s p owd e r i s l e vi ga t ed wi t h a s m al l am o un t o f 1% m e th y l c e l lul o se s o lu t io n . Th e n 2 0 m L o f s im pl e s yr u p a r e a d de d a nd m i x e d . Th e m i xt u r e i s b r ou gh t t o t he fi n al v o lu m e wi th si m p l e s yr u p . “ S h ak e we l l ” an d “ r e f r ig e ra t e ” l ab e ls a r e at t a c h ed t o t he p re sc r ip t io n c o nt a in e r .
V. EMULSIONS A. D e f i n i t i o n. Em u ls io ns a r e tw o- p h as e s ys t e m s i n wh ic h o n e l iq ui d i s d is p e rs ed t h r o ug ho u t a no t he r li q uid i n t he f or m o f s m a ll d ro p le t s ( se e Ch a pt e r 3 . V I. D ) . B . G e n e r al ch a r ac t e r is ti c s . E m ul si on s c an be us e d e x te r n al l y a s l ot i ons an d c r e am s o r i n te r n a ll y t o m as k t h e t as t e o f m ed ica t i on s . 1 . Th e t wo li q ui ds in an e m ul s i o n a re im m i s c ib le a n d re qu i r e t he us e o f an e m u ls i f yi n g a g e n t . 2 . Em u ls io ns a re c l as s i fie d as e i th e r o i l - in -w a t e r ( o /w ) o r w a t e r - in - o il (w / o ) ; t h e r e c a n a ls o b e m ul ti p le em ul s io ns , s uc h a s o i l -i n -w at e r - i n - oi l ( o/w / o ) a n d w a t e r - i n o i l - i n -w at e r (w /o /w ) , a s we l l a s em u ls io n -g e ls , i n wh i c h th e e xt e r n a l p h a s e o f a n o il i n wa t e r e m u ls i on is t h ic k e ne d wi t h a ge ll i ng ag en t . 3 . Em u ls io ns a re u ns t abl e b y na t ur e , a n d t he fo l lo wi n g s t e ps s h ou ld be t ak e n t o p r e ve n t t he t wo p ha s e s o f an em ul s i o n f r om s e pa r a ti n g i nt o t wo la ye r s a ft e r p r e pa r a ti o n. a . Th e c o r re c t p r o po r t i on s o f oi l a n d wa t e r s h o uld b e us e d d u ri ng p re p a ra t i on . Th e i n t er n al ph as e s ho u ld r ep r e s e n t 4 0% - 60 % o f th e t o t al vo lu m e .
b . A n e m u ls i f y in g a g en t i s n e ed e d f o r em u ls io n fo r m at i on . c . A h a nd h om o ge n iz e r , wh i c h re d uc es th e s i z e o f gl o bu le s o f th e i n te r na l ph as e , m a y be us e d; if s m al l q ua n t it i es a r e c om po u nd e d, t wo 6 0 -m L s y r i ng es at ta c he d wi t h a L eu r - Lo c k ad ap t e r c an b e u s e d a n d t h e m a t e ri al s p us h ed ba c k an d f o r th b e t we e n t h e t wo s y r i n ge s . d . P r e se r va t i ve s s h ou ld b e a d de d i f th e p r ep a r ati o n i s i nt e nd ed t o l as t l on g e r t h an a f e w d a y s . G e ne r al l y , a c om b in a ti o n o f m e t h y lp ar a b en ( 0. 2 % ) a nd p ro p y lp a r ab e n ( 0 . 0 2% ) m a y be us ed . e . A “ s ha k e w e l l” la b el s h ou l d b e p la c e d o n t h e f i n al pr e pa r a ti on . f . Th e p re p ar a ti o n s ho uld b e p r o t ec t ed f ro m l ig ht a nd e xt r e m e t em pe r a tur e . B ot h f r e e zi ng an d h ea t m a y ha v e a n e f fe c t on s t a bi li t y . C . E m u ls i f yi n g a g e n t s 1 . G u ms , s uc h a s a c a c i a o r t ra g ac an t h, a re us ed t o f or m o / w e m u ls i on s . Th e s e e m ul si f y i ng ag e nt s a r e fo r g en e ra l u s e , e s pe ci al ly f o r em ul si o ns i n te n de d f o r i n t er n al ad m i n is t ra t io n (Ta b l e 5- 2 ) . a . U se 1 g o f ac ac ia po wd e r fo r e v e r y 4 m L of fi x e d oi l o r 1 g t o 2 m L fo r a vo l at i le oil. b . I f u s i ng t ra g ac an t h i n p l ac e o f a ca c i a , 0 . 1 g o f t r a g ac an t h is us ed f or e ve r y 1 g o f a c ac ia . 2 . M e t h yl c e l l u l o se a nd c a r b ox ym e t h yl c e l l u l o se a r e us e d f o r o / w e m u ls i o ns . Th e c o nc en t r at i on s o f t h es e a g e nt s v a r y , d ep en d in g o n th e g r a de th a t i s us ed . Me t h yl c e l lu lo s e is a v ai l ab l e i n s e v e ra l v isc os i t y g r a d es , ra n gi ng f ro m 1 5 to 4 00 0 a n d d e si g na t ed b y a c e n ti po is e n um b e r, wh i c h is a u ni t of vi sc os it y . P.105
Table 5-2. Agents Used in Prescription Compounding Ointments Oleaginous or hydrocarbon bases
Hydrous emulsion bases (w/o)
Anhydrous
Hydrous
Nonhydrophilic
Will absorb water
Insoluble in water
Insoluble in water
Not water removable (occlusive)
Not water removable (occlusive)
Good vehicles for antibiotics Example Petrolatum Absorption bases
Examples Cold cream Hydrous lanolin Emulsion bases (o/w)
Anhydrous
Hydrous
Will absorb water
Hydrophilic
Insoluble in water
Insoluble in water
Not water removable (occlusive)
Water removable
Examples Hydrophilic petrolatum Lanolin USP (anhydrous)
Can absorb 30-50% of weight Examples Hydrophilic ointment USP Acid mantle cream Water soluble Anhydrous or hydrous Soluble in water Water removable Hydrophilic
Example Polyethylene glycol ointment Suspending Agents Acacia 10%
Methylcellulose 1%-7%
Alginic acid 1%-2%
Sodium alginate 1%-2%
Bentonite 6%
Tragacanth 1%-3%
Carboxymethylcellulose 1%-5%
VEEGUM 6%
Preservatives Methylparaben 0.02%-0.2%
Propylparaben 0.01%-0.04% Emulsifying Agents
Hydrophilic colloids
Surfactants, nonionic
Acacia
Concentrations used (1-30%)
Tragacanth
Tweens (e.g., polysorbate 80)
Pectin; favor o/w
Spans
Carboxymethylcellulose Methylcellulose Proteins
Soaps
Gelatin
Triethanolamine
Egg whites; favor o/w
Stearic acid
Inorganic gels and magmas
Others
Milk of magnesia
Sodium lauryl sulfate
Bentonite; favor o/w
Dioctyl sodium sulfosuccinate Cetyl pyridinium chloride
o/w, oil-in-water; w/o, water-in-oil P.106
3 . S oa p s c an be us ed to p r e pa r e o / w o r w/ o em uls i on s f o r e xt e r n a l p r ep a ra t i on s . 4 . N o ni o n ic em u ls i f yi n g a ge n t s c an be us ed for o / w a n d w/ o e m u ls i on s. D . F o r ma t i o n a nd p r ep ar a t i o n o f em u ls i o ns . The p r oc ed u re f or p re p ar i ng a n e m ul si o n d ep en ds on t he d es i r ed em ul si f y i ng ag en t i n th e fo r m u la t io n . 1 . A m o r t a r a n d p es t l e a r e f re qu e nt l y al l th e e qu i pm e nt th a t i s n ee de d . a . A m o r ta r wi t h a r o ug h s u r f ac e (e . g. , W ed g wo od ) sh o ul d b e u se d . Th i s ro u g h s u r fa ce al l o ws m a xi m al d i s p e rs io n o f gl ob u le s t o p r o du c e a f in e p a r ti cl e s i z e . b . A r ap i d m o t io n i s e s s e n t ia l wh e n t r it u ra t in g a n e m u ls i on us in g a m o r ta r a n d p e st l e. c . Th e m o rt a r s ho u ld be a b le t o h ol d a t l e as t t h ree t im es th e q u a nt i t y b e i n g m a de . Tr i t u r a ti o n s el do m r e qu i re s m o re t ha n 5 m i n t o c re a t e t he em ul s i o n. 2 . E le c t r ic m ix e r s a nd ha n d h om o ge ni z e r s a r e us e fu l fo r p r o du c i ng em u ls i on s a f te r t h e c oa r s e em ul s i o n is fo r m ed in th e m o rt a r . 3 . Th e o rd e r of m i xi n g of i ng r e di en t s i n a n em u lsi o n d ep e nd s o n t h e t yp e o f e m ul si o n b ei ng p re p ar e d ( i . e. , o/ w o r w/ o ) a s we l l a s t h e em u ls if y i n g a ge nt c ho s e n . Me t h o d s u s ed fo r c om p ou n di n g i nc lu d e t he f ol lo wi n g : a . D r y g u m ( c o n ti n en t al ) m e th od is us ed fo r fo r m in g em ul s i o ns u s i n g n at ur a l e m ul si f y i ng ag e nt s a nd re q ui r es a s pe c i f ic o r d er o f m i xi n g . b . W et g um ( E ng li s h ) m e t h od is u se d fo r fo r m i ng e m u ls i on s us i ng na t u ra l e m ul si f y i ng ag e nt s a nd re q ui r es a s pe c i f ic o r d er o f m i xi n g . c . B o t tl e m e t ho d i s u s ed f o r f o rm in g e m u ls i on s u s in g n a tu r al em ul si f yi ng a g en ts a n d re qu i r es a s p ec i fi c or d e r o f m i xi n g . d . B e ak e r m e t ho d i s u s e d to p re p ar e e m ul si on s u s in g s yn t he ti c e m u ls i f yin g ag e nt s a n d p r od uc e s a s at is f ac to r y p r ep a r at i on r eg a rd l es s o f t h e o r de r of m i xi n g. 4 . P r es e r va t i ve s . I f th e e m ul s i o n is k e pt f or a n ext e n d e d pe r io d o f ti m e , r e f r ig e r at i on i s u s u a ll y s u f f ic ie n t. Th e p re pa r a ti on sh o ul d n o t b e f r o zen . If a p r e se r va ti v e is us ed , i t m us t be s o lu bl e i n th e wa t e r p h as e t o b e e f fe ct i ve .
5 . F la vo r i n g a g en t s . I f th e ad di t io n o f a f la v o r is n e ed e d t o m a sk th e ta s te o f t h e o il p h as e , t he f la v o r s h ou ld b e ad d ed to th e e xt e r n a l p h as e b ef o r e em u ls if ic at i o n ( Ta b le 5-3). E . E x am p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Mineral oil
18 mL
Acacia
qs
Distilled water, qs ad
90.0 mL
Sig:
1 tablespoon q.d.
b . C o mp o u nd i n g p r o ced u r e . W ith t he dr y g um m e th o d, an in i ti a l em u ls io n ( pr im a r y e m ul si o n) is fo r m e d , us in g 4 p a rt s ( 1 8 m L ) of oi l , 2 pa r ts ( 9 m L) o f wa t e r , a n d 1 pa r t ( 4 . 5 g ) of po wd e r e d a c a c i a . Th e m i n e ra l o il is t ri tu r a t ed wi t h t h e a ca c i a i n a W edg wo o d m o r t a r. Th e 9 m L o f wa t e r is ad d ed al l a t on c e an d , wi t h r ap i d tr i t u ra t io n , f o r m t he p ri m a r y em u ls ion , wh i c h is t ri t u ra t ed fo r a b o ut 5 m i n . Th e r em ai n in g wa t e r i s i nc o r po r at e d i n s m al l a m ou n ts wi t h t r i tu r a ti on . Th e e m u ls i on is tr a ns fe r re d to a 9 0 - m L pr e s c ri p ti o n b ot t le, a nd a “ s h a ke we l l ” l ab el is at t ac h ed to th e c o nt ai n e r.
Table 5-3. Flavor Selection Guide Taste
Masking Flavor
Salt
Butterscotch, maple
Bitter
Wild cherry, walnut, chocolate mint, licorice
Sweet
Fruit, berry, vanilla
Acid
Citrus
P.107
2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Olive oil
30 mL
Zinc oxide
8g
Calamine
8g
Lime water
30 mL
b . C o mp o u nd i n g p r o ced u r e . Th e o li v e oi l i s p lac e d i n a s ui t ab l y s i z e d be a k e r . U s i ng an el ec t r ic m i xe r , t h e z in c o xi d e , th e c al am i n e , a nd th e l im e wa t e r ar e a dd ed i n th a t o r de r . Th is y ie l ds a w/ o em u ls io n . Th i s p ro c ed u re is k n o wn as th e n a sc en t s o ap m e th o d . Th e ol i v e o i l r e ac ts wi t h th e c al ci um h y d ro xi d e s o l ut i on (l im e wa t e r ) a n d f o rm s a s o ap . F o r t hi s re ac t io n t o o c c u r , f r es h l im e wa t e r (c a lc iu m h yd r o xi d e s o lu t io n ) i s r eq u i re d . A s m a ll qu an t i t y o f ol ei c a c id ca n a ls o b e a d de d to fu r t h er s t ab i li ze th e e m u ls i on . 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Mineral oil
50 mL
Water, qs
100 mL
Sig:
2.5 mL p.o. h.s.
b . C o mp o u nd i n g p r o ced u r e . Us in g a co m b in a tio n of no n io ni c e m u ls i f y ing a ge n ts , s uc h a s Sp a n 4 0 a nd Tw e e n 4 0 , t he c o r r ec t h y d ro p hi l ic - li po p hi li c b al a nc e ( H L B ) is o b t ai ne d . Ne xt , t h e m in er a l o i l is wa r m ed in a wat e r ba t h t o a bo u t 6 0 ° C , an d th e S p a n 4 0 i s d is s o l v ed in th e he a te d m in e ra l o i l. The wa t e r is wa r m ed to abo u t 6 5 ° C , a n d t h e Twe e n 4 0 i s d is s o l v e d i n t h e h ea t ed wa t er . Th i s m i xt u r e i s a dd e d t o t he
m i ne r al oi l a n d d is s o l v ed S p a n 4 0 a nd s t i r re d u n til co o le d . A n “e xt e r n a l u s e o nl y ” l a be l i s a dd e d t o t h e c o nt a i ne r .
VI. POWDERED DOSAGE FORMS A. D e f i n i t i o n. P ow de r s a r e i n ti m a t e m i xt u r es o f d r y, f in e l y d i v i de d d r ug s a n d /o r c h em ic al s t ha t m a y be int e n de d f o r i n te r na l (o r al p o wd e r s ) o r e xt e r n a l (t op i c a l p o wd e r s ) u s e . Th e m aj o r t y p e s a r e p o wd e r p ap e rs , bu lk po wd e r s , a nd in s u f f la t io ns . B . G e n e r al ch a r ac t e r is ti c s 1 . P o wd e r d os a ge fo r m s a r e us ed wh e n d r u g s t ab i l i t y o r s o l u b i li t y i s a c o n ce r n . Th e s e d os a ge f or m s m a y a ls o b e u s e d wh e n t h e p o wd e r s a r e t o o b ul k y to m ak e i n to c a ps ul es an d wh e n t h e pa t i en t h as di f fi c ul t y s wa l lo wi n g a c ap s u l e. 2 . S om e d i sa d va n t ag e s t o po wd e r s i nc l ud e u n pl ea s an t - ta s ti ng m e di ca t io ns an d , o cc a si on a ll y , th e ra p id de t e ri o r at i on of po wd e r s . 3 . B l en d i ng of po wd e r s m a y be ac co m p l is he d b y u si n g t r it u r at i on i n a m or t a r , s t i r ri ng wi t h a s p a tu l a, an d s i f ti ng . G eo m e t r ic d i lu t i on s h ou l d b e us e d i f ne e d ed . W hen h ea v y p o wd e r s a re m i xe d wi t h l ig h te r on es , t h e h ea v i e r p o wd e r s hou l d b e p l ac e d o n t op of t he li gh te r o ne an d t h en bl en d ed. W hen m i xi n g t wo o r m or e p o wd e r s , e ac h p o wd e r s h o ul d b e pu l v e ri z e d s epa r a t el y t o a bo u t t h e sa m e p a rt ic l e s i z e b e fo r e b l en di n g t oge t h e r. a . Th e m o r ta r a n d p es t le m e th od is pr e fe r r e d wh e n p u l ve r iz a ti o n a n d a t ho r o ug h m i xi n g of in g r ed ie n ts ar e d es i r ed (g e om e tr ic di l ut i o n ) . A W edg wo o d m o rt a r i s p r e f er a bl e , b ut gl as s o r p o r c e la i n m a y a ls o b e u s e d . b . Li g ht po wd e r s ar e m i xe d be s t b y us in g t h e s i f ti n g me t h od . Th e s if t in g i s r e p ea t ed t hr e e t o f o u r t im es t o e ns u re th o ro u gh m i xi n g of t he po wd e r s . C . P r e p a ra t i on o f p ow de r d o sa g e f o r ms 1 . B u lk p ow de r s , wh i c h m a y be us e d i nt e rn a ll y or t o pi c a ll y , i nc lu d e d us tin g p o wd e r s , d ou c h e p o wd e rs , la xa t i v e s , a n ta ci ds , a nd i ns uf f la t io n p o wd e r s . 2 . A f te r a b ul k p o wd e r ha s b e en pu l v e ri z e d an d b l en d e d , i t s h ou l d b e di sp e ns e d i n a n ap p ro p r ia t e c o n ta i ne r. a . H yg r o s c o p i c o r e f f e rve s c e n t s al ts sh ou l d a l wa ys be pl a ce d i n a ti gh t , wi d e m o ut h j a r . b . D u s ti n g p o wd e rs s h ou l d b e p la c ed i n a co n ta in e r wi t h a s i f te r to p . P.108
3 . E u te c t ic mi x t u re s o f p o wd e r s c an c a us e p r ob le m s be c au s e th e y m a y l iq u e f y . O n e r em ed y i s t o a dd an i n er t po wd e r , s uc h as m a g n es iu m o xi d e , t o s e par a t e t h e e u t ec ti c m at e ri a ls . 4 . P ow de r p ap e r s a r e a ls o c al l ed di vi d ed po wd e rs . a . Th e en ti r e p o wd e r is in i t ia ll y b le n de d . E ac h d os e i s t h en in di v i d ua ll y w e i gh e d. b . Th e do s a g e sh o ul d b e we i g h e d, th e n t r an s fe r re d on t o a p o wd e r pa p er a n d f o ld e d. Th i s t ec hn iq u e r e qu i re s p r a c t ic e . H yg r o sc op ic , de l i q u es c e n t, an d e f fe r v es c e n t p o wd e r s re qu i r e t he us e o f gl as si n e p ap e r a s a n in s id e l in i ng . Pl as t ic ba gs o r e n ve l op es wi t h s na p - an d- s e al c l os ur e s o ff e r a c on v e n i en t a l te r na t i v e t o po wd e r p a p er s .
c . Th e f o ld e d p ap e rs ar e d is p en s e d i n a po wd e r b o x o r o t he r s u it a bl e c ont a i ne r ; h o we ve r , t he s e c o n ta i ner s a re no t c hi l d r es is t an t. D . E x am p l es 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Camphor
100 mg
Menthol
200 mg
Zinc oxide
800 mg
Talc
1.9 g
M foot powder Sig:
Apply to feet b.i.d.
b . C o mp o u nd i n g p r o ced u r e . Th e c am ph o r a nd m e nt h ol a re t ri t ur a te d tog e t he r in a g l as s m o r t a r, wh e r e a li qu i d e u te c t ic is fo r m e d . Th e zi nc o xi d e a nd t al c a re b le nd e d a n d m i xe d wi t h th e e u te c t i c , us i ng ge om e tr ic di l uti o n . Th i s m i xi n g r es u lt s in a d r y p o wd e r , wh i c h is pa s s ed t h r ou g h a wi r e m es h s i eve . Th e f in al p re p a ra t io n i s d i sp e ns ed in a c o n ta i ne r wi t h a s i ft e r to p . 2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Citric acid
0.3 g
Sodium bicarbonate
0.25 g
Psyllium mucilloid
2g
Powdered flavor, qs M. Ft d.t.d. charts v
Sig: Empty the contents of one chart into a glass of water and take h.s.
b . C a lc u la t i o ns . Ca lc u lat e f or on e e xt r a p o wd e r p a p er :
Citric acid 0.3 g × 6 doses
=
1.8 g
Sodium bicarbonate 0.25 g × 6 doses
=
1.5 g
Psyllium mucilloid 2 g × 6 doses
=
12 g
Total wight
=
15.3 g
15.3 g/6 doses
=
2.55 g/dose
N o t e : Al s o c o ns id e r t h e we i g h t of t he po wd e r e d fl a v o r . c . C om p o un d i ng p r oc ed u r e . Th e i ng r ed i en ts a re f i rs t p ul v e r i z e d a nd we i g he d . Th e c i t ri c ac i d a nd s o di um bic a r bo na t e a r e m i xe d to ge t h e r f i rs t; t he ps y l li um m uc i ll oi d i s t h e n a dd e d a lo ng wi t h the p o wd e r ed fl a vo r , us i ng g e om et r ic di l ut io n . Ea c h d os e ( 2 . 5 5 g ) o f t h e r es u lt a nt m i xt u r e is we i gh e d a nd pl a ce d i n to a p o wd e r p a pe r . Th is p r e pa r a ti o n is an ef f e r v es c e n t p o wd e r . W hen di s s o l v e d i n wa t e r, t he c i t ri c a c id an d s o di um bi c a r bo n at e re ac t t o f o rm c a r bo n ic a ci d , wh i c h yi el ds c a r bo n d i o xi d e , m a k i n g t h e s ol u ti o n m o r e p a la t ab l e .
VII. CAPSULES A. D e f i n i t i o n. C a ps u le s a r e s ol i d d os ag e f o rm s in wh i c h t h e d ru g i s e nc los e d wi t h i n e i t he r a h ar d o r s o f t s o l ub l e c on t ai n er o r s h e ll . Th e s h el ls a re us ua ll y m ad e f ro m a s u it a bl e g el a ti n . Ha r d g el a t in c a ps ul es m a y b e m a n u al l y fi ll e d f o r e xt e m po r a ne o us c om p ou n di ng . P.109
Table 5-4. Approximate Amount of Powder Contained in Capsules Capsule SizeRange of Powder Capacity (mg) No. 5
60-130
No. 4
95-260
No. 3
130-390
No. 2
195-520
No. 1
225-650
No. 0
325-910
No. 00
390-1300
No. 000
650-2000
B . C a p su l e s iz e s 1 . A l is t of c a ps ul e s i z es a n d t he ap p r o xi m at e a m o u n t o f p o wd e r th a t m a y b e c o nt a in e d i n t he c a ps ul e a p pe a r o n t h e si d e o f t he ca ps u le bo x ( Ta b l e 5 - 4) . 2 . C ap s ul e s i z es f o r o r a l a dm i ni st r a ti o n in hu m ans r an g e f r om n o . 5 , t h e s m a ll es t , t o n o . 0 0 0, t he la r ge s t. 3 . N o . 0 i s u s u al l y t he lar g e s t o ra l s i z e s u i ta b le fo r h um an pa t ie n ts . 4 . C ap s ul es fo r v e te r i na ri a ns a re a v ai la b le in no . 1 0 , n o . 1 1 , a nd no . 1 2 , c o n t ai ni n g a p p ro xi m a t el y 3 0 , 1 5, and 7 .5 g , r es p ec ti v e l y . C . P r e p a ra t i on o f h a r d a n d s o f t c a ps u l es 1 . A s wi t h th e b u lk p o wd e r s , a ll in g re d ie n ts a r e t ri t u ra t e d a nd bl en d ed , u sin g g e om e t ri c d il u ti on . 2 . Th e c o r re c t s i z e c a ps u l e m us t b e d e te r m i ne d b y t r y i n g d if f e re n t c ap su le s i z e s , we i g h i ng t he m , an d t h en c ho os i ng th e a p p ro p ri a te s i z e . 3 . B ef o r e f il li n g c ap s u le s wi t h t h e m e d ic at i on , t h e b o d y a n d c ap of th e c a ps u le a re s e pa r a te d . F il li n g is ac c o m pl is h ed b y u s i n g t he “p u nc h ” m et h od ( Al t e rn a tive l y, sm a ll c a ps ul e m ac hi n es a r e c om m o n l y u s e d to p re pa r e u p to 30 0 c ap s ul es at a ti m e, e xt e m p o r an e ou s l y ) . a . Th e po wd e r f or m u l at i on is c o m p r es se d wi t h a sp a t ul a o n a pi ll ti l e o r p ap e r s h ee t wi t h a un i fo r m d ep t h o f ap p r o xi m a te l y ha l f t he le ng t h o f th e c ap s u l e b od y.
b . Th e em pt y c ap s u l e b od y i s r e pe a te d l y p r es se d i n to th e po wd e r un t il fu l l. c . Th e c ap s u l e is t he n we i gh e d t o e ns u re an ac c u r a t e d os e. A n em p t y ta re c a ps u le o f t he s am e s i z e i s p la c ed o n t he pa n c o nt ai n in g th e we i g ht s . 4 . F or a l a rg e n um b er o f c a ps ul es , c a ps ul e -f i ll in g m ac h in es ca n b e u se d f or sm a ll s ca l e us e to s a v e ti m e . Mo s t c om m o n l y, c ap s u l es m a c h in e s a re us e d c a pa b le o f p r e pa r i ng 10 0 t o 3 0 0 c ap s ul es at a t im e . 5 . Th e c a ps ul e i s wi p e d c l ea n o f a n y po wd e r o r oi l an d d is pe n s e d i n a s u it a b le p r e sc ri p ti o n v i a l. D . E x am p l es 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Rifampin
100 mg
dtd #50 Sig:
1 cap p.o. q.d.
b . C a lc u la t i o ns . Co m p ou n d t h is p r es c ri p ti on us in g th e c om m e r c i al l y a v ail a bl e 3 0 0 m g c ap s ul es as t h e d r ug s ou r c e . C al c u la t e f o r a t l e as t o n e e xt r a c ap su le .
51 caps × 100 mg/cap
=
5100 mg rifampin
5100 mg rifampin ÷ 300 mg/cap
=
17 caps
P.110
c . C om p o un d i ng p r oc ed u r e . Us e 1 7 ri fa m pi n c ap s ul es , e a c h c o nt a in in g 3 0 0 m g r i f am pi n . Th e c o n te n t o f e a c h c a ps ul e i s e m p t ie d , a n d t he po wd e r is we i g he d . Th e p o wd e r e qu i v al e nt t o 1 00 m g r if am p in is p l ac ed in a c ap s ul e ( e .g . , i f th e to t a l c o nt e nt s o f o n e c a p s u le we i g h 3 60 m g ; t h en 10 0 /3 0 0 = x / 3 60 ; x = 1 20 m g o f ac t i v e d r u g p o wd e r re q ui r ed f rom t he c a ps ul e c on t en t s to p r o vid e 1 00 m g ac ti v e d r u g ) a nd s u f fi ci en t la c t os e a d de d t o fi l l t he c a ps ul e . Th e to t a l f il le d c a ps ul e c on t en t s we ig h 2 0 0 m g. Th e we i g ht of t he ac t i v e d r ug po wd e r is s u bt r ac t ed f ro m 2 00 m g t o ob t ai n t h e a m o u nt o f l ac to s e r eq u i re d p e r c ap s u l e, wh i c h i s 20 0 m g - 12 0 m g = 80 m g . Th is i s m ul t ip li e d b y 5 1 c a ps ul e s . E no u gh la ct os e (5 1 c a ps ul es × 8 0 m g/ c a p = 4 . 0 8 g ) i s a d d ed to m a k e a t ot a l o f 1 0 .2 g o f p o wd e r . Th e po wd e r s a re c om b in e d, usi n g g e om e t ri c d il u ti on , a n d 50 c a ps u le s c an be pu nc he d ou t . E a c h c a ps ul e s ho u ld we i g h 2 0 0 m g ( 1 0. 2 g / 51 c a ps ). 2 . E xa m pl e 2 a . M e d ic a t io n o rd e r . Thi s o r d er is fo r v e te r i na r y u s e o nl y.
Castor oil
8 mL
Disp
12 caps
Sig:
2 caps p.o. h.s.
b . C a lc u la t i o ns . No c a lc u l a ti on s a r e n ec es s a r y. c . C om p o un d i ng p r oc ed u r e . A n o. 11 v e t e ri na ry c a ps ul e i s u s e d . U s in g a c a li b ra t ed d ro p pe r o r a pi p e tt e , 8 m L o f th e o il is c a r ef u ll y a dd ed t o t he ins i de of e a ch c a ps ul e b o d y . Ne xt , t h e lo we r i ns i de po r t io n o f th e c ap is m oi s te n ed , u s i n g a g l as s r o d o r b r us h . Th e c a p a nd bo d y a re jo in e d t o g et h e r, us in g a t wi s ti ng m o t io n , t o f or m a ti g ht s e al . Th e c a ps ul es a re pl ac e d o n a p ie c e of f il te r pa p e r a nd c h ec k ed f o r s i gn s o f l ea k ag e . Th e c ap s u l es ar e d is p en se d i n th e a p p ro p ri a te s i z e an d t ype o f p r e sc ri p ti o n v i a l. Th e y c a n be s t o re d i n a r ef r i ge ra t o r i f d es i r ed .
VIII. MOLDED TABLETS (TABLET TRITURATES) A. D e f i n i t i o n. Ta b le t tr i tu r a t es a r e s m a ll , u s u a ll y c y l in d ri c al m ol d ed o r com p r es s e d t a b le ts . Th e y a re m a de of p o wd e rs c re a te d b y m oi s te n in g t h e p o wd e r m i xt u r e wi t h a l co h ol a n d wa t e r o r b y th e p ro c e ss o f s i nt e ri n g. Th e y c a n b e u s e d f o r c om p ou n di ng p o t en t d r u gs i n s m a ll dos es an d fo r pr e pa r a ti on o f a r a pi dl y d is i nt e gr a ti ng / d iss o l v in g d o sa g e f o rm . B . F o r m ul a t io n a n d p r ep a r a t io n o f t a bl e t t ri t u ra t e s u s in g m o i s te n ed pow de r s
1 . Ta b le t t ri tu r a te s a r e m a d e i n s pe c i a l m o l ds c ons is t in g o f a p eg bo a r d a nd a c o r re s po nd i ng pe r f or a ted p la t e. 2 . I n a dd i ti on t o t he m o ld , a d il u en t , u s u al l y a m ixt u r e o f la c to se an d s uc ro s e ( 8 0 : 20 ) , a nd a m oi s t e ni ng a ge n t, us ua l l y a m i xt u r e o f e t h y l a lc oh ol an d wa t e r ( 6 0 : 40 ) , a r e r e qu i re d . 3 . Th e di lu e nt is t ri tu r a ted wi t h t he ac ti ve in g r ed ie n ts . 4 . A p a s t e i s t he n m ad e , u s i n g t he al c o h ol an d wa t e r m i xt u r e . 5 . Th i s p as te is s p re a d in t o th e m ol d ; t he ta b le ts a r e p u nc he d o u t a nd r em a in on th e p e gs un t il d r y . C . E x am p l e 1 . M e d ic a t io n o rd e r
Atropine sulfate
0.4 mg
Disp
#500 TT
Sig:
u.d.
2 . C a lc u la t i on s . F o r 5 0 0 TT: 5 0 0 × 0 . 4 m g = 20 0 m g a t r op i ne s u lf a te 3 . C o mp o u nd i ng p r oc ed u r e . Th e m o l d p r ep a re s 7 0 -m g t a bl e ts . Th e 2 00 m g o f a t r o pi ne s u l fa t e, 6. 8 g o f s uc r os e , a nd 28 g o f l ac t o se a re we i g he d a n d m ixe d b y g e om e t ri c d il u ti on . Th e po wd e r i s we t wi t h a m i xt u r e of 40 % p u ri f ie d wa t er a n d 6 0% e t h yl a lc o ho l (9 5% ) . Th e p as t e t h at is fo r m e d i s s p r e ad on t o t h e t ab l et t ri tu r a t e m o ld ; th e t a bl e ts a r e t h en p un c h e d o ut o f t he m o ld a nd al lo we d t o d r y o n th e pe gs . Th i s p ro c e d ur e i s re pe a te d un t il th e re q ui r ed num b e r o f t ab l et t ri t u ra t es h a s b ee n p r e pa r e d. P.111
D . F o r m ul a t io n a n d p r ep a r a t io n o f t a bl e t t ri t u ra t e s u s in g si n t e ri n g 1 . Th e se ta b le t t r i tu r a te s a r e m ad e i n s pe c i a l m o ld s c on s i s ti n g o f m a t e ri a ls t ha t c an t o l er a t e h ea t t o a b ou t 1 00 ° C . 2 . I n a dd i ti on t o t he m o ld , a d il u en t , u s u al l y a m ixt u r e o f ac t i v e d r ug an d d i lu e nt , wh i c h m a k e up ap p ro xi m a t e l y 6 5 % o f t h e t ab l et we i gh t , a r e b l en de d to ge th e r . Ma n n i t o l i s g oo d t o u s e in c o m b i na t io n wi t h l ac tos e fo r p a r ti c l e s i z es of 60 - 8 0 m es h f r a ct i on . 3 . Th e m i xt u r e is t r i tu r a te d wi t h p o l yet h yl en e g l yc o l 3 35 0 wi t h a p a r ti cl e s i z e o f 80 1 0 0 m es h f r ac t io n .
4 . Th e po wd e r m i xt u r e is p l ac ed in t o a pp r op r i at e m o ld s a nd li gh t l y ta m p e d. 5 . Th e m o ld s c o n ta i ni ng t h e p o wd e r a re pl ac ed in a n o v e n a t ab o ut 90 ° C fo r 1 0- 2 0 m i n, r em o v ed an d a l lo we d t o c oo l . D e pe n di ng on t h e m ol ds us e d, th e ta ble t s c an be d i sp e ns ed in th e m ol ds or r e m o v e d f r om th e m ol ds an d p a c k ag ed an d l a bel e d . E . E x am p le 6 . M e d ic a t io n o rd e r
Homatropine hydrobromide
300 mg
Mannitol
3.5 g
Lactose
3.47 g
Flavor (dry powder type), qs Polyethylene glycol 3350
3.5 g
7 . C a lc u la t i on s . As p r es e n t ed , th is fo r m u la is fo r 1 0 0 r a pi d -d is s o l v i ng ta bl e t t r i t u ra t es . 8 . C o mp o u nd i ng p r oc ed u r e . Bl e nd th e h om a t rop i ne h yd ro b r om id e , m a nn i t ol , l a ct os e , a nd d r y fl a v o r t og e t he r un t il fi ne an d un i fo r m l y m i xe d . Se p a ra t el y , r e d uc e t h e p a r ti c l e s i z e o f t h e po l y e t h y le n e g l yc o l 3 35 0 to 1 00 - 20 0 m es h f r ac t io n . L i gh t l y b l en d i n th e p ol y e t h y l ene g l yc o l 3 35 0 i n to th e p re v i o us l y bl e nd ed po wd e r s . Pl a ce 1 0 0 m g o f t h e p o wd e r i n to t he c a vi t ie s o f a m ol d (s om e b l is te r pa c k s wo r k we l l ; o t h e r wi s e , o b ta i n a ta bl et t r it u r at e m ol d o r a s pe c i a l m ol d f o r p r ep a ri n g t he s e t a b le ts ) . Pl ac e th e m ol d c o nt a in in g th e p o wd e r i n a n o v e n a t 80 - 90 ° C f or 1 5 - 20 m i n . Th e t im e de pe n ds o n th e m ol d , f o rm ul a ti o n, o v en , e t c . R em o v e f r om th e ov e n a nd p l ac e i n a r ef r ig e r at o r f or a p pr o xi m a te l y 5 m in . Re m o v e f r om th e re f ri g e rat o r an d l e t s e t a t ro om te m p e r at u r e. P a c k ag e a n d l ab e l.
IX. OINTMENTS, CREAMS, PASTES, AND GELS A. D e f i n i t i o ns 1 . O i n tm e n ts , c r e am s , a n d pa s te s a r e s em is ol id d os ag e f o rm s i n te nd e d f o r to pi ca l a p pl ic a ti o n t o t h e s k in o r m uc ou s m em b ra ne s . O in t m e nt s ar e c ha r ac t e ri ze d as b e in g o l ea g in ou s i n n a tur e ; c re a ms a re ge ne r a ll y o / w o r w/ o e m u ls io ns , an d pa s t es a r e c h ar a c t e ri z e d b y t h eir h ig h c o nt e nt of s o li d s (a b o ut 25 % ) . 2 . G e ls (s o m e ti m es c al l ed j el li es ) a re s em is o li d sy s t e m s c on si s ti n g o f su s p e ns i on s m a de up of ei t he r s m al l in o r ga n ic p a r ti c l es o r l arg e o rg an ic m o le cu l es i n t er p en e t ra t ed b y a li q ui d . B . G e n e r al ch a r ac t e r is ti c s . Th es e d os ag e f o rm s a r e s em is ol i d p re p a ra t ion s g e n er a ll y a pp li e d e xt e r na l l y . Se m i s o li d do s a ge fo r m s m a y c o n ta i n ac t i ve d r u gs i n t en de d to :
1 . A c t s o le l y on th e s u r fa c e o f t h e s k in t o p ro d uce a l oc a l e f fe c t ( e. g . , a nti f u ng al a g e nt ; to pi c a ls ) 2 . R el e as e t h e m e d ic at i on , wh i c h , in tu r n , p en e t ra t es in t o t h e s k in ( e. g . , h yd r o co r ti s on e c r ea m ) 3 . R el e as e m ed ic a ti on f or s y s te m i c a bs o rp t io n t h ro u g h t he s k i n (e . g ., ni t r og l y c e ri n ; t r a ns d er m al s ) C . T yp e s o f o in t me n t ba s e s 1 . H yd r op h ob ic ba s e s f ee l gr e as y a nd c o nt a in m ixt u r e s o f f a ts , o i ls , a nd wa xe s . H yd r o p h ob ic ba s e s c a n no t be wa s h ed of f u s i n g w a t e r . P.112
2 . H yd r op h il ic ba s e s a r e u s ua ll y e m u ls i on ba se s . Th e o / w- t y p e em u ls io n ba s es c a n b e ea si l y wa s he d o f f wi th wa t e r , bu t t h e w/ o t y p e i s s li gh t l y m o re di f fi c ul t t o r em o v e . D . P r e p a ra t i on o f o i n tme n t s , c r ea m s, p as t es , an d g el s 1 . Mi xi n g c a n b e d on e i n a m o r ta r o r o n a n o in tm e n t s la b o r ti l e o r u s i n g a n oi n tm en t m i ll . 2 . Li q ui ds a re in c o r po r a te d b y g r a du al l y ad d in g th e m t o a n a bs o rp t io n - t y pe b as e a nd m i xi n g . 3 . I ns ol ub l e p o wd e rs a re r e d uc ed to a f in e po wd er a n d t he n a d de d t o th e b a s e , u s in g g e om et r ic di lu t io n . 4 . W at e r -s ol u bl e s ub s t a nc es a re di s s ol ve d wi t h wa t e r a n d t he n i nc o r po r ate d in t o t he b a se . 5 . Th e fi na l p r e pa r a ti on s h ou l d b e s m oo t h ( im p alp a bl e ) a n d f r ee of an y ab r a si ve p a r ti c l e s . E . E x am p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Sulfur Salicylic acid, aa
600 mg
White petrolatum, ad
30 g
Sig:
Apply t.i.d.
b . C o mp o u nd i n g p r o ced u r e . Th e p a rt ic l e s i z e s o f t he s u lf u r a nd s a li c y lic ac id a re r e d uc ed s e p ar a te l y in a W edg wo o d m o r t a r a nd the n bl en d ed t og e th e r. U s in g a p il l t i l e, th e p o wd e r m i xt u r e is le v i g at e d wi t h t he ba s e. U s in g g e om et r ic di lu t ion , t he
b a se an d p o wd e r s a r e b le n d ed to th e fi na l we i gh t. A n o i nt m e n t j a r o r p l as ti c tu be is u s ed fo r di s p e ns in g , a nd a n “e xt e r n a l u s e on l y” la b el is pl ac e d o n t he c on t a in e r . c . Al t e r n a te me t h od . Sup p os e y ou ha v e s u l fu r 5% i n wh i t e p e t ro l at um oin t m e n t a nd a sa l ic y l ic a c i d 5 % o i nt m e n t . How c an yo u p r e p a r e t h e p r e sc r i p ti o n u s in g t he s e a n d di l u ti n g w i th w h i te p e t r o la t u m?
H o we ve r , s i nc e we a r e us i ng t wo di f f er e n t 5 % oi nt m en t s, 2 p a rt s o f e ac h , t h is l e a ves 1 p a rt f or t he wh i te p et r o la t um . A t ot al o f 5 p a r ts i s t o b e u se d to m a k e 3 0 g ( 6 g p e r p a rt ) : 2 p ar t s ( 12 g ) o f th e s ul f u r 5% , 2 pa r t s ( 1 2 g ) o f th e s al ic y l ic ac id 5% , a n d 1 pa r t (6 g ) o f t he wh i t e p et r ol a t um c ou l d b e u s ed . To c h ec k :
12 g × 0.05
=
600 mg of sulfur
12 g × 0.05
=
600 mg of salicylic acid
12 g + 12 g + 6 g
=
30 g
2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Methylparaben
0.25 g
Propylparaben
0.15 g
Sodium lauryl sulfate
10 g
Propylene glycol
120 g
Stearyl alcohol
250 g
White petrolatum
250 g
Purified water
370 g
Disp
60 g
Sig:
Apply u.d.
P.113
b . C a lc u la t i o ns . Th e q ua n t it y o f e ac h i n gr e di e nt r e q ui r e d t o p r ep a re 60 g i s o b t ai ne d as f o ll o ws . Th e m ed ic a ti o n o r de r i s f o r 1 0 0 0 g ; t he r e fo r e , t he m u l t ip li c a t io n f a c to r i s 6 0 /1 0 00 = 0 .0 6 .
0.25 g × 0.06
=
0.15 g methylparaben
0.15 g × 0.06
=
0.009 g propylparaben
10 g × 0.06
=
0.6 g sodium lauryl sulfate
120 g × 0.06
=
7.2 g propylene glycol
250 g × 0.06
=
15 g stearyl alcohol
250 g × 0.06
=
15 g white petrolatum
370 g × 0.06
=
22.2 g purified water
S i n ce th e 0 . 00 9 g o f p rop y l p a ra b en is to o sm a ll to ac c u r a te l y we i g h, a d ilu t i on c a n b e p re pa r e d as f ol lo ws , a s s u m i ng a m i n im um we ig h a bl e q ua n ti t y o f 1 20 m g . W ei gh 1 2 0 m g o f p r op y l p a ra be n a n d a dd to 40 m L of p rop yl e n e gl yc o l, r es ul t in g in a p r o p ylp a r ab en c o nc e nt r at i o n o f 3 m g /m L. Ta k e 3 m L o f th is s o lu t io n t o o b ta i n t h e p r o p ylp a r ab en an d s u bt ra c t t h e 3 m L f r om th e q ua n t it y o f p r op yl e ne gl yc ol r eq u i re d i n th e f o rm u la . c . C om p o un d i ng p r oc ed u r e . Th e s te a r y l a lc oh ol a nd th e wh i te pe t r ol a tum a re m e lt e d o n a s t ea m b at h a n d h e at e d t o a bo u t 7 5 °C . Th e o th e r i ng r e di en t s , p r e v i ou sl y d i ss ol ve d i n p u ri f ie d wa te r a t a bo u t 7 8 ° C, a re add e d . Th e m i xt u r e is s t i r re d un t il it c o ng e al s . A n o in tm e nt jar i s us e d f o r d is pe ns i ng , a n d a n “e xt e r n a l u se on ly ” l a b el i s p l ac e d o n t he ja r . 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Scopolamine hydrobromide
0.25%
Soy lecithin
12 g
Isopropyl palmitate
12 g
Pluronic F-127 20% gel, qs
100 mL
Sig:
Apply 0.1 mL t.i.d.
b . C a lc u la t i o ns . Th e q ua n t it y o f s co po l am in e h y d r o b ro m i d e r eq u i re d f o r th e p r e sc ri p ti o n wi l l be 0 . 0 02 5 × 10 0 m L = 0. 2 5 g o r 2 5 0 m g
c . C om p o un d i ng p r oc ed u r e . Mi x t h e s o y l e ci th in wi t h t he is op r op y l pa lm i t a te . D i s so l v e t h e s c op o la m i ne h y d r ob r om id e i n a b ou t 3 m L o f p ur i fi e d wa t e r and a dd to a b o ut 70 m L o f th e Pl u ron i c F - 12 7 g e l. A dd th e so y l ec i th i n -i s o p ro p yl p a lm i ta t e m i xt u r e , a n d m i x we l l . Ad d s u f fi c i en t Pl u r on ic F -1 2 7 g el t o v o l um e, an d m i x we l l u s in g a s h ea r in g te c h ni qu e . Pa c k ag e a n d l ab e l.
X. SUPPOSITORIES A. G e n e r a l ch a r ac t e r is ti c s 1 . S up p os it o ri e s a re s ol id b o di e s o f v a ri ou s we i gh t s a nd sh a pe s , ad a pt e d f o r i n t ro d uc t io n i n to th e re c ta l , v ag i na l , o r u r e th r al o ri f ic es o f t he hu m a n b o d y. Th e y a r e u s ed to de l i v e r d ru g s f o r t h ei r lo ca l o r s ys t em ic ef f e ct s. 2 . S up p os it o ri e s di f f e r i n s i z e an d s h ap e a n d i nc lu d e a . R ec t al b . V ag i na l c . U r et h ra l B . C o m mo n s u p po s i to r y b a s e s 1 . C o co a b u t t e r ( t he o b ro m a o il ) , wh ic h m el t s a t b o d y te m p e r at u r e, is a fa t - s o l ub le m i xt u r e of t ri g l yc e r id es th a t i s m os t o f te n u s e d f or r e c t a l s u p po si t o ri es . W i t e ps ol is a s yn th e ti c t r ig l y c e r id e . F a t t y ac id ba se s i nc lu d e F a t ti b as e . 2 . P o l ye t h yl e n e g l yc o l ( P E G , c a rb o wa x) d e r i v a t iv e s a re wa t e r -s o lu b le bas es s u it a bl e f o r v ag i na l a nd re c ta l s up p os it o r ie s . P ol y b a s e is a n e xa m p l e . 3 . G l yc e r i n a t e d g el a t in i s a wa t e r -m is ci b le ba se o f t en us ed in v a gi n al and r ec t al s u pp os i to r ie s . P.114
C . S u p po s i to r y m o l d s 1 . S up p os it o r y m o ld s c an b e m a d e o f r u bb e r , p las t ic , b r as s , s t a in le s s s t ee l , o r ot h e r s u it a bl e m at e r ia l. 2 . Th e fo r m u la t io n a n d v o l um e o f th e b as e d e pe nd o n t he s i z e of t he m o ld u se d , l e ss th e d is pl ac e m e n t c au s ed b y th e a c t i ve i n g red i e n t . D . M e th o ds o f p r e pa r i ng a n d d is p e ns i ng s up po s i t o r ie s 1 . M o l de d su p po s i to r i es a r e p re p a re d b y f i rs t m e l t in g t h e b as e a nd th e n i n co r po r a ti n g t he m e di c at i o ns u n if o rm l y in t o t he ba s e. Th i s m i xt u r e is t he n p o u re d i n t o t he s u pp os i to r y m old ( f us io n m et h od ) . 2 . H a nd - r o l le d s u p po s i to r i e s re qu i r e a s pe ci a l te c hn i qu e . W ith p r o pe r tec h ni q ue , i t i s p os si b le to m a k e a p re p a ra t io n e q ua l i n q u al ity t o t he m o ld e d su p po s i to r i es . 3 . C o n ta i ne r s fo r t h e su p p o si t o r ie s a r e d e te r m i n ed b y th e m e th od a nd b a se us ed i n pr e pa r a ti o n. H an d - ro l le d an d m ol d ed s u pp os i tor i e s sh o ul d b e d is pe n se d i n s p ec ia l b o xe s t ha t p r e v en t t he s u pp os i to r ie s f r om c om in g i n c on t ac t wi t h ea c h o th e r . S u p po si t o ri es m a de us ing p la s t ic st r ip m o ld s a r e e a s i l y di s p e ns ed in v a ri ou s t y pe s o f pa ck a ge s . 4 . S t o ra g e c o nd i t i on s . If a pp r o pr i at e , a “ re f r ig e ra t e ” l a be l s ho ul d a p pe a r o n th e c o nt a in e r . R e ga r dl es s o f t h e b as e o r m e di c a t io n u s ed in th e fo rm u la t io n , t h e p a ti e nt s h ou l d b e i ns t ru c t e d t o s t o r e t h e su p po s i t o ri es in a co o l, d r y p l ac e .
E . E x am p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Naproxen suppository
500 mg
Disp
#12
Sig:
Insert u.d. into rectum
b . C a lc u la t i o ns . Ea c h s ta n d ar d a d ul t s up p os it o r y s ho u ld we i g h 2 g , bu t i t d e p en ds o n th e m ol d u s e d a n d s ho u ld be c a li b r at e d b ef o re c o m p o un d in g . A ls o , t he d i sp la c em en t m us t b e d et e r m i n ed fo r th e a d de d po wd e r . 2 g (t o ta l we i gh t ) - 0 .5 4 0 g ( we i g ht of b as e d is pl ac e d b y t he 50 0 -m g t a bl e t) p e r s u pp os i to r y
=
1.46 g cocoa butter per suppository × 13 suppositories
=
18.98 g cocoa butter
c . C om p o un d i ng p r oc ed u r e . Th e 1 3 n ap r o xe n 50 0 - m g ta b le ts a re t ri t u ra te d to a f i n e p o wd e r , us i ng a W ed g wo o d o r p or ce l ai n m o rt a r . Th e 1 8 .9 8 g c oc o a bu t t e r b as e i s m el t ed in a b ea k e r , u s i n g a wa t e r b a th . Th e t em p e ra t ur e o f th e wa t e r ba t h s ho u ld n o t e xc e e d 36 ° C . Th e p owd e r i s th en ad d ed an d s t i r re d u n ti l m i xe d . Th e m i xt u r e is p o u re d i n to an ap p r op r iat e r ec ta l s up p os i to r y m o ld ( a bo u t 2 g pe r s u pp os it o r y) a nd p l ac e d in t o a r ef r ig e r at o r u n ti l t h e s up po si t o ri es c o n g ea l. A n y e xc e s s i s s c r a p ed f r o m t he t op of t he m o ld , a n d a s up p os it o r y bo x i s us ed f o r di s pe ns in g . A “ r e f r ig e ra t e ” l ab e l is pl ac e d on th e b o x. 2 . E xa m pl e 2
a . M e d ic a t io n o rd e r
Progesterone
50 mg
Disp
#14
Sig:
1 per vagina once daily on days 14-28 of cycle
b . C a lc u la t i o ns . To ta l we i gh t of ea c h v a gi n al s up p os i to r y is 1. 9 g. As s um i ng 50 m g p r o ge s te r on e d is p la c e s 5 0 m g P E G b as e : 5 0 m g p r o ge s t e r on e /s upp o s i t o r y × 15 = 7 5 0 m g pr o g es t er o ne 1 . 9 g ( to t al we i g ht ) - 0 . 05 0 g p r og es t e ro ne = 1 .8 5 g P E G × 1 5 s up po s it o ri e s = 2 7. 7 5 g P E G to t al P.115
c . C om p o un d i ng p r oc ed u r e . Th e P E G is m e lt e d t o 55 - 57 ° C , a n d 7 50 m g p r o ge s te r on e i s a dd e d. Th i s m i xt u r e is po u re d i nt o a v ag in a l su p po s i t o r y m o ld , a l lo we d t o c oo l , c l e an e d, a n d d is pe ns e d.
XI. PARENTERAL PREPARATIONS A. G e n e r a l r e qu i r em e n ts . Th e e xt e m p o r an eo us c om p ou n di ng o f s te r il e pr e p a ra t io ns o cc u rs in m a n y ph a rm ac y e n v i r o nm en ts , in cl ud i ng co m m un i t y, h om e h e al th c a re , h o sp i ta l , a nd nu c l e ar . Mi n i m u m r e qu i re m e n ts i n c lu d e 1 . P r op e r e qu i pm en t a n d s up p li es 2 . P r op e r f ac il i ti es , in c l ud i ng a l am in a r - fl o w c le an b en c h an d a cl ea n ro om o r i s ol a ti on ba r r ie r t ec hn ol og y e q ui pm e nt 3 . P r op e r d oc um e nt a ti on o f al l p r ep a ra t io ns m a de 4 . Q u al i t y c on t r ol , i nc l udi n g b a tc h s te r il i t y te s t i ng 5 . P r op e r s to r ag e bo t h at t h e f ac il i t y a n d i n t r an sp o r t t o th e p a ti en t ' s h om e 6 . P r op e r l ab e li ng o f t he p r e s c ri p ti o n p r ep a ra t io n 7 . K no wl e d g e o f p r od uc t 's / p re p ar a ti o n 's s t a bi li t y a n d i nc om p at i bi li t ie s 8 . K no wl e d g e o f a ll an c i ll a r y e qu ip m e n t i n v ol ve d in c o m p o un d in g o r de li v er y o f t he m e di ca t io ns B . C o m po u n di n g o f pa r e n t e r al p r ep a r a ti o ns
1 . C om p ou nd i ng of s t e ri le p r ep a ra t io ns , i nc l ud i ng i n t ra v e n ou s a dm i xt u r es , r e q ui r es s p ec ia l s k i ll s a nd t ra i ni ng . C om p ou nd i ng pa r en t er a l p r e pa r a ti on s o r p r o v id i ng t hi s s e r vic e wi t ho u t p r op e r t ra i ni n g sh o ul d n o t b e a t tem p te d . 2 . Th e se pr e pa r a ti on s m u s t b e c om po u nd ed in a c l ea n e n vi ro nm e nt , us ing as e pt ic t e ch n iq u e ( i .e . , wo r k i ng u n d er c o n t ro ll e d co n di t ion s to m i ni m i ze c o nt am i na t i on ) . 3 . D r y p o wd e rs of pa r e nte r a l d r ug s f o r r ec o ns ti t u ti o n a r e u se d f o r d r ug p rod u ct s o r p r e pa r a ti o ns t h at a re uns t ab l e as so lu t io ns . I t is i m po r t an t t o k no w t h e cor r e c t d i lu e nt s t h at c a n b e u s ed t o y ie ld a s ol u ti on . 4 . S ol u ti o ns o f d r u gs fo r p a r en t e ra l a dm i ni st r a ti on m a y al so be fu r t he r di lut e d b e fo r e a d m i ni s t ra ti o n . I f f u r th e r d i lu t io n i s r e qu i re d , t h en t h e p ha r m a c i s t m u st k no w t h e s t ab i li t y an d c om pa t ib i li ty o f t he d ru g i n t h e d il uen t . C . R e c on s t i tu t i on o f a d r y p o w de r f r o m a vi al 1 . W or k t ak es pl ac e i n a c l ea n -a i r e n v i ro nm e nt , ob s e r v in g a se p ti c t ec hn i qu e . 2 . Th e m a nu f ac tu r e r 's ins t r uc ti o ns s h ou ld be ch ec ke d to de t e rm in e t h e r eq u i re d vo l u m e of di l ue n t. 3 . Th e ap p ro p ri a te ne e dle s i z e an d s yr i ng e a r e c h o s e n , k ee pi n g i n m i n d th a t th e c a pa ci t y o f t he s y ri n ge s h o ul d b e s li g ht l y la r g e r th a n t h e v o l um e r e qu i re d f o r r e c on s t i tu t io n . 4 . U si ng t he c o r re c t d il ue n t , t h e s u r f ac e o f t h e c o n t ai ne r is c l ea ne d , u si ng a n a l co h ol p r e p p ad , a f t er wh i c h th e a lc o ho l i s p e rm it t e d t o e v a p o ra t e. 5 . Th e s y r i ng e i s f i ll ed wi t h t h e d il u en t t o th e p r op e r vo lu m e . 6 . Th e s u r fa c e of t he v i al c o n ta i ni ng t he s t e ri le po wd e r i s cl e an e d, us in g a n al co h ol p r e p p ad , af t e r wh i c h i t is pe r m i t te d to d r y . Th e di l ue n t i s i nj ec t ed in t o t he v i a l c o nt a in in g th e d r y p o wde r . 7 . Th e v i al i s g e nt l y s h ak e n o r ro ll e d, an d th e p owd e r i s a l lo we d t o d is s o lve . 8 . A f te r th e p o wd e r ha s d i s s ol v e d , t he vi al is in v e r t e d a nd th e d es i r ed v ol u m e is wi t h d r a wn . 9 . Th e v e hi c l e i s p re p a red b y s wa b bi ng t he m e di c a t i on po r t o f th e b ag o r bo t t le wi t h a n al co h ol pr e p p ad . P.116
1 0 . Th e s ol u ti on in t he s y r i n g e i s i nj ec t ed in t o t he v e h ic le . If a p la s t ic c on t a in e r i s u s ed , c a re m u s t be t ak en n ot t o p un ct u r e t he s i de wa l l s o f t h e co n ta i ne r wi t h t h e t i p o f t he ne ed l e. 1 1 . Th e c on t ai ne r s h ou l d b e s ha k en or k n ea d ed or r o t at e d t o e ns u re th o r ou g h m i xi n g of t he c o nt e nt s . 1 2 . Th e c on t en ts o f t he c o n t ai ne r s h ou l d b e c h e ck e d f o r p a rt ic u la t e m a t t er . 1 3 . A s te r il e s ea l o r c a p i s a p pl ie d o ve r t he po r t o f t he c o nt a in e r. 1 4 . Al l n e ed le s a nd s y r ing e s s h o ul d b e p r o pe r l y di s c a r de d . 1 5 . Th e b ag is la be l ed . D . R e m o vi n g t h e f l ui d co n t e n ts f r om an am p u le 1 . Th e am pu le is he ld upr i g ht t o o pe n i t , a nd t he to p is ta pp e d t o r e m o v e an y s o lu t io n t r a pp ed in t hi s ar e a . 2 . Th e ne c k o f th e a m p u le is s wa b be d wi t h a n a lco h ol s wa b .
3 . Th e am pu le is gr as p ed o n e ac h s i d e o f t h e n ec k wi t h t he t hu m b an d i nd e x f i n g e r o f ea ch ha n d a nd qu ic k l y s na p pe d o p en . 4 . A 5 - µ m f i lt e r n e ed le is a t t ac he d t o a s y ri n ge of t h e a pp r o pr i at e s i ze . 5 . Th e am pu le is ti l te d , an d th e n e ed l e is in s e r t ed. 6 . Th e ne ed l e is po s i t io ne d ne a r t h e n ec k o f t he a m pu l e, an d t h e s o l ut i on i s wi t h d r a wn f r om t he am pu l e . 7 . I f t he s o lu t io n i s f o r an i nt r a v e no us pu s h ( bo lus in j ec ti o n ), th e fi lt e r n ee d le is r e m o ved f ro m t he s y r in ge a nd r ep la c e d wi t h a c ap . 8 . I f t he s o lu t io n i s f o r an i nt r a v e no us in f us io n , th e n t h e f il t e r n ee dl e i s re m o ved an d r e p la ce d wi t h a ne w n e ed l e o f t h e a pp r o pr i at e s iz e . Th e d ru g i s i nj ec t ed in t o th e a p p ro p r ia t e v e h ic le . 9 . A ll m a te r i al s s h o ul d be d is c a r de d p r op e r l y , a nd t h e fi n al p ro d uc t o r p r ep a r a ti on s h ou l d b e l ab el e d. E . R e m o vi ng d r ug s ol u ti o n f r om a vi a l 1 . Th e ta b a r ou n d t he r ub b e r c lo s u r e o n t h e v i a l is r em o v ed , an d t h is s u rfa c e is s wa b b e d wi t h an al c oh ol p r e p p ad . 2 . A n e qu i v a le n t am o un t o f s t e ri l e a i r is in je c te d in t o th e v ia l t o p r e v e nt a n e g at i ve va c u um f ro m b ei ng c r e a te d an d t o a l lo w t h e d r u g t o be r em o ved . 3 . U si ng t he ap p ro p r ia t e n e e dl e si ze a nd s y r i n ge , t h e n ee d le is i ns e r te d i nt o t he r u b be r c l os u re . 4 . Th e pl un g e r is pu s h e d d o wn , a nd ai r i s r e le as ed i n t o t h e via l; wh e n th e p l un g e r is p u ll e d b ac k , th e s ol u ti o n i s wi t hd r a wn . 5 . Th e s o lu ti o n i s t he n i nj e c t e d i nt o th e a pp r o pr i at e v e hi cl e . F . E xa m p le s 1 . E xa m pl e 1 a . M e d ic a t io n o rd e r
Progesterone
5g
Benzyl alcohol
10 mL
Sesame oil, qs
100 mL
b . C o mp o u nd i n g p r o ced u r e . Di ss ol v e t he p ro ges t e ro n e i n t he be n zy l al c o h ol . A dd s u f fi ci en t s es am e o i l t o m ak e 1 0 0 m L. S te r il i z e by f i l t ra t io n t h r ou g h a s te ri l e 0 . 2- µ m f i l te r or b y d r y h e at ( 17 0° C f o r 1 . 5 h r ) . P ac k ag e in s te r il e via ls an d l a be l. 2 . E xa m pl e 2 a . M e d ic a t io n o rd e r
Fentanyl (as the citrate)
2 mg
Bupivacaine hydrochloride
125 mg
0.9% sodium chloride injection, qs
100 mL
P.117
b . C a lc u la t i o ns . Si nc e 15 7 µ g f e nt a n y l ci t r at e i s e q ui v a l en t to 10 0 µg f en ta n yl , th e q u a nt i t y o f fe n ta n y l c it r at e r eq u ir e d is ( 15 7 /1 0 0 ) × 2 m g = 3 .1 4 m g f en t any l c i tr a te . Th i s is th e q u an t it y o f f en t a n y l ci t r at e th a t wo u l d b e r eq ui r e d i f c o m p o un d in g as a h i gh - r is k p r ep a ra t io n f r om bu lk po wd e r s . I t wo u ld a ls o re q ui r e 1 25 m g b u pi va c ai n e, a n d t h e r em a in de r is th e 0 . 9% s o di um c h lo r i de inj e c t i on . Ho we v e r , c om m e r c ia l p r o du c ts a r e a v a i la bl e s o we c a n c a lc u la t e h o w m uc h o f ea ch m i gh t b e re q ui r e d u s in g f e nt a n y l 5 0 µ g /m L i n je c ti on an d b u pi va c a i ne h y d r oc hl o ri d e 0 .5 % i n je c ti o n.
B u p i vac ai n e h y d r oc hl o rid e 0. 5 % i nj ec t io n c on t ain s 5 0 0 m g / 1 00 m L ; t he r ef o r e ,
I f 4 0 m L of f en t an y l in je c t i o n is us ed , an d 2 5 m L o f bu p i vac ai n e h yd r oc hl or i d e i n je c ti on is us ed , th en 40 + 2 5 = 6 5 m L ; th e q u an t i t y of 0. 9 % s o d iu m c hlo r i de i n je c ti on r eq u ir e d is 1 00 m L - 6 5 m L = 3 5 m L . N o te : I f t h e o r d e r i s to b e fi l l e d i n a 2 0 - m L pu m p w it h de l i ver y f o r 3 0 d a ys , w h a t i s t h e de l i ve r y r a t e i n µ L/h r ?
c . C om p o un d i ng p r oc ed u r e . Us in g c om m e r ci al ly a va i l ab le in j ec ti o ns , a c c u r at e l y m e as u re th e v ol um e o f ea c h a nd fi l l i nt o a s t e ri l e a m b u la t o r y p um p re s e r vo i r . An ai r b u b bl e c an be in je c te d an d us ed to t ho r ou g hl y m ix t h e s o lu t io n . R em o v e th e ai r f ro m t h e re se r v o i r , a nd ti g ht l y s ea l /c lo s e t he ou t le t . L ab e l . 3 . E xa m pl e 3 a . M e d ic a t io n o rd e r
Morphine sulfate
5g
Citric acid
100 mg
Sodium chloride, qs to isotonic Methylparaben
150 mg
Sterile water for injection, qs
100 mL
b . C a lc u la t i o ns . Us in g a s od i um c hl o r id e e qu i va le n t o f 0. 0 9 f o r a 5 % m o rp h in e s u lf a te s o lu t io n , 0 . 18 fo r c i tr ic ac id , 1 f o r s o d iu m c h lo r id e , a nd ig n o ri ng t he m e th y l p a ra be n , t h e c a lc u l a ti on s c an be m a de as f o ll o ws : 5 g m o rp h in e s ul f at e i s eq u i v al e nt t o 4 50 m g s o diu m c hl o r id e ( 5 g × 0 . 09 = 4 50 m g ) . 1 0 0 m g ci t r ic a c i d i s e q ui v a l en t to 18 m g s o di um c h lo r id e (1 0 0 m g × 0 . 18 = 1 8 ) 4 5 0 m g + 18 m g = 46 8 m g To b e is o to ni c , t he s o lu t io n ne e ds t h e e qu i v a le n t o f 90 0 m g o f s od i um c hlo r i de in t h e 1 0 0 m L : 90 0 m g - 468 m g = 4 3 2 m g s o di um c h l o ri d e n ee ds to be ad d ed . c . C om p o un d i ng p r oc ed u r e . Di ss ol v e t he m e thy l p a r ab e n i n a bo u t 9 0 m L o f s te r i l e wa t e r f o r i n je c t i on . A s m a l l a m o un t of he a t m a y be r e qu i re d . C o ol th e s o lut i o n t o r o o m t em pe r a tu r e ; t he n a d d t h e m o r p hi ne s u l fa t e, c it r ic ac id , a n d s o d iu m c h lo r id e . A d d s u f fi c i en t s t e ri le wa t e r f o r i nj ec t io n t o v ol um e a n d m i x we l l . S te r il i ze by f i l t ra t io n t h ro u gh a s te r ile 0 .2 - µ m f i lt e r i n to a s t er i l e vi a l o r re s e r v o i r. P ac k a ge an d l a be l . 4 . E xa m pl e 4 a . M e d ic a t io n o rd e r
Mefoxitin Diluent to final concentration of 125 mg/mL
P.118
1g
b . C a lc u la t i o ns . A 1 - g v i a l o f Me f o xi n ( c e f o xi t i n fo r in j ec ti o n ) is r ec on s ti tut e d wi t h 1 0 m L o f di lu e nt t o p ro v id e fo r ap p ro xi m a t e wi t hdr a wa l o f 1 0 .5 m L an d a n a p p ro xi m a t e a v e r ag e c on c en t r at i on of 95 m g /m L . W h a t q u an t i t y o f d i l u en t s ho u l d b e ad d e d t o p r o vi d e a n a p p r ox i ma t e a ve r a g e co n c en t r a t io n o f 1 25 m g /m L ?
c . C om p o un d i ng p r oc ed u r e . As ep t ic al l y , wi t h dra w 7 . 5 m L of di l ue n t a nd i n je c t in t o t h e via l t o be re c o n s t i tu te d , u s i n g a n a pp r op r i at e v e n t ed ne e dl e . G e n tl y s wi r l u n ti l d i ss ol ve d . P.119
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 3 : E ac h q ue s ti on o r in c om pl e te s t a te m e n t i n th i s s ec t io n c a n b e c o r r ec t l y a n s we r e d o r c om pl e te d b y o n e o f th e s ug g es te d a n s we r s o r p h r as es . Ch o os e t h e b es t a ns we r . Th e fo ll o wi n g m ed ic a ti o n o r de r i s g i v en t o t h e p h a rm ac is t b y t h e p h ys ic i a n .
Olive oil
60.0 mL
Vitamin A
60,000 units
Water
120.0 mL
Sig:
15 mL t.i.d.
1 . T he f in a l d o sa g e f o rm o f th i s p r e sc r i p t io n w i l l b e ( A ) a s o lu ti o n. ( B ) a n e li xi r . ( C ) a n e m u ls i on . ( D ) a s us p en s i o n. ( E ) a l o ti o n. V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . W h en pr e p a r i ng t h is p re s c r ip t io n , t h e ph a r ma c is t ne e ds to a d d ( A ) Twe e n 8 0 . ( B ) a ca c i a . ( C ) g l yc e r in .
( D ) a lc o ho l. ( E ) p r op y l e ne gl y c ol . V i e w A n s we r 2 . T h e a n sw e r i s B [ se e] . 3 . W h ic h o f t h e f o l low i n g c a ut i on l a b e ls sh o ul d t he ph a rm a c is t af f i x t o th e co n ta i n e r w he n d i s pe n si n g t h i s p r e p a r at i o n? ( A ) D o no t re f ri g e ra t e. ( B ) S h ak e we ll . ( C ) F o r e xt e r n a l u s e on l y. ( D ) N o p re s e r v a t i v es a dd e d . V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . F o r 1 - 3 : Di r e c t i on s fo r q ue s t io n s 4 - 9 : E a c h q ue s t i on o r s ta t em e n t i n t h is s ec t io n c an be c o r r ec t l y a ns we r e d o r c om p le t ed b y o n e o r m o re of t he s u g g es te d a ns we r s o r p h ra s es . Ch o os e t he co r r ec t a ns we r , A-E: 4 . W hi c h s t a te me n t s a bo u t t he f o ll ow i ng p r es cr i p t i o n a r e c o r r ec t ?
Morphine
1 mg/mL
Flavored vehicle, qs ad
120 mL
Sig:
5-20 mg p.o. q 3-4 hours prn pain
I . T he am o u nt o f m o r p hi n e ne e de d i s 24 0 m g . I I . P ow de r e d m o r ph i n e a l k al o i d s ho u l d b e u s ed w h e n c o mp o u nd i ng th i s p r e s c r ip t i on . I I I . Th e fi n al d os a ge f o rm o f th i s p r e sc r i p t io n is a s o l u ti o n . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 . T h e a n sw e r i s B [ se e] . 5 . W h en pr e p a r i ng t he f o ll ow i n g p r e s c r ip t i on , t he ph a r ma c i s t s ho u l d
Podophyllum
5%
Salicylic acid
10%
Acetone
20%
Flexible collodion, ad
30 mL
Sig:
Apply q h.s.
I . t r i t u ra t e 1 . 5 g of p odo p h yl l u m w i t h th e 8 m L o f ac e t on e . I I . ad d 3 g o f sa l ic yl i c a c i d t o t h e c ol l o di o n w i th t r i t u r a ti o n. I I I . a f f i x a n “ ex t e r na l us e on l y” l a b e l t o th e c on t a i ne r . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 5 . T h e a n sw e r i s B [ se e] . P . 12 0
6 . W hi c h s t a te me n t s a bo u t t he f o ll ow i ng p r es cr i p t i o n a r e c o r r ec t ?
Sulfur
6g
Purified water Camphor water, aa qs ad
60
I . P r e ci p i ta t e d s ul f u r can b e u s ed t o p r e pa r e thi s p r es c r ip t i o n. I I . Th e su l f u r c an b e t r it u r a t e d w i t h gl yc e r i n be f o r e m i x in g w i th o th e r i n g r e di e n ts . I I I . A “ sh a ke w e ll ” l a be l s h o ul d be af f i xe d t o t he b o t tl e . A i f I o n l y i s c o r re c t
B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 6 . T h e a n sw e r i s E [s e ea n d] . 7 . W h ic h s ta t em e n ts ab o u t t he f o l l ow i ng p r es c r ip t i o n a r e co r r e c t ?
Starch
10%
Menthol
1%
Camphor
2%
Calamine, qs ad
120
I . T he p ow de r s s h o ul d b e b le n de d to g e th e r in a m o r ta r , us i n g g eo m e tr i c d i l u t io n . I I . Th e p re s c ri p t i on sh ou l d be p r ep a r ed b y d i s s o l vi n g th e c a mp h o r i n a s u f f i ci e n t a mo u n t o f 9 0% a l c o h o l . I I I . A e u t ec t ic m ix t u r e sh o u l d b e a vo i d ed . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 7 . T h e a n sw e r i s A [ se e] . 8 . W h en pr e p a r i ng t he f o ll ow i n g p r e s c r ip t i on , t he ph a r ma c i s t s ho u l d
Salicylic acid
3g
Sulfur ppt
7g
Lanolin
10 g
White petrolatum
10 g
I . r e du c e t h e p a r t ic l e s iz e of t he p ow de r s , u s ing a m o r t a r a n d p e st l e or u s i ng t h e p il l ti l e w it h a s pa tu l a . I I . p la ce o n a n o i n tm e nt t i l e a n d l e vi g at e th e ing r e d i en t s , u si n g g e om et r i c d i l u t io n . I I I . pa ck a ge t he o in t m en t i n a n o i n tm e n t j a r o r t u b e . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 8 . T h e a n sw e r i s E [s e ea n d] . 9 . An e q u al vo l u me o f a i r i s i n j e ct e d w he n re m o vi ng d r u g s o lu t i o ns f r om I . vi a l s. I I . am p ul e s . I I I . s yr i n g e s . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 9 . T h e a n sw e r i s A [ se e] . P . 12 1
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C [ s ee V . B . 1 .] . 2 . T he an sw e r is B [ s ee V . B . 2 ; V . C .1 ] . 3 . T he an sw e r is B [ s ee V . B . 3 ]. F o r 1 -3 : B e c au s e ol i v e oi l an d wa t e r a re t wo im m i sc i bl e l iq u id s, t he i r i nc or p o r at i on r e q ui r es a t wo - p h as e s ys t em in wh i c h on e l iq u id i s d is p e rs ed th r o ug ho u t a n o th e r l i qu i d i n t he f or m o f s m a ll d ro p le t s . To ac c o m p li s h t hi s , a n em u ls if yi n g a ge n t i s
n e ce ss a r y . Ac ac ia is th e m os t s ui t ab l e em u ls if yi ng a ge n t wh e n f or m i n g a n o i l- i n wa t e r e m u ls i on th a t i s i nt e n de d f o r i n te r na l u se . E m u ls io ns a re ph y s ic al l y u ns t ab l e, an d th e y m us t b e p r o te c t e d a ga i ns t t he e f fe ct s o f m ic r o bi al c o n ta m i na t io n a n d p h ys i ca l s ep a r at i on . S h ak i ng be f o re us e r e dis t r ib u te s t h e t wo la y e r s o f e m u ls ion . B ec au se li g ht , ai r , a nd m i c ro o rg a ni sm s a ls o af f e c t th e s t ab i li t y o f a n em u ls io n , p r e s e r va ti ve s c an be add e d . 4 . T he an sw e r is B (I I I ) [ s ee I II . A . C .3 ] . Th e c on c e n t ra t io n o f m or p h in e n e ed e d f o r t he p re s c r i pt i on de s c r ib ed in th e qu es t io n i s 1 m g /m L , a nd be c a us e 1 2 0 m L is th e f i na l v ol um e , 1 20 m g of m o r ph i ne i s n e ed e d t o co m p ou n d t hi s p r es c rip t i on . Mo r p h in e a lk al o id h a s p oo r s o lu bi l it y; t he r ef o r e , o ne o f t he s a lt fo r m s s h ou ld b e us ed . Be ca u s e m o rp hi n e i s d iss o l v ed in th e v eh i cl e , r e s ul ti n g i n a l i qu i d p re pa r a ti o n , t he fi n al do s a g e f o rm is a s o l ut i on . 5 . T he an sw e r is B (I I I ) [ s ee I II . C . 1. ; II I . C .5 ; II I .D . 3 ] . C a l cu l at i ng fo r th e a m o un t o f e ac h i ng r ed i en t o f th e p re sc ri p ti o n i n t he que s ti o n r e q ui r es 1. 5 g o f p od o phy l l u m , 3 g of s a li c yli c ac i d , an d 6 m L of ac e to ne . Th e c o r re c t p r oc ed u re wo u l d b e to t ri t u ra t e t he po d oph y l l um wi t h th e a ce t on e , t h e n a dd t h e tr i tu r a te d s al ic y l ic ac i d to a c al ib r a te d b o tt l e c o nt a in in g th e p o do ph y l lu m a n d a c et o ne . Fl e xi b l e c o l lo dio n is th en ad d ed up t o th e 30 - m L c a li b ra t io n . A n “ e xt e r n a l u s e o nl y ” l ab el s h ou l d be a f fi xe d t o t h e c on t ai ner . 6 . T he an sw e r is E ( I , II, a nd I II ) [s e e I V . B. 2 ; I V .C . 5 ; I V. D . 1 a n d 2 ]. W hile pr ec i pi t at e d s u l fu r c an be us e d t o p r ep a re t h e p r es c ri p ti on de sc r ib ed i n t he q u es t io n , i t i s di f f ic ul t t o t r i tu r a te ; th e re f o re , i t m u s t f i rs t b e l e v i ga t ed wi th a s ui t ab l e l e vi ga t in g a g en t (e . g ., gly c e r i n) . A ll s us p en si on s , o wi n g to t he i r i ns ta b il i t y, r e qu i re s h ak in g b e fo r e u s e to r ed i s t r ib u t e t he in s o l ub le in g r ed i en ts . 7 . T he an sw e r is A ( I ) [s e e V I. C . 3 ; V I . D .1 ] . Th e p r o pe r p r oc e du r e f or c om po u nd in g th e p r es cr i p ti o n d es c r i be d i n t h e qu e st i on is t o fi r s t f o rm a li q ui d e u tec t ic . Th is i s d on e b y t r i tur a t in g th e m en t ho l a n d c a m ph o r t o g et h e r i n a m o rt a r . Th is eu t ec t ic i s t h en bl en d ed wi t h t he po wd e r e d s ta rc h a n d c a la m i n e, us in g g e om et ri c d i lu t io n . 8 . T he an sw e r is E ( I , II, a nd I II ) [s e e I X. D . 1 an d 3 ; I X. E . 1] . Th e p r o pe r p r oc e du r e f or p r ep a r in g t h e p re s c r ip t io n gi v e n i n t h e q ue s t i on i s to r e d uc e t h e p a rt ic le s i z e o f ea c h po wd e r a nd m i x t h em t og e th e r, us i ng ge om e t ri c d i lu t io n . Thi s e ns u re s t he p r op e r b le n di ng o f t he p o wd e r s . N e xt , t h is po wd e r ed m i xt u r e is i nc o r po r a te d , g e om e t ri ca ll y , wi t h th e pe t r ol a t um . Th e n , t h e l ano l in is a d d ed ge om e tr ic a ll y . 9 . T he an sw e r is A ( I ) [s e e XI . E . 2 ]. A n e qu al v o lu m e o f a ir m u s t b e i nj ec t ed wh e n rem o vi ng a d r ug s o lu t io n f ro m a v i al . Th i s is do ne t o p re v e n t th e fo r m a t io n o f a va c u um wi t h in t he v i al . Th is p ro b le m d o es n o t o cc u r wi t h am p ul es an d s y r i n ge s c o n ta i ni n g dr u g s o lu t io ns ; t h e re f o re , i t is u n n ec es s a r y t o in j ec t a ny a i r wh e n re m o vi n g t hem .
6 Basic Pharmacokinetics R i c c a r do L . B o n i L e o n Sh a r ge l
I. PHARMACOKINETICS A. I N T R O D U C T I O N 1 . P ha r m ac o k in e t ic s i s t h e q u an t it a ti ve m e as u rem e nt o f d ru g a b so r pt i on , d i st r ib u ti o n, a nd el im in a ti o n ( i .e . , e xc r e t i on an d m e ta b ol is m ) a nd in c l ud es t h e ra t e p r oc es s e s f o r d ru g m o v em e n t in t o t h e b od y , wi t h i n t h e b od y , an d o u t o f th e b o d y . 2 . C om m o nl y u s e d u n it s i n ph a rm ac ok in e ti cs a re t a b ul a te d i n Ta bl e 6 - 1. 3 . R a te s a n d o r d e r s o f r e a c t io n s . Th e r a te of a c he m i ca l re ac t io n o r p h a rm ac ok i ne ti c p r oc es s i s t h e v e l oc it y wi t h wh i c h i t o c c ur s . T h e o r de r o f a r e a ct i on is t h e wa y i n wh i c h t he co nc e nt r a ti on o f a d r ug or r ea c ta n t i n a c h em ic al r ea c t i on af f ec ts t h e r a te . a . Z e ro - o r de r r e ac t i on . Th e d r u g co nc e nt r a ti o n c h a n ge s wi t h r es pe c t t o t i m e a t a c on s ta n t r a te , a c c o r di ng t o t he f ol lo wi n g e qu a ti o n:
Table 6-1. Common Units in Pharmacokinetics Pharmacokinetic Parameter
Abbreviation
Fundamental Units
Units Example
Area under the curve
AUC
Concentration X time
µg X hr/mL
Total body clearance
ClT
Volume/time
Liters/hr
Renal clearance
ClR
Volume/time
Liters/hr
Hepatic clearance
ClH
Volume/time
Liters/hr
Apparent volume of distribution
VD
Volume
Liters
Volume of distribution at
Vss
Volume
Liters
steady state Peak plasma drug concentration
Cmax
Concentration
mg/L
Plasma drug concentration
Cp
Concentration
mg/L
Steady-state drug concentration
Css or Cav
Concentration
mg/L
Time for peak drug concentration
Tmax
Time
hr
Dose
Do
Mass
mg
Loading dose
DL
Mass
mg
Maintenance dose
DM
Mass
mg
Amount of drug in the body
DB
Mass
mg
Rate of drug infusion
R
Mass/time
mg/hr
First order rate constant for drug absorption
ka
1/time
1/hr or hr-1
Zero order rate constant for drug absorption
ko
Mass/time
mg/hr
First order rate constant for drug absorption
K (sometimes referred to as kel)
1/time
1/hr or hr-1
Elimination halflife
t½
Time
hr
Fraction of drug absorbed
F
(no units)
Ranges from 0 to 1 (0 to 100%)
P.123
wh e r e C is t he d ru g c on c e n t r at i on an d k 0 is t he z e r o - o r d e r r a t e c o ns t an t e xp r e s s ed in un i ts o f c on c en t r at i on pe r ti m e ( e. g. , m i ll i g ra m s p e r m il li l it e r p e r ho u r ). In t e gr a ti o n o f t h is eq u at i on y i el ds th e li n ea r (s t r ai g ht - li n e ) e q u at io n : C = -k0t + C0 wh e r e k 0 i s t he s l op e o f th e li ne ( s e e F ig u r e 3 - 5) a n d C 0 is th e y in t er ce p t , o r d ru g c o nc en t ra t io n , wh e n t im e (t ) eq u al s z e r o . Th e n eg a ti v e si gn i n di ca t es th a t t h e s l o pe is de c re as i ng . b . F i rs t - o r de r r e ac t i on . Th e c ha n ge in d ru g c on c e n t r at i on wi t h re s p ec t to t i m e eq u al s t he p ro d uc t o f t he ra t e c on s t a nt an d t h e c on c en t ra t io n o f dr ug r e m ai ni n g, ac c o r di n g t o th e fo l lo wi n g eq ua t io n :
wh e r e k i s t h e f i rs t -o r de r r a t e c o n st a nt , e xp r e s s ed i n u ni ts o f r ec ip r oc a l t i m e , or ti m e
-1
-1
( e .g . , 1 / h r o r h r ) .
( 1 ) I nt e gr a ti o n o f t h is e qu a t io n yie ld s t h e f ol l o wi ng m a t he m a t ic al l y e q ui va l en t eq ua t io ns :
( 2 ) A gr a ph of t he eq ua t io n in Fi g ur e 6 - 1 s ho ws th e li ne a r re la t io n o f th e lo g o f t he c o nc en t r at i on v e rs u s ti m e . I n Fi gu r e 6 - 1 , t he s l o pe of t he li ne is e q u al to -k / 2. 3 , a n d t he y in t e rc ep t i s C 0 . Th e v alu e s f o r C a re pl o t te d o n l o ga r i th m i c c oo r di n at es , a n d t h e v a l ue s f o r t a re s h o wn on li n ea r c o o rd in a te s .
( 3 ) Th e ha l f - li f e (t ½ ) o f a r e ac ti o n o r p r oc es s is th e ti m e r eq u ir e d f o r t he c o nc en t r at i on of a d r ug to d ec r ea s e b y o n e h al f . F o r a f i rs t -o r de r r ea ct i on o r p ro ce s s , th e h al f - li f e is a c on st a nt an d i s r e la te d to t he fi r st - o rd e r ra t e c o ns ta n t , ac c o r d in g t o the f ol l o wi ng e qu a ti on :
2 . M o d el s a n d c o mp a r tm e n t s a . A m o d el is a m a t he m a t ic de s c r ip t io n o f a bi o lo g ic s y s t em a n d is us e d t o e xp r e s s q u an t it a ti v e r el at i o ns hi ps . b . A co m pa r t m en t i s a gr o u p o f t is s u e s wi t h s i m i la r bl o od fl o w a n d d r ug a f f in i t y . A c o m p a r tm en t is no t a r ea l p h ys io lo g ic o r a na t om ic re gi o n. 3 . D r u g d i s t ri b u t io n a . D r ug s d is t ri b ut e ra p id ly t o t is s u es wi t h h i gh bl oo d fl o w a n d m or e s lo wl y t o ti ss u es wi t h l o w b lo o d f l o w. b . D r ug s ra pi d l y c r os s c a p il l a r y m em b ra n es i n to t i ss ue s b ec a us e o f p a ssi ve d i f f u si o n a n d h yd r o s t a t i c p r es s u re . D r u g p e rme a b i li t y a c r o ss c ap i ll a r y m em b r an es v a r ie s . ( 1 ) D r ug s e as il y c r os s t he c a p il la r i es o f th e g lo m e r u l u s o f t h e k i d ne y a nd t h e s in us o id s o f t h e l i v e r. ( 2 ) Th e c a pi ll a ri e s o f t he b r ai n ar e s u r ro u nd ed b y g l i a l c el ls th a t c re a te a b l o o d -b r a i n b a r r ie r , wh ic h a c ts a s a th ic k l ip i d m e m b ra ne . P ol a r a nd io nic h yd r o ph i li c d r ug s c ro s s th i s b a rr i e r sl o wl y . ( 3 ) I n d is ea s e s t a te s , m em b r an es m a y be c om e m o r e pe rm e ab l e t o d r ug s . F o r e xa m pl e , i n m e n in g iti s , t h e bl o od b ra i n b ar r i er b ec om es m o r e p e r m e ab l e t o t h e p en e t ra t i on of d ru gs in t o b r ai n . c . D r u gs ma y a c c u m ul at e i n t i ss u es as a r es u lt o f th ei r ph y s ic oc h em ic al c h a ra ct e ri s ti c s o r s p ec ial a ff i ni t y o f t he ti ss u e f o r t h e d r ug . ( 1 ) Li p id - s o lu b le d ru gs m a y a c c um u la t e i n a di po s e ( f at ) ti ss u e b ec au se of p a r ti t io n in g o f th e d r ug . ( 2 ) Te t r ac y c li n e m a y a c c u m ul a te in bo n e b ec au s e c om pl e xe s a re f or m e d wi t h c al c i um . P.124
d . P l as ma p r o te i n b i n din g o f d r ug s a ff e c t s d r ug d i st r ib u ti o n. ( 1 ) A dr u g b ou n d t o a p ro t e in fo r m s a c o m p l e x t ha t is to o l a rg e to c r os s c e l l m em b r an es . ( 2 ) Al b u m i n is th e m aj o r p l as m a p r o te i n i n v ol v e d i n d r u g p ro t e i n b i nd in g . α 1 - G l yc o p r o t e i n , a ls o fou n d i n p la s m a , is im po r ta n t fo r th e b in d in g o f s uc h b a si c d r ug s as p ro p r an olo l . ( 3 ) P o te n t d ru gs , s uc h as ph e n yt oi n, t ha t a r e h i gh l y b ou n d ( > 9 0 %) t o p l as m a p ro t ei ns m a y be d i s p la c ed b y o t he r hi gh l y b o un d d r ug s . Th e d i sp la c em en t o f th e b o un d d ru g r e su lt s i n m o re fr e e (n o nb o un d ) d r ug , wh i c h
r a p id l y r ea c h es t he dr u g r e c ep t or s a n d ca us es a m o r e i nt e ns e p h a rm ac ol o gi c r es p on s e . ( 4 ) A fe w h o r m o n al dr u gs bi n d t o s pe ci f ic p l as m a p r o te i ns . F o r e xa m p le , p r e dn is o ne bi n di ng t o t ra n s c o rt i n ( a nd al bu m i n ) r e s ul ts in do se - d ep en d en t p h a rm ac ok i ne ti c s of p red n is o ne . Th is n o nl in e a r p h a rm ac ok i ne ti c s is d u e t o s a tu r a bl e p r ot e in bi n di ng. Tr a n sc o r ti n h as hi gh a ff i n it y a nd lo w c a pa c i t y wh i l e al b um in ha s l o w a ff i n it y a nd a h ig h c ap ac i ty . B . O n e - co m pa r t m en t mo d e l 1 . I n t ra ve n o us b ol u s i nj e c t io n . Th e e nt i r e d ru g d o s e en t e rs th e b od y r a p id l y , an d t h e r a te of ab s o rp t io n i s n eg le c te d i n c al c u l at i on s ( F ig u re 6 -1) . Th e e n ti r e b o d y a c ts a s a s i n gl e c om pa r tm e nt , an d th e d r u g r ap i dl y e q ui l ib r a te s wi t h al l o f the t is s u es in th e b o d y. a . D r u g e l im i na t i o n is a f i rs t - o rd e r k i n e ti c p ro c es s , ac c o r d in g t o t h e e q u at io n s i n I . A. 1 . b. ( 1 ) Th e fi r s t - o rd e r e li m i na t i on r at e c on s ta n t ( k o r k e l ) i s t h e su m o f t h e r a te c o ns ta n ts fo r r em o v al of d r u g f r om th e b o d y , i nc lud i ng t he r at e c on s ta n ts f o r r en al e xc r e ti o n a nd m e ta b ol is m ( b i ot r a n sf o rm a t i on ) as d es c ri b ed b y t h e fo ll o wi n g e q ua t io n : k = ke + km wh e r e k e i s t he r at e c on s t a n t f o r r e na l e xc r e t i on an d k m i s t h e r a te c o ns ta nt f o r m e ta b ol is m . Th i s e qua t i on ass um e s t ha t a l l r at e s a r e f i rs t -o r d er p r o ce s s es .
Figure 6-1. Generalized pharmacokinetic model for a drug administered by rapid intravenous bolus injection. , extrapolated drug concentration; VD, apparent volume of distribution; DB, amount of drug in the body; k, elimination rate constant; t1/2, elimination half-life. [Adapted with permission from Gibaldi M, Perrier D. Pharmacokinetics, 2nd ed. New York, Marcel Dekker, Inc., 1982. Copyright © 1982 Routledge/Taylor & Francis Group, LLC.]
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( 2 ) Th e el i mi n a ti o n h a l f- l i f e (t 1 / 2 ) is gi v e n b y t h e f o ll o wi n g e q ua ti o n :
b . Ap p a r e n t vo lu m e o f d i s t r i bu t i on ( V D ) i s t h e h y p o t he t ic al vo lu m e of b o d y fl u id in wh i c h th e dr u g i s d is s o l v e d. Th is v a l u e is n o t a t ru e a n at om ic o r p h ys ic a l v o l um e. ( 1 ) V D i s n e ed ed t o es t im a te t he am ou n t o f d r ug i n t h e b od y r e la t i v e t o th e c o nc en t r at i on of d ru g i n t h e p l asm a , a s s h o wn i n t h e fo ll o wi n g : VD × Cp = DB wh e r e V D ( li t e rs ) i s t h e ap p a re n t v ol um e o f d is t r ibu t i on , C p ( m g / li t er ) is th e p l as m a d ru g c on c e n t ra t io n , a n d D B ( m g ) is th e am o un t o f dr u g i n t he bo dy . ( 2 ) To c a lc u la t e t he V D af t e r a n i n t ra v e n ou s b ol us i n je c t i on , t h e e qu a ti o n is r e a r r an ge d to gi v e :
wh e r e i s t he do s e ( D B ) of d r ug gi v e n b y i nt r a v e nou s b o lu s a nd is th e e xt r a p o l a te d d r ug c o nc en t r a ti o n a t z e r o tim e o n th e y a xi s , a f t er t he dr u g e q ui l ib r a te s ( F ig u re 6 -1 ) . ( 3 ) A cc or d in g t o th e e q ua t i on , V D is in c re as e d a nd is de c re as e d wh e n t he d r u g i s d is t ri bu t ed m o r e e xt r a v a s c ul a r l y i n to th e ti s s u es . W hen m o r e d ru g i s c o nt a in e d i n t he v a s c ul ar s pa c e o r p la sm a, is in cr e a se d a nd V D is d e c re as e d. 2 . S i ng l e o r a l d o se . I f th e d ru g i s g i ven in an ora l do sa g e f o rm (e . g. , t a b le t , c ap s u le ) , th e d r ug is ge n e ra ll y a bs o rb e d b y f i rs t - o rd e r k in e ti cs . E l i m i na t io n o f th e d r ug al s o f ol l o ws th e p r in c i p le s o f fi r s t - o rd e r k in e ti cs ( F i gu r e 6 - 2 ) . a . Th e fo ll o wi n g e q ua t ion d es c r i be s t he ph a rm ac o k in e ti cs o f f i rs t - o r de r a b s o r pt i o n a n d e li m i nat i o n :
wh e r e k A is th e f i rs t - or d er a bs o rp t io n ra t e c on s t an t an d F is th e fr a ct io n of d r u g b io a v a il ab l e. C h an ge s i n F, D 0 , V D , k A , an d k a f f ec t t he pl a sm a d ru g c o nc en t r at i on . b . Th e ti m e f or m a xi m u m , o r pe ak , d r ug ab s o r pt io n is gi v e n b y t he f o l lo wi n g e q ua t io ns :
wh e r e t m a x d e p e nd s o nl y o n th e ra t e c on st a nt s k A a n d k , n o t o n F , D 0 , or V D .
Figure 6-2. Generalized plot for a onecompartment model showing first-order drug absorption and first-order drug elimination. [Adapted with permission from Shargel L, WuPong S, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005.]
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c . A ft e r t m a x i s ob t ai n ed , t h e p e ak d r u g co nc e n tr a ti o n ( C m a x ) i s ca lc ul a te d , u s in g t h e e qu a ti o n i n I . B. 2 . a a nd s u bs t it u ti n g t m a x f o r t. d . Th e a re a u nd e r t h e c ur v e ( A U C ) m a y b e d e te rm i ne d b y i nt e g ra t io n o f C P d t u s i ng t he t ra pe z o i da l ru l e o r b y t h e f ol l o wi ng e qu a ti o n:
c h an g es i n F , D 0 , k , an d V D a f f ec t t he A U C . Mi n o r c ha n ge s i n k A do no t a f f ec t t h e A U C . e . To o bt ai n , o bt a in th e [ A U C ] f r om 0 t o t b y t h e t r a p e z oi da l ru l e a nd ad d o n th e e xt r a p o l at e d s e c tio n of A U C , wh i c h i s t h e la s t m ea s u r ab l e d r ug c o nc en t r at i on at ti m e t d iv i d e d b y t he s l op e of th e t e rm i na l e li m i n at i on c u r ve , a s s h o wn i n t he fo l lo wi n g eq u at i on :
f . L a g t i me oc c u rs at t he b e gi nn i ng of s ys t em ic dr u g ab so r p ti on . Fo r s om e i n di vi d ua ls , s y s te m i c d r ug a bs o rp t io n i s d el a y ed a f t e r o r al dr u g a d m i ni s t ra ti o n b ec au s e o f de l a y ed s t om ac h e m p ty i n g o r o th e r f ac t o rs . 3 . I n t ra ve n o us i nf u s io n a . I nt r a v en o us in f us io n is an e xa m pl e of z e r o- o r de r a bs or p ti o n a nd fi r s to r d e r e li m i na t io n (F i gu r e 6 - 3 ) . b . A fe w o r a l c on t r ol le d - re l ea s e d ru g p r o du ct s r e le a s e th e d r u g b y z e r o o r d e r ki n et ic s a n d h a v e z e r o - o rd e r s ys t e m i c abs o r p t i on . c . Th e p l as m a d r u g c o nc e n t r at i on at an y t im e a f te r t he s t a r t o f a n i n t ra ve n ou s i n fu s i on is gi v e n b y th e f o ll o wi n g e qua t i on :
wh e r e R is t he z e r o- o r der r a t e o f i nf us i on gi v e n in u ni ts as m i ll ig r am s p e r h o u r o r m il l ig r am s p er m in u t e. d . I f t h e i nt r a v en o us i n f us i on is d is co n ti n ue d , t he p l asm a d r u g c o nc en t r at i on de c l in e s by a f i rs t -o r d e r p ro c es s . Th e el im in a ti o n h al f -l i fe , or e l im in a ti o n r a te c o ns t an t, k , m a y b e o b ta i ne d f r om t he de cl in i ng pl as m a d r u g c on c e n t ra t io n v er s us t im e cu r ve . e . A s t he d ru g i s i nf us e d, t h e pl a sm a d ru g c o nc en t r a ti o n in c re as e s t o a p l a te au , o r s te a d y- s t a t e c o nc e n t ra t i o n ( C S S ) .
Figure 6-3. Generalized semilogarithmic plot for a drug showing zero-order absorption and firstorder elimination. Css, steady-state concentration; k, elimination rate constant. [Adapted with permission from Gibaldi M, Perrier D. Pharmacokinetics, 2nd ed. New York, Marcel Dekker, Inc., 1982. Copyright © 1982 Routledge/Taylor & Francis Group, LLC.]
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( 1 ) U n de r s t ea d y- s t a te c o n di t io ns , th e fr ac t io n o f d r u g a bs o rb ed eq u al s t he f r a ct i on of d ru g e l im in a te d f ro m t he bo d y. ( 2 ) Th e pl as m a c o nc en t ra t i on at s t e ad y s ta t e ( C s s ) i s g i v en b y th e f o ll o win g e q u at io n :
W her e, C l T i s t o ta l b o d y c l ea r an c e ( se e Se c t i on I.E . ) ( 3 ) Th e ra t e o f d r u g in f us i on ( R ) m a y b e c a lc ul a te d f ro m a re a r ra n ge m e n t o f t h e e q ua t io n i f th e d es i re d C s s , t he V D , a n d t he k a r e k no wn . Th e s e v a l ues c a n o f te n b e o b ta in e d f ro m th e d r ug li t e ra t ur e . To c a lc u la t e t he r at e of i n f us io n , t he f ol lo wi n g eq u a ti on is us ed : R = Css VDk = Css ClT wh e r e C s s is th e d e s i r ed ( t a r ge t ) p l as m a dr u g c o nc e nt r a ti o n a nd C l T i s t o ta l b o d y c l ea r an c e. f . A l oa d in g do s e ( D L ) is gi v e n a s a n i ni t ia l i n t rav e n o us bo l us d os e to p r o du c e t he C s s a s r a pi dly a s po s s ib l e. Th e i n t ra ve n o us i n fu si o n i s s t a r te d a t t he s am e tim e as t h e D L .
( 1 ) Th e ti m e to r ea c h C s s d e pe n ds o n t h e e li m i n ati o n h al f - li f e o f t h e d ru g . R e a ch i ng 90 % , 9 5% , o r 9 9 % o f th e C s s wi t h o ut a D L t ak es 3 .3 2 , 4 .3 2 , o r 6 . 6 5 h al f -l i v e s , r es pe c t i ve l y . Th u s, fo r a d r ug wi th a n e li m i na t io n t 1 / 2 o f 8 h r , i t wi l l t ak e 3. 3 2 × 8 h r, or 2 6 .5 6 h r , t o re ac h 9 0 % o f C s s i f no lo ad i ng do s e i s g i v e n. ( 2 ) Th e D L is t he am ou n t o f dr u g t ha t , wh e n d is sol v e d in th e a p pa r en t V D , p r o du c e s t h e d es i re d C s s . Th u s D L is c a lc ul a te d by t h e fo ll o wi n g e q ua t io n :
g . A n i n tr a v e no us in f us ion p r o v id es a r el a ti v e l y co n s t a nt pl as m a d ru g c o nc en t r at i on an d i s p a rti c ul a rl y u se f ul fo r dr u gs t h a t h a v e a na r r o w t h e r ap eu t ic ra n ge . Th e IV i n fu s i o n ke e ps th e p las m a d ru g c on ce n t ra t io n b e t we e n th e m in im um toxi c c o nc e nt r a ti on ( MTC ) a n d t h e m i n im um e f f ec tive c o nc en t r at i on ( ME C ) . 4 . I n te r m i tt e n t i n t r a ve no u s in f u si o ns a . I nt e rm i tt e nt in t r a v en ou s i n fu si o ns a r e i n fu s i o ns in wh i c h t he d ru g i s i n f us ed fo r s h o rt pe r i od s t o pr e ve nt ac c u m u l at i on a n d t o xi c i t y . b . I nt e rm i tt e nt in t r a v en ou s i n fu si o ns a r e u s e d fo r a f e w d r ug s, s u c h as the a m in o gl y c os id es . F o r e x a m pl e , g en t am ic in m a y be g i v en as a 1 -h r in f us ion e ve r y 1 2 h r . In th is c a s e , s t ea d y- s t a te d ru g c on cen t r a ti o ns a r e n o t a c hi e v e d. c . Th e p e ak d r u g c o nc e nt r a t io n i n t h e p la s m a f o r a d r ug gi v e n b y i n t er m i t t en t i n t ra v e n ou s in f us i on m a y b e c a lc u la t ed b y t he fo l lo wi n g e q u at io n :
wh e r e C p , n i s t h e p ea k d ru g c o nc en t r at i on , R i s t he r a te of d ru g i n fu s i o n, C l i s to t al b o d y c l ea r an c e , k is th e d os a ge in t e r val , n is t he nu m b e r o f i n f us io ns , t is th e ti m e for t h e i nf us i on , a n d τ i s t he d os ag e i n te r va l . 5 . M u l t ip l e d o se s . Ma n y d r u gs a r e g i ve n in t e rm i tt e n tl y i n a m ul t ip l e -d os e r e g im en f or c o n ti nu o us or p r ol o ng e d t he r ap e ut ic a c ti vi t y . Th is r eg im e n is o f t en us ed t o t r ea t c h ro ni c d is e as e. a . I f d r ug do s e s a r e g i v en f r eq u en t l y b e fo r e t h e pr e v i o us do s e is c om pl e tel y e l im in a te d , t h en pl as m a d r u g c on ce n t ra t io ns ac cu m ul a te an d i nc r ea s e t o a s t ea d y - s ta t e l e v el . b . A t s t ea d y s t a t e , p l as m a d r u g c o nc e nt r a ti o n f lu c tu a te s b e t we e n a m a xi m um ( ) a n d a m in im u m ( ) v a l ue ( Fi gu r e 6 - 4 ) . c . W he n a m ul t ip le - d os e r e g im en is c a lc ul a te d , t he s up e r p os i t io n p r in c ipl e a ss u m e s t ha t p r e v i ou s dr u g do s e s h a v e n o e f fe ct o n s ub s eq ue n t d os es . Th u s t he pr e di c t e d p la s m a d r u g c o nc e nt r a ti o n is t h e t o ta l p la sm a d r ug c o nc en t r at i on ob t ai ne d by a d d in g t h e r es i du al d rug c o nc e n tr a ti o ns fo un d a f t e r e ac h p r e v io us do s e. d . W hen a m u lt i pl e -d os e r e gi m en i s d es i gn ed , onl y t h e d o si n g ra t e ( D 0 / τ ) c a n b e a dj us t ed ea s i l y .
( 1 ) Th e do s i ng r at e i s b as e d o n t he s iz e o f th e do s e ( D 0 ) an d th e i n t e r val ( τ ) b e tw e en d os e s, o r th e f r eq u en c y o f d o s in g. P.128
Figure 6-4. Generalized plot showing plasma drug concentration levels after administration of multiple doses and levels of accumulation when equal doses are given at equal time intervals. τ, time interval between doses (t), or the frequency of dosing. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGraw-Hill, 2005]
( 2 ) Th e do s i ng r at e i s g iv e n b y t he fo l lo wi n g eq ua t i on :
( 3 ) A s l on g a s t he do s i ng r a te is th e s am e, t he exp e c t e d a ve r ag e d r u g c o n ce n t r a ti o n a t st e ady s t a t e ( ) is t he s am e (Fi g u re 6 -4 ) . ( a ) F or e xa m pl e , i f a 60 0- m g d os e i s g i v en e v e r y 1 2 h r, th e d o s i ng r at e i s 6 0 0 m g/ 1 2 h r , o r 5 0 m g /h r . ( b ) A do s e of 30 0 m g e v e r y 6 h r o r 2 0 0 m g e v e r y 4 h r a ls o g i v es th e s am e d o si n g r a te (5 0 m g /h r ) , wi t h t h e s am e e xp e c t ed . H o we v e r , t h e a nd v a lu es wi l l b e d i ff e re n t . ( c ) F or a l a rg e r d os e g i ve n o v e r a l o ng e r i nt e r va l ( e . g. , 60 0 m g e v e r y 12 h r ) , th e i s h ig h er an d th e l o we r co m p a r ed wi t h a s m a ll e r d os e g i ven m o r e f r e q ue n tl y ( e .g . , 2 00 m g e v e r y 4 h r ). e . C e r ta in an t ib i ot ic s a r e g i v e n b y m ul t i pl e r ap i d i n t r a ve n ou s b o l us i n j e ct i o ns . ( 1 ) Th e pe ak , o r ma x im um , se r u m d r u g c o nc e n tr a t i o n a t s t ea d y s t a te m a y b e es ti m a t ed b y th e fo ll owi n g e q ua t io n :
( 2 ) Th e mi n im u m s e r um d r u g c o n ce n t r at i o n ( ) a t s t e ad y s ta t e is th e dr ug c o nc en t r at i on af t e r t he dr u g de cl in es on e d o s a ge i n te r v a l . Th u s i s d e t e rm in ed b y th e fo ll o wi n g e qu a ti o n:
( 3 ) Th e a ve r ag e d r u g co n c en t r a t io n ( ) a t s te a dy s t a te is es ti m a t ed wi t h t h e e q ua t io n u s e d f o r m ul t i pl e o r al do s e s :
F o r in t r a v en ou s b ol u s in je c ti o ns , F = 1 . P.129
f . O r a ll y a dm in is t e re d d ru g s g i v en in im m ed i a te -r e l e as e do s ag e fo r m s ( e . g ., so lu t io ns , c o n v en t io n al t ab le t s , c a ps ul e s) by m u l ti pl e o r al do s es a r e u s ua ll y r a pi d l y a bs o r be d a n d s l o wl y e l im in a te d k A ≥ k ) . a nd fo r th e s e dr u gs a r e ap p ro xi m a t ed b y th e e q u at io n s s h o wn i n I . B .5. e . ( 1 ) a nd (2 ) . ( 1 ) F or m o r e e xa c t c a lc ul a t io ns of an d a f t er m u l tip l e o r al do s e s , t he f o l lo wi n g e q ua t io ns a re u s ed :
( 2 ) Th e c a lc ul a ti on o f is t h e s am e a s f o r m u l ti p le i n t ra v e n ou s b ol u s i n je c ti on s , us i ng th e e q ua t i on s h o wn in I . B. 5 .e . ( 3) . ( 3 ) Th e te r m 1 / (1 - e
-kτ
) is k n o wn as t he ac c um u la t i o n ra t e .
( 4 ) Th e f ra c t i on of d ru g re m ai ni n g i n t he bo d y ( f ) a f t e r a d os a ge in t e r v al is g i ve n b y t he f ol lo wi n g equ a t io n : f = e
-kτ
g . L oa d i ng d os e . A n i ni ti a l l oa d in g d os e ( D L ) i s gi v e n to ob t ai n a t h e r ap eu t ic s t ea d y - s ta t e d r u g l e v el qu ic kl y. ( 1 ) F or m u l ti pl e o r al do s e s , D L is c a lc ul a te d b y :
wh e r e D M i s th e m ai n te na n c e do s e . ( 2 ) I f D M i s g i v e n a t a d os a ge in t e r v al eq ua l to the e li m i na t io n h a lf - li f e o f t h e d r u g, th e n D L eq u al s t wi c e th e m ai n te n an c e do s e. C . M ul t i co m pa r t m en t mo d e ls 1 . D r ug s t h at e xh i b it m u lt i c o m p a r tm en t ph a rm ac ok i ne t i cs di s tr i bu t e i nt o d i f fe r e nt ti s s ue g ro u ps at d if f e re n t r a te s . Ti s s u es wi t h h ig h b l oo d f l o w e q ui l ib r a te wi t h a d ru g m o r e ra p id l y th a n t is su es wi t h l o w b l oo d f l o w. D r ug c o nc en t r at i on in v a ri o us t i s s ue s d e pe nd s o n t h e p h y s ic al an d c he m i c a l
c h a ra ct e ri s ti c s o f th e d r ug a nd th e n a tu r e o f th e t is s u e . F o r e xa m p l e, hi g hly l i pi d -s o lu bl e d r u gs a c c um u la t e sl o wl y i n fa t (l ip id ) t iss u e. 2 . Tw o -c o mp a r t me n t mo d e l (i n t r a ve no u s b o lus i n je c t io n ) a . A f te r an i n t ra v e n ou s bo l us in je c ti on , th e d r u g di s t ri bu t es an d e q ui li b r at es r a p id l y in t o h ig h l y p e r fu s e d ti s s ue s (c e nt r a l c o mp a r t m en t ) an d m or e s lowl y i n t o p e ri ph e r al ti s s ue s ( ti s s ue c om pa r t m en t ) .
b . Th e in i ti al r ap id de c l in e in pl as m a d ru g c on c en t r a ti o n is k n o wn as th e d i s t r i bu t i on p ha s e. Th e s lo we r r a t e o f d ec li n e i n d r u g c o nc e nt r a ti o n a ft e r c om p le t e e qu il i b ra t io n i s a c h i e v ed is k n o wn as the e l im i na t i on p ha se ( F i gu r e 6 - 5 ) . P.130
Figure 6-5. Generalized plot showing drug distribution and equilibration for a twocompartment model (intravenous bolus injection). The distribution phase is the initial rapid decline in plasma drug concentration. The elimination phase is the slower rate of decline after complete equilibration of the drug is achieved. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005.]
c . Th e p l as m a d r u g c o nc e n t r a ti o n a t a n y ti m e is t h e s um o f t wo fi r s t- o r de r p r o ce s s es , a s g i v en in the f ol l o wi ng e qu a ti on : Cp = Ae
-at
+ Be
-bt
wh e r e a an d b a re h y b ri d f i rs t - o rd e r r a te c o ns t an ts an d A a nd B ar e y i n t er c ep ts . ( 1 ) Th e h yb r i d f i r s t - o r de r r a t e c o ns t a nt b i s o bt a i ne d f r om th e s lo p e o f t h e e l im in a ti on ph as e o f t h e c u r v e ( F ig u r e 6 -5 ) and r e pr es e n ts t h e f i rs t o r d e r e li m i na t io n o f dr u g f r om t he bo d y af t e r t he d r u g e qu i li b ra t es wi t h a l l t i ss ue s . ( 2 ) Th e h yb r i d f i r s t - o r de r r a t e c o ns t a nt a i s o bta i ne d f ro m t he s l op e o f th e r e s id ua l l i ne of th e d is t r ib u t io n p h as e a ft e r th e e li m in a ti on ph as e i s s u bt r ac t ed . d . Th e ap p a re n t vo l um e o f d is t r i bu t i o n d ep e nds on t he t ype o f p h a rm ac ok i ne ti c c al c u l ati o n . V o lu m e s o f d is t ri b ut io n in c l ud e th e vol um e o f t h e c en t r al c o m p a rt m e n t ( V p ) , th e v ol um e o f di s t r ib u t io n a t s t ea d y s t a te ( V s s ) , an d t h e v ol um e o f t h e ti s s ue c om p a rt m e n t (V t ) . P.131
3 . Tw o -c o mp a r t me n t mo d e l (o r a l d r u g a d mi n ist r a t i o n ) a . A d r u g wi t h a r a pi d d is t r ib u ti o n p ha s e m a y no t s ho w t wo - c o m pa r tm e nt c h a ra ct e ri s ti c s a f t e r o ra l a dm i ni s t r a ti o n. As t he dr u g i s a bs o r be d , i t e q ui l ib r a te s wi t h t he ti s s u e s s o t ha t th e e li m i n at i o n ha l f -l if e o f th e e l im in a ti o n p o rt i on of th e c u r v e e qu a ls 0 . 69 3 /b . b . Two - c o m pa r tm e nt c h ar a c te r is t ic s a re s e en if th e d ru g i s a bs o rb ed r ap id l y a n d t h e d is t ri b ut i on ph as e is s l o we r . 4 . M o d el s w i th a dd i t io na l c om pa r t m en t s a . Th e ad di t io n o f ea c h n e w c o m p a rt m e n t t o th e m o de l re qu i r es a n a d di t io n al fi r s t - o r de r p l ot. b . Th e ad di t io n o f a t hi r d c om pa r t m e n t s u g ge st s th a t th e d r ug s l o wl y e q ui l ib r a te s i nt o a de e p ti s s u e sp a ce . I f th e d r u g is gi ve n a t f re q ue n t i n t er va l s , th e d r u g b eg ins t o ac cu m u l at e i n to t he t h i rd c o m p a r tm en t . c . Th e t e rm i na l l in e ar p ha s e g en e ra l l y re p r es en ts t h e e li m i n at i on of th e d r u g f r om th e b o d y a f t er e q ui l ib r a ti on oc c u r s . Th e r a t e c o n s t a nt f ro m t h e e l im in a ti o n p ha s e is u s ed t o c al cu la t e d os a ge reg i m e ns . d . A de q ua t e p ha r m a c o k in e t ic d es c ri p ti o n o f m ul tic om p a rt m e n t m od el s i s o f t en di f fi c ul t a n d d ep end s o n p r o pe r pl as m a s am p li ng an d d e t er m i n at i on o f d r u g c on c e n t ra t io ns . 5 . E l im i na t i on r a te c ons t a n ts a . Th e el im in a ti o n r a te c o n s t a nt , k , re p r es en ts d ru g el im in a ti o n f r om th e c e nt r a l c o m p a r tm en t . b . Th e te r m i n al e l im in a tio n r at e c on s ta n t ( λ o r b in t he t wo - c om pa r tm e nt m o de l ) r e p re s e n ts d r u g e l im in a ti o n a f te r d r u g d is t r i bu t io n i s m os tl y c om p le t ed . D . N o n l in e a r p h a rm a cok i n e ti c s a r e a ls o k n o wn a s c ap a c i t y- li m i t ed , d o s ed e p en de n t , o r s at u r at i on p h a rm ac ok in e ti cs . No n lin e a r p ha r m a c o ki n et ic s do n o t fo ll o w f i rs t - o rd e r k ine t ic s a s t he do s e in c re as e s (F i gu r e 6 - 6 ). N on l in ea r
p h a rm ac ok i ne ti c s m a y r es u lt f ro m t h e sa t u ra t io n o f an en z ym e o r c a rr i e rm e di a te d s y s te m . 1 . C h a ra c te r i s t ic s o f n on l i n ea r p ha r m ac o ki n e tic s in c l ud e a . Th e A U C i s n o t p ro p o rt i o na l t o t h e d os e . b . Th e am ou n t o f d r ug exc r e t e d in th e ur i ne is n ot p r op o r ti on a l t o t h e d os e . c . Th e e li m i n at i on ha l f -l ife m a y i nc r ea s e a t h ig h do s es . d . Th e r at io o f m e t ab o li te s fo rm e d c ha ng e s wi t h in c r ea se d d os e . 2 . M i c ha e li s -M e n te n k i ne t i c s d es c r i be th e v el oc it y o f en zy m e re a ct i on s . Mi c h a e li s - Me n t en k i ne t ic s a re us ed t o d es c r i be no n l i n ea r ph a rm ac ok in e tic s .
Figure 6-6. Generalized plot showing plasma drug concentration versus time for a drug with Michaelis-Menten (nonlinear) elimination kinetics. For this one-compartment model (intravenous injection), the doses are 1 mg, 10 mg, and 100 mg; and the apparent in vivo rate constant (kM) is 10 mg. The maximum velocity of the reaction (Vmax) is 0.2 mg/min. [Adapted with permission from Gibaldi M, Perrier D. Pharmacokinetics, 2nd ed. New York, Marcel Dekker, Inc., 1982. Copyright © 1982 Routledge/Taylor & Francis Group, LLC.]
P.132
a . Th e M i ch a el i s -M en t en e q ua t i on de s c r ib es the r a te of c h a ng e ( v e l oc ity ) o f pl as m a d ru g c on c e n t ra t i on af t e r a n i nt r a v e no us bo l us i n je c t i on , a s f o l lo ws :
wh e r e V m a x i s t he m a xi m u m v el oc i t y of t he re ac t io n , C p is th e s u bs t ra t e or p l as m a d ru g c on c e n t ra t io n , a n d k M is th e Mi c ha el i s co ns t an t eq ua l to th e C p a t 0 .5 V m a x . b . A t l o w C p v a l ue s , wh er e C p << k M , t h is e q ua t ion r e du ce s t o a fi r s t - o rd e r r a t e e q ua t io n b ec au s e bo t h k M a nd V m a x a r e c o nst a n ts .
c . A t h ig h C p v a lu e s , wh e r e C p > > k M , t he Mi c h ael i s - Me n t e n eq ua t io n i s a ze r o - o r de r ra t e e qu a ti o n, a s f o ll o ws :
3 . D r ug s t h at fo l lo w n o n li n ea r ph a rm ac ok i ne t ic s m a y s h o w ze r o - o rd e r e l im in a ti o n r a te s a t h ig h d r u g c on c e n t ra t io ns , f r ac t i o na l -o r de r el im i na t io n r a t es at in t e rm ed i at e d r ug c o nc e n tr a ti o ns , a nd f irs t - o rd e r e li m i n at i on ra t es a t lo w d r u g c on c e n t ra t ion s (F i gu r e 6 - 6 ). E . C l e a ra n ce is a m e as ur e m en t o f d r u g e li m i na t ion f r om th e b od y . U n it s f or c l ea r an c e a re v o lu m e per t im e (e . g. , li t er s p e r h ou r ) . 1 . T o ta l b o d y c l e a r a n c e ( C l T ) i s t he d ru g e li m i n at i o n r a te di vi d ed b y t h e p l as m a d ru g c on c e n t ra t io n . Ac c o r di n g t o t he c o nc e pt o f c l e ar a nc e , t he bod y c o nt a in s a n a pp a r en t v olu m e o f d is t ri b ut i on in wh i c h t he d ru g i s d is s o l v ed. A c on s ta n t p or t io n o f th is v o lu m e is c l ea r ed , or re m o v ed , f ro m t he bo d y pe r u n i t t im e. a . Th e fo ll o wi n g e q ua t ion s e xp r e s s t h e m e as u r em e nt o f t ot a l b od y c l ea r an c e :
b . F o r d ru gs t ha t fo ll o w f i r s t -o r de r (l i ne a r ) p ha r m a c ok in e ti c s , t o ta l b o d y c l ea r an c e is th e s um of a l l t h e cl e ar a nc es in th e b o d y, a s s ho wn i n th e f o l lo wi n g e q ua t io n : CLT = CLR + ClNR wh e r e C L R is re n al c l ea ra n c e an d Cl N R is no n re na l c l ea r an c e . N on r en a l c l ea r an c e , C l N R , is of t en e q u at e d wi t h he p at ic c l ea r a nc e , C l H . c . Th e re la t io n b e t we e n C l T an d t 1 / 2 is ob t ai n ed by s u bs t it u ti n g 0 .6 9 3/ t 1 / 2 fo r k in t he eq ua t io n i n I. E . 1 a t o o bt a in th e f o ll o wi n g e xp r e s s i o n:
wh e r e V D a nd C l T ar e c on s id e re d i n de p en de n t v ar i a bl es , an d t 1 / 2 is c o ns id e re d a d ep en d en t v a r i a bl e . d . A s c l e a ra nc e d ec r ea s e s (e . g. , in re n al di s e as e) , t ½ i nc r ea s e s . C h an g es i n V D a ls o c au s e p ro p o rt io n al c h a ng es in t ½ . 2 . R e na l d r u g e x c re t i o n i s t h e m a j or r ou t e o f d r ug e li m i na t io n fo r p o la r d r u gs , wa t e r -s ol u bl e d r ug s , d r ug s wi t h l o w m o l ec u l a r we i g h t ( < 50 0 ), an d d r u gs th a t a r e b io t r an s f or m e d s l o wl y. Th e r el a ti on b et we e n t he dr u g e xc r e t i o n r a te an d t h e p la s m a d r u g c o nc e n tr a ti o n i s s ho wn P.133
i n Fi g ur e 6 - 7 . D r u gs ar e e xc r e t e d th r ou g h t he ki dn e y i nt o th e u r in e b y g l om e ru l a r f il t ra t io n , t u bu l a r r e ab s o r p ti on , an d ac t i v e t u bu la r s e cr e ti o n.
Figure 6-7. Generalized plot showing the excretion rate versus plasma drug concentration for a drug with active tubular secretion and for a drug secreted by glomerular filtration only. [Adapted with permission from Shargel L, WuPong S, Yu ABC. Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005.]
a . G l o me r u la r f i l t ra t i on i s a pa s s i ve p r oc es s b y wh i c h s m al l m o l ec ul es an d d r u gs ar e fi l te r ed th r o ugh t he gl om e r ul us of th e ne p h ro n . ( 1 ) D r ug s b ou n d t o p la s m a p r o te i ns a r e t o o l a rge t o b e f il t e re d a t th e g l om e ru l us . ( 2 ) D r ug s s uc h a s c r ea t in i n e a n d i n ul i n a r e n o t a c ti ve l y se c re t ed or r e a bs o rb e d. Th e y a re us e d to m e as u re t he gl o me r u l a r fi l t r a ti o n ra t e (GFR). b . T ub u l a r r e a bs o r p ti on is a p as s i v e p ro ce s s tha t f ol lo ws F ic k 's la w o f d i f fu si o n. ( 1 ) Li p id - s o lu b le d ru gs ar e r ea bs o r be d f r om th e lu m en of t he ne ph r o n b ac k i n t o t he s ys t em ic c i rc ul a ti o n . ( 2 ) F or we a k e l ec t ro l y t e d r u gs , u r in e p H a ff e c t s th e r at i o o f n on i on i z ed and i o ni ze d d r u g. ( a ) I f t he d ru g e xi s t s p r im a r il y in t he no ni o ni z e d o r li p id - s o lu b le fo r m , t hen i t is re a bs o rb ed m o r e e as i l y fr om t he lu m e n o f t he n ep h ro n . ( b ) I f t h e d ru g e xi s t s p r im a r il y in t he io ni z e d o r wa t e r - s o lu bl e fo rm , th e n i t i s e xc r e t e d m or e e a s i l y in t he u ri n e. ( c ) D e pe nd i ng on th e p K a o f t h e d r ug , a l te r a ti on o f u ri n e p H a l te r s t he r ati o o f io n i zed to no n io ni z e d d r u g a nd a ff ec t s t he r at e o f dr u g e xc r e t io n . F o r e xa m p l e , a lk al in i z a ti o n of t h e u ri n e b y t he ad m i nis t r at i on of s o di um b i ca r bo n at e i nc r e as es the e xc r e t io n o f s a li c y la t es ( we a k ac id s ) i nt o th e u r i ne . ( 3 ) A n i nc r ea s e in u ri ne fl o w c a us ed b y s im u lt a neo u s a dm in is t r at i on of a d i u re t ic de c r e as es th e t im e fo r d r u g r e ab s o r pt i on. C o ns e qu en t l y , m o re d ru g i s e xc r e t e d i f g i v e n wi t h a d iu r e ti c . c . Ac t i ve t u bu l a r s e c re ti o n is a ca r r ie r -m e di a te d a c ti v e t ra ns p or t s y s t em t h a t r e qu i re s e ne r g y . ( 1 ) Two a c t i v e t u bu la r s ec r e ti o n p at h wa y s e xi s t i n t h e k id ne y : o ne s y s t em f o r we a k a c i ds an d o n e s y s t e m f o r we a k ba se s . ( 2 ) Th e ac ti v e t ub ul a r s ec r e ti o n s y st em s h o ws c om p et i ti o n e ff e c t s . F or e xa m p l e , p r o be n ec i d (a we a k a ci d ) c o m pe t es f o r t h e s am e s y st em as
p e ni ci l li n , d ec r ea s i ng t he r a te of pe n ic il li n e xc r e t i o n , r es u lt in g i n a lo n ge r p e ni ci l li n t 1 / 2 . ( 3 ) Th e re n al c l ea r an c e o f d ru gs th a t a r e a c t i v e l y s ec r e te d , su c h as p a m i no h i pp u r a te ( P AH ) , i s u s e d to m e as u re ef f e ct i ve r e n a l b l oo d fl ow (ERBF). 3 . R e na l c l ea r a nc e i s t he v o l um e o f d r ug c o n ta ine d in th e p l as m a th a t is r e m o ved b y th e k id ne y pe r u ni t t im e . Un i t s f o r r en a l cl e a ra n ce a re e xp r e s s ed in v o lu m e pe r t im e (e . g ., m i ll il i te r s p e r m in u te o r l it e rs pe r ho u r) . a . R en a l c l e a ra nc e m a y b e m e as u re d b y d i v id i ng t h e r a te o f d r ug e xc r e ti on b y t h e p la s m a d r ug c o nc e n t r at i on , a s s ho wn i n t he f ol l o wi ng e qu a ti on :
P.134
b . Me a s u re m en t o f re n al c le a r an c e m a y al s o be e xp r e s s ed b y th e f o ll o win g e q u at io n : ClR = keVD wh e r e k e i s t he fi r s t - o r der r e na l e xc r e t i on r at e c on s ta n t a nd
wh e r e i s t he t ot a l am o unt o f p a re n t ( u nc ha n ge d ) d r u g e xc r e t e d i n t he u ri ne . c . R en al c l e ar a nc e is m ea s u re d wi t ho u t r e ga r d t o t h e p h ys i ol o gi c m ec h an is m o f re na l d r u g e xc r e t i on . Th e p r ob a bl e m ec ha n ism f o r r en a l c l ea r an c e is ob t ai ne d wi th a c l ea r a n ce r a ti o , wh ic h re l at es d ru g c le a ra nc e t o in u li n c le a ra nc e (a m ea s u re of G F R ) . ( 1 ) I f t he c l ea r a nc e r a ti o i s < 1. 0 , t h e m e c h a ni s m f o r d r u g c l e ar a nc e m a y r e s ul t f r om fi l t ra t io n p l us r e a bs or p ti o n. ( 2 ) I f t he r a ti o is 1 .0 , th e m ec ha n is m m a y b e f il t ra t i on on l y . ( 3 ) I f t he r a ti o is > 1 . 0, th e m ec h an is m m a y b e f i lt r a t io n p lu s a c t i v e tu b ul ar s ec r e ti o n. 4 . H e pa t i c c le a r an c e is t h e v ol um e o f pl as m a c on t a in in g d r u g t ha t i s c l ea r ed b y th e l i v e r p e r u n i t t im e. a . M e as u r e me n t o f he pa t i c c l ea r a nc e . He p at ic c l ea r an ce is us ua ll y m e as u re d i nd i r ec tl y , as th e di f fe r e nc e b et we e n tot a l b o d y c le a r an c e an d r e n al cl ea r a nc e, as s h o wn i n t he f ol lo wi n g eq u at io n : ClH = ClT - ClR wh e r e C l H is th e h e pa ti c c l ea r an c e . H ep a ti c cl e a ra n ce is g e ne r al l y c o ns id e re d to be eq ui v a le n t to C l N R , o r n on r en a l d r u g c le a ra nc e . He p at ic c l ea r an c e c a n a ls o b e c al c ul a te d a s t he p r o du c t o f t h e l i ve r b lo o d f l ow ( Q ) a n d t he ex t r a c ti o n ra t i o ( E R ), as s h o wn in th e fo l lo wi n g eq ua t io n : ClH = Q(ER)
( 1 ) Th e ex t r ac t i o n r a t io i s th e f r ac t io n o f d r u g t ha t is i r r e v e rs ib l y r em o v ed b y a n o r g an o r t is s u e a s t h e p l as m a -c o nt a in in g d ru g pe r f us es th a t t is s u e . ( 2 ) Th e e xt r a c t i on r at i o is ob t ai n ed b y m e as ur i ng t h e p la sm a d r ug c o nc en t r at i on en t e ri ng th e li v e r an d t h e p la s m a d r u g c on c e n t ra t io n e xi t i ng t h e l i ve r :
wh e r e C a is th e a r t e ri al p l as m a d ru g c on c e n t ra t io n en t e ri ng t he li v e r a n d C v i s th e ven ou s p la s m a d ru g c o nc en t r at i on e xi t i ng t h e l i v e r . ( 3 ) V al u es fo r th e E R r an g e f r om 0 t o 1 . F o r e xa m p le , i f th e E R is 0 .9 , t he n 9 0 % o f th e i nc om in g d r ug is r em o v ed as th e p l as m a p e r fu s e s t h e li v e r . If t h e E R i s 0 , t he n n o dr ug is r em o ved b y th e l i v e r. b . B l o od f low , i n t ri n s ic c l e a ra n ce , an d p r o t ei n b i n d in g af f ec t h e pa t ic c l ea r an c e . ( 1 ) B l oo d f low t o t h e li v e r is ap p ro xi m a t el y 1 . 5 L/ m in an d m a y be al t er e d b y e xe r c i s e , fo o d, di s e as e , o r d r ug s. ( a ) B lo o d e nt e rs th e l i v e r t h r ou g h t he he p at ic po r ta l v e in an d h e pa t ic a r t ery a n d l ea v e s t h r ou g h t he he p a ti c ve i n. ( b ) A f te r o ra l d r ug ad m i ni s t ra t io n , t he d ru g i s a bs o r b ed f ro m t h e g a st r o in t es ti n al t ra c t in to t he m e se n te r ic v es se ls a n d p r oc ee ds to t he h e p at ic po r t al v e in , l i v e r , a n d s y st em ic ci r cu la t io n. ( 2 ) I n t ri n s ic cl e a ra n ce , C l i n t d es c r i be s t he ab i li ty o f t he li v e r to r em o v e th e d r u g i nd e pe n de n tl y o f b lo o d f l o w. ( a ) I nt r in s i c d r ug c l ea r a nc e p r im a ri l y oc c u r s b ec au s e o f t h e i nh e re n t a bi l ity o f t he bi o t r a ns f o rm a t ion e nz ym e s ( m i xe d - f u nc t io n o xi d as es ) to m e t ab ol iz e t h e d r u g as it en t e rs th e l i v e r . ( b ) N o rm al l y , ba s a l l e v e l m i xe d - f un c ti on o xi d as e e n zy m e s b io t ra ns f o rm d r u gs . L e v e ls o f th es e en z y m e s m a y be i n c r e as ed b y v a r io us d ru gs ( e. g . , p h e no ba r b it al ) an d e n v i ro n m e n ta l a g en ts ( e. g . , to b a c c o sm ok e ). Th es e e n zym e s m a y b e i nh i bi t ed b y o th e r d r ug s a nd en vi r o n m en t al ag e nt s ( e .g . , c im e ti d in e , ac u te le a d po i s o ni n g ). P.135
( 3 ) P r o te i n b i n di n g . D r ug s th a t a re b ou nd t o p ro te i n a r e n o t e as il y cl e ar ed b y t h e l i v e r o r k id n e y b ec a us e o nl y t h e f r ee , o r no n pl a sm a p ro t ei n - bo un d , d r u g c ro s s es t he c e ll m em b r an e i n to th e t is s ue . ( a ) T he f r ee d r ug is a v ail a bl e to dr u g -m et a bo li zi ng e n zy m es f o r b i o tr a ns f or m a t io n . ( b ) A s u dd e n i nc re a s e i n f r e e -d r ug pl as m a c o nc en t r a ti o n r es ul t s i n m o r e a va i la b le d ru g a t p h a rm ac o lo gi c re c e p to r s, p ro duc i n g a m o r e i n te ns e e f f ec t i n th e o r g an s ( e .g . , k id ne y , l i v e r ) i n v ol v e d i n d r ug r em o va l.
( c ) B l oo d f low ( Q ) , in t r in s i c c l ea r a nc e ( Cl i n t ) , an d f ra c t i on of f r ee dr u g in p l as m a ( f ) a r e r e la t ed to h e pa t ic c le a r an c e as s ho wn i n th e fo ll o wi n g e q u at io n :
( 1 ) Th e he pa t ic c l ea r an c e o f d r ug s t h at ha v e hi gh e xt r a c ti o n r a ti os an d h ig h C l i n t va lu es ( e. g ., p ro p r an o lo l ) i s m o s t a f fe c t e d by c h an g es in bl oo d fl o w a n d i nh i bi t o rs o f th e d r ug m e t ab o li s m e n zy m es . ( 2 ) Th e he pa t ic c l ea r an c e o f d r ug s t h at ha v e lo w e xt r a c t i on r at i os a n d l o w C l i n t va lu es ( e. g ., t he o phy l l i ne ) is m os t a f f ec te d by c h an g es in C l i n t an d i s a f f ec t ed on l y s l ig h tl y b y c h an g es i n h e pa t ic b l oo d f l o w. ( 3 ) O n l y d r u gs th a t a re hi g hl y p la s m a p r o te in bo un d (i . e ., > 9 5% ) an d h a ve a l o w i nt r i ns ic c le a ra n c e ( e . g ., ph e n y t oi n ) a r e a ff ec t ed b y a su d de n s hi f t i n p r o t ei n b in d in g . Th i s s hi ft c au s e s a n i nc r ea s e in fr e e - d ru g p la s m a c o nc en t r at i on . c . B i li a r y d r u g e x c r e t ion , a n ac t i v e t r an s p o r t p ro c es s , is a ls o i nc l ud e d in h e p at ic c l ea r an c e. S ep a ra t e a c ti v e s ec r e ti o n s y ste m s e xi s t fo r we a k ac i ds a n d we ak ba s e s . ( 1 ) D r ug s t h at a re e xc r e te d in bi le a re us ua l l y h i gh m o l ec ul a r we ig h t c om p ou n ds (i . e. , > 5 00 ) o r p ol a r d r ug s , s u ch as re s e rp in e , d ig o xi n , an d va r i o us gl uc u ro n id e c on ju g a te s . ( 2 ) D r ug s m a y b e re c y c le d b y th e e n te r o h ep a t ic c i r c ul a t io n . ( a ) S om e d r ug s a r e a bs or b e d f r om th e g as t r oi n tes t in a l t r ac t t h ro u gh t he m es e nt e r ic a n d h ep a ti c p o r t al v e in s, p ro c e e di ng t o t he l i v e r . Th e li v e r m ay s ec r e te s o m e of t he dr u g ( u nc h an ge d or as a g lu c u r o ni d e m e t ab o li t e ) in t o t h e b i le . ( b ) Th e bi le an d d r u g a re s to r ed in th e g a ll bl a dde r a n d wi l l e m p t y in t o t he g a st r o in t es ti n al t ra c t t hro u g h t he bi le d uc t a nd the n m a y be r ea bs o r be d . ( c ) I f t he d ru g i s a gl u cur o n i d e m e ta b ol i t e, ba c te r i a i n t he g as t ro in t es t ina l t r a ct m a y h y d r ol y z e t he g l uc u ro n id e m oi e t y, a ll owi n g t h e r e le as e d d ru g to b e r ea bs o rb e d. d . F i rs t - p as s e f f ec t s (pr e s ys t e m i c el i mi n a ti o n ) o c c u r wi t h d ru g s gi v e n o r a ll y. A po r ti o n o f t h e dr u g i s e li m i n at e d b ef o r e s y s t em ic a bs o r pt i on o cc u rs . ( 1 ) Fi r s t- p as s e ff e c t s g en e r al l y r es ul t fr om r ap i d d r u g b io t r an sf o rm a ti o n by l i ve r e n z y m es . O t he r m ec h an is m s i n cl ud e m e ta bo l is m o f t h e d ru g b y g a st r o in t es ti n al m uc os a l c e ll s , in t es t in al fl o r a, and b il ia r y s ec re t io n . ( 2 ) Fi r s t- p as s e ff e c t s a r e u s u a ll y o bs e r ved b y m ea s u ri ng t he ab s ol u t e b i o a va i la b i li t y ( F ) o f the d r ug (s e e C h ap t e r 7 ) . If F < 1 , t h en s om e o f th e d r u g wa s e li m i na t ed b efo r e s y s t em ic d r u g a bs orp t i on oc c u r r ed . ( 3 ) D r ug s t h at ha v e a h ig h h ep a t ic ex t r a ct i o n ra t i o , s uc h as p ro p r an ol ol a n d m o rp hi n e, s h o w f i rs t- p a s s e f f ec ts . ( 4 ) To o bt a in be t te r s y s te m ic a bs o r pt i on of a d r ug t ha t de m o ns t r at es hi g h f i r s t - p as s e ff ec t s , th e n ei t h er
( a ) Th e dr u g d os e c ou ld b e in c re as ed ( e .g . , p r op ra n ol o l, pe n ic il li n ) ( b ) Th e d ru g c ou ld be giv e n b y a n al t e rn a te r ou te o f a dm in is t r at i on ( e. g ., n i t ro g l yc e r in s u bl i ng ua l , i n s u li n s ub c ut a ne ou s , est r a di o l t r an sd e rm a l) ( c ) Th e do s a g e f o rm c oul d be m o di f ie d a s a d e laye d - r e l e as e d r u g p ro d uc t ( e . g ., en t e ri c -c oa t ed as pi r i n, m e sa la m i n e ) so t ha t t h e d r ug m a y b e a bs o rbe d m o r e d is ta ll y i n t h e G I t ra c t F . N o nc o m pa r t me n t m et h o d s. S om e p ha r m a c o k i n e ti c p a ra m e t er s f o r a b so r p ti on , di s t r ib u ti o n, a n d e li m i n at i on m a y b e e s ti m a t ed wi t h n o nc om p a rt m e n t m e t ho ds . Th es e m e th od s u su al ly r e q u i r e c om p ar is o n o f t h e a r e as u n de r th e c u r ve . 1 . M e a n r e si d e nc e t i me a . M e a n r e si d e nc e t i me ( M R T ) i s t he a v e ra g e t im e fo r th e d r ug m o le cu l es t o r es id e i n t h e b od y . M R T i s a ls o kn o wn a s t he m e a n t ra ns i t t i m e a nd m e a n s o jo u rn t i m e. b . Th e MR T d e p e n ds on t h e ro u te of ad m i n is t ra t io n an d a s s um es th a t t h e d r u g i s e lim i na t ed f ro m th e c e nt r a l co m p a r tm en t . P.136
c . Th e MR T i s t he t ot a l re s id e nc e t im e f o r a ll m o le c ul es in th e b o d y di v i ded b y t h e t o ta l n um b e r o f m o l ec ul e s in t he bo d y , a s s h o wn in t he fo ll o wi n g e q u at io n :
d . M RT a f te r I V b o l us inj e c t io n ( 1 ) Th e MR T a f t e r a b o lus in t r a v en o us i n je c t i on is c al c u l at e d b y t he f o l lo wi n g e q ua t io n :
wh e r e A U MC i s t h e a r ea u n d er t he fi r s t m o m e n t ve r s us tim e c u r v e f r om t = 0 t o t = i nf i ni t y an d A U C 0 - ∞ i s t he a re a u n de r th e p l as m a d ru g c on c e n t ra t io n ve r s us t im e c u r v e f ro m t = 0 to t = in f in i t y . A U C 0 - ∞ i s a ls o k no wn a s t h e z e ro m om e nt c u r v e . ( 2 ) Th e MR T I V i s r e la t ed t o t he el im in a ti o n r a te c on s ta n t b y t he f ol lo wi n g e xp r e s s io n : MR T I V = 1 / k ( 3 ) D u ri n g MR T I V , 6 2 . 3% o f th e i n t ra ve no u s b ol us d os e i s e li m i n at e d. ( 4 ) Th e MR T f o r a d ru g gi v e n b y a no n in s t a n ta neo u s i np u t is lo n ge r th a n th e MR T I V . 2 . M e a n a bs o r p t io n ti me ( M AT ) is th e d i ff e r en ce b e t we e n MR T a n d MR T I V a f t e r a n e xt r a v a s c u l ar r ou t e i s u se d . MA T = MR T e v = MR T I V
W hen f i rs t -o r de r ab s o r p tio n oc c u rs , MA T = 1 / k a. 3 . C l ea r a nc e i s t h e v o l um e o f pl as m a c l ea r ed o f d r u g p e r u ni t ti m e an d m a y b e c a lc ul a te d wi t ho u t c on s id e ra t io n o f th e c om par t m en t m od e l.
A f t e r a n IV do s e, F = 1. 4 . S t ea d y- s t a t e vo l um e o f d i st r i b u ti o n ( V s s ) a . Th e s t ea d y- s t a te v o lum e o f di st r ib u ti o n is t he r a t io o f t he am ou n t o f d ru g i n th e b o d y a t s t ea d y s t at e an d th e a ve r ag e s t ea dy - s t a t e d ru g c o nc en t r at i on . b . A f te r an in t ra v e n ou s bo l us in je c ti on , V s s i s c a lcu l a te d b y t he f ol lo wi n g e q u at io n :
II. Clinical Pharmacokinetics i s th e a pp l ic at i on of ph a rm ac o k i ne t ic p r i nc ip le s f o r t h e r a ti o na l d es ig n o f an i n di vi d ua li z e d do s a ge r eg i m e n . Th e t wo m a i n o bje c ti v e s a r e m a in t e na n ce o f a n o p t im u m d r u g c on c e n t ra t i on a t t h e re c ep t o r s i te to p ro du c e t he d e si r ed t he r ap e ut ic r es po n s e fo r a s pe ci f ic p e ri od a nd mi n i mi z a t i on o f an y a d ve r s e o r t o xi c e f f ec ts o f t h e d ru g .
III. Toxicokinetics i s th e a pp l ic at i on of ph a rm ac o k i ne t ic p r i nc ip le s t o t h e d es ig n , c on d uc t, and i n t er p r et a ti o n o f d r ug s a fe t y e v a lu a ti o n s tu di e s . A. T o x i c ok i n et i cs is al s o us e d t o val id a te do s e- re l a te d e xp o s u r e in a n im al s . To xi c o k in e ti c s tu d ie s a r e p e rf o rm e d i n an i m a ls du r in g p r ec li n ic al d r u g d e v el o pm en t to ai d i n pr e di c ti on o f h um an dru g to xi c i t y . To xi c o k in e ti c ( n o nc li n ic al ) s t ud i es m a y c on t in u e a f te r th e d r ug h a s b ee n t e s t e d i n h u m a ns . B . C l i n ic a l t o xi c o lo g y i s t he s t ud y o f a d ve rs e e ff e c ts o f dr u gs a n d t o xi c s u bs ta n c e s ( p oi s o ns ) i n t h e h um a n b od y . Th e pha r m ac ok in e ti cs o f a d ru g i n a n o ve rm ed ic a te d (i n to xi c a te d ) p a ti e nt m a y b e ver y d i f fe r e nt f ro m t h e p h a rm ac ok i ne ti c s of t he s am e d r u g g i v en in th e r ap e u ti c d os es . F o r e xa m p l e , a v e r y hi gh t o xi c d os e m a y s h o w n on l ine a r ph a rm ac ok in e ti c s due t o sa t ur a ti o n k i n et ic s P.137
c om p a re d t o th e d r ug gi v e n at lo we r t h e ra p eu t ic do s es i n wh i ch th e d r ug lev e l s f o l lo w l i ne a r p h a rm ac ok in e t ic s .
IV. Population Pharmacokinetics i s th e s tu d y o f s o u rc es an d c o r re l at e s o f v a r i ab il it y i n dr u g co n c e n tr a ti o ns a m o n g i n di vi d ua ls wh o a re th e ta r g e t p at i en t p o pu la t io n . P o p ul a ti on ph a rm ac ok i ne t ic s i s
m os t of t en ap p li ed t o t he c li n ic al pa t ie n t wh o is re c ei vi n g r el e v a nt do s es o f a d r ug o f in t e re s t . B ot h p h ar m ac ok i ne t ic a n d n on p ha r m ac ok i ne t ic d a ta m a y b e c on s id e re d , i n cl ud i ng ge n de r , a g e, we i gh t , c r ea t in i ne c l ea r anc e , a nd co nc om i ta n t d is ea s e. P.138
STUDY QUESTIONS D i r e c t i on s : E a c h qu es t io n , s t at em e nt o r i nc om ple t e s t at em e nt in th is s e c t i o n c a n b e c o r re c tl y a ns we r e d o r c om p le t ed b y on e o f th e s ug g es t ed an s we r s o r p h r as es . C h o os e th e b e st an s we r . 1 . C r e at i n in e c l e a ra n ce i s us e d a s a m e as u r eme n t o f ( A ) r e na l e xc r e t i on ra t e . ( B ) g lo m e r ul a r fi lt r a ti o n ra t e ( G F R ). ( C ) a ct i v e re n al s ec r e ti on . ( D ) p as s i v e r en al a bs or pt i o n. ( E ) d r ug m e ta b ol is m r a te. V i e w A n s we r 1 . T h e a n sw e r i s B [ se e] . F o r q u es ti o n s 2 - 5 : A ne w c e ph a lo s p o ri n a n ti b io ti c wa s g i ve n a t a do se o f 5 m g /k g b y a s in gl e i n t ra ve n o us b o lu s i nj ec t io n to a 5 8 - ye a r - ol d m an wh o we i g hed 7 5 kg . Th e a n ti b io t ic f ol l o ws th e p h a rm ac ok i ne ti c s of a on e - c o m p a r tm en t m od e l an d ha s a n e li m i n at io n h al f - li f e o f 2 h r . Th e a p pa r en t v o lu m e o f di s t r ib u ti o n is 0 .2 8 L /k g , a nd t he d ru g i s 3 5% b o u nd to p l as m a p ro t ei ns . 2 . W ha t is t he i ni t i al p la s m a d r u g c on c en t r a t io n ( ) in t hi s pa t ie n t ? ( A ) 0 . 24 m g /L ( B ) 1 . 80 m g /L ( C ) 1 7 .9 m g /L ( D ) 5 6 .0 m g /L ( E ) 1 33 9 m g /L V i e w A n s we r 2 . T h e a n sw e r i s C [ se e] . 3 . W h a t is t h e p r e di c t ed pl a sm a d r u g c o n ce n t r a ti o n ( C p ) a t 8 h r a f t e r t h e d o se ? ( A ) 0 . 73 m g /L ( B ) 1 . 11 m g /L ( C ) 2 . 64 m g /L ( D ) 4 . 02 m g /L ( E ) 1 5 .1 0 m g/ L V i e w A n s we r 3 . T h e a n sw e r i s B [ se e I . A . 1. b . (1 ); ] .4 . H ow m u ch d r ug r e m a in s in t he pa t i en t 's b o d y ( D B ) 8 h r a f t e r th e d os e ? ( A ) 1 5 .3 m g ( B ) 2 3 .3 m g ( C ) 8 4 .4 m g ( D ) 1 0 0. 0 m g ( E ) 1 12 . 0 m g V i e w A n s we r 4 . T h e a n sw e r i s B [ se e] . 5 . How l on g a f te r t he d os e i s e xa c t l y 7 5 % o f t h e d r ug el i m ina t e d f ro m th e p a t ie n t 's b o d y?
( A ) 2 hr ( B ) 4 hr (C) 6 hr (D) 8 hr (E) 10 hr V i e w A n s we r 5 . T h e a n sw e r i s B [ se e] . C D C V t F o r q u es t i o ns 6 -1 1 : A 35 - y e a r o l d m an wh o we i g hs 7 0 k g a n d h as no rm a l r e na l f u nc t io n n e ed s a n i nt r a ve n o us i n f us io n o f th e a n ti bi o ti c c a r be ni c i l li n . Th e de s i r ed s te ad y - s t at e p l asm a d ru g c o nc en t r at i on is 1 5 m g /dL . Th e ph y s ic ia n wa n ts th e an t ib io t ic to be in f us ed i nt o t h e p a t ie n t f o r 1 0 h r . C a r be ni c il li n h as an el im i na t io n h a l f- l if e (t 1 / 2 ) o f 1 hr an d a n a p p ar e nt v o lu m e di s t ri but i o n ( V D ) of 9 L i n th is pat i e nt . 6 . As s u m in g th a t n o loa d i n g d os e w as g i ve n, w h a t r a t e o f i n t r a ve n ous i n f us i on i s r e co mm e n de d fo r t h is p a ti e n t? ( A ) 9 3 .6 m g /h r ( B ) 1 35 . 0 m g/ h r ( C ) 4 6 8. 0 m g/ h r ( D ) 9 3 6. 0 m g/ h r ( E ) 1 35 0 .0 m g / hr V i e w A n s we r 6 . T h e a n sw e r i s D [ se e] . 7 . As s um in g t ha t n o l oa d i ng i n t r a ve n o us do s e w a s g i ve n , how l o ng a f te r th e i ni t i a ti o n o f t he in t ra ve n o u s i n f u s io n w ou l d th e p l asm a d r ug co n ce n t r a ti o n r e a c h 9 5 % o f t h e t h e o re t i c s t e a d y- s t a t e d r u g c o nce n t r a t io n ? (A) 1.0 hr (B) 3.3 hr (C) 4.3 hr (D) 6.6 hr ( E ) 1 0 .0 hr V i e w A n s we r 7 . T h e a n sw e r i s C [ se e] . P . 13 9
8 . W ha t is t he r ec o mm en d e d l o ad i n g d o se ? ( A ) 9 3 .6 m g ( B ) 1 35 . 0 m g ( C ) 4 6 8. 0 m g ( D ) 9 3 6. 0 m g ( E ) 1 35 0 .0 m g V i e w A n s we r 8 . T h e a n sw e r i s E [s e e] . 9 . T o i n f us e t he an t i b io t i c a s a s o l u t io n c o n ta i n in g 1 0 g d r u g i n 5 0 0 m L 5 % d e x t r o s e, h ow m a n y m i l l i li t e r s pe r h o u r o f t h e s o lu t i on w ou l d be i nf u se d in t o th e p a t i en t ? ( A ) 1 0 .0 m L /h r ( B ) 4 6 .8 m L /h r ( C ) 1 0 0. 0 m L/ h r ( D ) 9 3 6. 0 m L/ h r ( E ) 1 14 1 .0 m L / hr
V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . 1 0. W ha t i s t he t o ta l bo d y c l e a r a n c e r a t e f o r c a r be n ic i l li n in t h i s p a t ie n t ? ( A ) 1 00 m L / hr ( B ) 9 36 m L / hr ( C ) 4 8 62 m L /h r ( D ) 6 2 37 m L /h r ( E ) 9 00 0 m L /h r V i e w A n s we r 1 0 . T he a nsw e r i s D [ se e] . 1 1. I f t h e p a t i en t ' s r e n al cl e a ra n ce f o r c a r be n ic i l li n is 86 m L /m i n , w h a t i s th e hep a t i c c le a r a nc e f o r ca rb e n ic i l l in ? ( A ) 1 08 m L / hr ( B ) 1 07 7 m L /h r ( C ) 3 8 40 m L /h r ( D ) 5 1 60 m L /h r ( E ) 6 84 4 m L /h r V i e w A n s we r 1 1 . T he a nsw e r i s B [ se e] . C R k V C C CC D C l C l C l C l C l C l C l C l 12 . T h e e a r l ie s t e vi d e nc e th a t a d r u g i s s t o r ed i n t i s s ue is ( A ) a n i nc r ea s e in pl as m a p r ot e in bi nd i ng . ( B ) a l a r ge ap p ar e nt v o lum e o f di st r ib u ti o n ( V D ) . ( C ) a de c re as e i n t h e r a te o f f o rm a ti on o f m e t ab ol i t es b y t h e li ve r . ( D ) a n i nc r ea s e in t he num b e r o f s i d e e f fe c t s p r odu c ed b y th e d r ug . ( E ) a de c r e as e i n t h e am o u n t o f f r ee d ru g e xc r e t ed i n t he u ri n e. V i e w A n s we r 1 2 . T he a nsw e r i s B [ se e] . V 1 3. T he i n t e ns i t y o f t h e p h a r ma c o lo g ic ac t i o n of a d r ug is m os t de p end e n t o n t he ( A ) c on c e n t ra ti o n o f t h e d r u g a t t h e r ec e pt o r s it e . ( B ) e li m i n at io n ha lf - l if e (t 1 / 2 ) o f th e d r ug . ( C ) o ns e t t im e o f t h e d r ug a f te r o r a l a dm in is t ra t ion . ( D ) m in im um to xi c c on c en t r a ti o n ( MTC ) o f t h e dr ug i n p la sm a. ( E ) m i n im um e f f ec ti v e c on c en t r at i on ( ME C ) o f th e d r u g i n t he bo d y. V i e w A n s we r 1 3 . T he a nsw e r i s A [ se e] . 1 4. D r u gs t h a t s h ow no n li n ea r p h a r ma c ok i n et i cs h a ve w h ic h p r o p e r t y? ( A ) A co ns t an t ra t io of d ru g m e ta b ol i te s is f or m e d a s t h e a dm in is t er e d d os e i n c re as es . ( B ) Th e el im i na t io n h al f - li f e (t 1 / 2 ) i nc re as e s as th e a dm i ni st e r ed do se in c rea s es . ( C ) Th e a r ea un de r th e pl a s m a d r ug c o nc en t r at i on v e r su s t im e c u r v e ( A UC ) i n c re as es in di r ec t p r op or t i on t o a n i nc r ea se in the a dm in is t e re d d os e . ( D ) B o t h l o w a nd hi g h d os es f ol lo w f i r s t -o r de r el im i na t io n k in e ti cs . ( E ) Th e s t e ad y - s ta t e d r ug c o nc e n tr a ti o n i nc r ea s es in di r ec t p r o po r ti o n t o th e do s i n g rate. V i e w A n s we r 1 4 . T he a nsw e r i s B [ se e] . 1 5. T he l oa d i n g d os e ( D L ) o f a d r u g i s u su a ll y b a s e d on t he ( A ) t o ta l b od y c le a ra n c e ( C l T ) o f th e d r ug . ( B ) p e rc en t ag e o f dr u g bo u n d t o p la sm a p r ot e in s . ( C ) f r ac t io n o f d r u g e xc r e t e d u nc ha n ge d i n t h e u ri n e . ( D ) a p pa r en t v ol um e of di s t ri bu t io n ( V D ) a nd de si re d d ru g c on c e n t ra t io n i n p l asm a . ( E ) a r ea un d er t he pl as m a d r ug c o nc en t r at i on ve rs us t im e c u r ve ( A U C ) .
V i e w A n s we r 1 5 . T he a nsw e r i s D [ se e] . D D V 1 6 . Th e r e na l c l ea r a nc e o f i n u l in i s u se d a s a m eas u r e me n t o f ( A ) e f fe c t i v e re n al bl oo d f l o w. ( B ) r a te o f r en a l d r ug e xc r e ti o n. ( C ) i n tr i ns ic en z y m e a c tiv i t y . ( D ) a ct i v e re n al s ec r e ti on . ( E ) g lo m e r ul a r fi lt r a ti o n ra t e ( G F R ). V i e w A n s we r 1 6 . T he a nsw e r i s E [s e e] . P . 14 0
1 7 . Al l o f t h e f o l low i n g s t a t em e n ts ab o u t p l asm a p r ot e i n b i nd i n g o f a d r u g a r e t r u e ex c ep t w h ic h on e ? ( A ) D i sp la c e m e n t o f a d ru g f ro m p la sm a p r ot e in bi n di n g si t es r es ul ts in a tr a n s i en t i n c re as ed v o lu m e o f d is tr i b ut i on ( V D ) . ( B ) D i sp la c e m e n t o f a d ru g f ro m p la sm a p r ot e in bi n di n g si t es m ak e s m o r e f r e e d r ug a va i la b le fo r gl om e r ul a r f i l t ra t io n . ( C ) D i sp l ac em en t o f a p ot e n t d r ug th a t i s n o rm al ly > 9 5 % b ou nd m a y c a us e t o xi c i t y . ( D ) A l bu m i n i s t h e m a j or p r o t ei n i n v ol ve d i n p r o te i n b in di n g o f d r ug s . ( E ) D r u gs th a t a r e h ig hl y b o un d t o p l as m a p r o te i ns ge n e ra ll y h a v e a g re a te r V D c om p a re d wi t h d r ug s t hat a r e h ig hl y b o un d t o t is su e p ro t ei ns . V i e w A n s we r 1 7 . T he a nsw e r i s E [s e e] . V 18 . Th e o n s e t t i me f o r a d ru g g i ve n o r al l y i s t h e ti m e f o r t h e d r u g t o ( A ) r e ac h t he pe a k p la s m a d r u g co nc e nt r a ti o n. ( B ) r e ac h t he m i ni m u m ef f e c t i v e c on c e n t ra t io n ( ME C ) . ( C ) r e ac h t h e m i n im um to xi c c on c en t ra t io n ( MTC ) . ( D ) b e gi n t o b e e li m i n at ed f r om th e b od y . ( E ) b eg i n t o b e a bs o rb e d f r om t he s m a l l i nt es t in e . V i e w A n s we r 1 8 . T he a nsw e r i s B [ se e] . 1 9. T he i ni t i a l d i s t ri b u t io n of a d r u g i nt o t is s ue is de t er m i n e d c hi e f l y b y t h e ( A ) r a te o f b lo od f lo w t o t i s s ue . ( B ) g lo m e r ul a r fi lt r a ti o n ra t e ( G F R ). ( C ) s to m a c h em p t y in g t im e . ( D ) a f fi n it y o f t h e d r ug for t is s u e . ( E ) p la s m a p r ot e in bi n din g of t he dr u g. V i e w A n s we r 1 9 . T he a nsw e r i s A [ se e] . 2 0. W hi c h t i s su e ha s t h e g r e a te st c a p ac i t y t o b i o t r a n s f o rm d r u gs ? ( A ) b r ai n ( B ) ki d ne y ( C ) l i ve r ( D ) l un g ( E ) sk i n V i e w A n s we r 2 0 . T he a nsw e r i s C [ se e] . 2 1. T he pr i n c i pl e of s up e r p os i t ion i n d es i gn i n g m u lt i p le - do s e re g i me n s a ss u me s t h a t ( A ) e ac h d os e a f fe c ts the n e xt s ub s e q ue n t d os e, c au s i n g n on l in ea r el im ina t i on . ( B ) e ac h d os e o f d r u g is e l im in a te d b y z e r o - o rd e r e l im in a ti on .
( C ) s te a d y -s t a te pl as m a d r u g c on c e n t ra t io ns ar e r e a ch ed a t a pp r o xi m a te ly 1 0 ha l f l i ve s. ( D ) e a rl y d os es of d ru g do n ot a ff ec t s u bs eq ue n t d o s e s. ( E ) t h e f r ac ti o n o f d r ug ab s o rb ed is eq u al to th e fr a c ti o n o f d r ug el im in a ted . V i e w A n s we r 2 1 . T he a nsw e r i s D [ se e] . C l F o r q u es t i o ns 22 - 2 4 : A ne w c a r di ac gl y c os id e i s d e ve l op e d f o r o r al an d i n t rav e n o us ad m i n is t ra t io n . Th e d ru g h a s a n e li m i na t io n h a lf - l if e ( t 1 / 2 ) o f 2 4 hr an d a n a p p ar e nt vo lu m e o f d is t rib u t io n (V D ) o f 3 L /k g . Th e e ff ec t i v e d r u g c on c e n t ra t io n i s 1 .5 n g /m L . To xi c e f f ec ts of th e d ru g a r e ob se r v e d a t d r ug c on c en t r at i on s > 4 ng / m L . Th e d r u g is bo u nd to pl as m a p r o t ei ns at ap p ro xi m a t ely 2 5 % . Th e d ru g i s 7 5% b i oa v a i la b le af t e r a n o r al d os e . 2 2 . W h a t i s th e o r a l m ai n t e na n ce d os e , i f gi ve n o n ce a d a y, f o r a 6 8 - ye a r - o ld m a n w ho w e i gh s 6 5 k g a n d ha s c o ng e s ti ve h ear t f a i l u re ( C H F ) a n d n o rm a l re n a l f u n c t io n ? ( A ) 0 . 12 5 m g ( B ) 0 . 18 0 m g ( C ) 0 . 20 3 m g ( D ) 0 . 27 0 m g ( E ) 0 . 33 3 m g V i e w A n s we r 2 2 . T he a nsw e r i s D [ se e] . 2 3. W ha t i s t he l oa d i ng do s e ( D L ) f o r t h i s p a ti e n t? ( A ) 0 . 27 0 m g ( B ) 0 . 29 3 m g ( C ) 0 . 45 0 m g ( D ) 0 . 49 8 m g ( E ) 0 . 54 0 m g V i e w A n s we r 2 3 . T he a nsw e r i s E [s e e] 2 4 . I f th e d r u g is a va i la b le i n t a bl e t s o f 0 .1 2 5 m g a nd 0. 2 50 m g , w ha t is t he pa t i en t 's p l as ma d r ug c on c en t ra t i o n i f he h a s a d os a ge r eg i me n o f 0 .1 2 5 m g e ve r y 1 2 h r? ( A ) 1 . 39 ng /m L ( B ) 1 . 85 ng /m L ( C ) 2 . 78 ng /m L ( D ) 3 . 18 ng /m L ( E ) 6 . 94 ng /m L V i e w A n s we r 2 4 . T he a nsw e r i s A [ se e] . D F V k Fk VD F D k V C C D P . 1 41
D i r e c t i on s fo r q ue s t io n 2 5 : Th e q ue s t i on in th is s ec t io n c an be c o r r ec tl y a ns we r e d b y o n e o r m o re of t he s u g g es te d a ns we r s . C ho os e th e c o rr ec t an s we r , A- E . 2 5 . W h i ch eq u a ti o n i s tr u e f o r a z e r o - o rd e r r eac t i o n ra t e o f a d r u g?
A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 5 . T he a nsw e r i s A [ se e ] . A t k Ak t A tP . 1 4 2
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee I . E . 2. a ]. A s ub s ta nc e t h at is us ed t o m e as u re th e G F R m us t be fi l te r ed bu t no t re ab s o rb ed o r a c ti ve l y s e c re t ed . Al t ho ug h in ul i n c l e a ra nc e g i v es a n a c c u ra t e m ea su r em en t o f G F R , c r e at i ni ne c l ea r a nc e is ge n e ra l l y u se d b e c a us e no e xo g e n ou s d r ug m us t b e gi v e n . H o we ve r , c r ea t in i ne fo rm a ti o n d ep e nd s o n m u sc l e m as s a nd m u s c le m e ta b ol is m , wh i c h m a y c h a ng e wi t h ag e an d va ri ou s d is e as e c o n di t io ns . 2 . T he an sw e r is C [ s ee I . B . 1. b . (2 ) ] . 3 . T he an sw e r is B [ s ee I . A . 1. b . (1 ) ; I . B . 1] . 4 . T he an sw e r is B [ s ee I . B . 1. a . (2 ) ] . 5 . T he an sw e r is B [ s ee I . B . 1. a . (2 ) ] . S u b st i tu t in g t h e d a ta fo r t h is pa t ie n t i n t h e e qu a tio n fo r th e i n it i al pl as m a d r u g c o nc en t r at i on ( ) g i v es
To o b t ai n t h e p a ti en t ' s p la s m a d r u g c o nc e n tr a ti o n ( C p ) 8 h r a f t er t he do s e , t h e f o l lo wi n g c al c ul a ti on is pe r f o rm ed :
Th e a m o u nt o f d ru g i n the p at i en t ' s b od y a t 8 h r is c a lc ul a te d a s f o ll o ws : D B = C p V D = ( 1 . 11 ) ( 0. 2 8)( 7 5 ) = 2 3. 3 m g F o r an y f i rs t -o r d er el im i na t i on p ro c e s s , 5 0% o f t he i ni t ia l a m o un t of d ru g is e l im in a te d a t th e e n d o f t h e fi rs t ha l f- l if e , a nd 50% o f t h e r em ai n in g d r ug ( i . e ., 75 %
o f t he or i gi n al a m o u n t) is el im i na t ed at t he en d of t h e s e c o n d h al f -l i fe . B ec a us e t h e d r u g i n t h e c u r r en t c as e h a s a n e li m i na t io n h a lf - l i f e ( t ½ ) of 2 h r , 7 5 % o f t he d os e is e l im in a te d i n t wo ha l f- l i ve s , o r 4 h r . 6 . T he an sw e r is D [ s ee I . B . 3. e . (3 ) ] . 7 . T he an sw e r is C [ s ee I . B . 3. c ]. 8 . T he an sw e r is E [ s e e I . B . 3. f . (2 ) ] . 9 . T he an sw e r is B [ s ee I . B . 3. e . (3 ) ] . 1 0 . Th e a n sw e r i s D [ s ee I . B .3 . e. ( 3 ) ; I . E .1 . a] . 1 1 . Th e a n sw e r i s B [ s ee I . E .4 . a] . Th e e q ua t io n f o r t h e p las m a c o nc e nt r a ti on a t s tea d y s ta t e ( C s s ) p r o vi de s t h e fo rm u la f o r c a lc ul a ti n g t he r at e of a n i nt r a v e no us in f us io n ( R ) . Th e eq ua t io n i s
wh e r e k i s t h e f i rs t -o r de r e l im in a ti on r at e c on s ta nt a nd V D i s t h e a pp a re n t v o l u m e of d i st r ib u ti o n. R e ar r a ng in g t h e e qu a ti o n a nd s u bs t itu t i ng th e d a ta f or t hi s p at i e nt gi ve t h e fo ll o wi n g c al c u l at i ons :
P.143
Th e t im e i t ta k e s f o r a n in f us e d d r ug to r ea ch th e C s s d ep e nd s o n t he el im i n a ti on h a l f- l if e o f th e d r u g. Th e t im e re q ui r ed t o r ea c h 95 % of t he C s s i s e qu al t o 4 . 3 t im es t h e h a lf - li f e , wh e r e as th e t im e re q ui r ed t o r ea c h 99 % of t he C s s i s e qu al t o 6 . 6 t im es t h e h a lf - li f e . B ec a us e t he h al f -l i fe in t he c u r re n t c as e i s 1 h r, th e ti m e to r e a ch 95 % o f t he C s s i s 4 .3 × 1 h r, o r 4 .3 h r. Th e l o ad in g d o s e ( D L ) is c a lc ul a te d a s f ol l o ws :
Th e a ns we r t o qu es t io n 6 s h o ws t ha t th e i n fu s i on r a t e s h o ul d b e 9 3 6 m g / hr . Th e r e f o re , if a d r ug s o lu ti o n c on t ai ni n g 1 0 g i n 5 00 m L is us ed , th e r e qu i red i nf us i on rate is
Th e p a ti e nt ' s to t al bo d y c l ea r an c e ( C l T ) i s c al c u la t e d as f ol lo ws :
Th e h e pa t ic c le a r an c e (C l H ) is th e di f fe r en c e be twe e n t o t al c le a r an c e ( C l T ) an d re n al c l ea r an c e ( C l R ): ClH = ClT - ClR C l H = 62 37 - (8 6 m L /m in × 6 0 m i n /h r ) = 1 07 7 m L /h r 1 2 . Th e a n sw e r i s B [ s ee I . B .1 . b. ( 1 ) ]. A l a rg e a p pa r e nt v o lu m e o f di s t r ib u ti o n ( V D ) i s a n e a rl y s ig n t h at a d r ug is n o t c o nc en t r at e d i n t he pl as m a , b u t is di st r i bu t ed wi d e l y in ti ss ue . A n in c re as e i n
p l as m a p ro t ei n b in d in g s u g g es ts th a t t he d ru g i s lo c at e d i n t he pl as m a r a th e r th a n i n t i ss ue . A d ec r ea s e i n h ep a t ic m e ta bo l is m , an in cr e a s e in s i de ef f ec ts , o r a d ec r ea s e i n ur i na r y e xc r e t io n o f f re e d ru g i s c a us e d b y a de c r ea s e in d ru g e li m i n at io n . 1 3 . Th e a n sw e r i s A [ s ee I . A .3 . d. ( 3 ) ]. A s m o r e d r ug is c on c e n tr a t e d a t t he r ec ep t o r s i t e, m or e re c e p to r s i nt e r ac t wi t h t h e d r u g t o p r od u c e a p ha rm a c ol o gi c e ff ec t . Th e i nt en s it y o f t h e r es p on s e in cr e a s e s u n t il it r ea c h es a m a xi m u m . W hen al l o f t h e a va ila b le r ec ep t o rs ar e o cc u pi e d b y d r u g m ol ec ul es , ad di t io na l dr u g d oe s n o t p r od uc e a m o r e i nt e ns e r es p on s e . 1 4 . Th e a n sw e r i s B [ s ee I . D ]. N o n l in ea r ph a rm ac ok i ne ti c s is a t e rm u s e d to in dic a te t ha t f i rs t - o rd e r e li m in a t io n o f a d r ug do es no t o c c u r a t a l l d ru g c o nc en t ra t io n s . W ith s o m e d ru gs , s uc h as p h e n yto i n, as th e p la s m a d r ug c o nc en t r at i on in c re a s e s , t he el im in a ti o n pa t h wa y f o r m e ta b ol is m o f t h e d ru g be c om es s a tu r a te d a n d t he h al f -l i fe in c re as es . Th e a r e a u n d er t he pl as m a d ru g c o n c e n t ra t io n ve rs us tim e c u r ve ( A U C ) o f t he d ru g i s n o t p r o po r t io n al to th e d os e ; n e it h e r is th e ra t e o f m et a b ol i te fo r m a t io n . Th e m e ta b ol ic r a t e i s r e la t ed to th e e f f ec t s o f t h e d ru g . 1 5 . Th e a n sw e r i s D [ s ee I . B .1 . b. ( 2 ) ; I . B .5 . g. ( 1 )]. A l o ad in g d os e ( D L ) o f a d r u g i s g i v en to ob t ai n a t h e r ap eu t ic pl as m a d ru g l e ve l a s r a p id l y as po s s ib le . Th e D L i s c a lc u la t ed on th e ba s is o f th e a p pa r en t vo lum e o f d i st r ib u ti o n ( V D ) an d t h e d e s i r ed pl as m a le v e l o f th e d ru g . 1 6 . Th e a n sw e r i s E [s ee I . E .3 .c ] . I n u li n i s n ei t he r re a bs o rb e d n o r a c t i v e l y s ec r e ted . Th e r ef o r e, it is e xc r e te d b y g l om e ru l a r f il t ra t io n o n l y. Th e in u li n c le a ra nc e ra t e is us ed as a s t a nd a rd m e as u re o f t he G F R , a te s t t ha t i s u s e f ul bo t h i n a c l in ic al s i tu a ti o n a nd in th e d e v el o pm e nt o f ne w d r u gs . 1 7 . Th e a n sw e r i s E [s ee I . A .3 . d] . D r u g s t ha t ar e h i gh l y bou n d t o p l asm a p r o te i ns di f f us e p oo r l y in t o t is s u e a n d h a ve a l o w a p p ar e nt v o l um e o f d i s t r ib u ti o n ( V D ) . 1 8 . Th e a n sw e r i s B [ s ee I . B .3 . g] . Th e o ns e t t im e i s t he t im e f r om th e a dm in is t r a ti on o f th e d r ug t o t he ti m e wh e n a b so r be d d r u g r e ac he s P.144
t h e ME C . Th e ME C i s t he d r ug c o nc en t r at i on in th e pl as m a th a t i s p r op o rti o na l , b u t n o t n ec e s s ar i l y e q ua l , t o t h e m in im um dr u g c o n c e n t r at i on at th e re ce p to r s i te t ha t e l ic i ts a ph a rm ac o lo gi c re s po ns e . 1 9 . Th e a n sw e r i s A [ s ee I . A .3 . a] . Th e i n it i al d is t r ib u ti o n o f a d ru g i s c h i ef l y de t e rm in e d b y b lo o d f lo w, wh e r e a s th e a f f in i t y o f th e d r u g f o r t is s u e d et e rm i ne s wh e t h e r t h e d r u g c o nc e nt r a te s a t t h a t s i t e. Th e G F R a f fe c ts t h e r e na l c l ea r an ce o f a d r u g, no t it s i ni t ia l d is t r ib u ti on . Th e g as t r ic e m pt y i n g t im e a nd de g r ee o f p la sm a p r ot e in bi n din g af f ec t d r u g di s t ri bu t ion b ut a re l e ss i m p o r ta n t t ha n th e ra t e o f bl oo d fl o w t o t is s ue . 2 0 . Th e a n sw e r i s C [ s ee I . E .4 . b. ( 2 ) ].
Th e k id n e y , l un g , s k i n, an d in t es ti n e a ll ha v e s om e ca p ac it y t o b i ot r a ns fo rm , or m e ta b ol i z e , d r ug s ; bu t the b r ai n h as li t tl e c ap ac i ty f o r d ru g m e ta bo l is m . Th e li ve r h a s t he hi g he s t c a p ac it y f o r d ru g m et a bo li s m . 2 1 . Th e a n sw e r i s D [ s ee I . B .5 .c ] . Th e s up e r po s i t io n p r in c ip l e , wh i c h u nd e rl i es th e d e s i g n o f m u l ti p le - do s e re g im e ns , a ss u m e s t ha t e a r li e r d r ug d os es do no t a f fe c t s ub s eq u en t d os es . If t he eli m in a ti on r a t e c on s ta n t o r t o ta l b od y c le a r an ce of t he dr u g c h an g es d u ri n g m ul ti p le d o si n g, t h e n t he s u pe r p os it i on pr i n c i pl e i s n o l on g er v a lid . C ha n ge s i n t h e t ot a l bo d y c l ea r an c e ( C l T ) m a y be c a u s e d b y e n zy m e i nd uc t io n , e n z y m e i n hi bi t io n , o r s a tu r a ti o n o f a n e li m i n at io n pa t h wa y . A n y of t he se c h a ng es wo u l d c au se n o nl i ne a r p h a rm ac ok i ne ti c s . 2 2 . Th e a n sw e r i s D [ s ee I . B .5 . e. ( 3 ) ]. 2 3 . Th e a n sw e r i s E [s ee I . B .5 . g. ( 1 ) ] 2 4 . Th e a n sw e r i s A [ s ee I . B .5 . d. ( 2 ) ; I . B .5 . e. ( 3 )]. Th e o r al m a in t e na nc e d os e ( D o ) sh ou l d m a i nt a in th e pa t ie n t 's a v e ra g e d rug c o nc en t r at i on at t he ef f ec t i v e d r ug c o nc en t r a ti on . Th e b io a v a il ab i li t y o f t he d r ug ( F) , t h e a p pa r en t v o lu m e of di s t ri bu t io n ( V D ), t he do sag e in t e r v al (τ ) , a n d t he exc r e t i o n r a t e c on s ta n t ( k ) m u s t be c o ns i de r ed in ca lc ul a tin g th e d os e . Th e e qu a ti on us e d is
F o r th is d ru g , F = 0 .7 5 , k = 0 . 69 3 /2 4 h r , V D = 3 L/ k g × 65 k g , τ = 2 4 h r , an d = 1 . 5 n g /m L , o r 1 . 5 µg / L . Th e re f o r e, b y s u bs ti t ut i on , D o = 27 0 µ g, o r 0 .2 7 0 m g. W hen t he m a in t en a nc e d os e is gi v e n at a d os ag e f re qu e ncy e q u al to t he ha l f- l if e , th e n t h e l o ad i ng do s e is eq ua l to t wi c e t he m a in t en a nc e do s e , in t hi s ca s e 54 0 µ g, o r 0. 5 40 m g . To d e te r m i ne t he pla s m a d r u g c o nc e n tr a ti o n f o r a do sa g e r e gi m e n o f 0 . 12 5 m g e ve r y 1 2 h r , th e f o rm ul a i s u s e d . Th is t im e , F = 0. 7 5 , D o = 0 . 12 5 m g, k = 0 . 6 93 / 24 h r , V D = 3 L /k g × 6 5 k g , a n d τ = 1 2 h r . Th e r e fo r e , = 1 .3 9 n g /m L. F or ca r dia c g l yc os id es , th e p e ak ( C m a x ) a n d t ro ug h ( C m i n ) c o nc e nt r a ti o ns a r e c al cu l at ed , an d p l as m a d ru g c on c e n t ra t io n s a r e m o n it o r ed af t e r d o s i n g. Th e l o ad in g d o s e ( D L ) m a y b e gi ve n i n s m a ll in c re m e n ts o v e r a s p ec if i ed pe ri o d , ac co r d in g t o t h e d os a g e r e g im en s u gg e s t e d b y the m a n uf ac t u re r . 2 5 . Th e a n sw e r i s A ( I ) [ s ee I . A. 1 .a ] . Th e f i rs t eq ua t io n i n th e q u es t io n d es c ri b es a z e ro - o r de r re a ct i on (d A / d t) in wh i c h t h e re ac t io n ra t e i nc r ea s e s o r de c re as es a t a c ons t an t ra t e (k ) . A ze r o -o r de r r e a ct i on pr o du c e s a gr a ph o f a s t r ai gh t li ne wi t h th e eq u at i on of A = - k t + A o wh e n A i s p lo t te d a g ai ns t ti m e ( t ) . Th e o t he r eq u at i on s in t he qu es t io n re p r es en t f i rs t o r d e r r e ac ti o ns .
7 Bioavailability and Bioequivalence L e o n Sh a r ge l
I. BACKGROUND A. B i o a va i l a b il i t y a n d b i o e q ui va l e nc e s t u di e s a r e i m po r ta n t f o r t h e d e ve l op m en t o f bo t h n e w d r ug p ro d uc ts ( ne w d r u g a p pl ic a ti on [N D A ] ) a nd ge n e ri c d r ug p r o du c ts ( a b b re vi a te d n e w d r u g ap p li c a t io n [ A N D A] ) B . B i o a va i la b il i t y s t u d i e s a re us ed fo r es ta b li s hi n g d os a ge re g im en s o f n e w d r u g p r o du c ts C . B i o e qu i va l en c e s t udi e s c an be us e fu l d u ri n g t h e i n v es t ig a ti o na l n e w dr u g ( I N D ) d e ve l op m e n t o r N D A d e ve l op m en t p e ri o d t o e s t a bl i s h li nk s b et we e n 1 . E a rl y a nd la t e c l i ni c a l t r i al f or m ul at i on s 2 . F or m u l at i on s us e d i n c l in ic al t ri a l a nd s t ab i li t y s t ud ie s , i f d if f e re n t 3 . C li n ic al t ri al f or m u l at io n s a nd to - b e -m ar k et e d d r u g p r od uc t D . B i o e qu i va l en c e s t udi e s a r e a c r i ti ca l c om po ne n t o f A N D A s ub m i s s io ns 1 . Th e pu r po s e o f t he s e s t ud i es i s t o d em o ns t ra te b io eq u i val e nc e b et we e n a p h a rm ac e ut ic al l y eq u i v ale n t g e ne r ic dr u g p r od uc t a n d t he co r r es po n di ng re f e r en c e l i st e d d r ug (u s u a ll y t he br a n d d r ug p ro d uc t ). 2 . To g e th e r wi t h t he de te r m in a ti on o f p ha rm a c e ut i ca l e q ui va le n c e , e s t a bl is h in g b i oe q ui v a l en c e al lo ws a r e g ul a to r y c on c l us io n o f t h e r ap eu t ic eq ui va l en c e . E . S c al e - up a nd po s t - ap p r o v al ch a n ge s ( S U P A C ) — A f t e r m a rk et ap p r o va l , a d ru g p r o du c t m a y m ak e a m anu f ac t u ri n g c h a ng e . A bi oe q ui v a l en c e st u d y m a y be n ee d ed t o sh o w t h at t he ne w f o rm u la t io n o r ne w m e th o d o f m a nu f ac t u re ( te st p rod u ct ) an d t h e p r i or f or m u l at i on o r m e th o d o f m an u fa ct u r e (r e f e re nc e pr o du ct ) a re eq u i v al e nt . 1
II. DEFINITIONS
A. B i o a va i l a b il i t y i s a m e a s u r em e nt of t he ra t e an d e xt e n t ( a m o un t ) to wh i c h t he a c ti ve in g r ed ie n t o r a c ti v e m o i et y b ec om es a vai l ab l e a t t h e s it e o f a c ti on . B i o a vai l ab il i t y is a ls o c on s id e re d a m e as u re o f t he r a te an d e xt e n t o f t he ra p e ut ic al l y a c ti ve d ru g t h a t is s y s t em ic a ll y a bs o rb ed . Fo r d ru g p ro du c ts th a t a re no t i n t en de d to b e ab so r be d i n to t he bl oo d s t r e am , b io a v a il ab i li t y m a y be as s e s s ed b y m e as u re m e n ts i n te n de d t o r ef l ec t t h e r a te an d e x t e n t t o wh ic h th e a c t i v e in g r ed i en t o r ac t i ve m oi et y b ec om es a v ai l ab le a t t he s i t e o f a c ti o n. B . B i o e qu i va l en t d r ug p r o d u c ts . A g en e ri c d r ug p r od uc t i s c on s i de r e d b i oe q ui v a l en t t o th e re f er e n c e l i s te d d r u g ( R D L) p r o d uc t if bo t h p r od uc ts a re p h a rm ac e ut ic al eq u i v al en t s a nd t he ge n er ic d ru g p r o du c t ' s ra t e a nd e xt e nt o f s ys t em ic d r u g a bs o rp t ion ( bi o a v ai l ab il i t y ) d o n o t s h o w a s t at is t ic al l y si gn if i c a n t d i f fe r e nc e wh e n ad m i n is te r e d i n t h e s a m e m o la r do s e o f t h e ac t i v e i ng r e die n t , i n t h e s am e c h em i c al fo r m , in a s i m i l ar do s ag e f o rm , by t h e s am e ro u te of ad m in i s t r a ti o n, a n d u n de r th e s am e e xp e r i m e n ta l c on di t io ns . The R D L is g e ne r al l y th e b ra n d p r o du c t. P.146
C . G e n e r ic d r ug p r od u ct 1 . Th e ge ne r ic d ru g p r odu c t r e qu i re s a n a b b re vi a t e d new d r u g a p pl i ca t i on ( A N D A ) f o r ap p ro v a l b y t h e U . S . F o o d a nd D r ug A dm in is t ra t i on ( F D A ) a nd m a y be m a rk e te d a f t e r p at e nt e xp i r a ti o n o f t h e r e fe r e nc e d r ug pr o du c t ( s ee C ha p te r 1) . 2 . Th e ge ne r ic d ru g p r odu c t m us t b e a t he r a pe u ti c e qu i va l en t to t he re f er e n ce dr u g p r o du c t b ut m a y d if f e r i n c e rt a in c h a ra c t e r is ti c s , in c lu di n g s ha pe , s c o r i ng c o nf i gu r a ti on , pa c k ag in g, a nd e xc i pi e nt s (s uc h as c ol o rs , fl a v o rs , p r es e r vat i v e s , e xp i r a t i on da t e , a nd m i no r as p ec ts of la b el in g ) . 3 . F D A b e li e v es th a t p r od u c t s c la s s if i ed as th e rap e u ti ca ll y e q ui v a le n t c an b e s u bs ti t u te d wi t h t he f ul l e xp e c t a ti o n t ha t th e s ubs t i tu t ed pr o du c t wi l l p r o du c e t he s am e c li n ic al ef f ec t a n d s a fe t y p r of il e a s t h e p r es c r i be d p r od uc t . D . P h a r ma c eu t i ca l e q u iva l e n t s a r e d r ug p ro d uc ts t ha t c on t ai n th e s am e t h e r ap eu t ic al l y ac t i v e d ru g in g re d ie n t (s ) ; c o n ta i n t h e s am e sa l t , es t e r, o r c h em ic al f o r m ; a re of t he s am e d os a ge fo r m ; a nd ar e i d en ti c al in s t r en g th , c on c en t ra t i on , a n d r o u t e o f a dm in is t r at i on . P h a r m a ce u ti ca l e qu i va len t s m a y d i ff e r i n c ha r ac te r i st ic s s uc h a s s ha p e, s c or i ng c o n f ig u ra t io n , r e le as e m ec h an is m s , p ac k a g in g , a nd e xc i p i e nt s ( i nc lu di n g c o lo r s , f la v o r i ng , a n d p r es er v a t i v e s ). E . T h e r e f e re n ce l is t ed d r u g p r od u c t is us ua l l y t h e c u r re n tl y m a r ke t ed , b r a nd n a m e p ro du c t wi t h a f u ll n ew d r u g a p pl i ca t i on (N D A) a p p r o v e d b y t h e FD A . Th e R L D i s t he r ef e r en c e dr ug p r od uc t i d en t if i ed b y FD A ( s ee “ E le c t r o ni c O r an g e Bo ok ” a t ww w. f d a . g o v / c d e r /o b /d e f au l t. h tm ) . F . T he r a pe u t ic e qu i va l en t d r u g p r o du c t s a r e p ha r m ac eu t ic al eq ui v a l en t s t h a t c a n b e e xp e c te d t o h a v e t h e s am e c li n ic al ef f ec t a n d s a fe t y p r of il e wh e n a dm in i st e r ed to p a t ie n ts u n de r th e s am e c o nd i ti on s s pe c i f ie d i n t he l ab el i ng . Th e ra p eu t ic eq u i val e nt d r u g p r od uc t s h a v e t he fo l lo wi n g c r i te r ia : 1 . Th e pr o du c t s a r e s af e a n d e f fe ct i ve . 2 . Th e pr o du c t s a r e p ha rm ac e ut ic a l e qu i va le n ts th a t c on t ai n th e s am e ac ti v e d r ug i n g re d ie n t i n t he s a m e do s ag e f o rm , gi v e n b y t he s am e r o u te of ad m i ni s t ra t i on ; m ee t c om p en d ia l o r o t he r ap p li c ab le st a nd a rd s o f s t re ng t h , q ua l it y , p ur i t y, a n d id e n ti t y; a n d m ee t a n a c c e pt a bl e i n v i t ro s t an d a rd . 3 . Th e dr u g p r od uc ts a re b i oe qu i v a le n t i n t ha t th ey d o no t pr e s e n t a k no wn p ot e nt i al p r o bl em an d a r e s ho wn t o m e e t a n a pp r o p ri at e bio e q u i va le nc e s t an d ar d . 4 . Th e dr u g p r od uc ts a re a d eq u at e l y l a be le d . 5 . Th e dr u g p r od uc ts a re m an u fa c tu r ed in co m p lia n ce wi t h c u r re n t g oo d m a nu f ac tu r i ng p ra c t ic e re g ul a ti o ns . G . P h a r ma c eu t i ca l a l t e rn a t i ve s a r e d r ug p ro d uc ts t ha t c on t ai n th e s am e t h e r ap eu t ic m o ie t y bu t are d if f e re n t s a l ts , e s te rs , o r c o m p l e xe s (e . g. , te t r ac y c li n e h yd r o ch lo r i de v e rs us t et ra c y c l i ne ph os p ha t e ) o r ar e di f f e re n t d os ag e f o rm s ( e. g . , t a b le t ve rs us c a ps ul e ; im m e di a te - r el e as e d os ag e f o r m v e r su s c on t r ol le d - re l ea s e d o sa g e f o rm ) o r s t r en g ths .
III. BIOAVAILABILITY AND BIOEQUIVALENCE. Th e s e m a y be de t e rm in ed d ir e c t l y us in g p h ar m ac o k in e ti c s tu di es ( e .g . , p la s m a d r u g c o nc en t r at i on v e rs us t im e p r of il e s, u ri na r y d r ug exc r e t i o n s t ud ie s ), m e as ur e m en ts o f a n ac ut e p h a rm ac od y n am ic e ff ec t , c om pa r a ti v e c l in ic al s t u di es , o r in v i t ro s tu di es .
Th e c ho ic e o f s t ud y u s ed is ba s e d o n th e s it e o f a c ti o n o f t h e d ru g an d t he a bi li t y o f t h e s t ud y d es ig n t o c om p a r e d r ug de l i v er e d t o t ha t s i t e b y th e t wo p ro d uc t s . A. Ac u t e p ha r m ac o d yn a m i c e f fe c t s, s u ch as c h a n ge s i n h ea r t r a t e, bl oo d p r e ss u re , e l ec t ro c a r di o gr a m ( E C G ) , c l o tt i ng ti m e , o r fo r c e d e xp i r a t o r y v o lu m e i n 1 s ec ( F E V 1 ) c a n b e u s e d to m e as u r e b io a v ai l ab il i t y wh e n n o a s s a y fo r p l as m a d r u g c o nc en t r at i on is a v a i la ble o r wh e n t he pl as m a d ru g c o nc en t r at i on do es no t r el a te to t h e p h a rm ac ol og ic a l r es p o ns e (e . g. , a b ro nc h od il a t o r P.147
s uc h a s a l bu t er o l g i v en b y i n ha la t io n ) . Qu a nt i ta t io n of t he ph a rm ac ol o gi c a l ef f ec t ve r s us t im e p ro f il e c an be us e d a s a m ea s u r e o f b i oa v a i la b il it y a n d/ o r b i oe q ui v a l en c e ( Fi gu r e 7- 1 ) .
Figure 7-1. Generalized plasma drug concentration versus time curve after oral drug administration. MEC, minimum effective concentration; MTC, minimum toxic concentration. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGraw-Hill, 2005, p. 6.]
1 . O n se t t im e . A s t h e d ru g is s y s te m i c a l l y a bs o rb e d , t he d ru g c on c e n t ra ti o n a t t h e r e c ep t or r is es to a m i nim u m e f f ec t i ve co n ce n t ra t i o n ( ME C ) a n d a p ha rm ac o lo g ic al r e s po ns e i s i ni t ia t ed . The t im e f r om dr u g a dm in ist r a t io n t o th e ME C i s k nown a s t he o n se t ti m e . 2 . I n te n si t y. Th e i n t en s it y o f th e p h a rm ac ol o gi cal e ff e ct is p r o po r ti o na l t o t h e n u m b e r o f re c e p to r s oc c u p ie d b y t h e d r ug up to a m a x i m u m p ha r m a co l ogi c al ef f ec t . Th e m a xi m um ph a rm ac olo g ic al e ff ec t m a y oc cu r b e f o re , a f te r , or a t p ea k d r u g a b so r p ti on . 3 . D u r a ti o n o f ac t i on . As lo n g as t he d ru g c on c en t r a ti o n r em ai ns ab o v e th e ME C , p h a rm ac ol o gi c a l a c t i v i t y i s o bs e r ve d. Th e du r at i on o f a c t i on is t h e t im e f or wh i c h th e d r u g c on c e n t ra t io n r em a in s a b o v e t h e ME C . 4 . T he r a pe u t ic w i n dow . A s th e d r ug c o nc e nt r a tio n in c re as es , o t he r r ec ep t o rs m a y c om b in e wi t h t h e d ru g to e xe r t a t o xi c o r ad v e r s e r e s p o ns e. Th i s d ru g c o nc e nt r a ti o n i s th e m i ni m um t ox i c c on c e n t ra t i on ( MTC ) . Th e d r u g c on ce n t ra t io n r a nge b et we e n t h e ME C a n d t h e M TC i s t h e t h er a pe u ti c wi n d o w. B . P l a sm a d r u g c o nc e nt r a t i o n . Th e pl as m a d rug c o nc e n tr a ti o n v e r su s t im e c u r ve i s m os t of t en us ed t o m e as u r e th e s y s te m i c b io a v a ila b il i t y of a d r ug f ro m a dr u g p r o du c t ( F ig u re 7 -2 ) .
1 . T im e fo r pe a k p l as ma d r u g c o nc e nt r a t i on ( T m a x ) r e l a t es t o t he r at e c o n s t a nt s f o r s ys t em ic d r u g a bs o rpt i o n a nd el im in a ti o n. I f two o r a l dr u g p r od uc t s con t a in th e s am e a m o u n t o f ac t i v e dr u g bu t d i ff e r en t e xc i p i en t s , t he do s a g e f o rm th at yi e ld s t h e f a s te r ra t e o f d r ug ab s orp t i on ha s t he s h o r te r T m a x . 2 . P ea k p l as m a d r u g c on c e n t ra t i on ( C m a x ) . Th e p l as m a d ru g c on c e n t ra t io n at T m a x r e l at e s t o t he in t en s i t y of t h e p ha rm a c o lo g ic al res p on s e . Id e al l y , C m a x s h o u ld be wi t h i n th e th e ra p eu t ic win d o w. 3 . Ar e a u n de r t he p la sm a d r ug co n ce n t r a ti o n ve r s u s t im e c u r ve ( A U C) r e la t es to t h e a m o u nt o r e xt e n t of d r u g a bs o rp t io n . Th e am o u n t o f s y s te m i c d r ug abs o r pt i on is d i r ec tl y r e la t ed t o t he AU C . Th e A U C is us ua l l y c a lc ul a te d b y t he t r a pe zo i d a l r u l e a n d i s e xp r e s s e d i n u ni ts o f c o nc en t r at i on m u lt ip l i e d b y ti m e (e . g ., ) . C . U r i n a r y d r u g e x c r e t io n . Me a s u re m e n t o f u r ina r y d r ug e xc r e t io n c an de t e rm i ne b i oa va i la b il it y f r om a d r ug p r od uc t . Th i s m et h od is m o st ac c u r a te i f th e a c t i v e t h e r ap eu t ic m o ie t y is e xc r e t e d u nc ha n ge d i n si g nif i c a n t q ua n ti t y i n t he u rin e ( Fi gu r e 7-3). P.148
Figure 7-2. Generalized plasma drug concentration versus time curve, showing peak time and peak concentration. AUC, area under the curve; MEC, minimum effective concentration; MTC, minimum toxic concentration. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005, p. 7.]
Figure 7-3. These corresponding plots show the relationship of the plasma drug concentration versus time curve to the cumulative amount of drug in the urine versus time curve. [Adapted with permission from Shargel L, Wu-Pong S, Yu ABC: Applied Biopharmaceutics and Pharmacokinetics, 5th ed. New York, McGrawHill, 2005, p. 463.]
P.149
1 . T he cu m ul a t i ve a m ou n t o f a c ti ve d r u g e xc re t e d i n t he u r in e () is dir e c tl y r e l at e d t o t h e e xt e n t of s y s t e m i c d r ug ab s o r p ti on . 2 . T he r a te o f d r u g e xc re t i o n i n th e u r i n e ( d D U /d t ) is d i r ec tl y r e la t ed to th e r at e o f s ys t em ic d r u g a bs o rp t ion . ∞
3 . T he t im e fo r t he d r ug t o b e c om p le t e l y e x c r e t e d ( t ) c o r re s p o nd s t o th e to t al t i m e f or t he dr u g t o b e s y s t e m i c a ll y a bs o rb e d a nd c o m p l et e l y e xc r e t e d a ft e r a d m i ni s t ra ti o n . D . C o m pa r a t i ve c l i ni c al t r i a l s t o a d r u g ca n b e u s ed to m e as u re bi o a v ail a bi l it y q u a nt i ta t i v el y . C li n ic al s tu d ie s a r e h ig h l y va ri a bl e a n d l ess p re ci se t ha n o th e r m e th o ds b e c a us e o f i n div i d u al di f f er e nc es in dr ug p ha r m a c o d y n am ics and s u b je c t i v e m e as u re m e n ts . E . I n vi t r o m ea s u r em e nt s o f b i o eq u i va le n ce . Bio e q ui va le nc e m a y s om e ti m es b e d e m o ns t r at e d us i ng an in v i t r o b io e qu i val e nc e s ta n d ar d , e sp ec i al l y wh e n s uc h a n i n vi t r o te s t h as b e en c o r r el a t ed wi t h h um a n i n v i v o b i oa v a i la b il it y d a ta . Fo r e xa m p l e , t h e ra t e o f d r ug di s s ol u tio n in v i t ro fo r c e r ta i n d r ug p r od uc ts c o r r el a te s wi t h d r ug b i oa va i la b il it y i n v i v o. I f t h e d is s o l ut i on te s t i n v i tr o is c o ns id e r ed s t at is t ic a l l y a d e qu a te to p re di c t d r ug b i oa v a il a bi li t y , t he n , i n s om e c as es , di ss ol u ti on m a y be u s ed in pl ac e o f a n i n v iv o b i oa va il a bi l it y s tu d y .
IV. RELATIVE AND ABSOLUTE BIOAVAILABILITY A. R e l a t i ve b i oa va i l ab i li t y ( R B A ) i s t he s ys t em ic a v a i la bi l it y o f t h e d r ug fr o m a d o sa g e f o rm a s c om pa r ed t o a re f e re nc e s t an da rd g i v en b y th e s am e r o ute o f a d m i ni s t ra ti o n . R e la t i v e b i oa v a i la b il it y i s c a lc u la te d as th e r a ti o o f th e A UC f o r th e d o sa g e f o rm to th e A U C f o r th e re f e re nc e d os a ge f o rm gi ve n i n th e s am e d o se . A r e l at i ve bi oa v a i la bi l it y o f 1 ( o r 1 00 % ) im p li es th a t d r u g b io a vai l ab il i t y f ro m b o th d o sa g e f o rm s is th e s am e b ut do es no t in di ca t e th e c om p le t en es s o f s ys te m ic d r u g
a b so r p ti on . Th e d e te r m in a t io n o f re l at i ve b io a v a il a bi l it y i s im p or t an t in gen e r ic dr u g s t ud i es (e . g. , bi oe q ui v a le n c e s t u di es ) . B i oe q ui v al e nc e i s a re l at i v e b i oa va i la b il i t y s t ud y.
B . Ab s o l u t e b i oa va i l a bil i t y ( F ) i s th e f r ac t io n o f d r u g s ys te m i c a ll y a bs o rbe d f ro m t h e d os a ge fo r m . F i s c alc u la t ed as th e ra ti o of the A U C f o r t he do sa g e f o rm gi v e n o r a ll y t o t h e A U C o bt a ine d af t e r i nt r a ve no us ( I V ) d r u g a dm in is t ra t io n (a d ju s te d fo r d o se ) . A p a re n te r al d ru g s ol u ti o n g i v en b y I V a dm i ni st r a ti on is c o ns id e red t o h a v e 1 0 0 % s y s t em ic ab s o r p ti on ( i .e . , F = 1 ) . A n F v a l ue o f 0 . 80 (o r 80 % ) i nd ic at e s t h at o n l y 80 % o f th e d r ug wa s s ys t em ic al l y a vai l ab l e f r o m t he o ra l d os a ge fo rm .
V. BIOEQUIVALENCE STUDIES FOR SOLID ORAL DRUG PRODUCTS A. O b j e c t i ve o f b i o eq u iva l e n c e s t ud i es . Th e o bj e ct i v e o f a b io eq u i val e nc e s t ud y is t o m e as u re an d c om pa r e f o rm u la t io n p e r fo rm a nc e b et we e n t wo o r m o re p h a rm ac e ut ic al l y eq u i v ale n t d r u g p ro d uc ts . B . D e s ig n o f b i oe q ui va le n c e s t ud i es 1 . Th e F D A 's D i v is io n o f B i o eq u i v al e nc e, O f fi c e of G e n e ri c D r u gs p r o vi de s g u id an c e f o r th e p e r fo r m a nc e o f i n v i t r o d is so l ut i on an d i n v i v o b i oe q ui v a le nc e s t udi e s. Th e se g u id a nc es ar e a v ai la b le a t ww w. f d a . g o v / cd e r /g u id a nc es . 2 . F as t i ng s tu d y. B i o e q u i v a le n c e s t ud i es a r e u s u a ll y e va lu a t ed b y a s i ngl e - do s e , t wo - p e r i od , t wo - t r ea tm e nt , t wo - s eq u en ce , o p en - lab e l , r a nd om i z ed c ro s s o ve r d es ig n , c om p a ri ng eq u al do s e s of t h e t es t (g en e r ic ) a nd re f e r en c e ( br a nd ) pr o du c ts in f a s te d , a du l t, he a lt h y s ub j ec ts . a . B ot h m e n a nd wo m en m a y be us e d i n t he s t udy. b . B lo o d s a m pl in g i s p e rfo r m ed ju s t be f o re th e d os e ( z e ro ti m e ) an d a t a pp r o p ri a te i n t er va l s a ft e r t h e d os e to o bt a in an ad e qu a te des c ri p ti o n o f t he pl as m a dr u g c o nc en t r at i on v e rs us t im e p r of il e . P.150
3 . F oo d in t e r ve n t io n s tu d y. I f t h e b io a v a il a bi li t y o f th e a ct i ve dr u g i ng r ed i en t is k n o wn t o b e a ff e c t e d b y f o o d, t he ge ne r ic d ru g m a n u fa c t u r e r m u s t in c l u de a si ng l e d o se , ra n do m i z e d , c ro s s o v e r , fo o d e f fe c t s s tu d y c om p a ri ng eq u al do s e s of t h e t es t p r o du c t a nd r ef e re nc e pro d uc ts gi ve n i m m e di a te ly a f t e r a s t an d a rd hi gh - fa t - c o n te n t b r e ak f as t . 4 . O t h e r s t u d y d e s i g n s . C r o s s o v e r s tu d ie s m a y n o t b e p r ac t ic al in d ru gs wi t h a l o ng ha l f -l i fe in th e b o d y, a nd a p a ra l le l s tu d y de s i gn m a y be us e d i ns te ad . A l t e rn a te s t u d y m e th o ds , s uc h a s i n vi t r o s tu di es o r e qu i val e nc e s tu di e s wi t h c li n ic al o r p ha rm a c o d y na m i c e n d p o in ts , ar e u s ed fo r dr ug p r od uc ts wh e r e p l as m a
c o nc en t r at i on s a r e n ot us e fu l to de t er m i n e d el i v er y o f t he d ru g s ub st a nc e t o t he s i te o f ac t i v it y ( s u c h as in ha le r s , n as al s p r a y s, an d t op i c a l p r od uc t s a pp li e d t o t h e s k i n) . 5 . Wa i ve r o f a n in vi vo b i o e qu i va l en c e s t ud y ( B i ow a i ve r ) a . A c om p ar a ti v e in v i t ro d is s o l ut i on ( dr u g -r e le ase ) s t u d y be t we e n t h e t est a nd t he r e f e re nc e pr o du c t s m a y b e us ed in li eu o f a n i n v i v o b io eq u i v al e nc e s tu d y f o r s om e i m m e di a te - r el e as e ( c o n ve n t io na l ) o r al d ru g p r o duc t s . b . N o b i oe qu i v a le nc e s t ud y i s r e qu i re d fo r c e r ta in d r u g p ro d uc ts gi v e n a s a so l ut i on s uc h a s o r al , pa r en t e ra l , o p ht h al m i c , o r o th e r s olu t i on s b ec au se bi o eq ui va l en c e is s e lf - e vi de n t. In t hi s c a s e, t h e d ru g i s i n a pu r e a qu e o us s ol u ti o n a nd th e r e i s n o d r u g d is s o lu t io n ra t e c ons i de r a ti on . c . Im m e di a te r el ea s e ( I R) s ol id o ra l d r u g p ro d uc ts t ha t m ee t bi op h a rm ac eu t ic c l as s i fi c a t io n ( B C S ) s y s te m c la s s 1 d r ug s , i. e . , h ig h l y wa t e r s ol u bl e , r a pi dl y d i ss ol vi n g, an d ra pi d p e rm e at i on of c e ll u la r m em b r a ne s m a y o b ta i n a b i owa i v e r . d . D r ug p ro d uc ts c o nt a ini n g a lo we r d os e s t re n gth ( e .g . , 2 00 m g , 1 0 0 m g , a n d 5 0 m g I R t a bl e ts ) . Th e d ru g p r od u c t m u s t be in t he s am e d os ag e f o rm , l o we r s t re n g th , a n d i s p r o po r ti o na t el y s i m i l a r i n i ts ac t i ve a nd in ac t i ve i ng r ed i en ts . B . P h a r ma c ok i ne t i c e val u a t i on o f t h e d a ta . Ph ar m ac ok i ne t ic a n al y s is i nc l ud es c a lc ul a ti on f o r e ac h s u b je c t o f t h e A U C t o t h e la s t q ua n ti f ia b le c o nc en t r at io n ( A U C O t)
a nd to in f in i t y ( A U C 0 - ∞ ) , T m a x , a n d C m a x . I n a dd it i o n, th e el im in a ti o n r a te c on s ta n t
( k ) , t h e e li m i n at io n ha lf - li f e (t 1 \ 2 ), an d o t he r pa r am e te r s m a y b e e s tim a t ed . C . S t a t is t i ca l e va l u a ti on o f t he da t a 1 . Th e s t at is t ic al m e t ho do l og y f o r a n al yz i n g b io eq u i v al e nc e s tu d ie s is c a ll e d t h e t wo o n e -s id e d t es t p r oc e du r e. Two s i t u at i on s a r e t es te d wi t h th is s t a ti s t ic a l m e th o do l og y . a . Th e fi r s t of t he t wo one - s id ed t es ts de t er m i n es wh e t h e r a ge n e ri c p ro d uc t ( te st ) , wh e n s ub s ti t ut e d f o r a b ra n d -n am e p r o du c t ( r ef e re n c e ) is s ig n if ic a nt l y le ss b i oa va i la b le . b . Th e s ec o nd o f t he t wo o n e -s id ed t es ts de t er m in e s wh e t h e r a b r a nd - nam e p r o du c t ( r e f e re nc e ) wh e n s u b s t i tu t e d f o r a g e ne r ic p ro duc t ( te s t ) is s ig n if ic a nt l y le s s b i oa va i la b le . c . B as ed on th e o p in io ns o f F D A m e d ic al e xp e r ts , a di f fe r e nc e o f > 20 % f or e ac h o f t h e a b o v e t es ts wa s de t er m i ne d t o b e s ig n if ic a nt a n d , t he r e fo r e , u nd es i rab l e f o r a ll d r u g p r od uc t s . 2 . A n a na l y s i s o f v a ri an c e ( A N O V A ) s h ou l d b e p er f o r m e d o n t h e l og t ra ns fo r m ed A U C a n d C m a x v a l u e s o b ta i ne d f ro m e ac h su b je ct . Th e 9 0% co n fi de nc e i n te r va l s f o r b o t h p ha r m a c o k i n et ic par a m et e rs , A U C a n d C m a x , m us t b e e n ti r el y wi t h i n th e 80 % t o 1 2 5 % b ou nd a r ie s b as ed o n lo g t r a ns fo r m a t io n o f t h e d a ta . Th e ra t io of th e m ea ns o f t h e s t ud y d at a (t es t to r ef e r e nc e) sh o ul d l ie in th e c en t e r o f t h e 9 0% c o nf id e nc e i n t er va l , o r c l os e t o 1 00% ( e qu i val e nt t o a t es t to r e fe r en c e r a ti o o f 1 ) ( Ta b le 7 -1 ) . 3 . D i ff e re n t s ta t is t ic al c r it e r ia a re so m e t im es u s ed wh e n bi o eq ui v a l en ce is d e m o ns t r at e d t h ro u gh c om p a ra t i v e c l i ni c a l t r ia ls , p h a rm ac o d y na m i c s tu di es , or c om p a ra t i v e i n v i t r o m e th o d ol og y. 4 . Th e bi oe q ui v a le n c e m e t h od ol o g y an d c ri t e ri a de sc r i be d a bo v e s i m u l ta ne o us l y c o nt r o l f o r b ot h d i ff e r en c e s i n th e a v e r ag e re sp o ns e b e t we e n t es t an d r e fer e n ce p r o du c ts a s we ll as th e pr e c is io n wi t h wh i c h t he av e r a g e r e s p on s e in t he po p ul a ti o n
i s e s ti m a t ed . Th is p r ec is i o n d ep e nd s o n t h e wi t h in - s ub je c t ( n or m a l v ol u nte e r or p a t ie n t ) v a r ia b il i t y i n t h e p h a rm ac ok in e ti c p a ra m e t e rs ( A U C a n d C m a x ) o f t h e t wo p r o du c ts a n d o n t he nu m b e r of s u bj ec t s i n t he s t ud y . Th e wi d t h o f th e 9 0 % c o nf i de nc e i n te r v a l i s a re f l ec ti o n i n p a rt of t he wi t h i n- s ub je c t v a r ia b il i t y o f t h e t es t a n d re f er e nc e p r od uc t s in t he bi o eq ui va l en c e st ud y . P.151
Table 7-1. Bioavailability Comparison of a Generic (TEST) and Brand (Reference) Drug Product LN-Transformed Data 90 % Confide nce Geometric Mean Interval
PK Variabl e Units
x
ng/ mL
AU C0-t
ng hr/ mL
Cma
AU Cinf
ng hr/ mL
Test
344. 79
265 9.12
270 8.63
(Lower % Limit, Referenc Ratio Upper e T/R Limit)
96. 6
(89. 5, 112 )
0.3 586
0.8 791
17.9 0%
99. 4
(95. 1, 104 )
0.8 172
1.0 000
12.6 0%
271 8.52
99. 6
(95. 4, 103 )
0.8 865
1.0 000
12.2 0%
356. 81
267 4.92
hr
4.29
4.24
10 1
1/h r
0.09 61
0.09 80
98. 1
Tma x
keli m
Pvalues Power for of Product ANOV ANOVA Effects A % CV
t1/2
hr
8.47
8.33
10 1.7
AUC, area under the curve; Cmax, peak plasma drug concentration; Tmax, time for peak plasma drug concentration. The results were obtained from a two-way crossover, single-dose, fasting study in 36 healthy adult volunteers. Mean values are reported. No statistical differences were observed between AUC and Cmax values for the test and reference products.
P.152
VI. BIOEQUIVALENCE ISSUES A. P r o b l e m s i n d e t e rm in i n g b i o eq u i va le n ce in cl u de la ck of an ad e qu a te s t ud y d e si g n; in a bi li t y t o ac c u ra t e l y m ea su r e th e d r ug an a l y t es , i nc lu d in g m et a bo l i te s a nd e n a nt io m er s ( c hi r al d ru gs ) ; a n d l ac k o f s y st em ic d r u g a bs o rp t io n ( Ta bl e 7- 2 . ) B . B i o e qu i va l en c e s t udi e s fo r wh i ch ob je c ti v e bl o od d ru g c on c en t ra t io ns c an n ot be o b t ai ne d re q ui r e e i th e r a p h a rm ac od y n am ic st u d y, a c li n ic al t ri a l, o r a n i n v i t r o s t ud y t h at ha s b ee n c o r re l a te d wi t h h um an in v i vo b io a v ai l ab i li t y da t a. 1 . P ha r m a c o d y n am ic m ea s u re m e n ts a r e m o re di ff i c u l t t o o b ta in , an d t h e d a t a t en d t o be va r ia b le , re qu i r in g a l ar g e r n um be r of su bj ec t s c o m p a r ed to t he b i oe q ui v a l en c e s t ud i es fo r s y s t em ic a ll y a bs o rb ed d r u gs . a . A b i oe q ui v a le nc e s t udy u s in g p h a rm ac od y n am ic m e as u re m e n ts t ri es to o b t ai n a p h a rm ac o d y na m i c e ff e c t v e r s us t im e p ro f il e fo r the d r ug in ea c h s u bj ec t . b . Th e a re a u nd e r t h e e ff e c t v e r s u s t im e p r o fi le , p e ak ef f ec t , a nd t im e f o r p e ak e f f ec t a r e o b ta in e d f o r t he t es t a n d r e fe r en c e p rod u ct s a n d a re t he n s ta t ist i ca l l y a n al yze d . 2 . C om p ar a ti v e c l in ic a l tr i a ls a r e m o re di f fi cu l t t o r u n , d o n ot ha v e e as il y q u a nt i fi ab l e o bs e r v at i ons , an d a r e q ui t e c os tl y . 3 . I n vi t r o s tu di es m a y r eq u i re t he de v e lo pm e nt o f a r el ia b le s u r r og a te m a rk e r t h at m a y be c o r r el a te d wi t h hu m an in vi v o b i oa v a i la bi li t y d a ta . F o r e xa m p l e, t he p e n et r a ti on o f d ru g i n to la y e r s o f s k i n wi t h r es p ec t t o t im e ( d e r m a to p ha r m a c o k i n et ic s ) h as be en s u g ge st e d a s a m e t ho d f o r m ea su r in g th e b i oe q ui v a l en c e of t op ic al d r u g p ro d uc ts in t en d ed f o r lo c a l a c t i vi t y.
VII. DRUG PRODUCTION SELECTION A. G e n e r i c d r ug s ub s t itu t i o n 1 . G e ne r i c d r u g s u bs t i tu t i o n i s t he p ro c e s s of di s pe ns i ng a g en e ri c d r ug p r o du c t in p l ac e o f th e p r es c r i be d dr u g pr o du c t ( e .g . , g en e ric p ro d uc t f o r b r an d - na m e p r od uc t , g e n er ic p ro d uc t f o r a no th e r ge ne r ic p ro d uc t, b ran d - na m e p ro d uc t f o r g ene r i c
p r o du c t) . Th e s ub s ti t ut ed p r od uc t m us t b e a th e ra p e ut ic eq u i v al en t to th e p r es c ri be d p r o du c t. 2 . G e ne r ic dr u g p r od uc t s t h a t a re c l as s i f ie d a s t he r a pe u ti c e qu i v a le n ts b y t h e F D A a r e e xp e c t e d t o p r od uc e t h e s am e c li ni c a l e f f ec t a n d s af e t y p ro f il e a s t he p r e s c ri b ed drug.
Table 7-2. Problem Issues in the Determination of Bioequivalence Problem Issues
Example
Drugs with highly variable bioavailabilitya
Propranolol, verapamil
Drugs with active metabolites
Selegiline
Chiral drugs
Ibuprofen, albuterol
Drugs with nonlinear pharmacokinetics
Phenytoin
Orally administered drugs that are not systemically absorbed
Cholestyramine resin, sucralfate
Drugs with long elimination halflives
Probucol
Variable-dosage forms
Dyazide, conjugated estrogens
Nonoral drug delivery Topical drugs
Steroids, antifungals
Transdermal delivery systems
Estrogen patch
Drugs given by inhalation aerosols
Bronchodilators, steroids
Intranasal drugs
Intranasal steroids
Biotechnology derived drugs
Erythropoietin, interferon
Bioavailable drugs that should not reach peak drug levels
Potassium supplements, hormone replacement therapy
Target population used in the bioequivalence studies
Pediatric patients; renal disease
a
These drugs have high intrasubject variability.
P.153
3 . P r es c r i ba b i li t y r e f e r s t o th e m ea s u r em e nt of a v e r a ge bi o eq u i v al en c e in wh i c h t h e c om pa r is o n o f p op u la t i on m e an s o f t h e t es t an d r ef e re n c e pr o du ct s f al l s wi t h i n a cc e pt a bl e s t at is t ic al c r it e r ia . P re s c r ib a bi li t y is th e c u r re n t b as is fo r F D A a p p ro v a l o f t he r ap e ut ic eq u i v al en t g e ne r ic dr u g p r od uc ts . 4 . Sw i t ch a bi l i t y r e f e r s to t he m e as u re m e n t o f i nd i v i du a l b io e qu i v al e nc e, wh i c h r e q ui r es k n o wl e dg e o f i nd i v i du a l va r i ab il i t y (i n t ra s u bj ec t va ri a bi li t y) an d su b je c t -b y f o r m u l at io n ef f ec ts . S wi tc h ab il i t y en su r es th a t t he su bs t i tu t ed ge n er ic d rug p r od uc t p r o du c e s t h e s a m e r es po n s e in th e i n di vi d ua l p at i e n t . B . T h e ra p e ut i c s u bs t i t ut i o n 1 . Th e r ap e ut ic s u bs t it u tio n is th e p r oc es s o f d is pe n s i n g a t h e ra pe u ti c a l ter n a ti ve i n p l ac e o f th e p r es c r i be d dr u g pr o du c t. Fo r e xa m ple , am o xi c il l in is d is p en s e d fo r a m pi ci ll i n. 2 . Th e s u bs ti t ut e d d r ug p r o du c t is us ua l l y i n t h e s am e th e ra p eu t ic c la s s (e . g . , c a lc iu m c h a nn e l b lo c k e r) a n d is e xp e c te d t o h a v e a s i m i la r c l in ic al p ro f il e . C . F o r m ul a r y i s s u e s 1 . A fo r m u la r y i s a li s t of d r ug s . A po s i ti ve f o rm u l a r y l is t s a ll th e d r u gs th a t m a y be s u bs ti t u te d , wh e r e as a ne g a t i ve f o rm u la r y li s ts dr u g s f o r wh i c h t he p ha rm a c is t m a y n o t s ub s ti t ut e . A r e st r i c ti ve f o rm u la r y l is ts on l y th o s e d ru gs th a t m a y b e re i m b u rs ed wi t h o u t j us t i fi c a t io n b y th e p re s c ri b e r; f or d ru gs n o t l is t ed in th e re s tr ic t ive f o r m u l ar y , t he p re s c r ib e r m us t j us t if y t h e n ee d f o r t h e n on l is te d d r u g. 2 . Ma n y s t a te s h a v e l ega l re q ui r em e nt s t ha t ad dr e ss t he i ss u e o f d r ug p ro d uc t s e le ct i on . St a t es m a y pro v i d e i n fo r m a t io n a nd gui d an c e in d ru g p r o du ct s e l ec t io n t h r o ug h p os i ti v e , n e ga t i ve , o r r es t r ic ti v e f or m u l a rie s . 3 . Th e F D A a nn u al l y pu bl i s h es A pp r ov ed D r ug P ro d uc ts w i th Th e r ap eu t ic E q u iv al e nc e E v a l ua t io ns ( t h e “ O r a ng e Bo ok ” ) . Thi s p u bl ic a ti on is al so r epr o d uc ed in t h e Un i te d S ta t es Ph a r ma c op e ia ( U S P ), D I Vo l . I II , A pp r ov e d D r u g P r o du ct s an d L e g al R eq ui r e m e nt s , p ubl i s h ed an n ua l l y b y t h e US P C o n ve nt i on . Th e “ E l e c t r on ic O r a n g e B o ok ” m a y be fou n d a t h t t p: / / ww w. f d a . g ov / c d e r /o b /d e fa ul t . ht m .
a . Th e “ O r an ge B oo k ” p ro v i d es th e r ap e ut ic e v al ua t i on c o de s f o r d r ug p rod u c t s ( Ta b l e 7 - 3 ) .
Table 7-3. Therapeutic Equivalence Evaluation Codes A Drug products that are considered to be therapeutically equivalent Codes to other pharmaceutically equivalent products AA
Products in conventional dosage forms not presenting bioequivalence problems
AB
Products meeting bioequivalence requirements
AN
Solutions and powders for aerosolization
AO
Injectable oil solutions
AP
Injectable aqueous solutions
AT
Topical products
Drug products that the FDA does not at this time consider to be B therapeutically equivalent to other pharmaceutically equivalent Codes products BC
Extended-release tablets, extended-release capsules, and extendedrelease injectables
BD
Active ingredients and dosage forms with documented bioequivalence problems
BE
Delayed-release oral dosage forms
BN
Products in aerosol-nebulizer drug delivery systems
BP
Active ingredients and dosage forms with potential bioequivalence problems
BR
Suppositories or enemas for systemic use
BS
Products with drug standard deficiencies
BT
Topical products with bioequivalence issues
BX
Insufficient data
FDA, U.S. Food and Drug Administration.
P.154
( 1 ) “ A - “ ra t ed ” d ru g p r od uc t s a r e d ru g p r o du ct s t ha t c o n ta in ac t i v e i ng r ed ie n ts an d d o sa g e f o rm s t ha t a r e no t r eg a rd e d a s p re se n ti ng e it h e r ac t ua l o r po t en t ia l b i oe q ui v a l en c e p ro bl em s o r d ru g q ua l it y s ta n da r ds i s s u es . H o we v e r , a ll o ra l do sa g e f o r m s m us t m ee t an ap p ro p r ia t e i n vi t r o b io e qu i v al e nc e s ta n da r d t h at is ac c e pt a bl e t o t he F D A t o b e a pp r o ve d as th e ra p eu t ic al l y equ i v a le n t a n d m a y b e i nt er c h an ge d . ( 2 ) “ B “ - ra t ed ” d ru g p r od uc t s a r e d ru g p r o du ct s f o r wh i c h a c tu a l o r p o te n ti al b i oe q ui v a l en c e p ro bl em s h a v e n o t b ee n re s o l v e d b y a d eq u at e e vi d en ce of b i oe q ui v a l en c e . Th es e pr o d uc ts o ft e n h a ve sp ec if i c d os ag e fo r m p ro b le m s r at h e r t h a n a p r o bl em wi t h th e a c ti v e in g r ed ie n ts (e . g ., t wo d i f f er e nt ni c ot in e pa tc h es ) . “ B “ r a t ed ” d ru g p r od uc t s a re n ot c o ns id e r ed th e r ap eu t ic a ll y e qu i val e nt t o o the r p h a rm ac e ut ic al l y eq u i v ale n t p r o du ct s a nd a re no t i n te r c h a ng ea b le . ( 3 ) C e r ta in p ro d uc ts pr es e nt s p ec i al s i tu a ti on s t ha t de s e r v e a m or e c om p le t e e xp l a n a ti o n t h an c a n b e p r o v i de d b y t h e t wo - c ode s u s e d i n th e “ O ra n ge B o o k . ” Th e s e d r u gs h a v e p a r ti c u l a r p r ob le m s wi t h s t an da r d s o f i de n ti t y, an al yt i ca l m e th o do l og y , o r b io eq u iv a l e nc e t h at a re co ns id er e d i n di vi d ua ll y . F o r t he s e d r ug s , c o ns ul t th e “ O r a n ge B ook . ” b . F o r s o m e d ru g p r od uc t s , b i oe qu i v a le nc e h as no t be e n es t ab l is he d o r no g en e ri c p r o du c t is c u r r en t l y a v a i la b le . 4 . V a ri ou s h os p it al s , i ns ti t u ti o ns , i ns u ra nc e p l an s, h ea l th m a in t en a nc e o r ga n i za ti on s ( H M O s ) , a nd ot h e r t hi r d -p a r t y pl a ns m a y ha ve a fo r m ul a r y th a t p r o v id es gu i da n ce f o r d ru g p r od uc t s u bs ti t ut i o n. P.155
STUDY QUESTIONS
D i r e c t i on s fo r q ue s t io ns 1 - 3 : E ac h o f t h e q ue s tio n s , s t a te m e n ts , o r in c om p le t e s t a te m e n ts i n th is s ec t ion c a n b e c o r re c t l y a ns we r e d or co m p le t e d b y o ne o f th e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r . 1 . T he pa r a me t e r s u se d t o d es c r ib e b i o a va il a b il i t y a r e ( A ) C m a x , A U C 0 - t , an d A UC 0 - ∞ . ( B ) C m a x , A U C 0 - t , A U C 0 - ∞ , a nd T m a x . ( C ) C m a x , A U C 0 - t , A U C 0 - ∞ , a nd t 1 \ 2 . (D) Cma x a n d AUC0- t. ( E ) C m a x , A U C 0 - t , A U C 0 - ∞ , a nd T m a x , a n d t 1 \ 2 . V i e w A n s we r 1 . T h e a n sw e r i s B [ se e] . C T t 2 . T o d e t e r mi n e t h e a bs o l u te b i o a va i la b i li t y o f a d r ug g i ve n a s a n o ra l e x t en d e d - re l ea s e t a b le t , t he b i o a va i la b i li t y o f t h e d ru g m us t be co m pa r e d to t h e b i oa va i l ab i l i t y o f t h e d r ug from ( A ) a n im m ed ia t e - re le as e o r al ta bl e t c on t ai ni n g th e s am e a m ou n t o f ac t i ve i n g re d ie n t. ( B ) a n o r al s o lu t io n o f the d r ug in th e s am e d os e . ( C ) a pa r en t e ra l s ol u ti o n o f th e d r ug gi v e n b y i n t ra v e n o us (I V ) bo lu s o r I V i n f us io n . ( D ) a r ef e re n c e (b r a nd ) e xt e n d e d - re l ea se ta b le t t h a t i s a p h ar m a c eu t ic al e q ui v a l en t . ( E ) a n im m ed ia t e - re le as e h a rd ge la t in c a ps ul e co n t a i ni n g t he s a m e am ou n t o f ac ti ve d r u g a nd la c to s e . V i e w A n s we r 2 . T h e a n sw e r i s C [ se e] . F 3 . A s i ng l e - do s e , tw o -w a y c r o s so ve r , f a st i n g, c om p a r a ti ve b i oa va i l ab i l i ty s t u d y w as pe r f o r me d i n 2 4 h e a l th y, a d u l t ma l e s u bj e c t s. P la s ma d r ug co nc e n t r a ti o ns w e r e o b t ain e d fo r e a c h s ub j e ct , an d th e re s u l ts sh ow n in Ta b le 7- Q 3 w e r e ob t a in e d . T he r e l a t i ve b i o a va i la b i li t y o f t h e d ru g f r o m t h e g en e r i c t a bl e t co m pa r e d t o t he r e fe r e n ce tablet is
Table 7-Q3 Drug Product
Dose (mg)Cmax (µg/mL)Tmax (hr)AUC0-∞ (µg hr/mL)
IV bolus injection
100
Oral solution
200
21.3
1.2
3143
Generic tablet
200
17.0
2.1
2822
Reference tablet
200
16.5
1.9
2715
IV, intravenous. ( A ) 8 2 .3 % . ( B ) 6 9 .8 % . ( C ) 9 1 .7 % .
1714
( D ) 9 6 .2 % . ( E ) 1 03 . 9% V i e w A n s we r 3 . T h e a n sw e r i s E [s e e] . D i r ec t i o ns f o r qu e s ti o ns 4 -6 : Th e q u es t io ns an d i nc om p le te s ta t em en ts in t hi s s e c ti o n c an be c o r r ec tl y a ns we r e d o r c om p le t ed b y on e o r m or e o f t h e su g ge s te d a nswe r s . C h o os e t he an s we r , A- E . P.156
4 . F o r tw o d r ug p r od u ct s , ge n e r ic ( te s t ) a n d br a n d ( r ef e r e nc e ) , t o b e c o n si d e r ed b io e qu i va l en t I . t h e re sh o u ld be n o s ta t i s t ic a l d i f fe r e nc e b e tw e en t he ex t e nt o f b i oava i l a b i li t y o f t h e d r u g f r o m t h e t es t p r o du c t c o mp a r ed t o t h e r ef e r e nc e p r o d uc t . I I . t he 90 % c o n f i d e nc e in t e r va l s a b o ut t h e r a t io o f t he me a ns o f t h e C m a x a nd AU C va l u e s fo r t h e t es t p r o d uc t t o r e f e re n ce pr o d u c t m u st b e w i t h in 8 0 %- 1 2 5 % o f t h e r e f e re n ce p r od u ct . I I I . th e r e s h ou l d b e n o s t a t is t i ca l di f f e r en c es b e tw e e n t h e m ea n C m a x a n d AU C va l u e s fo r t h e t es t p r odu c t co m pa r e d t o t he r e fe r e n ce p r od u c t. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 4 . T h e a n sw e r i s E [s e e] . T C 5. F o r w h ic h of t h e f o ll ow i n g p r o d u c ts is me a su r i n g p l a sm a d r u g c o n ce n t r at i o n s n o t a p p r op r i a te fo r e s t i ma t i ng b io e qu i va l en c e ? I . m et e r e d- d os e in h al e r c o n ta i n in g a b r o nc h odi l a t o r I I . an t i f un g a l a ge n t fo r t h e t r ea t me n t of a va gin a l in f e ct i o n I I I . e n t e r ic - co a t ed t ab l et c o n ta i n in g a n on s te r oi d a l a n t i -i n f la m ma t o r y a g e n t A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 5 . T h e a n sw e r i s C [ se e] . 6 . Bi o e qui va l e n ce s tu d i es co m par e t h e b io a va i la b i li t y I . o f th e g e ne r i c d r u g pr o d u c t t o t he b ra n d d r ug p r o d uc t . I I . o f a r ef o r m ul a t ed b ra n d d ru g p ro d u ct t o the o r i gi n a l f o r mu l a ti o n of t h e b r a n d p r o d u c t. I I I . of a t o - be - m a rk e te d b r a n d p r o d uc t t o t h e d ru g p r o du c t u s ed i n t h e c l i n ic a l trials. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t
V i e w A n s we r 6 . T h e a n sw e r i s E [s e ea n d] . P . 15 7
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee I I I . B] . A U C r e l at es t o t he e xt e nt o f d r ug ab s or p ti o n. C m a x a n d T m a x r e l a t e to th e ra t e o f d r u g a bs o rp t io n . Th e el im i na t io n t 1 / 2 o f t h e d ru g i s u s u a ll y i nd e pe nd e nt of t h e r ou t e o f d ru g a dm i ni s t r a ti on and is no t us ed as a m e as u r e of bi o a vai la b il i t y. F or t h e F D A , o n l y th e C m a x a n d A U C pa r a m e t er s m us t m ee t 9 0% c o n fi d en c e in t e r v al s of 8 0 -1 2 5% o f t he re f e re nc e (b r an d ) p r o du c t ( Ta b le 7 .1 ) . 2 . T he an sw e r is C [ s ee I V . B ] . A f t e r a n IV bo l us i n je c t i on o r I V in f us io n , a ll th e do s e is ab s or b ed in t o t he b o d y. Th e r a t io o f t he A U C of t he dr u g gi v e n o r al l y to t he AU C o f th e d r u g g i ven b y I V i nj ec t io n i s u se d to ob t ai n t h e a bs o l u te bi oa v a i la b il it y ( F ) of t h e d ru g . 3 . T he an sw e r is E [ s e e I V . A ] . Th e r e la t i v e b io a v a il a bi lit y i s d e te r m i ne d f ro m t he r a t io of t he A U C o f th e g e n er ic ( t e st ) p ro d uc t t o t h e A UC o f th e re f e re nc e s ta n da r d . Th us th e re la t i v e b io a v a il a bi li t y c a n e xc e e d 1 00 % , wh e rea s th e a bs ol u te bi o a v ai la b il i t y c a nn o t e xc e e d 1 00 % . 4 . T he an sw e r is E [ s e e V . C ] . A l t h ou gh T m a x i s a n i n di c a t i on of r at e o f dr u g a bs o r p ti o n , i t is a d is c r e te m e as u re m e n t a nd us ua l ly t o o v a ri a bl e t o u s e f o r s t a ti s t ic a l c o m p a ri s on s in b i oe q ui v a l en c e s t ud i es . S t a t is ti ca l c om p ar is o ns u s e A U C a nd C m a x v a l u e s f ro m t es t a n d re f er e nc e d r ug p ro du c ts as th e b as is of bi o eq u i val e nc e . 5 . T he an sw e r is C [ s ee V . A ] . A l t h ou gh s o m e s y s t em ic a b s o r p ti on m a y b e d em on s t ra t ed af t e r a dm in is t e ri n g a m e te r e d d os e i nh al e r c on t a in in g a b ro nc h od il a t or o r a v a g in a l a nt i fu n ga l ag e n t, b i oe q ui v a l en c e c a n b e de t e rm i ne d o nl y b y us i ng a c l i ni c a l r e s p on s e m e as u r e m e n t. 6 . T he an sw e r is E [ s e e I . A , B, C , D a n d E ] . B i o eq u i v al e nc e s tu di es c o m pa r e t h e b io a v ai l ab il i ty o f a d r ug f r om o n e d rug p r od uc t t o an o th e r d r ug p ro d uc t c o nt a in in g th e s am e a ct iv e i n g re di e nt . D r ug pr o du c ts s uc h a s c ap s ul es th a t a r e us ed i n c l i ni c a l t r ia ls sh ou l d b e b i oe q ui va le n t t o t h e m a rk e te d d r u g p r od uc t wh i c h m a y b e a t ab l et . G en e r ic d r ug p r o du c t s a nd t he c o r re sp o n di ng b r a nd d ru g p r o du c t m u s t b e b i oe q ui v a le n t . F o r an y c ha n ge a f o rm ul a ti o n, t h e m a nu f ac tu r e r (b r an d o r ge n e ri c ) m u s t d em on s t r a te t ha t th e f o rm u la t io n c ha n g e d oe s n o t a f f ec t t h e bi o a v ai l ab il i t y c o m p a re d t o th e o r ig in a l p r od uc t .
8 Functional Group Chemistry and Biochemistry M a r c W . Ha r r o l d
I. FUNCTIONAL GROUP CHEMISTRY A. I n t r o d u c t io n . D ru g m o l ec ul e s ca n b e v ie we d a s a c o ll ec t io n o f fu nc t ion a l g r ou ps ( i . e ., g ro u ps o f at om s p re s en t wi t hi n th e d r ug t hat c on f er s p ec i fi c c h e m i c al a nd p h ys ic al p ro pe r t ie s [ F ig ur e 8 -1 ] ) . F u nc ti o na l g r oup s d e te r m i n e s u c h c h a rac t e ri st ic s a s i o ni z a t io n , s o l ub il i t y in a qu e ou s a nd li pi d e n v i r o n m e n ts (a k a po l ar i t y ) , r e a ct i vi t y, c h em ic al s t ab i li t y , an d i n v i v o m et a bo li c s ta b il i t y . A d d i ti on a ll y, t he se fu nc t io n al g r o up s a r e c a pa b le o f fo r m i n g s pe c i fi c bo n ds ( p r im a r il y n on co v a le n t ) wi t h t h ei r r e c ep t or s a n d a re t hu s ext r e m e l y im p o rt a nt in d rug ac t i v i t y a n d p ot e nc y. 1 . F un ct i on al g ro u ps t h at i m p a r t h yd r o p h i l i ci t y a r e li k e l y t o i nc r ea s e th e d r u g 's wa t e r s ol u bi li t y , wh i l e f un c ti o na l g r ou ps t ha t i m pa r t l ip o ph i l ic i t y ( h yd r o p h o bi c i t y) a r e l ik e l y to in c re as e t h e d r u g 's te n de nc y t o c r oss ce ll u la r m em b ra n es th ro u g h p a ss i ve d if f us io n . Se e Ch a p te r 12 V II I B 1 fo r a fu r t h er di s c us s i o n o f wa t e r a nd li pi d s o lu bi l it y . a . A c i di c a nd ba s i c f u nc ti o na l g r o up s a ll o w f o r d r u g i on i za t i on an d , i n m o s t c as es , i m pa r t e n ha nc ed wa t e r s o l ub i li t y t o t he m o le c u l e. O n e no t ab l e e xc e p ti o n to t hi s i s s e en in am p ho t e r ic d r ug s ( i. e ., t ho s e c o m p ou n ds po ss es s i n g b ot h a c i d ic a n d b as ic f u nc t io n al g ro up s ). A s e xe m pl i fi ed b y am pi c i ll i n i n F i gu r e 8 - 2 , am p ho t er ic c om p ou n ds c an f o rm z w it t e r i o ns , or i n te r n al sa lt s . S in c e th e z wi t t e ri o n fo r m o f a m pi ci ll i n h as a ne t o v e ra l l c ha r ge o f z e r o , i t h as d i ff ic u lt y d is s o l v i ng i n aq u e ou s e n vi r on m e n ts s uc h as t he g as t ro i nt es t in a l ( G I ) t ra c t . b . N e ut r al f un c t i on al g rou p s ( i .e . , t h os e t ha t ar e in c ap a bl e o f i o ni za t io n ) c a n e n h an c e ei t he r wa t e r o r li p id s o lu b il i t y d e pe n di ng o n th e i r a bi li t y t o f o rm hyd r o g e n b o n d s w i t h w a te r . H y d ro g e n b on di n g is t he pr im a r y m ec ha n ism f or in c rea s in g t h e wa t e r s ol u bi li t y o f n on e le c t ro l y t es (i . e ., c om p ou nd s th a t d o n ot po s s es s ac i di c , b a si c, o r q ua t e rn a r y am m o ni um fu nc t io n al g ro ups ) . 2 . F un ct i on al g ro u p r e act i vi t y a f f e c t s d r u g s h el f l i f e , s ta b i li t y, a n d s to r a g e . Th er e a r e a n um be r of fu nc t io na l gr o up s t h at wi l l d e gr ad e , p r im a ri l y t hr o ug h a i r o xi d a t i on a n d h yd r ol y s is , u n de r nor m a l e n vi r o n me n t al c ond i t i o ns . Two e xa m p l es of t hi s l a t te r c o nc e rn a re s e en wi t h a s p i r in an d n i tr o gl y c e r in . Bo t h co m p o un ds ar e s u b je c t t o r ap i d h y d ro l y s i s i f e xp o s ed to m o is t e n v i r on m en t s . 3 . F un ct i on al g ro u ps a ls o a f fe c t i n vi vo s t a bi l i t y a n d t he du r a ti o n o f d r ug a c ti on . Th e s us c e p ti bi l it y o f a giv e n d r ug to m e t ab ol ic bio t r a ns fo r m a t io n d e pe nd s i n p a r t u p o n t he fu nc t io n al g ro up s th a t a re p re s e n t ( s ee C h a p te r 17 I I, I II ) . a . D r ug s t h at c o n ta in a la r g e n um be r o r p e rc en t ag e of h yd ro p hi li c f u nc ti on a l g r ou ps a r e of t en el im in a te d f rom t he bo d y un c h a ng ed or wi t h m i n im al m e ta b ol ism . b . D r ug s t h at c o n ta in a la r g e n um be r o r p e rc en t ag e of li p op hi l ic fu nc t io nal g ro u ps o f t en r eq u ir e e xt e n s i v e m e ta b ol is m .
Figure 8-1. Ibuprofen, a nonsteroidal antiinflammatory agent, is comprised of an ionizable, hydrophilic carboxylic acid and three hydrophobic functional groups: an isobutyl alkyl chain, an ethyl alkyl group, and an aromatic ring.
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Figure 8-2. Ampicillin is an amphoteric compound. It contains an acidic carboxylic acid and a basic amine and exists in vivo as a zwitterion. The proton from the carboxylic acid binds to the basic amine, producing a molecule with an overall net charge equal to zero.
B . Ac i d i c f un c t io n al g ro u p s 1 . T yp e s . S h o wn i n F i gur e 8 -3 a re e xa m pl es o f th e s i x m o st c o m m on ac id i c f u nc t io n al g ro up s . I n g ene r a l, c a r bo xy l i c a ci ds ten d to be m o r e a c i di c t h an a n y o f t h e o t he r fi v e f un c t i on al g r o up s . Th e te t r a z ol e ri ng p r o vid es th e b es t c h a rg e d e lo c al i z at i on s i nc e r es on a nc e a ll o ws t he c h a rg e t o be eq u al l y s h a re d a m o n g a ll f i ve a to m s i n t h e r i ng . 2 . C o mm o n a t t r ib u t es a . A c i di c f un c ti o na l g r oup s i m p a r t h yd r o p h i l i c it y t o a d ru g m ol ec u le du e to t he i r p o t en t ia l f o r i on i z a ti o n. b . A ci di c f u nc ti o na l g r oup s c an f o rm i o n ic , io n - di p o l e, an d h yd r o g e n b on d s wi t h r e c ep t or s , e n z y m es , t r ans p o rt p ro t ei ns , a n d o th e r m ac r om ol ec u le s . c . Ac i di c f un c t i on a l g ro up s c an f o rm s a l ts w h en c o m bi n e d w i t h b a se s .
d . C a r b ox yl i c a c id s a r e o f t en es t e r if i e d f o r t he p u r po se s o f p r o dr u g f o rm a ti o n ( s e e C h a p te r 17 , s ec t io n VI for a d di ti o na l i n fo r m a t io n ). Th e y c a n a ls o u nd e rg o a c id - or e n zym e c a t al y z e d de c a rbo x yl a t i o n r ea c ti on s . e . M e t ab o l is m . A c i d ic fun c ti o na l g r ou ps ca n u n de r g o c o nj u ga t i o n wi t h glu c u ro ni c a c id , g l y c i n e, an d g l ut am i n e .
Figure 8-3. Examples of drugs that contain an acidic functional group as part of their chemical structure.
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C . B a s ic f un c t io n a l g r ou p s 1 . T yp e s a . Al i p h a ti c an d a l i c yc l i c a mi n es a re th e m os t co m m o n b as ic fu nc t io n al g r o up s . A s s h o wn in Fi g u re 8 -4 , t h es e a m i n es c a n b e p r i mar y, s e c o n d a r y, o r t e r t i a r y, d e p en di n g o n t he nu m b er o f s ub s ti t ue n ts a t t ac hed t o t h e n it r og e n. b . Ar o m a t i c a mi n es , s uc h a s t h at s e en in p ro c a in a m i d e ( Fi g u re 8 -4 ) , a r e m uc h l es s b a si c a nd fo r al l i n te n ts a n d p u rp os e s ca n b e c on s i d e re d n e ut r a l. c . Ar o m a t ic , he t e r oc yc l i c n i t ro g en s v a r y in th e ir b as ic i t y, b u t i n g en e ra l a r e m uc h l e ss b as ic t ha n a li p ha t ic a n d a li c yc l ic am in es ( Fi g u r e 8- 5 ) . d . A dd i ti o na l b as ic fu nc t io n al g ro u ps i nc l ud e i m i ne s , h yd r a z i n e s , a mi d i ne s , a n d g u a n id i ne s (F i gu r e 8 - 6 ). I m i n es te n d t o b e l es s ba s ic th an al i ph a ti c a nd al i c yc l ic a m in es , wh e r ea s g ua n id in e s t en d to be m uc h m o re b as ic . Th e b as ic it y o f th e ot h e r t wo f u n c t i on al g ro u ps l i es s o m e wh e r e i n b e t we e n. 2 . C o mm o n a t t r ib u t es a . B as ic fu nc t io n al gr o ups im pa r t h yd r o p h i l i c i t y t o a d r u g m o l ec ul e d ue t o t h ei r p o t en t ia l f o r i on i z a ti o n an d th e i r a bi li t y t o f o rm hyd r o g en bo n ds . b . B as ic fu nc t io n al g ro ups c a n f o rm i on i c, i on - d ip o l e , a nd h yd r o g e n b on d s wi t h r e c ep t or s , e n z y m es , t r ans p o rt p ro t ei ns , a n d o th e r m ac r om ol ec u le s . c . B as ic f u nc ti o na l g r ou ps c a n f o rm sa l t s w h e n co m b i ne d w i th ac i ds . d . M e t a bo l is m . Co m m on m e ta bo l ic p a th wa y s f o r p r i m a r y am in es a re o xi da t i ve d e a mi n a ti o n , a ce t yl a t i o n , a nd N - ox i d at i o n. C om m o n p a th wa ys f o r s ec on d a r y an d t e r t ia r y am i ne s a r e a ce tyl a t i o n ( s ec o nd a r y a m i ne s o n l y) , o x id a t i ve N -d ea l k yl a t i o n , a n d N -o x id a t io n . A ro m at i c a m i ne s c an be ac e t yl a t e d , wh i l e a r om a ti c h ete r o c yc l ic
n i t ro g en s c an un d er g o N - o x i da t i on o r N - de a lk yl a t i o n . Im i ne , h y d r a z i ne , a m id in e , a n d g u an id i ne g ro up s c an u nd e rg o s im il a r re ac t ion s a s t h os e l is te d fo r p r im a r y , s ec o nd a r y , a n d t e r ti a r y am i ne s . A dd i ti o na ll y , am in e s c a n be gl u cu r o n i dat e d , s u l f a te d , a nd me t h yl a t e d b y p ha s e I I c o n ju g a tio n r ea c ti on s . D . Ad d i t i o n al h yd r o p h i l i c f u nc t i on a l g r o up s 1 . S im il a r t o a m i n es , h yd r o x yl g r o u p s (o r a lc o ho l s ) m a y be c l as s i fi e d as p r im a r y, s e c on d a r y, o r t e r t i a r y, d e p en di n g o n t he nu m b er o f s ub s ti t ue n ts a t t ac hed t o t h ei r r e s pe c t i v e c a rb o ns . A g oo d e xa m pl e o f th is is s een wi t h t he gl uc oc o r ti c o id f l u dr o co r ti s o n e ( F ig u re 8- 7 ) . a . H yd r o xy l g r o up s c an fo r m i o n - di p o le an d h yd r o g e n b o n ds wi t h re ce p to r s , e n zym e s , t ra ns p o rt p ro t ei n s , an d o t he r m a c r om o le c ul es .
Figure 8-4. Examples of drugs that contain a primary, secondary, tertiary, or aromatic amine as part of their chemical structure. Whenever an amine is part of a nonaromatic ring (e.g., ticlopidine), it is referred to as an alicyclic amine. Whenever an amine amino is part of a side chain or is attached to a nonaromatic ring, it is referred to as an aliphatic or alkyl amine. Whenever an amine is directly attached to an aromatic ring (e.g., procainamide), it is referred to as an aromatic amine.
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Figure 8-5. Examples of drugs that contain aromatic, heterocyclic nitrogens as part of their chemical structure.
b . H yd r o xy l g r o u ps e n han c e w a te r so l u bi l i t y d u e t o t h ei r a b il i t y t o fo r m h yd r o ge n b o n ds wi t h wa t e r.
c . H yd r o xy l g r o up s a r e of t e n e s te r i f ie d in or d e r to p r od uc e p r od r u gs . S e e C h a pt e r 1 7 V I f o r a dd i ti o na l i n fo rm a ti o n o n p r od r ug s . d . M e t a bo l is m . P r im a r y h y d r o xyl g r o u ps a re i n it ia l l y ox i d iz ed t o a l de h yd e s an d t h e n t o c a r bo x yl i c a c i ds . S ec on d a r y h y d r o xyl g r o u ps a re ox i d iz ed t o k et o n e s, wh i l e t e rt i ar y h y d r o xy l g ro u ps a re no t u su a ll y o xi d i z e d . H yd r o xy l g r o u ps m a y al so u n d er g o p h as e I I gl u cu r o n i d e o r su l f at e c o n ju ga t i o n .
Figure 8-6. Examples of drugs that contain a basic imine, hydrazine, amidine, or guanidine functional group as part of their chemical structure.
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Figure 8-7. Examples of drugs that contain a hydroxyl group, phenol, catechol, or quaternary ammonium functional group as part of their chemical structure. Fludrocortisone contains a primary, secondary, and tertiary hydroxyl group. This designation is similar to that used for amines and depends on the number of substituents attached to the respective carbons. As illustrated with levodopa, a catechol is simply two phenol groups that are ortho to one another.
2 . P he n o ls , a s e xe m p l if ie d b y e s t ra di o l ( F ig u re 8- 7 ) , ar e h y d r o xy l g r o u ps t h a t a r e d i r ec tl y a t ta c h e d t o a n ar o m at ic r in g . a . D ue t o r es o na nc e s tab i li z a t io n o f th e a r om a ti c r i ng , ph e no ls c a n b e i oni z e d in b a si c e n v i ro nm e nt s ; ho w e v e r , m o s t ph e no ls ar e pr i m a r i l y u n i o n i z ed at p h ys io l og ic al p H a nd as s uc h s h ou ld be t re a te d as n eu t r a l, no n io ni za b le fu n c t i on al g r o up s .
b . S im il a r t o a lc o ho ls , ph e n ol s p ri m a r il y f o rm i on - d i p ol e a n d h yd r o g e n b o n d s. Th e y c a n a ls o e n ha n ce w a te r s ol u b il i t y a n d b e e s te r i fi e d t o f o rm p r o d rug s (s ee C h a p te r 17 V I ). c . D r ug m o le c u le s c on t ain i ng ph e no ls o r c a te c hol s (s e e l e vo d op a i n Fi gur e 8 -7 ) a r e s us c e p ti b le to a i r o xi d a t i on an d t o ox i da t i on o n co n t ac t w i t h f e r r ic io n s . d . M e t a bo l is m . P h en o ls u n d er g o s u lf a t io n , g l u cu r o n i da t i o n, a r om a ti c h yd r o x yl a t i o n , an d O - me t h yl a t i o n . 3 . Q u a te r n a r y a m m o n i um s al t s , as e xe m p li fi e d b y i p r at r op i um b r om i de (F i g ur e 8 7 ) , a re ne i th e r a c i di c n o r b as ic bu t c o nt a in a p e rm a n en t po s i ti ve c h a rg e. a . Th e se s a lt s e n ha n ce w a te r s ol u b il i t y; h o we v e r , du e t o th e p e rm an e nc e o f th e p o si t i ve c h a r ge , c om po un d s c o n t ai ni n g t hi s f un c ti o n a l g r o up of t en ha ve di f f i c ul t y p a s si n g th r o u gh l ip i d m e m b ra n es . b . S im il a r t o a m i n es , q ua t e r na r y am m o n iu m s a l ts c a n p a r ti ci pa t e i n i o nic a nd i on d i p o le b on d s. c . Q ua t e rn a r y am m o ni um s al t s a re ge n e ra ll y n o t m e ta b ol i z e d; ho we v e r , N d e a lk yl a t i o n c o u ld oc c ur i n s om e c as es . E . F u nc t i on a l g r o u ps w i t h i n te r m ed i a te po l a r i ty 1 . K e to n es a re le s s pr e v a l en t th a n a lc oh o ls a n d p h e no ls i n th e s t ru c tu r es o f dr u g m o le cu l es . O n e e xa m p l e i s s ee n i n t h e o ra l h y p og l yc em ic a g en t , a ce t oh exa m i d e , s h o wn in Fi g u re 8 -8 . a . K et o ne s a r e p r im ar i l y l i pi d s ol u bl e ; h o we ve r , th e y a r e a bl e t o f o rm h yd r o g e n b o n d s wi t h al c o h ol s a nd c e rt a in am in es . Th e y c an a ls o f o rm io n - di p o le bo n ds . P.163
Figure 8-8. Examples of drugs that contain a ketone, ester, amide, lactone, or lactam as part of their chemical structure.
b . M e t a bo l is m . K e to n es a r e v e r y s t ab l e. Th e i r p r im a r y r ou t e o f m et a bo li sm is r e d u c ti o n to an a lc o ho l. 2 . C om p ou nd s c on t ai ni ng e s te r s , a mi d es an d the i r re s p ec t i ve c y cl ic f o rm s , l a c t on e s, a nd la c t am s c a n be s e en in Fi g u re 8- 8. a . Th e se fu nc t io n al gr o up s a r e c ap a bl e o f fo rm i ng h yd r o g e n b on d s wi t h r e c ep t or s , e n zym e s , t ra ns p o rt p ro t ei n s , o th e r m a c ro m o l ec ule s , a nd wa t e r . Si m i la r to k e to ne s ,
e s te r s a nd la c to ne s c an f u nc t io n a s h yd r o g e n - bo n d ac ce p t o r s, wh i l e am i de s a nd l a ct am s c an fu nc t io n a s e i t he r h yd r o g e n - b o n d do n o r s o r a cc e pt o r s . b . M e t a bo l is m . E n z y m a ti c h yd r o l ys i s i s t h e p ri m a r y r o u te of m e t ab ol is m fo r t he se f u nc t io n al g ro up s . E s t e rs a n d l ac to n es a r e h y d r o ly z e d t o al c o h ol s a nd c a rb o xyl i c a c id s, wh i l e am i de s a nd l a c t am s a r e h yd r ol yz e d to a m i ne s a nd c a r bo xyl i c a c id s. E s t e rs a n d l ac to n es ar e m o r e s u s c ep t ib l e t o h y d ro l y s is th an a re am id es an d l a ct am s . A d di ti o na l l y , s om e l ac t am s m a y u nd e r go N - d e al k yl a t i o n p ri o r t o o r in pl a ce o f h yd ro l y t ic c le a v a ge . F . L ip o p hi l i c f u nc t i on a l g r o u ps 1 . Al k yl g r o u p s a re sa tu r a t e d h yd r o c a r b o n c ha i n s , l i nk s , a nd r i ng s tha t ca n v a r y i n s i ze fr om s i ng l e -c a rb on m e th yl a n d me t h yl e n e g r o up s t o l a rg e c ha i ns . S i m il a r t o t h e d es i gn a ti o ns p r e v io us l y gi v e n fo r a m i n es , t h e d es i gn a ti o n a li c yc l i c r e f e r s t o a l k yl g r ou ps th a t a r e p a rt o f a no n ar om a ti c ri ng , wh i l e t he de s i g na t io n a l ip h a t ic r e f e rs to t ho s e th a t a r e pa r t of a s id e c ha in o r t h at f u nc ti o n t o c on ne c t, o r b r i dg e , o t h e r f un c t i on a l g ro u ps . E xa m p l e s o f a lk yl gr o ups a re il lu s t ra t ed in Fi gu re 8 - 9. a . A lk yl g r o up s c a n pa r tic i pa t e i n va n de r W aa l s i n t e r ac t i o ns (i . e ., in du c e d di po l e i n du c ed di po l e b on ds ) an d h yd r o p h o b i c b on d ing . b . M e t a bo l is m . O xi d a ti on is t he m a jo r ro u te of m e t a bo li s m . Al k y l si d e c hai n s a r e u s ua ll y o xi d i z e d at ei t her t h e t e r mi n a l ( ω ) o r p en u l t im a t e ( ω- 1 ) c a rb o n a t om s . 2 . Al k e n es , a ls o k no wn a s ol e f in s , a r e u ns a t u rat e d an al o gs of al k y l g r oup s (s ee F i g ur e 8 - 9 ) . a . Th e bi nd i ng ab il i t y of a l k e n es i s s i m i l a r t o t ha t o f s a tu r a te d a lk y l g ro ups . P.164
Figure 8-9. Examples of drugs that contain alkyl groups and alkenes as part of their chemical structure. For the sake of clarity, only certain functional groups have been highlighted.
b . M e t a bo l is m . A lk e ne s a r e s om e wh a t m o re r ea ct i ve t ha n a lk y l gr o up s a nd a r e s u bj ec t to m e ta b ol ic h yd r a t i o n , e po x i da t i on , pe ro x i da t i o n, an d r ed u ct i on . 3 . Mo s t a r om a ti c h yd r o c a r b o ns ar e an al o gs o f e i t he r be nz e ne o r n a ph th a l en e ( s e e F ig u re 8 -1 0 f o r e xa m p le s ). W he n a t ta c h e d to a d r u g m o l ec ul e , b en z e n e i s r e f e r re d t o a s a p he n yl g r o u p .
a . S im il a r t o a lk y l g ro up s a n d a lk en es , a r om a ti c hyd r o c a rb on s c an pa r t ic ipa t e i n va n d e r W aa l s i n te r a c ti o ns a n d h yd r o p h o b i c b o n din g . A dd i ti on a ll y , a ro m a t ic r in gs ca n p a r ti c i p a te i n ch a r ge - t r an s f e r in t e r ac t i on s . E l ec t r o n - ri ch a ro m a t ic ri n gs (i . e ., t ho se wi t h e l ec t ro n - do na t in g g ro u ps ) c a n f o rm d i po l e- l ik e i nt e r ac ti o ns wi t h e le c tro n - po o r a r o m a t ic ri ng s (i .e . , t h os e wi t h el ec t r on - wi t h d ra wi n g g ro up s ) . b . M e t a bo l is m . O xi d a ti on is t he pr im a r y r ou t e o f m e ta b ol is m f o r a r om at ic h yd r o ca r bo ns , wi t h h yd r o x yl a t i o n , ep o xi d a t io n , a n d d i o l f o r ma t i on c o m p r i si ng t he t h r e e m o s t c o m m on pa t hwa y s . 4 . E t he r f un c t i on al g ro up s c on t ai n a n o xy g e n a to m b o un d o n b o th s i de s b y e i th e r a l k yl o r a r om a ti c c a r b ons . Th e y c a n b e p r es en t as ei t he r a t e rm in a l f un c t io n al g r o up , s uc h a s t h e m e tho x y g r o u p o f n a pr o xe n , o r as pa r t o f a c e n t ra l c h ai n /b ac k b o ne , s uc h a s t h a t s e e n i n g em fi b ro zi l ( F i gu r e 8 - 1 0) . a . Th e c o nt r ib u ti o n o f e th e r s t o d r ug bi nd i ng is m i n i m al ; ho we v e r , t he s e fu n c t i on al g r o up s c an pa r t ic ip a te in d i p ol e - in d u ce d d i p ol e i n t e r ac t i o ns an d c an s er ve a s h yd r o g e n - b o n d a c ce p t or s . b . M e t a bo l is m . Me t h y l an d et h yl e t he r s c an un der g o O - de a lk yl a t i o n , wh i le t ho se l a r ge r do no t g e ne r al l y un d e rg o m e ta bo l ism . W hile e th e rs us ed as o rg an ic s ol v e n ts ( e . g ., di e th y l e th e r ) c an fo r m p e r o xi d es an d m a y e x p lo d e, t hi s p ro p e rt y is ge n e ra ll y n o t p r es e nt in d ru g m ol ec u le s . 5 . Al k yl a n d a r o ma t i c ha l i d es ar e e l ec t r o n -w i thd r aw i n g f u nc ti o na l g r o up s . Th e y a r e of t en us ed t o “ lo c k ” a d r ug m o le c u le in a d es i r e d c on f or m a t io n a n d/ o r t o d e c re as e a r om a ti c o xi d at i o n o f t h e d ru g . F l uo r in e i s t h e s m al l es t h al o ge n , wi t h i ts s i z e ve r y s im il a r to th a t o f h y d ro g en . Ch l o ri ne is t h e s ec o nd s m a l le s t , fo llo we d b y b r o m i ne an d i o di ne , r es pe c ti v e l y . S ee Fi gu r e 8 - 10 f o r s p e ci fi c e xa m p l es . P.165
Figure 8-10. Examples of drugs that contain an aromatic hydrocarbon, ether, and/or alkyl or aromatic halide as part of their chemical structure. For the sake of clarity, only certain functional groups have been highlighted.
a . W it h t h e e xc e p ti o n o f f l u or i ne , wh i ch c a n s e r v e a s a h y d ro ge n - bo nd ac c e p t o r, h a li d es d o no t d i re c tl y pa r t ic ip a t e in t he bi nd i ng o f d ru gs to t he i r r ec e pt o rs o r o th e r m ac r om o le c u le s .
b . M e t a bo l is m . A r om a ti c h a li de s a r e n o t n or m a l l y m e ta bo l i z ed . Al k y l h al i de s c an u n d er g o o x id a t i ve d e ha lo g e na t i o n t o f o rm al de hyd e s .
II. BIOCHEMISTRY A. I n t r o d u c t io n . B i oc hem is t r y is th e s t ud y o f c he m ic al p ri nc ip l es th a t sup p o r t li f e p r o ce s s es . I t i n fl u en c e s d r u g m et a bo li sm , t h e ra pe u t ic e f f ec ti v e n ess , an d b i o tr a ns f or m a t io n . Bi oc he m ic al l y s i gn i fi c a n t m o l ec u le s i nc lu d e am i no ac ids , c a r bo h yd ra t es , l i pi ds , p y r i m i d in es , p u r in es , a n d bi o po l y m er s —p r o te in s a nd e n zym e s , wh i c h a re bu i lt f r om am in o a ci d s; po l y sa c c h a ri de s , wh i c h a r e b ui l t f r om c a r bo h yd ra t es ; a n d n uc le i c ac i ds , wh ic h a r e b ui l t f r om p y r im id i ne s a nd pur i n es . B . Am i n o a ci d s a r e t he m o no m e r ic un i ts o f pr o tei n s a nd en zy m e s a nd hav e t h e f o l lo wi n g g e ne r al f o rm ula :
1 . W it h t h e e xc e p ti o n o f g l y c in e , n at u r al l y oc c u r rin g am in o a ci ds a re L, α -a m in o a c id s. P r ot e in s a r e m a d e u p o f th e 2 0 d i ff e r en t am i no ac id s , wh i c h d if f e r in t he si de c h ai n ( R ) a tt ac h ed t o P.166
t h e α -c a r bo n . Th e 20 di f fe r e n t s i d e c h a in s v a r y i n s i ze , s h a pe , c ha r g e, h yd r o ge n b o n di ng c a pa c i t y , an d c he m ic al r ea c t i v i t y . A p ro t ei n c a n b e h yd r ol yz e d in to i ts c om p on e nt α - am i no ac ids b y ac id s, ba se s , o r e n zy m e s . a . Am i no ac id s wi t h a ci di c s id e c h ai n s i nc lu d e as p a rt ic ac id an d g l ut am ic a ci d . b . A m i no ac id s wi t h b as ic s i de ch a in s i nc l ud e a rg i ni n e, l y si ne , an d h is t am i ne . c . Am in o ac id s wi t h p ol ar , n o n io n ic s id e c h ai n s i nc l ud e g l y c i n e, s e r in e , c ys t ei ne , t h r e on in e , t y r o s i ne , as par a g in e , a nd gl u ta m i n e. d . A m i no ac id s wi t h n o np o l a r , h yd r o p h o b i c s i de c ha i n s in cl u de al a ni ne, v a l in e , l e uc in e , i s o le u c i ne , ph eny l a l an i ne , m e th io n in e , p ro l in e , a nd t r y p to p ha n . 2 . Am i no ac id s h a v e a z w i t te r i o n s t r u ct u r e , wh i c h a c c o un ts fo r t he i r h igh m e l ti n g p o in t an d l o w wa t e r s o l ub i li t y . Am i no ac id s i n so lu t i on ha v e th e fo ll o wi n g g e n er a l f o r m u l a:
3 . I on i z a t i on of am in o ac i ds to th e z wi t t e ri o n f o rm o r o th e r f o rm s d ep e nds on p H ( F i gu r e 8 - 1 1) . C . C a r b o h yd r a t e s . Th e s e a r e p ol y h yd r o xy a l d ehy d e s o r k e t on es . Th r ee m a jo r c l as s e s o f c a r b oh y d r a te s e xi s t . 1 . M o n os a cc h a ri d es ( s im p le s u ga r s ), s u c h as g lu c os e o r fr uc t os e , co n s is t of a s i ng le po l y h y d r o xy a l d ehy d e o r k e to ne un i t . a . Al d e h yd i c m o n os ac c ha r i de s a r e r e du c i n g su g ar s .
b . Mo n o s ac c h a ri de s c an b e li nk ed t og e th e r b y g l yc o s id i c b o n ds , wh ic h a re h yd r o l yz e d b y a c i ds bu t n o t b y b as es . 2 . O l i go s ac c ha r i de s , s uc h a s s uc r os e, m a l to s e , a n d l ac t os e, co ns is t o f sh o r t c h ai ns of m o n os ac c h a ri de s j o in ed c o v a l en t l y. a . S uc r o s e c a n no t b e a bs o r be d b y t he in t es t in e un t i l i t is co n v e r te d b y suc r as e i n to i t s c om po ne n ts , g l uc os e a n d f r uc t os e . b . M a l t os e i s h y d r ol y z e d b y m al t as e i nt o t wo m o le c ul es of gl uc o s e . c . La c t os e ( o r m il k s ug ar ) c an no t be ab s o r be d by t h e in t es ti n e u nt i l i t is c o n ve rt e d b y l ac t as e i n to it s c om pon e n ts , g al ac t os e a n d g luc os e . 3 . P o l ys a c c h a r i de s , s uc h as ce l l ul o se an d gl yc o g e n , c o ns is t of lo n g cha i ns of m o no sa c c ha r i de s . D . P yr i m i d i n e s a n d p u r in e s . Th es e a re ba s es t ha t , wh e n b o nd ed wi t h ri bo s e, f or m n u cl e os id es , wh ic h wh e n s ub s e q ue n tl y b on d ed to p h os ph o ri c a c i d f o rm n u cl e ot id e s— t he s t r uc t u ra l bu il d in g b lo c k s o f n uc le i c ac i ds . 1 . P yr i m i d i n e b a se s i nc l u de : a . C yt o s i n e ( C ) , f ou n d in d eo xy r i b o n u cl ei c a c i d (D N A ) a n d r i bo nu c l e ic a cid ( R N A ) b . U r a ci l ( U ) , f ou n d i n RN A o n l y c . Th ym i n e ( T) , f o un d i n D N A o nl y
Figure 8-11. Amino acid ionization in solution. The carboxyl and amino groups are either in ionized or unionized form depending on the pH of the solution.
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2 . P u r in e ba se s i nc l ud e : a . Ad e n i ne ( A ) , f ou n d i n D N A a n d R N A b . G u a ni n e ( G ) , fo u nd in D N A a n d R N A 3 . P y r im i di ne s a n d p ur i ne s e xh i b i t ta u t om e r is m ( a f o rm o f s t e re oi s o m e r is m ) a nd c a n e xi s t in ei t he r k e t o (l a c t am ) o r e no l (l ac t im ) fo r m s . E . B i o po l ym e r s 1 . P r o te i n s a re p ol y m ers o f am i no ac id s t ha t ar e l i nk ed to g et h e r b y pe p t id e b on d s ( i . e ., li nk s b e t we e n c a r bo n y l c a r bo ns an d a m i n o n i t ro g en s [ F ig u re 8 -1 2 ] ). P r o t ei ns h a ve fo u r s t ru c tu r al le v e ls .
a . P r i ma r y s t r u c tu r e r e fer s to t he s e qu e nc e o f a m i n o a c i ds an d l oc a ti o n o f d is u lf i de b o n ds i n t h e p r ot e in . b . S ec o n da r y s t r u c tu r e re f e rs to t he s p at i al a rr a ng e m e n t o f s eq u en ce d a m i n o a c i ds ( f o r e xa m pl e , α - c on f o rm a t i on [h e li c a l c oi l ] o r β -c o n f o rm at i on [p l ea t ed s h ee t ] ) . c . Te r t i a r y s t r u c t u re re f er s to t he th r e e- d im en si on a l s t ru c t u r e o f a s i ng le p r o t ei n . d . Q u a te r n a r y s t r u c t u re r e f e rs to t he ar r a ng em e nt o f i nd i vi du a l su b un i t c ha i ns in t o c om p le x m o l ec ul es . 2 . E nz ym e s a r e p r ot e in s c ap a bl e o f a c ti ng as c a ta l y s ts fo r bi ol o gi c r e ac tio n s . Th e y m a y be s i m p le o r c om pl ex a n d m a y r eq ui r e c of a c to r s o r c o en z y m e s f o r b iol o gi c a c ti vi t y. a . A n e n z y m e e nh a nc es t h e ra t e o f a s p ec if ic c h em ic a l r e ac ti o n b y lo we r i ng t he a c t i va t i on en e r g y o f t h e r e ac t io n . I t d o es n o t c ha n g e t he r ea ct i on ' s e q ui li b r iu m p o in t , a n d i t is n ot us ed u p o r p er m a n en t l y c h an ge d b y th e r e ac t io n . b . A c o fa c to r m a y be an i n o r g an i c c o mp o ne n t (u s ua ll y a m e ta l i o n ) o r a n o n p r o te i n o r g an i c m o le c u le . A c of ac t o r m a y be b io lo g ic al l y in ac t i v e wi t h o ut an a p o en z y m e (t h e p r ot e in p o r ti o n o f a c om p le x e n z ym e ) . A c of ac t o r f i rm l y bo u n d t o t h e a p oe n z y m e i s c a l le d a p r o st h e t ic g ro u p . A n o r g an ic c o f ac to r th a t i s no t fi r m l y b o u nd bu t i s ac t i v el y i n vo l v e d d u ri n g c a t al ys is is c a ll ed a c o en z ym e . c . A c om pl e te , c a ta l y t ic al l y ac t i ve e n z ym e s ys t em i s r e fe r r ed t o as a h o l oe n z ym e . d . E n zy m es fa ll in t o s i x m a jo r c l ass es . ( 1 ) O x i do r e du c t as e s ( e .g . , de h y d ro g en as es , o xi d a se s , p er o xi d a s e s ) a r e i m po r t an t i n th e o xi d a t i v e m e ta bo l is m o f d r u gs . ( 2 ) T r an s f e ra s es c a ta l yz e t h e t r an s fe r of g ro u ps , s uc h as ph os p ha t e a nd a m i n o g r o up s . ( 3 ) H yd r o l a s e s ( e .g . , p ro t e ol y t ic en z y m e s , am y la s es , e st e r as es ) h y d r ol y z e t h ei r s u bs t ra t es . ( 4 ) L ya s e s ( e . g. , de c a r bo xy l a s e s , d e am in as es ) ca t a l yz e th e r e m o va l o f f un c ti o na l g r o up s b y m e a ns ot h er th a n h y d r ol ys is . ( 5 ) L ig a se s (e . g. , D N A l ig a s e , wh i c h bi nd s n uc leo t i de s t og e th e r d u ri n g D N A s yn t he s i s ) c at a l y z e th e c o u pl i ng of t wo m o l ec ul es . ( 6 ) I so m e ra s es c a ta l y z e v a r i o us i so m e r i za ti o ns , s uc h a s t h e ch a ng e fr om D t o L f o r m s o r t he c h an ge f r om c i s i s o m e r s t o t r an s i s om e rs . 3 . P o l ys a c c h a r i de s (a ls o c a l le d g l y ca ns ) a re l o ng - c ha in po l y m e r s o f c a rbo h y d r a te s a n d m a y b e l i ne a r o r b r an c he d . Th e y a r e c la ss if ie d as h om o po l ys a c c h ar id e s o r h e t e ro po l y s a c c h ar i de s . a . H o mo p o l ys a c c h a r i des ( e .g . , s ta r c h , g l y c og en, c el lu l os e ) c o n ta i n o nl y o n e t yp e o f m o no m e r ic un i t. ( 1 ) S t a rc h (a r es e r v e f oo d m a te r i al of pl an t s ) is c om p os ed o f t wo g lu c o s e p o l ym e r s —a m y lo s e (l i nea r a nd wa t e r s ol u bl e ) a nd am y l o pe ct i n ( h ig hl y b ra n ch e d a nd wa t e r i ns o lu bl e ) . I t y ie l ds m a in l y m a l to s e ( a gl u c o s e d is ac c h a ri d e) a ft e r en z ym a t ic h yd r o l ys i s wi t h s a li v a r y o r p an c r e a ti c am y l as e ; on l y g lu co s e af t e r c om pl et e h yd r o l ys i s b y s t r o ng ac ids .
Figure 8-12. Peptide bond formation occurs as a result of the condensation of the carboxyl group of one amino acid with the amino group of another. Water is eliminated during this process.
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( 2 ) G l yc o g e n , l ik e a m y lop e c t i n, is a h ig hl y b r an ch e d , c o m p a c t c h ai n o f D- g l uc os e . Th e m ai n s t or a ge po l y s ac c h a r id e o f a n im al c e ll s , i t i s f o un d m os tl y i n l i v er a n d m us c l e a n d c an be h y d rol y z e d b y s a li va r y o r p a nc r e a ti c a m y la se in t o m al to s e a nd D - g l uc os e . ( 3 ) C e ll u l os e (a wa t e r -i ns o lu bl e s t r uc tu r al po l ys ac c h a r id e f o un d i n p la n t c e l l wa ll s ) i s a li n ea r , u n br a nc he d c h a in o f D - g lu co s e . It c a nn o t b e d i ge st e d b y h um an s b e ca us e th e h um an in t es t i n al t ra c t se c re t es n o e nz y m e c ap a bl e o f h y d r ol y zi n g it . b . H e te r o p o l ys a c c h a r i de s ( e. g ., he p a ri n , h ya lu ro n ic ac id ) c o nt a in t wo o r m o re t yp e s o f m on om e r ic u n its . ( 1 ) H e pa r i n (a n a c i d m uc o po l y s a cc ha r i de ) c o ns is t s o f s ul f at e d e ri va t i ves o f D g l uc u ro n at e , D -g lu c o s am i n e a nd L -i d u ro na t e . I t ca n be is ol a te d f r om lu n g t i ss ue an d i s u se d m ed ic a ll y t o p r e ve n t b l oo d c lo t fo rm a ti o n. ( 2 ) H ya l u r o n i c a c id , a c o m po n en t o f b a ct e ri a l cel l wa l ls as we l l as o f t he v i t r e o us h u m o r an d s y n o v ia l f l ui d, c on s i st s o f a l te r na t in g u n i ts o f N - ac et y l - D - gl uc os am i ne a n d N -a c e t y l -m u r am i c a c i d . 4 . N u cl e ic ac i d s a re li ne a r po l ym e r s o f n uc le o tid e s —p y r i m i di n e a nd pu r in e ba se s l i nk ed t o r ib o s e or de o xy r i b os e s ug a rs (n u c l eo si de s ) a n d b ou n d t o p ho sp ha t e g r o up s . Th e ba c k bo n e o f t h e n uc le ic ac id co ns is ts o f a lt e rn a ti n g p ho s p h ate a nd p e n to se un i ts wi t h a pu r in e o r p y r im id i ne ba se at ta c he d t o e a c h . a . N uc le ic ac i ds a r e c lo s e l y as s o ci a t ed wi t h c e ll ul a r c at i o ns an d s uc h b as ic p r o t ei ns as h i s to n es a nd p r o ta m i ne s . b . Th e t wo m a in t y p es o f n uc l ei c ac i ds a r e D N A an d R N A. R N A e xi s t s i n th r e e forms. ( 1 ) R i bo s om a l R N A ( r RN A ) f u nc ti o ns as a f ra m ewo r k t o bi nd bo t h m es s en g e r a nd t r a ns f e r R N A . I t is c om p ri s ed of nu m e r o us s ub u nit s wi t h t h e 4 0 S a nd 60 S b e in g th e m os t we l l k no wn . ( 2 ) M e ss e n ge r R N A (m RN A ) s e r ves a s t h e t em pla t e fo r p r o te i n s y n th es is a n d s p ec if i es a po l y p ep t id e ' s a m i n o ac i d se q ue nc e .
( 3 ) T r an s f e r R N A ( t R N A) c a rr i es ac ti v a t ed am in o a c i ds t o t he r ib os om es , wh e r e t h e a m in o a c i ds a re in c o r po ra t e d i nt o th e g r o wi n g p oly p e p t id e c ha i n. c . In bo t h D N A a nd R N A , t h e s ucc es s i v e n uc le o tid e s a r e j oi ne d b y p h os ph o d i es t e r b o n d s b et we e n th e 5 ′ - h yd r o xy g r o u p of on e n uc l eo t i de ' s p e nt os e a n d t he 3 ′ - h y d r o xy g r o up o f t he ne xt n u c le ot i d e 's pe n to s e . d . D N A di f fe r s f r om R N A i n t h at i t l ac k s a h yd r o x yl g r o u p a t t h e p en t os e ' s C 2 ' p o si t io n , a nd it c o n ta in s T r a t h e r t h an U . e . D N A s t r uc t ur e c on s i s ts o f t wo α - h e li c a l D N A s tr a n ds c o il ed a ro u nd th e s am e a xi s t o f or m a do ub l e h el i x. T h e s t r an ds a re an t ip a ra l le l — t he 5 ′, 3 ′ -i n te r nu cl e ot i d e p h os p ho di es t e r l in k s ru n i n o p po s i t e d i re c t i on s. ( 1 ) H yd r o g e n b o nd i ng be t we e n s p ec i fi c b as e p air s A - T a nd C - G ho l ds t he t wo D N A s t r an ds t og e th e r. Th e s t ra n ds a re c om p le m e n ta r y ( t h e b as e s eq ue nc e of on e s t r an d d e t e rm in es th e b as e s equ e nc e o f th e o t he r ) . ( 2 ) Th e h yd r o p h o b i c bas e s a r e o n t h e i ns id e o f t h e h e li x; t h e h ydr o ph i li c d e o xyr i b o s e- p ho s p h at e b a c k bo n e is on t he ou ts id e .
III. BIOCHEMICAL METABOLISM A. O ve r vi e w . B io c h em ic a l m e ta b ol is m is t he re vie w o f p a th wa ys t h at le a d t o th e s yn t he s i s o r br e ak do wn o f c o m p ou n ds im po r ta n t t o t he l i fe o f a n o r ga ni sm . 1 . C o n t ro l o f m et a b ol i sm . Me t a b ol is m i s c o n t ro ll e d b y s u b st r a te c o nc en tr a t io n , e n zym e s ( c o ns t it u ti v e o r i n du c e d ) , a ll os t er ic ( r egu l a to r y ) en z ym e s , h or m on e s, an d c om p a rt m e n ta t io n . 2 . C a ta b o li s m is t he s um o f d eg r ad a ti o n r ea c ti on s th a t us u al l y r el ea s e en e r g y fo r u s ef u l wo r k ( e. g . , m e c h an i c a l , os m o t ic , b i os y n th et i c ). 3 . An a b o l is m i s t he s u m o f bi os yn t he t ic (b ui l d -u p) r e ac t io ns th a t c on s u m e e n e rg y t o f o r m n e w b io c h em ic a l c om p ou n ds (m et a bo li t es ) . 4 . Am p h i b ol i c p a thw a ys a r e t ho s e t ha t m a y b e u s ed fo r bo t h c at a bo li c as we l l a s a n a bo li c p u rp os es . K r ebs c yc l e b r e a k s d o wn m et a b ol i te s p ri m ar i l y t o re le a s e 90 % o f t he to t al en e rg y o f a n o r g an is m . I t a ls o d r a ws o f f m e ta b ol it e s t o f o rm c o m po u nd s s uc h a s a m i n o ac i ds (e . g. , as p ar t ic , g l ut am ic , al an i ne ) . H em og lo b in ha s i ts he m e m o ie t y f or m e d f ro m s u c c i n y l c o en zy m e A (s ucc i ny l C o A ) an d g l y ci n e f ol l owe d b y a c om p le x s e t of r ea c ti on s . P.169
B . B i o e ne r g e ti c s 1 . S u bs t r a te le ve l p ho sp h o r yl a t i o n en t ai ls t he fo r m at i on of on e u n it of ad e n os in e t r i ph o sp ha t e ( A TP ) p e r un i t o f m e ta b ol it e t ra ns f orm e d ( e .g . , s uc c i n y l C o A t o s uc ci n at e , p h os ph oe n ol py r u v a t e t o p yr u v a te ) . The s e r e ac ti o ns d o n o t n eed o xyg e n . 2 . O x i da t i ve ph o sp h o r yl a t i o n e nt ai ls t he fo r m a t io n of on e - an d -a - h al f o r two - a n d - a h a l f u ni ts o f A TP p e r u nit o f m et a bo li t e t r a ns fo r m e d b y o xi d o r e d uc ta se enz ym e s ( e . g ., de h y d r og e na s e s ); t h es e e n z ym es us e f l a v in A di n uc le o ti de ( F A D ) fo r m ed f ro m +
t h e vi ta m i n r i bo f la v i n , o r n ic o ti n am id e A d in uc le ot i d e ( N A D ) f ro m t h e v i t am i n n i co t in am id e a s c of a c t o rs . Th e re ac t io ns a re c o up l ed t o t he el ec t r on t ra ns p o rt s ys t em , a nd t he en e rg y re l ea s ed i s u s e d t o fo r m A TP i n t he m i to c ho nd r i a.
C . C a r b o h yd r a t e m e t a bo l i sm 1 . C a ta b o li s m. Th is p roc es s re le as es s t o r ed ene r g y f r om c a rb o h y d ra t es . a . G l yc o g e n o l ys i s i s the b r ea k d o wn o f g l y co ge n i n to gl uc os e p h os ph a te i n th e l i ve r a n d sk e le t al m u s c le . I t i s c on t r ol l ed b y t h e h o rm on e s g lu c a g on an d e pi n eph r i ne . b . G l yc o l ys i s i s t he br ea k do wn o f s u ga r ph os pha t es ( e. g . , g lu c o s e , fr u cto s e, g l yc e ro l ) i nt o p y r u v a t e (a e r ob ic a ll y ) o r l ac t at e (an a e ro b ic al l y) . 2 . An a b o l is m . Th i s p r oc e s s c o ns um es en e r g y to b u il d u p c om pl e x m o l ec ul e s f r om s im p le r m o le c u le s . a . G l yc o g e n e s i s i s t he fo r m at i on of gl yc og e n i n th e li v e r an d m us c l es fr om gl uc os e c o ns um ed in t he di et ; it s s y n t he s i s is c o n t ro ll e d by t h e pa nc r ea t ic ho rm o ne i ns ul in . b . G l u co n eo g e ne s is is th e fo r m a t io n o f g l uc os e fr o m n o nc a rb oh y d r a te s ou r c es , s uc h a s l ac t at e , a la n in e , p y r u v a t e , a nd K re bs c yc l e m e ta b ol i te s ; f at t y ac ids c a nn o t f o r m g lu c o s e . D . K r e b s c yc l e . Th i s p ath wa y i s al s o k n o wn a s t he c i t r ic a c i d c y c le , s e r v es bo t h b r e ak do wn a n d s y n th e ti c p u r po s e s, an d o c c u rs in t h e m it oc h on d ri a l c o m pa r t m e n t. 1 . C a ta b o li s m. Th is p ath wa y c o n v e r ts p yr u vat e ( g l y c ol y s is ) , ac e t y l Co A ( f a t t y ac id d e g ra d at i on ) , a n d am i no a c i ds t o c a r b on di o xi d e a n d wa t e r wi t h a r e le as e o f en e rg y. Th e c yc le is s t ri c tl y o xy g e n - de p en d en t (a e ro b ic ) . Ma t u r e r e d b lo o d c el ls l ac k m i to ch o nd r ia ; he nc e , t her e is no K r eb s c y cl e a c t ivi t y. 2 . An a b o l is m . Th i s p at hwa y f o r m s a m i n o ac i ds s u c h as as p ar t a te an d g lut a m a t e f r o m c yc l e i n te r m e di a te s ; a ls o , t he po r ph yr i n ri n g o f he m e (e . g ., he m o g lob i n , m yo g lo b in , c y t oc h ro m e s ) i s f o rm ed f ro m a c y c l e in t e rm e di a te . 3 . An a p l e r ot i c re a ct i o ns . B ec au s e m e t ab ol i te s a r e us ed to m a k e am in o a c id s o r h e m e ( e. g ., s u c c in y l C oA ) , t he m e t ab ol i te m u s t b e r ep la c e d b y i n te r m e dia t es f ro m o t h e r so u rc es ( e. g . , gl u ta m at e fr om t he b re ak down o f p r o te in f or m s α - k et o g lu t a ra t e) . 4 . E le c t r o n t r a ns p o r t . Th e el ec t r on t ra ns p or t s ys t e m a c c ep ts el ec t r on s an d h yd r o ge n f ro m t he o xi d a ti o n o f K re bs c y c le m e t abo l i te s a nd c o up l es t h e en e r g y r e l ea se d to s y n t he s i z e ATP i n t he m i t oc ho nd r i a. E . L i pi d me t ab o l is m 1 . C a ta b o li s m. T r ig l yc e r i d e s (t r ia c y lg l yc e r o ls ) st o r e d i n f at ce ll s ( a di p oc yt e s ) ar e h yd r o l yz e d b y h o rm on e -s e ns it i v e l i pa s e s i nt o th re e fa t t y ac id s a nd gl y c e ro l . a . F at t y a c i d s a r e b r ok en d o wn b y be t a o xi d a t io n t o ac et y l C o A ( t wo c a rbo n un i ts ) , wh i c h en t e r t he K r eb s c yc l e t o c om pl e te th e o xi d a t i on to ca r bo n d i o xi d e an d wa t e r wi t h r e l ea s e of c o ns id e ra b le en e r g y . To o r ap i d br e a k d o wn o f f a tt y a ci ds le a ds to k e to n e b od i es (k et o ge n es is ) as i n d i ab e te s m el li tu s . b . G l yc e r o l e n te rs gl y c ol y s is an d i s o xi d i ze d to py r u v a t e an d , v ia th e K reb s c y c le , t o ca r bo n d i o xi d e a nd wa t e r . c . S te r o i ds m a y b e c o n ve r t e d t o o th e r c om po u nds su c h as b i le ac id s , v i t am i n D , or s t e ro i da l h o rm on es ( e. g ., c or t is on e , e s t r o ge ns , an d r og e ns ) ; t h e y a r e n o t b r o ke n d o wn c om pl e te l y . 2 . An a b o l is m . B i o s yn t h e s i s f o rm s f at t y ac i ds , s te r o id s , a nd ot h er t e rp ene - r e la t ed m e ta b ol i te s . a . F at t y a c i d s a r e f o rm ed i n t he c yto p la s m , a nd u n s a t u ra t io n o c c u rs i n t he m i to ch o nd r ia P.170
o r e nd op l as m ic r e ti c u lum . H um an s c an no t m ak e l i no le ic ac id ; th us , i t is im p o rt a nt t h a t i t b e i nc lu d ed in th e d i et ( es s e nt i al fa t t y ac id) . b . T e rp e ne c om p ou n ds a r e de r i v ed f ro m a c e t yl C o A v i a m e v al o na t e a nd i n c l ud e : ( 1 ) C h ol es t er o l a nd ot h er s te r o id s ( 2 ) F at - s o lu b le v i ta m i ns ( i . e ., A , D, E , K) ( 3 ) B il e a c i ds c . S ph i n go l i pi d s c o n ta in s p h in g en in e fo rm e d f r om pa lm i to yl C o A a nd s e ri n e . S p h in g en i ne fo r m s a c e ra m id e b ac k b o ne wh e n j oi n ed t o f a tt y a ci ds . Th e ad d i ti on o f s u ga r s , s i al ic ac id , or c ho l in e p h os ph a te f or m s co m po u nd s s u ch as c e r ebr o s id es , g a n gl io s i d es , o r s ph i ng om y e l in fo u nd in ne r ve ti s s u es a n d m em br a ne s . d . P h os p ha t i d yl c o m p ou n d s , s u ch as ph os p ha t id yl ch o li ne ( le c i t hi n ) , p ho s ph a ti d y l s e r in e , o r e t ha no l am in e , a r e al s o im po r ta n t p a r ts o f m e m b r an es . F . N i t r o ge n m e ta b o li s m. N i t ro g en m e t ab ol is m i nvo l ve s a m i n o a ci d m et a bo l is m a nd n u cl ei c a c i d m et a bo l is m ( s e e C h ap t e r 9 f o r a di s cu s s i on of t he nu cl ei c a c id r ol e i n c e ll ac ti v i t y ) . 1 . C a ta b o li s m a . Am i n o a c i ds . Th e am i n o g r ou p i s r em o v e d b y a t r an s a m i n as e e n z ym e. Th e c a r bo n sk e le t on is b r ok en d o wn t o ac e t y l C o A (k e t o ge ni c a m i n o ac i ds ) o r t o c i t ri c a c id c yc le in t e rm ed i at es ( g l y c og en ic am in o a ci d s) a n d o xi d i z e d t o c a rb o n d i o xi d e a n d wa t e r f o r e ne r g y . G ly c o g en ic am in o a c i ds f orm gl uc os e a s n e ed ed v i a g l uc o ne og e ne s i s ; s o m e a m in o a c i ds a re bo t h k e to g e ni c a nd gl y c og e ni c ( e. g . , t yr o s in e ) . b . P u r i ne s a r e s al v a ge d ( 9 0 %) , an d t h e r em ai n ing 1 0% a re de g ra d ed in a s eq u en c e t h a t i nc lu d es xa n t hi n e oxi d a s e fo r m i n g u ri c a c i d i n hu m a ns . c . P yr i m i d i n es a re c a tab o li z e d to β - al an i ne , a m m o ni a , a nd c a r bo n d io xi d e . 2 . An a b o l is m a . Am i n o a c i ds ar e fo r m e d f ro m t he ci t ri c a c i d c yc l e i nt e rm e di a te s ( s e e I I I D 2 ) ; o t h e rs m us t b e e a te n d a il y i n d i et a r y p ro t ei ns . The l at t e r a r e c a l le d e s s en ti a l a m i no a c id s ( p he n y la l an i ne , v ali n e , t r yp to p ha n [ P V T] ; t hr e o ni n e, is ol e uc in e , m e th i on i ne [ TI M] ; h i s t i di ne , a r g in in e i n i n fa n ts , l y s in e , l eu c i ne [ H A LL ] ) . b . P u r i ne s a r e f o rm ed by c o m p le x r e a c t io ns us ing c a r b am o y l p ho s p h at e , a s pa r t at e , g l u ta m i ne , gl y c in e , c a r bo n di o xi d e , a n d f o rm y l t et r a h yd ro f ol a te . c . P yr i m i d i n es a re fo r m e d f ro m a s p a rt a te an d c a r b am o y l p ho s ph a te in a m ul t is t ep p r o ce s s . G . N i t r o g en ex c r e ti o n . E xc e s s ni t r og en m u s t be e l im in a te d b ec a us e i t is t o xi c . H u m an s p r im a ri l y e xc r e te u r ea bu t a ls o e xc r e t e ur i c a c i d . 1 . U r e a s yn t h e s i s . Th e K r e b s - H e ns e le i t p a t hw a y i s u se d to fo r m u r ea p r i nc ip a ll y i n th e l i v e r . Th e am m o nia is r em o ved f ro m a m i no a c i ds b y am in o a c i d t r an s fe r as es ( t r a ns am in a s e s ) t ha t u s e p y r i d o xa l ph os p ha t e ( v i ta m in B 6 ) as a c oe n z ym e. G l u t a m in e i s f o rm ed f rom gl u ta m a t e ( a n i nt e rm ed i a te ) an d a m m on ia ; gl u ta m in e a n d c a r bo n d io xi d e f o rm c a rba m o y l p ho sp h at e , wh ic h e n t e rs t h e u r ea c yc l e a nd a f te r s e ve r al s t ep s f o rm s u r ea. 2 . U r i c a ci d s yn t h e s i s . A l t h ou gh m o s t pu r i ne s ar e s a l v a ge d , h um an s e xc r e t e t h e r e m ai ni n g p u ri ne s a s u ric ac id .
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STUDY QUESTIONS D i r e c t i on s : E a c h of t he n u m b e re d i t em s o r i nc om p le t e s ta t em en ts in t his se c t i on is f o l lo we d b y an s we r s o r by c o m p le t io ns o f t he s t a te m en t . Se le c t t he o ne l et t e r ed a n s we r o r c o m p l et i on tha t is be s t i n e ac h c as e. 1 . W hi c h o f th e fo l l ow in g f u nc t i on a l g r o u ps ca n r ea c t w i th h yd r o c h l o r i c ac i d t o f o r m a s a lt ? ( A ) Te r t i a r y a m i n es ( B ) C a r bo xy l i c a c i ds ( C ) A m id es ( D ) E t h er s ( E ) S ec o nd a r y al c o h ol s V i e w A n s we r 1 . T h e a n sw e r i s A [] .2 . T h e c om po u n d s h ow n c o n ta i ns al l o f t h e f ol l ow i ng f un c t i on al g r o u ps E X C E P T :
( A ) a ph en o l ( B ) a s u bs ti t ut e d p he n y l r i n g (C) an ester ( D ) a n a li c y c l ic ni t r og en ( E ) a k e to n e V i e w A n s we r 2 . T h e a n sw e r i s C [] .3 . W h ic h o f th e f o ll ow i ng f u nc t i on a l g r o u p s i s m o st s us ce p ti b l e to h yd r o l ys i s ? (A) R—CO—R (B) R—COOR (C) R—O—R (D) R—NH—CH3 (E) R—COOH
V i e w A n s we r 3 . T h e a n sw e r i s B [] .4 . M o no m e r u n i t s o f p ro t e in s a r e know n as ( A ) m on os ac c h a ri d es ( B ) p r os th e ti c g r ou ps ( C ) a m i n o ac i ds ( D ) p u ri n es ( E ) n uc le os i de s V i e w A n s we r 4 . T h e a n sw e r i s C [] .5 . W h ic h o f th e f o ll ow i ng f o r mu l as r e p r e se n t s t h e z w i t te r io n f o r m o f a n a m i no aci d ?
V i e w A n s we r 5 . T h e a n sw e r i s D [] .6 . G lu c os e is a ca r b o h yd r a t e t h a t c a n no t be h yd r o l yz e d i n t o a s i mp l e r s u bs t an ce . I t i s b e s t d es c r i be d as ( A ) a s u ga r ( B ) a m o no s a c c ha r id e ( C ) a di s a c c ha r id e ( D ) a po l y s a c c ha r i de
( E ) a n o li g os ac c h a ri de V i e w A n s we r 6 . T h e a n sw e r i s B [] .7 . Al l o f t h e fo l l ow i ng ca r b o h yd r a t e s a r e co n s id e r ed t o b e po l ys a c c h a r i de s E X C EPT ( A ) h ep a ri n ( B ) s ta r ch ( C ) g l yc o g en ( D ) m al t os e ( E ) c el lu l os e V i e w A n s we r 7 . T h e a n sw e r i s D [] .8 . W h ic h o f th e f o ll ow i ng c om p ou n ds a r e co n s id e r ed t he b ui ld i n g b l o ck s o f nu c le i c a c i ds ? ( A ) N u c l eo t id es ( B ) N u c l eo s i d es ( C ) Mo n o s ac c h a r id es ( D ) P u r in es ( E ) A m i n o ac i ds V i e w A n s we r 8 . T h e a n sw e r i s A [] .P . 17 2
9 . W hi c h o f th e fo l l ow in g t e rm s be s t d es c r i bes a c o f ac t o r th a t i s fi r ml y b o u n d t o a n a p oe nz ym e ? ( A ) H o lo e n z y m e ( B ) P r os t he t ic gr o up (C) Coenzyme ( D ) Tr a n s fe r as e ( E ) H e t er o po l y s a c c h ar i de V i e w A n s we r 9 . T h e a n sw e r i s B [ an d] . O 10 . En z ym e s t h a t u nc o up l e p ep t i d e l i n k ag e s a r e b es t cl a ssi f i e d a s ( A ) h yd r ol as es ( B ) l ig as es ( C ) o xi d o r e du c t a s e s ( D ) t r a ns fe r as es ( E ) is o m e r as es V i e w A n s we r 1 0 . T he a nsw e r i s A [] .1 1 . T he s ug ar t h a t is in h e r en t in t he n u c le i c a c id s R N A a n d D N A i s ( A ) g lu c o s e ( B ) s uc ro s e ( C ) r i bo s e ( D ) d ig i to xo s e ( E ) m al to s e V i e w A n s we r 1 1 . T he a nsw e r i s C [] . Di r e c ti o ns : E a c h i te m b el o w c o nt a in s t h r e e su g ge s t e d a ns we r s o f wh i ch on e o r m o r e is c o r re c t . C ho os e t h e a nswe r . 1 2 . W h i ch o f t h e f o l low in g f u nc t i on a l g r o u ps ca n f o rm a h yd r o g e n b on d ? I . An a r o m at i c a m in e I I . A t e r t i a r y h yd r o x yl I I I . An a r om a t ic h yd r o c a r b o n
A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 2 . T he a nsw e r i s C [] .1 3 . W hi c h o f t h e f ol l ow i ng f un c t i on al g r o u p s c om m on l y u n d er g o e s c o nj u g at i o n w i t h g l u cu r o n ic ac i d ? I . A c a r b o x yl i c a c i d II. A primary amine I I I . A p h en o l A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 3 . T he a nsw e r i s E [] . Q u e s ti o ns 14- 1 6 Th e f o ll o wi n g q u es ti o ns r e f e r t o t h e d r ug m o le c u le s h o wn b el o w.
1 4 . Th e fu n c ti o na l g ro up s t ha t en h an c e t h i s c om p o u nd ' s a b il i t y t o c r o s s ce l l m e m b ra n es i nc l ud e : I . t h e p he n yl r i n g s I I . t he ce n t r al a lk yl c h ai n I I I . th e s e co n d a r y a n d t e r t i a r y h yd r o x yl s A if I only is correct B i f I I I o nl y i s c o r r e c t C i f I a n d I I a re co r r e c t D i f I I a n d I I I a r e c o r r ect E i f I , I I , a nd I I I a r e c o r re c t 1 5 . Ba s ed u po n t he f unc t i o na l g ro u p s p r es e n t, t h i s d r u g w ou l d b e e x pe c t e d t o b e ab l e to f o rm : I . va n de r W aa l s i n te r ac t i o ns
I I . i on i c b o nd s I I I . h yd r o g e n b o n ds A if I only is correct B i f I I I o nl y i s c o r r e c t C i f I a n d I I a re co r r e c t D i f I I a n d I I I a r e c o r r ect E i f I , I I , a nd I I I a r e c o r re c t 1 6 . Po s si b l e m et a b ol i c p a t hw a ys f o r t h i s d r ug i n c l ud e : I . r e du c t io n o f t h e c a rbo x yl i c a c i d I I . h yd r o l yt i c c l e a va g e I I I . a r o ma t i c o x id a t io n A if I only is correct B i f I I I o nl y i s c o r r e c t C i f I a n d I I a re co r r e c t D i f I I a n d I I I a r e c o r r ect E i f I , I I , a nd I I I a r e c o r re c t V i e w A n s we r 1 4 -1 6 . T h e a n s w e r s a r e : 1 4 - C [] , 15 -E ( I , II , an d I I I )[ ] , 1 6 - B ( I I I )[ ] . P. 1 73
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is A [ I C 2 c ]. S u b st a nc es th a t r e ac t wi t h ac id s t o f o rm sa l ts m us t be ba se s . O n l y o r g an ic c om p ou n ds th a t c o n ta i n t h e n i t ro g en -c o nt a in i ng a m in e g r ou p a r e b as es . W hile a m id es c o nt a in ni t r og en , t h e a dj ac e nt c a r bo n y l g ro u p d ec r ea s es t h e b as ic it y; t h e r ef o re , th e y a re es s en t i al l y ne u tr a l. 2 . T he an sw e r is C [ F igu r e s 8 -4 , 8 -7 , 8 - 8 , 8 -1 0 ] . A s sh o wn in F ig u re 8 -8 , e s te r s h a v e a c a r bo n yl at o m d i re c t l y bo n de d to an o xy g e n a t om . Th is s t r uc t ur a l f eat u r e i s n ot p re s e n t i n t his co m p o un d . H o we ve r , th e c om p ou n d d oe s h a v e t h re e s u bs ti t u te d p h en y l ri ng s , t wo p h en o ls , a te r ti a ry a l ic y c li c n i t ro g en , a k e t on e , a nd a n et h e r. 3 . T he an sw e r is B [ I E 2 b ] . H yd r o l ys is i s a do u bl e de c om po s i t io n re ac t io n i n wh i c h wa t e r i s o ne of t he r e a ct a nt s . E s t e rs , p a r ti c u l a rl y s i m pl e e st e rs , c om m o nl y u nd e rg o h y d r o l ys is . C e rt a in t yp e s o f e t he r s s uc h as g l y c os id es al so un d e rg o h y d r o l y si s , bu t th e y us ual l y r eq u i re s t r on g l y a lk a li ne c o nd i ti on s o r a c at al ys t s uc h a s a n en z ym e . Ke t on es , a m i n es , o r c a r bo xy l i c ac i ds d o n o t un d e rg o h y d r o l ys is . 4 . T he an sw e r is C [ I I B 1 , II E 1 ] . P r o t ei ns a re la r g e m o l ec u l es wi t h m ol ec u la r we i gh t s r a ng i ng f ro m 5 00 0 t o m o re th a n 1 m i l li on da l to ns . Al l p r ot e i ns a r e c om po s e d o f c h a in s o f a m i n o ac i ds a n d c an be h yd r o l yz e d t o y ie l d a m i xt u r e o f th ei r r es pe ct i ve am i no ac id s. Th e r e a r e 2 0 α - a m in o a c id s, wh i c h a re c o m m on l y f ou n d i n p r ot e in s. A ll t h e n a tu r al l y oc c u r r in g a m in o a c i ds i n pr o t ei ns ar e L - e na n ti om e rs , wi t h t h e e xc e p t io n o f gl y c in e . A ll ha ve a t l ea s t o ne a m in o g r ou p a n d o ne c a rb o xy l g r o u p . Th e am in o a c id s a r e l in ke d t o ge t he r t h r ou g h
t h e a m i n o g r ou p o f o n e a m in o a c i d a n d t he c a r bo xy l g r o u p of an o th e r a m i n o a ci d wi t h t h e s pl i tt i ng ou t o f a wa t e r m ol ec ul e to fo r m a n am id e l in k a g e , wh i c h i n a p r o t ei n i s r e fe r r ed to as a p ep t id e . Mo n o s ac ch a rid e s a r e s i m p l e, no n h yd ro l yz a b l e s u ga r s . P u ri ne s a n d p y r im i di ne s a r e o r ga n ic b as e s , wh il e a p ro s th e ti c g ro u p i s a c o fa c to r th a t is f ir m l y b ou n d t o a n a p oe n zy m e . 5 . T he an sw e r is D [ I A 1 a , I I B 2 , 3 , II E 1 , Fi gu r e s 8 -2 , 8 -1 1 , 8 -1 2 ] . A zwi t t e r i o n is a s in gl e s p e c i es c o n ta in i ng bo t h ne g a ti ve an d p os i ti v e ch ar g e s . I t s om e ti m e s i s r e fe r r ed to a s a n i n te r n al s a lt . Am ino ac i ds h a ve an am in o gr o u p a nd a c a r bo xy l g r o u p i n t h e s am e m ol ec u le . Th e a m i no g r o u p , wh ic h i s b as ic , at t r ac t s t he p r o t on f ro m t he c a r bo xy l g r o up an d b ec om es po si t i v e l y c ha r g ed , wh i le th e c a rb o xy l g r o up be c o m es n e ga t i v ely c h a rg e d wh e n it do n a te s i t s p ro t on t o t he am ino g r ou p . A m i no ac id s e xi s t as z wi t t e r io ns at ne a r n e ut r a l pH s uc h a s o c c u rs wi t hi n a c e l l o r i n t h e b l oo ds t r ea m . 6 . T he an sw e r is B [ I I C 1 ] . W hile gl uc os e i s a s ug a r, i t i s m o r e s pe c i f ic al l y a s im pl e s ug a r t h at c a n not b e h yd r o l yz e d i n to m o r e s im p le s u ga r s —t h us , i t i s c l as s i fi e d as a m on os acc h a ri de . S u g a rs m a y be s i m p le , s u c h as gl u c o se , o r c om p le x, s u c h as su c ro s e , a n d a r e c l as s i fi e d as di s a c c h ar i de s o r ol i go sa c c ha r id es , re s pe c t i v e l y . Po l y sa c c ha ri d es c o ns is t o f l o ng c h ai ns of m on os a cc ha r id es su c h a s c el l ul os e a n d g l yc o gen . 7 . T he an sw e r is D [ I I C 2 b , 3 , E 3 a , b ] . P o l ys ac c h a ri de s a r e l ong - c ha in po l y m e r s o f s uga r s . A s t h e p r ef i x “ p o l y” in d ic a te s , t h e r e a re m a n y s u ga r uni t s i n t he m o le c ul e . Ma l t o s e is c o m p os e d o f t wo m o le cu l es o f gl uc os e a n d is c l as s i f ie d as a di s a cc h ar i de o r a n ol ig os a c c ha r id e . 8 . T he an sw e r is A [ I I D, E 4 ]. N u c le ic ac id s a r e l in e ar p o l y m e r s o f n uc le o ti d es t h a t c on s i s t o f t h re e d i ffe r e n t m o le cu l es t h at a re c o v a le n t l y l i nk ed to f or m o ne u n i t: ( 1 ) a n o rg a ni c b as e o f ei th e r a p u r in e o r a p y r im i di ne ; (2 ) a 5 - c a r bo n s ug a r (e . g., p en t os e ); a nd (3 ) a p hos p ho r ic a c id g ro up . A n uc l eo s i de c on s i s ts o f th e o r ga n ic b a se an d t h e p en t os e . A m o no sa c c ha r i de is a s im p l e n on h yd r ol yz a b l e ca rb o h y d ra t e , wh i c h m a y b e c o ns id e re d a b ui ld i ng blo c k o f p ol y s ac c h a ri d es . P u r i ne s a r e h et e r oc y c l ic b a se s . A d e ni n e a nd gu a ni ne a re t h e t wo p u ri n es fo u nd in d e o xyr i b o nu cl e ic ac id (D N A ) a n d r i b on uc l ei c ac i d ( R N A ) . A m i no ac id s a r e t he bu ild i n g bl oc ks of p ro t ei n . P.174
9 . T he an sw e r is B [ I I E 2 b , c a nd d ]. C o m pl e x, o r c o nj u ga t ed , e n z y m es c o n ta in a n on pr o t ei n gr o up c a ll e d a c ofa c to r , wh i c h is re q ui r ed f or bi o lo g ic ac ti vi t y . In m a n y c as es , th e c o fa c t o r i s q ui t e f i rm l y b o u nd to th e p r o te i n. In o t h e rs , t he bi n di n g oc c u rs on l y du r i ng th e re ac t ion t ha t th e e n zym e c a ta l y z e s . C o fa c t o r s t ha t a re fi r m l y b ou nd t o t h e p ro t ei n a r e k no wn as p r o st h et ic g ro u ps , wh e r ea s th os e t h at a re ac ti v e ly b o u nd to t he p ro t ei n on l y d u ri ng c a ta l ysi s a r e r e fe r r ed t o a s c oe n z ym es . A h o lo en z y m e is a c o m p le t e , c at a l y ti c a l l y a c ti ve en z y m e s ys t em . A t r an s fer a s e is an e n zym e th a t c a t al y z e s the t r an s f e r o f gr o up s f r om o n e s u b st a nc e t o a no t he r , s u ch a s c a te c h o l- O - m et h y l t r an s fe r as e ( C O MT) . A h e t er o p ol ys ac c h a ri d e is a
p o l ysa cc ha r i de th a t c o n ta i ns t wo o r m or e d i f fe r ent m on om e ri c u ni t s , s uc h a s h e p ar i n. 1 0 . Th e a n sw e r i s A [ I I E 2 d] . A p e pt i de li nk ag e i s a n am i de fu nc t io n al g ro up f orm e d f r om th e l os s o f a m o l ec ul e o f wa t e r f r om t wo am i no ac i d s . U nc o up li n g t hi s l in ka g e i s t he r e ve rs e o f t h is r e ac t io n , a h yd r ol y s is re ac t io n . A h y d r o la se is an en zy m e th a t c a ta l yz e s h y d r ol y s is r e a c t i on s . Mo r e s p ec i fi c t e rm s f o r an e n z y m e t ha t c a ta l y ze s t h e h yd r o l ys is o f p ro t ei ns a re a m id as e o r pe p ti da s e. A l i ga s e ca t al yz e s th e c oup l i n g o f t wo m o le c u l es . A n o xi d o r e d uc ta s e c a t al y z e s o xi d a ti o n r e ac ti o ns . A tr a n s f e ra s e c a t al yz e s th e t r a ns fe r o f g ro u ps f r om on e s u bs ta n c e to an o th e r . A n i s om e r as e c a t al yz e s th e i n t er c on v e r s i on o f o ne is o m e r t o a no t he r . 1 1 . Th e a n sw e r i s C [ I I E 4 ] . N u c le ic ac id s a r e b io p oly m e r s c on si s t i ng of lo n g c h ai ns of nu c l e ot i de s . Nu c le o ti de s c o nt a in a p en t os e m on os a c c h a ri de as on e o f th ei r t h r ee c o ns ti t u en ts . R N A c on t ai ns , a s th e n am e s ug g es ts , th e m o no s a cc ha r i de ri b os e , wh e r e as D N A c on t ai ns d e o xyr i b o s e. Th e o n l y d if f e r en c e be t we e n th es e two s u g a rs i s t h e a bs en c e o f o xyg e n i n th e 2 p os it io n o f t he ri b os e r i ng . G lu cos e , a ls o k no wn a s d e xt r o s e , i s a h e xo s e . D ig i to xo s e is a d e o xy h e xo s e p r es e nt in t h e d i gi t al is gl y c os id es . S u c r os e a n d m al t os e a r e d is ac c ha r i de s . 1 2 . Th e a n sw e r i s C ( I , II ) [ I C 2 b, D 1 a , F 3 a ]. H yd r o g e n b on ds a re a s p e c i al i z e d t y p e o f d i po l e b o n d in wh i c h a h y d r oge n at om s e r ves as a b ri d ge be t we e n t wo e l ec t ro n eg a ti v e a t om s . H yd r o ge n -b o nd do n o rs i n cl ud e h y d r o xy l g r o u ps , p h en ol s , am i ne s , an d am i de s. H y d r og e n -b o nd ac ce p to r s i n cl ud e h y d r o xy l g r o u ps , p h en ol s , u ni o ni ze d n i tr og e n a t om s , k e to n es , a n d e t he r s. H yd r o c a rb o ns , r e ga r dl es s i f t he y a r e a li ph a ti c , a li c yc li c , o r a r om a ti c , a re no t c a pa b le of fo r m i n g h y d r og e n b o nd s . 1 3 . Th e a n sw e r i s E ( I , II , a nd II I ) [I B 2 e , C 2 d , D 2 d] . G l u c ur o ni d e c o n ju ga t io n i s th e m os t c om m o n p has e II m e ta b ol ic pa t h wa y fo r t wo r e a so ns : (1 ) Th e b o d y ha s a r ea d il y a va il ab l e sup p l y of gl uc u r on ic ac id , a n d (2 ) t h e r e a re a l a rg e n um b e r o f fu nc t io n al gr o up s t h at c an re a c t wi t h th is c om p o u nd . I n cl u de d a m o n g t he s e f un c ti o na l g r ou ps a re ca r bo xy l i c a c i ds , p ri m a r y , s ec o nd a r y a n d t e r ti a r y am in es , a n d p h e no ls . 1 4 - 16 . Th e a n sw e rs a r e: 1 4 - C ( I , II ) [I A 1, D 1 b, F 1, 3 ], 15 - E ( I, I I, an d I I I ) [I B 2 b , C 2 b , D 1 a , F 1 a , 3 a ] , 16 - B ( II I ) [ I B 2 e, E 2 b , F 3 b ] . L i po p hi li c f u nc ti o na l g r ou p s i nc r ea s e a d r ug ' s a bi l it y t o c r os s ce l l m e m b ra n es . Th e t h r e e a ro m a t ic ph e n y l r ing s , a s we l l as th e a li p ha ti c b u t y l c ha in co nn e c t i ng t h e c e nt r a l p he n y l r i ng to t he n it r o ge n o f t h e p ip e ra di n e r i ng , a r e a l l li p op h il ic ( i . e. , h yd r o ph o bi c ) a nd c o nt r i bu t e to th e d r ug ' s pa s s age t h ro u gh c e ll m em b r an es . Th e h yd r o xyl g r o u ps , a s we ll a s th e a c i di c c a rb o xyl i c a c id an d t h e b as ic al ic y c l i c am i ne , a r e al l h y d r op h il ic a n d en h a nc e t he o ve ra ll wa t e r s ol u bi li t y o f t he co m p o un d . Th e p h en y l r in gs , a s we ll a s t h e ce n t ra l a lk y l c h ai n a nd th e m e th y l g ro up s , a r e c a pa b le of fo r m i n g v a n de r W aals in t e ra ct i on s wi t h a r om at ic an d a l ip ha t ic h yd r o ca r bo n re g io ns on r e c ep t or m o le c ul es . Th e c a r b o xy l i c ac i d a nd th e ba s ic n i t ro g en a re c a pa b le of fo r m in g b o th io ni c a nd h yd r o ge n b o nd s , wh i l e t h e h y d r o xy l g r o up s a r e a ls o c ap ab l e o f f or m i n g h yd r og e n b ond s .
O f t h e m et a bo li c p a th wa y s l is t ed , a r om a ti c o xi d at i o n is th e on l y pl au s i b le c ho ic e . Th e t wo u n s u bs t it u te d ph e n y l ri ng s a r e v e r y s us c e pt i bl e t o h y d r o xy l a t i o n, e p o xi d a ti o n , a nd / or di o l fo r m at i on . Ca r b o xyl i c a c id s a r e n o t n o rm al l y r ed uc e d, bu t r a t h er c o nj u ga t ed wi t h eit h e r g l uc ur o ni c a c i d, gl y c i ne o r g lu t am in e . E s t e rs , a m i de s a n d t h ei r c y c li c d e ri v a t i ve s , l ac t on es an d l ac t am s , a r e t he p ri m a r y f un c ti on a l g r ou ps t h a t u nd e r go h y d ro l y s i s . N o n e o f th es e f u nc ti o na l g r o up s a r e p re se n t i n t he c om p ou n d s h o wn .
9 Microbiology G a i l G o o dm a n- S n i tk o f f
I. SCOPE OF MICROBIOLOGY. Mi c r o b i ol o g y i s t h e s t u d y o f or g an is m s f ro m t h re e d om a in s as we l l as a c e ll u la r e n t it i es t h a t a re no t c o ns i d e re d to be li v i ng in th e b i ol og ic a l s e n s e . A. D o m a i n s o f li vi n g o rg a n is m s 1 . Ar c h a e a i nc lu de p ro k a r y o t es wi t h c e ll wa l ls tha t a re bi oc h em ic al l y di f fe r e n t f r om b a ct e r ia an d t h at in h ab i t e xt r e m e en v i r on m e n ts of h ea t , c ol d , p H , o r s a lt s . A r c ha e a a r e no t a m e di c a l l y i m p or t a n t d om ai n o f m ic r oo r ga n i s m s . 2 . E uk a r ya c o n t a in s s om e m i c ro o rg a ni sm s — f o r exa m p l e , fu ng i ( y ea s ts a nd m o l ds ) , p r o t o zoa , a n d a lg ae — a lon g wi t h m ac r os co pi c o r ga n is m s s uc h a s m us hr o om s , p l an t s, an d a n im al s . D i mo r p h i c f u n gi a re th os e th a t c an e xi s t i n e i th e r t he u n ic el l ul a r ( y e a s t ) or t he f i la m e n to us (m o ld ) ph as e , de p en d in g o n t h e i nc ub a t io n t e m p e r at u re ( e .g . , H i s t op l as m a an d Bl as t o my c es ) . a . F un g i a r e c la s s if i ed in t o p h y l a b as ed on t he ty p e o f r e p ro d uc ti v e st r uct u r es o b se r v e d o r th e l ac k o f ob s e r v ab le s e xu a l r ep r o du c ti v e s t r uc t u re s . ( 1 ) As c o m yc o t a ( a s c u s ) ( e . g. , C an di d a a nd H is to p la s m a ) ( 2 ) B a si d i om yc o t a ( b a s id i um ) (e . g ., C ry p to c oc c us ) ( 3 ) Z yg o m yc o t a ( z y g o t e) ( e . g. , R hi zo p u s ) ( 4 ) D e u te r o m yc o t a ( a s exu a l , a ls o c al l ed fu n gi im p e r f ec ti ) (e . g ., C oc c i di o id e s ). R e c en t l y, s om e s e xu a l re p r od uc t i v e s ta t es ha v e b e e n id e n ti fi e d i n f un g i cl a ss if i ed a s b e lo n gi ng t o D e ut e r om y c o ta . b . P r o t oz oa , un ic el l ul a r , n o np h ot os y n t he t ic eu kar y o t e s c ha r ac t e r i ze d b y m o de of m o ti l it y , in c l u de th e fo ll owi n g : ( 1 ) M a s ti g o ph o r a (f l ag ell a t es ) (e . g. , G ia r di a ) ( 2 ) S a rc o d in a (a m o e ba e) ( e . g. , En t a m oe b a ) ( 3 ) C i l io p ho r a (c il i at es ) ( e . g ., B al a nt i di u m ) ( 4 ) S p o ro z oa (n o nm o ti le) ( e . g. , Pl as m o d iu m ) 3 . B ac t e r i a c o n ta i n a wid e v a r ie t y of p ro ka r y o t es , i nc lu d in g g r am - po s i t i ve a n d g r am n e g at i ve b ac t e ri a . S ec t ion s II - V I I ch a r ac te r i z e b ac t e ri a i n m o re de t ai l . B . N o n l i vi n g, bu t me d i ca l l y s i g n i f ic a n t e n ti t i es a r e t h e f ol l o wi n g 1 . V i r us e s ( s e e VI I I ) , wh i c h a r e c l as s i f ie d b y : a . C a ps i d s t r uc t u r e , wh i c h is t he pr o te i n co a ti n g a r o un d t h e n uc le ic ac id b . T yp e a n d s t r a nd e dn es s o f n u cl e ic ac i d , wh i ch c o u ld be D N A or R N A , e i t he r s i ng le o r d ou b le s t r an d ed c . P re se n c e or ab s e n c e o f a l i p id en ve l o p e s u r ro u n di ng t he pr o te i n ca p s i d d . P r es en c e o f e nz ym e s , wh i c h m a y b e e i th e r i nco r p o ra t ed in t o t he li p id en v e l o pe o r f ou n d i n t he c a ps id nea r t he nu c l e ic a ci d 2 . P r i on s , i n f ec t i ou s p r o t e i ns , ar e i m p l ic at e d i n s om e s po n gi f or m e n ce p ha lo p at h ie s ( e .g . , m a d c o w d i s ea s e , C re u tz f e l d t -J ak ob di se as e , a nd ku r u ) .
II. TAXONOMY AND NOMENCLATURE OF BACTERIA
A. T a x o n om y i s c la s s if ic a t i on o r o rd e r in g i n to gr ou p s b as ed on de g r ee of r e l at e dn es s . B ac t e ri a a re p r o ka r yo t e s t h at be l on g to t he B ac te r ia do m a in a nd th e E u b ac t e ri a k in gd om an d a r e gr o up e d a nd na m e d p r i m a r il y b y m o r ph o lo g y , b i oc h em ic al an d m et a bo li c d i ff e r en c e s, a nd i m m un o lo g ic a n d g en e ti c r e la ti o ns hi p s. D N A t e c h n ol og y h as le d t o t he re c l as si f ic a ti on o f s om e o r g an is m s b a s e d on D N A s e qu e nc es a n d h om ol o gy . B a c te r ia a re na m e d us i ng th e Li n na e an o r b in o m ia l s ys t em a s a ge n us a n d s p e c i es ( e. g ., H o m o s ap i en s i s t h e g en us an d s pe c i e s f o r h u m a ns ) . P.176
B . M o r ph o l og y i s t he c la s s i fi c a t io n o f ba c t e ri a by s h ap e an d s t ru c t u r e. 1 . C u l tu r a l m o r p ho l og y i s b as ed on t he s i ze , s ha p e , a nd te xt u r e o f c ol on i es th a t a r e gr o wn i n p u re c u lt u re o n a n a ga r pl a te . Ea c h c ol o n y o r i gi na t es f ro m a c o l on yf o r m i n g u n it ( C F U ) , c o ns is t in g o f a si n gl e c el l o r g r o up of ad h er e n t c e ll s . 2 . M i c r os c op i c m o r p ho lo g y d e s c ri b es ba ct e ri a on t he ba si s o f th e s i z e, s h a p e, an d a r r a ng em e nt o f t he c e ll s ( s e e I I . C a nd D ) . C . S t a i ns . Be c a us e o f the i r s m a ll s i z e an d re la t i ve t r an s p a r en c y, b ac t er i a m us t be s t ai n ed to be v i s i bl e u n de r t he li gh t m ic r os co p e. S t a i ni ng is al so us ed as a c l as s i fi c a t io n s y s te m . Th e m a j o r t yp es of s t ai n in g r e ac t io ns a re th e fo ll o wi n g : 1 . S im p l e s ta i n . A s i ng le d y e (e . g. , G e nt ia n v i ole t , s a f ra ni n ) t h a t c o l or s th e c e ll s . 2 . G r a m s t ai n . A d if f e ren t i al s t ai n in g p r oc ed u r e th a t d i v i de s b ac te r i al c e lls in t o e i t he r gr am - p os it i v e (p u rp l e ) o r g r am - ne g a ti v e (p in k ) . 3 . Ac i d - f as t s ta i n. A pr oc e du r e t h at s t a in s ce l ls th a t h a ve a n o u t er la ye r o f a wa xy l i pi d (a c i d fa s t ) bu t no t c e l ls th a t l ac k t ha t l a ye r (n o n -a c i d - fa s t) . 4 . S p o re s ta i n. A pr oc ed u r e t h at us es he a t t o he l p d ye en t e r t he s p o re . 5 . C a ps u le s ta i n . Two d y e s a re us ed t o s ta in t he c el l a n d t he ba c k g ro u nd, a ll o wi n g vi s u al i za ti on o f t he un s ta i ne d c a ps ul a r m a t e ri a l. D . B a c te r i a l c el l sh a pe a n d a r r a n ge m en t 1 . C o cc i a r e s ph e ri c a l an d e xi s t i n c ha in s (S t r ept o co c c us py og e ne s ), pa ir s o r d i pl oc o c c i ( S t re p to c o c c us pn e u m on i ae , Ne is s e r i a g o no r r ho e ae ) , c lu s t e rs ( s t ap h yl oc oc c i ) , a nd pa c k e ts of f ou r o r ei g ht (s a rc i na e ) . 2 . B ac i l l i a re c y li nd r ic a l a n d ro d -s ha p ed o rg an ism s ( p s e ud om o na ds , Es ch e r ic hi a ) . 3 . C o cc o ba c il l i a r e s ho rt r o un d ed ro d s ( B r uc el la ). 4 . S p i ro c he t e s a nd s pi ri l l a a r e h el ic a l, li k e a c or k sc r e w ( T r ep o ne m a pa lli d u m ) ; s p i ri ll a a r e r i gi d h el ic e s , wh e r e a s s pi r oc h et es a re f l e xi b l e h el ic es . 5 . F us o ba c te r i a h a v e tap e r ed en ds a nd ar e s li g ht l y c ur ve d (i . e ., fu si f o rm ; F u so b ac te r i u m m o rt i fe r um ) . 6 . F il a me n t ou s o r g an is m s a r e b r an ch i ng or g an is m s an d a r e a s s oc ia t ed wi t h m ol d l i ke ba ct e r ia ( Ac ti n o m y c e s b ov is ) . 7 . V i b ri o s a r e c om m a s ha p e d r od s (V i b ri o c ho le ra e ) . 8 . P le o m o rp h i c o rg a ni s m s e xi s t in v a r ie d f o rm s ( H a e m o p hi lu s , L eg io n el la , C o r y ne b ac te r ia ) . E . O t h e r c l as s i f ic a ti o n p a r a me t e r s 1 . P r es e nc e o r a bs e nc e o f
a . S p o re s u s e d fo r s u r v iv a l ( B ac il l us a n th r ac is ) . b . C a ps u le s o r s li me l aye r s u s e d fo r a d he r e nc e. C a ps ul e s a re al so an t iph a g oc y t ic ( S t r e p to c o c c us p n eu m o ni a e , N e is s e r ia m e ni ng i ti di s ) . 2 . M o t i li t y a n d t he t y p e o f f la g e ll a a . M o n o t ri c h ou s . A s i ngl e fl a ge ll um b . L op h o t r ic h o us . A t uf t o f fl ag e ll a a t o n e p ol e c . Am p h i t r ic h ou s . A f lag e ll um a t b ot h p o le s d . P e r i t ri c h ou s . F la g el la d is t ri b ut e d e v e nl y o ve r t h e e n ti r e ce l l e . Ax i a l fi l am e n ts . Pe r ip l as m i c f la g el la wr a p p ed a r o un d s pi r oc he t es f . G l i d in g m o t i li t y. A s de m on s t r a te d b y s li m e m ol d s P.177
III. STRUCTURE OF THE PROKARYOTIC CELL A. O ve r vi e w . P ro k ar y o t ic c e ll s ( b ac t er i a ) a re sma l l an d r e la t i v el y s im p l e ( F i gu r e 9 1 ) . Th e y ha v e t he fo l lo wi n g c h a ra c t e r is ti cs : 1 . C o n ta i n n o i n t e r na l m e m b ra n e b o un d o rg a ne l l es bu t ha ve c om p le x c e ll wa l l s t r uc t ur es 2 . La ck a t r ue nu c l e us , a n uc l ea r m em b r an e , a nd i n t ra c y t op l asm ic m e m b r an o us o r g an e ll es ( e. g ., pl as t id s , e nd o pl as m i c r e ti c u l um , va c uo l es ) 3 . Mu l t i pl y a s e xu a l l y b y b i n a r y f i s s i o n r a th e r t ha n b y m i to s i s o r m ei os is 4 . P r o te i n s yn t h e s i s i s m e di a te d b y 7 0s ra t he r th a n b y 8 0s ri b os om es . 5 . B ac t er i al ge ne t ic in f o rm a ti o n is a r ra ng e d o n a s i ng le s u p er co i le d c i rc ula r st r a nd o f do u bl e -s t ra n de d D N A ; t h e n u cl e o id is th e a r ea o f th e c el l c on t ai n in g t he t ig h tl y c o il ed c h r om os om e . 6 . S om e b ac t er i a c o n t ai n s t or a ge g ra n ul es , o r in c l u s i on bo d ie s , t he s t ai n in g of t he se g r a nu l es m a y al s o be us e f u l i n i de n ti f y i ng th e b ac t e ri a . B . E x t e r na l s t r u c tu r e s 1 . C a ps u le an d sl i me laye r a . Th e ca p su l e is an adh e r en t , s u rf ac e c o at m a de u p o f l on g c ha i n r e pe at s of c a r bo h yd ra t es o r p ep ti d es . Th e c ap su l e d if f e rs i n c om p os it i on am on g b ac te r i a o f d i f fe r e nt ge n us a n d s p ec i e s . A nt i ge n ic d i ff e r en c es am on g c a ps ul es c a n be us e d t o i d en t i f y s t ra i ns wi t hi n a s i ng le s p ec i es o f b a c t e ri a ( S t r ep t oc oc c us pn e u mo n ia e ) . C a p su l es a r e u s u a ll y p oly s a c c h ar i de in na t u re ; ho we v e r , t h e c ap su l e o f Ba c il lu s i s p o l yp ep ti d e . Th e c a ps ule h as s e v e ra l fu nc t io ns : ( 1 ) I nc r ea s e s t he vi r u l en c e (d e gr e e o f o r ga n is m p a th o ge n ic it y ) o f a m ic ro o r ga n is m ( 2 ) P r e v en t s p ha g oc yt o s i s o f th e o r ga n is m b y m a c r op ha g es an d n eu t r oph i ls ( 3 ) A id s i n a d he r e nc e o f t h e o r ga n is m to h os t c e ll s b . I f t h e p ol y s ac c h a ri de is no n ad h er e n t, it is c a ll ed a s l i me la ye r .
Figure 9-1. Structure of a procaryote cell. [Adapted with permission from Winn WC Jr, Allen SD, Janda WM, et al. Koneman's Color Atlas and Textbook of Diagnostic Microbiology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.]
P.178
c . T ra n s fo r m a ti o n f r om s m o o th t o r o ug h c ol on i es on m e di a i n di c a t es c ap s u le l os s . C o n cu r r en t l y , t h e re is a lo s s o f vi r ul e nc e . Th i s c ap s ul a r m at e ri a l is im m u no g e ni c, t h e r eb y i nd uc in g th e p r od u c t i on of a nt i b od i es , wh i ch ac t a s o ps on i ns t o en h a nc e p h a go c y to s i s ( o p so n iz a ti o n ) . 2 . F la g el l a a r e p r ot e in ac e o us , h e li ca ll y c oi le d or ga n s us e d f o r m o v em en t th a t e xt e n d o ut wa r d f r om th e c y t o pl as m t h r ou gh t he c e l l wa ll in t o t h e e n v ir o nm e nt ( F i gu r e 9 - 2 ) . F la g el la r ota t e e i th e r c lo ck wi s e o r c o u n te r c l oc k wi s e , al lo wi n g a s e ri es o f r un s a nd t um bl es in res p on s e t o c h em ic a ls i n th e en vi r on m e n t . Th e di re c ti o n o f m o vem e nt is c o nt r o ll ed b y a c o m p le x m e c ha n is m i n v o l v in g c he m o r ec e pt or s an d a n i n t ra c el lu l ar c a s c ad e o f m e th y l a ti o n a nd ph os p hor yl a t io n re ac t io ns , c a us in g ba ct e r ia t o m o ve to wa r d n ut r ie n t c h em oa t t ra c ta n ts a n d a wa y f r om r ep e ll an t s. a . S t r uc t u r e ( 1 ) Fl a ge l la ar e c om p os ed o f f l a ge l li n , a p ro t ei n c a ll ed H a n ti g en , wh i ch is a n t ig en ic a ll y d is ti nc t f rom o th e r f la g el la in eu c ary o t e s . ( 2 ) Fl a ge l la ha v e t h re e p a r t s : ( a ) B a sa l b o d y ( i ) A t ta c h es t he fl a ge ll a to t he c yto p la s m ic m em b ra n e a n d c e l l wa l l
Figure 9-2. Structure of a procaryote flagella from a Gram-negative organism. [Adapted with permission from Winn WC Jr, Allen SD, Janda WM, et al. Koneman's Color Atlas and Textbook of Diagnostic Microbiology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.]
P.179
( i i ) Th e n um b e r o f r i ng s t h a t m ak e u p t he ba s a l bo d y d if f e r i n g r am -p o si ti ve ( t wo ) a n d g r am - ne g at i v e (f o u r) o r g an is m s . Th e L a n d P r i ng s a r e a bs e nt in G r am - p os it i ve o r g an is m s . ( b ) H o ok ( c ) F il a me n t b . P e r ip l as m ic f la g e ll a , a ls o c al l ed ax i al f i la men t s , o c c u r i n s pi r oc he t es a n d a r e e m be d de d i n to th e c el l wa l l 's ou t e r m em br a ne . Bec a u s e t h e y c au se a c o rk s c re w t yp e o f m o t io n o n c on t r ac t io n , t h es e o r ga ni s m s ar e n ot hi n de r ed b y th e vis c o si t y o f m e di a . 3 . P i li ( f im b r ia e ) a r e p r ot e i na c e o us , h ai r - li k e e xt e n si o ns t h at a re s h o rt e r t h a n f l a ge ll a a n d c o m po s e d of r e gu l ar l y a r ra ng e d p r ote i n s ub u ni ts c a ll e d p i li n o r f i m b r i li n . Th e y a r e m o re c om m o n i n g r am - ne g at iv e o r g an is m s b u t c an be f o un d i n g r a m - p os it i v e o r g an is m s . Th e r e a r e t wo m o rp h olo g ic a l an d fu nc t io n al va ri e t ie s: a . C o mm o n ( a tt ac h m e n t) p il i ( 1 ) A pp e a r i n g re a te r num b e rs t h an s e x p i l i ( 2 ) H a ve a d he s i v e p ro per t i es , wh i ch ar e i m p o r ta nt i n t he f o rm at i on of bi o fil m s ( 3 ) A r e l ec ti ns , wh i c h a re r es p on si bl e fo r t ro ph ism , th e a b il it y o f th e o r gan i s m to b i nd t o sp ec i fi c r e c e p to rs on ho s t ce l ls b . S ex ( c o nj u ga t i v e o r F ) p i li ( 1 ) A r e l on g er t ha n c om m o n p il i ( 2 ) F or m i n g r ou ps o f < 1 0 ( 3 ) A r e i n v ol v e d i n t h e t ra n s p o r t o f D N A b et we e n d o n or an d re c i p ie n t c e l ls C . T h e c el l w a ll , pe r i p las m i c s pa c e, a nd c yt o p l a s m ic me m b ra n e 1 . Th e ce l l w a l l i s r ig i d. A l t h ou gh i t p ro v i d es th e g e n er a l s h a pe of t he c e ll, i ts f u nc t io n i s t o p r o te c t t he c el l f r om os m o t ic s ho c k . I f th e c el l wa l l is de s tr oy e d , t he b a ct e r ia l c el ls ar e s us c ep t i bl e t o a l te r a ti on s i n t he t on ic i t y of th e e n v i r onm e nt . Th e wa l l i s c o m p o s e d o f a bas ic p ep t i do g l yc a n l a ye r , wh i c h i n t u rn is c om p os e d of r e p ea t in g d is ac c ha r id e un i ts ( a p ol y m e r o f N- a ce tyl g l u c o s a m in e a n d N -
a c e t yl m u r a m i c ac i d ), wi t h a f o ur - am i no - ac id s i de c ha i n t ha t is c o val e nt l y l i nk ed t o a m in o a c i ds f ro m n ei g hbo r i ng di s a c c ha r i de un i ts , f o rm i ng a s ta bl e c r os s -l in k ed s t r uc t ur e . Mo s t b ac t er i a a r e de s i gn a te d a s e i th e r g r am - po s i t i ve o r gr am - ne g a ti v e , b a se d o n f u nd am e nt a l d if f e r en c e s i n t h e co m p o ne n ts o f t he ce ll wa l l . O wi n g to t he u n iq u en es s a nd t he im por t a nc e o f th e c el l wa ll t o b a ct e r ia l v ia bi l it y, i t is the t a rg e t o f m a n y an t ib io t ic ag en ts . a . G r a m -p o si t i ve o r ga n is m s h a ve a th ic k c el l wal l , wh ic h i s 9 0% pe p ti d ogl y c a n , wi t h e xt e n s i v e c r os s - l in k i n g t h at is ap p ro xi m a t el y 4 0 l a ye rs th ic k a n d f o rm s a l a ye r ed ne t wo r k a ro un d th e c y t o pl a sm i c m em b ra ne . W i t hi n th e c el l wa ll , a v a r i e t y of e l em e nt s s e r v e t o s ta bi l iz e t h e c el l wa ll , m a in t ai n i t s as s o ci a ti o n wi t h t he c yt o pl as m i c m em b ra ne , a n d a c t as r ec ep t o rs a n d a n ti g en ic de t e rm in an t s . Th e s e e l em e nt s i nc lu d e p ro t ei ns , po l y s a cc ha r id e s a nd te i c h oi c a c i d (g l y c e r ol o r r i b it o l p h os p ho di es t e rs ) . ( 1 ) T ei c ho i c a c id s (g l y c e r o l o r ri bi t ol ph o s p ho d ie s te r s ) ( a ) M e m b ra n e -a ss o c ia te d t ei c h oi c a c id s (l ip o te i c h oi c a c i d ) a r e c o v al ent l y l in ke d to g l yc ol ip i ds o f th e c y t o pl as m i c m em b ra ne . ( b ) W al l - as s oc i a te d te ic h o ic a ci d s a r e c o va l ent l y l in ke d to th e g l yc a n c h a in o f p e p ti do g l y c a n . b . G r a m -n e ga t i ve o r ga ni s m s' c e ll wa l ls a re m u lti l a ye re d wi t h a th i n p ep t id o gl y c a n l a ye r th a t h as no te ic h oic ac id s . E xt e r n a l t o th is is t he ou t e r m e mb r a ne , a c o m p l e x c e ll wa l l l a y e r , wh i c h is li n k e d t o th e p ep t id o gl y c a n la y e r b y t h e l i po p r o te i n l a y e r . Th e o u te r m em b r an e a c ts as a h y d r op ho b ic d i f fus i on ba r r ie r an d c on s i s t s o f ( 1 ) P h os p ho l i pi d , a bi la y e r s i m i l ar t o t he c y to p la s m ic m e m b r an e wi t h p ro t e in c h an n el s , c a ll e d p o r in s , f o r n u t ri e nt t ra ns p o rt . Th e ph os p ho li p id la y e r of t h e o u te r m em b r an e f ac es t he c y t o p la s m ic m em b r an e . ( 2 ) Th e li p o po l ys a c c h a r i d e ( LP S ) c om p on e nt p ro j ec ts f ro m t h e c e l l s u r f ac e a n d is b o t h t o xi c an d a n ti ge n ic ( O a n t i ge n ) . I n a gr a m - ne g a ti v e o rg an is m , t he L PS b l o ck s d i f f u si o n o f l o w m ol ec u la r we i g h t su bs t an c es i n to t he c e ll , s o a n ti b io ti c s a n d c h em ic al s t ha t at t ac k t he c el l wa l l ( e .g . , l ys o zy m e, p en ic i ll in ) c a nn o t e as ily p a ss t h r o ug h . L P S , a ls o k n o wn as e nd o t ox i n , is to xi c t o hu m a ns a nd i s c om pos e d o f t h r e e p ar t s : ( a ) L ip i d A: t o xi c p o r ti o n t h a t c a n e i th e r s lo u gh of f in t ac t c el ls o r b e r e le as e d i nt o c i rc u la ti o n u po n l y s is of t h e c el l , c au si ng no n s p ec i fi c i nf l am m a ti o n, in cl u di n g d i a r rh e a, fe v e r , an d s ep ti c s ho c k P.180
( b ) C o r e p o l ys a c c h a r i de : s i m i la r wi t h in ge n e ra ( c ) O - s pe c i fi c s i d e c ha in : s p ec i es s p ec if ic ( 3 ) P r o te i n 2 . Th e pe r i p la sm i c s p ac e , a n a r e a b et we e n th e c e ll wa l l a nd t he c y t o pl as m i c m em b r an e , c o n ta i ns a ge l of s e v e r al t y p es o f m ol e cu le s (e . g. , h y d r o l y ti c e n z ym e s , p e r ip l as m ic - b in di n g p r ote i ns ) th a t p r oc es s m o le cu l e s be f o re th e y en t e r t he c yt o pl as m . I t a ls o c on t ain s p r o te i ns t h a t ac t a s c h e m o r ec e pt o rs fo r c h em o t a xi s ,
o t h e rs t h at ac t a s c a rr i e rs o f n ut r ie n ts (s im il a r t o c a r ri e rs in th e c y t o pl as m i c m em b r an e ), a nd an t ib io t ic - i na c t i va ti n g e n z y m e s . 3 . Th e c yt o p l a s m i c m em b r a ne is a p ho sp h ol ip id b il a ye r m at r i x o f a f a tty a c id c o r e ( h y d r o ph o bi c ) a nd gl y c e ro l ph os p ha t e ( h y d ro p hi lic ) . In th e p r es e nc e o f p ro t e in s e m be d de d i n t h e m a t r i x, t h es e m em b ra n es a r e a c t i ve l y an d p as s i v e l y e nga g e d in s e ve r al ce l lu l a r fu n c ti on s . a . T r an s po r t a t io n of nu tr i e nt s t h r ou gh ( 1 ) P as s i v e di f fu s i o n ( 2 ) F ac il it a te d d i f fu s i on ( 3 ) A ct i v e t r a ns po r t (t h is m e th od is th e o n l y o n e th a t a c ti v e l y us es e n e rg y b e c a us e m o le cu l es a r e m o v in g i n to t he c e ll ag a in st a c on c e n t r at i on gr a di e nt ) b . Th e s i te o f r e sp i r a t ion p r o t ei n s u s e d f o r e l ect r o n t r a ns p o r t a nd en e rg y f o r m a t io n c . E nz ym e s i n v o l v e d i n th e as s e m b l y of th e c el l wa l l c om po n en ts d . S ec r e t i on o f e xo t o xin s an d o t he r s u bs t an c e s f o r th e b r ea kd o wn o f m ac r om o le c u le s D . I n t e rn a l s t r u ct u r e s 1 . S t o ra g e g r a n ul e s a re i nc l us io n b o di es us ed for f o od o r e ne r g y s t o ra g e ( e . g ., p o l yp ho s p ha t e c om pl e xe s , c a r bo h y d ra t e ). 2 . R i bo s om e s a r e c e l lu la r u ni ts th a t s yn th es i ze p r o t ei n b y t he t ra ns l at i on o f m es s en ge r R N A (m R N A ) b as e s e qu en c e s i n to am i n o a c i d p r o te in s e qu e nc e s . Th es e r i b os om es , u n li k e th os e in e uk a r yot ic c e ll s , a re 70 s u n it s a nd a re no t as s o c ia t ed wi t h m em b ra n es s uc h a s m it o c h on d r ia or r ou g h en d o pl as m i c r e ti c u lu m . 3 . Th e nu c le a r r eg i o n of b ac t er i a is a c on d en s ed a r ea (a nu c l e oi d ) c on ta i ni n g t he b a ct e r ia l c hr om o s o m e , wh i c h la ck s a n uc l ea r m em b r an e a nd c o ns is t s o f a l on g , d o u bl e -s t ra n de d , s u p e rc o i le d , c ir c ul a r D N A m o lec u le . 4 . S om e o r ga n is m s c on ta i n p l as m id s , c ir c ul a r do u bl e -s t r an d ed pi ec es of D N A t h at a r e fo u nd ou ts i de of t he b a c t e r ia l c hr om o s o m e . Th e s e s t r uc t ur e s a re au t on o m o us ( n o t c on t r ol le d b y t h e b ac t e ri al c h r om os om e ) , c on t a in in f or m at io n fo r he av y m e t a l a n d a n ti bi o ti c re s i s t a nc e, a r e c o n ju nc t i v e , a nd c ar r y g e ne t ic el em e nt s c a l le d t r a n s po s o ns .
IV. MICROBIAL PHYSIOLOGY A. N u t r i t i o n a l t yp e s 1 . Au t o t r o p hs us e c a rb on d io xi d e as th e i r s o l e o r m ai n c a rb o n so u rc e . a . P h ot o a ut o t r o ph s u s e l i gh t a s a n e ne r g y so u rc e . b . C h em o au t o t r op h s o x i d i z e o r ga n ic o r in o rg a nic c o m p o un ds to p ro d uc e e n e rg y. 2 . H e te r o t r o ph s u s e o rga n ic c om p ou n ds a s t h ei r m ai n c a rb o n s o u rc e . a . P h ot o h et e r o t r op h s us e l i gh t a s a n e ne r g y s ou r c e. b . C h em o he t e r o t r op h s o xi d i z e o r ga n ic a n d i no rg a ni c c om po u nd s t o p r od u ce e n e rg y. 3 . P r o t ot r o p hs a re pa r en t c e ll s t h at ha ve no s p ec i al nu t ri t io n al r eq ui r em en t s . Th e y r e q ui r e t h e s a m e n ut r ie nt s as t h e m aj o r n um be r of t h e n at u ra l m em be r s o f t h e s p ec ie s .
4 . Au x o t r o p hs ar e m u tat e d s o t h at t he y c a n no t sy n t h es i z e th e s am e e s s en t i al n u t ri e n ts (u s u al l y am in o a c id s ) as t he i r p a re n t c e l l . 5 . S u bs e ts a . H o lo p h yt i c . O r g a n is m s wh o s e n ut r ie n ts m us t be i n a s ol u bl e , d if f us ib l e f o r m b . H o l oz oi c . O rg a ni s m s t h a t n ee d c om pl e x n u t r ien t s , o ft e n s ol id m a te r i al s t h a t a re i n ge s te d a n d t he n b r ok en d o wn c . S ap r o p h yt i c . O r g a n is m s wh os e n u t ri en t s a r e o b t ai ne d f ro m d ea d o r de c a y in g o r g an ic m a t te r P.181
d . P a r as i t ic . O r ga ni s m s wh o s e nu t r ie n ts a r e o b tai n ed f r om a n d a t t he e xp e n se of a l i vi ng o rg a ni s m (h um a n p a t ho g en s ) B . N u t r i t i on a l r e q ui r e me n t s . B ac t e ri a u se a wi d e v a r i et y o f n u t ri en t s t o o b t ai n e n e rg y a nd t o c o ns t r uc t n e w c e ll u la r c om p on en t s . Th e s i x e l e m e n ts us ed a s th e m a in c om p on e nt s o f c a rb o h y d ra t es , l i pi ds , p r o te in s , a nd nu c l e ic a ci d s a re c a rb o n, o xyg e n , h y d r o ge n , n it r o ge n , p h os ph o r us , a nd su lfu r . S e ve ra l m in o r a nd t rac e e l em e nt s as we l l as c at io n s p la y va r i ou s r o le s i n t h e m ic ro o r ga ni s m s . C . T e mp e r a tu r e r el a t ion s 1 . P s yc h r o p h i l e , a n o r ga n is m t ha t gr o ws we l l at 0 ° C , ha s o p ti m a l g r o wt h a t 15 ° C o r l e ss , a nd a m a xi m um g r owt h t e m pe r a tu r e o f 2 0 ° C 2 . M e s op h i le : a n o r g an is m wi t h o pt im a l g r o wt h at 2 0 ° -4 5 ° C , m i n im um g r owt h t e m p e r at u re s b e t we e n 15 ° a nd 20 ° C , a n d a m a xi m um g ro wt h t em p e ra t ur e o f a p p ro xi m a t el y 4 5 ° C (h um a n p at h og e ns ) 3 . T he r m op h i le : a n or g an i s m th a t ca n g r o w a t 55° C o r g re a te r , wi t h a m ini m um g r o wt h t em pe r a tu r e o f ap p r o xi m a te l y 45 ° C . D . O x yg e n r e q u i r em e n ts . H o w o r ga n is m s u se oxy g e n c an be a m a j or f ac t o r i n t he i r c l as s i fi c a t io n . 1 . Ae r o b e s h a v e t h e a bi li t y t o g r o w i n t h e p r es enc e o f at m o s p h e ri c o xyg e n . a . O b l ig a t e a e ro b es de pe n d c om pl e te l y on o xy g e n f o r g r o wt h . O xy g e n se rv e s as t e r m i n al e l ec t ro n a c c e pto r in a er o bi c r es p ir a ti o n. b . F ac u l ta t i ve ae r o be s h a v e th e a b il i t y to gr o w wi t h o r wi t h ou t m o le c u la r o xyg e n . 2 . An a e r o be s h a v e th e a b il i t y to g ro w wi t h o u t o xyg e n . a . O b l ig a t e a na e r ob e s d o no t to le r a te o xy g e n at a ll an d d i e i n i ts p r es e nc e . Ma n y s t r ai ns la c k c a ta l as e a nd s up e r o xi d e d is m u t as e, wh i c h p ro t ec t c el ls f ro m t h e d e st r uc t i v e o xi d i z i n g c a pa b il i ti es o f h yd r og en pe ro xi d e a n d s u p e ro xi d e ion s , wh ic h a r e no rm a ll y p r od uc e d un d e r a e ro b ic c on d it i on s . b . F ac u l ta t i ve an a e ro b es d o n ot r eq u ir e o xy g e n b u t g r o w b e t te r i n i t s p res e nc e. 3 . M i c r oa e r o ph i le s re q ui r e o xy g e n l e v e ls be lo w n o r m a l a tm os p he r ic pr e ss u r es fo r g r o wt h ( e .g . , He li c o b ac te r py l or i ) 4 . C a pn o p hi l es r eq ui r e h i gh e r l e ve ls o f c a rb o n di o xi d e t ha n a r e f o un d a t n o r m a l a t m o s p h e ri c p r es s u r es fo r g ro wt h ( e . g. , N ei ss e ria s p . an d St r ep t oc oc cu s p n e u m on ia e ) . E . B a c te r i a l g r ow t h c u rve . B a c te r ia l g r o wt h is de f i ne d a s a n i nc r ea se in t h e n u m b e r o f c el ls p re s e n t. B e c au se ba c te r ia r ep r odu c e b y b in a r y f i s s i o n, gr o wt h c an
b e pl o tt e d as t he lo g o f th e c e ll nu m b e r v e rs us t im e to pr o du c e a c ur ve wi t h f o u r d i st i nc t p ha s e s (F ig u r e 9- 3 ) . 1 . L ag ph a se . A t r an s i t io n pe r io d d u r in g wh ic h th e ba c t e r ia ar e re p li c a t in g D N A an d t h e e n zy m es ne e de d f o r t h e n e w e n v i r on m e n t a r e b e in g i nd u c e d . Th e c e lls a re i n c re as in g i n s i z e b u t n ot i n n um be r . D ur i ng th is p h as e o f g r o wt h , th e c el ls a re m o st p e r m e ab l e. 2 . L og a r i th m ic ( l og ) pha s e . D i vis i on oc c u r s a t co n s t a nt an d m a xi m a l r a te , an d th e n u m b e r o f c el ls in c re as es in a g eo m e t r ic p r o g re s s i on . Th e g en e r at i on ti m e , wh i ch va r i e s am o ng s p ec ie s , is u s u a ll y 1 5 -2 0 m in u te s (E s c h e r ic hi a ), bu t m a y be h o u rs ( My c o b ac t e ri u m ) . Be c a us e th e c el l wa ll is be in g s y n t he si z e d s o ra pi d l y , ba c te r i al c e ll s a r e m o s t s u s c ep t ib le t o c el l wa l l in h ib i to rs du r i ng t hi s p ha s e . 3 . S t a ti o na r y p h a s e . The g r o wt h ra t e t ap e rs o ff a n d g r o wt h an d d e at h rat e s a r e n e a rl y e qu a l. A fa i rl y c on s ta n t p op u la t io n o f v ia bl e c e ll s r es u lt s. D u ri n g th i s p ha se , c e ll ul a r m et a bo l it es a re p o ll u ti n g t he en vi r o nm ent . 4 . D ea t h ph a se . W hen th e c o nc en t r at i on of vi ab le ce l ls d ec r e as es b e ca us e o f th e a cc u m u la t io n o f to xi c wa s t es an d a u to l y t ic e n z y m e s .
V. METABOLISM AND ENERGY PRODUCTION. Mi c r o o r g an is m s de r i v e en e r g y f ro m n ut r i en ts b y a se r i es o f c h em ic al re ac t io ns b y wh i c h th e en e rg y s to r ed i n c h em ic al bo n ds i s t r ans f e r re d t o n e wl y f o r m e d c h em ic al b o n ds t o p r o v i de en e rg y s t o ra g e i n a u se f ul f or m , s uc h a s a de n os in e t r ip ho s ph a te ( A TP ) . P.182
Figure 9-3. Growth curve of bacterial culture. [Reprinted with permission from Winn WC Jr, Allen SD, Janda WM, et al. Koneman's Color Atlas and Textbook of Diagnostic Microbiology, 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2006.]
A. AT P g e n e r at i o n 1 . S u bs t r a te - l e ve l p h osp h o r yl a t i o n r el e as es e ne r g y t h ro u gh di r ec t t r an s f e r of h i gh - e ne r g y ph os p ha t e gr o u ps f ro m a n i nt e rm e dia t e m e ta bo l ic c om p ou nd t o a d e no s i ne di p ho s p h at e (A D P ) . N o m ol e cu la r o xyg e n o r ot h er in o r ga ni c f in a l e le c t ro n a cc e pt o r i s r e qu i re d .
2 . O x i da t i ve ph o sp h o r yl a t i o n r em o ves el ec t r ons f ro m o r ga n ic c om po u nd s a n d p a ss es th es e e l ec t ro ns th r o ug h a s e r ie s o f e l ec t ro n ac c e p to rs al o ng an ele c t ro n t r a ns p or t c h ai n , wi t h m o le c ul a r o xyg e n o r s om e ot h e r i n or g an ic c o m p ou n d a s t h e f i n al acc e pt o r . B . F e r me n t at i o n r e fe r s to e ne r g y- p ro d uc in g o xi d a t i v e s eq u en ce s , i n wh i ch o r ga ni c c om p ou n ds s e r v e a s b oth e le c t r o n d on o rs an d a c c e pt o rs . Th is p ro c e s s o cc u rs in th e a b se nc e o f e xt e r na l e l ec t r o n a c c ep t o rs . 1 . G l yc o l ys i s i s th e fi rs t s t ep in fe r m e n ta t io n a nd r e s p i ra t io n a n d ca u s e s th e o xi d a t i on o f g lu c o s e to py r u v i c ac id wi t h a y i e ld of t wo m ol es o f A TP . Th e re a r e d i f fe r e nt pa t h wa y s fo r p yr u v i c a c i d p r o du c t i on i n m ic r o or g an is m s : a . Th e Em b d en - M e ye r h o f ( g l yc o l yt i c ) p a t hw a y i s th e m aj o r p at h wa y . b . Th e E n tn e r - D ou d o r o ff p a t hw a y i s a n a l te r na te . c . Th e h e xo s e m o no p hos p h a te sh u n t u s e d wi t h t h e g l yc o l y t ic pa t h wa y i s a n a l t er n a ti v e . 2 . S ec o n da r y f e r m e n t a ti o n p r oc es s . Ma n y b ac te r i a u s e p y r u v at e t o o xi d i ze r e d u ce d ni c o ti n am i d e ad e n i ne di n u cl e o ti d e ( NAD H ) , p r o d uc e d i n g l yc ol ys is , to m a nu f ac tu r e a v a r ie t y o f f i n al pr o du c ts . a . L ac t ic ac i d fe r m en t at i o n . Th e s i m p l es t p r oc es s , wh i c h c on v e r ts p y r u va t e to l a ct a te ( La c t o ba c i l lu s , S tr e p t oc oc c us ) . b . Al c o h o l f e r me n t at i o n. P y r u va t e i s co n v e r te d to e th a no l a n d ca r bo n di oxi d e ( S a cc h ar o m y c es ) . c . M i xe d a c i d f e r me n ta ti o n . A co m bi na t io n o f l ac t ic , f o rm ic , an d a ce t ic ac i ds i s p r o du c e d wi t h e t ha n ol , hy d r o g en , an d c a rb on di oxi d e ( E s c h e ri c h i a c ol i ). d . B u t an e di o l fe r m en t a ti o n . P y r u v at e i s c on v e r te d to ac e to in , wh i c h is re d uc e d t o 2 , 3 - bu t an ed i ol ( En t e ro b ac t e r ). e . B u t yr i c a c id f e rm e n ta t i o n . B u ta no l , i s o p ro p an o l , a nd ac et o ne a re p rod u c e d ( C l o st r id i u m ) . P.183
f . P r o p io n i c a ci d fe r m en t a t i on . P y r u v a te is c onve r t e d t o o xa l o a c e t a te wi t h t h e a d di t io n o f c a r bo n d io xi d e a nd th e n t o p r op i on ic a c id ( P ro p io ni b ac t er i u m ). C . R e s pi r a t i on r ef e rs to e n e rg y - p r o du ci ng o xi d a tive s eq u en ce s , i n wh i c h in o r ga n ic c om p ou n ds a c t as t he las t el ec t ro n a c c e pt o r i n a s e r ie s o f r e ac ti o ns . Th is p r o c e ss i n cl ud e s g l yc o l ys i s , t h e t r i c a r b ox yl i c a c i d ( T C A) c yc l e , a nd th e el e ct r on t r a n s po r t s ys t e m , wh i c h y i e ld s A TP wh e n c ou ple d wi t h o xi d a t i v e p h os p ho r y l a ti o n . 1 . Ae r o b i c re s pi r a t i on . O xy g e n s e r ves as t h e f ina l el ec t r on ac c e pt o r . a . P y r u v a te is c o n v e rt e d t o ac e t yl c o e n z ym e A a n d c a r bo n d io xi d e a nd wa t e r t h r o ug h t h e T C A c yc l e . b . Th e el e c t ro n t r an s por t s ys t e m p la ys a r ol e i n t h e t r an s p o r t o f e l ec t ro ns al o ng a s e r ie s o f c ar r i er s f o un d in t he c y to p la sm ic m em b ra n e , e ac h wi t h su c c es si ve l y h ig he r o xi d a t i on p ot e nt i al s . Ma j o r c o m p o ne n ts o f th e e l ec t r on t ra ns p o rt s ys t em i nc l ud e ( 1 ) C yt oc h r om es ( 2 ) Fl a v o p ro t ei ns ( 3 ) U bi q ui n on es
2 . An a e r o b ic r es p i r at i on . A n i no r g an ic el ec t r on a cc e pt o r o t he r th a n o xyg e n ( e. g ., n i t ra t e , s u l fa t e , c a r b on a te ) s e r v e s a s t he fi n al el ec t r on ac c e p to r .
VI. GENETICS A. D e f i n i t i o n a nd t e rm s. G e n et ic s i s t he s t u d y of wh a t g en es a re , h o w t he y c a r r y i n f or m at io n , a n d h o w t hey a r e r ep li c a t ed an d pa ss e d o n. 1 . C h r om o s om es a re bod i es c om p os ed o f D N A th a t c on t ai n g e ne t ic i n fo rm a ti o n. B a c te r ia h a v e o nl y o ne c h r o m o so m e — a s in gl e , co n t in u o u s ( c l os e d) , do ubl e s t r an d ed , c i rc ul a r p ie c e o f D N A . a . D u pl i ca t i o n oc c u r s by s e m i c o ns e r v a ti ve r ep lic a ti o n, in wh i ch t he t wo s t r an ds o f t h e h e li x s e p a ra t e ( o r i gin ) a nd at t hi s p oi n t ( tw o r e p l i ca t i on f o rk s ) n e w s t r a n ds a r e s yn t he s i z e d , b i di r ec ti o nal l y , wi t h th e o r ig i na ls s e rv i n g as te m p la t es . b . S t r u ct u r e . Th e c e ll m e m b ra ne is at t ac he d to th e c h r om os om e; as th e c e ll gr o ws , i t se pa r a te s t h e d au gh t er c h ro m o s o m e s . Th e r e for e , ea ch da u gh t e r ce l l ha s o n e o r i gi n al an d o ne ne w s t ra n d . 2 . G e ne s a r e D N A s eg m e n ts t ha t a r e p r oc es se d in t wo s te ps t o p r od uc e va r i ou s p r o t ei ns . A n o rm al ba c t er i a l c e l l is h ap l o id . B . R e g u la t i on an d ex p re s s io n o f g en e t ic i nf o rm a t i on 1 . D N A h a s m an y f u nc t io n s . a . I t is d up l i ca t ed f or t ra n s f e r t o p r o ge n y du r in g c el l d i v is i on . b . I t i s t r a ns c r ib e d i n to R N A , wh i c h c an be t ra n s l a t ed in t o a p r o te in . c . It co n ta in s c o n t ro l sig n a ls , wh i ch ul t im at e l y c o n t r ol th e s yn t he s i s o f p ro t e in . d . I t c an be mu t a te d to a l t er s p ec i fi c ch a r ac te r ist i cs en co d ed b y g e ne s . e . I t ca n b e du pl ic a te d an d t ra ns f e r re d t o o t h e r ba c t e r ia l c e l ls in pr o ce s s e s o t he r t h a n ce l l d i v is io n (e . g. , c o n ju g at i on ) . 2 . D N A r e p l i ca t i o n, t r ans c r i p t io n , a nd t r a ns l at io n a ff ec t c e ll ul a r g r o wt h a n d d e ve l op m e n t. a . B ac t er i al r ep l i ca t i on in v o l v e s a c c ur a t e d up li cat i o n o f c hr om o s o m a l D NA , wh i c h e n a bl es th e f o rm a ti o n o f t wo i d e nt ic a l d au g ht e r c e l ls . b . T r an s c r ip t i on o f i nf o rm a ti o n f r om D N A t o R N A i s t h e f i rs t o f t wo s t ep s n e e de d t o p r o du c e ne c es s a r y p ro t ei n s . O n e g en e c an be t ran s c r i be d i n to m a n y c op i es o f R N A . S i m pl is ti c al l y , R N A p ol y m e r as e l oc at es t he be gin n in g o f th e g e ne ( pr o m o t o r ) , a nd t h is a re a u n de r go es lo c al i z e d u n wi n di n g t o a ll o w R N A p o l y m e r as e t o t ra ns c r i be R N A ( c al l ed m R N A) f r om t h e D N A t em pl a te . Th e R N A i s n o t p r oc ess e d, as in e u ka r y o t es . Th er e a r e no i nt r o ns a n d e xo n s , n o c a pp i ng of th e 5 ′ en d , a nd n o p o l ya de ni n e t ai ls ad d ed t o t he 3 ′ e nd . c . T ra n s la t i on is th e p r oc es s i n g o f g e ne ti c i n fo rm a ti o n t o s yn th es i z e p r ot e i ns . B e f o re t r an s c ri p ti o n is c o m pl e te d , a ri b os om e wi l l a tt a c h to th e 5 ′ en d o f th e m es s ag e . Th e 70 s P.184 b a ct e r ia l ri b os o me is c om p os ed of t wo s ub un i ts , 3 0 s a nd 50 s . Th e r ib os om e t r a n s la t e s t he m e s s ag e i n t o p r ot ei n b y re ad i ng th e t r i pl e t c o do n ( th r ee n u cl e ot id e s ) wh i c h c o d e f o r a s p e c i fi c a m i no ac i d. Th i s a m i n o ac i d is c a r rie d to t he s i te b y t r an s fe r R N A ( t R N A) a n d p ai r s wi t h t he c o d o n b y an an t i co d o n. A m i no
a c id s a r e j oi ne d , a nd t he r i bo s om e m o v e s t o t h e n e xt c o d on . Th is c on t in ue s u n ti l t h e c om p le t e p r ot e in is s y n th e s i z e d . 3 . R e gu l a ti o n . Th e p ro du c ts of ce ll u la r g r o wt h m u s t b e p r od uc e d i n c o r r ec t p r o po r t io ns fo r t he c e ll to l i v e a nd fu nc t io n . Th e two m o s t c o m m o n m e ch an i s m s o f m e ta b ol ic an d g e ne t ic reg u la t io n a r e a s f o ll o ws : a . F ee d ba c k i nh i b i ti o n o f en z y m e ac ti vi t y ( m e t ab o li c r e gu l at i on ) i n hi bi t s t h e s yn t he s i s o f th e c el l g r owt h p r o d uc t . Th e p ro d uc t b i nd s wi t h an al l os te r ic s i te on t he e n zym e , t h e re b y in ac t i v at i n g t he ac t i v e s i t e. b . R e p re s si o n o f e n z y m e ac t i v i t y (g en e ti c re gu l at i o n) in h ib i ts th e s y n th e s i s o f th e e n zym e at th e tr a ns c r i pt io n al le ve l . c . In d u ct i o n o f e n z y m e a c ti v i t y ac t i va te s t he s y nt h es is o f t he en zy m e at th e t r a ns c ri p ti on le v e l . C . O t h e r me t h od s o f DN A t r a n s f e r . Mi c r o o rg ani sm s c an c h an g e t he i r ge n e ti c c o ns ti t u ti on b y th e tr a ns fe r o f g en e ti c m a t e ri a l f r om a d on o r c h ro m o s o m e to a r e c ip ie n t c hr om o s o m e ( re c om bi n at i on ) . Re co m b in a t io n o c c u rs b e t we e n ho m ol o go us s e gm en t s ( t ho s e th a t h av e s im il a r n uc l eo t id e s equ e nc es ) . Th e re a re th r e e g e ne r al m ec h an is m s : 1 . T r an s f o rm a t io n i n v o lv e s t he r ec ip ie n t c el l t aki n g u p c el l -f r e e, f ra gm e nt e d (i . e. , n a ke d ) D N A a nd r ec om bin i ng ge n e ti c el e m e n ts . a . Th i s p ro c e s s is p ri m i ti ve a n d oc c ur s n a tu r al l y wi t h i n on l y a f e w g e ne r a. b . R e qu i re m e n ts in c l ud e c om pe t en t r ec ip ie n t c el ls ( e xh i b it i ng D N A re c e p to r s ) o r a “ l ea k y” b a c t e r i a l c el l w a l l , s o t ha t D N A c a n b e in t r o du c e d i n to th e c el l . c . It is ge ne r a ll y as s o c i at e d wi t h re c om b i na n t DN A t e c h n o l o g y o r c l o n in g , a t e ch n iq u e t o am p li f y a s p e c i f ic g e ne in p re pa r a tio n fo r an a l ys is . In th is pr o c es s , th e b a ct e r ia l c el l wa l l s a r e m a d e l ea k y b y c h em ic al t re a tm e nt . ( 1 ) C lo n in g i n v o l v es s pl ic i ng a g en e i n to a p la s m i d D N A ( ve c to r ) . Al l v ec to r s s ha r e s e ve r al c om m o n c h ar ac te r i s t ic s : ( a ) Ty p i c al l y s m a l l, we l l -c h a ra c t e ri z e d m o le cu le s o f D N A ( b ) C o nt a in at le as t on e r e p li c o n a n d c a n b e re p lic a te d wi t hi n th e h os t e v en wh e n t h e vec t o rs c on t ai n f o r eig n D N A ( c ) C o de fo r a p he no t y p ic t ra i t t h at c a n b e u s e d to d et ec t th e p r es e nc e o f f o r ei g n D N A , wh i c h c an o ft e n b e u s e d to di s t i ng ui sh pa r en t a l f r om re c o m b i na n t vec t o rs ( 2 ) S e le c ta b le ma r k e r s a r e us ed to fi n d c el ls th at c on t ai n t h es e ve c to r s. ( 3 ) P l as m id s c an n ot m a in t a in s t ab i li t y un l es s t hey a r e be n ef ic i al to th e h os t , s o t h e p l as m i d s ho u ld c o nt a in a g e ne es se n ti al fo r c e ll u la r s u r vi va l —e i th e r a n e nz y m e r e q ui r e d in a m et a bo li c pa t h wa y o r a g en e th a t r es i s t s c e r t ai n a n ti bi o ti cs (s e e I I I . D .4 ) . 2 . C o nj u g at i o n is an im p o r t an t m ea ns o f g en e t ra n s f e r , p a rt ic u la r l y am ong g r am +
n e g at i ve o r ga n is m s . Th is p ro c e ss in vo l ves t wo m a ti n g t y p es — t he do no r ( F ) a nd -
r e c ip ie n t ( F ) c e l ls — an d t h e e xt r a c h r om os om al pie c e kn o wn a s t he s e x o r f e r t il i t y f a c to r (F f ac t o r ) . Th e F fa c to r ( e. g . , F p l asm i d o r e p is om e ) i s n ot un d e r t he c o n t ro l o f t he c h ro m os om e a nd c a n r e pl ic a te au t on om o us l y . Pl a sm i d -m e di a te d exc h a n g e o f g e n et ic in f o rm at i on c a n o c c u r o n l y th r ou g h t he exp r e s s i on of t ra ns f e r g ene s . Th e g e n es e nc o de d o n t h e p la s m i d r es u lt in th e tr a ns fe r o f a s in g le s t r an d o f DN A t h r o ug h t h e s e x p i l us in to t he r ec ip i en t c el l . Th e F f ac t o r h as s e v e ra l g e ne s th a t
c o de fo r fo r m a t io n a n d ai d in do no r a tt ac hm e nt of s e x p i li . D ur i ng th is p roc es s , a +
c o p y i s m ad e , a s in g le s tr a n d i s t r an s f e r re d , a nd th e r ec ip ie n t b ec om es F . R p l as m i ds al s o e xi s t , wh i c h e nc od e f o r re si s t a nc e to c e r t ai n a n ti b io ti cs o r he a v y m e ta ls . W he n a n F p l as m i d i nt e gr a t es i n to th e c e l lu l a r ch r om os om e , t h e b a c t e r ia l s t r ai n i s s a i d t o b e a hi gh - f r e q ue n c y r e c o m b i n at i o n ( H f r ) s t ra in . D u ri ng t h e c o nj u ga l t r an s fe r i n v o l v in g an H f r s t ra in , de pe n din g on th e a m o u nt o f t im e, t h e wh o l e b ac te r ia l c h ro m o s o m e m a y b e t r a ns fe r r ed . A n t i b i ot ic - r es is ta n ce gen e s a r e o f t en pa r ts o f t r a ns p os on s (s e e I I I. D . 4 ) , wh i c h ar e r es po n si bl e f o r a d di t io n s , d e le t io ns , an d i n v e rs io ns o f l a r ge ( 4- 8 0 k i l ob as es) s eq u en c e s . W hen d i ff er e n t t r a ns p os on s “ j um p” in t o tr a n s f e ra b le pl as m i ds , c on t a gi ou s re s i s t a nc e t o m u l t ip le a n t ib io t ic s c a n o c c u r . 3 . T r an s du c t io n is t h e t ra n s f e r o f g e ne t ic m a te r ial b y b ac t e r io p ha g es ( vi ru s es th a t i n f ec t b ac t er i a ). S uc h v i ru s es c a n b e c l as si f ie d i nt o t wo g r ou ps : P.185
a . L yt i c p h a g e s e nt e r t he c e l l, r ep li c a t e , a nd pa c k a ge th e i r D N A ; th e y t hen l ys e t he c e ll to r el ea s e m a t u re in fe c ti v e vi r io ns . b . L ys o g e n i c ( t em p e ra te ) p ha g es c a n a l te r na t e b e t we e n t wo pa t h wa y s : ( 1 ) Th e l y ti c p at h wa y ( 2 ) Th e l ys o ge ni c p a th wa y- i n t eg r at i ng in t o t he ho s t D N A a nd r em ai ni n g do r m an t ( a ) Th e v i ra l D N A d o es no t r ep li c at e b u t is in t eg ra t e d i nt o th e h os t g e no m e a nd is k n o wn as p r op h ag e . ( b ) Th e p ro ph a ge s u pp r es s e s t h e l y t ic s t at e b y s yn t h es i z in g a p ro t ei n k nown a s a r e p r es so r , wh ic h p r o te c ts t he c e ll f ro m f u rt h e r i nfe c ti o n b y a v ir u s . ( c ) S om e p r op h ag es c a n c ha n ge th e c el l ' s p he n ot yp e ( p ha g e o r l ys o g e n ic c o n ve r s i on ) , wh ic h a l lows t h e o rg an is m t o e l abo r a t e m a t e ri al s ( e xo t o xi n s o r vi r u l en ce f ac to r s ) t ha t a re d et r im e nt a l t o t he hu m a n ho s t . L ys o ge n ic c on v e r s io n t h e r eb y i nc r ea s e s t he v i ru l en c e o r t h e s y m p t om s o f a s pe c i f ic p a th o ge n — fo r e xa m p l e , C o ry n eb ac t e ri um d i p ht h e ri ae ( di p ht h er ia t o xi n ) , S tr e pt oc o c c us py o ge n es ( e r yt h r og e ni c t o xi n in s c a r l et f e v e r) , an d Cl os t r idi u m t e ta ni ( te t an us t o xi n) .
VII. EXAMPLES OF UNIQUE BACTERIA A. C h l a m y d ia ar e o b li g at e in t r ac el lu l a r p a ra si t es t h a t 1 . L ac k t h e a b il i t y t o g e n e r a t e AT P ; h e n c e t h e y m us t ob t ai n i t f r om th e ho s t c el l 2 . H a ve a tw o - ph a se li fe c yc l e a . Th e i n fe c ti o us f o rm , or e l em e n ta r y b o d y, i s a d e ns e , n on r e pl ic at i ng c el l th a t is r e s is ta n t t o d r y i ng in t he e n v i r on m e n t. b . Th e r e ti c u la t e b o d y f o r m s f ro m e ng u lf e d e le m e n t a r y b o d y a n d u nd e rg oe s b i na r y f i ss io n . A f t e r m u l ti pl e d i vi s io ns , th e r e ti c u l at e b o di e s b ec om e t h e d en s e , el e m e n ta r y b o di e s, wh i c h a re r el ea s e d f ro m t he ho s t c e l l ( e .g . , C hl a m yd ia t r ac ho m a t is , wh i ch c a us es bl in d ne s s a n d s exu a l l y t r a ns m i t te d d is e as e s ) . B . R i c ke t t s ia , o bl i ga t e in t r ac e ll ul a r p a ra si t es t ran s m i t te d b y a r th r op o ds , a p p ea r to h a ve th e a b il i t y to ge ne ra t e A TP , bu t i ns t ea d u s e t h e ho s t c e ll p r od u c ts , i n c lu d i ng
AT P , a m i n o a c id s , n i cot i n a mi d e a de n i ne d in u cl e o t i de ( N AD ) , a n d c oen z ym e A ( e . g ., R ic k e t ts ia r ic k e t ts ii , wh i c h c a us es R oc k y Mo u n ta in sp o tt e d f e v e r ). C . My c o p l a sm a , t h e s m a l le s t b ac te r i a, a re un iq ue i n t ha t 1 . Th e y l ac k a ce l l w al l . 2 . Th e pl as m a m em b r ane c o n ta i ns s t e r o ls fo r add e d s t re n gt h (e . g. , My c op l as m a p n e u m on ia , wh i c h c a us es an a t y pi ca l o r wa l k i ng p n e um on ia ) .
VIII. VIRUSES A. V i r a l s t r u ct u r e 1 . Th e ba s i c s tr uc t u re o f a v i r us i s t h e vi r i o n o r n u c le o ca p s id . Th is s t r uc t u re is c om p os ed o f a p r o te in c o a t , wh ic h s u rr o un ds t he v i r a l g e no m e . Th e s h a pe o f t h e n u cl e oc ap s i d i s o ne c om p o n en t t h at de t e rm in es th e c l ass i fi ca t io n o f th e vi r u s . As n o t ed in I .B . 1 .b , th e v ir a l g e no m e is c om p os ed of e i t he r R N A o r D N A an d m a y be s i ng le o r d ou b le s t r an d ed . Th e nu cl eo c a p s i d o f vi r u s e s t ha t i n fe c t h um ans ha s t wo b a si c sh a pe s . a . I co s ah e d ra l . A r eg u lar g e om e t r ic s t r uc t u re wi t h 12 o r m o r e fa c e s ; r ese m bl es a s oc c er ba l l b . H e li c al . Th e p r o te i ns t h a t m ak e u p t he s t r uc t ur e wr a p in a h el ic a l f as hio n . He l ic al c a ps id s o f te n h a v e c on e o r b ul le t s h ap es . P.186
Table 9-1. The Multiplication of Animal Viruses NumberStep
Action(s)
1
Attachment (adsorption)
Virus attaches to a protein or polysaccharide molecule (receptor) on the surface of a cell
2
Penetration
Entire virus enters the cell, in some cases because it was phagocytized by the cell
3
Uncoating
Viral nucleic acid escapes from the capsid
4
Biosynthesis
Viral genes are expressed, resulting in the production of pieces or parts of viruses (i.e., viral DNA and viral proteins)
5
Assembly
Viral pieces are assembled to create complete virions
6
Release
Complete virions escape from the bacterial
cell by lysis or budding Reprinted by permission from Burton GRW, Engelkirk PG. Microbiology for the Health Sciences, 7th ed. Philadelphia: Lippincott Williams & Wilkins, 2004.
2 . Th e v i ri o n m a y h a v e a l i p id e n ve lo p e, wh i c h is p ro d uc ed wh e n th e v iru s b u ds f r o m t he ho s t c e l l. Th e en v e l o pe i s c om po se d o f th e ho s t c e ll pl as m a m e m b r a ne an d vi r a l l y c o de d g l y c o p ro t ein s . B . V i r a l re p l ic a ti o n . V i ru s es a r e n o nl i v in g e n ti t ie s th a t m u s t e nt e r a ho st c el l t o r e p l i ca t e . O n c e in th e ho s t c el l , t he v i r us i s a bl e t o re p li c a t e i ts ge no m e a n d p r o du c e m o r e v ir us e s , wh i c h wi l l i n fe ct o th e r c e l ls . Th e s te p s i n t he m u lt ip l ic a ti on o f a n im al v i r us es ar e ou tl i ne d in Ta b le 9- 1 a n d i n volv e : 1 . Th e v i ru s a t ta c h es ( a tt a c h me n t ) t o t h e h os t c el l us in g vir a l p r ot e in s o r g l yc op r o te in s , wh i c h b ind t o r ec e pt o rs on t he hos t c e ll s u r fa ce . 2 . Th e v i ri o n t he n e n t e rs ( p e ne t r a t io n ) th e h os t ce l l . E n t r y m a y be acc om p l is he d b y f u si o n o f a v i ra l e n v e lo pe wi t h t he c e ll m em b r ane o r b y u pt a ke of th e v i rio n in t o a n e n d oc yt ic v es ic l e. I f t he v i r u s e n te r s t he c e ll t hr ou g h a n e n do c y ti c v es ic le, t h er e a r e s e ve r al wa y s f o r i t t o l eav e t h e e nd o c y ti c v e s ic le a n d e n te r th e c yt o pl as m o f t he h o st ce ll . 3 . O nc e i n th e h os t c el l , t h e v i ru s u n co a ts , an d th e nu c l ei c a ci d i s r e le ase d f ro m t h e c ap s i d . Th e f r ee nu c le i c ac i d t he n i s a bl e to be g in t he p ro ce s s o f re p ro d uc t io n . 4 . P r o te i n s yn t h e s i s o c c u rs in t wo s t a ge s . E a r l y p r o t e in s a r e n ec es s a r y f o r th e s yn t he s i s o f a ne w v i r a l g e n om e a nd ar e s y n t he s i z e d im m e di a te l y af t e r i nf e c ti on . L a t e p r o t e in s a r e s y n the s i z ed af t e r t h e v i r al ge no m e h as b e en c o pi e d; t he s e a r e t h e p r o te i ns n ec es s a r y fo r t he as se m b l y of th e ca p s i d , g l yc o p ro t ei ns fo r th e e n ve l op e , a nd an y e n z ym es in c l u de d i n t h e n uc le o c a p s i d. a . F or vi r us es wi t h a si ng l e - s t ra n de d R N A g e n om e , th e R N A m a y b e a pl u s ( + ) s t r an d o r a m i n us ( -) s t ra n d . P l us -s t r an d R N A g en o m e s a r e m R N As an d ar e t r a ns l at e d d ir ec t l y to p rot e i ns . Mi n us - s t r an d R N A g e no m e s h a ve a n R N A -d e p en de n t R N A p o l y m e r as e t h at c op i es th e g e no m e in t o a s t r a n d o f m R N A f o r tr a ns c r i p ti o n. b . D o u bl e -s t r a n de d R NA g e n o m e s us e a n R N A -d e p en de n t R N A p ol y m e ra s e t o t r a ns c ri be t he m i nu s s t ran d of R N A in t o a m es s a ge f o r t r an s l a ti o n. c . S om e p lu s - s t ra nd R NA v i r u s e s a r e m e m b e rs of t h e r e t r o vi r u s f am il y (e . g . , h um an i m m u no d ef ic i en c y v i ru s ). Th e s e v ir u se s h a ve a n e n z y m e c a ll ed r e v e rs e po l ym e ra s e , wh i c h t ra ns c ri b es th e RN A t o do ub l e -s t ra n de d DN A . Th e d ou bl e -s t r an d ed D N A i s i n t eg r a te d i n to th e h os t c e ll c h r om os om e ( a p r o vi r u s ) an d t h en t ra ns c ri bed t o
m R N A us i ng ho s t c e ll enz y m e s . Th e vir a l m R N A is t he n t r an sl a t ed i n t o v i ra l p r o t ei ns . d . I n vi r us es wi t h a D N A g e n om e , t he D N A m a y b e do u bl e s t ra nd e d o r s in g le s t r an d ed . I n ei th e r c as e , t h e D N A is t ra ns c ri b ed to m R N A a n d t he n t r a ns la t e d i nt o p r o t ei ns . 5 . A f te r ge no m e an d p r o te i n s y n th e s i s , th e vi ru s is as s em b le d in t o n e w v ir i o ns . 6 . A f te r as s em b l y , t h e v ir i o ns ar e r el e as e d f r om t h e h os t c e ll . F o r n o ne n ve l op e d vi r u s es , t h e v i r io ns a re re l ea s ed wh e n t h e h os t ce l l l y s es . E n v e lo p ed vi r us es a re r e l ea se d fr om t he ho s t c e l ls b y b u dd i ng ou t o f the h os t c el l m em b ra ne . P.187
IX. TRANSMISSION OF INFECTIOUS AGENTS A. I n f e c ti ou s a ge n ts a re f o u nd in a n um be r of di f fe r e n t e n vir o nm en t s , c a lle d r e s e r vo i r s . 1 . H u ma n s a re r e se r vo ir s f o r d is ea s e s t h at a re o b li g at e h um a n p a th og en s , wh ic h i n cl ud e a lm o s t al l v ir a l in f ec t io ns an d m a n y b ac te r i al di s e as es . W he n h um a ns a r e t h e re se r v o i r f o r t h e d is ea s e, t he y a r e s a i d t o b e c a r r i e r s. a . As ym p t o m a t i c c a r r i er s h a rb o r a n i n fe c t i on but h a v e n o s ym p t om s . S om e a s ym pt om a ti c c a r r ie r s c a r r y t h e i nf ec t io us ag e nt a s p a rt o f t he i r n o rm al flo r a ( S t r e p to c o c c us p y og en es ) . b . S ym p t o m a t i c ca r r i e rs h a v e o b vio us si gn s a nd s y m p t om s o f d is ea s e . 2 . A n a n im a l r e se r vo i r e xi s t s wh e n t h e p r im a r y h o st is an an im al . S uc h a n im al s m a y be wi l d (e . g ., fo xe s , r a c c oo ns ) o r d om es ti ca te d (l i ve s t oc k a nd pe t s ). 3 . E n vi r o nm e n ta l r es e rvo i r s i nc lu d e s oi l, la ke s , a n d p la n ts . B . Th e t r a ns m is s io n o f i n f e c ti o us a ge n ts de p en d s o n t he s o u rc e o f i n fec t io n . F o r d i se as es wi t h hu m a n re s e r v o i rs , th e m ec ha n is m s o f t ra ns m i s s io n i nc lu d e 1 . C o n ta c t a . D i r ec t co n t ac t re q ui re s p h y si c al c o nt ac t be t we e n a n i n fe c t e d i nd i v i dua l an d a s us c ep ti b le in d i v id ua l (s e xu a l l y t r a ns m i tt e d d is eas es ) . b . I nd i r e ct c on t ac t in v o lv e s a s us c e p ti bl e i n di vi du a l c om in g i n c on t ac t wi th a c o nt am i na t ed s u r fa c e ( m a n y v i r us es an d b a ct e ri a) . F om i t es a re s u r fa ce s t h a t c an b e an d f r e qu en t l y a re c on t am i na t ed wi t h m ic r oo rg a ni s m s ( d oo r k n ob s, cou n t e rs a n d o t h e r su r f ac es , c om pu t e r k e y bo a r ds , t o y s ). 2 . D r o p le t t ra n sm i ss i o n. I n fe c t e d d r op le t s a r e f or m e d wh e n an in f ec te d in d i v id u al c o ug hs o r s n e e z es . Th e i n f ec te d d r o pl e ts t r a nsm it t h e di s ea se to a s usc ep t i bl e i n di vi d ua l wh e n t he y c om e i n c on t ac t wi t h t h e m u c ou s m em br a ne s o f t h e i n di v i du a l 's n o se , m ou t h , o r e y e s ( m e a s l es ) . 3 . Ai r b o r n e t ra n sm i ss i on . W hen s m a ll c o nt am i na t e d d us t p a r ti c l es or t he r es i du e f r o m d r ie d d r op l et s ( d r opl e t n uc l ei ) re m a i n s u sp en d e d in t he ai r fo r lo ng pe r i od s o f t i m e , th e y c a n t r an s m i t di s ea s e ( in f lu en z a , pn eum o ni a , t ub e rc u lo s i s ). The s e sm al l n u cl ei ca n i n fe c t bo t h t he u pp e r a nd t he lo we r r es p i ra t or y t r ac t . 4 . F oo d a n d w at e r co n ta m i na t i on . Fo o d o r wa t er c on t am in a te d wi t h b ac te r i a f r om h u m a n o r an im al f ec es le a ds to t ra n s m is s i on of d i s e as e t h r ou g h t he fe c al - o r al ro u t e.
C . V e c to r s ar e a n im al s c a pa b le of t ra ns m i t ti n g di s ea se s . Th e m os t c om m o n vec t o r f o r di se as e i s t h e m o s q ui t o (m al a ri a ) , b ut o th e r in s ec ts ( fl e as , t ic k s a n d fl i es ) a r e a l so vec t o rs ( R oc k y Mo u n t a in s p ot t ed f e v e r) . In ad d i ti on , m am m a ls ( do gs , m ic e a nd r a t s ) c a n b e v ec t o rs f o r d i s e as e . D . E n t r y i n t o a ho s t . B ac t e ri a c an en t e r a h os t th r o ug h i n ge st i on of f oo d o r wa t e r , i n ha l at i on of d ro p le ts o r d u s t pa r t ic le s , in j ec ti o n b y a n i ns e ct vec t o r , o r by c o nt am i na t io n o f a wo u nd .
X. MECHANISMS OF PATHOGENICITY A. Mi c r o o r ga n is m s c au s e d is ea s e in di f fe r e nt wa ys . A l th o ug h s ig ns an d sy m p t om s o f t h e d is e as e a r e o f te n t he r es u lt of t he ho st r es po n se , m ic r oo r g an is m s c an d am ag e t i ss ue t hr o ug h th e p r od uc t io n o f e xo t o xi n s a n d en d o to xi n s , a n d b y d ir ec t e f f ec ts . In a d di t io n , m ic r ob ia l v i ru len c e f ac t o rs c on t r ib u te to t h e a bi l it y o f a m ic r o or ga n is m t o i n f ec t a ho s t an d c au s e d i s e as e . 1 . V i r ul e nc e fa c t o rs a re t h e c ha r ac t er is t ic s o f a n o r g an is m t ha t a l lo w i t t o e i th e r d a m a g e t he ho s t o r e v a de h os t d e fe ns es . a . E xo t o xi n s a r e t o xi n s t h a t a r e s e c re t ed b y th e m ic r o or g an is m e it h e r i nto t he e n vi r on m e n t o r af t e r c o lo n i z a ti on o f a h os t . ( 1 ) E xo t o xi n s s e c re t ed int o f oo d o r wa t e r t h at a re t h e n i ng es t ed b y a h os t c a us e i n t o xi c at i on ( bo t ul is m a nd s ta ph y l o c o cc al fo o d p oi s on in g ) . ( 2 ) E xo t o xi n s p r od uc ed a f t e r i nf ec t io n a n d c ol on iz a t i o n i nt e r fe r e wi t h c e l l f u nc t io n o r p h ys ic al l y da m a g e t he c e l l ( B o r de t el la pe r t us s is , C o r y n e ba ct e r iu m d ip h the r i ae , V i b r io c h ol e ra ) . P.188
Table 9-2. Important Human Pathogens and Their Diseases Infectious Agent
Typical Infection
Bacteria Gram-positive cocci Staphylococcus aureus
Abscess, skin infections, toxic shock
Streptococcus pyogenes
Strep throat, erysipelas, rheumatic fever
Streptococcus pneumoniae
Pneumonia
Gram-positive rods Bacillus
Anthrax
Clostridium
Gas gangrene, tetanus
Corynebacterium
Diphtheria
Acid-fast rods Mycobacterium tuberculosis
Tuberculosis
Mycobacterium leprae
Leprosy
Nocardia
Nocardiosis
Gram-negative cocci Neisseria gonorrhoeae
Gonorrhea
Neisseria meningitidis
Meningitis
Gram-negative rods Bordetella
Pertussis
Brucella
Brucellosis
Escherichia coli
Sepsis, diarrhea, urinary tract infection
Haemophilus influenzae
Meningitis
Legionella
Legionnaires disease
Pseudomonas
Opportunistic lung and burn infections
Salmonella
Typhoid fever, salmonellosis
Shigella
Dysentery
Vibrio cholerae
Cholera
Yersinia pestis
Plague
Spirochetes Borrelia
Lyme disease
Treponema pallidum
Syphilis
Mycoplasma
Pneumonia, urinary infections
Rickettsia
Rocky Mountain spotted fever
Chlamydia
Urethritis, vaginitis
Fungi Systemic mycoses Aspergillus
Aspergillosis
Blastomyces
Blastomycosis
Candida albicans
Candidiasis
Coccidioides immitis
Valley fever
Cryptococcus neoformans
Cryptococcosis
Pneumocystis (carinii) jiroveci
Pneumonia (PCP)
Sporothrix schenckii
Sporotrichosis
Protozoa Entamoeba histolytica
Amoebiasis
Giardia lamblia
Giardiasis
Plasmodium
Malaria
Toxoplasma gondii
Toxoplasmosis
Trichomonas vaginalis
Trichomoniasis
Trypanosoma brucei
Sleeping sickness
Helminths Ascaris
Acariosis
Cestodes
Tapeworm
Schistosoma
Schistosomiasis
Various fluke infections Various roundworm infections
Adapted with permission from Cowan MK, Talaro KP. Microbiology: A Systems Approach. 1st ed.: McGraw-Hill, 2005. With permission of The McGraw-Hill Companies, Inc.
P.189
Table 9-3. Important Human Virus Families and Their Diseases Family
Virus
Disease
DNA viruses Poxviridae
Variola and vaccinia
Smallpox, cowpox
Herpesviridae
Herpes simplex 1 virus (HSV-1)
Fever blister, cold sores
Herpes simplex 2 virus (HSV-2)
Genital herpes
Varicella zoster virus (VZV)
Chickenpox, shingles
Human cytomegalovirus (CMV)
CMV infections
Human adenoviruses
Adenovirus infection
Adenoviridae
Papovaviridae
Human papillomavirus (HPV)
Several types of warts
JC virus (JCV)
Progressive multifocal leukoencephalopathy (PML)
Hepadnaviridae
Hepatitis B virus (HBV; of Dane particle)
Serum hepatitis
Parvoviridae
Parvovirus B19
Erythema infectiosum
Poliovirus
Poliomyelitis
Coxsackievirus
Hand-foot-mouth disease
Hepatitis A virus (HAV)
Short-term hepatitis
Human rhinovirus
Common cold, bronchitis
Calciviridae
Norwalk virus
Viral diarrhea, Norwalk virus syndrome
Togaviridae
Eastern equine encephalitis virus
Eastern equine encephalitis (EEE)
Western equine encephalitis virus
Western equine encephalitis (WEE)
RNA viruses Picornaviridae
Yellow fever virus
Yellow fever
St. Louis encephalitis virus
St. Louis encephalitis
Rubella virus
Rubella (German measles)
Dengue fever virus
Dengue fever
West Nile fever virus
West Nile fever
Bunyamwera viruses
California encephalitis
Sin Nombre virus
Respiratory distress syndrom
Rift Valley fever virus
Rift Valley fever
Crimean-Congo hemorrhagic fever virus (CCHF)
Crimean-Congo hemorrhagic fever
Filoviridae
Ebola, Marburg virus
Ebola fever
Reoviridae
Colorado tick fever virus
Colorado tick fever
Human rotavirus
Rotavirus gastroenteritis
Influenza virus, type A (Asian,
Influenza, flu
Flaviviridae
Bunyaviridae
Orthomyxoviridae
Hong Kong, swine) Paramyxoviridae
Parainfluenza virus, types 1-5
Parainfluenza
Mumps virus
Mumps
Measles virus
Measles (red)
Respiratory syncytial virus (RSV)
Common cold syndrome
Rhabdoviridae
Rabies virus
Rabies (hydrophobia)
Retroviridae
Human T-cell leukemia virus (HTLV)
T-cell leukemia
HIV (1 and 2)
AIDS
Arenaviridae
Lassa virus
Lassa fever
Coronaviridae
Infectious bronchitis virus (IBV)
Bronchitis
Enteric corona virus
Coronavirus enteritis
SARS virus
Severe acute respiratory syndrome
Adapted with permission from Cowan MK, Talaro KP. Microbiology: A Systems Approach. 1st ed.: McGraw-Hill, 2005. With permission of The McGraw-Hill Companies, Inc. P.190
b . E n do t o xi n s ( s e e II I . C. 1 . b ) a r e i nt e gr a l p a rt s of t h e o ut e r m em b ra ne o f g r a m n e g at i ve b ac t e ri a . D u r ing a n i nf ec t io n , e nd o to xi n s a re ab l e t o i nd uc e fe ver a n d s h oc k in t he ho s t . c . C ap s u le s ( s e e II I . B. 1) a r e u se d f o r a d he r en c e t o ho s t s u r fa c e s a n d h elp t he b a ct e r ia e v ad e p h ag oc y to s is b y t h e h os t c el ls . 2 . M e c ha n is m s o f d i se as e . Th e re a re th r e e m a i n p a t te r ns b y wh i c h m ic r oo r g an i s m s c a us e d is ea s e : a . I n to x ic a t io n [s ee X. A . 1 . a .( 1 ) ] b . I n fe c t io n i s s uf f ic ie n t t o c a us e d is ea s e fo r som e m ic r oo r ga n is m s , e s pe c ia ll y f o r d i se as es s u c h as p n eu m o n ia , in wh i ch th e c a ps ule su r r ou n di n g t he ba c te ri a s t im ul a te s a s t r on g i n fl am m a t o r y re s p o ns e . Th i s r e s po ns e i s r es p on s i bl e f o r m a n y of t h e s ym pt om s o f th e d is e a s e . In s om e c as es , i n fe c ti o n m a y b e f o ll o we d by t o xi n p r o du c ti on ( s e e X. A . 1. a .( 2 ) ) , a s i n d ip h th e r ia . c . In va s i o n o f h o s t t i ssu e s a n d t he n g r o wt h in th e ti ss ue is th e m ec ha n is m o f d i se as e i n fe c t i on b y v i rus es an d ba c t e ri a s uc h a s My c o b ac t e ri a . S om e b ac t e ri a ( e . g ., S hi g el la s p . ) a r e ab l e t o p r o du ce to xi n s a fte r t he in v a si o n o f h os t t is su e .
XI. DISEASES CAUSED BY INFECTIOUS AGENTS A. D i s e a s es ca u se d b y b a c t e ri a , f u n gi , p ro t o zoa , a nd he l mi n t hs ( Ta b le 9 - 2 ) B . D i s ea s es ca u se d b y vi r u s e s ( Ta bl e 9 - 3 ) P.191
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 12 : E a c h qu e st io n , st a t em en t , o r in co m p le t e s t a te m e n t i n th is s e c t i on c a n b e c or r e c tl y a ns we r e d o r c om p l e te d b y o n e o f t he su gg e s t e d a n s we r s o r p h r as es . Ch oo s e t he b es t a n s we r . 1 . C e ll w a l ls o f b o th g ra m - p os i t i ve a n d g r a m- ne g a t i ve b a c te r i a a r e c om p o se d of c o m pl e x m ac r o m ol e cu le s . W h i ch o f t h e f o l low in g s ta t e me n ts d es c r ib es b o th t yp e s o f c e ll w a l ls ? ( A ) Th e y c on t ai n s ig n if ic a n t a m o u nt s o f te ic ho ic a c id . ( B ) Th e y c on t ai n p o re s m a de f ro m p r ot e in s . ( C ) Th e i r a n ti g en ic s p ec if i c i t y is de t e rm in ed b y the p ol y s ac c h a ri d e O a nt i ge n . ( D ) Th e y c on t ai n p e pt i dog l y c an . V i e w A n s we r 1 . T h e a n sw e r i s D [ se e] . 2 . W h ic h o f t h e f o l low i n g d e s c ri p t i on s b e s t c ha ra c t e r iz es se x p i l i? ( A ) Th e y e n ab le D N A t ran s po r t b e t we e n b ac t er i a d u r i n g c on j ug a ti o n. ( B ) Th e y p l a y a r ol e i n t he a dh es i on of ba c te r ia to t h ei r ta r g et c e ll s . ( C ) Th e y a r e n um e r ou s on t he ba c te r ia l c el l s u rf ac e . ( D ) Th e y a r e f o un d o n l y o n g ra m - p os it i v e or g an is m s . V i e w A n s we r 2 . T h e a n sw e r i s A [ se e] . 3 . T h e m od e o f g e ne t r an s f e r i n w h ic h na ke d D N A i s t ake n u p i s c a ll e d ( A ) t r an s fo r m a ti o n.
( B ) t r an sd u c t io n . ( C ) c on j ug a ti on . ( D ) c el l f us i on . V i e w A n s we r 3 . T h e a n sw e r i s A [ se e] . 4 . Ba c te r ia t h a t m ak e e i t he r a f e r m e n ta t i ve o r r e sp i r at o r y s e t o f e nz ym e s a r e k n ow n a s ( A ) o bl i ga t e a na e ro b es . ( B ) o bl i ga t e a er o be s . ( C ) m ic r oa e ro p hi le s . ( D ) f ac u lt a ti v e o rg a ni s m s . V i e w A n s we r 4 . T h e a n sw e r i s D [ se e] . 5 . W h ic h o f t h e f o l low i n g s t a te me n t s d e s c ri b es p la s mi d s? ( A ) Th e y a r e s in gl e -s t r and e d D N A m ol ec ul es . ( B ) Th e y c a r r y o p ti o na l ge n es . ( C ) Th e y c a r r y g e ne s e s s e nt i al fo r g ro wt h . ( D ) Th e y a r e a l wa y s f oun d in li ne a r f o rm . V i e w A n s we r 5 . T h e a n sw e r i s B [ se e] . 6 . Al l o f th e f o ll ow i ng s ta t e me n ts d e s c ri b e th e n u cl e a r bo d y e x c e p t w h ic h o n e? ( A ) I t i s r e fe r r ed t o as nuc l eo id . ( B ) I t i s f r ee o f r ib os o m es . ( C ) I t i s c om po s e d o f ri bo s om es . ( D ) I t l a c k s a n uc le a r m em b r an e . V i e w A n s we r 6 . T h e a n sw e r i s C [ se ea n d] .7 . Ba ct e r i a th a t g r ow a t t e m p e ra t u r es as hi g h as 5 5 ° C a r e k n ow n a s ( A ) p s yc h r op hi l es . ( B ) t h er m o p hi le s . ( C ) m es op h il es . ( D ) a u xo t r o ph s . V i e w A n s we r 7 . T h e a n sw e r i s B [ se ea n d] .8 . W h ic h o f t h e f o l low i n g o r g a n is m s c an us e on ly m o l e c u l a r o x yg e n a s t h e f in a l a cc e p to r ? ( A ) o bl i ga t e a na e ro b es ( B ) f ac u lt a ti v e an a er o bes ( C ) o bl i ga t e a e ro b es ( D ) s t ri c t an a e ro b es V i e w A n s we r 8 . T h e a n sw e r i s C [ se ea n d] .9 . Vi ru s e s a r e c l as s if i e d b y a l l o f t h e f ol l ow i ng ex c ep t b y ( A ) s t ru c t u r e o f c a p s i d. ( B ) t yp e o f n u c l ei c a c i d. ( C ) o xyg e n r e q ui r em en ts . ( D ) p r es en c e o f l ip id en v e l op e . V i e w A n s we r 9 . T h e a n sw e r i s C [ se e] . 1 0. P r o t oz o a a r e c l as s i fi e d b y ( A ) s ha pe . ( B ) c el l wa l l t y p e. ( C ) s e xu a l re p ro d uc ti v e s t r uc t ur es . ( D ) m od e o f m o ti li t y .
V i e w A n s we r 1 0 . T he a nsw e r i s D [ se e] . 1 1. W hi c h o f t he f o ll ow i n g i s n o t p a r t o f t h e vi r us e 's i n fec t i o us c yc l e ? ( A ) a t ta c h m e n t ( B ) u n wi n di n g ( C ) r e pl ic a ti o n o f t h e g en o m e ( D ) p r o te in s y nt h es is ( E ) r e le as e V i e w A n s we r 1 1 . T he a nsw e r i s B [ se ea n d] .P . 19 2
1 2 . In f ec t i o us ag e n ts ar e t r a ns m i t te d to p eo p le f r o m r e se r vo i r s . Th e se r e s e r vo i r s i n c lu d e ( A ) d r op le t s . ( B ) a ni m a ls . ( C ) f om i te s . ( D ) c on t am in a te d f o od . V i e w A n s we r 1 2 . T he a nsw e r i s B [ se ea n d] . Di r e c ti o n s fo r q ue s ti o n s 1 3- 20 : Th e q u es ti o ns a n d i nc om p l e te s t a te m e n ts i n t h is s ec t io n c a n b e co r r ec t l y a n s we r e d o r co m p l et e d b y o ne o r m o r e o f th e s ug g es t ed an s we r s . Ch o os e t he c o r re c t a ns we r , A-D. 1 3 . G r am - n eg a t i ve a n d g r a m - po s i ti ve c e ll w a lls s ha r e w h ic h o f t he f ol l ow i n g c h a r ac t e r is t i cs ? I . p ep t i de c r os s - li n ks be tw e e n p o l ys a c c h a r i d es I I . h yd r o l ys i s b y l ys o z ym e I I I . r ig i d p o l ys a c c h a r i de f r a mew o r k A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 3 . T he a nsw e r i s E [s e ea n d] . 1 4. A d e c l in i ng g r ow t h r a t e o c c u rs d u r in g w h ic h o f t h e fo l l ow in g ph a se s of b a c te r i al ce l l g r ow t h ? I . l ag p ha s e I I . ex p on e n t ia l p h as e I I I . de a th p ha s e A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 4 . T he a nsw e r i s B [ se ea n d] .1 5 . T he p ep t i d og l yc a n b a c kb o ne o f a ba c t e ri a l c e l l c on t a in s I . d ip e p t id e c h ai n s . I I . N - ac e t yl m u r a m i c ac id . I I I . N -a c e t yl g l u c o s am i ne .
A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 5 . T he a nsw e r i s D [ se e] . N N 1 6 . E n ti t i e s t h a t a r e a ce l l ul a r d o n o t f i t t h e c la s si c al d e fi n i t i on o f l i vi n g th i ng s . T h e y a r e I . vi r u s es . I I . f un g i . I I I . p ri o ns . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 6 . T he a nsw e r i s C [ se ea n d] .1 7 . D im o r p h ic f un g i h a ve I . a ye a s t p h a se . I I . a s ex u al p ha s e. I I I . a m ol d p h as e . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 7 . T he a nsw e r i s C [ se ea n d] . Bl a s to m y ce s , C o c c i di o i de s , Hi s t op l asm a 1 8. T ra n sm i ss i o n o f a n i n fe c ti o u s d is e as e by t h e f ec a l- o r a l r o u t e o ccu r s w h e n I . i n fe c t io u s a ge n t s a r e d e p os i t ed on s u r fa ce s s u c h a s d o o r k n ob s . I I . an i nd i vi d u al co u g hs o r s ne ez e s a n d d r o pl e ts w i t h in f ec t i o us ag e n ts a r e e x p el l e d. I I I . fo o d o r w a t e r i s c o nt a m i na t e d w i t h h u ma n o r a n im a l f e ce s . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 8 . T he a nsw e r i s B [ se ea n d] .1 9 . V ir u l e n ce f ac t o r s t h at e n h an c e m ic r o b ia l pa t ho g e n ic i t y i n c l u d e I . c ap s ul e s. I I . en d o to x i ns . I I I . e x o to x i ns . A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t
E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 1 9 . T he a nsw e r i s E [s e e] . 2 0. O n F rid a y, J a n u a r y 1 3 , a n u m be r o f p a t r o ns o f M o m ' s D i n e r b e ca me i ll 2- 6 h r af t e r e a t in g at t he r e s t a u ra n t . T h e h ea l t h d e p a r tm e n t w a s c a ll e d i n t o i n ve s t ig a t e. D u r ing t h e i n ve s t i ga t i o n, i t w a s fou n d t ha t a l l th e in d i vi du a l s w ho be c am e i l l h ad e a te n b a n an a c r e am p ie , M o m' s s pe c ia l i t y, b u t h a d no t e a te n a n yt h i n g e ls e in c o m mo n . T h e i n ve s ti g at o r s f ou n d n o vi a bl e pat h o g en s in t he p ie , b u t t e s t s i n d i ca t e d t h e p r es e nc e o f s t ap h yl o c o c c a l co n ta m i na t i on o f th e c r e am p i e . I l l n es s re s u lt i n g f r o m th i s co n t am i na t i on w o u ld b e c o ns i de r e d a n I . i n fe c t io n . I I . i n vas i o n. I I I . in t o xi c at i o n. A i f I o nl y is c o r r ec t B i f II I on l y is c o r re c t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I a nd I II a re c o r r ec t V i e w A n s we r 2 0 . T he a nsw e r i s B [ se e] . S t a ph y loc o c cu s a u r e us P . 19 3
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is D [ s ee I I I . C .1 ] . Th e c el l wa l l o f g r am - pos i ti v e ba c te r ia is a t hi c k l a y e r of pe p ti d og l yc a n wit h a l a rg e a m ou n t o f t e ic ho ic ac id s ( s u r fa ce an t ig e ns ) . G r a m - n e ga t i ve b ac t e ri a h a ve o n l y a s m a l l am o un t o f pe p ti dog l y c an , n o te ic ho ic ac i d, a n d a n o u te r m em b r an e c om p os ed o f li p op r ot e in an d l i po po ly s a c c h ar i de , o f wh i c h the p ol y s ac ch a ri d e m a k e s u p th e O a n t ig en . 2 . T he an sw e r is A [ s ee I I I . B. 3 .b ] . S e x p i l i ar e fo un d o n l y on g r am -n e ga t i ve o r ga n is m s a nd in v e r y s m al l n um b e rs (< 1 0 ) . Th e y a c t as f ra g il e tr a n s p o rt t ub es fo r D N A exc h a n g e . Co m m on pi li a re a d h es io ns . 3 . T he an sw e r is A [ s ee V I . C . 1] . O f t h e t h re e m e th o ds o f D N A t r a ns f er , on l y t ra ns fo r m at i on ta ke s u p D N A wi t h o u t a n i n t er m ed ia r y . 4 . T he an sw e r is D [ s ee I V . D . 1. b ] . F a cu l ta t i v e o r ga n is m s c an g r o w wi t h o ut ai r an d m a k e e it h e r a f e rm e nt a ti v e o r a r e s pi r at o r y s e t o f e n z y m e s , d ep e nd i ng on th e c on d i ti on s . 5 . T he an sw e r is B [ s ee I I I . D .4 ; VI . C . 2] . Th e c h ro m o s o m e c a r r ie s a l l o f t he ge n es es s e nt ia l fo r g ro wt h , wh e r e as p la sm i ds a r e e xt r a c h r om os om a l, do u bl e - s t r an d ed , c i rc ul a r p ie ce s o f D N A th a t c a r r y o pt io n al g e n es t h at ad d e xt r a pr op e r ti e s . 6 . T he an sw e r is C [ s ee I I I . D .2 an d 3 ] . R i b os om es a re fo u nd in t h e c y t o pl as m , no t in th e n uc l eo id ( a l on g , c ir c u l ar , d ou b le s t r an d ed D N A wi t h ou t a n u c l e ar m e m b r an e ) .
7 . T he an sw e r is B [ s ee I V . C . 1, 2 a nd 3 ]. Th e r m o ph il es g ro w a t 5 5° C a n d a r e f ou n d i n h ot s p r i n gs an d c om po s t pi l es . Me s o p h i le s g ro w a t a pp ro xi m a t e l y 3 7 ° C , p s yc h r op h il e s g ro w a t 1 5 ° C a nd l o we r , a nd a u xo t r o p hs a re m u ta n t or g a ni s m s. 8 . T he an sw e r is C [ s ee I V . D . 1 a nd 2] . O b l i ga t e a e ro b es re qu i r e o xy g e n a n d l ac k a n a lt er n a ti v e f e rm en t at i ve p a thwa y . O b l i ga t e a na e r ob es ar e s t r ic t a na e r ob es th a t c ann o t l i v e i n t h e p r es en ce o f o xyg e n . F a cu l ta t i v e a na e r ob es c a n us e o xyg e n a s t he fi na l ac c e pt o r o r to p ro vi d e a n a l t er n a te fe r m e n ta t i v e pa t h wa y . 9 . T he an sw e r is C [ s ee I . B . 1; V I II . A ] . V i r us e s a re c l as s i f ie d b y t h e s t ru ct u r e o f t he c a ps i d, t he t ype an d s t ra n ded n es s o f t h e n uc l ei c ac i d, t he p res e nc e o f a li pi d e n ve lo pe , an d th e p r es en ce o f en z ym e s . V i r us e s d o n ot ge n er a t e t h e ir o wn e ne r g y , h e nc e t h e r e is no ne e d f o r o xyg e n . V i r us e s us e t h e e ne r g y in t he ho s t ce l l. 1 0 . Th e a n sw e r i s D [ s ee I . A .2 . b] . P r o t o zo a a re un ic e ll ul a r , n o np h ot os y n t he t ic eu k ar y o t e s t h at a re c l as s i fi e d b y t h ei r m o de of m o t il it y o r la c k o f m o t il it y. Th e t y p es o f m o ti l it y a r e f la g el la , c il i a, a nd a m oe b oi d m o v em en t . 1 1 . Th e a n sw e r i s B [ s ee V I I I. B . 1, 2 , 3 , 4 , 5 an d 6 ] . Th e v i r a l i n fe c t i ou s c y c l e c on s i s ts o f at t ac hm en t , e n t r y , u n c o a ti ng ( no t u nwi n d i n g ), p r o t ei n s y n th es is , ge nom e re p li ca ti o n , as se m b l y, a nd r el e as e. 1 2 . Th e a n sw e r i s B [ s ee I X. A . 1 , 2 an d 3 ] . I n f ec t io us ag en t s c a n b e f o un d i n m an y d i ff e re n t e n vi r on m e n ts , i nc l ud in g p e o pl e, a n im al s , a nd th e n a tu r a l e n v i r on m e n t . A n im al s a re a re se v o i r ; f om i te s , d ro p le t s a nd c o nt am i na t ed fo o d o r wat e r a re m ec h an is m s o f t ra n s m is si on . 1 3 . Th e a n sw e r i s E ( I , II , I I I) [s e e I I I. C . 1 a n d 2 ]. P e p t id og l y c a n i s t h e b as i c l a y e r o f th e c el l wa ll i n b ot h g r am - p os it i ve a n d g r am n e g at i ve o r ga n is m s . I t p ro v i d es a r i gi d f r am e wo r k t h a t is s u sc ep t ib le t o t he ac t io n o f l ys o zym e . G r a m -p os i ti v e c el ls a re de f ic ie n t i n l ip i d s ; h o we v e r , g ra m - n eg a ti v e ce l ls a r e ri c h in c o m p le x l i p i ds ( e. g . , l ip op o l ys a cc ha r id e ) . Bo t h t y p es of ce ll wa l ls ha v e c r os s -l in k s be t we e n p o l ys ac c ha r id es . P.194
1 4 . Th e a n sw e r i s B ( I I I) [ s e e I V. E . 1, 2 , 3 a n d 4 ]. D u r i ng t he la g p ha s e, the c e l ls p r e pa r e f o r g r o wt h , so th e re is no ac tu a l gr o wt h . G r o wt h i s m a xi m al du r i ng t he e xp o n en t ia l p h as e a n d l e v el s o u t d u ri ng t he s t at i on a r y p h as e wi t h n o n e t i nc re as e i n c el l n um b e r. Th e r e i s a de c l i ne in o rg an is m n u m b e r d u r in g th e d ea t h p ha s e be c au s e t he r e a r e m o r e or g a n i sm s d yi ng th a n a r e b e in g p r o du c e d . 1 5 . Th e a n sw e r i s D ( I I , I I I ) [s ee I II . C . 1] . Th e c el l wa l l o f b o th gr am - p os it i ve a n d g r am -n e ga t i ve o r g an is m s i s c om po s ed of r e p ea t in g d is ac c ha r id e un i ts . Th es e u n it s c on t ai n N - a c e t yl gl uc os a m i ne and N a c et yl m u r am ic ac id , to wh i c h te t r ap e pt i de c h ai ns a r e c r os s -l in k e d . On l y g ra m p o si t i ve o r ga ni s m s h a v e t e ic h oi c ac i d.
1 6 . Th e a n sw e r i s C ( I , II I ) [s e e I . B .1 an d 2 ] . V i r us e s a re ba s i c al l y p r ot e i ns a n d n uc le ic ac id s , wh e r e a s p r io ns a re p ro t ei n s, n e i th e r o f wh ic h a r e c el ls . B ac te r ia a re p ro k a r yo ti c c el ls , an d f u ng i a r e e uk a r yo ti c c e ll s. 1 7 . Th e a n sw e r i s C ( I , II I ) [s e e I . A .2 . a. ( 1 ) , ( 2 ), (3 ) a nd (4 ) ] . D i m o rp hi c f u ng i l ik e Bl as t o m y c e s, C oc c i d io id es , an d H is to p la s m a c an be gr o wn i n e i t he r a y e as t (u n ic el lu l ar ) o r m ol d (f i la m e n to us ) p h as e , d ep e nd in g o n th e t e m p e r at u re o f i nc ub a ti on . F un gi a re pl ac e d i n ph y l a ba s e d o n t h e t y p e of s e xu a l r e p r od uc t io n o bs e r v e d: ei t h er as cu s , b as id iu m , o r z y g o t e . F u ng i i m p e r fe c t i c on s i s t o f sp ec ie s wi t ho u t o bs e rv a b l e s e xu a l re p ro d uc ti v e s tr u c t u re s . 1 8 . Th e a n sw e r i s B ( I I I) [ s e e I X. B . 1, 2 , 3 a n d 4 ]. Th e f e ca l -o r al r ou t e o f t ra n s m is si on in v o l v es c o n ta m in a ti on o f f oo d o r wa t e r wi t h a n im al f ec es . 1 9 . Th e a n sw e r i s E ( I , II , I I I) [s e e X. A . 1 ] . C a p su l es a c t as v i r ul e nc e f ac t or s b y i nh i bi ti n g p ha g oc y t o si s a nd ac ti n g t o a t t ac h m ic r o or g an is m s to ho s t s u r fa c e s . E xo t o xi n s a r e s ec r e te d b y m ic r oo r ga n is m s an d e i t he r al te r c e ll fu n c t i on s o r c a us e c el l d ea t h . E ndo t o xi n s i n du ce s h oc k i n m am m a l ia n h os ts t h ro ugh t he li p id A c om po n en t o f t he m o le cu le . P ep ti d og l yc an is t h e b ac k bo ne o f t he ba c te r i al c e ll wa l l . 2 0 . Th e a n sw e r i s B ( I I I) [ s e e X. A . 1 .a . ( 1) ; X. A . 2 ]. S t a p hy lo c o c c us au r eu s c a n p ro du ce a n e xo t o xi n , wh i c h r es ul ts in ga s tr o int e s ti na l d i se as e . W hen th e re is di s ea s e in th e a bs e nc e o f i n fe c ti on o r i n vas io n o f th e ti s s ue s b y a li v e o rg a ni s m , t h e di s ea s e is c al l ed an in t o xi c a ti o n.
10 Immunology G a i l G o o dm a n- S n i tk o f f
I. THE PHYSIOLOGY OF THE IMMUNE SYSTEM A. I m m u n o ge ns , an t i gen s , an d h a p te n s 1 . I mm u no g en s a r e c hem ic a l c o m p o un ds t ha t c au s e a s p ec if ic i m m u ne r es po ns e . 2 . An t i g e ns a re c h em ic al c o m p o un ds t ha t b in d to p r o du ct s o f a n i m m u ne r es po ns e . W hen t h e a n ti ge ns a re r ec og ni ze d b y a n ti b od y o r ac t i vat e d c el ls , t h e y c a n be el im in a te d b y a s pe c if ic im m u ne r e s po ns e . 3 . I mm u no g en - a n ti g en s. C o m p o un ds ass oc i at e d wi t h o r s ec r e te d b y p a r as it ic ba c te r ia , p r ot o z o a , f u ng i , a nd v i r us es a n d o f m ol ec ul a r we i g h t (m o l wt ) > 5 00 0 da l t on s m a y a c t as bo t h im m u n og e ns a n d a n t ig en s . a . Mo l e c u l a r c o m p l e xi t y is as im po r t an t a s m o l ecu l a r we i g h t i n d e t e rm in in g th e s ta t us of a c o m p ou n d a s a n im m un o g en . F o r a m o le cu l e t o b e im m u n oge n ic , i t m us t c o nt ai n p r o te i n o r pe p ti de . Th e r e f o re , pr o te i ns , g l y c o p r o te in s , li p op r o te i ns , an d nu cl e op r ot e in s a r e th e m os t p o te n t im m u n o ge n -a n ti g en s. b . D r ug s o f s u ff ic i en t m ol e c u la r we i g ht ( e. g . , i ns ul i n ) c a n ac t as i m m u no g en - an t ig e ns . Th e c e l ls o f an o th e r i nd i v i du a l a nd t he c e ll s o f on e ' s o wn b od y ( s ee II I ) c a n a ct as im m u no g en - a n ti ge ns . I m m u no g en - an t ig e ns c a n b e c on t ac t ed en v i r on m en t a ll y ( e .g . , p o ll e ns ) . 4 . H a pt e ns a re lo w m o lec u la r we i gh t c om p ou n ds t h a t a c t as i m m u no g en s a ft e r c o v al en t l y bi n di ng t o a l a rg e r m o l e c u l e o r c el l s u r fa ce . A ft e r t h e y s t im ul a t e t he im m u ne s ys t em in t hi s c om pl e x, t h es e c om p ou nd s c an ac t a s a nt i ge ns in th e u n bou n d o r bo un d s t a te . a . H ap t e ns m a y be pr es en t in th e en v i r on m e n t ( e .g . , p e n ta d ec ac at ec h ol of poi s on i v y ) . b . S e ve ra l t y p e s o f d r ugs ac t a s h ap t en s (e . g. , pe n ic il l in ) . 5 . T ol e r o ge n s a re c h em ic a l c o m p o un ds t ha t e li ci t s pe c i f ic n o n re sp o ns i v en es s . Th i s s pe c i f ic no n re s p o ns i v ene s s m a y b e c a us ed b y th e a b il it y o f th e c om p ou n d t o b e b r ok e n do wn b y t h e b o d y o r b y t he ro u te o f ad m in is t r at io n of th e c om p o u nd (e . g ., o ra l a d m i ni s t ra ti o n o f te n c aus es s p ec i fi c n on r es p on siv e n e ss ) . 6 . I n t hi s c h a p te r , t h e t e rm an t ig e n is us ed f o r c om p ou n ds a n d c e l ls t h a t a r e b ot h i m m un o ge ns an d a n ti g en s. B . C e l ls o f t h e i m mu n e s ys t e m
1 . B l ym p h o c yt e s a n d T l ym p h o c yt e s a r e th e p ri m a r y c el ls of s p ec if ic im m u ne r es po ns e s . Al l B an d T l y m p h oc yt e s a r e a nt i ge n s p ec if ic be c au s e th e y hav e s pe ci f ic an t ig en r ec ept o r s em b ed d ed in t h e ir pl a s m a m e m b r a ne s . I n t h is c ha p t er , th e t e rm s B ce ll a nd T c e ll ar e us ed in s t e ad of B l y m ph oc y t e an d T l y m p h oc y t e . 2 . An t i g e n r e ce p t o r s o f B c e ll s a r e a n ti b od y m ol e c u le s . a . B c el ls ha v e t ho us a nds o f i de n ti c a l a n ti bo d ie s i n th e ir m em b r an es th a t a ll o w t he m to bi nd t o a s m a ll g rou p of c h em ic al l y r e l at e d a n ti ge ns . Th is g ro u p d e fi n es t h e a nt i ge n s p ec if ic i t y of ea ch B c el l . D i f fe r en t B c el ls h a v e di f fe r e nt an t ig e n spe c if ic i ti es , bu t e a ch B c el l h as on l y on e s pe c i f ic i t y. B c e ll s t h at re c og n i z e s p ec i fi c a n t ig en s d i v i de to fo r m ne w B c e ll s ( m em o r y B c e l l s ) a nd p la sm a c e l ls ( an t i b od y- f o r m i n g c e l ls ) , wh ic h s ec r et e fre e , s ol u bl e ( h u m o r al ) an t ib od y m ol ec u le s i nt o e xt r a c e ll u la r flu i ds ( Fi gu r e 1 0 - 1) . b . V i rg i n B c e ll s h a v e n ot r es p on d ed to an an t ig en s i nc e th ei r r e l ea se in t o t h e c i r c u la t io n f ro m b on e m a r ro w. T h e i r m em br a ne a n t ib od i es ar e o f th e i m m u no g lo bu l in M ( I g M) a n d D ( I g D) cl as s e s (see I.D). c . Me m o r y B c el ls a re der i v e d b y c el l d i v is i on f rom an o th e r B c e l l t h a t h as re s po nd e d t o a n a n ti g en . Th ei r m em b r ane a nt i bo di e s a re o f im m u no g lo b ul in c l as s e s A ( I g A ), E (I g E ) , o r G ( I g G ; s e e I . D ) . P.196
Figure 10-1. B cells: antigen specificity and activation.
3 . An t i g e n r e ce p t o r s o f T c e l l s h a ve t wo m em b ra n e p r o te in s ( α a n d β o r γ an d δ ) , wh ic h d e f in e t h e a nt i ge n s pe c i fi c it y o f e ac h T c e ll , a n d s e v e r a l o th e r i nt e g r al m em b ra n e p r ot e ins k n o wn as C D 3 +
c o m pl e x. Th e r e fo r e, T c e l ls ar e C D 3 . E ac h T c el l ha s t ho us a nd s o f id e nt ic a l a nt i ge n r e c ep t o rs in it s m em b ra ne . Di f f e re n t T c e ll s o f d i f fe r e nt an t ig e n s p ec i fi c i t i es d i ff e r i n t h e c on f orm a ti o n o f t h ei r a n t ig en r ec ep t o rs .
a . M a j o r h i s to c om p a ti b il i t y c o m p l e x ( M H C ) p r ot e i n s. Th e an t ig en r e c ep t or s o f T c e l ls d o no t r ec og n i z e a nt i ge ns alo n e . R a t he r , t h e y n o r m a ll y r ec o gn i z e p e p t id e ep i t o pe s (f r ag m e n ts o f an t ig e n ) t ha t a r e c h em ic al l y c om b in e d wi t h MH C p r o t e i ns o n the s u r f ac e o f o t he r b o d y c e ll s ( F ig u re 10 - 2 ) . MH C p r o t e i ns a re di v i ded i nt o tw o m aj o r c l a ss e s : ( 1 ) C l as s I p r o te i ns , wh ic h a r e p r es e nt on th e s ur f a c e s o f a lm os t a l l b od y c el ls ( 2 ) C l as s I I p r ot e i ns , wh i c h a re pr e s e n t o nl y o n t h e s u rf a ce s o f s p ec ia l a n t ig e n -p r e se n ti n g ce l ls ( AP C s ) b . T h ym u s g l a n d. T c el ls do no t en t e r t he c i rc u la t i on di r ec tl y f r om b o n e m a r r o w b u t f i rs t e nt e r th e th y m us g l an d t o m a tu r e . Mo s t d e ve l op in g T c e ll s d ie in t h e t h ym u s . Th e c e ll s t ha t di e e i th e r d o n o t re co g ni z e no r m a l s elf - a n ti g en s o r p r od uc e a re s po ns e a g ai ns t n o r m a l s el f -a n ti g en s . ( 1 ) T c el ls th a t a r e r e le as e d f r om th e t h y m u s i n to t h e c ir cu l at i on a r e vi r g i n T c e l ls . ( 2 ) T c el ls th a t o r ig i na t e t h r o ug h c el l d i v is io n fr om t he re s po ns es of o t h e r T c el ls a re me m o ry T c e l l s o r e f f ec t o r T ce l l s . c . G l yc o p r o t e i n s . Mo s t T c e l ls c a n b e c l as si f ie d b y t h e p r es en c e o f a m e m b r a ne gl y c op r o te in k n o wn a s C D 4 — th e hel p e r , o r T H c e ll — o r t h e p r es e nc e o f C D8 — t he c yt o t o x i c T l ym p h o c yt e ( C T L ), o r T C cell. ( 1 ) T H c e ll s c a n b e d i v ide d in t o t wo f u nc ti o na l g ro u ps : T H 1 an d T H 2 . Th e s e c el ls ha v e di f f e ren t f un c t i on s i n t he im m un e r es po ns e a n d r e g ul a te im m u ne r es po ns es t h ro ug h th e p r od uc t io n of in t e rl e uk in s ( I L ; a ls o c al l ed l ym p ho k in e s ), wh i c h a re p ro t ei ns t h a t a ct on c e ll s i n a n au t oc r in e , p ar a c r i ne , o r e nd oc r in e m an n e r. P.197
Figure 10-2. Helper T cell (TH cell) antigen recognition. MHC, major histocompatibility complex; APC, antigen-presenting cell.
( a ) T H 1 c el l s a c t i v a te oth e r c e ll s , in cl u di ng so m e T H c e ll s , T C c e ll s , a n d m ac r op h ag es . I n a dd i t io n , t he y c an de c re as e a nt i bo d y ( A b) p r o du c ti on b y in hi b it i ng th e fo r m a t io n o f T H 2 c e ll s. ( b ) T H 2 c el l s a c t i v a te B c e ll s t o d i vid e a n d p r od uc e Ab . Th e y c a n a l so in hi b it t he fo r m a t io n o f T H 1 c e ll s. ( 2 ) T C c e ll s a r e a b le to k i l l c el ls th a t a r e i nf ec t ed b y v i r u s e s . Th e y d o th is t hr o ug h d i re c t b in d in g wi t h t h e i nf ec t ed ce l l o r th r ou g h t he r e l ea se o f c y t ot o xi n s . ( 3 ) T r ce l ls , or T r e g ul ato r y c el ls , h a ve re c e n tl y b e e n d es c r ib e d . +
+
Mo s t o f th e s e c e ll s a re CD 4 , a lt h ou gh t he r e i s a C D 8 s ub s e t as we l l . A ll o f t he s e c e ll s s u p p re s s im m u ne r es po nse s th r ou g h t he s ec r e ti o n o f I L -1 0 a n d t ra n s f o rm i ng gr o wt h f ac t or β ( TG F - β ) ; i n +
+
a d di t io n , c el ls de s i g na t ed C D 4 C D 2 5 a r e a ls o ab l e t o i n hi bi t ot h er T c e l ls th r ou g h d i re c t c on t ac t . ( 4 ) I nt e rl e uk in s a r e p a rt o f a l a rg e r n e t wo r k o f r eg u la t o r y c yt o k i n e s . Th is ne t wo r k i nc l ud es s e cr e ti o ns o f ot h e r c el l t y p es in a d di t io n to th os e o f l ym ph o c y te s . Ta b l e 1 0 -1 li s t s t h e s ou r c e s a nd a c ti o ns o f im po r ta n t c y t ok i ne s t ha t re g ul a te t he im m u n e s y st em a nd i n f la m m at i on . 4 . N a tu r a l k i l le r ( N K ) c el l s ar e l a r ge , g r an u la r l ym p ho c y t es wi t ho u t a sp ec i fi c T o r B c e ll an ti g en r ec ep t o r. Th e i r c y t ot o xi c i t y is s im i la r t o t ha t o f C TL ( T C ) c e l ls . N K c el ls re c og ni z e an d d e s t r o y t um or s , a n d a r e i m p o rt a nt f o r c on t r ol l in g v i ra l i n fe ct i on s p r i o r t o t h e d e ve l op m e n t o f a da p ti v e i m m un i t y . 5 . AP C s a r e e s s en t ia l f or m os t i m m un e re s p on s es an d a r e f o un d i n t h e s i te s a t wh i c h t h es e r e s po ns es o ri gi n at e . a . Th e be s t un d e rs to o d A P C s a re th e m a c r op h ag e s a n d d e nd r i t ic c e l ls o f t he l ym p h n o d es , s pl e en , a n d o t he r l ym p h o id t is s ue . Mo s t i m m u ne r es po ns es wi t h i n th es e o r g an s b eg in wh e n t he s e c e ll s p r e se n t e pi t op es bo u nd to t he i r s u rf ac e MH C c l as s I I m o l ec ul es t o T H c e l ls an d s ec r et e c y t ok i ne s as ac ce s s o r y s i gna l s ( F ig u re 10 - 2 ) .
A P C s , es pe c i al l y m a c ro ph a g es , a r e a bl e t o c on t ro l th e t y p e of i m m u ne r es po ns e g e ne ra t e d. Th e y d o t hi s b y s ec r e ti n g d if f e re n t c yt o ki ne s i n re s p on s e t o d i f fe r e nt t ype s o f p a th o ge n s ( e .g . , e xt r a c e l lu la r ba c t e r ia , i nt r a c e ll u la r ba c t e r ia , vi rus es ) . P.198
Table 10-1. Major Cytokines and Their Actions Cytokine
Sources of Secretiona
Major Actions
IL-1
Macrophages, APCs, others
T and B cell activation, pyrogenic, proinflammatory
TNF-α, TNF-β
Macrophages, TH1 cells, TC cells
Similar to IL-1, but including cytotoxicity
IL-2
TH0 cells, TH1 cells
T cell, B cell, and NK cell activation
IFN-γ
TH1 cells
Induction of MHC, activation of macrophages and NK cells, formation of memory B cells, antiviral
IFN-α, IFN-β
Leukocytes, fibroblasts
Induction of MHC, antiviral, and growth inhibition
IL-3
Macrophages, TH cells
Proliferation of multilineage marrow stem cells
IL-4
TH2 cells
B cell activation and memory B cell formation, increased mast cell precursors, activation of mast cells
IL-5
TH2 cells
Memory B cell formation, eosinophil production
IL-6
TH2 cell, other types
Plasma cell maturation, others similar to IL-1
IL-7
Bone marrow stroma
Lymphocyte maturation
IL-8 (CXCL8)
Monocytes, macrophages, endothelial, fibroblasts cells
Chemokine, attraction and activation of neutrophils, attraction of T cells
IL-9
TH1 cells
Proliferation and differentiation of bone marrow cells and thymocytes
IL-10
Macrophages, TH2 cells CD8+ T cells, B cells
Increased humoral (antibody) immunity, decreased cellmediated immunity, mast cell growth
IL-11
Bone marrow stroma
Proliferation and differentiation of bone marrow cells and thrombocytes
IL-12
Macrophages, B cells
Promotion of cell-mediated immunity, activation of TC and NK cells, suppression of humoral immunity
IL-13
TH cells
IL-4-like effects on B cells, inhibition of production of inflammatory cytokines by monocytes
IL-14
TH cells
Important for the generation of B memory cells
IL-15
Endothelial cells, epithelial monocytes, muscle cells
IL-2-like effects
GM-CSF
TH1 cells, macrophages
Marrow proliferation of myeloid precursors
G-CSF
Fibroblasts, endothelial cells
Proliferation and survival of neutrophil precursors
M-CSF
Fibroblasts, endothelial cells
Survival of monocyte macrophages
APC, antigen-presenting cell; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; M-CSF, macrophage colony-stimulating factor; MHC, major histocompatibility complex; NK cell, natural killer cell; TCcell, T cytotoxic cell; THcell, T helper cell; TNF, tumor necrosis factor. a
Not all sources are listed.
b . A n y c e ll in th e b o d y c a n ac t a s a n A P C f or im m u ne r es po ns es i n vo l vin g C TL c e ll s . N uc le a t ed c e ll s c a n p r es e nt fr a g m e n ts o f +
a n t ig en s b o un d t o t h ei r s u r f ac e MH C c l as s I m ol ec u l e s t o T c ( C D 8 ) l ym p ho c y t es . c . B ot h T an d B c el ls c on t i nu al l y ci r c u la t e f r om th e bl oo d th r ou g h t h e l ym ph no d es , s pl e en, a nd o th e r s ec on da r y l y m p ho i d t is s u e a nd t h e n b ac k in t o t h e b lo o d. I f th e r e is an t ig e n p re s en t in th e s ec o nd a r y l ym p ho i d t is s u e th a t b in ds s p ec i fi ca ll y t o th e re ce p to r on t h e T o r B c e ll , th e n a n im m u n e r es p on se c a n b eg i n . P.199
6 . N e ut r o p h il s , m ac r o ph a g es , eo s in o p hi l s, b as o p h il s , p l a te l et s , a n d m a st ce l l s as s i s t i n e l im in a ti n g a nt i ge ns f rom t he bo d y. Th ei r f u nc t io ns m a y b e p ha g oc y t i c , p r oi n fl am m a t o r y , c y t o t o xi c , r e g ul a to r y , o r a c om b in at i o n o f t h es e. C . H u m o ra l im m un i t y: p r i m a r y a n d m em o r y r e s p o n se s th a t p r o d u ce an t i b od i es 1 . O ve r vi ew . I n m os t h um o r al i m m u ne re s p o ns es, a n ti ge ns a re r e c og ni z e d b y a n ti g en -s p e c i f ic B c el ls a n d T H c el l s ( no n - an t ig e ns p ec if ic B an d T H c e ll s do n ot r es po n d ). In i ti a ll y , B a n d T H 2 c el ls d i vi de t o i nc r ea s e th e ir c e l l n um be r s . R es p on d in g B c el ls p r o du c e b o t h m e m o r y B c e ll s a n d p l as m a c el ls , ai de d b y c yt o k in es s e c re t ed b y T H 2 c e ll s . T -i n d ep e nd e n t re s p on s es to c e r tai n ba c t e r ia l p o l ysa cc ha r i de an t ig en s d o no t re q ui r e T H c e ll s . D u r i ng Ti n de p en d en t re s p o ns es , a s u bc l as s o f B ce ll s ( B 1 B c el ls ) re sp o nd s a l on e a n d p r od uc es pl as m a c el ls t ha t s ec r et e IgM a n t i b o di es , b u t n o m em o r y B c el ls a re pr o d uc ed .
2 . P r i ma r y i m m u n e re sp o n se . Th e f i rs t ti m e a sp e c i f ic a n ti g en is e n co u nt e re d , o nl y vi r g i n B c e ll s a n d vi r g i n T H ce l l s a r e p r es en t to r e s po nd t o t he an t ig e n. In i t ia ll y , t he T H c el ls be c o m e T H e f f ec t or c e ll s, an d th e B c e ll s p r od u c e pl as m a ce ll s t h at s e c r et e I g M a n t ib od y . L at e r i n t h e im m u ne r es po ns e , p la s m a c e ll s p r od uc in g o t h e r cl as s e s o f a n ti b ody d e v e l op . Th e p r im a r y im m u n e r es p on s e is d e t ec te d i n th e s e ru m a fte r 4 d a ys a nd pe ak s i n 7- 1 1 da y s . I n a p r i m a r y im m u ne r es po ns e , I g M i s p r od uc e d f i rs t a n d i s f ol l o we d b y I g G . Me m o r y B an d T H 2 c e ll s a r e a ls o p ro d uc ed . Me m o r y B c el ls c a n a ls o b e a c t i v a te d t o p r o du c e t he ot h e r c l as ses o f a nt i bo d y in s u bs eq u en t i m m un e re s po n s e s . 3 . M e m o r y i m m u n e r esp o n se s . Th e s e co n d o r s u bs eq u en t e n co u nt e r wi t h t he s a m e a n ti g en o r a c lo s e l y r el at e d a n ti g en p r o du c e s re s p on s es b y m em o r y B c el ls an d m em o r y T H 2 c el ls . Th e s e re s p o ns es ar e m or e r ap i d b ec au s e m e m o ry c e ll s r e qu i re le s s a n t ig en f o r s t im u la t io n an d a re of g re a te r m a gn i tu d e b ec a us e t he r e a r e m o re an t ig e n -s pe c i f ic B an d T c e ll s t o r es p ond . Mo s t s e r um a n t ib od y p r od u c e d i s I gG , wi t h s m a ll e r am o un t s o f I gA an d Ig E . S i g ni f ic an t am ou n ts o f an t i bo di es a re p ro d uc ed as r ap i dl y as 2 -3 d a ys a f t e r t he r ee nc o un te r wi t h an t ig e n, an d th e a b s o l ut e a m o u nt o f an t ib o d y (m ea s u r e d i n m il li g r am s pe r de c i l it e r o f se r um ) i s g r e a te r th an in p ri m a r y im m u n e r es p on s e s . Th e d u r a ti on o f m e m o r y va r i e s am o ng an t ig e ns an d p ro ba b l y a m o n g i nd i vi d ua l s . S om e, bu t n o t a l l, m e m o r y is li f el ong . 4 . M a j o r ro l es o f a n t ib od i e s a . Th e fi r s t fu nc t io n o f an a nt i bo d y is to ac t a s an a n ti g e n r e ce p t o r f o r B c el ls s o th a t t he B c e ll s c a n re c o g ni z e an d r e s po nd t o a n t ig en s . b . Th e s ec o nd f un c t i on of a n a n ti bo d y is to ai d i n t h e e l i mi n a ti o n o f a n ti g en . E li m i na t io n o c c u rs t hr o ug h n o ns pe cif i c f u nc ti o ns , s uc h a s p h ag oc y t o s i s o r c om pl e m e n t ac t i v a ti on . Th e m e c ha n ism of e l im in a ti o n d ep e nd s o n th e c l as s o f a nt i bo d y in v ol v e d . c . Th e t h i rd fu nc t io n o f an a nt i bo d y is ne u t r al iz a ti o n o f t o xi n s. N e u t r al i z a ti on oc c u r s wh e n an an t ib o d y b i nd s t o th e to xi n a n d p r e ve n ts i t f ro m r ea c hi ng t h e t a rg e t c el l o r re c e p to r . D . I m mu n o gl o bu l i ns : a n t i g en b in d i ng a nd cl a ss - s p ec i f ic f u n c t io n s. Th e te r m s a nt i b od y a nd i m m u no g lo bu li n ar e us ed i n t er c ha ng e ab l y . 1 . S t r uc t u r e . Th e s t a nda r d i m m u no gl o bu li n u n it h a s f ou r p o l yp ep ti d e c ha in s : t wo id e n ti c a l l ig h t ( L ) p o l y pe p t i d e c h a in s a nd t wo i d e nt ic a l h ea v y ( H ) po l y p e pt id e c h ai ns . Th e s t r u c t u r e is r e p r es en t ed as H 2 L 2 . Eac h c ha i n c an be di vi de d in t o a C - t e rm i n al c o n s ta n t re g i on an d a n N - t e r m i na l va r i ab l e r e gi o n of am in o a c i ds ( F i gu r e 1 0 - 3) . Th e N -t e rm i na l v a ri ab l e r eg i on fo rm e d f r om th e H a n d L v a r ia bl e d om a in s is r es po ns i bl e f o r a n ti g en b i nd in g b y t h e
i m m u no gl o bu l in . Th e C - te r m in al c o ns t an t re gi o ns o f th e H c ha in d e t e rm in e t h e c l as s o f t he im m u n og l ob ul i n. 2 . C l as s . Th e r e a r e f i v e g e n er a l h ea v y - c h ai n , c on s ta n t - re gi o n a m in o a c i d s eq u en c e s . Th e s e de t e rm in e t h e f i ve g e n e ra l cl a ss e s o f i mm u n og l o bu l in s : I gM , Ig G , I g E, I g A, an d IgD . W ith in s o m e c l as s e s, v a r ia n ts o f th e h e a v y - c ha i n s e q ue nc e yie l d s ub c l as se s : I g M1 - 2 , I g G 1 -4 , a n d I g A1 - 2 . Th e c l as s o f a n i m m u n o gl ob u li n d e f in es it s n on s p e c i fi c an t i ge n e li m i n at i on o r i nf l a m m a to r y f u nc ti o n. Th e s e fu nc t io ns a re ac tiv a t e d o n l y a f t e r a nt i ge n -a n t ib od y c om p le xe s a r e f o rm ed , no t b y un bo u nd an t ib o di es . a . I gM i s t h e f i rs t im m u no g lo b ul i n s e c re t ed du r ing p ri m ar y i m m un e r e s po ns es . It pl a y s a m in o r ro l e i n m e m o r y r es po n s e s. I t d oe s n o t l e a ve t h e b lo o d i n s i g ni fic a nt am ou n ts be c a us e o f i t s p en t am er ic s t r uc t ur e a n d l a rg e s i z e ( m o l wt 9 0 0 ,0 00 da l to ns ). I t a cc o un ts fo r a p p ro xi m a t el y 2 0% o f t he a du l t s e r um im m u no g lo b ul i n . I g M i s t h e m os t po t en t a c t i va t o r o f t h e c o mp l em e n t s ys t e m ( se e I . E . 2) . It s s e r um h a lf - li f e i s 9 -1 1 da y s . P.200
Figure 10-3. Immunoglobulin molecule. Fc, fragment, crystallizable.
b . I g G i s t h e p re d om in a nt s er um im m u n og lo b ul in s ec r e te d a t th e e n d o f t he p r i m a r y im m u ne r es po ns e s a n d d u ri ng m e m o r y r es p on se s . I t c an di f fu se f r o m b lo o d i nt o o t he r e xt r a c el lu l ar f lu id s , p a rt ic ula r l y in in f la m e d m ic r o v as c u l at u r e, an d i t c r os s e s t h e p la ce n ta to e n t e r t he fe t al c i r cu la t ion . I t ac co u nt s f o r a pp r o xi m a t e l y 7 0 % o f a du l t s er u m i m m un o gl o bu li n . I t o p s o ni z e s a n t i ge n s f o r p h a g oc yt o s i s a nd ac t i va t e s t h e c o mp l em e n t s ys t e m . I ts s e r um ha l f- l if e is 25 - 35 da y s . c . Ig E is s ec r e te d d u ri n g m em o r y re sp o ns es an d m a y al so be se c re t ed la te d u r in g a p ri m a r y r es p on s e . I t n o rm al l y ac c o un ts fo r < 1 % o f s e ru m i m m u no gl o bu l in . I t bi n d s t o I g E r e ce p t o rs l oc a ted o n th e c e l l s u r fa c es o f
b l o o d b as o p hi l s a n d o n m u co s al a nd co n n ec t ive t i s s ue ma s t c e ll s t o t r i gg e r th e s ec r et i on of in f l am m a to r y m ed ia t o rs fro m th es e c el ls in th e p r e se nc e o f s pe c i f ic an t ig e ns . Ig E m e di a te s a ll e rg i c r e ac ti o ns . I ts s e r um h a l f- l if e i s 2 - 3 d a y s , bu t i t s m as t c el l -b ou n d h al f - li f e i s s e v er a l m o n th s t o ye a r s . d . I g A i s s e c re t ed du r in g m em o r y re sp o ns es an d m a y al so be se c re t ed la te d u r in g a p ri m a r y r es p on s e . I t ac c ou n ts f o r 1 0 % o f s e ru m im m u n og l ob ul i n. H o we ve r , i t is s e c re t e d in l a r ge q ua n t it i es a c ros s mu c os a l s u r fa c es i nt o g a s t r oi n t es t i na l , re s p i ra t o r y, l a c h r ym a l , m amm a r y, a n d g en i t o u ri n a ry s e c r e ti o ns , w h e re i t p ro t e c ts m uc o sa f r om co lo n i z a t i on b y ba ct e r ia and o t h e r m i c ro o rg a ni s m s . Its s e r um ha l f- l if e i s a pp r oxi m a t e l y 5 d a ys . e . I g D a c c ou n ts fo r < 1 % o f s e ru m i m m un o gl ob u lin a nd ha s n o k no wn f u nc t io n a s a s ec r e te d im m u n og l ob ul i n. 3 . S pe c i fi c i t y. Th e s pe c if i c i t y o f e ac h im m u n og l ob u li n fo r a n ti g en bi n di ng r e s id es in th e t wo i d en t ic a l a nt i ge n -b i nd in g s i te s, e ac h f o rm e d b y th e c om b in a ti o n o f t he v a r iab l e r e gi o ns o f he a v y a nd l i gh t c ha i ns . I g G , I g E , an d I g D as we l l a s s er um I g A h a v e t wo an t ig e n- b in di ng s i t es . I g M a n t ib o di es h a ve 10 id e nt ic a l a nt i gen - b in d in g s it es t hr o ug h th e c om b in a ti o n o f P.201
f i ve H 2 L 2 un i ts wi t h a jo in i ng po l y p ep t id e c ha i n to f o rm a pe n ta m er . L i ke wi s e , s ec re t e d I g A ty p i c al l y e xi s ts as a di m er wi t h f ou r bi n di ng si t es . 4 . Q u a nt i t a ti o n o f im m un o g l ob u l in : a n t i ge n bi nd i n g a n d c r o ss 8
r e a c t i vi t y. B e t we e n 1 0 a n d 1 0
11
un i qu e i m m un og l ob u li ns wi t h di f fe r en t
a n t ig en - b in di n g s pe c i fi c it i es a re fo r m e d b y t h e im m u ne s ys t em . a . E ac h i m m un og l ob ul i n s p ec if ic i t y c a n b in d t o s ev e r a l di f fe r en t , b u t c l o s el y s t r uc t ur a ll y r el a te d , a n tig e ns . Th is ab il i t y i l lu s t r at e s t h e p he no m en on o f c r os s - re ac t i v it y o f a s i ngl e an t ib od y f o r m ul t ip le an t i ge ns . Ea c h i m m u no gl o bu l in - an t ig e n i n t er a c t i on i s q u an t it a te d b y i ts as s oc i a ti o n c o n s ta n t ( K a ) . b . C r os s -r e ac t i v it y m a y a l s o oc c u r th r ou g h t he sh a r in g o f s om e , b u t n ot a l l , a n t ig en s b y t wo s t ra i ns of b ac t er i a, v i r us es , o r oth e r m ic r oo r g an is m s . c . B ec au s e ea c h m ic r o o rg a ni s m ha s s e v er a l a nt i ge n s, ea c h el ic i ts th e p r o du c ti on o f m u l ti pl e ant i b od ie s wi t h u ni q ue s p ec i fi c i t ie s b y t he im m u ne s ys t em . Th is re s p o ns e is k no wn a s a p ol yc l o n a l r e s p o ns e a nd r es ul t s i n a c om b in a ti o n o f a nt i bo di es k n o wn as a p o l yc l o n a l a n t is e r um a nd de fi n es t h e s e ro t y p e o f t h e im m un i z i ng o rg a ni sm . 5 . F r ag m en t s o f im m uno g l o bu l i n f o r cl i n ic a l us e . Im m u no gl o bu li n s c a n b e en zy m a ti c al l y c l ea v ed i nt o f r a gm en ts — f o r e x a m pl e , F ab a nd F (a b ' ) 2 ( a n ti g en - bi n di n g f r ag m en t s ), F c ( c r ys t al l i zab le f ra g m e n t ), an d F v ( va r i a ble r e g io n fr a gm en t ) . F ab a nd F ( ab ' ) 2 f ra gm en t s a r e c l in ic al l y us e fu l b ec a us e t h e y r et a in an t ig e n s p ec if i c i t y , bu t n o t c la s s -s p ec i f ic ( e. g . , in f la m m a to r y ) f u nc t io ns , an d a r e r e ad ily e xc r e t e d re n al l y. C on ve r s el y , th is c h a ra c te r is tic l i m i ts th e i r e ff e c t i v e ne s s i n c e rt a in s i tu a ti o ns .
E . An t i g e n e l i mi n a ti o n a n d a c u te i n fl a mm a to r y m e ch a ni s ms o f h u mo ra l i m m un i t y 1 . O p s on iz a t io n i s t h e pr e p a ra t io n o f a n y e xt r a c e l lu l a r a nt i ge n f o r p h a go c y to s i s t h ro u gh bin d in g o f an t ib o d y. N e u tro p hi ls an d m ac r op h ag es h a ve a v a r i et y o f re c e p tor s fo r th e c o ns ta n t r e gi on o f I g G an t ib od i es (F C γ R ) , wh i c h bi n d a nt i ge n -a n ti bo d y c o m pl e xe s . W hen the a nt i ge n i s so l ub l e, th e i m m u ne c om p le xe s m us t b e s u ff ic i en t l y l a rg e to in d uc e t h is re ac t io n . Thi s b i nd i ng t ri g ge r s p ha go c yt o s i s o f t h e a n ti ge n - an ti bo d y c o m pl e x a n d a c t i v a te s t h e m e ta bo l is m o f t he pha g oc y t e , s hi f ti n g i t t o wa rd t he p ro d uc ti o n o f b a ct e r ic id al o xy g e n r ad ic a l s ( e .g . , s up e ro xi d e a nio n , h y d r o ge n p e ro xi d e ) . 2 . C o mp l em e n t is a g r ou p of ap p r o xi m at e l y 2 0 s e r u m p ro t ei ns t ha t , wh e n a c ti va t ed , fo r m a p r o te o ly t i c c as c a d e s i m i l a r t o t he c l o t ti ng an d fi b ri no l yt ic s e qu e nc e. W it hi n th is c om p le x o f p r ot e in s, t he r e a r e s om e th a t in h ib i t c om p le m e n t a c t i v a ti o n. C o m pl em e nt is re s p o ns ib l e f o r i nc r ea s i n g t he i n f la m m at o r y r es po ns e , p h a go c yto si s o f a n ti g en , l y s is of c e ll s ( us u al l y p a t ho g en s ) , an d c le a ra nc e o f im m u ne c om p le xe s . a . I n t he cl a ss i c a c ti va t i o n pa t hw a y, i m m u ne c om p le xe s o f I g M o r I g G a n t ib od i es bo un d to an t ig e n b in d s u bu ni t s o f c om p le m e n t c o m p o ne n t 1 (C 1 ) a n d t r i gg e r a n i ni t ia l s er ie s o f pr o te o l y ti c c le a va ge s . b . I n t he a lt e r n at i ve ac ti va t i o n pa t hw a y, t h e c ell wa l l s o f c er t ai n m ic r o or g an is m s (e . g ., g ra m - ne ga t i v e b ac t e ri a ) a re a bl e t o b i nd C 3b an d o t h e r co m p l em en t p r o te in s th a t i ni ti a te a d i ff e r ent s eq ue n ce of p ro t eo l yt ic c l ea va g es , l ea d in g t o t he s a m e en d po in t a s t h e c l ass ic ac t i v at i on pa t h way . c . In th e m a n no s e- b i nd in g p at hw a y, m a n n o s e - bin d in g p r o te i n ( MB P ) i s p r o du c e d b y t h e l i v e r d uri n g t h e ac u te - p ha s e r es po n s e . MB P b i nd s t o m a nn os e o n th e s ur f ac e o f ba c te r ia an d , i n c on jun c ti o n wi t h as s o ci a te d s e r um p r o te as es , t ri gg e rs p ro t eo l y t ic c le a va ge s id e n ti ca l t o th os e s ee n i n t h e c la ss ic pa t h wa y o f c o m pl em e nt . d . C 3 b, C 4b , an d a s s oc ia t e d d eg r ad a ti o n p r od uct s pr o v i de op s o n i z at i on , v i a c om p le m e n t r ec e pt o rs on c e l ls s uc h a s m a c ro p ha g es an d n e ut r o ph il s , in a d di t io n to th a t p r o v id e d b y I g G in im m u ne c om p le xe s . e . P r o in f l am m at o r y f r a g m e n ts of c e r ta i n c o m ple m en t p r o te i ns a c t b ot h b y d i r e c t a c ti vi t y o n t h e mi c r o va s cu l a t u re , p r om o ti n g a r t er i ol e d il a ti o n a nd i n c re as ed v a s c ul a r p e rm e a bi l it y , a nd b y tr i gg e ri ng t he r el e as e o f h is t am i ne a n d o t he r pr o in f la m m at or y m e di a to r s f r om m as t ce l ls an d b as o ph il s . f . A c o m p le x o f c om pl em e n t p r o te i ns k no wn a s t he m em b r an e a t t a ck c o m pl e x ( M AC ) c an in s er t i nt o a n y li p id bi la y e r m e m b ra ne , fo r m i ng a l a rge c h an n el th r ou g h wh i c h i on s a n d wa t e r di f f us e. Ma n y b ac t e ri a , e n vel o pe d vi r u s es , a nd s o m e hu m an o r m am m a li a n c e l ls a re s u b j e ct t o t hi s o s m ot ic l ys is . P.202
3 . C i r cu l a ti n g b a so p h ils a nd c on n ec t i ve t is s ue m as t ce l ls a re m a in l y p r o in f la m m a to r y c e ll s t ha t r ap i dl y in i ti a te ac u te i n f l am m a ti o n. Tr i g ge r s o f
s ec r e ti o n i nc lu de m e c h an i c a l a nd t he r m a l t r au m a a n d im m u n ol o gi c t r ig ge rs , c om p le m e n t, an d Ig E . a . I g E a n ti b o di e s, r eg a rd l es s o f a n ti ge n s p ec if ic it y , e q ui li b ra t e b e t we e n s e r um a n d b in di n g n on c o v a l e nt l y to hi g h -a f fi ni t y I g E r ec ep t o rs o n m as t c e l l a n d b as o ph il s u r fa c es . Th i s ac t i v i t y a r m s th e m as t c el ls an d b as op h il s, but t h e tr i gg e ri n g o f s ec r et i on b y t he se c e ll s r e qu i re s t h a t a nt i ge n b in d to an d c r os s -l in k a n ti g en -s p ec ifi c Ig E m ol e c u le s a l re a d y a f fi xe d t o th e i r r ec e pt o rs . b . Ma s t c e ll s a nd b as oph i ls , wh e n t r ig g er e d, im m e di a te l y s ec r e te t he c o nt e nt s o f th ei r s t o ra g e g r a nu le s , i nc lu di n g h is ta m in e , t um o r n ec r os is f a c to r α ( TN F - α ) , pr o te as es , an d c he m o t ac ti c p ro t e in s f o r n eu t r op hi ls and e o si n op hi ls . In ad d it io n , a c ti v a t io n o f ph os p ho li pa s e A 2 re l ea se s a r a ch id o ni c ac i d f r om m e m b ra ne ph o s p ho l ip id s an d r e s ul ts in th e s y n t he s i s o f va r io us le uk o t ri en e s , p r o s t a gl an d in s, an d th r om b o xa n es . Th e p r im a r y e f f ec ts o f t he s e m e di a to rs a re ( 1 ) V as c u la r di l at io n ( 2 ) I nc r ea s e d v as c u la r pe r m ea bi l it y ( 3 ) C o nt r ac t io n o f re s p i ra t o r y an d g as t r oi n te s t i nal s m oo t h m us c l e ( 4 ) N e ut r op h il an d e os i no p hi l c he m ot a xi s 4 . An t i b o d y- d e p e n d e n t c e l l -m e di a t ed c yt o t o x i c i t y i s m ed i at e d b y ce ll s wi t h c yt o to xi c p o te n ti al as we l l a s re c e p to r s f o r I gG . Th e s e c el ls , N K c el ls , m ac r o ph a ge s , an d s om e T C c e l ls , b i nd to an d l y s e t a rg e t c e l ls c o at e d wi t h IgG. 5 . Ac u t e in f l am ma t i o n a l lo ws i nc r ea s ed ea s e of m o v em en t of c r u c i al c om p on e nt s o f t h e b lo o d i n to th e ti s s ue s , in c l u din g ph a go c yte s ( e s p ec ia l ly n e u t ro ph i ls ) , I g G a n ti b odi e s , c o m p le m e n t , c l o t ti ng p r o te i ns , a nd ki ni ns . The a d a pt i ve re s u l t is th e i s ol a t io n a nd r em o v al o f i n va d in g m ic r oo r g an is m s a nd n e c ro t ic t is s ue s , fo l lo we d b y t is s u e r e pa i r a nd r eg e n er a ti o n. F . C e ll - m ed i a te d i m mu ne r es p on s e s ( c el l - me d iat e d im m un i t y) a r e t ho se i n wh i c h an t i b od y i s n o t i n vo l ve d i n t h e e l im i nat i o n o f a n ti g en . 1 . N o n vi r a l i n t ra c el l u lar p a r a si t e s o f m a c ro p hag e s , su c h as My c ob ac t e ri a , L i st e ri a , a n d c e r t ai n p r o to z o a , a r e p r im a ri l y el im in a t ed b y T c e l l+
m ac r o ph a ge i m m u ni t y . CD 4 T H 1 c el ls r ec og n i z e in f ec t ed m a c ro ph a ge s a nd s ec r e te l y m p ho k i n es , p ar t i c u la r l y in t e rf e r on γ ( I FN - γ ) . Th es e l y m ph ok i ne s a c ti va t e m ac r op ha g es to p r o du c e m o r e b ac te r ic ida l o xy g e n r ad ic al s (e . g. , s u pe r o xi d e a n io n , h y d r og e n p e ro xi d e ) a nd al s o to i n c r ea s e th e s ec r e to r y f u nc t io n o f th e m ac r op h ag e s a nd in h ib it p ha go c y to s i s , e na b li n g t he m ac r o ph a ge s t o k i l l t he p a r as i te s i n t he ex t r a ce ll u l a r e n vi r on m e n t. 2 . V i r us e s m u s t b e e li m in a t ed f ro m b ot h e xt r a ce llu l a r s i t es an d i n fe c t e d c e ll s. a . An t i b o d ie s o ps o ni z e v i r u s p a r ti c l es in bl oo d an d ti s s ue f lu id s f o r p h a go c y to s i s , b ut an t ib od i es a re ge ne r a ll y i ne f fec t i v e a ga i ns t i n fe ct e d ce ll s . b . C T L c e ll s re c o g ni z e in f ec t ed ce ll s a nd di r ec t ly k i ll th e m in an a nt ig e n s p ec if ic m a nn e r , s ec r et in g l ym p ho k i n es , s uc h as TN F - β a s we l l a s g r a n zy m es a n d g r an ul y s in s . I n a d di t io n , C TL c an i n du c e a po p to s i s v i a F AS l i ga n d b in di n g t o F A S on t h e t a rg e t c el ls . O f te n , th e c e ll s a r e ki ll e d b e fo r e
i n f ec ti o us v i ru s p a rt ic l es a r e a s s em bl e d. W he n k il l ed ce ll s r e le as e i n f ec ti o us v i ra l p a r ti c l es , t h e y m a y be op s o n i z ed b y a n a n ti b od y . C e ll m e di a te d i m m un i t y a n d hu m o ra l i m m un it y m us t f un c ti o n i n co nc e r t t o p r o vi de op t im al an t i v i ra l d e f en s e s . c . N K c e l ls k i ll in f ec te d ( a n d t um o r ) c el ls i n a n on - a n ti ge n -s p ec if ic m a nne r , b i nd i ng to MH C - l i k e m ole c ul es us in g a va r ie t y o f r e ce p to r s . N K c e ll s ki l l t h e ir t a rg e t c e l ls u s i n g m e c ha n is m s s im i l a r t o t h os e u se d b y C TL s. d . I F N - γ (s ec r e te d b y C TL , N K , a n d T H 1 c el ls ) a nd I F N - α a n d I F N -β ( s ec r e te d b y f ib r o bl as ts a n d o t he r c e ll s) p ro v i d e a d di t io n al an t i vi ra l i m m u ni t y b y bi nd i ng to re c ep t o rs o n o t he r c e ll s an d in du ci n g s y n th es is o f k i na se s a nd en d on uc l eas es ( i. e . , a nt i v i ra l p r o te in s ) , wh i c h i nh i bi t vi ra l an d c e ll ul a r g r o wt h . In t e rf e ron s a ls o u p r eg ul a te c l as s I MH C p r o t e i ns , wh ic h m ak e i n fe c te d c el ls m o r e v i s ib l e t o C TL c el ls . 3 . T um o r s a r e m o d if i ed h o s t c e ll s a nd m u s t be eli m in a te d b y t he im m u ne s ys t em , u s u al l y b y c e ll -m e di a te d i m m un i t y . a . N K ce l ls a re p ri m a r il y r e s p o ns ib le f or ki ll i ng tum o r c el ls . Th e y ac t b y r e c og ni z i n g c h a ng es in c e l l -s u rf ac e p r o te i ns o r by a n t i b od y- d e p e n d en t c e l l -m e di a t ed c yt o t o x i c i t y. P.203
b . C T L c e ll s re c o g ni z e tu m o r c e l ls i n a n a n ti g en -s p ec if ic m a nn e r a n d k i l l t h em b y s ec r e ti n g l y m p ho k in es , s uc h a s TN F - β , a n d b y i nd uc i ng ap op t os is t h r o ug h t h e b in di n g o f FA S a n d F A S -l i ga n d. c . M a c ro p h ag e s al s o k i ll t u m o r c el ls in a n on s pec i fi c m an ne r , th r ou g h t he r e l ea se o f TN F - α . 4 . G r a f t re j ec t i o n ( s e e V )
II. Hypersensitivity Reactions are exaggerated, inappropriate, or prolonged immune responses that cause damage to otherwise normal tissue. F o u r t yp e s o f h y p e rs en s it i v i t y r ea c ti on s a r e r ec o gn i z e d , p r im ar i l y o n th e b a si s o f t h e m e c h a ni s m s o f pa t ho ge n es is ( Fi gu r e 1 0 - 4) . Ma n y d i f fe r en t d i se as es a re in c l u de d wit h i n e ac h t yp e . Al l e r g e ns a r e b ro a dl y d ef i ne d a s a n t ig en s o r ha p te ns th a t i n du c e h y pe r s e ns i ti v i t y r e a c t i on s, an d th e y ar e u s ua ll y n o np a th og e ni c , no n t o xi c a g en t s.
Figure 10-4. The four main types of hypersensitivity reactions. RBC, red blood cell.
P.204
A. I g E - m e d ia t e d t yp e I h yp e r s e n s i t i vi t y r e a c t io n ( im m ed i a te h yp e r s e n s i t i vi t y) 1 . A t ype I h y p e rs en s i t i v it y r e a c t io n i s c au se d b y i n a p p ro p r i a te p r od u c tio n a n d h yp e r s e c r e t i on o f Ig E t o s pe c i f ic a l le r ge ns p l us au xi l i a r y f ac to r s , s uc h a s i nc r e as ed m uc o s a l p er m e ab il i t y to ir r i ta n ts (e .g . , S O 2 , N O 2 , di es el f u m e s ). Th e t en d en c y t o h yp e r s e c r e te I g E i s in h e r i ta b l e ; a c hi ld ' s p r o ba b il i t y o f be in g a h yp e r s e c re t or is 50 % i f o ne p a re n t is a h yp e rs ec r eto r a n d 7 5 % i f b ot h p a r en ts a r e h y pe r se c r e t or s . Th es e i n di v i du a ls ar e c o ns id e re d to be at o pi c . a . I gE is p ro du c e d l oc a lly a f t e r n on s ys te m i c e xp o s u r e t o a n a n ti ge n . ( 1 ) I n n or m os ec r et o rs (1- 1 0 µ g/ d L o f I g E ) , a rm ing o f l oc al m a s t ce ll s o c c u r s ( s e e I . B .6 ) . ( 2 ) I n h y p e rs ec r et o rs ( t yp i c a ll y 1 00 µ g - 1 m g / dL of I g E ), I g E sp i ll o ve r o cc u rs , ar m i n g b as op h il s a n d n on l oc al m as t c el ls a n d c au s i n g i nc r ea se d o cc u pa nc y o f m as t c el l an d ba s o p hi l I g E r e c e p to rs b y Ig E . b . B ec a us e t he r e i s a l ag p e ri od f or I g E s y nt h es is an d c el l a r m i n g, a t y p e I r e a ct i on us ua ll y d oe s n ot o c c u r o n t he fi r s t ( o r f i rs t s e as on a l) e xp o s ur e to a s p ec if ic al l e rg en . 2 . C o mm o n a l le r g en s a . R es p i r a to r y a l l e r g e ns i nc lu de p ol le ns o f v a r io u s p la n ts (e . g ., r ag we e d , g r a ss es , t r ee s ) , f un g i, an i m a l f u r , c a r p et m i te s , a n d o t he r s h ed al le r g en s . b . G a s t r oi n t es t i na l a l ler g e n s i nc lu d e d ai r y p r odu c ts , s he l lf is h , t r ee nu t s, a n d p e an u ts . c . S ki n a n d m o u th al l e rg e n s i nc lu d e t op ic a ll y ap p li e d d r ug s ( e .g . , p r o ca in e ) . d . I n t ra ve n o us a ll e r ge ns i nc lu de in s ec t v e n om s a n d d r ug s t h at ac t a s c ell o r pl a sm a p ro t ei n - bo u nd h a pt e ns (e . g ., pe n ic il li n , c ep h al os p or i ns ,
va c ci n es ) . Th es e d r ug s m a y c a us e t y p e II o r I I I h y p e r s e ns i ti vi t y r ea ct i ons in p e o pl e wh o d o n o t h y p e rs ec r e te I gE in r es po ns e t o t he s e dr u gs . 3 . Ac t i va t i o n o f ma s t ce l l an d b a so p h il se c r e t io n b y an al le r g en r eq ui re s t wo o r m or e re c e p to r - bou n d I g E m ol ec u le s t o b e c r os s -l in k ed b y a sp ec i fic a l le r g en . Ha p te n -s i z e d ru g s t ha t pr o vo k e th is r eac t io n b o th s e ns i ti z e th e i m m u ne s y s t em a n d t r ig ge r m a s t c e ll s wh e n t he dr u g i s b o un d t o a la r ge r m o le cu l e ( e .g . , a p r o te i n) . A c ti v a ti o n l ea ds t o a t ra n si e nt in c re as e i n t h e c yc li c a de n os in e m on o ph o s p h at e (c A MP ) l e v e l , fo l lo we d b y a n i nc r ea s e in t h e l e ve l o f c y c l ic gu a nos i ne m o no p ho sp h at e (c GMP ) r e l a t i v e to c A MP . T h i s i s fo ll o we d b y p h os ph o lip a s e C pr o du c i n g s e c o nd m e s s e ng e rs , wh ic h l e ad t o a r a pi d i nc r ea s e in c y to p la s m ic c a lc iu m i on s ( Ca c yt o pl as m i c Ca
++
++
) . W ith t h e i nc r ea s e in
, th e r e is im m e di a te f us io n o f v es ic l es c on t ai n in g
i n f la m m at o r y m e di a to r s wi t h t h e c el l m em b ra ne a n d re le as e o f th es e m e di a to r s i nt o t h e e xt r a c e l lu l a r m i li e u. I n a dd i ti o n, a f te r de g ra n ul a ti on , m as t c e ll s p r od uc e a dd i tio n al c yto ki n es , l eu k ot r ien e s, an d p r os t ag l an di n s. Th e s e a c ti v a t e t he la t e -ph a s e r es po ns e , wh i c h f ur t h e r a ct i va te s t h e l oc al i n f la m m at o r y r es po ns e . P r o l on g ed in c r e as es in cA MP l e ve l s in hi b it m a s t c e ll ac ti v a t io n . 4 . E f f ec t s o f m e d ia t o r s s e c r e te d f ro m m a s t c el ls a nd b as o ph i l s a . V as od i la t io n a nd in c rea s ed c a pi ll a r y pe r m e a bi lit y a r e c a us ed b y h i st am i ne ; th e l eu k o t r ie ne s C 4, D 4 , a nd E4 ; an d p r o st a gl an d in D 2 (P G D 2 ) s ec r e te d b y m as t c el ls . b . G a s t r oi n te s ti na l a n d re s pi r a to r y sm oo t h m u s c le co ns t r ic ti o n is c a us e d p r i m a r il y b y hi s ta m i ne , th e le uk o t ri en es C 4 , D 4 , a n d E4 ; P G D 2 ; a nd p l a te le t - ac ti v a t i ng fa c t o r s ec r e te d b y m a s t ce l ls an d ot h e r l eu k o c y te s . c . E os in op h il an d n eu t r op h il in f il t r at i on is c au s e d b y c he m o t ac ti c f ac t o rs s ec r e te d b y m as t c el ls . 5 . L oc a l s ym p t o m s o f pa t h o ge n es i s i nc lu d e i nf la m m a ti o n o f t h e u pp e r ( r h i ni t is ) a n d lo we r r e s p ir a t o r y t ra c t ( as t hm a) , gas t r oi n te s t i na l t r ac t , a n d s ki n . a . C om m o n c li ni c al s y m pt o m s in c l ud e u r t ic a ri a , p ru r i tu s (i tc h in g ), na s al c o ng es t io n , b r on c h oc o ns t r i c t i on , m uc us an d l ac h rym a l h y p e rs ec r e ti o n, l a r yn ge a l e de m a , v om i tin g , a n d d ia r r he a . b . S ym pt om s m a y b e c on f i ne d t o th e p o rt a l o f a lle r g en en t r y ( e .g . , r e s pi r at o r y al l er g en : re s p i r at o r y s ym p to m s ) or m a y b e m o re wi d es p r ea d a s a r es u lt of al l e rg en s p il l ov e r i n to th e c i rc ul a ti o n (e . g . , f oo d a ll e r ge n : g a st r o in t es ti n al , s k i n, r es p i ra t or y s y m p t om s ). c . At o p i c d e r ma t i t is t y pi c al l y in c l ud es s e ve r e p ru r i ti c d e rm a ti ti s , a nd m ay a l so in cl ud e rh i ni t is o r as t hm a , f oo d a l le r gi es , a n d c h a ng es in th e c e ll m e di a te d i m m un e s y s tem . d . Th e lo c a l i n tr o du c ti on o f al le r ge n s om e ti m e s le a ds to an a ph y l a xi s . e . A pp r o xi m a te l y 50 % o f p a ti e nt s wi t h as t hm a h yp e r se c re t e I g E. Th i s t e n de nc y i s p ro b ab l y c o nt r i bu t o r y, b u t a nc il l ar y, to t he un d e rl yi ng b ro nc h ia l h yp e r r ea c ti v i t y p re s e n t in t he s e pa t ie n ts (s e e C ha p t e r 4 8) . P.205
6 . S ys t e m i c a n ap h yl a c t i c ma n i fe s t at i o ns o f p at h o g en e si s . I n s en s i t i zed i n di vi d ua ls , i n t ra v e n ou s in j ec t io n o f a n a l le r ge n (e . g . , b ee v e no m ) o r a b so r p ti on ac r os s t he m u c ou s m em br a ne s ( e .g . , p e a nu ts ) c a n c a u s e s ys t em ic e d em a a nd h y po v o l em ic s h oc k , wi t h c a rd i ac a rr h y t hm ia , a s ph yxi a t i o n a s a re s u l t o f b ro nc h oc on st r ic t io n an d m uc o us h ype r s e cr e ti on , a n d u r t ic ar i a. D e at h u s ua l l y oc c u rs be ca u s e of as p h yxi a t i on . W hil e o t he r s e ns it i z e d i nd i v i du al s m a y h a v e on l y m il d l oc a l s ym p t om s u po n e n co u nt e ri n g t he al l e rg en , t he s e re s ul ts de m o ns tr a t e d i ff e r in g h os t r e s po ns es to id e nt ic a l p ro t e in s . 7 . T im e c o u rs e . I m m ed ia t e h y p e rs e ns it i v i t y re a ct i o ns h a ve t wo ph as es . Th e e a r l y r e a c t i o n, r es ul t in g f r om m e di a to r s e cr e ti o n b y m as t c el ls , b e gi ns wi t h i n 1 -2 m i n a ft e r a l le rg e n c on t ac t a n d p ea ks wi t h in 1- 2 h r . Th e l a t ep h a se r ea c t i on be gi n s 6- 1 2 hr a ft e r c on t ac t wi t h t h e a l le r ge n a n d l as ts for s e ve r al ho u rs . Th e l at e -p h as e re ac t io ns a re in i tia t e d b y ne wl y s yn t h es i ze d l e uk o t ri en es an d p r os t agl a nd i ns a l on g wi t h c y t ok in e s , ch em ok i ne s, an d o t h e r i nf la m m a to r y m e d ia t o rs . Th e l a te - ph as e rea c ti o n is ch a ra c te r i z ed by i n c re as ed nu m be rs o f e os i no p hi ls a n d i s m a i nt ai ne d b y th e p r od uc t s o f t h es e c el ls . 8 . D i ag n os i s . I n s c r a tc h t e s t s , a va ri e t y o f al le r ge n s a r e i nj ec t ed i n t ra d e rm al l y to s c r ee n fo r t he p re s e nc e o f a wh e a l an d f l ar e (i . e. , ed em a a n d e r yt h em a ) r es p on s e i n th e s k i n . R a d io a ll e r go s o r b en t ( R AS T ) a nd r a d i o im m un o so r b e n t ( RI S T ) as s a ys u s e r ad io l ab e le d re a ge n ts to de t ec t s e r um I g E c o nc en t ra t io ns . Th e re s u l ts o f th es e as s a ys do no t a l wa y s a g re e wi t h e ac h ot h er o r wi t h c l i ni c a l m an i fe s ta t io ns of t y p e I h y p e rs e ns it i vi t y. 9 . P r o ph yl a x i s a . I de n ti f y i ng an d a v o id in g al le r g en s is t he m os t i m po r t an t f o rm of p r o ph y l a xi s . b . H yp o s e n s i ti z at i o n ( de s e ns i t iz a ti o n ) is p er f o rm e d b y in j ec ti n g we e k l y, i n c re as in g d os e s o f a ll e rg e n i n t ra m u sc ul a rl y t o e li c it an al l er g en - s p ec i fi c I g G r es p on s e an d d ec r ea s e t he al l e rg en - s p ec i fi c I g E . On c e d es en si t i z at io n h a s b ee n a c h i e v ed , m on th l y i nj ec t io ns a re us ed to m a i nt a in th e Ig G le ve ls . I g G is ab l e t o b in d to th e a l le r ge n a n d i nh ib i t i ts bi n di n g t o t h e m a s t- c el l b o u nd Ig E . 1 0 . Th e r ap y a . C o mp e t it i ve H 1 - an t ago n is ts o f h is ta m i n e a r e us e fu l i n l oc a l f o rm s bu t do n o t c om pl e te l y r e v e rs e th e in f la m m at i on be ca us e h is t am in e i s n o t t he on ly i n f la m m at o r y m e di a to r in t h e r e ac ti o n. C om p et i ti v e H 1 - an t ag o ni s t s h a v e l i t tl e e f fe c t o n a na p h y la x i s . b . E p in e p h ri n e r e v e rs es a n ap h yl a xi s t h r ou g h i ts α - a g o ni s t an d β -a g on is t e f f ec ts . Pa t ie n ts wi t h s y s t em ic al le r gi e s a re gi v en e pi ne p h ri ne se l f a d m i ni s t ra ti o n k it s . β 2 - ag o ni s ts (e . g. , al bu t e ro l ) a r e ab le t o p ro m o t e b r o nc ho d il a ti on , an d α 1 -a g o ni s t s ( e .g . , p h en yl p rop a n ol am in e ) d ec r ea s e n a sa l c on g es ti o n.
c . C r om o l yn s o d i u m (c ro m og l y ca t e ) is a l oc al l y a d m i ni s te r ed in h ib i to r o f m as t c e ll de g ra n ul a ti on . G l u c o co r t i c oi d s a r e a ble t o b lo c k th e l a te ph as e o f t he re ac t io n b u t a r e l es s e f fe c ti v e du r in g t h e ea r l y p ha s e . An t i l e u k o t r ie n e t h e ra p ie s a re al so ab le t o b lo c k t h e l at e ph as e o f t h e r e a ct i on . d . T op i ca l s te r o id s i n hib i t i n fl am m a t io n a n d im m u ne r es po ns es . To pi c al a p pl ic a ti o n v i a s p ra y o r in h al e r l im i ts th e s id e e f fe c ts s e en wh e n g l uc oc o r ti c o id s a r e a dm in i s t e r ed s y s t em ic al l y. I n a d di t io n to us in g t o pi c a l s t e ro i ds a l on e , t he y a r e a l s o c om b in e d wi t h lo n g -a c ti n g β 2 - ag o ni st s a s t h e r ap y f o r as t hm a . e . An t i - I g E th e r ap y i s c o m po s e d o f a hi g h -a f fi n ity m o no cl o na l a n ti b od y t o t h e Fc re gi o n o f I g E . I t is ab l e t o b in d Ig E an d p re ve n t s e ns it i za ti on o f m as t c e ll s a nd ba s o p hi ls . Th is t h e ra p y is u s ef u l in hi g h l y a t op ic in d i v id ua ls a nd i s u se d fo r i n di v i d ua ls wi t h s e v e r e a st hm a fo r wh o m o t he r th e r ap ie s h a v e p r o ve n i ne f f ec ti v e . B . N o n - I gE - m ed i a te d t yp e I h yp e r s e n s i t i vi t y r e a c t i on s a r e p r ob a bl y t h e r e s ul t o f s e v e ra l p o o rl y un d e rs t oo d c au se s a nd a re s o m e t im es c a ll ed a n a ph yl a c t o i d r ea c t io ns . Th e fo ll o wi n g fa c t o rs m a y c o n t ri bu t e t o a n d e xa c e r b a te no n - Ig E -m e di a t ed t ype I re ac t io ns . 1 . R es pi r a to r y β 2 - r ec ep to r u nr es p on s i v e n es s , wh i c h l ea ds to a d im in i s h ed b r o nc ho d il a to r y e ff e c t of t h e s y m p a th e ti c n e r v ous s ys t em . 2 . H yp e r re ac t i v it y o f m as t c el ls th r ou g h H 2 - r ec ep to r u nr es p on s i v e n es s . Thi s d e c re as es th e n e ga t i v e fe e d ba c k o f hi s t am i ne on t h e a c t i v a ti o n o f m a s t c e ll s. P.206
C . T yp e I I h yp e r s e n s i t ivi t y r e a c t i o ns 1 . P a th o ge n es i s . A n ti b od y - m e di a te d c y t o to xi c i t y o cc u rs t hr o ug h t h e p r o du c ti on o f I g M a n d I gG . Th e s e a n ti bo d ie s a r e a b le t o b in d t o s pe ci f ic a l le r g en s l oc at e d o n c e l l s u rf a c e s . a . Th e s e al le r g en s m a y b e in t ri n s i c t o t he ce ll ( i.e . , na t ur a l ce l l -s ur f ac e c om p on e nt s ) o r e xt r i n s ic c om po u nd s ( i .e . , d r ug s ) a ds o r be d t o th e c el l s u r fa ce . b . C yt o t o xi c it y m a y r e s u lt f r om ac ti v a t io n o f c om pl e m e n t, ph a go c y t os is o f t h e Ig G op s o n i z ed c e ll , or b o th . c . A t h ir d c y t o to xi c m ec ha n is m , k n o wn as an t ib o dy- d e p en d en t , c el l m e di a te d c y t o to xi c i t y , inv o l v e s th e d i re c t k i ll i ng o f an t ib o d y -c o at e d ce l ls b y N K c el ls , m ac r o ph ag es , o r e os in op h il s . d . Typ e I I re ac t io ns m a y e xh i b i t an a ph y l ac t ic s ig ns an d s ym pt om s i f e n ou gh c om p le m e n t is ac t i v at e d; h o we v e r , t he y us u al l y do n ot p ro g re ss to t hi s s t ag e . 2 . C o mm o n a l le r g en s . Ty p e I I a ll e r ge ns a re di ver s e . I t i s t h e p at h og en ic m ec h an is m t h at is c om m o n to al l t h e r e ac ti o ns .
a . F or e ig n b lo o d s ur f ac e a n ti g en s m a y a c t as al ler g e ns to p ro d uc e t r a n s f us i on m is ma t c hes o r Rh d is e as e . b . D r ug al l e rg en s (o r d r ug m e t ab o li t e a ll e rg e ns ) ac t i n g a s h ap t en s a r e t h e l e a d in g c a us e o f he m o lyt i c a n e m i a. ( 1 ) Th e s e al le r g en s m a y d i r ec tl y a ds o r b t o c e l l s ur f a c e s a nd be sp ec i fi c a lly b o u nd b y a n ti b od ie s ( e . g. , p en ic il li n s , c e ph a lo s p or i n s , qu i ni di n e) . ( 2 ) A lt e r na t el y , t he y m a y f o rm s e r um - ph as e i m m un e c om p le xe s , wh i c h a d so r b n on s pe c i f ic al l y to b l oo d c el l s u rf ac es . Th is m a ke s t he c e ll s us c ep ti b le to l y s i s o wi ng t o t h e “ in n oc en t b ys t and e r ” e f f ec t ( e .g . , ri f am pin , s u lf o na m i d es , c hl o rp r om a z i n e ) . c . S el f - an t i ge n s a r e t he a l le r g en in c e r ta in a ut oim m u n e d is ea se s ( e .g . m ya s th e ni a g r a v is , a u to im m u n e h em ol y t ic a ne m ia ; se e I I I ) A u to im m u n e h e m o l yt ic a n em ia is s om e t im es as s o ci a te d wi t h ad m in is t r at io n of α m e th y l d op a , wh i c h i nd uc e s a u to a nt i bo d ie s a ga in s t t h e r ed bl o od c e ll s u r fa ce . d . H yp e r a c u t e re j ec t i o n o f t ra ns pl a nt e d t is s u e (se e V ) 3 . C h em i ca l m e di a t o rs . C o m pl em e nt p ro t ei ns p ro d uc e c y t o to xi c i t y a nd i n f la m m at i on , wh ic h s t im u l a te ma c r op h a ge s a n d g r a n u lo c yt e s t o s ec r e te c yt o ki ne s a n d e n z y m e s , wh i c h in tu r n e n ha nc e i nf l am m a t io n . 4 . C l in i ca l s ym p t o m s de p e nd on th e t y p e of an ti g en o r a ll e rg e n i n vol v e d ( s e e I I . D. 2 ) . H e m o l y t ic an e m i a a n d t h ro m b oc yt o pe n ia a re t he m a jo r c li n ica l s i gn s o f t y p e II h y pe r s e ns i ti v i t y r ea c ti on s . I n h ype r a cu t e g r af t re j ec ti o n, th e t r a ns p la n te d t is s u e d o es n o t s ucc es s fu ll y p e r fu s e b ec a us e o f a n ti b od y m e di a te d c y t o to xi c i t y t o t h e tr a ns pl a nt e d v a sc ul at u r e . 5 . T im e c o u rs e a . I n t he fi r s t s e ns i ti z a t io n to a d r ug al l er g en , the b lo od c e ll l y s i s a nd i n f la m m at i on be gi n 7 - 1 0 d a y s a f t e r in i ti a ti o n o f d ru g th e r ap y. Th e s ec o nd e xp o s u r e t o th e d r ug c a us es s ym p to m s wi t h in 3 da y s . b . T r an s f us i o n m is m at ch . H em o l ys is be g in s 1 - 2 h r a ft e r t r a ns fu si o n. P eak e f f ec ts oc c u r af t e r a pp r oxi m a t e l y 12 h r. +
c . R h d i se a se do es no t o c c u r i n t h e f i rs t Rh D p re g n an c y o f an R h D
-
m o th e r . Ma t e r n a l I g G i s p r o du c e d i n th e s ec on d a n d s ub s e q ue n t +
p r e gn a nc ie s a f te r t ra ns pla c en t al m a te r n al s e ns it i za t i on to t he R h D f e ta l r e d bl oo d c el ls . Th is s e ns i ti z a t io n u s u a ll y t ak es pl a ce in th e th i rd t ri m e s t er . Ma t e r n a l an t i- R h D Ig G c r o s s es t he pl ac en t a , b ind s to th e f e t al re d b l oo d c e ll s, an d a c ti v a t es th e fe t a l c o m p l em en t s y s te m p r e na t al l y, wh i c h le ad s to p e r in a ta l h em o l y ti c a nem i a. 6 . P r o ph yl a x i s a nd t he ra p y. I n d r ug - i nd uc ed h yp e r s e ns i ti v i t y r ea c t i on s, wi t h d r a wi n g th e d r ug us u a ll y r e ve rs e s t he l ys is . P r e ve n ti n g r ec o nt a ct is th e b e st p ro p h y la xi s . I n R h di s ea s e , a n ti - R h D i s a dm in i s t e r ed du r in g p r eg n an c y +
a n d wi t hi n 7 2 h r po s t p a rtu m fo r e a c h R h p r eg n anc y. Th e s i m p le s t e xp l a n a ti o n f o r t h e e ff ic ac y o f a n ti - R h D i s t h at th is pa s s i v e i m m un i z a ti o n ( s e e V I . B. 2 . d) bi n ds to fe t a l r e d bl o od ce ll s i n t he m a t e rn a l c i r c u la t io n a nd p r e ve n ts s en s i t i z a ti on o f t h e m at e rn a l im m u n e s ys t em .
D . T yp e I I I h yp e r s e n s i t ivi t y r e a c t i o ns in vo l ve the p e rs is te nc e o f im m u ne c om p le xe s i n t h e c i r c u la ti o n o r at lo c a l t is su e s i tes wh e n th e y a re no t r e m o ved af t e r p r od uc t ion o f s pe c i f ic a n ti b od ie s a n d a n ti g en - an t ib o d y c om p le xe s . Th e s u bt y p es o f t y p e I I I h y p e rs en s i t iv i t y r e a ct io n s h a ve d i v e rs e c a us es , a n d o nl y t he pa th o g en ic m ec h an is m is co m m o n t o t h em a l l. P.207
1 . P a th o ge n es i s . Im m une c o m p l e xe s ac ti v a t e c om p le m e n t, ca us e i n f la m m at i on , a n d i nd uc e p os it i v e c he m ot a xi s in n e u t ro ph i ls . P e rs is t en ce o f i m m u ne c om p le xe s m a y b e c a us ed b y th e f o ll o wi n g : a . A hi g h c o nc e n t ra t i on o f a nt i g en o r a n t ib o d y, wh i c h l e ad s t o a di s p a rit y i n th e m ol a r ra ti o of an t ig e n t o a n ti b od y a nd t he p r o du c ti on o f sm al l i m m u n e c om p le xe s . b . C h r o ni c fo r m a ti o n o f i m mu n e c o mp l ex e s i n th e c i rc u la t io n a s a re s u l t o f p e rs i s te n ce o f a n ti ge n as wi t h s om e c h ro ni c i n f ec ti o ns . c . O t he r fa c t o rs t ha t c aus e i ns o lu bl e i m m u ne c om p le xe s t o f o rm an d p r e ci pi t a te i n t ra v a s c ul a r ly o r o n b as em en t m em b ra n e s . 2 . C o mm o n a l le r g en s a . S el f - a n ti g en s in mo st n o n -o r g a n -s p ec i f ic ( rhe u m a t ol o gi c ) a ut o i mm un e d i s o r de r s (e . g. , s y s t em ic lu p us e r yt h em a to su s , rh e um a to i d a r th r it is ) b . B a ct e r i al o r p r o t oz oa n an t i g en s i n pe r s is t en t o r ch r o n ic i nf e c ti o ns a n d i n t h e i ni t ia l s ta g es o f v i r em ia fo r c e r ta i n v i ra l in f ec ti o ns (e . g. , p r o d ro m e of h ep a ti ti s B v i r u s i n fe c t i on ) . c . D r u gs ( e. g ., pe n ic il li n, s ul f on am id es , th i ou r ac il ) . d . An t i s e r a f r om an o th er s pe c i es ( e. g . , h or s e) , c a n c a us e s er um s i ck ne ss wh e n u s e d fo r p a s s i v e im m u n i z at i on . e . F un g al a nd ba c t e ri a l s p o r es in th e l oc a l r es pi r a to r y f o rm of t he re ac t io n 3 . C h em i ca l m e di a t o rs . C o m p l em e nt p r o te i ns c a u s e in f la m m at i on an d s t i m ul a t e m as t c e l l a nd b a so p h il se c r e t io n s, wh i ch en h an c e i n f la m m at i on . Th e i nc r eas e d v a sc u la r p e rm e ab il i ty a l l o ws i m m un e c om p le xe s t o l e a v e t he c i r c ul at i on an d a t t ac h t o ba s em en t m em b ra n es , wh i c h un d e rl a y th e e n dot h e li al li n in g o f b l oo d v es s e ls . Th e k id n e y g l om e ru l us a n d s m al l a r te r i es ar e p a r ti c u l ar l y s u sc e pt i bl e . C om p le m e n t a nd m as t c e ll pr o te i ns a t t r ac t n e ut r o ph il s ; t he s e c e ll s c a n p ha g oc yt i z e i m m un e c om p le xe s a nd r el e as e en z y m e s t h at da m a g e l oc a l ti s s ue , th us in t en si f yin g i n f la m m at i on . I n a d di t io n, p la t el e t a gg r e ga ti o n a nd m i c ro t h ro m b us fo r m a t io n m a y oc c u r . 4 . C l in i ca l s ym p t o m s de p e nd on th e s e ve ri t y and s y s t em ic o r l oc al na t u re o f im m u ne c o m p le x d e p os i ti o n a nd pe r s i s t e nc e. a . Th e fi r s t s y m p to m s of s y s t em ic re ac t io ns a re l ym p ha d en op a th y , s p le n om eg al y , f e v e r, and r as h . Th e s e a re c o m m o n in d ru g -i n du ce d a nd vi r e m ia - in d uc ed t y pe I II h y p e r s e ns i ti v i t y r ea c t i ons . b . Mo r e s e ri ou s s y m p t om s i nc lu d e va s c u li ti s a nd g lo m e r ul o ne p hr i ti s , b oth o f wh i c h m a y b ec om e n ec ro t i z i ng . Th es e s y m p t om s o f t en oc c u r wi t h s y st e m ic
l u pu s e r y t h em at os u s ( S LE ) . A r t hr a lg i a a nd ar t h ri ti s o cc u r i n b ot h s y s t em ic a n d l oc al r ea c ti on s . c . Th e m os t c om m o n t y pe s o f lo c a l t yp e II I h y p e rs e ns it i v i t y re a ct io n s a re p n e um on i ti s f r om i n ha led f un g i a nd ba c t e r ia to wh i c h th e p a ti e nt is o cc u pa t io n al l y e xp o s e d (e . g . , m o l d y h a y in f a rm er ' s l un g ) a n d r e ac ti o ns to s p o re s b o rn e i n a e ro s o l m ic r o dr o pl e ts f ro m d ir t y u l t ra s on ic hu m i di f ie r s ( e . g ., h um i d if i e r l u n g) . Th e c au se o f t he s e di s ea s es i s n o t c o m p l et e l y u n d er s to od , bu t b o th I g E a n d I g G a r e i n v o l v ed . IgE c au s e s t h e i ni t ia l i n f la m m at i on an d t r a pp ing o f a n ti ge n , a nd I g G i s r e s po ns ib l e f o r t he lo n g t e r m e f fe c t s . S y m pt om s in c lu d e ( 1 ) N as a l c o n ge s t i on and b r on c h oc o ns t ri c t i on ( 2 ) Jo in t pa in an d i n fl am m a ti o n o f r h eu m a t oi d a r th r i ti s c au s e d b y j oi n t l o ca li ze d i m m u ne c om p le xe s i n vo l vin g rh e um at o id f ac t or an d ne u tr o ph il p h a go c y to s i s ( s ee C ha p te r 4 9) 5 . T im e c o u rs e a . S ys t e m i c . I n p a ti en t s wi t h n o p r i or e xp o s ur e to t h e a ll e rg e n , t he s ym p to m s a p pe a r i n 1 - 2 we e k s (p o s s ib l y l o ng e r ) a f t e r e xp o s u re . In pa t ie nt s wi t h p r e e xi s ti n g a nt i bo die s , s y m p t om s a pp e ar wi t h i n s e ve ra l h ou r s t o 1 day a f t e r e xp o s u re . Se v e r e s y m p t om s , s u ch as g l om er u l on e ph r it is , us ua ll y r e q ui r e 2 we e k s o r m o r e t o ap p ea r . b . L oc a l. I n p at i en ts wi t h p r ee xi s t i ng an t ib od i es , h y p e rs e ns it i vi t y p n e um on i ti s s y m p t om s ap p e ar 6 -8 h r a f te r e xp o s u r e to th e a n ti g en . 6 . P r o ph yl a x i s a nd t he ra p y. I n d r ug - i nd uc ed r eac t io ns , w i t hd r aw i n g t h e d r u g us ua l l y re v e r s e s t he r e ac ti o n. Tr e a tm en t i nc l ud es an t ih is t am in es o r c o r ti co s te r oi ds . Tr a ns ie nt i nf e c t io u s f o rm s r es ol v e sp o nt a ne o us l y a s i m m u ne c om p le xe s a r e re m o v ed b y ph ag oc y t e s. E . T yp e I V h yp e r s e n s i t ivi t y r e a c t i o ns 1 . P a th o ge n es i s . Ty p e IV r e ac t io ns in cl u de pr o lon g e d in a pp r o pr i at e a n d a p p ro p r ia t e im m u n e r es po n s e s m ed ia t ed b y an t ige n - s p ec i fi c T H 1 c el ls i n c o nc e rt wi t h ac ti v a t ed m a c r op ha g es . P.208
Th e T H 1 c e ll s i nf il t r at e tis s u e s in wh i c h t he an t ige n is p r es e nt e d a nd r ec ru i t a n d a ct i v a te m a c ro ph a ge s . Th e r el e as e o f e n z ym es an d c yt o k i ne s b y t he s e c e ll s r es u lt s i n i nf l am m a ti o n a nd di s ru p ti o n o f t is s u e s t r uc t ur e i n th e a b se nc e o f an ti b od y . a . R ea c t i on s to in f e c ti on s in v o l ve a T H 1 r es p ons e a g ai ns t s p ec if ic i n t ra c el lu l ar ba c te r ia l (e .g . , My c ob ac t e ri a ) a nd p ro t o z o an pa r as i te s . W hen t h e re sp o ns e is p ro l on ged a nd in e ff ec t i v e , g r an ulo m a f o rm at i on wi l l o c c u r. b . C o n ta c t d e r ma t i t is is a n i n ap p ro p r ia t e s k in r ea c ti o n t o h ap t en s (e . g. , p e n ta d ec ac at ec h ol s o f po i s o n i v y) , wh i c h b in d to e p id e rm a l c e l l su r f ac es a n d e li c i t a C TL a nd T H 1 c el l re sp o ns e. c . Tu b e r cu l in r e ac t i on is ob s e r ve d i n th e d e rm is a n d is an ap p r op r ia t e r e a ct i on to m y c o ba c t e ri al a nt i ge ns . Th is re ac t io n i n di c a t es a s ta t e o f a c t i ve T H 1 i m m u ni t y ( o wi n g t o an ac t i v e i n fe c t i on ) o r T c e l l m em o r y t o th e
o r g an is m . ( I n p at i en ts wh o ha d a po s i t i ve t ub e rcu l i n r ea c ti on , a s u bs e que n t n e g at i ve re ac t io n wo u ld in d ic a te im m u no l og ic an er g y o r un r es po n si ve ne s s . ) 2 . C o mm o n a n ti g e ns a . I n fe c ti o u s a ge n t s i nc l u de My c o ba c te r iu m t ub er c u lo si s, M. l e p ra e , L i st e ri a m o no c y to g en es , t r yp a no so m e s , a nd v i r us es . b . H a p te n a l le r g e ns , s uc h a s p e nt a de c a ca t ec ho ls f ro m p oi s on i vy , p o is on o a k, ch r om a te s , ni c k el ion s (l e ac he d f r om wa t c h b a c k s a nd ot h er je we l r y ) , a c r yl at es , ha i r d y es t ha t c o nt a in p -p he n y l en e d i am i ne , p a r a- am i no b en zo ic a c id , a n d c e r t ai n a n ti b io ti c o i nt m e n ts (e . g ., t op ic al n eo m yc i n ), m a y i nd uc e c o n t ac t de r m a ti t i s. c . A nt ig e ns th a t i nd uc e a t u be r c u l in re ac t io n i nc l ud e pu r i fi ed p ro t ei n d e r i v a ti v e ( P P D ), t ub e rc u l in ( Ma n t o u x r e a c t io n ) , C a n d id a , m u m p s , a nd oth e r a n t ig en s f r om m i c r o o rg an i s m s . 3 . C h em i ca l m e di a t o rs a r e i m po r ta n t i n t yp e I V r e a c t i on s . Th e s e m e di a to r s a r e c yt o k i ne s p r od uc e d b y a c ti v a t ed T H 1 c e ll s . Th e c y t o ki n es a t t ra c t a nd a c ti va t e m ac r op ha g es to t h e s it e (s ) wh e r e t h e p at h o ge n /a ll e r ge n i s l oc at ed . I n t ur n , t h e ac t i v a te d m ac r o ph ag e s s e c re t e c y t ok in e s , wh i c h a re r es po ns i bl e f o r in f la m m at i on an d c y to t o xi c i t y (e . g ., TN F - α ) . 4 . C l in i ca l s ym p t o m s de p e nd on th e s ub t y p e o f r e a ct i on . a . G r a nu lo m a s a r e l oc al a g g re g at i on s o f T H 1 c el ls , m ac r o ph ag es , an d g ian t e p i th el i oi d c el ls ( de r i v ed f r om f us io n o f a c ti va t ed m ac r o ph a ge s ) . Th e y oc cu r a t si t es o f c h ro n ic i n fe c tio n an d s e r v e t o r e s t r ic t th e s p r ea d o f th e i n fe c t i on . b . I n co n ta c t s e ns i ti v i t y , c e ll ul a r i n fi l tr a ti o n o f t h e e p id e rm is b y C TL , T H 1 c e ll s, an d m ac r op h ag es p r o du c e s m ic r o ves ic le for m a ti o n wi t h sp on g io s i s . c . Tu b er c ul in te s ts c au s e e r y t he m a an d i n du r a ti on as a r e su lt o f ce l lu la r i n f il t ra t io n o f th e d e rm is , b u t n o e pi d e rm al s p on gi o s is i s o bs e r v ed . 5 . T im e c o u rs e a . G r a nu lo m a s f o rm at v a r i ou s t im es af t e r t h e o ns e t o f a c h r on ic im m u ne r e s po ns e b u t g en e ra l l y re q ui r e a m i ni m u m o f 2 we e ks . b . C o nt ac t s e ns it i v i t y m ay n o t occ u r wi t h t h e f i rs t t r a ns i en t e xp o s u r e. H o we ve r , i n a s e ns i ti z e d i n di v i du a l, sk in in f la m m a t i on wi l l a pp e a r 1 2 -2 4 hr a f t e r co n ta c t wi t h t he an ti g en an d pe ak s b et we e n 4 8 an d 7 2 h r af t e r e xp o s u r e . c . Tu b er c ul in r ea c t i on s fo l lo w t h e s am e ti m e c o u rs e a s c on t ac t s en s i t i vit y . Th i s r ea c t i on is o f t en c a ll e d d e la ye d c u t a ne o us h yp e r s e n s i t i vi t y, o r d e la ye d - t y pe h y p er s en s it i v i t y . 6 . P r o ph yl a x i s a nd t he ra p y. Tr e a t m e n t o f g r an ulo m as d e pe n ds o n th e o r g an is m i n v ol v e d . Pr o pe r t r ea tm e nt t o r es ol ve th e in f ec ti o n wi l l al so ai d i n r e s ol vi ng t he c h r on ic i m m u ne r es po ns e . F o r c on ta c t s en s i t i vit y , i t is n e ce ss a r y to id en t i f y t h e a n ti g en / al le r g en in v o l v ed . R em o va l a nd a v oi da nc e o f t he al le r g en i s i m p o r ta n t fo r p r o ph y l a xi s . Fo r tr e a tm e nt , to pi ca l c o r ti co s te r oi ds s u pp r es s T c e ll an d m ac r op h ag e fu n c t i on . In s e v e r e c a se s , o r a l c or t ic os t e ro id t he r ap y m a y be r eq ui r e d.
III. Autoimmunity
i s a ti ss u e- d am ag i ng im m u ne r es po ns e d i re c te d s p ec i f ic a ll y a nd i n ap p r op r ia t el y a ga i ns t on e o r m o r e s el f - an ti g en s . A. Th e o r i g i n of au t o re ac t i v e i m m un e r e s p on s e s i s n o t g en e r al l y k n o wn , bu t i t r eq ui r es lo s s of s e l f- t ol e r an c e an d d e r eg ul a ti o n o f th e c on t r ol ne t wo r ks t h a t n o rm al l y p re v e n t d ev e l o pm e nt of au t oi m m u ne d is ea s e . Su c h d e r eg u la t io n m a y i nc l ude l ac k o f r eg u la t io n o f T H a n d T C c e ll s , P.209
c r os s - re ac t i v it y wi t h a nt ig e ns f ro m m i c ro o r ga ni s m s , l os s o f se l f -t o le r an ce o r f a i lu r e t o d e v e lo p t ol e r an c e, an d a b e r ra n t p re s en t a ti o n o f s el f -a n ti g en on s p ec if ic H L A m ol ec ul e s . B . E p i de m io l o g y 1 . F am i li a l c l us t e r in g i s e v i d en t fo r m an y , i f n o t m os t , a u to im m u n e r e a ct i on s r e pr es e nt i ng a c om p le x i n h e ri t ed p re d is p o si t io n t o wa r d a u t oi m m un i t y . I n m os t c a s es , t h is p r e di s p os i ti on i s a s s oc ia t ed wi t h s p ec if i c MH C t yp e s , u s u a ll y c l as s I I m o l ec ul es ( e. g . , r heu m at o id a rt h ri t is wi t h t h e MH C c l as s I I m ol ec u le HL A - D R 4 ) . 2 . Th e se re a c t io n s a re m o r e c om m o n i n wo m e n . Th e fe m a l e -t o -m al e ra t io in m ya s th e ni a g r a v is i s a ppr o xi m a t e l y 2 : 1 a nd in S LE i s a pp r o xi m a te l y 10 : 1. I n c o nt r as t , Sj ög r e n 's di s e as e a n d G o o dp as t u re s y nd r o m e ar e m o re c o m m on i n m e n t ha n i n wo m en . C . P a t h og e ne s is 1 . O ve r vi ew .
In a specific autoimmune disorder, the primary pathogenic
mechanism may be humoral (mediated by antibodies with or without a contribution by complement), T cell mediated, or involve both humoral and cell-mediated components. These diseases are commonly associated with exacerbation and remission of the disease. 2 . E n vi r o nm e n ta l fa c t o rs a r e t ho u gh t t o c o nt r ib ut e t o p at h og en e s i s . H o we ve r , s p ec if ic as s o c ia t i on s h a v e b ee n fo un d in o nl y a fe w c as e s; th es e i n cl ud e S tr e pt o c o c c us g ro u p A p ha r y n gi t is , rh eum a ti c f e ve r , e xp o s u re to o r g an ic s o l v en t s , G o od pa s tu r e s y n d ro m e , ul t ra v io l e t i r ra d ia t io n , a nd S LE. I t i s l ik e l y t h a t e n v ir o nm ent a l f a c t o rs ac t i n c on ce r t wi t h g en e ti c p r e di sp os i ti o n t o i nd uc e d i s e as e . 3 . O r g a n -s pe c i f ic an d sys t e m i c ( n o n -o r g an - s pe c i f ic ) di s o r de r s a . O r g a n -s pe c i f ic di s o rd e r s (e . g ., an t it h yr o id au t o im m u ni t y ) a re li m i t ed t o a n d d i re c te d s pe c i f ic al l y a g ai n s t s e lf - a nt i ge n i n a s i ng le o rg a n. Le si o ns a nd c l in ic al s ym p to m s a re lim i te d p r im a ri l y t o t ha t o rg a n . C e ll ul a r d am a ge m ay b e m e di a te d t h r ou gh an t ib o d y- m e di a te d a n d c om pl e m e n t -m ed ia t ed c yt o t o xi c it y ( t y p e I I h y per s e ns it i v i t y ) a n d/ o r t h r oug h c e ll - m e di a te d c yt o t o xi c it y ( t y p e I V h y pe r s en s i t i v it y) . b . S ys t e m i c d i s o rd e r s (e . g . , S L E ) ( 1 ) Th e s e di s o r de r s a r e a l s o k n o wn as c o nn ec t i ve t is su e , co l la ge n vas c u la r , o r r he um a to l og ic di s o r d er s . Au t oa n ti b od ie s a r e f or m e d a ga in s t a nt i ge ns
f o u nd in m os t or al l ti s s ue s , e s p ec i al l y th os e l oc at e d i n t h e n uc le i o f c e ll s a n d c on t ai n in g D N A, R NA , o r n uc l ea r - as so c i a te d p r o te i ns (a n t in u cl e a r a n t i bo d i es ) . Pa t ho lo g ic c h an g es o c c u r s y s te m a t ic a ll y , p ri m a r i l y i n t he c o nn ec t i v e t is s u e a n d a re a t l ea s t p ar t ia l l y c au s ed b y t y p e I I I h yp e r se ns i ti v i t y r ea c t i ons . S y m p t om s m a y b e s een i n t he bl o od v es s el s , k i dn e y gl om e ru l i, s k in , j oi n ts , an d s er o us m em b r an e s . ( 2 ) N o n- o r ga n -s pe c i f ic dis o r de r s a re so m e t im es di f f ic ul t to di st i ng ui s h f rom o n e a n ot h er be c au s e of th e s im i la r it i es i n a u to a nti g en s a n d p at h og en e s i s . F o r e xa m pl e , m o s t p at i en t s wi t h S L E h a v e c i rc ula t i ng an t in uc le a r a n t ib od i es ; h o we v e r , th es e a ls o o c c u r i n 5 0 -6 5 % o f pa t ie n ts wi t h Sj ö gr e n 's s yn d r om e a nd r he um a to id a r th r i ti s as we l l a s i n a s m a ll pe r c e n ta g e o f c l in ic al l y no r m a l i n di v i dua l s . B y co n t ra s t , rh e um at o i d f ac t or ( an t i -I g G ) i s s e en in 75 - 90 % o f pa t ie nt s wi t h rh e um at o id ar t h rit i s o r Sj ö gr e n 's s ynd r om e a s we l l as in 35 % o f pa t ie n ts wi t h S L E. Th e s y n ov i t i s o f rh eu m a t oi d a r t h rit i s i s o f t en a c l i ni c a l f in d in g i n SL E , a n d t he v a sc ul i ti s o f SL E is fo u nd in r h e um a to id a rt h r it is (s e e C h a pt e r 4 9 ) . D . O r g a n - sp e ci f i c a u to im m u ni t i es 1 . R h eu m at i c f e ve r is no t t ec hn ic al l y an au t oi m m u ne r es po ns e b ec a us e a n t ib od i es ar e p r o du c e d a g ai n s t g ro up A s t r ep t oco c c i a n d c ro ss - r ea c t wi t h c a r di ac m us c l e fi be r s t ha t a re da m a g ed b y c om pl e m e n t. I nc re a se d r is k i s r e l at e d t o a s t r on g i m m un e r es po ns e t o s t r ep t oc oc c a l M a n t ig en . 2 . An t i t h yr o i d a u t o im mu n i t i es (s ee C h ap t er 5 2). A s pe c t s o f s e v e ra l s u bt yp e s m a y o c c ur in t he s a m e pa t ie n t . I nc r ea s ed r is k is as so c i a te d wi t h MH C c l as s I I t y pe s D R 3 a n d D R5 . a . P r i ma r y a u t o i m mu n e m yx e d e m a . A n ti b od ie s a g ai n s t th e th yr o id s t im ul a ti n g h o rm on e ( TS H ) r e c e p to r on th y r o i d f ol l i c le ce ll s a c t as a n t ag o ni s t s t o t h e s ti m u la t i on of g ro wt h o f t h e f oll i c l e c el ls no rm a ll y p r o vo k e d b y TS H . Th e r es u lt is th yr o id a tr o ph y wi t h h y po t h y r oi d is m . P.210
b . H a sh i mo t o 's t h yr o i d i t i s . An t ib o di es ag ai n s t th yr o i d p e ro xi d a s e o n f o l li cl e c el ls c a us e c y t oto xi c i t y a nd in f la m m a ti on t h r o ug h t h e ac t i v a ti on o f c om p le m e n t. A n ti bo d ie s a g ai n s t th y r o g lo bu l in (c ol l o i d ) a ls o m a y be pr es en t . C e l l -m ed i at e d im m u n it y m a y c a us e s om e c y t o to x i c d am a ge . Th e r e su lt i ng h yp o t h yr oi di s m is tr e at ed wi t h s ynt h et ic t h y r oi d h o r m o ne . c . G r a ve ' s d is e as e . A n tib o di e s ac t a s a g on is ts of TS H , b i n di ng to t he TS H r e c ep t or a nd s t im ul a ti ng h y p e r s e c re t io n o f t h y r o id h o rm o ne ( th y r o id s t im ul a ti n g im m u n og lo b ul i ns ) . Th e r es u lt is h yp e rt h y r o i di sm , wh i c h i s t r e a te d b y a n ti th y r o i d d ru g s ( e .g . , p r op y l t hi o u ra c i l ) o r th yr o i d a bl a ti on wi t h s u r ge r y o r r a di a ti o n. 3 . M ya s t h e n i a g r a vi s a . P a th o ge n es i s . A n ti b od i es ag ai n s t th e n ic o ti n ic a ce t y l c h ol i ne r ec ep t o r on s ke l et a l m u s c le pl a s m a m em b r an e a t n e u ro m u s cu l a r j u n c ti on s a ct as c om p et i ti v e an t ag o ni s t s o f ac e t yl c h o l i n e bi n di ng. Th i s a c t i v i t y c a us es
we a k n es s a n d f at i gu e i n s k e l et a l m u s c le s . I n a dd it i o n t o t hi s d i re c t b l oc ka g e o f n eu r om us c u la r t r an sm is s i on , d o wn r eg u la t io n o f r ec ep t or s a nd c om p le m e n t d am ag e to m us c l e fi be r s o c c u r. Ma n y p a ti e nt s h a v e s wa l l o wi n g a n d re sp i ra t o r y m us c l e dy s f u nc t io n t h at m a y b e ca u s e d b y p en ic i ll am in e t h e r ap y. In c re as e d r is k is as s o c i a te d wi t h MH C c l a s s I t yp e B 8 . b . T he r a p y. A n t i c h ol in es t e r as e t h e ra p y ( e. g ., n eos t ig m i n e ) in c re as e s a c et yl ch o li n e s y na p ti c c o n c e n t ra t io ns ( pr es e r va tio n of en d og e no us a c et yl ch o li n e) . Im m u no s u p p re s s io n wi t h c o rt ic os te r o id s i s us e d i n s e v e r e c as e s; pl as m a p he r es is to r em o ve a u to r e ac ti v e an t i bo di es f r om t h e b lo o d i s a l so he lp f ul . Th y m ec t om y h e l ps m an y p a ti e nt s. 4 . Au t o i m mu n e p e r ni c io u s a n em i a a . P a th o ge n es i s . A n ti b od i es ag ai n s t in t r in s i c f ac t o r a re s ec r e te d i n to th e s t om ac h l um e n, wh e r e t he y i n hi bi t th e a s s oc ia t io n o f i n t ri ns ic f ac to r wi t h vi t a m i n B 1 2 . Th us th e a bs o r pt i on of v i ta m i n B 1 2 is d ec r e as ed . Th is c o nd i tio n a l so c a n r es u lt f ro m a n tib o di e s a ga in s t g as t ri n rec e pt o rs on pa r i et al ce ll s o f t h e s t om ac h m u c o s a t ha t b l oc k st im u la t io n o f t h e c e ll s b y ga s t ri n a nd d e c re as e t h ei r s ec r e ti on o f in t r in s i c f ac t or . b . T he r a p y i s i n t ra m u s c u l a r i nj ec t io n o f c ya n oc ob a la m i n o r o ra l a d m i ni s t ra ti o n o f c on c e nt r a t ed in t r in si c f ac t or p rep a r a ti on s . 5 . G o o dp a st u r e 's s yn d r o m e a . P a th o ge n es i s . A n ti b od i es ag ai n s t g lo m e ru l a r c a p i ll a r y b a s e m e n t m e m b ra n e ( G B M ) a c ti v at e c o m p le m e n t a n d n eu t ro p hi l -m e di a te d d am a ge . Th i s ac t i v at i on l e ad s t o g l om e ru l on e ph r it is , wi t h r a p id de t e ri o ra t io n o f re na l f u nc t io n . Th es e a nt i bo die s c r os s - r e ac t wi t h p ul m o n a r y c a pi ll a r y ba se m e nt m em b r an e , p r od uc in g p ul m on a r y he m o r r ha g e i n s m ok e rs . In c re as e d r is k is a ss o ci at e d wi t h MH C c l as s I I t y pe D R 2 . b . T he r a p y. I m m u no s u pp r e s s i v e t he r a p y i nc l ud es co r ti c os te r oi ds , wi t h p l as m a p he r es is to r em o ve a ut o r ea ct i v e a n ti b od ies . 6 . Au t o i m mu n e h em o l yt i c a ne m ia ( r ed b lo o d c el l ) , t h ro m bo c yt o p e n i a ( p l a t el e t ), n eu t r o pe n i a ( n e u t r op h i l ), an d l ym p h o p e n ia ( l ym p h o c yt e ) a . P a th o ge n es i s . A n ti b od i es ag ai n s t m em b r an e a n t ig en s o f o n e o r m o re o f t h e i n di c a t ed c e ll t y pe s m a y ac t i v at e c om pl em e nt a nd op so n i ze t h e c e ll s f o r r a p id sp le n ic p h ag oc y t o s i s . I t m a y al s o oc c u r a s p a r t o f th e s pe c t r um o f a u t oi m m un i t y i n n o n -o r ga n - s p ec i fi c d is o rd e rs , p ar t i c u la r l y S L E. Th e s e a u t oi m m un e v a ri e ti es m us t be di s t i ng ui s h e d f r om t h os e p r ec i pi t at e d b y r e s po ns es to e xt e r n al ant i g en s ( e .g . , d r ug s ) b ut th e c l in ic al e ff ec t s a re s im i la r . b . T he r a p y. Th e s e d is o rd e r s a re o ft e n ac u te an d s el f - li m i t in g , b ut th e r apy i s re q ui r ed wh e n th e y are c h r o ni c. In a du lt s , t r eat m en t be gi ns wi t h c o r ti co s te r oi ds . Ad d it i ona l op t io ns a re c y c lo p ho s p h am i de , c hl o ra m b u ci l, a n d i n t ra ve n ou s i m m un e g lo bu l in ( I V I G ). 7 . I ns u l in - d ep e nd e n t d ia b e t es me l li t u s ( I D D M; s e e C h ap t e r 5 1 ). P r o g r ess i v e a n d u lt im a tel y c om pl e te de s t ru c t i on o f pa nc r e at ic B - is le t c el ls o cc u rs in di a be t es . Al th ou g h t h e y a r e p r e di ct i v e l y u s e f ul , an t ib od i es a g ai ns t i n su li n a n d s ur f ac e c y t opl a s m ic a n ti g en s o f t h e B -i s le t c el l a r e p r es en t
b e f o re c l in ic al on s e t . The m a i n c y t ot o xi c m e ch a ni s m s a pp e a r t o b e m e di a te d b y T c e ll s a nd m ac r o ph a ge s . Th is vi e w i s s up p o rt e d b y t he b e n ef ic ia l e f f ec ts of c yc lo s po r in e th e ra p y in pa t ien t s wi t h e a rl y - s ta ge I D DM a t le ve ls t ha t h a v e l i tt l e e f f ec t o n a n ti b od y p r od uc t io n . I nc r ea s ed ri s k is a ss o ci at e d wi t h MH C c l as s I I t y pe s D R 3 an d D R4, a nd D Q 2 an d D Q 8. 8 . M u l t ip l e s c le r o si s (M S ) a . P a th o ge n es i s . T c el ls a n d m a c ro p ha g es , wh i ch a r e t ho u gh t t o be c yt o ci da l fo r o l ig o de nd r oc y t e s , in f il t r at e t h e c en t ra l ne r v o us s ys t em ( C N S ) a n d a t t ac k th e b a si c p ro t e i n o f P.211 m ye l i n a s a n a u to a nt i gen . Th e i m m u no lo g ic c om p o n en t m a y be s ec o nd a ry t o o th e r, un k no wn i ni t ia t in g ag e nt s. C N S de m ye l i n a t i on w i t h s c le r o t ic p l a q ue s l ea d s t o s p a s t ic i t y . I nc r ea se d ri sk i s a s so c ia t ed wi t h MH C c l as s II t yp e D R 2 . Gu i ll ai n - Ba r r é s y n d ro m e is a r el a te d co n di t io n th a t i n v ol v e s p e r ip h e ra l n e r v ou s s y s tem ( P N S ) d em y e l in a ti on th a t , u nl ik e MS , c an be a c ut e . b . T he r a p y. S p a s t ic i t y i s t r e at e d wi t h b ac l o fe n wi t h va ri a bl e e f fe ct i v e ne ss . Th e p e ri p he r al s k el e ta l m us c l e re l a xa n t da n t r ole n e i s e f fe ct i ve i n s om e p a t ie n ts . Ad r e n oc o r t ic ot r o p i c h o r m on e ( AC T H ), r a th e r t h an c o r ti co s te r oi ds , i s t h e f av o r e d im m u no s u p pr es s i ve t he r a p y . R e c o m b i na n t I F N - β - 1 b ( B e ta s e r o n) , IFN - β - 1 a , a n d g la t ir am e r ac e ta t e a r e a pp r o ve d b y th e U . S . F oo d a n d D r u g A dm i n is t ra t io n (F D A ) as a t r ea t m e n t f o r MS . E . N o n - o rg a n -s p ec i f ic au t o i mm u n it i es . Th e s im il a r it i es a n d d if f e re nc es in t h is cl as s o f d is o rd e rs a re s h o wn b y a c om pa r is on o f S j ög r en ' s s y n d r om e a n d SL E . Rh e um at o id a rt h r i ti s is di sc us s e d i n Cha p t e r 4 8. 1 . S j ög r e n 's s yn d r o m e a . D i ag n os i s i s us u al l y b a s e d o n l y m ph oc yt i c i nfi l t ra t io n a n d t he p re s e nc e o f au t oa n ti b od i es a g ai ns t s al i v a r y g l an d a n ti g en s a n d e xo c r i ne gl an d s o f t h e e ye s , g as t ro i nt es t in al a nd r es pi r at o r y s ys t em s , an d v ag in a . H yp e r g am m a g lo bu l in em ia ( 5 0% ) a s a r es ul t o f h y p e r ac t i v e B c e ll s , a n t in uc le a r a n ti b od ie s (50 - 6 5% ) , a n d r h eu m a t oi d f a c to r s ( an t i -I g G ; 7 5 - 90% ) a r e pr es e n t in t he in di c at e d p e rc e nt a ge s o f p a ti en t s . b . P a th o g en e si s . P r im a ry s y m p to m s in c l ud e in h ib i t i o n o f e x oc r i n e g la nd s e c r e ti o n , wi t h d r y ne s s o f t he e y es , m ou t h, an d g a st r o in t es ti n al , r e s pi r at o r y , an d v ag in a l m uc o us m em b ra n es ; a n d p a in an d e d em a i n t he s a li va r y g la nd s . P a ti e nt s wi t h h yp e rg am m a g lo b ul in e m i a o f te n h a ve t y pe I II h yp e r se ns i ti v i t y r ea c t i ons ( e. g . , va s c ul i ti s wi t h CN S i n v o l v em en t a n d k id ne y d i se as e ; s ee II . D ) . c . Th e r a p y. Mi l d c as es ar e t r ea t ed wi t h a r t i f ic i a l t e a r s a n d f r eq ue n t d r i nk in g o f wa t e r . F o r m o r e s e ri o us c as es ( e. g . , v a s c ul it is ) , tr e a tm en t i s s im i la r to th a t f o r S L E (sys t e m i c c o r t ic o s te r o i ds ) . 2 . S L E ( S ys t e m i c Lu p us E r yt h e m a t o s us ) a . D i ag n os i s i s c o m p l ic a t e d a nd de p en ds on th e p r es e nc e o f 4 or m o r e of 1 1 c r i te r ia . Th e m os t u s ef u l c r it e ri o n i s a h ig h c o nc e nt r a ti o n o f a nt i nu c l e ar
a n t ib od i es di r ec te d a g ain s t d ou b le - s t r a nd ed D NA a n d t he Sm i th ( Sm ) n u cl e ar an t ig e n, bo t h o f wh i c h a re c o ns id e re d s pe c i f ic f or S L E. O t he r d i ag n os ti c c r it e ri a i nc l ude t he p re se nc e o f th e l up u s e r y t he m a t os us c e ll (a n e u t ro ph i l t ha t ha s p ha go c y t os e d n uc le i ); a d is c oi d er yt h em a to us f ac ia l r a s h; ph o to s e ns i ti v i t y ; o ra l ul c e r s ; a rt h ri t is ; p e rs is t en t pr o te i nu r ia ; an d a n t ic a rd io l ip in , an t ie r y t hr o c y t e , o r a n ti le uk oc y t e a n t ib od i es . b . P a th o g en e si s i s t ha t o f t yp e I I I h yp e r s e n s i t i vi t y. P a t i e n ts ha ve h yp e r a c t i vi t y o f B c e l l s o f un k n o wn o ri g in . Th is h yp e r r ea c ti vi t y c a us es h yp e r ga m m a gl ob u li ne m ia , wi t h c i rc ul a ti n g im m u ne c o m p l e xe s of D N A an d o t h e r n uc le a r a nt i ge ns th a t p r ec i pi t at e o n to v a sc u l a r b as em en t m em b r ane s a n d a ct i v a te c o m p l em en t. ( 1 ) Mi l d a rt h r it is , fe v e r , ra s h, an d fa t ig ue oc c u r . ( 2 ) P r og r es s i v e ne c ro t i z in g v as c ul it is wi t h C N S i nv o l v e m en t a n d g l om e ru l on e ph r it is a re the m o s t s e r i ou s c o ns e qu en c e s , o cc u r ri ng in a p p ro xi m a t el y 5 0% o f p at i e nt s . ( 3 ) H yp e r te ns io n m a y dev e l o p s ec on d a r y t o k id n ey d i se a s e . ( 4 ) H em o l y ti c a ne m i a a nd t h ro m b oc y t o pe n ia a re c om m o n . ( 5 ) B eh a vi o ra l c ha ng e s o c c u r i n a p p ro xi m a t el y 25 % of p a t ie n ts . ( 6 ) S e ve ra l d r ug s (e . g. , p r o c a in a mi d e, h yd r a l a z i n e , q u i ni d i ne , m e t h yl d o p a , i s on i az i d , p h e n yt o i n , c h l o r p r om az i n e) p ro vo k e a l up us - l ik e s yn d r om e t ha t us ua ll y r es o l v es wh e n t h e d r ug i s wi t h d r a wn . Th e ba si s f o r t h is s ynd r om e i s n ot un de r s to o d. N o r e na l d is o rde r oc cu r s i n d r ug - in d uc ed SLE. c . Th e r a p y. Mi l d d is ea s e ( e . g. , lo w- g r a d e f e v e r, ar t h r i ti s) is m a na ge d wi t h n o ns t e ro id a l a nt i -i n fl am m a to r y d r ug s ( N S A I D s) . Th e r a p y f o r p at i en ts wi t h s e ve r e s y m p t om s is us ua l l y or a l m e t h y l pr e dn is o lo n e . C yc l op ho s p h am id e m a y al s o be us e d, an d pl a s m ap h er e si s t o r em o ve c i rc ul a ti n g im m u n e c om p le xe s m a y b e h e lp fu l . F . P r o sp e c ts f o r m o r e sp e c i fi c im mu n o lo g i c t he r a p ie s . Cu r r en t th e ra p ie s i n vo l ve a p pr o ac he s t h at s u pp r es s a ll im m u ne r es p o ns es ; ho we v e r , cu r r ent c l in ic al t ri a ls s ee k t o s upp r e s s o n l y l ym ph oc yt e s th a t a r e a c t i v a t ed — fo r e xa m p l e : 1 . F ee d in g a u t oa n t i ge ns t o p a ti en t s t o i nd uc e im m u n ol o gi c su p pr e s s io n 2 . V ac c in a t io n w i t h a u to r e a c ti ve T c e l ls to in du c e im m u n ol o gi c s u pp r es s i o n P.212
3 . A dm in is t r at i on of an t i- T H m o n oc lo n al an t ib od ie s (p a r ti cu la r l y an t i - C D4) t o e l im in a te au t o re ac t i v e T c e ll s 4 . A dm in is t r at i on of co n ju g a t es o f I L -2 a nd t ox in s f ro m p la n ts or b ac te r ia t o el im i na t e a ut o re a c t i v e T c e ll s wi t ho u t g en e r al iz e d T c e ll s u pp r es s i on
IV. Immunodeficiency
i s e i th e r p r im a r y o r s e c on d a r y . P r im a r y i m m u n od e f i ci e nc i es a re ei t he r h e r e d it a r y o r c o n ge n i tal , a nd at le as t o n e e le m en t ba s i c t o t h e im m un e s ys t em d o es no t f u nc ti o n p r o pe r l y o r is a b se n t. Se c o nd a r y i m m un o d ef i c ie n ci e s a re t he r e su l t o f an o t he r s ys t e m i c di so r d er o r a r e i a t r o ge n i c i n p a t ie n t s gi ve n i mm u n os u p p re s sive t h e r a p y. Th e y u s ua l ly d e ve l op i n pa ti e n ts wh o p r e v i ou s l y s ho we d n o rm a l im m u ne fu nc t io n . Th e e xp e c t e d c li ni c a l o u tc om e o f a n i m m un od e fi c i e ncy i s go v e r ne d b y t h e s p ec if ic po r t io n o f th e i m m u ne s y s t em th a t is a ff ec t ed ( e. g . , B an d T c e ll s , p h a go c y ti c c el ls , a n d c om p le m e n t ). A. P r i m a r y i m m u n o d e fic i e nc i es a re , wi t h o n e exc e p t i o n, r a re . E xa m pl es a r e th e f o ll o wi n g : 1 . X - li n ke d ag a mm a gl ob u l i ne m ia ( h ypo g am m a gl o bu l in em i a) is an in he r i te d d e f ic ie nc y i n a nt i bo d y p ro d uc t io n (h um o ra l i m m un i t y ) in wh i c h T c el l f u nc t io n i s r e la t i v el y n o rm a l, bu t B c el ls do no t fu l l y m a tu r e b ec a us e o f a f a i lu r e o f B c e l l s i g na li n g. S e r um i m m un o gl o bu li n l e v e ls a re lo w. B e c a us e t h is di so r d er is li nk ed t o t h e X c hr om o so m e , i t o cc u rs p ri m a r il y i n m e n . a . P a th o ge n es i s o c c u rs 6 - 9 m o nt hs a ft e r b i rt h a nd r e pr es e n ts s it u at i on s in wh i c h an t ib o d y fu nc t io n is de f ic ie n t b u t T- c e ll fu nc t io n i s i n ta ct , s uc h a s r e c ur r e nt in f ec ti o ns wi t h e xt r a c e l lu la r p y og e ni c ba c te r i a ( e .g . , s t re p to c o cc i , p n e um oc oc c i , Ha e m o ph ilu s ) . I m m un i t y to fu n gi and m o s t vi r us es is g e n er a ll y f un c ti on a l. b . C l i ni c al s ym p t o m s i nc l ud e p n eu m o ni a , s in us i ti s , o ti t is , m en i ng i ti s , an d s e pt ic em i a. c . Th e r a p y i s p a ss i ve im m u ni z a t i o n w i t h h u man i n t r a ve no u s i m m un o g lo b u li n ( IV I G ; s e e V I . B .1 .c ) . 2 . C o mm o n va r i a b le imm u n o de f ic i e nc y i s a n ac q ui r ed de f ic ie nc y o f B c e l l m a tu r a ti o n t o p la s m a c ell s . I t c an oc c u r at an y a ge a nd in ei t he r s e x. S ym p t om s a nd t re a tm en t a r e s im il a r t o t h os e f o r X- l i n k ed a g am m a g lo bu l in em ia ; the p at h og e ne s i s a nd o ri gin v a r y s ig ni f ic an t l y. 3 . S el e c ti ve I g A d e f ic i en c y i s t h e m o s t c o m m on p r im a r y im m u no de f ic ie nc y , a f f ec t in g a pp r o xi m a te l y 0 . 5 % o f t h e U . S . p op u la ti o n . I t a p pe a rs to be i n he r i te d . Th e lo w s e c re to r y I g A (s Ig A ) co nc en t r at i o n p r ed is po s e s p a ti en ts t o e xt r a c el lu l ar ba c te r ia l i n fe c ti on s o f t h e m u c os a l s u r fa c e s , le a di n g t o r e s pi r at o r y , ur o ge n it al , an d ga s t r o in t es ti n al in f ec ti o ns . So m e a ff ec t ed i n di vi d ua ls a re as y m p t om a ti c f o r u nk n o wn r ea s on s . Ce r t ai n a u to im m u ni t ie s m a y be m o r e p r e v al e nt . Th e r e is no s p ec if ic im m u n ol o gi c t h er a p y. 4 . D i G e o rg e s yn d r o m e re s ul ts f ro m d e v e lo pm en ta l fa i lu r e o f t h e t h ym u s a n d p a ra t h y r oi d g l an ds , a c c o m p an i ed b y c a rd i o va s c u l a r an d o t he r d e ve l op m e n ta l a no m a l ies . P at ie n ts ha ve a d ec r ea s e i n t o ta l T c e ll nu m b er s b u t re l at i v el y n o rm al im m u no g lo bu l in le v e ls . a . P a th o ge n es i s i n s e v er e c a s e s ( i .e . , l i tt l e f un c ti o na l th y m ic ti s s ue ) r e p r es en t s c o n di t io ns inv o l v i n g T c e ll de f ic ie nc y, s uc h a s r ec u r re n t i n f ec ti o ns o f th e s k i n , lun g s , ge n it o u ri na r y t r ac t , a n d b lo o d wi t h o p p or t un is t ic pa t ho ge n s , p a r ti c u l ar l y v i r us es (e . g. , h er p es v i ru s e s ) , f un gi ( e . g ., C a nd id a ) , a nd p ro to z o a ( e. g ., P ne u m o c y s t is c a r in ii ) ; i n cr e as ed
i n ci de n c e of c e r ta i n c a nc e r s ; g r af t - v e rs us - h os t ( G V H ) d is e as e ( se e V. C ) a f t e r t r an s fu s i on o f wh o le b lo od ; an d d e at h i n i n fa n c y o r ea r l y c h il d ho od . b . T he r a p y f o r s e v e r e T c e ll de f ic ie nc ie s i s b on e m a r ro w t r a n sp la n ta t io n , a l t ho ug h th y m us gr a f ts m a y be a tt em p te d i n Di G e o r ge s y nd r om e ( s ee V .C ) . 5 . N ez e lo f s yn d r o m e i s p r o ba b l y i n he r i te d a nd c a u s e s l ym ph op e ni a a n d t h ym ic ab no r m a l it i es b u t n o rm a l o r e le va t ed se r um i m m u no g lo b ul in le ve ls . G r a m - ne g at i v e s ep s i s m a y o c c u r i n a dd i ti o n t o t he o pp o r tu ni s ti c i nf ec t io ns a ss o ci at e d wi t h T c el l d ef i c i e nc y . 6 . S e ve r e c om b i ne d imm u n o de f ic i e nc y d i s o r de r s ( S C I D s) a re a h e t e ro ge n eo us g ro u p o f i n he r i te d d is o r de rs wi t h d e f ic ie nc ie s i n T c e ll s , B c e ll s ( va r ia b le ) , a n d s e r um im m u no g lo b ul in . In f ec t i o ns wi t h o pp o r tu n is ti c o r g an is m s oc c u r i n t h e f ir s t fe w m o nt h s p os tn a ta ll y , a nd su r v i v a l f o r l on g er t h a n 1 y ea r is ra r e wi t hou t s u c c es s f ul bo n e m ar ro w t r a n s p l an t at i on . Th r ee f o r m s i n v o l v e f ai l u re of D N A b i os y n t he si s o r re pa i r , a n d a f o u rt h d e fe c t is t h e re su l t o f d e fi c i en c y of t h e γ c ha in o f t he IL - 2 re c ep t o r. P.213
7 . C h r o ni c g r a n ul o ma t ou s d is e as e ( C G D ) is a de f ec t in th e a b il it y o f p h a go c y te s t o k il l b ac t e ri a . Th e d is ea s e is c a us ed b y a g en e ti c d e fe c t in th e p r o du c ti on o f o xy g e n r a di c al s t ha t ar e i m p o r ta n t fo r in t r ac el l ul a r a nd e xt r a c e l lu la r k i ll in g o f bac t e ri a . Th e de f ec t c an oc c u r i n a n y of t he fo u r p r o t ei ns es s e nt i al fo r p ro d uc i ng o xy g e n r ad ic al s , b u t t h e m o s t co m m on d e f ec t i s X- l i nk e d. C G D is c h a ra c te r i zed b y c h ro ni c i n fe c ti on wi t h or g an ism s s uc h a s St a ph y l oc oc c u s a u r eu s a nd is us ua ll y f a ta l . 8 . L eu k oc yt e a d h e si o n d e f i ci e nc y ( L A D ) i s as so c ia t ed wi t h a de f ec t i n th e p h a go c y ti c c el ls . Th es e c e ll s l ack in t e rc el l ul a r ad h es i on m o le c u le s , t he p r o t ei ns ne c e s s a r y fo r b in d in g to th e e n do t he li a l c e ll s o f t h e b lo od ve s s els a n d o t he r c e ll m em b r an es . Th is de f ec t l ea d s t o an i na bi l it y o f p h ag oc yt ic c e ll s t o e xi t t h e b lo o d a nd e nt e r t h e t is su es . In ad d i ti on , th e p h ag oc yt e s h a ve a d ec r ea s e d a b il it y t o bi nd t o ac t i vat e d c om p o n en ts of co m p l em en t o n a b ac te r i al s u r fa c e , l e ad in g to a d ec r ea s e in ph a go c y t os is . Pa t ie n ts ha v e s e ve r e b ac te r i al i n fe c ti on s , e s p ec i al l y i n th e m out h an d g as t r oi n te s ti na l t r a ct . 9 . C h éd i ak - H i ga s h i s yn d r o m e i s a d e fi c i e nc y in t h e fu s i on o f l y s o so m e s wi t h p h ag oc y t i c v e s i c l es . Th e c au s e is u nk n o wn , b u t th is s yn d r om e l ea ds t o b a ct e r ia l s ur v i v a l i n th e p h a go c y te , wi t h a n i nc r ea s e i n b ac te r i al in f ec ti o ns . 1 0 . De f e c ts in c om p le me n t m a y be t he r es ul t o f d e f ec ts in th e a c ti v a t io n p a t h wa y s , m em b ra n e a tta c k c o m p l e x, o r re g ul at or y p r o t ei ns . De f ec ts in t he a c ti va t io n p a th wa y s a n d i n th e m em b ra n e a tt a c k c om p le x a r e as so c i a t ed wi t h i nc r e as ed in f ec ti o ns o wi n g to p y o ge ni c b ac t er i a a n d wi t h i nc re a se d r a t es of im m u n e c o m p l e x d is e as es , s uc h a s S L E . D e f e c t s i n r e gu la t io n c an b e ob se r v e d a s a ng i on eu r o ti c e d em a a nd no c t u rn a l p a ro xs ys m a l h e m o g lo bi n u ri a.
B . S e c on d a r y i m m u n o de f i c ie n ci e s i n v ol ve de c re a se d i m m un o lo gi c r e s po ns i v e ne s s . 1 . C yt o t o x i c d ru g s p r e ve n t th e d i vis io n o f re s pon d in g l ym p ho c yte s , s u pp r es s t he p ro d uc ti o n o f bl o od c e ll s i n b on e m a r r o w, a n d m a y d i re c t l y k i ll c e ll s. P at i en ts wh o r ec e iv e c he m ot h er a p y an d e xh i bi t a s i g ni f ic an t l os s o f n e u t ro ph i ls m a y be t re a te d wi t h fi lg r as t im o r r ec om b in a nt g ra nu l oc y t e c o lo n y - s t im u la t in g f ac t o r ( G - C S F ; N eu p og e n) , to r e s to r e t h e wh i t e b l oo d c e ll c o un t to no rm a l l e v el s . Tr ea t m e n t t o i nc r ea s e n e ut r o ph il le v e ls in th e s e p a t ie n ts re s u l ts i n d e c r ea s ed m o r bi di t y r a te s f r om ba c te r ia l i n fe c t i on . C o r t ic os t e ro i ds b r o ad l y s u p p re s s im m u ne s ys t em c e ll s, in c l u di ng de c re as ed d i vi si on , c y t o k i ne s e c re t io n , a n d c h e m o t a xi s (e m ig r a ti o n f r om th e b l oo d i nt o t i ss ue s ) . 2 . L eu k em i as , l ym p h o ma s , a n d m ye l o m a s a r e as so c i a te d wi t h d ec r e as ed i m m u ne r es po ns i v e ne s s , a t l e as t s om e o f wh ic h re s ul ts f ro m d es t r uc ti o n of t h e a r ch i te c t u r e o f l y m pho i d o r ga ns ( e. g . , sp l ee n , l y m ph no d es ) . Ma l i g n a nc y - r e la t ed im m un o d ef ic ie n c y a ls o o cc u rs i n o t he r c a nc e rs . 3 . P r o te i n -c a l o ri e m a l nu t r i t i o n s i g ni f ic an t l y d ec r e a s e s im m u n e c om p et e nc e , p ar t ic ul a r l y i n c hi l dr e n. 4 . Ag i n g is a s s oc ia t ed wi t h d ec r e as ed im m u no lo gi c c om pe t en c e. 5 . Ac u t e in f e ct i o ns p rod u c e a t r an s i e nt im m u nod e f ic ie nc y. 6 . AI D S i s a s ec o nd a r y im m u n od e fi c i e nc y t ha t i s u s ua ll y p e rs is t en t a n d is a n in di r ec t c o ns eq u en c e o f i n fe c ti o n b y H I V -1 o r H I V - 2 . H I V -1 i s t h e m o r e c om m o n s u bt y p e i n t h e U n i t ed S ta t es an d we s ter n E u ro p e. a . P a th o ge n es i s . Th e v ir a l e n v e lo p e g l yc o p ro t ein 1 20 ( gp 12 0 ) h as a s t ron g a f f in i t y fo r C D 4 ( s e e I. B .3 . c ), al l o wi n g t he vi r us to d ir e c t l y in f ec t TH c e ll s . I n ad d it i on , t h es e p r ot e in s u s e o ne of t wo c h em ok i ne r ec ep t o rs : C C R 5 to g a in en t r y t o m a c ro p ha ge s a n d d en d ri t ic c e ll s a nd C XC R 4 t o ga i n e nt r y i nt o +
C D 4 T c e ll s . B ec a us e i t i s a re t r o vi ru s , vi r al en t ry a n d u n c o a ti ng r el ea s e t h e vi ra l R N A g en om e a nd t he as so c i a te d re v e r se t r a ns c r i pt as e e n z ym e , wh i c h s y nt h es i z es a do ub l e -s t ra n de d D N A c op y of t h e g en om e ( p r o vi ru s) . Th e p r o v i ra l c op y i s i nt eg r a t ed in t o t he ge n om e o f t he i n f ec te d c el l , a nd t h e vi r u s e n te r s a p e r io d o f la t e nc y , du r in g wh ic h i t is e s s en t ia l l y h i dd e n f r om t h e i m m un e s y s te m . ( 1 ) D u ri n g i n i ti a l i n fe c t io n , th e r e m a y b e a n a cut e il l ne ss th a t la s ts a n a ve r a ge o f 3 we e k s a n d r e s em bl es m o no n uc le os is ; s om e i n di v i du a ls h a ve n o s ym p to m s . ( 2 ) S e r oc o n ve r si o n (i . e., t h e a pp ea r a nc e o f a n tiv i r a l a n ti b od i es ) o c c u rs 3 we e k s to 6 m on t hs a f te r t h e i n it i al e xp o su r e t o H IV - 1 . A p e ri o d o f a s ym p t o m a t ic i n fe c ti o n t y p i c a ll y f o ll o ws s e r oc on v e r s io n . P.214
( 3 ) I nf ec t ed T H c el ls a re k i ll ed wh e n vi r a l g e ne s a r e r ea c t i va t ed f r om l a t e nc y a n d v i r us es bu d f r o m t he ce ll . In ad d it i on, i nf e c t e d T H c el ls m a y f u se t o f o rm s y n c y ti a . Thi s fu s i on m a y h as te n th e s p re a d o f v i r us t o
u n in f ec t ed T H c el ls an d c o n t ri b u te to c e ll k i ll in g . A p r o g r es s i ve de p le t i on 3
o f T H c e ll s oc c u r s ( n o rm a l c o un t : 8 00 - 1 00 0 /m m ). H o we v e r , e v e n b ef o r e a n +
+
o b vi o us l os s o f C D4 T c e l ls oc c u rs , th e re is e v ide n c e of a d e fe ct in C D 4 T c e ll fu nc t io n . Th e f un c t i on a l d e fe c t is a f ai l ur e o f t h es e c el ls t o r es p on d t o a n t ig en s t o wh i c h th e y we r e pr e vi ou s l y s en s i t i zed ( e . g. , te t an us t o xo i d ). +
Th e d e fe c t i n r es p on s i v en e s s m a y be a f un c ti o n o f t he C D 4 T c e ll s, t he A P C s , or bo t h . ( 4 ) Ma c r o ph a ge s m a y p ro d uc e n e w v i r u s wi t ho u t b e in g k i l l ed an d m a y +
s p r ea d t h e v i r us to un i nfe c te d T H c e l ls a n d o th e r c e ll t ype s . C D 4 c e ll li nes t h a t a r e s u s c e pt i bl e t o HI V i nf ec t io n i nc l ud e n e uro n s , li v e r , a n d f ib r o bl as ts . I n di r ec t c el l - to - c e ll t ra ns f e r o f t h e vi r us , m in im a l e xp o s u r e t o t h e e xt r a c e l lu la r im m u ne s y s t e m ( e .g . , a n ti b od y ) m a y o c c u r . ( 5 ) AP C s a r e a ls o a f fe c te d b y th e i n fe ct i on . Th e re is a l os s o f f ol l ic ul a r d e n dr i ti c c el ls an d i n te r di g i ta t in g c el ls in th e l y m p h oi d ti s s ue . Th is lo s s +
l e ad s t o d ec r e as ed an t ige n p re s e n ta t io n t o th e CD 4 T c e ll s . I n a dd i ti on , +
t h e c yt ok i ne s p r od uc e d b y t h e AP C s m a y pr o du ce C D 4 T c el ls th a t i n c re as e B c e l l ac t i v at i on b ut do no t pr o du ce t he a p p ro p ri a te c y t o k i n es f or T c e ll pr o li f e ra t io n . Th i s ac t i v i t y c h a ng es th e T H c e l l r a t io s . b . C l i ni c al s ym p t o m s ( 1 ) P e rs i s te n t ge n e ra l iz e d l ym p h a d e n o pa t h y ( e xt r a i n g u in a l) is an i n di ca t o r o f i m p e nd in g p ro g r es s i on t o f ul l d is e as e. U n e xp l a in e d f e ve r, ni gh t s we a t s , d ia r r he a , a nd o th e r s y m p to m s k no wn a s AI D S - r e l a t e d co m pl e x ( AR C ) m a y o c c u r . ( 2 ) P r og r es s i on t o f ul l -b lo wn A I D S m a y o c c u r 8 ye a r s o r l on g e r a f te r th e 3
i n i ti al in f ec ti o n. D e pl e ti on o f t h e T H c el l l e v e l t o < 2 0 0/ m m a n d o ra l +
c a nd i di as is s u gg es t i m m i n en t di s e as e . B ec a us e C D 8 T c e ll s a r e n ot +
+
s i gn i fi ca n tl y a f fe c t e d, the r a ti o o f c i rc ul a ti n g C D4 t o C D8 c e l ls i s i n v e rte d . I n ad d it i on , t h e n um be r o f v i r gi n T H c e ll s r e la t i v e t o m em o r y T H c el ls i n c re as es . TH c e l ls a r e lo s t , a nd m em o r y T H c el ls a r e l os t i n re l at i vel y l a r ge r nu m b e rs . Th e re is a ls o a sh i ft in th e t y pe of T H c e ll he lp be i ng g e n er a te d . ( 3 ) A di ag n os is o f A I D S in v o l v e s t h e oc c u r r en c e o f o pp o r t u ni s t ic i n f e c ti o ns o r n e op l as ms a s a r es u l t o f th e p r og r e s si ve i m m un o d ef i c ie n c y c a u s e d b y s e v e re de p le t io n of T H c e ll ( C D 4 ) f un c ti on . A l s o i nc lu de d i n th is di ag n os is a re th e H I V wa s t in g s y n d r om e a nd e n ce p ha lo p at h y . ( a ) O p po r t un is t ic i n fe c ti on s a r e t h e m aj o r c o ns e qu e nc e o f A I D S, pa r t ic ul ar l y b y P . ca r in i i ( as m a n y as 8 0 % o f p a ti en t s ) , C an d id a al bi c a n s, My c o b a c t e ri u m av iu m - i n tr a c el lu l ar e , h e rp es s i m p le x v i r u s ( H S V ) , c yt o m e g al o v i ru s ( C MV ) , a n d o t he r s. Tu b e rc ul os is o c c u rs as a r ea c t i va ti o n o f a l at e n t in f ec t io n i n c ar r i e rs . C um ul a ti v e l y , th es e op p o r t un i s ti c i n f e c ti o ns a r e t h e p r ima r y c a u s e o f d e at h . ( b ) K a po s i s a r co m a, an o t he r wi s e ra r e c an c e r , oc c u r s i n f e we r t ha n o n e h a l f o f p a ti en t s wi t h A I DS . N o n - Ho d gk in l ym p hom a i s a ls o m or e c om m o n i n t h es e i n di v i d ua ls th a n i n t h e g en e r al po pu l at i on .
( 4 ) H I V -a s so c i at e d d eme n t i a c om p le x ( H AD C ) a f f ec ts m o r e t ha n o n e h al f o f pa t ie n ts wi t h AI D S . In H A D C , m a c ro p ha g es i n fi l t ra t e t h e b r ai n a nd a re t h e m os t p r o du c t i v e l y i n fe c te d c el l i n c om pa r is o n t o ne u r on s o r g li a . So m e p a t ie n ts s ho w d e m y e li nat i o n. ( 5 ) O t he r im m u ne s ys t em ab n o rm al i ti es i n c l ud e p o l y c l o n a l B c e ll ac t i v at io n a n d h yp e rg a m m ag lo b ul ine m ia wi t h a co nc om i ta n t d e c re as e d a bi li t y t o m o un t h u m o r al im m u ne r es po ns e s to s p ec if ic an t ig e ns . C h e m o t a xi s , c yt ok i ne s ec r e ti o n, an d c y t o to xi c a b il i t y of m o no c yt e- m ac ro p h ag es ar e al l d i m i ni s h e d. Th e s e p ro ble m s a re c o ns eq u en ce s of im p a i r ed T c el l r e g ul a ti o n. c . Th e r a p y ( 1 ) C u r re n t t he r a p y i nc l ud e s p r op h y la c ti c us e o f a n t ib io t ic s a nd an t if u ng al a g e nt s. O p ti m a l a n ti - H I V t h e ra p y is c om b in a ti on th e r ap y wi t h t h re e a n t ir e t ro v i r a l d ru gs . A t pr e s en t , t he r e a r e f o u r cl as s e s o f a n ti r e t ro v i r al d r u gs ap p ro v e d b y t h e FD A . Th e s e a r e n uc le os ide r e v e rs e - tr a ns cr i pt as e i n hi b it o rs ( N R TI s ; e . g. , zi d o v u di ne - A Z T, la m i v u d in e , s t a v ud in e , zal c i t ab ine d d C , d i da n os in e -d d I , a nd a ba c a v i r ) , n o nn uc le os id e r e v er s e- t r an s c r ip t as e i n hi b it o rs ( N N R TI s ; e . g. , n e v i r ap in e , d el a vi r di ne , e f a v i r en z ) , p ro t ea se i n hi b it o rs ( e. g . , s a q ui na v i r , in di n a vi r, r it o na vi r , n el f i na v i r ) a n d i nt e g ra s e i n hi b it o rs ( e. g . , r al t eg r a vi r ) . IF N - α is r ec om m e nd ed f o r t he t re a tm e nt of K a p os i s a rc om a. O t he r dr u g s a nd im m u no m o d ul a to r s a r e c u rr e nt l y un d e r d e ve l op m e n t a nd te s ti ng. P.215
( 2 ) A n e f fe c t i v e a c ti v e va c c i ne is n e ce s s a r y t o l im i t t h e sp r ea d o f H I V i n f ec ti o n. B ec au s e o f v i ra l an t ig en ic v a r ia t io n , c el l - to - c e l l t r an s m is s i on , an d t h e u nc e r ta i n r ol e o f an t ib o di e s in p ro t ec t io n , t he p r o c e s s o f v ac ci n e d e ve l op m e n t is di f fi c u l t . A l i v e , a t te nu a te d vac ci ne ( se e VI . C . 2 ) is c o ns id e re d to o g r ea t a r is k . Tr i a ls of su bu n it v a c c i ne s a r e u nd e r wa y .
V. GRAFT REJECTION A. O ve r vi e w . In d i v id u al d i f fe r e nc es i n t h e m ol ec u l a r s t ru ct u r es o f c el ls an d t i ss ue s o c c u r, e xc e p t i n id e n ti c a l t wi n s , b ec a us e o f t he ge ne t ic v a ri a ti o n i n he r e nt in hu m a ns . B ec a u s e of t he se m o le c u l ar d i f fe r e nc es , t r an sp l an t ed t i ss ue s o r or g an s ( i .e . , gr a f ts ) a re li k e l y to be an ti g en ic a ll y d if f e re n t f r om t h e re ci p ie n t a nd th e re f or e m a y s ti m u la t e a n i m m u n e re sp on s e. 1 . A lt h ou g h MH C c l a s s I a n d I I gl y c op r o te in s p la y a n e ss e nt ia l ro l e i n al l T c e ll im m u ne r es po ns es (s e e I . B .3 . a ), th e se m o lec u le s a r e p a rt ic ul a r l y a n t ig en ic a nd v a ri a nt in s t r uc t ur e a m o n g d if f e re nt h um an s (p ol ym o rp h ic ) . 2 . E ac h p e rs on ' s s e t o f MH C g l yc o p ro t ei ns is c all e d h is o r h er h um a n l e u ko c yt e a n t i ge n ( H L A) , o r h i s to c om p a ti b i li t y t yp e . C l a s s I g l yc op r o te in s a r e k no wn a s H LA - A , - B, an d - C a n ti g en s . C l as s I I g l yc op r o te in s a r e k no wn a s H LA - D R , - D P , a nd - DQ a n t ig e ns . E ac h p e rs o n
r e c ei ve s o ne s e t o f g e nes ( a h ap l ot y p e ) e nc o di ng t h es e p r ot e in an t ig e ns f r o m e ac h p a re n t. 3 . I de n ti c a l t wi n s h a v e th e s am e h is t oc om p at i bi lit y t y p e . Fo r ot h er s i bl i ngs , t h e p r o ba bi l it y i s a pp r o xi m a te l y 25 % (0 . 25 ) th a t two s i b li n gs wi t h t h e s a m e p a r en t s a r e H L A i d en ti c al , o r m a t ch ed , an d a p pr oxi m a t e l y 50 % th a t t he y ar e o n e h al f H L A m a t c h e d, or h a pl oi d en t ic al . Pa r en t s a n d c h i ld r en a re al m o s t a l wa ys h ap l oi de n ti c a l . So m e t r an sp l an t ed ti s s ues a re r ej ec t ed be c a us e of H L A i nc om pa t ib il i t y . I n ot h e r c as es , t h e r e as on for r e je c ti on is th e re s u l t of m i no r hi s t oc om p at i bi li t y a n t ig en s o r is u nk n o wn . H L A m a t c h in g i s n o t a l wa ys a fa c t o r i n re je c tio n . B . C o m mo n s o l id - o r g an t r a n sp l a n ts ar e k id n e y , h e a rt , l i ve r , h ea r t -l u ng , a n d p a nc re a s . O r ga n s a re o bt a in e d f r om c ad a v e rs o r l i v in g d o no rs . Th e p r o ba b il i t y o f an e xa c t HL A m a t ch in a ca d a v e r gr a f t i s a pp r o xi m a te l y 1 i n 1 0 m i ll io n . 1 . H L A m a t ch i n g a . Th e pr im a r y p ro bl e m wi t h o r g an do n at io n i s rej e ct i on of t he t ra ns pl a nt ed o r g an b y th e h os t ' s i m m u n e re s p on s e. D on a ti o n o f an o rg a n b y an H L A m a tc he d s ib l in g i s t he bes t wa y t o a v oi d t h is p r o bl e m . b . A l th ou g h H L A - D R an d H L A - B m a tc hi n g d ec r eas es t he r ej ec ti o n r e ac ti on i n re n al an d c a rd i ac g r a ft s , re je c ti on do e s oc cu r i n H L A -m a tc he d s i tu a ti ons . H L A m a t c h in g i s n o t im po r t a nt in li v e r t ra ns pl a nta t i on . 2 . T yp e s o f r e j ec t i o n o f o r g a n g r a f ts a . H yp e r a c u t e re j ec t i on i s m ed ia t ed b y pr e e xi s t in g an t ib o d y i n t h e r e c ip ie n t , us u al l y ag ai ns t A B O m i sm a tc he s . C om p l em e nt is a c ti v a t ed , c l ot t in g o c c u rs , a n d t he v a s c ul at u r e o f t h e t r an s pl a n te d o r ga n i s o c c lu de d. R e j ec t io n o c c u rs wi t h in 2 d a ys a ft e r t r a ns pl an t a ti o n . A n A B O -m is m a tc h ed g r a f t is r a re l y at t em p te d . R e j ec ti o n is es s e n ti al l y u n t r ea t ab le . b . Ac u t e r ej e c ti o n i s a T c e l l -m ac r op ha g e -m ed ia t e d a t ta c k o n th e g r af t b a se d o n HL A an d o t he r t i s s ue an t ig e n m i sm a tc he s . T c e ll s a nd m ac r o ph a ge s i nf il t r at e the g r af t a n d, in 10 - 1 4 d a ys , c a us e c e l lu la r ne c ro sis a n d i n fl am m a t io n p e ri v as c u l a rl y . Th e e n ti r e g r a ft b e gi ns to ne c ro s e i f u n t r ea t ed . c . C h r on i c r e j ec t i on oc c u rs s e v e r al m o n th s t o se v e r a l yea r s a ft e r t r a ns p la n ta t io n . I t c au s es f ib r os is a n d o cc lu s i on o f s m al l a r te r i es a n d a r t e ri o le s i n t he k i dn e y s a n d a t he r os c l e ro s i s i n t h e h ea r t . I t i s c on t ro l le d by i m m u no lo g ic i n ju r y a nd m e di a te d p r im a ri l y b y a nt i b o d y a nd in c l u de s t he r e l ea se o f i nf l am m a to r y c y t o k i ne s b y m ac ro p ha ge s . De sp i te th e h i gh s uc c ess r at e o f MH C - m at c he d , p ha r m a c o l og ic a ll y t r e at e d g r af t s i n t he fi r s t ye a r a ft e r tr a ns pl a nt a ti on ( 8 5- 9 0% k i dn e y g ra f ts ), t h e r ej ec t io n ra t e a f te r 5 ye a r s i s n ea r l y 50 % . Th is f or m o f re je c ti o n is r ela t i v e l y re si st a nt t o t he r ap y, a l t ho ug h t re a tm en t wi t h c o r ti c o s te r oi ds c a n b e he l p fu l . C . B o n e m a r r ow t ra n sp la n t a t io n i s s om et im es at t e m p t ed in pa t ie n ts wi t h i m m u no d ef ic i en c y d is e as e s , a pl as t ic an em ia s , som e l e uk em ia s , an d c e r tai n g e n et ic di s e as es . Th e g ra f t c o nt a in s a P.216
h i gh p ro p o rt i on of do n or l y m p ho c yt es t h at r es po nd t o t h e h os t HL A an d o t h e r a nt i ge ns . Th is re s po n s e c a us es g ra f t - v er s us - h os t ( G V H ) d is ea s e . 1 . G r a ft T c el l re c o gn i ti on o f t h e h os t i s im po r t ant i n G V H d is ea se , as s h o wn b y th e d ec r e as ed i n c i de n c e of G V H di se ase a f te r p r oc e du r es th a t p u r ge m a t ur e T c e l ls fr om t he do no r m a r r o w. 2 . C l in i ca l s ym p t o m s o f G V H d is e as e a r e s e e n in t he s k in (e . g ., r as h, d e sq u am at i on ) , g as t r oi n te s ti n al t ra c t ( e. g . , p ai n , vo m i ti n g, in t es ti n al b l ee d in g ) , a nd li v e r (e . g ., n ec r os is i n di c a t ed b y i n c r ea s e d s e ru m b il i ru bi n l e ve ls ) . De a th c o m m on l y o c c u rs . 3 . H L A m at c h i ng is i m p or t a n t i n b on e m a rr o w t r an s pl a nt a ti o n, bu t th e f a ilu r e r a t e e ve n o f m a tc he d g ra f t s as a r es u lt o f G V H di s ea se is h i gh . 4 . B ec au s e t he r ec ip ie n t o f t he m a r ro w ( h o s t) is im m u n os up p r ess e d, o wi ng t o p ri m a r y im m u n od e fi c ie n c y o r b y dr u gs or r ad ia t i on , h os t re j ec ti o n o f t r a ns p la n te d b on e m a r row i s l es s im p o rt a nt . D . P r o p h yl a x i s a n d t r e at m e n t o f g ra f t r ej e c ti o n 1 . I mm u no s up p r e ss i on o f t h e g r a f t r e c ip i en t a . C o r t ic o s te r o i ds (e . g ., m et h y l pr e dn is o lo ne , pre d ni s on e ) a r e a dm in is t e re d j u st be f o re t ra ns p la n ta t io n an d ra pi d l y ta pe r e d be c au s e o f t he i r s id e e f f ec ts . C or t ic os t e ro id s a r e us ed in c om b in a ti on wi t h a z a t hi o p ri ne , c yc lo s po r in e , o r a n t il ym p h o c yt e g l o b u l i ns / an t i th ym o c yt e g l o b u li n s ( AL G s / AT G s ) . b . Az a t h io p r i ne is gi v e n b e fo r e t r a ns pl an t a ti on . Ma i n t e n a nc e d os es a r e g i ve n a f te r wa r d . c . M e t ho t r e xa t e is us e d p r i m a r il y f o r b on e m a r row t r a n s pl a nt a ti o n i n c om b in a ti o n wi t h A L G / ATG . I t i s a dm in is t e re d e i th e r a f e w d a ys b ef o r e o r a t t h e ti m e of t ra ns p la n ta t io n . 2 . S pe c i fi c su p p re s si o n o f T c e ll s a . C yc l o s p o r i n e A ( c y c lo s po r in ) bi n ds t o a n i n t ra c el lu l a r p ro t ei n k n o wn a s c yc lo p hi li n a n d b lo c k s t he t r an s c r ip t io n o f c y t ok i ne g en es in a T c e ll th a t h a s r ec o gn i z e d a nt i ge ns . I n t h is wa y , i t i nh i bi ts T H c el l s ec r e ti on of I L -2 an d p r o du c ti on o f t he hi g h- a ff i n it y I L -2 r ec ep t o r a nd pr e ve n ts c o m p le t e T c e ll a c ti va t io n . I t i s a dm in is te r e d p r op h yl ac ti c a l l y b ec a u s e it is m o re e ff ec t i ve i f i t is p r es e nt be f o re r ej ec t i o n b eg in s . C y c l os po r ine A is c om m o n l y c om bi ne d wi t h o t he r ag e nt s . Th e m a j o r s i d e e f fe ct is ne p hr ot o xi c i t y . b . T ac r o l im u s ( F K - 50 6 ) i s a n i m m un os u pp r es s i v e a ge n t t ha t in hi b it s TH c e ll fu nc t io n i n t h e s am e wa y a s c y cl os p o ri ne A . B o t h d r u gs f u nc ti o n t h r o ug h t h e s a m e pa t h wa y a n d a r e n ot us ed t og et h e r . c . R ap a m yc i n ( s i r ol im us ) i nh i bi ts T H c el l re sp o ns e t o I L -2 an d p r e v e nt s T H c e ll ac ti v a t io n . I t wo r k s th r o ug h a di f f er e nt pa t h wa y t h an ei t he r c yc l os po r in e o r t ac r ol im us an d i s es pe c ia ll y e f fe c ti v e in c om b in a t io n wi t h t he o th e r d r u gs . d . AL G a n d AT G a r e a nti s e ra de r i ved f ro m a ni m al s . Th e y c on t ai n a v a r ie ty o f an t ib o d y s pe c i f ic i ti es a g ai n s t T c el l a n ti ge ns . Th e y a r e us ed bo t h
p r o ph y l ac t ic al l y an d th e ra p e ut ic al l y in bo n e m ar ro w a n d o rg a n t r a ns p la n ta t io n . e . M u r o mo n a b- C D 3 ( O KT3 ) i s a m o us e m on oc l on a l a n ti bo d y s p ec i fi c f o r t h e C D 3 a n ti ge n , wh ic h i s p re s en t o n a l l p e ri ph e r al T c el ls . O K T3 is us ed t h e r ap eu t ic al l y t o h al t a nd r e v e rs e a cu t e r e je c t i on a s s oo n a s i t i s d i ag n os ed . ( 1 ) I ts m ai n a c ti o n is th e o ps o ni za t io n o f T c e l ls fo r e nh an c e d ph ag oc yt o s is . I t is ad m i ni s te r ed da i l y fo r 1 0- 1 4 d a y s. O n l y o n e c o u rs e is t y p ic al l y us ed b e ca us e i t c a us es a n i m m u ne r es po ns e a g ai ns t th e fo r e ig n m ou s e an t ib od y . ( 2 ) A cu t e s i d e e ff e c t s a re c o m m on , p ro ba b l y b e ca u s e of no n s p ec i fi c T c ell a c ti va t io n th a t c a us es t he r el e as e o f c y t ok i ne s . Si d e e f fe c ts i nc l ud e h ig h f e ve r , c hi l ls , b lo o d p r es s u r e c h an ge s , v o m i t in g , di a r r he a , a nd r es pi r at o r y d i st r es s . O K T3 i s c o n t ra in d ic a te d i n p a ti e nt s wh o h a v e fl ui d o v e r l oa d b e ca us e i t m a y c a us e f a ta l pu lm on a r y ed em a . ( 3 ) O K T3 m a y a ls o b e u s e d in v i t ro to pu r g e d on or b o ne m a r ro w o f T c el ls t o r ed uc e t h e r is k o f G VH d is e as e . 3 . I n ve st i g at i o na l a g e nts b ei ng t es te d to p re v e nt o r re v e r s e g ra f t r e je c t io n i n cl ud e a n ti - T c el l i m m un o t o xi n s ( s e e VI I . C .1 ) , c o n ju g at e s o f I L -2 an d a t o xi n , a nd o th e r m on oc lon a ls th a t p r e v en t T c e l ls f r o m a dh e ri n g t o f o r ei gn g r a f t c e l ls . Th es e a ge n ts a r e a dm i ni st e re d to th e g r a f t r ec i pi en t . I n a d di t ion , m o no cl o na l a n ti bo d ie s ar e us e d t o m ask H L A a n ti g en s o n t h e g r af t ti s s ue b e f o re it is tr a ns pl a nt e d i n t o t he r ec ip i en t . P.217
VI. VACCINATION A. O ve r vi e w 1 . P as s i ve va cc i na t i o n i s th e i nt r am us c ul a r o r i nt r a v e n ou s i nj ec t io n o f a n t ib od y p r ep a r at i on s t o e n ha nc e a pa t ie n t 's im m u n e c om pe t en c e . P r o t ec t io n d e pe nd s o n th e s e r um h a lf - li f e o f t h e i n je c te d a n ti bo d y a nd is l i m i t ed to s e v e r al we e k s t o s e v e r al m o n th s f o r e ac h a dm i ni s t r a ti o n o f h um a n s e r a. 2 . Ac t i ve va c c i na t i on is t h e i nt r am us c ul a r, s u bc u t a ne o us , o r o r al i n t ro d uc t io n o f o n e o r m o r e an t ig en s d es ig n ed t o s t im ul a te th e i m m un e s ys t em to pr o du c e a s pec i fi c im m un e r es p on se . Th i s r es po ns e g e ne r a te s a n t ib od y , ac t i v a te d T c e ll s , a nd sp ec i fi c m e m o r y. P r o t ec t io n t h r ou gh m em o r y v a r ie s wi t h t he va c c i ne , b u t i m m un i t y i s lo n g l as t in g . B . P a ss i ve va c ci n a t io n ( Ta b l e 1 0 - 2 ) 1 . P r e pa r a t io n s. D os es o f in t r am us cu la r p re pa r at i o ns a r e s om e ti m e s g i v en i n un i ts p e r k il o gr am an d s om e ti m e s i n m i ll i li t e rs p e r k il o g ra m . Th e do s e va r i e s wi t h t he v ac c i n e an d pa t ie n t p op u la ti o n. I nt r a ve n ou s p r ep a ra t io ns ar e c om m o n l y u s ed in hi gh do s es .
a . S t an d a r d h um a n s e ru m im m u no g lo b u li n f o r i n t r am u sc u l a r va c c i n a ti o n i s a p o l yc l on a l a n ti s e r um pr e pa r e d fr o m p o ol ed pl a s m a o f d o n or s . I t c on t ai ns 16 5 m g /m L h um an im m u n og lo b ul i n, P.218
p r e do m i n an t l y th e f o ur s u b c l as s e s o f I g G . Si d e ef f e ct s a r e r a re , m i ni m a l , a n d u su a ll y c o n fi n ed to m i no r i n fl am m a t io n a n d p a in a t t he si t e o f i nj ec t io n . Th i s p re p ar a ti o n is un s u it a b le fo r in t r a ven ou s i nj e c t io n b ec a us e a n ti bo d y a g g re g at es f o rm a n d m ay a c t i v at e c om pl em e nt an d pl a te le t s.
Table 10-2. Passive Vaccines Illness
Vaccine
Rationale
Intramuscular Hepatitis B (HBV)
Hepatitis B immunoglobulin (HBIG)
Prophylaxis
Hepatitis A (HAV)
Immunoglobulin, intramuscular (IGIM)
Prophylaxis
Non-A, non-B hepatitis
IGIM
Prophylaxis, therapy
Measles
IGIM
Prophylaxis, therapy
Rabies
Rabies immunoglobulin (RIG)
Prophylaxis
Rubella
IGIM
Fetal prophylaxis in exposed mother
Varicella
Varicella zoster immunoglobulin (VZIG)
Prophylaxis and therapy in immunocompromised individual
Tetanus
Tetanus immunoglobulin
Prophylaxis
(TIG) Hypogammaglobulinemia
IGIM
Therapy for antibody deficiency
Rh disease
Rho (D) immunoglobulin (RhoGAM)
Prophylaxis during pregnancy and after delivery of Rh+ fetus by Rh- mother
Botulism
Botulism antiserum (equine)
Prophylaxis, therapy
Snakebite
Polyvalent antivenin (equine)
Prophylaxis, therapy
Black widow bite
Black widow antivenin (equine)
Prophylaxis, therapy
Hypogammaglobulinemia
Intravenous immunoglobulin (IVIG)
Therapy for antibody deficiency
Idiopathic thrombocytopenic purpura (ITP)
IVIg
Therapy
Chronic lymphocytic leukemia
IVIg
Therapy for antibody deficiency
Cytomegalovirus (CMV) infection
CMV IVIG
Therapy in renal transplant patients
Intravenousa
Acute renal rejection
Muromonab-CD3 (murine)
Reversal of acute rejection
a
U.S. Food and Drug Administration-approved uses; many others currently in trials result from vaccine preparation in cells of nonhuman origin. The valence of a vaccine indicates the number of strains of organism included (e.g., trivalent polio vaccine includes three strains of poliovirus).
b . S p ec i al i nt r a m us c ul ar i m m un o g lo b ul i n s ( I G IM s ) a r e i nd i v i du al s e r a p r e pa r e d f r om p l as m a l ot s of s u bj ec t s ac t i vel y im m u ni z e d a g ai ns t o r r e c o ve ri ng f ro m s pe c i f ic d i s e as es . Ea c h s e r um is e n ri c he d f o r a n ti bo d ie s o f t h e d es i r ed s p ec if ic i t y (e. g . , t e ta n us i m m u no gl o bu l in c o n ta in s m o re a n t ib od i es ag ai ns t te t anu s to xi n t h an wo u l d b e fo u n d in I G I M) . c . I VI G s a re pr e pa r e d f ro m p o ol e d h um an s e r um a n d m o d if i ed to m i ni m i z e a n t ib od y a g gr e ga t io n . C h i ll s , n au s e a , a nd ab d om i na l p ai n o c c u r i n a p p ro xi m a t el y 1 0% o f p at i e nt s . S id e e f f ec ts ar e di m in is he d b y r e du c i n g t he r a t e o f i n t ra v e n ou s i nf us io n . P re m e di c at i on wi t h c o r t ic os t e ro id s i s r e c om m e nd e d, an d i n t rav e n o us ep i ne ph r i ne is u s e d if an a ph yl a xi s oc c u rs . d . An i m a l a n t is e r a. E qui n e ( h o rs e ) a nt is e r a a re u s ed in c e r ta i n s i t ua t io ns ( Ta b l e 1 0 - 2 ). Mo u s e m on o c l o na l a n ti bo d y (m u r om o na b - C D 3 ) is us ed in a c ut e re n al re j ec ti o n ( s ee V . D . 2. e ) . Th e ha l f -l i v es o f a ni m a l a n ti bo d ie s a re s h o rt e r i n h um a ns . 2 . R a t io n al e s f o r pa s sive va c c i n a ti o n a . P r o ph yl a x i s o f i n f ec ti o u s d i se a se . An t ib o di es a re gi v e n p r o ph y l ac t ic al l y t o p re v e n t c l in ic a l s y m p t om s o f a v i r a l o r ba c t e ri a l i n f ec ti o us p r oc es s , p a rt ic u la r l y i n a p at i en t wi t hou t p re vi o us e xp o s u r e a nd t h e r ef o re wi t h o ut im m u no l og ic m e m o r y . Th e v ac c i n e p r o te ct s t h e r ec ip i en t d u r in g th e i nc ub a ti o n p er i o d f o r i n fe c t i on . F o r e x a m pl e : ( 1 ) C lo s t ri di u m t et a ni i n fe c ti o n h as a n i nc u ba t io n p e ri o d o f a p pr o xi m a te l y 5 d a ys b e f or e s ig n if ic a nt qu a n ti t ie s o f t e ta n us t o xi n a r e p r od u c e d . A p rim a r y i m m u ne r es po ns e o f 7 - 10 d a ys is to o s lo w. P a ss ive v a c c i n at i on wi t h t e ta nu s i m m u no gl o bu l in ( TI G ) bin d s t he t o xi n an d p r e v ent s di s e as e . ( 2 ) H e pa t i t is B im mu n og l o b ul i n ( H B I G ) is ad m in i st e r ed to in d i v id ua ls as s o on as po s s ib le a ft e r exp o s u r e to p re ve n t v ir a l in f ec t io n . b . P r o ph yl a x i s o r t he r ap y p r e v e n t s or a tt e nu a tes t he ef f ec ts of in f ec t io n i n s p ec ia l p o pu la t io ns . E xa m p le s a r e t he us e o f va ri c e l la z o s te r i m m un o g lo b u li n ( VZ I G ) i n i m m un oc om p r om is ed p a t ie n ts a n d t he us e o f I G I M i n p r e gn a nt wo m en wh o a r e e xp o s e d t o ru be l la an d h a ve no t b e en a c ti ve l y v a c c in a te d .
c . T re a t me n t o f an t i bo dy d e f i c i e n c y. I n d i v i d ua ls wh o a r e d e fi c i e nt in a n t ib od y p r od u c t io n , e i the r b ec au se of p ri m a r y im m u no d ef ic i en c y (s ee I V ) o r as a r es u lt o f c h r on ic l y m p ho c yti c l eu k em ia , rec e i ve i nt r a v e no us i m m u no gl o bu l in ( I VI G ) or I G I M e v e r y 2 - 4 we e k s to m a i nt a in hu m o r al i m m u ni t y . I VI G is p re f e rre d . d . O t h e r s i t ua t i on s . I V IG i s u s e d fo r i d io p at h ic (a u t oi m m un e ) t h r om b oc y t op e ni a p u rp u ra . I nt r am us cu l ar R h o ( D) im m u n og l ob ul i n ( R h o G AM) i s u se d p r o ph y l ac t ic al l y fo r R h d is e as e ( s e e II . C .5 . c ). Mu r o m on a b - C D3 (s e e V . D . 2 . e) is us ed fo r ac u te r e na l g r af t re j ec ti o n. C . Ac t i ve va c c i n a ti o n (Ta b l e 10 - 3 ) is us ed f o r pr o p h y la xi s . 1 . O ve r vi ew a . C o n te n ts . Ac t i v e v ac c i n es c o nt a in on e o r m o r e s ub u ni ts o f a p a th o ge n o r wh o l e p at h og en ic o rg a nis m s bu t m a y al so c o nt a in p r e s er v a t i v es , l o w d o se s o f an t ib i ot ic s , a nd ot h er c om p ou n ds th a t d o n ot af f e c t th e i m m un e r e s po ns e . b . Ad m i n i st r a t i on . Ac t i ve v a c c in e s a re ad m i n is ter e d s u bc ut a ne o us l y, i n t ra m us c u la r l y , i n tr a de rm a ll y , o ra ll y , o r i n t ra na s a l l y . So m e a re in t ro d uc ed a d so r be d to al um in um hy d r o xi d e o r al um in um pho s ph a te ad j u v an ts . A n a d ju va n t i nc r ea s es t h e an t i ge ni ci t y o f t h e v a c c in e. c . S e ro c on ve r s i o n. F or m os t ac ti v e va c c in es , the s u cc es s o f t h e se r i es of va c ci n at i on s i s in d ic at e d b y s e ro c o n v e rs io n o f the p at i en t . S e r oc on v e r si on i n di ca t es th a t a pe r s o n wh o p r e vi o us l y d i d n ot ha v e sp e c i fi c s e ru m a n t ib od i es (i . e ., s e r on ega t i v e ) n o w h as t he se an ti b od i es (i . e. , s e r op os i ti v e ) . S e r o co n v e rs io n d o es n o t i n di c a t e es t ab l is he d i m m u ni t y f or c e r t ai n vac c i ne s ( e . g ., ba c i l lu s C a lm et t e -G u é r i n va c c in e fo r tu b erc u lo si s ). d . A s c h ed u l e o f a c t i ve va c c i na t i o n is r ec om m e n d ed fo r in f an ts an d c h il d re n ( Ta bl e 1 0 -3 ) . The f i rs t v ac c i na t io n i s g i ve n af t e r t he in f an t is 6 we e k s ol d b ec au s e r es po n s e s a r e n o rm al l y in ade q u at e i n n e wb o r ns an d b e ca us e m a te r na l a n ti b od i es r em ai n i n t h e n e wbo r n c i rc ul a ti o n; s o m e va c ci n es (e . g ., he p at i ti s B v i r u s ; H B V ) , h o we v e r , m a y be gi v e n i m m e di at e ly a f t e r b i rt h . S om e v ac c i ne s a r e i n te n de d f o r u s e p r i m a r il y i n n on in f an t p o p ul at i on s . P.219
P.220
Table 10-3. Commonly Administered U.S. Food and Drug AdministrationApproved Active Vaccines
Vaccine
Target Populationa
Number of Vaccinations Schedule
Notes
Live, attenuate d viral Oral polio (OPV; trivalent)
Infants, children, healthcare and daycare workers
4
2, 4, 15-18 months; 1 at school entry
Approxim ately 1 in 2.6 million risk of vaccinein duced paralysis; no longer recomme nded because of risks; substitute killed vaccine
Measles, mumps, rubella (MMR)
Infants, children
2
15 months (< 12 months if high risk); 1 at school entry
Generally affords lifelong immunity
Rubella
Adolescent girls not previously vaccinated
1
Postpubert y
Protects future fetus from congenital rubella injury
Varicella
Children, other at-risk individuals
1 (if ≥ 13 years old, 2)
1 between 12 and 18 months or 2-3 years; after 13 years old,
Duration of immunity or effect on developm
Influenza (trivalent)
2-4 weeks apart
ent of shingles unknown
Individuals between 5 and 59 years old at risk for infection
1 per year
Annually for maximum protection
Administe red intranasall y
Individuals exposed to sputumpositive tuberculosis patients
Varies
Depends on success or initial vaccinatio n
Unpredict able effectiven ess; induces cellmediated immunity
Influenza (trivalent or polyvalent )
Geriatric patients, healthcare workers, individuals at risk for complications
1 per year
Annually for maximum protection
Variant strains may appear each year; vaccine must be updated annually
Hepatitis B (HBV)
All
3
Between 1 and 2 months, 2 and 3 months,
Recombin ant, subunit
Bacterial BCG tuberculos is
Killed, inactivate d viral or viral subunit
after 6 months Inactivate d polio (IPV; trivalent)
All children; as booster in healthcare and day-care workers
4
2, 4, 15-18 months; 1 at school entry
No slgA; thus reduced protection ; no paralysis risk
Killed, inactivate d viral or viral subunit Animal-care workers
4 or 5b, with boosters
7 days apart; boosters as required to maintain immunogl obulin
Two doses to exposed, already immune individual
Diphtheri a, tetanus, pertussis (DTP)
Infants, children
4, with boosters
2,4, 15-18 months; 1 at school entry
Tetanus toxoid (Td) booster every 10 years or on exposure through a wound
Tetanus and diphtheria
Children ≥ 7 years old; adults with no
3, with boosters
Second dose in 4-8 weeks;
Td booster every 10
Rabies (HDCV)
Bacterial, subunit
toxoids (Td)
vaccination
third dose 6 months later
years or on exposure through a wound if more than 10 years or vaccine history unavailabl e
Haemophi lus b (Hib)
Infants, children, HIVinfected adults
Depends on formulati on
Depends on formulatio n
Polysacch aride capsule is poor antigen; conjugate vaccines enhance potency
Pneumoco ccus (polyvale nt)
At-risk adults or children ≥ 2 years old (e.g., immunocompr omised patients, geriatric patients)
1 or 1 per year
As necessary in at-risk patients; not given during active infection; 1 per year in geriatric patients
Poor response to polysacch aride antigen in children < 5 years old
Meningoc occus (quadrival ent A, C Y, W135)
College freshmen living in dormitories; high-risk adults or children ≥ 2 years old, including individuals
1, subcutane ously
As necessary in at-risk individuals at 3- to 5year intervals
Polysacch aride vaccine give poor response in children < 2 years old; does not
with complement component deficiencies or anatomic or functional asplenia
protect against serotype B, which accounts for 46% of cases
BCG, bacille Calmette-Guérin; HDCV, human diploid cell vaccine; slgA, secretory immunoglobulin A. a
Entire target population is not listed in all cases.
b
Five doses to already exposed individuals.
P.221
e . Mo s t v a c c in es r eq ui r e a se r i e s o f va cc i na t i ons ; o t h e rs a re ef f ec ti v e wi t h a si ng l e v a c c i na ti o n. F o r t h os e t ha t re q ui r e a s e r i es , i nt e r v a ls b e t we e n va c ci n at i on s g r ea t e r t han t ho s e r ec om m e nd e d do n ot ge n e ra ll y d im in is h p r o t ec ti o n. Th e d u r at i on o f m e m o r y v a r ie s wi t h ea c h va c c i ne , a n d b o os t er va c c i n a ti o ns a re of t en n e c e s s a r y . f . S i de e f fe c ts in c l u de in f l am m a ti o n a t t h e s i t e of v a c c i na t io n , m a l ai s e , m i l d f e ve r , c hi l ls , h ea d ac he , m y a l gi a , a nd a rt h ra l gi a . Mo r e s e ve r e s id e e f fe c ts i n cl ud e fe b ri l e il l ne s s , s o m no l en ce , s ei z u r es , o r a n a ph y l ac t ic h yp e r se ns i ti v i t y t o v a c c in e an t ig e ns o r ac c es s ory c o m p o ne n ts (e . g. , a n t ib io t ic , c hi c k en p ro t ein ) . S e v e re re a c t io n s c o nt r a in d ic a te c o nt i nu a ti on o f a se r i es . A pe r s o n wi t h s e v e r e fe b ri l e i ll ne s s s h ou l d n o t b e ac t i v el y va c ci n at e d u n ti l t he il l nes s r e s o l v es . 2 . T yp e s o f a c t i ve vac ci n e s a . L i ve , a t te n u at e d vacc i n es c o ns is t o f wh o le or g a ni s m s ( us u al l y v i ru ses ) . Th e s e o r g an is m s m ul t ip ly a f t e r v ac c i na t io n , b ut ar e a tt e nu a te d t o re d uc e t h e ir p at h og en ic i t y . ( 1 ) A s m a ll d os e p ro d uc e s a s t r o ng i m m u ne re s po n s e be c a us e th e a n ti gen c o nc en t r at i on in c re as es wh e n t h e o r ga n is m m u lt ip l ie s . S om e vac c i ne s e lic i t l i f el on g i m m un i t y in t wo d o s e s —f o r e xa m p l e, t he m e as le s , m u m p s , r ub e ll a ( M M R ) v a c c i ne . Be c a us e o f th ei r r el a ti ve ge n et ic i n st a bi li t y , v i r us es c a n r e v e r t to v i r ul en c e a nd c a u s e th e d is e as e a ga i ns t wh i c h th e p a ti en t is va c ci n at e d . Th i s is a p a rt i c u l ar p ro b le m wi t h on e o f t he s e ro t y p es of t he o r a l p ol i o v a c c in e ( O P V ). ( 2 ) Li ve , at t en u at e d v i r a l v a c c i ne s a r e n o t r ec om m e nd e d f o r p r eg na n t wo m e n o r t ho s e in t en d ing t o b ec om e p r eg n an t wit h i n 3 m on t hs of
va c ci n at i on . L i v e , a t te n ua t e d v i r a l o r b ac t e ri al v ac c i n es a r e n o t g i v en t o i m m u no c o m p r om is e d i ndi v i d ua ls . b . K i l le d , i n ac t i va t ed va c c in e s m a y c on t ai n who l e k il le d c el ls ( e. g . , p h e no l -k il le d Bo r d et e ll a p e r t us s is ) o r a n y a n ti g eni c fr ac t io n i s o l at e d f r om t h e o r g an is m . Th e y a re u s ua ll y g i v e n a ds o rb ed to a dj u va nt . c . S om e is o la t ed an t ig ens ( su b u ni t va c ci n es ) m a y r e q ui r e i na ct i v a ti o n b e f o re th e y a re us ed in a v a c c in e — fo r e xa m p l e , f o rm a ld e h y de - m o di f ie d t o xi n o f C lo s t r id i u m te t an i , k no wn a s te t an u s t ox o i d (T d ) a f te r m o di f ic at i on . I n ac t i v at i on e li m i na t es pa t ho g en ic ity , b u t p r es e r ves s om e a n t ig en ic i t y . O th e r s ub un i t v ac c i ne s i nc lu d e p r ote i ns an d g l y co p r ot ei n s of a n o rg an is m t h at a re p rod u c e d b y r ec om b in a nt DN A t e c h no l og y i n b ac t er ia , ye a s t , o r m am m a li a n c e l ls an d a r e t h en us ed as th e an t ig e ns f o r va c ci n at i on . Th e H B V v ac c i n e c o n t ai ns pr o te i ns pr o d uc ed b y r ec om bi na n t g e n et ic te c h n ol o gi es an d i s a pp r o v e d b y t he F D A f o r us e i n h um an s . ( 1 ) B ec au s e n o li v e o rg an i s m s a re p re s e n t, r e v e rs i on to pa t ho g en ic i t y i s n o t a p r ob le m . H o we v e r , do s e s o f c e ll s o r a n ti ge n s m u s t b e h ig h e r t ha n i n l i v e, a t t en u at e d v a c c i ne s , and h y p e rs en s i t i v it y r e ac tio n s t o v ac c i ne c o m p on en t s a r e m o re c o m m on . Mi n im um e ff ec t i ve d os es a re u s u a ll y m e as u r ed in n u m b e rs of c e ll s o r m ic ro g r am s o f a n ti ge n . ( 2 ) V ac c i ne s i n wh ic h t he a nt i ge ni c f r a gm en t i s a p o l ys ac c ha r id e (e . g. , H a e m o p hi lu s b ) ar e u s u al l y p oo r at el ic i ti ng im m un e r es po ns es an d m em o r y, pr o ba b l y b ec a us e th e y do no t e vo k e T c e l l a ct i v a ti o n. Th e se va c ci n es ha v e be e n im p ro v e d b y c o nj ug a ti n g t he p o l y sa c c ha r i de to an o the r a n t ig en ic c o m p o un d (e . g. , Td ) . Th es e a r e k no wn a s c o n ju g a te va c ci n es . 4 . E xp e r i me n ta l va cc i ne s in c l ud e ot h er s u bu n it v a c c i n es ; p e pt i de s p r o du c e d b y c he m i c a l , c e l l -f r e e s y n th es is ; re c o m b i n a n t D N A vi r us es c o nt a in in g ge ne s f o r t h e a n t ig en s o f m ul t ip l e o r gan i sm s ; an d a n ti - id i ot yp e a n t ib od i es us ed fo r ac ti v e v a c c in a ti o n. 5 . S pe c i fi c va cc i n es i n c om m o n u s e a nd re c om m e nd e d a dm in is t ra t io n s ch e du l es a r e l is t ed in Ta b le 10 - 3 . D . S i m ul t a ne o us a dm i ni s t r a t io n o f a ct i ve a nd p a s si ve va c c in e s. S o m et im es ac t i v e a nd pa s s i v e v ac c i n es a g ai ns t a p at h og e ni c o rg a ni s m ar e a d m i ni s te r ed s i m u l ta ne ou s l y to m a xi m i ze p os t e xp o s u r e p r op h y l a xi s . Th e i m m u no gl o bu l in of f e rs im m e d ia t e p r ot ec t io n , a nd t he ac t i v e v a c c in e s t im ul a te s a n i m m un e res p on s e . Th es e v ac ci ne s a r e gi v e n a t s ep a r at e s ite s t o p re ve n t a n ti bo d y ( pa s s i v e ) a n d a nt i ge n ( a ct i v e) f r om r ea ct i ng an d i n ac t i vat i ng on e a n ot h er . 1 . I nf a nt s wi t h H B V wh o a r e bo r n t o m ot h e rs wh o h a ve th e h ep a ti t is B s u r fa ce an t ig e n ( H B s Ag ) a r e s ig n if ic a nt l y p ro t ec te d f ro m b ec om in g c h ro n ic c a r ri e rs b y th is c o m b in ed p r op h yla xi s . 2 . R a bi e s. P os t e xp o s u r e p r o ph y l a xi s t y pi c a l l y i ncl u de s t h e co m bi ne d u s e o f a c ti ve an d p a s s i v e v a c c in e s b ec au s e o f t he le t hal n at u r e o f t he un c he c k ed i n f ec ti o n. Th e e xc e pt i on i s p a ti e nt s wi t h a p r e v i ou s a c ti v e v ac c i n at i on wh o h a ve s u f fi c i en t e xi s ti n g s e r u m a nt i bo d y c o nc en t r at i o n. P.222
3 . T et a n us . Co m b i ne d pr o p h y la xi s i s s o m e t im es u s ed , d e pe n di ng on t he t yp e o f wo u n d a n d t he pa t i en t ' s h is to r y o f a c t i ve v a c c i n at i on . R ec om m e nde d g u id e li n es a r e a s f ol l o ws : a . A t e t a n us - p r on e w oun d is on e t h at p ro d uc es a n a er o bi c co n di t io ns ( e.g . , d e e p p un c t u r e) o r o ne in wh i c h e xp o s u r e t o Cl os tr i d iu m o r i t s s p o re s i s p r o ba b le ( e. g ., c o n ta m i na t e d wi t h an im a l f ec es ) . I f t he pa t ie n t 's hi s t o r y o f a c ti ve va c c in a ti o n is un c e r t ai n or in c l u de s f e we r th a n t h r ee do s e s, bo t h TIG a n d Td a r e a dm i ni s t e re d. Th e p at ie n t re t ur ns t o c o m pl e te th e to xo i d s e r ies . ( 1 ) I f t he wo u n d i s t et a nu s - pr o ne bu t th e p a ti e nt r e c ei v e d a fu l l s e r ie s o f a c ti ve va c c in a ti o n, no t re a tm e nt is ne c e s s a r y i f th e la s t Td d os e wa s r e c ei ve d wi t hi n t h e l as t 5 y e a rs . ( 2 ) I f t he la s t d os e wa s re c ei v e d m o re th a n 1 0 y ea r s a g o, Td , bu t n o t TI G , i s g i v e n t o b oo s t m e m o ry i m m u ni t y a nd an t ib od y p r o du c ti on . b . F o r a c l ea n , m i no r w o u n d , i f t h e p at i en t ' s h is t o r y o f a ct i v e vac ci n at ion i s u nc e r ta i n o r i nc lu d es fe we r t h a n t h re e d os es , Td is ad m i n is te r e d. ( 1 ) I f t he pa t ie n t r e c e i v ed a fu ll s e r ie s o f a c t i v e va cc i na t io ns , n o t re a tm ent i s n ec es s ar y i f t h e l as t Td d os e wa s r ec e i v ed wi th i n 1 0 yea r s . ( 2 ) I f t he la s t d os e wa s re c ei v e d m o re th a n 1 0 y ea r s a g o, Td , bu t n o t TI G , i s g i v e n t o b oo s t m e m o ry i m m u ni t y a nd an t ib od y p r o du c ti on .
VII. PROSPECTS FOR IMMUNOMODULATION A. F a b a n ti d i go x i n a n tib o d y p r e p a r at i on s o bt a in e d f r om s h ee p a r e a p p ro ve d fo r th e re v e r s al o f t o xi c i t y a s s oc i at e d wi t h t o xi c d ig o xi n se r um l e ve ls . Th e a n ti bo d y bi nd s d i go xi n a n d p re ve n ts i t f ro m b in d in g t o i t s n orm a l r e c ep t or s i t e. Th e Fa b -d ig o xi n c om pl e x i s e xc r e ted r e na ll y. B . M on o c lo n al a nt i b od ie s a re ge ne r a ll y p ro d uc ed t h ro u gh th e i n v it r o f u si o n o f a c a nc e ro us pla s m a c el l (m ye lo m a ) wi th a n ac t i v a te d m ou s e B c e ll . Th e r es u lt i ng h yb r i d o m a s ec re t es m u r in e (m o us e ) a nt i bo di es o f a s i ng le de f in e d s pe c i f ic it y a n d h as th e i m m o rt al i t y c h a ra c t e ri s ti c o f t h e m ye l om a. Te c hn iq u es for t h e p r od uc t io n o f h um an m o n oc lo n al an t ib od i es a n d a va r ie t y o f h y b ri d m o u s e - hu m an m o no c l on a l a n t i b od i es ar e a ls o a va i la b le . 1 . M o n oc l o na l a n t ib o d ie s — f or e xa m p le , wh o le a n t ib od i es or F ab or F (ab ' ) 2 f r a gm e nt s —a r e r o ut i ne l y u s e d fo r i n vi tr o di ag n os t i c t es ts ( e .g . , b lo o d g rou p a n d t is su e t y pi ng f o r H LA ) , s c r ee n in g f o r c an ce r -r e l at e d a n ti ge ns ( e. g . , c a rc i no em b r y on ic an t ig en ; C E A ) , u r in e t es t in g for d r ug s a n d m e t ab o li te s , a n d t es t in g fo r H I V i nf ec t i o n. In t he se an d m an y o t h e r d ia gn os t ic a p pl ic a ti o ns , m on oc l on al a n ti b od ie s a r e o f te n c onj u ga t ed t o e n z ym es , r a d io is o to p es , o r fl uo r es c e nt d y es . 2 . M u r o mo n a b- C D 3 is us e d t o t r ea t ac ut e g r a f t re j ec t io n . O t h e r m o n oc lon a l a n t ib od i es ar e u s e d fo r tr e a tm e nt of b re as t c a nc er a n d l eu ke m i a . 3 . I n cl in i c a l t r ia ls , th e us e o f mo n oc l o na l a n t i bo d i es a ga i ns t T c e ll s c a us es i m pr o v em e n t in c e r t ai n au t oi m m un e d is o rd e r s.
4 . M o n oc l o na l a n t ib o d ie s ag a i ns t ne o pl a s ti c ce l l s s ho w s o m e s uc c e ss , a n d a r e u s e f ul in t re a ti ng c e r t ai n l e uk em ia s a nd l y m p ho m a s , as we l l a s b r e as t a n d c o l on c a nc e rs . C . M on o c lo n al a nt i b od ie s a re c on j ug a t ed t o e nz ym e s , d r u gs , p ro d r u gs , r a d i o is o t op e s, o r pl a n t a n d ba c te r i a l t o xi n s t o p r o v i de s p ec i fi c d el i ve r y o f t he c o nj ug a te d a g en t t o on e o r m o r e f oc us e d in v i v o si t es o f ac ti o n. S e ve r a l p r ob le m s a re as s oc i at e d wi t h t he us e o f t h es e a g en t s. 1 . I mm u no t o xi n s a r e us u a ll y p r od uc e d b y t he c on j ug a ti o n o f a m o no c l o na l a n t ib od y t o a bi o lo gi c p ol y p e p ti de t o xi n ( e. g ., di p h t h e ri a t o xi n ) t ha t i s m o di f ie d t o re d uc e n on s p e c i f ic to xi c i t y . 2 . A lt h ou g h t he y a r e b ein g te s te d f o r g r a ft r ej ec t io n an d a u to im m u n it y , i m m u no t o xi n s a r e p ri m ari l y us e d as an t in e op l as tic a g e nt s . C l in ic al t ri a ls s h o w m od e ra t e s uc c es s i n t re a ti ng le u ke m i a a nd l y m p ho m a , wi t h l o we r s uc c ess r at es ag a in s t t um o rs s u c h as b r e as t c arc i no m a . 3 . M o n oc l o na l a n t ib o d ie s co n j ug a te d t o r a d io is o t o pe s (e . g. ,
90
Y) c a use
r e m iss i on s i n p at i en ts wi t h H od g ki n d is ea s e an d a c u t e T c e l l le u ke m i a . 4 . M o n oc l o na l a n t ib o d ie s co n j ug a te d t o e nz ym e s t h at ac t i vat e a p ro dr u g t o t he ac ti v e d ru g a t a s p e c i f ic ti ss ue s i te ( e. g . , n e o pl as ti c c el l s u rf ac e ) a r e i n hu m a n t r i al s . P.223
D . I m mu n os t i mu l a ti o n h a s b ee n a t te m pt e d wi t h a v a r ie t y o f c o m p o un ds , r a n gi n g f r om c y t ok i ne s to b ac te r i al pr o du c t s ( Tab l e 1 0 -1 ) . 1 . I F N - α h as m a n y s u bt y p e s . Two a r e c u r r en t l y FD A a p p ro ve d . B ec a us e i t i n hi b it s c el l g r o wt h , i t i s u s ed to t re a t h ai r y c el l le u k e m i a , K a po s i s a rc om a i n pa t ie n ts wi t h AI D S , a nd g en i ta l wa r ts . A t l o w do s es , i n te r fe r o ns s t im ul at e i m m u ne c e ll ul a r f u nc t io n ( e . g. , T c e l ls , N K ce l ls , m ac r o ph a ge s) , bu t a t hi gh d o se s, t he y a r e im m u n os u p p re s s i ve . Th e us e o f IF N - α a g ai ns t o t he r c a nc e rs p r o du c e s v a r i abl e re s ul ts . 2 . I F N -γ p r o v i de s g r ea t er i m m un os t im ul a ti o n in th e in t ac t i m m un e s y s te m , b u t i t s e ff ec t s d ep e nd on d os e a n d t im in g . Th e c om b in e d us e o f IF N - α a nd I F N - γ yie ld s b e tt e r re s u l ts . Th e m os t c om m o n s ide e f fe ct s o f i n te r f er o n t h e r ap y a r e in f lu e n z a -l ik e s y m p t om s . IF N - γ i s a pp r o ve d f o r u se as a m ac r o ph a ge - ac ti v a t in g fa c to r in c h r on ic g ra nu l om a to us di s e a se . 3 . S e ve ra l p r o to c o ls us ing I L -2 s h o w p r om is in g res u lt s , wi t h ap p a re n tl y c om p le t e r em is s i o ns i n s o m e p at i en ts wi t h m e la no m a. W it h t h is te c h ni q ue, k n o wn as ad op t i v e i m m un o t he r ap y , a p a ti e nt ' s p er i p h e r al bl o od l ym p ho c y t es , o r t u m o r - inf i l t ra t in g l ym ph oc y t es , a re r em o v e d. Th e y a re c u lt u r ed wi t h I L - 2 a nd r ei n f us ed wi t h a d di t io n al IL - 2 . Th es e I L -2 - r es po n s ive c e ll s a r e li k el y T c el ls and N K c e ll s . S e ve re c a pi l la r y l e ak ag e s y n d ro m e , o cc a si on a ll y l ea di n g t o de a t h, is a p ro b le m a t ic s id e ef f ec t . 4 . H o r mo n es o f t h e t h ym u s t h a t in d uc e T c e ll m a t u r at i on an d o t he r f u nc t io ns a re us ed t o i nc r e a s e c e r ta i n ce ll - m e d ia te d im m u ne fu nc t io n s, wi th va r i a bl e re s u l ts .
5 . S ul f u r- c on t ai ni n g c o m p o u nd s , su c h as le va m is o l e ( a p h en y l im i do t hi a zo l e a n t he lm in t ic ) an d d ie t h y ld i t hi oc a rb am a te ( Im u t h io l ) , ha v e i m m u no s t im u la t o r y a c ti v it y . Th e i r ef f ec t i s g r ea t er o n c el l -m e di a te d i m m u ni t y t ha n o n h um o ra l im m u ni t y . Le v a m i so le i s a p p ro v e d a s a n o r al a g e nt fo r us e i n c ol on c an c e r i n c o m b i na t io n wi t h f l u or o u ra c i l . 6 . I no s in e p ra n o be x i s li c en s e d f o r u s e in m a n y c o un t r ie s as an i m m u no s t im u la n t. I t i nd uc es T c el l d i ff e r en t ia t io n a n d a u gm en ts ce ll m e di a te d i m m un e f u nc ti on s , wi t h m i n im al to xi c i t y. 7 . A s a c om po n en t o f m y c o ba c t e r ia l c el l wa ll s , mu r a m yl d i p e p t i d e ( M D P ) s t im ul a te s m ac r op ha g e ac t i v a ti on an d m a y be us ed as an ad j u van t , g i ve n wi t h a n ti g en (s e e I ) , o r gi v e n al on e as a n i m m un os t im ul a nt . P.224
STUDY QUESTIONS D i r e c t i on s : E a c h qu es t io n , s t at em e nt , or i te m o r i nc om p le t e s ta t em en t i n t h is se ct i on c a n b e c o r r ec t l y an s we r ed o r c om pl e te d b y on e o f th e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r . 1 . A m a n h a s s ym p t o m s o f a vi r a l in f ec t i o n o f a b o u t 4 da ys ' d u r a t i o n . T o c on f i r m t h e d i ag n osi s , t he ph ys i c i a n d raw s a b lo o d s am p l e a nd r e q u es t s th e a n t i bo d y t i t e r ( le ve l ) f o r t h e s u spe c t e d a ge n t . T h e f i r s t b l o o d s am p le s how s a low ti t e r of a nt i b od y. A w e ek la t e r , a n ot h e r b l oo d s a m pl e is d raw n , a n d th e t i te r a ga i ns t t he vi r us i s m u ch hi g h e r. T hi s s i t u a ti o n i s a n e x am p le o f ( A ) a n i nf l am m a t or y r e s po n se to t he v i r al i n fe c ti on . ( B ) a pr im a r y im m u ne r es p on s e t o t he v i r al i n f ec ti o n . ( C ) a s ec o nd a r y im m u ne r e s p o ns e t o t h e vi r al in fe c ti o n. ( D ) a c e ll ul a r re s p o ns e to t he v i r al in f ec ti o n. V i e w A n s we r 1 . T h e a n sw e r i s B [ se ea n d] .2 . W h ic h c la ss o f a n t i bo d y h a s t h e l o ng es t s e ru m h a l f -l i f e a n d op s o n iz es an t i ge n s f o r p h a g oc yt o s i s t h r ou g h tw o d i f f e re n t pa t hw a ys ? ( A ) I m m un o gl ob u li n G (Ig G ) ( B ) I m m un o gl ob u li n M ( Ig M) ( C ) I m m un o gl o bu li n A ( Ig A ) ( D ) I m m un o gl o bu li n E ( Ig E ) V i e w A n s we r 2 . T h e a n sw e r i s A [ se e] . 3 . U r ti c a ri a t ha t ap p ea r s r a p i d l y a f t e r t h e i ng e st io n o f fo o d u s ua l l y i n d i c a t es w h i ch t yp e o f h yp e r s e n s i t i vi t y r e a c t io n ? ( A ) Ty p e I ( B ) Ty p e I I ( C ) Ty p e I I I ( D ) Ty p e I V
V i e w A n s we r 3 . T h e a n sw e r i s A [ se ea n d] .4 . I n w h ic h au t o im m un e d i s o r de r i s t h e m ec h ani s m o f p at h o ge n es i s c la s s i fi e d a s t yp e I I h yp e r s e n s i t i vi t y? ( A ) S y s t em ic l u pu s e r y t he m at os u s ( S L E ) ( B ) I ns u li n -d e pe nd e nt dia b e te s m e l li t us (I D D M) ( C ) G r a v e ' s di s e as e ( D ) H a s h im o to ' s th y r o id i ti s V i e w A n s we r 4 . T h e a n sw e r i s C [ se ea n d] .5 . A pa t i e n t r e ce i ve s l o n g - te r m , h i g h- d o se t he r a p y w i t h a s ul f o na m id e . Af t e r a pp r o x im a te l y 3 w e ek s o f t he r a p y, t h e p a t i e n t h as a l ow - g r ad e f e ve r , r a s h, an d m u sc l e a n d jo i n t p a in . Wh i ch typ e o f h yp e r s e n s i t i vi t y a c co u n ts f o r th e se s ym p t o m s ? ( A ) Ty p e I ( B ) Ty p e I I ( C ) Ty p e I I I ( D ) Ty p e I V V i e w A n s we r 5 . T h e a n sw e r i s C [ se ea n d] .6 . I n w h ic h t yp e I V h yp e r s e n s i t i vi t y r e a c t io n i s t h e t i ss u e -d a ma g in g d is o r d e r c o ns i de r e d a n i na p p r op r i a te r es p on s e b y t h e i m m un e s ys t e m ? ( A ) P o is on i v y d er m a t i ti s ( B ) C h r on ic t ub e rc ul os is ( C ) A c ut e g r a ft r ej ec t io n ( D ) Tu b e r c u li n te s t V i e w A n s we r 6 . T h e a n sw e r i s A [ se e] . My c o b a c te r i u m .7 . W h i ch a g e n t i s c om m o nl y u s e d t o t r ea t m u l t ip l e s cl e ro s i s ( M S )? ( A ) N e os t ig m i ne ( B ) C y a n oc o ba la m i n ( C ) I F N - β - 1b ( D ) P r o p y lt h io u ra c i l V i e w A n s we r 7 . T h e a n sw e r i s C [ se e] . 8 . T h e t he r a p eu t i c ro l e o f m u r o m on a b - C D3 i n a cut e r e na l g ra f t r ej e c ti o n i s p r ob a b l y b a s e d o n ( A ) a c t i v a ti o n o f T c e ll fun c ti o n a nd s e c r e ti o n o f cy t o k in es . ( B ) d es t ru c ti on o f T c el ls b y c om pl em e nt . ( C ) o ps o ni z a t io n o f T c e ll s fo r p h ag oc y t o s i s . ( D ) s el ec t i v e i nh i bi ti o n of T H c e ll fu nc t io n . V i e w A n s we r 8 . T h e a n sw e r i s C [ se e] . 9 . W h ic h i s a c u r r en t c li n ic a l a p p l ic a t io n o f i n t ra ve no u s hu m an im m un o g lob u l i n ( I V I G ) ? ( A ) P r o ph y l a xi s af t e r h epa t i ti s B v i r us ( H B V ) e xp o s u r e ( B ) Tr e a t m e n t o f h um o ral im m u n od e fi c i en c y ( C ) P r o ph y l ac t ic in f an t im m u n i zat i on fo r po l io ( D ) P r o ph y l a xi s f or R h d is e as e b y i nf a nt im m u ni za t i on V i e w A n s we r 9 . T h e a n sw e r i s B [ se e] . 1 0. W hi c h c yt o k i n e i s a p p r o ve d fo r t he t r ea tm e n t o f ce r t a in f o rm s of c a nc e r ? ( A ) I n te r le uk i n 2 (I L - 2) ( B ) I n te r f er o n α ( I F N - α )
( C ) I n te r f e ro n γ (I F N - γ ) ( D ) I m u t hi o l V i e w A n s we r 1 0 . T he a nsw e r i s B [ se e] . P . 22 5
F o r q ue s t io n s 1 1 a n d 12 : A 6 - y e a r - ol d c hi ld ha s a de e p p un c t u r e wo u n d . Th e p a r en t i s u ns u re of th e c h il d ' s hi s to r y o f vac c i n a ti on . 1 1 . If n o o t he r i n fo r m a ti o n is a va i la b le , w ha t sh o u l d t h e p h ys i c i a n r e c o mm e nd ? ( A ) N o v ac c i n at i on ( B ) Te t a n us i m m un o gl obu l in ( TI G ) ( C ) Te t a n us to xo i d ( Td ) ( D ) B o t h TI G a n d Td a t s e p a ra t e s it es V i e w A n s we r 1 1 . T he a nsw e r i s D [ se e] . 1 2. I f t h e c h i l d r e ce i ve d a f u l l se r i es o f d i ph t h e r ia, p e r t us s is , te t a nu s ( DP T ) va c c in a t io n s, t he la s t a t e n t r y i n t o s c h oo l , w h a t sh o u ld t he p h ys i c i a n r e c om me n d ? ( A ) N o v ac c i n at i on ( B ) Te t a n us i m m un o gl obu l in ( TI G ) ( C ) Te t a n us to xo i d ( Td ) ( D ) B o t h TI G a n d Td a t s e p a ra t e s it es V i e w A n s we r 1 2 . T he a nsw e r i s A [ se e] . 1 3. P e r sis t e n t i n f ec t i on s b y o p p o r t un i s ti c pa t h og e ns , s uc h a s Ca n d id a a l b ic a n s a nd P n eu m oc y st i s c a r i n ii , co u ld i nd i ca t e a l l o f t h e f o ll ow i n g e xce p t ( A ) i nh e ri t ed T c el l i m m un o d ef ic ie n c y. ( B ) h um o ra l i m m un o de f ici e nc y . (C) AIDS. ( D ) c om bi n ed im m u no de fi c ie nc y . V i e w A n s we r 1 3 . T he a nsw e r i s B [ se e] . 1 4. W hi c h s t a te m en t ab o u t H I V i n f ec t i on is n o t c o rr e c t ? ( A ) I n di v i du a ls wh o b e c om e i n fe c te d wi t h H I V - 1 al wa y s s h o w o ve r t s y m p to m s s h or t l y af t e r in f ec t io n . ( B ) S e r oc on v e r s i on t o p os i ti v e s t a tu s f o r a n ti - H I V- 1 a nt i bo di es is th e p r i m a r y c ri te r i on fo r di agn o si s o f a vi ra l c a r ri e r . ( C ) Th e i nc ub a ti o n p er i od f o r t he pa t ho g en es is of A I D S is b e li e v ed t o be 8 y ea r s o r l on g e r af t e r th e i ni t ia l i n fe c t i on wi t h H I V. +
( D ) C D 4 T c el ls an d m ac r o ph ag e s m a y b e a bl e to s p r e ad H I V t o +
u n in f ec t ed C D 4 c el ls wi t h o ut r el e as in g a n y e xt r ac e ll ul a r vi ru s p a r ti c l e s . V i e w A n s we r 1 4 . T he a nsw e r i s A [ se e] . D i r e c ti o ns : Th e q u es t io ns a n d i nc om p le t e s t a te m ent s in th is s e c t io n c a n b e c o r re c tl y a ns we r e d o r c om p le t ed b y on e o r m or e o f t h e su g ge s te d a nswe r s . C h o os e t he an s we r , A-E. 1 5 . W h i ch s ta t em e n ts ab o u t th e c u r r e n tl y a p p r o ve d s he e p F a b f r a gm en t u s e d t o co u n te r a ct d igo x i n o ve r d o se a r e t r u e?
I . I t i s ob t a in e d b y t h e im m u ni za t i o n o f s h ee p w i t h a di g ox i n -p r o t e in c o n j ug a te a nd su b se q ue n t p r ot e o l yt i c c l e a va ge o f th e c o l le c te d a n t i bo d y. I I . I t s pe c i fi c al l y b i n d s d i g o xi n , p r e ve n t in g i ts a c t i vi t y. I I I . It h as a s e ru m ha l f -li f e o f a p p ro x im a t el y 3 w e ek s . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t +
V i e w A n s we r 1 5 . T he a nsw e r i s C [ se e] . 1 6. C D 4 T c e l l s s p e ci f i ca l l y r e c o g n i z e a n t i ge n s i n w hi c h fo r m? I . B o u nd t o m aj o r h is t oc o m pa t i bi l i t y ( M H C ) c l as s I m o le c ul e s o n th e s u r f a ce o f a n y b o d y c e l l I I . I n f r e e, so l u bl e fo r m i n ex t r a ce l lu l a r fl u i ds I I I . B ou n d t o M H C c la s s I I mo l ec u l es on t he sur f a c e o f sp e ci a l a n t ig en p r e s en t i n g c el l s ( AP C s ) A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 6 . T he a nsw e r i s B [ se e] . 1 7. W ha t i s a n o r ma l o u t c om e o f t he ac t i va t io n o f th e c o mp l em e n t sys t e m b y e i t h e r t h e c l a ss i c o r al t e r na t i ve pa t hw a y? I . Ac u t e in f l am m a ti o n I I . O p so n iz a t io n of i mmu n e c o m pl e xe s I I I . C yt o l yt i c a c t i o n A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 7 . T he a nsw e r i s E [s e e] . 1 8. I n a n tivi r a l i m mu n i t y, w h a t d i r ec t l y r e c o g n i z es a nd k il l s vi r al - i n fe c ted c e ll s ? I . C yt o t o x i c T c e ll s ( CTL s ) I I . An t i vi r a l an t i b od i es I I I . In t e r fe r o n s A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 8 . T he a nsw e r i s A [ se e] . P . 22 6
1 9 . A p a t ie n t i s t re a t ed w i t h p en i c il l i n a nd p r od u c es an t i b od i es ag a i ns t t h e d r ug . Th e y a r e s t i l l m o s t l y p r e s e n t . An e mer g e n c y s i t u a t i o n r e q u i r es ad m i ni s t r at i o n o f a n i n t ra ve n o us d ose o f pe n ic i l li n . I f t he p a t i en t ha s a t yp e I p e ni c i l li n h yp e r s e n s i t i vi t y r e a c t io n , w hi c h p a t h ol o g ic co n se q u en ce w o u l d b e e xp e c te d , an d w i t h in w h a t t i me c o u r se o f c l in i c al on s et ? I . H e mo l yt i c a n em i a, w it h a n o n se t o f 1 -2 h r a ft e r t h e i n t r a ve no u s d ose I I . An a p h yl a x i s , w it h an o n se t o f a few m i nu t es a f t e r th e i n t r a ve n ou s dose I I I . C ut a ne o u s u r t ic a r i a a n d p r u r i t us , w i th a n on s e t o f a f ew mi n u te s a f t e r t he in t r a ve n o us do s e A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 9 . T he a nsw e r i s D [ se ea n d] .2 0 . Wh i c h s i t ua t i on o c c u rs i n a l l t yp e I V h yp e r s en s i t i vi t y r e a c t i o ns ? I . I n fi l t r a ti o n o f t he a ff ec t e d ti s su e b y m o n o n uc l e a r c e ll s I I . A d e l a y o f 1 2 h r o r lo n g e r i n t he on s e t o f c li n i c al s ym p t o m s a f te r a l l e r ge n c o n ta c t I I I . Si g n i fi c an t be n e fi c ia l e f fe c t o f th e ad m in i st r a t i o n o f H 1 -a n ta g o ni s ts A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 0 . T he a nsw e r i s C [ se ea n d] .2 1 . Wh i c h i m mu n o lo g ic f i n d i ng is n o t u n iq u e t o s ys t e m i c lu p u s e r yt h e m a t o su s (S L E ) ? I . H yp e r g a m m ag l o bu l i ne m i a I I . Th e p re s en c e o f c i r cu l a t i ng an t i nu c le a r an t ib o d i es I I I . Th e p r e se n ce o f c i rc u l a ti n g rh e um a t oi d fac t o r s A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 1 . T he a nsw e r i s E [s e e] . 2 2. An o rg a n do n o r w ho i s h u m an l eu k oc yt e a n t i ge n ( H L A) m a tc h ed w i t h t h e r ec i p ie n t o f a g r a f t i s s o u g ht . Wh i c h i n di vi d ua l i s a t l e as t so mew h a t l i k el y t o p r o vi d e a t o t al HLA match? I . A s i b l in g o f t h e g r a f t r e c i p ie n t I I . A p a r e n t o f th e g r a f t r e c i pi e n t
I I I . A c a da ve r A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 2 . T he a nsw e r i s A [ se e] . 2 3. G r a f t -ve r s u s - h os t ( G V H ) d i s ea s e i s a ss o c ia t ed pr i m a r i l y w i t h w hi c h t yp e o f t ra n s pl a n ta t i on ? I . K i d ne y I I . H ea r t I I I . B on e m a r r ow A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 3 . T he a nsw e r i s B [ se e] . 2 4. T he pr o p h yl a c t i c us e o f c yc l o s p o r i n e i n g r a f t rej e c t io n is p r ob a bl y b a s e d o n i t s a b il i t y t o I . i nh i b i t s yn t h e s i s o f an t i b o di e s, t he r e b y p r e v e n t i ng h yp e r a c u t e r e j e c ti o n . I I . i nh i bi t ac t i va t i on o f T c e l l s , t h e re b y p r e ve n t i n g ac u te r e je c t io n . I I I . bl o ck t r an s c r ip t i on o f t h e i n te r l e uk i n 2 ( IL -2 ) g en e a n d s yn t h e s i s o r s e c r e ti o n o f IL - 2 . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 4 . T he a nsw e r i s D [ se e] . 2 5. W hi c h i s a va l i d c o m pa r i s on o f l i ve , a t te n u a te d a n d k i ll e d , i nac t i va t e d a c ti ve va c c i nes ? I . R e pl i ca t i o n o f th e o r g a n is m s i n a l i ve , a t te nu a t e d va c c in e in c r ea s es t h e s ti m ul a t io n o f t h e im m u ne s ys t e m a n d a l ow e r d o se i s o f t en r e q u i r ed . I I . At t e n u a te d va cc i ne s o f t e n r e q ui r e m u l t ip l e d o s es . I I I . A k i l le d , i n ac t i va t ed va c c i ne p r ob a b l y p r o d u c e s l i fe l o ng im m u ni t y i n o n e o r tw o d os es . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 5 . T he a nsw e r i s A [ se ea n d] .2 6 . Wh i c h a c t i ve va c c i n e i s re c om me n d ed f o r he a l th c a re w o r ke r s b u t i s n o t r ou t i ne l y g i ve n t o i n f an t s ? I . M e a sl e s, mu m ps , r ube l l a ( M M R ) va cc i n e
I I . I nf l u en z a p ol yva l e n t I I I . Te t an u s t o x oi d (T d ) A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 6 . T he a nsw e r i s D [ se e] . 2 7. W hi c h s t a te m en t ab o u t p n e um o c oc c us an d m en i n g oc o cc u s va c c in e s is t r u e? I . T he y a r e c o m po s ed of p u r i f ie d p o l ys a c c h a r id e s . I I . Th e y a r e r e c om m en de d f o r c h il d r e n < 2 ye a r s o f a g e . I I I . Th e va cc i ne s p r o t ect a g ai n s t a l l s e ro t yp e s o f d i se as e c a us i n g p n e um o c oc c us o r m en in g o c oc c us . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 7 . T he a nsw e r i s A [ se e] . P . 22 7
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee 1 . C . 2 a nd 3] . A p r im a r y i m m u ne re s pon s e t o a n i n fe ct i on is c ha r a c t e ri ze d b y t h e i ni t ia l p r o du c ti on o f I g M, b e gi nn i ng ab o u t 4 d a ys a f te r a n t ig en is en co u nt e re d . A s wi t c h t o a di f f er e nt im m u n o gl ob u li n i so t y p e ( i .e . , I g G , Ig E , o r Ig A ) occ u rs b e f o re th e p e ak o f an t ibo d y p r od uc t io n i s r e ac hed . Th e pe ak pr im a r y i m m u ne r es po ns e o c c u rs 1 0 - 14 da y s a f t er t he an ti g en is en c o u nt e re d , a n d t h e s e ru m c on t ai ns bo t h I g M a n d I g G . 2 . T he an sw e r is A [ s ee I . D . 2. b ; I . E ] . I g G h as a s e r um ha l f- l if e o f 25 - 35 da y s , l o ng e r t ha n th a t o f a n y o th e r cl as s , a l t ho ug h m as t c el l - bo und I g E h as th e l o ng es t h al f - l i f e . I n g en e ra l , i m m une c om p le xe s c on t ai ni n g I gG a r e op s o ni ze d fo r ph ag o c y to s i s t h r ou gh bi n di ng t o t he Ig G r ec e pt o rs on n e u t ro ph i ls a n d m a c ro p ha g es an d a d di t io na l l y t h r o ug h t h e ac t i v a ti on o f c om pl em e nt . Ig M a l s o op s on i z es , bu t o nl y t h r oug h t h e a c ti v a t io n o f c om pl em e nt . 3 . T he an sw e r is A [ s ee I I . A .5 . a a nd b ]. F o o d a ll e rg i es a r e u s u a lly t y p e I re ac t io ns . In a pa t i en t wi t h p r ee xi s t i ng h yp e r se c re t ed Ig E s p ec i fi c to a f oo d a ll e r ge n a n d b o un d t o m as t c el ls , th e a l le r g ic re s p o ns e us u al l y o c c u rs s h o rt l y af t e r i ng e s t io n . Ma s t c el l s ec re t ion s l e ad t o vo m i t in g . S y s t em i c s pi l lo v e r of al le r g en int o t he c i rc ul a ti o n m a y l ea d t o m i ld e r e f fe c ts i n o t he r t i s s ue s ( e .g . , u r ti c a r i a) . 4 . T he an sw e r is C [ s ee I I . C .1 a nd 2. c; I II . D . 2. b ].
I n G r a ves ' d is ea s e , a n an t i bo d y ac ti n g as a TS H a g o ni s t h ype r s t im u la t es t h e th yr o id . In S LE , pe r s i s te n t c ir cu l at i ng im m u ne c om pl e xe s a re r e s po ns ib l e f o r m uc h o f th e pa t ho g en es is ( t y pe I II) . I n I D D M, T c e l l c yt o t o xi c it y t o b e ta is le t c e ll s is p ro b ab l y re s po ns i b le f or t he m a jo r p a t ho g en es is ( t y pe I V ). In H a s h im o to ' s t h y r oi d it is, a n ti bo d ie s t o t h y r oi d p e r o xi d as e m a y in i ti a te in f l am m a ti o n b ut T H 1 c e l ls an d m ac r op h ag es i n f il t ra t e t h e o rg a n ( Ty p e I V ) . 5 . T he an sw e r is C [ s ee I I . D .2 . c ; I I. D . 4 .a an d b ; I I . D . 5. a ] . O n e o f t he m o s t c o m m on c au s e s o f t y pe I II h ype rs e ns it i vi t y is t h e r es p on se t o d ru gs . Th is t y pe o f r ea c ti o n is o ft e n se e n a f te r l o ng - t er m , h ig h -d os e t h e r ap y. Th e t re a tm en t of c ho ic e i s t o d is c o n ti nu e t r e at m e n t a nd s u bs t it u te a n un r el a te d d r u g. 6 . T he an sw e r is A [ s ee I I . E .1 ] . P o i so n i v y c on t ai ns a h ap t e n, pe n ta d ec y l c a te c ho l , wh ic h i s n o t kn o wn t o b e t o xi c . Th e r e fo r e , i ts c apa c it y t o e l ic it an im m u ne r e s p o ns e is in a pp r op r i ate b e ca us e i t s e r v es no us ef u l f u nc ti o n . I n c h r o ni c tu b e rc ul os is , th e i m m un e r e s po ns e i s a t te m p t in g , a l t ho ug h un s u cc es s f ul l y , t o el im in a te th e m yc o ba c t e ri a l p at h og e n. A c u te gr a f t r ej ec t io n i s a l s o ap p ro p r ia t e, bu t u n f o rt u na t e, be c a us e i t is a r e s p on s e ag a in s t f o re i gn t is s u e. A tu b er cu l in t e s t is an ap p r op r ia t e m an i f es ta t io n o f th e e xi s t e nc e o f ac ti v e im m u ni t y o r m em o r y t o My c o ba c te r ium . 7 . T he an sw e r is C [ s ee I I I . D .8 . b] . Tr e a t m en t wi t h I F N - β - 1b l o we r s th e f r eq u en c y of a t t ac ks b y 3 3 -5 0 % a t 2 ye a r s i n MS p a ti e nt s . N eo s ti gm i ne is u s e d a s a n a n t ic ho li n e rg ic ag e nt in m ya s th e ni a g r a v is . C y ano c ob a la m i n i s a dm in is t ere d i n au t oi m m un e p e r ni ci o us a n em ia to r epl a c e no n ab s o r be d vi ta m in B 1 2 . P r op yl t hi o u ra c i l is u s ed as an an ti t h y r oi d i n G r a v e s ' di s e as e . 8 . T he an sw e r is C [ s ee V . D . 2 .e ] . Mu r o m o n ab - C D 3 is a m ou s e a nt i - C D 3 m on oc lo n al a nt i bo d y th a t b in ds t o al l T c e l ls be c a us e C D3 is a c on s ta n t p a rt of t he an t ig e n re c e p to r of ea c h T c e ll . Th e b in d in g o f m u rom o na b - C D 3 o ps on i z es t he T c e ll s f o r p h a go c y to s i s . Th e r e fo r e , t h e t o ta l n um b er o f T c el l s is r ed uc e d. Mo u s e a n t ib od i es ar e i n ef f ic ie n t a t ac ti v a t in g h um a n c om p le m e n t. S om e T c e ll a c ti va t io n wi t h c y t ok in e s ec r e ti o n oc c u r s , b ut it is an un d es i ra bl e s id e e f fe c t o f m u r om on a b - C D3 ad m in i s t r a ti o n. 9 . T he an sw e r is B [ s ee V I . B . 1. c ; Ta b le 10 - 2 ]. I V I G s ar e u s e d to r ep la c e a nt i bo d y in im m u no d efi c ie n t i nd i vid u al s. H e pa t it i s B i m m un o gl ob u li n ( H BI G ) i s a dm in is t e re d i n tr am us cu l a rl y . A nt i - R h a nt i bo dy i s a ls o a dm i ni s t e r ed in t ra m us c u la r l y to t he m o the r im m e d ia t el y p os tp a r tum ( s om e ti m e s d u ri n g p re g na n c y ) , b u t n ot to t he in f an t . P ro p h y la ct ic in f an t i m m u ni z a t io n f o r p o li o is p r o v i de d t h ro u gh ac t i v e, n o t p as si ve , vac ci n at io n. P.228
1 0 . Th e a n sw e r i s B [ s ee V I I . D] .
I F N - α i s a pp r o v ed f or us e i n p at i en ts wi t h ha i r y c e l l l eu k e m i a a n d i n p a t ie n ts wi t h AI D S an d Ka p os i s a rc om a. S om e o f i t s b en e fi c i a l e ff e c t s p r o ba b l y d e r i v e f r om i t s a b il i t y to in h ib it g ro wt h . Th e o t he r c y t o k i n es a r e in va r i o us s t ag es o f c l i ni c a l t r i al s as an t in e op l as ti c th e r ap i es , a l th ou g h I F N -γ i s a p p ro v e d f o r u s e in pat i e nt s wi t h c h r o ni c g ra n ul o m a t ou s d is ea se . I m u th io l i s n ot a c y t ok ine b ut a s y n th e ti c d r ug . 1 1 . Th e a n sw e r i s D [ s ee V I . D .3 . a; Ta b le 10 - 3 ]. A p a ti e nt wi t h an un c e r tai n hi s t o r y of v a c c in a ti o n a n d a te t an us - p r on e wo u n d r e qu i re s b ot h a c tiv e a n d p as s i v e v ac c i n at io n . TI G p ro v i d es i m m e di a te p ro t ec ti o n i f th e in di v i d ua l d o es n o t ha v e m e m o r y. Td b eg i ns th e s e r ie s t ha t l e ad s t o t h e es t ab l is hm en t o f m em o r y . A t e ta nu s -p r o ne wo u n d i n a n in di vi d ua l wi t h a fu ll s e r i es of ac ti v e v a cc in a ti on s re q ui r es no t re a tm en t i f th e l as t v ac c i n a ti on in t h e s e ri es wa s ad m i ni s ter e d l e s s t h an 5 yea r s e a r li e r . Th e s e r ec om m e nd a t io ns a re ge ne r a l g ui de l in es . 1 2 . Th e a n sw e r i s A [ s ee V I . D .3 . a; Ta b le 10 - 3 ]. 1 3 . Th e a n sw e r i s B [ s ee I V . A ; I V . B. 6 ] . O p p o r tu n is ti c i n fe c t i on s b y f u ng i , vir us e s , an d p ar a s it es ot h e r t ha n e xt r a c e l lu la r p y og e ni c ba c te r i a s u g ge st a d e fi ci en c y o f T c el l fu nc t io n . I n h e ri t ed T c e l l im m u n ode f ic i en c y a n d A I D S ar e in h e ri t ed an d a c q u i re d T c e ll de f ic ie nc ie s , r es p ec ti v e l y . C om bi n ed im m u nod e f ic ie nc y i nc lu d es b o th h u m o r al an d T c e l l d ef ic ie n c y . O nl y h um or a l im m u n o d e fi c i e nc y is a p r im ar i l y h u m o r al de f ic ie nc y i n whi c h t he e xp e c te d s ig ns ar e r ec u r re n t i nf ec t io ns by e xt r a c e l lu la r p y og e ni c ba c te r i a. 1 4 . Th e a n sw e r i s A [ s ee I V . B .6 . a. ( 1 )] . I t is no t k no wn wh a t p e rc e n t ag e o f i n di vi d ua ls s ho ws o v e r t s y m p to m s a f t er i n i ti al in f ec ti o n. Th o s e wh o do , h o we v e r , ge n e ra lly s h o w m on o nu cl e os is -l ik e s ym p to m s fo r a p p ro xi m at e l y 3 we ek s . S om e i nd i vi d ua l s di s p l a y no o ver t s ym p to m s . 1 5 . Th e a n sw e r i s C ( I , II ) [ s e e I . A .4 ; I. D . 2 ; I . D .5; V I I . A] . D i g o xi n is a h ap t en , a m o l ec ul e th a t is t oo s m a l l t o st im u la t e r es po n s e s (b e a n im m u no g en ) i n i t s f r ee f o rm , b u t c a n b e re co gn i z e d b y a nt i bo d ie s . To o b t ai n s he e p a nt i di go xi n a n ti b od ie s , t he sh ee p i s i m m un i z e d wi t h di g o xi n t h a t h as be en c o u pl ed t o a la r g er m o le cu l e, in t his c a s e , a p ro t ei n . Th e a n t ib od i es ob t ai ne d fr om t h e s he ep a re c l ea v e d wi t h p r o te o l y ti c e n z y m es t o yi e l d t h e F ab f ra gm e nt . Th i s f ra gm e nt is s p ec if ic t o an d c an bi nd di g o xi n , b l oc ki n g i ts b i ol og ic ac t iv i t y . A n im al an t ib o di es h a ve a s h or t e r s e r um ha l fl i f e wh e n in je c te d i n to hu m an s , an d al l F ab f ra gm e n t s , e v e n h um an , h a ve a s h o rt ha l f -l i fe c om p ar e d t o c o m p le t e a n ti bo d y m ol e c u le s . O n l y c o m p le t e h u m a n I g G ha s a ha l f- l ife o f a pp r o xi m a te l y 1 m on t h . 1 6 . Th e a n sw e r i s B ( I I I) [ s e e I. B . 3; I . B. 5 ] . +
C D 4 , o r h e lp e r, T c el ls h a v e r ec ep t o rs t h a t r ec og n i ze f r a gm en ts ( ep i to p es ) o f im m u ni z i n g a nt i ge ns (i m m u no g en s ) on l y wh e n t h e fr a gm en t s a re bo u nd t o an MH C c l a s s I I m o lec u le on th e s u r fa c e of AP C s . As a r es u lt , T c e l ls +
c a nn o t b e a c t i v a te d i n app r o p ri a te l y b y s ol u bl e a nt i g en s. C D 8 T c e l ls r e c og ni z e f r ag m e n ts b o un d to MH C c l a s s I m o le c u l es .
1 7 . Th e a n sw e r i s E ( I , II , I I I) [s e e I . E .2 ] . W hen co m p l em en t i s a c t iv a t e d , d i ff e re n t p r o te in s o f t he c om p le m e n t s e qu e nc e h a v e f un c ti on s t h a t le a d t o a ll t hr e e a c ti o ns . Ac u te i n fl am m at io n a l lo ws g r ea t e r m o v em en t o f pl as m a pr o te i ns an d p h a g o c y te s f r om bl oo d to t i ss ue . O ps o ni z a ti o n o f im m u n e co m pl e xe s en han c es th ei r ph a go c yto si s . C yt o l ys is of m i c ro o rg a nis m s of t en r es ul ts in t he i r k il li n g . 1 8 . Th e a n sw e r i s A ( I ) [ s ee I .F . 2 ]. A n t i vi ra l a n ti b od ie s a r e p r o ba b l y m os t i m p o r ta n t i n e xt r a c e l lu la r im m u ni t y t o vi r u s es , b in d in g v ir u s p ar t i c l es fo r op so n i zat i on a n d p re ve n ti ng ad d it i on a l i n f ec ti o n o f c el ls . I n te r f er o n s a re s e c re t ed f ro m v i r a l -i n fe ct e d a nd ot h e r c e ll s ( e .g . , m ac r op ha g es , T c e ll s ) a nd , a f te r bi n din g to r ec ep t o rs , i nd uc e t h e a p pe a ra n c e of an t i v ir a l p r o te i ns i n o t he r c e lls . C TL s r e c o gn i z e vi ra l i n f ec te d c el ls an d c a us e d i r ec t c y t o to xi c i t y. P.229
1 9 . Th e a n sw e r i s D ( I I , I I I ) [s ee I I. A . 2. d ; I I . A .6 an d 7; I I. C . 1 .b ; II . C . 5] . I f t he pa t ie n t p r od uc e d an t i bo di es t ha t a r e s ti l l p re s en t a n d t he h yp e r se ns i ti v i t y r ea c t i on i s t y p e I , th es e a n ti b od ie s a r e I g E , m os tl y b ou n d t o m a st c e ll an d b as o ph il I g E re c e p to r s . Th e i r h alf - l i fe is s e v e ra l m on t hs to ye a r s . I n t ra v e no u s i nt r odu c ti o n o f p en ic i ll in c a us e s r ap i d ac t i vat i on of a nd s ec r e ti o n b y bl o od ba s op h il s . S ym p to m s o f t y pe I h y p e rs en si t i v it y o c c u r wi t h i n m i nu t es . Th es e s ym p to m s m a y be s e ve r e (a n a ph y l a xi s ) o r le ss s e ve r e ( c u t an e ou s , ga s t ro i n te s t i na l , o r re s p i ra t o ry ) , d e pe n di ng on t he i n di vi d ua l . H e m o l y ti c a ne m ia is a n e xp e c t e d r esu l t o f a t yp e I I h yp e r se ns i ti v i t y r ea c t i on t o pe ni c i l li n , b as ed on th e p re se nc e o f Ig M o r I gG a n t ib od i es i n th e s e ru m . Th e o ns e t i s d el a yed b y a f e w h o ur s i n a pa t ie n t wi t h p r e e xi s ti n g a nt i bo die s . 2 0 . Th e a n sw e r i s C ( I , II ) [ s e e I I . E .3 , 4 , 5 a nd 6]. Typ e I V h y p e rs e ns it i v i t y r e a c t i on s a r e d el a y ed a fte r t he in t r od uc t io n o f a l le r g en be c a us e a l le r gen - s pe c i f ic T c e ll s b ec om e a c t i v a te d a nd a tt r ac t o t h e r ce l ls , s u c h as m a c r o p ha g es , t o th e s it e o f a l le r g en in t ro d uc ti o n ( e .g . , t h e e p id e rm is of th e s k i n i n c on t ac t s en si t i v i t y, t he l un gs in tu b e rc ul os is ) . Th e s e s i te s a r e in f il t r at ed b y m o no n uc le a r c el ls . I n f la m m a ti on is pr im a r il y c a us ed b y ti s s ue di s ru p tio n an d n ec r os is as we l l a s b y s ec r et i on of c yt o ki ne s b y t he in f il t r at in g c e ll s. A lt h ou g h h is tam i ne s ec r e ti o n c a n a ls o o cc u r fr om lo c a l m as t c el l s , H 1 -a n ta g on is t s o f h is t a m i n e us u al l y do no t h av e s i gn i fi ca n t e f fe c t s b ec aus e T c e l l a nd m ac r o ph age ac t i v a ti on , m i gr a ti o n, a n d s ec r et i on a re no t g re a t l y a f f ec te d b y t h es e dr u g s . 2 1 . Th e a n sw e r i s E ( I , II , I I I) [s e e I I I. C . 3 .b ] . A l l th r ee f in di n gs a r e c om m o n to m o r e t ha n o n e n o n -o r g an - s p ec i fi c a u t oi m m un e d is o rd e r , b ut t h e y o c c u r i n d if f e re n t p e r c e n ta ge s o f p a ti e nt s wi t h s pe c i f ic di s o r de r s . F o r e xa m pl e , a nt i nu cl e ar a n ti b od ie s a r e p r ob a bl y p r e se n t i n a ll pa ti e nt s wit h S L E b ut a re fo u nd in o n l y a f r ac ti o n o f p a ti en ts wi t h r h e um at o id a rt h ri t is a n d Sj ög r e n 's s y n d r om e. R h e um a to id f ac to r s a r e
m o r e co m m on in r he um at o i d a r th r i ti s t ha n i n SL E o r S jö g re n ' s s y nd r om e , a n d h yp e rg a m m ag lo b ul ine m ia is m o re p re va le n t in S L E t h an in S jö g re n ' s s yn d r om e. 2 2 . Th e a n sw e r i s A ( I ) [ s ee V . A .3 ; V. B ] . P a r e nt s a n d c h i ld r en a re r a r el y H L A m a tc he d b u t a r e us ua ll y h al f m a tc he d. A n H L A m a tc h f r om a c ad a v e r - de r i v e d o rg a n is un l ik el y. Th e p ro b ab il i t y th a t t wo s i bl i ng s a r e H L A m a tc h ed is 2 5 %; t he p ro ba b il i t y th a t t h e y a r e h a lf m a tc he d i s 5 0% . 2 3 . Th e a n sw e r i s B ( I I I) [ s e e V . C. 1 ] . I n bo n e m a r r o w t r a ns pl an t a ti o n, m a r r o w c o n ta i nin g c om p et e n t l y m p h oc yte s i s tr a ns pl a nt e d t o a ge ner a l l y i m m u no s u pp r es s e d h o s t . Th e g r ea t es t p r o bl em is an im m u ne res p on s e b y th e g r a ft ag a in s t HL A s a nd ot h e r t is sue a n t ig en s o f th e h os t . I n re n al an d c a rd i ac tr a ns pla n t at i on , th e g r ea t es t p r o bl em is re j ec ti o n o f t he f o re i gn or g an b y th e im m u n e s y st em o f t he hos t ( H V G d i s e as e ) . 2 4 . Th e a n sw e r i s D ( I I , I I I ) [s ee V . B .2 ; V. D . 2 .a ] . C e l l -m ed i at e d im m u n e m e c ha n is m s a r e t ho u gh t to b e m o r e i m p o r ta n t i n a c ut e g r a ft r ej ec t io n , a nd t he in h ib i ti on o f T c el l a c ti v a t io n a p pe a rs to be t h e k e y el em e nt in im m un o s u p pr e s s io n . R es p on di n g T c e ll s r e qu i re s i gn al i ng f ro m I L -2 t o r ea c h f ul l a c ti va t io n a nd p ro g r es s t o c el l d i v is io n . IL - 2 i s p r o du c e d b y ac t i v a te d T c e ll s a n d c a n a c t in an a ut oc r i ne m a nn e r . C yc l o sp o ri n e b lo c k s t ra ns c ri p ti o n o f t he I L -2 ge ne d u ri ng T c el l a ct i v a ti o n, i n hi b it s t h e s y n th es is of I L - 2 , a nd p re ve n ts fu ll T c e ll ac ti v a t io n a n d d i vi si on . I ts e f fe c ts a r e l im i te d to ac ti va t ed T c el ls . B ec au s e it ha s n o d i rec t e f f ec t o n a n ti b od y s y n the s is , i t i s n ot us e fu l i n t he h yp e ra c u t e r e je ct i on p h e no m e na t ha t a r e b as e d on an t ib o d y-m e di at e d m ec ha n is m s . H y p e r ac u te r e j ec ti o n i s es s e n ti a ll y un t r e at a bl e b ec au s e i t d ep e n ds o n t h e p r es en c e of a n t ib od i es i n th e g r a ft r ec i pi en t . 2 5 . Th e a n sw e r i s A ( I ) [ s ee V I . C. 2 . a a nd b] . L i ve , a t t en ua t ed v a c c in es in t r od uc e o r g an is m s t ha t a re c o m p e te n t t o r e p li ca t e . Th i s r e pl ic a ti on s ti m u la t es th e i m m un e r e s p o ns e. F or t hi s a nd p r o ba b l y o t he r r ea s o ns , a l i v e, at t e nu a te d vacc i ne ( b ut no t a k i ll e d, i n ac t i vat e d v a c c i ne ) p r ob a bl y p r o vid es li f el o ng im m u n it y i n o ne o r t wo d o se s. 2 6 . Th e a n sw e r i s D ( I I , I I I ) [s ee V I . C. 1 .d ; Ta b le 1 0 - 3 ]. Th e M M R v a c c in e i s a dm i n is t er e d t o i n fa n ts wi t hin o r s ho r t l y a f t er t he 1s t ye a r o f l if e . A s e c o n d d os e i s r e c o m m en de d a t s ch o ol en t r y . In f lu e n z a a c ti ve va c c in e i s t a rg e ted t o wa r d s pe c i f ic ad ul t po p ul a ti o ns . He a lt hc a r e wo r k e r s a r e i nc lu d ed in th i s t a rg e t p op u la t io n , as a r e i n f an ts an d c hi l dr e n a t r i sk ; h o we v e r , t he v a c c ine is no t ro u ti n el y a dm in is t e re d t o i n fa n ts . Td i s no t r o u ti n el y a dm in is t e re d t o i n fa n ts , wh o i ns t ea d re c e i v e D TP . Td is us ed p r i m a r il y f o r i ni t ia l v ac c in a t io ns in ad ul t s wh o we r e n ot p re v i ou sl y va c ci n at e d a nd f or 10 - y ea r b oo st e r v ac c i na t io ns in a ll in di vi d ua ls , i nc l ud ing h e al t hc a re wo r k e rs . P.230
2 7 . Th e a n sw e r i s A ( I ) [ s ee V I . C. 2 ; Ta bl e 1 0 -3 ] . Th e p n eu m o c o c c al an d m e ni n go c o c c al vac c i n es a r e m u l t i v al e n t a nd c o nta i n p u r if i ed po l y s a c c h ar i de fr o m a nu m b e r o f d i f fe r ent s er o t y p es . H o we ve r , t h es e vac c i n es d o n o t c on t a in po l y s a cc ha r i de f rom al l t h e r e le va n t i n f ec ti o us a g en ts . P ur i fi ed p ol y s ac ch a ri d es d o n o t s t im ul a te i m m u ne r e s po ns es in c h il d re n y ou n g er t ha n 2 y e a rs o f a ge . F or po l ys a cc h ar i de va c ci n es to be ef f ec t i v e in y o u ng c h il d re n , t h e p ol y s a cc h ar i de m u s t be c o nj u ga t ed to a p r ot e in a s i n th e Hi b v ac c i ne .
11 Biotechnology Drug Products Godwin W. Fong Charles Lee I. INTRODUCTION. Advances in biotechnology have made many formerly unstable or difficult-to-produce biologic products available for therapeutic use. Some life-threatening diseases are now treated with biotechnology products. A. Interferon (INF) is an example of a drug that was genetically engineered to inhibit certain types of cancer cells and some viruses. B. Cellular hormones known as interleukins, lymphotoxins, and tumor necrosis factor are now used to treat cancer and immunodeficiency diseases. C. Monoclonal antibodies (MAbs) can deliver toxins specifically to cancer cells and destroy them. MAbs are also used with radioisotopes to diagnose and visualize cancer cells. Monoclonal antibodies have been developed to target signaling pathways associated with immune response and are being used to treat various immunological disorders, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and moderate to severe asthma. D. Many biopharmaceutical products derived from the body tissues (through cell lines) are now produced on a large scale. Modified natural products also may be further improved. E. A synthetic analogue of thyrotropin-releasing hormone prevents paralysis after spinal cord injuries in animal studies. F. Superoxide dismutase may be useful in preventing damage to tissues that are deprived of oxygen. G. New biotechnologic treatments have been developed for emphysema, congestive heart failure, ulcers, atherosclerosis, and an increasing number of medical conditions. Table 11-1 lists the biotechnology products that are approved for human use. II. BASIC TERMINOLOGY A. An antigen is a substance that stimulates the production of antibodies. B. An antibody is an immunoglobulin produced by the body in response to stimulation from an antigen. C. Antisense DNA is a complementary strand of DNA that is specifically synthesized to attach to the sense DNA and prevent genetic transcription. The sense DNA that carries the information that affects the disease process is usually elucidated before an antisense drug is designed. D. Colony-stimulating factors (CSFs) are a class of glycoprotein hormones. CSFs regulate the differentiation and formation of blood cells from precursor cells. E. Cytokines are a group of special proteins (nonantibodies) released by cells to trigger action in other cells. F. DNA is the molecule that contains the genetic instructions of a cell. DNA consists of deoxyribose, phosphate, and repeating bases as building blocks. The four bases are adenine, guanine, thymine, and cytosine. P.232
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Table 11-1. Approved Recombinant Therapeutics and Vaccines Drug (Trade Name) Indication(s) Company; Year Introduced Human insulin (Humulin) Diabetes Eli Lilly, Genentech; 1982 Somatrem for injection Human growth hormone deficiency in Genentech; 1985 (Protropin) children Interferon α-2a (Roferon- Hairy cell leukemia Hoffmann-La A) Roche; 1986 Interferon α-2b (Intron A) Hairy cell leukemia Schering-Plough, Biogen; 1986 Extension of therapy for chronic 1997 hepatitis C from 6 months to 18-24 months Follicular lymphoma in conjunction 1997 with chemotherapy Hepatitis B vaccine Prevention of hepatitis B Merck, Chiron; recombinant (Recombivax 1986 HB) Muromonab-CD3 Reversal of acute kidney transplant Ortho Biotech; (Orthoclone OKT3) rejection 1986 Somatropin for injection Human growth hormone deficiency in Eli Lilly; 1987 (Humatrope) children Alteplase (Activase) Acute myocardial infarction Genentech; 1987 Acute pulmonary embolism 1990 Restoration of function to central 2001 venous access devices (as assessed by the ability to withdraw blood) Interferon α-2a (Roferon- AIDS-related Kaposi sarcoma Hoffmann-La A) Roche; 1988
Interferon α-2b (Intron A) AIDS-related Kaposi sarcoma Genital warts Hepatitis C Interferon n3 (Alferon N Genital warts injection) Hepatitis B vaccine Hepatitis B prevention (Engerix-B)
Schering-Plough, Biogen; 1988
1991 Interferon Sciences; 1989 SmithKline Beecham, Biogen; 1989 Chronic hepatitis C infection 1998 Erythropoietin (Epogen) Anemia associated with chronic renal Amgen, Johnson & failure Johnson, Kirin; 1989 Erythropoietin (Procrit) Anemia associated with AIDS or Amgen, Ortho zidovudine administration Biotech; 1990 Anemia associated with chronic renal 1990 failure Chemotherapy-associated anemia in 1993 patients with nonmyloid malignancy Anemia associated with cancer and 1993 chemotherapy PEG-adenosine ADA-deficient severe combined Enzon, Eastman (ADAGEN) immunodeficiency Kodak; 1990 Interferon γ-1b Management of chronic granulomatous Genentech; 1990 (Actimmune) disease Delaying time to disease progression in InterMune patients with severe, malignant Pharmaceuticals osteopetrosis (2000) CMV immunoglobulin Prevention of CMV in kidney Medimmune; 1990 (CytoGam) transplant recipients Filgrastim; G-CSF Chemotherapy-induced neutropenia Amgen; 1991 Acute myeloid leukemia 1998 Glucocerebrosidase Type I Gaucher diseasea Genzyme; 1991 (Ceredase) Glucocerebrosidase Type I Gaucher diseasea Genzyme; 1994 (Cerezyme) Sargramostim (GM-CSF) Autologous bone marrow Hoechst-Roussel, (Prokine) transplantation Immunex; 1991 Sargramostim (GM-CSF) Neutrophil recovery after bone marrow Immunex, Hoechst(Leukine) transplantation Roussel; 1991 Antihemophilic factor Hemophilia B Armour; 1992 (Mononine) Antihemophilic factor Hemophilia A Genetics Institute, (Recombinate) Baxter Healthcare; 1992 Interleukin 2 (Proleukin) Renal cell carcinoma Chiron; 1992 Metastatic melanoma 1998 111 Indium-labeled Detection, staging, and follow-up of Cytogen, Knoll; antibody (OncoScint colorectal cancer 1992 CR103)
111
Indium-labeled antibody (OncoScint OV103) Interferon β-1b (Betaseron) DNase alfa (Pulmozyme) Factor VIII (Kogenate) Filgrastim (G-CSF) (Neupogen) PEG-l-asparaginase (Oncaspar) Human growth hormone (Nutropin) Abciximab (ReoPro)
Detection, staging, and follow-up of ovarian cancer
1992
Relapsing/remitting multiple sclerosis Chiron, Berlex; 1993 Cystic fibrosis Genentech; 1993 Hemophilia A Genentech, Miles; 1993 Bone marrow transplant Amgen; 1994
Refractory childhood acute Enzon; 1994 lymphoblastic leukemia Short stature caused by human growth Genentech; 1994 hormone deficiency Antiplatelet prevention of blood clots Centocor; 1994 Treatment of a broader range of patients undergoing percutaneous coronary intervention; revised dosage and patient management to reduce bleeding Unstable angina that does not respond to conventional medical therapy when percutaneous coronary intervention is planned within 24 hr Live varicella virus Active immunization of persons 12 Merck; 1995 vaccine (Varivax) months of age and older RSV immunoglobulin Prevention of serious lower respiratory Massachusetts (RespiGam) tract infection in children younger than Public Health 24 months old Biologic Labs; 1996 Inactivated hepatitis A Immunization against hepatitis A in Merck; 1996 vaccine (Vaqta) children older than 6 years of age Interferon β-1a (Avonex) Multiple sclerosis Biogen; 1996 Human antihemophilic Hemophilia A Centeon; 1996 factor Haemophilus b conjugate Immunization of individuals 6 weeks Merck; 1996 (meningococcal protein to 15 months of age born of HBsAgconjugate) and hepatitis B negative mothers (recombinant vaccine) (Comvax) Cryoprecipitated Control of bleeding associated with Blood Bank of the antihemophilic factor A Factor VIII deficiency Redwoods; 1996 Reteplase (Retavase) Acute myocardial infarction in adults Boehringer Mannheim; 1996 DTaP vaccine (Infanrix) Primary and booster immunization of SmithKline infants and children except as a fifth Beecham; 1997 dose in children who previously received four doses of DTaP Recombinant coagulation Control and prevention of hemorrhagic Genetics Institute; Factor IX (BeneFix) episodes in patients with hemophilia B, 1997
including perioperative management of patients with hemophilia B who are undergoing surgery Autologous cultured Repair of clinically significant, Genzyme Tissue chondrocytes (Carticel symptomatic, cartilaginous defects of Repair; 1997 SM Service) the femoral condyle (medial, lateral, or trochlear) caused by acute or repetitive trauma Interferon alfacon-1 Treatment of chronic HCV infection in Amgen; 1997 (Infergen) patients 18 years of age or older who have compensated liver disease and anti-HCV serum antibodies or HCV RNA Subsequent treatment of HCV-infected 1997 patients who tolerated an initial course of interferon therapy Rabies vaccine Preexposure and postexposure Chiron; 1997 (RabAvert) immunization of children and adults Oprelvekin (Neumega) Prevention of severe thrombocytopenia Genetics Institute; and reduction of the need for platelet 1997 transfusions after myelosuppressive chemotherapy in patients with nonmyeloid malignancies who are at high risk for severe thrombocytopenia Rituximab (Rituxan) Treatment of patients with relapsed or Genentech; 1997 refractory low-grade or follicular B cell non-Hodgkin lymphoma Daclizumab (Zenapax) Prophylaxis of acute organ rejection in Hoffman-La patients receiving renal transplants; Roche; 1997 part of an immunosuppressive regimen that includes cyclosporine and corticosteroids Becaplermin (Regranex) Lower-extremity diabetic neuropathic OMJ ulcers that extend into the Pharmaceuticals; subcutaneous tissue or beyond and 1997 have an adequate blood supply HTLV-I and -II Detection of antibodies to HTLV-I and Organon Teknika; (Vironostika HTLV-I and -II in human serum or plasma 1998 -II MicroELISA System) Fibrin sealant (Tisseel VH Adjunct to hemostasis in surgeries that Osterreichisches kit) involve cardiopulmonary bypass Institut fur Haemoderivate; 1998 Treatment of splenic injuries caused by blunt or penetrating trauma to the abdomen when control of bleeding by conventional surgical techniques, including suture, ligature, and cautery, is ineffective or impractical Closure of colostomies
Pooled plasma, solvent detergent treated (VIPLAS/SD)
Basiliximab (Simulect)
Palivizumab (Synagis)
Sacrosidase (Sucraid) Eptifibatide (Integrilin)
Diphtheria and tetanus toxoids and acellular pertussis vaccine adsorbed (Certiva) Infliximab (Remicade)
Documented deficiencies of V.I. Technologies; coagulation factors for which there are 1998 no concentrate preparations available, including congenital single-factor deficiencies of Factors I, V, VII, XI, and XIII and acquired multiple coagulation factor deficiencies Reversals of warfarin effect Thrombotic thrombocytopenic purpura Prophylaxis of acute organ rejection in Novartis; 1998 patients undergoing renal transplantation Part of an immunosuppressive regimen that includes cyclosporine and corticosteroids Use in renal transplantation in 2001 combination with triple immunosuppressive therapy Use in pediatric renal transplantation Use of an IV bolus injection Prophylaxis of serious lower Medimmune; 1998 respiratory tract disease caused by RSV in pediatric patients at high risk of RSV disease Congenital sucrose isomaltase Orphan Medical; deficiency 1998 Acute coronary syndrome COR Therapeutics; 1998 Treatment of patients undergoing percutaneous coronary intervention Active immunization of individuals 6 North American weeks to 7 years of age (before the 7th Vaccine; 1998 birthday) Treatment of moderately to severely Centocor; 1998 active Crohn disease to reduce the signs and symptoms in patients who have an inadequate response to conventional therapies Treatment of patients with fistulizing Crohn disease to reduce the number of draining enterocutaneous fistula(s) For reduction in signs and symptoms 1999 of rheumatoid arthritis in patients who have had an inadequate response to methotrexate Inhibition of progression of structural 2000 damage in patients with rheumatoid arthritis who have had an inadequate response to methotrexate
Improving physical function in patients 2002 with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate Reducing signs and symptoms, and 2002 inducing and maintaining clinical remission in patients with moderately to severely active Crohn disease who have had an inadequate response to conventional therapy Reducing the number of draining 2003 enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn disease Improving physical function in patients 2003 with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate Primary immunization of infants at 2, Wyeth-Ayerst 4, and 6 months of age Laboratories; 1998
Rotavirus vaccine, live, oral, tetravalent (RotaShield) Trastuzumab (Herceptin) Metastatic breast cancer in patients Genentech; 1998 whose tumors overexpress the HER-2 protein and who have received one or more chemotherapy regimens for metastatic disease Median survival 2001 (Etanercept) Enbrel Reduction in signs and symptoms of Immunex; 1998 moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to one or more DMARDs Reducing the signs and symptoms and 2000 delaying structural damage in patients with moderately to severely active rheumatoid arthritis, including those who have not previously failed treatment with a DMARD Reducing signs and symptoms of 2002 active arthritis in patients with psoriatic arthritis Recombinant OspA Active immunization against Lyme SmithKline (LYMErix) disease in people 15-70 years old Beecham; 1998 Vitravene (Fomivirsen) Local treatment of CMV retinitis in Isis patients with AIDS who are intolerant Pharmaceuticals, of or have a contraindication to other Ciba Vision; 1998 treatments for CMV retinitis or who were insufficiently responsive to previous treatments
Antithymocyte globulin (Thymoglobulin)
Acute rejection in renal transplant patients
Pasteur-Mérieux Serums et Vaccines—France; 1998 Denileukin diftitox Treatment of patients with persistent or Seragen; 1999 (Ontak) recurrent cutaneous T cell lymphoma whose malignant cells express the CD25 component of the interleukin 2 receptor Hepatitis B Treatment of acute exposure to Nabi; 1999 immunoglobulin (Nabi- HBsAg, perinatal exposure of infants HB) born to HBsAg-positive mothers Sexual exposure to HBsAg-positive individuals Household exposure of infants to people with acute hepatitis B virus infection Recombinant coagulation Treatment of bleeding episodes in Novo Nordisk factor VIIa (NovoSeven) hemophilia A or B with inhibitors to A/S— Denmark; Factor VIII or Factor IX 1999 Interferon α-n1, Chronic HCV infection in patients 18 GlaxoWellcome; lymphoblastoid years of age or older who do not have 1999 (Wellferon) decompensated liver disease Antihemophilic factor/vonUsed in adult patients for treatment and Centeon Pharma— Willebrand factor prevention of bleeding hemophilia A Germany; 1999 complex (Humate-P) (classic hemophilia) Used in adult and pediatric patients for treatment of spontaneous and traumainduced bleeding episodes in severe von Willebrand disease Used in mild and moderate von Willebrand disease when use of desmopressin is known or suspected to be inadequate Hetastarch (Hextend) Plasma volume expander for treatment BioTime; 1999 of hypovolemia during surgery Pneumococcal 7-valent Immunization of infants 2, 4, 6, and Lederle conjugate vaccine 12-15 months of age to prevent Laboratories (diphtheria CRM197 invasive pneumococcal disease Division American protein) (Prevnar) Cyanamid; 2000 Immunization of infants and toddlers 2002 against otitis media caused by vaccine serotypes Antihemophilic factor Control and prevention of hemorrhagic Genetics Institute; (recombinant) (ReFacto) episodes and for short-term routine and 2000 surgical prophylaxis in patients with hemophilia A BCG, live (PACIS) Treatment of CIS in the absence of BioChem associated invasive cancer of the Pharma—Canada; bladder 2000
Tenecteplase (TNKase) Crotalidae polyvalent immune Fab (ovine) (CroFab) Botulinum toxin type B (MYOBLOC) Botulinum toxin type A (BOTOX or BOTOX COSMETIC)
Reduction of mortality associated with AMI Treatment of minimal and moderate North American Crotalidae envenomation Treatment of cervical dystonia to reduce the severity of abnormal head position and neck pain Treatment of cervical dystonia
Genentech; 2000 Protherics; 2000
Elan Pharmaceuticals; 2000 Allergan; 2002
Temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients ≥ 65 years of age Peginterferon α-2b (PEG- Treatment of chronic hepatitis C in Schering; 2001 Intron) patients not previously treated with interferon-α who have compensated liver disease and are at least 18 years of age Alemtuzumab (Campath) Treatment of patients with B cell Millennium and chronic lymphocytic leukemia who ILEX Partners; have been treated with alkylating 2001 agents and who have failed fludarabine therapy Hepatitis A inactivated Active immunization of people 18 SmithKline and hepatitis B years of age or older against disease Beecham (recombinant) vaccine caused by hepatitis A virus and Biologicals; 2001 (TWINRIX) infection by all known subtypes of hepatitis B virus Digoxin immune Fab Treatment of patients with lifeProtherics; 2001 (ovine) (DigiFab) threatening or potentially lifethreatening digoxin toxicity or overdose Darbepoetin α (Aranesp) Treatment of anemia associated with Amgen; 2001 chronic renal failure, including patients on dialysis and patients not on dialysis Treatment of anemia in patients with 2002 nonmyeloid malignancies when anemia is the result of the effect of concomitantly administered chemotherapy Hepatitis B Treatment of acute exposure to HBsAg Nabi; 2001 immunoglobulin (human) after acute exposure to blood (Nabi-HB) containing HBsAg, perinatal exposure of infants born to HBsAg-positive mothers, sexual exposure to HBsAgpositive persons, and household
exposure of infants to people with acute hepatitis B virus infection Anakinra (Kineret) Reduction in signs and symptoms of Amgen; 2001 moderately to severely active rheumatoid arthritis, in patients 18 years of age or older who have failed one or more DMARD Drotrecogin α (activated) Reduction of mortality in adult patients Eli Lilly; 2001 (Xigris) with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of dying from sepsis, as measured by a scoring system based on their general health and the severity of their illness (e.g., by APACHE II) Pegfilgrastim (Neulasta) To decrease the incidence of infection, Amgen; 2002 as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia Ibritumomab tiuxetan Treatment of patients with relapsed or IDEC (Zevalin) refractory low-grade, follicular, or Pharmaceuticals; transformed B-cell non-Hodgkin 2002 lymphoma, including patients with rituximab (Rituxan) refractory follicular non-Hodgkin lymphoma The therapeutic regimen includes rituximab, 111indium ibritumomab tiuxetan, and 90 yttrium ibritumomab tiuxetan Interferon β-1a (Rebif) Treatment of patients with relapsing Serono; 2002 forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability DTaP vaccine adsorbed Active immunization of infants and Aventis Pasteur— (DAPTACEL) toddlers at 2, 4, 6, and 17-20 months of Canada; 2002 age against diphtheria, tetanus, and pertussis Rasburicase (Elitek) Initial management of plasma uric acid Sanofi-Synthelabo; levels in pediatric patients with 2002 leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid Peginterferon α-2a Treatment of adults with chronic Hoffman-La (PEGASYS) hepatitis C who have compensated Roche; 2002 liver disease and who have not been
previously treated with interferon α Combination therapy with ribavirin, 2002 USP (Copegus), for the treatment of chronic HCV infection Peginterferon α-2a coPrefilled syringes of Pegasys 2004 packaged with ribavirin (peginterferon α-2a) for the treatment (Pegasys Copegus of chronic hepatitis C, as a Combination Pack) subcutaneous injection taken once a week Urokinase (Abbokinase) For adults for the lysis of acute Abbott massive pulmonary emboli, defined as Laboratories; 2001 obstruction of blood flow to a lobe or multiple segments For the lysis of pulmonary emboli accompanied by unstable hemodynamics (i.e., failure to maintain blood pressure without supportive measures) Adalimumab (Humira) For reducing signs and symptoms and Abbott inhibiting the progression of structural Laboratories; 2002 damage in adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more DMARDs Can be used alone or in combination with methotrexate (MTX) or other DMARDs Laronidase (Aldurazyme) For patients with Hurler and Hurler- Biomarin Scheie forms of MPS-I and for patients Pharmaceutical; with the Scheie form who have 2003 moderate to severe symptoms Alefacept (Amevive) Treatment of adult patients with Biogen; 2003 moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy Agalsidase beta For use in patients with Fabry disease Genzyme; 2003 (Fabrazyme) to reduce GL-3 deposition in capillary endothelium of the kidney and certain other cell types Tositumomab and Treatment of patients with CD20 Corixa; 2004 131 iodine tositumomab positive, follicular, non-Hodgkin (Bexxar) lymphoma, with and without transformation, whose disease is refractory to rituximab and has relapsed after chemotherapy Omalizumab (Xolair) For adults and adolescents (≥ 12 years Genentech; 2004 of age) with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a
perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids Bevacizumab (Avastin) First-line treatment for patients with Genentech; 2004 metastatic colorectal cancer Cetuximab (Erbitux) A monoclonal antibody that targets the Imclone Systems; protein EGFR 2004 99m Technetium For scintigraphic imaging of patients Palatin fanolesomab with equivocal signs and symptoms of Technologies; 2004 (NeutroSpec) appendicitis aged 5 years or older Natalizumab (Tysabri) Treatment of patients with relapsing Biogen Idec; 2004 forms of multiple sclerosis to reduce the frequency of clinical exacerbations Palifermin (Kepivance) Decreases the incidence and duration Amgen; 2004 of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support Galsufase (Naglazyme) Treatment of patients with MPS-VI Biomarin Pharmaceuticals; 2005 Alglucosidase alpha Infantile-onset Pompe disease (GAA Genzyme; 2006 (Myozyme) deficiency) Ranibizumab injection For the treatment of neovascular (wet) Genentech; 2006 (Lucentis) age-related macular degeneration (AMD) Panitumumab (Vectibix) For the treatment of patients with Amgen; 2006 EGFR-expressing colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens Eculizumab (Soliris) For the treatment of patients with Alexion paroxysmal nocturnal hemoglobinuria Pharmaceuticals; (PNH) to reduce hemolysis 2007 ADA, adenosine deaminase; AMI, acute myocardial infarction; CIS, carcinoma-in-situ; CMV, cytomegalovirus; DMARD, disease-modifying antirheumatic drug; DTaP, diphtheria and tetanus toxoids and acellular pertussis; EGFR, epidermal growth factor receptor; G-CSF, granulocyte colony-stimulating factor; GL, globotriaosylceramide; GM-CSF, granulocyte-macrophage colony-stimulating factor; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HER-2, human epidural growth receptor 2; HTLV, human T lymphotropic virus; MPS, mucopolysaccharidosis; PEG, polyethylene glycol; RSV, respiratory syncytial virus. a Gaucher disease is an autosomal dominant or recessive disorder caused by an excess of glucocerebroside in the reticuloendothelial cells because of the lack of the metabolic enzyme cerebrosidase. Proliferation of abnormal cells leads to splenomegaly, hepatomegaly, skeletal lesions, and other symptoms. Data from Biotechnology in the U.S. Pharmaceutical Industry. Research Triangle Park, NC, Institute for Biotechnology Information, 1995; and www.fda.gov. P.241
G. DNA ligase is an enzyme that seals single-stranded nicks between nucleotides in double-stranded DNA. DNA ligase enables DNA fragments from different sources to be joined. H. DNA polymerase is an enzyme that catalyzes the synthesis of DNA. It uses a single strand of DNA as the template and nucleotides as the substrates. I. An enzyme is a protein that catalyzes a substrate during its conversion to a product. J. A gene is a segment of DNA that codes for a specific polypeptide. K. A genome is the genetic information content of a cell. L. A hormone is an endogenous substance that is secreted by one type of cell and acts on another type of cell. M. A hybridoma is a hybrid cell produced by the fusion of a myeloma cell and a specific antibodyproducing B lymphocyte. A single hybridoma produces a single type of antibody. N. Interferon (INF) is any of a class of glycoproteins produced by animal cells in response to viral infection. O. Interleukin is a group of proteins synthesized by macrophages and T lymphocytes in response to antigen and other stimulation. P. A lymphokine is any of a class of soluble proteins produced by some white blood cells. These proteins stimulate other white blood cells as part of the immune response. Q. A plasmid is a circular piece of duplex DNA that is not part of a chromosome and can replicate independently. Plasmids are used as vectors for the transfer of DNA in recombinant DNA technology. R. RNA is a macromolecule that contains information for protein synthesis. The three types of RNA are ribosomal (rRNA), transfer (tRNA), and messenger (mRNA). RNA is also the genetic material of some viruses. S. Recombinant DNA (rDNA) is a hybrid DNA that is formed when pieces of DNA from different sources are joined. The process is also known as gene splicing. T. A restriction endonuclease is an enzyme that cleaves DNA at sequence-specific sites. U. Tumor necrosis factor (TNF) is a lymphokine produced by macrophages. It can be activated to kill tumor cells. V. Reverse transcriptase is an enzyme present in RNA viruses that catalyzes the formation of DNA from the viral RNA. III. PROTEINS AND PEPTIDES. Proteins and peptides play essential roles in all aspects of cellular function. Many endogenous substances synthesized in the body are essential proteins. Many enzymes that catalyze vital reactions in the body are proteins. A. Hemoglobin (Hb) is a large protein involved in oxygen transport. B. Globulins are special proteins in the plasma that are involved in immunogenic response and antibody formation. C. Albumin is a plasma protein that binds to many drugs and is used as a carrier for new drugs. D. Other well-known proteins include insulin and the enzymes involved in digestion. P.242
Table 11-2. Immunoglobulin Applications Gammaglobulinemia
Hepatitis A prophylaxis Measles and rubella prophylaxis Multiple myeloma with specific antibody deficiency Prophylaxis in infants and children with HIV exposure Chronic inflammatory demyelinating neuropathy Acquired hemophilia Orphan drug for the treatment of juvenile rheumatoid arthritis Respiratory tract infections Immune thrombocytopenic purpura Orphan drug for the treatment of polymyositis and acute myocarditis Acute exposure to hepatitis B surface antigen Kawasaki disease in conjunction with high-dose aspirin E. Protein is an important component of keratin in hair and myosin in muscles. F. Albumin (human) 5% USP is used to reverse hypovolemia in shock patients, burn patients, and those with chronic hypoalbuminemia. IV. Immunoglobulin (Ig) is an important class of globulin proteins involved in immunity and the allergic response. IgG is used therapeutically to modulate or replace antibody in various immunodeficiency and disease states. Intramuscular and intravenous preparations are available from a variety of manufacturers (Tables 11-2 and 11-3). Most of these products must be stored under refrigeration (2-8°C) and have a limited shelf life. V. RECOMBINANT HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR (G-CSF) A. CSFs are glycoproteins that regulate the production of many types of blood cells and components in the body. These include macrophages, eosinophils, neutrophils, basophils, and platelets. Natural and modified CSFs are used to treat a number of congenital disorders and several forms of cancer. B. Lenograstim is a recombinant human granulocyte CSF (rhG-CSF) derived from Chinese hamster ovary cells. It is glycosylated at the same site as natural hG-CSF (threonine-133) and consists of 174 amino acids. C. Filgrastim is an Escherichia coli-derived glycoprotein. It is not glycosylated, and it differs in structure from natural hG-CSF. Like natural hG-CSF and filgrastim, lenograstim selectively promotes the proliferation, differentiation, and maturation of blood cell precursors. Dose-related P.243 increases in blood neutrophil counts are observed after lenograstim administration. Lenograstim reduces the duration of neutropenia and the severity of infection in patients who are receiving cytotoxic chemotherapy for nonmyeloid malignancy. Colony-forming assays show that lenograstim is approximately three times as potent as filgrastim. These agents were similarly potent in cell-proliferation assays. Both natural and recombinant G-CSF products stimulate the release of mature neutrophils from hematopoietic tissue, prolong their survival, and enhance their phagocytic and cytotoxic activity. Table 11-3. Immunoglobulin Products Gamimune-NNabi-HB Gammagard RespiGam Polygram Sandoglobulin Gammar Polygam Iveegam Venoglobulin
D. Other actions of rhG-CSF include synergism with interleukin 3 (IL-3) to induce megakaryocyte formation and with granulocyte-macrophage CSF (GM-CSF) to stimulate granulocyte- macrophage colonies. VI. GLYCOPROTEINS A. Many special proteins acquire biologic activity as a result of their covalent linking with a polymer of sugar or carbohydrate. The covalently linked protein-carbohydrate molecule is a glycoprotein. Glycoproteins form natural structural membranes in the cells of unicellular (e.g., bacteria) and multicellular (e.g., humans, animals) organisms. B. N-acetylglucosamine (NAG) forms the cell membrane in bacteria. It is an example of a carbohydrate chain linked to a protein through a chain of amino acids. Bacterial resistance to penicillin is linked to the integrity of NAG in the cell membrane. C. The extent and site of glycosylation of a protein molecule may affect the physicochemical properties, stability, and specificity of a surface receptor in a cell. Glycoproteins on the surface of red blood cells are involved in recognizing the specific blood type. D. The charge at the site of a glycoprotein molecule may play a role in the orientation and interaction of the receptor. The charge may be modified by sialic acid, sulfate, and phosphate groups. The protein molecule presents potential sites for Nglycosylation and O-glycosylation. Change in glycosylation is a powerful tool for use in engineering the preferred configuration and stability when designing recombinant glycoprotein for therapeutic use. E. Carbohydrates contribute to activities in a number of ways, including recognition of the terminal sialic acids of glycoproteins by various viruses and bacteria, recognition of polylactosamines on erythrocytes by autoimmune antibodies, and recognition of sialylated, fucosylated lactosaminoglycans on leukocytes by E-selectin of endothelial cells. VII. DNA A. DNA is the genetic material of all organisms except some viruses, whose genetic material is in the form of RNA. Most organisms have double-stranded DNA. Some viruses contain single-stranded DNA. This type of virus replicates itself by entering a host cell, where it makes a complementary copy of itself and temporarily forms a double strand. B. All DNA molecules consist of many covalently linked subunits called nucleotides. The nucleotides consist of deoxyribose, phosphate, and one of the nitrogen-containing bases (adenine, guanine, thymine, or cytosine). DNA encodes information to produce all of the proteins needed by the organism. The DNA sequence may be modified or recombined with new strands. This recombinant technology may be used to correct genetic defects in living organisms. VIII. ANTISENSE DRUGS A. Many diseases occur because of genetic defects or errors in the gene involved in producing essential enzymes or proteins. Genetic information resides in chromosomes that house helical strands of DNA within the nucleus. The Human Genome Initiative was created several years ago to study all human genes. This national effort is now yielding information on many serious P.244 diseases that involve congenital defects, cancer, infection, AIDS, and other disorders of the immune system.
B. Strategies are now available to moderate many disease processes by altering or blocking the transcription of DNA. If the DNA sequence is altered so that the complementary strand is transcribed instead of the normal “sense” gene, then the DNA cannot make a copy of the normal RNA that participates in protein synthesis. The aberrant copies of RNA may pair up (hybridize) with other RNA strands that complement it and thereby block protein synthesis. This technique involves targeting DNA or RNA with antisense drugs. C. Many oligonucleotides are designed to target viral disease and cancer cells. To further stabilize the drug, phosphodiesters are chemically converted to phosphothioates. D. Antisense drugs against cytomegalovirus (CMV), HIV, and other viruses are in various phases of clinical trials. The first antisense drug, Vitravene, was approved by the U.S. Food and Drug Administration (FDA) in 1998. Vitravene is a potent biotechnology drug that is indicated for the local treatment of CMV retinitis in patients with AIDS who are intolerant of other treatments, who have a contraindication to other treatments, or who were insufficiently responsive to previous treatments. The recommended labeled dosage is an induction dose on days 1 and 15, followed by a monthly intravitreal injection of 330 µg. E. When the nucleotide base sequence of a gene that controls a specific body function is known, the antisense DNA strand can be synthesized. If necessary, the DNA strand can be modified to provide increased stability and potency. These strands can then be introduced into cells, where they attach themselves to the complementary sense DNA strands and depress transcription of these genes. This technique was performed successfully in cell culture for the gene that produces human squamous cell carcinoma of the larynx. F. If a duplicate copy of a gene is inserted into a chromosome in reverse orientation to the normal gene, then the antisense DNA strand of this gene is transcribed. This process yields an antisense mRNA strand that is complementary to the mRNA strand transcribed for the normal gene. The two complementary RNA strands bind to each other, thereby preventing the translation of the normal RNA strand that may control protein synthesis. IX. GENE THERAPY. The first example of human gene therapy is from 1990, when the FDA approved PEG-ADA (Enzon) for adenosine deaminase deficiency. This rare, but serious, genetic disorder weakens the immune system and causes increased susceptibility to infection. Two girls were reinfused with their own genetically altered white blood cells. The altered cells live and function normally, and the two girls were living a relatively normal life after 5 years. X. MISCELLANEOUS BIOTECHNOLOGIC PRODUCTS A. Alteplase (Activase, Genentech) is a thrombolytic agent formerly known as tissueplasminogen activator. Intravenous alteplase effectively produces recanalization of occluded coronary arteries after acute myocardial infarction. Intravenous alteplase is also effective in the treatment of acute massive pulmonary embolism. Adverse effects, including bleeding complications, reperfusion arrhythmias, and reinfarction, are the primary concerns with this therapy. Systemic fibrinolysis is less than that seen with streptokinase. The recommended dose to produce recanalization after myocardial infarction is 100 mg in divided doses. The recommended dose to treat pulmonary embolism is 100 mg infused intravenously over 2 hr. B. Antithrombin III (heparin cofactor, human antithrombin III, ATnativ, Pharmacia) is designated an orphan product. It is used as replacement therapy to prevent or treat
thromboembolic episodes in congenital deficiency states. The amount of intravenous antithrombin III concentrate to be administered is based on antithrombin III levels. In patients who have congenital or acquired antithrombin III deficiency, the goal is to maintain levels between 80% and P.245 120% of normal. Once-daily doses of antithrombin III should maintain serum levels above 80% of normal. Levels should be monitored twice daily until they stabilize, then daily thereafter immediately before the next dose is administered. C. IL-3 is a hematopoietic growth factor used to treat patients with bone marrow failure. Recombinant human IL-3 (rhIL-3) alone improves neutrophil and platelet counts in patients who have chemotherapy-related bone marrow failure and myelodysplastic syndromes. However, only minimal improvements in hematopoiesis are seen in patients who have aplastic anemia. Enhanced responses are seen with the sequential combined use of rhIL-3 and other hematopoietic growth factors (e.g., GMCSF). Recombinant human IL-3 is given subcutaneously or intravenously. Intravenous doses range from 30 to 1000 µg/m2/day infused over 4 hr. D. Aldesleukin, a lymphokine, is a hrIL-2 product that is used to treat metastatic renal cell carcinoma. The starting dose is 0.037 mg/kg every 8 hr by a 15-min intravenous infusion. Aldesleukin is absorbed erratically after intramuscular or subcutaneous injection. It follows two-compartment pharmacokinetics, with an α-half-life of 13 min and a β-half-life of 85 min. It is eliminated renally. The principal side effects are hypotension and flulike symptoms. Most adverse effects are dose related. E. Abciximab (c7E3 Fab, ReoPro) is a chimeric monoclonal antibody Fab fragment that is specific for platelet glycoprotein IIb-IIIa receptors. Abciximab is extremely effective in reducing fatalities (> 50%) in subjects who have unstable angina after they undergo angioplasty. The recommended dosage is an intravenous bolus of 0.25 mg/kg administered 10-60 min before the start of angioplasty, followed by a continuous infusion of 10 µg/min for 12 hr. Platelet aggregation is almost completely inhibited 2 hr after the initiation of abciximab therapy. The major complication of abciximab infusion is dose-related bleeding. F. Campath-1 is a MAb that targets human lymphocytes and monocytes. It is used for immunosuppression in patients who undergo organ transplant. The intravenous dose is 25 mg once or twice daily. Campath-1 is also used to treat refractory autoimmune disorders, including rheumatoid arthritis. It is used experimentally to treat vasculitis. Campath-1 antibodies are used to prevent graft-versus-host disease and to treat lymphoid malignancy caused by immunosuppression in patients who undergo organ transplant. G. Edobacomab is an immunoglobulin directed against gram-negative bacterial endotoxins. For septic shock, single doses of 2-15 mg/kg intravenously every 24 hr are used. The volume of distribution ranges from 4 to 8 L. The elimination half-life is 10-18 hr. The main side effects are hypersensitivity reactions and antibody production. The drug is also being investigated for the treatment of gram-negative sepsis and septic shock. H. Muromonab-CD3 is an immunosuppressive agent with specific targeting. It is effective in reversing acute renal allograft rejection. The usual dose is 5 mg/day intravenously for 10-14 days after the initial signs and symptoms of rejection. The volume of distribution is approximately 6.5 L, and the half-life is 18 hr. Side effects include flulike symptoms, which appear to be associated with the release of cytokines. Symptoms may be self-limiting or severe and life threatening.
I. Nebacumab is an immunoglobulin directed against gram-negative bacterial endotoxins. The drug is being investigated for the treatment of gram-negative sepsis and septic shock. Signs and symptoms of septic shock usually resolve during the first 7 days after treatment. Its half-life is 15.9 hr, and the volume of distribution is 48.5 mL/kg. J. Satumomab pendetide is an MAb conjugate produced from the murine MAb B72.3. It requires radiolabeling to form 111indium chloride satumomab pendetide. It is used as a diagnostic imaging agent in the staging of patients with known colorectal and ovarian carcinoma. The metabolic fate of this agent is unclear. The antibody conjugate is cleared slowly. It has a terminal half-life of approximately 56 hr. Approximately 10% of an administered dose appears in the urine. K. Zolimomab aritox (Orthozyme-CD5, Xoma/Ortho Biotech) is an immunoconjugate of monoclonal anti-CD5 murine IgG and the ricin A-chain toxin. Its primary use is in the treatment P.246 of steroid-resistant graft-versus-host disease after allogeneic bone marrow transplant for hematopoietic neoplasms (e.g., acute myelogenous leukemia). Other potential uses include the treatment of rheumatoid arthritis and insulin-dependent diabetes mellitus. After therapeutic doses, peak serum levels range from 1 to 5 µg/mL. The serum halflife is 1.5-4 hr. The dose varies, depending on the indications. L. Betaseron (INF-β, Berlex Laboratories) is a glycoprotein with antiviral, antiproliferative, and immunomodulatory activity. Many of its effects are similar to those of INF-α. Its uses include the treatment of multiple sclerosis, AIDS, malignant melanoma, herpesvirus, and papillomavirus infections. It is also recommended at a dose of 8 million units subcutaneously every other day to reduce exacerbations in patients who have relapsing-remitting multiple sclerosis. It is administered intravenously, intramuscularly, subcutaneously, intrathecally, topically, or intralesionally for a variety of indications. Its biologic activity is evident in the absence of detectable serum levels. Serum concentrations are not consistently detectable after subcutaneous or intramuscular administration. Interferon β may cross the disrupted blood-brain barrier. The compound does not appear in urine after systemic administration. Adverse effects include flulike symptoms, bone marrow suppression, neurotoxic effects with high doses, anorexia and other gastrointestinal symptoms, and elevations of liver enzymes and serum creatinine. P.247
STUDY QUESTIONS Directions: Each of the questions, statements, or items or incomplete statements in this section can be correctly answered or completed by one of the suggested answers or phrases. Choose the best answer. 1. Which type of cell contains double-stranded DNA? (A) Human cells (B) Bacteria cells (C) HIV cells (D) Viruses View Answer 1. The answer is A [see VII.A].
Human cells contain double-stranded DNA, whereas lower organisms (e.g., bacteria, viruses) do not. 2. Which enzyme is used by the human immunodeficiency virus (HIV) to form DNA in the host cell? (A) Restrictive endonuclease (B) DNA-directed polymerase (C) Reverse transcriptase (D) Both A and B (E) None of the above View Answer 2. The answer is C [see II.V]. Reverse transcriptase is the enzyme that a virus uses to assemble its DNA from RNA. Unlike higher organisms, viral particles have genetic material in the RNA and need a host cell for reproduction. 3. Gammaglobulin is considered to be (A) DNA. (B) RNA. (C) a protein. (D) None of the above View Answer 3. The answer is C [see III.C; Table 11-2]. Gammaglobulin is a subclass of immunoglobulin protein involved in immunity and allergic response. 4. Glycoprotein is considered to be a protein linked to (A) a carbohydrate. (B) a hormone. (C) a lipid. (D) DNA. (E) None of the above View Answer 4. The answer is A [see III.B; VI]. Glycoprotein consists of a carbohydrate linked to a protein. 5. An enzyme that cleaves DNA at a specific site is called a (A) restriction endonuclease. (B) restrictive ribonuclease. (C) trypsin. (D) None of the above View Answer 5. The answer is A [see II.T]. A restriction endonuclease is an enzyme that specifically cleaves DNA molecules. Ribonuclease will cleave RNA only, and trypsin is a digestive enzyme found in the gastrointestinal tract. 6. An example of a cytokine is (A) interleukin. (B) insulin. (C) gonadotropin. (D) thyroxine. (E) None of the above View Answer 6. The answer is A [see II.O;, X.C].
Interleukin is a “messenger” substance synthesized by the cell (cytokine) to communicate and trigger cellular response. 7. A common storage condition for most biotechnology products after reconstitution is (A) at room temperature. (B) in a cool place. (C) in a warm place. (D) no excessive heat. (E) in a freezer. View Answer 7. The answer is B [see I]. Most biologic compounds are heat labile and must be stored at low temperature. 8. What drug is used to prevent embolism in the lung and during myocardial infarction? (A) Alteplase (B) Human growth hormone (C) Granulocyte-macrophage colony-stimulating factor (GM-CSF) (D) Epogen (EPO) (E) None of the above View Answer 8. The answer is A [see X.A; Table 11-1]. Alteplase is a thrombolytic agent formerly known as tissue-plasminogen activator. 9. What base is found in DNA? (A) Cytosine (B) Adenine (C) Guanine (D) Thymine (E) All of the above View Answer 9. The answer is E [see VII.B]. All DNA molecules consist of nucleotides, which consist of deoxyribose, phosphate, and one of the following nitrogen-containing bases: adenine, guanine, thymine, and cytosine. P.248
ANSWERS AND EXPLANATIONS 1. The answer is A [see VII.A]. Human cells contain double-stranded DNA, whereas lower organisms (e.g., bacteria, viruses) do not. 2. The answer is C [see II.V]. Reverse transcriptase is the enzyme that a virus uses to assemble its DNA from RNA. Unlike higher organisms, viral particles have genetic material in the RNA and need a host cell for reproduction. 3. The answer is C [see III.C; Table 11-2]. Gammaglobulin is a subclass of immunoglobulin protein involved in immunity and allergic response. 4. The answer is A [see III.B; VI]. Glycoprotein consists of a carbohydrate linked to a protein. 5. The answer is A [see II.T].
A restriction endonuclease is an enzyme that specifically cleaves DNA molecules. Ribonuclease will cleave RNA only, and trypsin is a digestive enzyme found in the gastrointestinal tract. 6. The answer is A [see II.O;, X.C]. Interleukin is a “messenger” substance synthesized by the cell (cytokine) to communicate and trigger cellular response. 7. The answer is B [see I]. Most biologic compounds are heat labile and must be stored at low temperature. 8. The answer is A [see X.A; Table 11-1]. Alteplase is a thrombolytic agent formerly known as tissue-plasminogen activator. 9. The answer is E [see VII.B]. All DNA molecules consist of nucleotides, which consist of deoxyribose, phosphate, and one of the following nitrogen-containing bases: adenine, guanine, thymine, and cytosine.
12 Principles of Pharmacodynamics and Medicinal Chemistry M a r c W . Ha r r o l d N e l s o n S . Ye e
I. INTRODUCTION. P h a r m a c o d y na m i c s is a b r a nc h o f p h a rm ac ol og y t h a t f oc us es on t he s t udy o f t he b i oc h em ic al an d p h y s i olo g ic al e ff ec t s o f d r ug s an d th e m ec h an is m s b y w h i c h th e y p r o du c e s u c h ef f ec ts . A na l y s is o f dr u g a c t i on pr ovi d e s t he ba s i s f o r ra t io na l de s i gn o f t he r ap e ut ic ag e nt s a nd p r o v id es in s i gh t in t o t he r e gu la t io n o f c e ll ul a r fu n c t i on s.
II. EFFECTS OF DRUGS A. P e r t u r b a t i on o f n o rm a l p h ys i o l o g i c a l p r o ce s s es . Th e ac t io ns o f d ru g s a r e t he c o ns eq u en c e s o f t h e d y na m ic i n te r ac t io ns be t we en d r ug m o le c u le s a n d c el l ul a r c om p on e nt s . S uc h i n te r ac t io ns le a d t o a l te r at i on in t he f un ct i on s o f t h es e c om p on e nt s , c a l le d re c ep t o r s . Th e r es u lt in g bi oc h e m i c a l a n d p h ys i ol og ic c h an g es f o r m t he ba s i s o f th e c el lu l a r r es p on se t o t he d rug . D r ug s a c t b y m o du la t in g th e o n g oi ng p ro c e s s es in s i de t he c e ll s . B . Ag o n i s t s a n d a n ta g on i s t s 1 . P ot e nt i al l y , a n y m a c rom o le c u l ar c o m p on e n t m ay a c t a s a d r ug r ec e p to r. F o r e xa m p l e , c - Ki t t y ro s i n e k i n as e c an be in h ib i te d by i m a ti ni b m es y l a te ( G lee v e c ) , c yc lo o xy g e n a s e- 2 i s b loc k e d b y c el ec o xi b ( C e leb r e x) , a n d c h ro m o so m a l D N A i s c r os s -l in k ed b y c is pl a ti n ( P l a ti n ol ) . 2 . C e r ta in d ru g re c e p to rs no r m a l l y s e r ve a s r ec ep t o rs fo r en d og e no us li ga n ds an d t h us a re p h ys i o l o g i c al re c e p to r s . F o r e xa m p le , a d r en e r gi c r ec e pt o rs a re p h ys io l og ic al r ec ep t o rs fo r c a t ec ho l am in es ; e s tr og e n re c e p to r s f o r es t r ad io l . 3 . D r ug s wh os e re s p o ns e s re s e m b l e t he e ff ec t s o f t he en do g en o us m ol ec u le s a r e r e c ep t or a go n is t s . F o r exa m p l e , b e th a ne ch o l d ire c tl y s ti m u l at es c h ol i ne rg i c r e c ep t or s a n d is th u s a n a g o ni s t . 4 . P ha r m ac o l og i ca l an ta g o n is t s a r e d r ug s t ha t l a ck in t r i ns i c a c ti vi t y a n d p ro du ce e f f ec ts b y co m pe t i t i ve l y o r n on c om p et i t i ve l y i n h i bi t in g th e a c t i on of th e e n d og en o us m ol e c u le s at t h e r ec ep t o r . a . A c o m pe t i ti ve a n ta g on i s t a c ts b y i n te r fe r i ng wi t h b i nd in g of th e e n dog e n ou s l i ga n d t o t h e r ec e pt o r i n a r e v e rs ib l e m a n ne r . Fo r e xa m p l e, p ro p an ol o l com p et es wi t h c a te c h o la m i ne s f o r b i nd i ng wi t h ad r en e rg ic β - r e c ep t or s ; t am o xi f e n c o m pe t es wi t h e s t ro ge n re c e p to r s fo r bi n di n g wi t h es t ra d io l . b . A no n c om pe t i t i ve a nt a g o ni s t a c ts b y i n te r ac ti n g wi t h t he no n li g an d b in d in g s i te o f t he re c e p t or ( e. g . , t h ro u g h c o va l en t m od i fi ca t io n ) , s uc h t h at no r m a l b ind i ng o f t he e n d og en o us l i ga n d t o t he r ec e pt o r i s i r re v e r si b l y i n hi bi t ed . Fo r in st a nc e, m o no am i ne o xi d a s e ( MA O ) i n hi bi t o rs s uc h a s t r an yl c y p ro m i n e ( P a r na t e ) i ni t ia ll y i nt e r ac t wi t h MA O i n a re v e r s i bl e m ann e r bu t t h en fo r m c o v al en t ad d uc ts th a t i r r e v er sib l y i nh ib i t MA O .
5 . P a r ti a l a n t ag o ni s t s in h ib i t t h e e nd o ge no us lig a n d f r om b i nd in g th e r ec e pt o r b u t p o ss es s s o m e in t r in s i c ac t i v i t y . N a lo r p hi ne is a pa r t ia l a n ta g on is t fo r th e o p ia t e r e c ep t or . 6 . P h ys i o l o g i c a l a n ta g on i s m o c c ur s wh e n t he d ru g s ac t in de p en d en t l y a t d i ff e r en t r e c ep t or s i t es , o f te n y ie ld i ng op p os in g a c ti on s . Fo r e xa m p le , e p in ep h r in e a n d a c et yl ch o li n e ac t o n th e s y m p at h et ic an d p a ra s ym p at h et ic au t on o m i c n erv o u s s ys t em , r e s p ec t i v el y , and t he i r e f fe c ts a r e a n ta go n is t ic to ea c h ot h e r. P.250
7 . N e ut r a l iz i ng an t a go ni s m o c c u rs wh e n t wo d r ug s b i nd wi t h e a c h ot h er to f o rm a n i n ac t i ve c o m p o un d . F o r e xa m p l e , d ig o xi n - b in di n g a n ti b od y us e d i n d ig o xi n o ve r do se a c ts b y s eq u es t er i ng th e d r u g, r es ul t in g i n t h e f o rm a ti o n o f a n i na c ti v e c om p le x.
III. MECHANISMS OF DRUG ACTION A. C e l l s u r f ac e re c ep t or s 1 . R ec e pt o rs c a n b e p r ot e i n s o r gl yc o p r o t e i n s. F o r e xa m pl e , c el lu l ar de te r m in an t s s uc h a s C D2 0 a n ti g en on B l ym p ho c yt es c an bi nd wi t h r it u xi m a b ( R i tu xa n ) , a c h im e ri c m o n oc lo na l a n tib o d y ta r g et e d a ga in s t t he C D 2 0 a n ti ge n . 2 . Th e bi nd i ng of d ru gs to r ec e pt o rs is h i gh l y s p ec i fi c a nd ca n i n v ol v e a va r i et y o f i n t er a ct i on s , in c l u di ng hy d r o p ho b ic i n te r ac t io ns a n d van de r W aa ls f o rc es wi t h io ni c , h yd r o ge n , a n d c o v a l en t b o n ds . Th e t y p e o f i n te ra c ti o n a nd th e b i nd i ng aff i n it y c an i n f lu en ce t he du r a ti on and r e v e rs ib i li t y o f t he d rug ac t io n . 3 . Th e i n te r ac t io n a n d b in d in g a f f in i t y a r e re la t ed t o th e c he m i ca l s t ru c tu re o f b o th t h e d r u g a nd th e l i ga nd . C h e m i ca l m od i fi c a t io n o f t h e s t ru c t u r e o f t he d ru g m ol ec u le c a n ch a ng e th e p ha r m a c o l og ic a l a nd ph a rm ac ok in e t ic p r o pe r ti es o f d r ug s. 4 . Th r o ug h s t ru c tu r e -a c t iv i t y r e l at i on s h i p s t u di es , s yn t he t ic d r u g a na lo gs c a n b e d e ve l op ed t o ac h ie v e a h i gh s e le c ti v i t y o f d ru g ac t io n — a d es ir a bl e ra t io o f t h e r ap eu t ic to to xi c e f fe c t wi t h a b e tt e r - to l er a te d s i de ef f ec t p r o fi le . B . S i g na l t r an s du c t io n b y c e l l - s u r f ac e r ec e pt or s 1 . C el l -s u r fa c e r ec ep t o rs a r e c om po se d o f e xt r a c e l lu l a r d om ai ns th a t b in d t h e l i ga n ds (d r u gs o r ph y s io lo g ic al m o le c ul es ) . F o r exa m p l e , e p id e rm al g ro wt h f ac t or ( E G F ) r ec e pt o r n o rm al l y b i nd s E G F a nd t ra ns f o rm i n g g r o wt h fa c to r α , a n d i t is th e t a r g et of t he m o no c l o na l a n t ib od y c et u xi m a b ( E r bit u x) , wh i c h co m p e ti t i vel y b i nd s t o t h e E G F r ec e pt o r . 2 . Th e l i ga n d b in di n g s e rv e s as a t r ig g er i ng s i gn al t ha t c a n b e p ro p ag a te d i n t h e t a r g et c e ll th r o ug h i n tr a c e l lu l a r r eg u la t o r y m ol ec u l e s, k n o wn as se c on d m e s se n ge r s o r e ff e c to rs . F or e xa m pl e , i so p ro t er e n ol bi n ds wi t h t h e β - a dr e n e rg ic r e c ep t or , wh i c h is fu nc t io n al l y c o u pl ed t o a de n y la t e c y c la s e vi a t he st im ul a t or y G p r o t ei n ( G s ) . As a r es u lt , a d en y l a te c y c l as e is ac ti v a t e d, an d th e c y c l ic ade n os i ne m o no p ho s p h at e (c A MP ) le v e l in c re as es . 3 . Li g an d b in d in g o f re c ep t o rs of t en le a ds to in t e ra c ti o n o f t h e r ec e pt o rs wi t h t h e c yt o pl as m i c e f fe c to r s , wh i c h in tu r n b ec om e a c tiva t e d . I n te g r at io n of th e m u lt i pl e s i gn al t r an s d uc in g e v e n ts al o ng th e re c e p to r - e ff ec t o r s y s t e m m i gh t c h an ge t he c e ll ul a r p h en o t y pe o r g en e e xp r e s s io n , l ea di n g to n e w p r ot e in s yn t he s i s . F o r
e xa m p l e , b in di n g o f t h e li g an d s t o t he E G F re c e pt o r le a ds t o a c ti v a t io n o f t h e t yr o s in e k in as e o f th e i n tr a c el lu l ar do m ai n o f t h e r e c ep t or , wh i ch th e n a c t iv a t e s d o wn s t r ea m s i g na l in g p at h wa y s t h at r es ul t s i n ce ll u la r p ro li f e ra t io n . Th e m o n oc l on al a n t ib od y e r lo t in i b ( Ta r c ev a ) b i nd s t o t h e a de no s in e t ri p ho s p ha t e ( A TP ) po ck e t o f th e t yr o s in e k in as e o f th e EG F r e c e p to r an d i nh i bi ts n o r m a l A TP b i nd i ng , t h us in h ib i ti ng t h e a c ti v i t y of t he t y r os ine k i n as e. C . S i g na l i ng me d ia t e d b y i n t r a c e l l u la r r ec e p tor s . Th yr o i d h o rm on e , s ter o i d h o r m o ne s , v i t am in D , a nd t he r et i no i ds a ct t h ro ug h bi nd i ng c yto p la s m ic re c ep t o rs , wh i c h t ra ns l oc at e i n to t he n uc le us . Th es e re c e p to r s a r e s ol u bl e, D N A - bi nd i ng p r o t ei ns th a t r e gu la t e t he t r an s c r ip t io n o f s pe ci f ic ge n es . F o r e xa m p l e, all - t r an s r e t in o ic ac id ( A TR A ; V es a n oi d ) b i nd s t o r e ti n oi c ac i d r ec e pt o r i n t h e c y t os o l , r e s ul ti n g i n u p - re gu l at i on o f t a rg e t g en e e xp r es s io n an d d i ff e r en t ia ti o n o f l e uk em ic p r o m yel oc y t es . D . T a r ge t ce l l d e se n si t iz a t io n an d h yp e r s e n s i t iz a t io n 1 . C el ls ha v e t he ab il i t y t o r e sp o nd t o e nd o ge nou s re g ul a to r y m o l ec ul es o r e xo g e n o us l y ad d ed dr u gs o v e r a wi d e r a ng e o f c o n c e n t ra t io ns . Ho we v e r , p r o t ec ti v e m ec h an is m s ar e a v a i la b le f o r m a i nt a in in g h o m e os t a ti c co n t ro l t o p r e v e nt o ve r s ti m u l at i on or un d e rs t im ul a ti o n o f t h e t a rg e t c e ll s . 2 . C el l r eg u la t i on c a n oc c u r a t di f f e re n t l e v el s a lo n g t h e s i g na l t r a ns du c t io n p a t h wa y . R e gu la t io n c a n i n v o l v e ch a ng es in t he le ve l of t he re c ep t or s o r a l t er a ti o ns i n th e d o wn s t re am e ff ec to r m o l ec ul es . P.251
3 . Th e e xp r e s s io n o f re c e p t o rs i s n o rm al l y un d er h o m e os t at ic c o n t ro l t h rou g h r e c ep t or in t e rn a li z a t io n , r e c y c l i ng , a n d d e n o vo sy n t h es is . 4 . D ow n - r eg u la t i o n a nd d e se n s it i za t i on a . D ow n - r eg u la t i o n o f re c ep t o rs i s c au s e d b y c on t i nu ou s p r ol o ng e d e xp o s u r e o f r e c ep t or s t o d r u gs th a t di s r up t t h e h om eo s ta t ic eq u il i b ri um an d r es u lt in al t e re d l e ve ls of t he re c ep t or s . Th i s di s ru p ti o n in v o l v e s e n d oc y t os is of li ga n d -b ou n d r e c ep t or s , r es u lt i ng in s eq u es t r at i on of r ec ep t o rs f r o m t he ce ll su r f ac e a nd p os si b l y a cc e le r a te d d e gr a da t io n o f t he re c e p t or s o r i n ac tiv a t i o n o f t h e r ec e pt o rs . b . D e se n si t iz a t io n is t he r es u lt of do wn - r e g ul a tio n . Th e t a rg e t c el ls be com e d e se ns i ti z e d , a nd t he ef fe c t o f s ub s e q ue n t e xp o s u r e to th e s am e c on c e n t ra t i on of t h e d r u g is r ed uc e d. Th er e f o re , an in c r e as ed c o nc e nt r a ti o n o f t he d ru g i s r e q ui r e d t o p r o du c e an e ff ec t of th e s am e m ag n it u de as th e in i t ia l e xp o s u re wi t h a s m a l le r d ru g c o nc en t r at i on . c . R ep e at e d d os es o f bro n c h o di la t o r s u c h as al bu t e r ol i n ha l er f o r t he t rea t m e n t o f a s th m a c a n l e ad to do wn - r e g ul a ti on o f β - a d re ne rg i c r ec e pt o rs in th e b r o nc h ia l c el ls . Th e p a ti e nt de v e l op s t ole r a nc e a nd r eq u i re s i nc re a s e d d os a ge of t he dr ug t o a c hi e v e re li e f o f t h e i ni t ia l e xt e n t . I n t hi s c as e, t he t a rg e t ce l ls b e c o m e des e ns it i z e d o n l y to li g an ds th a t b in d t o t ho s e re c ep t or s ; t hi s is c a ll e d h om o l og o u s d e s en s i ti z a t i o n. 5 . H e te r o l og o u s d es e nsi t i z a t i o n. S om e f o rm s o f d es e ns it i z a ti o n i n v ol v e a l t er a ti o n o f co m p on e n ts i n t h e s i gn a li n g p at h wa y , s uc h a s a G p r ot e in . W hen c u lt u re d
f i b ro b la s ts a r e e xp o s e d to p r os ta g la nd i n E 1 ( P G E 1 ) , wh i c h no r m a l l y a c ti v at e s a d e n yla t e c y c l as e t h ro u gh a G s , t he c e ll s l os e re s p o ns i v e ne ss n o t o nl y t o P G E 1 b u t a l so to o th e r l ig a nd s b ind i ng t o o th e r re c e p to r s th a t a c t t h ro u gh th e G s -ad e n y l at e c yc la s e p at h wa y . 6 . H yp e r r e a c t i vi t y o r s up e r s en s i t i vi t y t o r e c e pto r a go ni s ts i s e xp e c t ed wh e n t a r ge t c e ll s a r e s u b je c t t o lo n g -t e r m e xp o s u re to r ec ep to r a nt a go ni s ts fo ll o we d b y a b r up t c es s at io n of ad m i ni s t ra t io n of t he dr u g. Th i s c a n i n v o l v e re c e p to r up - r e gul a t i o n t h r o ug h s y n th es is o f n e w r e c e p to r s . E . P h a rm a co l o gi c al e f fe c t s n o t m e di a t ed b y r e c e p t o rs . Th e e f fe c ts o f s o m e d r ug s d o no t i n v o l v e b in d in g wit h s p ec i fi c r ec e pt o rs be ca u s e of in t e ra c ti on wi t h m o le c u l es o r io n s, wh i c h a re no t t yp i c a ll y d e fi ne d a s re c e p to r s . 1 . C o ll i g at i ve d ru g e f f ec t s ar e c h ar ac t e ri z e d b y a l ac k o f re qu i r em en t fo r h i gh l y s p ec if ic c h em ic al s t r uc t ur e . a . V ol a ti le g en e ra l a n es th e t i c a ge n ts wi t h d i v e rs e s tr u c t u re s a r e l ip o ph il ic an d i n t er a ct wi t h th e l ip i d b ila y e r o f c el l m e m br a ne s , r e s ul ti n g i n d ep r es s e d exc i t a b i li t y. E xa m p l e s i nc lu d e ni t r ous o xi d e a n d d es fl u r an e . b . C a t ha r t i cs , s uc h a s m a gn es i um s ul f at e an d so r b it o l, ac t b y i nc r ea s i n g t h e o sm o la r i t y o f i n te s ti na l flu i ds an d t h us c h an gi n g th e di st r i bu ti o n o f wa t e r. 2 . Me t h o t re xa t e , c y t a ra bin e , a n d 5 - fl u or o u ra ci l a re e xa m p le s o f a n t im e tab o l i t es . A n t im e ta b ol i te s a re s t r uc t u r al a na lo gs o f e nd og e no u s m o l ec ul es an d a r e i n co r po r a te d i n to c e ll u la r c om po n en t s t ha t i n te r f er e wi t h th e n o rm a l c e l lu la r f u nc t io ns . 3 . C e r ta in d ru gs in t e ra c t wi t h s pe ci f ic i o ns n o rm al l y f ou n d i n b od y f lu i ds . F o r e xa m p l e , a n ta c id s s uc h a s a l um in um h y d ro xi d e , c a lc iu m ca r b on a te , a n d m a gn es i um h yd r o xi d e ac t b y n eu t r al iz i n g ga s t r ic ac id .
IV. RELATIONSHIP BETWEEN DRUG CONCENTRATION AND EFFECT A. D o s e - r e s po n se r e la t io n s h ip . In ge n er a l, t he la r g e r t he d ru g d os e , t h e h i gh e r th e d r u g c on c e n t ra t io n a t i ts s i te of ac ti o n a nd th e gre a t e r t he ef f ec t o f th e d ru g , u p to a m a xi m um e ff ec t . Hi g he r d r u g c on ce n t ra t io ns (o r d o se s ) wi l l no t p r o du ce a n ef f ec t g r e a te r th an t he m a xi m um e ff ec t . B . A q u a n t a l d os e - r es po n s e c u r ve de s c r ib es the r el a ti o ns hi p b e t we e n th e nu m b e r o f pa t ie n ts e xh i bi t in g a de f i ne d re s p on s e ( e .g . , a 5 0 % i nc r ea s e in pe a k f low) a n d t he s p ec if i ed do s e of t he d rug ( e .g . , m in im um do s e of a l bu t e ro l f o r 5 0% in c re as e i n p e ak fl o w) . Th i s re la t io ns h ip of t en f ol lo ws a ga us s i an ( be ll - s h a pe d ) d is t ri bu t i on ( F i gu r es 12 - 1 a n d 1 2 -2 ) . C . A g r a d e d d o se - r e sp on s e c u r ve d es c r ib e s t he r e la t io n s h ip be t we e n the m a gn i tu d e o f t he e ff ec t o f a d r ug ( e. g . , r ed uc t io n o f bl oo d p r es s u r e b y n ife d ip i ne ) in a n in di vi d ua l a n d t he dos e o f th e d r u g ( Fi g u re 12- 3 ) . P.252
Figure 12-1. Frequency distribution curve, plotting the number of patients showing a quantal response to a drug against the minimum dose needed to produce the response.
Figure 12-2. Quantal dose-response curve, cumulating the data used to plot Figure 12-1.
Figure 12-3. Graded dose-response curves for two drugs, A and B. DAand DB, amount (dose) of drug A and drug B, respectively, needed to produce the drug effect, E1; Emax, maximum effect.
P.253
Figure 12-4. Log dose-response curves for two drugs, A and B. ED50, smallest dose showing an effect that is 50% of the maximum effect (Emax).
1 . G e ne r al l y , as t h e d os e o f a dr u g i nc r ea s e s, t he e f fe c t p ro d uc ed wi l l r ea c h a m a xi m um le v e l . 2 . G r a de d d os e - re s p o ns e c u r v e s f o r d i ff e re n t d r ug s a l lo w c o m p a ri s o n o f th e i r e f f ic ac ie s a nd po t e nc ie s . a . E f f ic a c y o f a d r ug is m e as u re d b y i ts m a xi m um e ff ec t ( E m a x ) . b . P o te n c y o f a d r u g is a r el a ti v e m e as u r e t ha t c o m pa r es th e d i ff e r en t d os es ( m o la r d o se s ) o f d if f e re n t d r ug s n e ed e d t o p r od uc e t h e s a m e e f fe c t . F ro m a c li ni c a l vi e wp o i n t , p ot e nc y is c on s id e re d i n d r u g se l ec ti on ( e .g . , t r ia z o l am i s p r e fe r r e d f o r t h e tr e at m e n t o f i ns om n ia i ns te a d o f d ia z e p am ) . c . In c l in ic a l s i t ua t io ns , a d r ug wi t h g r e at e r e f fi c a c y m i gh t be ne e de d t o a c hi e v e t h e t h e r ap eu t ic ou tc om e (e . g. , h y d ro m or p ho n e is p re fe r r e d t o a c e t am in o ph en f o r c o nt r o ll in g b o ne pa in in a p at i en t wi t h m et as t a ti c b r e as t c an ce r ) . D . A l o g d os e - r es p on s e c u r ve d es c r ib e s t he r ela t i on s h ip b et we e n th e d ru g ef f ec t a n d t h e l og of t he do s e . Th i s c u r v e fa c i li t a te s com p a ri so n o f p o te nc y a nd e f fi c ac y a m on g d i ff e r en t d r ug s wit h t he s am e m ec ha n is m o f ac t io n ( wh i c h t h us h a ve t he s am e s lo p es ) (F i gu r e 1 2- 4 ) . 1 . Th e ef f i ca c y o f a d r ug is de t e rm in e d b y t he he i g h t o f i ts lo g d os e - re s p o ns e c u r ve ( E m a x ) ; th e h i gh e r t h e c ur v e , t he g re a te r th e E m a x a n d e f fi c a c y . 2 . Th e po t e nc y o f t wo d r u g s c a n be c om p a re d b y d e te r m i ni n g t h ei r E D 5 0 . Th e E D 5 0 i s th e d o se of ea c h d ru g p r o du ci ng 50 % o f th e c or r e s p o nd i ng m a xi m um e ff e c t ( 50 % o f E m a x ) . Th e s m al l e r t he E D 5 0 , th e g r ea t e r t he pot e nc y . 3 . A c o m pe t i ti ve a n ta g on i s t s hi f ts th e l o g d os e - re s po ns e c u r v e t o t h e r i gh t , an d t h e s hi f t i s p a r al l el . A g re a t e r c o nc e nt r a ti o n o f t he a go ni s t is r eq u ir e d t o p r o du c e t h e s am e re s p on s e t ha n wh e n t h e c om pe t it i v e a n ta g o ni st is a bs e nt . E v e n in t he p r e se nc e o f th e a n ta go n is t , t h e s am e E m a x c a n be ac h ie v e d i f e n ou g h a go n is t i s a d d ed ( Fi gu r e 1 2 -5 ) .
Figure 12-5. Shift in the log dose-response curve that occurs when an agonist is administered in the presence of a competitive antagonist. Emax, maximum effect.
P.254
Figure 12-6. Shift in the log dose-response curve and lowering of the maximum effect (Emax) that occur when an agonist is given in the presence of a noncompetitive antagonist.
4 . A no n co m pe t i t i ve a nt a g o ni s t b i nd s t o t h e s am e re ce p to r o r b in ds to a n o th e r s it e t h a t p r e v en t s t he ag o ni s t f r om p ro d uc in g a r es pon s e. Th e s h if t o f th e l o g d o se r e s po ns e c u r v e is t o t he r i g h t an d n o n pa r a ll e l , re s ul t in g i n a low e r E m a x . Th e a c ti o n o f t h e a nt a go ni s t c a nn o t b e o ve rc o m e e v en i f m or e a g on is t i s p r es e n t (F i gu r e 1 2 - 6 ).
V. ENHANCEMENT OF DRUG EFFECTS A. Ad d i t i o n o c c u rs wh en t wo d i ff e re n t d r ug s wi th t he sa m e ef f ec t a r e g i ve n t o g et h e r, r es ul t in g i n a dr u g ef f ec t t h at is eq ua l in m a g ni t ud e t o th e s um o f t he i n di vi d ua l e f fe c ts o f th e two d r u g s . F or e xa m pl e , tr i m et h op r im a n d s u l fa m et h o xa zo l e i n hi b it di f f er e nt s t e ps i n t h e s y n t he s i s o f f o li c ac id , r es ul t in g i n t h e s u p p re ss i on of b a ct e r ia l g r o wt h . B . S yn e r g i s m oc c u r s wh e n t wo d ru gs wi t h th e s am e e f f ec t a r e g i v en to g eth e r , p r o du c i n g a d r u g e f fe c t th a t i s g r ea t e r i n m a g ni t ud e th a n t he s u m o f t h e in d i v id u al
e f f ec ts o f t he t wo d ru gs . F o r e xa m pl e , p en ic i ll in an d ge n ta m i ci n a r e s y n e rg i s t ic in t h e ir a nt ip s eu do m o n al ac t i v i ti es . C . P o t e nt i a ti o n o c c u rs wh e n o n e d r ug , l ac k i n g a n ef f ec t o f i t s o wn , in c re a s e s t h e e f f ec t o f a n o th e r d r ug tha t is ac ti v e . Fo r e xa m p l e, c ar b id o pa is a n i n ac ti v e a na lo g of d o p a. W he n c a r b id op a b lo c k s t h e d eg r ad a ti o n o f d o p a a nd is g i ve n wi t h do p a , i t p r o lo n gs th e h al f - li f e o f d o p a a nd th e d u ra t io n o f t h e a n ti - P ar k i n s o ni a n e ff e c t.
VI. SELECTIVITY OF DRUG ACTION A. Th e t h e r a p eu t i c i n dex a nd th e m a r g in o f s a fe t y a r e t h e r e la t io ns h ip (r a t io ) b e t we e n th e d os e o f a d ru g r eq ui r e d t o p r od uc e un d es i re d e f f ec ts ( to xi c o r l e th a l) a n d t h e d os e r e qu i re d to p r o du c e th e d es i r ed ef fe c ts ( th e ra p eu t ic ) . 1 . Th e t he r a pe u t ic i nd ex o f a dr u g is a re la t i v e m e as u re of t he s a fe t y a nd e f f ec t i v en es s i n l ab o ra t or y s t u di es . 2 . Th e t he r a pe u t ic i nd ex is t he ra t io o f t he m i nim um do s e t ha t i s t o xi c fo r 5 0% of t h e p o pu l at io n (m e di a n to x i c d o se ; T D 5 0 ) to th e m i ni m u m d os e t ha t is e f fe c ti ve f or 5 0 % o f th e p op u la t io n (m e d ia n e f f e ct i ve d os e ; E D 5 0 ) . B . I n g e ne r al , th e g r ea t er t h e TD 5 0 o r t h e s m a ll e r t h e E D 5 0 , t h e g re a te r t he t h e r ap eu t ic in de x a n d t hu s th e s af e r t h e d r ug wh e n us ed at t he ef f ec t i v e d o s a g e. C . Th e m a rg i n o f sa f e t y i s a m o re p ra c ti c a l t e rm t o de s c ri b e t h e r el a ti ve s a fe t y a nd e f f ec t i v en es s o f a dr u g . Th e m a rg i n o f s a f e t y i s th e r at i o o f t he m i ni m u m to xi c d os e f o r 0. 1 % o f t h e p op ul a ti on ( m in i ma l t ox i c d os e ; T D 0 . 1 ) t o th e m in im um eff e c ti v e d o se fo r 99 . 9% o f t he pop u la t io n (m i n im a l e f fe c ti ve d o s e ; E D 9 9 . 9 ) . P.255
VII. DRUG SOURCES AND MAJOR CLASSES A. N a t u r a l p r od u c ts a re d r u gs o b ta i ne d f r om pl an t an d a n im al s o u rc es . 1 . Al k a l oi d s a r e n it r o gen - c on t ai ni n g c o m p o un ds o b t ai ne d pr im a ri l y f r om pl a n ts t h r o ug h e xt r a c t io n a n d pu r i fi c a t io n , wh ic h p os s e ss ph a rm ac o lo gi c al a c ti v i ty. Th e m a jo r it y o f a lk a lo id s a r e b a s i c c o m po un ds ( e .g . , m o r p h in e , f r om th e o p ium po p p y ; a t r o p i ne , f r om t he be ll ad o n na pl an t ) ; a l th ou g h so m e a r e n eu t r al a m i d es ( e . g ., c o l ch i c in e , f r om th e a u tu m n c ro c u s ). A ll al ka l oi ds en d i n th e s uf f i x - i n e; h o we v e r , i t i s i m p o r ta n t t o n o te th a t n o t a l l d ru g s t ha t e n d i n - i n e a r e a lk al oi d s ( e .g . , m e pe r id i ne ) . 2 . P ep t i de s a n d p o l yp e p t i d es a re po l ym e r s o f am i no ac id s , a re ob t ai n ed f r om e i t he r hu m a n o r a n im al s o u r c e s a nd a re s m a l le r th a n p r o t e in s . Th e am in o a ci d l e ng t h d is t in c t i on s b et we e n th es e th r ee cl as s i f ic at i o ns a r e v ag u e a nd of t en v a r y f r o m o ne s o u rc e t o a n oth e r . Na t u ra ll y o c c u r ri ng p e p ti de s h a v e l i tt l e t o n o o r al a c ti vi t y a nd s h o rt ha l f -l i ve s (e . g. , so m at o s ta t i n , a 1 4 -a m i no ac id pe p ti d e; g l u ca g o n, a 2 9 -a m i n o ac i d p ol yp e pt i de ) . 3 . S t e ro i d s a re c h em ic a l d e ri v a t i v es of c y cl op e nta n o pe r h y d ro p h e na n th r e ne a nd c a n b e ob t ai n ed f ro m e it h er h u m a n o r an im al s o u rc es ( e. g . , e s t ra d io l , te s t os t e r o ne , h yd r o c o r t i s o n e ). 4 . H o r mo n es a re c h em ic a l s u bs ta n c e s t ha t a r e for m e d i n o ne or g an o r p a rt o f t h e b o d y an d c a r ri ed in t he b l oo d to an o th e r o r ga n or p a r t. Th e y a re p ri nc i pa ll y p r o te i ns
o r st e r oi ds an d c an be ob t a in ed ei t he r s y nt h et ic al l y , th r o ug h re c o m b in a nt D N A t e ch n ol o g y (e . g. , in s u li n) , o r f r om an im a l s o u rc es ( e. g . , t h yr o i d h o r m one s an d c o n j ug a te d es t r o ge n s ). 5 . G l yc o s i d e s a re o rg a ni c s ub s ta nc es co ns is t in g o f a s u g ar m o ie t y b ou n d t o a n o ns u ga r (a g l yc o ne ) m o ie t y b y m e a ns o f a g l yc os i d ic bo nd ( i. e . , a b o nd be t we e n t he a n om e ri c c a rb on o f t he s u g a r a nd a h y d r o xy g r o up o n t he ag l y c o n e ). Th e y c an be o f e i t he r pl an t (e . g ., d ig i t ox i n ) o r m ic r o bi al ( e. g . , st r e p t o m yc i n , d o x o r ub i ci n ) o ri gi n . 6 . V i ta m in s a r e o r g an ic s u bs ta n c e s t ha t ar e p r es e n t i n f o od s a nd a re es se n t ia l t o n o r m a l m et a bo li s m . a . Wa t e r - so l u bl e vi t am in s a re th i am in e (B 1 ) , r i bo f l a v in ( B 2 ) , ni ac in ( B 3 ), p yr i d o xi n e ( B 6 ) , c ya n oc ob a la m i n ( B 1 2 ) , a s c o rb ic ac i d ( C ) , f o li c a c i d , p an t o th en ic ac id, a nd b i o ti n ( H ) . b . L ip i d -s o l ub l e vi ta m in s a re r et i no l ( A ) , e r g oc a l c i f er o l ( D ) , α - to c o p he ro l ( E ), an d p h yt o na d io ne ( K ) . 7 . P o l ys a c c h a r i de s a r e p o l y m e r s o f s ug a rs th a t c a n b e o bt a in e d f r om e i th e r hu m a n o r a ni m a l s ou rc e s . Th es e c o m p o un ds c a n b e u s ed e it h e r di r ec t l y (e . g ., hep a r i n ) , a f t e r p a rt i al de po l y m e r i za t i on ( e. g ., t i nz ap a r i n, en o x ap a r i n ), o r a f te r s t r uc t u ra l m o di f ic at i on ( e. g ., s uc r al f a t e ). 8 . An t i b i o ti c s a r e c h em ic a l s u bs t a nc es p r o du c e d b y m ic ro o r ga ni sm s t h at e i t he r s u pp r es s o r k il l o t he r m ic r o or g an is m s (e . g ., pe n ic i l l in , te t r a c yc l i n e , d oxo r u b i ci n ) . B . S yn t h e t i c p r o du c ts ar e d ru gs s ynt h es i zed f rom o rg a ni c c o m p o un ds . 1 . S y n t he ti c p r od u c t s c an h a v e c he m ic a l s t r u ctu r e s c l o se l y r e s e m b l i ng t h os e of a c t i ve na t u r al p r od u c ts ( e . g. , h yd r o x ym o r p h o n e , wh i ch r es em bl es m o r ph i ne ; a m p ic i l li n , wh ic h re s e m b l es pe ni ci l li n ) . 2 . S y n t he ti c p r od u c t s c an c o n ta i n s i m i l a r sp ac i ng o f fu nc t io n al gr o up s b u t l ac k t h e g e n er a l s tr u c t u re o f a n at u r al l y oc c u r r in g c om po un d . Pe p t id o m im e ti c s a re m o le cu l es wi t h n o p ep t ide b on ds , a m o le c ul a r we i g h t < 7 00 , a n d ac t i v it y s im i la r to t h e o r i gi na l p e pt i de (e . g ., l o sa r t a n is a p ep t id om im e ti c a nd an an g io t en s in I I r e c ep t or a nt a go ni s t) . 3 . S y n t he ti c p r od u c t s a ls o c a n b e c o m pl e te l y n e w p r od u c ts , o b ta i ne d b y s c r e en i ng s yn t he s i z e d m a te r ia ls f or d r ug ac t i v it y ( e .g . , b a rb i t u r a te s , a n t ib a ct e r i al s u l f on a mi d es , t hi az i d e d i u r e t ic s , p he n o t hi az i ne a n ti p s yc h o t i c s , be nz o d i az e pi n e a n x io l yt i c s ) . C . M aj o r ch e mi c al an d p h a r ma c o lo g ic c la ss e s o f d r u gs ( Ta b le 12 - 1; F ig u r es 12 7 , 12 - 8 , 1 2 -9 , 1 2 - 10 , a nd 1 2 -1 1 ) P.256
P.257
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Table 12-1. Major Chemical and Pharmacological Classes of Drugs Classificationa 1.
Polyhalogenated ethers and hydrocarbons
Acid/Base Characterb
Examplec (Structure)
Nonelectrolyte
Isoflurane (1)
Acidic
Phenobarbital (2)
Basic
Diazepam (3)
Acidic
Phenytoin (4)
Acidic or nonelectrolyte
Methsuximide (5)
Basic
Chlorpromazine (6)
Basic
Thiothixene (7)
General anesthetics 2.
Barbiturates Sedative/hypotonics; anticonvulsants
3.
Benzodiazepines Anxiolytic agents; sedative/hypnotics
4.
Hydantoins Anticonvulsants
5.
Succinimides
Anticonvulsants 6.
Phenothiazines
Antipsychotics; antihistamines; antiemetics 7.
Thioxanthenes
Antipsychotics 8.
Butyrophenones
Basic
Haloperidol (8)
Basic
Imipramine (9)
Basic
Fluoxetine (10)
Basic
Olanzapine (11)
Basic (weak)
Theophylline (12)
Basic
Codeine (13)
Basic
Meperidine (14)
Basic
Methadone (15)
Antipsychotics 9.
Tricyclic antidepressants Antidepressant agents
10.
Selective serotonin reuptake inhibitors Anxiolytic agents
11.
Benzazepines Atypical antipsychotics
12.
Methylxanthines CNS stimulants; bronchodilators
13.
Opioids Narcotic analgesics; antitussives
14.
4-Phenylpiperidines Narcotic analgesics
15.
Phenylpropylamines
Narcotic analgesics 16.
Direct-acting cholinergics
Quaternary ammonium salt
Bethanechol (16)
Basic or quaternary ammonium salt
Dicyclomine (17)
Basic
Benztropine (18)
Basic or quaternary ammonium salt
Biperiden (19)
Basic
Tripelennamine (20)
Basic
Chlorpheniramine (21)
GI smooth-muscle stimulant; cataract therapy 17.
Aminoalkyl esters
Anticholinergic agents 18.
Aminoalkyl ethers Anticholinergic agents; antihistamines (H1antagonists)
19.
Aminoalcohols
Anticholinergic agents 20.
Ethylenediamines
Antihistamines (H1antagonists) 21.
Alkylamines (propylamines)
Antihistamines (H1antagonists) 22.
Piperazines
Basic
Cyclizine (22)
Acidic
Cromolyn sodium (23)
Basic
Albuterol (24)
Basic
Guanabenz (25)
Basic
Terazosin (26)
Basic
Propranolol (27)
Acidic
Misoprostol (28)
Antihistamines (H1antagonists); antivertigo; antiemetics 23.
Mast cell degranulation inhibitors Antiallergenics
24.
Phenylethylamines Sympathomimetics (αand β-adrenergic agonists)
25.
Adrenergic α2-agonists Antihypertensive agents
26.
Adrenergic α1-agonists Antihypertensive agents
27.
Aryloxypropanolamines β-adrenergic blockers
28.
Prostaglandins Eicosanoids
29.
Salicylates
Acidic
Aspirin (29)
Acidic
Mefenamic acid (3)
Acidic
Phenylbutazone (31)
Acidic
Tolmetin (32)
Acidic (weak) or nonelectrolyte
Celecoxib (33)
Basic
Sumatriptan (34)
Basic
Ondansetron (35)
NSAIDs 30.
Fenamates
NSAIDs 31.
Pyrazolidinediones
NSAIDs 32.
Arylacetic acids (includes indoleacetic acids, pyrrolacetic acids, and propionic acids) NSAIDs
33.
Selective COX-2 inhibitors
NSAIDs 34.
Triptans 5-HT1B/1D agonists
35.
Serotonin 5-HT3 antagonists Antiemetic agents
36.
Coumarins
Acidic
Warfarin (36)
Acidic
Heparin (37)
Acidic
Chlorothiazide (38)
Acidic
Furosemide (39)
Nonelectrolyte
Isosorbide dinitrate (40)
Basic (weak)
Nifedipine (41)
Acidic
Losartan (42)
Amphoteric
Enalapril (43)
Oral anticoagulants 37.
Sulfated polysaccharides Anticoagulants
38.
Benzothiadiazides (thiazides) Diuretics; saluretics
39.
High-ceiling (loop) diuretics Diuretics; saluretics
40.
Organic nitrates
Antianginal agents 41.
Dihydropyridines Antihypertensives; antianginal agents; antiarrhythmics
42.
Angiotensin II receptor antagonists Antihypertensive agents
43.
ACE inhibitors
Antihypertensive agents 44.
HMG-CoA reductase inhibitors
Acidic
Pravastatin (44)
Basic or quaternary ammonium salt
Cholestyramine (45)
Acidic
Gemfibrozil (46)
Nonelectrolyte
Dexamethasone (47)
Basic
Raloxifene (48)
Nonelectrolyte
Finasteride (49)
Cholesterol-lowering agents 45.
Bile acid sequestrants
Cholesterol-lowering agents 46.
Fibrates Cholesterol- and triglyceride-lowering agents
47.
Steroids
Estrogens; progestins; androgens; adrenocorticoids 48.
Selective estrogen receptor modulators Estrogen receptor agonists and antagonists
49.
5α-Reductase inhibitors
Antiandrogen 50.
Androgen receptor antagonists
Nonelectrolyte
Nilutamide (50)
Acidic
Tolbutamide (51)
Acidic
Repaglinide (52)
Amphoteric (acid stronger than base)
Pioglitazone (53)
Basic
Miglitol (54)
Basic
Cimetidine (55)
Basic
Omeprazole (56)
Nonelectrolyte
Carmustine (57)
Antiandrogen 51.
Sulfonylureas Oral hypoglycemics
52.
Meglitinides Oral hypoglycemics
53.
Thiazolidinediones (glitazones)
Insulin sensitizers; antidiabetic agents 54.
α-Glucosidase inhibitors Antidiabetic agents
55.
H2-receptor antagonists Antiulcer agents
56.
Proton pump inhibitors Antiulcer agents
57.
Nitrosoureas
Antineoplastic agents 58.
β-Chloroethylamines (nitrogen mustards)
Basic
Mechlorethamine (58)
Amphoteric
Methotrexate (59)
Basic
6-Mercaptopurine (60)
Basic
Cytarabine (61)
Basic
Doxorubicin (62)
Basic
Topotecan (63)
Basic
Saquinavir (64)
Antineoplastic agents 59.
Folate antimetabolites Antineoplastic agents; antibacterial agents; antifungals
60.
Purine antimetabolites
Antineoplastic agents; Antiviral agents 61.
Pyrimidine antimetabolites Antineoplastic agents; antiviral agents
62.
Anthracyclines Antineoplastic agents
63.
Topoisomerase inhibitors Antineoplastic agents
64.
HIV protease inhibitors
Antiretroviral agents 65.
Sulfanilamides
Acidic
Sulfamethoxazole (65)
Acidic
Ampicillin (66)
Acidic
Cefoxitin (67)
Amphoteric
Tetracycline (68)
Basic
Gentamicin (69)
Basic
Erythromycin (70)
Amphoteric
Ofloxacin (71)
Basic
Terbinafine (72)
Antibacterial agents 66.
Penicillins Antibacterial agents
67.
Cephalosporins Antibacterial agents
68.
Tetracyclines Antibacterial agents
69.
Aminoglycosides Antibacterial agents
70.
Macrolides
Antibacterial agents 71.
4-Quinolones Antibacterial agents
72.
Allylamines
Antifungal agents 73.
Polyenes
Amphoteric
Amphotericin B (73)
Basic
Oxiconazole (74)
Antifungal agents 74.
Imidazoles Antifungal agents
ACE, angiotensin-converting enzyme; COX, cyclooxygenase; 5-HT, 5hydroxytryptamine (serotonin), Gl, gastrointestinal; HMG-CoA, β-hydroxyβ-methylglutaryl coenzyme A; NSAID, nonsteroidal anti-inflammatory drug. a
Organized according to chemical structure. Not an inclusive list; includes only classifications that contain multiple compounds with a similar structure. In some instances (e.g., direct-acting cholinergic agonists and H2-receptor antagonists), drugs are chemically similar but are usually denoted only by pharmacological classifications. b
A general notation; some specific singular agents fall outside these general notations (e.g., ampicillin is amphoteric, whereas the penicillins are generally acidic). c
Structures are given in Figures 12-7, 12-8, 12-9, 12-10 and 12-11.
P.259
Figure 12-7. Chemical structures (1-19) representing the major chemical classes of drugs listed in Table 12-1.
P.260
Figure 12-8. Chemical structures (20-37) representing the major chemical classes of drugs listed in Table 12-1.
VIII. DRUG ACTION AND PHYSICOCHEMICAL PROPERTIES A. D r u g a c t i on r es ul ts f ro m th e i n te r ac ti o n o f d r ug m o l ec ul es wi t h ei th e r no r m al or a b n or m a l p h y s i o lo g ic al pr o c es s es . D r ug s n o rm al ly i n t e ra c t wi t h r ec ep t o rs , wh i c h c a n b e ei t he r pr o te i ns , e n z y m es , c e ll li pi ds , o r pi ec es o f D N A o r R N A . P.261
Figure 12-9. Chemical structures (38-53) representing the major chemical classes of drugs listed in Table 12-1.
1 . S y s te m i c a l l y a c t i v e dru g s m u s t e n te r an d be tr a n s p o r te d b y b o d y f l u i d s . a . Th e dr u g m u s t p as s va r i o u s m em b r an e ba r r ie r s , es ca p e e xc e ss i ve d i s t r i bu t i on in t o s it es o f l os s , a nd pe n e t ra t e to th e ac t i ve si t e . b . A t t h e a c t i v e s it e , t h e d r u g m ol ec ul es m u s t o rie n t th em s e l v es an d i n te ra c t wi t h t h e re ce p to r s t o a l te r f un c t i on . P.262
Figure 12-10. Chemical structures (54-68) representing the major chemical classes of drugs listed in Table 12-1.
c . Th e d r ug m u s t be r em o v e d f ro m t h e ac t i ve si t e a n d m e ta b ol i z e d t o a f or m th a t i s e a si l y ex c r e te d b y t he bo d y . 2 . D r ug ab s o r p ti o n, m e t ab o li s m , u t il i za ti o n, an d exc r e t i o n a l l d ep en d o n the d r u g' s p h ys i c o c h em i ca l p r op er t i e s a n d t he h os t ' s p h ys i o l og i ca l an d b i oc h emi c a l p r o p e r t ie s . A d ru g ' s p h ys ic oc h em ic al p ro p er t ie s c a n b e a lt e r ed v i a t he s yn t h es is o f c h em ic al an a lo gs , wh e r ea s th e h os t ' s p r op e r ti es u s ua ll y c an n ot be al t e red . P.263
Figure 12-11. Chemical structures (69-74) representing the major chemical classes of drugs listed in Table 12-1.
B . Two o f t h e m os t i m p or t a n t p h ys i c o c h e m ic a l p r o p e r t ie s o f a d ru g m ole c ul e a r e i t s p ol a ri t y a nd it s a c i d -ba s e n at u r e. 1 . D r u g p o la r i t y i s a re la t i v e m ea s u r e o f a d ru g 's li p id an d wa t e r s o l ub il it y a n d i s u s ua ll y e xp r e s s e d i n t e rm s o f a pa r t i t i on co e f f ic i e n t. a . Th e pa r ti t io n c oe f f ic ien t ( P ) o f a d ru g i s d ef i ned as t he ra t io o f t he s o lub i li t y o f t h e c om po u nd in an o rg an i c s o l ve nt t o t he s o lu b ili t y o f t h e s a m e c o m p o und i n a n a q u eo us en v i r on m e n t :
Th e p a r ti t io n c oe f fi c i e nt i s o f t en e xp r e s s ed as a lo g v a lu e . b . W at e r so l u bi l i t y ( o r h yd r o p h i l i c i t y) d e p e nd s p r i m a r il y o n t wo f ac t o rs : i o ni c c h a ra ct e r a n d h y d r og en -b o n di ng ca pa b il i ti es . The p r es en c e of o xy g e n - an d ni t r og en c o nt a in in g fu nc t io n al gr ou p s us u al l y en h an c e s wa t e r s o lu b il it y. W ate r s ol ub i li t y is r e q ui r e d f o r: ( 1 ) D is s o l ut io n i n th e g as t r oi n te s t i na l ( G I) t ra c t ( 2 ) P r ep a ra t io n o f pa r en te r a l s ol u ti on s ( as op p ose d to su s p e ns io ns ) ( 3 ) P r ep a ra t io n o f op h tha l m i c s o l ut i on s ( 4 ) A de q ua t e u r in e c on c e n t r at i on s ( pe r t ai ns p ri m a r i l y to an t ib io t ic s ) c . Li p i d s o lu b il i t y ( o r l ip o p h il i c it y) i s e nh a nc ed b y n on i on i za bl e h y d r oc ar b o n c h ai ns an d ri ng s ys t em s . L i pi d s ol ub i li t y is re q ui re d fo r : ( 1 ) P en e t ra t io n t h r ou gh th e li pi d b i la ye r i n th e Gl t r a ct ( 2 ) P en e t ra t io n t h r ou gh th e bl oo d - b ra in ba r r ie r ( 3 ) P r ep a ra t io n o f in t ra m u s c u la r ( I M) d e po t i nj e c ta b le f o rm ul a ti on s ( 4 ) E nh a nc ed pu lm o na r y a bs o r pt i on wi t h in th e res p i ra t o r y t r ac t ( 5 ) E nh a nc ed to p ic al po te n c y (s ee n wi t h m an y t op i ca l g lu c o c or t ic oi ds ) ( 6 ) E nh a nc ed pl as m a p ro t e in bi nd i ng 2 . I on i za ti on o f a ci d s a nd b as e s p la ys a r ol e wi th su bs t a nc es t h a t di s s oci a t e i nt o i o ns .
a . Th e io n iz a t io n c o n sta n t ( K a ) i nd ic a te s t he r ela t i v e s t re n gt h of th e a c i d o r ba s e . A n ac i d P.264 wi t h a K a o f 1 × 1 0
-3
-5
is s tr o n ge r (m o r e io n i zed ) tha n on e wi t h a K a o f 1 × 10 ,
wh e r e a s a ba s e wi t h a K a o f 1 × 1 0
-7
i s we ak e r (le s s io n i z ed ) th a n o ne wi th a K a o f 1
-9
× 10 . b . Th e ne g a ti ve l o g o f th e i on iz a t io n co n s ta n t (p K a ) al so in d ic at es t he re l a ti ve -5
s t r en g th of t he ac id o r ba s e. A n a c i d wi t h a p K a o f 5 ( K a = 1 × 10 ) is we a k e r ( le s s -3
i o ni ze d ) th an on e wi t h a p K a of 3 ( K a = 1 × 1 0 ), wh e r e a s a ba s e wi t h a pK a o f 9 ( K a -9
-7
= 1 × 1 0 ) i s s t r o ng e r (m o r e i on i z ed ) th a n o ne wi t h a p K a o f 7 ( K a = 1 × 1 0 ) . c . S t ro ng ac id s — fo r e xa m p le , h yd r o c h l o r i c a c i d ( H C l ) , s ul f u ri c a c i d ( H 2 SO 4 ) , n it r ic a c id ( H N O 3 ) , h y d r ob r om ic ac id ( H B r ) , i od ic ac id (H I O 3 ) , an d pe rc h lo r ic ac id ( H C l O 4 ) — a r e c o m p l et e l y i o ni z e d . A lm os t a l l o th e r a c i ds , i n c l ud i ng o rg an ic a c i ds , ar e we a k . O r g a ni c ac i ds c on t a in on e o r m o re o f t hes e fu nc t io na l g r o up s: ( 1 ) C a rb o xy l i c ac id g ro up ( — C O O H ) ( 2 ) P he n ol ic g ro up ( A r —O H ) ( 3 ) S ul f on ic ac id g ro u p (— S O 3 H ) ( 4 ) S ul f on am i de g ro up (— S O 2 N H — R ) ( 5 ) Im i de gr o up ( — C O —N H — C O — ) ( 6 ) β - C a rb o n y l g r ou p ( —C O — C H R — C O — ) ( 7 ) Te t r a z ol e ri n g ( f i v e -m em b e r C H N 4 r in g ; s e e F i g ur e 1 2 - 9, 42 , fo r e xa m p le ) d . S t r o ng b as es — f o r e xa m pl e , s o d iu m h y d r o xi d e ( N a O H ) , po t as si um h y d ro xi d e ( K O H ) , m ag n es iu m h y d ro xi d e ( Mg ( O H ) 2 ) , c al c i um h y d ro xi d e ( C a ( O H ) 2 ), b a r iu m h yd r o xi d e ( B a ( O H ) 2 ) , and q ua t e rn a r y am m o ni um h y d r o xi d e s —a r e a ls o c om p le t el y i o ni ze d . Al m o s t al l o t he r b a s e s , in cl u di n g o rg a ni c b a s e s, a re we a k . ( 1 ) O r g a ni c ba se s c on t ai n a p ri m a r y, se c o n da r y, o r t e rt i ar y a li p ha t ic o r al ic y c li c a m in o g r ou p ( — N H 2 , — NH R , o r — N R 2 ). ( 2 ) Mo s t a ro m a t ic o r un s a t u r at e d h et e ro c yc l ic ni t ro g e ns a r e s o we a k l y ba si c th a t t h e y do no t r ea di l y f or m s a lt s wi t h ac i ds . Sa t ur a te d he t e ro c yc l ic n i t ro g ens , in c o nt r as t , a r e s im il a r t o al i ph a ti c a m i ne s . ( 3 ) A dd i ti o na l b as ic fu nc t i o na l g r ou ps in c l u de im in e n i t r og en s ( — N = C — ) , h y d r a z i ne n i t ro g en s ( — N H — N H 2 ) , a m id in e n i t ro g en s ( — N H— C = N — ) , an d g u an i di ne n i t ro g en s ( f o u r a t om f u nc t io na l g r ou p , C H 4 N 3 ; s e e F ig u r e 12 - 8 , 2 5 , f o r e xa m p le ) . e . We a k a c id s . I on i z a ti on o f a we a k ac i d ( e .g . , ac e ti c a ci d , wh i c h h as a pK a o f 4 . 76 ) t a ke s p la c e as fo l lo ws :
( 1 ) W hen a we a k ac i d ( s u c h as ac e ti c ac i d ) is pl ac e d i n a n a ci d me d iu m , t h e e q ui l ib r iu m s hi f ts to th e le f t , s up p re s s i ng io ni z a t io n . Th is de c r e as e i n i on iza t i o n c o nf o rm s t o L e C ha t e li er ' s p r i nc i pl e , wh ic h s t ate s th a t wh e n a s t re ss i s p l ac e d o n a n eq ui l ib r iu m r e ac ti o n, th e r ea ct i on wi l l m o v e i n t h e d i r ec ti o n t ha t te nd s to r el i e ve t h e s t re s s .
( 2 ) W hen a we a k ac i d is p l ac e d in a n a lk a li n e m ed i u m , i on i z a ti on in c re as e s . Th e H
+
-
i o ns f ro m t he ac id a nd the O H io ns f ro m t h e al k ali n e m ed iu m c om bi n e t o fo r m wa t e r , s hi f ti ng t he eq u il ib r i um to th e ri g ht . ( 3 ) W ea k l y a c i d i c d ru g s a r e l es s i on i ze d i n ac i d m e di a t h an in al k a li n e m e d ia . W hen t he p K a o f a n ac i dic d ru g i s g r ea t e r t ha n t he p H o f th e m ed i um i n wh i ch it e xi s t s , i t wi l l b e > 50 % in i ts no ni o ni z e d (m ol ec ul a r ) f or m a n d t hu s m o r e l ik e l y to c r os s l ip i d c e l lu la r m em br a n es . f . W ea k ba se s . I o ni z a t ion o f a we a k b as e i s t he o p p os it e o f th a t f o r a wea k a c i d . ( 1 ) W eak b as es a r e l es s i o ni z e d i n a b as i c ( a lk a li n e ) m e d iu m a nd m o r e io n i z e d in a n ac i d m e di u m. ( 2 ) W ea k l y b a s i c d ru gs a r e l e s s i o ni ze d i n a lk al in e m e di a t h an in a c id m e d ia . W he n t h e p K a o f a b as ic d r u g is le s s th a n t he p H o f th e m ed i um i n wh ic h i t e xi s ts , it wi l l b e > 5 0% in it s n on i on i z e d (m o le c u l ar ) fo r m a nd t hu s m o re li k e l y to cr o ss l i pid c e l lu la r m em b r an es . g . P e r ce n t i o n iz at i o n c a n be ap p ro xi m a t e d b y us i ng th e r ul e of n in e s. I f t h e | p H p K a | = 1, th e n a 90 : 10 rat i o (n o te th a t t h er e i s o ne n in e i n t h e r a ti o ) e xi s ts . If t he | p H - p K a | = 2 , t h e r a ti o b e c o m e s 9 9 :1 ( t wo ni n es i n t h e r a ti o ) , a nd if t he | p H - p K a | = 3 , t h e r a ti o i s 9 9. 9 :0 . 1 ( t h r ee ni n es i n th e r a ti o ). Th e p re d om in a nt fo r m , i o ni z e d o r u n io n i z ed , i n th es e ra t ios c a n e as il y b e d e te r m i ne d (s e e V I I I. B . 2. e . (3 ) ; V I I I . B .2 . f .( 2 ) ) . 3 . A s a l t i s t he c om b in a ti o n o f a n a ci d a n d a b a s e . a . W it h a fe w m i no r e xc ep t i on s ( m e r cu r ic an d c adm i um h a li de s a n d le a d ac e ta t e ), a l l sa l ts a r e s t r on g el ec t r o l yt e s . P.265
b . B ec a us e t he v a s t m a jo r i t y of d ru gs a re o rg an ic m o le c u l es , d r ug s a l ts c a n be d i vi de d i n to t wo c l as s es b a s e d o n t h e c he m i c a l na t u r e o f t he s u bs t an c e fo r m in g t h e s a lt . ( 1 ) I no r g a ni c s a l ts a re m a de b y c om b in in g d r u g m ol ec u le s wi t h in o r ga ni c ac id s a n d b a se s, s u c h as h y dr o c h lo r i c ac i d, s u lf u r ic a ci d , po t as s i um h y d ro xi d e , an d s od i um h yd r o xi d e . Th e s al t fo r m o f t he dr u g h as i n cr e as ed wa t e r so lu b il i t y i n c om p a r is on wi t h t h e p a re n t m ol ec ul e. I n or g an ic s a lt s a r e g ene r a ll y u se d t o i nc r ea s e th e a q u eo us di s s ol u ti on o f a c om po u nd . ( 2 ) O r g a ni c s a l ts a re m a d e b y c om bi ni n g d r ug m o le c u l es wi t h e it h e r s ma l l , h yd r o p h i l i c o rg an ic c o m p o u nd s ( e .g . , s ucc i ni c ac i d , c it r ic ac id ) o r l i po p h il i c o r g an ic c o m p o un ds (e . g ., p r oc ai n e) . W at e r- s ol ub le o r ga ni c s al ts a re us ed t o i n c re as e d is s o lu t io n a n d b i oa v a i la b il it y a s we l l as t o ai d i n t he p re p a ra t io n o f p a r en t e ra l a n d o ph t ha lm ic f or m u l at i on s ( e .g . , t im o l ol m a le a te ) . L i pi d -s ol ub l e o r ga n ic s a lt s a r e p r im a ri l y u s ed to m a k e de p o t in j ec ti o ns ( e . g ., p ro c a i ne pe ni ci l li n) . c . Am p h o te r i c c o mp o u nd s c o n ta in bo t h a c i di c an d ba s i c f un c ti on a l g r oup s a n d a r e c a pa b le of fo r m i n g i n te rn a l sa l ts , or z wi t t e r i on s, wh i c h o f t en ha ve di s s olu t i on p r o bl em s . d . D i ss o l ut i o n o f s a l ts c a n a lt e r t h e p H of an aqu e o us m ed i um .
( 1 ) S al t s o f s t r o ng ac i ds ( e .g . , H Cl , H 2 S O 4 ) an d b a s ic d ru g s ( e . g. , c im et i d in e ) d i ss oc ia t e i n a n a qu e ou s m ed i um to y i el d a n a c idi c s ol u t io n . ( 2 ) S al t s o f s t r o ng ba s es ( e .g . , Na O H , K O H ) an d a c i di c d r u g s ( e .g . , p hen o b ar b it a l) d i ss oc ia t e i n a n a qu e ou s m ed i um to y i el d a ba s ic s o l u ti o n. ( 3 ) S al t s o f w e a k a ci d s a n d w ea k b a se s d is s o cia t e i n a n a q ue o us m ed i um t o y i e ld a n ac i d ic , b a si c , o r ne ut r a l s ol u t io n , d e pe nd i ng o n th e r es p ec t i v e i on i z at i o n c o ns ta n ts in v o l v e d. ( 4 ) S al t s o f s t r o ng ac i ds a nd s t ro n g b a se s (e . g. , N a C l ) d o n ot s i gn i fi c a nt l y a lt e r t h e p H o f a n a qu e ou s m e d iu m . 4 . A ne u t r al i z a t i on r ea ct i o n m ig h t o cc u r wh e n an ac i di c so l ut i on of an o rg a ni c s al t ( a so l ut i on of a s a l t o f a s t r on g a ci d a n d a we a k b a s e ) is m i xe d wi t h a b as ic s o lu t io n ( a so l ut i on of a s a l t o f a we a k a ci d a nd a s t ro n g b a s e ) . Th e n on i on i z ed o rg a ni c a ci d o r t he no n io ni z e d o r g an ic ba s e is li ke l y to p r ec i pi t a t e i n t h is c as e . Th i s re a ct i on is t h e b as is f or m a n y d r ug i n c om p a ti b i li t i es , pa r ti cu l a rl y wh e n in t r a ven o us s o lu t io ns a r e m i xe d . N eu t r al i z a ti on r e ac ti o ns c an be a voi de d b y k n o wi ng ho w t o p re d ic t th e a p p ro xi m a t e p H of t he aq u e ou s s o l ut i on s o f c om m o n d r ug s a lt s . a . G e ne r al l y , a d ru g ' s s al t f o r m c an be re c og ni z ed wh e n t he ge ne r ic o r t ra d e n am e c o ns is ts of t wo s e p a ra t e wo r d s , in d ic at i ng a c a ti on a nd an a ni o n . b . D r ug s wi t h n i t r at e , s ul f a t e , o r h yd r o c h l o r i d e n o t a t io n s ( e .g . , p il o ca r pi n e n i t ra t e , m o r p hi ne s u l fa t e, m ep e ri di n e h y d r oc hl o rid e ) ar e s al t s o f s t r o ng ac i d s . Th u s t h es e d r u gs (e . g. , pi lo c ar p i ne , m o rp h in e , m e p e rid i n e ) m u st be ba s es . c . D r ug s wi t h s od i um o r p o t a ss i um ca t i on s (e . g ., wa r f a r i n s o d iu m , po t as s i um p e ni ci l li n G ) a r e s a l ts of s t r o n g b a se s . Th u s t h ese d r ug s ( e .g . , wa r f ar i n, pe n ic il l in G ) m us t be ac i ds . d . D r ug s wh os e c a ti on na m e e nd s wi t h t he s u f fi x “ - o n iu m” o r “ -i n i um ” a nd wh o s e a n io n i s a c h lo r id e , b r om i d e , i od id e , n i tr a te , or s ul f a te ( e. g . , b en za lk o ni um c hl o ri d e , c e t ylp yr i d in iu m c hl o ri d e), a r e k n o wn a s q ua t e rn a ry a m m o ni um sa l ts a n d f or m n e u t r al a qu e ou s s o l u tio n s .
IX. STRUCTURAL FEATURES AND PHARMACOLOGIC ACTIVITY. D r u g s c a n b e c l as s i fi e d a s s t r uc tu r al l y no ns p ec i fi c o r s t r uc t ur a ll y sp e c i fi c . A. S t r u c t u r a l l y n o n s p ec i f i c d r u gs a re th os e fo r wh i c h th e d r ug ' s i n te r act i o n wi t h t h e c el l m em b ra n e d ep en d s m o r e o n th e d r ug m ol e cu le ' s ph y s ic al c h a ra c te r i s t ic s t h a n o n i ts c h em ic al s t r uc t u re . Us u al l y , t h e i nt e r ac t io n i s b as ed on t he ce ll m e m b ra n e' s li p i d n a tu re a nd th e d ru g ' s l i pi d a tt r a c t i on . Mo s t ge n e ra l a n e s th e t ic s , as we l l a s s om e h yp n o t i c s an d s om e ba c te r i c id a l a ge n t s, a c t t h r o ug h t h is m ec ha n is m . B . S t r u c t u ra l l y s p e c i f i c d r u g s a r e t ho s e f or wh i c h p h a rm ac ol o gi ca l a c t i vi t y i s d e t e rm in ed b y th e d r u g 's a b il i t y t o b i nd to a s p eci f i c e n d og e no u s re c ep to r . 1 . R ec e p to r - s i te t he o r y d es c ri b es th e p ha r m a c ol o gi c a l a c ti v i t y o f s u c h dr u g s . a . Th e lo c k -a n d -k e y t h e o r y p o s t u l at es a c om pl e te l y c o m p l em en t a r y re l at io n sh i p b e t we e n th e d r ug m o le c u l e a nd a s pe ci f ic a r e a on t he s u r fa c e o f t he r ec ep t o r m o le cu l e ( i. e . , t he P.266
a c t i ve , o r ca t a l yt i c , s i t e) . Th i s t h eo r y d oe s n ot ac c o u nt f o r c o n fo r m a t io n al ch a ng es i n ei t he r d r u g o r re c e p tor m ol ec u le s a nd is a n o v e r s im pl if ic a ti o n o f a c om p l e x p r o ce s s . b . Th e in d u ce d - fi t t he o ry a l s o p os tu l at es a c om pl e m e n ta r y r el a ti o ns hi p be t we e n t h e d r u g m o l ec ul e a nd i ts ac t i v e s i t e ; h o we ve r , i t p r o v i de s f o r m u tu a l c o n f o rm a t io n a l c ha n ges b et we e n t he dr u g a nd it s re c ep t or . C on f o rm at i on a l c h an g es i n t h e r ec e pt o r m o le c u l e a re t he n t r an sla t e d i nt o b i ol og ic a l r es po n s e s. Th i s t h e o r y e xp l a i ns m a n y m or e p he no m e n a ( e .g . , a l l os t e r i c i n hi b i t o rs ) th a n th e lo ck a n d -k e y m o de l . c . Th e o c cu p a ti o n al t heo r y o f r e s p o n se f ur t h er p o s t u la t es th a t, f or a s t ru c tu r a ll y s p ec if ic d ru g , t h e in t e ns it y o f th e p h a rm ac ol o gi cal e ff e ct is d i r ec tl y p r op o rt i o na l t o t h e n um b e r o f r ec e pt o rs o c c u pi e d b y t he dr u g. 2 . R ec e p to r - s i te b in d i ng . Th e ab i l i t y t o b i n d t o a s pe c if i c re c ep t o r , a l th o u gh no t i n de p en d en t o f th e d r ug ' s ph y s ic al ch a ra c te r is ti c s , is p r im a ri l y de t e rm in ed b y t he d r u g 's c he m ic a l s t r uc t ur e . a . I n su c h an in t e ra c t i on , t h e d r ug ' s c h em i ca l r eac t i vi t y p l a y s a n im p o rt an t r ol e , r e f le c te d i n i ts b on d i ng a b i l i t y a n d i n t h e e xa c tne s s o f i ts f i t t o t h e r ec ep t o r . b . D r u g i n t e ra c t io n wi t h a s p ec i fi c r ec e pt o r i s a na l og o us to th e fi t ti n g t oge t h e r o f j i gs a wp u z z l e pi ec es . O nly d r u gs o f s i m i la r s h ap e ( i . e ., s i m i la r c h em ic al s t ru c tu r e ) c a n b in d t o a s p ec i fi c r ec e pt o r a n d i ni t ia t e a b i ol o g ic al r es po ns e . c . O f te n , o nl y a c ri t i ca l p o r t i o n o f th e d ru g mo le c u le ( r at h er t ha n t h e wh o le m o le cu l e) is i n v o l v ed in r e c ep t or - s i t e b in d in g . ( 1 ) Th e fu nc t io n al gr o up m ak i ng up th is c ri ti c a l po r t i o n i s k no wn a s a p h a r ma c o ph o r e . ( 2 ) D r ug s wi t h s im i l a r c ri t i c al r e gi o n s b ut di f fe r en c es i n o t he r pa r ts m a y h a ve s im i la r q u al i ta t i v e ( a lt h ou g h n o t n ec es s a r il y q uan t i ta t i ve ) p ha r m a c o lo g ic a l ac ti vi t y . d . I n g en e ra l , t h e b e tt e r a d r u g f i t s t he r ec ep t o r s i te , th e h i g he r t he a f fin i t y b e t we e n th e d r ug an d t he r ec e pt o r a n d t he g r ea te r t h e o bs er ve d bi ol o gi ca l r e s po ns e . A d ru g t h at bin d s t o a re c ep t or an d e l ic i ts a b io lo g ic al r es po nse is c a ll e d a n ag o n is t . e . S om e d r ug s , la c k in g th e s p ec if ic ph a rm ac o ph or e f o r a p a r ti cu la r r ec ep to r , c a n n o n et h el es s b in d t o t h a t r e c ep t or . S uc h a d r u g wi l l ha v e li t tl e o r no ph a rm a c ol o gi ca l e f f ec t a n d m i g ht al s o p rev e n t a m ol ec ul e h a v i ng th e s p ec if ic ph a rm ac o ph or e f r om b i nd i ng , b l oc k i ng t he e xp e c t e d b io l og ic al r es po ns e . A d ru g th a t b lo ck s a n a t u ra l a g o ni st an d p r e v e nt s i t fr o m b i nd in g to i t s r ec e pto r is c a ll e d a n a n ta g on is t . 3 . Th e st e r e oc h em i st r y o f bo t h t h e r ec e pt o r -s it e s u r fa ce an d th e d r ug m o le c ul e h e lp s d e te r m i ne t he na t ur e a nd ef f ic ie nc y o f t h e dr u g - r ec ep t o r i nt e ra c ti on . S t e r eo is o m e rs c a n b e d iv i d e d i n to th r e e m a i n g rou p s : o p ti c al is o me r s , ge o m e t ri c i s o me r s , a n d c on f o r ma ti o n a l i so m e rs . a . O p t ic a l i s om e r s c o n ta i n a t l e as t o ne as y m m et r i c , o r c h i r al , c a rb o n a tom ( i. e . , a c a r bo n a t om th a t is c o v al e n tl y b on d ed to fo u r d i ffe r e n t s u bs t it u en t s) . E ach a s ym m e t ri c c a r b on at om c an e xi s t i n o n e o f t wo n o ns u pe r im po sa b le is om e r i c f o rm s ( F i gu r e 1 2 - 12 ) .
( 1 ) E na n t i om e r s a re o pti c al is om e rs t h at a re m i rr o r im ag es o f o ne an o the r . E n a n ti om e rs ha v e id en t ic a l p h ys ic a l a nd c h em ica l pr o pe r t ie s e xc e p t t h at o n e r o ta t es t h e p l an e o f p o la r i z ed li gh t in a c l o c k wi s e d i re ct i on ( d ex t r o r o ta t o r y; d e s i gn a t ed D o r + ) a n d t he ot h e r i n a c o un t e rc lo ck wi s e d i re c t io n ( le vo r o t a t o r y; d e s i g na t e d L o r ). ( 2 ) A n e qu a l m i xt u r e o f D a n d L en an t io m e r s is ca l le d a r a ce m ic mi x t u re a n d is o p t ic al l y in ac t i v e. ( 3 ) E na n ti om e rs c a n h a ve l ar g e d if f e re nc es in pot e nc y , r ec e pt o r f i t, bi o log i c a l a c ti vi t y, t ra ns p o rt , a n d m e t a bo li s m . Th es e d i ff e ren c es re s u l t wh e n t he d rug m o le cu l e h as a n a s y m m e t r ic in t e ra ct i on wi t h a re c ep t o r, a t r an s p o r t p r ote i n , o r a m e ta b ol i z in g e n z y m e . F or e xa m p l e, le vo r p h a n ol h a s n a rc ot ic , an al g es ic , a n d a n t it us s i v e p ro p e rt ie s , w h e r ea s i ts m i r r or im ag e , d e x t r o r ph a no l , h as on l y a n t it us si v e ac t i v it y . ( 4 ) D i as t e r eo m e rs a re s t e r e oi s o m e r s, wh i c h a re n e i th e r m i r r o r i m a ge s n or s u pe r im po s ab le . A d r ug m us t ha ve at le as t t wo ch i r al c e n te rs t o e xi s t in d i as t e re om e rs . Un l ik e e na n t io m e r s, in wh i ch al l s te r e oc he m i c al c e nt e rs a re o p p os it e , d ia s t e r eo m e r s h a v e P.267 s om e s t e re oc he m i c al c en t e rs th a t a r e i de n ti c a l an d s om e th a t a r e o pp os i te . D i a st e r eo m e r s p os s e s s d i f fe r e nt ph ys ic oc he m i c al p ro p e rt i es a n d t hu s d i ffe r in p r o pe r t ie s s uc h as s o lu bi l it y , v o l at i li t y, an d m el tin g po in t .
Figure 12-12. The two enantiomers of 2hydroxybutane. The chiral, or asymmetric, carbon is bonded to four different groups: a methyl group, an ethyl group, a hydroxy group, and a hydrogen. The structures shown are mirror images, which cannot be superimposed.
Figure 12-13. Epimerization of tetracycline to 4epi-tetracycline. The stereochemistry of the 4dimethylamino group is inverted; however, the stereochemistry of all other chiral centers remains unchanged.
( 5 ) E p im e r s a r e a s pe c ia l t y pe o f d ia st e re o m e rs b e c a us e a l l e pi m e rs a re a l so d i as t e re om e rs ; h o we v e r , t h e o pp os i te is no t t r u e. E p im e rs a re c om p ou n ds t h a t a re s t r uc t ur a ll y i de n ti c a l i n al l re s p e c t s e xc e p t f o r th e s t er e oc he m i s tr y o f o n e c h i ra l c e nt e r . Th e p ro c e s s of ep i m e r iz a ti o n ( i n wh i c h th e s t e re oc h em is t r y of one c h i r al c e nt e r i s i n v e rt e d ) is im po r t a nt in d ru g d eg r a da t ion a nd in ac t i v at i on ( Fi g ure 1 2 -1 3 ). b . G e om e t r ic i so m e rs (c i s - t r an s i s om e r s ) oc c ur a s a re su l t o f re s t r ic t ed r o t at i on a r o un d a c h em ic al b on d , o wi n g to do u bl e b o nd s o r r i g i d r in g s ys te m s in th e m o le cu l e. ( 1 ) C i s -t r a n s i so m e rs ar e n ot m i r ro r im ag es an d h a v e d i f fe r en t p h y s ic och e m i ca l p r o pe r t ie s a nd ph a rm ac ol o gi c a ct i v i t y . ( 2 ) B ec au s e t he fu nc t io na l gr o up s o f t h es e i s o m er s a re s e pa r a te d b y d if f er e n t d i st a nc es , t h e y g e ne r al l y d o n o t f i t t he sa m e r ec ep t o r e q ua ll y we l l . If t he s e f u nc t io n al g ro up s a r e p ha r m ac op h or es , th e i s o m e r s wi l l d i f fe r i n b i ol o g ic a l a c t i vi t y. F o r e xa m p le , c is - d ie t h yls ti l -b es t r ol ha s o n l y 7% of t he es t ro g en ic ac t i vit y o f t ra ns - d ie t h y ls ti l be s t r ol ( F i gu r e 1 2 -1 4 ) . c . C on f o r ma t i o na l i s ome r s , al so k n o wn as r o tam e r s o r co n f o rm e r s , a re n o ns u pe r im po s a b le o ri en t a ti o ns o f a m o l ec ul e t ha t r es ul t fr om t he r ot a ti on o f a t om s a r o un d s in g le bo n ds . A lm os t e v e r y d r u g ca n e xi s t in m o re t ha n o n e c o n fo r m at i on , a n d t h is a b il i t y a l lo ws m a n y d r ug s t o b in d to m u lti p le r ec ep t o rs a n d r ec e pto r s u bt yp e s . Fo r e xa m pl e , th e t ra ns c o n fo rm a ti o n o f a c e t yl c h ol i ne bi n ds t o th e m us c ar i ni c r ec e pt o r , wh e r e as th e g a uc he c o n fo rm a ti o n b in ds to t he ni c o ti n ic r e c ep t or ( Fi g u re 12 - 15 ) . d . B i o is o st e r es a re m o le c ul es c o n ta in i ng gr o up s t h a t a re s p a ti al l y an d e l ec t r on ic al l y eq u i v al e nt a n d t h us a r e i n te r c h a ng ea b le wi t h o ut s i gn i fi ca n tl y a l te r in g t h e m ol ec u le s ' p h y s i c o c he m ic al p ro pe r t ie s. I so s te r i c r ep l ac e me n t o f fu nc t io n al g r o up s c an in c re as e p o te n c y , P.268 d e c re as e s id e e f fe c ts , s e p a ra t e b io l og ic al ac t i v iti e s , an d i nc r e as e t he du ra t i on of a c ti o n b y al t e ri n g m e t abo l is m . I n a dd it i on , is o ste r i c an a lo g s m a y a ct a n t ag o ni s t ic a ll y t o t he pa r e n t m o l ec ul e .
Figure 12-14. The presence of the double bond in diethylstilbestrol allows for the formation of cis and trans geometric isomers. Only the trans isomer has estrogenic activity.
Figure 12-15. The trans (A) and gauche (B) conformations of acetylcholine occur as the result of rotation around the carbon-carbon single bond.
( 1 ) P r o ca i na m id e , a n am i de , h as a l on g e r d ur a tio n of ac t io n t h an p r oc a in e , an e s te r , b e c a us e o f t h e i s os t e ri c r e pl ac em e nt of t he e s te r o xy g e n wi t h a ni t ro g e n a to m ( F i gu r e 1 2 - 16 ) . ( 2 ) Al l o x a nt h i ne is a n i nh i bi t o r o f xa n t hi n e o xi d as e . I t i s a ls o a n i s o st e r e o f x a n t hi n e , t he no r m a l s ub s t ra t e f o r t h e e n z ym e (F i g ur e 1 2 - 16 ) .
X. MECHANISMS OF DRUG ACTION A. I n t e r a c t io n w i th r e cep t o r s (s ee I X. B . 1 a n d 2 ) 1 . Ag o n i s ts in t e ra c t wi t h s pe c i f ic c e ll ul a r c on s ti tue n ts , k n o wn as re ce p t ors , an d e l ic i t a n o bs e r v ab le bi o lo g ic al r es po ns e . Ag on is ts ha ve b ot h a f f i ni t y f o r th e r e c ep t or a nd in t r i n si c ac t i vi t y.
Figure 12-16. Bioisosteric pairs procainamide/procaine and alloxanthine/xanthine. The isosteric replacements are boxed.
P.269
2 . P a r ti a l a g on i s ts in t e ra c t wi t h t he sa m e r ec ep to r s a s f ul l a g on is t s b ut ar e u na bl e t o el ic i t t he s a m e m a xi m u m re s p o ns e. P a rt i al ago n is ts ha ve lo we r i n t ri ns ic ac t i v it y t h a n f ul l a g on is ts ; ho we v e r , th e i r a ff i ni t y f or t he re c ep t o r c a n b e g r e at e r th a n , l es s t h a n, o r e qu a l t o t ha t of f u l l a go ni s ts . 3 . An t a g o ni s t s i nh ib i t t he ac t io ns o f a go ni s ts . a . P ha r m ac o l og i ca l an ta g o n is t s b in d t o th e s am e re c e p to r as th e a g on is t , e i th e r a t t h e s am e s it e o r at an al lo s te r ic si te . Th e y ha v e af f i ni t y f o r t he r ec ep t o r b ut l ac k i n t ri ns ic ac t i v it y . P h ar m ac o lo gi c al a n t ag on is t s c an b e s u b di v i d ed in t o r e ve r s ib le , i r r e ve rs i bl e , c o m p e ti t i v e, a n d n on c o m p e ti t i v e c ate g o ri es s i m i la r to en zy m e i nh ib i to r s ( s e e X. B . 2 ) . b . C h em i ca l a n t ag o n is ts r e ac t wi t h o ne an o th e r, r e s u l ti n g in t he in ac t i vati o n o f b o t h co m p o un ds . ( 1 ) Th e an t ic oa gu l an t hep a r i n , a n a c i di c p ol y s acc h a ri de , is c he m i ca l l y a nt a g on i z e d b y p r o t a mi n e, a b as ic p ro t e in , via an ac id - b as e in t e r ac ti o n. ( 2 ) C h el a t in g ag e n ts c an b e us e d a s a n ti d o te s fo r m e ta l po i so n i ng . E t h yl e n e d i a mi n e te t r a ace t i c a c id ( E D TA ) ch e la te s c al c i um an d l e ad ; pen i c i ll a mi n e c h el a te s c op pe r ; a n d d im e r c ap r o l c he l at es m e rc u r y , go ld , a n ti m o n y , and a rs e ni c . c . Fu n c ti o n al ( o r p h ys i c a l ) a n t ag o n is t s p r od uc e a nt a go n is ti c p h ys i ol o gic a l ac t io ns t h r o ug h b in d in g a t s ep a ra t e re c e p to r s . Th e ad r ene r g ic an d c ho li n e rg ic ne rvo u s s ys t em s f r eq ue n tl y p r odu c e t hi s t y p e o f an t ag on is m . Ac e t yl c h o l i n e c on s tr i c ts th e p u pi l b y a c t i ng on r ec ep to r s t h at co n t ro l t h e c i r c ul a r m us c l es o f t he e ye, wh e r ea s n o r e p in e p h ri n e d il a te s th e pu pi l b y a c t i ng on r ece p t o rs t h at c o n t ro l o cu lar d il a to r m us c l e s . B . I n t e ra c t io n w i th e nz ym e s 1 . Ac t i va t i o n , o r i n c r eas e d e n z ym e a c t i vi t y, c a n r es u lt f ro m i nd uc t io n of e n z y m e p r o t ei n s y n th es is b y s uc h d r ug s as ba r b it u ra t es , p h e n yto i n a nd ot h er a nt ie p il e pt ic s , r i f am pi n , a n ti hi s ta m i ne s , g r is e of u l vin , a n d o ra l c o n t r ac e pt i v es .
a . Al l o s t e ri c bi n d in g . A d r u g c a n e n ha nc e e n z y m e a c ti vi t y b y al lo s te r ic b i nd i ng , wh i c h t ri g ge r s a c on f o rm a t i on al ch a ng e i n t h e e nz ym e s y s te m a nd th u s alt e r s i ts a f f in i t y fo r s u bs t ra t e b ind i ng . b . C o en z ym e s p l a y a r o le i n o pt im i z i ng en zy m e ac t i v i t y . C o en z y m e s i nc lud e vi t a m i n s ( p ar t ic ul a r l y t he vi t a m in B co m pl e x ) an d co f a ct o r s —m ai n l y m e t a ll ic io ns +
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s uc h a s s od i um ( Na ) , po t as s i um ( K ) , m ag n es ium ( Mg (Zn
++
) , an d i r on ( Fe
++
++
) , c al c i um ( C a
++
), z i n c
) . C o e n z y m es ac ti v a t e e n zym e s b y c o m pl e xa t i on an d
s t e re oc h em ic al in t e ra c t io n . 2 . I nh i b i ti o n, o r d e c re as e d e n z ym e a c t i vi t y, c a n r es u lt f ro m d r ug s t ha t in t e r ac t wi t h t h e a po e n z y m e, t he c oe n z ym e , o r e v e n th e wh o l e e n z ym e co m p le x. Th e d r u g m i gh t m od i f y or de s t ro y th e ap o en z ym e ' s p r ot e in c o nf o rm a ti o n, r ea ct wi t h t h e c o en zym e ( th us r ed uc in g t h e e n z ym e s ys t em ' s c ap a ci t y t o f un c ti on ) , o r bin d wi t h th e e n zym e c om p le x ( r e n d e ri n g i t u n ab le t o b in d wi t h i t s su bs t r at e ) . a . R e ve r s ib l e i n hi b i t io n r e s u l ts fr o m a n o n co va le n t i nt e r ac t i o n b et we e n t h e e n zym e an d t h e d ru g . The d r ug is f r e e t o a s s oc ia te a nd di ss oc ia t e wi t h t he e n z y m e , a n d a n e q ui li b ri um e xi s ts b e t we e n b ou n d a nd f re e d r u g. b . I r r e ve r s ib l e i n hi b i t ion r es u lt s f r om a s ta bl e , c o va l e n t i n te r a c ti o n b et we e n t h e e n zym e an d t h e d ru g . On c e b ou n d t o t h e e n z y m e , t he dr u g is no t ab le t o d is s o c i a te . c . C om p e ti t i ve i nh i b it i on o c c ur s wh e n t he r e i s m u t u al l y e x c l u si ve b i nd i n g o f th e s u bs t ra t e a nd t he in hi b ito r . W hi le it is p os s i b le for c om pe t it i v e i n hi bi t o rs to b in d t o a l lo s te r ic s i te s , t he s e inh i bi t o rs ar e u su a ll y s t ru ct u r al l y s i m i la r to t he na tu r a l s u bs t ra t es an d c om pe t e wi t h t h e s ub s t r a te s f o r co m m o n b in d in g s it es . C om p et i ti v e i n hi b it i on c a n b e o v e rc om e b y i nc r ea si n g t he c on c en t r at i on of th e s u bs t ra t e . d . N o nc o m pe t i ti ve i n hib i t i o n oc cu r s wh e n a d ru g bi nd s t o a n a l l os t e r ic s i t e o n t he e n zym e . Th is b i nd in g i n du c es a co n fo r m a t io na l c h a n g e i n th e e n z y m e t h at i nh i bi ts e n zym e ac ti o n, e v en if a s ub s t ra t e is bo u nd to the e n zy m e. In c re as i ng s ub s t ra t e c o nc en t r at i on do es no t ov e r c om e th is t y pe o f in h ib i t io n . C . I n t e ra c t io n w i th D N A / R N A f o r m a t i o n a n d f u nc t i o n 1 . I nh i b i ti o n o f nu c le o t id e b io s yn t h e s i s oc cu r s wh e n f o la t e, pu r i ne , a n d p yr i m id in e a n t im e t ab o li te s in t e rf e re wi t h th e b i os yn t h es is o f p u ri ne an d pyr i m i di ne b u il d in g b lo c k s . a . F ol i c a c id an a l og s (e. g . , m et h ot r e xa t e , t ri m e t re xa t e ) i n hi bi t pu r in e a n d t h ym id y l a te s y nt h es is b y i n hi bi t in g d i h yd ro f ol a te r e d uc t as e. P.270
b . P u r i ne an a lo g s ( e .g . , 6 - m e r ca p to p ur i ne , th io gu a ni n e ) ac t as a n ta g on is t s in th e s yn t he s i s o f p u r in e b as es . Th es e a n al og s d o n o t a c t a s ac t i v e i nh i bi t or s un t i l t he y a r e c o n v e rt e d t o t he i r res p ec ti v e n uc le o ti de s . c . P yr i m i d i n e a na l o gs (e . g . , 5 - fl uo r o ur a ci l ) i nh ibi t th e s yn t he si s o f t h ym id y l i c ac i d b y i n hi bi t in g th y m id in e s y n t h e ta s e. As wi t h pu r ine a na lo g s , p y r im id in e a na l og s a r e n o t a c ti v e un t il th e y a re c o n v e rt e d t o t h ei r re s p ec t i v e nu c l e ot i de s . 2 . I nh i b i ti o n o f D N A o r R N A b i o s yn t h e s i s oc cu rs wh e n dr u gs i n te r f e re wi t h n uc l ei c a c id s yn t h es is . Th e s e d ru g s a r e us e d p r im ar i l y as an t in e op l as ti c a ge n ts fo r ca nc e r c h em ot h e ra p y .
a . D r ug s t h at in t e rf e re wi t h D N A r ep li ca t io n a n d fu n c t i on in c l u de i n t er c a l at i n g a g e nt s ( e .g . , t h e a n th r ac yc l i n e s , da c t in o m yc i n ) , a lk y l at i ng ag e nt s ( e .g ., n i t r og e n m u s t a rd s , n i t r os o u r ea s) , a nd an t im et a bo li t es . b . D r ug s t h at c a n d am a ge a nd de st r o y D N A in c l ud e c om p ou n ds th a t p ro du c e f r ee r a d ic al s ( e .g . , b l e om yc i n , t he an t h r ac yc l i n e s ) an d c om p ou n ds th a t i nh ibi t t o p oi so m e r as es ( e. g ., e pi p o d op h yl l o t o x i ns , mi to x a n t ro n e , i r i no t e ca n , t o p o t ec a n ). c . D r ug s t ha t i n te r f e re wi t h m i c r o tu b ul e a s s em bl y i n th e m e ta ph as e o f ce l l m i t os i s i n cl ud e th e vi nc a a l ka l oi d s an d p a cl i t ax e l. D . I n h ib i t io n o f p r o te i n s yn t h e s i s 1 . T et r a c yc l i n e s i nt e r fe re wi t h p ro t ei n s y n t he s i s b y i n hi bi t in g tr a ns f er R NA ( t R N A ) b i nd i ng to t he ri b os om e a n d b lo ck i ng th e re le as e o f c om p le t ed pe p ti de s f ro m th e r i b os om e . 2 . C h lo r a m ph e ni c o l a nd e r yt h r o m yc i n ( wh i c h c om p et e fo r th e s am e b in d in g s i te ) b i nd t o t he r ib os om e a n d i n hi bi t pe p ti d y l t r an s fe ra s e, bl oc k i n g f o rm a ti on o f t he p e p ti de b on d a nd in t e r rup t i ng fo r m a t io n o f th e p ep t i de c h ai n . 3 . Am i n o g l yc o s i d e s d ec r e a s e th e f i de l it y o f t r ans c ri p ti o n b y bi n di ng t o t he r i b os om e , wh i c h p e rm it s f o r m a t io n o f a n a b no r m al i ni ti a ti o n c om pl e x a n d p r o hi b it s a d di t io n o f am in o a c i ds to t he pe p ti d e ch a in . In ad d i ti on , am in og l yc os id es c au s e m is r e ad in g o f th e m es s en g e r R N A ( m R N A ) t em pla t e , s o t ha t i n co r r ec t a m i n o a c i ds a r e i n co r po r a te d i n to th e g r o wi n g p ol y p e p ti de c h ai n . 4 . Q u i nu p r i st i n a n d d a lf o p r i s t in , i n c om bi n at i on, c on st r ic t th e e xi t c ha n ne l on r i b os om al R N A ( r R N A ) . Th i s ac t io n p r e v en t s n e wl y s y n t he s i z e d p o l ype p tid e s f r om b e in g re l ea s e d a n d i n t ur n in h ib i ts fu r t he r p r o te i n s y n t he s i s . E . I n te r a c ti o n w i th ce l l m e m b ra n es 1 . D i gi t a l is gl yc o s i d e s in h ib i t t h e ce l l m e m b r a ne' s so d iu m -p o ta s s iu m p um p , +
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i n hi b it i ng th e i n fl u x o f K a n d t he ou t f lo w o f N a . 2 . Q u i ni d i ne af f ec ts t he m em b r an e p o te n ti al o f m y o c a r di al m e m b r an es b y p r o lo n gi ng bo t h t h e p ol ar i z e d an d d ep o la r i z ed s ta t e s . 3 . L oc a l a ne s t he t i cs blo c k im pu ls e c o nd uc t io n in n e r ve ce l l m e m b r a ne s b y +
+
i n t er f e ri n g wi t h m e m b r ane p e rm ea bi l it y t o Na a nd K . 4 . P o l ye n e a n t i f un g al dr u g s (e . g ., am ph o te r ic i n B , n y s ta t in ) af f ec t c el l m e m b ra ne p e r m e ab i li t y , c a us in g l eak a ge of ce ll u la r c o ns ti t ue n ts . 5 . C e r ta i n a n t ib i o t ic s (e. g . , p ol ym y xi n B , c ol is t in) a f fe c t ce l l m e m b r a ne p e r m e ab i li t y t hr o ug h a n u n k n o wn m e ch a ni s m . 6 . Ac e t yl c h o l i n e i nc r eas es m e m b r an e p e rm e ab ili t y t o c at i on s . +
+
7 . O m ep r a z o l e a nd la n so p r a z o l e i nh i bi t t h e H / K p u m p (l oc a te d i n p a r ie ta l c e ll m em b r an es ) , t h us d e c r ea s in g t h e e f fl u x o f p ro t on s i n to t he s t om ac h . 8 . S e ve ra l a n t in e op l a st ic a ge n ts e xe r t t h e ir ac t io n s b y in i ti a ll y b in di n g to c el l u la r d e t e r mi n an t s ( C Ds ) e xp r e s s e d b y t um o r ce ll s . a . G e m tu z u m ab oz o ga mi c i n b in d s wi t h C D 3 3 e xp r e s s ed b y l e uk em ic c e lls an d i m m a tu r e m y e lo m o n oc y t ic c e ll s . b . Al e m t uz u ma b , a m o no c lo n al a n ti b od y , b in ds to t he C D 5 2 a nt i ge n e xp r e s s e d o n B l ym p ho c y t es , T l y m p ho c y t e s , a n d v a r i ou s o th e r c e l ls . P.271
F . N o ns p ec i f ic ac t i o n 1 . S t ru c tu r al l y no ns p ec if ic d ru gs f or m a m o no m o le c ul a r l a y e r o ve r e n ti r e a r e as of c e r ta i n ce l ls . B ec a us e t he y i n v o l ve s uc h l ar g e su rf a c e s , t he s e d ru gs a re us u al l y g i ve n i n re la t i v el y l a rg e d o s e s . 2 . D r ug s t h at ac t b y n ons p ec if ic ac t io n i nc lu d e t he vo l a t i le ge n e ra l an e sth e t i c g a s es ( e. g ., e th e r, ni t r ou s o xi d e ) , so m e de p r es sa n t s (e . g. , e t ha n ol , c hl o ra l h yd r a t e) , an d m an y a n ti s e p t ic c om po u nd s ( e .g . , ph e n ol , ru bb i ng al c o h ol ) . P.272
STUDY QUESTIONS D i r e c t i on s : E a c h of t he q u es t io ns , s t at em e nt s , or i nc om p le t e s t a te m en ts i n th is s ec t io n c a n b e c o r r ec t l y a n s we r e d o r c om pl e te d b y o n e o f th e s ug g es te d a n s we r s o r p h r as es . Ch o os e t h e b es t a ns we r . 1 . A 4 0 - ye a r - o l d m a n co m p la i n s o f d ys u r i a a nd u r i na r y u r g e n c y a n d i s d i a g no s ed t o h a ve un co m p l ic a te d go n oc o cc a l u r e t h r i ti s . He is g i ve n p r o c a in e p e n ic i l l in G i nt r a mu s cul a r l y. I n a d di t i o n, p r ob en e c id i s g i ve n to p r ol on g t he d u r a t i on o f a c ti o n o f pen i c i ll i n . T h is t yp e o f c om b i ne d d r ug e ff e c t i s kn ow n as ( A ) s yn er g is m . ( B ) c om pe t it i v e a n ta g on is m . ( C ) a d di ti o n. ( D ) p o te n ti a ti on . ( E ) n on c o m p e ti t i v e a n tag o ni s m . V i e w A n s we r 1 . T h e a n sw e r i s D [ se e] . 2 . A 4 0 - ye a r - o ld t ea c he r w a s p r e s c r ib e d l o va s ta t i n fo r t h e t re a tm e n t o f h yp e r c h o le s te r o l em i a. S he w an t e d t o k n ow t he me c ha n is m of t h e d ru g be f o r e t ak i n g i t . H e r p h a r ma c is t e x p la i n ed t o h e r t ha t l o va st a t in ac t s b y b l o c k i n g t h e s ub s t ra t e - b in d in g si t e o f t he e n z ym e β h yd r o x y- β - m e t h yl g l u t a r yl - c o e n z ym e A ( H M G - C o A) r e d u c t as e , w hi c h ca t a l yz e s t h e r a te - l im i t in g st e p i n c h o le s te r o l b i o s yn t h e s i s . S uc h d r u g e f f ec t is k n ow n a s ( A ) a dd i ti o n. ( B ) s yn er g is m . ( C ) n o nc om pe t it i v e a n tag o ni s m . ( D ) p o te n ti a ti on . ( E ) c om pe t it i v e a n ta g on is m . V i e w A n s we r 2 . T h e a n sw e r i s E [s e e] . 3 . A 7 0 - ye a r - o l d m a n h ad p r o lo n ge d b l e ed i n g d u r i ng an e le ct i ve k n ee su r g e r y. S u b s e q ue n t l y, t h e p a t i en t a d m i t te d to t h e su r g e on t ha t he had b ee n se l f -a d m in i s te r in g 81 m g as p i r in da i l y. T h e c o n su l t an t p ha r m ac i st e x p la i n ed t o t h e p a ti e nt t h a t , a l th o u gh as p i r in h a s a s h o r t pl a sm a h a l f -l i f e, it c a n i r r e ve r s ib l y i n h i b it p l a te l e t f u nc t i on b y a c e t yl a t i n g t h e no n s ub s t r at e - bi n d in g s i te o f t h e p la t e le t cyc l o o x yg e n a s e , r e su l t in g i n p r o l o n ge d e f f ec t on p lat e l e t a g g re g a ti o n . T h is d r u g e ff e c t i s k n ow n a s ( A ) p o te n ti at i on .
( B ) c om pe t it i v e a n ta g on is m . ( C ) s yn e rg is m . ( D ) a d di ti o n. ( E ) n on c o m p e ti t i v e a n tag o ni s m . V i e w A n s we r 3 . T h e a n sw e r i s E [s e e] . 4 . A 6 5 - ye a r - o l d w om a n w i t h i n t r a c ta b le p ai n s e co n da r y t o b o n y m e t a s t a si s o f b r ea s t c a nc e r ha d be e n r e c e i vi n g e sc a la t i ng d os e s o f mo r p h in e s u l fa te i n t r a ve no u sl y. At 1 0 A. M . , s h e w a s f o un d to b e u n r es po n s i ve , h e r r es p i ra t o r y r a t e w a s 4 b r e a th s pe r m i n u te , a n d he r p up i ls w e r e p i n- p o i n te d . Na l ox o n e, a co m p e ti t i ve an t a go n i st o f t h e o p i a te r e ce p to r , w a s g ive n i n t r a ve n ou s l y a n d r e p e a te d o n ce . S he g r ad u a l l y b e c am e c o ns c io u s a n d b e g an t o c o mp l ai n o f pa i n un r e l ie ve d b y m o r p h i n e g i ve n a t t h e p r e vi o us do s e. Th i s is mo s t l i ke l y b e c au s e ( A ) n al o xo n e di r ec t l y a gg r a v a t es th e p ai n c au s ed b y t he bo n y m e ta s ta s i s. ( B ) n al o xo n e r ed uc es the E m a x f o r m or p hi n e. ( C ) n al o xo n e r ed uc es t he E D 5 0 f o r m or p hi n e. ( D ) n al o xo n e in c re as es th e Em a x f o r m o r ph i ne . ( E ) n al o xo n e in c re as es th e E D 50 fo r m o r ph i ne . V i e w A n s we r 4 . T h e a n sw e r i s E [s e e] . 5 . W h ic h o f t h e f o l low i n g s t a te me n t s r e g a r d in g si g na l t r an s du c t i on i s i n co r r e c t? ( A ) Th yr o xi n e - b o un d re c e p t o rs a c t o n D N A an d re g ul a te sp ec i fi c t r an sc r ip t i on of g e n es . ( B ) C yc l ic a d en os i ne m on o p ho s p ha t e c an ac t a s a s e c o n d m es s e ng e r . ( C ) Th e l e v el of d ru g re c e p t o rs a t th e c el l s u rf ac e i nc r e as es wi t h c h ro ni c s t i m u l at i on b y r e ce p to r ag o ni s t s . ( D ) B i nd i ng of li g an d t o c e ll - s u r fa ce r ec ep t o rs c an l ea d t o s y n t he si s o f p ro t e in s. ( E ) A n ta c i d s ac t b y i n te ra c ti n g wi t h sm al l i on s n or m a ll y f ou n d i n t he ga s t ro i n te s t i na l t r a ct . V i e w A n s we r 5 . T h e a n sw e r i s C [ se e] . 6 . A p h a rm a c is t is co n s ul t e d a bo u t s e l ec t i ng a d r u g t h a t i s r e l a t i ve l y s a f e a n d e f fec t i ve f o r t re a t in g t he pa t i e n t. H e s e a r ch e s t h e l i te r a t u r e a n d ob t a in s th e fo l l ow in g d at a th a t m a y h e l p g u i d e h i s d e c is i o n. T he T D 0 . 1 a n d E D 9 9 . 9 f o r d r ug A a r e 20 m g a nd 0. 4 m g , r e sp ec t i ve l y; w h e re a s t h e T D 0 . 1 a nd E D 9 9 . 9 fo r d r u g B a r e 1 5 m g a n d 0 .2 m g , re s pe c ti ve l y. W h i c h o f th e fo l l ow in g s t a t em e n ts is t r ue ? ( A ) D r u g A ha s a hi gh e r TD 0 . 1 a n d t h us s ho u ld be t h e d r ug of ch oi c e. ( B ) B o th d ru gs ha v e t he s am e m a rg i n o f s af e t y, so m o r e i n fo r m a t io n i s n ee d e d. ( C ) D r u g B h as a hi g he r m a r gi n o f s af e t y an d t h us is pr e fe r r e d t o d r ug A . ( D ) D r u g A is p re f e rr e d be c au s e it ha s a g re a te r m a r gi n o f s af e t y th a n d ru g B . ( E ) Th e in f o rm a ti on ob t ain e d i s i r re l e van t . V i e w A n s we r 6 . T h e a n sw e r i s C [ se e] . P . 27 3
7 . W hi c h o f th e fo l l ow in g s ta t e me n ts c on c e rn in g a d r u g re c ep t o r is t ru e ? ( A ) I t m ed i at es t he no ns p e c i f ic a c ti on o f vo l at i le a n es t he t ic s . ( B ) I ts e xp r e s s io n i s i ndu c ed on l y b y e xo g en o us ly a d d ed d ru gs . ( C ) I t c a n b in d e nd o ge n ou s l i ga nd t o p r od uc e p h ys i o l og ic a l ac t i v i t y .
( D ) I t m e di a te s t he c a t har t i c ac t i v i t y o f m a gn es ium c i t ra t e . ( E ) D o wn - r e g ul a ti on o f re c ep t o r l e v el c a n l ea d t o s en s i t i za ti on o f t he ta r ge t ce ll to t h e re ce p to r ag o ni s t . V i e w A n s we r 7 . T h e a n sw e r i s C [ se ea n d] .8 . W h ic h o f t h e f o l low i n g s t a t em e n ts co n ce r n i ng m o r p h in e a n d h yd r o m o r p h o n e i s t r u e ? ( A ) H yd r o m o r ph o ne is a m o r e e ff e c t i v e a n al ge si c b ec a us e i t h as a s m al l er E D 5 0 th a n m o r ph in e . ( B ) Mo r p h i n e a nd h y d rom o r ph on e a r e e q ua ll y p ot e n t b ec au s e t he y h a v e th e s am e E max. ( C ) Mo r p h i n e h as a g re at e r E D 50 an d i s t h us a les s e f fe c ti v e an al g es ic tha n h yd r o m o r ph o ne . ( D ) H yd r o m o r ph o ne is a m o r e p ot e nt an a lg es ic be c au s e it ha s a g re a te r E m a x t h a n m o r ph in e . ( E ) H yd r o m o r ph o ne ha s a s m al l e r E D 5 0 a nd t hu s i s a m o r e p ot e nt a na lg esi c th an m o r ph in e . V i e w A n s we r 8 . T h e a n sw e r i s E [s e ea n d] . 9 . A 72 - ye a r - o l d m an w i t h h yp e r t e n s i o n h a s b ee n t a k i ng h ig h - do s e p r o p ra n o l ol f o r 2 0 ye a r s . H e l e f t ho m e f o r a w ee k a n d fo r g o t to b r i n g h is me d i ca t i on w i t h h im . O n e d a y, h e w a s f o un d c o l l ap s ed on t he f l oo r a n d w as b r ou g h t t o t he e m e rg e nc y r o o m . H i s b l o o d p r e s su r e w as 3 00 / 18 0 , h e a r t ra t e w as 18 0 b e a ts p e r m i nu t e , a n d r e t ina l h e m o r r ha g e w a s o b se r ve d . W h ic h of t he f o ll ow i ng b es t ex p la i ns t h is s i t ua t i o n? ( A ) Th e β - ad r e ne r gi c r ec e p t o rs i n t h e c ar d ia c m us c l es un d e r we n t s po n ta ne o us m u ta t io n a n d b ec am e h y p e r ac t i ve. ( B ) R e du c ti on in t he c h ro n ic an t ag o ni s m o f th e β- a d r en e rg ic r ec ep t o r l ed t o do wn r e g ul a ti o n o f t h e β - ad r e ne r g ic re ce p t or . ( C ) Th e p r op r an o lo l t h at h e ha d p r e v io u sl y in g es te d r em ai ne d i n h is bo d y a n d a c t e d a s a r ec ep t o r a go n is t. ( D ) L o ng - te r m a dm in is t ra t i on of p ro p ra n ol o l r es ul t s i n d es en s i t i za ti on o f c a r di ac m us c l e s t o e nd o ge no u s β - a d r en e r gi c st im u la t io n . ( E ) R e du c ti on in t he c h ro n ic le v e l o f re c e p to r bl oc k a d e r es u lt s i n s up e rs en s it i v i t y to s t im ul a ti o n wi t h en d og e no u s c a t ec h ol am in es . V i e w A n s we r 9 . T h e a n sw e r i s E [s e e] . 1 0. A 4 2 - ye a r - o ld ma n w i t h c h r oni c l ym p h o c yt i c l e u k em i a un d e r g oi n g th e r ap y m e n t i o n ed t o h i s p h a rm a cis t t h at h is d o c t o r h a d p r e sc r i be d r i t u x im a b fo r t r ea t i ng hi s ca n ce r . Th e pa t i en t as k e d w h a t r i t u x im a b i s a n d h ow i t w o r ks . H is p ha r m ac i st e x p la i n ed t o h im t ha t r it u x i ma b i s a m o no c lo n a l a n ti b od y t h a t ( A ) i nh i bi ts D N A s y n t he s i s . ( B ) b lo c k s c e l l c y c l e p r og r e s s io n . ( C ) b in d s t o c e l l s u r f ac e m o le c u l es . ( D ) b o os ts th e i m m un e re s po ns e . V i e w A n s we r 1 0 . T he a nsw e r i s C [ se e] . 1 1. A 6 5 -ye a r - o l d w om a n e x p e ri e nc e d a n gi n a l p ai n w i t h ST se g me n t e l eva t i o n o n E K G . S he w as t r e a te d w i t h I V he p a ri n , n i t r o glyc e r i n , a n d a t e no l o l f o r a c u te m yo c a r d i a l in f a rc t i o n . T h e n 2 h r l a te r , w h en he r n u r se r e pl a ce d h e r Fo l e y b a g , sh e no t i ce d fr a n k b l o o d d r a in i n g o u t o f th e F ol e y c a t h e t e r . Th e p h ys i c i a n ch e ck e d t h e p a t i en t ' s
p a r t i a l t h r om b i n t i me w h i c h w as > 1 50 s . Th e pa t i e n t w a s t h e n a dm i n is t e r e d p r o t a mi n e , w h i ch ac t s b y ( A ) p r om ot i ng th r om b os is . ( B ) r e ac ti n g wi t h he p a ri n a n d t hu s n eu t r al i z i ng the e f fe ct of h ep a ri n . ( C ) d i re c tl y i nh ib i ti n g b lee d in g . ( D ) e n ha nc in g s ec r e ti on o f p ro c o a gu la n ts . V i e w A n s we r 1 1 . T he a nsw e r i s B [ se e] . 1 2. A 4 5 -ye a r - o l d m a n w i th ac u te p r o m ye l o c yt i c l e u k em ia i s b e in g t r ea t ed w i t h a l l - t r an s - r e ti n o ic ac i d (AT R A) . H e a s k s t h e p ha r m ac i s t i f AT R A w o rk s li k e vi t a m in A a s a h e al t h su p pl em e n t . T he p h a r ma c is t ex p la i n ed th a t AT R A i s a f o r m o f vi t a m in A t h a t ac t s b y ( A ) im p r o v in g i m m un e f un c ti o ns . ( B ) i nh i bi ti n g l eu k e m i c c e l l s ec r et i on . ( C ) l im i ti ng le uk em ic c e ll g r o wt h . ( D ) i nd u c i ng di f fe r e nt i at io n of le uk em ic c e ll s . V i e w A n s we r 1 2 . T he a nsw e r i s D [ se e] . 1 3. A 5 5 -ye a r - o l d m a n w i th a h i s t o r y o f h e a v y s m o k in g h ad be e n d i ag n o se d w i th n on - sm a l lc e ll l ung c an c e r , w h ic h w as t r ea t e d w i t h c h e mo t h e ra p y; h i s d i s ea s e p r o g r es s ed . H e i s n ow r e c e i vi n g e r l ot i n ib , an d h e as ks h is p ha r ma c i st h ow e r lo t i ni b w o r ks . T h e p h a r ma c is t ex p la i n s t ha t e r l ot i n ib ac t s b y ( A ) i nh i bi ti n g p r ot e in t y ro s in e k in as e a c ti vi t y of tu m o r c e l ls . ( B ) d ec r ea s i n g l e v el of pr o t ei n t yr os in e k in as e o f t u m o r c e ll s . ( C ) i nc r ea s i n g l ig an d bi nd i ng o f p r ot e in t y r os in e k i n as e o f tu m o r c el ls . ( D ) i nd u c i ng t um or c e ll di f f e re n ti a ti on . V i e w A n s we r 1 3 . T he a nsw e r i s A [ se e] . P . 27 4
1 4 . W h i ch o f t h e f o l low in g d r u g- a c ti o n p a i rs i nvo l ve s s p ec i f ic r e ce p t or s ? ( A ) Ma g n e s i um s u l fa t e fo r t r ea tm e nt o f c o ns t ip a ti o n . ( B ) C a lc iu m c a rb on a te f or r e li e f o f h e ar t bu r n . ( C ) D e s fl u ra n e f o r i nd uc in g s e da t io n . ( D ) Ta m o xi f e n fo r th e ra py o f b re a st c a nc e r. ( E ) S o r bi t ol fo r re d uc in g i n t ra c ra n ia l h y p e r te ns io n . V i e w A n s we r 1 4 . T he a nsw e r i s D [ se e] . 1 5. W hi c h o f t he f o ll ow i n g s al t s w i l l m os t li k el y yi e l d a n a q ue o us so l u t io n w i th a p H < 7? ( A ) S o di um s a li c y la t e ( B ) P o ta s s i um c hl o ri d e ( C ) Ma g n e s iu m s u l fa t e ( D ) P o t as s i um p e ni c i ll i n ( E ) A t r op i ne s u lf a te V i e w A n s we r 1 5 . T he a nsw e r i s E [s e e] . 1 6. Wh i c h o f t he f o ll ow i n g c h e mi c al / p ha r m ac o lo g ic a l c l as s es o f a ge n t s is i n co r r e c tl y m a t ch e d w i t h i t s a c i d -b a se na t u r e? ( A ) A d r en e rg ic β 2 -a g on is t s : b as ic ( B ) P r os t ag l an di n s : ac id ic ( C ) O r g a ni c n it r a te s : n one l ec t r ol y t es
( D ) Me g l i t in i de s : ac id ic ( E ) 4 - Q ui n ol o ne s : ba s i c V i e w A n s we r 1 6 . T he a nsw e r i s E [s e ea n d] . 1 7. Al l o f t he f ol l ow i ng m e d ic i na l ag e n ts a re c la s s i fi e d a s n a tu r a l p r od u c t s e xc e p t ( A ) a t ro p in e . ( B ) d ia z e p am . ( C ) d ig i to xi n . ( D ) p e ni c i ll in . ( E ) m or p hi n e. V i e w A n s we r 1 7 . T he a nsw e r i s B [ se ea n d] .1 8 . Al l o f t he f ol l ow i ng s t a t em e n ts ab o u t a s t ru c t u r al l y s p e c i f ic ag o ni s t a re t r u e e xc e pt w h i ch o n e? ( A ) A c ti v i t y is de t er m i n ed m o r e b y i ts c h em ic al s tr u c tu r e t h an b y i t s p h ys ic a l p r o pe r t ie s . ( B ) Th e e nt i re m o le c u l e is in v o l ve d i n b in di n g t o a s p ec i fi c e nd o ge n ou s re c ep t o r. ( C ) Th e d r ug c a nn o t ac t u n le s s it is fi r st bo u nd to a r ec ep t o r. ( D ) A m i n or s t r uc t u ra l c ha n g e in a p h ar m a c op ho re ca n p r o du ce a l os s in a c ti v i t y. ( E ) Th e hi g he r th e a f fi n ity b e t we e n th e d r ug a nd it s re c ep t or , th e g r ea t e r th e b i ol o gi c a l re s p on s e. V i e w A n s we r 1 8 . T he a nsw e r i s B [ se e] . 1 9. T he de x t r o ( D ) f o r m o f βm e t h ac h ol i ne ( s t ru c t u re s how n ) i s a pp r o x im a te l y 5 0 0 t i me s m o r e a c tive t h a n t h e le vo ( L ) e n a nt i o me r. T h e o bs e r ve d di f f e r enc e i n p ha r m ac o l og i ca l a c t i vi t y b e tw e e n t h e tw o is o mer s i s m o s t l ik e l y t h e r e s u l t of d i ff e r e nc es i n
( A ) r ec e pt o r s el ec t i v i t y . ( B ) d is s o lu t io n . ( C ) d is t ri b u ti on . ( D ) i n te r a to m i c d is ta nc e b e t we e n p h a rm ac op h or e g r o u p s . ( E ) s ol ub i li t y . V i e w A n s we r 1 9 . T he a nsw e r i s A [ se e] . e na n t i ome r 2 0 . T h e c om p o un d s h ow n be l ow c a n b e c la s s i fi e d a s a
( A ) p en ic i ll in . ( B ) t hi a z i de . ( C ) c ou m a r in . ( D ) p h en o th ia z i n e. ( E ) h yd an t oi n . V i e w A n s we r 2 0 . T he a nsw e r i s B [ se ea n d] .2 1 . Wh i c h o f t he f ol l ow i ng aci d s h a s th e hi g he s t d e g re e o f i o ni za t i o n i n a n a q ueo u s s o l u ti o n ? ( A ) A sp i r in ; p K a = 3 .5 ( B ) I n do m e t ha c i n ; p K a = 4 . 5 ( C ) W ar fa r in ; pK a = 5 .1 ( D ) I b up r o fe n ; p K a = 5. 2 ( E ) P h en o ba r bi t al ; p K a = 7 . 4 V i e w A n s we r 2 1 . T he a nsw e r i s A [ se e] . P . 27 5
2 2 . W h i ch o f t h e f o l low in g s ta t e me n ts c on c e rn in g t he s t r uc t u r e s how n b e l ow i s n o t co r r e c t ?
( A ) Th e c o m p o un d i s a n a c id . ( B ) Th e c o m p o un d c an be us e d t o t r e at a rt h ri t is . ( C ) Th e c o m p o un d i s a fe n am a te . ( D ) Th e c o m p o un d i nc r ea s es p r os t ag l an d in pr o du c ti o n . ( E ) Th e c o m p o un d i s a no n s t e r oi da l a n ti - in f la m m a t o r y d ru g ( N S AI D ) . V i e w A n s we r 2 2 . T he a nsw e r i s D [ se e] . 2 3. Al l o f t h e f ol l ow i ng c la ss e s of d r u g s a r e us e d t o t re a t h yp e r t e n s i o n e xc e p t ( A ) a r yl o xy p r o p a no la m i ne s . ( B ) t hi a z i de s . ( C ) f i br a t es . ( D ) d ih yd r o p y r id in es . ( E ) a ng i ot e ns in - c o n v e r tin g en z ym e ( A C E ) i nh ib i to r s . V i e w A n s we r 2 3 . T he a nsw e r i s C [ se e] . 2 4. F lu r a z e p a m h as p K a o f 8 . 2 . W h a t p e r ce n t ag e of f l u ra z ep a m w i l l b e io n iz e d a t a u r i n e p H o f 5 .2 ? ( A ) 0 . 1% (B) 1% (C) 50% (D) 99% ( E ) 9 9 .9 % V i e w A n s we r 2 4 . T he a nsw e r i s E [s e ea n d] . D i r e cti o n s fo r q ue s ti o n s 2 5- 29 : Th e q u es ti o ns a n d i nc om p l e te s t a te m e n ts i n t h is s ec t io n c a n b e co r r ec t l y a n s we r e d o r co m p l et e d b y o ne o r m o r e o f th e s ug g es t ed an s we r s . Ch o os e t he an s we r , A - E . 2 5 . D r ug s th a t a c t s ys t e m i ca l l y m u s t I . u nd e r g o b i o t ra n s fo rm a t i on i nt o an ac t i ve fo r m a f te r r ea c h in g th e ir a c t i ve site. I I . be i n a fo r m ca p ab l e o f p as sa g e t h r o ug h var i o u s m e mb r a ne b a r ri e rs . I I I . be in o r b e c o n ve r t ed t o a f o r m t h a t i s r e a di l y e x c r e t e d f r o m th e bo d y. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t
D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 5 . T he a nsw e r i s D [ se ea n d] .2 6 . E xa m p le s o f s t ro n g e l e c t ro l yt e s ( i . e. , co m pl e t e l y d i s s o c i at e d i n a n a q ue o u s s ol u t i on ) in c lu d e I . a ce t ic ac i d . I I . pe n t ob a r b i ta l s o d ium . I I I . di p he n h yd r a m i n e h yd r o c h lo r i d e. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 6 . T he a nsw e r i s D [ se e] . p e nt o b a rb i t a l s o d i um d ip h e nh y d ra m ine h yd r o c hl o r i de 2 7. P r ec i p i ta t i o n m a y o c c u r w h e n m i x in g aq u eo u s s o lu t i on s o f m ep e r i di n e h yd r o c h l o r id e w i th w h i ch o f th e f o l l ow i ng so l u t io n s? I . S o di u m b i ca r b o na t e in j e c ti o n I I . At r o p i n e s u lf a t e i n jec t i o n I I I . So d i um ch l o r id e in je c t i on A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 7 . T he a nsw e r i s A [ se ea n d] .2 8 . D ru g s c l a ss i f ie d a s a n t i me t a bo l i te s i n c lu d e w h ic h o f t he f ol l ow i ng? I . 5 - fl u o r ou r a c il I I . su l f is o xa z ol e I I I . di g ox i n A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 8 . T he a nsw e r i s C [ se e] . 2 9. T he ex c r e t io n o f a w ea k l y a c i d ic d ru g is ge n e r al ly m o r e r a p i d in a lk a li ne u r i ne t ha n in ac i d ic ur i n e . T h i s p r o c es s oc c u rs be c au se I . a w ea k a c id i n a lk a li ne m ed i a w il l e x is t p r ima r i l y i n i t s io n iz e d f o r m, w hi c h c a n no t be r e ab s o r be d ea s i l y. I I . a w e a k a ci d in al k al in e me d ia w i l l e x is t in i ts l i po p h il i c f o r m , w h i ch c a nn o t b e r ea b s o rb e d e as i l y. I I I . a l l d r u g s a r e e xc r e te d mo r e r ap i d l y i n a n al k a l in e u r i n e. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t
D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 9 . T he a nsw e r i s A [ se e] . P . 27 6
Q u e s t i on s 3 0 - 33 , re f e r to t he d ru g m ep e ri d in e (s t r u ct u r e sh o wn ) . 3 0 . Fu n c ti o na l g ro u p s p r e s en t i n t h e m ol e cu l e s h ow n i n cl u d e I . a n e s te r . I I . a t e r t ia r y a m i n e . I I I . a ca r b o x yl i c a c i d .
V i e w A n s we r 3 0 . T he a nsw e r i s C [ se ea n d] .3 1 . M e p e r i di n e i s c l as s i fi e d a s a I . w e ak ac i d . I I . sa l t . I I I . w ea k b a se .
V i e w A n s we r 3 1 . T he a nsw e r i s B [ se ea n d] .3 2 . As s u m in g t ha t m e pe r i d i ne i s a bs o r be d a f t e r o r a l ad m i n is t r a t io n a n d t h a t a l a r ge pe r c en t a ge o f th e d os e i s e x c r e te d u n ch a n ge d , t he e f fe c t o f al k a li n iz a ti on o f t he u ri n e w il l in c r ea s e i t s I . d u ra t i o n o f a c t io n . I I . r a te o f e xc r e t io n . I I I . io n iz a ti o n i n t he gl om e r u la r f i l t ra t e .
V i e w A n s we r 3 2 . T he a nsw e r i s A [ se ea n d] .3 3 . T he a pp r o p r i at e c h em i ca l c l a ss i f ic a t io n fo r m ep er i d i n e i s I . p he n yl p r o p yl a m i n e . I I . p ip e r az i ne . I I I . 4 - p he n yl p i p e r i d in e .
V i e w A n s we r 3 3 . T he a nsw e r i s B [ se ea n d] . Di r e c ti o n s fo r q ue s ti o n s 3 4- 38 : Th e r e la t io n s h ip of e ac h p a i r o f s t ru c tu r es s h o wn i n th is s e ct i on is m os t c lo s el y a ss o ci at e d wi t h o ne o f th e fo l lo wi n g te r m s . Th e te r m s m a y b e us e d m o r e t h a n o nc e o r n ot at al l . Ch oo s e t he b e s t a ns we r , A- E . 34.
A G e o m e t r ic i s o m e r s B E n a nt i om e rs C D i a s t e re om e rs D B i o is os te r es E C o n fo r m a t io n al is om ers V i e w A n s we r 3 4 . T he a nsw e r i s C [ se e] . 3 5.
A G e o m e t r ic i s o m e r s B E n a nt i om e rs C D i a s t e re om e rs D B i o is os te r es E C o n fo r m a t io n al is om ers V i e w A n s we r 3 5 . T he a nsw e r i s B [ se e] . P . 27 7
36.
A G e o m e t r ic i s o m e r s B E n a nt i om e rs C D i a s t e re om e rs D B i o is os te r es E C o n fo r m a t io n al is om ers V i e w A n s we r 3 6 . T he a nsw e r i s A [ se e] . 3 7.
A G e o m e t r ic i s o m e r s B E n a nt i om e rs C D i a s t e re om e rs D B i o is os te r es E C o n fo r m a t io n al is om ers V i e w A n s we r 3 7 . T he a nsw e r i s D [ se e] . 3 8.
A G e o m e t r ic i s o m e r s B E n a nt i om e rs C D i a st e re om e rs D B i o is os te r es E C o n fo r m a t io n al is om ers V i e w A n s we r 3 8 . T he a nsw e r i s E [s e e] . P . 27 8
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is D [ s ee V . C ] .
P r o b en ec i d a lo ne is in ac t i v e ag a in s t go n oc oc c i . H o we ve r , i t c a n co m p e t e wi t h p e ni ci l li n f o r u r in a r y e xc re t i on . Th us pr o be n ec id c a n r ed uc e t h e e li m i na t ion r a te of p e ni ci l li n , wh o s e d u ra t ion o f a c t i on be co m e s p r olo n g ed . Th e re f or e , p r ob en e c i d p o t en t ia t es th e a c t i v i t y of p en ic i ll in wh e n th e t wo a r e gi v e n t o ge t he r . 2 . T he an sw e r is E [ s e e I I . B .4 . a; I V . D .3 ] . L o va st a ti n re v e r s i b l y b i nd s to th e s ub s tr a te - b in din g s i te o f t he en z ym e HM G - C o A r e d uc t as e, wh i c h c a t al y z e s th e r a te - l im it in g s t ep i n th e s y n t he s i s o f c ho les t e ro l , t h us lo we r i n g t h e c h o le s te r o l l e vel . Th e re f o re , l o va s ta t in in h ib i ts t h e e n zy m e b y c om p et i ti v e an t ag o ni s m . 3 . T he an sw e r is E [ s e e I I . B .4 . b; I V . D .4 ] . A s p ir i n ca n c o v a le n tl y m o d i f y th e p la t el e t c yc l o o xy g e n as e th r ou g h ac e t y lat i o n o f t h e e n zym e ot h er t ha n t h e s u b s t r a te - bi n di n g si t e, c au s in g i r r e v e rs ib le in h ib i tio n of p l a te le t ag g re g at i on . The r e f or e , a s p i ri n i n hi bi t s p l a te le t fu nc t io n b y n on c o m pe t it i v e a n t ag o ni s m o f c y c lo o xy g e n as e . 4 . T he an sw e r is E [ s e e I V . D . 3] . N a l o xo n e is a c o m p e ti t i ve a nt a go n is t o f o pi a te r ec e pt o r . I f o n e c o m p a r es t h e l o g d o se - r es po ns e c u r v e o f b o t h m o r p hi ne an d n a lo x o n e t o th a t o f m o r p hi ne a l on e , t h e m o r ph in e - na lo xo n e c ur v e is s h i ft e d t o t he r ig h t. A s a r es u lt , th e E D 5 0 fo r m o r ph in e i s i n c re as ed . Th is m e an s th a t a la r g er t ha n p r e v io us do s e o f m o r p hi ne is req u i re d fo r a c hi e v i ng th e s am e a na lg e s i c e f fe ct . 5 . T he an sw e r is C [ s ee I I I . D .4 ] . Th e l e ve l o f d r ug r ec ep to r s a t th e c el l s u rf ac e u s u a ll y d ec r ea s e s wh e n t he t a rg e t c e ll s a r e c h r o ni c a ll y s ti m u l a te d b y r ec e pt o r a g on is t s . D o wn - r e gu la t io n o f re c ep t o rs i s a p ro t ec ti v e m e c h a ni s m t ha t c an p re v e n t t he ta r g e t c e l ls f r om be i ng o ve r s ti m u l at e d. 6 . T he an sw e r is C [ s ee V I . C ] . Th e m a rg i n o f s a f e t y o f th e t wo d ru gs ca n b e h e lp f u l i n g ui di n g s e l ec ti o n o f a d r ug . Ma r g i n o f s af e t y is th e ra t i o o f TD 0 . 1 t o E D 9 9 . 9 . Th u s t he m a r gi n o f s a fe t y f o r d ru g A i s 2 0 m g ÷ 0 .4 m g , o r 50, wh e r e as t he m a r gi n o f s a fe t y f o r d r ug B i s 1 5 m g ÷ 0 .2 m g , o r 7 5 . Be c a us e d r ug B h as a g re a te r m a r gi n o f s a f et y t h an dr u g A , dru g B i s r e l at i ve l y s a fe at t he do s a g e g i v e n t o p r od uc e t h e d es i r ed ef f ec t . 7 . T he an sw e r is C [ s ee I I . B .2 ; II I . D .4 ; II I . E .1 . a a n d b ] . A d r ug r ec ep t o r, s u c h as m us c a r in ic ch ol i ne r gi c re c ep t o r, wh i c h ca n b in d a t r o pi ne , n o r m a ll y b in ds en d og e nou s a c e t yl c h o li ne to p ro du c e t he ph ys i ol og ic a l r es p o ns es c o nt r o ll ed b y th e p a r as ym p at h et ic au t on o m i c n ervo u s s y s t em . V o la t il e a ne s th e ti cs a c t c ol li g at i v e l y a s s ol u te s i n th e l ip i d b il a ye r o f t h e c el l m em b ra n e. D r ug r e c e p to r s a r e en do g en o us l y e xp r e s s e d , b u t t he i r l e vel c a n b e m o du l at e d b y e xo g e no u sl y a d d ed dr u gs . Th e c a t ha rt i c a c t i v i t y o f m a gn es i um c i tr a te is a c o ns e qu e nc e o f i n c re as e i n t h e os m o l a ri ty o f t he ga s tr o in t es ti n al f l u id s . D o wn - r e gu la t io n of r ec e pt o r l e ve l c an le a d t o d es en s it i z a t io n , n o t se ns i ti z a t ion , o f t he ta r g et c e ll to t he r ec e pt o r a g o ni st . 8 . T he an sw e r is E [ s e e I V . D . 1 a nd 2] . Th e e f fi c ac y o f a d r ug is d e t e rm in ed b y it s E m a x , wh e r e a s i ts po t en c y is m e a su r ed b y t h e E D 5 0 . H y d ro m o r p ho ne h as a sm al le r E D 5 0 a nd t hu s i s a m o re po t en t an a lg e s i c t h a n m o r p hi ne . H y d r om or p h on e a n d m o r p hi ne a re b ot h a g on is ts f o r o pi a te
r e c ep t or s , a nd th e y h a v e t h e s am e a na lg e s i c e ff ic a c y ( i. e . , t he y h a v e t h e sa m e E m a x ) i f s u ff ic i en t a m o u n ts o f b ot h d r u gs a r e u se d. 9 . T he an sw e r is E [ s e e I I I . D .6 ] . A c h ro ni c l e v e l o f b lo c k in g th e β -a d r en e rg ic r ec ep t o rs b y pr o p ra no l ol r esu l ts in up r e g ul a ti o n o f t h e r ec ep t or l e v el . W he n t he pa t ie n t c ea se d ta ki n g t he d ru g , t h e c a r di ac m us c l es be c am e s up e rs e ns it i v e to s t im ula t i on wi t h e n do g en ou s c a te ch o la m i n es . Thi s re s u l t ed in th e h yp e r te ns i v e c r is is th a t c a us e d c er e br a l h e m o r r ha g e a nd lo s s o f c o ns c i ou sn es s . P.279
1 0 . Th e a n sw e r i s C [ s ee I I I. A . 1] . R i t u xi m a b is a m on oc l ona l an t ib od y t h at sp ec i fi c a l l y bi nd s t o C D 20 an t ige n on m a li gn a nt an d no rm a l B ly m p h oc y t es , l e ad i ng to th e i r d es t ru c ti on . 1 1 . Th e a n sw e r i s B [ s ee X. A . 3 . b .( 1 ) ]. P r o t am in e i s a c h em ic al a n t ag o ni st of he p a ri n t ha t ac ts vi a a n a ci d -b as e i n t er a c t i on . 1 2 . Th e a n sw e r i s D [ s ee I I I. C ] . A TR A b i n ds t o r e ti no ic ac i d r ec e pt o r o n t h e c e l l m em b r an e , l ea di n g t o e xp r e ss io n o f t a r g et ge n es a n d r es u lt in g in di f fe r e nt ia t io n o f leu k em ic p r om ye l oc y t es . 1 3 . Th e a n sw e r i s A [ s ee I I I. B . 3] . E r l o ti n ib bi nd s t o th e A TP p oc k e t of th e t y r os in e k i na se of t he E G F re ce p to r a nd t h us in h ib i ts t y ro s i n e k i na s e ac t i v i t y. 1 4 . Th e a n sw e r i s D [ s ee I I . B. 4 .a , II I . E .] . Ta m o xi f e n an d i t s m e t abo l i te s b in d t o e s tr o ge n re c ep t o rs , a nd p re ve n t t he m fr om b i nd i ng es t ra d io l . Th i s r es u lt s i n s up p re ss io n o f es t r og e n- d ep e nd e nt g ro wt h i n b r e as t c an c e r c e ll s . Th e p h a rm ac ol o gi ca l e f fe c ts o f t he ot h er d ru gs a re not m e di a te d b y r ec e pt o rs . 1 5 . Th e a n sw e r i s E [s ee V I I I. B . 3. d ] . Th e s ol u ti o n m u s t c o n ta in a n ac i di c s u b st a nc e t o h a ve a p H < 7 . A t r op i ne s u lf a te is a sa l t o f a we a k b as e a nd a s t ro n g a ci d ; t he r e fo re , it s a q ue ou s s ol u ti on is ac id ic . S o d iu m s al ic y l a te an d po t as s i um pe n ic il li n a r e bo t h s al t s o f s t ro ng ba s es a n d we a k a c id s; t he r ef o r e, t he i r a qu e o us s ol u ti o ns a r e a lk al i n e . Ma g n e s i um s u lf a te a n d p o t ass i um c hl o r id e a r e s a l ts o f s t r o ng ba s e s a nd s t r on g a c i ds ; th e re f o re , th e i r a q u eo us s o lu t io ns a re ne u t r al . 1 6 . Th e a n sw e r i s E [s ee Ta b l e 1 2 -1 ; F i gu r es 12- 8 , 12 - 9 , a nd 12 - 11 ] . 4 - Q u i no lo n es ar e a m p h ot e r ic c om p ou n ds . Al l c om p ou n d s i n t h is c h em ic al c l as s c o nt a in a c a r b o xy l i c a c i d a s we ll as a b as ic n i t ro g e n . Mo s t 4 - q ui no l on es c o n t ai n a b a si c p ip e ra z i n e r i ng and b as ic h e te r oc y c li c r i ngs ; ho we ve r , s o m e o f t he o l de r c om p ou n ds i n th is c l as s o n l y ha v e th e b a s i c h et er o c yc l ic r in gs . Al l o t he r c o m po u nd s a r e c o r re c tl y m a t c h ed wi t h t he i r ac i d -b as e n a tu r e. 1 7 . Th e a n sw e r i s B [ s ee V I I . A a nd B ]. D i a ze p am i s a be n z od i a ze p in e a n xi o l y t i c , wh i c h —a l t h o ug h i t is a he t e ro c yc l ic n i t ro g en - c o n ta i ni ng m o lec u le — is no t a n a lk a lo id a n d i s p r ep a re d s yn t he t ic a ll y . N a t u r al pr o du c ts re f e r t o s ub s ta nc es bi os yn t he siz e d i n p la n ts o r an im a ls . N a t u ra l p r o du c ts i nc l ud e a lk al o ids , s uc h a s a t r op in e a n d m o r ph in e ; p ep t id es , s uc h as
g l uc a go n ; s t e r oi ds , s uc h a s e s t r a di ol ; h o rm o ne s, s uc h a s i ns u li n; gl y c os i de s , s uc h a s d i gi t o xi n ; v i ta m i ns , s uc h a s ri bo f la v i n ; p ol ys ac c h a ri de s , s u ch as he p ar in ; an d a n t ib io t ic s , s u c h as p e nic i ll in . 1 8 . Th e a n sw e r i s B [ s ee I X. B ] . Th e b i nd in g o f a d r ug to i t s r ec e pt o r u s u a ll y i n v ol ve s on l y s p ec i fi c f un c ti on a l g r o up s . Th e s e g ro u ps m a k e u p wh a t is k n o wn as t h e p ha r m a c o p ho r e o f th e d ru g m o le cu l e. A lt h ou gh t he en t i re d ru g m ol ec u le is p re s en t a t th e re ce p to r s i te , on l y a p o r ti o n o f i t , t h e p ha rm ac o ph o re , is re q ui r ed fo r a b io lo g ic al r es po ns e . 1 9 . Th e a n sw e r i s A [ s ee I X. B . 3 . a; Fi g u re 12 - 12 ]. Th e t e rm en a nt i o m e r a nd t he D an d L in di c at e t ha t t he β -m e th ac h ol in e h as a c hi r al c e nt e r a n d e xh i b i ts o p ti c a l is om e ri s m . B ec a us e th e op t ic al is om e rs h a ve d i f fe r e nt o r i en t a ti on s i n s pa c e , o ne o ri e n ta ti o n wi ll gi v e a b e t te r fi t th a n t he ot h e r a n d wi ll m os t li k e l y ha v e g re a te r b i ol o gi ca l a ct i v i t y th a n th e ot h e r. D is so lu t io n , d is t r ib u ti o n, i n t er a t om i c d is t an c e s , an d s o lu bi l it y a r e a ll r el a te d to t he ph y s ic al an d c h e m i c a l p r o pe r t ie s o f t h e t wo c om p ou n ds , wh i c h a r e i de nt i c a l b ec a us e t he c o m p ou n ds a re e n a nt io m er s . 2 0 . Th e a n sw e r i s B [ s ee Ta b l e 1 2 -1 ; F i gu r es 12- 7 , 12 - 8 , 1 2- 9 an d 1 2 -1 0] . K e y s t ru c tu r al f ea t ur es of a th ia z i d e —a be n z o th i ad i a z in e ri n g wi t h an el ec t r o n wi t h d r a wi n g c h lo r id e a t om an d a su l fo n yl g r ou p on t he be n z e ne r in g —i d ent i f y t hi s c om p ou n d as a t h ia z i de . P.280
2 1 . Th e a n sw e r i s A [ s ee V I I I. B . 2. b ] . Th e p K a (t h e n eg a ti v e log o f t h e ac i d i on i z a ti on c o n st a nt ) in d ic at es t he re la t i ve s t r en g th of a n ac i di c d rug . Th e l o we r t he p K a o f an ac i di c d r ug , t h e s t ro nge r i t is as a n ac id . A s t ro ng ac id is d e f in ed as on e t h at is c om p le t el y i on i z ed o r d is s oc i at e d i n a n aq u eo us s o lu t io n ; t her e f o re , th e s t ro n ge r th e a c id , th e g r ea t e r t he io n iz a t i o n. 2 2 . Th e a n sw e r i s D [ s ee Ta b l e 1 2 -1 ; F i gu r e 1 2 -8 ] . Th e c a rb o xy l i c ac id id e nti f i es t h is c om p ou nd as an ac i d. O t he r st r uc t ur a l fe a t u re s i d en t i f y i t a s a fe n am at e . F e na m a t es a re N S A I Ds t h a t c an be us ed fo r in f la m m a to r y d i so r de r s ( e .g . , a r t hr i ti s , b u rs i ti s ). Th e m ec h an is m o f ac t io n o f N S A I Ds i s i n hi bi t io n o f c yc l oo xy g e n a s e, wh i c h r es u lt s i n a d e c r e as e in t he p ro d uc ti o n o f p r os ta g la n di ns . 2 3 . Th e a n sw e r i s C [ s ee Ta b l e 1 2 -1 ] . F i b ra t es de c re as e c ho l es t e ro l a n d t r ig l y c e r id e l ev e l s . Al l o f t h e o th e r c hem ic a l c l as s e s c a n b e u s e d to tr e a t h y p e r te ns i on . A r y loxy p r o p a n ol am in es a re β -b l oc k e r s , t h i a zid es a re di u re t ic s , di h y d r op y r i d in es ar e c a lc i u m c ha n ne l b l oc k e rs , a nd A C E i n hi b it o rs de c re as e t h e s y n t h es is o f a ng io t e ns in II , a p o te n t v a s oc on st r ic to r . 2 4 . Th e a n sw e r i s E [s ee V I I I. B . 2. f an d g ; Ta bl e 1 2 - 1 ]. F l u ra ze p am ( ta k e no t e of t h e s u f fi x, wh i c h h el ps c l as s i f y th e c om po u nd ) is a b e n zo di a z ep i ne an d t h us a ba s i c c om po u nd . Be c a u se th e p H is le s s th a n t h e p K a , f l u ra ze p am is i n a n a c i d ic en v i r o nm en t a n d, t he r ef o r e , e xi s t s p r im ar i l y i n th e io ni ze d f o r m . Th e pe r c e n t i on i z ed c a n b e e a si l y c al c ul a ted b y us in g th e ru le o f ni ne s . Th e | p H - p K a | is 3 , s o t h e r at i o i s 9 9. 9 %: 0 . 01 % i n f a vo r o f t he io n i z ed fo r m . 2 5 . Th e a n sw e r i s D ( I I , I I I ) [s ee V I II . A .1 an d 2 ] .
G e n e r al l y , d r u gs m us t be l ip op h il ic to pa s s th r o ug h li po p r ot e in m em b r an es an d h yd r o ph i li c t o b e e xc r e t ed b y t he k i dn e y . D ru gs do n ot ha v e t o b e c o n v e r te d in t o a n a c ti ve f or m a t th ei r ac ti v e s i t e , al t h ou gh m o s t d rug s m us t b e i n th ei r ac ti ve f o rm wh e n t h e y re a c h th ei r ac t i v e s i t e. Ma n y d r u gs a r e a c ti ve in th e f o rm in wh ic h th e y a r e ad m i ni s te r ed . So m e d r u gs , u s u a ll y r e fe r r ed to as p ro d r ug s , a re bi o tr an s fo r m e d i n t o t he i r a c t i v e fo rm a fte r a dm in is t ra t io n . Th eo re t ic a ll y , d ru gs th a t re ac h t h ei r a c ti ve si t e a nd th e n a r e m e ta b ol ic al l y ac t i v at e d sh o ul d b e m o re s p ec i fi c in t he i r a c ti o n a nd ha v e f e we r s id e ef f ec ts . C u rr e nt l y , re se a r c h ef f o rt s a r e u nd e r wa y t o d e ve l op s i te - s p ec i fi c d el iv e r y s y s t em s a nd p ro ce s s es . 2 6 . Th e a n sw e r i s D ( I I , I I I ) [s ee V I II . B .2 . c ; V I II . B. 3 . a ; V I II . B . 4. a ]. A l m os t a ll s a lt s ( wi t h v e ry f e w e xc e p t i o ns ) a r e s t ro n g e le c t ro l y t es , a nd t he t e r m i n ol og y p en t ob a r bi t al s o d iu m a nd di p he nh y d ra m i n e h y d r oc hl o r id e i nd ic a te t ha t e a ch c o m p ou n d is s a l t. A c e ti c a ci d i s a we ak ac id ; t he r ef o r e, it is a we a k e l ec t r ol y t e . 2 7 . Th e a n sw e r i s A ( I ) [ s ee V I II . B .3 a nd 4] . W hen m e p e ri di n e h y d r oc h l o ri d e so l ut i on is m i xe d wi t h t h e a lk al in e s ol u ti on o f s o di um bi c a r bo n at e , a ne u t r al i z a ti on r ea ct i on oc c u rs wi t h th e p os si b le p re c ip i ta t io n o f t he wa t e r -i ns o lu bl e f re e ba s e m e pe r id i ne . A ne u t r al i za ti on r ea c t i on oc c u rs wh e n a c id ic s o lu t io ns a re m i xe d wi t h ba s i c s ol u ti on s , o r c on v e r se l y. N o r e ac ti o n, i n t e rm s o f ac id - b as e, oc c u r s wh e n s o l ut i on s a r e m i xe d wi t h o th e r a ci d ic o r ne u t ra l s o lu t io ns o r wh e n ba s i c s ol ut i on s a r e m i xe d wi t h o th e r b as i c o r ne u t ra l s ol u ti on s . Th e r e s h ou l d b e n o r ea c ti on , the n , wh e n t h e m e p er i di n e h y d r oc h lo r id e s ol u ti o n, wh i c h is a c id ic , i s m i xe d wi t h th e a c id ic s o lu t io n o f a t r op i ne s u l fa t e o r th e n e ut r al s o l u ti on o f s o di um c h lo r id e . 2 8 . Th e a n sw e r i s C ( I , II ) [ s e e I X. B . 3 . d ; X. C . 1 ; X. E . 1 ] . B o t h s ul f is o xa z o l e a n d 5- f l uo r o u ra c i l c om pe t e wi t h a nd an t ag o ni z e is os te ri c n o rm a l b i ol o gi c a l m ol ec u le s a nd t h us ar e a n ti m e t a bo li t es. D i go xi n i s a dr u g t h at is t ho ug h t +
+
t o in h ib i t N a / K - A TP a s e o r to a ff ec t i n t ra c e l lu la r i n f lu x o r u s e of c a lc iu m io n ( C a
++
).
B e c au se di g o xi n is s te r oi d al , it is n o t i s o st e ri c wit h ei t he r an en zy m e , wh ic h i s a p r o t ei n , o r a n i on ; th e re fo r e , i t i s n o t c l as s i f ie d as an an t im e ta bo l it e . 2 9 . Th e a n sw e r i s A ( I ) [ s ee V I II . B .1 ; V II I . B .2 . e] . A we a k l y ac id ic d ru g wi l l b e m o re io n i z ed in an alk a li ne u ri n e; t he r ef o r e, it wi l l b e m o r e p ol a r a nd th u s m o re s o l ub le in t he aq u eo us u r i n e . I t wo u ld al s o b e le ss l i po so l ub l e, le s s l ik e l y to u n de r go t ub ul a r re ab s orp t i on , a n d t hu s b e m o re li k el y t o b e e xc r e te d . 3 0 . Th e a n sw e r i s C ( I , II ) [ s e e VI I I . B. 2 a n d 3 ; F ig u r e 1 2 -7 ] . 3 1 . Th e a n sw e r i s B ( I I I) [ s e e V II I . B .2 an d 3 ; F i gu r e 12 - 7] . P.281
3 2 . Th e a n sw e r i s A ( l ) [s e e V I I I. B . 2 a nd 3 ; F ig u re 1 2 -7 ] . 3 3 . Th e a n sw e r i s B ( I I I) [ s e e V II I . B .2 an d 3 ; F i gu r e 12 - 7] . Th e m ol ec u le c o nt a in s a b as ic ni t r og e n, wh i ch is b o n de d t o t h r ee c a r bo n a t om s ( i . e ., a t e r ti a r y a m i n e ), an d an et h y l c a rb o xyl a t e , wh i c h is a n es te r gr o up . A n es t e r i s th e p r od uc t of th e re ac t io n o f an al co ho l wi t h a c a r b o xy l i c a c i d th a t f o rm s a n a lk y l
c a r bo xy l a t e . Th e r e is no f r e e c a rb o xy l i c ac id p re s e n t . Ho we v e r , i f t hi s m ole c ul e i s s u bj ec t ed to h y d ro l y s i s , it f o rm s a c a rb o xyl i c ac id a n d e th y l al co h ol . B e c au se m e pe r id i ne c o nt a i ns a t er t ia r y a m i ne , i t i s c la ss i fi ed as a b as e; be c au s e it i s a n o r g an ic ba s e , i t i s c o ns id e re d we a k . Th e nit r o g en is n o t p r ot o na t ed . I t is n o t i o ni c a nd , th e r ef o re , is no t a s al t . A l k al in i za ti o n o f t h e u ri ne d ec r ea se s t he io n i z at io n of m e pe r i di ne , m ak i ng i t m or e l i po so l ub l e a nd th us m o re l ik el y t o u nd e r go re a bs o r p ti o n i n t h e ki d ne y t ubu l e . Th i s r e s ul ts in a d ec r ea s e d rat e o f e xc r e t io n a n d a n i nc r e as ed du r a ti on o f ac t ion . Th e s i x- m e m b e r , n on a ro m a t ic r in g i s a p i pe r id i ne ri ng t ha t i s s ub s ti t ut e d a t th e 4 p o si t io n (n it r o ge n i s p os it i o n 1 ) wi t h a p h en y l r in g. Th e co m p o un d d o es n ot c on t ai n a p ip e ra z i n e r i ng or a p ro p y l g ro up . 3 4 . Th e a n sw e r i s C [ s ee I X. B . 3 . a. 4 ; F ig u r e 1 2- 13 ] . Th e s e m ol ec u le s a r e is om e rs th a t h a v e t wo a s y m m e t ri c c a r b on at om s . Th e y a r e n o t s u pe r im po s ab le an d a r e n o t m i r ro r i m a g es ; t h e re fo r e , t h e y a r e k no wn a s d i as t e re om e rs . 3 5 . Th e a n sw e r i s B [ s ee I X. B . 3 . a. 1 ; F ig u r e 1 2- 12 ] . Th e s e m ol ec u le s a r e is om e rs th a t h a v e o n e as ym m e t r ic c a rb o n a to m . Th e y a r e n o ns u pe r im po s a b le m i r ro r im a ge s ; th e r ef o r e, th ey a r e en a nt i om e rs . 3 6 . Th e a n sw e r i s A [ s ee I X. B . 3 . b; Fi g u re 12 - 14 ]. Th e s e m ol ec u le s h a v e d if f e r en t s pa t ia l a r r an g em e n ts ; ho we v e r , t he se m ol e c u le s d o n o t h a ve a n a s y m m e tr ic c e nt e r . Th e p re s e nc e of t h e d o ub l e b on d , wh i c h re s t ri c t s t h e ro t at i on of t he gr o ups on ea c h c a r bo n a t om in vo l ve d i n t h e d ou b le bon d , c h a ra c t e ri z e s t h is t y pe of i s o m e r ism as ge om e t ric . 3 7 . Th e a n sw e r i s D [ s ee I X. B . 3 . d; Fi g u re 12 - 16 ]. Th e s e m ol ec u le s a r e n eit h e r i s o m e r s n o r t he sa m e c o m p o un d b ec a us e o ne c o n ta i ns t h r e e o xy g e n s , wh e re a s t h e o t he r c o n ta in s t wo ox yg e n s an d a s u lf u r . B ec a u se o xyg e n a n d s ul f u r a r e i n t h e s am e p e ri o di c f am il y , t h e y a r e i so s t e r ic a n d ar e k n o wn a s b i oi so s t e r es . 3 8 . Th e a n sw e r i s E [s ee I X. B . 3 .c ; Fi gu r e 1 2 - 15 ]. Th e s e s t r uc tu r es a re ac tu a ll y t wo v i e ws o f th e s am e c om po u nd . R ot a ti o n a r o un d th e s i de c h ai n s in g le bo nd s c o nn ec t in g t h e r i ng ni t rog e n t o th e t e r ti a r y ni t ro ge n p r o du c e s t h es e t wo d i ff er e n t c on f o rm at i on s. Th u s t h es e a r e c on f or m a t io n al is om e rs .
13 Medicinal Chemistry and Pharmacology: Drugs Affecting the Nervous System H a b i b a O . U . Vo n g ta u As h iw e l S. U n di e h
INTRODUCTION. D r u g s a f fe c t i ng th e n e r vo u s s y s t em m o d ul at e neu r o t ra ns m i s s i on i n th e ce n t r a l n e r vo u s s ys t e m ( C N S ) , wh i c h co ns is ts o f t he b rai n an d t h e s p i na l c o rd , or i n t h e p e r i p he r a l n e r vo u s s ys t e m ( P N S ), wh i c h in c l u de s th e a u t on o mi c ne r vo u s s ys t e m ( AN S ) a n d t he s o m a ti c s y s t e m t ha t i n ne r v a t es the s k el e ta l m us cl es . Th e A N S , i n t u r n , c o n s i s t s o f s y m p a th e t ic (o r ad r en e r gi c ) an d p a r as ym p a th e ti c ( o r c hol i ne r g ic ) b r a nc he s . A g en ts ac t in g i n th e A N S i nc lu d e a dr e ne r g ic ag on is t s a nd an t ago n is ts , c h ol in e r gi c a go ni s ts a n d a n t ag o ni s t s , an d i n di r ec tl y a c ti ng ag e nt s t h at c o ul d af f ec t o n e o r bo t h A N S s y s t em s . D r ug s a ff e c t i ng th e PN S a r e u se f ul fo r t re a ti ng a v a ri e t y o f ai lm e nt s i nc lu d in g b loo d p re s s u re di st u rb a nc es , br o nc hi a l as t hm a , ca rd i ac d ys f un c ti o ns , a na p h y la c ti c re ac t io ns , n a sa l c on ges t io n , a nd s k el e ta l m usc le s p as ti ci t y . D r ug s a f fe c t i ng t he C N S p ro v i de an e sth e si a a n d s e d at i on , re li ev e p a in a n d a n xi e t y , s u p pr es s m o v e m en t d is o r de r s a nd ep i le p ti c s ei zu r es , a n d t r ea t p s yc ho ti c a n d a ff e c t i v e di s o rd e rs . Th es e d r ug s i nc l ud e g e ne r al an d l oc a l a n es t he t ic s , an xi o l y t i c s a n d s ed a ti ve - h y p no t ics , o p io i d a na l ge s i c s , a n ti par k i ns on ia n a g e nt s, an t ie p il e pt ic s , an t i ps y c h o ti cs , a n d a nt i dep r e s s an ts .
I. GENERAL MECHANISMS OF DRUG ACTION IN THE NERVOUS SYSTEM. D r u g s ac t in g i n th e n e r vo u s s y s t em ac h ie v e th e ir p h a rm ac ol og ic e ff ec t s by m o di f yi ng th e s y n a pt ic c o n c e n t ra t io ns o r r ec ep t or a c t i on s o f n e ur o t ra ns m it t e rs . O t h e r dr u gs m o du la t e t he i nt r ac e ll ul a r r e s p on s e p a t h wa y s b y wh ic h th e re c ep t o r a c ti o ns o f th e tr a ns m i t ter s a re c o n v e yed t o y i e ld t h e u l ti m a t e p h ys i ol o gi cal r e s po ns e . Th e m a jo r ne ur o t r an s m i tt e rs in th e n e rvo u s s y s t em , t he i r p r im ar y r e c ep t o r s u bt yp e s , an d t h e p r ed om i na n t e f fe c t s o f re ce p tor s ti m u l at i on on ne u ro t r an sm is s i o n a r e s h o wn in Ta b le 13 - 1 . S o m e ge n e ra l m ec ha ni s m s b y wh i c h d i v e rs e d r ug s m o du l at e t h e ac t i v i t y o f th e ne r v o us s y s t em a r e s u m m a r i z ed in Ta b le 13 - 2, wi t h e xa m p l es d ra wn f r om t he a d re ne r g ic a n d c h o li ner g i c co m p o ne n ts o f th e PN S . I n a d di t io n , t h e re ar e v a ri ou s c la s s es of d ru gs t ha t m o du l at e n e ur a l f un c ti on b y i n t er a ct i ng wi t h t h e p o res o f i on c h an ne ls o r b y bi n di n g t o a ll os t e ri c s i t es o n th e p r o t ei n s ub un i ts th a t c ons t i tu t e t he c h an n el .
II. ADRENERGIC AGONISTS A. C h e m i s t r y 1 . D i r ec t - ac t i n g a d re n er g i c ag o n is t s i nt e r ac t d ir e c tl y wi t h a dr e ne r gi c r ec e pt o rs t o e l ic i t a re s p o ns e. Th e s e a g o ni s t s i nc lu d e n or e pi ne p h ri n e a nd ep i ne ph r i ne , wh i c h a r e e n d og en o us o r na t u ra ll y o c c u r ri n g c at ec h ol am in es . Th e c at e c h ol am i ne s ar e b i os yn t he s i z e d fr om t y r os i ne , a n a m i n o ac i d ( F igu r e 13 - 1 ). E xa m p le s o f ot h e r d i re c ta c ti n g a d re ne r g ic a g on is t s in c l ud e n a ph a z o li ne , te r b u ta li n e, an d d o bu t am in e ( Fi gu r e
1 3 - 2 ). Th e c l as s i fi c a t io n o f ad r e ne r gi c a go n is ts an d an t ag o ni s t s s ho wn i n Ta b l e 13 3 s h o ul d p r o v id e a b ro a d p e rs p ec ti ve on t he v a ri et y o f ag e nt s t h at ac t o n th i s s ys t em to pr o du c e t he i r p h a rm ac ol o gi c a nd t he r ap e u ti c e f fe ct s . a . Th e et h y l am in e c ha in c om m o n to th es e a g on is ts is es s e nt i al to t he i r a d re n e rg ic a c ti vi t y. b . N - su bs t it u ti o n a lt e rs dr u g ac ti vi t y . Sm a ll s u bs tit u e nt s ( e .g . , h y d r o ge n , α - m e th y l g r o up ) p ro du c e α - r ec e pto r ac t i v it y , as wi t h no r epi n ep h r in e ; l ar g e r s u bs t i tu e n ts (e . g. , i s op r op y l g ro u p) p ro d uc e β - r e c e p to r ac ti vi t y , as wi t h i s o p r ot e re n ol . c . R em o v al of t he pa r a (4 ) h y d ro xy l g r o u p l e a ves o n l y α - re c ep t or ac t i vit y , a s wi t h p h e n yle ph r i ne . P.283
Table 13-1. Major Neurotransmitters in the Nervous System, Their Major Postsynaptic Receptors, and Receptor Effects on Ionic Conductance and Second Messenger (Signaling) Pathways Primary Receptor Neurotransmitter Subtypes Acetylcholine
Dopamine
GABA
Effects of Receptor Stimulation
Muscarinic M1 (and M3 , M5 )
Excitatory (↑IP3/DAG)
Muscarinic M2 (and M4 )
Inhibitory (↓cAMP)
Nicotinic (N1 and N2)
Excitatory (↑cation conductance)
D1 (and D5)
Excitatory (↑cAMP; ↑IP3/DAG)
D2 (and D3, D4)
Inhibitory (↓cAMP; ↑K+ conductance)
GABAA
Inhibitory (↑Cl- ion conductance)
GABAB
Mixed (cAMP modulation; ↓Ca2+; ↑K+ fluxes)
Glutamate
Histamine
Norepinephrine
Serotonin (5HT)
Opioid peptides
Ionotropic-NMDA
Excitatory (↑Ca2+ ion conductance)
IonotropicAMPA/Kainate
Excitatory (↑cation conductance)
Metabotropic
Excitatory (↑IP3/DAG; modulate cAMP)
H1
Excitatory (↑IP3/DAG)
H2
Excitatory (↑cAMP)
α1
Excitatory (↑IP3/DAG)
α2
Inhibitory (↓cAMP)
β1
Excitatory (↑cAMP)
β2
Inhibitory in ANS (↑cAMP)
β3
Excitatory (↑cAMP)
5HT1
Inhibitory (↓cAMP)
5HT2
Excitatory (↑IP3/DAG)
5HT(3/4/5/6/7)
Mixed (type 4,6,7 ↑cAMP)
Mu (µ)
Mixed (↓cAMP; Ca2+ & K+ channel effects)
Delta (δ)
Mixed (↓cAMP; Ca2+ & K+ channel effects)
Mixed (↓cAMP; Ca2+ & K+ channel effects)
Kappa (κ)
Table 13-2. Some General Mechanisms of Drug Action in the Nervous System Exemplified by the Adrenergic and Cholinergic Neurotransmitter Systems Mechanism
Adrenergic System
Cholinergic System
1.
Ganglionic stimulation
Nicotine
2.
Ganglionic blockade
Hexamethonium, trimethaphan
3.
Inhibition of neurotransmitter synthesis
Metyrosine, carbidopa
Hemicholinium
4.
Inhibition of neurotransmitter release
Bretylium, guanethidine
Botulinum toxin
5.
Facilitation of neurotransmitter release
Amphetamine, tyramine
α-Iatrotoxin
6.
Depletion of vesicular transmitter storage
Reserpine
Vesamicol
7.
Blockade of
Cocaine,
See notea
8.
neurotransmitter reuptake
desipramine
Inhibition of neurotransmitter metabolism
Clorgyline (inhibits MAO-A)b
Neostigmine and other AChE inhibitors
Selegiline (inhibits MAO-B) Tolcapone (inhibits COMT) 9.
Direct interaction with postsynaptic receptors
Adrenoceptor agonists
Cholinergic agonists
Adrenoceptor antagonists
Cholinergic antagonists
a
Reuptake is not a major mechanism for termination of acetylcholine's action; most of the released transmitter is metabolized by acetylcholinesterase (AChE). b
COMT (catechol-O-methyl transferase); MAO-A, MAO-B (monoamine oxidase-A, -B). P.284
Figure 13-1. Synthesis of catecholamines from the amino acid tyrosine. In the presence of tyrosine hydroxylase, (A) tyrosine is converted to (B) dihydroxyphenylalanine (dopa). Further substitutions permit the synthesis of (C) dopamine, (D) norepinephrine, and (E) epinephrine.
Figure 13-2. Structural formulas of representative direct-acting sympathomimetic amines. (A) Naphazoline, (B) terbutaline, (C) dobutamine.
P.285
Table 13-3. Classification of Adrenoceptor Agonists and Antagonists*
Class A.
Nonselective
A.1
Indirect-acting
Adrenoceptor Agonist Adrenoceptor Antagonist
Tyramine Ephedrine Amphetamine Cocaine
A.2
Direct-acting
Norepinephrine
Labetalol
Epinephrine
Carvedilol
B.
α-Receptor-Selective
B.1
Nonselective α
Oxymetazoline
Phenoxybenzamine
Xylometazoline
B.2
Selective α1
Tetrahydrozoline
Phentolamine
Phenylephrine
Prazosin
Methoxamine
Terazosin
Metaraminol
Doxazosin Indoramin
B.3
Selective α2
Clonidine
Rauwolscine
Guanabenz
Yohimbine
Guanfacine
Tolazoline
Rilmenidine Moxonidine α-Methyldopa C.
β-Receptor-Selective
C.1
Nonselective β
Isoproterenol
Propranolol Nadolol Pindolol Carteolol Timolol Sotalol Penbutolol
C.2
Selective β1
Xamoterol
Acebutolol Atenolol Betaxolol Celiprolol Esmolol
Metoprolol C.3
Selective β2
Metaproterenol
Butoxamine
Fenoterol Terbutaline Albuterol (Salbutamol) Ritodrine Salmeterol Formoterol Pirbuterol Bitolterol C.4
Selective β3
BRL37344; CL316243
*
To describe the classification of a particular drug, the receptor selectivity class on the left is combined with the receptor activity descriptor on the top of the column; for example, tyramine is an indirect-acting adrenoceptor agonist, and tolazoline is a selective α2-adrenoceptor antagonist. P.286
d . Th e m e ta ( 3 ) h y d r o xy l g r o up is e s s en t ia l f o r d ir e c t α - a nd β - ac ti v i t y. H owe ve r , d r u gs in wh i c h th e m e ta h y d r o xy l i s r ep l ac ed b y a m e th o xy g r o u p ( e .g . , m e th o xa m i ne ) r et ai n α - ac t i v i t y . e . C a te c h o la m i ne s a r e i na c ti v a t ed b y m e th yl a ti o n o f t he m e ta h y d ro xy l g r o u p ( c a ta l yz e d b y c at ec h ol O- m e th y l t r an s f e r as e [ C O M T] ) a n d b y o xi d a t i v e d e am i na t io n ( c a ta l yz e d b y m on o am i ne o xi d a s e [ MA O ] ) .
2 . I nd i r ec t - a ct i n g a d r ene r g i c a g on i s ts a re c h em ic a ll y r el a te d to th e c a te ch o la m i n es , b u t t he y d o n o t s ig ni f ic an t l y in t era c t d i re c t l y wi t h ad r en e rg i c r e c ep t or s . Th e s e m o s t l y s y n t he t ic c om p ou n ds i n du c e t he i r p h ar m ac ol og ic a l ef f ec ts b y e n ha nc i ng th e re le a s e o f t h e e nd og e no us ne ur o t r a n sm i tt e rs . Ph y s io l ogi c al l y , t h e r ef o re , th e y ha v e e ff ec t s s i m i l ar t o t he ca t ec ho l am in e n e u ro t r an sm it t e rs , he nc e t h e ir ni c k n am e o f s y m p at h om im e ti c a m i ne s . E xa m p le s i nc lu d e am p he t am i n e , e p h ed r in e , p he n y l ep h ri ne , an d t y ra m i n e ( F ig u re 1 3 - 3 ). a . I nd i re c t - ac t in g s y m pa th o m i m e t ic a m i n es m a y ha v e t wo , o ne , o r no h yd ro xy l g r o up s . Th e fe we r t h e h y d r o xy l g r o u ps , t h e h ig h er t h e l ip o ph il ic i t y , a n d t he g r e at e r t h e a bs o r pt i on an d t h e du r a ti o n o f a ct i vi t y af t e r or a l a d m i ni s t r a ti o n. Fa s ter a n d g r e a te r a b s o r pt i on al s o im p li es le ss i n te s ti na l d es t r uc ti o n o f t h e d r ug . b . A lk yl s u bs ti t u ti on a t th e α - c a r bo n (a d ja c e n t t o t h e a m i no g ro u p) r e ta r ds d e st r uc t io n o f ph en o l a nd p he n yl c om po u nd s a nd i nc r e as es l i po ph i li c c h a ra c te r , c o nt r i bu t in g t o p r ol o ng ed ac t i v i t y. c . N -s u bs ti t ut i on wi t h bu lk y g r ou ps in c re as es di r ec t β - re c e p to r ac t i v it y , as wi t h t h e d i r ec t ac ti n g a ge n ts . B . P h a r ma c ol o g y 1 . Ad r e n e r g ic pe r i p he ra l r e sp o ns e s a r e m e d ia te d b y b o th α - an d β -a d r en o ce p to r s ( Ta b l e 1 3 - 4 ). A d re ne r g ic ( a n d o th e r A N S) r ec ep to r s m a y be lo ca t ed at the ce l l m em b r an es of ne r v e t erm i na ls ( pr e ju nc t io n al re c e p t o rs ) o r at th e m em b ran e s o f p o st j un c t i on a l c e ll s wh ic h r ec e i ve t he ne u r al i n put f r om th e n e r ve t e rm i na ls . P r e j un ct i on a l a nd po s t j un c ti o na l re c e p to r s a re als o c al l ed p re s y na p ti c a nd p o st s yn ap t ic re c e p to r s , re s pe c t i v e l y , wh e r e b ot h th e p re ju nc t io n al c e ll an d t h e p o st j un c t i on a l c e ll a re ne r v e c e l ls s ep a r at e d b y a s y na p ti c s pa c e . a . α - R ec e p to r s fa ll in t o t wo m a in g ro u ps . ( 1 ) P os t j u nc t i on a l α 1 - ad r e n e r gi c r ec e pt o r s a r e f o un d i n th e r a di al s m oot h m u s c le o f t he i r is ; i n th e a r t er i es , a r te r i ol es , a n d v e i ns ; in t he pi l om ot o r s m o ot h m us cl e o f h a i r f ol l ic le s ; in t he he a rt ; a nd i n th e s ph i nc te r s of t h e g as t ro in t es t in al ( G I) t r ac t . D r u g s t ha t ar e α 1 -s e le c ti ve a g o ni s t s c a us e e xc i t a t o r y r es po ns es s u ch as va s o co ns t ri c ti on an d s m o o t h m u s c le c o n t ra ct i on , a n d i nc lu d e p he n yle p h rin e an d m e th o xa m i ne . ( 2 ) P r e ju n c ti o na l α 2 -a d re n e r g ic r ec e p to r s m ed ia t e th e i nh i bi t io n o f a d ren e r gi c n e u ro t r an s m it t e r r e le as e. D r u gs th a t a r e α 2 - se l ect i ve a g o ni s ts al so in h ib it l ip o l ys is i n fa t c el l s a nd pr om o te p l a te le t ag g re g at i on . E xa m pl es of s u ch d ru gs in c l u de c l on id i ne an d g u an a be n z.
Figure 13-3. Chemical structures of some indirect-acting sympathomimetic amines. (A) Hydroxyamphetamine (Paredrine), (B) ephedrine or pseudoephedrine (Sudafed), (C) methamphetamine (Methedrine), (D) tyramine.
P.287
Table 13-4. Adrenoceptor-Mediated Responses to Adrenergic Agonists Organ/Tissue Heart
Receptor Type
Response
β1
Increases conduction velocity (dromotropic)
β1
Increases contraction force (inotropic)
β1
Increases contraction rate (chronotropic)
α1
Constricts cerebral arterioles
α1
Constricts cutaneous arterioles
α1
Constricts visceral arterioles
β2
Dilates skeletal muscle arterioles
Eye
α1
Contracts iris sphincter muscle, producing mydriasis
Lung
β2
Relaxes tracheal and bronchial muscles
Arterioles
Intestine
α, β
Decreases peristalsis
α1
Contracts sphincters
Urinary bladder
α1
Contracts trigone and sphincter muscles, inhibiting micturition
Uterus
β1
Relaxes detrusor muscle
α1
Excites uterine contractions
β2
Inhibits uterine contractions
β3
Causes adipolysis; mobilizes fatty acids
Adipose tissue
b . β - R ec e pt o r s f a ll in t o t h r e e m a i n g ro u ps . ( 1 ) P os t j u nc t i on a l β 1 -ad r e n e r gi c r ec e pt o r s a r e f o un d m ai n l y i n th e m y oc a r di um , wh e r e t h ei r s t im ul a ti on in c r ea s e s m y oc a ri d al c o nd u c t i on s p ee d (d r om o tr op i c e f fe c t ) a n d t h e f o rc e ( i no t r op ic e f f ec t ) a nd r a te (c h ro n otr o p ic ef f ec t ) o f m yo c a r dia l c o nt r ac t io n . D r u gs th a t ar e β 1 -s e le c t i ve a g on i s ts i nc l ud e xa m ot e r ol an d to s o m e e xt e n t d ob u ta m i n e. ( 2 ) P os t j u nc t i on a l β 2 -ad r e n e r gi c r ec e pt o r s a r e f o un d i n th e sm o ot h m us c l e o f th e va s c ul at u r e, b ro nc h io le s , a nd u te r us ; s ti m u l at i on o f t he se re c ep t or s c au s es s m oo t h m us c l e re l a xa t i on . D ru gs t h a t a re β 2 -s e le c ti ve a go n i s ts in cl u de al bu t e ro l a n d t e r b ut a li ne . ( 3 ) P os t j u nc t i on a l β 3 -ad r e n e r gi c r ec e pt o r s a r e e xp r e s se d o n fa t c el ls , a n d t h ei r s t im ul a ti o n c a us e s li p ol y s is . A n um b er o f β 3 - ag o ni s ts ar e u n de r de v e l op m e n t a s p o t en t ia l t r e at m e n ts fo r o b es i t y , n on - i ns ul in - d epe n d en t d i ab e te s m e l li tu s, a nd f r e q ue n t u ri n at i on . 2 . D i r ec t - ac t i n g a d re n er g i c ag o n is t s ( e .g . , n o re p in e ph r in e , p h en y l ep h r in e , c l on id i ne , te r bu t al i ne ) p ro d uc e t h ei r ef f ec ts p ri m a r i l y b y di r ec t s ti m u l at i on o f a d r en e r gi c r ec e pt o rs . The y m a y be r ec ep t o r- s e l ec t i v e , as wi t h th e d r ug s li s te d p r e vi ou s l y , o r t h e y m a y b e no ns e le c t i v e . F o r e xa m p le , th e a d re n er g ic n e u ro t r an s m it t e r n o re p ine p h ri n e a f fe c t s a ll ad r ene r g ic re c e p t or s , es p ec ia ll y α 1 - , α 2 - , a n d β 1 - r ec e pt o rs , wh e r ea s th e a d re n al m e du ll a r y h o rm o ne e p in e ph r in e a ff e c ts α 1 -, α 2 - , β 1 - , a n d β 2 - re c ep t ors . Is op r o te r en o l a f fe c t s b o t h β 1 - a n d β 2 - r ec ep t o rs bu t no t α r e c ep t or s . 3 . I nd i r ec t - a ct i n g a d r ene r g i c a g on i s ts wo r k th ro u g h o th e r p r im a r y m ec ha n is m s , wh i c h ul t im at e l y l e ad to r e c ep t or e ff ec t s . Fo r e xa m p le , t yra m i n e a c t s b y re l ea s i n g
n o r ep i ne p hr i ne f ro m s to ra g e s it es in ad r e ne r gi c ne u r on s , wh i l e c oc ai n e b lo ck s t h e r e u p ta ke of no r e pi ne p h rin e , th e re b y in c re as i ng the d u ra t io n a nd ac t i vit y o f t h e t r a ns m i t te r at t he s y n a ps e . 4 . C e r ta in ag o ni s t s ( e .g . , e p he d ri n e, m e t ar a m i no l , m ep h en t e rm in e ) p r od uc e t he i r e f f ec ts t hr o ug h b o th di r ec t an d i nd i r ec t m e c ha ni s m s . C . T h e ra p e ut i c i n d ic a tio n s 1 . E p in e ph r i n e, an α - an d β - ad r en e r gi c a go ni s t, i s i nd ic a te d to t re a t b ron c ho s p as m a n d h yp e rs e ns it i v i t y re ac t i o ns a n d is t he ag en t of c h oi c e fo r an a ph y l ac t ic re a c t i on s. I t is us ed to P.288 p r o lo n g t he ac t i v it y o f l oc a l a ne st h et ic s o lu t io n s a n d t o re s t o r e c a r d ia c ac t i v i t y in c a r di ac ar r es t . Ep in e ph r in e is a ls o u s e d to pi c al l y i n th e t r e at m e n t o f g l au c o m a, p r e su m a bl y d ec r ea s i n g in t r a oc ul a r p r es s u r e b y en h a n c in g t h e o ut f lo w o f a q u eo us h u m o r an d t h r ou gh v a s oc o ns t ri c ti on - in d uc ed de cr e a s e in pr o du c ti on o f aq u e ou s h u m o r . L oc a l a pp li c a t io n o f ep in e ph r in e i s u s e d to a r re s t b lo od f lo w i n ep is t a xi s an d g i ng i va l s u r g e r y . 2 . P he n yl e p h r i n e , a n α 1 - s e le c t i v e a g on is t , i s us ed t o p r o v id e p r es so r ac tiv i t y i n h yp o t en s i v e em e rg e nc ies , to p ro lo n g t he ac t i v it y o f lo c a l a n es th e ti c s ol u tio n s , an d t o r el ie v e p ar o xy s m a l a t ri a l t ac h y ca r d ia . Ph e n y lep h r in e o r ph e n y lp r op a no la m in e i s g i ve n s y s te m i c a ll y f o r n as a l d ec on g es ti o n. O xy m e t a z o li ne a nd xy l o m e ta z o l in e , a ls o α - r e c ep t o r a go n is ts , a r e a p pl i ed lo ca l l y t o re l ie ve n as a l co n ge s ti on . 3 . C l on i d in e a n d re l a ted α 2 - s e le c ti v e ag on is t s (e . g . , m e t h y ld o pa , g u an f ac i ne , g u a na be n z ) a re us ed as a n t ih y p e r te ns i ves ba s e d o n th e i r in h ib i ti o n o f c e nt r a l s ym p at h et ic ou t fl o w. A p ra c lo ni d in e i s u se d t o pi c al l y i n t he e y e t o d ec r e as e i n t ra o c u la r p re s s u re du r in g s u r ge r y . 4 . I so p r o te r e n ol , a β - adr e n e rg ic ag o ni s t , i s u s e d a s a br o nc ho d il a to r an d a s a c a r di ac s t im ul a nt in s h oc k an d c a rd i ac a r r es t . 5 . D o bu t a mi n e, a r e la t i ve l y β 1 -s el ec t i v e a go n is t , i s u s e d to im pr o ve m yo c a r d ia l f u nc t io n i n c on g es ti v e he a r t f a il u re , es pe ci al l y in e m e r g en c y s i tu a ti on s . 6 . Te r b ut a li ne an d ot h er β 2 - s e l ec ti v e ag o ni s t s ( e .g . , m e ta p ro t e re n ol , a l bu te r o l, b i t ol t er o l, s a lm e te r ol ) a re us e d a s s y s t em ic o r l oc a l b r on ch od i la t o rs i n t he t r ea tm e nt o f b ro nc h os pa s t ic c o n di tio n s s u c h as as t hm a. 7 . Th e β 2 - s e le c ti v e ag o ni s ts , e s p ec i al l y ri t od r i ne , m a y be us ed to r el a x u te r i ne s m o o th m u s c le in th e tr ea t m e n t o f p r em a tu r e l abo r . D . Ad ve r s e e f f ec t s . A d re n e rg ic ag o ni s t s m a y c au s e c a r d ia c d ys rh yt h m i as , c e r eb r al h e m o r r ha g e, pu lm o na r y h y p e r t en s i on a nd ed em a, a n xi e t y , he a da ch e , a nd r e b ou nd n a sa l c on g es ti o n.
III. ADRENERGIC ANTAGONISTS A. C h e m i s t r y 1 . α - Ad r e n e r g ic an t a gon i s t s ( α - b lo ck e rs ) h a v e v a r i e d s t ru c t u r es a n d b ea r li t t le r e s em bl an c e t o t he ad r en e r gi c a go n is ts . An t ag o ni s ts in cl ud e th e e r go t al ka l oi ds ( e . g ., e rg o ta m i n e) , th e d ib e n z am i ne s ( e .g . , p he n ox y b e n z a m in e ) , t he be n z ol i ne s ( e . g ., t ol a z ol i ne ) , a n d t he q ui na zo l in es ( e. g . , p raz o s i n ) ( F ig u re 13 - 4 ) .
2 . β - Ad r e n e rg i c a n t ag on i s t s ( β - bl o ck er s ) a r e s tr u c tu r al l y si m i la r to β - ago n is ts ( F i gu r e 1 3 - 5) . Th e c a te ch o l r i ng c a n b e r e pl ac e d b y a va ri e t y of o th e r r i ng s y st em s wi t h o u t l os s o f a n ta g on is t i c a c t i vi t y. Th e l en g th of t h e s id e c ha in is im po r ta n t a n d t h e s id e c ha i n h y d r o xy l , a s we l l as a p r op yl o r o th e r bu lk y s u bs t i tu t io n o n t h e c ha in n i t ro g en , ar e e s s e nt i al fo r in t e ra c ti on wi t h β - re c e p t o rs . B . P h a r ma c ol o g y 1 . A d re n er g ic a n ta g on is ts in h ib i t o r b lo ck ad r en e rg i c r ec e pt o r -m ed i at e d r es p on s e s .
Figure 13-4. The structural formulas of (A) phenoxybenzamine (Dibenzyline) and (B) prazosin (Minipress), representative α-blockers.
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Figure 13-5. The structural formulas of (A) propranolol (Inderal); (B) pindolol (Visken); (C) atenolol (Tenormin), and (D) timolol (Blocadren), representative β-blockers.
2 . α - Ad r e n e r g ic an t a gon i s t s m a y b e α 1 -s el ec t i ve ( e .g . , p r a z os in ) o r n ons e le c t i v e ( e . g ., ph e no xy b e n z a m i ne ) . P he n o xy b e n z a m i n e is an i r re v e r si bl e a n ta g oni s t b ec au s e i t fo r m s c o v a le n t b on ds wi t h α - r e c ep t or s , t he r e by i n ac t i v a ti ng t he re c ep to r s . 3 . β - Ad r e n e rg i c a n t ag on i s t s m a y b e β 1 - s e l ec ti v e ( e .g . , m et o p ro lo l ) o r no n s e l ec ti ve ( e . g ., p ro p ra n ol o l) . G en er a l l y , h o we v e r , β 1 -s el ec t iv e a g en t s m a y l os e t h ei r s e le ct i v i t y at hi g he r d o s e s a n d t hu s b lo c k β 2 - re c e p t o rs a s we ll ( a p ot e nt ia l pr o bl em i n as th m a t ic s ). C . T h e ra p e ut i c i n d ic a tio n s 1 . P r az o si n a n d r e la t ed α 1 - s e le c t i v e a n ta g on is ts ( e . g ., do xa zo s i n , t e r a z osi n , t r i m a zo s i n , a lf u z o s i n ) p ro d uc e vas od i la t io n ( b y blo c k i ng ba s a l v as cu la r ton e m a in t ai ne d b y c i rc ul a ti ng c a te c h ol am i ne ac ti va t ion o f vas c u la r α 1 - re c e p to rs ) . Th e y a r e th us im po r t an t a n ti h yp e r t en si ve ag e nt s. Th e y a r e al so us ef u l i n t he s ym p to m a t ic t r e a tm en t o f be ni g n p r os t a t ic h y pe r pl as i a. P.290
Figure 13-6. The structural formula of acetylcholine.
2 . P he n o x yb e n z a m in e an d ph e n to l am i n e ( n on sel e c t i v e α - bl oc k e r s) c a n be us e d t o r e l ie ve v a s o s p as m i n R ay n a u d ' s s ynd r om e a n d f or a cu t e h yp e rt e ns i v e e m e r g en c i es r e s ul ti n g f r om ph eo c hr om oc y t o m a o r f r om i n ta ke o f MA O i n h ib i to r s o r s ym p at h om i m et ic s . To l az o l i ne , a s i m i l ar ag e nt , is us ed t o t r ea t p e rs is t ent n eo n at a l p u lm o na r y h y p er t en s i o n. 3 . L ab e ta l o l, an ag e nt th a t p os s ess es bo t h s el ec t i v e α 1 - b lo ck in g a c ti vi t y a n d n o ns e le c t i v e β -b l oc k i ng a c ti v i t y , is u s ed i n th e t re a tm e nt o f h y p e rt e ns io n . 4 . P r o p ra n o lo l , a no ns e le c ti v e β - an t ag o ni s t , is us e d f o r t he p ro p h yla xi s of a ng i na p e ct o r is , s up r a v en t r ic ul ar a n d v e n t ri cu la r d ys r h yth m ia s , an d m ig r a in e h ead a c h e . I t i s a ls o u s e d a s a n a n ti h yp e r t en si v e , a ne g at i v e i no t r o pi c a ge n t i n h y p e rt r op h ic o b st r uc t i v e c ar d io m y op at h y , a nd a n eg a ti v e c h r on o t r op ic ag en t in an xi e t y a n d h yp e r t h y r oi di s m . 5 . β 1 - Se l ec ti v e an t ag o nis t s ( e .g . , m et o pr o lo l , b eta xo l o l , at e no lo l , a c e b ut ol o l ) a r e u s ed in th e tr e at m en t o f h y p e r t en s i on , ta c h ya r r h yt h m i as , an d a ng i na . 6 . B ot h β 1 -s el ec t i v e ( b eta xo l o l ) an d n o ns el ec t i ve ( t i m o lo l ) b l oc k e rs de c re as e c il i ar y b o d y p ro du c ti o n o f a qu eo u s h um o r a nd m a y be us e d i n t he t op ic al t re a tm e n t o f g l au c om a. D . Ad ve r s e e f f ec t s 1 . P r az o si n c a n c a us e s u d d en s y n c o p e wi t h t he fi r s t d os e, o r th os t at ic h y po t e ns io n , d i zzi n es s , h ea da c h e , d r ows i n e s s , p a lp i ta ti o ns , f l ui d re t e nt io n , a n d p ri a pi s m . 2 . P he n o x yb e n z a m in e c a n c a us e o r th os t a ti c h y po t e ns io n , t ac h y c a r di a , i nh i bi t io n o f e j ac ul a ti o n, m i os is , a n d n a s a l c on g es ti o n. 3 . P r o p ra n o lo l c a n c a us e b r ad y c a rd ia an d c on g es t i ve h ea r t fa il u r e , in c rea s ed a i r wa y r e s is ta nc e , i nc r eas e d s e r um t ri g l yc e r id es , d e c re as e d hi g h -d e ns it y li p op r o te i n c h ol es t e ro l , b lo od d y s c ra s ia s , ps o ri as is , de p re ss i o n , h al lu c i n at i on s , an d tr a n s i en t h e a ri n g l os s . S ud de n wi th d r a wa l c a n b e c a r di o toxi c d u e to re b ou n d s ym p at h om i m et ic ac ti v i ty . 4 . M e t o p ro l o l h as a d v e rs e e f f ec ts s im il a r to th ose o f p r op r an o lo l , e xc e p t t h a t i t i s l e ss l ik e l y to in c r e as e a ir wa y r e s i s t a nc e g i v en i ts β 1 - s e l ec ti v i t y.
IV. CHOLINERGIC AGONISTS
A. C h e m i s t r y 1 . Ac e t yl c h o l i n e , t he nat u r al e nd og e no us m e di a to r a nd th e m os t p o te n t ch o li n e rg ic a g o ni st , i s a n e s t e r o f a c e t ic ac id an d c ho l in e —a q u a te r na r y a m i no al c o h ol ( F ig u re 1 3 - 6 ). A c e t y lc h ol in e i n th e bl oo d i s u ns t ab l e as it i s q ui c k l y i n ac ti v a t ed t hr o u gh h yd r o l ys i s b y ac e t y lc ho lin e s t e r as e. Th u s, it is e xt r e m el y sh o r t ac t in g a n d u s ua ll y i s n o t a sa t is fa c to r y t he r ape u t ic a g en t . 2 . T he r a pe u t ic a l l y u s e f u l c ho l i ne r g ic a go n is t s m a y be di r ec t a c t i ng o r in d i re c t a c ti n g. a . D i r ec t - ac t i n g a go n is ts m a y b e p r od uc e d b y r ep l ac in g th e a ce t y l g r o up o f a c et yl ch o li n e wi t h a c ar ba m o y l g r ou p o r b y s ub s tit u t in g a m e t h yl g ro u p o f t h e β c a r bo n . Th e s e s u bs t it u tio n s p r od uc e c om po u nd s t h a t a r e m o r e re s i st a n t to a c e t yl c h o l i n e s te r a se an d th us ha v e lo n ge r du r at i o ns o f ac ti o n. S uc h s tab l e a g o ni st s i nc lu d e m e t ha c h o li n e ( P r o voc h ol in e ) a nd b e t h an ec h ol ( U re c ho lin e ) ( Fi gu r e 1 3 - 7 ).
Figure 13-7. Clinically useful direct-acting cholinergic agonists include (A) methacholine chloride (Provocholine) and (B) bethanechol chloride (Urecholine).
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Figure 13-8. The structural formula of neostigmine bromide (Prostigmin), a reversible acetylcholinesterase inhibitor.
b . I nd i r e ct - a c ti n g a g on is t s ar e g e ne r al l y ac e t ylc h o li n es te r as e i n hi bi t o rs a n d a r e d i vi de d i n to t wo m a j o r c la s s e s . ( 1 ) R e ve r s ib l e ( s h o r t- ac t i n g ) a ge n t s a r e p ri nc ip a ll y c a rb am a te s ( ca r b am ic ac id e s te r s ), s u c h as p h y s os tig m in e (E s er i ne ) , n e os ti gm i ne , a n d am b en o ni um (Me t yl a s e ) ( F i gu r e 1 3 - 8) . ( 2 ) I r r e ve r s ib l e ( l o ng - ac t i n g ) a ge n t s a r e p ri nc ip a ll y o r ga n op h os ph a te es t e rs , s uc h a s e ch o t hi op h at e ( Ph os ph o li n e ) ( F ig u re 13 - 9 ) . B . P h a r ma c ol o g y 1 . C h ol i n e rg i c re s po n se s a re m e di a te d b y b ot h m us c ar i ni c a nd ni c o t in ic r e c ep t or s ( Ta b l e 1 3 - 5 ). a . P N S m u sc a r i ni c r ec ep t o r s a r e p r es e nt a t p ara s y m pa t he ti c p os t ju nc t ion a l n e u ro e f fe c t o r s it es . b . P N S ni c o ti n i c r e ce p to r s a re p re s e n t a t t h e ga n gl i a o f b o th th e p a r as ym p at h et ic a n d s ym pa t he t ic b r an c hes o f t he A N S a n d a ls o a t t h e n eu r om us c u l a r j un c ti o ns of t h e s om a ti c n e r v ou s s y s te m . 2 . C h ol i n e rg i c a g on i s ts a c t b y m i m i c k in g th e ac t i vi t y o f e n d o g en o us a c e t yl c h o l i n e at m us c ari n ic an d n ic o ti ni c re ce p to r s i t es . a . D i r ec t - ac t i n g a go n is ts i nt e r ac t d i re c t l y wi t h the s e r ec e pt o rs . b . I nd i r e ct - a c ti n g a g on is t s i n hi b it o r b lo ck th e ac t i vi t y o f c h ol in es t e ra se e n z ym e s ( e . g ., ac e t y lc ho li n es t er as e , b u t yr y lc h ol in es t e ra se) , wh i c h b r ea k d o wn en do g e no us a c et yl ch o li n e t o i na c t i v e m e ta b ol i te s . Th u s , fo l lo wi n g p h y si ol o gi c a l re le a s e o f a c et yl ch o li n e f r om n e r v e t e rm i na ls , th es e a g en ts a l lo w t h e ne u ro t r an s m i tte r t o a cc u m u la t e a t c ho li n e rg ic s y na ps es , th e re b y e nha n c i n g c h o li ne r gi c re c e pt o r s t im ul a ti o n. O r g an op h os p h a te c h ol i ne s t e ra s e in hi b i to rs , s uc h a s c e rt a in ag r i c u lt u r al i n se ct ic i de s a nd th e s o -c a l le d n e r ve g as e s , c a n be e xt r e m el y t o xi c as th e y b i nd to t h e e n zy m e t o fo rm a n i rr e v e r s i b le o r l on g -l as t in g e n z ym e i nh i bi t o r c o m p l ex. C . T h e ra p e ut i c i n d ic a tio n s 1 . D i r ec t - ac t i n g a go n is ts a r e i nd ic a te d t o : a . I ni ti a te m i c t u ri t io n i n a c ut e n o no bs t r uc ti ve u rin a r y r e te n ti on ( e .g . , b et ha n ec h ol ) b . P r od uc e m io s i s i n t h e t r e a tm en t o f gl au c om a (e . g . , pi l oc a rp i ne ) 2 . I nd i re c t - ac t in g a g on is ts a re in d ic at e d t o: a . P r od uc e m io s i s i n t he t r e a tm en t o f gl au c om a (e . g . , p h ys os t ig m i n e, ec ho t h io ph a t e) b . A id in t he di f fe r en t ia l d i ag n os is of m ya s th e ni a g r a vi s ( a d is e as e c a us e d b y n i co t in ic r ec ep t or h yp of un c ti o n a t t h e n eu r om us c u l a r j un c ti on ) an d h yp e rc h o li n e rg ic c r is is ( wh i c h p ro du c es de p ol a r i zat i on bl oc ka d e of t h e n eu r om us cu la r ju nct i o n) . E d r o ph o ni um is u s e d fo r t h is pu r po se . c . Tr e a t m y as t he ni a g r a vi s (e . g. , am be no n iu m , n eo s ti gm i ne , p y r i d os ti gm i ne ) d . C o un t e ra c t in t o xi c at i on o r a d ve rs e e f fe c ts fr om c o m p ou n ds wi t h a n ti c h o li n e rg ic a c ti vi t y ( e .g . , p h y s o s t i gm i ne ) e . Im p ro v e c o g ni ti v e f unc t io n i n Al z h e im er ' s di sea s e p at i en ts ( e .g . , t ac r ine , d o n ep e z il , ga la n ta m i n e, a n d ri v a s t i gm in e ) f . Tr e a t p a r al y t ic il e us o r c a rd i ac t a rc h y a r r y t hm ias ( e. g . , e d ro ph o ni um ) .
Figure 13-9. The structural formula of isoflurophate (Floropryl), an irreversible acetylcholinesterase inhibitor.
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Table 13-5. Cholinoceptor-Mediated Responses to Cholinergic Agonists Organ
Response
Heart Atrioventricular node
Decreased conduction velocity (negative dromotropy)
Atria, ventricles
Decreased contraction force (negative inotropy)
Sinoatrial node
Decreased contraction rate (negative chronotropy)
Sphincter muscle
Contraction, producing miosis
Ciliary muscle
Contraction, accommodates for near vision
Eye
Lung
Bronchial muscle
Contraction (bronchoconstriction)
Bronchial glands
Increased secretion
Gastrointestinal tract Intestine
Increased motility (peristalsis)
Sphincters
Relaxation of sphincters
Glands
Increased secretions
Urinary bladder Detrusor muscle
Contraction
Trigone and sphincter
Relaxation
Glands (sweat, salivary, nasopharyngeal, lacrimal)
Increased glandular secretion
D . Ad ve r s e e f f ec t s 1 . T op i ca l ad ve r s e e f f ec t s i n c l ud e c on g es t ed c o n ju n c t i v a e, m y o p ic ac c o m m o da t i o n , a n d t r a ns ie n t l en t ic ul a r op a c i t y . 2 . S ys t e m i c a d ve r s e e f fe c t s i nc lu d e h ea d ac he , s yn c op e , n au s e a , v o m i t in g , b r a d yc a r di a , h y p o te ns ion , b ro nc h os pa s m , a b do m i n al c r a m p s, di a r rh e a, epi g as t ri c d i st r es s , s a li v a t io n , s we a t i ng , l ac r im a ti on , fl us h i n g , a n d t r em o rs .
V. CHOLINERGIC ANTAGONISTS b l oc k t he ac t io ns of ac e ty l c h ol in e a t m us c ar i ni c or n ic o ti ni c c ho li n oc ep t o rs . A. C h e m i s t r y 1 . At r o p i n e , a n a lk al oi d e xt r a c t e d f r om th e b e ll ado n n a pl a n t, i s th e p r ot o ty p i c al c h ol in e r gi c a nt a go n is t ( an t ic h ol in e r gi c a ge n t ). A p o r ti o n o f t h e a t ro p in e m o l ec ul e i s s t r uc t ur a ll y s i m i l ar t o ac e t y l c h o li ne ( Fi g u re 13 - 10 ) , p e rm it t in g t h e m o l ec ule t o b in d t o po s tj un c ti on a l r ec e pt or s . P.293 H o we ve r , t h e m ol ec u le ha s n o i n t ri ns ic ac ti vi t y , an d it s b ul k y s h ap e p r e ven t s a c et yl ch o li n e f r om b i nd ing t o t h e r ec e pt o r .
Figure 13-10. Structural formula of atropine, a cholinergic antagonist.
Figure 13-11. Structural formula of propantheline bromide (Pro-Banthine), a synthetic cholinergic antagonist.
2 . S yn t h e t i c a n t ic h o li ne r g i c a g en t s (e . g. , d ic y cl o m i ne [ B en t y l ], gl y c o p y rr o l at e [ R o b in u l] , p r o pa n th el i ne [ P r o - B an t hi n e] , p i r en z e pin e an d t r o pi c a m i de ) a re a l so a va i la b le . Th es e a g en ts , l ik e a t r op in e , a r e b ul k y a n al o gu es o f ac e t y lc ho l in e ( Fi gu r e 1 3 - 11 ) . 3 . A n im p o rt a nt f ac to r tha t de t e rm in es th e ph a rm a c ol o gi c s p ec t r um o f a n t ic ho li n e rg ic ag e nt s is t h e p r es en c e o f a q u a ter n a r y n i t r o g e n ( as i n p r o pa n th e li ne , gl y c op y r r o l a te , a n d i p ra t ro p iu m ), wh i c h r ed uc es pa ss ag e a c r os s t he b l oo d - b ra in ba r r ie r , o r a t e r t i a r y n i t r o g e n ( as in d i c yc l om in e , p i re n z ep i ne, t r o pi c am id e , a nd be n z t r op i ne ) , wh i c h pe r m i ts a b ro a d er v o lu m e o f d is t ri bu ti o n ( o r a cc e ss ib il i t y to a wi d e r ra n g e o f t is s u es ) . B . P h a r ma c ol o g y 1 . C ho l in e rg ic an t ag o ni s ts c om p et i t i ve l y i n h i b i t th e ac ti vi t y o f e nd o ge n ous a c et yl ch o li n e. 2 . A nt a go n is ts th a t i nh i bit m us c a ri n ic re c e p to r - m ed i a te d re s p on s es a r e c all e d a n t i mu s ca r i n ic ag e n ts ; t h os e th a t i nh ib i t n ic o ti nic r ec ep t o r -m ed ia t ed r es p o ns es a t t h e g a ng li a a r e c al l ed gan g l i on i c -b l o ck i ng a ge nt s , wh e r e as t h os e t h at inh i bi t
n i co t in ic r ec ep t or - m e d ia te d r es po ns es at t he ne u ro m us c u la r ju nc t io n a r e ca l le d n e u r o mu s cu l a r -b l o ck i ng a ge n t s . C . T h e ra p e ut i c i n d ic a tio n s 1 . An t i m u sc a r in i c a g ent s a re in d ic at e d t o : a . R ed u c e gl an d ul a r a nd b r o nc hi ol a r s ec r et i on s be f o r e a ne s t h es ia ( e. g ., at r o pi n e , g l yc op yr r o la t e ) b . I nd uc e s ed a ti o n ( e .g . , s c o po l am in e ) c . Al l e v ia t e m o t io n s ic k ne s s ( e .g . , sc o po la m i n e) d . R e du c e v a ga l s ti m u l ati o n o f t h e m y oc a r di um (e. g . , a t r op in e ) e . P r od uc e o p ht h al m i c m y d r i a s i s a nd c yc lo p le g ia ( e . g ., ho m a t r op i ne ) f . R e du c e G I s m o o th - m us c l e s pa sm s ( e .g . , p r op an t h el in e ) g . Tr e a t b r on c h o s p as m as s o c i a te d wi t h c h ro ni c ob s t ru c ti v e pu lm on a r y di s e a s e ( e. g ., i p r at r o pi um ) h . C on t r ol P a rk in s o n ' s d is e as e s ym p t om s a nd s om e n e u ro le p ti c -i n du ce d e xt r a p yr a m i da l r e ac ti o ns ( e . g. , be n zt r op in e , t r ih ex yp h e n i d yl) i . Tr e a t i n to xi c a t io n b y c h o li n e rg ic ag on is t s o r b y a c u t e m us h ro om po is o nin g ( e. g ., a t r o pi ne ) 2 . G a n gl i on i c -b l o ck i ng a g e n ts a re in di c a t ed t o tr e a t h y p e r te ns i v e c r is is (e . g . , t r i m e t ha p ha n , m e c a m y lam i ne , h e xa m e th o ni um ) . B y b l oc ki n g g an g li on ic t r a ns m i s s io n , t h es e a gen t s r e du c e s ym p at h et ic a c ti v i t y , r es ul t in g i n a h yp o t en si v e e f f ec t . D . Ad ve r s e e f f ec t s 1 . T op i ca l ad ve r s e e f f ec t s i n c l ud e h y p e r op ic acc om m o d at i on an d i nc r e as e d i n t ra o c u la r p re s s u re . 2 . S ys t e m i c a d ve r s e e f fe c t s i nc lu d e h ea d ac he , n e r v o us n es s , dr o ws i ne s s , d i zzi n es s , p al pi t at i on s , ta c h y c a r di a , d r y m o u th , m y d r i as is , b lu r r ed vi si on, n au se a , vo m i ti n g, c o ns t ip a ti on , ur i n a r y re t en t io n , a nd f e ve r . P.294
Figure 13-12. Structural formula of tubocurarine chloride (Tubarine), a competitive nondepolarizing agent.
VI. NEUROMUSCULAR BLOCKING AGENTS
a c t b y b lo c k in g t h e e f fe c t s of ac e t y lc ho li n e a t t h e n e r ve -m us c l e j u nc ti o n of s k e le t al m us c l e s . A. C h e m i s t r y 1 . N e u ro m us c u la r b lo ck i n g a g en t s c an be c o m p e t it i ve (a s wi t h t he p ro to t yp ic a l c u r ar e a lk a lo i ds ) o r de pol a r i z in g (a s wi t h s u cc in y l c h ol in e ) . Me m be r s o f e ith e r c a te g o r y u l ti m a t el y p r e ve n t th e a c t i on of ac e t ylc h o li n e a t n ic o ti ni c r e c e p to r s l oc a te d i n th e n e r v e -m us c l e j u nc t i o n. 2 . Th e co m pe t i t i ve n o nd e p o la r i zi n g a ge n t s i ncl u de t he na t u ra ll y o cc u rr in g a l ka lo i ds o f cu r a r e , wh i c h a r e b ul k y a n d r ig i d m o le c ul es , a s we l l as s e v e ra l s yn t he t ic an al o gu es . a . Th e p ri n c ip a l a c ti ve a l k al o i d i n c u r a re is tu bo c u ra r in e (F i gu r e 1 3 -1 2 ). A cl os el y r e l at e d t r im e th y l a te de r iv a t i v e is m e to c u r i ne ( Me t u b in e ) . Th e i r m os t im p or t a n t s t r uc t ur a l f ea t u re is th e p r e s e nc e o f a t er t ia r y- q ua t e r na r y am in e i n wh i ch t h e d i st a nc e b et we e n t he t wo c a t io ns is ri g id l y fi xe d a t ab o ut t wi c e t he le n gt h o f th e c r i ti ca l re c e p to r - bi nd i ng m o ie t y o f ac e t y lc ho l in e . b . A nu m b e r o f p o t en t syn t h e t i c a n al o g ue s h a ve b ee n d e v e lo pe d . Th ese i nc lu de t h e s t ru c tu r al l y s i m i la r iso q u i no l i ne s a t r ac u ri um ( Tr a c r i um ) , d o xa c u ri um (N u r o m a x) , a n d m i v ac u ri um ( Mi v a c r on ) , as we l l a s t he s te r o id d e r i va t i ve s p an c u r on iu m ( P a vu l on ) , v ec u ro n iu m (N o r c u ro n ), an d pi pe c u r on i um ( A rd u an ) . 3 . Th e no n co m pe t i t i ve d e p o la r i zi n g a ge n t s i ncl u de s u cc in y l c h o li ne ( A ne c ti n e ) a nd g a ll am i ne ( Fl a xe d i l ) ( F igu r e 13 - 13 ) . a . U nl ik e th e l a rg e , b ul k y c o m p e ti t i ve a ge n ts , n on c om pe t it i v e a g en t s a re s l en d er a l ip h at ic m o le c u l es . b . S u cc i n yl c h o l i n e h as a s h o r t d u ra t io n o f a c ti on co m p a r ed wi t h th e o t he r n e u ro m u s c u la r b l oc k i ng a g e nt s . Th i s r es ul t s f r om i t s s i m p l e es t e r f un c ti ona l gr o up , wh i c h is ra p id l y h y d ro l y z e d b y p l as m a an d l i ve r ps e ud oc h ol in es t e ra se ( b u t yr yl ch ol i ne s te r as e ). It s ac ti o n m a y b e p r ol o nge d , h o we v e r , in pa t ie n ts wi t h a n a b n or m a l g e ne t ic v a ri a nt o f ps eu do c ho li n es te r as e , wh i ch h as o n l y a b ou t 2 0 % t h e a c ti vi t y o f n o rm al ps eu do c ho li n es t er as e . B . P h a r ma c ol o g y 1 . Th e co m pe t i t i ve n o nd e p o la r i zi n g a ge n t s c om p et e wi t h a ce t y lc h ol i ne f o r n i co t in ic r ec ep t or s a t th e n e u ro m u sc ul a r j un c ti on . Th e s e a ge n ts de c re as e t h e e n d p l a te po t en t ia l s o t ha t the d ep ol a r i zat i on th r es h ol d is no t re ac h ed . C om pet i t i v e n o n de po l a ri z i ng ag e nt s p r o du c e P.295 a su r m o u nt a bl e b lo c k a de o f ne u ro m u s c ul a r t r a nsm is s i o n i n t ha t ad m i ni s tra t i on of c h ol in e s t e ra s e in h ib i to r s o r p re ju nc t io n al r el ea se o f a la r g e q ua n ti t y o f ac e t y l c h o li ne c a n r e li e v e t h e b lo c k ad e.
Figure 13-13. Structural formula of succinylcholine chloride, a noncompetitive depolarizing agent.
2 . Th e no n co m pe t i t i ve d e p o la r i zi n g a ge n t s d es e ns it i z e th e n ic o ti ni c r ec e pt o rs a t t h e n e u ro m u s c ul a r j un c tio n . Th es e a ge n ts r ea ct wi t h t h e n ic o ti ni c r e ce p to r s , d e c re as in g re c e p to r s e ns i ti v i t y in a m an n er si m i la r t o t ha t of e xc e s s re l ea s ed a c et yl ch o li n e. Th e y de p ol a r i z e t h e e xc i t ab l e m e m b r a ne f or a p r ol o ng ed p er i o d ( 2 - 3 m i nu t es ) ; t he m e m b r an e t h e n b ec om es un r es po ns i v e ( d es en s i t i z ed ) . C . T h e ra p e ut i c i n d ic a tio n s . Ne u r o mu s cu l a r b lo c k in g ag e n ts , wh ic h c au s e o nl y s ke l et a l m u s c le p ar a l ys is ( th e p a ti e nt r em ai ns c on s c i ou s a nd c a pa b le of s e n sa t io n ) , a r e us ed to : 1 . P r om ot e s k e le t al m u s c l e r el a xa t i o n a nd f ac il ita t e e n do t r ac he al in t ub a tio n , a s a n a d ju n ct to s u r gi c a l a n es th e s i a 2 . Li m i t th e t r a um a t ha t c o ul d re s u l t f r om e xc e s s iv e s k e le t al m u s c le c o nt ra c ti o n d u r in g e l ec t ro c o n v u ls i v e s h oc k t he r ap y 3 . R el a x t h e s k e l et a l m us c l es an d fa c i li t a te bo ne p l a c em en t a n d m an ip u lat i o ns d u r in g o r t ho p ed ic pr o c e du r e s D . Ad ve r s e e f f ec t s 1 . C o mp e t it i ve n on d e po l a r iz i n g a ge n t s c a n c au s e r es p ir a t or y p a ra l y s i s , h is t am in e r e l ea se , br o nc ho s p a s m , a n d h y p o te ns i on ( e. g ., tu b oc u ra r i ne ) o r r es pi r a tor y p a r al ys is , t a c h y c a rd ia , an d h y pe r t en s i o n ( e .g . , pa n c u r on i um ) . 2 . N o nc o mp e t i ti ve d ep ol a r i z i n g a g en t s (e . g. , s uc ci n ylc h ol i ne , g a ll am in e ) c an c a us e r es p i ra t or y p a ra l ys is , m us cl e fa s c ic ul a ti on wi t h p ai n , e xt r a o c ul a r m u sc l e c o nt r ac t io n wi t h i nc r ea s ed i nt r a oc ul a r p r es s u r e, an d in c re as ed in t r ag as t r ic p r es s u r e . I n ad d it i on , s uc c i n y lc h ol in e m a y c a us e m us ca r in ic r es po ns es su c h as br ad yc a r di a , i n c re as ed gl a nd u la r s ec re t i on s , an d c a rd i ac a r r es t . I n c o m b i na t io n wi t h t he a n es t he t ic h a lo t ha n e, s uc c i n y lc h ol i ne m a y ca us e m a l i gn a nt h y p er t he r m i a in g e n et ic al l y p re d is po s e d in d i v id u al s .
VII. GENERAL ANESTHETICS i n du c e a c om bi n ed s t a te o f an al g es ia , a m n es i a, lo s s o f co ns ci o us ne s s , i nh i bi t io n o f s e ns o r y a n d a ut o no m i c re f l e xe s , a nd sk el e ta l m us cl e re l a xa t i on . I d ea l g en e r al a n es t he t ic s in d uc e a ne s th e s i a ra pi d l y a n d s m o oth l y a nd pe r m i t ra pi d re c ov e r y o f t he p a t ie n t o nc e a dm in is t r at io n of t he ag en t c e as es .
A. C h e m i s t r y 1 . V o la t i le o r i n ha l a ti o n a n es t h e ti c s a re d ru gs in h al e d a s g as es o r v a por s . Th es e d i ve r se dr u gs ar e re l at i ve l y s i m p l e l ip op h il ic m o le c ul es . Th e y in cl ud e th e i n or g an ic a g e nt ni t r ou s o xi d e ( N 2 O) a n d t he n on f l am ma b l e h a lo ge n a te d h y d r oc a rb on s (e . g. , h a lo t ha n e ) a nd et h e rs (e. g . , m et h o xyf l u r a ne , i so f lu r a ne , de s f l ur a ne , s e v o flu r a ne ) . 2 . N o n vo la t i le o r in t r a ve n o us a ne s th e t ic s a r e a d m i ni s te r ed in t r a v en o us l y o r o cc a si on a ll y i nt r am us c u la r l y a nd c om e a s a qu e ou s s o l u ti o ns , a qu e ou s p ro p yl e ne g l yc ol s o lu t io ns , o r em uls i on s . a . Th e w a te r - s ol u b le and r el a ti ve l y sh o r t- a c t i ng a g e nt s i nc lu d e u lt r a -s ho rt - a c t i ng b a r bi t u ra t es (e . g ., th i op en t a l, m e t ho he xi t a l , th i am yl a l ) , c yc l o he xy l a m i n es (e . g . , k e ta m i n e ), be n z o - di a z epi n es ( e. g ., di a z e pa m , m id a z o l am ) , b ut y r o p he no ne s (e . g. , d r o pe r i do l ), an d o p io id an a lg e s i c s (e . g. , m o rp h ine , f en t an yl ) . b . Th e im id a z ol e , e t om ida t e , i s p re p a re d a s a n aq u e o us p r op yl e n e g l yc o l s o l u t io n , wh i c h i s c o m pa t i bl e wi t h m a n y p re a ne s t h e ti cs . c . Th e d i al k y lp he n ol , p r op o f ol , i s a dm in is t e re d a s a n e m u ls i on , wh i ch s h ou l d n o t b e m i xe d wi t h o th e r t h er a peu t ic ag e nt s b e fo r e a dm ini s t ra t io n (F ig u r e 1 3 -1 4 ). B . P h a r ma c ol o g y 1 . G e ne r a l a n es t h et i cs d e p re s s th e C N S , p r od uc i ng a r e ve rs i bl e l os s o f c o ns ci ou s n es s a n d l os s o f al l f o rm s o f s en s a t io n . P.296
Figure 13-14. Structural formulas of nonvolatile general anesthetics: (A) thiopental sodium (Pentothal), (B) ketamine hydrochloride (Ketaject), (C) fentanyl citrate (Sublimaze), (D) midazolam (Versed), (E) etomidate (Amidate), and (F) propofol (Diprivan).
2 . I nh a la t i o na l a n es t h eti c s a r e a bs o r be d a nd p rim a r il y e xc r e t ed th r o ug h th e lu ng s . F r e q ue n tl y , th es e dr u gs a r e s u pp le m e n te d wi t h an a lg e s i c s , a s k e l et al m us c l e r e l a xa n t , a n d a n a nt im us c a r in ic ag en t . a . An a l g es i cs pe r m i t a re d uc t io n i n t h e r e qu i re d c o nc en t r at i on of in h al a tio n al a n es t he t ic . b . S ke l e ta l m u sc l e re l ax a n t s c a us e a d eq u at e m u s c l e r e la xa t i o n d u ri n g su r g e r y. c . An t i m us c a ri n i c a ge nt s d ec re a s e bu c c al an d b r o nc hi o la r s ec r e ti o ns .
3 . N o n vo la t i le a ne s th e ti c s a r e u s u a ll y a dm in is te r e d i n tr a v e no us l y ( e. g . , t h i ob a rb i tu r a te s , be n z o dia z e p i ne s ) , bu t s om e a gen t s m a y a ls o b e g i v e n i n t ra m us c u la r l y (e . g ., k e ta m in e ) . C . T h e ra p e ut i c i n d ic a tio n s 1 . I nh a la t i o na l a n es t h eti c s a r e i n di c a t ed to p ro v i d e g en e r al s u r gi c a l a nes t he s i a . 2 . N o n vo la t i le a ne s th e ti c s (e . g. , th i op en t al , di aze p a m , m i da z o l am ) a r e in d ic a te d t o i n du c e d ro ws i n es s a nd pr o v i d e r e la xa t i o n b e fo r e t h e i n du c t i on of in h al a ti on a l g e n er a l a ne s t h es ia . P.297
3 . U se of s o m e p re v i ou s ly p o p ul a r v ol a ti le an es t he t ic s h as be e n di sc o nt i nu e d b e ca us e o f s e ri o us to xi c it y ( e . g ., c h lo r o fo r m ) o r be c au se o f t he fl am m a b le a n d e xp l o s i v e p r op e r ti es o f th e c om p ou n ds (e . g. , c y cl o p ro p an e , d ie t h y le t he r ) . D . Ad ve r s e e f f ec t s . Ge ne r a l a ne s th e ti c s d e p re s s r e s p i ra t io n , c ir c u l at i on , a n d t h e C N S . Th e y c an al s o d ec re a s e he p at ic an d k id n e y f u nc t io n (e . g. , m e th o xy f l u r a ne ) a n d c au s e c a r di ac d y s r hy t h m ia s a s a re su l t o f i nc r e as ed m y o c ar d ia l s en s i t i vi t y to c a te ch o la m i n es (e . g. , hal o t ha ne ) .
VIII. LOCAL ANESTHETICS A. C h e m i s t r y. Mo s t l o c al a ne s t h et ic s a r e s t ru c t u ra l l y s im i la r to th e a lk a lo id c o ca i ne ( F i gu r e 1 3 - 15 ) . Th es e d ru g s c o n si st of a h y d r op hi l i c am in o g r ou p l i nk ed th r o ug h a n e s te r o r am i de c o nn ec t ing g r ou p t o a li p op hi l ic a ro m at ic m o ie t y . A fe w p he n ol s a n d a r o m a t ic a lc o ho ls al s o ha v e l oc al an es t he t ic ac tivi t y. 1 . E s t e r -t y p e ag en t s a re g e n er a ll y s h o r t a ct in g due t o r a pi d h yd r ol ys is b y p l as m a e s te r as es . Th es e a g en ts i nc l ud e c oc ai n e, p ro c a ine , ch lo r o pr o c a in e , b en z oc a in e , b u t am be n , a nd te t r ac ai ne . 2 . Am i de - t y p e a ge n ts are g en e ra l l y l o ng e r a ct i ng a n d a r e m e t ab o li z e d i n th e li ve r . E xa m p l e s o f t h e am i de - ty p e l oc al an es t he t ic s i nc l u de li d oc ai n e, di b uc ai ne, p r i lo ca i ne , m ep i v ac a in e , b u pi v a c ai ne , an d e t id oc ai n e . 3 . Th e dr u g 's p K a ( o r d is s oc i at i on c o ns t an t ) i n fl ue n ce s i ts c h em ic al s t a te , wh i c h i n t u r n d e te r m i ne s t h e a ne s t h e ti c e f fe ct i ve ne s s of t he c o m p o un d . Th e s i t e o f a n es t he t ic a c ti on is at t he i nn e r s ur f ac e o f th e c el l m em b r an e . A t t is s ue pH , t h e d r u g i s i n t he fo r m o f a lip o p hi li c, un c ha r ge d , s e c o n d ar y o r te r ti a r y am in e , a n d t hu s d i f fu se s a c ro s s c on n ec tiv e t i s s ue an d c el l m em b ra n es an d e n te r s n e r ve ce l ls wh e r e i t is i o ni z e d t o a c h a rg e d a m m on i um c a ti on . Th e c a ti o ni c f o rm o f th e d r u g i s t h e a c ti ve f or m o f th e d r ug th a t b l oc k s t h e g en e ra t ion o f a ct i on po t en t ia ls at t h e m em b r an e r e c e p to r c om p l e x. A l so , b e c a us e o f i ts c h a rg e d am m o n iu m c ati o n , t he i n t ra c el lu l ar io n i z ed m o le c ul e p o or l y pe n et r a te s th e c e ll m em b r an e a nd t hu s re m a i ns t r a p pe d wi t hi n t h e c e l l, th e r eb y e nh a nc in g i t s d ura t i on of ac t io n . B . P h a r ma c ol o g y 1 . Lo ca l a n es th e ti c s r e ve r s i b l y b l o c k n e r ve i m pu l s e c o nd u c ti o n a nd p ro d u ce r e ve r s i b l e l os s o f s en sa t i o n a t t h ei r ad m i ni s tr a ti o n s it e . Th e y d o n o t p r od u ce a l o ss o f c o ns c i ou s n es s .
a . Sm a ll , n o nm y e li n at e d n e r v e fi b er s , wh i c h c on du c t p ai n a n d t em pe r a tu re s e ns at i on s , a re a ff ec t ed f i r s t . b . L oc al an es t he t ic s ap pe a r to be c o m e en t r ap p ed wi t h i n th e n e r ve m em bra n e o r to +
+
b i nd t o sp ec i fi c m em b ran e s o di um io n ( Na ) c h an n el s , r es t r ic ti n g N a per m e ab il i t y i n r e s po ns e t o p a r ti al d ep ola r i z a ti o n . 2 . Lo ca l a n es th e ti c s ol u ti o ns f re q ue n tl y c o n ta i n th e v as o c o ns t ri c to r ep i nep h r i n e, wh i c h r ed uc es v a s c ul a r b l oo d fl o w a t th e a dm in is t r a t io n s it e . Thi s p r ol o ngs t he d u r a ti on o f ac t io n , a nd re d uc es s ys t em ic ab s o r p ti o n , a nd he nc e s y s te m i c t o xi c i t y .
Figure 13-15. Structural formulas of local anesthetics structurally similar to cocaine: (A) procaine (Novocaine) and (B) lidocaine (Xylocaine).
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C . T h e ra p e ut i c i n d ic a tio n s . L oc a l a ne s t h et ic s ar e in d ic a te d t o : 1 . P r od uc e re gi o na l n e r ve b lo c k fo r th e re li e f o f pa i n wh e n i nj ec t ed c l os e to t he i n ne r va t in g n e r v e 2 . P r o v id e a n es th es i a f or m in o r o pe r a ti o ns wh e n i n f il t ra t ed a ro u nd th e ti s s u e s i t e 3 . P r o v id e a n es th es i a f or s u rg e r y of th e l o we r l im bs an d p e l v is an d f o r ob s te t r ic s u r ge r y wh e n in je c te d i nt o t he ep id u r al s p ac e o r t h e s ub a r ac hn o id s p ac e o f t he s p in al c o r d 4 . P r o v id e a n es th es i a o f t h e s k i n a nd m u co us m em b r an es wh e n a p pl ie d l oc a ll y. Th i s i n cl ud e s t wo m i s c e ll an e ou s l oc a l a ne s t h et ic s : d yc l o n i ne , u s ed pr im a r il y i n t h r oa t l o ze n ge s a nd s p r a ys , and p r am o x in e , u s e d p r im a r i l y i n a n ti h em o r rh oi d al p r e pa r a ti o ns . D . Ad ve r s e e f f ec t s 1 . E s t e r -t y p e l o c a l a ne s th e t ic s ca n c au se h y pe r s e n s i t i v it y r e ac ti o ns i n s us c e p ti b le i n di vi d ua ls . 2 . S y s te m i c a bs o rp t io n of t o xi c c o nc en t r at i on s o f l o c a l a ne s th e ti c s c a n c au s e s e i zu re s ; C N S , re s p i ra t or y , a n d m y oc a r di al de p res s i o n; an d c i rc ul a to r y c ol l ap se .
IX. ANTIPSYCHOTICS. Th e c la s s ic an t ip s yc h ot ic ag e nt s a r e t h e p he no t hi a z i ne s , t hi o xa n t h en es , a n d b u t yr o ph en o ne s . C h em ic a l c l as s es o f n e we r c om p o u nd s h a vin g a n ti ps yc ho t ic
a c ti vi t y i nc lu de t he di h y dr o i nd o lo ne s (e . g. , m ol i nd o n e ) , d ib en z o xa ze p i n es ( e . g ., l o xa p i n e ), di b en z o d ia z e pi n es ( e. g ., c l o z a pi ne ) , d ip h e n y lb u t ylp ip e ri d in es (e . g . , p i m o zi d e) , an d b en z i s o xa z o l es ( e. g ., r is pe r i do ne) . A. C h e m i s t r y 1 . P he n o t hi az i ne s (e . g ., c hl o r pr om a zi ne , t ri fl u p ro m a z in e , t hi o r id a zi n e , p r o ch lo r p er a z i ne , t ri fl u op e r a z in e , f l up he n a zin e ) m u s t ha ve a n i t r og e n -co n t a in i n g s i d e -c h ai n su b s ti t u en t o n th e ri n g n it r og e n f o r an t i ps yc h o ti c a c t i v i t y ( Ta bl e 13 - 6 ). Th e r i ng a nd s i de -c h ai n n i t ro g en s m us t b e s ep a ra t e d b y a t h r ee -c a r bo n c h a in ; p h e no t hi a z in es in wh i c h t h e ri n g a nd s i de -c h ai n ni t r og e ns ar e s e pa r at e d by a t wo c a r bo n c ha in h a v e o nl y a n t ih is t am in ic o r s e d at i ve a c t i vi t y. a . Th e s i de c h ai ns a re eit h e r a li p ha t ic , p ip e r a zin e, o r p i pe r id i ne de r i va ti v es . P i p e ra zi n e s i d e c h a in s c o n f e r t he g re a te s t po t enc y a nd t he hi gh e s t ph a rm ac o lo g ic al s e le ct i v i t y . b . F lu ph e na z i n e a nd lo ng - c ha in al c o h ol s f o rm s ta b le , hi g h l y l i p o p h i l ic es t e r s (e . g. , e n a nt h at e , d ec an o at e ) , wh i c h po s s es s m a r k e d l y p r o lo n ge d a c t i v i t y . 2 . T hi o xa n t he n es ( e. g . , c h lo r p ro t hi xe n e , th i ot h i xe n e ) l ac k t he r in g n i tr o ge n of p h e no t hi a z in es an d h a v e a s i de c h ai n a t t ac he d by a d ou b le bo n d ( F ig u re 1 3 - 16 ) . 3 . B u t yr o p h e n o ne s (e . g. , h al op e ri d ol ) a re c h em ic a ll y u n re la t ed t o p h e no th i a z in e s b u t h a ve s im il a r a c t i v i t y ( F i gu r e 1 3 - 17 ) . 4 . N e we r ag e n ts d e ri v e fr o m d i v e rs e c he m i c a l c las s e s a n d i nc lu de cl o zap in e , o l an za p in e , l o xa p i ne , p im o z i de , m ol i nd o ne , q u eti a pi n e, r is pe r id o ne , re m oxi p r i d e , zi p r a si do n e a nd a r ip i p r az o l e. B . P h a r ma c ol o g y 1 . Th e se ag en t s h a v e g en e r al l y s im i la r ph a rm ac o d yn am ic ef f ec ts in t he tr e a tm e nt of p s yc ho ti c i ll n es s . Th e ir an t i ps y ch o ti c a c t i on ( i. e ., i m p ro v e m e n t o f c og ni t i ve a nd b e h a vio r al ab n or m a l it i es ) r e s u l ts p r im a ri l y f ro m th e i r b lo ck ad e o f do pa m in e r e c ep t or s i n c o rt ic a l a nd l i m b ic ar e as of th e b r a in , wh e r e a s t he i r a d v e rs e e xt r a p yr a m i da l e f fe c t s s u c h as p ar ki ns o ni a n r eac t io ns r es ul t f ro m a nt a gon i s m o f d o p am in e r ec e pt o rs in t he b as al ga n gl ia . 2 . O t he r ef f ec ts v a r y am o n g t h e c l as s es o f a n ti psy c h o ti c s . Th es e i nc lu d e a n t ie m e t ic a c ti vi t y a nd bl oc k a d e o f m us c ar i ni c , se r ot o ne r gi c , α 1 - a d re ne r g ic , a nd H 1 h i st am i ne r gi c r ec e p to rs . 3 . Th e at y p ic a l a nt i ps y c ho t ic s ( e .g . , c lo z a p in e , a r ip i p ra z o l e ) a re ne we r a g en t s t h at s h o w s t ro ng a nt a go ni s ti c p r o pe r ti es a t se r o to n in re c ep t o rs i n a d di t io n t o t he i r b l oc ka d e o f d op am i ne r ec e pt o rs . C om pa r ed t o t he p he n ot h ia z i ne s , b ut y r op h e no ne s , a n d o t he r c l as s ic an t ip s yc h ot ic d ru gs , th e a t y p ic al a ge n ts a r e e f fe c ti v e in a m el io r a ti n g a wi d e r r ang e of s ym p to m s , i nc l ud ing n eg a ti ve s ym p to m s , a nd t he y a l so a re le s s l ik e l y t o i nd u c e e xt r a p y r am i da l s ide e f fe c t s . P.299
Table 13-6. Antipsychotic Phenothiazines
General Phenothiazine Structure*
Drug
XSubstituent
R-Substituent*
Chlorpromazine (Thorazine)
-Cl
-(CH2)3-N(CH3)2
Triflupromazine (Vesprin)
-CF3
-(CH2)3-N(CH3)2
Thioridazine (Mellaril)
-SCH3
Prochlorperazine (Compazine)
-Cl
Trifluoperazine (Stelazine)
-CF3
Fluphenazine (Prolixin)
-CF3
*
Antipsychotic phenothiazines have the general structure illustrated in the table. Substituents at positions marked X and R result in different drugs.
Figure 13-16. Thioxanthenes, similar to phenothiazines, have substituents at X and R positions that alter drug activity. Chlorprothixene (Taractan) has a —Cl substituent at X and CH—(CH2)2—N(CH3)2 at R. Thiothixene (Navane) has a—SO2 N(CH3)2 substituent at X and the group:
Figure 13-17. Structural formula of haloperidol (Haldol), a butyrophenone antipsychotic.
P.300
Figure 13-18. Structural formulas of (A) phenelzine (Nardil), a hydralazine derivative monoamine oxidase (MAO) inhibitor, and (B) tranylcypromine (Parnate), a cyclopropylamine derivative MAO inhibitor.
C . T h e ra p e ut i c i n d ic a tio n s . An t ip s yc h ot ic s a r e in d ic a te d p r im a ri l y fo r the t r ea tm e nt o f ps yc ho s i s a s s oc ia t ed wi t h s c h i z o ph r en i a ( e .g . , h a lo pe r i do l , a ri p ip r a z ol e) , p a r an o ia , a n d To u r e tt e ' s s y n d ro m e ( e. g . , p im o z ide ) . P r om et h a z in e a nd o th e r c l as s ic a g e nt s a r e us e d as a nt iem e ti c s ba s e d o n t h ei r blo c k a de o f d op am in e re ce p t o rs i n t h e c he m o r ec e pt o r t r i gge r z o n e o f t h e m e d ul la an d i n th e s t om ac h. D . Ad ve r s e e f f ec t s 1 . C e nt r a l l y m e d i a t e d ad ve r s e e f fe c ts in cl u de dr o ws i n es s ; e xt r a p yr a m i da l s ym p to m s s uc h a s a k a t hi s ia , a c u t e d y s to n ia , a ki ne s ia , a n d t a rd i v e d y s k i nes i a; a l t er a ti o n o f t em p e ra t ur er e g ul a ti n g m e ch a ni s m s in c l u di n g p oi k i l ot h er m y ; in c r ea s e d a p p et i te an d we i gh t g a in; a nd al t e ra t io ns in h y po th a la m i c a n d e nd oc r in e fu n c t i on s uc h a s i nc r ea s ed re l ea s e o f c or t ic o t ro pi n , g on a do t r o pi ns , p r ol ac t in , gr o wt h h o r m o ne , an d m el an o c y te - s ti m u l at in g ho rm o ne . 2 . P e r ip h e ra l ad ve r s e ef f e c t s i nc lu de po s tu r al hyp o t e ns io n a n d r e fl e x t ac h y c ar d i a ; h e p at o to xi c i t y an d j a un di c e; f ai lu r e o f e j ac ul a ti on ; b on e m a r ro w d e p r es s i on ; p h o to se ns i ti v i t y ; xe r o s tom i a; an d b l u rr e d vi si o n.
X. ANTIDEPRESSIVE AND ANTIMANIC AGENTS m a y be b ro a dl y c l as s i f ied i nt o f i ve s t r uc tu r a ll y a nd m e c h a ni st ic a ll y u n re la te d g r o up s : t he MA O i n h i bi t or s , c la s s ic a l o r t r ic yc li c a n t id ep r es s a n ts , s el ec t i ve s e r ot o ni n r e up t ak e i nh i bit o r s ( S S R I s) , th i rd - g en e ra t i on o r a t y pi c a l a n ti d ep re ss a nt s , a n d a n ti m a ni c a n ti d ep r es s a n ts o r m o o d s ta bi l i zer s . A. C h e m i s t r y 1 . M AO i n h ib i t o rs m a y b e we a k l y p o te n t h yd r a l a z i ne s ( e .g . , p h en el z i n e) o r e xt r e m e l y po t en t ph e n yl c yc l o p r o p yl a m i n e s s uch as t ra n yl c y pr o m i ne wh ic h i s a r i n g -c lo s e d a m p h et am i ne d e ri v a t i v es (F i gu r e 1 3 -1 8 ) . 2 . T r ic yc l i c a n ti de p r es s a n ts , wh i c h a re us ed c om m o n l y , a r e s ec on da r y o r t e rt i ar y a m in e d e ri v a t i v es of m o le c ul es th a t h a v e a fu s e d t h r ee - r in g s y s te m . a . Th e pr i nc ip al t ri c y c l ic a n t id ep r es sa n ts a re de r iva t i ve s o f d i be n z a ze pi ne ( e . g. , i m i p r am i ne , d e s i p ra m i ne , c l om ip r am i ne , t r im i pr am i ne ) an d d ib e n z oc y c lo he p t ad ie n e ( e . g ., am i tr i pt y l i ne , n o r t ri p t y l in e , p ro t r ip t yl in e ) ( F ig u r es 13 - 19 an d 1 3 - 20 ) .
Figure 13-19. Structural formulas of tricyclic antidepressants derived from dibenzazepine: (A) imipramine (Tofranil) and (B) desipramine (Norpramin).
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Figure 13-20. Structural formulas of tricyclic antidepressants derived from dibenzocycloheptadiene: (A) amitriptyline (Elavil) and (B) nortriptyline (Aventyl).
b . O t h er c l os el y r e la t ed tr i c y c l ic an t id e pr e s s an ts in c lu d e d o xe p in , a d ib en zo xe p i n e , a n d a m o xa p i n e , a d i be n zo xa z e p i n e . 3 . At yp i c a l a n t id e pr es s an t s h a ve v a ri ed s t r uc t u res r an g in g f r om th e s im ple p h e ne t h y la m i ne v e nl a fa x i n e a nd t he ph e n y lp ip e r az i n e ne f a zod o ne to t he a m in ok e to n e b up r op i on a n d t h e c o m pl e x h e t er oc y c l ic s m ap r o ti li n e a nd m ir t a z e p in e . 4 . S S R I s h a v e v a r ie d c he m ic al s t r uc t ur es an d a re r el a t ed on l y b y t h ei r p h a rm ac ol o gi c a l l y c om m o n ab il i t y to in h ib it t he re u p ta ke of se r o to ni n fr om t he s yn a pt ic c l e ft . Th es e c om p ou n ds i nc l ud e f l uo xe t i n e , p a r o xe t i ne , s e rt r a li ne , an d f l u v o xa m i ne ( Fi g ur e 1 3 - 21 ) . 5 . L i th i um is an al k a li m e t a l t ha t i s u s e d i n t h e fo r m o f th e c a rb on a te s a lt i n t he t r e a tm en t o f m a ni c d ep re s s i on o r b ip ol a r d is e ase . O t he r ag e nt s i n t hi s t he r a pe u ti c c a te g o r y i nc l ud e t h e o r ga n ic c om p ou n ds va l p ro ic a ci d an d c a r ba m az ep in e . B . P h a r ma c ol o g y 1 . M AO i n h ib i t o rs ap p ea r t o p r od uc e t h ei r an t ide p r es s a n t e f fe ct s b y b loc k i n g t he i n t ra n eu r o na l o xi d a t i v e de a m i n at io n o f b ra in bi o ge n ic am in es ( e. g ., d op am i ne , n o r ep i ne p hr i ne , s e ro t on in ) . Th is ac t io n i nc r ea s e s t h e a v a il a bi li t y o f b io g en i c am i ne s a t ce n tr a l am i ne r gi c s y na p s e s , a nd he nc e t h e p ro b a bi li t y o f i nt e ra c ti on wi t h p o st s yn ap t ic re c e p to r s to e li c i t t h e d es i re d t h e rap e u ti c e f fe c t s . O t h er bi oc h em ic al e ve n ts ( e .g . , t he do wn - r e g ul a ti o n o f c en t r al β -a dr e n e rg ic an d s e ro t on e rg ic r e c ep t or s ) t h at r es ul t fr om c h r on ic in h ib i ti on of M A O a n d re up t ak e b lo c k ad e c a n a ls o e xp l a i n th e t h e ra pe u ti c ac t io n o f an t id ep r es s a n ts . Th i s e xp l an a ti o n is su gge s te d b y t h e l a te nc y p e ri o d o f MA O i n hi b it o rs , wh i c h ta k e 2 - 4 we e k s to be co m e ef fe c ti v e . 2 . T r ic yc l i c a n ti de p r es s a n ts ap p ea r to ac t p r in cip a ll y b y r e du c i ng C N S ne u r on a l r e u p ta ke of t he bi og e ni c a m in es no r ep i ne p hr i ne an d s e r ot o ni n . Th i s p r ol ong s th e s yn a pt ic a v a il ab i li t y of bio g e ni c am i ne s a nd he nce t he i r a c t i on at c e n t ra l a m in e rg ic r e c ep t or s .
Figure 13-21. Structural formulas of (A) trazodone (Desyrel) and (B) fluoxetine (Prozac), atypical antidepressants.
P.302
3 . S S R I s a nd a t yp i c a l an t i de p re ss an t s h a ve va ry i n g ef f ec ts on r eu p ta ke o f bi o ge ni c a m in es . Th e SS R I s s el ec t i v el y i nh i bi t s e ro t on i n re u p ta k e in t o t he ne r ve te r m in al , t h us p ro l on gi n g t he s y nap t ic ac t i v it y o f t h e am i ne. Tr a z o d o ne an d o t he r h e t e ro c yc l ic s al s o in h ib i t a m i n e t r an s m it t e r r e up ta k e. W hile bu p r op io n a pp e a rs to s e le ct i v e l y i n hi bi t do p am i n e r e up t ak e , i ts m ec h ani s m m a y i n vol v e ad di t io na l c u r re n tl y u nk n o wn ac ti o ns s i nc e s om e o th e r i n hi bit o r s o f d op a m i ne r eu p ta k e m a y n o t e xh i b i t a n ti d ep r es s i v e e f fe c t s . +
4 . L i th i um ap p ea r s t o i nt e r f e re wi t h tr a nsm e m b ra n e Na e xc h a ng e , a lt e rs t he r e l ea se o f am i ne r gi c n eur o t r an s m i tt e rs , a n d b lo c k s in os i to l m e ta bo l ism , ul ti m at e l y l e ad i ng to de p le t io n o f c e l lu l a r in o s i t ol a n d i nh i b it i o n o f p ho s p h ol i pa s e C -m e di a te d s i gn al t r an s d uc t io n . Th e r e l e v an c e o f t he se ac t ion s to th e m oo d -s t ab i li z i ng e f fe c t s o f li t hi um , h o we v e r , h as n o t b e en es ta b li s h e d. C ar b a m az ep i n e a nd va l p ro i c ac i d a r e k n o wn to in t e rf e r e wi t h io n ic c on d uc ta n ce s i n n e r ve c e ll s , an d to m o dul a t e o th e r i n t ra c el lu l ar s i gn a li n g c as c a d es , b u t t he c o n t ri bu ti o ns of t he s e ac ti o ns to th e i r c l in ic al e ff ec t i v en es s i n b i po l a r d is or d e r r em a in u n cl e ar . C . T h e ra p e ut i c i n d ic a tio n s 1 . M AO i n h ib i t o rs a re ind i c a t ed to t re a t d e pr es sio n , p h ob ic an xi e t y , a n d n a r c o le ps y t h a t h as no t re s p o nd ed to o th e r t r e at m e n ts . Ho w e v e r , th e i r us e i s l im it e d b y t h ei r a d ve r s e ef f ec ts (s e e X. D . 1 ) . 2 . T r ic yc l i c a n d a t yp i c a l a n ti de p r ess a nt s a nd t he S S R I s a re t he ag e nt s o f c h oi ce f o r en d og en o us de p re s s io n . Ad d it i on al l y, i m i p r am i n e i s us e d t o t r ea t en u re s is ; c l om ip r am in e , f lu o xe t i n e, a nd fl u v o xa m i ne a re us e d in ob se s s i ve -c om pu ls i v e d i so r de r ; a n d d o xe p i n, fo r a n xi e t y . 3 . L i th i um an d va l p r oi c a c i d a re in d ic at e d f o r t he t r ea tm e nt o f m a n ic - dep r e s s io n ( o r bi p ol a r d is ea s e ) . Th e a n ti e pi le p ti c d r ug , c a rb a m a z e pi n e, ha s a ls o b ee n u s e d a s a m o o d -s ta b il i z e r i n b ip ol a r i l ln es s . D . Ad ve r s e e f f ec t s
1 . M AO i n h ib i t o rs in t e rac t wi t h s y m pa t ho m i m e t ic d r u gs a n d wi t h f oo ds tha t ha v e a h i gh t yr am i ne c o nt e nt s uc h a s c he es e , wi n e , an d s a us ag e . H y pe r t en si ve cr i s es c an r e s ul t . I n a dd i ti o n, MA O i n hi b it o rs ca n c au s e a wi d e r an ge o f a d v e rs e e ff ec t s, i n cl ud i ng : a . C N S ef f ec ts , s uc h a s C N S s t im ul a ti on , t re m o rs , ag i ta ti o n , o v e ra c ti v i t y , h yp e r r ef l e xi a , m a ni a, and i ns om ni a f o ll o we d b y we a k n es s , f a ti gu e , a nd dr o ws i n es s b . C a rd i o v as c u la r ef f ec ts , s uc h a s p os t u ra l h yp ot e ns i on c . G I e f fe c ts , s uc h as n au s ea , a b do m i n al pa in , an d c o ns ti p at i on d . A n ti m u s c a ri ni c e f fe c t s , s uc h as d r y m o ut h , u r ina r y r e t en t io n , a nd c o ns tip a t io n 2 . T r ic yc l i c a n ti de p r es s a n ts c a n c au s e ad v e r s e e f f ec ts , i n cl ud i ng : a . C N S ef f ec ts , s uc h a s d r o ws i n ess , d i zz i n es s, we a kn es s , f at i gu e , a nd c on f us i on b . C a rd i o v as c u la r ef f ec ts , s uc h a s o r t ho st a ti c h y p o t en si o n, ta ch y c a rd i a, a n d i n t er f e re nc e wi t h a t r io v en t r ic ul a r c on d uc ti o n c . A nt im us c a r in ic e ff ec t s , s uc h as d r y m o ut h , u r ina r y r e t en t io n , a nd c o ns tip a t io n d . G I ef f ec ts , s uc h a s n au s ea , v om i ti ng , di a r rh ea , a n d a no r e xi a e . B on e m a r ro w d e p re s s io n f . Ma n i a p re c i pi t a ti on ( in p a ti e nt s wi t h m a n ic - de pr e s s i v e i ll n es s) 3 . At yp i c a l a n t id e pr es s an t s c an c a us e a d v e rs e ef f e c t s, in c l u di n g: a . C N S ef f ec ts , s uc h a s d i z z i n es s, ni g ht m ar es , c o n f us io n , d r o ws in es s , f ati g ue , h e a da c h e , i ns om ni a , im pa i r ed m e m o r y, ak at h is ia , n um b ne ss , a n d t on ic - c lo n ic s e i zu re s b . C a rd i o v as c u la r ef f ec ts , s uc h a s h y p e r te ns io n , h yp o te n s i on , ta c h yc a rd ia , ch es t p a in , an d s y n c o pe c . G I e f fe c ts , s uc h as n au s ea , v om i ti ng , di a r rh ea , a n d c o n st ip a ti o n d . B lu r r ed v i s i on an d ti nn i t us e . A nt im u s c ar i ni c e f fe c t s , s uc h as u ri n ar y r e t en tio n , d r y m ou t h, an d c on s ti p a ti on f . B o ne m a r ro w d e p r es s io n g . S e xu a l d y s f un c ti on and m e ns t r ua l i r r eg u la r it i es 4 . L i th i um t he r ap y m a y b e as s o ci a te d wi t h d e v elo p m e n t o f f i ne ha nd t rem o rs an d i n c re as ed u ri n at i on ; t h es e s i d e e f fe c t s , h o we v e r , u s ua ll y d im in is h wi t h c ont i n ue d t h e r ap y. P.303
XI. ANXIOLYTICS AND SEDATIVE-HYPNOTICS. A n t i an xi e t y a n d s e d at i v e- h y p n o ti c a ge n ts i n c u r ren t us e c om p ri s e th e h i ghl y e f f ec t i v e b en z o di a z e pi n es ( e. g . , a lp r a z ol am , di a ze p am , fl u ra z e p am ) a n d th e at y p ic a l a za s pi r od e c a ne d io n es (e. g . , b us p ir o ne ) an d i m i daz o p yr i d in es ( e .g . , z o l pi de m ) . D i v e r s e c l as s es o f a g en ts p re v i o us l y u s e d a s a n xi o l yt ic s an d s ed a ti v e - h y pn o t ics ( e . g ., ba r b it u ra t es , m ep ro b am a te , a n d h y d r o xy zi n e ) a re no lo n ge r fa vo r e d b e ca us e o f t he i r l ia bi l it y t o p r od uc e to le r a nc e, ph ys ic al dep e n de nc e , s e ve r e wi t hd ra wa l r e a ct i on s , an d s e ri o us t oxi c i t y wi t h o v e r d os ag e . A. C h e m i s t r y
1 . B e nz od i az e pi n es ( e.g . , al p ra z o l am , d ia z e p am , c h lo r di a ze po xi d e , c l o n a z e p am , c l o ra z e pa t e , l or a z e pa m , a n d o xa ze p a m ) h a ve v a ry i n g du r a ti on s o f a c ti on , wh i c h ca n b e c o r re l at e d wi t h t he i r s t r u c t u r es i n s om e c as es ( Ta b l e 1 3 - 7 ). a . A ge n ts wi t h a 3 -h y d r ox y l g r o u p a r e e as il y m e ta b ol i z e d b y p ha se I I g l uc u ro n id a ti on a nd ar e s h o rt ac ti n g ( s e e R 3- s u bs t i tu en t c o lu m n in Ta b le 1 3 - 7 ). b . A ge n ts la c k in g a 3 -h y d r o xy l g r o u p m us t u nd e rg o c o ns id e ra b le ph as e I m e ta b ol is m , in c l u di ng 3 -h y d r o xy l a t i o n . Th e se age n ts a re lo n g ac t in g . Mo s t lo ng a c ti n g a ge n ts fo r m t he int e r m e d ia t e m e t ab o li t e d es m e t h y ld i a z ep am , wh i ch h a s a ve r y l o n g h al f -l i fe . Th us , t h es e a ge n ts c a n h a ve a cu m u l at i v e a c ti on . c . Tr i a zol o be n z o di a z e pi ne s (e . g. , al p ra zo l am ) u nd e r go a d i ff e re n t p a tt e r n o f m e ta b ol is m a nd a re in t erm e di a te in ac ti v i t y. d . A ge n ts la c k in g a n a m in o s i de c h ai n a r e n o t b as ic en o ug h t o fo r m wa t e r- s o lu bl e s a lt s wi t h ac i ds . F o r e xa m p le , i n t ra v e n ou s s o l ut io n s o f d ia z e p am c o nt a in p r o p y le ne g l yc ol as a s o l v e nt . P re c i p i ta t io n c an oc c u r i f th es e s ol u ti o ns a r e m i xe d wi t h a q u eo us s o lu t io ns . 2 . Az a s pi r o d ec a ne d io ne s o r a za p i r on e s ( e .g . , b u s p i ro n e, ge p i ro ne , ip sa p i ro n e, t i as p ir o ne ) a re c h em ic al ly u n r e la t ed to th e be n z od i a z e pi ne s . R e p re s e n te d b y b u sp i ro n e, t he s e ag e nt s h a v e an xi o l y t i c a c t i v i t y re s em bl i ng th a t o f t h e b e n zo di a z ep i ne s . U n li k e t h e b en zo d ia z e p in es , bu s pi r on e l ac ks C N S de p re ss a nt a c ti vi t y a nd is c on s i d e red a n a t ypi c a l a n xi o l y t ic (F i g ur e 1 3 - 22 ) . 3 . Th e im i da z op yr i d i n e z o l p id e m is a n on b en zo di a ze pi n e s ed a ti ve - h y pn o ti c wi t h a c ti o ns g e ne r al l y r es em b l in g th os e o f th e b en zo d i a z e pi ne s . 4 . B a r bi t u r a te s a r e 5 , 5 -d i s u bs t it u te d d e r i v at i ves o f ba r bi t u ri c ac i d, a s atu r a t ed t r i k e t op y r i m i di n e ( Ta b l e 1 3 - 8 ). a . Two s i d e c h a in s i n p os i ti o n 5 a r e e s s en t ia l f o r s ed a ti ve - h y p no t ic a c ti v i ty . b . L on g -a c t i ng ag e nt s h av e a ph e n y l a nd an e th yl g r o u p in po s i t io n 5 . c . B ra nc h ed s i de c h ai ns , u ns a tu r a te d s id e c ha i ns , o r s id e c ha i ns l o ng e r t ha n an e t h yl g r o up in c r e as e l ip op h il ic i t y an d m et a bo li s m r a t e . I nc r ea se d l i po p hi li ci t y l ea ds t o a s ho r te r on s e t of ac t io n , a s h o rt e r d u r at i on of a c ti o n, an d i nc r e as ed pot e nc y . d . R e pl ac em e nt of t he po s it i on 2 o xyg e n wi t h su lf u r p ro du c es a n e xt r e m e ly l i p op hi l ic m o le cu l e t ha t d is t r ib u te s r a pi d l y i n to li p id ti s s ue s o u ts id e th e b r ai n . ( 1 ) Th e s e ul t ra - s h o r t -a c ti n g b a rb i tu r a te s a r e n ot u s ef u l as s e d at i v e -h y p n ot i c s bu t a r e ef f ec ti v e in f ac il i ta ti ng t he in d uc ti o n o f a ne s the s ia (s e e XI I . C . 4 ) . Th e ac t io n o f t h es e d r u gs i s t e rm in a ted v e r y q ui ck l y . ( 2 ) Th e pr o to t y p e u l t ra -s h o r t -a c ti ng ba r b it u ra t e i s t h io p en t al ( Pe n to t ha l ) , th e 2 -t h io i s os te r e o f p e n to ba r b it al. e . Th e ba r bi t u ra t es a n d m a n y o f th e ir m e t ab ol i tes a re we a k a c i ds , a n d c ha n g es i n u r i na r y p H gr e at l y in f lu en c e t he i r e xc r e t i on . Th is i s p a r ti cu l ar l y t ru e wi t h ov e r d o s e s , wh e n a r el a ti v e l y la r ge am o un t o f un ch a ng ed d rug a p p e ar s i n t h e g lo m e r ul a r fi l tr a te . f . P h en o ba r bi t al is o n e of t h e m o s t p o we r f ul a n d ve r s a ti l e a ge n ts th a t ca n i n du c e c e r ta i n e n z y m e s ys t em s ( e . g ., t he c y t o c h r om e P -4 5 0 m et a bo li c s ys te m ). Th i s i n c re as es th e p o te n ti a l fo r d ru g i n te r ac t io ns an d i n c l ud e s in t e ra c ti on wi t h a n y d r ug m e ta b ol i z e d b y th is s ys te m . O th e r b a rb i tu r a te s ha ve l es s e n zy m e - in d uc ing e f fe ct , e xc e p t wh e n th e y a re us e d c o nt i nu o us l y i n h i gh er - t h an - n or m al d o se s .
5 . P i pe r i d in e di o n es (e .g . , gl ut e t him i de , m e th yp ry l o n ) an d a l de h yd e s ( e . g . , p a r al d eh y d e , c hl o ra l h y dr a t e ) d i ff e r s t ru c t u r al l y (F i g ur e 1 3 - 23 ) an d a r e u s e d le ss c om m o n l y th a n t he be n zo d ia z e p in es as s e da t i v e -h y p n o ti c s . B . P h a r ma c ol o g y 1 . B e nz od i az e pi n es ap pe a r to p ro du c e t he i r c alm i ng an d h y p n ot ic ef f ec ts b y d e p re ss in g th e l im bi c s ys t em an d re ti c ul a r f o rm at i o n t h ro u gh po t en t ia t io n o f th e i n hi b it o r y ne u r ot r an s m i tte r γ -a m i no b ut y r i c a c i d (G A B A ) . P.304
Table 13-7. Benzodiazepine Anxiolytics and Sedative-Hypnotics General Benzodiazepine Structure*
Drug
R1
R2
R3
X (R2′) Comments
Diazepam (Valium)
—CH3
=O
—H
— H
Chlordiazepox ide (Librium)
= (Ring double bond)
— NH — CH3
—H
— H
Halazepam (Paxipam)
—CH2CF3
=O
—H
— H
Clorazepate (Tranxene)
—H
=OH (— OK)
— COO H (— COO K)
— H
—O (Noxide) at positi on 4
Oxazepam (Serax)
—H
=O
—OH
— H
Lorazepam (Ativan)
—H
=O
—OH
— C l
Alprazolam (Xanax)
R1C(CH3)=N -N=R2 (Fused R1R2 triazolo ring)
—H
—H
Flurazepam (Dalmane)
CH2CH2N( C2 H5)2
=O
—H
— F
Quazepam (Doral)
—CH2CF3
=S
—H
— F
Triazolam (Halcion)
R1C(CH3)=N -N=R2 (Fused R1R2 triazolo ring)
—H
—H
Temazepam (Restoril)
—CH3
=O
—OH
*
— H
Benzodiazepine anxiolytics and sedative-hypnotics have the general structure illustrated in the table. Substituents at the positions marked R1, R2, R3, R7, and X (R2′) and the ring nitrogen at the position 2 result in different drugs and clinical properties. All compounds shown have Cl substitution at position R7. Clonazepam, not shown, has an NO2 substituent at R7 and is used primarily as an anticonvulsant.
Figure 13-22. Structural formula of buspirone (Buspar), the prototypical azaspirodecanedione anxiolytic.
P.305
Table 13-8. Barbiturate Sedative-Hypnotics General Barbiturate Structure*
Drug
R1Substitue nt R2-Substituent
Phen obar bital (Lu mina l)
— CH2 CH3
Amo barb ital (Am
— CH2 CH3
Duratio n of Action Lon g
—CH2CH2CH(CH3)2
Inte rme diat e
ytal) Buta barb ital (But isol)
— CH2 CH3
Inte rme diat e
Pent obar bital (Ne mbu tal)
— CH2 CH3
Sho rt
Seco barb ital (Sec onal )
Sho rt
— CH2 CH =C H2
*
Barbiturate sedative-hypnotics have the general structure illustrated in the table. Substituents at R1 and R2 positions result in different drugs with different durations of action. a . A n xi o l y t ic a c ti v i t y c o r re l a te s wi t h t he d ru g 's bin d in g a f f in i t y t o a m a c rom o le c u l ar c om p le x c o n s i s t i ng of GA B A A r ec e p to rs an d c hl or i d e c ha nn e ls . b . Th e in t er a c t i on of be nz o d i a z e pi ne s wi t h G A B A c au s e s a n i nc r ea s e in th e f r e q ue nc y o f c hl o ri d e c ha n n el o p en i ng e ven ts , lea d i n g to a f ac il i ta t io n o f c h lo r id e i o n c on d uc ta nc e , m em b ra n e h y p e rp o la r i z a ti on , an d ul t im at e l y s yn ap t ic inh i bi t io n .
Figure 13-23. Structural formulas of (A) glutethimide (Doriden), a piperidinedione sedative-hypnotic and (B) chloral hydrate (Noctec), an aldehyde sedative-hypnotic.
P.306
c . In ad d it i on to th e i r a nxi o l y t i c p ro p er t ie s , m o s t b e n zo di a zep i ne s h a ve o th e r s i gn i fi ca n t C N S ac t io ns , i n c l ud i ng h y pn o ti c , a ne sth e t ic , a n ti c o n v ul sa n t , a nd m u s c le r e l a xa n t ef f ec ts at ap p r op r i at e do s e s. d . B en zo d ia z e p in es in c re a s e th e d e p re s s an t ef f ec t s o f a lc oh o l a nd ot h e r C N S d e p re ss a nt d ru gs . 2 . Az a s pi r o d ec a ne d io ne s ha v e m u lt i pl e b io c hem ic a l ac t io ns , bu t t h ei r pr i n c i pa l m ec h an is m o f a n xi o l y t ic e f f ec t i s s ti ll un k n o wn . a . B u sp i r o ne bi n ds t o c e n t r al do pa m i n e a nd s e ro t o ni n re c e p to r s r a th e r th a n t o G A B A - c h lo r id e i o no ph o re r ec e pt o r c om pl e xe s . Int e r ac t io ns of a z a pi r on es wi t h s e r ot o ni n r e c e p to rs m a y b e ag o ni s t ic wh e n a c ti ng a t s om a to d en d ri t ic 5- H T1 A a u t o re ce p to r s o r a n ta g on i s t ic wh e n ac ti n g a t p ost s y n ap t ic 5 - H T1 A r ec ep t or s . b . B us pi r o ne po s s es s e s n o h y pn o ti c o r a n ti co n v ul s an t p r o pe r ti es an d do es no t a p p ea r to en ha n c e th e de p r es s a n t e f fe ct s o f a lc oh o l o r ot h er C N S de p re ss a nt d ru gs . c . B us pi r on e h as m i ni m al a bu s e li ab i li t y an d d o es n o t p r od uc e re b ou nd anxi e t y f o l lo wi n g a b r up t d is c o n tin u a ti on . 3 . T he im i da z op yr i d i n e s h a v e s t ro ng s e da t i ve ef f e c t s wi t h m i ni m al c li n ica l a n xi o l yt i c ac t io ns . a . Z ol pi d em i s a s e ff ec t iv e a s t h e b en z o d ia z e pi ne s i n s ho r t en i ng s l ee p l at e nc y a n d i n pr o lo n gi ng t ot a l s l e ep t i m e in pa t ie n ts wi t h i ns om n ia . b . Z ol pi d em i s r a r el y as s o c ia t ed wi t h p h ys ic al dep e n d e nc e , r e bo un d i ns om n ia , o r r e s pi r at o r y de p r es s i on ev e n i n o v e r do s a g e. 4 . B a r bi t u r a te s a r e l es s s el ec t i v e t h an be n z o di aze p i n es a n d p r od uc e g en e r al i ze d C N S d e p re s s io n . a . B a rb i tu r at e s b in d t o a s i te t ha t i s d is ti nc t f ro m t h e b e n z od i a z ep in e b i nd in g s i te on a m a c ro m o l ec ul a r G A B A- c h lo r id e i on o ph o r e r ec ep t o r c om pl e x. B a r b it u ra te b in di n g i n du c es a n i nc r e as e i n th e du r a ti on o f c h a nn el op e n i n g e v e n ts , a nd t hu s m im ic s o r e n h an c e s t he in h ib i to r y a c ti o ns o f G A B A . b . B a rb i tu r a te s h a v e a wi d e r a ng e o f do s e - de p end e n t p ha r m a co lo g ic al ac t i o ns r e l at e d t o C N S d ep r es s io n , i nc l ud in g s e da t io n , hy p n o s i s, a nd an es t he si a . Th e y a l so a c t a s p ot e nt r es pi r a to r y d e p re ss an ts an d i n du c er s of he p at ic m i c ro s o m a l d r u gm e ta b ol i z in g e n z y m e a c ti v i t y . 5 . P i pe r i d in e di o n es , a ld e h yd e s , a n d ot h er no nb a r bi t u ra t e s e d at i ve - h y pn o t ics ha ve s im i la r p h a rm ac ol o gi c a l a c ti o ns re l at e d t o C N S de p r es si on . a . C hl o r al h y d ra t e is c om m o n l y u s e d to in d uc e sl e ep i n pe d ia t r ic o r ge r iat r i c p a t ie n ts . I ts lo w c o s t is th e m a jo r fa c t o r a c c ou n tin g fo r it s p r ef e r r ed us age i n i n st i tu t io n al s e tt i ng s . b . C h lo r al h y d ra t e is bi o tr a n s f o rm e d t o t r ic hl o ro e th a n ol , wh ic h i s r es p on sib l e f o r t h e p h a rm ac ol o gi c a l a c t i v i t y o f t he dr u g. C h lo r al h y d ra t e i n du c e s h ep a ti c m i c ro s om al d r u g -m et a bo l i z in g e n z y m e ac t i v i t y . C . T h e ra p e ut i c i n d ic a tio n s 1 . B e nz od i az e pi n es a nd t h e a za s p i ro d ec a ne d i on e b us p i r on e a r e i nd ic at e d to t r e a t a n xi e t y . B us pi r on e i s m o re ef f ec t i ve i n p at i en t s wi t h g en e ra l i zed an xi e t y o f m i ld to m o de r a te s e v e r ity . Th e a n ti a n xi e t y ef f ec ts o f b us pi r on e m a y re q uir e u p t o a we e k t o b e e s t a bl is h ed .
2 . B e nz od i az e pi n es a nd t h e im i da zo p yr i d i n e a re i nd ic a te d t o p r o du ce dr o ws i n es s a n d p r om o te s l ee p . 3 . B e nz od i az e pi n es a re i n di c a t ed fo r us e a s a pr e a ne s th e ti c m e d ic at i on , a s a n t ic on v u ls a nt s , a nd du ri n g a c u t e a lc oh o l wi t h d rawa l . 4 . B a r bi t u r a te s a r e n o lo n g er c o ns id e r ed ap p ro pr i a te as an xi o l y t i c s or sed a t i v e h yp n o ti c s i n v ie w o f t he a v a i la b il i t y o f th e s a fe r be n zo d ia ze pi n es . L o ng - ac t i n g b a r bi t u ra t es c o nt in u e t o b e wi d e l y u s e d a s a n ti epi l ep t ic s , wh i l e t he ul t r a -s h o r t a c ti n g b a rb i tu r at es a re us e d f o r t he in d uc ti o n o f g e n er a l a ne st h es ia an d a s g e ne r al a n es t he t ic s ( in c o m b in a tio n wi t h a n a n al g es ic ) f o r s ho r t s u rg ic a l p r oc ed u res . 5 . C h lo r a l h yd r a t e i s i nd i c a t ed fo r us e a s a p e dia t r ic o r g er i at r ic h y pn o tic , an d a ls o a s a p re a ne s t h et ic ag e nt f o r m in o r s u rg ic al an d de n t al p ro ce du r es . P.307
D . Ad ve r s e e f f ec t s 1 . A d ve rs e e f fe c t s a s s oc i a t ed wi t h be nz o d ia z e p in e s i nc l ud e : a . C N S ef f ec ts , s uc h a s C N S d e p re ss io n , d r o ws in e ss , s ed a ti o n, at a xi a , c o n f us io n , a n d d ys a rt h r ia b . G I ef f ec ts , s uc h a s n au s ea , v om i ti ng , an d d ia r rh e a c . Ps y c hi a t ri c e f fe c t s a r e r a r e a nd in c l u de pa r ad oxi c a l e xc i t em en t , i ns om ni a , p a r an o ia , a n d r a ge re a c ti o ns d . P o te n ti al f or ab us e and d ep e nd en c e 2 . A d ve rs e e f fe c t s o f b us p i r o ne a re li m i t ed to r es t le ss ne ss , d i zz i n es s , hea d ac h e, n a us e a, di a r rh e a, an d pa r e s t h es ia s. 3 . B a r bi t u r a te s c an c a us e a v a r ie t y o f a d v e rs e ef f e ct s, in c l u di n g: a . C N S ef f ec ts , s uc h a s d r o ws i n ess , c o nf us i on , nys t a gm us , d ys a r th r ia , d ep r e s s ed s ym p at h et ic ga n gl io n ic t ra n s m is s i on , h y p e r al g es ia , im pa i re d j u dg m e n t , im p a i re d fi ne m o to r s k i l ls , p a ra d o xi c al e xc i t e m e n t ( in ge r i at r ic p a t ie n ts ) , a nd po t en t ia t io n of o th e r C N S d e p re s s an t dr u gs . b . R es p ir a t or y a nd c a r dio v a s c u la r ef f ec ts , s uc h as r es pi r a to r y d ep r es s i on , b r a d yc a r di a , a nd o rt h os ta t ic h y po t en s i o n. c . G I e f fe c ts , s uc h as n au s ea , v om i ti ng , c o ns ti p ati o n , d ia r r he a , a nd ep i gas t r ic d i st r es s . d . E xf o l i a ti v e de rm a ti t is a n d St e v e ns -J o hn s o n s yn d r om e . e . H ea d ac he , fe v e r , h e pa t o to xi c i t y, an d m eg a lo bla s ti c a ne m i a ( wi t h t h e chr o n ic us e o f ph e no b ar b it a l ). 4 . T r ic h l o ro e t ha n o l, th e a c ti v e m e ta b ol i te of ch lo r a l h yd r a t e , i s m et a bo li ze d to t r i c h lo r o ac et ic ac id , wh i c h is hi g hl y t o xi c an d t e nd s to ac c um u la t e wi t h r ep e a te d a d m i ni s t ra ti o n o f c hl o ra l h y d r a t e. U s e of ch lo r a l hy d r a t e i s a s s oc ia t ed wi t h t h e f o l lo wi n g a d v e rs e ef f ec ts . a . G I ef f ec ts , s uc h a s G I i r r it a ti o n a nd up s e t , n a us e a, an d v om i ti ng . b . C N S e ff ec ts , s uc h a s C N S d e p re ss io n , d is o ri en t a ti o n, in co h e re nc e , d ro ws i n es s , a t a xi a , he a da c h e , a nd po t e nt i at i on of o th e r C N S d e p re s s a nt s ( p a rt ic ul a r l y a lc o ho l ) . c . Le uk o pe ni a
XII. ANTIEPILEPTICS A. C h e m i s t r y. A n t i e p i lep t ic s ( a nt ic o n vul s a n ts ) va r y wi d e l y i n s tr uc t u re ( Fi g u re 13 24). 1 . O l d e r a ge n t s, wh i c h a r e s t il l wi d el y us e d, in c lu d e d e ri v a t i ves o f t he lon g - ac t in g b a r bi t u ra t es (e . g ., ph e nob a r bi t al , m e ph ob a r bi t al , m e th a r bi t al , p r im id o ne ) , h yd a n to i ns (e . g. , ph en y t o i n , e th o to i n ), s uc ci n im id e s ( e .g . , e t ho su xi m i d e, p h e ns u xi m id e ), o xa z o l i din e di o ne s ( e .g . , t r im e th ad i o n e , d im e th a di on e ) , a nd d i al k yla c et a te s ( e .g . , v alp r o ic ac id ) . 2 . N ew e r a g en t s , wh i c h a r e m o re s t r uc t u ra ll y d i ve r s e, in cl u de th e i m i n os ti l be n es ( e . g ., ca r ba m a z e p in e ) , be n z o d ia z e pi n es (e . g ., dia z e p am , c lo n a zep am , c lo r a ze pa t e ) , G A B A a n al o gs ( v ig a ba t rin , ga b ap e nt i n, p re ga b al in ) , an d t h e m i s c el l an e ous ag e nt s l a m o t ri g in e , f el b am at e , le v e t i r ac et am , z o ni sa m i de , an d to pi r am a te wh i c h i s a c tu al l y a su bs t i tu t ed m o no s a c c ha r i de . B . P h a r ma c ol o g y 1 . A nt i ep il e p ti c s p r e v e nt o r r ed uc e e xc es s i ve di s ch a r ge an d re d uc e t he s pr e a d o f e xc i t a t io n fr om C N S s e i zu r e fo c i . 2 . Th e m ec h an is m s o f ac t i o n o f a n ti ep i le p ti c s a p pe a r to be al t e ra t io n o f Na
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n e u ro n al c o nc en t r at i on s b y p r om o ti o n o f N a ef f lux ( e . g . , h y d an t oi ns ) an d r e s to r a ti on o r e nh a nc em e n t o f G A B A - er g ic i n hi bi to r y n e ur o na l f u nc ti o n ( e .g . , b a r bi t u ra t es , b en z o d ia z ep i ne s , v a l p ro ic ac id ) . C . T h e ra p e ut i c i n d ic a tio n s . Th es e a ge n ts ar e ge n e ra l l y c a te go r i z e d b y th e t y pe o f s e i zu re ag ai ns t wh i c h the y a r e e f fe c ti v e . 1 . D r ug s t h at a re in di c a te d fo r th e tr e a tm en t o f to n i c -c l o ni c (g r a n d m al ) s e iz u r es i n cl ud e p h en o ba r bi t al , ph e n y t oi n , p r im id on e , a nd c a rb am a ze pi n e. 2 . D r ug s t h at a re in di c a te d fo r th e tr e a tm en t o f ab s e nc e (p e t i t m al ) se iz u r e s i n cl ud e p h en o ba r bi t al , eth o s u xi m i d e, t ri m e t ha d ion e , c lo n a z ep am , an d v alp r o ic ac id . P.308
Figure 13-24. Structural formulas of the antiepileptic agents: (A) primidone (Mysoline), (B) phenytoin (Dilantin), (C) ethosuximide (Zarontin), (D) trimethadione (Tridione), (E) clonazepam (Klonopin), (F) carbamazepine (Tegretol), and (G) valproic acid (Depakene).
3 . C lo n a z ep am is in di c a te d fo r th e tr e a tm en t o f myo c l o n i c s ei z u re s .
4 . A ge n ts th a t a r e e f fe c t iv e a g ai ns t pa r t i al se i z u re s in cl ud e c l or a z e pa t e, fe l ba m at e , g a b ap en t in , an d l am o tr i gi n e . 5 . P he n y t oi n , p he n ob a rbi t a l, p ri m i do n e, an d c a rba m a z e p i ne ar e e f f ec ti v e a g ai n s t p s yc h o m o t o r se iz u r es . 6 . I nt r a v en o us di a z ep am , p he n y t oi n , a nd ph e no ba r b it a l a r e i nd ic a te d f o r th e t r e a tm en t o f s ta t us e pi le p t i cu s . 7 . To p i ra m a t e h as m ul t ipl e m ec h an is m s of ac ti o n a n d e xe r t s be n ef ic i al ef fe c ts a g ai n st a b r oa d s pe c t r um o f s e i zu r es . D . Ad ve r s e e f f ec t s 1 . B a r bi t u r a te s (s ee XI I .D . 3 ) an d be nz o d ia z e p ine s (s e e XI I . D . 1 ) u s e d a s a n t ie pi l ep t ic s ha v e t he s a m e a d v e rs e e f fe c t s a s wh e n u s e d fo r a n xi o l y t ic o r s e da t i ve -h y p n ot ic pu r pos es . In t r a ven o us u s e o f th e s e ag e nt s c ou ld ca us e c a r di o vas c u l ar c o ll a ps e a n d re s p i ra t o r y d e p re s s io n . P.309
2 . A nt i ep il e p ti c a ge n ts ge n e ra l l y h a v e th e p r op e ns i t y to c a us e t h e f ol l o wi ng s i d e e f f ec ts : a . G I i r r i ta t io n , n au s e a , a n d v om it i ng b . C N S s e da t io n , d ip l op ia , n y s t a gm us , a t a xi a , d i zzi n e ss , a n d c o n fu s i o n c . Bl o od d y s c r as ia s , in c lu d in g a p la s ti c a ne m i a a nd b le ed i ng di so r d er s d . A ll e r gi c - t y p e r e ac t io ns , in c l ud i ng S te v e ns - J o hn s on s y n d r om e e . V a ri ou s o r ga n -s y s t em t o xi c i ti e s, in c l u di ng r ena l a n d l i ve rf a il u re , pa nc re a t it is , a n d c a r di o to xi c i t y 3 . Th e h y da n to in s (e . g. , p h e n y to i n) c a n a ls o c au s e sp ec i fi c a r r h yt h m i a s an d g i n g i va l h yp e r p l a s ia . 4 . A nt i ep il e p ti c s a s a c l as s a ls o h a ve t h e p ot e nt ia l to c a us e v a ri ou s b i r t h d e f ec t s , i n cl ud i ng c l ef t pa la t e ( e .g . , c a rb a m a z e pi n e, ph e ny t o i n ) a n d n eu r al tu b e de f ec t s ( e . g ., va lp r o ic a c i d ) . Th es e e f f ec ts pr e s e n t a u n iqu e p ro bl em in t re a ti n g p re g n an t wo m e n wi t h c o n v ul s i v e di s o rd e rs . Di s c on t in u at i on o f an ti c on vu ls an t th e r apy c a n r e s ul t i n a s e i z u re s t a te t h a t c ou ld ha r m t h e f et us . H o we ve r , c o n ti n ue d t h er a p y ca n i n c re as e t h e r is k o f b i rt h d e fe c ts a n d p la c e th e m o t h e r a t r is k o f b l ee di n g d i so r de r s d u r in g d e li v e r y . Mo r e o v er , p r eg na n c y b y i ts el f c an e it h e r in c re as e o r de c re a s e s e i zu re in c i de nc e of th e m o th e r . R i sk /b e ne f it e v alu a t io n o f th e ra p y sh ou l d b e m a de o n in di vi d ua l c as es ba s ed o n t he pa t ie n t 's hi s to r y .
XIII. ANTIPARKINSONIAN AGENTS A. C h e m i s t r y. Th e p r i nc i p al an t ip a rk i ns on ia n a ge n ts a re ei t he r do p am i ne r g i c a g o n is t s o r c h o li n e r gi c a n t ag o n is t s . 1 . S om e a n t ic h ol i ne r g i c a n t i pa r k in s on i a n a ge n ts a re st r uc t ur a ll y r e la t ed t o a t r o p i ne ( e. g ., be n z t r op in e , tr i he xy p h e n i d yl ). O t he r a nt i pa rk i ns on i an an t ic h o li n e rg ic a g e nt s i nc lu d e p ro c y c l i din e ( Ke m ad r in ) , o r ph e na dr i n e ( N o r fl e x) , a n d b ip e rid e n ( A k in e to n ) . 2 . Th e pr o to t y p ic al d op am i n e r gi c a n ti p ar ki n so nia n ag e nt is th e c a te c ho la m i ne l e vo d o p a ( F ig u re 13 - 2 5), a pr o d ru g t h at m u s t be c o n ve rt e d i n v i v o t o d opa m in e b y
d o p a d e ca r b ox yl a s e . D ir e c t r ec e pt o r -a c ti ng d opa m in e rg ic s i nc lu d e e r g oli n e s s uc h a s b r om oc r i pt in e ( Pa r lo de l ) P.310 a n d p e rg o li de ( P e rm a x) , t h e p h en a nt h re n e a p omo r p h i ne , an d t h e n e we r n o n er g ol in e d o pa m i n e ag o ni s ts p ra m ip e xo l e ( Mi r a p e x) a n d ro p i ni r o l e ( Re q ui p ) .
Figure 13-25. Structural formulas of antiparkinsonian agents: (A) benztropine (Cogentin), (B) trihexyphenidyl (Artane), (C) ethopropazine (Parsidol), and (D) levodopa (Larodopa).
3 . S e ve ra l a g en ts a re a va i la b le to im p ro v e th e the r a pe u ti c e f fi c a c y an d s a f e t y of l e vo d op a . a . C a r bi d o pa , a le v o d opa a na lo g ue t ha t d o es n o t c r os s t he bl o od - b ra in bar r i e r , is a d e c a rb o x yl a s e i n h i bi t or t h a t d im in is he s t h e d ec a r b o xy l a t i on an d s u bs equ e n t i n ac t i vat i on of le v o d op a i n pe r i p he r a l t i ss u es . W hen c o a dm in is t e re d , m o r e l e vo d op a i s p re s er v e d to e n te r th e C N S . A c o m b in a t io n o f l e v o do p a a nd c a r b id o pa ( S i n em et ) is a v ai la b le for c li ni c a l u s e. b . S e le g il i n e ( d ep r e n yl ) , i s a s e le c t i ve m o no a mi n e ox i da s e - B ( M AO - B ) i n h i bi t o r t h a t i nh i bi ts th e i n t ra c e re b r al de g r ad a ti on o f e ndo g e no us or le vo d op a - de ri ve d d o p am in e . c . To l ca p o ne o r e n ta cap o n e a r e s el ec t i v e i nh ib it o r s o f C O MT, t h u s re d uc i ng th e c o n ve rs io n o f l e v o do p a to 3 - O -m e th y l d op a , a n i na c ti ve m e t ab ol i te t ha t a ls o i n hi bi t s l e vo d op a u p ta k e in t o t he b r ai n . Ad di t io n al l y, i n hib i t io n o f d o pa m i ne b re ak d o wn b y C O MT m a y p r o l on g th e av a i l ab i li t y an d a c ti on o f th e t ra ns m i t te r in th e C NS . B . P h a r ma c ol o g y. A n t i p a r k in s o ni a n a ge n ts ac t by r e s t or i ng th e s t ri a ta l ba l an c e o f d o p am in e rg ic an d c ho l ine r g ic ne u ro t r an s m is s i on , wh i c h i s d e ra n ge d i n p ar k i ns on is m a s a r es ul t o f de g en e ra t io n of do p am in e rg ic ne u ro n s t ha t s u pp l y do p am ine t o t h e b a s al g an g li a (c a ud a t e -p u t a me n ) . 1 . L e vo do p a, wh i c h c a n c r os s t h e b lo od - b ra i n b ar r i e r , is t he im m e di a te pre c u rs o r o f t h e s t ri a ta l n e u ro t ra n s m it t e r d o pa m i n e a nd is c onv e r t e d t o d o pa m i n e i n t he b od y . 2 . Am a n t ad i n e, an an t i vi r a l a ge n t, a pp ea r s t o s tim u la t e t he r el e as e o f d op a m i n e f r o m i nt ac t s t r ia t al te r m in a ls of r em ai n in g d op am i n e rg ic ne u r on s. As t he d i s e as e p r o g re ss es an d f e we r d op a m i n er g ic n e u ro ns r em a i n , a m a nt a di n e b ec om es p r o g re ss i v el y i ne f f ec ti v e.
3 . Ap o m o r p hi n e, b r om oc r i p t i ne , p e r g ol i d e, p r am i p ex o le , an d r op i n i r ole , wh i ch a r e di r ec t d op a m i ne r gi c r e c ep t or a go ni s ts , m i m i c t h e a c t i v i t y o f do p am i n e i n t h e c a ud a te - pu t am e n. N e v e rt h e le s s , t h e d r ug s c a n not r e p ro du c e t he pu ls a ti le r h y t hm o f e n d og en o us d o pa m i n e re l ea s e. 4 . S el e g il i ne , an in hi b it or o f th e c en t r al MA O - B i so e n z y m e , bl o c k s t he c e nt r a l c a ta b ol is m o f d op a m i ne , i nc r e as in g i ts a vai l ab il i ty i n t he c a ud a te - pu t am en . 5 . An t i c h ol i n e rg i cs , s uc h as t ri h e xy p h e n id y l , b en z t r o p in e , a nd or p he n ad r i n e, bl o c k t h e e xc i t a t or y c ho l in e rg ic s ys t em , t h us re d uc in g t h e fu nc t io na l i m b a la nc e b e t we e n d o p am in e a nd ac e t y lc ho li n e i n t h e s tr i at um . 6 . Th e en z y m e i n hi bi t o rs , c a r bi d o pa an d to l ca po n e , i nc r ea s e t he t ra ns po r t an d b i oa va i la b il it y o f l e v o do pa i n t he b ra i n a nd ar e th u s g i ve n a s a dj un c ti v e t re a tm e nt s wi t h l e v o do p a. C . T h e ra p e ut i c i n d ic a tio n s 1 . L e vo do p a, c u r r en t l y th e m os t ef f ec t i v e t r ea tm e n t fo r p a rk i ns on is m , is in d ic a te d t o t r e a t i di op a t hi c , po s t e nc e p h al it ic , or a r te r io s c le ro t ic f or m s of t he di s e as e. 2 . Am a n t ad i n e is in d ic ate d to t re a t i di o pa t hi c, pos t en ce p ha l it ic , o r a rt e ri os c l e r ot ic p a r k i ns on is m , as we l l a s e xt r a p y r a m id al s ym p t om s ( e xc e p t t a rd i v e d y s ki nes i a ) i n du c ed b y a n ti ps y c ho t ic d r u gs . 3 . Ap o m o r p hi n e ( A p ok yn ) h as b e en ap p ro v e d for t r e at i ng th e ri gi d i t y a nd a ki n es ia o r im m o b il it y a s s oc ia t ed wi t h P a r ki ns o n d is ea se . 4 . B r o mo c r i p ti n e is in d ic a te d to t re a t i di op a th ic o r p os te nc e ph a li ti c p a rk in s on is m . 5 . S el e g il i ne , an t i ch o l in e r g i cs , a n d a n ti h i st a mi n e s a r e i nd ic a te d f o r u s e as a d ju n ct i v e t h e ra p y fo r al l t y p e s o f p a rk in so n is m , in c lu di n g d r ug - in d uc ed e xt r a p yr a m i da l s y m p t om s ( wi t h th e e xc e p t io n o f ta r d i ve d y s k i ne si a ) . D . Ad ve r s e e f f ec t s 1 . L e vo do p a is as s o c i a te d wi t h th es e a d ve rs e e ff e c ts : a . G I ef f ec ts , s uc h a s G I u ps e t , n au s e a , v o m i t in g, a no r e xi a , an d e xc e s si ve s a li va t io n b . C a rd i o v as c u la r ef f ec ts , s uc h a s o r t ho s t a ti c h yp o t en s i o n, ta c h yc a rd i a, a n d d ys r h yt hm ia s c . C N S e f f ec ts , s uc h a s h e a da c h e , d i zz i ne ss , a nd i ns om ni a P.311
d . A bn o rm a l i n v ol un t a r y m o v em e nt s , s u c h as d ys k i ne s i a a n d ch o r ei fo r m or d y s t on ic m o vem e nt s e . P s yc h ia t ri c e f fe c ts , s uc h a s d el u s i on s , h al lu ci na t i on s, c o n fu s i on , ps y c ho s es , a n d d e p re ss io n 2 . Ap o m o r p hi n e c an c au s e n au s e a a n d v o m i t in g, s om no le nc e , d i z zi n e s s , a n d h a ll uc i na t io ns , a n d m a y e xa c e r b a te e xi s ti n g d y sk i n e s ia . Th e d r u g h as a re a so n ab le p o t en t ia l f o r a b us e d ue p r i m a r il y t o i ts pe r ce i ved p r o -l i bi do e ff ec t s . 3 . Am a n t ad i n e is as s o c ia t e d wi t h t he s e ad v e r s e e f f ec ts : a . C N S ef f ec ts , s uc h a s d r o ws i n ess , i ns o m n ia , diz zi n e s s , s l u rr e d s pe ec h , a n d n i gh t m a r es b . U r in a r y r et e nt i on an d a n k l e e d em a
c . Li ve do r et ic u la r is (m o tt l i ng of s k in on th e e xt r e m i ti es ) d . P s yc h ia t r ic e f fe c ts , s uc h a s h al l uc in a ti o ns a n d c o nf us i on 4 . B r o mo c r i p ti n e a nd r el a t ed e rg ol i ne s a r e as soc i at e d wi t h na u se a , h yp ot e ns i on , p s yc hi at r ic e ff ec t s s u c h a s c on f us i on an d h al l uc in a t io ns , l i ve do r et ic u la r is , an d a b n or m a l i n v o lu n at r y m ov e m e nt s s uc h a s d ys k in es i a a nd c h o re i fo r m o r d y s t on ic m o vem e nt s . 5 . S el e g il i ne is as s o c i ate d wi t h a d v e rs e e f f ec ts th a t a r e s im il a r t o t h os e o f b r o m o c ri pt i ne , i nc l ud i ng d y s k i n es ia s a nd ha l lu c i na t i on s . 6 . A nt ic h ol i ne r gi c a nt i par k i ns on ia n a g en t s h a v e th e s am e a d ve rs e ef f ec ts a s o t he r c h ol in e r gi c a nt a go n is ts (s e e V I . D ) .
XIV. OPIOID ANALGESICS and ANTAGONISTS. A n a lg es ic op i oi ds a re opi o id r ec ep t o r a go n is ts tha t co ns is t o f na t ur a l o pi at e a l ka lo i ds a n d t h ei r s y n t he t ic de r i v a ti v e s . A. C h e m i s t r y. Th e o p ia te a lk al oi ds a re de r i v e d f ro m o p iu m , wh i c h is c o nsi d e re d th e o l de s t d r ug on re c or d . Op i u m ( t h e d ri e d e xu d a t e o f t he po pp y s ee d c ap s ul e ) c o nt a in s a bo u t 2 5 d if f e ren t al k a l oi ds . O f t h es e, m o r p hi n e is t he m os t i m p or t a n t, bo t h q u a nt i ta t i v el y a nd ph a rm a c ol o gi ca ll y ( F ig u re 1 3- 26 ) . 1 . M o r p h in e 's p he n ol i c h yd r o x yl g r o u p i s e xt r e m e l y i m p o r ta n t f o r a c t i v i ty; h o we ve r , a na l ge s i c ac t i vi t y a pp e a rs t o de pe n d o n a p -p h en y l - N - al k y lp i pe r id i ne m o ie t y, in wh i c h th e p i per i d in e ri ng is in th e c ha i r f o rm an d i s p e rp e nd ic ula r t o t he a r o m a t ic ri ng . Th e a lk y l g r o up is us ua ll y m et h y l . Th e m o r p hi n e m o le c ul e c an be a l t er e d i n a v a ri e t y of wa y s ; r el a te d c om p ou nd s al s o ca n b e s y n t he s i z e d fro m o t he r s t a rt i ng m a te r i al s . 2 . N a tu r a l o r s yn t h e t i c o p i o id s m a y be c l as s i fi ed i nt o f o u r c h em ic a l g r oup s (F i gu r e 1 3 - 27 ) : a . P he n a nt h r e ne s (e . g. , m o rp h in e a nd h y d ro m o rp h o ne , c od e in e a nd h y d ro c od o ne , n a lb u ph i ne an d b u pr e no rp h in e , a n d n al o rp hi n e , na l t re xo n e , a nd na lo xo n e ) . Me t h yl a t i o n o f t h e p he nol i c ( 3 ) -h y d r o xy l g r o up wi t h o r wi t ho u t m od if ic a ti o n o f th e 6 h yd r o xyl g r o u p o f m o rp hin e y i el ds ag e nt s wi t h r edu c ed ag o ni st po t en c y but e n h an c e d o r al bi o a v ai lab i li t y ( e .g . , c od ei n e, h y dr o c od on e , o xy c o d o n e ). b . P h en yl h e p t yl a m i n e s ( e . g ., m e t ha do n e a nd p ro p o xy p h e n e ) a r e b is ph en yl d e r i va ti v e s o f h ep t y l am ine t ha t ha v e s t r on g (m et ha d o ne ) o r m o de r a te ( p r o po xy p h e n e ) ag on is t p o t en c y an d e xc e l le n t o ra l b i oa v a i la b il it y. c . P he n yl p i p e r i d i n e s i nc l ud e m ep e ri d in e , f en t any l , a nd s u f en t an il , wh i c h a r e s t r on g a g o ni st s t ha t a re m o re ef f e c t i v e wh e n g i v en pa r en t e r al l y , a n d t he m o de r at e ag o ni s t s d i ph e no xy l a t e a nd lo p e ra m id e . d . Th e mo r p h in a n l e v o rp h a no l is a s t ro n g a go nis t wi t h h i gh or a l b io a va ila b il i t y.
Figure 13-26. Structural formula of morphine.
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Figure 13-27. Structural formulas of selected opioid agonists, including (A) codeine, (B) heroin, (C) hydromorphone (Dilaudid), and (D) oxycodone (Percodan), morphine analogues; (E) meperidine (Demerol) and (F) diphenoxylate (Lomotil), piperidine analgesics; and (G) methadone (Dolophine) and (H) propoxyphene (Darvon), methadone analgesics.
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3 . O p i oi d an t ag o n is t s ar e d er i ve d b y r ep l ac in g th e m e th yl g ro u p o n t he ni t r og e n a t om wi t h m o r e b ul k y s ub s ti t u ti on s . Th u s , na l bu ph i ne an d bu p re n or p hi n e a r e p h e na n th r en e m i xe d a go n i s t -a n t ag o ni s t s ; n al t re xo n e a n d n al o xo n e ar e p h e na n th r en e p u r e a n t ag o n i st s ; a n d b ut o r ph an ol a nd le v a ll o r ph an a re m o r p hi n an d e r i ved an t ag o ni s t s (F igu r e 13 - 28 ) . 4 . A ge n ts ha v i ng bo t h a f r e e p h en ol ic h yd ro xy l g r o u p a n d a t e r ti a r y am in e f u nc t io n ( e . g ., m o r ph i ne an d n al bu p hi n e ) a r e c h em ic a ll y am p h o t e ri c . Am p ho t e ri c i t y p r o ba bl y a cc o un t s f o r t he e r ra ti c a b s o r p ti on o f m o r p hi ne wh e n a dm i ni s t e r ed or a ll y .
5 . S om e n e we r op i oi d a na l ge s i c a g en ts , s uc h a s tr a m a do l , a r e c he m i c a l l y u n r el a te d t o t he na t ur a l, s e m i s y nt he t ic , an d s y n th e ti c o pi a te d e ri v a t i v es . 6 . N um e ro us an a lo g ue s o f en d og e no us op io i d p ep t i de s h a ve b ee n s y n t hes i z e d a nd a r e be in g u s e d i n re s e a rc h . B . P h a r ma c ol o g y 1 . O p i oi d an a lg e si c s m im ic t he ac ti o ns o f en do ge n o us o p io id pe p ti d es a t C N S o p io i d r ec e pt o rs , ra is i ng t h e p a in th r es h ol d a nd in c r e as in g p ai n to le r a nc e. Th e a n al g es ic ac ti o ns a r e m ed i a te d p r im a ri l y th r o ug h t h e µ -s ub t yp e o f o p io i d re c ep t o rs . 2 . O t he r ac ti o ns at t r ib u ta b le t o s ti m u la t io n o f op io i d r e c e p to r s in c l u de in du c ti o n o f e u p ho r ia , s ed a ti o n, c o u gh s u p p re ss io n , a nd c h em o r e c e p to r t ri gg e r - z on e s ti m ul a ti on l e ad i ng to na u s e a a nd v o m it i ng . 3 . T r am a do l a p pe a rs to a c t v ia a m e t ab o li t e, wh ic h i s s el ec t i v e f o r t he µ -o p io i d r e c ep t or a nd al s o i n hi b its r eu p ta k e o f n or e pi n ep hr i n e a nd se r ot o ni n . I ts no n o pi at e c h a ra ct e r a p pe a rs to c o nf e r no c l ea r be ne f i ts o ver t h e o pi a te s . 4 . P u r e o p io i d a n ta g o nis t s s uc h a s n al o xo n e blo c k t he ac ti o ns o f op io i d a g on i s ts . M i xe d ag o ni s t - an t a go n is t s s uc h a s n al b up h in e , b u p re n o rp hi n e, bu t o rp h an o l , a n d p e n ta zo c i n e b lo c k th e a c t i o ns o f ag on is t s a t s om e r ec e pt o rs wh i l e d ir ec t ly s t im ul a ti n g o th e r re c e p tor s to p ro d uc e a go n is ti c ef f e c t s . C . T h e ra p e ut i c i n d ic a tio n s 1 . O p io id an a lg es ic s a r e i n di c a t ed t o r e li e ve m o de r a t e to se ve r e pa i n , s uc h a s t h e p a in as s o c i a te d wi t h m yo c a rd ia l i n fa r c t i on , c an ce r , an d l a bo r . I n t h e l at te r us e , m e pe r id i ne is p r e fe r r ed to m o r p hi ne be ca u s e m e pe r i d i n e is le s s l ik e l y to in d uc e n e o na t a l re s pi r a t o r y d e p r e s si o n . 2 . O p io id s a r e u s e d a ls o a s p r e an e s th e t ic me d ic a t i on s , a s a na l ge s ic ad j u n ct s d u r i n g a n es t he s ia , an d o c c a s i on a ll y as a p r im a ry a n es t h et ic ag e nt . 3 . Mi l d to m o d er a te ag o ni s ti c o pi o id s a r e us e d as a n t i tu s si ve s ( e. g ., co de i ne an d d e xt r o m e th o r ph an ) an d a s a n t i di a r r h ea l s ( e .g . , d i ph e no xyl a t e a nd lo p e ra m id e ) .
Figure 13-28. Structural formulas of opioid antagonists: (A) naloxone (Narcan), (B) pentazocine (Talwin), and (C) butorphanol (Stadol).
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4 . P u re op io i d a nt a go n is t s ar e u s ed as a n ti d ot es t o r e ve rs e t he ad ve r s e ef f e c t s ( e . g ., r es pi r a to r y d ep r es s i on , c a rd i o vas c u la r de pr e s s i on , s ed a ti o n ) o f o pio i d a g o ni st s o r o p io id ag o nis t - an t ag o ni s t s . N a lt r e xo n e is a n o r a ll y ac t i v e c om p ou n d t ha t p o ss es s e s p u re an t ag on is t ic ac ti v i t y a nd i s u se d in t he t re a tm en t of op i oi d a d di c ti on . D . Ad ve r s e e f f ec t s 1 . O p i oi d an a lg e si c s a re as s o c i a t ed wi t h t h e f ol lo wi n g a d ve rs e e ff e c t s : a . C N S ef f ec ts , i n c l ud i ng C N S d e pr es s i o n, m i os is, d i z z i ne ss , s ed a ti o n, c on f us i on , d i so r ie n ta t io n , a nd c o m a b . G I ef f ec ts , i n c l ud i ng na u s e a , vo m i t in g , c on st i pa t i on , b i li a r y s p as m , a n d i nc r e as ed b i li a r y t ra c t p re s s u re c . C a rd io v a s c ul a r e f f ec ts , s uc h as o rt h os t at ic h y po t e ns io n , p e ri ph e r al c i rcu l a to r y c o ll ap s e, d y s r h y t hm ia s , a n d c a rd ia c a r r es t d . R es p ir a t or y d ep r es s i on e . B r on c h oc o ns t ri c t i on f . P s ych ia t r ic e f f ec ts , s uc h a s e u ph o ri a , d y s p h o ria , an d h a ll uc in a ti o ns g . A bu s e p ot e nt i al a n d de p e nd en c e h . P r ec ip i ta t io n o f wi t hd ra wa l s y m pt om s i n o pi o id- d e pe n de n t p at i en ts ( wh e n op io i d a g o ni st - an t ag o ni s t s , s u c h as pe n ta z o c in e o r n a lbu p h i n e, a re us ed as an a lg e s i c s ) i . C l as s ic op i oi d a na l ge s i c s c a n a ls o p r om p t t he re l e a s e o f h is ta m i n e, c a us i ng i n t en se p ru r it us , v as o di la t i on , a n d b r on c h oc o ns t ri c ti o n, wh i c h c a n b e c on fu s ed wi t h a t r ue al le r g ic re ac t io n . j . Tr a m ad ol ap p ea r s t o ha v e s i g ni f ic an t l y fe we r re s pi r a to r y d ep r es sa n t e ffe c ts th a n t h e c la ss ic op io i ds . I t al s o d oe s n ot ap p ea r to c a us e th e r e le as e o f hi s t am in e . It ha s f e we r c a rd i o v as c u la r ef fe c ts wi t h th e e xc e p t io n of o r th os t a ti c h yp ot e ns io n, wh i c h i s p r o du c e d . Tr am a do l d oes po s s es s t h e t yp ic al µ - re c ep t o r- m ed ia t ed s i de e ff e c ts o f c o ns ti p at i on , n a us ea , v om i ti n g, an d s ed a ti o n. 2 . O p i oi d an t ag o n is t s ar e as s o c i a te d wi t h t h e f ol l o wi n g a d ve rs e e f fe c t s : a . P u re op io i d a nt a go n is t s c a n p r ec ip it a t e a wi t hd r a wa l s ynd r om e i n o pi o id d e p en de n t p a ti en t s . P u re a nt a go n is ts , g i ve n in th e ab s e nc e o f op io i d a go n is ts o r a g o ni st - an t ag o ni s t s , p r od u c e no c l in ic a ll y s i g ni fic a nt e ff ec t s. b . I n t he ab s e n c e of op io i ds , m i xe d ag o ni s t - a nt ag o ni s ts p r o du c e op i oi d -l ik e e f f ec ts , s uc h a s re s p i ra t o r y d e p re s s i on . P.315
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 14 : E a c h o f t he qu es t i o ns , s ta t em en t s , o r i nc o m pl e te s t a te m e n ts i n th is s ec t ion ca n b e c o r re c t l y a ns we r e d or co m p le t e d b y o ne o f th e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r . 1 . W hi c h o f th e fo l l ow in g d r u gs w o ul d m o s t l ik e l y b e u s e d i n t h e t r e at m e n t o f b r o n c ho s pa s m t h a t i s as s o ci a t ed w i t h c h r on i c o b s t r uc t i ve p ul m on a r y d i s ea s e? ( A ) e d ro p ho ni um ( B ) i p ra t r op iu m
( C ) a m b e no ni um ( D ) p r op a nt h el in e ( E ) h om a tr o pi n e V i e w A n s we r 1 . T h e a n sw e r i s B [ V . C. 2 . b, c ; V I .C . 1 . e -g] . 2 . Al l o f t he f o l l ow i ng ad ve r s e e f f e ct s a r e m an i f es t a ti o n s of c h o li n e rg i c a g on i s ts e x c ep t ( A ) b r ad y c a rd ia . ( B ) b r on c h oc o ns t ri c t i on . ( C ) xe r o s t om i a. ( D ) l ac r im a ti on . ( E ) m yo pi c ac c o m m od a tio n . V i e w A n s we r 2 . T h e a n sw e r i s C [] .3 . W h ic h o f th e f o ll ow i ng d r u gs is c o n si d e r ed t o b e t h e ag e n t o f ch o i ce f o r a na ph yl a c t i c r e ac t i o ns ? ( A ) cl o ni d in e ( B ) is o p ro t e re no l ( C ) e pi n ep h ri n e ( D ) p h en y l ep h r in e ( E ) t e rb u ta l in e V i e w A n s we r 3 . T h e a n sw e r i s C [] .4 . W h ic h o f th e f o ll ow i ng n e u r o mu s cu l a r b l oc k i ng a ge n t s c an c au s e m us c a r in i c re s po n se s s u ch a s b r a d yc a r d i a a n d in c r eas e d g l a nd u la r s ec r e t ion s ? ( A ) t u bo c u r a ri ne ( B ) s ucc i n y lc ho li n e ( C ) p a nc ur o ni um ( D ) d ec am e th o ni um ( E ) g al l am in e V i e w A n s we r 4 . T h e a n sw e r i s B [ V II . D . 2] . 5 . W h ic h o f t h e f o l low i n g a g en t s w o ul d no t be a pp r o p r iat e i n t h e t r e a tm e n t o f gl a u co m a? ( A ) a t ro p in e ( B ) p il oc a rp i ne ( C ) p h ys o s ti gm in e ( D ) t im o lo l ( E ) e pi n ep h ri n e V i e w A n s we r 5 . T h e a n sw e r i s A [ an d] .6 . Ad ve r s e r e ac t i o ns t o a t r op i ne i n c l ud e a l l o f t he f ol l ow i ng e xc ep t ( A ) p ho t op h ob i a. ( B ) d r y m o u th . ( C ) s ed a ti o n. ( D ) d ia r r h ea . ( E ) t ac h y c a r d ia . V i e w A n s we r 6 . T h e a n sw e r i s D [] .7 . W h ic h o f th e f o ll ow i ng d r u gs is a vo l a t i l e s u bs t a nc e t h a t i s a dm i ni s t e re d b y i n h a l a t i o n? ( A ) t hi o pe n ta l ( B ) h al o th a ne ( C ) a lp r a z o la m ( D ) b us p ir o ne
( E ) p he n y t oi n V i e w A n s we r 7 . T h e a n sw e r i s B [] .8 . T h e s t r u ctu r e o f p r o c hl o r p e ra z i n e i s s h ow n . W h ic h o f t h e f ol l ow i n g m ed i ca t i o ns , be c a us e o f i ts ch e mi c al r e l a t i on s hi p to p r oc h l or p e r a z i n e , w o u ld m os t li k e l y c a u s e s im i la r s ide e f fe c t s?
( A ) f lu p he n a z in e ( B ) t hi o r id a z in e ( C ) a lp r a z o la m ( D ) b us p ir o ne ( E ) p en t ob a r bi t al V i e w A n s we r 8 . T h e a n sw e r i s A [] .9 . T h e b r i e f du r a t i o n o f a c t io n of a n u l t r a - sh o r t - ac t i ng b a rb it u r a t e i s th e r es u l t o f a ( A ) sl o w r a t e o f m e ta bo l is m i n t h e li v e r . ( B ) l o w l ip i d s o l ub il i t y , re s ul t in g i n a m i ni m a l c o nc e nt r a ti o n i n t he b ra in . ( C ) h ig h d e g re e o f b i nd ing t o p la sm a p r ot e in s . ( D ) r a pi d ra t e o f r e di s t r ib u t io n f r om th e b r a in o win g to it s h i gh l i po so l ub il it y . ( E ) sl o w r a t e o f e xc r e t i on b y t he k i dn e y s . V i e w A n s we r 9 . T h e a n sw e r i s D [ X II . A . 4. c , d ;] . P. 3 1 6
1 0 . W h i ch o f t h e f o l low in g me c ha n i sm s o f ac t io n i s t r u e a n d m os t li ke l y c o n t r i bu t es t o th e t re a tm e n t o f pa r k i ns o ni s m? ( A ) Th e di r ec t - ac ti n g d opa m in e rg ic ag o ni st am an ta d i n e m im ic s t he ac t i vit y o f s t r ia t al d o p am in e . ( B ) Th e a nt im us c a r in ic ac t i v i t y o f d i ph e nh yd r am ine c o n t ri b ut es t o t he r es to r a ti o n o f s t r ia t al do p am in e rg ic - c ho l in e r gi c n eu r o tr a ns m i t ter b al a nc e . ( C ) S t r ia t al H 1 - re c e p to r s a r e b l oc k e d b y t he an t ihi s ta m i n ic tr i he xy p h e n i d yl. ( D ) Th e e r go li n e b r om oc r i p ti n e s ti m u la t es th e re le a s e of s t r ia t al do p am ine f r om i n t ac t t e rm in a ls .
( E ) Th e a bi li t y o f d op am in e to c r o s s t h e b lo o d- b ra i n b a r ri e r a ll o ws i t t o r es t o re s t r ia t al do p am in e rg ic - c ho l in e r gi c n eu r o tr a ns m i t ter b al a nc e . V i e w A n s we r 1 0 . T he a nsw e r i s B [] .1 1 . Al l o f t he f o l l ow in g a d ve r s e e f f ec t s a r e as s oc i a te d w i th t he u s e o f le vo d o pa ex c ept ( A ) si a lo r r he a . ( B ) o r th os t a ti c h y p ot e ns io n . ( C ) d el u s i on s , c o n fu s i o n, a n d d ep r es s i o n. ( D ) d ys k i ne s i a a n d d y s ton i a . ( E ) l i ved o re t ic ul a ri s . V i e w A n s we r 1 1 . T he a nsw e r i s E [] . 1 2. T he ac t i vit y o f w hi c h o f t he f o l l ow i ng d r ug s de p en ds o n a p -p h en yl - N - a l k yl p i p e r id i n e m oi e t y? ( A ) p he n ob a rb i ta l ( B ) c hl o rp r om a z in e ( C ) d ia ze p am ( D ) i m i p ra m i n e ( E ) m ep e ri di n e V i e w A n s we r 1 2 . T he a nsw e r i s E [ X V. A . 1 , 2 ;] .p NN p 1 3 . O pi o i ds a re us e d a s a l l o f t h e f o ll ow i n g a gen t s ex c ep t ( A ) a n ti tu s s i v es . ( B ) a na l ge s i c s . ( C ) a n ti - in f la m m at o r ie s . ( D ) a n ti di a r rh e al s . ( E ) p r ea n es th e ti c m ed ic a t i on s . V i e w A n s we r 1 3 . T he a nsw e r i s C [ X V . C] . 1 4. Wh i ch o f t he f ol l ow i ng ag e nt s w o ul d no t be a n a l te r n at i ve t o p he n ob a r b it a l i n t h e t re a t me n t o f pa r t i al s e iz u r e s? ( A ) t r im e th ad i on e ( B ) g ab a pe n ti n ( C ) f e lb am a te ( D ) l am o t ri gi n e ( E ) N o ne o f t he ab o v e V i e w A n s we r 1 4 . T he a nsw e r i s A [] . Di r e c ti o ns f or q u e st i o ns 15 - 1 9 : Th e q u es t io ns an d i nc om p le te s ta t em en ts in t hi s se c ti o n c an be c o r r ec tl y a ns we r e d o r c om p le t ed b y on e o r m or e o f t h e su g ge s te d a nswe r s . C h o os e t he an s we r , A- E . 1 5 . C ho l i ne s te r a se i nh ib i t o r s c a n b e u se d t he ra p e u ti c al l y I . a s m io t i c a ge n t s i n th e t r ea t m en t o f g la u c om a . I I . t o i n c re a se sk e le t al m u s cl e to n e i n th e t re at m e n t o f m ya s t h e n i a g ra vi s . I I I . to d ec r e as e g a st r o in t e s t in a l ( G I ) an d u ri n ar y b l a d d e r s m oo t h m u sc l e to n e . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t
V i e w A n s we r 1 5 . T he a nsw e r i s C [] .1 6 . An t i m u sca r i n i c a ge n t s a r e u s ed i n t h e t r ea t me n t of P a rk i ns o n di s ea s e a nd i n t h e c o n t r o l o f s o me ne u r o le p t i c i n d u ce d e x t r ap yr a m i d a l d i s o rd e r s . T he s e a ge nt s i nc l u de I . i p ra t r o p iu m . I I . be n z t r o p in e . I I I . t r ih e x yp h e n i d yl . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 6 . T he a nsw e r i s D [ V I. C . 1 .g , h] . 17 . C e r t a i n d r u gs a re s o m e ti me s in c o r po r a t ed i n t o l oc a l a n es t h et i c s o l u t io n s t o p r o l o ng t he i r a ct i vi t y a n d r ed u ce t he i r s ys t e m i c to x ic i t y. T h e s e d r ug s i nc l ud e I . d ob u t am i ne . I I . ph e n yl e p h r i n e . I I I . e p i ne p h r in e . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 7 . T he a nsw e r i s D [ II I . B .1 . b ,] . 1 8. Im p r o p e r a dm i n is t r a t io n o f l o c a l a ne s t he t ic s c a n ca u s e t o xi c pl a sm a c o nce n t r a t io n s t h a t m a y r e s u l t i n I . s ei zu r e s a n d c en t r a l n e r vo u s s ys t e m ( C N S ) d e p r es s i on . I I . r es p i r a to r y a n d m yo c a r d ia l de p r es s i on . I I I . c i r c ul a t o r y c o l l a p s e. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 8 . T he a nsw e r i s E [] . P . 31 7
1 9 . In ad d i t io n to t he i r a n x io l yt i c p r o p e r t ie s , be n z od i az ep i n es a re i ndi c a t ed f o r use I . a s p r ea n es t h e ti c m e di c a t io n s . I I . as an t i co n vu l s an t s . I I I . du r i n g a cu t e w i th d raw al f r om a lc o ho l . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t
V i e w A n s we r 1 9 . T he a nsw e r i s E [] . F o r q u es t i o ns 2 0 -2 2 : A 58 - y e a r -o l d wh i t e m a l e wh o h as a h is t o r y of es s e n ti al h y pe r te n s i o n a nd br o nc hi a l as th m a h as r e c en t l y b e en di ag n os ed wi t h p r os t at ic h y pe r t r oph y . H i s m e d ic at i on hi s t o ry i n cl u de s t h e fo ll o wi n g d r ug s : D i r e c t i on s : Th e f ol l o wi ng q ue s t i on s c an be an s we r e d b y o ne o f t he li s t e d d r u gs . C h o os e th e b e st an s we r , A- E . 2 0 . W h i ch o f t h es e a g en t s an d us es c ou l d w o rs e n th e u ri n a r y r e t e n t i o n h e i s e x p e ri e nc i n g a s a r es u lt o f h is p ro s t a te p ro b l em s ? ( A ) p r op r an o lo l , f o r h y p er t e ns i on ( B ) i p ra t r op iu m , f o r as t hm a ( C ) m et a p ro t er e no l , f o r as t hm a ( D ) f i na s t e r id e ( P r os c a r ), f o r p r os t at ic h ype r t r op hy ( E ) p r a z os in , fo r h y pe r ten s io n V i e w A n s we r 2 0 . T he a nsw e r i s B [] .2 1 . W hi c h a ge n t an d us e c o ul d w o r se n o r c a us e a n a c u te as t hm a a tt a ck ? ( A ) p r op r an o lo l , f o r h y p er t e ns i on ( B ) i p ra t r op iu m , f o r as t hm a ( C ) m et a p ro t er e no l , f o r as t hm a ( D ) f i na s t e r id e ( P r os c a r ), f o r p r os t at ic h y pe r t r op hy ( E ) p r a z os in , fo r h y pe r ten s io n V i e w A n s we r 2 1 . T he a nsw e r i s A [ I V. D . 3] . 2 2. W hic h ag e n t a c ts se l ec t i vel y a t β 2 - re c ep t o r s? ( A ) p r op r an o lo l , f o r h y p er t e ns i on ( B ) i p ra t r op iu m , f o r as t hm a ( C ) m et a p ro t er e no l , f o r as t hm a ( D ) f i na s t e r id e ( P r os c a r ), f o r p r os t at ic h y pe r t r op hy ( E ) p r a z os in , fo r h y pe r ten s io n V i e w A n s we r 2 2 . T he a nsw e r i s C [] .F o r qu e st i o ns 2 3 -2 5 : A 55 - y e a r -o l d b l ac k f em al e h a s a h is t or y o f m o d er a te h y pe r t ens i on , g l au c o m a , a n d m i l d o s te o a rt h ri t is . He r m e di c a t i on hi s t o r y in c l u de s t he f ol l o wi ng d ru gs : D i r e c t i on s : Th e f ol l o wi ng q ue s t i on s c an be an s we r e d b y o ne o r m o r e o f th e li s t e d d r u gs . Ch o os e t h e b es t a n s we r s , A- E . 2 3 . W h i ch o f h e r g l a uco m a m e di c i ne s a c ts vi a a n in d i r ec t m e ch a n is m? ( A ) m et o pr o lo l , f o r h y p e rt e ns i on ( B ) p il oc a rp i ne ge l , f o r gl a uc om a ( C ) e pi n ep h ri n e d r op s , fo r gl a uc om a ( D ) i so f lu r op h at e , f o r g lau c om a ( E ) t im ol o l, f or gl a uc om a V i e w A n s we r 2 3 . T he a nsw e r i s D [] .2 4 . W hi c h tw o a ge n t s c o ul d ha ve a n a d d i t i ve e f f ec t to p r o duc e ex c es s i ve b r a d yc a r d i a ? ( A ) m et o pr o lo l , f o r h y p e rt e ns i on ( B ) p il oc a rp i ne ge l , f o r gl a uc om a ( C ) e pi n ep h ri n e d r op s , fo r gl a uc om a ( D ) i so f lu r op h at e , f o r g lau c om a ( E ) t im ol o l, f or gl a uc om a
V i e w A n s we r 2 4 . T he a nsw e r s a r e A a nd E [ I V. B . 3, D . 4] .2 5 . W h ic h tw o g l a uc o ma a ge n ts c ou l d l e ss e n t h e e f f ec t s o f th e o th e r ? ( A ) m et o pr o lo l , f o r h y p e rt e ns i on ( B ) p il oc a rp i ne ge l , f o r gl a uc om a ( C ) e pi n ep h ri n e d r op s , fo r gl a uc om a ( D ) i so f lu r op h at e , f o r g lau c om a ( E ) t im ol o l, f or gl a uc om a V i e w A n s we r 2 5 . T he a nsw e r s a r e B a nd D [] . D i rec t i o ns f o r q u es t i on s 2 62 8 : E a c h s t a te m en t i n t hi s s ec t io n d es c ri be s o n e o f th e f o ll o wi n g d r ug s . C h o os e th e b e s t a ns we r , A- E . P.318
2 6 . An a nx i o l yt i c d r u g th a t do e s n o t p o ss e ss ei t h e r h yp n o t i c o r an t i con vu l s a n t p r o p e r t ie s ( A) t r a n yl c yp r o m i n e ( B ) i m ip r a m in e ( C ) b u sp i r o ne ( D ) f l u ox e t in e ( E ) p h en e lz i ne 2 7 . A p r o t o t yp e t r i c yc l i c a n ti d e p re s sa n t w it h an t i m us c a ri n i c p r o pe r t i es t h a t m a k e i t u s e fu l in t he t re a t me n t of e nu r e si s ( A) t r a n yl c yp r o m i n e ( B ) i m ip r a m in e ( C ) b u sp i r o ne ( D ) f l u ox e t in e ( E ) p h en e lz i ne 2 8 . An a n ti d ep r e ss a n t th a t i nh i bi t s s e r o to n i n r e u p t ak e a n d m a y c a u s e a d ve r s e e f f e c ts su c h a s i m pa i r ed m em o r y, a k a t h is i a, an d me n s t r ua l i r r e g u la r it i e s ( A) t r a n yl c yp r o m i n e ( B ) i m ip r a m in e ( C ) b u sp i r o ne ( D ) f l u ox e t in e ( E ) p h en e lz i ne V i e w A n s we r 2 6 -2 8 . T h e a n s w e r s a r e : 2 6 - C [] , 27 -B [ ] ,2 8 - D [] . D i r e c ti o ns f or q u e s ti o ns 29 - 3 1 : E ac h s t r uc t ur e i n th is s ec t io n c a n b e d es c r i be d b y o n e o f th e f o l lo wi n g p h a rm ac ol o gi c a l c a te g o ri es . Ch o os e t he b es t an s we r . 29.
( A) g e n e r a l a n es t he t i c ( B ) l o ca l an e st h e ti c ( C ) a n t id e p re s sa n t ( D ) a n xi o l yt i c ( E ) o p io i d a n t ag o n is t 30.
( A) g e n e r a l a n es t he t i c ( B ) l o ca l an e st h e ti c ( C ) a n t id e p re s sa n t ( D ) a n xi o l yt i c ( E ) o p io i d a n t ag o n is t 31.
( A) g e n e r a l a n es t he t i c ( B ) l o ca l an e st h e ti c ( C ) a n t id e p re s sa n t ( D ) a n xi o l yt i c ( E ) o p io i d a n t ag o n is t V i e w A n s we r 2 9 -3 1 . T h e a n s w e r s a r e : 2 9 - B [] , 30 -D [ ] ,3 1 - C [] . p F o r q u es t i on s 3 2 - 33 : A 3 8 - y e a r- o ld m an h as a hi s to r y o f a f fe ct iv e d is o r de r s , in c l u di ng s ch i zo ph r e ni a, d ep r es s i on , ob s e s s i ve -c om p ul s i v e d is o r de r , a nd s i t ua t io na l a n xi e t y . H i s p a st m e di c a t io ns in c lu d e t h io t hi xe n e , c h lo r p rom a z i ne , a m i t r ip t y l in e , a nd d i a ze pa m . H is c u r re n t m e d ic a ti on p ro f il e i nc l ud es t wo o f t h e f ol l o wi ng d ru g s : D i r e c t i on s : Th e f ol l o wi ng q ue s t i on s c an be an s we r e d b y o ne o f t he li s t e d d r u gs . C h o os e th e b e st an s we r , A- D . 3 2 . W h i ch ag e n t i s m o st l i ke l y b e i n g us e d t o t re a t hi s s c h iz op h r e ni c p s yc h o s i s ? ( A ) cl o za pi n e ( B ) f lu o xe t i n e ( C ) b us p ir o ne ( D ) r i sp e ri d on e V i e w A n s we r 3 2 . T he a nsw e r i s A [] .3 3 . W hi c h a ge n t is m os t li k el y b e i n g u s e d t o t r ea t de p r es s ion a n d o bs e ss i ve - c om p ul s i ve d is o r de r ? ( A ) cl o za pi n e ( B ) f lu o xe t i n e ( C ) b us p ir o ne ( D ) r i sp e ri d on e V i e w A n s we r 3 3 . T he a nsw e r i s B [] .P . 31 9
D i r e c t i on s fo r q ue s t io ns 3 4 -4 0 : E ac h o f th e q u es t io ns , s t a te m e n ts , o r i nc om p le t e s t a te m e n ts i n th is s ec t ion c a n b e c o r re c t l y a ns we r e d or co m p le t e d b y o ne o f th e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r . 3 4 . T yr a m i n e e xe m pl i f ie s t he p ha r ma c o lo g ic m e c ha n is m o f
( A ) g an g li on ic bl oc k ad e . ( B ) i nh i bi ti o n o f t r a ns m i tte r r el e as e. ( C ) f ac i li t at i on of t ra ns m it t e r re l ea se . ( D ) i n te r f er e nc e wi t h v e s i c ul a r s to r ag e . ( E ) b lo c k ad e o f t ra ns m i t te r r eu p ta k e. V i e w A n s we r 3 4 . T he a nsw e r i s C [] .3 5 . C o ns i d e rin g t he g en e r al c he m ic al s t r u c t u re s o f s ym p a t h o m i m e ti c a m in e s, d el e t io n o f th e 3 - h yd r o x y g r o u p o n t h e p h e n yl r i n g o f n o r ep i n ep h r i n e w o u l d l i ke l y p r o d u c e ( A ) i nc r ea s e d α - re c e p to r p o te nc y. ( B ) i nc r ea s e d β - re c e p to r p o te nc y. ( C ) i nd i r ec t s y m p a th om im e ti c a ct i vi t y . ( D ) d ec r ea s ed t ra ns p or t t h r o ug h t h e b lo od - b ra i n b a r r ie r . ( E ) l os s o f a n y bi ol o gi c a l a c ti v i t y in th e n e r v o us sy s t e m . V i e w A n s we r 3 5 . T he a nsw e r i s C [] .3 6 . S o me t ime s co m bi n a ti o n t re a tm en t o f P a r ki n s on d is ea s e i s w a r ra n t ed . Wh i c h o f the f o l low i n g d r u g c o mb in a t i on s c o u l d w o r k c o o pe r a t i vel y t o e n h a n ce a c l in i ca l a n t i pa r k in s on i a n r e spo n s e? ( A ) a m p he t am in e a n d r es e r pi ne ( B ) l e vod o pa an d c a rb ido p a ( C ) c a rb id o pa an d t o lc apo n e ( D ) a m a n ta d in e a nd ha l op e r id o l ( E ) d op am i ne an d t y r a m in e V i e w A n s we r 3 6 . T he a nsw e r i s B [] .3 7 . T e ra z os in i s a b le t o f a ci l i ta t e m i c t u ri t i o n w h e n u se d in t h e t r e a tm e n t o f b e n ig n p r os t a t ic h yp e r t r o p h y ( B P H ) b e c au s e t h e d r u g ( A ) r e la xe s t he p ro s ta t e g l an d . ( B ) c on s t r ic ts t he ne c k of t h e bl a dd e r . ( C ) p r e ven t s p en il e e r ec ti o ns ass o c i a te d wi t h B PH . ( D ) b lo ck s s em in al fl u id p r o du c ti on . ( E ) b lo c k s p r os ta t e c el l g r o wt h . V i e w A n s we r 3 7 . T he a nsw e r i s A [] .3 8 . B R L 37 3 44 i s a β 3 - a go n is t . I t m igh t b e o f i n t e re s t t o de ve l op t h i s a ge n t i n t o a cl i n ic a l l y u s a b l e d r ug be c au s e o f t he e x p ec t a ti o n th a t β 3 - ag on i s t s w o u l d ( A ) c on s t r ic t b l oo d v es s el s a n d i nc r ea s e bl oo d p re s s u r e i n sh oc k p a ti en t s. ( B ) i nd uc e l i po l y s i s a nd d e c re as e l ip oc yt e m a ss in o be se pa t ie n ts . ( C ) i nc r ea s e gl y c o ge no l ys is an d p r e v e nt gl yc og e n s t or a ge in li ve r c i r rh os is . ( D ) e n ha nc e r e na l v as odi l a ti on an d i nc r e as e u r ina r y e li m i n at i on of e th a nol i n a l co h ol ic s . ( E ) c au s e b ro nc ho d il a ti on a nd c o un t e ra ct t he ne ga t i ve e f f ec ts of as th m a t re a tm e nt a g e nt s. V i e w A n s we r 3 8 . T he a nsw e r i s B [ II I . B .1 . b] .3 9 . Th e p ha r m ac o lo g i c p r o f il e o f c a r ve d il o l i s m o s t s im i l a r to t ha t o f ( A ) e sm ol ol . ( B ) l ab e ta l ol . ( C ) m et o p ro lo l . ( D ) n a do lo l .
( E ) t im ol o l. V i e w A n s we r 3 9 . T he a nsw e r i s B [ I V. C . 3 ;] . 4 0. B es i d es b o th o f t h em be in g p h e na n t h r en e d e r i va t i ve s , a p om o r p h in e a n d mo r p h i ne a ls o h a ve t he co m m on property of ( A ) s ti m u la t in g b r a in ne ur o g en es is an d he nc e a n ti d e p r es s a n t a c t i v i t y . ( B ) e li ci t in g a po t en t n e rv e b l oc k a de an d h e nc e an e s t h et ic ac t i v it y. ( C ) s ti m u l at i ng µ - op io i d r e c ep t or s a n d h en c e an al g e s ic ef f ic ac y. ( D ) i m p r o v in g i m m ob i li t y a n d h e nc e a nt i pa r k i ns oni a n a c t i v i t y . ( E ) i nd uc i ng r e wa r di n g s t i m u l i a nd he nc e a d di c t ion l ia bi l it y . V i e w A n s we r 4 0 . T he a nsw e r i s E [ X V. A . 2 , C] . P .32 0
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ V . C. 2 . b , c ; V I . C .1 . e- g ] . I p r a t ro pi um is a n e wl y ap p r o v ed an t im us c a r in ic a g e n t us ed to t r ea t b r onc h os pa s m . P r o p an t he l in e a nd ho m atr o p in e a r e a n ti m u s c a ri nic ag e nt s u s e d a s a ga st ro i n te s t i na l ( G I ) a n ti s p as m o d ic a n d a s a m y d ri a ti c , r es pe ct i ve l y . E d ro p ho ni um an d am b en o ni um a r e i n di r ec t - ac ti n g c h o li ne r g ic ag on is t s a nd , a s s u c h, wo u l d b e e xp e c t ed to i nd uc e b r o nc ho s pa s m . 2 . T he an sw e r is C [ V I .D ] . Xe r o s t om i a, o r d r y m o uth , r es ul ts f r om re du c ed sa l i v a r y s ec r e ti o ns a n d, th e r e fo r e, i s n o t a m a ni f es ta t io n o f c h ol in e r gi c a go ni s t ac t i v it y . A l l o f t h e o th e r e f f ec ts li s te d i n t h e q u es ti o n a r e e xt e n s io n s o f t h er a pe u ti c e f fe c ts o f c h o li ne r g ic a g on is ts t o th e p o in t of be i ng ad v e r s e eff e c ts . 3 . T he an sw e r is C [ I I I .C . 1 ] . O f t h e a d re n er g ic ag on is t s li s t e d i n t he qu es t io n , o n l y ep in e ph r in e , b ec a us e o f it s b r o ad , no ns el e c t i v e α - an d β - ac ti v i t y, is a n a g en t o f c h oi c e fo r an a ph y l ac ti c r e a ct i on s . E pi n ep h ri n e im p r o v es c i rc ul a to r y a nd r e s pi r at o r y f un ct i on an d c o un t e ra c t s t h e vas cu l ar e ff ec t s o f h is t am in e - re l at e d a na p h y la xi s . 4 . T he an sw e r is B [ V I I .D . 2 ] . N e u r om us c u l ar bl oc k i n g a g e nt s i nt e r ac t wi t h n ic ot i n ic re ce p to r s a t t h e s k el e t al n e u ro m u s c u la r j u nc ti o n. S u c c i n ylc ho li n e is al s o c a p a bl e o f e li ci t in g a u to no m ic m us c ar i ni c r es p on s e s , s u c h as b ra d y c ar d ia , i nc re a s e d g l an du l a r se c re t ion s , a nd c a r di ac ar r es t . 5 . T he an sw e r is A [ V . B a n d C ] . B o t h d i re c t -a c t i ng (e . g ., p i lo c a r p in e ) a nd in d ir e ct- a c ti n g ( e .g . , p h y so s t i gm i n e ) c h ol in e r gi c s m a y be us ed i n g la uc om a t o i nc r e ase c h o li ne r g ic a c ti v i t y an d f a ci li t at e o u t fl o w o f aq ue o us hu m or . S im il a r l y, b o th β - ag on is t s ( e .g . , e pi n ep h ri n e ) an d a n t ag o ni s t s ( e .g . , t im o lo l) m a y b e us ed re s pe ct i ve l y t o i nc r ea s e ou t fl o w a n d d e c re as e p r od uc t io n o f aq u e ou s h um o r. A t ro pi n e i s c on t r ai n di c a t ed in gl au c om a b e ca us e i t s a nt ic h ol in e rgi c e f f ec ts c a n b lo c k th e o u t fl o w o f aq ue o us hu m or a n d, c o ns eq u en t l y , i nc r ea s e in t r a oc ul a r p r es s u r e. 6 . T he an sw e r is D [ V I .D ] .
C l a ss ic s i gn s a nd s y m p to m s o f m u sc a ri n ic b l oc ka d e , as wi t h at r o pi ne , inc l ud e m yd r i as is , wh i c h m a y c au s e l ig h t s e ns i ti v i t y ( ph ot o p ho bi a ) ; d r y m o u th and c o ns ti p at i on b y d e c r e as in g s ec r e to r y a ct i vi t y a n d m o ti li t y in t he G I t r ac t ; a n d t a ch yc a rd i a b y in h ib i ti ng t h e n o rm al in hi b it o r y cho l in e r gi c co n t ro l o f th e c a r d ia c s ys t em . Di a r rh e a is on e o f t he c om m o n s ig ns o f c h ol in e r gi c a go ni s ts (s uc h as s a li va t io n , l ac ri m at io n o r t e a ri n g, u ri na t io n , a nd di a r r he a ) . 7 . T he an sw e r is B [ V I I I. A . 1 ] . Th e g e ne r al an es t he t ic s a r e di v i de d i n to t wo m a jo r c l as s e s o f d r ug s : t ho se t ha t ar e g a se s o r v ol a ti l e l iq ui ds , wh i c h a r e a dm i ni s t e r ed b y i n ha la t io n , a n d t ho s e t h a t a r e n o n vo la ti l e s al ts , wh ic h a r e ad m i ni s te r ed as i n t rav e n o us so lu t io ns . H al o tha n e i s a h a lo g en a te d h y d r oc a r bon , wh i c h b el on gs t o t he fo r m e r cl as s . I t h as th e ad v a n t ag e o ve r o ld e r v o l at i le an es th e t ic s ( e. g . , e th yl e th e r, c yc lo p r op a ne ) o f be in g n o n fl am m a b le . Th io pe n ta l s o di um , a l p ra z o la m , bu s pi r on e , a nd ph e n yt oi n a r e al l n o n vo la ti l e s ub s t a nc es th a t a r e a dm i ni s t e re d o r al l y o r p a re n te r a ll y. Th i ope n t al is a g e n er a l a ne s t h et ic an d is s o m e t im es re f e rr e d t o a s a ba s al a n es t he t ic b ec a us e i t d o es no t p r o du c e s i gn i fic a nt t hi r d -s ta g e s u r g ic al a n es t he s i a . A l p ra z o la m a n d b u sp i ro n e a r e a n xi o l y t ic s , wh e r e as ph e n y t oi n is an a nt ic o n vul s a n t. 8 . T he an sw e r is A [ X. A . 1 ; Ta bl e 1 3 - 6] . F l u ph en a z i ne , l ik e p r oc hl o r pe r a zi ne , i s a p i pe r a z in y l p he n ot h ia zi ne an t ip sy c h o ti c a n d wo u ld be li k e l y to c au s e s i m i l a r s i d e e ff ec t s. W her ea s t hi o ri d a z in e i s a l s o a p h e no t hi a z in e a n ti ps y c ho t ic , i t is a pi p e ri d yl d e ri v a t i v e r at h e r t ha n a pi p er a z i n y l d e r i va ti v e . Al p ra z o l am , ph e n y t oi n , a nd pe n to b a rb it a l a r e n o t p he n ot h ia z i nes ; t h e r ef o re , s t r uc tu r a ll y , the y a r e n o t s i m i l a r t o p r oc h lo r pe r a z i ne . 9 . T he an sw e r is D [ X I I .A . 4 . c , d; Fi g u re 13 - 8 ]. U l t r a -s h or t - ac ti n g b a rb i tu r a t es a r e c ha r ac t e ri z e d b y h a vin g b r a nc he d o r un s at u r at e d 5 , 5 -s i de c h ai ns an d b y ha v i n g a s u lf u r a t om i n p la c e o f o xy g e n i n t h e 2 po s it i on of t h e b a r bi t ur ic ac id m o le c u l e . Th e s e m o di f ic a ti on s o f ba r bi t u ri c ac i d r es ul t i n an e xt r e m e l y li p os ol ub l e m ol e c u le t ha t i s ver y s ol u ble i n l ip id ti ss u es . A f t er a d m i ni s t ra ti o n , a n ul t r a -s h o rt - ac t in g b a rb i tu r a te re a di l y c ro ss es th e b lo o d- b r a in b a r r ie r bu t t h en is q u ic k ly r e d is t r ib u te d i n to e xt r ac e r eb r al ti ss u e, r es ul t in g i n a r ap id l o ss o f ac ti v i t y . W hi le the s e a ge n ts do re m a i n i n t h e b o d y fo r a lo n g t im e a n d s ee m t o ha ve s l o w r a t es o f m et a b ol is m a nd e xc r e ti o n, th e i r l on g re t en t io n t im e is du e m o r e t o t he i r s lo w r a t e of l ea c h i ng ou t o f li pi d t is s u e. P.321
1 0 . Th e a n sw e r i s B [ XI V . B ] . Th e H 1 - a nt a go n is t d ip h en h y d r am in e p o ss es s es an t im us c a r i ni c ac t i v it y, wh i c h al lo ws i t to be o f us e i n th e r e s to r a ti o n o f s t ri a ta l d o pa m i n e rg ic - c h o li ne r gi c n e u ro t r an s m it t e r b al a nc e. A m a n t ad in e a p pe a rs to s t i m ul a te th e re le as e o f s t r ia t al d o p am in e ; i t d oe s n ot m im ic t he ac ti o n o f d op am in e . Tr i he xyp h e n i d y l i s an a n t im us c a r in ic , n o t a n ti hi s ta m i n ic , a ge n t ; i t b lo ck s c h ol i ne r gi c , n ot H 1 , r ece p t o rs . B r o m oc ri p ti n e is a d op am i ne r gi c a go n is t a nd m im ic s t h e ac t i v it y o f s t ri a ta l d o p am in e . Th e ne u ro t r an s m i t te r d o pa m i n e is no t a b le to c r os s t h e b lo o d-b r a in b a r r ie r an d i s , th e r ef o r e, n o t e f fe c t i v e as a n a n ti pa r k in s o ni a n d r ug .
1 1 . Th e a n sw e r i s E [ XI V . D . 1 ] . L i ve d o r e ti c u la r is is a c i rc u la t o r y d is o r de r c ha r ac te r i z e d b y l ar g e, bl u is h a re a s o n t h e e xt r e m i ti es . It is an a d v e r s e ef f ec t a ss oc ia t ed wi t h t he us e o f a m a n tad i ne an d b r o m o c ri pt i ne bu t n o t wi th t he us e o f l e v o - do pa . 1 2 . Th e a n sw e r i s E [ X V. A . 1 , 2 ; F i gu r e 1 3 -2 7 E ]. Th e p - p he n y l - N -a lk y l p ipe r i di n e m o i et y i s c o m m on t o t h e s t r uc t u ra l l y s pe c i f ic op i oi d a n al g es ic s . Me p e r id i ne is an op i oi d a n al ge s i c a nd i s an N - m e t h y l- p - ph e ny l p i pe r i di ne d e r i va ti v e . I t s c h em ic a l n a m e is e t h yl 1 -m e th y l -4 - p he n y l pi p er i di ne - 4 -c a rb o xy l a t e . P h e no b a rb i ta l i s a b a rb i tu r a t e s e d at i ve . Ch lo r p rom a zi ne is a ph e no t hi a zi ne a n t ip s yc h o ti c . D ia z e p am i s a be n zod i a zep i ne an xi o l y t ic . I m i p ra m i n e is a t ri c y cl ic d i be n za z e pi n e a nt i de p res s a n t . 1 3 . Th e a n sw e r i s C [ X V. C ] . U n l ik e t h e s al ic y l at e s , op i oi ds do n ot po s s es s a nt i - in f la m m a to r y ac t i v it y . O p i o id s d o s u pp r es s t he c o u gh re f lex a n d a r e p r e em in en t ana l ge s i cs . O pi o id s c a us e c o ns ti p at i on an d a r e , t hus , ef f ec ti v e a nt i di a r rh ea l a g en ts . W he n us e d as p r e an es t he t ic m e di c a t ion , op i oi ds pe r m i t a r ed uct i o n i n t he am ou n t o f g en e r al a n es t he t ic re q ui r ed f or s u r g ic al an es t he s i a . 1 4 . Th e a n sw e r i s A [ XI I I . A . 1 , C . 2 ]. W hile m a n y a n al ep t ic s ar e us e fu l i n c on t r ol li n g m o r e th a n o ne s e i zu re t y pe , t r i m e t ha di o ne is ef f ec ti v e p ri m ar i l y a g ai ns t a bs en c e ( p et i t m a l ) s ei z u r es . A d d i ti on a ll y , it s s id e -e f f ec t pr o fi l e is m o r e e xt e n s ive t h an t he ne we r a g en ts ( e. g . , l a m o t ri g in e , g ab a pe n ti n , f e l ba m a t e ) t ha t a r e e f f ec t i v e in t re a ti n g p a rt i al s ei zu r e s. 1 5 . Th e a n sw e r i s C [ V .C . 2 ] . C h o l in es t er a s e i n hi b it o rs a r e i n di r ec t -a c t i ng c h ol i n e r gi c a go n is ts us ef u l i n t r e at i ng m ya s th e ni a g r a v is a n d g la u c o m a . Th ei r ef f ec ts on G I a nd u ri n ar y b la d de r s m o ot h m us c l e wo u ld be t o i nc rea s e s m o ot h -m us c l e t o ne , n o t d ec r ea s e i t. 1 6 . Th e a n sw e r i s D [ V I .C . 1 . g , h ] . A l l th r ee c o m p o un ds li s te d in th e q u es ti o n a r e an t i m us ca r i ni c a ge n ts ; h owe v e r , o n l y b e n zt r op in e a n d t r ih e xy p h e ni d y l a r e u se d to c o nt ro l pa r k i ns on is m a nd s o m e n e u ro l ep t ic -i n du c e d e xt r a p y r a m i da l d is o r de r s . Ip ra t r o pi um i s a ne wl y a p p ro ve d a g e nt fo r th e t re a tm en t of b r on c h os p as m . 1 7 . Th e a n sw e r i s D [ I II .B . 1 . b, C . 1, 2 ]. D o b u ta m i n e is a β 1 - s e lec t i v e a d re n e rg ic ag on is t . I t wo u l d b e i na pp r o p ri ate t o u se d o b ut am i ne to de c re as e b l oo d fl o w a t th e s it e o f lo c al an es t he t ic a d m i ni st ra t i on . E p i ne p h ri ne is a n on s e lec t i v e α - a nd β - ag o ni st , an d ph e n y le ph r i ne is a n α 1 - s el ec t i ve a g o ni st ; b o th o f t he s e d ru g s c a n be us ed to li m i t t h e s ys te m i c a bs o rp t io n o f lo ca l a n es t he t ic s a nd pr o lo n g t h e ir ac t i vit y . 1 8 . Th e a n sw e r i s E [ I X.D . 2 ] . C a r e f ul ad m i ni s tr a ti o n o f a lo c a l a n es th e ti c b y a k n o wl e dg e ab le p ra c t i ti o ne r is e ss e nt i al to p re v e n t s y s te m ic a bs o r pt i on an d c ons e qu e nt to xi c i t y. Th i s is e s pe ci a ll y i m po r t an t wh e n t he pa t ien t ha s c a rd io va s c ul a r d ise a s e , p o o rl y c o n t ro ll e d di a be t es , t h yr o t o xi c os is , o r pe r ip he r a l v a s c u la r di s e as e . 1 9 . Th e a n sw e r i s E [ XI I. C . 1 , 2 , 3] . B e n zo di a z e pi n es c an s e rv e a s i nd u c t io n a g en t s fo r g en e ra l a n es th es i a; th e y a ls o h a ve an xi o l y t i c p r op e r ti es . In ad d it i on , i n t ra ve no u s di a ze pa m is us e d t o t re a t s t at us
e p il e pt ic us , wh e r e as c lon a z e p am i s u s e d o r al l y fo r m yoc lo n ic a n d a bs en ce ( p et i t m a l ) se i z u re s . B e n z od i az e p i n es a ls o d im i ni s h alc o ho l wi t hd r a wa l s ym p tom s . 2 0 . Th e a n sw e r i s B [ V I .D ] . Th i s an t ic ho l in e rg ic , i f ab s o rb ed s ys t em ic al l y , c ou l d c au s e cl as s i c a nt ic ho l in e r gi c e f f ec ts , wh i c h in c l ud e u r in a r y r e te n ti on . P.322
2 1 . Th e a n sw e r i s A [ I V .D . 3 ] . B e c au se th is is a n on s e le c ti v e β - bl oc k e r , th e re c o u ld be so m e in h ib it i on o f β 2 r e c ep t or s i n t h e b r on c h ial t r ee , c au s i n g b r on c h oc o n st r ic t io n a n d p oss i bl e c om p li ca t io n o f th e p a ti en t ' s a s th m a . 2 2 . Th e a n sw e r i s C [ I II .C . 6 ] . P r o p r an ol o l is a n on s el ec t i v e β -b lo c k e r, a nd pr a zo s in is a se le c ti v e α 1 - bl oc k e r . N e i t he r ip r at r o pi um no r P r o s c a r wo r k s th r ou g h th e ad r en e r gi c s ys t em . Me t a p r o t e re n ol is a s e lec t i v e β 2 - a go ni s t. 2 3 . Th e a n sw e r i s D [ V .A . 2 , C .2 ] . P i l oc a rp i ne ac ts di r ec tl y a t t he m us c a r i ni c r ec ep to r , wh e r e as e p in ep h r in e a n d t i m o l ol bo t h ac t di r ec tl y a t β - r ec ep t o rs . I s o f lu r oph a t e i nh ib i ts th e m e ta bo li s m o f a c et yl ch o li n e, in di r ec t l y in c r ea s i ng le ve ls o f t he en d o ge no us ne u r ot r a nsm it t e r . 2 4 . Th e a n sw e rs a re A a n d E [ I V . B. 3 , D. 4 ] . Me t o p r o l ol , a β 1 -s e le c t i ve a ge n t, ca n c au se b ra dyc a r d ia al on e . Th e a dd i tio n of t o p ic al ti m o l ol , wh i le lim it i n g s y st em ic ab so r p ti o n , c ou l d h a v e a n a dd i ti v e β - b l oc k i ng e f f ec t t o d e c r e as e h ea r t r a t e (n eg a ti ve c h r on o t rop y ) . 2 5 . Th e a n sw e rs a re B a n d D [ V . C . 1, 2 ]. P i l oc a rp i ne an d i s o f lu r oph a t e c o u ld li m i t t h e e f fe c t s of ea ch o th e r, be c au s e , u l t im at e l y , b ot h ac t v i a c h o li n e rg ic re c ep t or s . P ilo c a rp in e a c ts d i r ec tl y o n t h e r e c ep t or , wh i l e is o fl u ro ph a t e i nd i re c tl y i nc re as e s a c e t y l c h ol i ne le ve ls . Pi lo c a rp in e a n d a ce t y l c h ol i ne c o ul d c om p et e fo r ea c h ot h e r a t t he re c e p t or si t e, ef f ec t i vel y d e c re as in g th e e f fe c ts o f b o th . Ep i ne p hr i ne an d tim o lo l a r e β - a go n is ts an d β a n t ag o ni s t s , r es pe c ti v e l y. A l th o ug h b o th ag e nt s ar e e ff ec t i ve i n t r e at in g g la u c o m a a l on e , t h e us e o f bo t h c on c om it a nt l y co ul d re su l t i n a p ha r m a c o lo g ic al an ta g o ni s m , e f f ec t i v el y d ec r ea s i ng t he e f fe c t s o f b o th . 2 6 - 28 . Th e a n sw e rs a r e: 2 6 - C [ XI I . B . 2 ], 27 - B [ XI . C . 2 ] , 2 8 - D [ XI . B . 3 , D. 3 ] . B u s pi r on e ' s m e c h a ni s m o f an xi o l y t i c a c t i on is u nk n o wn . U nl ik e t h e b en z od i a z e pi ne s , b u sp i ro n e l ac k s h y p n ot ic a n d a nt ic o n v ul sa n t p r ope r t ie s . Th e t ri c y cl ic an t ide p r es s a n t i m ip r am in e i s u s e f ul i n th e t re a tm en t o f en u re si s, b ec au s e t he c om p ou n d b l oc k s m us c ar i ni c r ec e pt o rs m ed i a ti ng m i ct u ri t io n . Tr a z od o n e is c a te g o ri z e d a s an a t ypi ca l a n t id ep r es s a n t t h at s e lec t i v el y b lo ck s s e r o to n in re u p ta ke . 2 9 - 31 . Th e a n sw e rs a r e: 2 9 - B [ I X. A ; F ig u re 13 - 15 ] , 30 - D [ XI I . A ; Ta b l e 1 3- 7 ] , 3 1 - C [ XI . A . 2 ; Fi g u re 13 - 19 ] . Th e s t ru c tu r e s ho wn i n qu e s t i on 29 is th a t o f p r oca i ne , wh i ch is a di e th yl am i no e th y l p - a m i no b en z o a te es t er . It c on t ai ns a h y d r op hi l ic a m i n o g r ou p i n th e a lc oho l po r ti o n o f t he m o le c u le an d a li po p hi l ic a r om a ti c a c i d c onn e c t e d b y t he es te r li nk ag e . Th e p r o ca in e m ol ec u le is t y pic a l o f e s t e r - t y pe lo ca l a ne s th e ti cs .
Th e s t ru c tu r e i n q ue s ti on 3 0 i s t h at of di a ze pa m , wh i c h ha s a be n z o -1 , 4 -di a ze pi n e a s i t s b as e n uc le us . Th e wi d e l y us e d b en z o - 1 ,4 -d i a z e pi ne de r i v a ti ve s h av e s i gn i fi ca n t a n xi o l y t ic , h y p n o ti c , an d a n ti co n v u ls an t ac t i v it i es . Th e s t ru c tu r e i n q ue s ti on 3 1 i s t h at of de s i p r am ine , wh i ch h as a di b en z a ze p in e a s i t s b as e n uc le u s . D ib e n za z e p i ne de r i vat i v e s t ha t h a v e a m e t h y l - o r d i m e t h yla m i n op r op y l g rou p at t ac he d to th e ri n g ni t r og e n h a v e s ig ni f ic an t a n t id ep r es s a n t a c t i v i t y . S i m il a rl y s u bs t i tu t ed di be n zo c yc l oh e pt a di e ne s a ls o h a v e a n t id ep r es s a n t a c t i v i t y . To g e t h e r, th es e t wo ch em ic a l c l as s e s m ak e u p th e m a jo r it y o f t he t ri c yc l ic a n ti d ep r es s a n ts . 3 2 . Th e a n sw e r i s A [ X. C ] . C l o za p in e , wh i l e t h e ra peu t ic a ll y d ef i ne d a s a g e ne r a l a n ti ps y c ho t ic , i s us ed a lm os t e xc l u s i v el y i n t he t r ea tm e n t o f s c h i z o ph r en i a. 3 3 . Th e a n sw e r i s B [ XI . A . 3 , C .2 ] . F l u o xe t i ne is m os t l ik el y b e in g u s ed in th is pa t ie nt i n a n a t te m p t to t re a t de p r es s i on a n d o bs es s i v e - c o m p u ls i ve d is o rd e r wi t h t he s am e d r u g. C li n ic al t ri al s h a ve s h o wn f l u o xe t i ne to im p ro v e bo th c o n di t io ns . Th e u s e of a si n gl e a g en t f o r b o th co n di t io ns wi l l m in im i z e t h e r is k o f d r u g -d r ug in t e ra c ti on s , as we l l a s re du c e t he c h an c es o f a d ve r s e ef f ec ts . 3 4 . Th e a n sw e r i s C [ I II .A . 2 , B .3 ; Ta bl e 1 3 -2 ] . Tyr a m i n e i s a n i nd i re c tl y a c ti ng s ym p at h om im et ic a m i n e t ha t en t er s t h e ne r ve t e r m i n al a n d d is pl ac es no r e pi n ep h ri n e f r om th e st o r a ge v es ic l es , t h us i ncr e a s i ng t he q u a nt a o f th e t r a ns m i tt e r r e le a s e d . P.323
3 5 . Th e a n sw e r i s C [ I II .A . 1 , 2 ] . B o t h a r om a ti c h y d r o xy l f u n c t i on s a r e im p o rt a nt for b o th al p ha an d b e ta r ec e pt o r b i nd i ng . H o we v e r , re m o v a l of on e o r bo t h o f t h e gr o u ps wo u l d in c re as e upt a ke o f t h e re su l ti n g c o m p o un d in t o th e b r ai n a n d a dr e ner g i c n er ve t e rm in al s , r esu l t in g i n t r a ns m i t te r di s p l ac em en t f r om v e si cu l ar st o ra g e an d in c re as ed t r an sm it t e r r e l ea s e . 3 6 . Th e a n sw e r i s B [ XI V . A . 2 , 3 ] . W hile l e v o do p a c a n c r os s t he bl oo d b r a in ba r r ie r t o ga i n ac ce s s in t o t he br a i n, a s i gn i fi ca n t p o rt i on of an o r a ll y a dm in is t e re d d os e g e ts c o n ve rt e d i nt o d o pa m in e a n d n o r ep i ne p hr i ne at pe r i phe r a l s i t es , l e ad i ng to pe ri p he r a l s i d e e f fe c t s a nd d e c re as e d b r a in bi o a v ai la b il i t y . Ca rb i do p a, a d o pa de ca r bo x yl a s e i nh ib i to r t ha t d o es n o t c r os s t h e b l oo d b r ai n b a r ri e r , is c o ad m i n is te r e d wi t h lev o d o p a t o d ec r ea se it s pe r i ph e r al c o n ve rs io n , i nc r ea s e c e nt r a l d el i v e r y o f t he d ru g a n d h e nc e t he t he r ap e ut ic r e s po ns e . 3 7 . Th e a n sw e r i s A [ I V .C . 1 ] . Te r a zo s i n b lo c k s al p ha re c ep t o rs o n th e p r os t at e g l an d t o c au se a re la xa n t e ff ec t , wh i c h r ed uc es t he pr es s u r e e xe r t e d b y th e p r os ta t e o n th e u r et h r a, t hu s e a s i n g u r i na r y v o i da nc e . 3 8 . Th e a n sw e r i s B [ I II .B . 1 . b] . S t i m u l at io n of be t a -3 re c e p t o rs i n du ce s t he m e t ab o l i c b r ea k d o wn o f f a t s to r e s i nt o f r e e f a t t y a c i ds t ha t c an b e fu r t he r c a ta b ol i z e d b y t h e b od y . Th e ho p e is th a t th is
c a te g o r y o f ph a rm ac ol o gi c a g en ts co ul d , wi t h r e pe a t ed us e, le a d t o a de c r e a s e in t h e c on t en t an d n um b er o f f at c e ll s, an d h e nc e an a nt i ob es i t y e f f ec t . 3 9 . Th e a n sw e r i s B [ I V .C . 3 ; Ta b le 13 - 3] . L i ke la be t al o l, c a r v e di l ol i s a no ns el ec t i ve a lp h a a n d b e ta r ec ep t o r a nt a go n is t u s e d i n th e t r e at m e n t o f h y p e rt e ns i on . Bl oc ka d e o f vas c u la r al ph a (a l ph a -1 ) re ce p t o rs wo u l d ca us e v as o di la t at io n an d d ec r e as ed pe r ip he r a l v a sc u la r re s i s ta nc e , wh i l e b l oc ka d e o f m y oc a r di al be t a (b e ta - 1 ) r ec e pt o rs wo u l d de c re as e c a rd i ac c o n t r ac ti li t y . Th e r e su l ta n t d ec r ea s e in c a r d ia c o ut p ut wo u l d pr o d uc e a fa l l i n bl o od p re s s u r e ( b l oo d p r es s u r e = c a r di ac ou t pu t × p e ri ph e r al re s i s ta nc e ) . 4 0 . Th e a n sw e r i s E [ XI V . A . 2 , D. 2 ; X V . A . 2, C ] . D e s pi t e t h e s i m i la r i ti es in t he i r n am es an d c he m ic a l s tr u c t u re s , t he s e t wo a g en ts h a ve ve r y di f f er e nt ph a rm ac o lo g ic al ef f ec ts an d th e r ap e ut ic us es . Th e o ne c om m o n al i t y a m o n g t h em is th a t b ot h p r o du c e re wa r d i n g e f fe ct s a nd t hus ab us e l i ab i li t y — m o r ph i ne p ri m ar i l y t h ro ug h i t s e up ho r i an t C N S ef f ec ts an d a p om o r p hi n e p r i m a r il y t h ro u gh it s p r o-l i bi d o ( e re c ti le ) ef f ec ts in m a l es .
14 Autacoids and Their Antagonists, Nonnarcotic Analgesic-Antipyretics, and Nonsteroidal Anti-inflammatory Drugs S c o t t F. L on g
I. INTRODUCTION A. Au t a c o i ds , al s o c a ll ed a ut o ph a rm ac ol o gi ca l ag e n ts o r lo ca l h o rm o ne s, h a ve wi d e l y d i ff e r in g s t ru c tu r es an d p h a rm ac ol og i ca l a c t i on s . A lt h ou g h th e t e r m r em a in s p oo r l y de f in e d , t he cu r r en t l y a cc e pte d c r i te r io n th a t d ef i ne s a s u bs ta n c e as a n a u ta c o id is lo c a l re le a s e an d a c t i o n l im i t e d t o a s pe c i f ic s i te . Two o f m o s t e xt e n s iv e l y i n ves t ig a te d a u t ac oid s a r e h i s ta m in e a n d t he p r o s t ag l a nd i ns . H o we v e r , se r o t o ni n , b r a d yk i n i n , a nd ka l li d i n a ls o f u nc t io n i n a s i m i la r m a nn e r . W hil e s om e a ut ac o id s (h is t am in e a n d s e r ot o ni n ) f un c ti on as neu r o t ra ns m i t t e rs , t he i r a u ta c oi d f u nc ti o n is t he fo c u s o f t hi s c h a pt e r . C u r r en tl y , t h er e a r e n o a g en ts t hat s pe ci f ic al l y m o du la t e t he f u nc t io n o f br a d y k i ni n o r k a ll id i n; ho we v e r , d r ug s o r a na lo gs t ha t m im ic , b l oc k, o r m od ul a te o th e r a u t ac oi d f u nc ti o ns ha v e i m po r t an t t h e ra pe u ti c r o l es . B . N o n n a rc o t ic an a l ge si c - a n ti p yr e t i c s ha v e di ss im i la r s t r uc tu r es bu t s h a re c e r ta i n t he r ap e ut ic a c ti on s , i nc lu di n g r e li ef o f pa i n, f e v er , an d s om e ti m e s i n fl am m a t io n . Me c h a n is ti ca l l y , t h es e ag e n ts a c t b y in h ib i ti ng s yn t he s i s o f p r os t ag l an din s . C . N o n s te r o i da l a n t i -i n fl a m ma t o r y d r u g s ( N S AI D s ) d if f e r i n s tr uc t u re and a c ti vi t y f r om th e n on n a rc o t ic an a lg es ic - an t ip y r e t ic s , b ut po ss es s a nt i i n f la m m at o r y p ro pe r t ie s . I n ad d it i on , m an y o f t h es e a ge n ts a ls o e xh i b i t a n t ip yr e t ic a n d a na lg es ic a c ti v i t y . N S A I Ds a ls o a c t b y i nh ib i ti o n o f p r o st a gl an d in s y n t h es is .
II. AUTACOIDS AND THEIR ANTAGONISTS A. H i s t a m i ne an d an t i his t a m in i cs 1 . C h em i st r y a . H i s ta m in e i s a b i oa m in e de r i ved p ri nc i pa ll y f r om di e ta r y h is ti d in e , wh i c h i s d ec a r bo xy l a t e d b y L - hi s ti d in e d ec a rb o xy l a s e (F i g ur e 1 4 - 1 ). b . An t i h i s ta m in i cs ( hi s ta m in e a n ta g on is ts ) c a n b e c l as s i fi e d as H 1 - o r H 2 r e c e p to r a nt a g on i s ts . ( 1 ) H 1 - r ec e p to r an t a go ni s t s , t he c l as si c a nt i hi sta m in ic ag e nt s , a re c h em ic al l y c l as s i fi e d a s e t h yl e n e d i am i ne s (e . g ., p y r i la m i n e ), a lk yl a m i n es ( e . g ., b ro m p h en i ra m i n e [D i m et a pp ] , c hl o rp h en i ram i ne [ Ch l o r- Tr i m et o n] ) , e t h a no l am i ne s (e . g ., dip h e nh y d r am in e [ B e na d r yl ] , c le m as ti n e [ Ta v i s t] ) , p i p e r az i ne s ( e .g . , h y d r ox y z i n e [ A t a ra x, V i s t a ri l ], c e ti r i z in e P.325 [ Z y r t e c] ) , ph e no t h ia z in es ( e .g . , p r om e th a zin e [Ph e n er g an ] ) , d i b e nz oc yc l o h e p t en e s ( c y p r o he p ta di n e [ P e ri ac ti n ] ) , p h th a la z in o ne s
( a z e l as t in e [ O p t i v ar , As te l in ] ) , a nd p ip e r i di n es (e . g . , a za ta d in e [ O p t im ine ] , l o r at a di n e [ C la r i ti n ], de s lo r a t ad in e [ Cl a ri n e x] , a n d f e xo f e n ad i ne [ Al l eg r a] ) . C e t i r i z in e , a z e la s t i ne , l or a t a di ne , de s l o ra t ad i ne , a n d f e xo f e n ad i ne m ak e u p t h e s ec o nd - ge n er a ti o n an t i hi s t am i ni cs , wh ic h a r e l e s s s ed a ti ng t ha n t h e o l de r , fi r s t - ge n e ra t io n d ru g s , o wi n g t o t h ei r l im i ted a bi li t y t o c ro ss th e b l oo d - b ra in ba r r ie r ( Fi g ur e 1 4- 2 ) .
Figure 14-1. Structural formula of histamine, an autacoid.
Figure 14-2. Structural formulas of representative H1-receptor antagonists. (A) Chlorpheniramine (alkylamine). (B) Diphenhydramine (ethanolamine). (C) Promethazine (phenothiazine). (D) Loratadine (nonsedating piperidine).
( 2 ) H 2 - r ec e p to r an t a go ni s t s a r e h e te r oc y c li c c o ng e n er s o f h is t am in e . Th e s e i nc l ud e c i me t i di ne ( Ta g am e t ), r a ni t i di n e ( Z a n ta c ), f am o t id i ne ( P e p ci d ), an d ni z a t i di n e ( A xi d ) ( F i gu r e 1 4 -3 ) . ( 3 ) Al t e r n a t i ve s t o t he H 2 - r e c e p to r a n t ag on is t s i nc l ud e o m ep r a z o l e ( P r i l os ec ) , l a ns o p ra z ol e ( P r e v a c i d ), r a be p r az o le ( A c ip H e x) , p a n to p r az o le ( P r o t on i x) , a n d e so m ep r a z o le P.326 +
+
( N e xi u m ) ; sp e ci f i c i n hi bi t o r s o f H / K - AT P a s e (p r o t on pu m p in hi b it o rs , or P P I s ) , t he ul t im a te m e dia t o r o f g as t r ic ac id s ec r et i o n. S t ru c tu r al l y, th es e
a g e nt s a r e s u bs t i tu t ed be n z im i da z o l es li nk e d t o a p y r i di ne r in g b y a +
+
s u lf i n yl b ri d ge , wh i c h is r e q ui r e d f o r H / K - A TP as e i n hi bi t io n .
Figure 14-3. Structural formulas of (A) cimetidine, an H2-receptor antagonist, and (B) omeprazole, a proton pump inhibitor.
2 . P ha r m ac o l og y a . H i s ta m in e h as po we r f u l ph a rm ac ol o gi c a l a c t i on s , m ed ia t ed b y t wo s p ec if ic r ec ep t o r t y p es (Ta b l e 14 - 1 ). A th i rd hi s ta m in e re ce p to r ha s b ee n i d en t i fi ed . It s f u nc ti o n h as y e t t o be el uc id a te d , bu t it is be li e v e d t o a c t , at l e as t i n p a r t, as an au t o re c ep t o r. ( 1 ) H 1 - r ec e p to r s m e di a te t y p ic al al l er g ic an d a na p h y l ac ti c r es p on s e s t o h i st am i ne , s uc h a s b r on c h o c o ns t r ic ti o n, va s o di l at io n , i nc r e as ed c a pi ll a r y p e r m e ab i li t y , an d s pa s m o d ic c o nt r ac t io ns o f g as tr o i nt e st i na l ( G I ) s m o o t h m us c l e . ( 2 ) H 2 - r ec e p to r s m e di a te o th e r re s p o ns es to hi s ta m in e , su c h as in c re as ed s ec r e ti o n o f g as t ri c a c i d , p e ps in , a n d C a s t l e 's fa c t o r ( in t ri ns ic f ac to r ) . b . H 1 - r ec e p to r a nt a g on is t s c om p et i ti v e l y bl oc k H 1 - r e ce p to r s , t hu s li m i t ing t h e h is t am in e ' s e f fe c t s on b r on ch ia l s m o o th m us c l e , c ap i ll a ri es , a n d G I s m o o th m u s c le . Th es e an t a go ni s ts a ls o p r e ve nt h i s t am i ne - in d uc ed pa i n a n d i t ch i ng of t he s k i n a n d m u c ou s m em br a ne s . c . H 2 - re c ep t o r a n t ag o n is t s c om p et i ti v e l y bl oc k H 2 - r e ce p to r s , t hu s li m i t ing t h e e f f ec ts of hi s t am i ne o n ga s t r ic se c r e ti o ns . +
+
d . Th e P P Is i rr e v e rs i bl y i n hi b it t he pr o to n p u m p H / K - A TP a s e b y c o val en t l y b i nd i ng to t he p ro t ei n . 3 . T he r a pe u t ic i nd i ca t io n s a . E xo g e no u s h i st a mi ne c a n b e u s ed as a d ia gn o s t ic a ge n t f o r t es t in g g a st r ic f u nc t io n . Ho we v e r , o th e r s t im ul an t s o f g as t ri c s ec r e ti o n ( pe n ta g as t ri n ) a re m o r e s u it a bl e a n d s a f e r. b . H 1 - r ec e p to r a nt a g on is t s ar e u s ed to p ro v i de s y m p to m a t ic re li e f o f a l le r g i c s ym p t o m s , s uc h a s s eas o na l rh in i ti s, co n ju nc t i vit i s , a nd th e s ym pt om s o f r h in o v i r al i n f ec ti o ns (c om m o n c ol d) . Th e i r a n ti hi s ta m i ni c e ff e c ts a ls o m ak e t h em u se f u l f o r s ym p to m a t ic re li e f o f u r t ic a r ia . Ag e nt s wi t h a h ig h d e g re e o f a n ti ch o li ne r g ic ac t i vit y ( e . g ., di p he n h y dr a m i ne ) a r e s om e ti m e s u s e d t o tre a t n a us ea an d v om i ti ng a ss o ci at e d wi t h m o t io n s i c k n es s a nd ve r ti go . In ad d i ti on , pr o m e t ha z i ne ( wh i ch al s o
h a s a h i gh de g re e o f an ti c ho li n e rg ic ac ti v i t y) is s o m et im es us e d as an an ti e m e t ic , a n d h yd r o xy z i n e p am o ate is oc ca si o na ll y e m p lo ye d as a m i ld an xi o l yt i c . Th e s ec o nd - g en e ra t io n d r ug s ( i . e. , l o r at a di ne , de sl o rat a d in e , P.327 f e xo f e n a di n e, ac r i v as ti ne , c e t ir i zi ne , a n d a ze la s ti n e ) p r o vid e t h e a dd e d ad v a n t ag e o f li t tl e to ne gl i gi bl e s eda t i on , o wi n g to t he i r r e lat i v e in a bi li t y t o c ro s s th e b l oo d b r a in ba r r ie r .
Table 14-1. Selected Actions of Endogenous Histamine Site
Receptor Type
Action Cardiovascular
Vascular
Heart
Arterial contraction
H1
Arteriolar relaxation
H1 and H2
Venule contraction
H1
Venule relaxation
H2
Endothelial cells, release of EDRF
H1
Endothelial cells, contraction
H1
Increased heart rate
H2
Increased force of contraction
H2
Slowed atrioventricular conduction
H1
Respiratory Bronchiolar smooth-muscle contraction Gastrointestinal (GI)
H1
Gastric mucosa
Increased secretion of acid and pepsin
H2
GI smooth muscle
Contraction
H1
Various Cutaneous nerves
Pain and itch
H1
EDRF, endothelium-derived relaxing factor. c . H 2 - re c ep t o r a n t ag o n is t s ar e u s ed to t re a t g ast r i c h yp e r s e c r e t o r y c o nd i t io ns , s uc h a s d u od en a l u lc e r a n d Z o ll in g e r- E l li s o n s y nd r o m e . Th e y ar e e f f ec ti v e i n r e d uc in g p a in as s o c i a te d wi t h g as t r oe s o ph a ge a l re f l u x d is e as e, bu t no t e th a t th e y d o no t p r e v e nt ac t ua l r e fl u x. d . Th e p r ot o n p u mp i nhi b i t o r s a r e us e d t o t r ea t d u o d en a l u l ce r s a n d a re t he d r u gs of c h oi c e f or t he t re a tm e nt o f Z o ll i n ge r - E l li s o n s yn d r o m e . 4 . Ad ve r s e e f fe c t s a . H i s ta m in e m a y c a us e n um e r ou s a d v e rs e e f fe ct s re l at e d t o i ts ba s i c p h a rm ac ol o g y (s ee I I. A .2 . a ) . b . H 1 - r ec e p to r a nt a g on is t s ar e a s s oc i at e d wi t h th e fo l lo wi n g ad ve r s e e f fe c t s : ( 1 ) C e nt r al ne r v o us s ys te m ( C N S ) e f fe ct s , s u ch a s C N S d e pr e s s io n , s e da t i on , f a t ig u e, ti n ni t us , h al l uc ina t i on s , an d a t a xi a ( 2 ) G I ef f ec ts , s uc h a s na u s e a a n d v o m i t in g ( 3 ) A n tim u s c ar i ni c e f fe c ts , s uc h a s d r y m o u th , u r in a r y r e te n ti on , an d c on s ti p a ti on ( 4 ) Te r a to g en ic ef f ec ts (p o s s ib l e wi t h pi p er a zi ne c om p ou n ds ) c . N on s ed a t in g H 1 - re c ep t o r a nt a g on i s ts , b ec a us e th e y po s s es s li t t le a n t ic ho li n e rg ic ac ti v i t y an d do no t c r os s t he bl o od - b r ai n b a r ri e r , a re r el a tive l y f r e e o f si de e ff ec t s . d . H 2 - r ec e p to r a nt a g on is t s ar e a s s oc i at e d wi t h th e fo l lo wi n g ad v e r se ef fe c ts : ( 1 ) C N S ef f ec ts , s uc h a s c on f us io n a n d d i z zi ne ss ( 2 ) H e pa ti c a n d r en a l d ys f un c ti on ( 3 ) I nh ib i ti o n o f t h e h ep at i c m i c ro s o m al d r u g -m eta b ol i z i ng en z ym e s ys t em ( wi t h c im e ti d in e ) ( 4 ) A nd r o ge ni c e f fe c ts (wi t h h i gh do se s o f c im et id i ne ) , s uc h a s i m p o te nc e a nd g yn e co m a s ti a i n m en and g al ac t o rr h ea in wo m en +
+
e . Th e H / K - AT P a s e i nh i b i t o rs ha v e be e n r e por t e d t o c au s e d ia r r he a , G I p a in , a n d h e a da c h e a s t he i r m os t fr e q ue n t a d ve rs e e f fe c ts . I n ad d it i on , t h e y m a y in te r f e re wi t h t h e m et a bo li s m of dia z e p am , wa r f a ri n , p he n yt o i n, an d th eo p h yll in e . B . S e r o t on i n 1 . C h em i st r y
a . S e r ot o n in ( 5 -h y d r o xy t r y p t a m i n e) is a b io am in e t h a t is s y n t h es i zed f ro m t h e a m in o a c i d t r y p t op h an by a t wo - s t ep en zy m a t ic pr o c es s c a t al y z e d b y t r y pto p h an h yd r o xyl a s e an d L - am in o a c i d d ec a r bo xyl a s e ( Fi gu r e 14 - 4 ). b . S e r o to n i n a go n is t s ( 1 ) 5 - H T 1 - r e ce p t o r a go ni s t s (i . e. , s um a t ri pt a n [ Im i t re x] , r i z a t r ip t an [ Ma x a l t ], n a r a tr i pt a n [ A m e r ge ] , z olm i t ri p ta n [ Z om ig ] , a lm o t ri p t an [ A xe r t ] , e l et r ip t an [R e l p a x] , a n d f r o v a t ri p ta n [ F r o v a] ) a r e i n do le de r i v a ti v e s s tr u c tu r al l y s i m i la r to s e r ot o n in ( F i gu r e 1 4 - 4) . ( 2 ) T eg a se r o d ( Z el n or m ), a n i n do l e d e ri v a t i v e , ac t s as 5 - H T 4 - r ec ep t o r a go n is t ( F i gu r e 1 4 - 4) . ( 3 ) E r g o t a lk a lo i d s ( e rgo t am i ne [ E rg om a r ]) ha v e s om e a c t i vi t y as a s e r oto n in a g o ni st / pa r t ia l a go n is t . c . S e ro t o ni n an t a go n is ts ( 1 ) E r g o t a lk a lo i d s a nd d e r i v a ti v e s wi t h an t ag o nis t / pa r ti a l a go n is t ac t i vi t y i nc l ud e e r g o n o vi ne ( E r go t ra t e ), d i h yd r o e r g o t a m in e , m et h ys e r g i d e , an d b r o m ocr i p t i n e ( P a r l od el ) . ( 2 ) 5 - H T 3 - a nt a go n i s ts m a y b e e i th e r i n d ol e d e r i va t i v es ( on d an se t r on [Z o fr a n ] ) o r b e n zi m id az o l es (g r a ni s e t r o n [ K y t r il ] ) . O t h e r d rug s o f th e c la ss in cl ud e do l a se t r o n ( A n ze m et ) , p a l on o se t r on ( A l o xi ) an d a l o se t r o n ( L o t ro n e x) ( F i gu r e 1 4 -4 ) . 2 . P ha r m ac o l og y a . S e r ot o n in e xe r t s a wi d e r an ge o f e ff e c t s v i a a f a m i l y of r ec ep t o rs t h at i n c l ud e s a t l e as t s e v e n t y p es an d s ev e r a l s u bt y p es . Ma j o r p hys i o lo gi c al e f f ec ts of s e ro t o ni n i n cl ud e v as oc o ns t ri c t i on ( 5 - H T 2 ) ; p la t el e t a gg r eg at i o n ( 5 - H T 2 ) ; i nc r e as ed re l ea s e o f a c et yl ch o li n e i n t he en t er i c re gi o n ( 5 - H T 4 ) ; n a us ea / em es is ( 5 - H T 3 ) ; a nd nu m e ro us b e h a vio r al ac ti o ns th a t in f l ue nc e a n xi e t y , d ep r es s i on , a g g re s s io n , im p ul s ivi t y , a n d a p p et i te ( 5- H T 1 , 5 - H T 2 , 5 - H T 3 ) . I n a d di ti o n, t he 5- H T 1 - r e c e pt o r a c t s a s a n a u t o re ce p to r to in hi b it p re s y n ap t ic ac ti v i t y a t b ot h s e ro t on e r gi c a nd ad r ene r g ic n e u ro n es i n th e C N S. F ur t h e rm o re , i t di r ec tl y c ont r i bu t es to v a sc ul a r t o ne t h r o ug h va s o co ns t ri c ti on . S er o ton i n m a y a ls o p r o du c e num e r o u s o th e r e f fe c ts , i nc l u di n g t he o p p os it e o f th os e j us t s ta t e d, de p en d in g o n t h e sp e c i f ic re c e p to r th a t m edi a t es th e e ve n t . P.328
Figure 14-4. Structures of (A) serotonin and representative serotonin agonists (B) sumatriptan, (C) tegaserod, and (D) the serotonin antagonist ondansetron.
b . S e r o to n i n a go n is t s ( 1 ) 5 - H T 1 - a go n is t s m im ic t he ac ti o ns o f s e ro t o nin a t t hi s re ce p to r to de c re a s e p r e s yna p ti c n eu r o tr a ns m i t t e r r el e as e . D i re c t v a s oc o ns t ri c ti on , d e c r e as ed re l ea s e o f i n f la m m at o r y an d v as od i la t i ng s u bs ta n ce s ( ne u r ok i ni n A, s u bs t an c e P ) , an d a d i re ct a n t in oc ic e pt i v e a c t i v i ti es a r e t h ou g ht to c o n t ri bu te t o t h e e ff ic a c y o f th es e d r u gs . ( 2 ) T eg a se r o d a c t i v a te s t h e s e ro t on e r gi c r ec ep t or ( 5 - H T 4 ) , c a us in g t h e r el e as e o f a c et yl ch o li n e, ot h e r n eu ro t r a ns m i tt e rs , an d c al c i to n in ge n e - re la t ed pe p ti de . Th e s e , i n tu r n , i nc r ea s e ga s t r ic a n d i n te st i na l m ot i li t y and t on e . I n a d di t io n , di r ec t a ct i on s o n th e g as t r oi n te s ti na l s m o ot h m us cl e i s t ho u gh t t o c o nt r ib u te i t i ts e f f ec t, t h us a cc o un t in g f o r b o th t he d i r ec t a n d i nd i re ct ac t io ns o f t eg as e r od . ( 3 ) E r g o t a lk a lo i d s p r odu c e a wi d e r a ng e o f p h a rm ac o lo g ic al ef f ec ts , i nc lu d in g b o t h a g o ni st ic an d a n ta g on is ti c a c ti v i t y at ad r e ne r gi c , d o p am in e rg ic , a n d s er o to n e rg ic r e c ep t or s . S p ec if ic ac t ion s d e pe n de n t o n d r ug and a ni m a l m od el s . c . S e ro t o ni n an t a go n is ts s u c h as o nd a ns e t r on a n d re la t ed d ru gs bl oc k th e io n c h an n el c o up le d 5 - H T 3 - r e c ep t o r, th u s i nh ib i ti n g th e ab il i t y of s e r ot o ni n t o c au se n a us e a a nd / o r em es is . Th i s ac t io n a p pe a rs to occ u r b o th lo ca l l y a t th e G I t r ac t an d c e nt r a ll y i n t he a re a p os tr e m a. In ad d it i on , a c ti v a ti o n o f p e ri p he r al 5 - H T 3 - re c ep t o rs wi l l i nc r ea s e pa i n, ab d om i na l d is t en t io n , a nd m ot o r r es po ns es of t he in t es t in a l t r ac t . B l o ck ad e o f th es e a c t i ons , th us sl o wi n g G I m o t il ity , b y a l os e t r o n is r es pon s ib le f o r i t s u se f ul ne s s in c e r ta i n c as e s o f i r ri t ab l e b o we l s y n d r om e ( I B S ) . 3 . T he r a pe u t ic i nd i ca t io n s a . S e r ot o n in a go n is t s ( 1 ) N um e ro us C N S ac t i ve d r ug s us e th e s e ro t on er g i c s y s t em to m o d ul at e b e h a v io r , s uc h a s t h e a no r e xi a n ts ( d e xf e n f l ur am i ne ) , a n xi o ly t i c s ( b us pi r on e ) , a nd s el e ct i ve s e r ot o ni n r e up t ak e i nh i bit o r s f o r d ep r es s i o n ( f lu oxe t i n e ) . Th es e d r u gs a r e a c ti ng m o r e o n t he ne u r ot r an s m i tt e r fu nc t io n o f s e ro t on i n a nd a re di s c us s e d he r e . ( 2 ) S om e e r g o t a lk a l oi ds , s um a t r ip t an , an d s im i l a r d r ug s ac t to m o du l ate t he a u t ac oi d f u nc ti o n o f s e rot o n in . Th e y ar e u s ed to p r e ve n t a nd t re a t p ai n as s o ci a te d wi t h m ig r a in e h ea d ac he s b y a l te r in g s e ro t on in ' s ac t io ns t ha t re s u l t i n ch a ng e s i n va s c ul a r t on e . P.329
( 3 ) I n a dd i ti on , s om e e r go t a lk a l oi d s a r e us e d t o p r e v e nt po s tp a rt um h em o r r h ag i ng ( t h r ou g h b ot h v as oc o ns t ri c ti v e an d u t e ri n e c o n t rac t il e a c ti on s ) a nd to p re v e n t p o st p a rt um b re as t e n go rg e m e n t ( b r o mo c r ip t i ne , t h r ou g h d op am in e r gi c ac t i v i t y ) . ( 4 ) T eg a se r o d is us e d i n t h e t r ea t m e n t o f I B S th at i s co ns t ip a ti o n p re d om in a n t. b . S e r o to n i n a n ta g on i s ts . Th e se ag en t s ( e .g . , on d a ns e t r o n, g r an i se t r on , d o l as e t r o n, pa l o no s e t ro n ) a re us ed to p re v e n t a n d t r e at na us e a a nd em e s is s ec o nd a r y to an t in e op l as t ic th e ra p y b y bl oc k i n g t h e a c ti on s o f s e ro t on i n a t t he 5H T 3 - r e c e pt o r . Al o s e t r o n i s u s e d f o r t h e t r ea tm e nt o f I B S th a t i s d ia r r he a p r e do m i n an t . 4 . Ad ve r s e e f fe c t s a . S e r ot o n in a go n is t s ( 1 ) 5 - H T 1 - a go n is t s m a y p r o du c e f ee li n gs o f wa r m t h , p ar e st h es ia s, di z z i ne s s , an d t i g ht n es s o r h ea v i n es s in t h e c he st . R a re l y, p a ti en t s m a y e xp e r i e nc e c he s t p ai n . B e c au se th e s e ag en t s m a y c au s e c o r o na r y v a so c o n st r i c t io n , t he y a r e c o nt r a in di c a t ed in an g ina p at i en ts an d s h ou ld be u s e d c a ut io u sl y in p at ien t s wi t h h yp e r t en s i on o r o t he r ri s k f ac to r s f o r is c he m i c h ea r t di se as e . ( 2 ) T eg a se r o d m a y p r odu c e d ia r r he a , a bd om i na l c r am p in g a nd pa i n, di z z i n e s s , a n d h e a da c h e a s s i d e e f fe c t s . ( 3 ) E r g o t a lk a lo i d s m a y c au s e G I up s e t a n d c ol d e xt r e m i ti es . As to xi c i t y p r o g re ss es , t h e p a ti en t m a y e xp e r i en ce em es is , d i a r rh e a, pe r ip h e ra l p ai n s ec on d a r y t o lo c a l i s c he m i a , a nd hal l uc in a ti o ns o r de l us io ns . b . S e r o to n i n a n ta g on i s ts . Th e 5- H T 3 - a n t ag on is ts wi l l p r o du c e he a da c h e , c o ns ti p at i on , a n d d i z z i nes s . I n a dd i ti o n, g ra ni s et ro n ha s b ee n re p or t ed t o p r o du ce s om n ol e nc e a nd di a r rh ea . Th e us e o f a l os e t r on i n pa t ie n ts wi t h d ia r r he a -a s s o ci at e d I B S h as re s u l te d i n s om e c a s e s o f i s c he m i c c ol i ti s a n d l if e - th r ea t en i ng c om p li ca t io ns f ro m s e v e re c o ns t ip a ti o n. S ub s e q ue n t to a se r ie s o f a d ve rs e d r ug r e a ct i on s i n t hi s m a n ne r , a l os et r o n is ge n er a ll y p re sc r i be d o nl y b y p h y s i c ia n s wh o h a ve be e n e n ro ll e d i n a p r e s c ri b in g p r og r am m e . C . P r o s t ag l an d i ns 1 . C h em i st r y a . P r os ta g la n di ns ( P Gs ) a r e de r i va t i ve s o f p r os ta n oi c a c i d , a 2 0 -c a r bo n fa t t y ac i d c o nt a in in g a 5 -c a rb o n r ing ( F ig u re 14 - 5 ) . I n t he bo d y , p ro s ta gl a nd in s a r e p r i nc ip a ll y s yn t he s i z e d f ro m a r ac hid o ni c a ci d , wh i c h i s f o rm e d f ro m t he m e m b r an e p h os p ho li p id s b y ac t io n o f ph os p ho l ip as e A 2 . Spe c if ic a ll y , p ro s t a gl a nd in s a r e s yn t he s i z e d f ro m a r ac hid o ni c a ci d b y t he e n zy m e c yc l oo xy g e n a s e ( C O X) , wh i c h e xi s t s as th r ee is o z y m es : C O X 1 , 2 , a n d 3 . C O X 1 a pp e ar s t o fu nc t io n c on s ta n tl y . I t s ro le s e em s t o b e t h e d a il y s yn th e s i s o f p r os tag l an d in s , wh i c h c o n t ri b ute t o n o r m a l h om eo s ta s i s , an d i nc l ud es p ro t ec ti o n o f t he g as t ri c m uc os a t h ro u gh t he p r o st a gl an d in s a nd he m o s ta s i s t h r ou gh t he s yn th e s i s o f t h ro m bo xa n e . CO X 2 i s e xp r e s s ed p ri m a r il y i n r es p on s e t o in f la m m a ti on o r in j u r y , c on t ri b ut i ng to t h e i n f la m m at o r y r es po ns e . It i s al s o im p or t an t in no rm a l ( n on in j ur y ) r e gu l at i on o f c a r di ac an d p e rh a ps o t he r f un c t i on s . C O X 3 i s t ho u g ht to be p re d om in an t ly a c t i ve wi t h i n th e C N S , c o n t ri b uti n g t o n o rm a l t he r m o r egu l a to r y c o n t ro l a nd p ai n p e r ce p ti on ,
t h r o ug h t h e s y n th es is of p r o s t a gl an d in s , c e n t ra ll y. N o t e t ha t th e p r od u ct s o f c yc lo o xy g e n a s e a re t he n c on v e r t ed in t o e it h e r p ro s ta g la n di ns b y p r os t ag la n di n s yn t ha s e o r t h ro m bo xa n e s b y t h r om bo xa n e s y nt ha s e. Th e th r om b o xa n es d i f fe r f ro m t h e p r os t ag l an di ns m a in ly b y t h e s ub s ti t ut i on of a t e t ra h yd r op y r a n r i ng s t ru c tu r e f o r t h e p e nt a ne r in g f o un d in p r os ta g la nd i ns . Th e o nl y c li n ic al l y re l e v an t th r om b o xa n e c u r re n tl y i de n ti f ie d i s t h ro m bo xa n e A 2 ( TxA 2 ) , wh i c h c au s es p l at e le t a g gr eg a t io n . b . C l as s i fi c a ti o n o f p r os t a g la nd i ns as p r os t ag la nd i n A ( P G A ) , p r os t ag l and i n B ( P G B ) , p r os ta g la n di n E (P G E ) , a nd s o fo r t h r e la te s to th e p r es e nc e o r a bs e nc e o f k e to o r h y d r o xy l P.330 g r o up s a t p os i ti o ns 9 and 1 1 ( F ig u re 14 - 5 ) . S u bsc r i pt s r e la t e t o t h e n um be r a nd p o si t io n o f d o ub l e b on ds i n t h e a li p ha t ic c ha i ns (F i g ur e 1 4 - 6 ).
Figure 14-5. Structural formula of prostanoic acid, from which the prostaglandins are derived.
Figure 14-6. Structural formula of misoprostol (Cytotec), a derivative of prostaglandin E1 (PGE1).
2 . P ha r m ac o l og y a . E n do g en o us p ro s ta gla n di n s a pp ea r to a ff ec t n u m e r ou s b o d y f u nc ti o ns . Th e y a r e r e l ea se d i n re s p o ns e t o m a n y c h em i c al , b ac t e ri al, m ec ha ni c a l , a nd o th e r in s ul ts ;
a n d t h e y a p pe a r t o c on t ri b u te to t he s i gn s a nd s ym p to m s of t he i n fl am m ato r y p r o ce ss , i nc lu d in g p ai n an d ed em a . b . P h ys i o l o g i c a l r e s pon s e s t o p r os ta g la n di ns in c lu d e v a so d il a ti on in m o s t vas c u la r b e ds , a l th o ug h v as oc on s t r i c t i on c a n oc c ur in is ola t e d a r ea s . P G I i n hi bi t s p l a te le t a g g re g at i on an d s ti m u l ate s g as t r ic re l ea s e of bi c a r b on a te an d m uc us , b o th o f wh ic h s e r ve to pr o te c t t he ga s tr i c e pi t h el iu m . Th e P G E s i n hi bi t pl a te le t a g g re g ati o n , r el a x b r o nc hi a l a nd G I s m o o th m us c l e , co n t ra c t u te r in e s m o o th m us cl e , a nd in h ib i t g as t r ic a c id s ec r e ti o n. A lt e r na t i ve l y , t he P G D s a nd P G Fs c on t r ac t b r on c h i al an d G I s m o o th m us c l e . Pr os t a gl an d in s a l s o in c re as e re na l b l ood f l o w, p r o m o t e di u r es is , n a t ri u r es is , a nd k a li u r es is ; bu t p a ra d o xi c al l y t he y i nc r e as e r e ni n s ec re t io n. Th e y a l so po s s es s d i v e rs e e nd o c ri ne an d m e ta b ol ic e ff e c ts . 3 . T he r a pe u t ic i nd i ca t io n s a . P G E 1 a n a lo g s ( 1 ) Al p r o s t ad i l ( Pr o s t i n V R P e d ia t ri c ) i s us e d f o r t e m p o ra r y m a i nt e na nc e o f a p a t en t d uc t us a rt e ri os u s wh e n a wa i t i ng c o r re c ti ve s u rg e r y fo r c o ng e ni t al he a r t d e f ec ts . ( 2 ) Al p r o s t ad i l ( Ca v e r j ec t ) i s u se d i n t r e at i ng i m p o t en c e o wi n g t o e r ec ti le d ys f un c ti o n. ( 3 ) M i s op r o s t ol ( C y t o tec ) is u s ed fo r th e p r e ve nt i o n o f N S A I D - in d uc ed GI u lc e rs ( F i gu r e 1 4 - 6) . b . P G E 2 an a lo g s a n d d er i va t i ve d i n op r o s t on e (P r o s ti n E 2 , P re pi d il , C ervi d i l ) a r e u s ed fo r th e i r a bo r ti f ac i en t e ff ec t s a nd to in d uc e c e r v ic a l- r i pe ni n g i n p r egn a nc y. c . P G F 2 α an a lo g s ( 1 ) C a r bo p r o s t ( H em a bat e ) , wa s u se d fo r i t s a bor t i f ac ie n t e f fe c t s . A hi gh i n ci de n ce o f ca r di o v as c u l a r c o l la ps e c a us e d i ts r em o v al f rom t he U . S. m a r ke t . ( 2 ) L at a n op r o s t ( Xa l a tan ) , t r a vo p r os t ( Tr a v a ta n) , b i ma t op r o s t (L um ig a n) , a nd u n o p r os t o ne ( R es c u la ) a r e us ed to p ic al l y to lo we r in t r ao c u l a r p re s s u re in g l au c om a. d . P G I an a lo g ep o p r os te n o l (p r os ta c y cl i n, [ Fl ola n ] ) i s us e d p r im a ri l y fo r t h e t r e a tm en t o f em e rg en t pu l m o n ar y h y p e r te ns io n . 4 . Ad ve r s e e f fe c t s as s oc i at e d wi t h P G E in c l u de t h e fo ll o wi n g : a . C N S ef f ec ts , s uc h a s C N S i r r i ta bi l it y, f e ve r, s ei z u r e s , an d h e ad ac h e b . C a rd i o v as c u la r ef f ec ts , s uc h a s h y p o te ns i on , d y s r h y t hm ia s , va s o d il a tio n , f l us h in g , a nd c a r di ac a rre s t c . R es pi r a to r y e ff ec t s , s u c h as r es pi r a to r y d ep r es s i o n a nd di s t r es s d . H em a to l og ic al e ff ec t s , s uc h a s a ne m i a , t h ro m bo c y t op e ni a , a nd di ss em in a t ed i n t ra va sc u la r c o ag ul a ti on ( D I C ) e . D ia r r he a f . D e cr e as ed r en a l f un c t io n g . S po t t y bl e ed in g a n d m e ns t ru a l i r re g ul a ri t ie s , a b o r ti on , an d p en i le pa in D . L e uk o t r ie n es 1 . C h em i st r y a . L eu k o t ri e ne s . The leu k ot r i en es ( L Ts ) a re 20 -c a r bo n d e ri va t i v es of th e f a t t y a ci d s t h a t a r e f o rm ed v i a t h e en z y m a t ic pa t h wa y c at a l yze d b y li p o xy g e n as e . Unl i ke th e
p r o st a gl an d in s , t he y c o nt a i n n o r in g s t r uc tu r e a nd a r e co v a l en t l y l i nk ed to t wo o r t h r e e am i no ac id s . P.331 Th e t wo i m po r t an t l eu k otr i e ne s i de n ti f ie d t o d a t e ( L TC 4 a n d L TD 4 ) d if f e r on l y b y t he p r e se nc e o f g l ut am i ne . Th e no m e nc l at u re o f t he le u k o t r ie ne s i s s i m i l ar t o t h a t u se d f o r th e p r os t ag l an di n s . b . L eu k o t ri e ne a nt a g oni s t s ( 1 ) L ip o x yg e n a s e i nh i b it o r s s u ch as z i le u t on ( Zyf l o ) a re be n zo th io p he n e d e r i va ti v e s . ( 2 ) L eu k o t ri e ne a nt a g on i s t s s u c h as z a f i r lu k ast ( A c c o la t e) an d m o n te lu k a s t ( S i n gu l ai r ) re p re s e n t a di v e r s e ch em ic a l g r ou p t ha t is pe p ti do m i m e t ic - li k e i n i ts s t r uc t ur e . 2 . P ha r m ac o l og y a . L eu k o t ri e ne s p l a y a ro l e i n n um e ro us ph y s i ol og i c a l f u nc ti o ns . Th e y h a ve b ee n i d en t i fi ed as th e s lo w- r e a c ti n g s u b st a nc e o f a nap h y l a xi s . Sp ec i fi c a ct i ons o f t he l e uk o t ri en es in c l u de th e f o l lo wi n g : (1) Heart ( a ) N e ga ti v e i no t ro p y ( b ) S m o o th - m u s c le c h em o t a xi s ( 2 ) G I t r ac t . Ne u t ro p hi l c h e m o t a xi s th a t h as b e en c o r re la t ed wi t h in f la m m a t o r y b o we l d is ea s e ( 3 ) P u lm o na r y. Th e a c t io n s o f t h e l eu k o t ri e ne s wi t h i n th e p u lm on a r y s y s t e m a pp e a r t o be m a jo r . Th es e a c t i on s a r e t h e m os t im p o rt a nt p ha r m a co l og ic al l y . ( a ) B r on c h oc o ns t ri c t i on ( b ) I nc r ea s e d p e rm ea b il it y ( c ) I nc r ea s e d m uc us s ec r e t io n ( 4 ) B l oo d / l ym p h . A s no te d p re v i ou s l y , t he le uk o tr i e ne s a c t as c h em ot ac t ic ag e nt s f o r ne u t ro ph i ls a n d e os ino p hi ls an d ac t t o m od i f y l y m p ho c y t e p ro l if e r at io n a n d d i f fe r e nt ia t io n . b . L eu k o t ri e ne a nt a g oni s t s ( 1 ) T he l ip o x yg e n a s e i nh i b i t o r z il e u to n pr e v e nts t he s yn t he s i s o f l e uk otr i e ne s b y i n hi b it i ng th e e n z y m e res p on s i b le fo r th e ir f or m at i o n —n am el y l ip o xy g e n as e . Th is a c ti o n p r e v en ts t he fo r m a t i on of al l l e uk ot r ie n es , t h us p re v e n ti n g t he i r c ont r i bu t io n t o va r io us in f la m m at o r y p r o c e s s es . ( 2 ) Th e le uk o tr i en e a n tag o ni s ts z a f i rl u ka s t a n d m o n t el u ka s t n o ns el ec t i ve l y a nd c om p et i ti v e l y in h ib i t t he e n d og en o us l e uk o tr i en es a t th ei r v a r io us r ec ep t o r s i te s . Th i s ac t io n b lo c k s t he e ff e c ts o f hi st am i ne , m os t n o t ab l y th e b r o nc ho c o ns t r i c t i on a n d p ul m on a r y e d em a a s s oc i at e d wi t h as t hm a a nd a ll e rg ic r ea c t i on s. 3 . T he r a pe u t ic i nd i ca t io n s fo r z il e u to n , z af i r l uk a s t , a nd mo n t e lu k as t a r e l im i te d t o t he t re a tm en t o f as thm a . Th es e a ge n ts re d uc e b r on c h os p as m an d a s so c ia t ed s ym p to m s th a t a r e m e d ia t e d t h ro u gh th e l e uk ot r ie n es . 4 . Ad ve r s e E f f ec t s
a . Z il e u to n pr es e nt s wi th r el a ti ve l y f e w si d e e f fec t s , p re d om in an t l y ga s t ro i n te st i na l i n na t u re (i . e ., d y s p ep s i a a n d n au s e a ) . H o we ve r , i t do es ca us e t r a ns ie n t in c r ea se s i n he pa t ic en z y m e s . Th is p o te n ti a l f o r h ep a to t o xi c i t y h as li m i te d i t s us e . b . Z af i rl uk a s t m a y p ro d uc e G I u ps e t a nd li v e r d ysf u nc t io n (n o t a s g re a t a s wi t h zi l e u to n ) , a nd m a y in h ib it t h e m e t ab o li s m o f th eop h yl li n e, wa r f a r in , a n d po t e nt i al l y o t h e r d ru g s . S ud de n wi th d r a wa l o f c o r ti c o st e r oi ds i n pa t ie n ts ta ki n g z a f i rlu k as t h as p r e ci pi t a te d a C hu r g - St ra u s s s y n d ro m e o f e os in op h il ic v a sc ul i ti s. P at i en ts s ho u ld be c o un se l ed to ta k e z a f i rl uk as t wi t h fo od t o e nh an c e i ts ab s o r pt i on . c . M o n te l uk a s t p r es en ts wi t h a s i de - ef f ec t p r o fi l e s im il a r t o t h a t f o r z a f i rl uk as t bu t t yp i ca l l y wi t h l es s i nc id en c e t ha n wi t h zaf i r lu ka s t. C h u rg - S t r au s s s yn d ro m e h as n o t b e e n r ep o r te d ; h o we v e r , t h is m a y s i m p l y re f le c t th e r el a ti ve l y re c e n t a p pea r a nc e o f t h e d r u g o n t he m a rk e t . Mo n t e l u k a s t m a y b e t ak en wi t h o ut r eg a r d t o f oo d .
III. NONNARCOTIC ANALGESIC-ANTIPYRETICS AND NSAIDS A. S a l i c yl a t e s 1 . C h em i st r y a . S al ic y l a te s a r e d e r i vat i ve s o f s a li c yl i c a c i d , wh i c h is fo u nd as t h e g l yc os i de s a li ci n i n wi ll o w b a rk . The p r ot o t y pi c a l d r ug is asp i r i n , t h e ac e t y l e s t e r o f s al ic yl ic a c id ( Fi gu r e 1 4 - 7) . P.332 A s im pl e e s te r , a s p i ri n hy d r o l y z e s e as i l y , i s u ns ta b le in aq u eo us m e di a , a n d i s a f f ec t ed b y m oi s tu r e.
Figure 14-7. Structural formula of aspirin, the prototypical salicylate analgesic-antipyretic.
b . M o r e st a b le s a li c y la te s i nc l ud e d i f l un i sa l ( Dol o bi d ) a n d t he t op ic al age n t m e t h yl s a l ic yl a t e ( wi n t e r g re e n o i l ) ( F ig u re 14 - 8 ) . O t h e r s a li c y la t es a r e s a ls a la t e ( D i s a lc i d) ; s o d i um t hi o sa l ic yl a t e ( R e s ol u te ; i n je c t a bl e ) ; c ho l i n e s al i c yl a t e ( Tr i l i sa te ; o ra l l i qu i d ); an d t h e s al ic y l ate d e r i va t i ves me s al a min e ( As ac o l ), o ls a la zi n e ( D i p en t um ) , a n d s u l fa s al az i ne ( A z u lfi d in e ) . c . Mo s t s a li c y la t es a r e w e a k a c id s . Th ei r e xc r e t io n is i n fl u en c e d b y c ha ng e s i n u r i na r y p H .
2 . P ha r m ac o l og y a . S al ic y l a te s i n hi b i t t h e e n z y m e c y cl o o xy g e n a se a n d t hu s i nh i bi t l oc a l p r o st a gl an d in s y n t h es is ( s e e I I . C. 1 .a ) . As a r es u lt , t he y a r e a na lg e s i c f o r l o wi n t en si t y in t eg um e nt a l pa i n , a nt i p y r et ic , a n d a nt i- i n fl am m at o r y . No t e t h at a s pi r in is t h e o n l y s al ic y l a te t ha t i rr e v e r s i b l y i n hi bi t s c y cl o ox yg e n a s e b y c o va le n t ace t y l a ti o n o f t he en z y m e . b . S al ic y l a te s a ls o b l oc k p l at e le t c y c lo o xyg e n a s e a n d s u b se qu e nt f or m a t io n o f t h r om b o xa n e A 2 . As a r es u lt , th e y in h ib it pl a te l et a g g re g at i on an d e ve n tu al t h r om b us fo rm a ti o n. 3 . T he r a pe u t ic i nd i ca t io n s a . S al ic y l a te s a r e i nd ic a te d fo r us e a s : ( 1 ) An a l g es i cs , fo r re l ief o f m us cu lo sk el e ta l p a in, h ea d ac he , n e u ra lg i as , m ya l gi as , a n d s pa s m od ic d y s m en or r h e a ( 2 ) An t i - i n f la m ma t o r y a g e n t s, f or r el ie f of v a r iou s a r t h ri t is s y m pt om s a nd ac u te r h e um a ti c f e v e r ( 3 ) An t i p yr e t i c a g e nt s , f o r r el ie f of fe v e r . ( Ch i ldr e n wi t h v a ri c e ll a o r in f lue n z a - t y p e vi r a l i n fe c ti on s s ho u ld no t be gi v e n s al ic y l a te s be c au se o f t he ob se r ve d a ss o c i at i on b e t we e n s al ic y l a te us e in t he s e si t ua t io ns an d Re ye s yn dr om e . ) b . As p i r i n i s a ls o i nd ic a te d fo r p r op h yl a x i s o f myo c a r d i a l i n fa r c t i on . c . M e t h yl s a l i c yl a t e ( wi n t e r gr e en oi l ) i s us e d t op i c a ll y a s a c o u n te r i r r i ta n t . d . S u l fa sa l az i ne , ol s al az i n e, an d m e sa l am i ne ar e us e d t o r e du c e th e i n fl a m m at i on a ss o ci at e d wi t h i nf la m m a t o r y bo we l d is ea s e an d C r o h n d is e as e. 4 . Ad ve r s e e f fe c t s a . S al i c yl a t e s a r e a s s oc i a t ed wi t h th e f o ll o wi n g ef f e c t s : ( 1 ) G I ef f ec ts , s uc h a s na u s e a ; v o m i t in g ; a nd G I i r r i ta t io n , d is c o m f o r t, ul ce r a ti o n , a n d h em o r rh a ge ( 2 ) I nc r ea s e d d ep t h o f res p i ra ti o ns ( 3 ) E xc e s s i v e b l ee d in g as s o c i a te d wi t h i n hi bi t io n o f t hr om b o xa n e s y n t he s is ( 4 ) U nc o up li n g o f o xi d a t iv e p h os ph o r y l at i on , h y pe r g l y c e m i a , g l yc os u r ia , an d r ed uc ed l i po g en es is
Figure 14-8. Structural formulas of salicylate derivatives. A. Diflunisal. B. Methyl salicylate.
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Figure 14-9. Structural formula of acetaminophen, the prototypical p-aminophenol derivative.
( 5 ) D el a y e d o ns e t o f l abo r ( 6 ) L ow d a i l y d o s e s of s a li c y la t es (2 g ) d ec r ea se r e na l u r at e e xc r e t i on an d i n c re as e s e ru m u ri c a c i d l e v e ls . Hi g h d a il y d o s e s ( 5 g ) ha v e th e o p po s i te e f fe c t . b . S u l fa sa l az i ne ha s a ls o b ee n s ho wn t o ha ve m a l e r e p ro d uc ti v e ef f ec ts , c a us in g i n f er t il i t y . c . S al i c yl i s m ( s al ic y l a te t o xi c i t y , u s ua ll y m ar ke d b y t i nn i tu s , n au se a , a nd v o m i ti n g ) d . I ng e s ti o n o f 1 t ea s p oo n of t he to p ic al ag en t m e t h yl s a l i c yl a t e ( wi n t er g r e en oi l ) c a n ca u s e fa t a l i n t ox i cat i o n . B . p - Am i n o p he n ol d e ri va t i ve s 1 . C h em i st r y. Th e p r o t ot y p i c a l p - am i no ph e no l de r i v a ti ve is ac e ta m i no ph e n ( Tyl e n o l ) , a n a c t i v e m e tab o li t e o f p h en ac e ti n a n d a c et a ni li d (F i gu r e 1 4 -9 ) . 2 . P ha r m ac o l og y a . p - Am in op h en o l d e ri v at i v e s i nh i bi t c en t r al p ro sta g la n di n s yn t he s i s ( s e e II . C . I .a ) , p r e su m a bl y t h r ou gh a s el e c t i v i t y fo r C O X 3 wi t h re l a ti v e l y li t tl e o r no ac ti v i t y o n C O X 1 o r C O X 2 . Th e y a r e a na lg es ic f or lo w- i n t en s it y p ai n a n d a r e a nt i p yr e t ic . b . B ec a us e t he y a r e l es s e f f ec ti v e th a n s al ic yl a tes in bl oc ki n g p e ri ph e r al p r o st a gl an d in s y n t h es is , t h e y ha v e n o a nt i -i n fl am m a to r y a c t i v i t y a n d d o no t a ff ec t p l a te le t fu nc t io n . 3 . T he r a pe u t ic i nd i ca t io n s a . Ac e t a mi n o ph e n is p rim a r il y us e d f o r i ts an a lge s i c a nd an t i p yr e t i c ac ti vi t y, p a r ti c ul a rl y i n a p a ti e nt u n a bl e t o t o le r a te s a li c y la t es . b . Ac e t a mi n o ph e n m a y b e s a fe l y us e d as an al te r n a t i ve a n t i p yr e t i c i n ch i ld r e n wi t h va r i c e l la or an in f lue n z a - t y p e v i r a l in f ec t io n ( s e e I I I. A . 3. a . (3 ) ) . 4 . Ad ve r s e e f fe c t s a . W he n g i v en in t he r ape u t ic d os e s , ad v e r se ef fe c ts a re l im i te d to : ( 1 ) S ki n r as h ( 2 ) H em o l y ti c a ne m i a ( wit h lo n g -t e rm ph en a c e ti n u s e ) ( 3 ) Me t h e m o gl o bi n em ia ( 4 ) R e na l d y s fu nc t io n a nd t ub u la r ne c r o s i s
b . A cu t e ac e ta m i n op h en o v e r d os e c au se s s e v e re h e p at o to xi c i t y wi t h ne c ros is an d l i ve r fa il u r e. C . P yr a z o l o n e d e r i va t i ve s 1 . C h em i st r y. Th e m o s t i m po r t an t p yr a zo l on e d e ri va t i ves a re p he n yl b u t a z o n e, it s m e ta b ol i te ox yp h e n b u t az o n e, an d t h e u r ic os u ri c a g e nt su l f i np yr a z o n e ( An t u r an e ). P h e n ylb u ta z o n e i s t he p ro t o t y pi ca l a g en t (F i gu r e 1 4 - 10 ) .
Figure 14-10. Structural formula of phenylbutazone, a pyrazolone derivative.
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2 . P ha r m ac o l og y a . P he n yl b u t a z on e , o x yp h e n bu t az o ne , a n d a z ap r o p az o ne in h ib i t p r os tag l an d in s yn t he s i s (s ee I I. C . I .a ) an d s t ab i li z e l ys os o m a l m e m b ra ne s . A s a re s u l t , th e y h a ve a n al g es ic , a n ti p y r e ti c , an d an t i -i nf l am m a t or y e f fec t s . Th e y al s o h a ve g ood u ri c os ur ic a c ti vi t y. b . S u l fi n p yr a z o n e i nh ib it s pr o xi m a l t ub u la r ab so rp t i on of u ra t e a nd ha s a u r i c o su r ic e f f ec t . H o we v e r , i t is de v o i d o f a n al ge si c , a nt i p y re t ic , or an t i -i n fl am m a t o ry e f f ec t s . 3 . T he r a pe u t ic i nd i ca t io n s a . P he n yl b u t a z on e a n d o x yp h e n b u t az o ne a re us e d f o r s ho r t -t e rm t re a tm e n t o f a c ut e rh e um at o id a rt h ri t ic c o nd i ti o ns a n d a cu t e go u t . Ho we v e r , t he y s ho u ld b e g i ven o n l y af t e r o th e r th e ra p eut i c m ea su r es ha ve fa i le d. b . S u l fi n p yr a z o n e is us e d to c o n tr o l h yp e ru r ic em i a i n t he t re a tm en t of in t e rm i tt e nt a n d c h ro ni c g o ut . c . Th es e a g en ts a re r a rel y u s e d , h a vin g b e en r epl a c e d wi t h r e la t i vel y sa f er c om p ou n ds . 4 . Ad ve r s e e f fe c t s a . Th e ad v e r s e ef f ec ts of p h e n yl b u t a z o ne , ox yp h e n b ut a z o n e, an d a z a p ro p a zo n e ( t o a m u c h le s s e xt e n t ) of t e n l im it t he i r us e an d in c lu d e ( 1 ) G I ef f ec ts , s uc h a s d is c o m fo r t , n au s e a , v om it in g , d ys p ep si a , a nd pe p tic u l ce r a ti on ( 2 ) B lo o d d y s c r as ia s , s uc h a s a g ra n ul oc yt o s i s, ap l as t i c a n em ia , h em o l ytic an em i a, t h r om b oc y t op e ni a , a nd pe t ec h ia e
( 3 ) C a rd i o v as c u la r ef f ec ts , s uc h a s c on g es ti v e hea r t fa i lu r e wi t h e de m a and d ys p ne a ( 4 ) R e na l e f fe c t s , s u c h as ne p h ro t ic l i th i as is , r e na l ne c ro s i s , im pa i re d re na l f u nc t io n , a nd r en a l f ai l ure ( 5 ) C N S ef f ec ts , s uc h a s d r o ws i ne ss , a gi t a ti on , c o n f us io n , h ea d ac he , l e tha r g y, n u m b n es s , we a k n es s , t in n i tu s , an d h e a ri ng lo s s ( 6 ) H yp e rg l y c em i a ( 7 ) S ki n r as h b . S u l fi n p yr a z o n e is as s oc i at e d wi t h t he fo l lo wi n g ad v e r s e ef f ec ts : ( 1 ) G I ef f ec ts , s uc h a s d is c o m fo r t a n d u ps et ( 2 ) B lo o d d y s c r as ia s , as wi t h p h en y l b ut a zo ne an d o xyp h e n b u ta z o n e ( 3 ) R e na l f ai l u re D . A g en t s us e d f o r t he t re a tm e nt o f g ou t 1 . C h em i st r y a . A c u t e a tt ac k s of go u t r e s ul t f r om an in f la m m ato r y r e sp o ns e t o j oi n t d epo s it i on s o f s o di um u ra t e c r y s t al s . Th e r ap e ut ic ag e nt s c ou n te r t hi s r es p on s e b y re d uc i ng pl as m a u r i c ac i d c o nc e nt r a ti o ns o r in h ib i ti n g t he in f la m m a t o r y r es po ns e . b . A ge n ts us ed fo r t he t re a tm e nt o f g ou t h a v e wid e l y va r y i ng s t r uc tu r es an d in c l ud e t h e p yr a z o l on e d e ri v a t i ve s u l fi n p y r a zon e (s ee II I .C . 2 . b ; I I I. C . 3 .b ; II I . C .4 . b) ; t he a l ka lo i d c o lc h ic i ne ; i s opu r i ne s , s u c h as al l o pu r in o l ( Z y lo p ri m ); an d b e n zo i c ac i d d e r i va ti v e s , s u c h as p rob e n ec i d (B e ne m i d ) ( F igu r e 14 - 11 ) . 2 . P ha r m ac o l og y a . C o lc h ic i n e' s m ec ha n is m o f a c ti on is pr es um ed t o b e r e la t ed to i ts a n tim i to t ic a c ti vi t y. I t i nh ib i ts tu b ul in s y n th es is , wh i ch i s re qu i r ed f or t he m o vem e nt o f i n f la m m at o r y c e ll s . P.335 Th r o u g h i ts ab il i t y to p rev e n t t ub ul i n p ol ym e ri z a t i o n , c ol c h ic i ne ap p ea r s to i nh ib i t c h em ot a xi s o f l eu k o c y t es an d o t he r in f la m m at o r y c el ls in t he af f ec te d j o int , t hu s r e d uc in g th e i n fl am m a t ory r e s po ns e to de po si t e d u r a t e c r ys t al s b y i nh ib i tin g l e uk oc yt e m ig r a ti o n a nd p h a go c yto si s . I t a ls o i n te r f e re s wi t h ki n in fo r m a t io n an d r e d uc es le uk oc y t e l a c t ic a c id p ro du c ti on .
Figure 14-11. Structural formulas of agents used in the treatment of gout. A. Allopurinol. B. Probenecid.
b . Al l o p u r i no l re d uc es s e r u m u ra t e l e vel s b y b loc ki n g u r ic a c i d p r o du c t i on . I t c om p et i ti v e l y in h ib i ts th e e n z y m e xa n t hi n e o xi d a s e , wh i c h c o n v e r ts xa n t hin e an d h yp o xa n t h i ne to u ri c ac id . c . P r ob e ne c i d, a u r ic os u r i c a ge n t, in h ib it s t h e pr o xi m a l tu b ul a r r e ab s o r pt i o n o f u r ic a c id , i nc r e as in g u r ic a c id e xc r e t io n , t h us re du c i ng p la s m a u r ic a c i d c on c en t r a ti o ns . 3 . T he r a pe u t ic i nd i ca t io n s a . C o lc h ic i n e is us ed p rin c ip al l y f o r t he t re a tm ent o f a c u t e g ou t at t ac ks . b . Al l o p u r i no l , wh ic h red u c e s u r ic a ci d s y n t he s is an d fa ci li t a te s t he di s s o l u ti on o f t o p hi (c h al k y u r a te de p os i ts ) , i s us e d t o p r e v en t t h e d e v e lo pm e nt o r p r ogr e s s i on of c h r on ic to p ha c e o us g o ut. c . P r ob e ne c i d is us ed t o t r e at ch r on ic t op ha ce o us go u t . I t i s a ls o us e d i n s m a l le r d o se s t o p r ol o ng th e e f fe c ti v e n es s o f p en ic il l in - ty p e a nt i bi o ti c s b y i nh i bi t in g th e i r t u b ul a r s ec r et io n . 4 . Ad ve r s e e f fe c t s a . C h ro n ic u s e o f c ol c h ic i n e i s as so c i a te d wi t h th e s e ad v e r s e ef f ec ts : ( 1 ) A g ra n ul oc y t os is , ap las t ic an em ia , m y o p at h y, ha i r l os s , a nd pe r ip h e ra l n e u ri t is ( 2 ) N a us ea , v om i ti ng , a bd o m i n al p a in , a n d d ia r r he a (i n di ca t io ns o f im p end i ng t o xi c i t y) b . Al l o p u r i no l i s a s s oc ia t e d wi t h t he fo l lo wi n g ad v e r s e e f fe ct s : ( 1 ) G I ef f ec ts , s uc h a s G I d is t re s s , n a us ea , v om i ti n g , a nd di a r rh e a ( 2 ) S ki n r as h , St e v e ns -J o h ns o n s ynd r om e , a nd he p a to t o xi c it y ( 3 ) P r ec ip i ta t io n o f a n a c u t e g o ut a tt ac k ( wi t h in i tia l al lo p u ri no l t h e ra p y o wi n g t o i n i ti al m o bi l i z at i on of s t or e d ur a te ) c . P r ob e ne c i d is as s o c ia t e d wi t h t he fo l lo wi n g ad v e r s e e f fe ct s : ( 1 ) H e ad ac he s , n au s e a , v o m i ti n g, u ri n ar y f r eq u enc y, so r e g um s , a nd de rm a t i ti s ( 2 ) D i zz i n es s , an em ia , he m ol y t ic an em i a, an d ren a l l i th ia s i s E . N S AI D s 1 . C h em i st r y a . Th e c l as s ic N S AI D s c o n s i s t o f m a n y st r uc t u ra ll y d i ve rs e a ci ds . Th es e in c lu d e p r o p i o ni c a c i d d e ri v a t i ve s (f e no p r of e n [ N al f on ] , f l u rb i p ro f en [ Oc u fe n ] , i bu p r o fe n [ Mo t r i n ] , k e to p r of e n [ O r ud i s ] , na p ro xe n [ A n ap r o x, N a p r os y n ] , a nd o xa p r o zi n
[ D a yp r o ] ), ac e t ic ac i d de r i v a ti v e s (d ic lo f en a c [ Vo l t ar e n ], et o do l ac [ L od i ne ] , i n do m et h ac in [I n do c i n ], k e to r o la c [ To r a do l ], s u li nd a c [ C li n o ri l ], an d t o lm eti n [ To l e c ti n] an d th e s ub c l as s o f t h e f e na m a t es o r an t h r an il ic ac id de r i v a ti v es m ec l of e na m a t e a nd m e f en a m i c ac i d [ P on s te l ]) , and t he e no l ic ac i d d e ri v a ti ve s ( p i r o xi c am [F e ld en e ] , m el o xi c a m [ Mo b i c ], an d n a bu m et o ne [ R el a fe n ]) ( Fi g ur e 1 4- 1 2 ). b . S e le c ti ve C O X 2 in h ib i t o r s c e le c ox i b ( C e le br e x) a n d r o f ec o xi b ( Vi o xx) , a n d va l d e c ox i b (B e xt r a ) a r e p y r a z o l e d e ri v a t i v es ( Fi gu r e 14 - 13 ) . 2 . P ha r m ac o l og y a . N o ns p ec i f ic N S AI D s h a v e an t i -i n fl am m a t or y ef f e c t s , r es ul t in g fr om t hei r ab i li t y t o i n hi b it t he c y c lo o xy g e n as e e n z y m e s y s te m a nd th u s r e du c e lo c a l p r os t agl a nd i n s yn t he s i s (s ee I I. C . 1. a ) . b . N S A I Ds al s o h a v e a na l ge s i c a n d a nt i p y re t ic ef f e ct s . I n a dd i ti on , s om e N S A I D s h a ve m i ld u ri c o s u r ic ac tiv i t y . S o m e ag e nt s a ls o ha v e we a k in hi b it o r y ac ti vi t y f o r l i po xyg e n a s e , m i l d s e l ec t i v i t y f o r C O X 2 , a nd we a k to m o de r a te ab il i t y to i n hi b it l e uk oc yt e pr o li f er a ti o n an d m i g ra ti o n a nd t o s t a bil i ze l ys os om a l m e m b r a ne s . Th e c l in ic al r el e v a nc e o f t h es e s e c o n da r y a c t io n s h as n o t b e en el uc i da t ed . c . C O X 2 i n hi b i to r s e xe r t a nt i -i n fl am m at o r y ef f ec t s b y s p ec i fi ca ll y i nh i bi ti n g p r o st a gl an d in s y n t h es is a s s o c i at e d wi t h t he in f lam m a t o r y re s p o ns e . Th e i r a b il i t y t o d e c re as e p ai n an d i nf l am m a t io n a ss oc i at e d wi t h a r t h ri ti c d is e as es i s a ppr o xi m a t e l y e q u al to th a t p r od uc e d by t h e no ns el e c t i v e N S AID s . Mo r e o v e r , b y v i r t ue o f t he i r s e le ct i v i t y , t h ei r ac ti o ns o n ga s t r ic m u c o sa an d pl a t el e t a gg r eg a ti o n a r e th e o ri ze d to b e le ss th an t he no ns e lec t i v e N S AI D s . P.336
Figure 14-12. Structural formulas of representative nonsteroidal anti-inflammatory drugs (NSAIDs). A. Ibuprofen (propionic acid derivative). B. Indomethacin (acetic acid derivative). C. Mefenamic acid (anthranilic acid derivative). D. Piroxicam (enolic acid derivative).
3 . T he r a pe u t ic i nd i ca t io n s a . N S AI D s , li k e as pi r i n, a r e ag en t s o f c ho ic e f o r t h e tr e at m e n t o f rh e um ato i d a r t h ri t is , o s t e oa r t h ri ti s , an d an k ylo si n g s p o nd yl i tis . Th e y m a y a ls o b e us ed as s ec o nd a r y t re a tm en t s i n g o u t y a r t h ri t is . b . C O X 2 i n h ib i t o r s a re a p p ro v e d fo r us e i n b ot h r h e um at o id ar t h ri t is a n d o s te o a rt h ri t is .
4 . Ad ve r s e e f fe c t s a . N S AI D s a r e as s o c i a t ed wi t h t he fo l lo wi n g a d v er s e e f fe c ts : ( 1 ) G I ef f ec ts , s uc h a s G I d is t re s s an d i r r it a ti o n, e r o si on o f g as t ri c m u c o sa , na us e a, vo m i ti n g, an d d y s p ep s i a ( 2 ) C N S ef f ec ts , s uc h a s C N S d e pr es s i o n, d ro ws in e s s , h e ad ac he , di zz i n es s , vi su a l d i st u r ba nc es , o t o to xi c i t y, a nd c o n fu s i on ( 3 ) H em a to l og ic ef f ec ts , s uc h a s t h r om bo c y to p en ia , al t e re d p l at el e t f u nc tio n , a n d p r o lo n ge d b le e di n g t im e
Figure 14-13. Structural formula of celecoxib, a COX 2 specific inhibitor.
P.337
( 4 ) S ki n r as h ( 5 ) N e ph r ot o xi c i t y b . C O X 2 i n h ib i t o r s d o n o t a p pe a r t o c au s e as gr e a t a n i nc i de nc e o f G I ul c e ra ti o n o r a nt i pl at e le t e f f ec ts as t h e n on se l ec ti v e N S A I Ds . Th e m os t c om m o nl y re p o r te d s i de ef f ec ts in c l u de G I up s et a t a l o we r i nc id en c e l e v e l. D es pi t e t h e p r om is e o f m i ni m a l G I u lc er a ti o n, m a n y p at i en ts e xp e r i en ced g as t ro i nt es t in a l b le ed in g wi t h t h es e d r u gs s oo n a f t e r th e i r r e le as e . Th i s i s t ho ug h t to ha v e be e n a n i ns ta n c e of o ve r u se / o v e rd os in g of the d r ug . Th is ri s k of ga s t ri c d am a ge an d p o te n ti a l u l c e r a ti on a p p ea rs t o i nc r ea s e wi t h c h ro n ic , h ig h d os e u s e o f t he s e dr u gs . Th e p ot en t i al fo r n e p hr o to xi c i t y d oe s e xi s t f o r th es e d r ug s , a nd pa ti e n ts s ho u ld be m o ni t o red f o r c h an g es i n re n al fu nc t ion . Mo r e r ec e nt ad ve r s e d r u g r e ac ti o ns ass oc i at ed wi t h t he s e d r u gs in c l ud e a n i nc r e as e d ri s k of t h ro m b o ti c e v en t s , l ea di n g t o m yoc a r dia l i n f ar c ti o n a nd s t r ok e, wh i c h c o u ld be po t en t ia ll y fa t a l. Th is is li k e l y th e res u lt o f a n i n hi b it i on of c a r di o v as c u la r C O X 2 a n d s u bs e qu e nt c lo t f o rm a ti o n. Th is ha s l e ad to t h e vol u nt a r y r em o v al of s om e o f th es e d r u gs fr om t he m a rk e t a nd c a u ti ou s , c lo s e l y s u pe r v i s e d u s e of t he oth e r s . P.338
STUDY QUESTIONS
D i r e c t i on s : E a c h of t he q u es t io ns , s t at em e nt s , or i nc om p le t e s t a te m en ts i n th is s ec t io n c a n b e c o r r ec t l y a n s we r e d o r c om pl e te d b y o n e o f th e s ug g es te d a n s we r s o r p h r as es . Ch o os e t h e b es t a ns we r . 1 . A 4 5 - ye a r - o l d l o n g - ha u l t r uc k e r s u f fe r s f rom s ea s on a l a l le r g i es . He a sk s a d vi c e on w h ic h o ve r - th e co u n te r p r o du c t i s be s t t o r e l ie ve h is s ym p t o m s . W h i c h o f th e fo l l ow in g c h o ic e s i s th e b e s t r e co m m en d a ti o n f o r t hi s pa t i e n t? ( A ) d ip h en h y d ra m i n e ( B ) p r om et h a z in e ( C ) c le m a s t i ne ( D ) c hl o rp h en i ra m i n e ( E ) l o ra t ad in e V i e w A n s we r 1 . T h e a n sw e r i s E [s e e] . 2 . W h ic h o f t h e f o l low i n g c h oi c es w o ul d be mo s t a p p r op ri a t e i n t r ea t i ng na u se a a n d vo m it i n g a ss o ci a t ed w it h m o t i on s ic k ne ss ? ( A ) d ip h en h y d ra m i n e ( B ) b r om ph e ni r am in e ( C ) o n da ns e tr o n ( D ) o m e p ra z o l e ( E ) r a ni t id in e V i e w A n s we r 2 . T h e a n sw e r i s A [ se e] . 3 . Es om ep r a z ol e w ou l d b e e f f e cti ve i n t h e t r e at m en t o f ( A ) g as t ro e s o ph a ge a l r e fl u x d i s ea s e . ( B ) p ep t ic ul c e r d is e as e . ( C ) Z o ll in g e r- E l li s o n s y nd r o m e . ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 3 . T h e a n sw e r i s D [ se e] . 4 . W h ic h o f t h e f o l low i n g a n t iu l ce r m e d ic a t io n s i s m o s t l ike l y t o c a u se d r ug i n te ra c t i on s a n d e n do c r i ne s i d e e f f e c ts ? ( A ) r a ni t id in e ( B ) o m e p ra z o l e ( C ) l an s op r a z ol e ( D ) c im et i di ne ( E ) f am o ti di n e V i e w A n s we r 4 . T h e a n sw e r i s D [ se e] . 5 . A p a ti en t h as j us t be e n d i ag n os e d w i t h r e c u r re n t m i g r ai n e h e ad a ch e s . W hi c h o f th e f o ll ow i ng p r ee x is t i ng c o n d it i o ns w o u ld p r ec lu d e th e us e o f su m a t rip t a n fo r t h is pa t i en t ? ( A ) l i ve r d is ea s e ( B ) r e na l f a il u re ( C ) i sc he m i c h ea r t d is e as e ( D ) i r r it a bl e b o we l s y n d ro m e ( I B S ) ( E ) g ou t y a r th r it is V i e w A n s we r 5 . T h e a n sw e r i s C [ se e] . 6 . W h ic h o f t h e f o l low i n g i s a n a p p r o p r ia t e i n di c a ti o n fo r t h e d r u g te g as e r od ? ( A ) a fe m a l e p at ie n t wi t h c on s ti pa t io n - re l at e d i r ri ta b le bo we l s y n d ro m e ( I BS )
( B ) a fe m a l e p at ie n t wi t h d i ar r h ea - r el a te d I B S ( C ) a m a le pa t ie n t wi t h Cr o h n d is ea s e ( D ) a m a le pa t ie n t wi t h di a r r he a - re l at e d I B S ( E ) a pa ti e nt wi t h Zo l li nge r - E l li s o n s y n d ro m e V i e w A n s we r 6 . T h e a n sw e r i s A [ se e] . 7 . W h ic h o f t h e f o l low i n g p r o s t ag l a nd i n a n al o gs i s u se d s p ec i f ic a ll y f o r t h e t r ea t me n t of g la u com a ? ( A ) a lp r os t ad il ( B ) l at a no p r os t ( C ) c a rb op r os t ( D ) d in o p ro s t o ne ( E ) e po p r os te n ol V i e w A n s we r 7 . T h e a n sw e r i s B [ se e] . 8 . T h e u se o f m i s op r o s to l to p r eve n t n o n s te r o i da l a n t i -i n f l am m a to r y d r u g - i n d u ce d u l c e rs c ou l d c a us e w hic h o f t h e f o l l ow i ng si d e e f f ec t s ? ( A ) f e ve r ( B ) g as t ro i nt es t in a l c ra m p i ng an d di a r rh ea ( C ) h e ad ac he / pa i n ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 8 . T h e a n sw e r i s D [ se e] . 9 . W h ic h o f t h e f o l low i n g a s th m a t h e r a pi e s h a s b ee n a s so c i a te d w i th a n a cu t e va s c ul a r s yn d r o m e t h a t i s a s s oc i a te d w i th su d d en w i th d r aw a l o f c o r t ic o st e r o i d a n t i -i n f la m ma t o ry d r u g s ? ( A ) za f i rl uk as t ( B ) zi l eu t on ( C ) m on t el uk as t ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 9 . T h e a n sw e r i s A [ se e] . 1 0. W hi c h o f t he f o ll ow i n g a st h ma t h e r a pi e s i s e f f ec t i ve by d e c r e a s i n g t h e a mo un t s o f r e l ea se d le u ko t r ie n e s? ( A ) za f i rl uk as t ( B ) zi l eu t on ( C ) m on t el uk as t ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 1 0 . T he c o rr e c t an s w e r is B [ se e] . P. 3 3 9
1 1 . R iz a t ri p t an i s e f fe c ti ve i n t r ea t i ng m ig r a in e h e ad a ch e b y ( A ) d i re ct l y v a s o c o ns t r ic ti n g i n v ol v e d bl oo d ves sel s . ( B ) i nh i bi ti n g t h e r el e as e o f i n fl am m at o r y ne u ro t ra n sm it t e rs . ( C ) d i re c tl y b lo c k in g p ain t r an s m is si on . ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e
V i e w A n s we r 1 1 . T he a nsw e r i s D [ se e] . 1 2. W hi c h o f t he f o ll ow i n g d r u gs , b a s ed o n i t s m ec h an i sm o f a c t io n , i s e f f ec t i ve i n t re a t in g di a r r he a - pr e d o m in a n t i r r i t a b le b ow el s yn d r o m e ( I B S )? ( A ) t e ga s e r od ( B ) n a ra t r ip t an ( C ) a lo s et r on ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 1 2 . T he c o rr e c t an s w e r is C [ se e] . 13 . W hi c h o f th e fo l l ow in g s a l ic yl a t e s h as be e n l in k e d t o m a le r e p r od u c ti ve t o x ic i t y w i t h c h r o n ic d os i n g? ( A ) a sp i ri n ( B ) d if l un is a l ( C ) s od i um t h io s a li c y l at e ( D ) o ls al a z i ne ( E ) s ul f as al a z in e V i e w A n s we r 1 3 . T he c o rr e c t an s w e r is E [s e e] . 14 . As p i r i n e x e r ts i ts an ti p l a t el e t e f f ec t b y i n h i b i t i n g ( A ) c ycl o o xy g e n as e ( C OX) 1 . (B) COX 2. (C) COX 3. ( D ) p r os t ag la n di n s y n t hes is . ( E ) l eu ko t r ie n e s y nt h es is . V i e w A n s we r 1 4 . T he c o rr e c t an s w e r is A [ se e] . 15 . Ac e t a mi n o ph e n h as a d va n t a ge s o ve r a sp i r in o r o th e r no n s te r o i da l a n t i -i n f la m ma t o r y d r u g s b y vi r t u e o f i ts ( A ) r e la t i v e l ac k o f a nt i -pl a t el e t e ff e c t s . ( B ) r e la t i v e l ac k o f g as t ro i n te s t i na l u lc e ra t i v e e f fe c ts . ( C ) b ei n g a s a fe al t e rn a ti v e f o r ch i ld r en wi t h v i r al i n fe c ti on s . ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 1 5 . T he c o rr e c t an s w e r is D [ se e] . 16 . Ac e t a mi n o ph e n t o xi ci t y i s c ha r a ct e r iz e d b y ( A ) p r of o un d v as oc on s t ric t io n a n d p ai n . ( B ) s e v er e ab do m i n al c ra m pi n g a nd di a r rh ea . ( C ) c en t r al ne r v o us s y s te m s t im ul a ti on an d s ei zur e s . ( D ) p r o fo un d l i v e r d am a ge a nd fa i lu r e . ( E ) A l l o f t h e a bo v e V i e w A n s we r 1 6 . T he c o rr e c t an s w e r is D [ se e] . 17 . W hi c h o f th e fo l l ow in g a n t i go u t m e d ic a t io n s i s s p ec i f ic a l l y u s e d i n a cu t e a tt a ck s ? ( A ) c ol c h ic in e ( B ) a ll o pu r in ol ( C ) p r ob e ne c i d ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e
V i e w A n s we r 1 7 . T he c o rr e c t an s w e r is A [ se e] 1 8. W h ic h of t he f o ll ow i ng a n t i go u t m e d ic a t io n s ac t s b y d e c r e a s i ng se r um l e ve ls b u t i nc r e as i n g u r i n e l e ve l s of u r ic ac i d , t h us i n c re a si n g t h e ri s k o f k i d ne y s t o n e de ve l o pm e n t ? ( A ) c ol ch ic in e ( B ) a ll o pu r in ol ( C ) p r ob e ne c i d ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 1 8 . T he c o rr e c t an s w e r is C [ se e] 1 9. T h e n o ns t e r oi d al a nt i i n f l am m a to r y d r u g s , as a c la ss , a re an t i - in f l amm a t o r y p r i m a r i l y t h r o u g h t he i r ability to inhibit ( A ) c ycl o o xy g e n as e ( C OX) 1 . (B) COX 2. (C) COX 3. ( D ) l eu k ot r ie n e s y n th es is . ( E ) t h ro m b o xa n e s y nt h es i s . V i e w A n s we r 1 9 . T he c o rr e c t an s w e r is B [ se e] 2 0. T h e s el e c ti ve c yc l o o x yg e n a s e ( C O X ) 2 i n hi b i to r s ha ve b ee n a s s oc i a te d w i th w h ic h o f t h e f o l l ow i ng ad ve r s e d ru g r e a c ti o n s? ( A ) s e v er e i s c h em ic c ol i ti s ( B ) t o rs ad e d e s p oi n te s ( C ) c a rd io v a s c u la r th r om b o t ic e v e n ts ( D ) a cu t e l i v e r f ai lu r e ( E ) C h u rg - S t ra u s s s y n d ro m e V i e w A n s we r 2 0 . T he c o rr e c t an s w e r is C [ se e] P.3 4 0
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is E [ s e e I I . A .1 . b. ( 1 ) ; I I . A. 3 .b ] . D i p h en h y d ra m i n e, p ro m et h a z i ne , a n d c l em a s t in e a l l p os se s s m o de r at e to s t r on g a n t ic ho li n e rg ic ac ti v i t y . Th i s wi l l i nc r ea s e t he r i sk o f s e d at i on , wh ic h c o uld p r o v e d a n ge r ou s i n t hi s p a ti en t. C h lo r p he ni r am i ne , wh i le t he le as t s e da t in g o f the f i rs t g e n er a ti o n d r ug s , s t il l m a y c r os s t he bl o od - b ra in b a r r ie r an d c au s e s o m e s e da t io n . L o r a ta di n e, as a s e c o n d -g e n er a ti o n d r ug th a t h as m i n im a l a nt ic h ol in e r gi c a c ti v i t y a n d d o es n o t c ro s s th e bl o od - b r ai n b a r ri e r ( t hu s p r o du ci n g n o c en t ra l e f fe c ts ) , i s l e as t l ik e l y to c a us e s e da t i on an d t h us a f f ec t h is j o b . 2 . T he an sw e r is A [ s ee I I . A .3 . b] . W hile on da ns e t ro n i s u s e d fo r na us e a as s o ci a t ed wi t h c h em o th e ra p y a nd a n a es th e ti c s , i t i s n o t t yp i c a ll y u s e d f o r n a us ea a s s o c i at e d wi t h m o t io n or v e r t i go . D i p h en h y d ra m i n e, wh i c h p os s e s s es a h ig h d e g ree o f a n ti c h ol i ne r gi c a c t i vi t y , is e f f ec t i v e i n r ed u c i ng na us e a a nd v o m i ti n g a ss oc ia t e d wi t h v e s t i bu lo c oc hle a r ac ti v i t y, ve r t i g o, an d m ot i on s i c k n e s s . No n e o f t h e o th e r c h oi c e s d i re c t l y r ed uc es n a us e a o r vo m i ti n g, t he r ef o r e, di p he n h y d ra m i n e is t he be s t c h oi c e . 3 . T he an sw e r is D [ s ee I I . A .1 . b. ( 3 ) ; I I . A. 3 .d ] .
B e c au se al l t h r ee of th es e d is ea se s t a te s r e p re sen t so m e ac ti o n o f e xc e ss i v e ac i d s ec r e ti o n, es om ep r a z o le, wh i c h a ls o b lo c k s t h e pr o t o n o r a ci d p um p , wo u ld b e e f f ec t i v e i n r ed u c i ng t he a c id - in d uc ed pa i n a nd da m ag e a s s oc ia t ed wi t h g a st r o es op h ag ea l re f lu x d i s e as e ( G E R D ) , p ep t ic u l ce r di se as e (P U D ) , and Z ol li n ge r E l l is on s y nd r om e . 4 . T he an sw e r is D [ s ee I I . A .4 . d] . O f t h e d r ug s l is te d , a n d s p ec if ic a ll y , o f t he H 2 -a nt a g on is ts , c im e ti d in e i s th e on l y d r u g t h at in h ib it s t h e h ep a t ic m ic r os om al m e t ab ol i z i ng s ys t em (s p ec if ic a lly t h e 3 A4 i s o zym e) an d th e o nl y d ru g th a t e xh i b i ts we a k a nd r o ge n ic a c ti vi t y. Th e f o rm e r i s r e s po ns ib l e f o r n um e ro us d ru g i n te r ac t io ns an d s o m e s i d e e f fe ct s , wh e r ea s th e l a t te r is re s p o ns ib le f or e n d oc ri n e ( sp ec i fi c a l l y a n d r og e n -l ik e ) si d e e f fe c ts . 5 . T he an sw e r is C [ s ee I I . B .2 . a; I I .B . 4 .a . ( 1) ] . S u m at r ip t an ( an d o t he r dr u g s i n t he c l as s) s p ec i fic a ll y c a us e v as oc o ns t ri c t i o n. Th is e f f ec t , wh e n p re s e n t i n c o r o no r y v e s s e ls , c an c a us e c he s t t ig h tn es s o f p a in as a n o r m a l s id e e f fe c t o f t he d r u g. H o we v e r , in pa t ien t s wi t h is c h em ic he a r t di s ea s e , a n gi n a, o r a ri s k fo r c o r on a r y a r te r y d is ea s e , th is a c ti o n c o u ld p re ci pi t a te a t t ac ks o f a n gi n a o r p o te n ti a ll y c a us e m y o ca r di a l i nf a rc t io n a n d s ho u ld no t b e u s e d in t ho s e p a t ie n ts . 6 . T he an sw e r is A [ s ee I I . B .1 . b. ( 2 ) ; I I . B. 2 .b . ( 2 ); I I . B .3 . a. ( 4 ) ]. C u r r e n tl y , d ru gs a re a v ail a bl e s pe ci f ic al l y f o r wo m e n wi t h I B S c ha r ac t e ri z e d b y e i t he r c o ns ti p at i on or di ar r h e a. Th e in t es ti n al s t i m u la n t ac t io n o f te g as e ro d m ak e s i t u s ef u l f o r t ho s e p at i en ts wi t h c on s ti p at io n as s o c i at e d IB S . Al t ho u gh t eg as er o d (a n d a l os e t ro n ) is ( a re ) be in g e v a l u at e d f o r us e i n m en wi t h I B S , t h e c ur r e nt r e c om m e nd a ti on is p ri m a r i l y fo r wo m en . Te ga se ro d , a s a pr o k i ne t ic ag en t, wo u l d wo r s e n I B S t ha t p re s e n ts p ri m a r il y wi t h d ia r r he a . B e c a us e i t ha s n o a nt i i n f la m m at o r y ef f ec t , i t wo u ld no t be ef f ec t i ve i n tr e a ti n g t h e p ri m a r il y i n fla m m a to r y n a t u re of C r oh n d is e as e. Te g a s e r o d h as n o e f f ec t o n g as t r ic a c i d s ec r e ti on a nd wo u l d , th e r ef o r e, no t b e u s ef u l i n Z ol li n ge r - E ll is o n s y nd r om e . 7 . T he an sw e r is B [ s ee I I . C .3 . c. ( 2 ) ]. A l t h ou gh m o s t p ro s t a gl an d in an a lo gs a re no ns p ec i fi c i n t h ei r s it e s o f ac t io n an d m a y p r o du c e s i m i la r ph y s io l og i c a l e f fe c ts , l at a no p r os t i s s pe c i f ic al l y fo r m u la t ed a nd m a rk e te d fo r u s e in t he tr e a tm e nt of gl a uc om a . I ts r el a ti ve s e le c t i vi t y fo r th e P G F 2 α r e c ep t or is r es po ns ib l e fo r i ts a b il i t y t o l o we r i nt ra o c u l ar p re s s u re an d , t he r e f or e , i ts b e n ef i t i n t r ea t in g g la u c om a . 8 . T he an sw e r is D [ s ee I I . C .2 . b ; I I . C .4 ] . A s no t ed in t he an s we r to q ue s t i on 7, m o s t p ro s ta g la n di n a n al og s h a v e ac t i v i t y a t r e c ep t or s t h r ou gh o ut t he b o d y , c au si n g a p r os t agl a nd i n -l ik e e f fe c t o n n um e r o us o r g an s ys t em s . Mi s o p ro s t o l , a s a re la t i v el y n on s el e c t i v e a g on is t , wo ul d c au s e c o nt r ac t io n o f ga s t r oi n tes t in a l s m oo t h m us c l e, s t im u la t e p ai n f i be r s, an d re s et t he t h e rm o re g ul a to r y c e n te r o f t he C N S , t h us c au s i n g a l l t he po t en t ia l s id e e f fe c ts l i st e d. P.341
9 . T he an sw e r is A [ s ee I I . D .4 ] .
Z a f i rl uk as t i s t h e o nl y d ru g th a t h as be e n as s o c ia t e d wi t h C h ur g - S t ra us s s y n d r om e, a co n di t io n o f e os i no p hi li c v as c u li t is th a t o c c ur s wh e n a pa t ie n t wh o i s o n b o th za f i r lu k as t a nd c o r ti c o s te r o id t he r ap y s ud de n l y di s c o nt i nu es th e c o r ti c o s te r o id . Th is e f f ec t h as no t be en ob s er v e d wi t h t he ph a rm ac olo g ic al l y s i m i la r d ru g m ont e l uk as t . N o t e th a t s l o w wi t h d r a wa l of th e c o r ti co s t e r oi d (wh i c h sh ou l d b e d on e a ny wa y, t o m i ni m i ze ac ut e a d r en al in s uf f ic ie nc y) wi l l p re ve n t t h is ad v e r s e dr u g r e ac tio n . 1 0 . Th e c o r r ec t an sw e r i s B [s ee I I. D . 2 .b ] . Z a f i rl uk as t a n d m o n te l uk a s t e xe r t t h ei r ef f ec t b y b l oc ki n g le u ko t ri e ne s a t t h e ir r e c ep t or . Zi l eu t on , wh ic h a c ts b y i nh i bi t in g l ip o -o x y g e n a s e , wi l l d ec r ea s e t h e s yn t he s i s o f th es e i n fl am m a to r y m ed ia t o rs . Th er ef o r e , i t i s t he on l y d ru g l is t ed t ha t wi l l d ec r ea s e t he s y n t hes is an d , c on s e q ue n tl y , the r el e as e o f l e uk ot r ie n es . 1 1 . Th e a n sw e r i s D [ s ee I I . B. 1 .b . ( 1 ); I I. B . 2. b . (1) ] . R i z a t r i pt a n ( a nd ot h er d ru g s i n t he cl as s ) a re ac t in g as 5 - H T 1 - a g on is ts . Thi s m ec h an is m r es u lt s i n t h re e di s t i nc t a nd be n ef ic i al p ha r m a c o d yn am i c e f fe c t s . F i rs t , i t c a us es di r ec t v as oc on s tri c ti o n, wh i c h r et u r ns th e b l oo d v es s e l t o i t s p r eh ea d ac h e d i am e te r . Se c o n d, b y ac ti n g o n n e ur o na l re c e p to rs , it in hi b it s t h e r el e as e o f a d di t io n al v a s o di l at i ng an d pa in - t r an s m it t in g s ubs t an ce s , s u c h as ne u r ok in i n A a nd s u bs ta n c e P . Th i r d , t hi s a c ti o n h as b e en sh o wn to h a ve a d i r ec t a n ti no c i c e p t i v e a c ti o n, p re v e n ti n g t he fi ri n g o f p a in ne u ro n es d i re c tl y. Th e r e fo r e a ll th r e e a ns we r s c o r re c tl y d es c r i be th e b en e f it of r i z a tr i pt a n. 1 2 . Th e c o r r ec t an sw e r i s C [s ee I I. B . 1 .c . (2 ) ; I I .B . 2 . c ; I I. B . 3. b ] . A l o se t ro n i s t h e a ge n t us e f u l i n t r ea t in g d ia r r he a -p r e do m i n an t I BS . B y bl oc ki n g t he 5 - H T 3 - r e c ep t or , it in hi b its t he s e r ot o ni n -i nd u ce d in c r ea s e in in t es ti n al m o ti l it y , t hu s s l o wi n g p er is t al s i s a n d gu t m o v e m e n t. Te g as e ro d wo u l d wo r s en di a r rh e a p r e do m i n an t I BS , be c a us e i t s s e r o to n er g ic a c ti on s a r e a g on is t ic a n d wo u l d s t im ul a te G I s m o o th m us c l e c o nt r ac t io n . Na r a tr i pt a n, ac t in g a s a 5- H T 1 - a g on is t , h as l i tt l e e f f ec t o n G I m ot il i t y . 1 3 . Th e c o r r ec t an sw e r i s E [s ee I II . A .4 . b ]. O f t h e s al ic y l a te s , s u l fa s a l a z in e h a s b ee n m os t as s o c i a te d wi t h t h is p a r ti cu l a r t o xi c i t y. I t is a t o xi c i t y tha t oc c u r s wi t h c h r on ic us e o f t h e d ru g i n m en wi t h C r o h n d i se as e o r ot h e r in f la m m a t o r y c o nd i ti o ns o f th e i nt e s ti ne . W it hd r a wa l o f the d r ug m a y al l o w r e p ro du c ti v e fu n c t i on to r et u r n, al t ho ug h th is is no t a l wa y s t he c as e . I n a d di t io n , i t m a y ta k e an e xt e n d e d p e ri o d o f t im e , a f t e r ce s s a ti o n o f t he r a py , f o r f u nc t io n to re t u rn . 1 4 . Th e c o r r ec t an sw e r i s A [ s ee I I. C . 1 .a ; II I . A .2. a ] . R e c al l t h at in p ro s ta gl a nd i n a nd t h ro m b o xa n e s yn t h e s is , C O X 1 is re s p o ns i bl e f o r m uc h o f th e d a il y p r od uc t i o n o f m ai nt e na nc e e ic os a no i ds . C O X 2 , wh i l e als o c o nt r i bu t in g t o d a il y p ro du c ti o n o f p r os t ag la n di ns a n d t h r om bo xa n e s , is m o r e i m po r t an t i n i n fl am m a t ion . C O X 3 i s t he ce n tr a l s o u r c e of p ro st a gl a nd in s th a t c o nt r i bu t e t o C N S f un c tio n of t he ei c o sa n oi ds . Als o re c a l l t ha t i t is t h r om b o xa n e t ha t s p ec if ic a ll y h as p l at e le t -a g g re g at i ng ab il i t y. Th e re f o r e, it is th r ou g h i nh i bit i o n o f C O X 1 a n d th e s u bs eq uen t de c re as e i n th r om bo x a n e (n o t p ro s ta gl a nd i n or l e uk o t ri en e ) s y n t he s i s t ha t t he an t ip la t el e t e f fe c t o f as pi r i n is ef f ec t ed . 1 5 . Th e c o r r ec t an sw e r i s D [s ee I I. C . 1 .a ; II I . B .3] .
Th e r o le s o f C O X 1 , 2, an d 3 a r e r e vie we d i n t h e a n s we r to qu e s t io n 1 4 . Be c au s e , m ec h an is t ic al l y , a c et am in o p he n i s t ho u gh t t o be r e l at i ve l y s e le ct i ve f o r CO X 3 , i t wo u l d n ot po s s es s a n y an t i pl a te le t ac ti v i t y , no r wo u ld i t r ed u c e th e s yn t hes is o f g a st r ic c y to p ro t ec t i v e p ro s ta g la n di ns . Th e re f or e , i t wo u ld no t in t er f e re wi t h p la t el e t f u nc t io n o r ot h e r a nt i pl a te l e t t he r a pi es an d i t wo ul d no t b e p r o ne to c a us e g as t r ic u l ce r a ti on . In ad d it io n , th e r el a ti on s h i p b et we e n a s pi r in an d Re y e s y nd r om e i n c h il d re n wi t h v ir a l i nf ec t io n s d oe s n o t a pp a re n tl y e xi s t wi t h ac e ta m i n op h en , m a k i ng i t a s af e a n ti p y r e ti c t o u s e i n t ho se pa t ie n ts . 1 6 . Th e c o r r ec t an sw e r i s D [s ee I II . B . 4. b ]. A c e ta m i n op h en to xi c i t y is c h a ra c te r i z ed b y a p ro fo u n d h ep a to xi c i t y, wh i c h i s m e di a te d b y a re ac t i v e in t e rm e di a r y fo r m e d o n sa t u r at i on an d d ep l et i on o f t he n o r m a l m et a bo li c p a th wa y s . Th i s d oe s n o t a ff e ct th e v as c ul a tu r e ( as wi t h th e e rg o t d e r i va ti v e s ) , th us no v a s o c on s t r ic t io n i s o bs e r v ed. N e i th e r is se v e r e G I u ps e t e vi d e nt ( al t ho ug h m il d GI u ps e t m a y o cc u r e ar l y in t o xi c i t y) . N o r d o es p r o fo u n d C N S s t im ul a ti o n oc c u r , a s i t do e s wi t h as p ir i n t o xi c i t y . Th e r e f o re an s we r D is c o r r ec t . P.342
1 7 . Th e c o r r ec t an sw e r i s A [ s ee I II . D . 1. a ; I I I . D.2 . a ; I I I . D. 3 .a ] A l l op u ri n ol an d p r o be ne c i d , wh i le ef f ec t i v e i n p rev e n t i ng at t ac ks o f go u t y a r t h ri t is b y l o we r i n g c i r c u l at i ng le v e ls o f u ri c a c i d , a r e n ot e f fe c ti ve in t re a ti n g t he ac ut e i n f la m m at o r y s i tu a ti o n t ha t c h a ra c te r i z es a n ac ute a t ta c k . Co lc hi c i n e, b y in h ib i ti n g t h e m ig r a ti o n o f p r oi n fl am m a t o r y c e ll s in t o t h e a ff e c te d j oi n t , wi l l re d uc e th e i n f la m m at o r y p ro c e s s , t hu s a l le vi a ti ng t he pa in an d ed em a a s s oc ia t ed wi t h ac u te a t t ac ks o f go u t y a r t h ri ti s . 1 8 . Th e c o r r ec t an sw e r i s C [s ee I II . D . 2. c ; I I I. D .3 . c ; I I I. D . 4 .c . (2 ) ] P r o b en ec i d, as a u ri c o s ur i c a n d p ro m o t in g th e e xc r e ti o n o f u r ic a c i d , wi ll e f f ec t i vel y l o we r p la s m a c on c e n t ra t io n of u ra t e. H o we v e r , it a l s o in c re as es th e u r i na ry l e ve ls o f u r i c ac i d. I f t hi s c on c e n tra t i on e xc e ed s t h e s o l ub ili t y c on st a nt o f u ri c a c i d in t he u r i ne , th e n i t m a y c r y s t a ll i z e an d p r ec ip i ta t e o u t, c a us in g s t on e f o rm a ti on o r u ri n a r y l i t hi as is . F o r t h is re as o n, p a ti e nt s t ak i ng pr o be n ec i d sh o ul d a l wa ys be c ou n se l ed to d r i nk c o pi ou s a m o u nt s of wa t e r . 1 9 . Th e c o r r ec t an sw e r i s B [s ee I I. C . 1 .a ; II I . E .2] Th e r o le s o f C O X 1 , 2, an d 3 a r e r e vie we d i n t h e a n s we r to qu e s t io n 1 4 . I t i s t h r o ug h t h ei r i n hi bi t io n of i nf l am m a t or y p r os t ag lan d in s y nt h es is b y i n hi bi t in g C O X 2 , t h a t t h e N S A I D s e xe r t t he i r a n ti - i nf l am m a to r y ac t io n s . 2 0 . Th e c o r r ec t an sw e r i s C [s ee I II . E . 4. b ] Th e p r im a r y s i de ef f ec ts t h a t h a v e b ee n ass oc i ate d wi t h th e C O X 2 s p ec ifi c i n hi b it o rs a re ga s t r o in t es t i n al bl ee d in g a n d, m o r e r e c en t l y , p ot e n ti al l y fa t al t h r om b ot ic e v en t s . Th e la t t e r is t ho ug h t t o re f le c t a t o xi c od y n am ic ef f ec t th a t re su l ts f r o m i nh ib i ti o n o f v as c u la r C O X 2 , wh i c h c on t ri bu t es t o t he da i l y c on t r ol o f pl a te l et a n d /o r v as c u l a r f un c ti on . S e v e r e i sc he m i c c ol it is h a s b ee n re p or t ed wi t h al o se t r on ; t o r sa d e d es p o in ts , wi t h o l de r , s ec o nd - ge n e ra t io n a n ti h is ta m i n ics ; an d c is a p r id e wh i c h a re no lo n ge r a v a il a bl e fo r u s e; ac ut e l i v e r f a il u re , wi t h a c e t am in o ph e n o ve r d os e ; a nd C hu r g - S tra u s s s y n d ro m e wi t h za fi rl u k a s t an d c o r ti c o st e r oi d
wi t h d r a wa l . N on e o f th es e a d v e rs e d r ug re a ct io n s h as be e n a ss oc ia t ed wi th t he C O X 2 sp ec i fi c i nh i bi t o rs .
15 Medicinal Chemistry and Pharmacology: Cardiovascular and Diuretic Drugs E dw a rd J . M o r e t o n
I. INTRODUCTION. Ma n y c a t e g or i es o f dr u gs a ff ec t th e c a rd io v a sc u la r ( C V ) a n d r e na l s y s tem s . C e r ta i n d r u gs c a n b e us e d t o t r ea t he a r t f ai l u re (e . g ., c a rd i ac gl yc os id es an d d i u re t ic s ), r e l ie ve an g in a p ec t o ri s (e . g . , a nt i an gi n al ag en t s ), a nd c o n tr o l d ys rh yt h m ia s (e . g. , a n t ia r r h y th m i c a g en ts ) . O t h e r s c a n re d uc e h y p e rt e ns i on ( e. g ., an t ih y p e r te n s i ve s , i n cl ud i ng a v a r i et y o f d i ur e t ic s , β - bl oc k i n g a ge n ts , a nd a rt e r io la r s m o o t h m us cl e d i la t o rs ) , t r ea t th e h y p e r li p id em i as (e . g ., an t ih y p er l i pi d em ic a g en ts ) , re d uc e cl o t ti ng a n d t r e at s u c h c o nd i ti ons as v e no us th r om b os is a n d p ul m on a r y e m bo li s m ( e . g. , a n t ic oa g ul an t s , th r om b oly t i c s ) , an d t r e at an em i as ( e . g. , an t ia ne m i c a ge n ts) .
II. CARDIAC GLYCOSIDES AND POSITIVE INOTROPES A. C h e m i s t r y 1 . A lm os t a ll o f t he c a r dia c g l y c o s i d es (a ls o c al l ed c a rd i o t on i cs ) a re na t ur a l l y o cc u r ri n g s te r oi d al gl y c os i de s o bt a in e d f r om p l ant s ou r ce s . D i gi t o xi n i s ob t a in ed f r o m D i gi t al is pu r pu r e a, d i g o xi n fr o m D i gi t al is l an a t a, an d ou a ba i n f r om S t r o ph a n th us gr a tu s . 2 . Th e c a rd i ac g l y c os id es a re c l os el y r e la t ed s t r uc t u ra ll y, co n s i s t in g of one o r m o re s u ga r s ( i .e . , g l yc o n e p o r t i o n ) an d a s t e ro id a l n uc l eu s ( i .e . , a g l yc o n o r g e n i n p o r t i o n ) b on de d th r ou g h a n e t h e r ( g l yc o s i d i c ) l in k a ge . Th es e a g en ts al s o h a ve a n u n s a tu r a t ed la c t on e sub s t i t ue n t (c yc l i c e s t e r ) o n th e g e ni n p o r ti on . The p r o t ot yp ic a l a ge n t is d igi t o x i n ( Fi g u re 15 - 1 ). a . D i go x i n ( La n o xi n ) has an ad d it i on al h yd ro xy l g r o up a t p os i t i on 12 ( Fi gu r e 15 - 1 ). b . O u a ba i n h as a r ha m no s e g l yc o ne po r t io n a n d a d di t io n al h y d ro xyl g r o up s a t p o si t io ns 1, 5 , 1 1, an d 19 ( F ig u re 15 - 1 ) . 3 . R em o v i ng th e g l y c o n e p o r ti o n c a us es de c re as e d ac ti v i t y a nd in c re as ed t o xi c i t y f r o m ch a ng es in po l a ri t y t h a t c au s e e rr a ti c a bs o rpt i o n f r om th e g as t r oi nt e st i n al ( G I ) t r a ct . 4 . Th e du r a t io n o f a c ti on o f a c a r di ac gl yc os id e i s in ve r s e l y p r o p o r t i o na l t o t h e n u m be r o f h yd r o x yl g r o u p s , wh ic h i nc r e as e p ola r i t y . In c r e as ed po l a ri t y r e s ul ts in d e c re as e d p ro t ei n b i nd ing , de c re as e d l i v e r bi o t ran s fo r m a t io n , a nd de c re as e d r e na l t u b ul a r r e ab s o r p ti on . a . D i gi t o xi n ha s a l o ng d u r a ti on o f ac t io n a n d m a y a c c um u la t e. b . O u a ba i n, in c o n t ra s t , h a s a n e xt r e m el y s ho r t du r a ti o n o f a c t i on an d i s ef f e c t i v e o n l y wh e n g i v e n i nt r a v e no u s l y .
Figure 15-1. Structural formula of digitoxin (Crystodigin), the prototypical cardiac glycoside.
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Figure 15-2. Structural formulas of bipyridine derivatives. A. Amrinone (Inocor). B. Milrinone (Primacor).
5 . Am r i n o n e, i na m r in o ne , a nd mi l r i no n e a r e b ipy r i d i ne de r i va ti v e s wi t h po s it i v e i n o tr o pi c a c t i on ( Fi gu r e 1 5 - 2 ). B . P h a r ma c ol o g y. C a r d i a c g l y c o s i d es in c r e as e m y o c ar d ia l c on t r ac ti li t y a n d e f f ic ie nc y , im p ro v e s y s t em ic c i rc u la t io n , im p r o ve r e n al pe r f us io n , a nd r edu c e e d em a . Th e el ec t r op h y s io l og ic a l e f fe c t s o f c a rd i ac gl y c os id e s a re s u m m a ri z e d in Ta b l e 15 - 1 . A ng i ot e ns in -c o n v e rt i ng en zy m e ( A C E) i nh i bi t o rs a n d p e rh ap s A T 1 a n gi o te n s i n - re c e p to r an ta g o ni s t s; v a so d il at o rs s uc h a s n i tr o p ru s s id e , n it r og l y c e ri n , a n d h yd r al a z i ne ; a n d d iur e t ic s m a y b e i m p o r ta n t a d j u n c t s t o c a rd ia c g l y c os i de s. A C E i n hi bi t o rs m a y be c o n s i d er e d as f ir s t -l in e t re a tm e nt . 1 . W he n g i v en in t he r ape u t ic d os e s , c a r di ac gl yc o s id e s p ro du c e p os it i v e in o t r op ic +
+
e f f ec ts b y in hi b it i ng m em b r a ne - b ou nd N a / K -a c tiv a t e d a d en os i ne t ri ph o s p h a ta s e ( A TP a s e ) . Th es e e f fe c t s o f c a r di ac gl y c os id es in cr e a s e th e ra t e o f t e ns io n d e ve l op m e n t, th e c o nt r ac t il i t y , a n d t he r at e o f re la xa t i o n of c a r di ac m u sc le . Th e e f f ec ts in c l u de
a . I nc re a s e i n i n t ra c e l lu la r s o d iu m c o nc e nt r a ti o n b . R e du c t i on in c a lc iu m tr a n s p o rt f r om t h e c el l b y t h e s od iu m -c al c i um e xc h a n ge r c . Fa ci li t a ti on o f c a lc i um e n t r y via v o l ta g e- g at e d m em b r an e c ha n ne ls d . I nc r ea s e d re le as e o f c a l c i um f ro m sa r c o p la s m ic r et ic u lu m 2 . Th e r ap e ut ic do s e s o f c a r di ac gl yc os id es al s o c a us e a . A n e ga t i v e c hr o no t r opi c e f f ec t f r om i n c r e as ed v a g a l t o ne of t he s i no a t ria l ( S A ) node b . D im i ni s h ed c e n t ra l n er v o u s s ys te m ( C N S ) s ym p a t he t i c o u t fl o w f r om in c r e a s e d c a r ot i d s i n us b a r or ec e pto r s e ns i ti v i t y c . S ys t e m i c a r te r io la r and v e n ou s c on s t r ic t io n , wh i ch in c re as es ve no us r et u r n a n d t h us in c re as es c a r di ac ou t p ut 3 . Am r i no ne a nd m il r i non e p ro du c e p os it i ve i no t ro p ic ef f ec ts an d vas o di lat i o n v i a s e le ct i v e i n hi bi t io n o f t yp e I II ph os p ho di e s t e ra s e ( P D E ) is o zy m e , le a di n g t o an i n c re as e i n c y c l ic ad e nos i ne m o no p ho s p h at e (c AMP ) i n c a r di ac an d sm o ot h m u s c le . I n h ib i ti on o f t y p e I I I P D E p r o du ce s
Table 15-1. Effects of Cardiac Glycosides on the Heart Effects Direct
Atria
AV Node
Contractility ↑
ERP ↑
Contractility ↑
ERP ↑
Conduction velocity ↓
ERP ↓
Conduction velocity ↓ Indirect
On electrocardiogram
Ventricles
Automaticity ↑
ERP ↓
ERP ↑
Conduction velocity ↑
Conduction velocity ↓
P changes
PR interval ↑
No effect
QT ↓
T and ST depressed Adverse
Extrasystole
AV depression or block
Fibrillation
Tachycardia
Extrasystole Tachycardia
AV, atrioventricular; ERP, effective refractory period; ↑, increased; ↓, decreased. Reprinted with permission from Jacob LS, Pharmacology, 3rd ed. Malvern, PA, Harwal, 1992:96.
P.345
a . V as od i la t io n a nd f al l in v a s c ul a r re s i s t a nc e b . I nc r ea s e d f o rc e o f c a rd i ac c o nt r ac t io n c . In c re as e d v e l oc it y o f c a r di ac re l a xa t i on C . T h e ra p e ut i c i n d ic a tio n s 1 . H ea r t fa il u r e ( s t a ge C o n l y ) 2 . A t ri a l f ib r il l at io n 3 . A t ri a l f lu t te r 4 . P a ro xy s m a l at r ia l t a c hy c a r d ia 5 . Am r i no ne a nd m il r i non e a re in di ca t ed f or sh o rt - t e rm t re a tm en t of c o nge s ti v e he a r t f a i lu r e o nl y . D . Ad ve r s e e f f ec t s 1 . E a r l y a d ve r s e e f f ec ts o f c ar d ia c g l y c o si de s re p r es en t th e e a rl y s ta g es o f t o xi c i t y, in c l u di ng a . G I ef f ec ts , s uc h a s a no r e xi a , n au se a , v o m i t in g, a nd di a r rh e a b . C N S e ff ec ts , s uc h a s h e a da c h e , v i s u a l d is tu r ba n ce s ( g r ee n o r yel l o w vi s io n ), c o nf us i on , d e li r iu m , n eu ra l gi as , an d m us c l e we a k n e s s 2 . L at e r ad ve r s e e f f ec ts r e pr es e n t in t o xi c a ti o n a n d i nc lu d e s uc h s e r i ou s c a rd i ac d i st u r ba nc es as p r em a tur e v e n t ri c u la r c o n tr ac t ion s , p a ro xy s m a l an d n o npa r o xys m a l a t r ia l ta c h y c a rd ia , at r io v e n t ri c ul a r ( A V ) d is s oc ia tio n o r b lo c k , v e n t ri c u l a r t a ch yc a rd i a, an d v en t r ic u l a r f ib r i ll at i on .
III. DRUGS FOR TREATMENT OF MYOCARDIAL ISCHEMIA A. C h e m i s t r y 1 . An t i a n gi n a l a ge n t s in c lu d e n i t r it e s ( i .e . , o r ga n ic es te r s o f n i t ro us ac id ) s u ch as a m yl n i t ri t e, n i t ra t es ( i. e. , o rg a ni c es t e rs of ni t r ic a c i d ) s uc h a s n it r og l y c er i n a n d i s os o rb id e , β - b lo c ke r s s u c h as p ro p r an ol o l, an d c a l ci u m a n ta g o ni s t s s uc h a s ve r a p am il an d n i fe d ip in e ( F i gu r e 1 5 -3 ) .
a . Am yl n i t r i t e i s a v ol a ti l e a nd f la m m ab le li q ui d a d m i ni s te r ed b y in ha l at io n . It r e q ui r es s p ec ia l p r ec a ut io n s ( es p ec ia ll y r e s t r ic t io n o f sm ok i ng ) du r in g a d m i ni s t ra ti o n . b . N i t r o gl yc e r i n i s a ls o a v o l at i le an d f l am m a bl e l i qu id an d re q ui r es gr e at c ar e d u r in g s t or a ge . It m u s t be d is pe ns e d f r om i t s o ri gi n al gl as s c on t ai n er s a nd p r o te c t e d f r o m b od y h ea t . ( 1 ) W hen g i v en in t r a v eno u s l y , ni t r og l yc e r in r eq u ir e s t h e u se of s p ec ia l p la s ti c a d m i ni s t ra ti o n s et s t o a v o i d a bs o rp t io n a n d l os s o f po t en c y . ( 2 ) N i t r og l yc e r i n is m e ta b ol ic a ll y u ns t ab le an d un d e rg o es e xt e n s i ve f i rs t -p a ss m e ta b ol is m . 2 . P e r ip h e ra l va s od i la to r s in c l u de th e d i pi p er i di n o -d i p y ri m i d in e d i p y ri d am o le ( F i gu r e 1 5 - 3) . B . P h a r ma c ol o g y 1 . N i t r i te s a n d n i t r a te s a r e fa s t - ac t in g a n ti a ng ina l ag en t s t ha t di r ec tl y r el a x va s c ul a r s m oo t h m us c l e b y f o rm a ti o n o f t h e f r ee ra d ic al ni t r ic o xi d e ( N O ) , wh i c h is i d en t ic al t o e nd o th el i um -d e r i v ed r el a xi n g fa c t o r (E D R F ) . N O ac t i v a te s g ua n y l y l c yc la s e t o i nc r ea s e s y n th e s i s o f c yc l ic gu a no si ne m o n op h os ph a te (c G MP ) wi t h i n s m o o th m u s c le , re s u l ti n g i n d e ph os p ho r y l at i on of l i gh t c h ai n m yos i n a nd m u s c l e r e l a xa t i on . Th is c a us es p e r ip h e ra l p oo l in g o f t h e b l oo d , d im in is he d v e no us r et u r n ( r e d uc ed p re lo a d ), de c rea s ed s ys t em ic v as c u l a r re s i s ta nc e , a n d d ec re a sed a r te r ia l p r e ss u re ( re d uc ed af t e rlo a d ) . Th e s e va s c ul a r e f fe c ts : a . R ed u c e m y o c a r d ia l o x y g e n de m a n d b . C a us e r e di s t r ib u ti o n of c or o na r y b lo o d f lo w a l on g th e c ol l at e r al c o ro n a ry a r t e r ie s , i m p ro vi ng pe r f us io n o f the is c h em ic m yoc a rd iu m 2 . β - Ad r e n e rg i c b l oc k e rs d ec r ea s e s ym p at h et ic -m e di a te d m yo c a r di al s t im u la t i o n ( s e e C h ap t e r 1 3, I V . A. 2 , I V . C . 4 ) . Th e r es ul t in g n eg a t i v e i no t r op ic an d n ega t i v e c h r on o tr o pi c e f fe c t s re duc e m y o ca r di a l o xy g e n r eq u i re m e n ts . P.346
Figure 15-3. Structural formulas of antianginal agents. A. Nitroglycerin (Nitrostat). B. Isosorbide dinitrate (Isordil). C. Nifedipine (Procardia). D. Dipyridamole (Persantine).
3 . C a lc i um an t a go n i st s ( a l s o k n o wn as ca l ci u m c h a nn e l b l oc k e rs ) bl oc k c al ci um e n t r y th r o ug h t h e m e m b ra n o us c al c i um io n ( Ca
++
) c ha n ne ls of c o r on a r y and
p e r ip h e ra l v a s c u la r s m oo t h m us cl e . a . P e ri ph e r al ar t e ri o le s di l a te an d t o ta l p e ri p he r al r e si st a nc e d ec r ea se s , re d uc i ng a f t e rl o ad an d r e du c i n g m y o c a r di al o xyg e n r eq u i rem e n t s . b . C a lc iu m a nt a go ni s ts al s o i nc r ea se o xy g e n de l iv e r y t o t he m yo c ar d iu m b y d i la t in g c o r on a r y ar t e ri es an d a r te r i ol es . 4 . D i p yr i d a m o l e r el a xe s s m o o th m us c l es , de c re as i ng c o r on a r y vas c u l a r re s is ta nc e a n d i nc r ea s i n g c or o na r y b l oo d fl o w. C . T h e ra p e ut i c i n d ic a tio n s 1 . N i t r i te s a n d n i t r a te s a r e us ed to r el ie v e ac u te a n gi na l a t t ac k s , as p ro ph y l a xi s d u r in g a n ti c i p at i on of an a c ut e a n gi n al at t ac k, and f o r l on g - te rm m a n ag em e nt o f r e c ur r e nt an g in a p ec t o ris . 2 . β - Ad r e n e rg i c b l oc k e rs a r e us e d f o r a dj u nc ti v e p r o ph yl a xi s of c h r on ic st a b le a n gi n a p ec t or is in c o m b in a t io n wi t h n it r i te s o r n i tr a t es . Th e y ha ve al s o bee n s h o wn t o in c re as e s u r v i v al ti m e i n h e a rt fa i lu r e a nd a ft er m yo c a r di al in f a rc ti o n (MI ) . Th r e e β - b l oc ke r s a re p ro v e n to r e d uc e m o r t al i t y i n h e a rt f ai l u re an d a r e n o w c las s I r e c om m e nd a ti on s f o r h ea r t fa i lu r e . 3 . C a lc i um an t a go n i st s a r e us ed to t re a t c hr o ni c s t ab le an g in a p ec t o ri s an d va r ia n t ( P r i n zm e t al ) an gi n a . 4 . D i p yr i d a m o l e is n o w u s ed p ri m a r il y as a p la t el e t a g g re ga t io n i n hi bi t o r. P.347
D . Ad ve r s e e f f ec t s 1 . N i t r i te s a n d n i t r a te s a r e as s oc i at e d wi t h : a . C N S ef f ec ts , s uc h a s h e a da c h e , a pp r eh e ns io n, d i zz i ne s s , a n d we a k nes s b . C V ef f ec ts , s uc h a s hy p o t e ns io n , t ac h y c a r di a , p a lp i ta t io ns , a n d s y nc op e c . Sk i n e ff ec t s , s u c h as ra s h a nd de r m a t it is d . Me t h e m o g lo bi n em ia 2 . β - Ad r e n e rg i c b l oc k e rs a r e as so c i a te d wi t h : a . W or se n in g o f c on g es t iv e h e a rt fa i lu r e b . B r ad y c a rd i a a nd h y pot e ns i on c . R ed uc e d k i d ne y b lo o d f l o w a nd de c re as e d g lom e r ul a r f il t r at i on 3 . C a lc i um an t a go n i st s g e n er a ll y p r od uc e o nl y m i ld ad v e r s e ef f ec ts . a . W he n g i v en in c o nj u nc t io n wi t h β -a d re n er g ic bl o ck e rs , t h e C V ef f ec ts of c al c i um a n t ag o ni s t s m a y b e e n han c ed , re s u l ti n g i n b ra d y ca r d ia , h ypo t en si on , pe r iph e r al e d em a , c o n ge s ti v e he a rt f a il u re , A V b lo c k , a n d as ys t ol e . b . V e r ap a mi l m a y al s o c a u s e s l ee p le s s ne s s , m us c l e f a ti gu e , n y s ta gm us , a n d e m ot i on al de p r es s i on . Du r i ng t he fi r s t we e k o f t he r a p y, ve ra p am il i n c r e ase s s e ru m d i gi t al is c o nc e nt r a ti on s a n d m a y c a us e d ig i ta li s to xi c i t y . 4 . D i p yr i d a m o l e is a s s oc i at e d wi t h : a . G I ef f ec ts , s uc h a s n au s ea , v om i ti ng , an d d ia r rh e a b . C N S e ff ec ts , s uc h a s h e a da c h e a nd di zz i n e s s c . C V e f fe c ts , s uc h a s h yp o t en s i o n ( wi t h e xc e s s i ve d os es )
d . B le e di n g
IV. ANTIARRHYTHMIC AGENTS A. C h e m i s t r y. A n t i a r r h y th m ic a g en ts h a v e wi d e l y d i v e rs e c he m i ca l s t ru c tur e s . Th e y i n cl ud e re p r es en t at i v es o f t he fo ll o wi n g g r o up s: 1 . C i nc h o na al k al o i ds —s uc h a s q u in id i ne (a n o pt i c a l i s o m e r of qu i ni ne ) 2 . Am i d e s —s uc h as p roc a in am i de ( P ro n es t y l ), fle c ai ni d e ( Ta m bo c o r ) , a nd d i so p yr am id e ( No r p ac e ) 3 . X yl yl d e r i va t i ve s — s uc h a s l id oc a in e ( Xyl o ca ine ) a nd m e xi l e t in e ( Me xi t i l ) 4 . Q u a te r n a r y a m m o n i um s al t s —s uc h a s b r et yl iu m ( B re t yl ol ) 5 . D i io d o be nz yl o x ye t h yl a m in e s —s uc h a s am i oda r o ne ( C o rd a ro n e ) 6 . β - B lo c ke r s —s uc h a s , n a do lo l ( Co r g ar d ) , p r op ra n ol o l ( I nd e r al ) , e sm ol ol ( B r e vi b lo c ), an d a c e b ut ol o l ( S ec t r al ) 7 . C a lc i um an t a go n i st s— s uc h a s d il t ia ze m ( C a rd i ze m ) a nd v e r ap am il ( Ca l an ) 8 . H yd a n t o i n s —s uc h a s p h e n y to i n ( D il a nt i n ) B . P h a r ma c ol o g y. A n t i a r r h y t h m i c a ge n ts a r e c las s i f ie d a c c o rd i ng to t he i r a b il i t y t o a l t er t he ac ti o n p ot e nt i al o f c a rd i ac c el ls ( Ta b le s 1 5 - 2 a nd 15 - 3 ) . Th e m yoc a r di al a c ti o n p ot e nt i al c u r v e i s s h o wn in Fi g u re 15 - 4 . 1 . C l as s I A d r u g s (e . g ., q u in i di n e, p ro c a in am i de , d is o p y r am id e ) p r od uc e s t a te d e p en de n t s od iu m c ha n ne l bl oc ka d e t o sl o w t h e ra t e o f ri s e o f p ha s e 0 ( t he p ha se o f r ap i d d ep ol a ri z a t i on an d r e v er s al of t ra ns m e m b r a ne v o l ta ge ) an d p r ol on g r e p ol a ri z a t io n an d e f fe c t iv e r e f r ac to r y p e ri od . 2 . C l as s I B d r u gs (e . g ., l i do c a i ne , to ca in i de , m e xi l e ti ne , ph en yt o in ) ha v e a m i n im al e f f ec t o n t h e r a te o f r is e o f ph as e 0 an d s h or t en re p ol a r i zat i on . 3 . C l as s I C d r u gs (e . g ., f l ec a in id e , p r op a fe n on e ) h a v e a m a r ke d e f fe c t in s l o wi n g t h e ra t e o f r is e of ph as e 0 a nd in s l o wi n g c o n du c ti o n . Th e y h a v e l i tt le e ff ec t on r e p ol a ri z a t io n . En c a in i de wa s wi t h d r a wn f r om th e m a rk e t b u t is a vai la b le on a l i m i t ed ba s i s . P.348
Table 15-2. Major Effects of Antiarrhythmic Drugs on Electrocardiogram
QRS
QT
PRa
↑
↑
→↑
Disopyramide
↑
↑
→
Lidocaine
→
↓
→↑↓
→
↓
→↑
Drug Quinidine Procainamide Amiodarone
Phenytoin Tocainide Mexiletine Propranolol
↑, increased; ↓, decreased; →, no change. a
All antiarrhythmic drugs have a variable response, usually with little observable effect. However, lidocaine hardly ever affects the PR interval, whereas phenytoin and propranolol usually increase the PR interval. Reprinted with permission from Jacob LS. Pharmacology, 3rd ed. Malvern, PA, Harwal, 1992:102. Table 15-3. Effects of Antiarrhythmic Drugs on Electrophysiologic Properties of the Heart
Drug Class
Automaticity SA Purkinje Node Fibers
Effective Refractory Period Purkinje AV Node Fibers
Membrane Responsiveness Purkinje Fibers
IA
→↑
↓→
↑→↓
↑↓
↓
IB
→
↓
→↓
↓
→↓
IC
→
↓
↑
↓
↓
II
↓
↓
↑
↓→↑
↓
III
↑↓
↑↓
↓→↑
↑
→
IV
↓
→↓
↑
→
→
↑, increased; ↓, decreased; →, no change.
Figure 15-4. Myocardial action potential curve. This curve represents ventricular depolarization/repolarization. 0, phase 0 (rapid depolarization); 1, phase 1 (early rapid repolarization); 2, phase 2 (plateau); 3, phase (final rapid repolarization); 4, phase 4 (slow depolarization).
P.349
4 . C l as s I I d ru g s ( e . g. , p r o p ra n ol ol , na do l ol , e sm o lo l , ac e bu t ol ol ) a re β -a d r en e r gi c a n t ag o ni s t s t ha t c om p et it i v e l y bl oc k c at ec h ol am in e - in d uc ed s t im ul a ti o n of c ar d ia c β r e c ep t or s a n d d ep r es s de p ol a r i z at i on of ph as e 4 .
5 . C l as s I I I d r u g s ( e .g . , b r e t y li u m , am io d ar o ne , so t a lo l , i bu t il id e , d of e ti l ide ) i n c re as e a c t i on po t en t ia l d u r at i on b y p r ol o ng i ng re p ol a r i zat i on vi a b lo ck ade o f t h e d e la ye d re c ti f ie r p o ta s s iu m c u r re n t I K r . 6 . C l as s I V d r ug s (e . g. , v e r a p am il , di lt i a zem , b ep r i di l ) a r e c al c i um an t ago n is ts t ha t b l oc k t he s l o w i n wa r d c ur r e n t c a rr i ed b y c al c i um d u r in g p h as e 2 (i . e. , lo ng - s us ta i ne d d e p ol a ri z a t io n o r th e p l at e a u o f t h e ac t io n p o te n ti a l ), in c re as e th e e f fe c ti v e r e f r ac t o r y p e ri o d, an d d ep r e s s p h as e 4 d e po l ar i za t i on . 7 . D i go x i n a nd a de n os in e . D ig i ta li s g l yc o s i de s (d i go xi n ) e l ic it a va g o to nic r es po ns e t h a t i nc r ea s e s A V no d al r e f r ac t o ri ne s s . Ad e no si ne ac t s a t G -p r o te in - c o u ple d a d e no s i ne r ec ep t o rs to in c r ea s e A V n o da l r e f ra c to r i ne ss . 8 . M o r i c iz in e i s a t y pe I a n t ia r r h yth m i c b u t n ot A , B , o r C . I t e xh i b i ts p o ten t lo ca l a n es t he t ic a c ti v i t y an d m y o c a r di al m e m b r an e s t ab i li z i n g ac t i v i t y. Mo r i c i z in e r ed uc es f a s t i n wa r d s od iu m c u rr en t , de c r e as in g th e a ct i on p o te n ti a l d u ra ti o n a nd ef f e c t i v e r e f r ac t o r y p e ri o d, an d i nc r e as es th e P R, Q R S , an d Q T e i nt e r v a l. C . T h e ra p e ut i c i n d ic a tio n s . An t ia r r h y th m i c a gen t s a r e u s e d t o re du c e a b n or m a l it i es o f i m pu ls e g e ne r a ti on ( ec to p ic pa ce m a k e r a ut om a ti ci t y ) and t o m od i f y t h e d is t u rb a nc es o f im pul s e c o n du c ti on wi t h in ca rd i ac ti s s ue . ( In di c at io n s f o r s p ec if ic ag e nt s a r e g i v en i n Ta bl e 1 5 -4 . )
Table 15-4. Use of Antiarrhythmic Drugs in Common Cardiac Arrhythmias Arrhythmia
Treatment of Choice Alternatives I. Supraventricular
Atrial fibrillation or flutter
Digital to control ventricular rate, DC shock for conversion
Quinidine to suppress recurrences after DC shock
Paroxysmal atrial or nodal tachycardia
Vagotonic maneuver; digitalis
Verapamil (quinidine, procainamide, disopyramide, and β-adrenergic antagonists may all be useful, especially prophylactically)
II. Ventricular Ventricular premature depolarization
Lidocaine
Procainamide, quinidine, or disopyramide for prolonged suppression
Ventricular
DC shock
Lidocaine, procainamide, or
tachycardia
mexiletine III. Digitalis-induced Lidocaine or phenytoin
Procainamide is somewhat useful; β-adrenergic antagonists are useful but have a high incidence of adverse effects
DC, direct current. Reprinted with permission from Jacob LS. Pharmacology, 3rd ed. Malvern, PA, Harwal, 1992:102. P.350
D . Ad ve r s e e f f ec t s 1 . C l as s I A d r u g s ar e as s o c i a te d wi t h C V e f fe c ts ( e. g . , m y oc a rd i al de p res s i o n, A V b l oc k, v e n t ri c u la r d ys r h yt h m i as , as ys to le , an d h y p o t en s i o n) an d wi t h G I ef f e c t s ( e . g ., G I up s e t , n au s e a , v o m i ti n g, an d d i a rr h ea ) . I n ad d it i on : a . Q u i ni d i ne c a n c a u s e c i nc ho n is m , wi t h t i nn i tu s , c on f us io n , p ho t op h ob ia, h e a da c h e , a nd ps y c ho s is . b . P r o ca i na m i de c a n c au s e s y s t em ic lu p us er y t he m at os u s- ( S L E- ) li k e s yn d r om e . c . D is o p yr a m i d e c an c au s e c o n ge s ti v e he a rt f ai lu r e an d a n ti m u s c a ri ni c ef f e ct s . 2 . C l as s I B d r u gs ar e as s o c i a te d wi t h C N S e f fec t s ( in c l u di n g C N S de p r es s i o n, d r o ws i n es s , d is o r ie n ta t ion , an d p a r es th es i as ) , C V e f f ec ts (i nc l ud in g h yp o te n s i o n a n d c i rc ul a to r y c o ll a ps e ), a nd he p at i ti s . I n a dd i ti o n : a . L id o ca i ne c a n c au s e s e i z u re s a nd r es pi r at o r y a r r es t . b . T oc a in i d e c a n c au s e p n e um on i ti s a nd bl oo d dy s c r as ia s . c . M e xi l e ti n e c an c a us e h e p at ic in ju r y a nd bl o od d y s c ra s i as . d . P h en yt o i n c an c a us e n y s t ag m us , d ec r ea s e d m e n t al fu nc t io n , a nd bl o od d ys c ra s i as . 3 . C l as s I C d r u gs ar e as s o c i a te d wi t h : a . C V ef f ec ts , i nc l ud in g wo r s e n i ng of a rr h y t hm i as in pa t ie n ts wi t h v en t r icu l a r a r r h yt hm ia s , p a rt ic u la r l y p a t ie n ts wi t h a hi st o r y of MI . Th e y c a n wo r s en s in u s n od e d ys f un c ti o n a nd he a rt f ail u r e. b . V is ua l d is t u rb a nc es s u c h as bl u r r ed or do u bl e v i s i o n 4 . C l as s I I d ru g s a r e a s s oc i at e d wi t h : a . C V ef f ec ts , s uc h a s hy p o t e ns io n , A V bl oc k , a nd as y s t ol e b . R es p ir a t or y e f fe c ts , s u c h as b ro nc h os pa s m
5 . C l as s I I I d r u g s a r e as s oc i at e d wi t h : a . C V ef f ec ts , s uc h a s hy p o t e ns io n a n d i ni t ia ll y in c r ea se d d ys r h y th m i as b . G I ef f ec ts , s uc h a s n au s ea an d v om i ti ng 6 . C l as s I V d r ug s a r e as s o c i a te d wi t h C V a d ve rs e e f f ec ts , s uc h a s h y p ote n s i o n, b r a d yc a r di a , A V bl oc k , c o n g es ti v e he a r t f ai l ur e , a n d a s y st o le . 7 . C a r di a c g l yc o s i d e s (s e e I I . D ). Ad e n o si n e c au s es a s y s to le la st i ng le s s t ha n 5 s ec an d i s t h e t he r a pe u tic ob j ec ti ve . 8 . B ec au s e o f i ts p r o a rr hy t h m ic ac ti v i t y , mo r i c iz in e is re s e r v e d fo r p a ti e nt s wi t h l i f e- t h re a te n in g v en t r ic ula r a r rh y t h m i as .
V. ANTIHYPERTENSIVE AGENTS A. C h e m i s t r y. A n t i h y p e rt e ns i v e a g en t s v a r y s o wi d el y i n c he m i ca l s t ru c t ur e t ha t t h e y a re us ua l l y c la s s i fi ed b y m e ch a ni sm o f a c ti on r a th e r t h an c h em ic al c la s s ( Ta b le 1 5 - 5 ). B . P h a r ma c ol o g y. A n t i h y p e r t e ns i ve a ge n ts l o we r b l oo d p r es s u r e b y r e d u ci n g t o ta l p e r ip h e ra l r es is t an c e o r c a r di ac ou t pu t th r ou g h a v a r i e t y o f m ec h an is m s (Ta b l e 15 5). 1 . D i u re t i cs s u c h as th iaz i d e s c re a te a n eg a ti v e s o di um ba l an ce , re d uc e b l oo d vo l u m e , a n d d ec r ea s e v as c u l a r s m oo t h m us c l e r es p on s i v e n es s t o v a s o c ons t r ic to r s (see VI.C). 2 . V as o d il a t o rs s u c h as d i a z o xi d e a n d m i n o xi d il a r e po t ass i um c ha n ne l ac t i v a to r s t h a t p r od uc e m em b ra n e h y p e r po l a ri za t io n , wh e r ea s h y d r a la z i ne m a y s ti m u l a te f o r m a t io n o f E D R F ( N O ) t o de c re as e a r t e ri al r es is t an c e . H um an b ra i n n atr i u r et ic p e p ti de ( B N P ) v ia r ec ep to r s t im u la t io n a n d s o d ium ni t r op r us si de v i a re le as e o f N O a c ti va t e g ua n y l y l c y c la s e, f o rm in g c G MP t o r e la x b o t h a r te r io l es a n d ve i ns . 3 . P e r ip h e ra l s ym p a t h o l yt i c s i n t e rf e re wi t h ad r en e r gi c f u nc ti o n b y bl oc k in g p o st g an g li on ic ad r e ne r gic r ec ep t o rs (e . g ., p ro p ran o lo l , p r a z os in ) , l im i ti n g t h e r e l ea se o f n eu r ot r a ns m i tt e r s f r om ad r en e rg ic ne ur o n s ( e .g . , g ua n et h id in e ), o r d e pl e ti n g i nt r a ne u ro n al c a t ec h ol am i ne s t o ra g e s i te s (e . g. , r es er p in e ) . 4 . C e nt r a l α 2 - s ym p a t h o m i m e ti c s ( e .g . , cl o ni d ine , m e t h yld op a ) a p pe a r to m e d ia t e t h e ir e ff ec t s b y s t im u la t in g p re s y na p ti c α 2 - i nh ib i to r y r e c e p to r s, r es ul t in g in a n e g at i ve s y m pa t he t ic o u tf l o w a n d l o we r e d p er i phe r a l r es is t an c e. P.351
Table 15-5. Classification of Antihypertensive Agents by Their Mechanism of Action
Mechanism of Action
Drug
Vasodilators Arteriolar
Diazoxide (Hyperstat IV) Hydralazine (Apresoline) Minoxidil (Loniten)
Arteriolar and venous Peripheral sympatholytics
Nitroprusside (Nipride) Acebutolol (Sectral) Atenolol (Tenormin) Betaxolol (Kerlone) Bisoprolol (Zebeta) Carteolol (Cartrol) Carvedilol (Coreg) Doxazosin (Cardura) Guanadrel (Hylorel) Guanethidine (Ismelin) Labetalol (Trandate) Metoprolol (Lopressor) Nadolol (Corgard)
Penbutolol (Levatol) Pindolol (Visken) Prazosin (Minipress) Propranolol (Inderal) Reserpine (Serpasil) Terazosin (Hytrin) Timolol (Blocadren) Central α2-sympathomimetics
Clonidine (Catapres) Guanabenz (Wytensin) Guanfacine (Tenex) Methyldopa (Aldomet)
Calcium channel blockers
Amlodipine (Norvasc) Diltiazem (Cardizem) SR Felodipine (Plendil) Isradipine (DynaCirc) Nicardipine (Cardene) Nifedipine (Procardia) SR
Verapamil (Calan) Angiotensin II receptor antagonists
Candesartan (Atacand) Irbesartan (Avapro) Losartan (Cozaar) Telmisartan (Micardis) Valsartan (Diovan)
Angiotensin-converting enzyme inhibitors
Benazepril (Lotensin) Captopril (Capoten) Enalapril (Vasotec) Fosinopril (Monopril) Lisinopril (Prinivil) Moexipril (Univasc) Perindopril (Aceon) Quinapril (Accupril) Ramipril (Altace) Trandolapril (Mavik)
Endothelin receptor antagonist P.352
Bosentan (Tracleer)
5 . C a lc i um ch a n ne l b l oc k e r s ( e .g . , a m l od i pi ne , d i l ti a zem , f e lo d ip in e , i s ra d ip i ne , n i ca r di p in e , n if e di pi n e, v e r a pa m i l ) l o we r v a s c ul a r r e si s t a nc e a nd bl o od p re ss u r e v i a b l oc ka d e o f v o l ta g e -g a ted c a lc i um c ha n ne ls . A rt er i o le s a r e m o r e s en si t i v e t h an ve i n s. 6 . AC E i n h i bi t o r s ( e . g. , c a pt o p ri l ) b lo ck th e c on ve r s io n o f i n ac ti ve an g io te n si n I t o t h e p o te n t v as oc on s tr ic to r a ng io t en s i n II . Th e r ed u c e d a n gi o te ns in I I c onc e nt r a ti o n a l so lo we r s al do s te r on e c o nc en t r at i on , wh ic h l im it s s o di um r et e nt io n . 7 . An g i o t en s i n I I re c ep to r a n ta g o ni s t s ( e .g . , l osa r t a n) a re no n pe p ti de a nt a g on is ts o f t he A T1 an gi o te n s i n I I r e c e p to r s u bt y p e l o c a t ed i n v a sc ul a tu r e , m y oc a rd i um , b r a in , k i dn e y , a n d a d re na l gl om e ru l os a. Th e y p rod u c e v a so di l at i on , c au s e l os s o f s a lt an d wa t e r t o d ec r e as e p l as m a v ol u m e , a n d de c r ea se m y o g en ic ac t i v ity . 8 . E n do t h el i n re c ep t o r a n t a go n is t s (e . g. , bo sen t a n ) a re po t en t o ra ll y ac t i v e n o n pe p ti de en d ot h el in r ec e pt o r a n ta g on is ts . C . T h e ra p e ut i c i n d ic a tio n s 1 . A nt i h y pe r t en s i v e ag e nt s ar e u s ed s e pa r a te l y or i n c om bi n at i on to t r ea t h i g h b l o o d p r e ss u r e. 2 . Th e se ag en t s m a y a ls o b e a dm in is t e re d p a re n te r a ll y t o t re a t h yp e r t e n si ve e m e r ge n ci e s s uc h as m a l ig n an t h yp e r te ns i on , ec l am ps ia , o r th e s e v e re h yp e r t en s i on as s o c i a te d wi t h e xc e s s c at ec h ol am in e s . P a re n te r al t he r ap y m a y i n cl ud e s om e c om bi n at i on o f t h e f ol lo wi n g ag e nt s : a . Ar t e r i o l a r a n d ve no us va s o d il a t o r s u ch as nit r o p ru ss id e or bo se n ta n ( i . e ., p u lm o na r y a rt e r ia l h y p e rt e ns i on ) b . Ar t e r i o l a r va so d i la t or s uc h a s d ia z o xi d e o r hyd r a l a z in e c . D ua l α -a d r e ne r g i c- an d β -a d r en e r g ic - r e ce p to r b l oc k e rs s u ch as l a be t a lo l d . β - B lo c ki n g a g en t s u c h as p ro p r an ol o l e . G a n gl i on i c -b l o ck i ng a g e n t s u ch as t ri m e t ha ph a n D . Ad ve r s e e f f ec t s 1 . D i u re t i cs ( t hi az i d es ) c a n c a u s e a . Fl u id an d s ol u te im ba la n c e s , su c h as h ypo k a lem i a, h ype r c a lc em i a, h yp e r u ri c e m i a , h y p om agn e s e m i a , h y p on a t re m i a , a n d h y p e rg l y c em ia b . I nc r ea s e d s e ru m l o w- d e ns i t y l i po p ro t ei n (L D L ) c ho l es te r o l a nd t ri gl yc e ri d e c o nc en t r at i on s c . O t he r e f f ec ts (s e e V I .C . 4 ) 2 . V as o d il a t o rs a re as s o c ia t ed wi t h : a . G I up s e t b . C N S e ff ec ts , s uc h a s h e a da c h e a nd di zz i n e s s c . C V e f fe c ts , s uc h a s t ac h y c ar d ia , fl ui d re t en t io n, a nd wo r s en i ng of an g ina d . O t h er e ff ec t s , s u c h as n as a l c o n ge s ti on , he pa ti t is , g l om e ru lo n ep h ri t is , a n d SL E l i ke s yn d r om e 3 . P e r ip h e ra l s ym p a t h o l yt i c s a r e as s oc i at e d wi t h a v a ri e t y o f ad ve r s e eff e c ts , d e p en di n g o n t he s p ec i fic ag e nt . a . β - B lo c ke r s (e . g. , pr op r a no l ol ) a r e a s s oc i at e d wi t h :
( 1 ) C V ef f ec ts , s uc h a s br a d y c a rd ia , c o ng es t i ve he a r t f a il u re , an d Ra yn a ud p h e no m e no n ( 2 ) G I up s e t ( 3 ) B lo o d d y s c r as ia s ( 4 ) C N S ef f ec ts , s uc h a s d e p re ss io n , h al lu c i n at i on s , o r ga n ic b r ai n s y n d rom e , a nd t r a ns i en t h e ar i ng lo s s ( 5 ) O t he r ef f ec ts , s uc h as in c re as e d a i r wa y r es is ta n c e , i nc r e as ed s e r um tri g l y c e r id e c o nc en t r at i on s , de c re as e d hi gh - d en s i t y li p op r o tei n ( H D L ) ch o le s t e r ol c o nc en t r at i on s , an d p s ori a s i s ( 6 ) C a rd i ac a r r h y t hm ia s if wi t h d r a wa l i s a b ru p t b . P r az o si n is a s s oc ia t ed wi t h : ( 1 ) C V ef f ec ts , s uc h a s s u d d en s yn c o p e wi t h t he fi r s t d os e, pa l pi t at i on s , an d fl u id r e t e nt i on ( 2 ) C N S ef f ec ts , s uc h a s h e ad ac h e, d ro ws i n es s , we a k n es s , d i z z i ne s s , a nd v e r t ig o ( 3 ) A n tim u s c ar i ni c e f fe c ts an d p r i ap is m P.353
c . G u an e t hi d i ne i s a s s oc i at e d wi t h : ( 1 ) C V ef f ec ts , s uc h a s br a d y c a rd ia , or t ho s ta t ic hyp o t e ns io n , a nd s o di um a n d wa t e r r e t e nt i on ( 2 ) D ia r r h ea ( 3 ) A gg r a v a ti o n o f b r on c h i al as t hm a d . R e se r p i ne is a s s oc ia te d wi t h : ( 1 ) C N S ef f ec ts , s uc h a s n i gh tm a r es , d ep r es s i o n, a n d d r o ws in es s ( 2 ) C V ef f ec ts , s uc h a s br a d y c a rd ia ( 3 ) G I ef f ec ts , s uc h a s G I u ps e t a nd ac ti va t io n o f p e p ti c u lc e r ( 4 ) N as a l s t u f fi ne s s 4 . C e nt r a l α 2 - s ym p a t h o m i m e ti c s al s o h a v e a d ve r s e e ff e ct s t ha t va r y wi t h t he s p ec if ic ag e nt . a . C l on i d in e i s a s s oc ia te d wi t h : ( 1 ) C N S ef f ec ts , s uc h a s s ed a ti o n a nd d ro ws i n ess ( 2 ) D r y m o u th an d s e v e re r e bo un d h y p e r te ns i on ( 3 ) I ns om ni a , h ea d ac he , a n d c a rd ia c d y s r h y th m i as ( wi t h s u dd en wi t h d ra w a l ) b . M e t h yl d o p a i s a s s oc ia t e d wi t h : ( 1 ) C V ef f ec ts , s uc h a s or t h os t at ic h y p ot e ns io n an d b ra d yc a r di a ( 2 ) C N S ef f ec ts , s uc h a s s ed a ti o n a nd fe v e r ( 3 ) G I ef f ec ts s u c h as c ol i ti s ( 4 ) O t he r ef f ec ts , s uc h as he p at i ti s , c i r r ho s i s , C oo m bs - po s i t i ve h em ol y t ic a n em i a, a n d SL E - li k e s y n d r om e 5 . C a lc i um ch a n ne l b l oc k e r s a r e as so c i a te d wi th C V e ff ec t s, r es ul t in g i n h yp o t en s i o n, di z z i n es s , h e a da c h e , a nd fl us h in g . W he n g i v en wi t h β -a d r ene r g ic b l oc ke r s , t he i r e f fe c t s m a y b e e n ha nc e d, r es ul t ing i n b r ad yc a rd ia , h yp o t en s io n , p e r ip h e ra l e de m a , c o ng es t i v e h ea r t fa il u r e, A V b lo c k , an d a s ys t ol e . L o ng -t e r m a d m i ni s t ra ti o n i s as s o c i at e d wi t h r is k o f g i ng i v al h y p e r pl as i a a nd B a rr e t t e s op h ag us .
6 . AC E i n h i bi t o r s a r e as s o c i a te d wi t h : a . C V ef f ec ts , s uc h a s hy p o t e ns io n a n d s y nc o pe b . H em a to l og ic ef f ec ts , s u c h as n eu t ro p en i a a nd a g r an u lo c y to s i s c . O t he r e f f ec ts , s uc h a s c h ro n ic c ou g h, an o r e xi a, p ol y u r i a, ol ig u r ia , a c u te r e na l f a i lu r e, c h ol e s t a ti c j au n di c e, an d ( ra r el y ) a ng io e d e m a 7 . An g i o t en s i n I I re c ep to r a n ta g o ni s t s a r e as soc i at e d wi t h ad ve r s e e ff ec t s s im il a r t o A C E i n hi b it o rs , e xc e p t t h a t c o u gh an d a n gi oe de m a, wh i c h a re in d ep e nde n t o f a n gi o te n s i n a n ta go n is m , o c c u r l es s f r eq ue n tl y . 8 . E nd o th e li n r ec e p to r an t a go ni s ts ( Bo s e n ta n ) ha v e t he po t en t ia l fo r s e rio u s l i v e r i n ju r y a nd da m a g e t o a fe t us .
VI. DIURETICS A. O s m o t i c di u r e ti c s 1 . C h em i st r y. O s m o t ic di u r et ic s (e . g. , m a nn it o l, u r e a , g l yc e ri n , i s o s o r bi de ) a re h i gh l y po l a r, wa t e r -s o lu bl e ag en t s wi t h a l o w r e nal t h re s h o ld ( Fi gu r e 1 5 -5 ).
Figure 15-5. Structural formulas of osmotic diuretics. A. Mannitol (Osmitrol). B. Urea (Ureaphil).
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2 . P ha r m ac o l og y a . O sm o ti c d iu r et ic s a r e r e l at i v e l y i n e rt c h em ic al s t h a t a re f re e l y fi l te r ed at t h e g l om e ru l us a n d p oo r l y r ea b s o r be d f ro m t he r en al t u b ul e . B y i nc r ea s i n g t he o sm o la r i t y o f th e g lo m e ru l a r f il t r at e , t h e y li m i t t ub u l a r re a bs o r p t io n o f w a t e r an d t h us p r om o t e d i u re s is . b . B ec a us e t he s e ag e nt s i nc r e as e wa t e r , s o di um , c hl o ri d e , a nd bi c a r bo n ate e xc r e t i o n, th e y c a us e a n i n c r ea s e i n u r i na r y p H . 3 . T he r a pe u t ic i nd i ca t io n s . Os m o t ic d i u re t ic s ar e us e d t o: a . H el p p r e v e nt an d tr e at o l ig u ri a a n d a nu r ia b . R e du c e c e r eb r al ed em a a n d d ec r ea se in t r ac ra n ia l p r es s u r e c . R ed uc e i n t ra oc ul a r p re s s u r e 4 . Ad ve r s e e f fe c t s. O s m o ti c d iu r e ti cs a r e a ss oc i a t ed wi t h : a . H ea d ac he an d b l u rr e d v i s io n
b . I nc r ea s e d b lo o d v ol um e th a t wo r s e ns c on g es ti v e h ea r t f a il u re B . C a r b o ni c a n h yd r a s e i n h i bi t o r s 1 . C h em i st r y. C a r b o n ic a n h y d ra s e in h ib i to r s a r e a r o m a t ic o r he t e ro c yc l ic s u lf o na m i d es wi t h a pr om i ne n t t hi a di a z ol e n u c l eu s . Ac e ta z ol a mi d e is t he p r o t ot yp ic a l a ge n t ( F ig u re 1 5 -6 ) . 2 . P ha r m ac o l og y a . C a rb o ni c a nh y d r as e in h ib i to r s n o nc o mp e t i ti ve l y i n h i b i t t he en z ym e c a r b o ni c a n h yd r a s e . Th is p re v e n ts t he en zy m e fr o m p ro v id i ng t he tu b ul a r h y d r og en i on s n e e de d f o r e xc h a n ge wi th s o d iu m i n t he p ro xi m a l t u b u l e, r es ul t in g i n s od iu m b i ca r bo n at e d i u re s i s . b . B ec a us e t he s e ag e nt s i nc r e as e wa t e r , s o di um , p o ta s s iu m , a nd bi c a r bon a t e e xc r e t i o n, th e y c a us e a n a l ka l i ne u r in a r y p H . 3 . T he r a pe u t ic i nd i ca t io n s . Ca r bo n ic an h y d ra se i nh ib i to r s a r e us e d t o : a . R ed u c e ed em a (a s a dju n c t di u r et ic th e r ap y ) b . R e du c e in t r ao c u la r p re s s u r e ( r e ta r d a qu e ou s h u m o r fo r m a t io n ) c . Al k al in i z e t h e u r in e , en h a nc in g e xc r e t i on of ac i d ic dr u gs an d t h ei r m e tab o li t es d . Tr e a t m ot o r d is o r de rs s uc h a s p e ti t m al ep i le ps y, p a r o xy s m a l ch o r ea and d ys t on i a, pe r i od ic at a xi a , a nd s o m e c as e s o f es s e n t ia l t r em o r 4 . Ad ve r s e e f fe c t s. C a rb o ni c a n h y dr a s e in hi b it or s a re as s o ci at e d wi t h : a . C N S ef f ec ts , s uc h a s C N S d e p re ss io n , d r o ws in e ss , s ed a ti o n, fa t ig u e, d i so r ie n ta t io n , a nd pa r es t h es i a b . G I ef f ec ts , s uc h a s G I u ps e t , n au s e a , v o m i t in g, a nd co ns t ip a ti on c . H em at o lo gi c e f fe c ts , s u c h as b on e m ar r o w d e pr e s s i on , t h r om bo c y t op eni a , h e m o l yt ic a n em ia , l e uk op e ni a , a n d a gr a nu l oc yt os is d . H yp e rc h lo r em ic m e ta bo l ic ac id os is e . S ul f on am i de - t y p e h y pe r s en s i t i vit y r e ac ti o ns C . B e nz o t h ia d ia z id e d iu r e t i cs 1 . C h em i st r y a . Th e c om m o n l y u s e d th i a z id e d i u re t ic s a re p rim a r il y c l os e l y re la t ed b e n zo t h ia d ia z id e s w i t h va r i a b l e s u bs t i t ue n t s. Th e p r o to t yp ic al ag e nt is c h lo r o th ia z i d e ( F ig u re 15- 7 A ) . b . O p ti m al d i u re t ic a c ti v it y d e pe n ds on c e r ta in s tr u c t u r a l f e at u r e s. ( 1 ) Th e be n z e ne ri n g m us t ha v e a s u lf o n am i de gr o u p ( p r ef e r ab l y un s u bs ti t u te d ) i n p o si t io n 7 an d a ha l o gen ( us u al l y a ch l o ro gr o up) o r a t r i f lu o r o me t h yl g r o u p in p o si t io n 6 ( Fi gu r e 1 5 - 7) . ( 2 ) S a tu r a t i on o f t h e 3 ,4 - d o ub l e b o n d i nc re a s es po t en c y , a s wi t h h yd r o ch lo r o th i a z id e (F igu r e 15 - 7 B ).
Figure 15-6. Structural formula of acetazolamide (Diamox), the prototypical carbonic anhydrase inhibitor.
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Figure 15-7. Structural formula of (A) chlorothiazide (Diuril), the prototypical benzothiadiazide diuretic, and (B) hydrochlorothiazide (HydroDIURIL). Structural formulas of (C) cyclothiazide (Anhydron) and (D) quinethazone (Hydromox), related compounds with substituents that prolong activity and enhance potency.
( 3 ) L ip o p hi l ic s ub s t i tu en t s at po si t io n 3 o r m e thyl g r o u p s a t p os i ti o n 2 en h a nc e p o t en c y an d p r ol o ng ac tiv i t y , a s wi t h c yc l o th ia z i de ( F ig u re 15 - 7 C ) a n d b e n dr o fl um e th i a z id e . ( 4 ) R e pl a ce m en t o f t h e s u l f on yl g r o u p i n p os it io n 1 b y a c a r bo n yl g r o u p p r ol on g s a c ti vi t y, as wi t h q u in e th az o n e ( Fi g ur e 1 5 - 7 D ). c . A f e w s u l f am o yl b e n z a m i de s (e . g. , in da p am ide , ch lo r t ha li d on e ) h a v e ac t i v i t y s im i la r to th a t o f t h e b enz o t h i ad ia z i d es ( Fi gu r e 15 - 8 ) . d . B e nz o th i a di az i n es w i t h o u t t h e s u l fo n am i de g r o u p (e . g. , di a z o xi d e ) e xh i b i t a n t ih yp e r te ns i v e a c t i v i t y b u t l ac k d iu r e ti c a ct i vi t y ( F i gu r e 1 5 - 9) . 2 . P ha r m ac o l og y a . B en zo t hi a di a z id e s d i re c t l y i n h i b i t s o di u m a nd c h lo r i d e r e ab s o r p ti o n o n th e l u m i na l m em b ra n e o f t h e e a rl y s eg m e n t o f t h e d is t a l c on v o l ut e d t ub u le .
b . Th e se ag e nt s i nc r ea s e wa t e r , s o di um , c hl o ri de , po t as si um , a n d b ic a rbo n a te e xc r e t i o n a nd de c re as e c a lc iu m e xc r e t io n a n d u ri c a ci d s ec r e ti on . Th e y m a y c a us e a n al k al i n e u r i na r y p H b y i n hi bi t in g c a rb o ni c a nh y d r a se .
Figure 15-8. Structural formula of indapamide (Lozol), a sulfamoylbenzamide with pharmacological activity similar to that of the benzothiadiazide diuretics.
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Figure 15-9. Structural formula of diazoxide (Hyperstat), a benzothiadiazine lacking a sulfonamide group and diuretic action.
3 . T he r a pe u t ic i nd i ca t io n s . Be n z o th ia d ia zi d es a r e us ed to t re a t : a . C h ro n ic e d em a b . H yp e r te ns i on c . C on g es ti v e he a r t f ai l ur e ( as ad ju n c t i v e e d em a t h e r ap y ) 4 . Ad ve r s e e f fe c t s. B enz o t h i ad ia zi d es ar e a ss oci a t ed wi t h : a . C N S ef f ec ts , s uc h a s h e a da c h e , d i z z i ne s s , p a re s th es i as , d r o ws i ne s s , an d r e s tl es sn es s b . G I ef f ec ts , s uc h a s G I i r r it a ti o n, na u s e a , v o m i ti n g , a bd om in a l b lo a ti n g, a n d c o ns ti p at i on c . C V e f fe c ts , s uc h a s o rt h os t a ti c h y p ot e ns io n , pa l pi t a ti on s , h em oc on c e n tr a t io n , a n d ve n o us t hr om b os is
d . H em a to l og ic ef f ec ts , s u c h as bl o od d y sc r as ia s , l e uk op e ni a , t h ro m b oc y to p e ni a, a g r an u lo c y to s i s , a pl as t ic a n em ia , h em o l y ti c a ne m i a , a n d r as h e . Fl u id an d e l ec t ro l y t e im b al a nc es , s uc h as h ypo k al e m i a, h y po n at r em ia , a n d h yp e r ca lc em i a f . Mu s c ul a r c r am ps g . H yp e r ur ic em i a a nd ac u t e g o ut a tt ac ks h . H yp e rc ho l es t er o le m i a a n d h y p e r t ri gl y c e ri d em i a i . S ul f on am i de - t y p e h y p er s e ns it i vi t y re ac t io n D . L o o p d i u re t i cs 1 . C h em i st r y. L o o p di u re t ic s a r e a nt h r an il ic ac id d e ri v a t i v es wi t h a s u l fo na m id e s u bs ti t ue n t ( e . g. , fu r os em i de , b um e ta n id e ) o r a ryl o xya c e t i c a ci ds wi t h ou t a s u lf o na m i d e s u bs t it u en t ( e . g ., e th ac r yn ic ac id ; F ig u r e 1 5 -1 0 ) . 2 . P ha r m ac o l og y a . Th e se ag en t s ac t pr i nc i pa ll y a t th e t hi ck as c e nd i ng li m b o f t he lo o p o f H e n l e, wh e r e t h e y in h i bi t t he co t r a n sp o r t o f s od i u m, p o t a ss i um , a n d c h l o ri de f r o m t h e l u m i na l fi l t r a te . b . L oo p d iu r e ti c s i nc r e as e e xc r e t io n o f wa t e r , so di u m , po t as s i um , c al ci um , a n d c h lo r id e ; d ec r ea s e u ri c ac i d s e c re t io n ; a nd ca us e n o ch a ng e in u r in a r y p H . 3 . T he r a pe u t ic i nd i ca t io n s . L o op di u re t ics a re u s ed to t re a t a . E de m a f ro m c on g es ti v e h ea r t f a il u re , he pa t ic c i r r h os is , a nd r en a l d is eas e b . P ul m o n a r y e d em a a nd a s c i te s 4 . Ad ve r s e e f fe c t s. Lo op d iu r e ti cs a r e a s s oc ia t ed wi t h : a . Fl u id an d s ol u te im ba la n c e s , su c h as de h yd ra t io n , h y p o k a le m i a , h y p e rur i c em ia , h yp e r ca lc iu r i a, an d a z o te m ia b . C N S e ff ec ts , s uc h a s h e a da c h e , v e r t ig o , b lu r re d v is i on , ti nn i tu s , a nd (r a r e l y ) i r r e ve rs i bl e h ea r i ng lo s s c . H em at o lo gi c e f fe c ts , s u c h as t h ro m b oc yt o pe n ia a n d a g ra nu l oc yt os is
Figure 15-10. Structural formulas of loop diuretics. A. Furosemide (Lasix). B. Ethacrynic acid (Edecrin).
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d . C V ef f ec ts , s uc h a s o rt h os t a ti c h y p ot e ns io n
e . G I ef f ec ts , s uc h a s n au s ea , v om i ti ng , an d d ia r rh e a f . L eg c r am ps g . H yp e rc h ol es t e ro le m i a a n d h y p e rt r ig l y c er i de m ia h . S ul f on am i de - t y p e h y pe r s en s i t i vit y r e ac ti o n E . P o t as s iu m - sp a r i ng di u r e t i cs 1 . C h em i st r y. Th e p o t a s s i um -s p a ri ng di u re t ic s a re p te r i di ne o r p y r a z i ne de r i v a ti ve s ( e . g ., t ri am t e re n e, am il o ri d e ) o r s t er o id an a lo g a nt a g on is ts o f a ld os t e ro ne ( e . g ., s p i ro no l ac to n e; F ig u re 15 - 1 1 ). 2 . P ha r m ac o l og y a . S p i ro n o la c t on e a n d ep l e r e no n e ac t as c o m pet i t i ve i n hi b i to r s o f a ld os t e r o ne a t m i ne r al o c o r ti c o i d r ec ep t o rs in th e l a te di s ta l t ub u le an d c o ll ec ti n g d uc t . Th e y i n t er f e re wi t h al do s te r one - m ed ia t ed s o di um - p ot as si u m e xc h a ng e , d ec r eas i ng p o t ass i um s ec r e ti on . b . T r ia m t e re n e a n d a mil o r i d e, wh i c h a re n ot al do s te r o ne an t ag o ni s t s , ac t d i re c t l y o n th e l a te di s ta l t u bu le a n d c ol le c ti n g d uc t. Th ey d i s ru p t s od iu m e xc h a ng e wi t h p o t ass i um a n d h y d r og e n b y b lo c k in g s o di um c h an n el s a n d d ec r ea s i ng t he d ri v i n g f o r ce fo r s e c r e ti o n o f p o ta s s i um a n d h y d r og e n. c . Th e p o ta s s iu m -s pa r ing d iu r e ti c s i nc r ea s e bi c ar b o na t e e xc r e t i on an d c au s e a n a l k al i n e u r i na r y p H . 3 . T he r a pe u t ic i nd i ca t io n s . Po t ass i um -s p ar i ng d i u re t ic s a re us e d a . A s a dj un c ti v e th e ra p y t o t re a t e de m a f r om c ong e st i ve h e a rt f ai lu r e , h ep a t ic c i r rh os is , ne p hr o ti c s y n dr o m e, an d h y p e r al do s te ro n i s m ( p ri m a r y a nd s e con d a r y ) b . A s a dj un c ti v e th e r ap y ( wi t h t h ia z i d es a n d l oo p d i u re t ic s ) t o t r ea t h yp e r te n s i o n c . To t re a t o r p r e v e nt h yp o k a l em ia 4 . Ad ve r s e e f fe c t s a . S p i ro n o la c t on e i s as s oc i at e d wi t h : ( 1 ) H yp e rk al em i a ( 2 ) G I ef f ec ts , s uc h a s G I u ps e t, G I b l ee d in g , g ast r i t is , n au se a , a bd o m i na l c r am ps , a n d d ia r r h ea ( 3 ) E nd oc r i ne ef f ec ts , s uc h a s g y n ec om as t ia , m en s t ru a l i r re g ul a ri t ie s, and h ir s ut is m ( 4 ) C N S ef f ec ts , s uc h a s m en t al c o n fu si on an d l et h a r g y b . T r ia m t e re n e a nd am i lo r i d e a r e a s s oc ia t ed wi t h : ( 1 ) H yp e rk al em i a ( 2 ) G I ef f ec ts , s uc h a s G I u ps e t, G I b l ee d in g , n aus e a, an d v om i ti ng ( 3 ) C N S ef f ec ts , s uc h a s h e ad ac h e a nd di zz i n es s ( 4 ) I nc r ea s e d u r ic a c i d c o n c e n t ra t io n i n p a ti en t s wi t h g o ut y a r t hr i ti s ( wi t h t r i am t e re ne ) ( 5 ) Me t h e m o gl o bi n em ia in p at i en ts wi t h al c o h ol ic c i r rh os is ( wi t h t ri am t er e ne , wh i c h i n hi b it s d ih y d r o fo l at e re du c ta s e )
Figure 15-11. Structural formulas of potassiumsparing diuretics. A. Triamterene (Dyrenium). B. Spironolactone (Aldactone).
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VII. ANTIHYPERLIPIDEMIC AGENTS A. C h e m i s t r y. A n t i h y p e rl i pi d em ic a g en ts v a r y i n c h em ic al s t r uc t ur e a n d ar e us u al l y c l as s i fi e d b y t he i r s i t e o f a c ti on — l oc al l y in th e i n te s ti n e ( n on ab s or b ab l e ag e n ts ) o r s ys t em ic al l y ( ab s o r ba b le a g en ts ) . 1 . N o na b so r b a bl e a g e nt s a re b il e a c i d s eq u es tr a n t s . Th es e a ge n ts a r e h yd r o ph i li c , wa t e r - in s o l ub l e r e s i ns th a t b in d t o b i le ac i ds i n th e i n te st i ne . E xa m p l e s i n cl ud e c ol e s e v e la m h y dr o c hl o ri d e; ch o l es t yr a m i n e ch l o r id e , a b a s i c a nio n e xc h a n g e r es i n c o ns is t ing o f t r im e th yl be n z yl a m m o n iu m g r ou ps in a l a rg e c o po l ym e r o f st yr e n e a nd di v i n y lb en z e n e ; c o le s ti p o l h yd r o c h l o r id e , a c o po l y m e r of d i e th y l pe n t am i n e a nd epi c hl o ro h y d r in ( Fi gu r e 1 5 -1 2 ) , a n d ez e t im i be , a 2 a ze t i di no n e b lo c k e r o f t he g as t ro i nt es t in a l c h o le s t e r ol t r an sp o rt e r . 2 . Ab s o r b a bl e a g en t s i nc l ud e n i c ot i n ic ac i d ( b ut n o t t he s t r uc t ur a ll y si m il a r n i co t in am id e ) , t h e a r y lo x y i s o bu t y r ic ac id de r i va ti v e s fe n o fi b r a te ( p ro d ru g ) a n d g e m f ib r o z i l , t h e 3 - h y d rox y - 3 - m e t h ylg l ut a r yl -c oe nzy m e A ( H MG - C o A ) r e d uc t as e i n hi b it o r l o va s t at i n , a nd t h e f a tt y f is h o i ls c on t ain i ng la r g e am o un ts o f e i c os a pe n t ae n oi c ac i d ( E P A) a n d d oc o sa h ex a en o i c a c id ( D H A; F i g u r e 1 5 - 13 ) . B . P h a r ma c ol o g y. A n t i h y p e r l ip i de m i c a ge n ts in cr e a s e c a ta b ol i sm o r r e du c e l i p o p r ot e i n p r o du c t io n ( e . g ., lo v a s ta t in , g em f ib ro z i l ) o r i nc r e as e th e e f f ic i e nc y o f l i p o p r ot e i n r e mo va l ( e.g . , c h ol es t yr am i ne , c ol es t i p ol ) . C . T h e ra p e ut i c i n d ic a tio n s . Th es e a ge n ts ar e us e d ( i n c o n ju nc t io n wi t h a p p ro p r ia t e d i e t a nd e xe r c is e ) t o r e du c e p la sm a l ip o pr o te i n co n c e n t ra t io ns . D . Ad ve r s e e f f ec t s 1 . N o na b so r b a bl e a g e nt s ( e .g . , c ho le s t y ra m i n e, c ol es t ip o l ) a re as so c i a te d wi t h G I d i st r es s , in c l u di n g a bd om i na l b lo a ti n g, na us e a, d ys p ep s i a , s te a to r r he a , a n d c o ns ti p at i on o r d ia r r he a . 2 . Ab s o r b a bl e a g en t s (e . g . , s t a ti ns , fi b ra t es ) are as s o ci a t ed wi t h G I d is tr e s s , s ki n r a s h, an d l e uk op e ni a.
Figure 15-12. Structural formulas of nonabsorbable antihyperlipidemic agents. A. Cholestyramine chloride (Questran). B. Colestipol hydrochloride (Colestid).
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Figure 15-13. Structural formulas of absorbable antihyperlipidemics. A. Nicotinic acid (niacin). B. Gemfibrozil (Lopid). C. Lovastatin (Mevacor). D. Eicosapentaenoic acid (found in Promega, ProtoChol, and others). E. Docosahexaenoic acid (found in Promega, Proto-Chol, and others).
a . L o va st a t in an d o t he r s t a ti ns (e . g ., s i m v as ta t in, p r a vas t at in , fl u v as t a ti n , a t o r vas t a ti n, ) m a y i nc r eas e b l oo d t r a ns am in as e an d c r e at i ni ne ph os p ho kin a s e a c ti vi t y as s o c i a te d wi t h m y o p at h y , es pe ci a ll y wh e n c om b in e d wi t h fi b r at es o r c yc lo s po r in s . b . G e m fi b r oz i l m a y a ls o c au s e s k el e ta l m us c l e pa i n , b lu r r ed v is i on , a n d an e m i a . c . N ic o t i ni c a c id p ro d uc e s fl us hi n g as s oc ia t ed wi t h p r u ri t us , wh ic h m a y be a l le vi a te d b y o n e as p ir i n p e r d a y. To le r a nc e t o n ic o ti n ic a c i d d e v e lo ps in 1 - 2 we e ks . H i g h d os es o f n ic ot i ni c ac i d ( 2 g / da y) m a y p r od uce h ep a ti c d am ag e .
VIII. ANTICOAGULANT, ANTIPLATELET, AND THROMBOLYTIC AGENTS A. An t i c o a g ul a n ts . Th e m a jo r an ti c oa gu l an t a g en t s a r e h e pa r i n , l ow m ol e c u la r w e ig h t h e pa r i n (L M W H ) a n d t he o r al an t ic oa g ula n ts . 1 . C h em i st r y
a . H e pa r i n i s a l a rg e , h ig h l y ac id ic m uc o po l ys a c c h a ri de co m p o s e d o f s ulf a t ed D g l uc os am i ne an d D -g lu c u r o ni c a c i d m ol ec ul es e xt r a ct e d f r om bo vi ne lu n g a n d p o r ci ne in t es t in e ( F ig u r e 1 5 - 14 ) . b . LM W H f r ag m en t s ( 1 -1 0 k D a ) e n o xa p a ri n , d a lt e p a r in , t in z a p a r in , an d a r d e pa r i n a r e pr o du c e d th r ou g h c on t r ol l ed de p ol ym e ri za t ion o f h ep a r in , b u t t he y a re n ot i n t er c ha ng e ab l e wi t h hep a r in in th e i r ac t io ns an d u s e . ( 1 ) B ec au s e t he y a r e h igh l y ac i di c , he p a ri n a nd LMW H f ra gm e nt s e xi s t as a n io n s a t p h ys io l og ic p H a nd a re po o r l y ab s o r be d fr om t he G I t r ac t . Th us th e y a re us u al l y a d m i ni s te r ed pa r e nt e r al ly a s th e s od i um s al t . P.360
Figure 15-14. Structural formula of heparin, a mucopolysaccharide anticoagulant agent.
( 2 ) Th e ac ti o n o f h ep a ri n a n d L MW H f ra gm e nt s is q u ic k l y t er m i n at e d b y p ro t a m in e s u l f a te , a hi g hl y b as ic pr o t ei n th a t c o m b i ne s c hem ic a ll y wi t h t he m i n a pp ro xi m a t e l y e q u al a m ou n ts (m g: m g ) . c . Low m o le c ul a r w ei g ht h e pa r i n oi d s ( d a na p a ro i d ) ar e gl yc o s a m i no g lyc a n s e xt r a c t e d f r om po r c i ne m u c os a. d . L ep i r u di n i s a r ec om b i na n t - D N A -d e r i v ed 65 am i no ac id po l y p ep t id e n ea r l y i d en t ic al t o h i r ud i n , wh i c h b e lo n gs t o th e g r ou p o f is op o l y pe p ti d es o f th e l e ec h H i r u do m e di c i n al is . e . Ar g a t r o b a n is an L -a rg i ni n e -b as e d st r uc t u re . f . B i va l i r u di n i s a 20 am i n o a c i d p e pt id e . L e pi r udi n , b i v a li r ud i n , an d a r ga tr o b an a re s yn t he t ic th r om b in i n hi b it o r s . g . D r o t r ec o g in α is a r ec om b in a nt fo r m o f h um an - a c t i v a te d p r o te in C th at i n ac t i vat es f ac to r s V a a nd V I I Ia . h . F on d ap a r i nu x i s a pen t as ac c ha r id e t h at r es em b le s t he an t i th r om bi n bi n di n g r e g io n o f he pa r i n. i . C o um a r i n d e r i va t i ves, wh i c h a r e h ig h l y e f f ec tiv e , a nd t he r el at i ve l y un i m p o rt a nt i n d a ne d io n e d e r i va t i ves a r e o ra l a n ti co a gu l an ts . ( 1 ) Th e co u ma r i n d e r i va t i ve s (e . g ., w a r f a ri n , di c u ma r o l ) a r e wa t e r in s ol u bl e , we a k l y a c i di c 4 - h y d ro xy c o u m a r in la c to ne s (F ig u r e 1 5 - 15 ) .
( a ) Th e s e ag e nt s a r e c he m i ca l l y r e l a t e d t o vi t am i n K , a nd th e i r m e c h a ni s m o f a c ti o n is di r ec t l y re l at e d t o t he i r a nt a go n is m of t he r e du ct as e re sp o ns ib le f o r r e d uc in g v i ta m i n K e po xi d e to t he re d uc ed h y d roq u in o ne . ( b ) Th e s e ag e nt s a r e a ls o h ig hl y p r o te in bo u nd an d e xt e n s i v e l y m e ta b ol i ze d in th e l i ve r . Th es e c h a r ac te r is t ic s , i n a dd i ti on t o a re la t ive l y n a r ro w t h e r a pe u ti c in d e x, m ak e th e c ou m a r in de r i va t i v es s u sc ep t ib l e t o s i gn i f ic an t d r u g i nt e ra c ti on s. ( 2 ) P he n i nd i o ne r ep r es en t s a t ypi ca l i n d an e di o ne d e r i va t i ve ( F ig u r e 1 5-1 6 ) . 2 . P ha r m ac o l og y a . H e pa r i n c at a l y z es t he i n hi bi t io n o f th r om bi n b y a n ti t h ro m b i n I I I ( he p a ri n c o fa c to r ) , p r e v en t in g t h e c on v e r s i o n o f f i br i no g en t o fi b ri n .
Figure 15-15. Structural formulas of coumarinderivative oral anticoagulants. A. Warfarin (Coumadin). B. Dicumarol.
P.361
Figure 15-16. Structural formula of the indanedione-derivative oral anticoagulant phenindione (Hedulin).
b . LM W H f ra gm e nt s a r e u n a bl e t o c at a l yz e i n hi b it i o n o f t h ro m b i n, bu t th ey c a t al y z e i n hi b it i on b y a n ti t h ro m b in I I I o f f ac t o r Xa , wh i c h is r es po ns i bl e f o r c on ve rs i on of p r o t hr om b in to t hr o m b in . H e p a ri n p r ol o ng s b lo o d c l o t t in g t im e b o t h in v i v o a n d i n vi t r o , wh e r ea s L MW H f rag m en ts ha v e m i ni m al i n vi t r o ef f ec t .
c . G l yc o s a m i n o g l yc a n s ( D a n ap a r o id ) in hi b it f ibr i n fo r m a t io n b y i nh ib i ti on o f c l ot t in g f a c t o rs Xa a nd I Ia ( le s s e r e f fe c t) . d . L ep i r u di n , d e si r u d in , a r g a t r ob a n, an d bi va l i ru d i n b i nd to an d b l oc k th e c a ta l yt ic ac ti v i t y o f t h rom b in . e . D r o t r ec o g in in hi b it s pr o t e ol y t ic in ac t i v at i on of f a c to r s V a a nd V I II a . f . F o nd a pa r i n ux fa c i l it a te s i n hi bi t io n o f fa c to r Xa b y a n ti t hr om b in b y 30 0 -fo l d b u t h a s n o d i re c t e ff ec t o n th r o m b in . g . O r a l a n t ic o ag u l an t s in t e r f e r e w i t h th e vi t am in K - d e pe n de n t h e pa t i c s yn t h e s i s o f t h e a c ti ve c lo t t i ng f ac t o r s II ( pr o th r om b in ) , VI I , I X, an d X a nd t he an t ic o ag u la n t p r o t ei ns C a n d S . Th es e a g e nt s p r ol on g b l oo d c lot t i ng ti m e in v i v o on l y . 3 . T he r a pe u t ic i nd i ca t io n s a . H e pa r i n i s i nd ic a te d ( 1 ) F or t he pr o ph y l a xi s an d t re a tm en t o f v e no us th r o m b os is , p u lm on a r y em b ol is m , p e r ip h e ra l a r te r i al e m bo li s m , an d a t ri a l f ib r il l at i on wi t h em bo l i z at i on ( 2 ) To p re v e n t c lo t ti n g du r i ng a rt e r ia l s ur g e r y a nd c a r d ia c su r g er y ( 3 ) To d ia gn os e a n d t r eat d is s e m i na t ed in t r a vas cu l a r c oa gu l at i on ( D I C ) ( 4 ) To p re v e n t p os t op e r at i v e v e no u s t h ro m b os is an d pu l m o na r y em b ol ism ( i n l o wd o se fo r m ) ( 5 ) To p re v e n t c e re b ra l th r o m b os is du r in g a n e vol v i n g s t ro k e ( 6 ) A s a dj un c t t he r a p y t o p r e v e nt co r on a r y occ l us i o n wi t h ac u te MI b . LM W H f ra gm e nt s a r e a p p ro v e d fo r t re a tm en t of t h ro m b o em bo l ic c om pl ic a ti o ns a ss o ci at e d wi t h s u r g er y , u n s t a bl e a n gi na , an d MI . c . D an a pa r o i d is ap p r o ve d fo r p re v e n ti on o f d eep ve i n t h ro m b os is . d . L ep i r u di n an d a r g a t ro b a n a r e i nd ic a te d fo r tre a tm e nt o f p at i en ts e xp er i e nc in g h e p ar i n -i nd uc e d t h ro m b oc y t o pe n ia . e . D es i r u d in is a p p ro v ed o f t r ea t m e n t o f d ee p ve i n t h r om bo s i s. f . D r o t r e co g i n α is ap p ro v e d fo r r ed uc t io n o f m or t a li t y i n a du l t p at i en ts wi t h s e ve re s e ps is a s s oc i at e d wi t h ac u te o rg a n d ys fu nc t io n . g . F on d a pa r i n ux i s a p pro v e d fo r th e pr o ph yl a xi s o f de e p v e i n t h ro m b os is i n p a t ie n ts u n de r go i ng hi p fr a c tu r e s u rg e r y an d h ip o r k n e e r e pl ac em en t s u rg e r y . Th e r e is no an t id o te fo r fo n d a pa r i n ux - in d uc ed ble e di n g. h . Wa r f a r i n s o di u m is an o r al an ti c oa gu l an t i n dic a te d ( 1 ) F or t he pr o ph y l a xi s an d t re a tm en t o f v e no us th r o m b os is , p u lm on a r y em b ol is m , a n d a t r ia l f ib r i ll at i on wi t h e m b o li z a t io n ( 2 ) A s a dj un c t t he r a p y t o p r e v e nt co r on a r y occ l us i o n wi t h ac u te MI 4 . Ad ve r s e e f fe c t s a . H e pa r i n ( 1 ) H e pa r in is a s s oc i at ed wi t h : ( a ) H em a to l og ic ef f ec ts , s uc h a s h em o r rh a ge , l oc a l ir r i ta t io n , t h ro m b oc y t op e ni a , h e m a t om a, ul c e r a ti o n, e ry t h e m a , an d p ai n ( b ) O t h er e ff ec t s , s u c h as h y pe r s e ns i ti v i t y r ea c ti on s , f e v e r , c h i ll s , an d u r t ic a r ia ( 2 ) S e ve re ad v e r s e ef f ec t s m a y be t re a te d b y a dm i ni s t e ri n g p r ot am i ne s ul f a te , th e s p ec if ic an t id o te f or h epa r i n.
b . LM W H f ra gm e nt s a r e a b s o r be d m o re un i fo r m l y t h an he p a ri n , h a v e a l on g e r b i ol o gi c a l h a lf - li f e, an d m a y be as so c i a te d wi t h a l o we r in ci de nc e of s i de e f f ec ts t h a n h ep a ri n . P.362
c . D an a pa r o i d is c o n t ra in d ic a te d i n va ri ou s b le ed i ng di s o r d e rs a n d p at i en t s h yp e r se ns i ti v e to po r k p ro d uc ts . D an a pa r oi d c on ta i n s s o di um s u lf i te , wh i c h m a y c a us e l if e - th r ea t en i ng al le r g ic re ac t io n s . d . L ep i r u di n m a y be as s o c ia t ed wi t h c e re b r al bl ee d in g a n d a ll e rg ic , s k i n , a n d a n a ph y l ac t ic re ac t io ns . e . D es i r u d in wh e n e m p lo y e d wi t h ep id u r al /s pi n al a n es th e si a o r s pi n al pun c tu r e m a y l e ad t o e pi du r a l o r s pi n al h em a to m a , r es ul ti n g i n l o n g - te rm o r p e rm an e nt pa r a l y si s. f . D r o t r e co g i n α - i nd uc ed b le ed i ng is th e m os t co m m o n s e r i ou s a d v e rs e r e a c t i on . g . F on d a pa r i n ux wh e n em p lo y e d wi t h e pi d ur a l/ s pi n al an es t h es ia or s p in a l p u nc tu r e m a y le a d t o e pi d u ra l o r s p i na l h em a to m a, r es ul t ing i n l on g -t e rm o r p e rm ane n t p a r al ys is . Th e m os t c o m m o n a d v e rs e r e ac ti o ns as s o c i a te d wi t h fo n da p a ri n u x a r e b l ee d in g c om pl ic a ti o ns . h . Wa r f a r i n ( 1 ) Th e or a l a nt ic o ag u lan t wa r f a r in s o di um is a s s o c ia t ed wi t h th e f o ll o wi ng a d v e rs e e f f ec ts : ( a ) H em o r rh a ge ( b ) A no r e xi a , u rt ic a r ia , pu r p u ra , a n d a lo p ec ia ( 2 ) B le e di ng m a y b e t r eat e d b y a dm in is t e ri n g v i t am i n K ( ph y t o na d io ne ) , the s p ec i fi c a n t id o te fo r wa r f a r in s o di u m . B . An t i p l a t el e t a g en t s 1 . C h em i st r y. A n t i p la t ele t d ru gs in c l u de as pi r in , a s a l ic yl at e ; t ic l op id i ne , a t h i en op y r i d in e ; d ip y r i dam o le , a di p ip e ri d in o -d i ni tr o p y r im id i ne ; p r os t ac y c li n an al o gs , a n d t h e F ab f ra gm e n ts of h um an m o no c l o na l a n tib o d y to t he gl yc op r o te in I I b / II I a ( G P I I b / I II a ) r ec e p to r . 2 . P ha r m ac o l og y a . As p i r i n i n l o w d os es in h ib i ts pl a te le t c yc lo o xy g e n as e p ro d uc t io n o f t h ro m bo xa n e A 2 , p re v e n ti n g pl a t el et ag g r eg a ti o n. C y c lo o xy g e n a s e is pe r m a n en t l y i n hi bit e d fo r t h e l i fe of t he pl a te le t (7- 1 0 da y s ) . b . T ic l o pi d i ne an d c l op id o g r e l i nt e r fe r e wi t h a den o s i n e di p ho s p h at e - ( A DP - ) i n du c ed m em b ra n e -m ed ia t e d p la t el e t -f ib r i no ge n b i nd i ng , l e ad i ng to in hi b it i o n o f p l a te le t - pl a te l et ag g re g at i o n. c . Fa b f ra g me n t s ( e .g . , a b c i xi m a b ) a r e m on oc lo na l an t ib od i es a g ai ns t th e G P I I b / II I a r e c ep t or t ha t p e rm a ne n tly i n h ib i t p la t el e t- p la t el e t i n te r ac t io n . d . G P I I b/ I I Ia - r e ce p t o r an t a g on i s ts ( e. g . , t i ro f ib an , ep t if i ba t id e ) a r e r e ve rs i bl e a n t ag o ni s t s o f f i br i no g en, v o n W ill e b ra nd f ac to r , a n d o t he r ad he s i o n l ig a nd s a t th e G P I I b / I II a re c e p to r , l e ad in g to in h ib i ti on o f p la t el et a gg r e ga t io n . e . An a g r e l id e d ec r e as es p l at e le t p r o du c t i on . f . C i l os t az o l a nd i ts m e ta b ol i te s a r e t y p e I I I P D E i n hi bi t o rs th a t i nc r ea se c A MP , l e ad i ng to v a s o d il a ti on an d de c re as e d p la t el et a gg r e ga t io n .
g . T r ep r o s t in i l i s a p r os t a c y c l in an a lo g o f p r os t ag l an d in I 2 ( P G I 2 ) , wh i c h is a d i re c t va s o di l at o r a nd in h ib i to r o f pl a te l et ag g r eg a ti on . h . D i p yr i d a m o l e m a y inh i bi t pl a te le t ag g re g at i on v i a in h ib i ti on o f: ( 1 ) R e d bl o od c e ll ad e nos i ne , wh ic h ac ts o n th r om b o xa n e A 2 r ec ep t o rs o f p l at e le ts ( 2 ) P ho s p h od i es te r as e to i nc r ea s e in t ra c el lu l ar c o n ce n t ra t io ns of c A MP ( 3 ) Th r om b o xa n e A 2 f o rm a ti o n 3 . T he r a pe u t ic i nd i ca t io n s a . As p i r i n i s i nd ic a te d fo r r ed uc t io n o f m o r ta li t y i n po st - MI , p r o ph y l ac t ic tr e a tm e nt o f MI t o p re v e n t r e in f a rc ti o n , a nd p ro ph y l a xi s a ft er t r a ns ie n t is c h em ic a tt ac ks an d m i no r s t r ok e. b . T ic l o pi d i ne is a p p ro v e d to r ed uc e th e r is k o f th r o m b o ti c s tr ok e i n p a ti en t s wi t h d e m o ns t r at e d r is k b ut wh o c a nn o t t ol e r at e a s p i rin . C l op i d og r e l i s a pp r o ve d to r e d uc e MI , s t r ok e , a nd v a s c u la r de a th s . c . Ab c i x im ab is in di c a t ed f o r us e wi t h a s p i ri n a nd h ep a ri n i n p a ti e nt s u nde r g oi n g p e r cu t an eo u s t r an s l um ina l c o r on a r y an gi o pl as t y (P TC A ) o r a t he r ec t om y . d . T i r of i b an an d ep t i f iba t i d e a r e a pp r o ved f or t re a tm e nt o f ac u te co r on ar y s yn d r om e a nd pa t ie n ts un d e rg o in g P TC A . e . An a g r e l id e i s a pp r o ve d to r ed uc e p l at e le t c oun t in pa t ie n ts wi t h e ss ent i a l t h r om b oc y t he m i a . f . C i l os t az o l i s a pp r o v ed f o r t r ea tm e n t o f i nt e rm it t e n t cl a ud ic a ti on . P.363
g . T r ep r o s t in i l i s a pp r o ve d fo r t re a tm en t of pu lm o n a r y ar t e ri a l h y p e rt e ns io n . h . D i p yr i d a m o l e is i n di c a t e d f o r p r op h yla xi s a g ain s t t h ro m bo em bo l i sm a fte r ca r di ac va l v e r e pl ac em e nt . 4 . Ad ve r s e e f fe c t s a . As p i r i n i n d os es us ed f o r tr e at m e n t o f th r om bot i c d is ea s e is as s oc i at e d wi t h e p ig a st r ic pa in , he a rt b u rn , na us e a, r as h , n as al po l y p s , go u t , a nd an a ph y la c ti c r e a ct i on s i n s e ns i ti v e in di v i d ua ls . b . T ic l o pi d i ne is a s s oc ia t e d wi t h a h ig h i nc i de nc e o f a d v e rs e r e ac ti o ns , in c lu di n g d i a r rh e a, r as h, na us e a, v o m i ti n g, G I pa in , an d ne u t r op en i a. c . Ab c i x im ab is as s o c i a te d wi t h m aj o r a n d m i n o r b l ee d in g e v e n ts , t h r om b oc y t op e ni a , h um an a nt ic h im e ri c a nt i bo d y fo r m a t i on , c a rd ia c a r r h y th m ia s, A V b l oc k, b ra d y c a r d ia , d i ar rh e a , a bn o rm al t hi nk in g , a n d d i zz i n ess . d . T i r of i b an an d ep t i f iba t i d e a r e as so c i a te d wi th b le ed i ng e v en t s a nd ble e di n g c om p li ca t io ns , n a us ea , fe v e r , an d h e ad ac h es ; i n t h e c as e o f e p ti f ib a ti d e, wi t h h yp o t en s i o n. e . An a g r e l id e c a r ri es a wa r n i n g fo r us e i n p at i ent s wi t h h e a rt di s e as e a nd m a y l ea d t o se r io us ad v e r s e e ff ec ts , in c l ud i ng c o ng es t i v e he a r t f a il u re , MI , h ea r t b lo c k , f i b ri l la t io n , a nd ot h e rs . f . C i l os t az o l i s c o n t ra ind i c a t ed in pa t ie n ts wi t h co n g es ti ve he a r t f ai l ur e . In d og s , c i lo st a z o l p r od uc e d c a r dio v a s c u la r le s i on s , i nc lu di n g e nd o c a r di al h em or r ha g e a n d h e m o si d er i n d ep os i ti o n, n e c ro s i s o f sm o ot h m us c l e , i n ti m a l t h ick e ni n g, and a r te r i ti s i n th e c o ro n ar y a r t er y .
g . T r ep r o s t in i l m a y p r od u c e h y po t en s i o n a nd ble e di n g wh e n co m b i ne d wi t h va s o di l at o rs an d a n ti pl a te l e t d r ug s. In j ec ti o ns m ay b e e xt r e m el y p ai n fu l an d a ss o ci at e d wi t h i nf us i on s i te e r yth e m a , i nd u r at i on, r as h , b le e di n g a nd br u is i ng . h . D i p yr i d a m o l e is a s s oc i at e d wi t h na u s e a , e pi ga s t ri c p ai n , d i zz i n e ss , h ea d ac h e, a n d ra sh . C . T h r o mb o l yt i c a g e n t s 1 . C h em i st r y a . Al t e p l as e , r e t ep l as e , a n d t e ne c te p l as e a r e re c om bi n an t D N A -d e ri v e d t i s su e p l a sm i n og e n a c ti va t o r s ( t - P As ) c on s i s ti ng o f 5 27 , 35 5 , a nd 52 7 a m i n o ac i ds , r e s pe c t i v e l y , o f t h e n at u ra l t - P A, wh i c h c a t al y z e s c o n ve rs io n o f p l asm i no ge n to p l as m i n . b . S t r e pt o k in a se is a non e n z y m a ti c 4 7- k D a p ro t ei n de r i ved f ro m c ul t ur e s o f G r o up C β - h em o l y ti c s t re p to c o c c i . c . An i s t r e pl a se (a n is o y la t e d p la s m in o ge n s t re p to k in as e a c ti va t or c o m p lex; A P S A C ) i s a co m p le x o f h um a n l ys - p la s m in og e n a nd s t r ept o k i n as e wi t h a n a ni s o yl g r o up b l oc ki n g t he c a ta l y t ic s i te . d . U r o k in a se is a t wo - c ha i n s e ri ne p ro t ea se ob t ain e d f r om cu lt u r ed hu m a n k id n e y c e ll s. 2 . P ha r m ac o l og y. Th r o m b ol y t ic ag e nt s f ac i li t at e t h e c on v e r s i on o f p la sm i n og e n t o p l as m i n , wh i c h s ub s e qu en t l y h y d ro l yz e s f i br i n t o d i ss ol ve c l ot s . a . Al t e p l as e a n d r e t ep l as e a re re f e r re d t o a s c lo t s el ec t i ve b ec a us e c o n ve r s io n o f p l as m i n og en t o p la s m in b y t - P A is e n ha nc e d s e ve r a l h un d r ed - fo l d i n t he p r e s e nc e o f f i b ri n . b . S t r e pt o k in a se , wh ic h h as no en zy m a t ic a c ti v i ty, f o r m s a on e - to - o ne c om p le x wi t h p l as m i n og en , re s u l ti n g in a c on f o rm a ti on a l c h a ng e th a t e xp o s es th e c a tal yt i c s it e o f p l as m i n og en . Th e s ta b le a c ti v a t ed c om p le x s u b s e q u en tl y c le a ves f re e p la s m i no g en t o f or m p la s m in . c . An i s t r e pl a se i s a p rod r u g a c t i va te d i n v i v o b y d e ac y l at i on of t he an is ol e m o ie t y f r o m t he ac t i v e s i t e o f t he p la s m in o ge n -s t re p to kin a s e c o m p le x. Th e a c ti v a t e d c om p le x c o n v e r ts pl as m in o g en to pl as m i n i n t h e b l oo d s t r ea m o r th r om bu s . d . U r o k in a se , i n c on t r as t t o s t re p to k i n as e, is en zy m a t ic an d d i re c tl y co n ve r t s p l as m i n og en t o p la s m in . 3 . T he r a pe u t ic i nd i ca t io n s a . Al t e p l as e a n d r e t ep l as e a re in di c a t ed f or t r ea tm e nt o f ac u te MI a n d a c u t e m as s i v e p ulm o na r y em bo l is m . b . S t r e pt o k in a se is i n dic a te d fo r a c ut e MI , d ee p ve i n th r om bo s i s , a r te r ia l t h r om b os is , a nd a rt e r ia l e m bo li , e xc e pt t ho se o rig i na t in g fr o m t he le f t s ide o f t h e h e a r t. c . An i s t r e pl a se i s i n di c at e d fo r tr e at m en t o f a cu te MI a n d l ys is o f co r on a ry a r t e r ia l t h r om b i. d . U r o k in a se is i n di c a t ed f o r t r ea tm e n t o f co r o nar y a r t e r y th r om b os is a n d p u lm o na r y em bo l i. P.364
4 . Ad ve r s e e f fe c t s a . t - P As a r e as s o c i a te d wi t h : ( 1 ) I nt e rn a l b le e di ng o f th e G I a n d g en i to u ri n a r y tr a c t, r et r o pe r i to ne a l b le ed i ng , an d i n t ra c ra n ia l b le e di n g ( 2 ) S up e r fi c i al bl e ed i ng a t c a t he t er in s er t io n s i tes , ar t e ri a l p un c t u r es , a nd s u r g ic al s i te s ( 3 ) O t he r ad v e r s e e ff ec ts , in c l ud i ng h ype r s e ns i tiv i t y r e a c t io n s, na us e a, vo m it i ng , h yp o t en s i o n, an d fe v e r b . S t r e pt o k in a se m a y be as s o c i a t ed wi t h : ( 1 ) I nt e rn a l a nd s u pe r f ic ia l bl ee d in g [ s e e V II I . C .4 .a . ( 1 ) a nd ( 2 )] ( 2 ) A ll e rg ic r ea c ti on s , i nc l ud in g b r o nc ho sp as m , an g io n eu r o ti c e de m a , u r t ic a r ia , h e a da c h e , a nd de la y e d h y p e r s e ns i ti vi t y r ea c t i ons c . An i s t r e pl a se m a y be a s s o c i at e d wi t h: ( 1 ) I nt e rn a l a nd s u pe r f ic ia l bl ee d in g [ s e e V II I . C .4 .a . ( 1 ) a nd ( 2 )] ( 2 ) C a rd i ac a r r h y t hm ia s a n d h y p o te ns i on ( 3 ) A ll e rg ic t y p e r e ac ti o ns s u c h as b r o nc ho sp as m , a ng i on e ur o ti c e de m a , ur t i c a r ia , a n d d el a y e d p u rp u ri c ra s h d . U r o k in a se m a y be as s oc i at e d wi t h : ( 1 ) I nt e rn a l a nd s u pe r f ic ia l bl ee d in g [ s e e V II I . C .4 .a . ( 1 ) a nd ( 2 )] ( 2 ) A ll e rg ic r ea c ti on s l ead i ng t o b r on ch os p asm an d s k i n ra s h
IX. ANTIANEMIC AGENTS A. C h e m i s t r y. Th e m a jor a n ti a ne m i c a ge n ts a r e ir o n pr e pa r a ti on s , c y an o c o b al a m i n ( vi t a m i n B 1 2 ) , f ol ic ac id , a n d h em a to p oi e ti c g ro wt h f ac t or s (e r yt h r o p o i e t in , c ol o n ys t i m ul a t in g fa c t o rs , and i n te r l e uk i n 1 1 ). 1 . M o s t i r o n p r e pa r a t i on s co n s is t o f f e r r ou s sa l t s , wh i c h a r e b et t e r a bs o r be d f r o m t he G I t ra c t t ha n f e rr i c s al ts o r e le m e n ta l i r on . P a re n te r al i ro n p r ep a ra t i on s — i n cl ud i ng so d i um f e r r ic g l u c on a te c o m p l e x i n s uc r os e (F e r r l ec i t ) , i r o n su c r o se ( S a c ch a r a te ) , a n d i r o n d e x t r an ( I N Fe D , D ex f e r ru m ) — s h ou l d b e em p lo yed o nl y wh e n c le a rl y i nd ic a t ed . a . Typ i c al or a l p r ep a ra t io n s i nc lu d e f e r r o us su l fa t e ( Fe os ol ) , fe r r o u s g lu c o na t e ( F e r go n ) , a nd f e r r ou s fum a r a t e ( F eo s t a t ). b . W hen p a re n te r a l a dm in i s t r a ti o n is in di c at e d, so d i u m f e r r ic g lu c o na t e i s p r e f er r e d o v e r i r o n de x tr a n be c au s e it is a s s oc ia t e d wi t h a l o we r r isk o f a n a ph y l ac t ic re ac t io n . I ro n s uc r o se m a y al s o h av e a be t t er s a f et y a n d ad v e r s e e f f ec t p r o fi le t ha n i r on de xt r a n . 2 . C ya n o c o b a l a mi n ( v i ta m in B 1 2 ) is a nu cl e ot i de- l ik e m ac r om ol ec u le wi t h a m o di f ie d p o r ph y r i n u n it ( a c o r r in ri n g ) c on t ai ni n g a tr i v a le nt c ob al t at om . A c y a ni de i o n i s a ls o c o o rd in a te d to th e c ob a lt a t om , a s is a b e n zim id azo l e g ro up . Th e b e n z im id a zo l e g r o up is bo nd e d t o a n α -r i b os y l ph os ph a t e. 3 . F ol i c a c id c o ns is ts of t h r ee m a jo r c om p on e nt s : a pt e ri d in e n uc l eu s b ond e d t o th e n i t ro g en o f p -a m i n ob e n zo i c ac i d, wh i c h is bo n ded t h ro u gh an am id e l in kag e to g l u ta m i c ac i d ( F ig u re 15 -1 7 ) .
4 . E p oe t i n α an d d a r b ep o e t in α a re gl y c o pr o te in s p r o du ce d v ia r ec om bin a n t D N A t e ch n ol o g y . E p oe t in α ( 16 5 am in o a c i ds ; 3 0 .4 k Da ) i s id e nt ic al t o n at u r al e r y t h r op o ie t in . 5 . C ol o n y -s t im ul a ti n g f ac t o r s f i l g ra s t im an d p e g fi l g r a s ti m (g r an u lo c yte c o l on y s t im ul a ti n g f ac t or ; G - C SF ) a nd sa r g r am o s ti m (gr a n ul oc y t e - m a c r o ph a ge c o lo n y s t im ul a ti n g f ac t or ; G M- C S F ) a re gl yc o pr o te i ns p ro d uc e d v i a re c o m b i na n t D N A t e ch n ol o g y .
Figure 15-17. Structural formula of folic acid, an antianemic agent.
P.365
6 . O p r e l ve ki n (i n t e r le u ki n 1 1) is a r ec om bi n an t D N A - p r o du ce d n o ng l y cos y l a te d p o l yp ep ti d e g r o wt h fa c t or t h at di f f er s f r om th e n at u r al c y to k i n e b y o ne am i n o a c i d . B . P h a r ma c ol o g y 1 . I r on p r ep a r a ti o n s ( f er r o us s a l ts ) a r e r e ad i l y ab s o rb ed f r om t h e G I t ra c t a nd s t o re d i n t h e b on e m a r row, l i v e r , an d s pl e en as fe r r i t i n a n d h em o si d e r in. Th e y a r e s u bs eq u en t l y i nc o r po r ate d as n e ed e d i nt o h em og l ob i n , wh e r e th e i r on r ev e r s i bl y b i nd s m ol ec u la r o xy g e n . A l ac k o f b o d y i r on c a us e s i r o n- d ef ic i en c y an em ia wi t h h yp o ch r om ic , m ic r oc y t ic r e d bl oo d c el ls , wh i c h t ra n s p o r t o xyg e n p oo r l y. 2 . C ya n o c o b a l a mi n is re a di l y ab s or b ed f ro m t h e G I t r ac t i n t h e p r es en c e o f i n t ri ns ic f a c to r ( Ca s tl e f ac t o r ), a g l y c op r o te in p ro d uc ed by g a s t ri c p ar i et a l c e l ls tha t is n e ce ss a r y fo r G I a bs o r pti o n o f c y a no c ob al am i n. a . C ya n oc ob al am i n is t ran s po r t ed to ti s s u e b y t ran s c o ba l am in II . It is es s e n t ia l f o r c e ll gr o wt h , fo r m a in t ai n in g no r m a l n e r ve c el l m ye l in , an d f o r t h e m e t ab o li c f u nc t io ns o f f ol a te . b . L ack of di e ta r y c y a noc o ba l am in (o r la ck of in t ri n s i c f ac t or ) ca us es a v i ta m in B 1 2 d e f ic ie nc y a nd m e ga l ob la s ti c a ne m i a wi t h h y p e rc h r o m i c, m a cr oc y t i c, im m a t u r e r ed b l oo d c el ls . D em y e li n at io n of ne r v e c e ll s a ls o o cc u rs , c a us in g i r r e v e rs ib le C N S d a m a g e. 3 . F ol i c a c id is re a di l y ab s o rb ed f r om t h e G I t ra c t , t r an s p o r te d t o t is su e , a n d s to r e d i n t ra c el lu l ar l y . It is a p r ec u rs o r o f s e v e ra l c oe n z ym es ( de r i v a ti v e s o f t e t rah yd r o f ol ic a c id ) th a t a r e i n v ol v e d i n s in g le c a r bo n a t om tr a ns f e rs . A l ac k o f di e t ar y fo l ic ac id
c a us es fo li c a c i d d e fi c i en c y an d m e ga lo b la s t ic an e m i a wi t h h yp e rc h ro m i c, m ac r oc yt i c , im m a tu r e red b lo od ce ll s . F ol ic ac id d e f ic ie nc y c au se s n o n eu r o lo g ic i m pa i rm en t , b u t f ol ic ac id d ef ic i en c y i s a ss oc ia t ed wi t h bi r t h d ef e c t s ( e .g ., s pi na b i f id a ). 4 . E nd o ge n ou s e r y t h ro po i e ti n , wh o s e p r od uc t io n i n t h e k i d ne y s is s t im ul at e d b y b l oo d l os s , a ne m i a , a nd h y p o xi a , is m i m i ck ed b y e p o e ti n α a n d d a r be p oet i n α to i n c re as e p r ol i fe r a ti on and d if f e re n ti a ti on o f e r y t h ro i d p r og e ni t o r c e ll s . 5 . F il g r as t i m a nd p eg f i lg r a s t im in c re as e p r ol i fe ra t i on , d i ff e r en t ia t io n , a nd a c ti va t io n o f ne u tr o ph i ls i n pa t ie n ts e xh i b i t in g n e u t r o pe ni a a f t er un d e rg oin g m ye l os up p r es s i v e c he m ot h e r ap y. S a r g ra m os t im s t im ul a te s m at u r at io n o f g r a nu l oc y t es an d m ac r op h a ge s a nd ac ti v a t io n o f m a tu r e c el ls via c e ll s u rf a ce r e c ep t or s . 6 . O p r e l ve ki n i nc r e as es p l at e le t p r o du c t i on v i a st i m u l at i on of he m a t op o iet i c s te m c e ll s, m e ga k a r y o c y t es p ro g e ni to r c e ll s , a nd m a tu ra t i on of m e ga ka r y o c yt es. C . T h e ra p e ut i c i n d ic a tio n s 1 . I r on p r ep a r a ti o n s ( f er r o us s a l ts ) a r e u s e d t o tr e a t i r on - d ef ic i en c y a n em i a. 2 . C ya n o c o b a l a mi n is us e d t o t r ea t m e ga l ob la s tic an em i a r es u lt i ng f ro m v i t a m i n B 1 2 de f ic ie nc y . 3 . F ol i c a c id is u s e d to tr e a t m eg a lo bl as t ic an em i a re s ul ti n g f r om fo li c a cid d e f ic ie nc y . 4 . E p oe t i n α an d d a r b ep o e t in α a re ap p ro v e d fo r t r ea tm e nt o f a ne m i a re s ul t in g f r o m ch r o ni c r e na l f ai l u re . 5 . F il g r as t i m a nd p eg f i lg r a s t im a re ap p ro v e d for t r e at m e n t o f c h ro ni c a nd c h em ot h e ra p y - in d uc ed ne u t r op en i a. S a r g ra m os t im is ap p r o v ed fo r m y e l oid r e c on s t i tu t io n i n p a ti e nt s wi t h n on - H o dg k i n o r H od g k i n d is e as e o r wh o h ave u n d er g on e b o ne m a r ro w t r a ns p la n ta t io n . 6 . O p r e l ve ki n i s a pp r o ve d fo r p re v e n ti on o f c h em o th e r ap y - r e la t ed t h r om b oc y t op e ni a . D . Ad ve r s e e f f ec t s 1 . I r on p r ep a r a ti o n s g i ve n o ra ll y a r e as s oc ia t ed wi t h G I e f fe c ts , s uc h as G I d i st r es s , n au s e a , h ea r t bu r n , d i ar r h ea , a n d co ns t ip a t io n . P a re n te r a l i ro n a d m i ni s t ra ti o n m a y b e as s o c i a te d wi t h f a ta l a n ap h yl a c t i c an d a n ap h y l act o i d r e a ct i on s . 2 . C ya n o c o b a l a mi n on l y r a r el y p r od uc es ad ve r s e e f f ec ts . 3 . F ol i c a c id is a s s oc i ate d wi t h o n l y ra r e a ll e r gi c r e ac t io ns af t e r p a re n te ra l a d m i ni s t ra ti o n . P.366
4 . E p oe t i n α an d d a r b ep o e t in α m a y in c re as e bl o od p re s s u re , wh i ch s h ou l d b e m o ni t o re d a nd e ff ec t i v ely m a na g ed . 5 . F il g r as t i m m a y p r o duc e a l le r gi c r e ac ti o ns i n vo l vi ng s k in , re s p i ra t o r y , o r c a r di o vas c u l ar s ys t em s a f t e r i ni t ia l o r s ub s eq ue nt d os in g . F i l g ra s t im an d p e g f i lg r a s ti m a r e c on t r ai n di c a t ed in pa t ie n ts al ler g i c t o E s c he r ic h ia c o li - de r i v e d p r o t ei ns .
6 . O p r e l ve ki n p r o du c e s f l u id re t en t io n , wh ic h m ay l e a d t o p e ri p he r al ed em a a n d d ys p ne a . P.367
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 7 : E ac h o f t h e q ue s tio n s , s t a te m e n ts , o r in c om p le t e s t a te m e n ts i n th is s ec t ion c a n b e c o r re c t l y a ns we r e d or co m p le t e d b y o ne o f th e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r . 1 . C a lc i um ch a n ne l b l oc k e r s h a ve a l l o f t he f ol l ow i n g c ha r a c te r i s t ic s e x c ep t ( A ) t h e y b l oc k t he s l o w in wa r d c u rr e nt c a r r ie d b y c al ci um du r i ng ph as e 2 o f t he c a r di ac ac ti o n p ot e nt i al . ( B ) t h e y d il a te p er i ph e ra l a r t e ri ol es an d re d uc e t o t a l p e ri p he r al r es is t an c e . ( C ) t h e y c o ns t ri c t c o r on ar y a r t e ri e s a nd ar t e ri o le s a n d d ec r ea s e o xy g e n de l i v e r y to t h e m yo c a r di um . ( D ) t h e y a r e u s e f ul in t rea t i ng s t ab l e a ng i na pe cto r i s a nd P ri n z m e t al an g in a . ( E ) a d ve rs e e f fe c t s i nc lud e ag g ra va t io n o f c o ng es t i v e h ea r t fa il u r e. V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . T h e t e rm i n a ti o n o f he p a r in a c t i vi t y b y p r o t a m i n e su l f a t e i s t h e r e s ul t o f ( A ) a c h el a ti ng ac t io n . ( B ) t h e in h ib i ti o n o f g as tr o i nt e s t i na l a bs o rp t io n o f h e pa r in . ( C ) t h e d is pl ac em e nt of h e p ar i n -p la sm a p r ot e in bi n d i n g. ( D ) a n a c i d -b as e i n te r ac ti o n . ( E ) t h e p ro t h ro m b i n- l ik e a c ti v i t y o f p r ot am i ne . V i e w A n s we r 2 . T h e a n sw e r i s D [ se e] . 3 . W h ic h o f t h e f o l low i n g c a r d i o vas c u la r ag e n ts is c la s si f i ed c he m ic a ll y a s a g l yc o s i d e ? ( A ) N i f ed ip i ne ( B ) D i go xi n ( C ) F l ec ai ni d e ( D ) C h o le s t y r a m i n e ( E ) W arf a r in V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . D i g i ta l is la n a t a. D i g i ta l is p u r p u r ea , S t r o ph a n th u s g r a t us . 4 . C a r d ia c g l yc o s i de s m a y b e u s e fu l in t r e a t i ng a ll o f t h e f o l low i ng c on d i ti o n s e xc e pt ( A ) a t ri a l f lu t te r . ( B ) p a ro xy s m a l at r ia l t a c h y c a r di a . ( C ) c on g es ti v e he a r t f ai lu r e . ( D ) ve n t r ic ul a r t ac h y c a r di a . ( E ) a t ri a l f ib r il l at i on . V i e w A n s we r 4 . T h e a n sw e r i s D [ se e] . 5 . I n ge s t io n o f w hi c h o f th e f o l l ow i ng vi t a mi n s s h ou l d be a vo i de d b y a p a ti e n t ta k in g an o ra l an t ic o a gu l a nt ? ( A ) V i ta m i n A ( B ) V i ta m i n B ( C ) V i t am in D
( D ) V i t am in E ( E ) V i ta m i n K V i e w A n s we r 5 . T h e a n sw e r i s E [s e e VI I I .4 . e] . 6 . T h e s t r u c tu r e sh ow n is c h a r ac t e r is t i c o f w h ic h o f t he f o ll ow i n g a ge n ts ?
( A ) O s m o t ic d i ur e ti c s ( B ) C a r bo n ic a n h y d ra s e in h ib i to r s ( C ) Th i a z i de s ( D ) L o op di u re t ic s ( E ) P o ta s s i um -s pa r i ng diu r e ti c s V i e w A n s we r 6 . T h e a n sw e r i s C [ se e] . 7 . W h ic h o f t h e f o l low i n g d i u re t ic s i s mo s t s i m il a r in ch e mi c a l s t r u ct u r e to t he ant i h yp e r t e n s i ve a ge n t d ia z ox i d e? ( A ) F u ro s e m i d e ( B ) S p i ro no l ac to n e ( C ) Ma n n i t ol ( D ) A c et a z o la m i d e ( E ) C h lo r o th i a z id e V i e w A n s we r 7 . T h e a n sw e r i s E [s e ea n d] . P . 36 8
D i r e c t i on s fo r q ue s t io ns 8 - 11 : Th e q ue s ti on s an d in c o m p l et e s ta t em e nts in t hi s s ec t io n c a n b e c o r r ec t l y a n s we r e d o r c om pl e te d b y o n e o r m o re of t he s u g g es te d a n s we r s . C h oo s e th e a ns we r , A- E . 8 . I n t h e o r a l t r e a tm e nt o f i r o n -d e f ic i en c y a n e m i a s, i r on i s p r e fe r a b l y a d m in i s te r e d a s I . f e r r ou s i ro n . I I . f e r r ic sa l ts . I I I . e l em e n ta l i ro n . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 8 . T h e a n sw e r i s A [ se e] . 9 . Pa r e n te r a l l y a d m i n i s t e re d a n t i h yp e r t e n s i ve a g en ts u se d in t r ea t i ng h yp e r t e n s i ve e m e rg e nc i es in c l u de t he I . c en t r a ll y a c t i n g an t i ad r e n e r gi c c l o ni d i ne . I I . a r te r i o la r an d ve n ous va s o d il a t o r n i t r op r u ss i d e . I I I . ga n gl i o ni c - bl o ck i n g a g en t t r i me t ha p ha n . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 9 . T h e a n sw e r i s D [ se e] . 1 0. C e r t ain f a c to r s c o n t r ib u t e t o t h e l o n g e r d u r a ti o n o f ac t io n o f d i g it o x in w h en c om p a r ed w i t h t h a t o f di go x i n . T h e se i nc l ud e I . g r ea t e r p r o t e in b in d in g . I I . r ed u ce d po l a r i t y. I I I . g re a te r t u bu l a r re a bs o r p t i on . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 0 . T he a nsw e r i s E [s e e] . 1 1. O r a l an t i c oa g u la n ts h a ve w hic h o f t h e f o l low i n g p r o pe r t i e s ? I . T he y i n t e r f e r e w i t h vi t a m i n K - d ep e n de n t s yn t h e s is o f a c ti ve c lo t t i ng f a c to r s I I , V II , I X, a nd X . I I . Th e y h a ve a d ve r s e ef f e c t s t h at i nc l u de he mo r r h a g e, u r t ic a r ia , pu r pu r a , an d a l o pe c i a I I I . Th e y p r o l o n g t h e c lo t t i n g t i me o f b l oo d bot h i n vi vo a nd in vi t r o . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t
E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 1 . T he a nsw e r i s C [ se e VI I . 4. e . (1 )] .D i r e c t i on s fo r q ue s t io ns 1 2 - 14 : E a c h g r ou p o f a dv e r s e e f f ec ts i n th is s ec ti o n i s m o s t cl os e l y re la t ed t o o n e o f t he fo ll o wi n g d r u g c l as s e s . Th e d ru g c la s s es m a y be us e d m o r e t h an o n c e o r n ot a t al l . C h oo s e t he be s t an s we r , A- E . 1 2 . B r ad yc a r d i a , h yp o t e n s io n , i n c r ea se d ai rw a y r e s i s t a n ce , a n d c o ng e s t i ve h e a r t fa i l u re ( A ) C a r di ac gl y c os id es ( B ) C a lc iu m c ha n ne l b loc k e r s ( C ) A n gi o te ns i n -c on v e r t in g en z ym e ( A C E ) i nh ib i to r s ( D ) β - A d r en e rg ic bl oc k ers ( E ) N i t ri t es an d n i tr a te s V i e w A n s we r 1 2 . T he a nsw e r i s D [ se e] . 1 3. V i su a l d i s t u rb a nc e s ( ye l l ow or g r e e n vi si o n ), c on f u si on , a no r e xi a , vo mi t i ng , a t r i o ve n t r i cu l a r ( AV ) b l o c k , a n d ve n t r i c u l a r t a ch yc a r d i a ( A ) C a r di ac gl y c os id es ( B ) C a lc iu m c ha n ne l b loc k e r s ( C ) A n gi o te ns i n -c on v e r t in g en z ym e ( A C E ) i nh ib i to r s ( D ) β - A d r en e rg ic bl oc k ers ( E ) N i t ri t es an d n i tr a te s V i e w A n s we r 1 3 . T he a nsw e r i s A [ se e] . 1 4. H yp o t e n s io n , a c u te r en a l f a i l u r e, ch o l es t a ti c j a un d i ce , an d a g r a nu l o c yt o s i s ( A ) C a r di ac gl y c os id es ( B ) C a lc iu m c ha n ne l b loc k e r s ( C ) A n gi o te ns i n -c on v e r t in g en z ym e ( A C E ) i nh ib i to r s ( D ) β - A d r en e rg ic bl oc k ers ( E ) N i t ri t es an d n i tr a te s V i e w A n s we r 1 4 . T he a nsw e r i s C [ se e] . D i r e c ti o ns f o r qu e s ti o ns 15 - 1 7 : E a c h s ta t em en t i n t h is g ro u p i s m o s t cl os e l y c ha ra c te r i z e d b y o ne of t he fo l lo wi n g d r u gs . Th e d r ug s m a y b e u s e d m o re t ha n o nc e o r n o t a t a ll . C ho os e th e be s t a n s we r , A- E . 1 5 . It i n te r f e r es w i t h d is t a l tu b u la r al d os t e r o ne - m e di a te d so d iu m - po ta s s iu m e x c ha n ge ; r e n d e r s t h e u r i n e a l ka l i ne ; a n d m a y c a us e h yp e r k a l e m ia , g yn e c o m a s t ia , a n d m e ns t r u a l i r r e g ul a r i ti e s. ( A ) F u ro s e m i d e ( B ) H yd r o c h lo r o th i a z id e ( C ) S p i ro n ol ac t on e ( D ) Ma n n i t ol ( E ) A ce t a z o la m i de V i e w A n s we r 1 5 . T he a nsw e r i s C [ se e] . 1 6. F r ee l y f i l t e re d , th i s d r u g l i mi ts t u b u la r r e ab s o r p ti o n o f w a te r an d is us e f ul i n r e d u c in g c e r e b ra l e d ema a nd i n t r a c ra n i al p r es s u re . ( A ) F u ro s e m i d e ( B ) H yd r o c h lo r o th i a z id e ( C ) S p i ro n ol ac t on e
( D ) Ma n n i t ol ( E ) A ce t a z o la m i de V i e w A n s we r 1 6 . T he a nsw e r i s D [ se e] . 1 7. T he pr i n c i pa l s i t e o f ac t i on of t h i s d ru g is on t he t h ick a sc e nd i n g l im b o f t h e l o o p o f H en l e ; i t is us ef u l i n t r e a t i ng p ul m on a r y e d e m a an d a s c it e s. ( A ) F u ro s e m i d e ( B ) H yd r o c h lo r o th i a z id e ( C ) S p i ro n ol ac t on e ( D ) Ma n n i t ol ( E ) A ce t a z o la m i de V i e w A n s we r 1 7 . T he a nsw e r i s A [ se e] . P . 36 9
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C [ s ee I I I . B. 3 ; I I I . C. 3 ; I I I . D. 3 ] . C a l ci um c h an n el bl oc k e rs a re us ed in t he t re a tm e n t o f an gi n a b ec au s e t he y d i la t e c o r on a r y ar t e ri es an d a r te r i ol es , th us de c re as i ng c o r on a r y v as c u l a r r es is ta n c e an d i n c re as in g c o ro n a r y b l ood f lo w. 2 . T he an sw e r is D [ s ee V I I I . A. 1 ; VI I I .A . 4 ; F ig u re 1 5 - 14 ] . H e p a ri n i s a hi gh l y ac id ic m u c o p ol y s acc h a ri de , wh e r ea s p r o ta m i ne is a hig h l y ba si c p r o t ei n . W hen a dm i ni s t er e d af t e r h ep a ri n , p r ot am i n e c he m i c a ll y c om bi n es wi t h i t ( p r es u m a bl y b y a n ac i d -b a s e in t e ra c t i on ) a n d i nac t i va te s i ts an ti c oa gu l an t e f f ec t. H e n ce it is an ef f ec t i v e an t i do t e f o r h ep a ri n . Ca u ti o n m us t b e e m p lo ye d wh e n u s i n g p r o t am in e b ec au s e a n exc e s s of p ro t am in e c an c a u s e an an t ic oa g ul an t eff e c t i ts el f . 3 . T he an sw e r is B [ s ee I I . A .1 ] . Mo s t g l y c os id es a re na t ur a l p r o du c t s o b ta in e d f r om pl a nt m a t er i al . Al t ho ug h th e r e a r e ve r y fe w m e d ic in al ag e n ts th a t a r e gl y c os i des , th e g r ou p k n o wn as the c a r d ia c g l yc os id es is e xt r e m e l y im p o rt a nt an d i s wi d e l y us e d f o r t r ea t in g c on g es tiv e h e a rt f a i lu r e. D i go xi n i s a c a rdi a c g l yc os i de ob t ai n ed f ro m Di g it a li s l an a ta . O th er c a rd ia c g l yc os id es in c l u de di gi t oxi n , wh i c h is ob t ai ne d f ro m Di g it a li s p u rp u re a , an d ou a ba in , wh i c h is o b t ai ne d f r om St r o p ha n th us g ra t us . 4 . T he an sw e r is D [ s ee I I . C ; Ta bl e 1 5 -4 ] . V e n t ri cu l a r t ac h y c a r di a is p ro d uc ed b y to xi c c a r di a c g l yc os i de do sa g e a nd wo u l d n o t b e a t he r a pe u ti c i nd ic a tio n fo r th e a g en t s. C a rd iac gl yc os id e s i nc re a s e s ys t ol ic c o nt r ac t io n v el oc i t y an d i n c re as e t h e r e f ra c t o r y pe r i od o f t he A V n o de . The y a ls o h a ve a p os it i v e i n ot r o pi c e f f ec t. 5 . T he an sw e r is E [ s e e V I I I . A. 2 .e ; V II I . 4. e ]. Th e o r al a nt ic o ag ul a nt s , s uc h a s wa r f a ri n , ac t b y i n hi b it i ng th e l i v e r b io s yn t h es is o f p r o t hr om b in , wh i c h is t he p r ec ur s or o f t he en z y m e t h ro m b i n t ha t c a ta l y zes t he c o n ve rs io n o f s ol u bl e f i br i n og e n t o t h e i ns ol ub l e p o l y m e r fi b ri n , wh ic h re s u l ts in c l o t f o r m a t io n . O n e o f th e p r in c ip al f ac to r s i n t he bi o s yn t h es is o f p r ot h ro m b i n is v i t am in K , wi t h wh i c h wa r f a r in c om p et es t o i nh ib i t t hi s p r oc es s . B ec a us e t hi s i s a re v e r s ib le c om p et i ti o n, v i t am in K ac t s as an an t ag o ni s t t o th e o ra l a n ti co ag u la n ts . 6 . T he an sw e r is C [ s ee V I . A ; F i gu r e 1 5 -7 ] .
Th e s t ru c tu r e c an be r ec o g ni z e d as a be n zo th i ad ia z i n e , wh i c h i s kn o wn a ls o a s a t h i a zid e . I t re p re s e n ts the s tr u c t u re o f h yd r oc hl o ro t h ia z i de , a su l fo n am id e d i ur e ti c . O t h e r s u lf o na m i de di u r eti c s in c l u de th e c a rb o ni c a n h yd ra s e in h ib i to r s, suc h a s a c et a zo la m i d e, an d t h e lo o p d iu r e ti cs , s uc h a s f ur o s em id e . N e it h e r o f t hes e s u bc la s s es c o nt a in s d r ug s wi t h a be n zo th i ad ia z in e n u c l e us . 7 . T he an sw e r is E [ s e e V I . C ; Fi gu r es 15 - 7 a n d 1 5 - 9 ]. D i a zo xi d e is a b en z o t hi ad i a z in e d e r i v at i v e ; t h er e fo r e , i t wo u ld be m o s t s im i la r to c h lo r o th ia z i d e, wh i c h is a l s o a b en z o t hi a di a z in e . A l t ho u gh bo t h t he t hi a z id e s a nd t h e d i a z o xi d es ha v e an t ih y p e r t en si ve ac ti vi t y , on ly t h e th i a z id es ha v e s i gni f ic a nt d i u re t ic ac ti v i t y . O ne o f th e s t r uc t ur a l r e qu i re m e nt s of th e th ia z i d e d iu r e ti c s is an e l ec t r on - wi t h d ra wi n g gr ou p , s uc h a s a h a lo g en , or t h o t o th e s ul f on am id e gr o u p o n t h e b e n z en e n uc l eu s . Th e d ia z o xi d e m o l ec ul e l ack s s uc h a g r o up . 8 . T he an sw e r is A ( I ) [s e e I X. A . 1 ]. A b s o rp ti o n o f o r al l y ad m in i s t e r ed ir o n is si gn i fi c a n t l y im p ro ve d wi t h f e r ro us i ro n t h an wi t h e i th e r f e r ri c s al ts o r e l em en t al ir o n, p re su m ab l y b ec au s e o f i ts b e t te r s o lu bi l it y c h a ra ct e ri s ti c s . I r o n p rep a r a ti on s ( f e r ro us s a lt s ) a r e m o re r ea d il y a bs o rbe d f ro m t he g a st r o in t es ti n al t ra c t an d a r e s to r e d i n t he bo n e m a r ro w, l i v e r , a n d s p l een as f er r i ti n a n d h em os i de r in . 9 . T he an sw e r is D (I I , II I ) [s e e V . B .4 ; V . C. 2 .a ; V. C . 2 . e] . C l o n id in e i s n o t r ec og n i ze d as a d ru g o f c h oi c e for h y p e r te ns i ve e m e r g en c i e s , p o ss ib l y be c a us e o f it s c e n t r al m ec h an is m o f a ct io n an d t h e l at e nt pe r i od r e q ui r e d f o r it s e f fe c t, c om p a re d wi t h o t he r pe r ip h e ra l a gen t s . 1 0 . Th e a n sw e r i s E ( I , II , I I I) [s e e I I . A; Fi g u re 15 - 1 ] . S t r u ct u r al l y , d ig i to xi n h as on l y on e a lc o ho l g r ou p o n i t s st e r oi da l n uc l eu s , wh e r e a s d i go xi n h a s t wo . Th i s s l ig h t d i ff e r en c e in s t r uc t ure h as a si gn i fi c a n t e f fe c t o n th e p o la r i t y of th e m ol ec u le . O wi n g t o it s g r ea t e r l ip os o lu bi l it y , d ig i to xi n i s m or e li k e l y t o u n d er g o t ub u la r re a bs o rp t i on , t o un de r g o e nt e r oh e p a t ic P.370 c yc li n g, t o p en e t ra t e i nt o t h e l i v e r m i c ro s o m e s a nd u nd e rg o m e ta b ol is m , an d to be p r o t ei n b ou n d, al l o f wh ic h c on t r ib u te t o i ts l o ng er d u ra t io n o f ac ti o n a nd p o t en t ia l c um u la t i v e e f fe c t s . 1 1 . Th e a n sw e r i s C ( I , II ) [ s e e VI I I . A. 2 .e , V II . 4. e. ( 1 ) ] . O r a l an t ic oa g ul a nt s a r e e f f ec t i v e o nl y i n vi vo be ca u s e th e y bl o c k h e pa t ic s yn t he s i s o f vi t am in K -d e pe n de n t c o a g ul at i on fa c to r s ( f ac tor s I I, V I I, I X, a nd X) . Th is al s o e xp l a i n s t he la t en c y pe r io d as s o c i a te d wi t h i ni ti a ti o n o f o r al a nt ic o ag ul a nt t h e r ap y . 1 2 . Th e a n sw e r i s D [ s ee I I I. D . 2 ]. 1 3 . Th e a n sw e r i s A [ s ee I I . D] . 1 4 . Th e a n sw e r i s C [ s ee V . D . 6] . N o n se l ec ti v e β - ad r e ne r gi c b l oc k e rs ( e. g . , p ro p r an o l o l ) p r od u ce ad v e r se ef f e c t s a ss o ci at e d wi t h t he i r m ec h an is m o f a c t i on on th e a u to n om ic n e r v o us s ys te m . Th us b r o nc ho s pa s m , l o we r i ng o f bl o od p re s s u re , a n d re d uc e d h ea r t ra t e r es ul t f r o m b l oc ka d e o f a ut o no m i c β- a d r en e rg ic r ec ep t o rs . Vis u a l di s t u r ba nc es ( y e ll ow o r g r e e n vi s i on ) ar e p e c u li a r t o c ar d i ac gl y c os id e o ve r do s e. A V di s s oc ia t io n a n d ve n t r ic ul a r t a ch yc a rd i a a r e o b v io us ly m o r e s i g ni f ic an t a d ve rs e e f f ec ts . A C E i nh ib i to rs
r e p o rt e dl y m a y c au s e blo o d d y s c r as i as i n a d di t ion t o c ho le s ta t ic j a un di c e a n d ac u te r e n al f ai lu r e . 1 5 . Th e a n sw e r i s C [ s ee V I . E .2 . a; V I .E . 4 .a ] . 1 6 . Th e a n sw e r i s D [ s ee V I . A .3 . a; V I .A . 3 .b ] . 1 7 . Th e a n sw e r i s A [ s ee V I . D .2 . a; V I . D .3 . a] . S p i r on o la c t o ne in t er f e res wi t h al do s te r on e -m e dia t e d s o d iu m -p o ta s s iu m exc h a n g e , r e d uc in g th e a m o u nt of po t as s i um e xc r e t ed an d i s o f t en us ed wi t h o t he r diu r e ti c s t h a t p r om ot e th e e xc r e t io n of po t as s i um , s uc h a s t h e b en z o t hi a di a z i de s . Ma n n i t o l i n c re as es th e o s m ol a r it y o f th e g l om er u la r fi l t ra t e b ec a us e i t i s r e ab so r bed p oo r l y . B y i n c re as i ng th e o s m ola r i t y of t he gl om e ru l ar f ilt r a t e, m a nn i to l l im i ts tu bu l a r r e a bs o rp t io n o f wa t e r , t hu s p r om o ti n g d iu r es is . I n t h is wa y, i t re du c e s c e re b r al e d em a a n d d ec r ea s e s i nt r a c ra ni a l p r es s u r e. Fu r os em i de is a di u r et ic of c h o ic e f o r t r e a ti n g ac u te c o ng es t i ve h ea r t f a il u re be c a u s e it p r om ot e s a s ig ni f ic a nt ra p id e xc r e t i o n o f wa t e r a nd s o d iu m .
17 Drug Metabolism, Prodrugs, and Pharmacogenetics M a r c W . Ha r r o l d
I. INTRODUCTION TO DRUG METABOLISM. D r u g m e ta b ol is m ( a ls o c a l le d bi o t r an s f o rm a t io n) r e f er s t o th e b io ch em ic a l c h an g es t h a t d r ug s a nd o th e r f o rei g n c he m i c a ls ( xe n ob i o ti c s ) u n de r go in th e b o d y, l ea d in g t o t he fo r m a t io n o f d i ff e re n t m e ta bo l it es wi t h di f fe r e n t e ff ec t s. Xe n o bi o ti cs ca n u n d er g o a v a ri e t y of bi o tr a n s f o rm a ti on p at h wa ys , r e s u l ti n g in t he p ro du c tio n of a m i xt u r e of in t e rm ed i at e m e ta b ol i te s a nd e xc r e ted p r od uc ts , i n cl ud i ng unc h an g ed p a r en t dr u g. R a re l y is onl y o n e m e t ab o li t e p r od uc e d f ro m a s in g le d ru g . A. I n a c t i ve me t a bo l i te s. S om e m e ta b ol it e s a re in a c t i ve (i . e. , th e ir p h a rm ac ol o gi c a l l y a c t i v e p a r en t c om po u nd s b ec om e i n ac ti v a t ed o r d e to xi f i e d ). 1 . Th e h y dr o l y s i s o f p r oc a i ne t o p -a m i n ob e n z oi c a c i d a n d d ie t h yle t ha n ola m in e r e s ul ts in a l os s o f a ne s th e t ic a c ti vi t y. 2 . Th e o xi d a ti on o f 6 -m er c a p t op u r i ne t o 6 -m e rc ap t u ri c a c i d re su l ts i n a los s o f a n t ic an c e r ac ti v i t y . B . M e ta b ol i t es t ha t r e tai n s im i la r a ct i vi t y. C e r t a i n m et a bo li t es r et ai n the p h a rm ac ol o gi c a l a c t i v i t y o f t he i r p a re n t co m p o und s to a g re a t er o r l ess e r d e g re e . 1 . I mi p r am i ne is de m e t hy l a t e d t o t h e es se n ti a ll y e q ui a ct i ve a n ti d ep r es s a nt , d e s ip r a m in e . 2 . Ac e t o he x am i de is r ed u c e d t o th e m o re ac ti v e h y p o gl yc em ic , l h yd r o x yh e x a m i d e. 3 . C o de i ne is de m e t h y lat e d to th e m o re ac ti ve ana l ge s i c , m o r ph i ne . C . M e ta b ol i t es w i t h a l ter e d ac t i vi t y. S o m e m e tab o li t es de ve l op ac ti v i t y di f f e re n t f r o m t ha t of th e i r p a re n t d r u gs . 1 . Th e an ti d ep r es s a n t i pr o n i az i d i s d ea lk y l a te d to t he an t i tu be r c u l ar , is on i a zi d . 2 . Th e v i ta m i n re t i n oi c ac i d ( v i ta m i n A ) is i s om eri z e d to t he an t i- ac n e a gen t , i s o r e t in o ic ac i d . D . B i o ac t i va t e d m et a b ol i t e s. S om e p ha r m a c o l og i c a ll y i na c ti v e pa r en t c om p ou n ds a r e c o n v e rt e d t o a c t i v e s p e c i es wi t h in th e b o d y . Th e se pa r en t c om p ou n ds a r e k n o wn a s p ro d r u gs . 1 . Th e pr o d ru g e n al a p r il i s h y d r ol y ze d t o e na l apr i l a t , a po t en t a n ti h yp e rte n si ve . 2 . Th e pr o d ru g s u li n d ac, a s u lf o xi d e , i s r e du c e d t o t he ac ti v e su l fi de . 3 . Th e an ti p a rk in s o n ia n le vo d o p a ( L - d op a ) i s d ec a r bo xy l a t e d in th e n e u ro n to a c ti ve d op a mi n e .
II. BIOTRANSFORMATION PATHWAYS A. P h a s e I r e ac t i o ns are t ho s e in wh i c h p ol a r f un c ti o na l g r ou ps a re in t r od u ce d i n to t h e m ol ec u le o r u nm as k ed b y o xi d a ti o n, r ed uc t io n, o r h yd r o l ys is . 1 . O x i da t i on is th e m os t c om m o n p h as e I b i ot r a ns f o rm at i on . a . Th e m a jo r it y o f o xi d a t io n s oc c ur in t he li ve r ; h o we v e r , e xt r a h e p at ic t is s u e s , s u ch a s th e i n t es t i na l m u co sa , l un g s, a nd ki d ne y, c a n a ls o se r v e as m e ta b ol ic s i t es .
b . Th e v as t m a jo r it y o f oxi d a t i o ns a re c a ta l yz e d by a g r ou p o f m i xe d - f un c tio n o xi d a s es k n o wn as c yt o c h r o me P 4 5 0 ( C Y P 45 0 ). Th e s e o xi d a s es ar e b o un d to t he s m o o th en d op l as ti c r e ti c u l um of t he l i v e r a n d r e qu i r e b o th N A D P H a n d a p o r ph yr i n p r o st h et ic g ro u p. U nl ik e m os t en zy m e s, C YP 4 5 0 u s es a v a r ie t y o f o xi d a t ive b i o tr a ns f or m a t io n s t o m et a b ol i z e a di v e r s e gr o up o f su bs t r at es . P.399
c . C YP 4 5 0 e xi s t s i n m u l ti p l e i s o fo r m s o r fa m i li es . Th e p r es e nc e o f t he s e d i ff e r en t i s of o rm s is r es po n s i bl e fo r t he la r ge su bs t r at e v ar i a ti o n s ee n wi t h C YP 4 5 0 . ( 1 ) C YP 4 5 0 i s o f o rm s a re n am e d us i ng th e ro o t “ C YP ” f o l l o we d b y a n a r ab ic nu m b e r d e si g na ti n g t h e f am il y , a l e tt e r d es i gn a ti n g t he s ub f am i l y, a nd a s ec on d a ra b ic n u m b e r i nd ic a ti n g t he ind i v i du a l g en e (e . g. , C YP 3 A 4 ) . ( 2 ) S i x m am m a li a n f am il ie s a r e i n v o l v ed in s t e ro id a nd bi le ac id m e t ab ol ism : C YP 7 , C YP 1 1 , C YP 1 7 , C YP 1 9 , C YP 2 1 , a n d C YP 2 7 . ( 3 ) F ou r m am m a li a n f am il i es ar e i n v o l v ed in xe n ob i o ti c , o r d r ug , m et a bo l is m : C YP 1 , C YP 2 , C YP 3 , a n d C YP 4 . E xa m p l es o f d ru g s m e t ab o li ze d b y t h es e f am il i es a n d s u bf am i li es a re s h o wn in Ta b l e 1 7 - 1. N ot e th a t a n u m b e r o f d r u gs (e . g. , t ri c y cl ic a n t id ep r es s a n ts , d i a z epa m , o nd a ns e tr o n, t he op hy l l i n e ) a re m e ta b ol i ze d by m u l ti pl e i s of o rm s . d . A dd i ti o na l o xi d a t io n s ( e . g ., e th an o l t o a ce t al de h y d e ) a r e c at a l y ze d b y n o nm ic r os om al o xi d a s e s l oc a te d i n c y t os o l a nd m i t oc h on d ri a o f e xt r a h ep at i c t i ss ue s . e . C YP 4 5 0 a n d n on m i c ros om a l o xi d a se s c at a l yz e a r om a ti c , al i ph a ti c , ol e fin i c , b e n zyl ic , a l l y li c , an d α - hy d r o xy l a t i o n s; N - , O - , a nd S - de a lk y l a ti on s ; o xi d a ti v e d e am i na ti o n; N - an d S- oxi d a t i o ns ; d es u lf u r at i on ; d e h al og e na t io n ; a nd o xi d a t io ns of a l co h ol s a nd al de h y d es (Ta b l e 17 - 2 ). f . Th e i nc r e as e d p o la r i ty o f t h e o xi d i z e d p r od uc ts (m e ta b ol i te s ) e nh a nc es t he i r wa t e r s ol u bi li t y a nd re d uc es t he i r t ub u la r r ea bs o rp t i on to s o m e e xt e n t , t hus f a v o ri ng t h e ir e xc r e t io n i n t h e u rin e . Th es e m et a bo li t es a re s o m e wh a t m o re p ol a r t h a n t he i r p a r en t c om p ou n ds a n d v e r y c om m o nl y u nd e r go fu r t h er bi o t ra ns f o rm at i on b y p h as e I I p a t h wa y s (s e e I I B) . 2 . R e du c t io n i s l es s c om m o n l y e nc o un t e re d t h an o xi d a t io n ; h o we v e r , the o ve r al l g o al is th e s am e : t o c re at e po l a r f un c t i on a l g ro u ps t ha t c an be el im i na t ed i n th e u r i ne . Th e re is e v id en c e s u gg es t in g t h at t he C YP 4 5 0 s y s te m m i g ht be in v o l v e d i n s om e re d uc ti o ns . Ad di t ion a ll y , b ac te r i a r es id e nt in t he G I t ra c t a re k n o wn t o be i n vo l ve d in a z o a n d n it r o r e d uc ti o ns . R e ac t io ns c a t a l y ze d b y r ed uc t as es ar e s h o wn i n Ta b le 17 - 3. 3 . E nz ym a t i c h yd r o l ys i s , t he ad di t io n o f wa t e r a c r os s a b on d , a ls o re s ul t s i n m or e p o la r m e t ab ol i te s ( s e e Ta b le 17 - 3 ) . a . E s te r a se en z ym e s , us u al l y p re s e n t i n p la sm a a n d va ri ou s t is s u es , a re n o ns p ec if ic an d c a ta l y z e d e - es te r i fi c a t io n , h yd r oly zi n g r e la t i vel y n on po l a r e s te r s i n t o t wo p ol a r , m o r e wa te r - s o l ub l e c o m p o un ds : an a l c oh ol a nd an ac id . Es t e ra se s a r e re sp o ns ib l e f o r c o n ve r t in g m a n y p r o dr u gs i n to t he i r a c t i ve fo r m s .
b . Am i d a se en z ym e s h y d r o l y z e am id es in t o am i ne s a n d a c i ds (d e am id a tio n ) . D e a m i d at i on oc c u rs p ri m a r i l y i n th e l i v e r. c . E st e r d ru g s s us c e p tib l e t o p l as m a e s te r as es ( e . g ., p ro c a i ne ) ar e u s u al l y s h o r te r a c ti n g t ha n s t r uc tu r al l y s i m il a r a mi d e d r u gs ( e .g ., p r oc ai n am id e ), wh i c h ar e n ot s i gn i fi ca n tl y h y d r ol y z e d u n t il th e y r ea ch th e l i v e r. d . L ac t o ne s a n d l ac t ams a r e c yc l ic es te r s a nd am i de s , r es pe c ti v e l y , a n d a r e th us a l so s us c ep t ib le to h y d rol y t i c m et a bo li s m . B . P h a se II r e ac t i on s a re t ho s e in wh i c h t he fu nc t i o na l g r ou ps o f t he o ri gin a l d r ug ( o r m e t ab ol i te f or m e d i n a p ha s e I r e ac t io n ) a r e m as k ed b y a co n j ug a t ion r e ac t i o n. Mo s t p h as e I I c o nj ug a tes a re v e r y po l a r, r es ul t ing i n r a pi d d r ug el im in a ti on f r om th e b o d y. 1 . C o nj u g at i o n r e ac t i o ns c o m b i ne th e pa r e n t d ru g ( o r i ts m e ta b ol i te s ) wi t h c e rt a in n a t u r al e nd o ge n o us con s t i t ue n t s, s u c h as g l uc u r o ni c a c i d , g l yc i ne , g l uta m in e , s u lf a te , gl u ta t hi on e , t h e t wo - c a r b on ac et y l f ra gm e n t , o r th e o ne - c a r b on m e t h yl f r a gm e nt . Th es e re ac t ion s g e ne r al l y r eq u ir e b o th a h ig h - en e r g y m o l e c u le a nd an e n z ym e . a . Th e hi g h -e n e r g y m o l e c u le c o ns is ts o f a c o enz ym e b o u nd to th e en dog e n ou s s u bs t ra t e , t he pa r en t d rug , o r t he d ru g ' s p ha s e I m e ta b ol i te . b . Th e en z ym e s ( c a ll ed t r a n s f e ra s es ) th a t ca t aly z e c o nj u ga t io n re ac t io ns a re fo u nd m a in l y in th e l i v e r a nd , to a l es s e r e xt e n t , i n t he i n t es ti n es a n d o th e r ti ss u e s. c . Mo s t c o nj ug a te s a r e hi g h l y p o l a r a n d u n a bl e t o c r os s ce l l m em b r an es , m a k i ng t h em al m o s t a l wa y s ph ar m a c ol o g ic a ll y i n a c t i ve a n d o f l it t le o r n o t o xi c i ty . E xc e p t i o ns to th is a re ac e t y l a te d a n d m e t h y la t e d c o nj u ga t es . Th e s e c o n jug a t es d o n o t p os s es s in c re as e d po l a ri t y ; ho we ve r , t he y a re us u al l y ph a rm ac ol o gi c a l l y i n ac t i ve. 2 . Th e r e a r e s ix co n j uga t i o n p a thw a ys ( Ta b l e 17 - 4 ) . a . G l u cu r o n id a t io n i s t he m os t co m mo n c o nj uga t i on pa t h wa y b ec au s e of a re a di l y a va i la b le s u pp l y o f g lu c ur o n ic ac id as we l l as a l a r g e va ri e t y of f un c t i on al g r o up s , wh i c h ca n e n z y m at ic a ll y r e a c t wi t h th is s u ga r de r iv a t i v e . P.400
Table 17-1. Examples of Drugs Metabolized by Specific Cytochrome P450 (CYP) Isoforms
CYP1A2 Acetaminophen Amitriptyline and other TCAs Diazepam Methadone Olanzapine Propranolol Riluzole Tacrine Theophylline CYP2B1 Chlorpheniramine CYP2B6 Bupropion Cyclophosphamide and ifosfamide CYP2C8 Diazepam
Diclofenac Mephobarbital Omeprazole Paclitaxel Retinoids Tolbutamide CYP2C9 Amitriptyline and other TCAs Chlorpheniramine Carvedilol Dapsone Diazepam Glimepiride Hexobarbital Losartan NSAIDs Phenytoin
Tolbutamide Torsemide Verapamil Warfarin Zafirlukast CYP2D6 Amitriptyline and other TCAs β-blockers Benztropine Captopril Chlorpheniramine Chlorpromazine Clemastine Clozapine Codeine Delavirdine Dextromethorphan
Diphenhydramine Dolasetron and Ondansetron Donepezil Encainide Fenfluramine Fentanyl Flecainide Fluphenazine Hydrocodone Hydroxyzine Imipramine Lidocaine Loratadine Meperidine Methadone Methamphetamine Mexiletine
Morphine Ondansetron Oxycodone Risperidone Selegiline SSRIs Tamoxifen Thioridazine Tolterodine Tramadol Trazodone CYP2E1 Acetaminophen Ethanol Felbamate General anesthetics Isoniazid
Ondansetron Tamoxifen Theophylline CYP3A4 Acetaminophen Alfentanil Benzodiazepines Amitriptyline and other TCAs Amiodarone Anastrazole Azole antifungals Buspirone Busulfan Carbamazepine Chlorpromazine Cimetidine Clozapine
Codeine Cyclophosphamide and ifosfamide Cyclosporin Dapsone Darifenacin Delavirdine Dexamethasone Dextromethorphan Dihydroergotamine Dihydropyridines (i.e., nifedipine) Diltiazem Disopyramide Docetaxel and paclitaxel Dolasetron and ondansetron Donepezil Doxorubicin Efavirenz
Enalapril Ergot alkaloids Erlotinib Estrogens Ethosuximide Etoposide Erythromycin and clarithromycin Felbamate Fentanyl Fexofenadine Finasteride Flutamide Glyburide Granisetron Haloperidol HIV protease inhibitors HMG-CoA reductase inhibitors
Hydrocodone Hydrocortisone Irinotecan Lansoprazole Lidocaine Loperamide Loratadine Losartan Midazolam Mifepristone Navelbine Nefazodone Nevirapine Norethisterone Omeprazole Ondansetron Oral contraceptives
Oxybutynin Pimozide Prednisone and prednisolone Quinidine Repaglinide Rifampin and analogs Risperidone Salmeterol Sildenafil SSRIs Sulfamethoxazole Tacrolimus Tadalafil Tamoxifen Teniposide Testosterone Theophylline
Tolterodine Tretinoin Valproic acid Vardenafil Verapamil Vinca alkaloids Warfarin HMG CoA, β-hydroxy-β-methylglutaryl-coenzyme A; NSAIDs, nonsteroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants. P.401
Table 17-2. Phase I Metabolism: Oxidative Pathways Type of Reaction (Examples) 1 .
Aromatic Hydroxylati on (phenytoin, phenylbutaz one)
2 .
Aliphatic Hydroxylati on (pentobarbit al, meprobamat
Reaction Pathway
e) 3 .
Olefinic Hydroxylati on (carbamazep ine, cyproheptadi ne)
4 .
Benzylic Hydroxylati on (tolbutamide , imipramine)
5 .
Allylic Hydroxylati on (pentazocine , hexobarbital )
6 .
Hydroxylati on-α to a Carbonyl (diazepam, ketamine)
7 .
Oxidative Deamination (amphetami ne, dopamine)
8 .
NDealkylation (morphine, ephedrine)
9 .
N-Oxidation (acetaminop hen, guanethidine )
1 0 .
ODealkylation (codeine, papaverine)
1 1 .
SDealkylation (6methylmerca ptopurine)
1 2 .
S-Oxidation (chlorproma zine, mesoridazin e)
1 3 .
Desulfuratio n (thiopental)
1 4 .
Dehalogenat ion (halothane, chloramphen icol)
1 5 .
Oxidation of Alcohols (ethanol, estradiol)
1 6 .
Oxidation of Aldehydes (acetaldehyd e, PGE2)
P.402
Table 17-3. Phase I Metabolism: Reductive and Hydrolytic Pathways Type of Reaction (Examples) Reduction 1 .
Carbonyl Reduction (acetohex amide)
2 .
Azoreduct ion (sulfasalaz ine, olsalazine )
3 .
Nitroredu ction (chloramp henicol, clonazepa m)
Reaction Pathway
Hydrolysis 4 .
Ester Hydrolysi s (procaine, meperidin e)
5 .
Amide Hydrolysi s (lidocaine, indometha cin)
( 1 ) Th e hi gh - e ne r g y fo r m o f gl uc u ro n ic a c i d , u r i d in e d ip h os p h at e gl u cu r o n i c a c id , r e a ct s wi t h a v a ri e t y o f fu n c t i on al g ro u ps u n de r th e in f lu en c e o f g lu cu r ony l t r a ns f e ra s e . ( 2 ) D r ug s t h at po s s es s hyd r o x yl o r c a r b o x yl f u n c t io n al g ro up s r e ad i l y u nd e r go g l uc u ro n id a ti on t o f o rm et h e rs an d e s te rs , r es pe c ti ve l y. I n a dd i ti on , N - , S - , a n d C g l uc u ro n id es a re al s o pos s i b le . ( 3 ) A s sh o wn i n Ta b l e 1 7- 4 , th e a d di t io n o f g l uc u ro n ic ac id to a d r ug m o lec u le ad ds t h r e e h y d r o xy l g r ou p s a nd o ne c a r bo xyl g r o u p . Th i s a d di t io n g r ea t l y i n c r e as es t he h yd r o p h i l i c i t y o f t h e d ru g m o le cu l e. As a r es u lt , i t i s u nl ik e l y to pe n et r a te c e l l m em b r an es an d e li c i t pha r m ac ol og ic a l ac t i v i t y . I t i s a ls o p oo r l y r ea bs o rb ed b y t he r e n al t ub ul es an d , t h us , is r ea d il y e xc r e t ed . ( 4 ) G l uc u ro ni d es wi t h h ig h m ol e cu l a r w ei g h t ( m o r e th a n 5 00 ) a r e o f t en e xc r e t e d i n t o t he bi l e a nd , e v e n tua l l y , i n to th e i n te s ti ne s . Th e i n te s ti na l e n z ym e β g l uc u ro n id as e c an t he n h y d r o l y z e th e c on j ug a te , r e l e a si ng t he un al t e re d d r u g ( o r i ts p r i m a r y m e t ab ol i te ) fo r re a bs o rp t io n b y t h e i nt es ti n e . b . S u l fa t e c o nj u ga t i o n is m u c h le ss c om m o n t h an g lu cu r on i de c o nj u ga t ion b ec au se t h e r e is no a v ai l ab le po ol o f e nd o ge n ou s s u l fa t e . A d d i ti on a ll y , t he r e a r e f ewe r f u nc t io n al g ro up s c ap a ble o f f o rm in g s ul f a te c o nju g a te s . Th e hi gh - e ne r g y f o rm o f s u lf a te , 3′ - p h os p ho a de no s i ne - 5 ′ - ph o sp h os u l fa te ( P AP S ) , r e ac ts wi t h phe n ol s , a l co h ol s , a r y la m i ne s , a nd N - h y d r o xy l c om po u nd s u n de r th e i n fl u en ce of s u l f o t ra n s fe r a se to f orm hi g hl y p ol a r m et a bo li te s . c . Am i n o a c id co n j ug a t io n in v o l ve s t he r ea c t i on o f ei t he r gl yc in e o r gl u tam i ne wi t h a l ip h at ic o r a r om at ic ac id s to fo r m am i de s . A dr ug m o l ec ul e i s f i rs t c on ver t e d t o a n a c yl c oe n z y m e A i nt e rm ed i a te . An N - ac yl t ra ns f e ras e e n z ym e t h en ca t al y ze s t he c o nj u ga ti o n o f t h e ac t i v at e d d r u g m o l ec ul e wi t h th e am in o a ci d . d . G l u t at h i on e c o n ju g a ti o n is e xt r e m e l y i m p o r tan t in p re v e n ti n g t o xi c it y fr o m a va r i e t y of ha r m fu l e le c tro p hi l ic a g en t s . G lu t a th ion e , a t ri p ep t id e c on t ai n ing a
n u cl e op hi l ic s ul f h y d r y l g ro u p , is p re s e n t i n a lm os t a l l m a m m al i an ti s s ue s . U n d e r t h e i n f lu en ce o f g l u ta t h io n e S - t r a n sf e r as e , g lu t a th ion e c a n r e ac t wi t h h al id es , e p o xi d e s , an d o t he r el ec t r o p hi li c c om po un ds t o fo r m h a rm le s s in ac t i ve p ro d uc ts . W hen g lu t at h io ne ha s rea c te d wi t h a n e le c t ro ph i le , it un d e rg o es a se r ie s o f r e a ct i on s t o p r od uc e a m e r c ap t ur ic ac i d d er i v a ti v e , wh i ch is el im in a te d . P.403
Table 17-4. Phase II Metabolism: Conjugation Pathways Type of Conjugate 1 .
Glucur onide (X = OH, NR2, CO2H, SH, acidic carbon atoms)
2 .
Sulfate (X = OH, arylami nes, NH— OH)
3 .
Amino Acid (Occur s only with acid functio nal groups)
Reaction Pathway R = Drug Molecule; X = Functional Group
4 .
Glutath ione (X = electro philic center such as halide, epoxid e, or Michae l accepto r)
5 .
Methyl (X = OH, NH2, SH)
6 .
Acetyla tion (X = NH2, NHNH 2, SO2NH 2, CO— NH2)
e . M e t h yl a t i o n o f o xy g e n - , ni t r og en - , a n d s ul f ur -c o nt a in in g fu nc t io n al gr ou p s r es u lt s i n m e ta b ol i te s t ha t ar e us u al l y le s s p o la r th a n t he u na l te r ed d ru gs . Me t h yl a t io n c an i n ac t i vat e c e rt a in c o m p ou n ds [e . g ., c a t ec ho l O -m e t h y l tr a ns fe r as e ( C O MT ) m e th y l a te s a nu m b e r o f c a te c h o la m i n e n eu r o tr a ns m i t t er s ], bu t o v er a ll it pl a y s a m i no r ro l e i n t he el im i na ti o n o f d r u gs . I ts m a jo r r ol e is i n t h e b io s y n th es is o f e n d og en o us c om p ou nd s ( e . g ., ep i ne p hr i ne ) . Th e h i gh - e ne r g y fo r m r e qu i red f o r m e th y l t r an s fe r as e e n z y m e s i s S- a de n os ylm e th i oni n e ( S A M) . f . Ac e t yl a t i o n c an oc c u r wi t h p r im a r y a m i n es , h y d r a z i de s , su l fo n am id es , a n d , o cc a si on a ll y , am id es . It le a ds to t he fo r m a t io n o f N - a c et yl a te d p r o du c t s . Th e s e
p r o du c ts a r e u s u a ll y l es s p o la r th a n t he un a lt e re d d r u g a nd c a n r e ta i n p h a rm ac ol o gi c a l a c t i v i t y . ( 1 ) N - ac e t y la t ed m e ta b oli t es c a n a cc um ul a te in tis s u e o r in th e k i dn e y s, as in t he c as e o f c e r ta i n a nt i ba c t er i a l s u l fo n am id es . C r y st al l u ri a a n d su bs e qu e nt ti s s u e d a m a g e m a y r es u lt . ( 2 ) Th e hi gh - e ne r g y m o le c ul e f o r a ce t y l a ti on is ac e t y l - Co A . Th e re ac t io n is c a ta l yze d b y N -a c e t y l t ran s fe r as e . P.404
III. FACTORS INFLUENCING DRUG METABOLISM A. C h e m i c al s t r uc t u r e s p e c i f ic al l y in f lu en c e s a dr u g ' s m et a bo li c p a th wa y . Th e p r e se nc e o r ab s e nc e o f c e r ta i n f un c t i on a l g ro u ps wi l l d et e rm in e th e n ec es s i t y, r o u t e, an d e xt e n t o f m e ta b ol is m . B . S p e ci e s d i f fe r e nc e s 1 . Q u a li t a ti ve d i f fe r e nce s in th e a c tu al m e t ab ol ic pa t h wa y . S uc h a v a r ia ti o n c an r e s ul t f r om a g en e ti c d e fi c ie nc y o f a pa r ti c ul a r e nzy m e o r a d if f e re nc e i n a p a r ti c u l ar e n d og en o us s u bs t ra t e. In g en e ra l , q ua l it a ti v e di ff e r e nc es o c c u r p r im a ri l y wi t h p h a se I I r e ac t i on s . 2 . Q u a nt i t a ti ve d i f fe r e nc e s a r e d i ff e re nc e s i n t he e xt e n t to wh i c h t he s am e t y pe of m e ta b ol ic r ea c t i on oc c u rs . S uc h a v a ri a ti on c a n re s ul t fr om a d i ff e re n c e in t he e n zym e l e v e l, t he p re s en c e o f s pe ci es s p ec i fi c is o z y m es , a di f f er e nc e i n t h e a m o un t o f en d og e no us in hi b it o r o r in d uc e r, o r a di f fe r en ce i n t he e xt e n t o f c om p eti n g r e a ct i on s . In g en e ra l , q ua n t it a ti v e di f fe r e nc es oc c u r p r im a ri l y wi t h ph a se I r e a c t io n s . C . P h ys i o l o g i ca l o r d ise a s e s ta t e 1 . B ec au s e t he li v e r i s t he m a j o r o rg a n i n vol v e d in b io t r an s f o rm a ti on , pa th o l o gi c al f a c t o r s t ha t a l t e r l i ve r fu n c t io n c a n a f fe c t a d r ug ' s he p at ic c l ea r a nc e. 2 . C o ng e s ti ve h ea r t f ai lu r e de c re as e s h ep a ti c b lo o d f l o w b y r ed uc i ng c a rd i ac o u t pu t , wh ic h a l te r s t he e xt e n t o f d r u g m e t ab o li sm . 3 . A n a l te r a t i on in a lb um i n p ro d u ct i o n ( t he pl as m a ' s m aj o r d r u g- b in di ng p r ot e in ) c a n a lt e r t h e f r ac t io n o f b o u nd to un b ou nd d ru g . Th u s , a d ec r ea s e in pl asm a a l bu m i n c a n in c re as e the f r ac ti o n o f u nb o un d (f re e ) dr u g, wh i c h t he n b ec o m es a va i la b le to e xe r t a m o re i n te ns e p h a rm ac ol o gi ca l e f f ec t. Th e re v e r se is t ru e wh e n p l as m a al b um in i n c r e as es . D . G e n e t ic va r i a ti o ns 1 . Th e ac e t yl a t i o n r a t e d e p en ds on th e a m o u nt o f N - ac e t ylt r an s fe r as e p re s en t , wh i c h is d e t er m i n ed b y ge n e ti c f ac t or s . Th e ge n er a l p o pu l at i on c a n b e d i vi d ed in t o f a s t a c e t yl a t o r s a n d s l ow ac e t yl a t o r s . F o r e xa m p l e , f as t a c e t yl a to rs a re m o r e p r o ne t o h ep a t o to x ic i t y f r o m t he an t i tu be r c u l a r ag e n t is o ni a zi d t ha n s lo w a c et yl a to r s , wh e r e as s l ow a c e t y l a to r s a r e m o r e pr o n e t o i so n ia z i d 's o th e r t o xi c e f f ec ts (s e e V I I . B. 4 .d ) . 2 . Th e di s c o v e r y o f i s o f or m s a nd f am i l ie s o f C YP 4 5 0 e n zy m es ha s s h o wn t h a t g e n et ic v a r ia t io ns e xi s t in is o fo r m s th a t o xi d i z e de b r i s oq u i ne . I n di vi d ua ls wh o a r e
p o o r m et a bo li z e r s o f t h is c om po u nd ( PM p he n o t yp e ) al so e xh i b it im pa i re d m e ta b ol is m o f m or e th a n 2 0 o t he r th e r ap e ut ic age n ts , in cl ud i ng β - bl oc k e rs , a n t ia r r h y th m i c s , o p io id s , a n d a nt i de p re s s a nt s . A pp r o xi m a t el y 5 %- 1 0% of wh i t e s , 2 % o f A si an s , a nd 1% of A r ab s e xp r e s s t h e P M p h e no t y p e a n d a r e a t r is k f o r a d v e r se d r u g r e ac ti o ns . E . D r u g do s ag e 1 . A n i n c re a se in dr u g do s ag e re su l ts i n i nc r e ase d d ru g c on c e n t ra t io ns an d c a n s a tu r a te c e r ta i n m e t ab o lic en z y m e s . A s d r ug c o nc e n t r at i on e xc e ed s 5 0% s a t u r at i on f o r a p a rt ic u la r e n z y m e , d r u g e li m i n at i on v i a t hi s p a t h n o l on g er f ol lo ws s o l el y f i rs t o r d e r ki n et ic s , b ut r at h e r i s a m i x o f ze r o - a nd fi rs t - o rd e r k in e ti cs . A t 10 0% s a tu r a ti o n, m e ta b ol is m v i a th is en zy m e fo l lo ws ze r o - o rd e r k i n e ti cs . 2 . W he n th e m e ta b o li c p a t hw a y i s s a t u r a t ed ( ei t h er b ec au s e of an e xc ee d in g l y h i gh d ru g l e v e l o r b ec a us e th e s up pl y o f a n e n dog e n ou s c o n ju ga t e d a ge nt i s e xh a u s t ed ) , a n a l te r n at i ve p at h wa y m a y be pu r sue d . Fo r e xa m p l e, a t n o rm a l d os es , 9 8 % o f a do s e o f ac e ta m i n op h en un d e rg oe s c on ju g a ti o n wi t h ei t he r gl uc ur o n ic ac id o r su l fa t e; ho we v e r , a t to xi c d os e s , c o nj u ga t io n p a t h wa y s be co m e s a tu r at e d a n d a c et am i no p he n u nd e r goe s e xt e n s i v e N -h y d r o xy l a t i on , wh ic h c a n le a d t o h e p at o to xi c i t y . F . N u t r i ti o n al s ta t us 1 . Th e l e v e ls of s o m e con j u g at i n g a ge n t s ( o r e nd o g en ou s s ub s t r a te s ), su c h as s u lf a te , gl u ta t hi on e , a nd ( r a r e l y ) g lu cu r o ni c ac i d, a r e s e ns it i v e t o bo d y nu tr i e nt l e ve ls . Fo r e xa m p l e, a l ow - p r o te i n d i e t c a n l e ad t o a d e fi c i en c y of c e r ta i n a m i n o a c id s, su c h as g l y c i n e . Lo w- p r o t e in di e ts al so dec r e as e o xi d a t i v e d r ug m e t a bo li s m c a pa ci t y . P.405
2 . D ie t s d e fi c ie n t in es se n t i al f a tt y a c i d s ( pa r t icu l a rl y l in o le ic ac id ) re d uc e th e m e ta b ol is m o f e t h y l- m orp h in e a n d h e xo b a r bi t al by d e c re as i ng s y n t h es is of c er t ai n d r u g -m et a bo l i z in g e n z y m e s . 3 . A de f ic i e nc y o f c e r t ai n d ie t a r y m i n e r a l s al so a f f ec ts dr u g m e t ab o li s m . C a lc iu m , m a gn es i um , a nd z i nc de fi c ie nc ie s d ec r ea s e d ru g -m e ta b ol i z in g c a pa c i t y , wh e r ea s i r o n d e fi c i en c y ap pe a rs to i nc r ea se it . A c op pe r de f ic i en c y l e ad s t o v a ri ab le e f fe ct s . 4 . D e f ic i en c ie s o f vi t a mi n s (p a r ti cu l ar l y vi t am in s A , C , E , a nd th e B g r oup ) a ff ec t d r u g -m et a bo l i z in g c ap ac i t y . F o r e xa m p le , a v i ta m i n C d e fi c i e nc y c a n re su lt i n a d e c re as e i n o xi d a t i v e p at h wa y s , wh e r e as a v it am i n E d e fi c i e nc y c a n r e ta rd d e al k y l at io n an d h y d r o xy l a t io n . G . Ag e 1 . Me t a b ol i z i ng en z y m e s y s t em s a re no t fu ll y d e ve l op e d a t b i r th ; t h us , i n fa n t s a n d yo u n g c h i l d r en ne e d t o r e c ei v e s m a l le r d o s e s o f d r u gs t h an ad u lt s t o a voi d to xi c s i de ef f ec ts . Th is is p a r tic u la r l y t ru e o f d r u gs t h at r e q ui r e g lu c u r on i de c o nju g a ti on . 2 . I n o l de r ch i l d re n , s om e d r u gs m a y be le ss a c t i v e t ha n i n a du l ts , p a r ti c u l a rl y i f t h e d os a ge is b a s e d o n we i g h t . Th e l i v e r d e vel op s fa s t e r t h an th e i nc r e as e i n g e n er a l b od y we i g h t a nd, t h us , r e p re se n ts a g re at e r f ra c t i on of t ot a l b od y we i g h t .
3 . I n t he el d e r l y, m e t a bol i z i ng en zy m e s y s t em s de c li ne . Th e l o we r e d l e v el o f e n zym e ac ti v i t y s l o ws the r a te of d ru g e l im in a ti on , c a us in g h i gh e r p la sm a d r ug l e ve ls pe r do s e th a n i n y o u n g a du l ts . H . G e n d e r. Me t a b ol ic di ff e r e nc es b e t we e n t h e s exe s h a v e b ee n o bs e r ved f o r a n u m b e r o f c om po u nd s , s u g g es ti n g t ha t a n d ro g en , e s tr o ge n , a nd / o r a d re noc o r ti co i d a c ti vi t y m i g ht af f ec t th e a c ti v i t y o f c er t ai n C YP 4 50 e n z ym e is o z y m es . 1 . Me t a b ol is m o f d i a z epa m , p r ed n is ol on e , c af f ein e , a n d ac e ta m i n op h en is s li g h tl y f a s t e r i n w om e n . 2 . O xi d a t i v e m e ta bo l is m o f p ro p ra n ol o l, c h lo r di a ze p o xi d e , l id o c a in e , a nd s om e s t e ro i ds o c c u rs fa s t e r i n m e n t h an i n wo m en . I . C i r ca d i an r h yt h m s . T h e no c t u r na l p l as m a l eve l s o f d r ug s , s u ch as the o p h y ll in e a n d d ia z e p am , a r e l o we r t h an t he di u r n al p la s ma l e ve ls . J . D r u g a d mi n is t r a t io n r o u t e 1 . O r a l a d mi n i st r a t i on . Th e d r u g is ab s o r b ed f rom t he G I t r ac t an d t r an s p o r t ed to t h e l i ve r t h r ou gh t he he pa t ic po r t al v e in be f o re en t e ri n g t h e s y s t em ic c i rc u l a ti on . Th u s , th e d r ug is s u bj ec t t o he pa t ic m e ta b ol is m be f o r e i t r e ac he s i ts s i te o f ac t io n . Th i s is an ef f ec t k no wn as t he f i rs t - pa s s e f f ec t , o r p r e s ys t e m i c e li m in a ti o n ( Ta bl e 1 7 - 5 ). a . Th e fi r s t - pa s s ef f ec t c a n c a us e s i gn i f ic a n t c l in i c a l p r o bl e ms . Be c a us e d r ug s a r e m e ta b ol i z ed in t he liv e r f r om t he i r ac t i v e f o rm s t o i n ac ti v e f or m s , t h is e ff ec t m us t be c o un t e ra c t e d t o a c hi e v e t h e d es i re d p la s m a o r ti ss u e d ru g l e v e l. b . A c om m o n a p p ro ac h is t o i nc r e as e th e o ra l do s e , o f fs et t in g th e l os s of d r ug a c ti vi t y f r om th e f i rs t -p as s e f fe c t.
Table 17-5. Examples of Drugs That Undergo First-Pass Metabolism Acetaminophen
Fluorouracil
Oxprenolol
Albuterol
Imipramine
Pentazocine
Alprenolol
Isoproterenol
Progesterone
Aspirin
Lidocaine
Propoxyphene
Cortisone
Meperidine
Propranolol
Cyclosporin
Methyltestosterone
Salbutamol
Desipramine
Metoprolol
Terbutaline
Dihydropyridines
Nortriptyline
Testosterone
Estradiol
Organic Nitrates
Verapamil
P.406
Table 17-6. Examples of Common CYP3A4 Inhibitors and Inducers Potent Inhibitors
Moderate InhibitorsInducers
Amiodarone
Amprenavir
Carbamazepine
Atazanavir
Ciprofloxacin
Efavirenz
Clarithromycin
Diltiazem
Nevirapine
Indinavir
Erythromycin
Phenytoin
Itraconazole
Fluconazole
Phenobarbital
Ketoconazole
Fluvoxamine
Rifabutin
Nefazodone
Grapefruit juice
Rifapentine
Nelfinavir
Norfloxacin
Rifampin
Ritonavir
Verapamil
St. John's Wort
Telithromycin Troleandomycin Voriconazole
2 . I n t ra ve n o us ad m i ni s tr a t i o n b y p as s e s t h e f i rs t- p a ss e f f ec t b ec au s e t he d r u g is d e li v e r e d d ir e c t l y to t he b l oo d s t r ea m wi t ho u t b ein g m e ta b ol i z e d i n t he li v e r . Th us , i n t ra ve n ou s d os es of d rug s u n de r go i ng c o ns id e r ab l e f i rs t - pa s s e f f ec ts ar e m uc h s m a l le r th a n o ra l d os e s . 3 . S u bl i n gu a l a dm i n is t ra t i o n a nd r e ct a l a d mi n is t r a t i on al so b y pa s s fi r st - p as s e f f ec ts , al th o ug h re c t a l ad m in is t r at io n c a n p ro d uc e va r i ab le e ff ec t s. K . C o n c u r re n t d r u g th er a p y. Th e c o - a dm in is t ra ti o n o f d r u gs t h at a re ca pa b le o f e i t he r i n hi b it in g or in d uc in g s p ec if ic C YP 4 5 0 i s o z y m e s c an in c re as e o r dec r e as e, r e s pe c t i v e l y , t h e p la s m a l e v e ls of o th e r d r ug s t hat r e qu i re t he se is o z y m e s f o r n o r m a l d r ug m e ta b ol is m . 1 . A s in d ic at e d o n Ta bl e 1 7 - 1 , m o s t d ru gs a re m et a b ol i z ed b y th e fo ll o wi ng t h re e i s o zym es : C YP 2 C 9 , C YP 2 D 6 , a n d C YP 3 A 4. Th e po t e nt i al fo r d ru g i n te r ac tio n s d ue t o en zym e in hi b it i on o r in d uc t io n i s t he r e fo r e g r ea t e r wi t h t he s e c o m p o und s . 2 . D r ug s t h at al t e r t he ac t i v i t y o f C YP 4 5 0 is o z y m e s a r e u s u a ll y su bs t r a tes o f t he se s am e i s o z y m e s . Th i s c an b e o bs e r v ed b y c om p ar i n g Ta b l es 17 - 1 a nd 17 -6 . 3 . Th e c li n ic al ou t c o m e o f t he s e t y pe s o f d r u g int e r ac t io ns de p en ds up o n t h r ee f a c to r s: a . Th e po t en c y o f th e i nh i bi t o r o r i n du c e r ( Ta bl e 1 7 - 6 ) b . Th e a v ai la b il i t y o f al t er n a t e e lim i na t io n p a th wa y s c . Th e e xt e n t t o wh i c h t he h ig he r o r l o we r pl as m a c on c e n t ra t io ns o f t he d ru g c a us es s ym p to m s a n d/ o r u n de s ir a b le e ff ec ts .
IV. EXTRAHEPATIC METABOLISM A. D e f i n i t i o n. E xt r a h e pat i c m et a bo li s m re f e rs to d r u g b io t r an s f o rm a ti o n th a t ta ke s p l ac e i n ti s su e s o t he r th a n th e li ve r . Th e m os t c om m o n s i te s i nc lu d e t he p o r ta l s o f e n t r y ( e . g . , G I m u c o s a , na s a l p as s ag es , l u ng s ) a n d t he p o r ta l s o f e x cr e t i o n ( e . g ., ki dn e y s ) . H o we v e r , m et a bo li s m c a n oc c u r th r o ug h ou t th e b od y . B . M e ta b ol i sm s it e s 1 . P la s ma c o n ta in s e s ter a s e s, wh i ch a re r es po ns i bl e p r im a ri l y fo r h y d ro lys i s o f e s te r s . S i mp l e e s te r s (e. g . , p r oc ai n e, s u cc in y l cho l in e ) a r e ra pi d l y h y d r o l yz e d i n t he b l oo d . Ad di t io n al l y , p l as m a e s te r as es c a n ac t i va te a v a ri e t y o f es te r p ro d ru g s.
2 . Me t a b ol i z i ng en z y m e s i n t h e i n t es t i na l m u co sa a r e es p ec ia ll y i m p o rt an t f or d r u gs un de r g oi ng m i c ro s o m al o xi d a ti on , gl uc u ro ni d e c on ju g a ti on , an d s ul fa t e c o nj u ga ti o n . a . A s a l ip i d -s ol ub l e d r ug p as s e s t h ro ug h th e i n te s ti n al m uc os a du r in g d ru g a b so r p ti on , it c a n b e m eta b ol i z e d i nt o p o la r o r in a c t i v e m et a bo li t es be f o re e n t e ri ng t h e b l oo d . Th e r es ul t i s c o m pa r a b le t o a fi r s t - pa s s e f f ec t . P.407
b . Th e in t es ti n al m uc os a' s d r ug -m e t ab ol i z i ng c a pa c it y c om pa r es to t ha t o f t h e l i v e r. H o we ve r , i t s h o ws m uc h g r e a te r i n di v i d ua l v a r i at io n be c a us e o f i t s g r ea t er e xp o s u r e t o t he en v i r on m e n t . 3 . I n te s ti n a l b ac t e r ia l flo r a s e c re t e a n um b e r o f e n z ym e s c a p ab le o f m e ta b ol i z i ng d r u gs an d o t he r xe n o bi o ti c s . a . A n y fa c t o r t h a t m od i f ie s t he i nt e s ti n al f l o ra m a y al s o m od i f y d r u g a c t i vi t y. A g e , d i et , d is e as e s ta t e, a n d e xp o s u re to en v i r o nm e nt a l ch em ic a ls o r d rug s m a y al l b e im po r t an t . ( 1 ) C e r ta in d is e as es , par t i c u la r l y i n te s ti n a l d is ea s e , a f fe c t in t es ti n al fl o ra . U l c e ra t i v e c o l it is , fo r e xa m pl e , p r om ot es ba c te r ia l gr o wt h . D ia r r he a re d uc es t he n u m b e r o f b ac t e ri a . ( 2 ) C e r ta in e n vi r on m en ta l c he m ic a ls an d d r u g s a ls o a c t o n i nt es t in a l f lor a . A n t i bi o ti c s , f o r e xa m p le , d e c re as e t h e n um be r of b a ct e r ia . b . B ac t e ri al fl o r a s ec r e te β - g lu cu r on i da se , wh i c h h y d r o l yz es t he po la r gl uc u r on id e c o nj u ga t es o f b i le an d a ll o ws t he f r ee , n o np ol a r bi l e a c i ds to be r ea bs o r bed . Th i s e n t e r oh e pa t i c c i r cu l a tio n pa r t ia l l y m ai n ta i ns t he p oo l o f b i le ac id s . Th i s s am e p r i nc ip l e a pp li es t o c e r t ai n gl uc u ro n id e c on j ug a tes o f d ru g s. c . C e rt a in ba c t e ri a l f lo r a c o n ve r t v i ta m i n p r ec u rso r s t o th ei r ac t i ve f o rm s, a s wi t h vi t a m i n K. d . B ac t e ri al fl o r a c a n a ls o c on ve r t c er t ai n s ub s tan c es to th e ir t o xi c fo r ms , as wi t h t h e c on v e r s i o n o f t h e a r ti f ic i al s we e t e ne r c yc la m a t e to c y c lo h e xyl a m in e , a s us p ec t ed c a rc i no ge n . e . I nt es t in a l b ac te r ia p rod u c e az o r ed u c ta se , wh ic h re d uc es th e p r od r u g s u lf as a la z i n e t o t he ac t i ve a nt i -i n fl am m a t o r y am ino s al ic y l ic ac id an d t h e ac t i ve a n t ib ac t e ri al s u l fa p y r id i ne . S ul f as al a z i ne is o n e o f t h e f e w a ge n ts ef f ec t i ve i n t he t r e a tm en t o f ul c e r a ti v e c o l i ti s . 4 . Th e ac i di c e n vi r o n me n t of t he st o ma c h p r odu c es n o ne n z y m a ti c d eg ra d a ti on o f a n u m b e r o f d r u g m o l ec ul es , in c l ud i ng pe ni c i l li n G , c a r be ni c i l li n , e r y t h ro m yci n , a n d t e t r ac yc li ne . Ad d it i on al l y, g as t ri c a c i d a ss is ts in th e de g ra d at i on of p ro t ein s a n d p e p ti de s (e . g. , i ns u li n ) . 5 . Th e na s al mu c os a p ro v i d es a h ig h l e v e l o f C YP 4 5 0 a c t i v i t y , wh ic h c an s i gn i fi ca n tl y a lt e r t h e am o u n t o f d r ug th a t re ac hes t he s ys t em ic c i rc ul a ti on . N as al d e co n ge s t a nt s , a ne s t h eti c s , ni c o t in e , co c a i ne , a nd o th e r c om po u nd s h a ve b e en s h o wn t o u nd e rg o n as a l m e ta b ol is m . 6 . Th e lu n g i s r es p on s i bl e fo r fi r s t - p as s m e t ab ol is m o f d r u gs a dm i ni st e red i n t ra ve n ou s l y , i nt r am us c u l a rl y , t r an s d e rm al l y , o r s u bc ut a ne o us l y .
a . Th e t ot a l a m ou n t o f m e t a bo l iz i ng e nz ym e s p r e se n t i n t he lu n gs i s l es s t h an th a t i n th e l i v e r ; h o we v e r , th e s pe c i f ic ac ti v i t ie s o f t h e e n zy m es a re c om p a ra ble t o t h os e i n th e l i v e r . b . Th e lu ng s p r o v id e s e co n d - pa s s m e ta b ol i sm fo r d ru gs le a v i ng th e l i v e r. C . P l a ce n ta l an d fe t a l m e t a bo l is m 1 . P la c en t a . I n g e ne r al , i f a d r ug o r o th e r xe n o bio t ic is l i pi d s ol u bl e e no ug h to be a b so r be d i n to t he c i rc u lat i o n wh e n ad m i n is te r e d to a p r e gn an t wo m an , i t wi l l l ik el y a l so pa s s th r ou g h t he pla c en t a. a . Th e pl ac en t a i s n ot a p h y s ic al o r m e t ab o li c b ar r i e r t o xe n o bi o ti cs . Ve r y l i tt l e xe n o b i o ti c m e ta b ol i z in g en z y m e ac t i vit y h as be e n d e m o ns t r at e d i n t he pl ac e n t a. b . D r ug s p r es e nt in th e ir a c t i ve fo r m i n th e m at er n a l c i r cu l at i on li k e l y pas s u n c ha n g ed in t o t he f et a l c i rc ul a ti o n. c . A n e xc e p ti o n t o t hi s l ac k o f e n zy m e a ct i v i t y in th e pl ac e nt a i s t he p re sen c e o f a s m a l l am o un t o f a r yl a r o m a t i c h yd r o x yl a s e , wh i c h i s i n d uc i bl e in p r eg na n t w o me n w ho sm o ke c ig ar e t t e s . A po t en t ia l c on s eq u e nc e is an in c re as e i n t h e p r o du c ti on o f p en ul t im a te c a r c i n og en s f r om th e ac t i o n o f th is en z y m e on th e p o l yc ycl ic a r om a ti c h y d ro c a rb on s p r es en t in c i gar e t t e s m ok e a n d o th e r e n vi r on m e n ta l s ou r c e s . 2 . F et u s . I n t e rm s o f f e ta l m e ta b ol is m , t he r e a r e va r yi n g de g re es o f d ru g m e ta b ol i z in g a c ti v i t y de pe n d en t u p on a n um be r of f a c t o rs in c l ud i ng fe t al ag e . a . A m a j o r d e fi c ie n c y i s t h a t o f g l uc u r o ni c a c id c o n j ug a t in g a c t i vi t y b o t h i n t he f e t u s a n d t h e n e on a te . b . Two c o n s e qu e nc es of t h is a re th e g ra y b a b y s yn d r o m e , r e su l ti ng f ro m d e c re as e d c h l or am p he n ic o l g lu cu r on i da t io n , a nd n e o na t a l h yp e r b i l i r u b ine m i a, r e s ul ti n g f r om a d ec r ea s e i n b il i ru bi n g l uc u ro ni d e f o rm a ti o n. P.408
V. STRATEGIES TO MANAGE DRUG METABOLISM. A va r i e t y o f m e th o ds h a ve b ee n u se d t o c i rc um v en t t he ra p id m e ta b ol is m o f c e r ta i n d r u gs . Th es e m et h od s s e e k t o i m p r o ve d r ug th e ra p y b y d ec re a s i ng th e ov e r a l l e xt e n t o f m e ta bo l is m and i nc r ea s i ng t he du r a ti on o f ac ti o n. In s o m e in st an c es , t h es e m e th o ds h a v e pr o v i de d in c r ea s e d s it e s pe ci f ic i t y. A. P h a r m a c eu t i ca l s t r a te g i es in vo l ve th e u s e of d i f fe r e nt do s ag e f o rm s to e it h e r a vo i d o r c om p en s a t e f o r r a p id m e t ab ol is m . 1 . S u bl i n gu a l t a bl e t s a re us e fu l fo r d e li v e r in g d ru g s d i re c t l y in t o t he s ys te m ic c i rc u la ti o n a nd b y pa s s i ng h ep a ti c f i rs t -p as s m et ab o li sm . N it r o g l yc e r i n , a r a p id l y a c ti n g a nt i an gi n al ag e nt , i s e s s en t ia ll y i ne f f ec ti v e wh e n a dm in is t e re d o r al ly d u e to a n e xt r e m e l y hi g h f i rs t -pa s s e ff ec t bu t i s v e r y e f fe c ti ve in t re a ti n g ac u t e at t a ck s o f a n gi n a i f g i v en s u b li ng ua l l y . 2 . T r an s de r m al p at c he s a n d o i n tm en t f o rm u l a tio n s p r o vi de a c o n ti n uo us s u pp l y o f d r u g o ve r an e xt e n de d pe r i od o f t im e a nd a re us e f u l f o r r a pi dl y m et a bo li z e d c om p ou n ds s uc h a s n it r og l y c e ri n . Th e s e de l i ver y s y s t em s , wh i le n ot s u it ed t o t r ea t
a c ut e a n gi n al s y m p to m s , a r e e f fe c ti v e in p ro v i di ng p r op h y la c ti c co nc e nt r at i o ns o f n i t ro g l yc e r in . 3 . I n t ra m us c ul a r de p o t i n j e ct i o ns al so p ro v i de a co n ti n uo us su pp l y o f dr u g o v er a n e xt e n d e d p e ri o d o f t im e . H i g h l y l ip i d s o l ub l e es t e rs o f e st r a d io l an d t e s tos t e r o ne ( e . g ., es t r ad io l b e n z oa t e, t es t os t er o ne en a nt h at e) a r e s lo wl y a b s o r b ed f rom t he i r a d m i ni s t ra ti o n s it e . H y d ro l y s is o f th es e p r o dr u gs ( s e e V I ) p r od u c e s a s t ead y s up p l y o f t he s e ra p id l y m e t ab ol iz e d h o rm on es . 4 . E n te r i c -c o a te d fo r m ul a t i o ns c a n p ro t ec t a ci d -s e ns it i v e d r u gs a s t h e y pa ss t h r o ug h t h e ac i di c e n v i ron m en t o f th e s t om ac h. M e t h e na m in e , e r yt h r o m yc i n , a n d o m e p ra z ol e a r e e xa m p le s o f ac id - s e ns i ti v e ag ent s th a t a r e a v a il ab l e a s en t e ri c c o at e d p r ep a ra t io ns . 5 . N as a l a d mi n is t r a t i on a l lo ws f o r t he d el i v e r y of p ep t id es , s uc h a s c a lc it o n i n s a l mo n , wh ic h h a v e v e ry l o w ( i f an y) o r al bi o a v ai l ab i li t y . C ha r ac t er is t ic s o f t he l u ng m ak e i t id ea l f o r th e a dm i n is t ra t io n o f pe p ti de s . Ae r o so li ze d d r u gs o n l y n ee d to p e n et r a te a t hi n e p it h el ia l la y e r to r ea c h ab u nd an t c a pi l la r y b ed s . A dd i ti on a ll y , t he l u ng s c on t ai n p r o te as e in h ib i to r s , wh i c h a ll o w f o r g r e at e r s ta b il i t y o f th e pe p t id es . B . P h a r ma c ol o g ic a l s t ra t e g ie s i n v o l v e t he co ncu r r e nt us e o f e n z ym e i n hi b i to rs t o d e c re as e d r ug m e t ab ol is m . In s o m e i n s t a nc es , t he co nc u r r en t u s e o f a n ad d i ti on a l a g e nt do es no t pr e v e nt m e ta b ol is m b ut r at h e r p re v e n ts t he to xi c i t y c a us ed b y m e ta b ol i te s o f t h e t he r ape u t ic a g en t . 1 . L e vo do p a ( L - do p a ), th e am in o a c i d p r ec u rs o r o f do p am in e , is us ed in th e t r e a tm en t o f pa r k i ns on is m . U nl ik e d op a m i ne , L- do p a c an pe n et r a te th e b lo o d -b r a in b a r r ie r an d r e ac h t h e c en t r al n er vo u s s y st em ( CN S ) . W hen i n th e b r ai n , it i s d e ca r bo xy l a t e d t o d op am i ne . To en s u r e t ha t ade q u at e c on ce n t ra t io ns of L - d op a r e a ch th e C N S , p e ri ph e ra l m e ta b ol is m o f t h e d rug m u s t b e b lo c k ed . Th e c o nc u r re n t a d m i ni s t ra ti o n o f c a r b ido p a , a do p a d ec ar b o xyl a s e i n hi bi t o r t h at c a nn o t pe n e t ra t e t h e b l oo d -b r a in ba r r ie r , p r e v e n ts p e r ip he r a l f o rm a t i on of do p am in e a n d a ll o ws si t e s p ec if ic de l i v e r y o f do pam i ne to t he C N S . 2 . β -L a c ta m a n t ib i o t ic s. Th e a nt ib a ct e ri a l ac t i v i ty o f a n um b e r o f β - l ac tam a n t ib io t ic s is r ed uc e d b y m ic r oo r ga n ism s c ap a bl e o f s ec r e ti ng t he en z ym e β l a ct am as e . Th is e n z y m e h y d r o l y ze s t he β - la c ta m r i n g a nd in ac t i v a te s t he a n t ib io t ic . To c o un t e r t hi s re s i st a nc e m e c h a ni s m , a β - la ct am a s e i nh ib i to r , s uc h a s c la vu l a n i c a c i d , is us ed in c o nj u nc ti o n wi t h a p e ni c i ll i n, su c h as am o x ic i ll i n , t o s uc c es s fu ll y t r e a t i nf ec t io ns c a us e d by β - l a c ta m a s e - p ro d uc in g b a c t e ri a . 3 . I f os f am i de is an al k y la t i ng ag e nt th a t m us t u nd e r go in vi v o m e ta b ol is m t o p r o du c e an ac t i v e n it r o ge n m us t a rd . In th e p r oc es s o f t h is m e ta b ol ic ac ti v a t i on , s i gn i fi ca n t c o nc e nt r a ti o ns o f a c ro l e in a re pr o du c e d . Th es e a c ro le i n m o l ec u le s r e ac t wi t h n uc l eo p hi le s o n r e na l pr o t ei ns an d p r od uc e h e m o r r ha g ic c ys ti t is . To p r e v e n t t h is t o xi c it y , i fo s f am i de is al wa y s c oa dm i ni st e r ed wi t h m es n a , a s ul f h y d r yl c o nt a in in g c om p ou nd t hat r e ac ts wi t h a n d n eu t r al ize s an y a c ro le i n t ha t is p r e se n t i n t h e k id n e y . 4 . H I V p r o t ea s e i n hi b i to r s a re e xt e n si v e l y m e tab o li z e d b y C YP 3 A i s o z ym es . In a d di t io n , c om po u nd s wi t h i n t h is c la s s c a n i nh ib i t t h es e s am e i so z ym e s . Th i s l at t e r a c ti o n h as b e en us ed t o o p t im i z e t he r a p y. R i t o navi r i s an H I V p r ot e as e i nh i bi t o r t h a t i s k n o wn t o c au s e he p a to xi c i t y a t t he r a pe u tic do se s . L o pi n a vi r is a n H I V
p r o t ea s e in hi b it o r t h at is i n ef f ec ti v e i f us e d a lo n e d u e t o r a pi d C YP 3 A o xi d a t io n . A c om b in a ti o n o f l o w d os e r i t on a v i r wi t h a th e r ap eut i c P.409 d o se of lo p in a v i r r es u lt s i n an in hi b it i on of C YP 3 A , t he es t ab li s hm en t o f ad e q ua t e p l as m a le v e ls of lo p in a v ir , a nd th e r ap eu t ic ef f ic ac y wi t h o u t h ep a to t o xi c it y.
Figure 17-1. Selected examples of chemical modification that eliminate metabolic transformations. Methylation of testosterone blocks the rapid oxidation of the 17-hydroxyl group and allows oral activity, whereas replacement of the metabolically labile paramethyl group on tolbutamide with a chloro group allows for a much longer duration of action.
C . C h e mi c al s t ra t e gi e s i n v o l v e t h e a dd i ti o n, de le t i on , o r is os te r ic m o di f ic a ti o n o f k e y f un c t i on al g ro u ps . Th e s e m o le c u l ar m o di f ic a ti o n s hi nd e r o r c o m p le t ely e l im i na t e m e ta b ol ic t ra ns f o rm at i ons ( Fi g u re 17 - 1 ). 1 . T es t os t e r on e i s n o t or a l l y a c ti ve du e t o ra p id o xi d a t i on o f i ts 17 - h y d roxy l g r o u p t o a k et o ne . Ad d it i on of a 1 7 α -m e th y l g ro up c o n ve r t s t he la b il e s ec on d a r y a lc o ho l t o a s ta bl e te r ti a r y al c o h ol . Th e r es u lt i ng c om p ou n d, m e th yl t e s t o s t e r on e , is o n l y h a lf a s p o te n t a s t es t os te r o ne ; ho we v e r , i t i s n ot s u bje c t t o ra pi d fi rs t - pa s s m e t a bo li s m a n d c an be us ed o ra ll y . A s im il a r s t ra t eg y h as bee n us ed to m a k e o ra ll y ac t i v e e s t ra d io l a na l og u es . 2 . T ol b u ta m id e i s a n o ra l h y po gl y c em ic wi t h a sh o r t d u ra t io n o f ac ti o n. Th i s s u lf o n ylu r ea r ap i dl y u nde r g oe s o xi d a t io n o f it s pa r a -m e th y l g ro u p. A s t r uc t u ra ll y s im i la r c om p ou nd , ch l o rp r o p a mi d e, ha s a no nm e t a bo li za b le pa r a -c hl o r o g r o up an d , a s a r es ul t , h as a m u c h lo n g er du r a ti o n o f a c t io n . 3 . I so p r o te r e n ol is a po te n t β -a d r en e rg ic ag o ni st u se d fo r th e re li e f o f b r o nc ho s pa s m a s s oc ia t ed wi t h b ro nc h ia l a st hm a . B e c a us e i t i s a c a te c ho l ( i . e. , 3, 4 d i h yd ro xy - s u b s t it u te d b en z e n e ri ng ) , i s o p r ot e r eno l is s ub j ec t t o ra pi d m e ta b ol is m b y c a te ch o l O - m et h y l tr a ns fe r a s e ( C O MT) a n d , t hu s , h as po o r o r al ac t i v it y . Al t e ra t io n o f t he 3, 4 -d i h y d ro xy s u b s t i tu ti o n t o a 3, 5 - di h yd rox y s u b s t i tu t io n p r o du ce s m e t a p ro t e r en o l , a b r o nc h o di l at o r t h a t is no t s us ce p t ib le t o C O M T, i s o ra lly a c t i v e, a n d h as a l on g er du r a ti on o f a c t i on th a n is o p ro t er e n ol . 4 . O c t r eo t i de is a s y n the t ic oc t ap ep t id e u s ed to s u pp r es s o r i n hi bi t s e ve re d ia r r he a a ss o ci at e d wi t h c e r t ai n tu m o rs . O c t re o ti d e m i m i cs t he ac ti o ns o f so m at os t a t i n, a n a t u ra ll y o c c u rr i ng , 1 4 - am i no ac id pe p ti d e. S om at o s ta t in un de r g oe s r a pi d p r o t eo l y s i s , ha s a ha l f- l ife o f 1 - 3 m i n ut es , an d m us t be ad m i ni s te r ed as a c o nt i nu o us i n t ra v e n ou s in f us i on . Oc t r eo t id e c on ta i n s th e a m i n o ac i ds e ss e n t ia l f o r
c l in ic al e ff ic ac y b u t r ep la c es t wo of t he am in o a c i d s wi t h t he i r D - e na n ti om e r s . Th e s e u n n at u ra l D -a m i n o ac i ds a r e m o re r es is ta n t t o h y d r o l y si s. As a r e s u l t, oc tr e o ti d e h as a n in c re as ed h al f -l i fe and c a n b e a d m i ni s t e r ed as a s ub c u t an e ou s i nj ec t io n .
VI. PRODRUGS. Th e s e d r u gs a r e m ol ec u le s th a t a re ei t he r in ac t i ve o r v e r y we a k l y ac t i v e an d r eq ui r e i n v i v o b i ot r a ns fo r m a t io n t o pr o du c e t he ph y s io log i c a ll y a ct i v e d r u g. Th e p h as e I m e ta b ol ic P.410 p r o ce s s es d is c us s e d p r ev i o u s l y a r e us e d t o a ct i va t e p r o dr u gs . A v a r i et y of a d va n t a ge s c an be ga i ne d b y u si n g a p r o d ru g i ns t ea d o f th e a c ti ve fo r m o f t he drug. A. A n i n c r ea s e i n w at e r s o l ub i l i t y i s u se f ul fo r th e p re pa r a ti o n o f o ph t hal m ic a n d p a r en t e ra l f o rm u la t io ns . S o d i u m s uc c in a t e e st e rs a nd so d i um ph o s ph a te e s te r s h a ve be e n us e d t o m ak e a nu m b e r o f wa t e r -s ol u bl e s t e ro i d p ro d r ug s . B . A n in c r ea s e i n l i p id s o l u bi l i t y i s u s ef u l f o r a v a r i e t y o f r ea so ns . 1 . I nc r e as e d d u r at i o n of a c t io n . L ip i d- s ol ub l e es t e rs of es t ra d io l , su c h as b e n zo at e , v a l e ra t e, an d c y p i on a te , a r e u s e d to pro l on g e s t ro ge n ic a c ti vi t y. I M i n je c ti on s o f th es e e s t e rs in oi l re su l t i n a d e po s it o f d r ug t ha t i s s l o wl y h y d r o l y ze d , t h e r eb y r el e as in g f r e e es t r a di o l o ve r a p ro l on ge d p e r io d o f ti m e (s e e V . A .3) . 2 . I nc r e as e d o r a l a bs o rp t i o n i s o bt a in ed b y c o nve r t i n g c a r b o xy l i c a c i d gr o u ps to e s te r s . Th e s e es t er s c an t h en be r ap i dl y c o n ve r ted t o t h e ac t i ve a ci ds b y p l as m a e s te r as es . E na l ap r i l a t is a po t en t an gi o te ns i n -c on v e r t i ng en zy m e ( A C E ) in h ib i to r t h a t i s us e d f o r p a re n te ra l ad m i ni s tr a ti o n, bu t , d ue t o i ts hi g h p ol a ri t y , i t is o ra ll y i n ac t i ve. I ts m o no m e t h y l e s te r , e n a la p r i l, is c o ns id e r ab l y m o r e l ip o ph il ic an d , th us , p r o vi de s g oo d or a l a bs o rp t i on . Th is s t r at e g y h as b e e n su c c es sf u ll y us e d fo r a va r i e t y of o th e r c om po u nd s , i nc lu d in g a d di ti o na l A C E i n hi bi t o rs , f i br ic ac id d e r i va ti v e s , am pi c i l li n, an d s e v e r al c e ph a lo s p o rin s . 3 . I nc r e as e d t o p ic a l a bs o r p t i on of s t e r oi ds is ob t a in ed b y m a sk in g h yd ro xy l g r o u p s a s e s te r s o r a c e t on i de s . Th e s e p r o dr u gs ar e m uc h l ess po l a r t ha n t h e p a re n t c om p ou n ds a n d a ll o w i nc r e as ed de r m a l p e rm ea bi l it y f o r t h e t r ea t m e n t o f i n f la m m at o r y , a l le r gi c , an d p ru r it ic sk in c o nd i ti on s . E xa m p le s i nc lu de t r i am c i no l o ne a c e t on i de , di f l o ra s o ne d i a ce t a te , an d b e ta m e th a s on e va l e ra t e . 4 . I nc r e as e d p a la t ab i l i ty. A n t i b i o ti c s s uc h a s s ul f i s ox az o l e h a ve a b i t te r t a s t e a n d a r e no t s ui t ab l e f o r a dm in i s t r a ti o n t o yo u ng ch il d re n wh o c a nn o t y et s wa llo w t a b l et s o r ca ps u le s . E s t e ri f ic a ti on t o p r od uc e s u l f is o xa z o l e ac e t yl d e c r e as es the wa t e r s o lu bi l it y o f t h e a n ti bi o tic an d , t h us , d ec r ea se s i ts in t e ra c t i on wi t h bi t te r ta s te r e c ep t or s o n t h e t on g ue . Th i s c om p ou nd is m a rk et e d a s a fl a v o r ed s us p ens i on . S i m il a r s tr a te g ie s h a v e be e n u s e d t o m as k t h e bi tt e r ta s te of ch l o r am p hen i c o l a nd o t h e r a nt i bi o ti c s . C . A d e c r e as e in G I i r r it a t i o n. N o ns te r oi d al an t i- i n fl am m at o r y ag en t s ( NS A I D s ) p r o du c e ga s t ri c i r ri t at i on a n d u lc e ra t io n v ia t wo m ec h an is m s : a di r ec t i r r it a n t e f fe c t o f t he ac id ic m o le c u le and i nh ib i ti o n o f g as t ro p r ote c ti ve p ro s ta gl a nd in p rod u ct i on . Th e p r o dr u gs su l in d ac an d na b um e t on e p r o du ce l es s G I i r ri t at i on be c a us e t he
g a st r ic an d i n te s ti na l m uc os a a r e n o t e xp o s e d t o h i gh c o nc e nt r a ti on s o f ac t i ve d r ug d u r in g o r al a dm i n is t ra t ion . A dd i ti o na ll y , n ab um e to n e i s a k e to ne , no t a n ac i d, an d l a cks an y d i re c t i r ri t an t ef f e c t s . D . S i t e s p ec i f ic i t y i s u s e f u l f o r i nc r ea s i ng t he c on c en t r at i on of d ru g a t the ac t i v e s i te an d fo r d e c r e as in g s i d e e f fe c ts . 1 . M e t h yl d o p a i s a pr o dr u g th a t is s t r uc t u ra ll y s im i la r to L -d op a . A s a r es u l t , m e th y l d op a i s t r an s p o r ted i nt o t h e C N S a nd m e tab o li z e d to th e a c ti v e c om p o u nd , α m e t h yl d o p a m i n e , v i a t he s a m e pa t h u s e d f o r t h e s yn t he si s o f d op am i ne . Th i s a l lo ws a s i gn i fi c a n t am ou n t o f α -m e t h yld op am i ne t o re ac h th e C N S a nd bin d to c e nt r a l α 2 - ad r e ne r gi c r ec e pt o rs . 2 . O m ep r a z o l e is us ed to t r ea t g as t r ic ul c e rs and o th e r h y p e rs ec r e to r y di s o rd e rs . A f t e r o r al ab s or p ti o n, i t is s e le c ti v e l y ac ti v a t ed a t t h e a c i di c p H le v e ls ( p H l es s t h an 1 ) se e n i n g as t ri c p a ri e ta l c e ll s . Th is al l o ws th e a c ti ve f or m o f th e d r ug to b e +
+
p r o du c e d i n c lo s e p ro xi m i t y to th e e n zy m e H / K - A TP a s e ( pr o t on pu m p ) , r e su l ti n g in i r r e ve rs i bl e i nh i bi t io n o f t h e e n z ym e a n d a d ec r ea s e i n g as t ri c a ci d s ec r et i o n. A c t i v a ti on in th e s t om ac h p ri o r to ab s o r p ti on ca n b e p r e v e nt e d b y t he us e o f en t er ic c o at e d f o rm ul a ti o ns (s ee V . A . 4 ). 3 . F o rm a ld e h yd e i s a n ef f e c t i v e u r in a r y t ra c t a nt is e pt ic ; ho we ve r , o r al a d m i ni s t ra ti o n r es u lt s i n s i gn i fi ca n t t o xi c i t y . To av o i d th is p ro b le m , th e p ro d r ug m e t h en am i n e is ad m i n is t e r e d i ns te a d. Me t h e na m i n e i s s ta bl e a n d n on t o xi c a t n o r m a l p h y s i ol o gi c a l p H , b u t i s se l ec ti v e l y h yd ro ly ze d t o fo r m a l de h y de and a m m o ni um io ns in th e a c i d ic ur i ne ( p H l es s t ha n 5 . 5 ) . A s wi t h om e p ra z o le, a c ti va t io n b e fo r e a bs o r pti o n c an be p re v e n te d b y t h e u s e o f e nt e ri c -c oa t ed f o r m u l at io n s ( s e e V. A . 4 ). P.411
4 . O l sa l az i ne is a hi g hl y p o la r dim e r o f 5- am i no sa l ic yl ic ac id th a t i s p oo r ly a b so r b ed a f t e r o r al ad m i ni s tr a ti o n. O n r e ac hi ng t he la r ge int e s ti ne , c o lo ni c b ac t e ri a c l ea ve t h e a zo bo n d a nd li b er a te t he ac t i ve a nt i -i n fl am m a t o r y ag e nt . O ls al a zi ne a n d a r e l at e d c om po un d , s u l fas a l az i ne , a r e u s e f ul in t re a t in g i n fl am m a t o r y b o we l di se as e . E . I nc r ea s e d s h el f l i fe of b o th s o li ds an d p a r en t er a l a d m i xt u r e s c an be obt a i ne d b y t h e u se o f p r od r ug s . C yc l o p h os p ha m i de i s a p rod r u g t h at r eq ui r es in vi vo o xi d a t i on , fo l lo we d b y non e n z y m a ti c d ec om po s i t io n , to pr o du ce t he ac ti v e p h os p ho r am id e m us t ar d . A s a r es ul t , a q ue ou s s olu t i on s o f c y cl o ph os p ha m i d e a r e m uc h m o re s t a bl e t h an th o s e of o th e r n it r o ge n m u s ta r ds ( i. e . , m e c h l or e tha m in e ) . M e ch l o r e th am i n e is hi gh l y r e ac ti v e , d o es no t req u i re in v i v o ac ti v a t io n , a n d c an r a p id l y de c o m p o s e i n aqu e o us e n vi ro n m e n ts b e fo r e ad m i ni s tr a ti o n.
VII. PHARMACOGENETICS A. G e n e s a nd t he i r in vo l ve m e n t i n d ru g r es p o ns e an d t ox i ci t y 1 . G e ne s c an be d ef in e d a s d is c re t e se gm e nt s o f D N A t h at a re c a pa b le of r e p r od uc t io n d u ri n g c el l r e p li c a t io n a n d t ha t ar e re s po ns i bl e f o r g ui d in g t he b i os yn t he s i s o f s pe c i f ic p r o t ei ns an d e n zy m es .
2 . G e ne s e nc od e p r o te i ns in v o l v e d i n t he a bs o r pt i o n , t ra n sp o r t , m e ta b ol i s m , a nd e l i m in a t io n o f dr u g m o le c ul es . Ad d it i on al l y , th ey e n c o d e p r ot e in s t ha t s e r v e as d r u g r ec e p to r s . I t is o bv i o u s t he n th a t a g e ne t ic d is p os it i on th a t wo ul d re s ul t i n e i t he r an o ve r - o r a n u nd e r e xp r e ss i o n o f th e se g e ne s c o ul d s ig ni f ic an t ly a l t e r d r u g r es p on s e an d to xi c it y . 3 . A s s um in g t h at a p at i en t ha s b ee n p r es c ri b ed a m ed i c a ti o n t ha t is i n di c a t e d f o r h is o r h er c o n di ti o n o r d is e as e s t at e , t h er e a r e s e ve ra l re a s o ns wh y a p at ie n t m a y no t r e s po nd o r m a y s u ff e r s ev e r e a d ve rs e e ff e c t s : a . I na p p r op r i a te d os i ng b . D r u g - d ru g in t e r ac t i on s c . D r u g a ll e r g ie s d . M e d ic a t io n e r ro r s e . G e ne t i c p r e di s po s i t io n 4 . I n i ts m os t s im pl is t ic fo r m , p h a rm a co g en e t ic s c an be de f in e d a s t he us e o f g e n et ic in f o rm at i on to s el e c t t he “ ri g ht d ru g f o r t he r ig h t p a ti e nt . ” Th is a r ea o f s tu d y p r i m a r il y s e ek s t o i d en t ify t h e in di vi d ua l g e ne ti c d i f fe r e nc es a n d p r ed is pos i ti o ns th a t i n f lu en ce d ru g re s p o ns e a n d s af e t y. B . G e n e t ic va r i a ti o n i n th e D N A s e qu en c e ca n ca u s e c e r ta i n p op ul a ti o ns o f i n di vi d ua ls to be m o re l ik e l y t o d e ve l o p s pe c i fic d i se as e s t a te s , t o b e m o r e li k el y t o f o l low a s p ec i f ic pa th o f di s ea s e p r o g re s sio n , to be mo r e li k e l y t o r e s p o nd t o s p e ci f i c d r u g t h e ra p y, a n d /o r to be mo r e li k el y t o d e ve lo p c e r t ai n ad ve r s e d r u g e f f e c ts . 1 . Th e ge ne t ic v a ri a ti o n b e t we e n a n y t wo u n re la te d in di vi d ua ls is a p p ro xi m a te l y on e b a se pa i r c ha n ge i n e v e ry 1 0 0 0 b as e p ai r s. 2 . Th e se c h an g es a r e ref e r r ed t o as s in g le n uc le o t i de p ol ym o r p h i s m s (S N P s ) a nd a r e th e m os t c om m o n f o rm o f g en e ti c v a r ia t io n . 3 . T he e ff e c ts o f S N P s va r y b a s e d u po n t h e t yp e a nd l oc a t io n o f th e v ar i a ti o n. a . An S N P l o ca t ed w i t h in t h e c o di n g re g i on of a g en e c ou l d p ro d uc e n o d i sc e rn ab l e e f fe c t s , n eg li g ib l e e f fe c t s , o r a s i gn i fic a nt al t e ra t io n i n e f fe c ts d e p en di n g u po n h o w t h e S N P a f fe ct e d t he am in o a c i d c od i ng . ( 1 ) A n S N P t ha t di d n o t a l t e r th e a m i no ac id se qu e nc e i n a p ro t ei n wo ul d p r o du ce n o d is c e rn a b le ef f e c ts . ( 2 ) A n S N P t ha t re s u l te d i n o n e am i no ac id be in g r e pl a ce d b y a s i m il a r am i n o a c id wo u l d h a v e a ne g li g i bl e e f f ec t ( e. g . , ch a ng in g a p o r ti o n o f t he ge n et ic c o d e f r om A U U t o G U U wo u l d r es u lt i n is o le uc i ne be in g re p la c e d b y va li ne , a s i m i la r h yd r o ph o bi c a m i no ac id ). ( 3 ) A n S N P t ha t re s u l te d i n o n e am i no ac id be in g r e pl a ce d b y o ne wi t h s ig n i f i ca n t l y d i f f e r en t ch e mi c al p r ope r t i e s wo u l d c au s e a s i gn i f i ca n t a l t e ra t i o n o f e ff e c t s ( e . g ., P.412 c h an g in g a po r ti o n o f t he g en e ti c co d e f r om G UU t o G A U wo u l d r es ul t in va l i ne b e in g re p la c e d wi t h t he a c id ic , a n d m o r e h y d r o ph i li c , as p a rt ic ac id ) . b . An S N P i n a s pl i ci n g c o n t r ol r e gi o n c ou ld r es u lt in th e fo r m a t io n o f a n o ve l p r o t ei n t h at is e i th e r l a rge r o r s m a ll e r i n s i ze t ha n t h a t wh i c h is na t u ra ll y oc c u r r in g .
c . An S N P i n a p ro m o ter r e g i o n c o u ld al t er t he tr a n sc ri p ti o n r a te , re s u l tin g in e i t he r an i n c r e as e o r a de c r ea s e in th e p r o du c t i on o f t h e t a rg e t p r ot ei n . d . A n S N P r es id i ng ou t s id e of an y o f th e a bo ve loc a ti o ns i s g e ne t i ca l l y s i l e n t a n d d o es no t p r o du c e an y o bs e r v a bl e e f fe c ts . 4 . E xa m pl e s o f k n ow n g e n e ti c va r i at i o ns an d t h e i r ef f e ct s on d r ug e ff i c a c y a n d safety a . Wa r f a r i n. P a ti en t s wi t h s p ec i fi c va ri at i on s i n th e ge n e f o r t he m e t ab ol iz i n g e n zym e C YP 2 C 9 re q ui r e l o we r d os es a n d a r e a t a n in c re as ed r is k o f b le ed i ng . b . S a lm e te r o l a n d a l bu te r o l . G en e ti c v a r i at i on s in t he ge n e c o d in g f o r the β 2 a d r en e r gi c r ec e pt o r ( A D B R 2 ) c a n re su l t i n a d ec re a s e d e f fi ca c y . c . 6- M e r c a pt o p u r in e . G e n e ti c va r i at i on s a ff e ct i ng t he en zy m e th i op u ri n e m e th y l t r an s fe r as e a r e k no wn t o p ro d uc e i nc r ea s ed t o xi c i t y . d . P r o ca i na m i de , h yd r a l a z in e , a n d i so n i az id . Ge n e ti c v a r i at i on s a ff e c t i ng t he r at e o f N - ac e t y la t io n a f fe c t bo t h th e e f fi c a c y an d a d ve r s e e ff e ct p ro f il es of the s e a ge n ts . Th e i d en t if ic a ti o n o f f as t a n d s l o w a c et y l a to r s is o n e o f th e b es t k no wn e xa m p l e s o f h o w g e n et ic v a r ia t io n c an a f fe c t th e r ap e ut ic s a fet y a n d e f fi c a c y . e . Q u i ni d i ne , c i sa p r i de , a n d c l a ri t h r o m yc i n . G e n e t ic va ri a ti o ns i n t h e g en e c o di n g f o r po t as s i um c h an ne ls c a n r es ul t i n i nc r ea s e d ri s k an d p r e va le nc e o f Q T- s y n d r om e a n d a r r h y t hm i a s . f . Z i le u t on . Pa t ie n ts wi th g en e ti c va r i at i on s i n t he g en e c od i ng fo r th e e nz ym e 5 l i po xyg e n a s e d o n o t r es p o n d t o t hi s d r ug . C . C l i n ic a l p h a rm a co g en e t i c a ss a ys 1 . Th e go a l o f a c l in ic al p h a rm ac o ge ne t ic as s a y is t o p la ce pa t ie n ts i n to on e of f ou r c a te g o ri es . a . I nd i vid u al s wh o a r e m o s t l ik el y t o re sp o nd an d a r e a t a lo w r i s k f o r a d ve r s e e f f ec ts b . I nd i v id u al s wh o a r e m o s t l ik el y t o re sp o nd an d a r e a t a hi g h r is k f o r a dv e r s e e f f ec ts c . In d i vid ua ls wh o a re les s l ik el y t o re s p o nd an d a r e at a l o w r is k f o r a d v er s e e f fe c ts d . I nd i v id u al s wh o a r e l es s l ik el y t o re s p o nd an d a r e at a h ig h ri s k fo r a d ve r s e e f f ec ts 2 . Is su es in t he de v e lo pm e nt o f p ha r m a c o ge n et ic as s a y s i n c l ud e : a . Im p ro v e m en t i n a m e di c al l y im po r ta n t re sp on s e ( i .e . , t h e as s a y s ho ul d a l lo w h e al t hc a re p ro v i d e rs t o m ak e a be t t e r d ec is io n th a n wo u ld ot h e r wi se be p o s s ib l e) . b . F al s e p os i t i ve s f o r ef f i c ac y- b a s e d as s a ys s h o u l d b e k e pt a t a m i n im u m i n o r d e r t o p r e v en t no n re s po n d er s f r om be i ng pr es cr i b e d d ru gs th a t wi ll no t p r o v i de t he d e si r ed t he r ap e ut ic ou t c o m es . F a ls e n eg a ti v e s ( i. e . , re s p on d e rs i d en t if i ed as n o n re sp o nd e rs ) ar e no t a s c r uc ia l s in c e t he y wo u l d b e p r es c ri be d a p p ro pr i a te a l t er n a ti v e th e ra p y . c . Fa l se ne g a ti ve s f o r sa f e t y- b a s e d a s sa ys s h o u l d be ke p t a t a m i ni m um i n o r d e r t o p r e v en t at - r is k pa t i en ts f ro m b ei n g e xp o s e d to po t en t ia l s e ri o us ad v e r s e e f f ec ts . A h ig h e r r a te of f a ls e p os i ti v e s ( i .e . , p a tie n ts id e nt i fi e d as “ at r is k” ) i s a cc e pt a bl e . E xc l u d in g a c e r ta i n p er c en t ag e o f p at i e nt s i n o r de r to a v oi d s e r i ou s a d ve r s e ef f ec ts ha s b een p r op os ed t o b e a re aso n a bl e t r ad e - of f .
d . Th e r es ul ts fo r t he as s a y s m us t b e b o th in t e rpr e t a bl e a nd p ro v i d e c l i nic a ll y us e fu l r e s ul ts . Th e a s s a y s s h o ul d be s im p le to us e i n a c l in ic al s e t ti n g a nd s h ou ld p r o vid e r e s ul ts th a t a r e e as il y u nd e r s t o od b y th e p a ti en t , p h y s ic ia n , p ha r m a c i s t , an d ot h e r h e al t h -c a re p ro v i d er s . e . A na l y t ic al an d c li n ic al v a l i da t io n o f t h e a s s a y m us t m e et F D A a p pr o v a l s t an da r ds . 3 . A s d ef in e d h e re , p h a rm ac o ge n et ic as sa y s d o n o t te s t fo r t he pr es e nc e o r ab se nc e o f a d is ea s e - s p ec i fi c m uta t i on , n o r d o t h e y pr o vi de a n y i n fo r m a t io n t h at c ou l d b e u s ed to p re d ic t d is ea s e s t a te s i n a n i nd i v id u al o r h is o r h e r f am il y . A s su c h , it ha s b e e n su g ge s t e d t ha t le ga l an d e t hi c a l i s s ue s s urr o u nd i ng di se as e -s p ec if ic ge n e t e s ts s ho u ld no t a p pl y t o p r e di c t i on s o f s af e t y a nd e f fi ca c y o f dr u gs (i . e. , t h e p r i m a r y f oc us o f ph a rm ac o ge n et ic s ). D . S N P m ap s a n d t h e i r p o t e n ti a l u s e 1 . A n S N P m a p f o r a n i nd i v i du a l c o n t ai ns th e s pec i fi c n um be r an d l oc a ti on s o f ba se p a i r va r i at i on s . S uc h a m a p c o ul d b e u s e d to pr e di c t p a ti en t re s p o ns e a nd s us c ep ti b il i t y to s e ri o us a d v e r s e r ea ct i on s . P.413
Figure 17-2. Hypothetical single nucleotide polymorphism (SNP) maps. At the top is a composite SNP profile developed by using genetic information from a large database of patients/volunteers. This overall SNP can then be compared to individual SNP maps (i.e., Patients A-D) to help determine the overall benefit/risk for the given drug in each of these four patients.
2 . A s i m pl i f i ed ex am p l e o f t h is is sh ow n in Fi gu r e 17 - 2. A l a r ge da t ab as e wo u ld i n i ti al l y be us ed t o i de n tif y S N P s th a t c ou l d b e us e d as p r e di c t o rs of e ff ic ac y a nd s a fe t y. A t t h e t op o f F ig ur e 1 7- 2 , t h e t wo o u ts id e , s ha d ed r eg io n s in t hi s h yp o t h e t i c a l m o de l s hou l d b e re ga r d ed as S N Ps t h a t wo u l d p r ed ic t th a t a p a ti e nt wo u l d f a v o ra bl y r e s p o nd t o th e d r ug . S im i l a rl y, the t wo i nn e r , b la ck re g io ns s h ou l d b e r eg a rd e d as S N P s t ha t wo u l d i nd ic a te th a t a p a t ie n t wa s m o r e p r on e to t he d e ve l op m e n t o f s er i ou s a d v e r s e ef f ec ts . O t he r SN P s ( i. e . , t he no n hi gh l igh t e d r e c ta n gl es s h o wn f or t he f o u r p at i en ts ) s h ou l d b e r e g ar d ed as i r r el e va n t he r e (i . e ., t h e y do no t p re di c t e it h er e f fi c a c y o r s a f et y f o r t he d r ug in qu es t io n ). a . P at i en t A wo ul d b e p re d ic t ed to r es po n d t o t r ea t m e n t wi t ho u t t he de v e lo p m e n t o f a n y se r i ou s a d v e rs e e f fec t s . b . P a ti en t B wo u ld be pre d ic t ed to r es po n d t o t r ea t m e n t b u t wo u l d a ls o be e xp e c t ed t o de ve l op s e r io us ad v e rs e e f f ec ts .
c . P at ie n t C wo u l d b e p re d ic t ed to be a n on r es p on d e r t o t r e at m e n t b u t wo u l d b e u n li k e l y t o e xp e r i en c e any s e r io us ad ve r s e e ff ec ts . d . P a ti en t D wo u ld be p re d ic t ed to be a n on r es p on d e r t o t r e at m e n t b u t wo u l d b e e xp e c t e d t o d e v e lo p s e rio u s a d ve rs e e f fe c t s . P.414
STUDY QUESTIONS D i r e c t i on s : E a c h of t he n u m b e re d i t em s o r i nc om p le t e s ta t em en ts in t his se c t i on is f o l lo we d b y an s we r s o r by c o m p le t io ns o f t he s t a te m en t . Se le c t t he on e l et t e r ed a n s we r o r c o m p l et i on tha t is be s t i n e ac h c as e. 1 . W hi c h o f th e fo l l ow in g s ta t e me n ts c on c e rn in g d r u g m et a b ol i sm is t r u e ? ( A ) G e n e ra ll y , a s in gl e m e t a bo li t e i s e xc r e t ed f or e a c h d ru g a dm in is t e re d . ( B ) O f t e n, a d r ug m a y und e r go a p ha s e I I r e ac ti on f ol l o we d b y a p h as e I re a c t i on . ( C ) D r u g -m e ta bo l i z in g en z y m e s a r e f o un d o nl y in t he li v e r . ( D ) A l l m et a bo li t es ar e le s s ac t i ve p ha r m a c o l og ic a l l y t ha n th ei r pa r en t d ru g s. ( E ) P h as e I m e ta b ol i te s m o r e li k el y a re ab l e t o c ro ss ce ll u la r m em b r an es t h a n p ha s e I I m e t ab o li te s . V i e w A n s we r 1 . T h e a n sw e r i s E [] . 2 . W h ic h of th e f o ll ow i ng me t a bo l i t es w o ul d be t he le a s t l i ke ly e x c r e t i o n p ro d u ct o f o r a l l y a d m i n i s t e re d as pi r i n ( se e s t r u c t u re be l ow ) ?
( A ) G l yc in e c on j ug a te ( B ) E s te r gl uc u ro n id e ( C ) U n c h a ng e d d ru g ( D ) E t h er gl u c u r on i de ( E ) H yd r o xy l a t e d m e ta b ol i t e V i e w A n s we r 2 . T h e a n sw e r i s C [ an d] .3 . Su l f asa l az i n e ( se e s t r u c tu r e b e l ow ) is a p r o d ru g t hat i s a c t i va te d in t he i n te s t i ne b y b a c t e r i a l e nz ym e s . T h e e n z ym e m o s t l ik e l y r e s p o n s ib l e i s ( A ) a zo r ed uc t as e
( B ) p se ud oc h ol i ne s t e r as e ( C ) N - a c e t y l t ra ns f e ra s e ( D ) β - g lu c u r o ni da s e ( E ) m et h y l t ra ns f e ra s e
V i e w A n s we r 3 . T h e a n sw e r i s A [] .4 . Ch l o r am p he n i co l ( se e s t r u ct u r e b e l ow ) is co n si d e re d t o b e t ox i c i n i n f an t s ( g r ay b a b y s yn d r o m e ) . T hi s i s du e to t i s s ue ac c um u la t i o n o f u n c ha n g ed ch l o r am p hen i c o l, r es u l t in g f r om an i m m a tu r e m e ta b o li c pa thw a y. W h i c h o f t h e f o l low in g en z ym e s w o ul d m o s t l i ke l y b e de f i c ie n t ? ( A ) P se u do c h o li ne s te r as e ( B ) G l uc u r on y l t ra ns f e ras e ( C ) N - A c et y l t r an s f e r as e ( D ) A zo r e du c ta s e ( E ) Me t h y l t r a ns f e ra s e
V i e w A n s we r 4 . T h e a n sw e r i s B [ an d] .5 . W h i ch o f t h e f o l low i n g t h e r a pe u t ic ad va n t a ge s c a nn o t be ob t a in e d b y t h e us e of p r od r u g s? I nc r e a se d
( A ) o r al ab s o r p ti on ( B ) wa t e r s o l ub il i t y ( C ) d u ra t io n o f ac ti o n ( D ) p o te nc y ( E ) p al a ta b il it y V i e w A n s we r 5 . T h e a n sw e r i s D [ an d] . P. 4 15
6 . W hi c h o f th e fo l l ow in g s ta t e me n ts r e ga r d i ng p h a rm a co g en e t ic s i s INCORRECT? ( A ) S i ng le n uc le o ti de po ly m o r p hi s m s ( S N Ps ) in a p r o m o t er r eg i on c a n r es u l t i n a d e c re as e d p ro d uc ti o n o f a t a rg e t p r ot e in . ( B ) I t i s c ru c i a l t ha t fa ls e p os i ti ve s f o r s af e t y - ba s e d as s a ys b e k ep t at a m i ni m u m . ( C ) Th e a r ea of ph a rm ac o g e ne ti c s fo c us es p r im ar i l y on t he ge n et ic va r ia t io n s t ha t a f f ec t d r ug e ff ic ac y a n d s a fe t y . ( D ) Th e e f fe c t s o f S N Ps v a r y b a s e d u p on th e t ype a nd lo ca t io n o f th e va ria t i on . ( E ) G e n et ic v a r ia t io n o c c u r s wh e ne v e r th e r e is a c h an g e i n t he D N A nu cl eo t i de ba se p a i r s eq ue nc e . V i e w A n s we r 6 . T h e a n sw e r i s B [ an d] . Di r e c ti o ns : E a c h q u es ti o n b el o w c o nt a in s t h re e s ug g es t ed a ns we r s , o f wh ic h on e o r m o re is c o r re c t. C hoo s e t he a n s we r . 7 . T e rm s th a t m a y b e u s e d to d es c r ib e th e fo l low in g me t ab o l ic r ea c t io n i nc l u de I . N - d ea l k yl a t i o n I I . ox i d at i ve d ea m in a t ion I I I . ph a se I m e ta b ol i sm
A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 7 . T h e a n sw e r i s D [] . N P. 4 16
8 . W hi c h o f th e fo l l ow in g r e ac t i on s c a n b e c l as s i f ie d a s ph a se II me ta b o l is m ?
A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 8 . T h e a n sw e r i s C [] .9 . Co n d i ti o ns t h a t te n d t o in c r ea s e th e a c t i on o f a n o r a l l y a d m i n i s te r e d d r u g th a t u n de r g o es p ha s e I I m e ta b ol i s m i n c l ud e I . e n te r o he p a ti c c i r c ul at i o n I I . en z ym e s a t u r a t io n I I I . fi r s t - pa s s e f fe c t A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 9 . T h e a n sw e r i s C [] .1 0 . W hi c h o f t h e f ol l ow i ng s ta t em e n ts c o n ce r n i ng C Y P 45 0 a r e c o r r e ct ? I . T he C Y P 7, C Y P 11 , and C Y P 2 7 s u bf a mi l i es a re i n vo l ve d in ch o le s t e ro l m e t a bo l is m . I I . A s i n gl e d ru g ma y b e m e ta b ol i ze d b y m u l t i p l e is o f o rm s o f C Y P 45 0. I I I . Th e m a jo r i t y o f x e no b i o t ic s , o r d r ug s , a r e m e t a bo l iz e d b y t h e C Y P 4 B a n d C Y P 1 A s u b f a mi l i es . A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 0 . T he a nsw e r i s C [ I. A . 1 .c ;] .1 1 . M e t a b ol i c re a ct i o ns l ik e ly t o b e a f fe c te d b y a p r o t e in - d e f ic i en t d ie t in c lu d e I . g l yc i n e c o n ju g a t io n I I . h yd r o l ys i s I I I . gl u cu r o n id a t io n A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 1 . T he a nsw e r i s A [] . Di r e c ti o ns : T h e g ro up o f i te m s i n th is s ec t io n c o ns is ts o f le t te re d op t io ns fo l lo we d b y a s e t o f n um be r e d i te m s . F o r ea c h i t em , s e le c t th e on e l e tte r e d o p ti on t ha t i s m o s t c l os el y as s oc ia t ed wi t h it . E ac h l e t te r e d o pt i on m a y be s e l ec t ed on c e , m o re t ha n o n c e , o r no t at al l . Q u e s t i on s 1 2 - 15 F o r ea ch d ru g , s e l ec t i ts m os t l ik e l y m et a bo l ic p at h wa y. 1 2 . Be n z o i c a c id
( A) E t h e r g l u cu r o n id a t io n ( B ) E s t e r g l uc u r o n id a t io n ( C ) N i t r o r e du c t io n ( D ) O x i d a ti ve d ea m in a t io n ( E ) E s t e r h yd r o l ys i s P.417
1 3 . P r oc a in e
( A) E t h e r g l u cu r o n id a t io n ( B ) E s t e r g l uc u r o n id a t io n ( C ) N i t r o r e du c t io n ( D ) O x i d a ti ve d ea m in a t io n ( E ) E s t e r h yd r o l ys i s 1 4 . Ac e t am i no p h en
( A) E t h e r g l u cu r o n id a t io n ( B ) E s t e r g l uc u r o n id a t io n ( C ) N i t r o r e du c t io n ( D ) O x i d a ti ve d ea m in a t io n ( E ) E s t e r h yd r o l ys i s 1 5 . Am p h et a mi n e
( A) E t h e r g l u cu r o n id a t io n ( B ) E s t e r g l uc u r o n id a t io n ( C ) N i t r o r e du c t io n ( D ) O x i d a ti ve d ea m in a t io n
( E ) E s t e r h yd r o l ys i s V i e w A n s we r 1 2 -1 5 . T h e a n s w e r s a r e : 1 2 - B [] , 13 -E [ ] , 1 4 - A [] , 1 5D [ ] .e t h e re s te r P . 41 8
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is E [ I ; I I .A . 1 , B ]. P h a se I m et a bo li t es ar e o f t en s o m e wh a t m o r e p ol a r th a n t he i r p a re n ts . W it h t he e xc e p t i on of ac e t y la t ed a n d m et h y l at e d m et a bo lit e s , p ha se I I m e t ab o li t es a r e a l wa ys m uc h m o re po l a r t ha n t he i r p a r en ts . Th us , ph as e I m e t ab o li te s a r e m o re li k el y t o r e t ai n s om e l i po s o lu b il i t y a n d a r e m o r e l ik el y t o c r o ss ce ll u la r m em b ra n es . I t is un us u al fo r a s i n gl e m e ta b ol i te to be e xc r e t ed f o r a g i v e n d r ug . Mo s t d r u gs yi e l d a m i xt u r e of m e t abo l i te s . B ec au s e o f t he hig h po la r i t y an d s ub se q ue n t h i gh e xc r e t i o n o f p ha s e I I m e ta b ol i te s , t he y a r e n o t li k e l y t o u nd e r go fu r t he r m e t a bo li s m . P h a se I m et a bo li t es , o n th e ot h e r h an d , a r e le s s p o la r an d a r e v e r y l ik e l y t o un d e rg o f u r t he r ph as e I I m e ta b ol ic r ea c ti on s . W her ea s t he m a jo r s i te o f m e t ab ol is m i s t he li ver , t he r e a r e m an y e xt r a he p a ti c s i t es t h a t s ec r et e d r ug - m e t abo l i z in g e n z ym es . Al t ho u gh m a n y m e t ab ol i te s a r e le s s p h a rm ac ol o gi c a l l y a c t i v e t h an t he i r p a re n ts , t h er e a r e m an y d r ug s wh o s e m e ta b ol i te s h a v e e qu a l o r g re a te r ph a rm ac o lo gic a l a c t i vi t y a n d s o m e t im e s g r e at e r t o xi c i t y as we l l . P r o d ru gs ( i. e . , d ru g s in a c t i v e i n t h e fo rm ad m i n is te r e d ) al wa y s f o r m a t le as t on e a c t i v e m e tab o li t e . 2 . T he an sw e r is C [ I I . A. 1 . e, 3. a , B. 2 .a . ( 2) , c ; Ta b le s 1 7 -2 , 17 - 3, a nd 17- 4 ] . B e c au se of t he t y pe s o f fu n c t i on al g ro u ps p r es e nt, a s p i ri n m a y u n de r g o a n u m b e r o f d i f fe r e nt m e ta b ol ic r ea c t io n s . Th e s e in c l ud e h y d ro xy l a t i o n of t he ar o m a ti c n uc l eu s , c o nj u ga ti o n o f t h e c a r b ox y l g r o u p wi t h gl yc in e , co n ju g at i on of t he c a r bo x y l g r o up wi t h g l uc u ro ni c a c i d wi t h t h e f o rm a ti on o f a n es t er g lu c ur o ni d e, h y d ro l y s i s o f th e a c et a te es t e r, an d c on j ug a t io n o f th e p he n ol g rou p ( re s u l ti n g f r om h yd r o lys i s o f t h e a c et a te es t e r) wi t h gl uc ur o n ic ac id to fo r m a n e t he r gl u cu r on i de . B e c au se th e a c et a te es te r is a s i m p l e es t e r , as p ir i n i s s us ce p ti bl e t o h yd ro l ys is i n t h e a ci d m ed i a o f t h e s tom ac h b e fo r e a bs o r pt i on ta k es p l ac e . I n a dd i ti on , a n y a c et yl a te d m ol e c u le s t h at a r e a bs o rb e d a re su bj ec t ed t o h y d r ol y s is a n d a re c a ta l yze d b y t h e m a n y es t e ra s e s p r es en t i n th e c i r c ul at i on . An y a c e t y l at ed m o le cu l es n o t h y d r ol y z e d i n t he c i rc u la t io n a r e s u b je c t t o h yd r ol ys is in the l i v er . A ll o f t he s e pr o c e s s es o c c ur b e fo r e t h e d r ug re ac h es t he gl om e ru l ar f il t ra t e ; t h e r ef o re , e xc r e t i o n o f t h e u nc ha nge d ac et yl a te d d r u g is hi gh l y u nl ik el y . 3 . T he an sw e r is A [ I I . A. 2 ; Ta bl e 1 7 - 3] . S u l f as al a z in e h a s b ot h an t i -i n fl am m a t o r y an d a n tib a c t e r ia l a c t i v i t y wh e n co n v e r t ed t o am in os a li c y li c ac i d a nd s u l fa p y r i di ne in t he bod y. Th i s re ac t io n o c c u rs b y r e d uc t i v e c l e a v ag e o f the “ a z o ” l in k a g e c on t ai ned i n t he s u l fa s a la zi n e m ol e cu le an d i s c a ta l y z e d i n t h e i nt es ti n e b y b ac te r i al a z or e duc t as e . Th i s is a f o rm of si t e -s p ec if ic d e li v e r y b ec au s e t he in ta c t d r ug is n o t a bs o rb e d f r o m t he st om ac h o r up pe r in t es t in e a n d re ac he s t h e c o l on , wh e r e i t i s m et a bo li ze d . S u l f as al a zin e i s o ne o f a f e w d r u gs t h a t i s e ff ec t i v e f o r t h e t re a tm e nt o f u lc er a ti v e c o li t is .
4 . T he an sw e r is B [ I I . B. 2 . a .( 2 ) ; I I I. G . 1 ; Ta bl es 1 7 - 2 , 1 7- 3 , a nd 1 7- 4 ] . Th e c hl o r am ph en ic o l m o le c ul e c on t ai ns an a ro m at i c n uc le us , wh i c h wo u l d b e s u bj ec t to h y d ro xy l a t i o n , a ni t r o g r ou p t h at is s u bj e c t t o r ed uc t io n , a n a m id e g ro up t h a t i s s u b je c t t o li v e r h yd r o l y s i s, an d a lc o ho l g r ou p s t ha t ar e s u bj ec t t o g l uc u ro n id a ti on . O f a l l t he e n z y m e s ys t em s r es p on s i b le f o r t he se r ea c t i ons , th e s ys t em re s p o ns ib le f o r gl u c u r on i da t io n i s d e v el op e d p o or l y in p re m a t u re i n f an ts an d i n f an ts up t o a pp r o xi m a te l y 6 - 8 we e k s o f a ge . 5 . T he an sw e r is D [ V I .A , B . 1 , 2 , 3 a n d 4 ] . B y d e f in i ti o n, p ro d ru gs ar e in a c t i ve o r v e r y we a k ly a c t i v e m o l ec ul es th a t re q ui r e i n vi vo a c ti v a t io n t o th e p a re n t m ol ec u le . Th us , c onv e r s i on of a d r ug m o le c ul e to a p r o d ru g d o es n o t i nc r ea s e p ot e nc y b ec au se th e or i g i n a l m o l ec ul e , wi t h wh a t e v e r p o t en c y i t c o nt a in s , is pro d uc e d a ft e r a dm i ni s t r a tio n . A va r i et y o f a d va nt ag e s, i n cl ud i ng in c re as e d wa t er s ol u bi li t y, du r a ti on o f a c t io n , o r al ab s o r p ti on , an d p a la t ab i li t y , c a n b e o bt a in e d t h r ou gh t he us e o f pr o d r ug s , b ut no n e o f t hes e a d va n ta g es re s u l ts i n a n i nc r e as e i n p ot e nc y o f th e pa r en t m o le c u le . 6 . T he an sw e r is B [ V I I .A . 4 , B .1 , 2 , 3 an d C .2 . c] . W hile k e ep in g fa ls e p os it i v e s a nd f al se ne g at i v es a t a m i ni m um i s a l wa y s d e si r ab l e, i t is m os t c r uc ia l t h at f als e n e ga t i v es be k e pt at a m i n im um fo r s a fe t y - b as e d as s a ys i n or d e r t o p r e v en t at - r is k pa t ie n ts f ro m b ei n g e xp o s e d t o p o te n ti a l s e r i ous s i de e f f ec ts . A h ig h e r r a te of f a ls e p os i ti v e s i s ac c e p ta b le si nc e p r e v e nt in g s er i o us a d ve r se ef f ec ts is pe rc e iv e d t o b e m o re i m po r ta nt t h an e xc l ud in g s om e pa t i en ts f r o m t he r a p y . P.419
G e n e ti c v a ri a ti on oc c u r s wh e n e ve r t he r e a r e b as e p a ir ch a ng es in th e D NA n u cl e ot id e s e qu en c e. The m o s t co m m on f or m o f g e n et ic v a r ia t io n i s a s ing l e n u cl e ot id e po l y m o r ph is m ( S N P ) . Th e c um ul a ti v e e f f ec ts o f t he se v a r ia t io ns va r y b a se d o n t h e t y p es an d lo c at i on s o f t h e S N P s . Va r i at i on s i n c od in g re g ion s c an al t e r p r o t ei n f u nc ti o n, wh i l e t ho s e i n sp l ic in g a n d p ro m o t e r re gi o ns c a n al t e r p ro t e in s i z e a n d p r o te in p ro d uc ti o n, re s pe c t i v e l y . So m e S N Ps p r o du ce no di s c e rn ab l e c h an g es a n d a r e t h er e fo r e g e ne t ic a ll y s i l en t . P h a rm ac og en e t ics p ri m a r il y s ee k s to u s e S N P s a n d o t he r ge ne t ic in f or m a t i on to p re d ic t p r ed is pos i ti o ns th a t i nf lu e nc e d r ug r e s po ns e a n d s a f et y i n in d i v id u al pa t ie n ts . 7 . T he an sw e r is D (I I , II I ) [ II . A ; Ta bl e 1 7 -2 ] . Th e r e ac t io n s ho wn i n the q ue s t i on in v o l v es t he c o n ve r s i on o f o ne fu nc t ion a l g r ou p t o an o th e r (a m i ne t o c a rb o n y l ) ; t hu s, i t is cl as s i fie d as a ph a se I r e ac ti o n. Th e i n t ro d uc t io n o f o xy g e n i nt o t he m o le cu le in d ic at es o xi d a t i on , a n d t he lo s s o f t he a m in o g r ou p s ig n if i es d ea m in a ti on ; th us , th e re act i o n a ls o ca n b e c la ss i fi ed as o xi d a t i ve de am i na t io n . N- D e a lk yl a ti on im pl i es th e r e m o va l o f a n a lk y l g ro up f r om a n i t ro g en . Th e n i t ro ge n i n t h e p a re n t m o l ec ul e d o es no t ha v e an al k y l g r oup a t ta c h ed t o it . 8 . T he an sw e r is C (I , II) [ I I . A, B ; Ta bl e 1 7 -4 ] . P h a se I I m e t ab o li c r ea c tio n s i n v ol v e m a s k in g a n e xi s t i n g f un c ti on a l g r ou p wi t h a n a t u ra l e nd o ge n ou s c o ns t i tu en t . Th e f o rm ul as sho wn i n c h oi c e s I an d I I re p r es en t
t h is t yp e o f r e ac ti o n, wi t h c h o ic e I be in g a n a c ety l a t i on r ea c t i on an d c ho ic e II , a g l yc in e c on j ug a ti on r ea c ti o n . C h oi c e I II r ep r es en ts a c ha n ge i n a n e xi s ti ng f u nc t io n al g ro up an d , t hu s , r e p re se n ts a p ha s e I r e a c t i on . I t is a n o xi d a t i ve d e am i na ti o n r e ac ti o n. 9 . T he an sw e r is C (I , II) [ I I . B. 2 .a . ( 4 ), I II . E .1 , 2; I V . B . 3 .b ] . E n t e ro h ep a ti c c ir c u l at i on r e f e rs t o th e p r oc es s b y wh i c h g l uc u ro ni d es , wh ic h a r e s ec r e te d i n to t he i n t es ti ne wi t h t he bi le , ar e h y d r ol y ze d b y in t es t in al ba c ter i a l β g l uc u ro n id as e . Th e h y d ro l y z e d f re e d r u g, wh i c h is n o lo n ge r po la r , b e c o m e s a va i la b le fo r in t es ti n al r ea b s o r p ti on in t o t h e s y s t em an d s ub s eq ue n t p en e tr a t io n to i t s a ct i ve s it e . I f a n e n z y m e s ys t em be c o m es s a tu r a te d , t he n t h e a c ti v e dr u g c an no t be ina c ti v a t ed b y t h a t p at h wa y . I f th e dr u g c a nn o t u nd e rg o a n al t e rn a ti ve p at h wa y, t h e in c r ea se d p l as m a le v e ls of an un c ha n g ed ac ti v e d ru g c an r es u l t in in c re as e d ac t i v it y o r t o xi c i t y. Th e f i rs t - pa s s ef f ec t re s u l ts in m e t ab ol is m o f a dr u g b y t h e l i v e r b ef o r e t he d r ug r e a ch es it s s it e o f a c ti on, r es u lt i ng in an o v e ra ll d e c re as e i n i ts ac t i vit y . D r u g s t ha t u n d er g o f i rs t -p as s m et a bo l is m g en e ra l l y a r e e f fe ct i ve in m u c h s m a l le r i n t ra v e n o us d o se s a s c o m p a r ed to o ra l do s e s . 1 0 . Th e a n sw e r i s C ( I , II ) [ I . A. 1 .c ; Ta bl e 1 7 -1 ] . Th e r e a re s i x m a m m al i an f am il i es i n vo l ved in s t er o i d a nd bi l e ac i d m e t abo l is m . Th e s e a r e C YP 7 , C YP 1 1, C YP 1 7 , C YP 1 9 , C YP 2 1, a nd C YP 2 7 . Si nc e c h ole s te r o l is t h e c om m o n i n te r m e di a te f o r t he bi os y n t h es is o f a l l e nd o ge n ou s s te r oi ds , s om e o f t h es e e n z y m es a re di r ec t l y i n v ol ve d i n c ho l es te r ol m e t ab o li s m . Th e f am il ie s l is t ed , C YP 7 , C YP 1 1 , a n d C YP2 7 , a l l m e t ab o li z e c h ol est e r ol , wh i l e t he ot h e r t h re e fa m i l ie s c a ta l yze a dd it i on a l o xi d at i o ns o f th e i ni t ia l m e ta b o l i te s . A s is e v id en t f ro m Ta b l e 1 7 - 1 , m u l ti pl e i s o f o rm s of C YP 4 5 0 c a n m et a bo li ze a s in g le d r u g . A n e xa m p l e o f t hi s i s s ee n wi t h im i pr a m i ne , a n a n ti d ep r es s a n t t ha t is m e ta b ol i z e d b y C YP 1 A , C YP 2 C , a n d C YP 2 D is o fo r m s . Ad d it i on al l y , Ta b le 1 7 - 1 i n di ca t es th a t t h e s u b fam i li es C YP 2 C , C YP 2 D , an d C YP 3 A m e t ab o li z e the m a j o ri t y o f d ru gs , o r xe n o b io t ic s . 1 1 . Th e a n sw e r i s A ( I ) [ I I I . F. 1 ]. P h a se I I m e t ab o li c r ea c tio n s r e qu i re na t u ra l e nd og e n ou s s u bs t r at e s , wh i ch n o rm al l y a r e s u pp li e d i n t he di e t . A d e fi c i e nc y o f t he se s ub s ta nc e s r es ul t s i n a d ec r e a se in t h e b i ot r a ns fo r m a t io n o f d r u gs th a t u s e th es e p a th wa y s . G l y c i ne c o nj u ga tio n is a p h as e I I re a c t i on . Gl y c i ne is an am in o a ci d th a t re q ui r es di e ta r y p r ot e in . A d i et d e f ic ie n t i n p r ot ei n , t h e re f o r e, c o ul d l e ad to a d ef i c i e nc y o f g l yc i ne an d , th u s , a d e c re as e i n g l y c i n e c o n ju g a ti on . G lu c ur o ni d at io n i s a ls o a ph as e I I re ac t io n th a t r e q ui r es en d og en o us gl uc u r on ic ac id , b u t t hi s s ub s ta nc e i s s up p li ed b y die t a r y c a r bo h yd ra t es . H y d ro xy l a t i on is a ph as e I m e t abo l ic re a c t i on an d d oe s no t r eq u ir e d i e ta r y p ro t ei n . 1 2 - 15 . Th e a n sw e rs a r e: 1 2 - B [ I I . B. 2 .a . ( 2 )] , 1 3 -E [ I I . A. 3 .a ] , 1 4 - A [ I I . B. 2 .a . ( 2 ) ], 15 - D [ I I . A .1 . e] . B e n zo ic ac id c o nt a in s a c a r bo xy l i c ac i d, a f u nc ti on a l g r ou p th a t c o m m on l y u n d er g oe s c on ju g at i on wi t h g l uc u ro ni c a c i d . Th e re s ul t in g c on j ug a ti on p rod u c e s a n e s te r . C ar b o xy l i c ac id s c a n al s o un d er g o c on ju g at i o n wi t h t he am in o a ci ds g l y ci n e
a n d g lu t am in e . Ad di t io n al l y , be n zo ic a c i d c an u nde r g o a r om at ic h yd ro xy l a t i o n , a c om m o n p h as e I pa t h way f o r d ru gs c o n ta in i ng uns u bs ti t u te d a r om a ti c r in gs . O f t h es e o p ti o ns , e s t e r g l uc u r o ni d at i on is th e o nl y an s we r a va il a bl e h e re . P.420
P r o c ai ne is an es te r - c o nt a i ni ng lo c a l a n es t he ti c . D u e to t he wi d e p h y si o log i c a l d i st r ib u ti o n o f e s t e r as e en z y m e s , i t i s e xt r e m el y s u sc e pt i bl e t o i n vi vo h ydr o l ys is . Th i s s u s c ep t ib il i t y to h y dr o l y s is i s t he m a jo r r ea s o n wh y e s te r - c o n ta in i ng l o c a l a n es t he t ic s h a v e s h o r te r d u r at i on s o f a ct io n as c o m pa r ed t o t ho se in o th er c he m i c a l c l as s e s. O n e o f t he p ri nc i pa l f u nc t i o na l g r ou ps in ac e ta m in o p he n i s t he ph e no l g r ou p . Si m i la r t o t he c a rb o xy l i c ac i d i n b e n z o ic a c i d , t he p he no l c om m o nl y u n de r go es glu c u ro ni d e c o nj u ga ti o n . Th e on e d i ffe r e nc e i s t ha t a p he no l (o r a n a lc oh ol ) p ro du c es a n e th e r g l uc u ro n id e , wh i l e a c a rb o xy l i c ac i d p r od uc es an e s t e r g lu cu r on i de . Ph e no l s a ls o c om m o n l y u n de r g o s u l fa te c o n ju g at i on re ac t io ns a n d o c c as io n al l y un d er go O m e th y l a ti o n r e ac ti o ns . Th e p r in c i p al fu n c t io n al g r o up in am ph e ta m i n e is i t s p ri m a r y a m i ne . O xi d a t i ve d e am i na ti o n is a v e r y c om m o n m e ta bo l ic p a th f o r p r i m a r y am in es . Oc ca s io n al l y, p r i m a r y am in es u nd e rg o p h as e I I ac et y l a ti o n; ho we ve r , th is is a l es s c o m m o n p a t h wa y . A r om a ti c h y d r ox y l a t i o n, s i m i la r to t ha t di s c us s ed ab o ve f o r b e n zo i c ac i d, i s a ls o p os s i b le fo r am phe t am i ne .
18 Drug-Drug and Drug-Nutrient Interactions Al i c e C . E n ge l b re c h t L e o n Sh a r ge l
I. INTRODUCTION A. D e f i n i ti on o f d r ug i n t er a c ti o n 1 . D r u g i n t e ra c t io n re f er s to an a d ve r se d ru g r es p on se p ro d uc ed b y th e a d m i ni s t ra ti o n o f a d ru g o r c o e xp o s u re of t he dr ug wi t h an o th e r s ub s ta nc e , wh i ch m o di f ie s t he pa t ie n t 's r es p on s e t o t he d ru g . S om e d r ug in t er ac t io ns a re in t e nt i on al i n or d e r t o p r o v id e i m p r ov e d t he r a pe u ti c r es p on s e o r t o d ec r e as e a d v e rs e d r u g e f f ec ts . A p r e ci p i ta n t d ru g is th e d r ug , c h em ic al , o r fo o d e le m e n t c au si ng t h e i n t er a ct i on . An ob j ec t d ru g is th e d r ug af f ec t ed by t h e in t er ac t io n . 2 . D r ug in t e ra c t i on s i nc lu d e : a . D r u g -d r u g i n te r ac t io ns b . D r u g - he r b al in t e ra c t io n s c . Fo o d -d r u g i n te r ac t io ns d . P h a rm a co g en e t ic in te r a c t i on s e . C h em i ca l - d ru g in t er ac t io ns , s uc h a s t h e i nt e ra c ti o n o f a dr u g wi t h a lc o h ol o r t o b acc o f . D r u g - la b o r at o r y t e s t i n t e r ac t i o ns s uc h a s c he m ic al in t er a ct i on s . B . C l a ss i f ic a t io n o f d r ug i n t e ra c t io n s. D r ug in te r a ct i on s t ha t oc c u r i n v iv o a r e g e n er a ll y c l as s i f ie d a s ph a r m ac o ki n e ti c o r p ha rm a c od yn a m i c in t e ra ct i on s . 1 . P ha r m ac o k in e t ic or bi o p h a rm a ce u t ic a l i nt e rac t io ns oc c u r wh e n t h e a bs o r pt i on , d i st r ib u ti o n ( p r ot e in an d t i s s ue bi n di n g) , or el im i na t i on ( e xc r e ti on an d / or m e ta b ol is m ) o f t he d ru g is a ff ec t ed b y an o th e r d ru g , c he m i ca l , o r fo o d el em e nt . 2 . P ha r m ac o d yn a m i c i nt e r ac t io ns oc c u r wh e n t he p ha r m a c o d y n am ic e f f ec t of th e d r u g i s a lt e re d b y a n ot he r d ru g , c he m i c a l , o r f o od e le m e n t, p ro d uc in g a n a n t ag o ni s t ic , s y n e rg is t ic , o r ad d it i v e e f fe c t. 3 . P ha r m ac o g en e t ic in te r a c t i on s oc cu r wh e n the p ha r m a co k i n et ic ef f ec t o f th e d r ug i s a l te r e d b y ge n et ic po ly m o r p hi s m s in a ff ec t in g p r o ce s s es . 4 . P ha r m ac e u ti c al in t e ra c ti o ns a r e c au s e d b y a c h em ic al o r p h ys ic a l i nc o m pa t ib il i t y wh e n t wo o r m o r e d r ug s a r e m i xe d t og e th e r . P h a rm ac e ut ic a l i nt e r ac ti o ns c a n occ u r d u r in g th e e xt e m p o ra ne ou s c om p ou nd i ng of d ru gs , in c l ud i ng th e p r e pa r at io n of i n t ra ve n ou s (I V ) s ol u ti o ns . Fo r e xa m pl e , a n I V s ol u t io n o f a m i n op h y ll i ne ha s a n a l ka li n e p H an d s ho ul d no t be m i xe d wi t h s u ch d ru g s as e pi ne p h ri ne , e r yt h r o m yc i n g l uc e pt a te , o r c e ph a lo t hin s o d iu m , wh i c h d ec om po s e i n a lk al in e p H . P he nyt o i n s o di um wi l l p r ec ip i ta t e f ro m a s o lu t io n th a t h as an ac i d p H , s uc h a s d e xt r o s e 5 %. P h a r m a c e u ti c a l i n te r ac tio n s a r e us u al l y c o ns id e re d du r in g th e d e vel o pm en t , m a nu f ac tu r i ng , a n d m a r k e t i ng of t he dr u g p r od uc t. O n l y d ru g i n te r ac t io ns in v o l v i n g p h a rm ac ok i ne ti c , p ha r m a c od y n am ic , or ph a rm aco g e ne ti c p r oc es s e s wi ll b e c o ns id e re d i n th is c h ap te r .
II. PHARMACOKINETIC INTERACTIONS A. A b s o r p ti on
1 . D r ug in t e ra c t i on s c an a f f ec t t h e r a t e a nd t he ex t e n t o f s ys te m i c d r ug ab s o rp t io n ( b i oa va i la bi l it y ) f r om th e a bs o r pt i on s i te , re s u l ti ng i n i nc r ea s e d o r d e c r e as e d d r ug b i oa va i la b il it y ( Ta b l e 1 8 -1 ) . P.422
Table 18-1. Drug Interactions That Affect the Bioavailability of the Drug from the Gastrointestinal (GI) Tract Drug Interaction Complexation/chelation
Adsorption
Examples (Precipitant drugs)
Effect (Object drugs)
Calcium, magnesium, or aluminum and iron salts
Levofloxacin complexes with divalent cations in the diet or tube feeding, causing a decreased bioavailability
Sodium polystyrene sulfonate
Cations in antacids bind to sodium polystyrene sulfonate, causing reduced renal clearance of bicarbonate, resulting in systemic acidosis
Cholestyramine
Decreased bioavailability of digoxin, levothyroxine
Kaolin
Decreased bioavailability of digoxin
Activated charcoal
Decreased bioavailability of many drugs
Acarbose
Decreased bioavailability of digoxin
Increased GI motility
Laxatives, cathartics
Increases GI motility, decreases bioavailability for drugs that are absorbed slowly. Will decrease the bioavailability of drugs from controlledrelease products.
Decreased GI motility
Anticholinergic agents
Propantheline decreases the gastric emptying of acetaminophen (APAP), delaying APAP absorption from the small intestine.
Alteration of gastric pH
H-2 blockers, antacids, and proton pump inhibitors
H-2 blockers, antacids and PPIs increase gastric pH. The dissolution of ketoconazole is reduced at basic pH, causing decreased drug absorption and therapeutic failure.
Alteration of intestinal flora
Antibiotics
Digoxin has better bioavailability taken after erythromycin. Erythromycin administration reduces bacterial inactivation of digoxin. Estrogen/progestin birth control requires intestinal flora to facilitate enterohepatic circulation. Antibiotics reduce intestinal flora and reduce estrogen/progestin levels resulting in
failure of ovulation suppression and menstrual changes. Inhibition of drug metabolism in intestinal cells
Monoamine oxidase inhibitors (MAOIs) (e.g., tranylcypromine, phenelzine)
MAOIs inhibit metabolism of albuterol and levalbuterol, leading to hypertension.
2 . Th e m os t c om m o n d r ug a bs o rp t io n s i te is in the g as t r o i n te s ti n a l ( G I ) tr a c t . H o we ve r , d r u g b io a v a il ab i li t y f r om o t he r ab s o r p tio n s i te s , su c h as th e s kin , c a n b e a f f ec t ed b y d r u g i nt e ra c ti o ns . Fo r e xa m p l e, ep i nep h r in e , a v as oc o ns t ri c to r, wi l l d e c re as e t h e p e rc ut a ne ou s a bs o r pt i on of t ra ns d er m a l li d oc ai n e o r t r a ns der m a l f e n ta n yl . 3 . O t he r p ot e n ti a l d r ug -d r u g a nd d ru g - fo o d in t e ra c ti o ns th a t a f fe c t bi o a va i la b il i t y i n t h e G I t r ac t c ou l d b e d ue t o : a . C o mp e t it i o n f o r c ar r ie r - m e d ia t ed d ru g a bs o rpt i o n i n wh i c h t he pa r t ic ipa n t d r u g c om p et e s f o r t he s a m e c a r r i e r as th e o b je c t i . C om p et i ti o n f o r t he P -g p s y s t em (a n A TP - d ep en d e nt ef f lu x p u m p o n e pit h e li al c e ll s o f t h e i nt es t in es ) is i n v o l v ed in t ra ns p or t of c y c lo s po r in an d d i go xi n . D i s pl ac em e nt c a n r e s u l t i n to xi c i t y o f t ho s e d ru gs . i i . G r ap e f ru i t j ui c e an d or a n ge ju ic e fr om S e v il l e o r a ng es in h ib i t O A TP ( o rg a ni c a n io n t ra ns po r t in g p o l y pe p t id es ) pr o te i ns i n th e e p i th el i al c e ll s o f t h e s m a l l i n t es ti n e, r ed uc i ng th e b io a v a il a bi li t y o f o r al fe xo f e n a di ne . b . Al t e r a t i on o f i nt es t ina l bl oo d fl o w c au s e d b y th e p re ci pi t an t dr u g. I n c o n g es ti ve h e a r t d is ea s e , th e b lo o d f l o w t o th e G I t r ac t i s p oo r a nd an or a ll y a dm in is te r e d d r ug can P.423 h a ve a s l o we r r a te o f a bs o r pt i on . Af t e r d ig o xi n t he r a p y , t h e p e rf us i on of th e G I tr ac t i s i m p r o v e d a lo ng wi t h bio a v a il a bi li t y o f t h e o bj ec t d r ug . B . D i s t r i bu t i on . Th e d is tr i b ut i on of t he d ru g m a y b e af f ec t ed b y p l as m a p ro t e in b i nd i ng an d d is p la c e m e nt i nt e r ac ti o ns o r ti s s u e an d c e ll ul a r i n te r ac t io ns . 1 . P la sm a p r ot e in bi nd i ng a nd di s p l ac em en t o n al b um in an d a l ph a 1- a c i d g l yc op r o te in c a r r ie r pr o te i ns . a . V al p r o ic ac i d d is p la c e s p h en y t o in f ro m p la s m a a lb um in p ro t ei n - bi nd i ng si t es an d r e d uc es he p at ic ph e n y toi n c l ea r an c e b y in hi b it i ng t he li v e r ' s m et a bo l is m o f p h e n yto i n, r es ul t in g i n h ig h e r p he n y t oi n l e v e ls . b . As p i r i n i s 9 0% t o 9 5% p r ot ei n bo un d a n d d is p l ac es wa r f a r in f ro m p r ote i n b in d in g s i te s r e s u lt i ng in hi g he r wa r f a r i n l e ve ls an d i nc r e a s ed bl e ed in g .
2 . T is s ue an d ce l lu l a r in t e r a c ti o ns . D ig o xi n t o xi c it y c an be en ha n c e d b y c o nc u r re n t a dm in is t ra t ion o f q ui n id in e . Qu i ni di n e r e d uc es d i go xi n c le a ra nc e a n d d i sp la c es d i go xi n f r om bo t h a l ph a -1 gl yc op r o te i ne a nd al b um i n ti s s ue - bi nd i ng s i t es , l e ad i ng to a h ig h e r p la s m a d i go xi n c on ce n t ra t ion . C . D r u g e li m i n at i on an d c l ea r an c e 1 . D r ug Me t a b ol is m a nd H e p a ti c C l ea r a nc e a . D r ug m e t ab ol is m ( h epa t ic c l ea r a nc e ) c a n b e a ff e c te d b y e n z ym e in d uc t io n , e n zym e i n hi b it io n , s ub s t ra t e c om pe t i ti on f or t he s a m e e n z y m e, an d c ha n ge s i n h e p at ic bl o od fl o w ( Ta b le 1 8 -2 ) . b . Ma n y d r u gs th a t s ha re t he s a m e d ru g -m et a bo li z i n g e n zy m es ha ve a p ot e n ti a l f o r a d r ug in t er ac t io n . F o r exa m p l e , fl uc on a z o le in h ib i ts t he he pa t ic m e ta b ol is m o f wa r f a r i n , c au s i n g i nc re as e d r is k o f b le e di n g. C a rb a m a ze p in e i s b ot h a s ub s t ra t e a nd a n in du c er o f t he C YP 3 A 4 is o en z ym e , t h e re b y ind u c i n g i ts o wn m e ta b ol is m an d t a ki n g 3 - 5 we e k s t o r e ac h s ta bl e b l oo d l e v e ls ( Tab l e 1 8 -3 ) . Ph e n y to i n is al s o a s u bs t ra t e o f t h e C YP 3 A 4 a n d i nd uc es it s o wn m e ta b ol is m . c . O ve r - th e -c o un t e r ( O TC ) d r u gs a n d h e rb al p rep a r a ti on s c an al s o be inv o l v e d in C YP 4 5 0 i s o e n z y m e m e t ab o li s m an d c an ca us e s er i o us d r u g -h e rb a l i nt e ra c t i o ns . F o r e xa m p l e , S t . J oh n ' s W ort m a y in du ce C YP 3 A 4 is oe n z ym e s a nd de c re as e c y c l os p o ri n t o su b th e ra p eu t ic l e v e ls . To b a c c o u s e (s m o k i n g ) c a n i nd uc e t h e C YP 1 A 2 is o en zy m e a n d d ec r ea s e c l o z a pi ne le v e l s , in c re as i ng th e ri sk o f t he r ap e u ti c f ai lu r e in t r ea t in g OCD. d . F oo ds m a y al s o in t e r fe r e wi t h h e pa t ic d r u g m et a b ol is m . F or e xa m pl e , gr a p e fr u it j u ic e i s a p o we r f u l i nh ib it o r of t he C YP 3 A 4 i s oe nz y m e , a nd wi l l i nc r ea s e b l oo d l e ve ls of C YP 3 A 4 s u bs t ra t es s u ch as ri t on a vi r , m e t h ad o ne , a m l o di pi n e, alp r a zo la m , c yc lo s po r in , a n d d il t ia z em , i f ta ke n to ge t he r .
Table 18-2. Drug Interactions That Affect the Drug Metabolism Examples (Precipitant Drug Interaction drugs)
Effect (Objective drugs)
Enzyme induction
Enzyme inhibition
Smoking (polycyclic aromatic hydrocarbons)
Smoking increases duloxetine metabolism and decreases duloxetine levels
Phenytoin
Tacrolimus levels are decreased because of increased metabolism
Mixed function oxidase
Cimetidine
Decreased atorvastatin clearance and increased drug levels
Induction of UDP-G metabolism
Phenytoin, cimetidine, midazolam, rifabutin
Decreased posaconazole levels due to induction of metabolism
Other enzymes
Monoamine oxidase inhibitors, MAOIs (e.g., pargyline, tranylcypromine)
Serious hypertensive crisis can occur following ingestion of foods with a high content of tyramine or other pressor substances (e.g., cheddar cheese, red wines, avocados), and catecholamines
P.424
Table 18-3. Drug/Herb/Food Actions with Cytochrome P450 Enzymes Enzyme CYP1A2
CYP2C9
Inhibitor
Inducer
Substrate
Ciprofloxacin
Phenytoin
Naproxen
Levofloxacin
Carbamazepine
Amitriptyline
Cimetidine
Charbroiled foods
Verapamil
Citalopram
Tobacco
Clopidogrel
Ketoconazole
Ritonavir
Duloxetine
Paroxetine
St. John's Wort
Ramelteon
Cimetidine
Rifampin
Tamoxifen
Fluoxetine
Carbamazepine
Losartan
Voriconazole
Phenytoin
S-Warfarin
Fluconazole
Celecoxib
Amiodarone
Phenytoin
Efavirenz
Carvedilol
Metronidazole
Voriconazole Glyburide Sildenafil
CYP2C8
Gemfibrozil
Phenobarbital
Paclitaxel
Nicardipine
Rifampin
Carbamazepine
Atazanavir
Carbamazepine
Amiodarone
Trimethoprim CYP2C19
Pioglitazone
Ketoconazole
Rifampin
Diazepam
Omeprazole
Carbamazepine
Phenytoin
Topiramate
Phenytoin
Citalopram
Fluoxetine
Omeprazole
Fluvoxamine
Diphenhydramine
Duloxetine R-Warfarin CYP2D6
CYP2E1
CYP3A family
Methadone
Carbamazepine
Amitriptyline
Cimetidine
Phenytoin
Metoprolol
Fluoxetine
Ethanol
Paroxetine
Ritonavir
St. John's Wort
Duloxetine
Haloperidol
Ritonavir
Haloperidol
Amiodarone
Venlafaxine
Paroxetine
Tramadol
Quinidine
Trazodone
Sertraline
Narcotic anagesics
Cimetidine
Ritonavir
Acetaminophen
Disulfiram
Isoniazid
Caffeine
Ethanol
Venlafaxine
Erythromycin
Carbamazepine
Atorvastatin
Ketoconazole
Phenobarbital
Warfarin
Saquinavir
St. John's Wort
Lidocaine
Verapamil
Nevirapine
Ethylestradiol
Efavirenz Metronidazole
Carbazepine
Cyclosporin
Amiodarone
Rifampin
Alprazolam
Cimetidine
Garlic Supplements
Ziprasidone
Diltiazem
Grapefruit
Doxorubicin
Posaconazole
Seville Oranges
Amitriptyline
Metronidazole
Bitter Orange
Methadone
Nifedipine
Cyclosporin
Voriconazole
Amlopdipine
Atazanavir
Indinavir Cyclosporin Paclitaxel Ritonavir Lidocaine Lovastatin
Midazolam Tamoxifen Zaleplon Atazanavir
P.425
e . N on h ep a ti c e n z y m es c a n b e i n vol v e d i n d r ug in t e r ac ti o ns . F o r e xa m p le, s er o to n in s yn d r om e h as b e en r ep or t e d i n p a ti e nt s r ec e i v in g a n ti d ep r es s a n ts s uc h a s c i ta l op r am (a n S S R I i nh ib i t or ) in c o m b in a ti o n wi t h a m on am i ne o xi d as e i nh i bi t o r, s uc h a s l in e z o li d . A c o ns i d e ra b le po r ti o n o f t h e CYP 3 A 4 e n z ym es a re fo un d no t o n l y i n th e l i v e r , b ut al s o in th e G I tr ac t , wh e r e s o m e o f t he s e s u bs t ra t es ar e m e ta b ol i z e d. f . A de c re as e i n t h e h epa t ic bl o od fl o w c an d ec rea s e t he he p at ic cl e ar a nce f o r h ig h e xt r a c t i on d ru gs , s uc h as p ro p ra n ol o l a nd m o r ph in e . 2 . R e na l d r u g c l ea r a n ce c a n b e a f f ec te d b y c han g es in gl om e ru l a r f il t ra ti o n , t ub u la r r e a bs o rp t io n , a c t i v e d r ug s ec r e ti on , a n d r e na l b loo d fl o w a n d n ep h r ot o xi c it y ( Ta b l e 1 8 - 4 ).
III. PHARMACODYNAMIC INTERACTIONS A. D r u g s th a t h a v e s im ila r p ha rm a c o d y na m i c a c t io n s m a y p r od uc e an e xc e ss i v e p h a rm ac ol o gi c a l o r t ox i c r e s p on s e. 1 . F or e xa m pl e , c en t r al n e r v o us s y s t em d e p re s s a n ts , s uc h a s t h e c o m b i na t i on of n a r co t ic s an d a n ti h is ta m in e s ( e .g . , d ip h en h y d r am in e , c hl o r ph en i r am in e ) c an p r od uc e i n c re as ed d ro ws i n es s i n t h e p a ti e nt . 2 . D r ug s h a v in g a n ti c h o lin e r gi c e f fe c t s , su c h as pr o m et h a zin e a nd O TC a n t ih is t am in es , c an c a us e e xc e ss i v e d r yn es s o f th e m o ut h , b lu r r ed vi si on , a n d u r i na r y r e te n ti o n. 3 . D r ug s t h at p ro lo n g t he Q Tc i n t er va l (s uc h a s pa l ip e r id on e , a m i od a r on e , s o ta lo l , m o xi f l o xa c i n, an d a t y p ic a l an t is p yc h ot ic s s uc h as z i p ra s i d on e ) h a v e a m u c h g r ea t e r r i sk of c a us i ng Q Tc in t e rv a l a r rh yt h m i as wh e n g i ve n to g et h e r.
Table 18-4. Drug Interactions That Affect the Renal Clearance
Drug Interaction
Examples
Effect
Glomerular filtration rate (GFR) and renal blood flow
Methylxanthines (e.g., caffeine, theobromine)
Increased renal blood flow and GFR will decrease time for reabsorption of various drugs, leading to more rapid urinary drug excretion.
Active tubular secretion
Probenecid
Probenecid blocks the active tubular secretion of penicillin and some cephalosporin antibiotics.
Tubular reabsorption and urine pH
Antacids, sodium bicarbonate
Alkalinization of the urine increases the reabsorption of amphetamine and decreases its clearance. Alkalinization of urine pH increases the ionization of salicylates, decreases reabsorption, and increases its clearance.
P.426
B . Th e p ha r m a c o d y n am ic e ff ec t of on e d r ug c a n b e an t ag o ni z e d b y t he op p os i te p h a rm ac o d y na m i c e ff e c t o f a s ec on d d r ug . Fo r e xa m pl e , t he an t ih y p e r te nsi ve e f fe c t o f be t a b lo c k e rs c a n b e o v e r c om e b y t he us e o f v a s o p re s s o rs . Ob v i o us l y, t hi s c an h a ve a d el e te r io us e ff ec t, b e a th e ra p eu t ic fa il u r e, o r b e a t he r ap e ut ic s t r at e g y in c l in ic al t re a tm e nt , d e pe nd i ng on t he s i tu a ti o n C . D r u g t h e ra p y c a n p r od u c e an ad v e r s e ef f ec t th a t re su l ts i n a n in c r ea se d s e n si t i vi t y o r t o x i ci t y w h e n a n ot h er d ru g i s g i v en . F or e xa m pl e , t h e a lt e ra t i on of e l ec t r ol y t e c on c e n t ra t io ns p ro d uc ed b y a di u r et ic , s uc h a s a th ia z i d e d e ri va t i v e , wi ll d e pl e te p ot as s i um , re s u lt i n g i n s e ns i ti z a t io n o f the h ea r t t o d i go xi n t h e ra py . D e p l et i on of s o di um b y a d i ur e ti c c an al s o r es ul t i n l it h iu m t o xi c it y . D . Th e r a pi es t ha t h a v e in t r i n s ic a ll y o p p o s i t e e ff e c t s o n t he sa m e ta r g et s y s te m c a n r es u lt in th e r ap e ut ic f a i lu r e. F or e xa m p le , n a lo xo n e c om pe t es wi t h n a rc o ti cs at t h e n a rc o ti c r ec e pt o r s ite , r es ul t in g i n t h e ra pe u tic f ai lu r e o f n a rc o ti c -b as ed a na g es ia t h e r ap y. E . P h a rm a co d yn a m i c dru g in t e ra c t i on s a ls o c a n o c c u r wi t h d r ug - h er b al int e r ac t io ns a n d d r ug - f oo d i n te r ac t ion s . F o r e xa m p l e, b y i n ges t i n g l a r ge am ou n ts o f vit a m i n K i n t h e d i et , th e e f fe c t o f a n ti c oa g ul at i on b y wa r f a ri n i s a n t ag o n iz ed .
F . S t ar t in g a n d s to p pi ng t h e r ap ie s t h at in f lu e nc e m e ta b ol is m o f o t he r d r u gs c a n r e s ul t i n t h e ra pe u ti c f a ilu r e i f th e i n du c e d m et a bo l is m r e du c e s t he bl o od l e ve ls of t h e ta r ge t d r u g. Fo r e xa m p le , s t ar t in g a pa t ie n t o n ni c o t in e p a tc he s r e pla c es s m o k i n g f o r a pa ti e n t. S in c e t he pa t ie n t i s n o l ong e r s m o ki n g t ob ac c o, the C YP 1 A 2 i s oe n z ym es ar e n o l o ng er i nd u c e d , a nd th e s ub s tra t es o f t he C YP 1 A 2 s ys te m ( c l o zap in e o r ha l op e ri d ol, f o r e xa m p le ) m a y b e i nc r e as ed to t o xi c l e v e ls . Th i s e ff ec t c a n oc c ur in s e v e r al en z y m e s ys t em s wh e n st o ppi n g p he n yt o in , a n i n du c er f o r s e ve r al C YP e n z y m e s y s t e m s .
IV. HERBAL-DRUG INTERACTIONS A. H e r b a l p r e pa r a ti on s ar e v a r io us c o m b i na t io ns o f he r bs , s om e ti m e s b ein g on e h e r b , o r a c om b in a ti on of h e rb s . S om e h e rb a l p r ep a r a ti on s r e p re se n t a s ing l e h e rb c o nt a in in g a v a r ie t y o f a lk a lo id s o r c o ns ti t ue n ts th a t m a y e xh i bi t a v a r i et y o f p h a rm ac ol o gi c a l a c t i v i ti es . 1 . S om e h e rb s c on t ai n a n um b e r o f d if f e re n t p ha rm ac o lo g ic al l y ac ti ve c o ns t i tu en t s . F o r e xa m pl e , S t . J oh n ' s W ort h as a t l ea st si x d i f fe r e n t co ns t it u en t s : h ype rf o r in , b i ap i ge n in , h y p e ri c i n , q ue r c it in , c h lo r og e ni c ac i d, a n d ps e ud o h y pe r ic in . Ea c h c o ns ti t ue n t h as it s o wn m e ta b ol is m , bi n di ng a nd p h a rm ac ol og ic ac t io n . Th e p r e do m i n an t e f f ec t o r i n te r a c t i on de pe n ds up on th e r el a ti v e po t en c y o f eac h c o ns ti t ue n t i n t h e h e rb . F o r e xa m pl e , t he c o ns t itu e n ts o f S t. Jo hn ' s W or t h a ve i n hi b it o r y ac ti v i t y o f t h e C YP 4 5 0 i so e n z ym e s 3 A 4, 2 C 9 , 1 A 2, 2 D6 , an d 2 D9 , bu t n o n e o f t he s e e ff ec t s a re c o ns i de r ed c l in ic a ll y s ig n i fi ca n t. S t . J o h n 's W ort a pp e a rs o ve r a ll t o b e a n i nd uc e r o f C YP 3 A 4 , a n d i ts c o nst i t ue n ts ha v e m a n y a d di ti o na l e f f ec ts on m e t ab ol is m an d bi nd i ng s i te s ( Ta bl e 18 - 5 ) .
Table 18-5. Pharmacokinetic Activity of the Constituents of St. John's Wort Activity
Site
Metabolized
CYP450, most notably by the 3A4 isoenzyme
Transported
Intestinal P-glycoprotein
Active at receptor sites
GABA, norepinephrine, dopamine, Lglutamate receptor sites
Active at reuptake sites
Seratonin reuptake and norepinephrine reuptake sites
Inhibits
MAO, and possibly the cellular phosphodiesterase sites
Inhibits
Beta-adrenergic and muscarinic receptor sites
Binding site competition
DNA sites in human leukemia cells
P.427
Table 18-6. St. John's Wort Drug Interactions Pharmacokineti c Process Site Metabolism
CYP3A4
Action Induces
Results in Lower levels of
Drug NNRTI
Protease Inhibitors Benzodiaze pines Calcium channel blockers Carbamaze pine Cyclospori n Irninotecan
Digoxin CYP2C9
Induces
Lower levels of
Warfarin
CYP1A2
Induces
Lower levels of
Warfarin
Transporter proteins
Intestinal Pglycoprot ein transporte r proteins
Increased catalyzed efflux of substrate drug
Lower levels of
Digoxin Calcium channel blockers Simvastatin
Pharmacody namic Toxicity
Serotonin reuptake receptor sites
Inhibits serotonin reuptake
Additive SSRI activity
SSRIs
Serotonin reuptake receptor sites
Serotonin agonist activity
Additive serotonin toxicity
Serotonin agonists (e.g. fenfluamin e) and “triptans”
MAO receptor sites
Increased MAOI and serotonin activity
Additive serotonin toxicity
MAOIs
Serotonin and norepinep hrine reuptake sites
Inhibits reuptake of norepinep hrine and serotonin
Norepinep hrine and serotonin toxicity
Nefazodon e
Pharmacoki netic
DNA binding sites in human leukemia cells
Distorts DNA binding sites
Reverses etoposidestabilized cleavage complexes
Antagonize s chemothera py effect of etoposide (in vitro)
2 . Ma n y h e r ba l d r u gs i n te r a c t at t he s am e tr a ns po r t , m e ta bo l is m an d re cep t o r s it es a s tr a di t io n al pr es c ri p ti on d r ug s ( Ta b le 18 - 6 ) . 3 . Tr a d it i on al C hi n es e m e d ic in e ( TC M) m a y c o nt ai n a c o m b i na t io n o f h e r bs . S om e i m po r t ed TC M p r o d u c t s h a v e be e n f ou n d t o c on ta i n u nl is t ed le g en d d r u gs . A n e xa m p l e i s a TC M m e d ic a t i on ad ve r t is ed to t re a t d i ab e te s t h at wa s fo u nd t o c o n ta in t h e p h a rm ac eu t ic al s g l y bu r i de an d p h en f o rm in . 4 . S om e h e rb a l p re p a ra t io n s m a y c on t ai n u n re c ogn i ze d c on t am in a nt s s uc h a s h ea vy m e ta ls , or a s im il a r -a pp ea r i ng he r b t h at is m is t ak e n l y ha r v e st e d. Th e s e a re q ua li t y c o nt r o l is s u es t ha t a r e t o a la r g e e xt e n t u n r eg ul a te d b y g o v e r nm en t a g en c i e s . B . D r u g -h e r ba l i nt e r ac ti on s c an oc cu r as p h a rm aco k in e ti c o r p h ar m ac od y na m ic i n t er a ct i on s ( Ta b le 18 - 7 ). C . D r u gs wi t h n a r r o w t her a p eu t ic wi n do ws a r e a t g r e a te r ri s k fo r dr u g -h e rb a l i n t er a ct i on s . Fo r e xa m ple , im po r t an t d r u g- h e rb int e r ac t io ns oc c u r wi t h p a ti e n ts t a ki n g wa r f a r i n. 1 . C oe n z y m e Q 10 ha s a c h em ic al s t r uc t ur e re l at ed t o v it am i n K . Th e c om bi n a ti on o f wa r f a r i n a n d Co en z y m e Q 1 0 r es ul t s i n a nt a go ni z e d wa r f a ri n ac ti vi t y an d in a d eq ua t e a n t ic oa g ul a ti on . P.428
Table 18-7. Table of Common Herbs and Potential Drug Interactions
Herb
Drug/Drug Class
Interaction
Effect
Black Cohosh
Antihypertensives
Pharmacodyna mic potentiation
Increased effect of antihypertensives (hypotension)
Coenzy me Q10
Warfarin
Pharmacodyna mic antagonism
Vitamin K antagonism (increased INR and risk of bleed)
Dong Quai
Beta blockers
Inhibition of CYP450 Enzymes
Increased level of beta blockers (increased hypotension)
Benzodiazepines
Inhibition of CYP 450 Enzymes
Increased benzodiazepine levels (increased drowsiness and CNS depression)
Echinace a
Immunosuppressa nts Monoclonal antibodies
Pharmacodyna mic antagonism
Decreased immunosuppressi on (flair of autoimmune disease, transplant graft rejection)
Ephedrin e Ma Huang
Beta blockers
Pharmacodyna mic antagonism
Sympathomimeti c effect (hypertension)
MAOIs
Blocked metabolism
Increased and prolonged sympathomimeti c effect (Hypertensive crisis)
Corticosteroids
Increased metabolism Induced hepatic metabolism
Decreased corticosteroid levels (decreased steroid effectiveness)
Antiplatelets
Pharmacodyna mic potentiation
Decreased platelet aggregation (increased risk of bleed)
Phenothiazines
Additive toxicity
Reduced seizure threshold (seizures)
Ginkgo biloba
Warfarin, LMWH
Pharmacodyna mic potentiation
Increased inhibition of platelet aggregation (increased risk of bleed)
Ginseng
MAOI
Pharmacodyna mic effect
Increased GABA metabolism and increased dopamine levels (mania symptoms)
Kava Kava
Acetaminophen Azole antifungals Statins
Additive toxicity
Increased otential for hepatic toxicity (elevated LFT, hepatic failure)
Barbiturates Benzodiazepines
Synergy
Increased GABA receptor binding affinity (increased drowsiness, CNS depression)
Evening Primrose Oil
Levodopa
Antagonism
Dopamine blockade (decreased effectiveness of levodopa)
Soy
Lethothyroxine
Impaired absorption
Decreased levels of levothyroxine (hypothyroid symptoms)
St. John's Wort
Irinotecan
Induced CYP3A4 Metabolism
Reduced levels of active irinotecan metabolite for chemotherapy (decreased myelosuppressio n)
Valerian
Sedatives
Pharmacodyna mic
Increased CNS depression (drowsiness and sedation)
Benzodiazepines
Displacement from binding sites
Displaced benzodiazepine but additive CNS depression (possible increased drowsiness)
P.429
2 . G i ng e r , g ar l ic , a nd f e ve r f e w a ls o i nc r e as e b le ed i n g in pa t ie n ts ta ki n g wa r f a ri n b y d i r ec tl y i n hi bi t in g p l at el et s an d c au si n g in c re as e d r i s k o f bl ee d in g . 3 . W he a t g ra s s ac tu a ll y c o nt a in s h ig h l e v e ls o f vit a m i n K wh i c h d i re ct l y an t a go ni ze s wa r f a r i n c a us in g i na d equ a t e a nt ic o ag u la t io n a nd t h e ra p eu t ic f a il u re . D . P o t en c y o f he r ba l p r ep a r a ti on s i s i nf l ue nc ed by a va r i et y o f fa c t o rs : 1 . Th e s t ag e o f g r o wt h du r i ng wh i ch t he he r b wa s h a r v es t ed 2 . Th e dr y i n g t im e
3 . Th e s o l v en ts us ed in e xt r a c t i on of t he he r b 4 . Th e s h el f l i fe an d s to ra g e c on d it i on s o f t he h erb a l e xt r a c t
V. Food-drug interactions A. F o o d c a n i nc r ea s e , de c r ea s e , o r no t a f f ec t t he a bs o rp t io n o f d r u gs ( Ta b le 18 - 8 ) . B . F o od c a n i nf l ue nc e t he b io a v ai l ab i li t y of a d r ug f r om a m o di f ie d - re l ea se d os ag e f o r m ( e .g . , c on t r ol le d re le a s e , d e la ye d re le a se [en t e ri c c oa t ed ] ) ra t he r th an f r om a n i m m e di a te - r el e as e d os ag e fo r m . F or e xa m p le , op e ni n g t h e c a ps u le of ent e r ic c o at e d o m ep r a z ol e b e ad s a nd gi v i n g i t i n a n a c i d ic f o od s u c h a s a p pl es au c e o r wi t h o r a ng e j u ic e , e as es a d m i ni s t r a tio n of t he dr u g wh i l e m ain t a in in g th e e n te r ic c o at in g on th e o m ep r a z ol e b e ad s u n ti l th e d ru g r e ac he s t h e b as ic p H o f th e d uo d en um wh e r e t h e o m ep r a z ol e b e ad s a r e un c oa t ed an d t h e d r ug is a b so r be d . C . C o m p l e xa t i on an d a ds o r pt i on of th e d r u g i n t he G I t ra c t wi t h an o th e r fo o d e l em e nt is a c o m m on d ru g in t e ra ct i on th a t r e du ce s th e e xt e n t o f d ru g a bs o r pt i on . F o r e xa m pl e , q ui n ol on e a n t ib io t ic s c o m p l e x wi t h c a l c iu m ( f ou n d i n m i lk p ro d uc ts ) . 1 . Q u in ol o ne an t ib i ot ic s wi l l c om pl e x wi t h c al c i um f ro m t h e d ie t a n d t he re s ul t wi l l b e r ed uc ed q ui no l on e a nt i b io t ic . 2 . I ba nd r o na t e f o r os t eop o r os is ha s s i g ni f ic an t l y r e d uc ed ab s or p ti o n wh e n g i v en wi t h f o od . Si n c e ab s o r p tio n is v e r y po o r, wi t h le s s t ha n 0 . 6% bi oa v a i la bi l it y i n f a s ti ng c i rc u m s ta nc es , an d up to 99 % p r o te i n b ind i ng , th e s ig n if ic a nt r ed uc t io n i n i b an d r on a te wh e n g i v e n wi t h f o od m a y r e du c e the d r u g to s u b th e ra p eu t ic l e v e ls . 3 . A n u m b e r o f d r ug s s uc h a s p h en y t o in an d q uin o lo n e a n ti bi o ti cs ar e a ds o r be d t o c a lc iu m a nd i ro n i n t u be f e e di ng s . D . F o od c a n b e m e t ab o liz e d b y t he s am e l i v e r e nz ym e s th a t m et a bo li ze dr u g s , c a us in g e n z y m e i nh i bi t ion o r i n du ct i on , a n d r es ult i n g i n t o xi c or su b th e ra pe u t ic d r u g l e ve ls . Fo r e xa m p l e, P.430 g r a pe f r ui t a n d v a l en c i a or a n ge s i nh i bi t th e C YP 3A 4 is o en z ym e s ys te m , c a u si n g i n c re as ed le v e ls o f s u bs tr a t e d r ug s s uc h a s s a q uin a vi r , i n di na vi r , m id a z o la m , n i m o di p in e , n if e di pi n e, lo v a s ta t in , c y c lo s p o r in , c a r b am a ze pi ne , a n d v er ap a m i l .
Table 18-8. Affect of Food on Drug Bioavailability
Reduced or delayed NSAIDs (nonsteroidal antiinflammatory drugs) naproxen, naproxen sodium
Increased
Not affected by food
Griseofulvin
Theophylline*
Metoprolol
Metronidazole
Aspirin
Phenytoin
Acetaminophen
Propoxyphene
Antibiotics (tetracycline and penicillin)
Dicumarol
Ethanol
Morphine
*
Food does not significantly affect drug absorption of theophylline in an immediate-release dosage form. However, food may affect theophylline absorption from a controlled-release formulation. E . F oo d c a n p ha rm a c o d yn a m i c a ll y a n ta g on i ze t h e e f f ec t o f s om e d r ug s . Fo r e xa m p l e , s p i na c h an d b ro c c o li p ro vi de di e ta r y s ou r c es o f v i ta m i n K, wh i ch a n t ag o ni z e s t he e ff ec t o f wa r f a r i n . G a r li c c an c a us e a d di t i v e a nt i pl a te le t ef f e c t in c om b in a ti o n wi t h wa r f a r in , he p a ri n , a nd L MW H , an d c a us e i nc r ea s e d ri s k o f b l ee d in g . F . F oo ds c a n c on t ai n p ha r m ac ol og ic a ll y ac t i v e c o m po u n d s t ha t i n te r ac t wi t h d r u gs m e an t to in hi b it en d og e no u s c o m po un ds . Mo n o am i ne o xi d as e i n hi bi t o rs (MA O I s ) p r e ve n t n o rm al m e ta b ol is m o f c a te c h ol am i ne s. Th e y a ls o i nh i bi t t h e m e t ab o li sm of t yr a m in e f r om t y r am in e c o n t ai ni n g f oo d s s u c h as r e d wi n e , ch e es e. Th e inc r e as ed l e ve ls of t y r am in e c a us e h y p e r t en s i v e c r is is .
VI. Chemical-drug interactions A. S m o k in g b y i nh al i ng ar o m at ic po l yc yc l ic h yd roc a r bo ns ( to b acc o ) c an ind u c e th e C YP 1 A 2 i s oe n z y m e m e t ab o li s m an d d ec r ea s e l e ve l s o f s ub st r a te d ru gs s uc h a s t h e op h yll i ne , d i a z ep am , t r i c yc l ic a n ti d ep r es sa n ts , d u lo xe t i n e , a nd r am el t eo n . B . E t h an ol c a n i nc r ea s e o r d ec re a s e th e a c ti vi t y o f he p at ic d ru g m e ta bo l iz i n g e n zym e s . 1 . C h ro n ic a lc o ho li s m c an i nc r ea s e th e ra t e o f m e t a bo li s m of t ol bu t am id e, wa r f a r i n, a n d p h en y t o in . 2 . A c u t e al c oh ol in t o xi c at i o n c a n i n hi bi t he pa t ic en z y m e s i n n o na lc oh o li c i n di vi d ua ls .
3 . E th a no l i n du c e s m e t ab o li s m in th e C YP 1 A 2 a nd 2 E 1 i s o en z y m e s . Le v e ls o f 1 A 2 s u bs t ra t es c l o z ap in e , c yc l ob e n z ap r in e , im i p ra m in e , n a p ro xe n a r e d ec r eas e d. Le ve l s o f t he 2E 1 s u bs t ra t es a c e t am i no p he n a r e r e du ced . 4 . D is ul f i ra m i nh i bi ts al c o h ol de h y d r og e na se , re s u l t i n g i n l im it e d m e t ab o lis m o f e t h an ol a nd c a us in g s e ve r e et h an ol in t ol e r an c e .
VII. Pharmacogenetics and Drug Interactions A. G e n e t i c di f f e re nc es in d r u g m e t ab o li s m a r e t h e r e s u l t o f g en e ti c a l l y b a s e d va r i a ti o ns in al l el e s f o r g e n es t h at co d e f o r e n zym es r es po ns i bl e f o r t h e m e ta b ol is m o f d ru gs . 1 . I n n or m a l e n z y m e f u nc t io n , t h e g en e e nc o di ng f o r th e e n zy m e is c o m po s ed of t wo n o r m a l a ll e le s . In P o l ym o r p h i sm s , t he ge n es c on t a in ab n or m a l p a i rs o r m u lt i pl es of a b n or m a l a l le le s l ea d in g t o al te r e d e n z ym e f un ct io n . 2 . P ol y m o rp hi s m s c an oc c u r i n a n y en z y m e s y s t em in c l u di ng t he C YP 4 5 0 h e p at ic e n zym e s , th e m i xe d o xi d a s e a nd n -a c e t yl tr a ns f era s e s ys t em s , a nd th e UG T m e ta b ol ic en z y m e s y s t em s . I n t he C YP 4 5 0 s y s t em , th e C YP 2 D 6 , C YP 2 C 9, a nd C YP 2 C 1 9 p o l ym o r ph is m s a re th e m os t e xt e n s i vel y s t ud ie d . 3 . D i ff e re n c e s i n e n z y m e a c ti v i t y oc c u r a t di f fe r ent r a te s a c c o rd in g to ra c ia l gr o up ( Ta b l e 1 8 - 9 ). 4 . P o l ym o r p h i s m s ( d if f er e n c e s i n t he al l el es ) c an a ls o va r y wi t h i n a ra c ia l gr o up b y g e o gr a ph ic di s t r i bu t io n . F o r e xa m pl e , i n W es t er n E u r op e an s p ol y m o rp h is m f or t he C YP 2 D 6 a l l el es c a n v a r y wi t h 1 0 t im es as m a n y ul t r a m et a bo li ze r s ( U M) i n G r e e c e a s i n Au s tr i a. 5 . Th e e xt e n t o f t h e d r ug i n te r ac t io n i s p r ed ic t ed b a s e d u p on th e b as e li ne a c ti v i t y of t h e e n zy m e i n a n i nd i v i du a l . B as e li ne en z y m e ef fi c i e nc y v a r i es g r e at l y am o n g i n di vi d ua ls de p en di n g u po n th e t y pe an d e xt e n t of p ol y m o rp h ic c ha n ge s to t he e n zym e . B . S i n g le N uc l eo t i de Po l ym o r p h i s m s ( S N P s ) ar e s i n gl e c ha ng e s in on e a l le le o f a g e n e r es po n s i bl e f o r a v a r i et y o f m e ta bo l ic p r oc es s e s i nc lu d in g e n z ym a ti c m e ta b ol is m . P.431
Table 18-9. Ethnic Differences in the CYP2D6 Enzyme Activity
Ethnicity
As a Percentage of the Population
Caucasians
7-10% PM / 1% UM
African-Americans
8% PM
Asians
>50% PM / 1% UM
Adapted from Zagaria MAE. The promise of pharmacogenomics. Available online at http://www.uspharmacist. com/index.asp?show=article&page=8_1190.htm. Retrieved January 18, 2006; and Johannson I, Oscarson M, Yue QY, et al. Genetic analysis of the Chinese cytochrome P4502D locus: Characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994;46:452-459. 1 . Th e ge ne t ic S N Ps c a n b e o f s e v e r al di f fe r en t k i n ds , re su l ti n g i n m a n y di f f e re n t va r i a n ts o f th e e n z y m e . C YP 2 D 6 h a s m or e th an 7 0 va r ia n t a ll el es . 2 . Th e c om b in a ti on o f a lle l es en co d in g t h e g en e d e t e rm in es th e a c ti v i t y of t h e e n zym e . Th e c o m b i na t ion s c an in c l u de m i s s in g al l el e s , de f ec ti ve al l el es , d u pl ic a te d , a n d m ul t ip le al l el es . In ad d i ti on , al le l es c an de m o n s t ra t e a m p li f ic at i on , s ub s ti t u ti on , o r d ef ec t i v e s pl ic in g . N u ll e n z y m e ac t i vit y , o r a bol i sh ed ac t i vit y c an occ u r f r o m e r r o rs in t ra ns c ri p ti o n, s p l ic in g , s ta r t a n d s to p c od o ns , a n d a m i no ac id cha n g es . 3 . Th e c om b in a ti on o f a lle l es in th e a f f ec te d g e ne r e s u l ts i n d i f fe r en c e s i n t h e e f f ec t i v en es s o f t h e e n z ym e . Th e o ve r al l f un c ti on o f t he en zy m e i s t h e p hen o t yp e o f e n zym e fu nc t io n . *
*
a . P oo r m e ta b ol i z e rs ( PM) c a r r y t wo d e f ec t i v e a ll e le s , f o r e xa m p le C YP 2 D 6 4 / 5 a nd *
*
C YP 2 D 6 4 / 4 . P Ms a l s o in c lu d e c o m b i na t io n o f a lle l es in c l ud i n g on e re su l ti n g i n n o *
*
e n zym e , f o r e xa m p l e C YP 2 D 6 5 an d C YP 2 D 6 4 /de l e ti on . b . I nt e rm e di a te m e ta b ol iz e r s ( I M) a r e h e te r o zy g ou s , t h at is , h a vi ng on e wi l d t y p e a l le l e a nd on e d e fe c ti v e a l le l e. c . N o rm al m e ta b ol i z e rs c a r r y “ wi l d t y p e” al l el es , fo r e xa m p le C YP 2 D 6 * 1 / * 33 . W il d t yp e al l el es en c o d e g en es f or no r m a l e n z ym e f u nc t io n . d . E xt e n s i v e m e t ab o li z e rs ( E M) c a r r y on e wi l d t ype a nd on e a m p l if ie d g e ne , f or *
*
e xa m p l e C YP 2 D 6 1 / 2 . An o t he r e xa m pl e o f E M c ar r y t h e f o ll o wi n g p ai r s : *
*
*
*
C YP 2 D 6 A / 1 a a n d C YP 2 D 6 1 A / 5 . e . U l tr a - r ap id m e t ab ol i z er s ( U M) c a r r y t wo o r m o re co p ie s o f a n a m p li f ie d g e n e, fo r *
*
e xa m p l e C YP 2 D 6 2 / 2 . 4 . G e ne t ic c ha n ge s m a y i n ac t i v at e o r r ed uc e e n zy m a t ic ac ti v i t y ( e .g . , p oor m e ta b ol i z e rs ) , l ea d in g t o i nc r e as es i n t h e s ub s t r at e d ru g . 5 . G e ne t ic d u pl ic a ti o n m a y i nc r e as e e n z ym at ic ac t i vi t y (e . g. , ul t ra - r ap i d m e ta b ol i z e rs ) , re s u l ti ng in l o we r le v e ls of t he s u bs t r at e d r u g.
6 . I n t he C YP 2 D 6 en z y m e , ge n et ic v a r ia t io n c an c a us e a 10 - to 30 - fo l d d if f e r en c e in t h e l e ve ls o f dr u gs m e tab o li z e d b y t h at en zy m e . Ta b l e 18 - 10 li s t s a fe w C YP 2 D 6 va r i a n ts a n d t he i r e f fe c ts o f th e d r ug m e t ab ol is m a c ti v i t y o f t he e n z ym e . C . P o l ym o r ph is m s af f ec t d r u g i nt e ra c ti on s b y a lt er i n g t h e e ff ec t of in h ib i tor s an d i n du c er s o n t h e e n z y m es . Th e r es ul t is a n e xa g g er a t e d e ff ec t o r m i ni m al ef f e ct on t h e s ub s t ra t e. 1 . I n a n E M , t he le v e l o f s u bs t ra t e d r ug is n o rm a lly l o w b e c au s e of t he ra pi d m e ta b ol is m b y t he en z y m e . A n in h i bi t o r to th e e n z ym e wi l l s ub st a nt i al l y i n hi bi t th e e xt e n s i v e m e ta b ol is m a nd c a us e s i gn if ic a nt el e v at i o ns i n t h e s ub s t r a te d ru g . Th e s u bs t ra t e l e v el s r is e d r am a ti c a l l y b ec a us e t h e e ffe c t o f t h e i nh i bi t or is m uc h g r e at e r i n an E M. Th e d r ug in t e ra c ti o n m a y o c c u r t o a gre a t e r e xt e n t th a n i t wo u ld i n n o rm al m e ta b ol i z e rs ( Ta bl e 1 8 - 11 ) . 2 . I n a PM , t h e l e v el of s u b s t r a te d ru g re m a in s h ig h be ca us e th e m et a bo lis m o f t h e s u bs t ra t e i s m u c h le s s tha n no r m a l . W hen a n i n h ib i t o r is a d de d t o th e r e gi m en , th e a d di t io n al P.432 i n hi b it i on of m e t ab ol is m i s n o t m uc h g r ea t er t ha n i s a l re a d y o cc u r ri ng in a P M. Th e r e f o re t he ef f ec t o f an i nh ib i to r on a P M i s l es s t ha n i t wo u ld be in no rm a l m e ta b ol i z e rs . Th e d r ug in t e r ac ti o n m a y n o t oc c u r.
Table 18-10. Allele Activity Patterns in the CYP2D6 Isoenzyme Gene
Polymorphism
Enzyme activity Phenotype
CYP2D6*1
Wild-type
Normal
EM or normal
CYP2D6*2
Same as 2D6*1 but possible
Increased enzyme
EM/UM
Duplication or amplification
Activity
CYP2D6*4
Defective splicing
Inactive enzyme
PM
CYP2D6*5
Gene depletion
No enzyme
PM
CYP2D6*10
Single AA substitution predominant
Reduction in
PM
CYP2D6*17
Variant in people of Asian descent
Enzyme activity
Single AA substitution predominant
Reduction in
Variant in people of African descent
Enzyme activity
PM
Adapted from Zagaria MAE. The promise of pharmacogenomics. Available online at http://www.uspharmacist.com/index.asp?show=article&page=8_1190.htm. Retrieved January 18, 2006; Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P4502D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J 2005;5:6-13; and Lee LS, Nafziger AN, Bertino JS Jr.Evaluation of inhibitory drug interactions during drug development: Genetic polymorphisms must be considered. Clin Pharmacol Ther 2005;78:1-6. 3 . I n a n E M , t he le v e l o f s u bs t ra t e d r ug is a g ai n lo we r t h a n e xp e c t ed i n a n o r m a l m e ta b ol i z e r b ec au s e o f th e r ap id m e t ab ol is m . Th e a dd i ti on o f a n i n du c e r d o es no t c a us e a gr e at di f f er e nc e i n th e l e v e l o f s ub st r a te b e ca us e th e m et a bo li s m i s a l re a d y i n c re as ed g re a tl y . Th e dr u g i n t er ac t io n m a y no t oc c u r . 4 . I n a PM , t h e l e v el of s u b s t r a te d ru g i s a ga i n hig h e r t h an e xp e ct e d i n a n o r m a l m e ta b ol i z e r b ec au s e o f th e lo we r m et a bo li s m of th e s u bs t ra t e . Th e ad d it ion o f a n i n d u ce r wi l l c au s e a s ign i f ic an t i nc r e as e i n t he m e ta b ol is m o f t h e s u bs t ra t e a n d c a us e a m uc h l o we r l e v el o f s ub s t r a te th a n e xp e c t e d i n a no r m a l m et a bo liz e r . Th e d r u g i n te r ac ti o n m a y o c c u r t o a g r e at e r e xt e n t t ha n in no r m a l m et a bo li ze rs , or t he d r u g i n te r ac ti o n m a y r e s u l t i n s ub s tr a te le v e ls sim i la r to th os e o f no r m a l m e ta b ol i z e rs . 5 . A s a g e ne r al r ul e , t he e f f ec t o f i n hi bi t o rs is g r ea t e r i n E Ms t ha n i n P Ms . Th e e f f ec t o f i n du c e r s is g re at e r in P Ms t h an in E Ms . 6 . Th e di f fe r en c e be t we e n E M a n d U M c a n b e d e sc r i be d a s t he di f fe r e nc e b e t we e n h e t e ro zy g o us an d h om o zy g o u s i nd i v i du al s wi t h du p li c a t ed o r a m p li f ie d g en e s . Th e a d di t io n o f an in hi b it o r to a n U M wo u l d be e xp e ct e d to s h o w a n e ve n g r ea t e r d r ug r e a ct i on th a n wo u l d b e s e e n wi t h a n E M. 7 . C om pl e x d r u g i n te r ac ti o ns c a n b e s ee n wh e n a s ub s t ra t e is m e ta b ol i z ed t h ro u gh m o r e t ha n o n e e n z y m e s y s t e m wh e r e on e o r m o re e n zy m es a r e a f fe c te d b y p o l ym o r ph is m . I n t h es e c as e s , th e s ub s t ra t e is m e ta b ol i z e d t h ro ug h a po l ym o rp hi c e n zym e an d b ec om es an a c ti v e m e ta b ol i te an d an i nh i b i to r o r i nd uc e r i n a s e co n d s ys t em . Po l y m o r ph is m i n t h e f i rs t e n zy m e c an c au s e t he le v e l o f th e i n hi bi t o r o r i n du c er t o b e g re a t er o r le s s t ha n
P.433 e xp e c t e d , t hu s c au s i ng th e e xt e n t o f th e e xp e c t ed i nh ib i ti o n o r i n du c t i on o f t he s ec o nd en z y m e to be s i gn i f ic an t l y c ha n ge d .
Table 18-11. The Effect of Inhibition of EM/UM and PM on CYP2D6 Substrates
Enzyme
Inhibitor
Substrate
Effect of Effect of EM/UM On PM On the the substrate substrate
CYP2D6
Diphenhydramine
Metoprolol
Increased 61%
Little change
CYP2D6
Quinidine
Svenlafaxine
Increased 4x
Little change
Rvenlafaxine
Increased 12x
No change
CYP2D6
CYP2D6
Diphenhydramine
Venlafaxine
Increased 2x
Little change
CYP2D6
Fluoxetine
Risperidone
Increased 4x
Increase 1.3x
Adapted from Lee LS, Nafziger AN, Bertino JS Jr.Evaluation of inhibitory drug interactions during drug development: Genetic polymorphisms must be considered. Clin Pharmacol Ther 2005;78:1-6. D . S p ec i fi c P h ar m a c o g en o m i c D r u g I n te r ac ti o ns f r o m t he li t e ra t u re . 1 . O m e p r a z ol e I n on e s t ud y o f o m e p ra z o l e a c t i vi t y on th e i n hi bi ti o n o f m oc lo b em id e i n CYP 2 C 1 9 E Ms a n d P Ms , t he e ff ec t o f i n hi b it i on v a ri e d ac c or d i ng t o t he de g re e o f gen e t ic p o l ym o r ph is m . O n e wo u ld e xp e c t i nh i bi t io n o f th e m e ta bo l is m o f t he su bs tr a t e m oc l ob em i de b y t h e i nh ib i t or om e pr a z o le . Bu t in E Ms , t h e A U C l e v e l o f t he s u bs t ra t e m oc lo be m i d e al m os t d ou b le d , r e fl ec t in g t h e g r ea t e r e f fe c t of in h ib i t io n o n m oc l ob em i de wh i c h wa s o r i gi n al l y e xt e ns i v e l y m et a b o l i zed . In co m p a ri so n, P Ms a l r ea d y s h o w p o or m e t ab o li s m of t he m ec l ob em id e . In hi b it i on of th e 2 C 19 e n z ym e b y o m e p r a z ol e i n P M d i d n o t s ho w a n e xt e n si ve ch a n g e i n th e A U C l e v el s o f m oc l ob em i de , b ec a us e m e ta b ol is m wa s a lr e ad y i m pa i re d .
1
2 . Fl u v o xa m i ne F l u vo xa m i ne in hi b it s t h e m e ta b ol is m o f d ip h en y d ra m i n e b y t he C YP 2 C 1 9 is o en zy m e . W hen E M t a k in g d i ph e n yd r a m i ne we r e gi ve n th e 2 C 1 9 i n hi bi t o r f lu vo xa m in e , th e
A U C a n d Cm a x l e v e ls o f d i ph e nh y d r am i ne in c r e ase d s i gn i fi ca n tl y o ve r p l ac e b o . W hen P M t a k in g d i ph e nhy d r a m in e we r e g i v en t he i n hi b i t o r f lu v o xa m i n e, t he A U C a n d Cm a x o f di p he nh y d ra m in e d id no t c h an g e s ig n i fi c a n tl y . Th e ef f ec t o f i n hi bi t io n o n th e s ub s t ra t e o f a n EM i n t h e C YP 2 C 1 9 wa s gr e a t er t ha n i t wo u ld ha ve b e en in a n o r m a l m et a bo li z e r . Th e e f f ec t o f i n hi bi t io n o n the su bs t r a te of a P M i n C YP 2 C 1 9 i s n o t s ig n if ic a nt . In ad d it ion , t ho s e E Ms wh o we r e h o m o z yg o us s h o we d g rea t e r i n hi b it i on th a n t he E Ms wh o we r e h e t e ro z y g o us . Th i s de m o ns t r a te s t ha t th e de g re e o f in h ib i ti on v a r ie s b y g en o t y p e. H om o z y g o us E Ms s h o we d gr e a te r re d uc tio n in e n zym e ac ti v i t y t ha t h e ter o z y g o u s E M. I n t he s a m e wa y , E M s h o w g r e a t e r i n hi b it i on t h a n P M b e c au s e P M a l re a d y ha ve r ed uc e d e n z ym e a c ti v i t y an d wi l l n ot s h o w a g r e a t ch a ng e i n Cm a x o r A U C , e v e n wi t h in h ib i ti on .
2
3 . D ip h en h y d r am in e D i p h en h y d ra m i n e i nh ib i ts t he m e ta b ol is m o f m eto p r ol o l. In E M i n t he C YP 2 D 6 , th e C m a x a n d A U C o f di ph en h y d r am in e i nc r e as ed b y 1 6 % a n d 61 % , r es p ec ti v e l y , as c om p a re d t o n o n -p ol y m or p h is m s . Th e in h ib i to r dip h e n h yd r am in e d ec r e as ed c o n ve rs io n o f m e to p ro l ol t o i t s m e t ab o li t e b y a f ac t o r o f 3 . In th e P M, t h e c h an g e i n m e to p r ol ol c o n v e rs io n wa s i ns i gn i fi c a n t. A ga i n, th e ef f ec t o f i n hi b it io n o n t h e s u bs t ra t e i n t h e E M wa s g r e a te r th an in P M.
3
4 . D ip h en h y d r am in e D i p h en h y d ra m i n e i nh ib i ts t he m e ta b ol is m o f v en la f a xi n e b y th e C YP 2 D 6 is o en z ym e . W hen d ip he n h y d ra m i n e is gi v e n to a E M wh o i s ta k in g ven l af a xi n e , t h e l ev e l s o f ve n l a fa xi n e r is e t wo f o l d. D i p he n h y d ra m i ne gi ve n t o a P M wh o i s t ak i ng v en l a fa xi n e c a us es i n s i gn i fi c a n t c han g e i n t h e l e v el s o f ven la f a xi n e . As wi t h t h e e xa m p le wi t h m e to p r ol ol ab o v e , t h e e xt e n t o f i n hi bi t io n i n E M is m u c h g re a te r th an in PM.
4
E . Th e e ff ec t of po l y m o rp h is m o n d r ug de v e l op m e n t a n d d r ug s a fe t y . 1 . Mo s t d ru g c om pa n ie s d u r in g d r u g d e vel op m e n t d o n o t g en o t yp e t he i r s u b je c ts fo r p o l ym o r ph is m s . In s m a l l s t ud i es , o r i n s t ud ie s o f g e n et ic al l y h om og en o us s u bj ec ts , t h e p h a rm ac ok in e ti c s d es c ri b ed fo r th e d r u g m a y b e s ke we d t o wa r d t h e p o l ym o r ph is m s p re v a le n t i n t h e s ub je c t p op ul a ti on . Th i s c a n o c c u r wh e n , f o r e xa m p l e , A s i a ns a r e t h e p r i m a r y su bj e ct po p ul a tio n fo r ph a rm ac ok i ne t ic s t u d ie s f o r a d r ug m e ta b ol i z ed b y CYP 2 C 1 9 . C YP 2 C 1 9 po l ym o r ph is m s o c c u r i n 2 0% t o 25 % o f t h e As ia n p o pu la t io n . 2 . W he n p ol y m o rp h is m s a n d p h ar m a c og en om ic s a r e no t c o n s i d e re d d u ri ng d r ug d e ve l op m e n t, th e re s u l t c a n b e t he de v e l op m e n t o f s o m e d ru gs th a t h a v e s h o wn t o xi c i t y i n c e r t ai n p op u lat i o ns , a nd ha v e b ee n wi th d r a wn f r om t h e m a r k e t a s a r e s ul t . Th e s e d ru gs in c l ud e t ro g li ta z o n e ( R e z u li n ) a n d m i b ef r a di l. 3 . P ha r m a c o g en om ic te s t i n g d u ri ng d ru g d e ve lo pm e nt c a n i de n ti f y t he dos i ng va r i a bl es in c e r ta i n p ol y m o r ph ic po pu l at i on s a nd c o u l d l ea d t o a g re a te r s a fe t y i n t h e u se o f t he s e P.434 d r u gs . Cl i ni c a l t r ia ls in wa r f a ri n th e ra p y wi t h ge n et i c t es t in g f o r p o l ym o r ph is m s in *
*
C YP 2 C 9 s u c h as t h e C YP 2 C 9 2 an d C YP 2 C 9 3 . 4 . Th e i d en t if ic a ti o n o f po l y m o rp hi c f ac t o rs i n a s p e c i f ic d r u g u nd e r d e v elo p m e n t m a y li m i t th e c li ni c a l u s e o f th a t d r ug to c e r ta i n ph a r m a c o g en om ic po pu l ati o ns .
5 . Th e F D A m a y m ak e r ec om m e n da t io ns , or r eq u ir e la b el i ng fo r ge n et ic tes t in g o f p a t ie n ts to de t er m i n e p oly m o r p hi sm s t ha t a f fe c t dr u g m e ta b ol is m o r t r a ns po r t . a . Th e i n v a de r U G T1 A 1 m o le c u l ar as sa y f o r U G T 1 A 1 de t ec ts po l ym o r ph is m s t h at c a n r e du c e th e m e ta bo l is m o f i r in o te c a n , a c h em o t h e ra p y fo r c o lo r ec t al ca n c e r . b . Th e F D A h as c l ea r ed t h e Am pl ic C h ip C yt oc h rom e P4 5 0 G e n ot y p i ng Tes t fo r p o l ym o r ph is m s in th e C YP 4 5 0 i s o en zy m e s ys t em wh i c h is e xt e n s i ve l y i n v ol ve d in d r u g m et a bo li s m . c . Th e F D A ha s a d de d l ab e li n g t o v a ri ou s d r ug s to t es t f o r g e ne t ic p o l ym or p h is m s t h a t a f fe c t m e t ab ol is m , s u c h as a nt ie p il e pt ic d ru gs . d . Th e F D A h as al s o m an d a te d t h e t es t in g o f H IV s t ra i ns fo r g u id a nc e i n u s i n g Ma r a vi r o c .
VIII. CLINICAL SIGNIFICANCE AND MAN AGEMENT OF DRUG INTERACTIONS A. P o t e n t ia l d r ug in t e ra c t i o ns 1 . M u l t ip l e -d r u g th e r apy, i n c l u di ng bo t h p r e sc r ip t i o n a n d n on p r e sc r i p tio n ( O TC ) m e di ca t io n , c a n p o te n ti al l y l ea d t o d r u g in t e ra c tio n s . Th e m o r e d ru gs us ed b y a p a t ie n t, t he gr e at e r t h e po t e nt i al fo r a d r ug in t er ac t io n . 2 . M u l t ip l e p r e sc r i b e rs . P a t ie n ts c a n b e se e n b y d i ff e r en t p r es c ri b er s who p r e sc ri b e i nt e r ac ti n g m ed i c a t io n . 3 . P a ti e n t c om p l ia n ce . P a t i en ts ne e d t o f o ll o w pr o p e r i ns t ru c ti on s f o r t ak i n g m e di ca t io ns . Fo r e xa m p le , a p a ti en t m i gh t t ak e te t r ac y c li n e wi t h f oo d r a th e r th a n b e f o re m e al s . 4 . P at i en t ri s k fa c t o rs a . O l de r pa ti e n ts a r e a t m o r e r is k f o r d r ug in t er ac t io ns t ha n y ou n ge r p a tie n ts . O ld e r p a t ie n ts m ig h t h a v e c han g es in th e i r p h ys i ol og ic a l an d p a th o ph y s io lo g ic al c o n di t io n t h a t l ea d to al t er e d b od y c om po s i t io n , a l te r ed G I t r a ns i t t im e a nd d ru g a bs o r p ti o n , d e c re as e d p ro t ei n b i nd ing , al t e re d d is t r ib u ti on , an d de c re as e d d ru g c le a ra n c e . Th e s e c ha n ge s c an e xa c e r b a te or in c re as e th e r is k o f a d ru g i n te r ac t io n . b . P a ti en t s wi t h p re d is pos i ng il ln es s (d ia b et es , as t h m a , A I D S, an d a lc o ho l is m ) a nd p a t ie n ts wh o ar e c li n ic al ly h y p e r se ns i ti v e ( at o pi c ) a r e m o re at r isk f or d rug i n t er a ct i on s t ha n n o n - a to p ic pa t ie n ts . c . P ha rm ac o ge n et ic po l ym o r ph is m s i n e n z ym e f un c ti o n c a n o c c u r a t d i ff e re n t ra t es i n di f fe r en t r ac ia l p op u lat i o ns , a nd t o a l es s e r e xt e n t , i n d if f e re n t n a ti on s . Th e s e p h a rm ac o ge ne t ic di f fe r en c es c a n l ea d t o a wi d e v a r i a ti o n i n t h e p ot e nt i al f o r a d ru g i n t er a ct i on . B . C l in ic a l s i g ni f ic an c e 1 . N o t a ll dr u g i nt e r ac ti on s a r e c li n ic al l y s i gn i fi ca n t o r c a u s e an ad v e r se ef f e ct . In s om e c as es , i n te r ac t in g d r u gs c a n b e p r es c r i be d f o r pa t ie n ts a s l on g as t he p at i en t i s g i v e n p r op e r i ns t ru c ti on s a n d is c o m p li a nt . Fo r e xa m p l e , ci m e t id i ne an d a n a n t ac id m i gh t b e p r es c rib e d t o th e p a ti en t , b u t t he p at i en t s ho u ld be in s t ru c te d to n o t ta ke bo t h m e d ic at i ons a t t he s a m e ti m e . 2 . C om bi n at i on d ru g t h e ra p y c a n ha v e be ne f ic ia l e f f ec ts . D ru g c om b in a ti on s a r e u s ed to im p ro v e t he th e ra p e ut ic ob j ec ti v e o r t o de c r ea se ad ve r se e v en t s . S o m e e xa m p l es in c l u de :
a . Tr i m e t ho p r im a n d s u l fa m et h o xa z o l e —c om b in a ti o n a n ti bi o ti c f o r i nc r ea s e d ef f ic ac y i n ur i na r y t r ac t i n fe c t i ons . b . A m o xi c i ll i n a nd c l a v ula n a te po t as s i um —c o m b in a t io n c on t ai ni n g a be t a-l a c t am as e i n hi b it o r (c la v u la n at e ) to i n hi bi t th e b r ea k do wn o f a m o xi c i l li n . c . H yd r oc hl o ro t hi a z i de an d t ri am t e re ne — c o m b i nat i o n d iu r et ic a nd an ti h ype r t e ns i v e t o m i ni m i z e po t as s i um exc r e t i o n . d . R i to n a v ir is gi v e n a s a “ b oo s t e r ” wi t h t ip r an a v i r . C oa dm i ni s t r a ti on in c re a se d t i p ra n a v i r l e v el s 3 0 -f o ld b y i n hi bi t io n o f th e C YP 3A 4 e n z ym e r es po ns i bl e fo r m e ta b ol is m o f t i pr a na v i r . e . P r ob e ne c i d i nh i bi ts r en a l t u bu la r se c r e ti o n o f p e n i ci l li n , t he r e b y p r ol o ng i ng t he p l as m a ha l f -l if e o f th e a nt i b io t ic . P.435
3 . S om e d r ug - f oo d i n te r ac t io ns a re ut i li z e d f o r t he i r b e ne f ic ia l e f fe c ts . Phe n y t o in is g i ve n wi t h d ie t a r y fa ts to i nc r e as e i ts b i oa v a i la bi l it y t h r ou g h e nh a nc ed ab so r p ti o n . 4 . A no t he r t y pe o f d r ug -d r u g i n te r ac ti o n oc c ur s wh e n t h e c on ve r si on o f a p r o- d r ug to t h e a c ti v e m e ta b ol i te is in h ib i te d o r in d uc ed at t he m e t ab o li zi ng e n zy m e . a . Th e c o n v e rs io n o f i n ac t i v e c od ei n e t o i ts ac t i ve m e t ab o li t e m o r p hi ne c a n be r e d uc ed b y C YP 2 D 6 is oen z y m e in h ib i ti on c a us e d b y c i m e ti di n e o r c it a lo p ra m . Th e r e d uc ed m e t ab ol is m c an r e s ul t i n s ub t he r ap e u ti c le v e l s o f m o rp hi n e, an d th e r ap e ut ic f a i lu r e i n p ai n t r e at m e n t . b . Th e in du c ti on o f t he m e ta b ol is m o f C YP 2 D 6 by p h e n y t oi n o r St . J o hn ' s W or t c an i n c re as e m et a bo li s m of c o d ei n e t o m o rp hi n e, r ai s e m o r p hi ne le v e ls , an d m a y r es ul t i n e xc es s i v e s e d at i on and n a rc ot ic to xi c i t y. c . O t he r p r o - dr u g d ep e nd e n t u po n m et a bo l ic c onv e r s i on to ac ti ve m e t ab ol i t es i n cl ud e e n al a pr i l, v a la c yc l o v i r, le v o d op a , a nd c a ri s op r od o l. 5 . Th e de t er m i n at i on of th e c l in ic al s i gn i fi c a nc e of a po t en t ia l d r ug in t e ra c t i o n s h ou l d b e d oc um en t ed in t h e l it e r at u r e. Th e l ik e lih o o d o f a d r u g i nt e ra c ti on c a n b e c l as s i fi e d as f ol lo ws : a . E s ta b li s he d — a d r ug in t e r ac ti o n s u p po r t ed b y we l l - p r o ve n c l i ni c a l s tu d ie s b . P r o ba b l e— a d r u g i nt er a c ti o n t ha t i s v e r y l ik e l y b u t m ig h t n ot be p ro v e n c li n ic al l y c . S us p ec t ed — a d r u g i nt e r ac t io n t h at m i gh t oc c ur ; s o m e d at a m ig h t b e a va i la b le d . P o ss i bl e — a d r ug i n t er a c ti o n t ha t c o ul d o cc ur ; l i m i t ed da t a a re a v ai l ab le e . U n li k el y— a d r u g in t era c ti o n t ha t is d o ub t fu l ; no g oo d e v i d en c e of an alt e r e d c l in ic al e ff ec t i s a v a il a ble 5 . Th e c li n ic al r el e v an c e o f a p ot e nt i al dr u g i nt e ra c ti o n s h o ul d a ls o c on sid e r th e : a . S iz e o f th e d os e a n d th e du r a ti on o f t he r ap y b . O n s et ( r ap id , de la y e d) a n d s e ve r i t y ( m a j o r , m o d e ra t e , m i n or ) of t he pot e n ti a l i n t er a ct i on c . E xt r a p ol a t io n to r el a te d d ru gs 6 . P ol y m o rp hi s m in ph a rm ac o ge n et ic s m a y a f f ec t t h e t o xi c i t y a n d t h e c l in ic a l e f f ic ac y o f c er t ai n d r u gs i n c e r ta i n p op ul a ti o ns . Kn o wn i n hi bi t o rs m a y po s e s i gn i fi ca n t r is k s to E xt e ns i v e Me t a bo l i z e rs o f en zy m e s ys t em s . C . Ma n a g e m e n t o f d r ug in t e r ac ti o ns
1 . R e vie w t h e pa t ie n t p ro f i le , i nc l ud in g d r u g h is to r y a n d p at i en t ri s k fa c t or s . Th e p a t ie n t 's pa s t m e di c al h is t o r y c a n r e v e al a t en d an c y f o r n on -c o m p li a nc e, p a st t h e r ap eu t ic fa i lu r es , a nd e v i d en ce fo r ph a rm ac o ge n e ti c c o n si de r a ti on s . 2 . A v o id c o m p le x t h e r a pe u t ic d r u g r eg im e ns . 3 . D e te r m i ne t he pr o ba b il i t y of a c li ni ca l l y s ig n if ic a n t d r u g i nt e ra c ti on . G ene t ic t e s ti ng m a y b e us e fu l ( Ta b le 18 - 1 2 ). 4 . S ug g es t a di f fe r en t dru g if th e r e is a h ig h p r o ba b il i t y fo r a cl i ni c a ll y s ign i f ic an t d r u g i n te r ac ti o n. F or e xa m p le , a c e t am in o ph e n c an b e us e d f o r h ea d ac he in s te a d o f a s pi r in f or a p a ti en t on an t ic o ag ul a n t t he r ap y . 5 . C a re f ul l y in s t r uc t th e p a t ie n t as t o t he ti m i n g of t h e m e d ic at i on . F o r e xa m p le , a n a n t ac id an d H -2 bl oc k e r s h ou l d n ot be ta k en at the s a m e t im e. Th e p a ti e nt s ho u ld u s e m a xi m u m s pa c i n g be t we e n d ru gs . In s t r uc t the p at i en t a s t o t h e t im in g o f m e di ca t io ns to be t ak en “ o n an em pt y s to m a c h . ”
Table 18-12. FDA Encourages Genetic Testing for Patients Who Will Take Specific Drugs Imatinib
Atomosetine
Venlafaxine
Voriconazole
Tamoifen
Omeprazole
Fluoxetine
Celecoxib
Tramadol
Capecitabine
Beta-blockers
5FU
Rifampin
Dapsone
Irinotecan
Rasburicase
Valproic acid
primaquine
Adapted from http://www.fda.gov/cder/genomics/genomics_biomarkers_table.htm P.436
6 . Mo n i t o r t he pa t ie n t f o r a d v e rs e e v e n ts . Su l fo n am i de s , s u ch as s ul f is o xa z o l e an d s u lf am e th o xa z o l e , c a n pr o l on g p r o th r om bi n ti m e i n p a t ie n ts g i v e n wa r f a r in t he r a p y. Th e p r o th r om bi n ti m e s s h o ul d b e m o ni t or e d i n t he s e p at i en ts . 7 . R ee va l ua t e t h e p at i ent p r of i le an d d r ug hi s to r y wh e n c ha ng i ng d ru g t h er a p y . Fo r e xa m p l e , wh e n di s c on t inu i ng t he di u re t ic of a c o ng e st i v e h e a rt f ai lu r e p a tie n t o n d i go xi n , a r e v ie w o f t he p r o fi l e m a y r e v e al a p o tas s i um su p pl em en t th a t s h o ul d b e d i sc on t in u ed as we l l.
8 . E v a lu a te t he ri s k s o f d r u g t h er a p y wi t h re s p ec t t o p h ar m a c og en e ti c p oly m o r p hi c s t a tu s o f m et a bo li s m . Con s id e r r is k s id e nt i fi ed wi t h r ac ia l g r ou ps an d ge og r a ph ic d i st r ib u ti o n. Te s t f o r e n zy m e ph e no t y p e wh e n f eas i bl e . S e le ct d ru g a n d ad j us t d os e s a s i n di c a t ed , a n d a c c or di n g t o c li n ic al re s po ns e . C o n s i d e r g en o t y pi ng f or p o l ym o r ph is m s wh e n u ne xp e c t e d v ar i at i on s i n cl in i c a l r e s p on se .
IX. References. A vast number of drug interactions are reported in the literature. Some general references that are updated periodically include: A. D r u g I n te r ac t io n F ac ts . S t. Lo u is , MO : F a ct s an d C om pa r is o ns . B . H a ns t en P D , Ho r n J R ( e d s ) . D r ug In t e ra c t i on s & U p d at es . V an c o u ve r , W A:A p pl ie d Th e r a p eu t ic s , In c . C . Z uc c h e r o FJ , H og a n MJ , S c h u lt z C D , ed s . E v a l ua t io ns o f D r u g I n te r act i o ns . S t . L o ui s , MO : P r o f e s s io n al D r u g S ys te m s . D . P D R G u i de to D r ug Int e r ac t io ns , Si d e E f fe c ts , a n d I n di c a t io ns . Mo n t va le , N J : Me d i c a l Ec on om ic s D a t a. E . MI C R O ME D E X ® S y s t e m s , D R U G D E X® S y s t e m , D r ug E v al u a ti on s . E ng l e wo o d , C O : A l t - Me d D e x. F . N a tu r al Me d i c i n es C om p r eh en s i v e D a ta b as e. A va i l ab l e o nl in e a t h t t p :/ / ww w. n a t u r a ld a ta b as e .c om . G . P 4 5 0 D r u g I n te r ac ti o ns Ta b le . In di a na U ni ve r s it y S c h oo l o f Me d ic i ne . Div i s i on of C l i ni c al Ph a rm ac o lo g y . A v a i l ab l e o nl in e a t ht t p :// m ed ic i ne . iu pu i .e d u/ cl i nic a l/ . H . P h a rm ac og e ne t ic a n d P h a rm ac o ge no m i c s K nowl e d g e B as e. In d ia n a U ni v e r s it y S c h oo l o f Me d ic i ne . Di v is i on of P ha r m a c o l og y. Av a i l ab l e o nl i ne at h t t p :/ /m e di c i n e. i up ui . ed u/ c li n ic al / . I . C D C N a ti o na l O ff ic e o f P u b li c H e al t h G e n om ics . A v a i la b le on li n e a t h t t p :/ / ww w. c d c . g o v /g e nom ic s / J . N a ti on a l I ns t it u te s o f G e n e r al Me d i c a l Sc ie nc es . P ha rm ac o ge n et ic R ese a r ch N e t wo r k . Li nk in g ph en o ty p e s a n d g en o t y pe s . O n t h e i n te r n et at w w w. n i g m s . n ih . go v / I ni t iat i v e s / P G R N / K . F D A ge n et ic t es ti n g an d d ru g l ab e li ng . O n t h e i n t er n e t a t w w w. f d a . g o v / c d e r /g en om i c s _ bi om a rk e rs _ ta bl e .h tm 1 . Yu K S , Yi m D S, C ho J Y, e t a l . E f fe c t o f o m e p ra zo l e o n t h e p ha r m a co k in e t ic s o f m oc l ob em i de ac c o r di ng to t he ge n et ic po l ym o r p his m o f C YP 2 C 1 9. C li n Pha r m a c ol T h e r 2 0 01 ; 69 ( 4 ): 26 6 - 273 . 2 . Ya s ui - F u ru k o r i N , S ai to M, U n o T, e t a l . E f f ec ts o f f lu v o xa m i n e o n l an s o p r a z ol e p h a rm ac ok i ne ti c s in r el at i o n t o C YP 2 C 1 9 ge n ot yp e s . J C l in P ha r m a c o l 2 0 0 4; 4 4( 1 1 ): 1 22 3 -1 2 29 . 3 . H am el i n B A , Bo u a y ad A , Me t h o t J , et al . Si g ni f ic a nt in t e ra c t i on be t we e n t h e n o n pr es c ri p ti o n a nt i hi s t am i ne di ph e nh y d r am i ne an d th e C YP 2 D 6 s u bs t ra te m e to p r ol ol in he a lt h y m en wi t h hi g h o r l o w C YP 2 D 6 a ct i v i t y . Cl in P ha r m ac o l T he r 2 0 0 0; 6 7( 5 ) :4 6 6 -4 77 .
4 . Le ss a rd E , Ye s s in e MA , H a m e li n B A, e t a l. D iph e n h y dr a m i ne al t e rs th e d i sp os i ti on o f v e n la f a xi ne t h ro u gh in hi b it i on of CYP 2 D 6 a c ti v i t y i n h um ans . J C li n P s yc ho p ha r m a c o l 2 0 01 ; 21 ( 2 ) :1 7 5 -1 84 . P.437
STUDY QUESTIONS D i r e c t i on s : E a c h qu es t io n be lo w c o n ta i ns th r ee s u gg es t ed an s we r s , o f wh i c h on e o r m o r e i s c o r r ec t . Ch oos e th e a ns we r 1 . D r u g i n t e ra c t io n s m ay b e c l a s se d as I . p ha r m ac o ki n e ti c in t er a c t i on s I I . ph a r ma c o d yn a m i c i nt e r a c t io n s I I I . ph a r ma ce u t i ca l i n t er a c t i on s A I o n l y i s c o r re c t B I I I on l y i s c o r r ec t C I a nd I I a r e c o r r ec t D I I an d II I a re c o r re c t E I , II , an d II I ar e c o r re c t V i e w A n s we r 1 . T h e a n sw e r i s E [] . 2 . S i t ua t i o ns t h a t ca n p o t en t i al l y l e a d t o d r u g i nt e r ac t i o ns in c l ud e I . m ul t i p le - d r ug t he r a p y I I . mu l t i pl e p r e sc r i b e rs I I I . pa t ie n t c o m pl i an c e A I o n l y i s c o r re c t B I I I on l y i s c o r r ec t C I a nd I I a r e c o r r ec t D I I an d II I a re c o r re c t E I , II , an d II I ar e c o r re c t V i e w A n s we r 2 . T h e a n sw e r i s E [a n d] . D i r e c ti o ns : Th e q u es t io n b e lo w i s f o l lo we d b y fo u r s ug g es te d an s we r s . S el ec t th e on e le t te r e d a ns we r t ha t is t he be s t r e s po ns e t o th e q ue s ti on. 3 . W hi c h o f th e fo l l ow in g s ta t e me n ts r e ga r d i ng d r u g i n t e ra c t io n s i s tr u e ? ( A ) A l l d r ug i n te r ac t io ns c a n p ot e nt i al l y c a us e a n a d v e rs e re s p o ns e i n t he p a ti e nt . ( B ) Th e c l in ic a l s i g ni f ic an c e f o r e ac h p o te n ti al d ru g in t e ra c t i on m us t be c o n s i d er e d i n di vi d ua ll y . ( C ) A p re c i p it a nt d ru g tha t in h ib i ts t h e m et a bo li s m o f t he ob j ec t d r ug c a us es a m o re s e r io us dr u g i nt e r ac ti o n c om p a re d t o a p re c i p it a nt d r ug c a us in g a n i nc r e as e i n th e b i oa va i la b il it y o f th e o bje c t d r ug . ( D ) I f th e p a ti e nt is p r es c r i be d d r ug s t h at c a n p ote n t ia ll y i n te r ac t , t he p res c ri b er s h ou l d b e c a l le d , a nd a d i f fe r e nt p re c i pi t an t dr u g s ho u ld be s u gg es t ed . V i e w A n s we r 3 . T h e a n sw e r i s B [] .4 . A p a t ie n t o n i nd i n a vi r An t i - R e t r ovi r a l T h e r a p y ( AR T ) b e g i n s ta k i ng S t . J o hn ' s W o r t fo r d e p re s si o n a n d s u f fe r s u n e xp e c te d re d u ct i o n in C D 4 co u n t . T h is is mo s t l ik e l y d u e t o : ( A ) P h a rm ac od y n am ic int e r ac t io n p r od u ci ng ad d iti ve t o xi c i t y.
( B ) P h a rm ac od y n am ic int e r ac t io n p r od u c i ng an t ag o ni s ti c t he r a pe u ti c e f fec t ( C ) E n z y m e i n du c t i on b y S t . J o hn ' s W or t ca u s i ng i nc r e as ed m e ta b ol is m of A R T. ( D ) E n z y m e i n hi bi t io n b y S t . J o hn ' s W or t c a u s i ng t o xi c l e v el s o f A R T. V i e w A n s we r 4 . T h e a n sw e r i s C [] .5 . W h ic h o f th e f o ll ow i ng i s a va l id t h e r a pe u t ic us e o f a d ru g i n te r a c ti o n? ( A ) Th e us e o f p r o be n ec id wi t h pe n ic il li n G to pr ol o ng hi g h p en ic i ll in le v e ls t o t r ea t a s e xu a l l y t ra ns m i t t ed di s ea s e. ( B ) G i vi n g as p i ri n wi t h wa r f a ri n to en ha nc e an ti c o a g ul at i on . ( C ) I ns t r uc ti n g t h e p at ien t t o t ak e l e v o fl o xa c in wi t h m i lk or an t ac id t o d ec re a se G I i n t ol e ra nc e to or a l t he r ap y . ( D ) Th e t r ea tm e nt o f d epr e s s i on wi t h a c o m b in a tio n of c i t al op r am an d a n MA O I . V i e w A n s we r 5 . T h e a n sw e r i s A [] .6 . W h ic h o f th e f o ll ow i ng i s n o t a h a r m f ul f o od - d r u g i n te ra c t i on ? ( A ) R a w g r e en s a la d s f o r p a ti e nt s o n wa r f ar i n D VT p r o p h y l a xi s . ( B ) G r a p ef r ui t j u ic e a nd c y c lo s po r in to p re ve n t g ra f t v s. h os t r e je ct i on of a t r a ns p la n te d k id ne y . ( C ) O m e pr a z o le be a ds i n a p pl es a uc e f o r a p a ti e nt wi t h p r ob l em s s wa ll o wi ng c a ps ul es s e c o nd a r y t o G E R D . ( D ) Mi l k wi t h do xy c y c l i n e t o t re a t h . p y l o ri . V i e w A n s we r 6 . T h e a n sw e r i s C [] .P . 43 8
7 . W hi c h o f th e fo l l ow in g s ta t e me n ts r e ga r d i ng p h a rm a co g en e t ic p o l ym o r p h i s m s i s n o t tr u e ? ( A ) A n E M t a k i n g m e t op ro l ol f or h yp er t en si o n b egi n s t o t ak e O TC Ta g a m e t r e g ul a rl y f o r he a r tb u rn . H e is at inc r e as ed ri s k fo r b ra d y c a rd i a a nd ca r di ac a r rh yt hm i a s . ( B ) A n E M t a k i n g m e t ha do n e , b eg i ns t ak i ng Te g r et o l f o r n e u ro pa t hi c p ai n . H e is a t r i sk fo r t re a tm en t fa il u r e a n d p ai n c r is is . ( C ) A P M t a k in g a t o r v as ta t i n f o r h y p e rl ip i de m i a i s p l ac ed on k e to c on a z ol e f o r a f u n ga l i n fe c t i on . He is at i nc r e as ed ri sk fo r m ya l gi a an d rh ab d om y o l y s i s . ( D ) A P M t a k in g m e to p rol o l f o r t ac h y ca r d ia be gi ns t ak in g Be na d r y l f o r s lee p . He is n o t a t ri s k fo r s i gn i fi c a n t b r a d yc a r di a a nd ca r di ac b l oc k . V i e w A n s we r 7 . T h e a n sw e r i s C [] .8 . As i a ns a re a t g r ea t es t r is k of a ll r a c i a l g r o up s fo r g en e ti c p ol ym o r p h i s m i n w h ic h o ne o f t h e f o l low i n g C Y P 4 5 0 i s o en z ym e s ? ( A ) C YP 2 D 6 ( B ) C YP 3 A 4 ( C ) C YP 2 C 1 9 ( D ) C YP 1 A 2 V i e w A n s we r 8 . T h e a n sw e r i s A [] .9 . W h ic h o f th e f o ll ow i ng s ta t e me n ts r e g a r d in g ph a r ma c og en e t i cs is f al s e? ( A ) P o l ym o r ph is m s o c c u r o n l y i n t h e C YP 4 50 he pa t ic en zy m e s . ( B ) P o l ym o r ph is m s re s u lt i n m an y v a r ia t io ns o f an is o en zy m e . ( C ) Th e o v e r al l e xp r e s s io n of t he c om b in ed al l ele s i s t h e p he no t y p e o f the e n z ym e.
( D ) S N P s c an oc c u r as er r o r s o f t r a ns c r ip t io n , d ef e c ti v e s p li ci ng , s t a rt and s to p c o do n es , a nd am in o a c i d c ha n ge s . V i e w A n s we r 9 . T h e a n sw e r i s A [] .1 0 . W hi c h o f t h e f ol l ow i ng s ta t em e n ts r e g a r d in g al l el e po l ym o r p h i sm s i s fa l se ? ( A ) W ild t y pe al le l es e nc o d e f o r “n o rm al ” m e ta b oli s m . ( B ) U Ms h a v e t wo o r m o re am p li f ie d a ll e le s . ( C ) P Ms c a r r y on e d e fe c t i v e al l el e a nd on e a m p l if i e d a ll el e . ( D ) E Ms wi t h h e t er o z y g ou s a l le le s a n d h a ve sl o we r m e t ab o li s m t h an m e t ab o li ze r s wi t h h om o z y g o us al le l es . V i e w A n s we r 1 0 . T he a nsw e r i s C [] .P . 43 9
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is E [ I . B ]. Mo s t d r u g i nt e r ac ti o ns i n v i v o a r e c au s e d b y p ha rm ac o ki ne t ic a n d p ha r m ac o d y na m i c i n t er a ct i on s . P ha r m a c e u ti c al in t er a c t io n s c a n o cc u r d ur i ng e xt e m po r an e ous c om p ou n di ng , pr e pa r a ti on o f i nt r a v e no us ( I V ) a dm i xt u r e s , a nd i m pr o pe r do s in g , as i n th e c as e o f g i v i ng as pi r i n wi t h ac i di c ju ic e s ( e .g . , or a ng e , c ra n be r r y ) . 2 . T he an sw e r is E [ I V .A . 1 , 2 an d 3 ] . P a t i en t p r o fi le s m ig h t n ot c on t ai n a ll th e dr u g h is t o r y i nf o rm a ti o n o f t he pa t i en t . P a t i en ts wh o t ak e n on p re s c r i pt i on ( O TC ) m ed ic at i o ns , g o t o s e ve ra l d i ff er e n t p h ys ic ia ns , or pu r c h as e d r u gs at va r io us ph a rm ac i es m a y ne gl e c t to in f o rm t he p h a rm ac is t o f al l t he m ed i c a t io ns be i ng ta k e n . 3 . T he an sw e r is B [ I V .B ] . N o t al l d r u g i nt e ra c ti on s a r e c li n ic al l y si gn i fi c a n t. S o m e po t en t ia l c li ni c al ly s i gn i fi ca n t d r ug in t er ac t io n s c a n be pr e v e nt e d b y p r o pe r p a ti e nt in s tr u c t i on a nd c om p li a nc e. Th e p o te n tia l fo r a c l i ni c a ll y s ig ni f ic a n t d r u g i nt e ra c ti on sh ou l d b e d o cu m e n te d b e fo r e c al lin g a p h y si ci an c o nc e rn i ng t h e p re s c r ib e d m e d ic ati o n . 4 . T he an sw e r is C [ I I . C. 1 .c ; Ta bl e 1 8 - 3] . S t . Jo h n 's W or t i n du c e s C YP 3 A 4 i s oe n z y m es i n cre a s i n g t he m e ta b ol is m of t h e i n di n a vi r a nd r es ul ti n g i n l o w i n di na v i r le v e ls an d t h e r ap eu t ic fa i lu r e o f A RT. S t . J o hn ' s W or t i ts el f ha s n o d i re c t e f fe ct on C D 4 . 5 . T he an sw e r is A [ I I . C. 2 ; Ta bl e 1 8 - 4] . P r o b en ec i d is gi v e n wi t h p e ni c i ll i n a nd s om e c e ph a l o s po r in s i n t r ea tm e nt o f s o m e s e xu a l l y t ra ns m i t t ed di s ea s es . Pr o be n ec id c om p et e s wi t h p en ic il l in s f o r r en a l e l im in a ti o n, p ro l on gi n g th e ha l f -l if e o f th e p e ni c i ll i n . A sp i ri n a n d wa r f a r in c a us e a d di t i ve a n ti c o a gu la t io n l e ad i ng to bl e ed i ng . L e vo f l o xa c in ta k e n wi t h m il k t o d e c re as e G I i r ri t a ti on c au s es c om p le xa t i o n o f t h e l e v o fl o xa c i n wi t h t he c a lc i um i n t h e m il k a nd r es ul ts in de c r ea s e d l e vo fl o xa c i n t o b e a vai la b le . C on co m m itt a n t t r e a tm en t o f de p re s s io n o f c i t al op r am an d MA O I r e s ul ts in S e ro t on in S y nd r o m e , a n a d di t i ve t o xi c i t y . 6 . T he an sw e r is C [ V . B] . O m e p ra z o l e b ea ds a re en t e ri c c oa t ed . G i vin g a n e n t e ri c co a te d b e ad wi t h a n a c i d ic f o o d su c h as ap p le s a uc e p r es e r v es th e e n t er ic c oa t i ng an d a ll o ws t he d rug t o p as s
i n t ac t t h ro u gh th e ac id ic s t om ac h e n v i ro nm e nt a nd i nt o t h e b as ic du od e num e n vi r on m e n t wh e re i t is a b s o r be d . Th e r es u lt is im p r o v ed d ru g a bs o rp t io n a n d d e c re as e d d ru g d e s t r uc t io n in th e a c i d ic s t om ac h i f th e b e ad s we r e n o t i n a n ac id ic f o o d. 7 . T he an sw e r is C [ V I I .C . 2 ] . Th e P M a l r e a d y ha s i nh ib i t ed m e ta b ol is m o f a t orv a s t a ti n . A d di ti o na l i n hi bi t i on wi l l n o t s ig n if ic a nt l y in c re as e t h e b lo o d l e v el s o f a t or v a s ta t in . Th e re f o re do s e - re l a te d t o xi c i t y is un l ik el y . Th e E M t a k i n g m et o pr o lo l a nd Ta g am e t ( c i m e t id i ne ) wi l l s ho w a g r e a te r i nc r e as e i n t he m e to p r ol ol le v e ls du e to t h e e xa g g e r a te d e f fe c t of t h e i n hi b it o r i n E M. Th e E M t a k in g m et h ad o ne an d Teg r e t ol (c a rb am a ze pi n e) wi l l h a ve i n c re as ed en z y m e in d uc ti o n a nd m e t ab o li sm o f the m e t ha d on e , l o we r i ng m e th a do n e l e ve ls an d p u tt i ng th e p at i e nt at r is k f o r t r ea tm e nt f a il u re o f h is p a in . Th e P M t a k i n g m e to p r ol ol an d Be n ad r y l ( d ip h en h yd r am in e ) wi l l s h o w i nh i bi ti o n o f t h e m et a b ol is m o f t h e m e to p ro l ol an d i nc r ea s ed le ve ls of m e t op r ol ol l ea di n g t o a hi gh e r ri s k o f b r a d yc a r di a a n d c a r d ia c b l oc k . 8 . T he an sw e r is A [ V I I .A . 3 ] . P o l ym o rp hi s m i s h i gh es t i n t h e C YP 2 D 6 i s o en z ym e i n As ia ns , re ac h in g in c id e nc e o f g r e a te r th an 50 % . 9 . T he an sw e r is A [ V I I .A . 2 ] . P o l ym o rp hi s m s c a n o c c ur i n a n y en z ym e s ys t em in c lu di n g m i xe d o xi d a s e a n d n a c et yl t ra n s f e ra s e s y s t em s a s we l l as th e C YP 4 50 h ep a ti c e n z ym e s ys t em . 1 0 . Th e a n sw e r i s C [ V I I. B . 3 .a ] . P o o r m e ta b ol i z e rs ( P M) c a r r y a n o rm al al le l e c om b in e d wi t h a d ef e c t i v e o r d el e te d a l le l e.
19 Nuclear Pharmacy S t e p h en C . D ra g o ta k es Jeffrey P. Norenberg
I. INTRODUCTION A. O ve r vi e w 1 . N u cl e a r p h a rm a c y i s d e f in ed as a “ p at i en t -o r ie n t ed s e r v ic e th a t e m bo d ie s t he s c ie n ti fi c k n o wl e d ge an d p r o fe s s io na l ju dg m e n t re qu i r ed to i m p ro ve an d p r om o te hea l t h t h ro u gh th e s a fe and e f fi ca c i ou s u s e of r a d io ac t i v e d r ug s f o r d iag n os is an d t h e ra p y. ”
1
2 . R a di o p ha r m ac e ut i ca ls a r e d ru g p r o du c t s t h at c o nt a in a b io lo g ic al m o ie t y an d a r ad i oa c t i v e e l em en t . Th e bi o lo g ic al c o ns t ru c t t a rg e ts a p h ys io l og ic al o r p at h op hy s i o lo gi c al p r oc es s o f i n te r e s t , a l lo wi n g th e l o ca li za t io n o f r ad ia t io n th a t , i n t u rn , m a y be im age d o r us e d t o e f fe ct t h e r ap y. Mo s t r ad io p ha rm ac e ut ic a ls a r e u s e d i n d i ag n os ti c m ed ic a l im a gin g ; h o we ve r , t he y a r e a ls o us e d i n t he r a pe u ti c a pp li c a t i on s, su c h as i n th e t r e a tm en t o f h y pe r t h y r oid i s m , t h y r oi d c a nc er , po ly c y t h e m i a v e ra , a n d i n th e a l le vi a ti o n o f b on e p a in . 3 . N u cl e a r p h a rm a c y p r a c t i ce en t ai ls th e : a . P r oc u re m e n t o f r a di o ph a r m a ce u ti ca ls b . C om p ou n di ng o f r ad i op h a rm ac e ut ic al s c . P er f o rm an c e o f r ou t ine q ua li t y co n t ro l p r oc e dur e s d . D is p en s i ng o f r a di op ha r m ac eu t ic al s e . D is t ri b ut i on of r ad i op ha r m ac eu t ic al s f . I m p le m e n ta t io n o f ba s ic r ad i at i on pr o te c ti on p ro c ed u re s a n d p ra c ti c e s g . C o ns ul t at i on wi t h a n d/o r e du ca t io n o f t h e n uc lea r m e d ic in e c om m u ni t y, p a t ie n ts , p ha r m a c i s ts , o th e r he al t h p r of es s i o na ls , a n d t he ge n e ra l p ub l ic r e g a rd i ng ( 1 ) P h ys i c a l a nd c h em ic a l pr o pe r t ie s o f r a di o ph ar m ac e u t ic a ls ( 2 ) P ha r m a c o k i n et ic s a nd b io di s t ri bu t io n o f ra d iop h a rm ac e ut ic al s ( 3 ) D r ug in t e ra c t i on s a nd o t he r fa c to r s t ha t a l te r p a t te r ns of di s t ri bu t io n h . Mo n i t o ri n g o f p at i en t o u tc om e s i . R es e a rc h a nd de v e l opm e nt o f r ad i op h ar m ac eu ti c al s B . P r o p e r t ie s o f r ad i o ph a r m ac e u ti c al s 1 . P ha r m ac o l og i ca l ef f ec t s . Ty p ic a ll y, r ad i op ha rm ac e ut ic a ls l ac k p h a rm ac ol o gi c a l e f fe c ts b e c a us e th e m as s qu a nt it i es r an g e f r om p ic o g ra m ( p g ) to na no g r am (n g ) pe r k i lo g r am (k g ) o f a dm in i s t e r ed do se . 2 . R o u te o f a dm i n is t r a tio n . Mo s t ra d io p ha rm a c eu t ic a ls a r e p r ep a r ed as s t e ri le , p y r og en - f r ee in t ra v e n o us (I V ) s o lu t io ns or s us pe ns i on s t o b e a d m i ni s te r ed di r ec t l y to th e pa t ie n t. O t he r r ou t es o f ad m i n is t ra t io n i nc lu d e i n t ra d e rm al , o r a l, in t e rs tit i a l, an d i n ha la t io n (e . g. , r a di o ac t i v e g as es , a e r os ol s ). 3 . R a di o n uc l id e s
a . Th e ra d io ac t i v e c om po n e nt of a r a di o ph a rm ace u t ic al is re f e rr e d t o a s a r a d io n uc li de . N uc li d es a re i de n ti f ie d a s a to m s havi n g a s p e c i fi c n um b er of p r o t on s a nd ne u t ro ns in t h e n uc l eu s . A nu c l id e i s t y p i c a ll y i de n ti f ie d b y t he c h em ic al s y m b ol of th e el e m e n t wi t h a m as s nu m b e r s h o wn as a s u pe r s c r ip t , i nd ic a ti ng t he s u m o f p r o to ns an d n eu t r o ns (e . g. , i o di d e- 1 31 is i n di ca t ed as
131
I ) . W hen t h e a t om is ra di o ac ti ve , it i s ca ll e d a ra d io n uc li de.
b . R a di on uc l id es un d e rgo s p o nt a ne o us ra d io ac t iv e d ec a y ac c o m p a ni e d by t h e re l ea s e of en e r g y . Th e di s t r i bu ti o n , m e t ab o lis m , a nd el im in a ti o n o f t he r a d io p ha r m a c e u ti c a l c an P.441 b e de t e rm in ed b y m e as ur i n g t hi s e n er g y wi t h im ag i ng eq u ip m e n t . Th e r e ar e f o u r m aj o r t y p es o f r ad i at i o n em i tt e d t h ro u gh th is p r oc es s : α - , β - , γ - , a nd xr a y s . α - a n d β - r a di a ti on s a r e n o t us e f ul i n m ed ic al im a gi ng an d a r e , t h e r ef o re , un de s i r a bl e i n d i ag no s ti c a pp li c at i on s . Mo s t d i ag n os ti c r a d io p ha r m a c e u ti c a ls us e p en e t ra t in g γ - ra d ia t io n, wh i c h c an be ea s i l y d e t ec te d a n d c on v e r t ed in t o i m a g in g d a ta . 4 . H a l f- l i ve s o f r ad i o pha r m a ce u t ic a ls a . Th e ph ys i c a l h al f - l if e o f a r ad i op h ar m a c eu ti c al is th e a m ou n t o f t im e n e ce ss a r y fo r th e ra di o ac t i v e a t om s t o d ec a y to o n e h al f th e i r o ri g in al n u m b e r . E ac h ra di o nu c l id e is c ha r ac t e ri z e d b y a s p e c if ic ha l f -l i fe th a t i s a p h ys ic al c o ns t an t . b . Th e bi o l og i ca l ha l f - lif e o f a ra d io ph a rm ac e ut ic a l is t he am ou n t o f t im e r e q ui r e d f o r t he bo d y t o m e ta b ol i ze o r el im in a te o n e h al f of t he a d m i ni s te r ed do s e o f a ny s u bs t an c e th r o ug h b i olo g ic al p ro c e s s es . c . Th e e f f ec t i ve ha l f - li fe o f a ra d io p ha rm a c e u ti c a l is t h e t im e re qu i r ed for a n ad m i ni s te r ed r ad i op ha r m ac eu t ic al do s e to be r e d u c ed b y on e h a lf as a r e s ul t o f b o th ph y s ic a l de c a y a n d b io l og ic al m e ch a n i s m s . I t is d ef in e d a s : Te = Tp + (Tb/Tp) × Tb wh e r e T e i s t h e e f fe c t i v e h a lf - li f e , T p i s t he ph ys ic a l h al f -l i fe , an d T b i s t he b i ol o gi c a l h a lf - li f e. C . O p t i ma l r ad i o ph a r ma c e u ti c al s 1 . O p t im a l d i ag n os t i c ra d i o ph a r ma c eu t i ca l s a . S ho u ld c o nt a in a r a dio n uc li d e wi t h a h a lf - li f e s h o rt en o ug h t o m in im i ze r a d ia t io n e xp o s u r e t o t he p at i en t , y et lo n g e no ugh t o a ll o w f o r c ol l ec ti o n o f i m ag in g i n fo r m a t io n . Th e o p ti m a l re la t io ns h ip is a p h y s i c a l h a lf - li f e e q ua l to a p p ro xi m a t el y 6 7% o f t he b io lo g ic al p ro c e ss o f in t e r es t. b . S ho u ld in c o r po r a te a γ - em i tt i ng r ad io n uc li d e, wh i c h de c a y s wi t h th e e m is s i on of a p ho t on e ne r g y b et we e n 10 0 a n d 30 0 k i l o el ec t r on v o l ts (k eV ) , wh i c h is e f f ic ie n tl y d et ec t e d wi t h c u rr e nt in s tr u m en t a ti o n c . S ho ul d c on t ai n a bi o log i c a l c om po n en t t h at al lo ws r a p id lo c a li z a t io n i n t h e o r g an s y s t em o f i n te re s t a nd be m e t ab ol i z e d o r e xc r e t ed f ro m t h e n o n ta r ge t ti s s ue s t o m a xi m i z e c o n t ra s t a nd m i ni m i z e t he r ad i at i on ab so r bed d o se to no n ta r g et o rg a ns d . S ho u ld be r ea di l y a v ail a bl e a n d c os t -e f fe c ti ve
2 . O p t im a l t h e r ap e u ti c r a d i o ph a r ma c eu t i ca l s, in a dd i ti on t o I . C .1 . c a nd d , s h ou l d c o n ta i n α - o r β- em i tt i ng r ad io n uc li d es t h at c an ef f ec ti v e l y d el i ve r r a d ia t io n i n q u an t it i es s uf f i c i en t to c a us e t h e d es ir e d th e ra p eu t ic e f f ec t . S u c h e f fe c t s i nc lu d e a pop t os is , D N A d am a ge , or i r r e pa r ab l e ce l l d am ag e l e ad i ng to t is s u e e f fe c t s .
II. SODIUM PERTECHNETATE
99M
TC GENERATOR
A. O ve r vi e w 1.
99m
Tc , t h e m os t c om m o n l y us ed r ad io n uc li d e in d ia gn o s t ic im ag i ng to da y ,
i s p r o du c e d b y t he r ad i oa c ti v e de c a y o f m ol yb d en u m -9 9 ( a.
99m
99
Mo ) .
Tc i s o b ta i ne d v ia c om m e r c i a ll y s u p pl ie d , st e r il e , p yr o ge n - f re e
g e n er a to r s ys t em s . A g en e r a to r i s a de vi ce us ed t o se pa r a te a s ho r t h al f l i f e r ad i on uc l id e f r om th e l o ng e r -l i v ed p ar e nt nu c l id e wh i l e r e ta in i ng th e p a r en t to p ro du c e m o r e o f t he da ug h te r nu c l i de . I n t hi s wa y , s h o rt ha l f -l ife n u cl id e s c a n b e m ad e a v a i la b le c o nt i nu o us l y a t gr e a t d is t an c e s f r om th e s i te s o f g e ne r a to r p r o duc t io n . b . A ll of t he c om m er c i a lly s u pp l ie d g e ne r at o rs cur r e n tl y u s e f r o m t he f is s i on of u ra niu m - 23 5 (
235
U ). Th i s
99
99
Mo o b t ai n ed
Mo p a r en t i s a bs o rb e d o n an 99m
a l um in a i o n ( A l 2 O 3 ) e xc ha n g e c o l um n, an d t h e
Tc f o r m ed f ro m i ts de cay
-
i s e xc h a n ge d fo r th e c hlo r i de io n ( Cl ) a v a il a bl e in t he 0 .9 % s al in e e l ua t e s o lu t io n wa s h e d t h ro u gh t h e c ol um n , as t he s o diu m p e r te ch n et a te + 99m
Na (
-
Tc O 4 ) f o r m . + 99m
2 . Th e c h em ic al v a le nc e s t a te of N a (
-
Tc O 4 ) as i t i s e lu t ed f r om t h e
c o lu m n is +7 . Ty p ic a ll y , it m us t b e r e du c e d t o a lowe r va l e n ce s t a te be f o re i t is a b le to r ea c t wi t h o th e r c om p ou n ds . A l th o ugh m a n y p ro ce s s es c a n 99m
r e d uc e u s ed in
Tc , t h e s t an n ou s i o n ( S n
99m
++
) re d uc ti o n m e th o d is m o s t c o m m on ly
Tc r a d io p ha rm ac e ut ic a l k i t s.
P.442
a . A ra d io ph a rm ac e ut ic a l k i t c o ns is t s o f s te r il e , pyr o g e n -f r e e v i a ls c o nt a in in g a r ed uc i ng age n t , t h e b io lo g ic al c om po u n d t o b e l ab e le d , a nd a n y a dd i ti o na l a dj u ta n ts n e c e s s a r y to ef f ec t t h e re a c t i on o r t o s ta bi l i z e t he l a be l ed p ro du c t. b . I n m o s t c a s e s , t he y a re l y o ph il i z e d u nd e r i ne r t a t m o s p h e re s, s o as to m i ni m i ze o xi d a ti on o f t he r e d uc in g a ge n t ( e . g. , Sn B . S o d iu m pe r t ec h n et a te Na
+99m
99m
++
).
T c U S P ( U ni t ed S tat e s Ph a r m ac op e ia ;
-
T c O 4 ) as el u te d fr o m a ge n er a t or in 0 .9 % s o di um c h lo r id e ( Na C l )
s o lu t io n i s a n is o to n ic , s t e r il e , n on p yr o ge n ic , d iag n os t ic r a d io p ha r m a c e u ti c a l s ui ta b le f o r I V i n je c t i on , o r al a dm i ni s t r a ti o n, an d d i rec t i n st i ll a ti on . 1 . P h ys i c a l p r o p e r ti e s a . Th e s o lu ti o n s ho ul d be c l e a r, c o lo r le s s , a n d f re e of v i s i bl e fo r ei g n m a te r i al . Th e p H i s 4 . 5 -7. 0 .
b. Na
+99m
-
Tc O 4 i s i ts el f a r a di o ph a rm ac e ut ic a l, o r i t m a y b e us e d t o
r a d io l ab el al l o t he r
99m
Tc r a di o ph a rm ac e ut ic a ls .
2 . B i od i s t r ib u t io n a.
99m
-
Tc O 4 i s h an dl e d by t h e bo d y in a f as hi o n s i m il a r t o
131
I— t ha t is , i t is
t a ke n u p a n d r e le as e d bu t no t or g an i fi e d b y th e th y r o i d . b . A f te r I V a dm in is t r at i on ,
99m
-
Tc O 4 c on c e n t ra t es i n t h e c ho r oi d p l e xu s ,
t h yr o i d g la nd , s a li v a r y gla n d , a nd s t om ac h , b ut r em a in s i n t he c i rc u la t io n l o ng en o ug h fo r fi rs t - pa s s bl o od - po o l s tu di es , o rga n pe r f us io n , a nd m a jo r ve s s el s t ud i es . c . It is pr im a r il y e xc r e t ed b y t h e ki d ne ys u n c h an ge d an d i s e xp r e s s e d i n th e u r i ne 15 - 5 0% b y 2 4 h r . d . B e t we e n 1 0 a nd 55 % o f t he ad m i ni s te r ed do se i s e li m i n at e d v i a f e ce s wi t h i n 3 d a y s . 3 . D ec a y d a t a a.
99m
Tc d e c a y s b y i s o m e r i c t r an si t io n wi t h a p h ys ic a l h al f -l i fe o f 6 h r .
b . Th e p ri m a r y r ad i at i on e m is s i on s a r e 1 40 k e V γ e n e rg y p ho t on s . 4. Purity a . U S P ra d io n uc li di c p u rit y r e q ui r es a µCi/mCi of
99m
99
Mo b r ea k th r o ug h l im i t o f < 0. 1 5
Tc a t t h e ti m e o f p a ti en t ad m i ni s tr at i o n.
b . U S P c h em ic al pu r i t y re q ui r es an al um i nu m i on ( A l
+3
) t es t r es ul t o f l es s
t h a n 1 0 µ g /m L . 5 . Ad m i n is t r a t io n an d do s a ge . Al l o f th e f o ll o win g im ag in g s t ud i es a r e a d m i ni s te r ed v i a I V , e xc e p t n as o la c ri m a l i m a gi n g, wh i c h i s i ns ti l le d i nt o th e l a c ri m a l c an al . a . B r ai n i m a gi n g: 10 - 2 0 m C i (3 7 0 -7 40 m e ga b ec qu e r el s ; MB q ) b . Th yr o i d i m a gi n g: 1 -1 0 m C i ( 3 7 -3 7 0 MB q ) c . S al i va r y g l an d i m a gi ng : 1 -5 m C i (3 7 - 18 5 MB q ) d . P la ce n ta lo c a l i z at i on : 1 - 3 m C i (3 7 -1 1 1 MB q ) e . B lo o d- p oo l i m a g in g : 10 - 3 0 m C i ( 3 70 - 74 0 MB q ) f . U r i na r y b la dd e r i m a g ing : 0 .5 - 1 m C i ( 18 - 3 7 MB q ) g . N as o la c ri m a l im a gi n g: < 10 0 µ C i ( < 3 . 7 MB q )
III. RADIOPHARMACEUTICALS FOR CARDIOVASCULAR IMAGING A. P e r f u s i o n a g en t s f o r c a r d ia c i m ag i n g. R ad i op h a rm ac e ut ic al s a r e u s ef u l i n c a r d ia c im a gi ng a s a ge n ts th a t p r o vid e in f o rm a ti o n o n t he r eg io na l m yo c ar d ia l b lo o d p e rf us io n . Th e y t y pi c a l l y a r e a dm i ni s t e r ed as p a r t o f a c a r di ac s t r es s t es t s o as t o pr o v i de in f o rm at i on at p ea k c a rd ia c o u tp u t. The p a t ie n t wi l l ru n on a t r ead m il l t o “s t re s s ” th e h ea rt . I V c o ro n ar y ve s s e l d i la t in g a g en ts a re us ed i n pl ac e o f th e t r ea dm i ll wh e n t h e p a ti en t i s n o t p h ys ic al l y ab l e t o e xe r c is e . E xa m pl es of t he s e ph a r m a co lo g ic al ag e nt s ar e d i p yr id am o le , a d en os i ne, a nd do b ut am i ne . Th e pa t i en t wi l l a ls o b e im a ged wh e n t h e h ea r t i s a t “r e s t . ”
1 . T ha l lo u s c h lo r i d e t ha l l i um - 20 1 (
201
Tl ) is a r ad i on u c l id e t h at is p ro du c e d
b y a c yc l ot r o n. I t is us ed f o r m y o ca r di a l p e rf us i on i m a g in g i n t h e d ia gn os is o f co r on a r y a rt e r y di s e as e a nd lo ca li z a t io n of m y oc a r di al in f a rc ti o n. P.443
a . B i od i s t r ib u t io n (1)
201
Tl is a m on o v al e n t c a ti on wi t h di s t r ib u ti o n a n al o go us t o a p o ta s s ium +
+
+
i o n ( K ) ; m y o c a r d ia l u p tak e i s b y ac t i ve t r an s po r t v i a t he N a / K -a d en os i ne t r i ph o sp ha t as e (A TP a s e ) p um p . ( 2 ) B io d is t ri bu t io n i s g ene r a ll y p r op o r ti on a l t o o r ga n bl oo d fl o w a t th e t im e o f in j ec ti o n, wi t h bl oo d c l e a ra nc e b y m y oc a r di um , k id n e ys , th y r o i d, li v e r , a n d s to m a c h. Th e re m a in d e r i s d is t ri bu t ed un i fo rm l y t hr o ug h ou t t h e r es t o f the body. (3)
201
Tl is e xc r e t ed s l o wl y a n d e qu a ll y in b ot h u r in e an d f ec e s .
b . D e ca y d a t a ( 1 ) P h ys i c a l h a l f -l i f e : 73 h r ( 2 ) E f f ec t i ve ha l f - li f e : 2. 4 da y s ( 3 ) B i o lo g ic a l h a l f- l i fe : 1 1 da y s ( 4 ) P r i ma r y r a d i a t i o n em i s si o ns : 6 8 - 8 0 k e V x- r a ys an d 16 7 a nd 13 5 k eV γ e n e rg y p ho t o ns . c . Ad m i n is t r a t io n a n d do s a ge . I V, 2 -4 m C i (7 4 - 14 8 MB q ) 2.
99m
Tc se s t am i bi (
99m
T c - M I B I) e xi s ts as a s te r ile , p y r og e n -f r ee I V
i n je c ti on a ft e r k it r ec on s ti t u ti o n wi t h N a
+99m
-
Tc O 4 a n d h e at i ng at 10 0 ° C f o r
1 0 m i n. a . B i od i s t r ib u t io n (1)
99m
Tc s e s t am i bi i s a c a ti o n co m p l e x t h a t h as b e e n f ou n d t o a c c um ul a te
i n v i ab le m y oc a rd iu m b y p a s s i v e d if f us io n i n to t he m y oc y t e wi t h s ub se q ue n t b i nd i ng to t he m i to c h o ndr i a wi t hi n th e c el l . ( 2 ) Th e m a jo r p a th wa y f o r c l e ar a nc e o f
99m
Tc s e s t am ib i i s t h e h ep a to bi l ia r y
s ys t em . Th is a g en t i s e x c r e te d wi t ho u t a n y e v id en c e o f m et a bo li s m v i a u r i ne an d fe c e s . b . D e ca y d a t a ( 1 ) E f f ec t i ve ha l f - li f e : 3 h r (m y o c a r d iu m ) ( 2 ) B i o lo g ic a l h a l f- l i fe : 6 h r (m yoc a r di um ) c . Ad m i n is t r a t io n a n d do s a ge . I V, 10 - 3 0 m Ci ( 37 0 - 11 1 0 MB q ) 3.
99m
Tc t e t ro f o sm i n e xi s t s as a s te r il e a n d p yr og e n - fr e e I V i n je c ti on a ft er
k i t r ec o ns ti t u ti on wi t h s od i um pe r t ec hn e ta t e a . D es c r i p ti o n .
99m
99m
T c in j ec ti o n U S P .
Tc t e tr o f os m i n i s a l i po p hi li c , c a ti o ni c
99m
Tc c o m p l e x t h a t
h a s b ee n f o un d to ac c um u la t e i n vi a bl e m yoc a r di u m . b . B i o di s t r ib u t i on . Th e m a jo r pa t h wa ys fo r c l ea ra n c e of
99m
Tc t e t r o fo s m in
a r e th e re na l s y s te m a n d t h e h ep a to b il ia r y s y s tem wi t h 26 % o f t h e a d m i ni s te r ed do s e e xc r et e d i n t h e f ec es an d 4 0 % e xc r e t e d i n t h e u ri n e wi t h i n 48 h r. c . P h ys i c a l p r o pe r t i es . S e e II . A ; I I . B .3 .
d . Ad m i n i st r a t i on an d do s a ge . I V d ur i ng e xe r c is e , 5 -8 m C i (1 8 5 -2 96 MB q ) ; d u r in g re s t , 15 - 24 m Ci (5 5 5 -1 4 43 MB q ) 4 . R u bi d i um - 82 (
82
Rb ) ch l o r i de is a g en e ra t o r -p ro d uc e d
r a d io p ha r m a c e u ti c a l o b ta i ne d b y t h e d ec a y of it s a c c el e r at o r -p r o du ce d p a r en t s t r on t iu m (
82
S r; ha l f -l i fe is 25 da y s ) a ds o rb e d o n a s t an n ou s o xi d e
c o lu m n . a . B i od i s t r ib u t io n ( 1 ) W hen e lu t ed wi t h 0. 9% N a C l a t a r at e o f 5 0 m L / m i n , a s o lu ti o n o f t h e s h o rt - li v e d d a ug h te r
82
R b is el u te d fr om t he ge ner a t o r f o r d i re c t I V
a d m i ni s t ra ti o n . ( 2 ) A f te r I V a dm in is t r at ion ,
82
Rb r ap id l y c l ea r s f r om t he bl oo d a n d is +
e xt r a c t e d b y t he m y oc a rd i al t is s u e i n a m an n e r an a l o g ou s t o K . ( 3 ) Myo c a r d ia l a c ti v i t y is v i s ua l i z ed wi t h in 1 m i n a f t e r a dm in is t r at i on . b . D e ca y d a t a ( 1 ) P h ys i c a l h a l f -l i f e : 75 s e c . ( 2 ) Th e de c a y m o d e is by p o s i t r on em is s i on . ( 3 ) Th e p r im a r y r a d i a t i o n e mi s s io n s a r e a nn ih i la t i on 51 1 k e V γ e ne r g y p h o to ns . ( 4 ) P a re n t
82
S r a nd c o n ta m in a nt
85
S r b re ak t h ro ug h m us t be c l os el y
m o ni t o re d . A c c ep t ab l e l ev e l s o f s t r on t iu m b r ea k t hr o u gh a re < 0 . 02 µ C i 82
S r /m C i
82
R b a n d < 0. 2 µ C i
85
82
S r /m C i
R b.
c . Ad m i n is t r a t io n a n d do s a ge . I V, 30 - 6 0 m Ci ( 11 1 0 -2 2 20 MB q ) 5 . Am m o n ia
13
N e xi s t s un d e r a U S P m on o gr a ph a s a n o n s i te c y c lo t r on
p r o du c e d , s te r il e I V s o l ut i o n o f
13
N H 3 , us e fu l a s a m yoc a rd i al pe r f us io n
a g e nt . P.444
a . D ec a y d a t a ( 1 ) P h ys i c a l h a l f -l i f e : 10 m i n . ( 2 ) D e ca y m o d e : p o s i t ron em is s i o n r es u lt i ng in th e p ro du c ti on o f t wo 5 11 k e V a n ni hi l at i on γ ph o ton s . b . B i o di s t r ib u t i on ( 1 ) A f te r I V i nj ec t io n , i t c i r c ul at e s as vi a d if f us io n a s
13
13
N H 3 bu t loc a li z e s i nt o th e m yoc yt es
N H 3 . I t i s t h en m e ta b ol i z ed t o gl u t am in e a nd r e ta in e d b y
t h e m yo c y te s . ( 2 ) A f te r I V i nj ec t io n , i t is c l ea r e d r a pi dl y f r om the b lo od ; < 2 % o f t h e a d m i ni s te r ed do s e r em ain s a f t er 5 m in po s t i nj ec t io n . ( 3 ) I t is p re d om in an t l y m e t a bo li ze d to
13
N - g lu t am in e b y d i f fe r en t o r g an s o f
the body. ( 4 ) B e t we en 1 0% an d 2 0% is e xc r e t ed vi a t he r ena l s y s t em . c . Ad m i n is t r a t io n a n d do s a ge . I V, 15 - 2 0 m Ci ( 55 5 - 74 0 MB q ) B . Ag e n t s us e d t o me as u r e c a r d ia c fu n c ti o n . R e g i on al m y oc a rd ia l wa l l m o ti o n
1.
99m
Tc - l ab e le d r ed b loo d ce l l s (
99m
Tc - R B C s ) ar e us e d f o r b lo od - p oo l
i m ag in g , i nc lu d in g c a rd iac f ir s t- p as s a nd ga t ed equ i li b ri u m im a gi ng ( r e g io n al c a rd i ac wa l l m o t i on ) . a . P h ys i c a l p r o p e r ti e s. A u t o lo go us R B C s c an be l a be le d b y a nu m b e r o f t e ch n iq u es t h at us e t h e S n
++
r a di o la be l in g m et h od wi t h t hr e e g en e r al s t eps .
( 1 ) Th e c e ll s a re t r ea t ed wi t h S n
++
t o p r o v id e a n in t r ac e ll ul a r s ou r c e of t he
r e d uc in g a g en t . Th is s t ep c a n b e c a r ri e d o ut wi t h e i th e r i n vi vo o r i n v it r o l a be l in g p r oc ed u r es . ( 2 ) Th e ne xt s t e p is th e re m o v al of e xc e s s Sn
++
e it h e r b y c he m i ca l o xi d a t ion
( i n vi t ro m e th o d) o r b y b io l og ic a l cl e a ra nc e (i n vi vo m e t ho d ) . ( 3 ) A ll of t he m e th o ds i nc l ud e t h e a dd i ti o n o f so di u m p e rt ec h ne t at e (
99m
-
Tc O 4 ) . Th is
99m
Tc , w h i le in t he +7 v a le nc e s ta t e , c ro ss es t he i n ta c t
e r y t h r oc y t e m em b ra n e an d bi nd s t o i n t ra c e l lu la r h e m o g lo bi n ( Hb ) af t e r b e in g re d uc ed b y th e a v a i la b le in t r ac el lu l ar S n
++
.
b . B i o di s t r ib u t i on . Af t e r I V in j ec ti o n, t he la be l ing R B C s d is t r ib u te wi t h in t h e b l oo d p o ol an d a r e w e l l m ai n ta in e d i n t he bl oo d po ol wi t h a b i e xp o n e n t ia l wh ol e b o d y c l ea r an ce o f 2 .5 - 2 .7 h r an d 75 - 17 6 h r ( e. g . , m a j or r o u t e o f e xc r e t io n i s v ia t h e u r i ne ) . c . Ad m i n is t r a t io n a n d do s a ge . I V, 10 - 2 0 m Ci ( 37 0 - 74 0 MB q ) 2 . P yr o p h o s p ha t e in j ect i o n U S P a n d p h os p ha te s U S P . Th e m a jo r us e fo r t h es e a g en t s in n uc le a r m e di c i n e is as c o n v en ien t a n d s t ab le s o u rc es of Sn
++
f o r t h e l ab el i ng of au t o lo go u s R B C s . I n t hi s a p pl i c a ti o n, t he k i ts ar e
r e c on s t i tu t ed wi t h no rm al s a l in e a nd in j ec te d v ia I V . 3.
99m
Tc al b u mi n (
99m
T c- H S A) i n j e c t i on
a . B i od i s t r ib u t io n (1)
99m
Tc a l b um in di s t r ibu t es in i ti a ll y wi t h i n t he in t r a va s cu l a r s p ac e a n d
l e a ves th is s p ac e a t a r at e s l o w e n ou gh t o p er m i t i m a g in g o f t h e b lo o d p oo l . ( 2 ) P la s m a c le a ra nc e i s b i - e xp o n en t ia l : a fa s t com p on e nt c l ea r in g wi t h a h a l f- l if e o f 2 h r a n d a s low c o m p on en t c l ea r in g wit h a h al f - li f e o f 1 0 -1 6 h r . ( 3 ) Th e m a jo r ro u te o f eli m in a ti on is vi a t he u ri ne. b . Ad m i n i st r a t i on an d do s a ge . I V, 20 m Ci (7 4 0 MB q ) C . Ag e n t s f o r i m ag i n g m yo c a r d i a l in f a r c ti o n in c lu d e p y r op h os ph a te i n je c ti on U S P an d p ho s ph a t es U S P . 1 . M e c ha n is m o f l oc a li z a t i o n . Th e s k e l et a l l oc al iz i n g r ad io p ha r m a ce u ti c al p yr o p ho s ph a te ha s b ee n s ho wn t o ac cu m u la t e a ls o i n z on e s o f m y oc a rd i al i n f ar c ti o n. Th is lo c a l i z at io n is th ou g ht t o b e t he re s ul t o f bi nd i ng of t he p yr o p ho s ph a te to m ic r oc a l c i f ic at i on wi t h h y d r o xy a p a ti t e c r ys t al s f o un d i n i n f ar c te d t is s u e . 2 . B i od i s t r ib u t io n of la be l ed p y r op h os ph a te de pe n ds on th e a b il i t y o f p h os p ha t es to be c o m e inv o l v e d wi t h c a lc iu m i on (C a n e c ro t ic c a rd i ac t is s u e .
IV. SKELETAL IMAGING A. S k e l e t al - i ma g i ng age n t s
++
) d ep o si ti o n i n
1 . O ve r vi ew .
99m
Tc - l a b e le d bo n e a ge n ts a r e u se fu l in th e d e te c ti on o f b one
l e si on s t h at a re as s o c i a te d wi t h m e ta s t a ti c n eo p la s m s , m e t ab o li c d is o rd er s , a n d i n fe c t i on s o f t h e b one . Th e i m ag in g a d va nt a ge s o f
99m
Tc , c ou p le d wi t h
t h e s en s i t i v i t y o f bo ne ag e n t l oc al i z a ti on in P.445 s ke l et a l b on e h y d r o xy a p a t i te , a l lo ws f o r d e te c t i on o f b on e p a th o lo g y be f or e e vi d e nc e is s h o wn b y c on v e n t io n al x- r a ys . 2.
99m
Tc b on e a g en t s . Th e r e a r e m a n y d if f e re n t fo r m s of
99m
Tc b o n e
a g e nt s, wi t h m i no r di f fe re n c e s i n t he i r i n di v i du a l c h em ic al s t r uc t ur e . C u r r e n tl y us e d b on e -i m ag i ng ag e n ts a r e b as e d on e it h e r t he P — C — P d i ph o sp ho n at e s t r uc tu r e , i nc l ud in g
99m
m e d r o na t e d i so di u m a nd
99m
Tc
o xi d r o n a te , or t he in o rg an i c P — O — P ph os p ha t e st r u c t u r e, su c h as p yr o p ho s ph a te . Th es e bo n e a g en ts a re S
++
99m
Tc
re d uc t io n m e th od k i ts , wh i ch
e xi s t a s s te r il e , p y r o ge n -f r e e I V r ad io p ha r m a c e u tic a ls a f t er r ec on s ti t ut i on wi t h N a
+99m
-
Tc O 4 .
a . P h ys i c a l p r o p e r ti e s ( 1 ) A ll of t he
99m
Tc b o ne- i m ag in g a g en ts a re s u s c e pt i bl e t o ra d io lo g i c al
d e co m p os i ti o n wi t h r eo xi d a t io n o f th e
99m
Tc t o a h i gh e r v al e nc e s ta t e.
Th e s e a g en t s s o m e t im es i nc l ud e a n ti o xi d a n ts (e .g . , as c o r bi c o r g en t is ic a c id ) i n th ei r f or m u l at i on t o i m pr o v e th ei r in vi t ro s t ab i li t y. ( 2 ) Th e y s h o ul d b e s to r ed a t r o om te m p e ra t u re be f o r e a nd af t e r r e c on s t i tu t io n . b . B i o di s t r ib u t i on ( 1 ) I t is be l ie v e d t h at t he l oc a li za t io n o f t h e d ip h os p ho n at es oc cu r s b y c h em is o rp t io n o n to th e hy d r o xy a p a t i t e m in e r al m a t r i x o f s k el e ta l b on e wi th u p t ak e r e la t ed to bo n e m e t a bo li c a ct i vi t y an d b one b lo od f lo w. ( 2 ) F or
99m
Tc m e d ro n at e d i s o di u m a nd
99m
Tc o xi d r o n a te , a p p ro xi m a t el y 5 0%
o f t he ad m i ni s te r ed do s e l oc a li z e s i n t he s k el e to n, a nd 50 % i s e xc r e t e d b y t h e k id n e y s wi t h i n t he fi rs t 4- 6 h r a ft e r I V in je c ti on . c . Ad m i n is t r a t io n a n d do s a ge . I V, 10 - 2 0 m Ci ( 37 0 - 74 0 MB q ) B . B o n e m a r r ow i m ag i ng . S ee V I . A. 1 ; V I . A .3 ; V I. B .
V. LUNG IMAGING. R a d i op ha r m a c e u ti c a ls a re us e d t o e va lu a t e b ot h p u lm o na r y pe r f us io n a n d p u lm o na r y v e n ti la t io n , t o d e te c t p ul m o na r y e m b oli sm an d to as s es s p u lm o na r y f un c t i on be f o re p ne um o ne c t om y . A. P u l m o n a r y p e r f u s i o n i m ag i n g 1.
99m
Tc al b u mi n (
99m
T c- M AA)
a . P h ys i c a l p r o p e r ti e s ( 1 ) Th e
99m
Tc a l bu m i n a gg r e ga t ed k i t c on t ai ns H SA a l bu m i n t h at ha s b ee n
a g g re g at e d b y h ea t d e nat u r a ti o n. ( 2 ) Th i s S n
++
re d uc ti o n m e th o d ki t e xi s ts as a s te r i le , p y r o g en - f re e
s us p en s i o n o f r a di ol a be le d ag g re g at e d p a rt ic l es a f t e r r ec o ns ti t u ti on wi t h Na
+99m
-
Tc O 4 .
( 3 ) I t sh o ul d b e s t or e d a t 2 ° - 8 ° C a f te r r ec on s t i tu t io n . b . B i o di s t r ib u t i on ( 1 ) A f te r I V a dm in is t r at ion o f
99m
Tc a l b um i n a gg r eg a t ed , 8 0 % o f t h e
r a d io l ab el e d a lb um i n p art i c l es be c o m e t r ap pe d by c a pi l la r y b lo ck ad e i n t he p u lm o na r y c i r c u la t io n . ( 2 ) A f te r t ra pp i ng , th e p ar t i c l es a re c l ea r ed f ro m th e lu ng s m ai nl y b y m ec h an ic a l b re a k u p . Th e s e s m al l e r p ar t ic le s a r e u l ti m a t el y c l e a re d f r om th e c i rc u la ti o n b y t he r et ic u lo e n do t he li a l s y s t em . ( 3 ) P a rt ic l e s i z e s h ou l d b e c o nt r o ll ed — t ha t i s , 90 % of t he pa r ti c l es s h o uld b e be t we e n 1 0 a n d 9 0 µ m , an d n on e s h ou ld be > 1 5 0 µ m , t o e ns u re a d e qu a te t ra pp i ng b y th e l u ng c a pi ll a r y be d b u t no oc c l us i on of t he la r ge b o r e ves s e ls . ( 4 ) P a rt ic l e n um be r s h oul d be be t we e n 2 0 0, 0 00 an d 70 0 ,0 0 0 p ar t ic le s p e r a d ul t do s e to ob t ai n u n ifo r m i m a g in g d a ta wi t h out c om pr o m i s i ng ca pi l la r y b l oo d fl o w. N e on a te s s ho u ld r ec ei v e < 1 2 5, 0 00 pa r t i c le s . c . D ec a y d a t a . B i ol o gi c al h al f -l i fe in th e l u ng : 2 - 3 h r d . Ad m i n i st r a t i on an d do s a ge . I V, 1 -4 m C i (3 7 - 14 8 MB q ) B . P u l mo n a r y ve n t i l a t i on i ma g i ng wi t h r ad io ac t ive g as e s is a r o ut i ne n u cl e ar m e di c i n e p r oc edu r e th a t c a n pr o vi de v a lua b l e in f o rm a ti on ab o ut r e g io n al lu ng v e n ti la t io n . R a d io p ha r m a c e u ti c a ls us e d a r e e it h er r ad i oa c t i ve g a se s o r ra d io ae r os o ls . 1 . X en o n -1 3 3 (
133
X e ) i s s u pp li e d a s a ra di o ac ti v e g as c o n ta in e d i n g la s s
s e pt um v i al s t o b e a dm i ni s te r e d b y in h al a ti on t hr ou g h a c l os ed r es pi r a to r y s ys t em o r a s pi r om et e r . It i s a b yp r od u c t of
235
U f is s i o n.
P.446
a . B i od i s t r ib u t io n (1)
133
Xe i s a re a di l y di f fu s ib le ga s , wh i c h i s n ei th e r us ed no r pr o du ce d by
t h e b o d y . I t pa s s es th r oug h m em b r an es an d f r e ely e xc h a n g es be t we e n b l oo d a n d t is s u e , t en d ing t o c on ce n t ra t e m o r e i n b o d y fa t . ( 2 ) I nh al e d
133
Xe di s t r ib ut e s wi t hi n t h e a l veo li an d e n te r s t he p ulm o na r y
ve n o us c i rc u la t io n v ia the c a p il la r i es ; m os t o f t h e a bs o r be d
133
Xe ia
r e t u rn e d a nd e xh a l ed f rom t he lu ng s a f te r a s i n gle p ass t h ro ug h th e p e r ip h e ra l c i r c u l at i on . ( 3 ) I n co nc e nt r a ti o ns u s ed f o r d ia g no s i s , th e ga s is ph ys io l og ic a ll y i na ct i ve. b . D e ca y d a t a ( 1 ) E f f ec t i ve ha l f - li f e i n t h e l un g : 2 m i n ( 2 ) P h ys i c a l h a l f -l i f e : 5 .2 d a ys . ( 3 ) D e ca y m o d e : β m in us an d γ de c a y . ( 4 ) P r i ma r y r a d i a t i o n em i s si o ns : 1 0 0 k e V β e ne r g y a nd 81 k e V γ en e rgy p h o to ns . c . Ad m i n is t r a t io n a n d do s a ge . In h al at i on , 2 - 3 0 m C i (7 4 - 11 10 MB q )
2 . X en o n -1 2 7 (
127
X e ) i s s u pp li e d a s a ra di o ac ti v e g as c o n ta in e d i n g la s s
s e pt um v i al s t o b e a dm i ni s te r e d b y in h al a ti on t hr ou g h a c l os ed r es pi r a to r y s ys t em o r a s pi r om et e r . It i s p ro d uc ed b y a c y c l o tr o n . a . B i od i s t r ib u t io n . L oc al i z a t io n i s t he s a m e as
133
Xe .
b . D e ca y d a t a ( 1 ) P h ys i c a l h a l f -l i f e : 36 . 4 d a y s ( 2 ) D e ca y m o d e : b y e l ec t r o n c ap t u re ( 3 ) P r i ma r y r a d i a t i o n em i s si o ns : 2 0 3 k e V , 1 90 k e V , 1 72 ke V , a n d 3 75 ke V γ en e r g y p h ot o ns . c . Ad m i n is t r a t io n a n d do s a ge . In h al at i on , 5 - 1 0 m C i (1 8 5 -3 70 MB q ) 3 . R a di o ae r o s ol s h a v e b e c o m e in c re as i ng l y us ed wi t h t he ad ve n t o f n e b ul i ze rs th a t p ro d uc e p a r ti c l e s o f a c o ns is te n t s i z e n ec e ss ar y f o r u n if o rm l u ng di s t ri bu t io n . a . B i od i s t r ib u t io n (1)
99m
Tc p e n te t a te ( D TP A ) r a di o ae r os ol s o f a p pro xi m a t e l y 0 . 25 µ m m as s
m e di a n a er o d y na m i c d iam e te r a re us ef u l i n d et e rm i ni ng lu n g v e n ti l at i on . ( 2 ) A f te r de po s i t io n o f the n eb ul i z e d d r op l et s wi t hi n th e a i r wa y s , th e
99m
Tc
p e n te t at e i s a bs o rb e d i nto t he pu lm o na r y ci r c u l at io n . ( 3 ) Th e m a te r ia l i s s ub s eq u e nt l y e xc r e te d b y t h e k i dn e y s. C l ea r an c e f ro m t h e l u ng s is s u f fi c i e nt l y s l o w t o al l o w f o r im a gi n g o f t he l u ng s i n m ul ti p le p r o je c ti on s f r om a s i n gl e a dm i ni s t r a ti o n. b . P h ys i c a l p r o p e r ti e s. S e e II . B . 3. c . Ad m i n is t r a t io n a n d do s a ge . In h al at i on , 3 0 µ Ci ( 11 1 0 MB q )
VI. HEPATIC IMAGING A. O ve r vi e w . H ep a ti c im a g in g re q ui r es th e u se of t wo d i ff e r en t c la s s es of r a d io p ha r m a c e u ti c a ls to e v a l u at e t h e t wo c el l t y pe s re s p o ns ib le f o r h ep a tic f u nc t io n . 1 . R e t ic u lo e nd o t he l i al s ys t e m i m a gi n g. Th e li v e r , s p le e n, an d b o ne m a r ro w a r e e v al u at e d wit h r ad i ol ab e le d c ol lo i da l m a te r i al , ra ng i ng in s i z e f r o m 0 .1 t o 3 .0 µ m . Th e s e p a rt ic l es a r e r a pi d l y c le a r ed f ro m t h e b lo od b y p h a go c y to s i s b y t he K upf f e r c el ls o r t r ap p ed in the s p ac e of D is s e , wh ic h is f o u nd be t we e n th e p ol y go n al he p a to c y te s a nd t he K u p f f e r c e l ls . 2 . L i ve r s p l ee n i m ag i n g. R a di o ph a rm ac e ut ic a ls a r e us ef u l i n im a gi ng s p ac e -o c c up y i n g p ri m ar y t u m o rs a nd m e ta s t a ti c ne o pl a s m s as we l l a s h e p at ic de f ec ts c a us ed by a b s c es se s , c y s t s , a nd t r a um a . 3 . B o ne ma r r ow i ma g i ng . Im a ge s t ha t lo c a li z e in t he bo n e m a r r o w a r e u s ef u l i n t he e v al u at i on o f pa t ho l og ie s t h at a ff ec t b o ne m a r ro w. 4 . H e pa t o bi l ia r y i m a g i ng . H e pa t oc yt e f u nc ti o n c a n be e v al u at e d b y s u bs ta n c e s m e e ti n g r e qui r e m e n ts o f m ol e c u la r we i gh t , l i po ph i li ci t y , a n d c h em ic al s t r uc t ur e , t o b e e xc r e t e d b y t he po l y g ona l c e ll s i nt o t h e h e p at o bi li a r y s y s t em . Hep a t ob il i a r y -i m a g in g ra di op h a rm ac e ut ic al s a r e u s ef u l i n t he di a gn os is of c y s ti c d uc t o bs t ru c ti on i n ac ut e c ho l ec y s ti t is a s we l l a s d ef i ni n g p os tc ho le c y s te c t om y a n at om y a nd p h ys i ol o g y . P.447
B . R e t i cu l oe n d o th e li a l -im a g in g ag e n ts 1.
99m
Tc su l f u r c o l lo i d (
99m
T c 2 S 7 ) is a s te r il e , p yr o g en - f r ee I V
r a d io p ha r m a c e u ti c a l f o rm e d v i a a ch em ic al r ea c ti o n b e t we e n
99m
-
Tc O 4 a nd
a n ac id i fi ed s o lu t io n o f s o d iu m t h io su l fa t e a t 1 00° C . a . P h ys i c a l p r o p e r ti e s ( 1 ) Tc 2 S 7 is t ho u gh t t o re m ai n i n t h e + 7 va l en c e s t a te as th e h ep t as ul f id e c o p re ci pi t a te of el em e nta l s u lf u r t h at oc c u r s d ur in g th e re ac t io n . ( 2 ) Th e us e o f Na
+99m
-
Tc O 4 wi t h A l
+3
le ve l s > 1 0 µ g / m L c a n l e ad to t he
f o r m a t io n o f p a r ti c l es > 5 µ m , wh i c h c an re s ul t in l un g u p ta k e . ( 3 ) H e at in g ti m e s s h o ul d b e c on t r ol l ed to p re c l ude l ar g e p a rt ic l e f o rm at i on . b . B i o di s t r ib u t i on . Af t e r a dm i ni s t r a ti o n, 80 % -9 0% o f t h e d os e is p h a go c y ti z e d b y t h e K u pf f e r c el ls o f t he li v e r or tr a p pe d i n th e s pa c e of D i s se , 5 % -1 0 % b y t he s pl e en , an d t h e b al a nc e b y t h e b on e m a r ro w. Th e b l oo d c le a r an c e ha l f -l i fe i s a p p ro xi m a t el y 2 .5 m i n. P a r ti c l es a re no t m e ta b ol i z e d a nd re s i d e in t he r et ic u lo e nd o th el i al s ys t em fo r a p ro l on ge d p e r io d . c . Ad m i n is t r a t io n a n d do s a ge . I V, li v e r /s p le en : 1 - 8 m C i (3 7 -2 9 6 MB q ) ; b o n e m a r r o w: 3 -1 2 m C i (1 1 1 -4 4 4 MB q ) C . H e p a to b i li a r y- i m a g i ng a ge n t s 1 . O ve r vi ew a . I mi n od i ac e t ic ac i d (ID A) d e r i va t i ve s , wh i c h a r e l i do ca i ne an al o gs , a re u s ef u l as he p at o bi l ia r y- im a gi n g a ge n ts b ec a us e o f t he i r l ip op h il ic i t y , wh ic h a l lo ws t h em to be s e le c t iv e l y c le a r ed b y c a r ri e r -m e d ia t ed h ep a to c yte m e ta b ol ic pa t h wa y s . Be c a u s e th e s e ag en t s s h a r e t h e s am e e xc r e t io n p a t h wa y a s b il i ru bi n , p a ti e n ts wh o ha ve in c r e as ed b il i ru bi n l e v e ls e xh i bi t d e c re as e d h ep a ti c c l e ara n c e an d a n i nc r e as ed re n al cl ea r a nc e. La ck of g a ll b la d de r v is ua l i z at i on i s a n a b no r m a l f i nd in g , s u g g es ti n g ac u te c h ol ec ys ti t is . b . C h o le c ys t o k i n e t i c a ge n t s , s u c h as s i nc al i de a n d c ho l ec y s to k i ni n , m ay b e us ed to em p t y th e c on t e nt s o f t h e g al l bl ad d e r i n f a s t in g pa ti e n ts b e fo re i n je c ti on o f I D A c om p oun d s i n a n a t te m p t t o pr om o te ga l lb la d de r fi ll i ng an d vi s u al i za ti on . Th es e a g en t s c an al s o be in je c te d a f t e r t he in j ec ti o n o f t h e I D A c om po u nd to c a us e a v i s u a li ze d g a ll bl a dd e r t o e m p t y . C h o l ec y s to k i ne t ic ag e nt s a r e u s e d t o i n c r e as e t he s pe c i f ic i t y a n d s e ns i ti v i ty o f t he i m ag in g p r oc e du r e. c . N a rc o t ic a na l ge s ic s , s uc h a s m o rp hi n e, ha ve b e e n us e d t o c on st r ic t the s p hi nc t e r o f O d d i t o p r odu c e i nc r ea s e d i n t ra du c tal p re s s u re s t o p r om o te r e t r og r a de ga ll b la d de r fi ll i ng . 2.
99m
Tc d is o fe n i n (
99m
Tc - D I S I D A)
a . P h ys i c a l p r o p e r ti e s. S e e II . B . 3. b . B i o di s t r ib u t i on (1)
99m
Tc - D I S I D A i s r ap id l y c l e a re d f r om th e b l ood ; 8% r em ai ns in th e b l oo d
after 30 min.
( 2 ) A pp r o xi m a te l y 9% of t h e a dm i ni st e r ed ac ti vi t y i s e xc r e t e d in t he u ri ne d u r in g th e f i rs t 2 h r. Th e r e m a i nd e r o f t h e ac t i vit y i s c le a re d t h r ou gh t he h e p at o bi li a r y s y s t em . ( 3 ) P ea k l i v e r u pt ak e i s wi t h i n 10 m i n; pe ak ga l lbl a dd e r u p ta k e is b y 3 0 - 40 m i n. ( 4 ) G a ll bl a dd e r a n d in t es t i n al v is u al i za ti on oc c u r s wi t h i n 6 0 m in p o st a dm in is t r at i on . c . Ad m i n is t r a t io n a n d do s a ge . I V, no n ja un d ic ed p a ti e nt : 1- 5 m C i (3 7 -1 85 MB q ) ; I V , j au n di c e d p a tie n t : 3 - 8 m C i ( 11 1 - 29 6 MB q ) 3.
99m
Tc me b r o fe n i n
a . P h ys i c a l p r o p e r ti e s. S e e II . B . 3. b . B i o di s t r ib u t i on (1)
99m
Tc m e b ro f en i n is ra p id l y cl ea r e d f r om th e bl o od ; 17 % re m a in s a f te r
1 0 m i n. O n l y 1 % o f th e ad m in is t e re d a c t i vi t y i s e x c r e te d i n t h e u r in e wi t hi n t h e fi rs t ho u rs ; t h e r em a in d e r o f t h e a c t i v i t y c le a rs t hr o ug h t h e h ep a to b il iar y s ys t em . ( 2 ) P ea k l i v e r u pt ak e oc c u r s wi t hi n 1 0 m in ; v is u al iz a t i o n o f t h e h ep a ti c d uct a n d g al l bl a dd e r, wi t h in 10 - 1 5 m in ; t h en in t es ti n al a c ti v i t y , wi t h in 30 - 6 0 m i n. c . Ad m i n is t r a t io n a n d do s a ge . I V, no n ja un d ic ed p a ti e nt : 2- 5 m C i (7 4 -1 85 MB q ) ; I V , j au n di c e d p a tie n t : 3 - 10 m C i (1 1 1 -3 70 MB q ) P.448
VII. RENAL IMAGING A. O ve r vi e w 1 . R ad i op h ar m ac eu t ic al s a r e u s e d i n re na l i m a g ing t o d e te rm i ne r en al f u nc t io n , r e na l v as c u la r fl o w, a n d r e na l m o rp ho l og y . Th e y a r e a ls o u se f ul f o r th e e v a l ua t io n o f re na l fu nc t io n i n p os t t ra n s p la n t p a ti e nt s f o r c om p li ca t io ns s u c h as ob s t ru c ti on , i n fa r c ti on , l ea k ag e , t ub u la r ne c ro s i s , a n d re je c ti on . 2 . Th e us e o f r a di op h a rm ac e ut ic a ls to de t e rm ine r e na l f u nc ti o n o r r e na l m o r ph ol o g y i s b as e d o n t h e t wo ph y s io l og ic al m ec h an is m s re sp o ns ib l e f o r e xc r e t i o n: gl om e r ul a r f il tr a t io n an d t u bu la r s e c r e ti o n . B . Ag e n t s cl e a re d b y g l o m e r u la r f il t r a t io n a re u s ef u l i n d et e rm i ni ng t he g l om e ru l a r f il t ra t io n ra t e ( G F R ) , r e na l a r te r y p e rf us i on , a n d t he v i s u al i za ti on o f t he c o ll ec t in g s y s te m . 1.
99m
Tc pe n t e ta t e (
99m
Tc - D T P A)
a . P h ys i c a l p r o p e r ti e s. S e e II . B . 3. b . B i o di s t r ib u t i on ( 1 ) A f te r ad m i ni s tr a ti o n,
99m
Tc p e n te t at e ra pi d l y di s t ri bu t es th r o ug ho u t
e xt r a c e l lu la r fl u id s p ac e, f r om wh i c h i t is r ap i dl y c l ea r ed b y gl om e ru l ar f i l t ra t io n o nl y . ( 2 ) U p t o 1 0 % m a y b e p ro t e in bo u nd , l e ad in g t o a d ec r e as e i n m e as u r ed GFR.
( 3 ) A f te r ad m i ni s tr a ti o n, 5 0 % o f th e d os e i s c l e a re d b y th e k id ne y s wi t h in 2 h r , an d u p t o 9 5 % is c l ear e d b y 2 4 h r . c . Ad m i n is t r a t io n a n d do s a ge . I V, 10 - 2 0 m Ci ( 37 0 - 74 0 MB q ) 2 . S o di u m i o t ha l am a te io d i n e- 1 25 (
125
I ) i n je c t i on is a c om m e rc i al l y
s u pp li e d, s t e r il e , p y r og en - f r ee in j ec ti o n c o n ta i ni n g 1 m g s od iu m i o th al am at e p e r m il l il i te r . a . B i od i s t r ib u t io n ( 1 ) S od i um i o th a la m a t e
125
I is u se d fo r d e te r m i n at i o n o f t h e G F R bu t no t fo r
i m ag in g b e c a us e o f p o o r i m a g in g e m i s s io ns of
125
I.
( 2 ) Th yr o i d b lo c k ad e wi th o r al po t as s i um i o di de (K I ) i s su gg es t ed . b . D e ca y d a t a ( 1 ) P h ys i c a l h a l f -l i f e : 59 d a ys ( 2 ) D e ca y m o d e : b y e l ec t r o n c ap t u re ( 3 ) P r i ma r y r a d i a t i o n em i s si o ns : 3 5 k e V γ en e rg y p h ot o ns an d x- r a ys . c . Ad m i n is t r a t io n a n d do s a ge . I V, 10 - 5 0 µ C i (3 .7 - 1 8 .5 MB q ) C . T u b ul a r s e c re t i o n a ge n t s a r e u s e d t o e v a l ua te r e na l t u bu la r fu nc t io n a n d m ea s u r e e f fe c ti v e r en a l p la sm a f l o w. 1 . I od o h ip p u r at e io d i ne- 1 3 1 (
131
I ) h ip p u ra n . No l o ng e r c om m e r ci al l y
a va i la b le 2.
99m
Tc me r t i a ti d e (
99m
T c - M AG 3 )
a . D es c r i p ti o n ( 1 ) S up p li ed as a s te r il e , p y r o g en - f re e , l y o ph i li z ed k i t c o nt a in in g b e ti a ti d e, p r e cu r so r o f m e r ti a ti de , a n d c he l at i on ad ju t an t s . ( 2 ) A f te r th e s od i um p e r te c hn e ta t e is ad d ed t o t he k i t , i t m us t b e h e at e d in a h ot wa t e r ba t h o r h ea t in g bl oc k a t 1 00 ° C f o r 1 0 m in t o f o rm
99m
Tc
m e r ti a ti de f r om t h e b et i at i d e p r ec ur s or . b . B i o di s t r ib u t i on ( 1 ) Me r t i a ti d e is r en a ll y e xc r e t e d , 9 0% o f t he adm i ni s t e r ed do s e is e xc r e t e d wi t h i n 3 h r p os t in j ec ti o n. ( 2 ) I t is p ri m a r il y c le a re d v i a ac t i ve t ub u la r s ec r e ti o n a nd t o a s m a ll e xt e n t vi a g lo m e r ul a r f i lt r a ti on . c . P h ys i c a l p r o pe r t i es . S e e II . B . 3. d . Ad m i n i st r a t i on an d do s a ge . I V, 5 -1 0 m C i ( 1 85 - 3 70 MB q ) D . R e n al c o r ti c al im a g in g a ge n ts a re us ed t o eva l u a te r en al an a to m y b e ca us e o f th ei r ab i li t y to ac c u m ul at e i n th e k id ne y a n d p r o vid e a n at om ic a l i m ag in g d a ta . 1.
99m
Tc g lu c ep t a te (
99m
Tc-GLH)
a . P h ys i c a l p r o p e r ti e s. S e e II . B . 3. b . B i o di s t r ib u t i on P.449
(1)
99m
Tc - G L H r a p id l y dis t r ib u te s t h ro u gh o ut th e b o d y, wi t h ra pi d b l oo d
c l ea r an c e v i a g lo m e r u la r f i lt r a ti o n a nd tu b ul a r s ec r e ti o n a nd re a bs o rp t io n.
( 2 ) A pp r o xi m a te l y 25 % of t h e a dm in is t er e d d os e is e xc r e t ed wi t h in th e f i rst h o u r ; 6 5% , wi t hi n 6 h r; an d 70 % , wi t h i n 2 4 h r . ( 3 ) A f te r 3- 6 h r , a m a xi m u m o f 5% - 15 % o f th e d os e a dm i ni st e r ed is c o nc en t r at e d i n t he p ro xi m a l r e na l t u bu la r c e ll s o f t h e r e na l c o rt e x. c . Ad m i n is t r a t io n a n d do s a ge . I V, 10 - 2 0 m Ci ( 37 0 - 74 0 MB q ) 2.
99m
Tc su c ci m e r (
99m
Tc - D M S A)
a . P h ys i c a l p r o p e r ti e s ( 1 ) S ee I I. B . 3. (2)
99m
Tc s u c c im e r c o m pl e x m u s t b e a ll o we d to inc u ba t e f o r 1 0 m i n
p o st r ec o ns ti t u ti on an d m u s t b e u s e d wi t hi n 4 h r po s ti nc u ba t io n . b . B i o di s t r ib u t i on ( 1 ) W it hi n 3 - 6 h r po s t a dm i ni s t r a ti on , 40 % -5 0 % of t h e d os e l oc al i zes in the r e n al co r te x, wh e r e i t is t a k e n u p b y t h e t ub u la r c e l ls . ( 2 ) E xc r e t io n i n to t he ur in e is s lo w; 5 % - 20 % i s e x c r e te d wi t hi n t h e f i rs t 2 h r , 1 0 % -3 0 % b y 6 h r , a n d < 4 0 % b y 2 4 h r . c . Ad m i n is t r a t io n a n d do s a ge . I V, 2 -6 m C i (7 4 - 22 2 MB q )
VIII. THYROID IMAGING A. O ve r vi e w 1 . Th e ba s i c f un c ti on o f th e th y r o i d g la nd is th e pr o d uc t io n o f t h yr o id h o r m o ne f or t he r eg ul a tio n of m e t ab ol is m . Th e thyr o i d ho rm o ne s a r e p r o du c e d wi t hi n th e g la nd t h ro u gh th e o r g an if ic a ti o n o f i o di ne ob t ai n ed f ro m t h e o xi d a t i on of a v ai l ab le i od id e c i rc ul a ti n g i n t h e b lo od . Th e i n ab il i t y of t h e b o d y to di s ti ng u is h b et w e e n t h e is o to p es of io di ne p r o vid es a p e rf ec t m e ta b ol ic t ra c e r fo r th e th y r o i d b io c h em ic a l s ys t em . 2 . Th e fu nc t io n o f th e t hy r o i d gl an d c an be e v al ua t e d b y t he up t ak e o f or
123
131
I
I , a l lo wi n g th e d e tec t io n o f h y po t h y r oi di sm wi t h d ec r e as ed up t ak e an d
h yp e r t h y r oi di s m wi t h i nc re a s e d u p ta ke . 3.
99m
-
Tc O 4 i s a m on o v a le n t a n io n wi t h a n i on ic ra d iu s s im il a r t o i od i de . As
a r es u lt , th e p e r te c h ne t at e io n i s t r ap p ed b y th e th y r o i d g la n d i n a fa sh io n s im i la r to io di d e. Th e t wo s p ec i es ar e s u ff ic i en t l y d i ff e r en t i n th a t
99m
Tc O 4
-
i s n o t o r ga n if i ed or in c o rp o r a te d i n to th yr o id ho rm o ne , a n d i t i s s u bs eq u en t l y re l ea s e d un c ha n ge d . B . T h yr o i d i m a gi n g a gen t s 1 . S o di u m i o di d e i o di ne - 1 23 (
123
I ) i s a ra d io ph ar m ac e ut ic a l a v a il ab l e i n
e i t he r s o lu ti o n o r c ap s ule f o rm fo r o r a l a dm in is t ra t i on . I t is p r o du ce d b y a c yc lo t r on . a . B i od i s t r ib u t io n ( 1 ) O r a ll y a dm in is t er e d io d in e i s ra pi d l y a bs o r bed f r o m th e g as t r oi n te st i na l ( G I ) t r ac t ; t h y r oi d g l an d u p t ak e is e v id e nt wi t h i n m i nu t es . ( 2 ) S od i um i o di de
123
I i s c o ns id e re d a n i d ea l ra dio p h ar m a c eu ti c al fo r i o din e
u p t ak e a nd im ag i ng s t udi e s b ec au se o f i ts s ho r t h a l f- l if e a n d u se f ul 1 5 9 ke V p r i m a r y γ em is s i o ns . b . D e ca y d a t a ( 1 ) P h ys i c a l h a l f -l i f e : 13 . 2 h r
( 2 ) B i o lo g ic a l h a l f- l i fe : 3 . 5 d a y s ( 3 ) D e ca y m o d e : b y e l ec t r o n c ap t u re ( 4 ) P r i ma r y r a d i a t i o n em i s si o ns : 1 5 9 k e V , 2 7 k e V , an d 5 2 9 k e V γ e ne r gy p h o to n s c . Ad m i n is t r a t io n a n d do s a ge . O r al th y r o i d u pt ak e : 1 00 - 2 00 µ C i ( 3 .7 - 7 .4 MB q ) ; t h yr o i d im a ge : 1 0 0- 5 00 µC i ( 3 .7 - 18 . 5 MB q ) 2 . S o di u m i o di d e
131
I is u s ed fo r th yr o i d u pt ak e an d im ag in g s t ud i es ; h o we v e r , it is
n o w u s ed le s s of t en be c a u s e of t he hi gh r ad i at i on d os e a bs o rb e d. a . B i od i s t r ib u t io n ( 1 ) O r a ll y a dm in is t er e d io d in e i s ra pi d l y a bs o r bed f r o m th e G I t r ac t ; wi t h t h y r o i d g l an d u p t ak e is wi t h in m in u t es . P.450
( 2 ) S od i um i o di de
131
I i s n o t c on si d e re d a n i de a l ra d io i od i ne ra d io p ha rm a ce u t ic al fo r
i o di n e u pt a k e an d i m a gin g s t ud i es b e c a us e o f i ts l o ng ha l f- l if e , p oo r im agi n g p r o pe r t ie s , an d th e h ig h r a d ia t io n d os e to th e t h yr o i d f r om it s β d ec a y c om p on e nt . ( 3 ) Th e ra d ia t io n d os e f ro m th e h ig h - en e rg y β p ar t i c l e wi t h t he im ag i ng po t e nt i al of i t s γ e m i s s io ns m a k e th is r ad i on uc li d e t he ag e nt o f c h oi c e f or t he r ap e ut ic t r e at m e n t o f h ype r t h y r oi di s m an d th y r o i d c an c e r . b . D e ca y d a t a ( 1 ) P h ys i c a l h a l f -l i f e : 8 .0 8 da y s ( 2 ) D e ca y m o d e : b y β de c a y ( 3 ) P r i ma r y r a d i a t i o n em i s si o ns : 6 0 6 k e V a nd 3 3 3 k e V β en e r g y ; 3 64 k e V , 63 7 k e V , a nd 28 4 k e V γ e n e rg y p h ot o ns . c . Ad m i n is t r a t io n a n d do s a ge .
131
I i s a va il ab l e as ei t he r a c a p su le o r i n s o l u ti on
f o r o ra l a dm in is t r at i on . ( 1 ) D i ag n os t i cs ( a ) Th yr o i d u pt a k e : 2 - 15 µ C i ( 0 .0 7 4 -0 . 55 5 MB q ) ( b ) Th yr o i d i m a ge : 30 - 50 µ C i ( 1 .1 1 -1 . 85 MB q ) ( c ) W hole bo d y im ag e : 1- 5 m Ci ( 37 - 18 5 MB q ) ( 2 ) T he r a pe u t ic s ( a ) H yp e r th y r o id is m : 1 0-3 0 m C i (3 7 0 -1 11 0 MB q ) ( b ) Th yr o i d c a rc in om a : 50 - 2 00 m Ci ( 18 50 - 7 40 0 MB q ) 3. Na 4.
201
+99m
-
T c O 4 . S ee I I. B.
T l . P a ra t h y r oi d i m ag i ng
a . B i od i s t r ib u t io n .
201
TI c on c e n t ra t es in th e t h yro i d a nd al s o in p ar a th yr oi d
a d e no m a s , wh i c h c a n b e d e te c te d b y a d u al is ot op e s u bt r ac t io n te c h ni q ue o f s u bt r ac t in g t h y r o id up t ak e c o u nt s f r om N a
+99m
-
Tc O 4 to un m a sk no n th y r o i d th a ll i um
u p t ak e c ou n ts (s ee I II . A .1 ) . b . Ad m i n i st r a t i on an d do s a ge . I V, 2 m C i ( 74 MB q )
IX. BRAIN IMAGING A. C e r e b r a l pe r f u s io n br a i n - im a g in g a g e nt s . Ra d io p ha r m a ce u ti c a ls f or e v a l u at in g b r a in pe r f us io n m us t p os s es s a li po p hi li c p a r ti ti on co e f fi c i en t s u f fi c i en t to d i ff u s e p a ss i vel y a c r os s t h e b loo d - b ra i n b ar r i er ( B B B ) a lm o s t c om p le t el y wi t h i n on e pa s s of
t h e c e re b r al c i rc ul a ti o n, a s we l l as b ei ng s u f fi ci e n t l y r et a in e d t o p e rm it da t a c o ll ec t io n . Th e r eg io n al u p t ak e o f t h es e a ge n ts is p ro p or t io n al to c e r eb r al b lo od f l o w. Th i s c la s s of r ad iop h a rm ac e ut ic al s i s us e ful i n t he di a gn os is of al t e re d r e g io n al bl oo d p e r fu s i o n i n s t r ok e. 1.
99m
Tc ex a me t az i me (
99m
T c - H M P AO ) e xi s t s a s a s te r il e , p y r o ge n - fr e e IV i nj e c t i on
a f t e r r ec o ns ti t u ti on wi t h s o di um pe r t ec hn e ta t e U S P , wh i c h m a y b e s t ab il iz e d wi t h t h e a d di t io n o f a m e t h y len e bl ue / p ho s p ha t e b u ff e r s t ab il i z i ng s o lu t io n . a . D es c r i p ti o n (1)
99m
Tc e xa m e t a z i m e is a n eu t r al , l i pi d -s ol u bl e c om p le x t h a t f re el y c r os s es t he
B B B . Th i s is a re la t i v el y u n s t a bl e c om pl e x, wh i c h r a pi d l y c o n ve rt s t o a s ec o nd a r y , l e ss l i po ph i li c c o m p l e x in c ap a bl e o f p e ne t ra t in g in t o th e b r ai n . Th e in vi t ro a dd i ti on o f a m et h y l en e b lu e /p h os p ha t e b uf f e r s ta b il i zin g s o lu t io n a f te r p re pa r i ng th e
99m
Tc
e xa m e t a z im e wi l l s ta bi l i ze t he li p id -s o lu b le c om p le x f o r 4 h r . ( 2 ) A dd i ti o na l l im it a ti o ns o n k i t p re p a ra t io n p a ram e te r s r e qu i re t he us e of h ig h m ol e f r a ct i on te c h n e ti um ge ner a t o r e lu a te s o f < 2 h r po s te l ut i on f ro m a g e ne r at o r p r e vi ou s l y e lu t ed wi t h in 2 4 h r. b . B i o di s t r ib u t i on (1)
99m
Tc e xa m e t a z i m e ra p id l y cl ea r s f r om th e b lo o d , wi t h a m a xi m um b r ai n up t ak e
o f 3 .5 % -7 % , a nd up to 2 .5 % r em ai ni n g a f te r 2 4 h r. ( 2 ) Th e ac ti v i t y is wi d e l y d is t r ib u te d t h r ou gh o ut th e bo d y; 3 0 % d is t ri b ut es t o th e G I t r a ct . ( 3 ) W it hi n 4 8 h r , 40 % o f t h e d os e i s e xc r e t e d t h rou g h t h e u r in e a nd 15 % i s e l im in a te d v ia t he fe c e s . c . P h ys i c a l p r o pe r t i es . S e e II . B . 3. d . Ad m i n i st r a t i on an d do s a ge . I V, 10 - 2 0 m Ci ( 37 0 - 74 0 MB q ) P.451
2.
99m
Tc b ic i sa t e (
99m
T c- E C D )
a . D es c r i p ti o n (1)
99m
Tc b i c i s a t e e xi s t s a s a s t e ri l e, p yr og e n -f r ee I V i n je c t i on af t e r r ec o ns t i tu ti o n
wi t h s od i um p e r te c h n et at e
99m
Tc U S P a n d t he add i t io n o f a ph os p ha t e b uff e r .
( 2 ) A f te r re c o n s t i tu t io n , a s ta bl e l i po ph i li c
99m
Tc b i ci sa t e co m p l e x i s f o rm e d , wh ic h
i s a b le to c r os s t h e B B B b y p as si ve d if f us io n . b . B i o di s t r ib u t i on (1)
99m
Tc b i c i s a t e i s r ap id l y c l e a re d f r om bl oo d ; a m a xi m um of 6. 5 % o f t h e
a d m i ni s te r ed do s e is lo c a l i z ed in t he b ra in , a n d 5% is le f t i n t h e b lo od a fte r 1 h r . ( 2 ) O nc e l o c a t ed i n th e br a i n c el ls ,
99m
Tc b i c is a te i s m et a bo li z e d b y e nd o ge n o us
e n zym e s t o a p o la r c om po u n d t ha t i s u na b le to di ff u s e ou t of t he br a in c e lls . (3)
99m
Tc b i c i s a t e i s p ri m a r i l y e l im in a te d v ia th e k i d ne y s ; 5 0 % is e xc r e t ed wi t h i n 2
h r , an d 7 4 % i n 2 4 h r . H ep a t ob il i a r y e xc r e t i on ac c o u n ts fo r a p p ro xi m a t el y 1 2 . 5% of t h e a dm i ni s t e r ed do s e aft e r 48 h r. c . R ad i o nu c li d e p r o p e r ti e s . S e e I I . B. 3 . d . Ad m i n i st r a t i on an d do s a ge . I V, 10 - 3 0 m Ci ( 37 0 - 11 1 0 MB q ) 3 . I o fe t am i ne h yd r o c h l o r i d e
123
I. N o t c o m m e rc ia l l y a v ai la b le
B . C a r r i e r - me d ia t e d t r an s p o r t ( c e re b r a l m e ta bo l i sm ) me c ha n is m s. Th e s e a r e r e s po ns ib l e f o r t r an s p o r ti n g g lu co s e ac r os s t he BB B . A g en ts su c h as
18
F
f l u de o xyg l u c os e a id in the e v a lu a ti o n o f ce r e b ra l f u nc t io n b y m ap pi n g t h e d i st r ib u ti o n o f g lu c os e m e t a bo li sm .
18
F f l ud e o xyg l u c os e is p ro d uc ed b y a cy c l o t ro n .
1 . B i od i s t r ib u t io n . Cu r re n t l y , t h er e i s a U S P m on o g ra p h f o r o n -s it e c y c lot r o n p r o du c e d
18
F fl ud e o xy g l u c os e, wh i c h is a g lu c o se a na lo g .
18
F f l ud eo xy g l u c os e
c o nc en t r at es in t he br a in, wh e r e it is ph os p ho r yl at e d b u t d oe s n o t u nd e rgo s u bs eq u en t m e ta bo l is m b e c a us e o f th e re pl ac em e n t o f th e h yd r o xyl g r o up i n t h e 2 p o si t io n wi t h a fl uo r i ne at o m . I t i s t he n m e ta bo l ic a l l y t ra p pe d f o r a s u f fi c ie n t ti m e to a l lo w i m a gi ng . 2 . D ec a y d a t a a . P h ys i c a l h a l f -l i f e : 109 . 7 m in b . D e ca y m o d e : b y p os i tr o n em iss i on c . P r im a r y r a d i a t i on emi s s i on s : 6 33 k e V en e rg y p os i t ro ns an d 5 1 1 k e V γ e n e rg y p h o to ns . 3 . Ad m i n is t r a t io n an d do s a ge . I V, 5 -1 0 m C i ( 1 85 - 3 70 MB q ) C . C e r e b r al ne u r o t r an sm i t t e r i m ag i n g : F lu o r od o p a f l u o r in e -1 8 (
18
F ) in j e c ti o n
1 . D es c r i p ti o n a . C e re b r al ne u ro t r an s m it t e r s y n t he s i s c an be s t ud i ed wi t h fl u o ro do p a
18
F i n je c ti on .
Th e i n t ra c e r eb r a l d is t ri bu t i on of t hi s n eu r ot r a ns m i t t e r t r ac e r c a n b e u s e d in t he a ss e ssm e nt o f n eu r od e ge n e ra t i v e d is ea s es s uc h a s p a rk i ns on is m . b . F lu o ro d op a
18
F i nj ec t io n e xi s ts un d er a U S P m o n o gr a ph as an on -s i te -p r o du ce d
s t e ri le I V s ol u ti o n o f a l ev o d o p a a na lo g i n wh i c h a p o rt i on of th e m ol ec u le h as be e n r e p la ce d wi t h
18
F , a p os it r o n -e m i t t in g r a di o nu c l ide .
2 . B i od i s t r ib u t io n a . A f te r I V i nj ec t io n , p la s m a a c ti vi t y de c re as es t o 1 0 % o f th e a dm in is t e re d d o se wi t h i n 5 m i n a f t er in j ec tio n . b . F lu o ro d op a
18
F i nj ec t io n is p r e do m i na n tl y m eta b ol i ze d i n p e ri ph e r y v i a d o pa
d e ca r bo xy l a s e , an d c a tec h ol - O - m e t h y l t r an s fe r as e . To m a xi m i ze b ra in up ta k e, c a r bi do p a m a y b e u s e d to d ec r ea se pe r ip h e ra l m e t a bo li s m . c . R ap id e xc r e t io n v ia r en a l s y s te m as do p am in e m e ta b ol i te s 3 . R a di o n uc l id e da t a. Se e I X. B . 2 . 4 . Ad m i n is t r a t io n an d do s a ge . I V, 10 - 2 0 m Ci ( 37 0 - 74 0 MB q ) D . C e r e b r os p in a l fl u id (C S F ) d yn a m i c s . R a di onu c li de ci st e r no g ra p h y i s u s ef u l i n t h e e va l ua t io n o f h y d r oc e p h al us an d i n d e te c t i ng C S F le a ks . I n C SF im agi n g , t he r a d io p ha r m a c e u ti c a l i n d iu m - 1 11 pe n t et a t e (
111
I n- D T P A) i s in t r od uc e d i nt ra t h ec al l y
i n t o t he s p in a l s u b a ra c hn o id s p ac e , a sc en ds th ro u g h t he ba sa l c is t er ns , p r o c e ed s o ve r t he c e r eb r al he m i s ph e r es , a n d e v e nt u al l y d ra i n s in t o t he s u pe r i or s ag i t ta l s i nu s.
111
I n p en t e ta t e is c om m e r c i a ll y s u p pl ie d as a s te r il e , p y r o ge n - f re e u n i t d os e
i n je c ti on . It is p ro du c e d b y a c yc l ot r o n. P.452
1 . B i od i s t r ib u t io n
a . A f te r i n t ra t he c a l i n je c ti o n , t hi s r a di o ph a rm ac eut i c a l n o rm al l y as c e n ds to t h e p a r as ag i t ta l r e gi o n wi t h in 2 4 h r . b . A f te r ab s o r p ti on in t o th e bl oo d s t r ea m v ia th e ar a c hn oi d v il l i, th e m aj o r r o u t e o f e l im in a ti o n is b y k i dn e y ; 6 5 % o f th e d os e i s e xc r et e d wi t hi n 4 8 h r ; a n d 8 5% , wi t h in 7 2 h r. 2 . D ec a y d a t a a . P h ys i c a l h a l f -l i f e : 67 h r b . C S F b i o lo g i ca l h a l f -li f e : 1 2 hr c . E f fe c t i ve h a l f -l i f e : 10 h r d . D e ca y m o d e : b y e l ec tr o n c a pt u r e e . P r i ma r y r a d i a t i o n e mi s s i on s : 1 71 k e V an d 2 45 ke V γ e ne r g y ph o to ns 3 . Ad m i n is t r a t io n an d do s a ge . In t r at h ec al , 5 0 0 µ C i ( 1 8. 5 MB q )
X. INFECTION AND INFLAMMATION. E va l u a ti on o f s i t es of in fe c ti o n i nc lu d e t he us e o f a g en ts t ha t c an as s o ci at e wi t h c om p on e nt s o f t h e n at u ra l de f en s e m e c h an is m s a n d c an ac c u m u la t e wh er e t he y l o ca li ze . A. G a l l i u m (
67
G a ) c i t r a te
1 . D es c r i p ti o n a . I t is s u pp l ie d a s a s t e ri l e , p y r o ge n -f r e e r ad i op ha r m ac eu t ic al wi t h p r es e rv a t i v e s . b . Th e m ec h an is m o f l oc a l i z a ti on is th o ug h t t o d ep e n d o n t he fo r m a t io n o f a ga l li um t r a ns f e r ri n c om pl e x i n the b lo od a nd on bi nd i ng to t r an s f e r ri n re ce p to r s as so c i a te d wi t h i n fe c ti on an d i n fl am m a ti o n. c . It ac c u m u l at es in a re as o f wh i t e b l oo d c el l (W BC ) l oc a li z a t io n . 2 . B i od i s t r ib u t io n a . A f te r ad m i ni s tr a ti o n, th e hi gh e st c o nc en t r at i on o f
67
G a c i t ra t e, o th e r t ha n at t he
s i te o f in f ec t io n , is in t he r e n al c o r te x. A f t e r 24 hr, t h e m a xi m u m c on c e n t ra t i on s h if t s t o bo n e a nd l ym p h n od es ; bu t a f te r 1 we ek , i t i s m a in l y c o nc en t r at e d i n th e li v e r an d s p le e n. b.
67
G a c i t r at e i s e xc r e t ed s l o wl y f r o m t he bo d y ; 2 6 % i s v i a u r i ne , a n d 9 % i s v ia
f e ce s . W hol e b od y r e te n ti o n i s 6 5% af t e r 7 d a y s . 3 . R a di o n uc l id e da t a a . M o d e o f p ro d uc t i o n : b y c y c lo t r on b . D e ca y m o d e : b y e l ec tr o n c a pt u r e c . P h ys i c a l h a lf - l i fe : 7 8 h r d . D e ca y e m i s s io n s : 9 3 k e V , 1 85 k e V , 3 00 k e V , a n d 3 9 3 k e V γ ph o t on s 4 . Ad m i n is t r a t io n an d do s a ge . I V, fo r in f ec ti o n, 3 - 8 m C i (1 1 1- 3 00 MB q ) . A d a il y l a xa t i ve o r a n e n em a s ho u ld be us e d b y t he pa t ie n t a f t er t he in je c ti on and b ef o r e t h e i m a g es to c l ea ns e t he b o we l o f ra d io ac t i v it y th a t m a y in t er f e re wi t h the im a ge s a n d p os s i b l y l e ad to a f al s e p os it i v e re su l t. B . W B C l ab e li n g a g en t s. R a di o la b el ed W BCs a re us e d i n t he de t ec t io n of a wi d e va r i e t y of in f ec t io us an d i n f la m m at o r y p ro c e ss es . C u r r e nt us e i nc lu d es the d ia gn o si s o f in t r a -a bd om i na l a bs c es s e s , i nf l am m a to r y b o wel d i s ea se , a p pe n di c i t is , fe v e r o f u n kn o wn o r ig in , an d o s te o m y el i ti s. W BCs c a n b e r a di o la b el ed wi t h 99m
Tc - e xa m e t a z i m e .
111
I n oxi n e o r
1.
111
I n o x yq u i n o l i n e so l u t i on (
111
In o xi n e )
a . D es c r i p ti o n 111
(1)
I n o xy q u i n o li n e is s u pp li e d a s a s te r i le pr es e r v a ti ve - f r ee , p y r o g en - fr e e ,
r a d io p ha r m a c e u ti c a l s olu t i on fo r us e i n t he r ad i ol a be l in g o f a u to l og o us l eu k oc yt es . 111
(2)
I n f o rm s a s a tu r ate d ne u t ra l l ip o ph il ic c o m p l e x wi t h o xyq u i n o l in e ( 1: 3 r at i o ),
wh i c h en a bl es it to p en et r a t e a c el l m em b ra n e. ( 3 ) A f te r i n c u ba t io n o f the
111
111
I n o xy q u i no l in e wi t h a po p ul a ti o n o f a u to lo g ou s le u ko c y t es ,
In is th o ug h t t o b ec om e fi rm l y bo u nd t o c yto p la s m ic c om p on e nt s , t he r e b y
a l lo wi n g th e f re e o xi n e to b e r e le as ed b y th e c el l. b . B i o di s t r ib u t i on ( 1 ) A f te r ra d io la b el i ng , th e au t ol o go us le uk oc yt es a re r ei nj ec t ed ; 30 % i s t a ke n u p b y t h e s pl e en , a n d 3 0% is ta k en up b y th e l i ve r , r eac h in g a pe ak at 2 -4 h r p o st i nj ec t io n . ( 2 ) P ul m o n a r y u p ta k e is i m m e di a te l y e v id e nt po s ti n je c ti on , bu t i t c le a rs , wi t h m i ni m a l v is ib le ac t i v it y , a f t e r 4 h r . P.453
( 3 ) Th e r e is a b ie xp o n e nt i a l b lo od c l ea r a nc e; 9% -2 4 % c le a rs wi t h a bi o lo gic a l h al f l i f e o f 2 - 5 h r , a nd th e rem a in in g 1 3 % -1 8% cl ea r s wi t h a bi ol o gi c a l h al f - li fe o f 6 4 -1 1 6 hr. ( 4 ) E li m i n at io n i s m ai nl y t h r o ug h r a di o ac ti v e de c ay ; < 1 % is e xc r e t ed in fec es an d u r i ne du r in g th e f i rs t 2 4 h r . c . R ad i o nu c li d e d a ta ( 1 ) M o d e o f p ro d uc t i o n : b y c y cl o t ro n ( 2 ) D e ca y m o d e : b y e l ec t r o n c ap t u re ( 3 ) P h ys i c a l h a l f -l i f e : 67 h r ( 4 ) D e ca y e m i s s io n s : 24 5 k e V a n d 1 71 k e V d . Ad m i n i st r a t i on an d do s a ge . I V, 20 0 - 50 0 µ Ci (7 . 4 - 8. 5 MB q ) 2.
99m
Tc - H M P AO . A s a s t e r il e a n d p y r o ge n - fr e e IV i nj e c t i on af t e r r ec o ns tit u t io n wi t h
s o di um pe r t ec hn e ta t e,
99m
Tc - H MP A O m a y b e us ed t o r a di ol a be l l e uk oc y t es .
a . D es c r i p ti o n (1)
99m
Tc - H MP A O i s a n eu t r al , li pi d -s o lu bl e c om ple x t h a t is ab l e t o p en e t ra t e th e
W BC m em br a ne . Th is li po p hi l ic c om pl e x i s r el a ti v e l y u ns ta b le an d ra pi d l y c o n v e rt s t o a s ec on d ar y c om pl e x i n c ap a bl e o f p e ne t ra t in g t h e W B Cs . ( 2 ) Th e m e th y l e ne bl ue /p h os p ha t e b uf f e r s ta bi l i ze d s o l u t io n i s n ot ab l e t o r a di o la b el c e ll s a nd s h ou l d n ot be u s ed . ( 3 ) A dd i ti o na l l im it a ti o ns o n k i t p re p a ra t io n p a ram e te r s r e qu i re t he us e of h ig h m ol e f r a ct i on te c h n e ti um ge ner a t o r e lu t es of < 2 h r p os t e l ut i on f ro m a g e ne r a to r p r e vi ou s l y e lu t ed wi t h in 2 4 h r. b . B i o di s t r ib u t i on ( 1 ) A f te r I V i nj ec t io n , t he r a di o la b el ed c e ll s l oc al iz e i n th e l un gs , li v e r , s ple e n , b lo o d p o ol , bo n e m a r r o w, a nd b l ad d e r. ( 2 ) E li m i n at io n i s p r im a ril y v i a t he li v e r . c . R ad i o nu c li d e d a ta . Se e I I. B . 1. b ; I I . B. 3 . a a nd b .
d . Ad m i n i st r a t i on an d do s a ge . I V, fo r in f ec ti o n, 7 - 2 5 m C i ( 2 60 - 92 5 MB q )
XI. BREAST IMAGING 99m
A.
Tc-MIBI
1 . D es c r i p ti o n a.
99m
Tc - MI B I i s u s e d f o r b o th b re as t an d c ar d ia c i m ag in g .
b.
99m
Tc - MI B I i s i n di c a t ed f o r p la n ar im ag i ng as a s ec on d l i ne of e val u at i ng b r ea s t
l e si on s i n p a ti en t s wi t h an a bn o rm al m a m m og r am o r a p al p ab le b re as t m as s . c.
99m
Tc - MI B I m a y n o t b e u s e d to s c re e n f o r b r eas t c a nc e r, to co n fi r m t he p r es e nc e
o r a bs en c e of m a li g na nc y , o r t o r e pl ac e a bi op s y . 2 . B i od i s t r ib u t io n .
99m
T c - MI B I i s p r im a ri l y e xc r et e d b y t h e h ep a to bi l ia r y s y s t em .
3 . P h ys i c a l p r o p e r ti e s. S e e II . B . 3. 4 . Ad m i n is t r a t io n an d do s a ge . I V, 20 - 3 0 m Ci ( 74 0 - 11 1 0 MB q )
XII. TUMORS A. Th e u s e fu l ne s s o f r adi o ph a rm ac e ut ic a ls i n th e d e te c ti on o f t um o rs v a rie s i n s e ns it i v i t y an d s pe c i f ic ity , wi t h d i ff e r en c e s i n t um o r l oc a ti o n a nd t ype . 1.
67
Ga
a . D es c r i p ti o n 67
(1)
G a is s u pp l ie d a s a s t er i le , p y r o g en - f re e ra di o ph a rm ac e ut ic a l wi t h
p r e se r va ti v e s . ( 2 ) Th e m ec h an is m o f l oc a li z a t io n i s t ho u gh t to de p e nd on th e f o rm a ti o n o f a g al l iu m t r a ns f e r ri n c om pl e x o r bin d in g to t ra ns f e r ri n r ec ep t o rs on tu m or c e ll s . ( 3 ) I t ac c um ul a te s i n p rim a r y m e t as ta t ic tu m o r s it e s a nd m a y d et ec t th e pr e s en c e of H o d gk i n d is ea s e , l y m ph om a , a nd b ro nc h og e ni c c a r c in o m a . b . B i o di s t r ib u t i on . Se e X. A . 2 . c . R ad i o nu c li d e d a ta . Se e X. A . 3 . d . Ad m i n i st r a t i on an d do s a ge . I V, fo r t um or , 10 m C i (3 7 0 MB q ) P.454
2.
111
I n p e n te t r e ot i d e
a . D es c r i p ti o n ( 1 ) I t is s u p pl ie d a s a s te r i le , p y r o g en - f re e k i t f or t h e p r ep a ra t io n o f
111
In
p e n te t r eo t id e . Th e t wo - c o m po n en t k it c o ns is ts o f a r e ac ti o n vi a l co n ta i ni ng a l yo p hi l i z ed m i xt u r e o f p en t e t re o ti d e wi t h s t a bi li z e r a dj u t an ts an d a s e co nd vi a l c o nt a in in g an i n di um
111
In c h l o ri de / f er r ic c h lo r id e s ol u ti o n.
( a ) Th e pe n te t re o ti d e m ol e c u le is a co n ju g at e o f p e n te t at e (d i et h y l en e tr i am i ne p e n ta ac e ti c a c i d; D TP A ) a n d o c t r e ot i de , wh ic h i s a s o m a t os t at i n a na lo g . (b)
111
I n p en t e t re o ti de is p r e pa r ed b y ad di n g t he
111
I n/ F e c h l o ri de s o lu t io n t o th e
vi a l c o nt a in in g th e p e nt et r e o ti d e. Th e p e nt e ta t e po r t io n of th e m ol ec u le ac t s as a b i f un ct i on al c h el a t e, li nk i n g t h e
111
I n ra di o nu c l i de t o th e b i ol og ic a l ac t i v e o c t re o ti d e
p o r ti o n o f t h e a ge n t. (2)
111
I n p en t e tr e ot i de is i n di c a t ed fo r lo c a li z a t ion o f p r im a r y a n d m e t as t at i c
n e u ro e nd oc r in e tu m o r s exp r e s s i ng s om a to s ta t in re c ep t o rs . b . B i o di s t r ib u t i on
( 1 ) W it hi n 1 h r a f te r I V in j ec t io n ,
111
I n p e nt e t re o ti d e d is t ri b ut e s f r om t h e p l as m a to
e xt r a va s c ul a r s pa c e ; le s s t ha n o ne t hi r d o f t h e ad m in is t e re d d os e re m a ins in t he p l as m a 10 m i n p os ti n je c ti o n . (2)
111
I n p en t e tr e ot i de loc a li z e s as a f u nc ti o n o f so m at os t a ti n r e c e p to r d e ns i t y , wi t h
a cc u m u la t io n i n n o rm al p i t ui t ar y, t h y r oi d , l i v e r, s p l ee n , a n d t he u ri na r y b la d d er . ( 3 ) E li m i n at io n i s p r im a ril y r e n al ; 5 0 % o f t he ad m in i s t e r ed do s e is e xc r e t ed wi t h i n 6 h r p os ti n je c t i on ; 8 5 %, aft e r 24 h r, an d < 90 % a f te r 4 8 h r . L es s t ha n 2 % of t h e a d m i ni s te r ed do s e is c l ea r e d v ia th e f e c e s wi t h i n 7 2 h r po s t - i nj ec t io n . c . R ad i o nu c li d e d a ta ( 1 ) M o d e o f p ro d uc t i o n : i b y c yc l ot r o n ( 2 ) D e ca y m o d e : b y e l ec t r o n c ap t u re ( 3 ) P h ys i c a l h a l f -l i f e : 67 h r ( 4 ) D e ca y e m i s s io n s : 24 5 k e V a n d 1 71 k e V d . Ad m i n i st r a t i on an d do s a ge . I V, 3 -6 m C i (1 1 1 -2 2 2 MB q ) 3 . I ob e ng u a ne
131
I i n j ect i o n (
131
I -M I B G )
a . D es c r i p ti o n ( 1 ) I t is s u p pl ie d a s a s te r i le , p y r o g en - f re e ra d iop h a rm ac e ut ic al f o r us e as an a d ju n ct i v e d i ag no s ti c a ge n t fo r th e l oc al i za ti o n of p r im a r y a n d m e t as t at ic p h e oc hr o m o c y to m a s a nd n e u ro bl as t om as . ( 2 ) I ob en g ua n e ( m e t a -i od o b en z yl g ua n id i ne ) l a be le d wi t h
131
I a c t s a s a p hy s i o lo gi c al
a n al o g o f n o re p in e ph r in e a n d is t ra ns p o rt e d a nd a c c u m u la t ed in th e a d r en a l m e du ll a . Th is a l lo ws f o r t h e d e te c ti on o f n eu r oe nd o c ri ne t um or s v ia th e s p e ci f ic u p t ak e o f l ab e le d i o be ngu a n e. ( 3 ) B ec au s e o f i ts ph y s iol o gi ca l s im il a ri t ie s t o n o re p in e ph r in e , m an y cl a ss e s o f d r u gs th a t i nt e r fe r e wi t h c a te c h o la m i n e t r an sp o r t a n d f u nc ti o n m a y a f fe c t th e up t ak e a n d l oc al i z a ti o n o f l ab e le d io be n gu a ne . b . B i o di s t r ib u t i on ( 1 ) A f te r I V i nj ec t io n , t her e is r ap id up t ak e i n t h e l i v e r , wi t h l ess e r a m o u nts a cc u m u la t in g i n t h e l un gs , he a rt , an d s pl e en . ( 2 ) N o rm al ad r e na l g la n d u p ta k e is lo w; b u t f o r t um o rs s u c h as p h eo ch r om o c y t om as a n d n e ur o bl as t om as , t h e u p ta k e is re l at i v e l y h i ghe r . ( 3 ) E li m i n at io n i s re na l ; m os t of th e dr u g is e xc r et e d m ai n l y u nc h an g ed . Be t we e n 4 0 % a n d 5 0% of th e a dm i n is t er e d d os e i s e xc r e t ed wi t h i n 2 4 h r , a nd 70 % -9 0 % i s e xc r e t e d wi t hi n 4 da y s po s ti n je c t i on . ( 4 ) A dm in is t r at i on of po ta s s i um i o di d e 1 d a y be f or e a nd fo r 10 da y s a f t e r a d m i ni s t ra ti o n i s s u g ge s te d to r ed uc e th yr o id up ta k e o f p o te n ti al r ad i oi od id e c o nt am i na n ts . c . P h ys i c a l d a ta . Se e VII I . B . 2. b . d . Ad m i n i st r a t i on an d do s a ge . I V, 0. 5 - 1 m Ci ( 18. 5 - 3 7 MB q ) 4.
201
T l . Th i s a ge n t h as u t i li t y as a t um o r- im a gi ng a ge n t b ec au se o f i ts ac c u m ul at i on
i n th e ra pi d l y m e ta b ol i z in g c e ll s o f c er t ai n tu m o rs in ac c o r da nc e wi t h i ts m ec h an is m o f lo c a l i z at i on (s e e I I I. A .1 ) . a . Ad m i n is t r a t io n an d do s a ge . I V, 1. 5 - 3 m Ci ( 55- 1 1 1 MB q ) 5.
18
F f lu d e ox yg l u c o s e U S P . C u r r en t l y , t h er e i s a U S P m o no g r ap h f o r o n- s i te
c yc lo t r on p r od uc ed
18
F f lu d e o xy g l u c o s e , wh i c h is a g lu c o se an a lo g . Th i s ag e n t h as
u t i li t y as a t um o r- im a gi ng a ge n t b ec au se o f a n i nc r e as ed de m a n d f o r g lu c o s e b y t u m o r s wi t h a n a d v an c e d s t at e o f m al i gn a nc y . N ot o n l y c an
18
F fl u de o xyg l u c os e
l o ca t e a nd di f fe r e nt i at e tu m o rs b u t P.455 i t ca n a ls o h el p d is t in g uis h b e t we e n r e c u r r en t b ra i n t um o r a n d r ad i at i on n e c ro s i s i n p a t ie n ts re c e i v i ng ra d ia t io n th e r ap y ( s e e I X. B ) . a . B i od i s t r ib u t io n .
18
F fl u de o xy g l u c os e c on ce n t ra t es in m e t ab ol ic a ll y ac t iv e c el ls ,
wh e r e i t i s p ho s p h o r y la te d bu t d o es n o t u n de r go s ub s e q ue n t m et a bo li s m b e ca us e o f t h e re p la c e m e n t o f t h e hy d r o xy l g r o u p in th e 2 pos i ti o n wi t h a f l uo r in e a t om . It is t h e n m e t ab o li c a ll y t r a ppe d fo r a s u f f ic ie n t t im e to a ll o w i m a gi n g. b . Ad m i n i st r a t i on an d do s a ge . I V, 5 -2 5 m C i ( 1 85 - 3 70 MB q )
XIII. THERAPEUTIC AGENTS. Th e t h e ra p eu t ic u s e o f ra d io p ha r m a c e u ti c a ls is ba s ed on th e c o nc ep t o f s e l ec t i v e l o ca li za t io n o f r ad io p ha rm ac e ut ic a ls c o up le d wi th t he le t ha l it y o f t h e sa m e b ec au s e o f t he ti s s ue da m a g e r es u l t in g f r om hi gh l y io n i z ing p a rt ic u la t e em is s i o ns s u c h as β p a r ti c l e s . A. C h r o m i c ph o s ph a te p h o s ph o r u s- 3 2 (
32
P ) s us p e ns i o n
1 . D es c r i p ti o n . A v a i la ble as a s te r il e , p y r o ge n - f re e aq u eo us s us p e n s i o n u s ed in th e t r e a tm en t o f pe r it o ne a l or p le u r al ef f us io ns c a us ed b y m e t as ta t ic di s e as e . A l s o us e d i n th e t r e at m e n t o f o v a r ia n an d p r os t at e c an c er . 2 . B i od i s t r ib u t io n a . C ol l oi da l s us p en s i on o f
32
P is r ap id l y t ak en up b y m ac r op ha g es ad he r in g to t he
c a vi t y wa l l , t he r e b y c on c e n t r at i ng an d l oc al i z i ng th e ir r a di a ti on e ff ec t of the
32
P
r a d io n uc li de β pa r t ic ul a te em is si o n. b . A f te r in f us io n , t he s u s p e ns i on ra p id l y di s t r i bu te s fr om wi t h i n t he c a vi t y a n d m a y l o ca li ze in t he lu ng s , a d re n al gl a nd s , k i d ne y s , l y m p h n od es , l i v e r , s pl ee n, b on e m a r ro w, p l as m a , e r y t h r oc y t e s , an d l e uk oc y t es , de p e nd in g o n c ol l oi da l p ar t i c l e s i ze. c . El im i na t io n i s p ri m ar i ly r e n a l. 3 . R a di o n uc l id e da t a a . M o d e o f p ro d uc t i o n : b y r e ac t o r b . D e ca y m o d e : β c . P h ys i c a l h a lf - l i fe : 1 4. 3 da y s d . D e ca y e m i s s io n s : 6 95 k e V m e an en e r g y β , 1 00 % ab u nd an c e 4 . Ad m i n is t r a t io n an d do s a ge a . I nt r ap e r it o ne al in s ti ll at i o n: 10 - 2 0 m Ci ( 37 0 -7 4 0 MB q ) b . I nt r a pl eu r al in s ti ll a ti on : 6 -1 2 m C i ( 2 22 - 44 4 MB q ) c . C a rc in om a i n te r s t i ti al : 0 . 1 -0 . 5 m C i ( 3 .7 - 18 . 5 M B q ) d . C a ut i on is a d v is e d f o r v i s ua l i ns p ec ti o n t o p r ev e n t m i s a dm in is t r a ti on of t h e s o di um ph os p ha t e f o rm (c l ea r , c ol o rl es s ) , wh i c h is de si g na t ed fo r in t r a v asc u la r us e o n l y. B . S o d iu m ph o sp h a te 1 . D es c r i p ti o n
32
P s o l ut i o n
a . I t is a v ai l ab le as a c om m e r c i a ll y su p pl ie d , s te ri l e , p y r o ge n -f r e e r a d io p ha r m a c e u ti c a l . b . I t i s p ri m a r il y u s e d a s a n a n ti n eo pl a s t ic fo r th e t r e at m e n t o f p o l yc yt h em i a ru b r a ve r a a nd is s el ec t i v el y us e d f o r t he p al li a ti v e t rea t m e n t o f m et a s t a ti c b one p ai n . c . It s t h e ra pe u ti c e f fe c t is o wi n g t o c el l d am a ge re s ul t in g f r om i rr a di a ti on p r o du c e d b y b e ta pa r t ic ul a te em is s i on . 2 . B i od i s t r ib u t io n a . I t co n c e n tr a te s a s p hos p ha t e wi t h i n t he D N A o f r a pi d l y di v i di n g h em at op o ie t ic c e ll s i n t he t re a tm en t of p o l y c y th e m i a r u b ra v e r a a n d a s p ho s p h at e i n a r ea s o f i n c re as ed bo n e f o rm a ti on . b . A f te r I V a dm in is t r at i on , it di f f us es ra p id l y in t o e xt r a c e ll u la r a n d i nt r ac el l ul a r s p ac e, c o nc e nt r a ti ng in th e bo n e m a r r o w, sp l ee n , a n d l i ve r. c . El im i na t io n i s p ri m ar i ly r e n a l; 5% - 10 % i s e xc r e t e d wi t hi n 2 4 h r , a n d 2 0% wi t h i n 1 we e k . d . W hole bo d y bi o lo g ic al h a lf - li f e i s a pp r o xi m a te ly 3 9 da ys . 3 . R a di o n uc l id e da t a a . M o d e o f p ro d uc t i o n : b y r e ac t o r b . D e ca y m o d e : b y β c . P h ys i c a l h a lf - l i fe : 1 4. 3 da y s d . D e ca y e m i s s io n s : 6 95 k e V m e an en e r g y β , 1 00 % ab u nd an c e P.456
4 . Ad m i n is t r a t io n an d do s a ge a . P ol y c y t h em ia ru b r a v er a : I V, 3 -5 m Ci ( 11 1 -1 8 5 MB q ) b . Me t a s ta t ic bo n e le s i on s : I V , 1 0 - 21 m C i (3 7 0- 77 7 MB q ) c . C au t io n i s a d v is ed fo r v i s ua l i ns p ec ti o n t o p r ev e n t m i s a dm in is t r a ti on of t h e c h r om ic p h os ph a te fo r m ( g r e en , c lo u d y ) , wh ic h i s d es i gn a te d f o r i n te r st i tia l us e o n l y. 131
C . S o d iu m io d i de
I (th e r a pe u t ic )
1 . D es c r i p ti o n a . I t is in d ic at e d f o r t r ea tm e nt o f h y p e rt h y r oi d ism a n d t h yr o id c a rc i no m a . b . I ts th e ra p eu t ic ac ti o n i s o wi n g to t he ac c um u lat i o n a nd r et e nt i on of io din e an d i ts i s ot o pe
131
I.
2 . B i od i s t r ib u t io n a . S ee V I II . A ; V I I I .B . 2 . b . B i o lo g ic a l h a l f- l i f e in t h e t h yr o i d : e u t h yr o i d p a ti e nt , 80 da ys ; h y p e rth y r o i d p a t ie n t, 5 -4 0 d a y s 3 . R a di o n uc l id e da t a. Se e V II I . B .2 . b. 4 . Ad m i n is t r a t io n an d do s a ge . O r al c a ps ul e o r or a l s ol u ti o n a . H yp e r th y r o id is m : 1 0- 30 m Ci ( 37 0 - 11 10 MB q ) b . Th yr o i d c ar c i n om a : 3 0- 2 0 0 m C i ( 1 11 0 -7 4 00 MB q ) D . S t r o n t iu m - 89 ( 1 . D es c r i p ti o n
89
S r ) ch l o r i de
a . I t is in d ic at e d f o r t he a l le v i a ti o n o f b on e p a in a r i s i ng f ro m m et as t a ti c bo n e d i se as e . b . A s a m e ta bo l ic a n al o g o f c a lc iu m ,
89
S r c o nc en tr a t es s e le c ti ve l y i n ar e as o f
i n c re as ed os t eo g en es is , t h us de l i v e ri ng a r a di a ti on d os e s uf f ic ie n t t o p r o v id e a p a ll i at i v e e f f ec t. c . P ai n r e li e f b eg in s 7 - 21 d a ys a ft e r a dm i ni s t r a tio n , wi t h m a xi m um re li e f b y 6 we e ks a n d a n a v e r a ge du r at i on o f 6 m o n th s . d . R e du c t i on in pa t ie n t an a lg e s i c us a ge oc c u rs in u p to 75 % o f p a ti e nt s t re a t ed ; c om p le t e p ai n re li e f is s e e n i n 2 0% o f t r ea t ed pat i e nt s , a nd no pa in r el i ef i n 2 0 %2 5 % o f tr e at e d p at i en ts . e . B on e m a r ro w s u pp r es s i on ef f ec ts li m i t
89
S r u s e t o p a ti en t s wi t h in i ti al W BC
c o un ts > 2 , 40 0 a n d p la t el e t c ou n ts > 6 0, 0 00 . 2 . B i od i s t r ib u t io n a . A f te r ad m i ni s tr a ti o n,
89
S r c l e ar s ra pi d l y fr om blo o d a n d l oc al i z es in th e b o n e
h yd r o xya p a t i t e. b . I ni t ia l b io l og ic al ha l f -li f e i n n o rm al bo n e is 1 4 d a ys ; l on g e r r e te n ti o n is s e en in m e ta s ta t ic b o ne le s i on s . B e t we e n 12 % a n d 9 0% of t h e a dm in is t er e d d os e is r et a in e d f o r up to 3 m on t hs a f t er a d m i ni s t ra ti o n . c . El im i na t io n i s p ri m ar i ly r e n a l; 66 % o f th e a dm in i s t e r ed do s e c l ea r s v i a G F R wi t h i n t h e fi rs t 2 d a ys , an d 3 3% i s e xc r e t e d v i a f ec e s . 3 . R a di o n uc l id e da t a a . M o d e o f p ro d uc t i o n : b y a c c el e r at o r b . D e ca y m o d e : b y β c . Em i s si o n d a ta : 1 . 4 6 Me V m a xi m u m β e n e rg y, 1 0 0% ab u nd an c e d . P h ys i c a l h a l f -l i f e : 5 0. 5 da y s 4 . Ad m i n is t r a t io n an d do s a ge . I V, 4 m C i ( 14 8 MB q ) , 40 - 60 µ C i /k g ( 1 .5 - 2 .2 MB q / k g ) E . S a ma r i um - 1 53 (
153
Sm ) l ex i d r on a m
1 . D es c r i p ti o n a.
153
S m is in d ic at e d f o r t h e re li e f o f p a in in pa t ien t s wh o h a v e c on f i rm ed m e ta s ta t ic
c a nc e r o f t h e b on e . b.
153
S m c on c e n t ra t es i n a r e as o f h i gh bo n e t u rno v e r a nd acc um u la t es m o r e i n
o s te o bl as t ic l es i on s t h an i n t h e n o rm al bo n e. c . Th e g o al of
153
S m t he ra p y is f or pa t ie n ts to be a b le t o r e du c e th e a m o un t o f
n a r co t ic a n al ge s i c s ne e de d to c o n tr o l t he i r p a in . P.457
2 . B i od i s t r ib u t io n a . Th e l e s i on t o n or m a l bo n e ra t io i s 5 : 1. b . Th e pe r c e n ta ge o f u pta k e o f
153
Sm i s d i re c tl y pr o p o rt i on al t o t he nu m b er o f
l e si on s t h e p at i en t h as . c . Le ss th an 1% o f t he do s e r em a in s i n t he bl o od 5 h r p os ti n je c t i on . d.
153
S m i s 1 00 % r e na ll y e xc r e t e d o v e r 1 2 hr .
e . Th e on s e t i s a pp r o xi m a t e l y 1 we e k . 3 . R a di o n uc l id e da t a
a . M o d e o f p ro d uc t i o n : b y c y c lo t r on b . D e ca y m o d e : b y β a nd γ d ec a y c . P h ys i c a l h a lf - l i fe : 4 6. 3 h r d . D e ca y e m i s s io n s : 6 40 k e V , 71 0 k e V, an d 8 4 0 k e V β e ne r g y an d 1 03 k e V γ e n e rg y p ho t o ns 4 . P r ec a u ti o n s.
153
S m m a y c au s e b on e m a rr o w s u p p re ss io n , wh ic h s ho u ld r e tu r n t o
b a se li n e wi t h i n 8 we e k s p o s t i nj ec t io n . 5 . Ad m i n is t r a t io n an d do s a ge . I V, 1 m C i/ kg ( 37 MB q / k g ) F . Y t t r i um - 90 (
90
Y ) i b ri tu m o ma b ti u xe t a n a n d
111
I n i b r i t um o ma b ti u xe ta n
1 . O ve r vi ew a.
111
I n i b ri t um om ab ti u xe t a n a nd
90
Y ib r i tu m o m ab t iu xe t a n a re pa r t o f a th e r ap e ut ic
r e g im en us ed in t he t re at m en t of no n - H od gk in l ym p ho m a ( N H L ) p at i en ts wi t h r e l ap se d re f r ac to r y l o w- gr a d e , f ol li c u l a r, o r t r an s fo r m ed B c el l N HL an d p at i e nt s wi t h r i t u xi m ab r ef r ac t o r y N H L . b . I b ri tu m om ab ti u xe t a n is an im m u no c on ju g at e c o n si st i ng of a m on oc lo n al a nt i bo d y i b r it um o m a b , wh i c h is li nk e d t o t h e c h e la t o r t iu xe t a n . c . Th e i b ri t um om ab an t ibo d y is a m u ri ne im m u no gl o bu l in G 1 (I g G 1 ) κ m ono c lo n al a n t ib od y p r od u c e d i n C h in e s e ha m s t er o va r y ( C HO ) c e ll s . Th e i b ri t um om ab a nt i bo d y i s d i re c te d a g ai ns t t h e CD 2 0 an t ig e n, wh i c h is e xp r e s s ed on th e s u r fa ce of n o rm al a n d m al ig n an t B l y m ph oc y t e s . d . Th e li nk e r c he la t o r t iuxe t a n p r o vi de s a h i gh - a ffi n i t y c he l at i on s i te f or c as e o f th e i m a g in g d os e a nd fo r
90
111
I n i n th e
Y in t he c as e o f th e t h e ra pe u ti c d os e .
e . Th e th e ra p eu t ic re g im e n is a dm i ni s t e r ed in t wo s ep a r at e d os es . Th is al lo ws f o r t h e q u al i ta t i v e e v a lu a ti on o f t h e b io di s tr i bu t io n to a v o id po t en t ia l t o xi c i tie s s uc h a s a b n or m a l l y h i gh bo n e m a r r o w l o c a li za t io n o r p ro lo n g ed re n al e xc r e ti o n. In e ac h a d m i ni s t ra ti o n , p at ie n ts m us t be p re m e di c a t ed wi t h di p he n h ydr am i ne 50 m g a n d a c et am i no p he n 6 50 m g 0. 5 h r b ef o r e r ec e i v in g t he r i tu xi m a b i n fu s i o n r eq ui r e d b e f o re ad m i ni s te r in g t h e r a d io l ab el e d a nt i bo d y . ( 1 ) S t ep 1 is th e a dm i ni s t r a t io n o f ri t u xi m ab fo l lowe d b y t h e
111
In ib r it um om a b
t i u xe t a n d i ag n os ti c im a gin g do s e . ( 2 ) S t ep 2 f ol lo ws s t ep 1 b y 7 - 9 d a y s a nd c o ns is ts o f a s ec on d ri t u xi m ab in f us i on f o l lo we d b y th e
90
Y i b r it um om a b t he r a p y d os e .
2 . D es c r i p ti o n a . S up p li ed as t wo s e p ara t e k i ts t o p r o du c e a s i ng l e d os e o f t i u xe t a n a n d a s in g le dos e o f
90
111
In ib r i tu m o m ab
Y i b r i tu m o m a b t i uxe t a n
b . E ac h k it c o ns is ts o f f ou r v i al s c on t ai n in g : ( 1 ) I br i tu m o m a b ti u xe t a n i n s al i ne , 3 . 2 m g ( 2 ) S od i um a c e t a te , 5 0 m M ( 3 ) F or m u l at i on bu f fe r (c o n t ai ns hu m a n s e ru m a lb u m i n ) ( 4 ) O n e em p t y r ea c t i on vi a l c . E xi s ts as a s te r il e , n on p y r o ge n ic I V s o l ut i on aft e r fo r m u l at i on wi t h e i th er 90
Y
3 . B i od i s t r ib u t io n a . Th e m e an ha l f- l if e f o r
90
Y i b r i tu m o m a b t i u xe t a n i n t h e b lo o d is 30 h r.
111
In or
b . A pp r o xi m a te l y 7 .8 % of t h e a dm in is t er e d d os e is e xc r e t ed in th e u r in e ov e r 7 d a ys . c . Th e e s t im a te d bi ol o gic a l h al f -l i fe is 48 hr . 4 . R a di o n uc l id e da t a a.
111
b.
90
I n . S e e XI I I . B . 1. c .
Y
P.458
( 1 ) M o d e o f p ro d uc t i o n : b y r e ac t or ( 2 ) D e ca y m o d e : b y β ( 3 ) P h ys i c a l h a l f -l i f e : 64 . 1 h r ( 4 ) D e ca y e m i s s io n : 9 35 m e a n k e V , 10 0% em is s i on 5 . P r ec a u ti o n s a.
90
Y i br i tu m o m a b ti u xe t a n s h ou l d n ot be ad m i n is t e re d t o p a ti e nt s wi t h a lt e r e d
b i od is t r ib u ti o ns o f th e b.
90
111
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( 4 ) H yp oc e ll ul a r b o ne m a r r o w ( 5 ) H is t o r y o f fa il e d s te m c el l c ol l ec ti o n c . Ib r i tu m o m a b t i u xe t a n is c o n t ra in d ic at e d i n p at ie n ts wi t h k n o wn h y pe r sen s it i v i t y or a n a ph y l ac t ic re ac t io ns to m u ri n e p ro t ei ns . d . P a ti en t s wh o h a v e p r ev i o u s l y r ec e i v ed m u r in e -b a se d p r o te in t he r ap y s ho u ld be s c re e ne d f o r h um a n a nt im o us e a nt i bo d ie s . e . I nf us i on - r el a te d a d v e rs e e v e n ts , i nc l ud in g as the n i a , c h il ls , a n d n au s e a , a r e c om m o n a n d a r e us u al l y s e lf - li m i t ed . Tu m o r l ys is s y n d r om e h as b e en r ep or t e d a f te r r i t u xi m a b in f us i on s , wh i c h a r e p ar t of
90
Y ib r i tu m o m ab ti u xe t a n th e ra p y . P a t i en ts
s h ou l d b e m o n it o re d c los e l y fo r th is po t en t ia ll y fa t a l a d v e rs e e v e nt . G . T o s i tu m om a b a nd I od i n e I 13 1 To s i tu m om ab 1 . O ve r vi ew a . To s it um om a b a nd Io d in e 11 3 1 To s it um om a b a re p a rt of a t h e ra pe u ti c r eg i m e n i n di ca t ed f o r t he t re a tm en t o f p at i en ts wi t h C D 20 a n t ig en - e xp r e s s i ng r el aps e d o r r e f r ac t o r y , l o w g r ad e , f oll i c u la r , o r t ra ns f o rm ed no n - H o dg k i n 's l ym p ho m a, i nc l ud in g p a t ie n ts wi t h Ri t u xi m ab - re f r ac t o r y n o n - Ho d gk in ' s l y m p ho m a . b . Th e To s i t um om ab an d I o di n e I 13 1 Tos i tu m o m a b th e r ap eu t ic re g im en is an a n t in eo p la s ti c r ad i oi m m un o t he r ap e ut ic m o n oc lo na l an t ib od y- b as e d r e gi m e n c om p os ed o f t he m o no c lo n al an t ib o d y , Tos i tu m om a b, an d th e r a di o la be l ed m o no cl o na l a n ti bo d y , Iod i ne I 1 3 1 To s i tu m o m a b . c . To si t um om ab is a m u ri n e I g G 2 a la m bd a m on ocl o na l a n ti b od y d i re ct e d ag a in s t t he C D 2 0 an t ig e n, wh i c h is fo u n d o n t he s u r fa ce o f no r m al an d m al ig n an t B l ym p ho c y t es . To s i tu m o m a b is p r o du c e d i n a n a n tib i o ti c- f r ee c u l tu r e o f m am m a l ia n c e ll s a nd is c om p os ed of t wo m u ri n e g am m a 2a he a v y c h ai ns of 45 1 a m i no ac i ds
e a ch an d t wo l a m b da li gh t c h ai ns o f 2 20 am in o ac i ds e ac h . Th e a pp r o xi m a t e m o le cu l ar we i g ht o f To s it u m o m a b i s 1 50 k D. d . Th e th e r ap eu t ic re g im e n is a dm i ni s t e r ed in t wo d is c re t e s te ps : th e d os im e t ri c s t ep an d th e ra p eu t ic s t ep . E ac h s te p c on s i s ts o f a s e q ue n ti a l in f us i on of To s i t um om ab f ol lo we d by I o d in e I 1 31 To s i t um om a b. Th e th e ra p eu t ic s t ep is a d m i ni s te r ed 7 -1 4 d a y s a f t e r t he do s i m e t r ic s t ep. e . To s it um om a b b in ds s pe c if ic a ll y t o t h e C D 2 0 ( hu m an B -l y m p ho c y te - r es t ri c te d d i f fe r e nt ia t io n a n ti g en . Bp 3 5 o r B1 ) an t ig en . Th is a n ti g en is a t ra ns m em bra n e p h os p ho p ro t ei n e xp r e s s e d on p re - B l y m ph o c yte s a n d a t h ig h e r d en s i t y on m a tu r e B l ym p ho c y t es . Th e an t ig en is al s o e xp r e s s ed on >9 0 % o f B -c el l n on - H o dg k i n ' s l ym p ho m a s ( N H L ) . Po s s ib l e m ec ha n is m s o f a ct i on o f t h e B E XXA R t h e r a pe u t ic r e g im en in c l u de in du c ti on o f a po p to si s , c o m p l em e n t - de pe n de n t c y t ot o xi c it y ( C D C ) , a n d a n ti b od y - d ep e nd e nt c e ll ul a r c yt o to xi c i t y ( A DC C ) m ed i at e d b y t he an t ib o d y . 2 . D es c r i p ti o n a . To s it um om a b is s u pp l ie d as a s t e ri l e, p y r og e n -f r e e , c l e a r t o o pa l esc e nt, c ol o rl es s t o sl ig h tl y y e l lo w, p r e s e rv a t i v e - f r ee li qu i d c o nc e n t r a t e. I t is su p pl ie d a t a n o m i n al c o nc en t r at i on of 14 m g /m L o f To s i t um om ab in 35 m g an d 2 2 5 m g s i n gl e -u s e vi a ls . Th e f o rm u la t io n c on t ai ns 1 0 % ( w/ v ) m a l to s e , 1 4 5 m M s o d iu m c hl o ri d e, 10 m M p h os p ha t e a nd W at e r f o r I n je c ti on , U S P . p H i s a pp r o xi m a t el y 7 .2 . b . I od in e I 1 31 To s i t um om a b is a r a di o -i o di n at e d d e r i v a ti v e of To s i t um om a b th a t h as b e e n co v a l en t l y l i nk ed to I o di n e -1 31 . Io d in e I 13 1 To s i t um om ab is s up p li ed as a s t e ri le , c l ea r , p r es e r v a tiv e - f r e e l iq u id fo r I V a dm in i s t r a ti o n. Th e d os im e t ric do sa g e f o r m is s u p pl ie d a t n om in a l p r o te in an d a c ti vi t y co n c e n t ra t io ns of 0 .1 m g /m L a n d 0 . 6 1 m Ci / m L P.459 ( a t da t e o f c al ib r a ti o n) , re s pe c t i v e l y . Th e t he r a peu t ic do sa g e f o rm i s s up pl i ed a t n o m i n al p r o te i n a nd ac tiv i t y c o nc en t r at i on s o f 1 .1 m g / m L an d 5 . 6 m Ci / m L ( a t d a te o f c a li b ra t io n ) , r es p ec ti v e l y. Th e f o rm ul a ti on f or t he d o s i m e t r ic a n d t he t he r ap e u ti c d o sa g e f o rm s c o n ta in s 4. 4 % - 6. 6 % ( w/ v ) p o v i d on e, 1 - 2 m g / m L m a lt os e (d os im e t ri c d o se ) or 9 -1 5 m g /m L m a lt o s e ( th e r ap e ut ic do s e ) , 8 . 5 - 9. 5 m g/ m L s o d iu m c h l o ri d e, a n d 0 . 9 -1 . 3 m g / m L as c o rb i c ac i d. p H i s a pp r o xi m a t e l y 7 . 0 . 3 . B i od i s t r ib u t io n a . Th e m e di an bl o od c l ea r a nc e f o ll o wi n g a dm in is t r a t io n o f 4 8 5 m g o f To s it u m o m a b i n 11 0 p a ti en t s wi t h N H L wa s 6 8 .2 m g /h r ( r an ge : 3 0 . 2 -2 60 . 8 m g/ h r ) . ( P a tie n ts wi t h h i gh t um o r b ur d en , s pl e no m eg a l y, o r b o ne m a r row i n v o l v e m en t ha ve a f as t e r c l ea r an c e , s h o rt e r t e rm in a l h al f - li f e, an d l a r ge r vo l um e o f d is t r ib u ti on . ) b . Th e m e di a n t ot a l b od y e f f ec ti ve ha l f -l i fe , a s m ea s u re d b y t o ta l b od y g am m a c am e r a c o u nt s , i n 9 80 pa t i en ts wi t h N H L wa s 6 7 h o u rs ( ra n ge : 2 8 - 11 5 h ou r s ) . 4 . R a di o n uc l id i e Da t a a . S ee V I II . B .2 . b . 5 . Ad m i n is t r a t io n & D os i n g a . D os im e t ri c s t e p ( 1 ) To s it um om a b 4 50 m g i n t ra v e n ou s l y i n 5 0 m l 0. 9 % So d iu m C h lo r id e o v e r 6 0 m i nu t es .
( 2 ) I od in e I 1 31 To s i t um o m ab (c o nt a in in g 5 . 0 m Ci I od i ne - 13 1 a n d 3 5 m g To s i t um om ab ) in t r a v en ou s l y i n 3 0 m l 0 . 9% So d ium C hl o r id e o v e r 20 m i nut e s . b . T he r a pe u t ic s te p ( 1 ) To s it um om a b 4 50 m g i n t ra v e n ou s l y i n 5 0 m L 0 . 9 % S o di um C hl o ri d e ov e r 6 0 m i nu t es . ( 2 ) Th e re c om m e nd ed I od i ne I 1 3 1 To s i tu m o m a b d o s e is th e a ct i vi t y of Iod i ne - 1 31 c a lc ul a te d t o d e li v e r 75 c G y t o t al bo d y i rr a di a ti on a nd 35 m g To si t um om a b , a d m i ni s te r ed in t r a v en o us l y o v e r 2 0 m in u te s . ( P ati e n ts wi t h N Cl G r a de 1 3
t h r om b oc y t op e ni a (p la t ele t c o un t s = 1 0 0 ,0 00 bu t < 1 50 , 00 0 p l at e le ts / m m ) : r e c om m e nd e d d os e is 65 c G y t o ta l b o d y i r r ad i at i on ) . 6 . P r ec a u ti o n s a . Th e r ap e ut ic Io d in e I 13 1 To s i t um om ab s h o ul d n o t b e a dm i ni st e r ed to pa t i en ts wi t h a l te r e d b io di s tr i bu t io n s o f t h e I od i ne I 1 31 To s it um om a b im a gi n g a nd d os im e t r y d o se . b . Th yr o i d -b l oc k i ng m e dic a ti o ns s h ou ld be in i ti a te d a t le as t 24 ho u rs be fo r e r e c ei vi ng t he do s i m e t ri c d o s e an d c on t in u ed un t il 1 4 d a ys a f te r th e th e ra pe u t ic d o se . c . Th e m os t c om m o n a d ve r s e r ea c ti o ns we r e s e ve r e or li f e -t h r ea t en in g c yt o p en ia s . d . I od in e I 1 31 To s i t um om a b is c o n t ra in d ic at e d in p at i en ts wi t h k n o wn h yp e r se ns i ti v i t y o ra n ap hy l a c ti c r e ac ti o ns to m u r in e p ro t ei ns . Pa t ie n ts wh o h a ve p r e vi ou s l y r e c e i v ed m u r in e - ba s e d p r o te i n t he r a py s h ou l d b e s c r ee n ed f or h um a n a n t im ou s e an t ib o di es . e . h ype r s e ns i ti v i t y r ea c tio n s , in cl u di n g f at a l o ut c o m e, ha v e b ee n r e po r t ed. E m e r ge nc y s u p pl ie s i nc lu d in g m e di ca ti o ns fo r the t r ea tm e nt o f h yp e rs en si t i v i t y r e a ct i on s , e. g . , e pi n ep h ri n e , a nt i hi st am i ne s a nd c o r t ic os t e ro id s , s h o ul d b e a va i la bl e f o r im m e di a te us e i n t he e v e n t o f an al le r g ic re ac ti o n d u ri n g a dm in is t r at io n.
XIV. REFERENCES A. A m e r ic a n P h a rm ac eu ti c al As so c i a ti o n. N uc le a r P h a rm ac y P r ac t ic e Gu i de l in es . A c a de m y o f P ha rm a c y Pr a c ti c e , 1 9 95 . B . B e r ni e r D R, C h ri s ti an P E , L an g an J K . N uc le a r Me d i c i n e Te c hn o lo g y and Te c h n iq u es . S t . L o ui s , Mo s b y 1 9 94 . C . C h il t on H M, W it c o f s k i R : N uc l ea r P ha rm a c y : An I n tr o du c t i on to t he C li ni c al A p p li ca t io ns o f R a di o ph ar m ac e ut ic a ls . P h il a de lp hi a , L e a & Fe b ig e r 1 98 6 . D . S wa n s o n D P , C hi lt o n H M, Th r a l l J H . Ph a rm ac e u t ic al s i n Me d i c al Im ag in g . Ne w Yo r k , Ma c m il l an 19 9 0. E . U n i te d S t a te s P h a rm ac o pe i a D r u g I nf o rm a ti o n ( U S P D I ) 2 00 2 . P.460
STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 7 : E ac h o f t h e q ue s tio n s , s t a te m e n ts , o r in c om p le t e s t a te m e n ts i n th is s ec t ion c a n b e c o r re c t l y a ns we r e d or co m p le t e d b y o ne o f th e s u gg es t ed an s we r s o r phr a s es . Ch oo s e t he be s t a n s we r .
1 . W hi c h o f th e fo l l ow in g em i ss i o ns f r om t he d e c a y o f r a d i o n uc l i de s i s mo s t c o m mo n l y u s e d i n nu c le a r me d ic i n e d ia g n os t ic i ma g i ng ? ( A ) x- r a y (B) β (C) α (D) γ ( E ) P os i t ro n V i e w A n s we r 1 . T h e a n sw e r i s D [ se e] . 2 . W h ic h o f t h e f o l low i n g r a d i o nu c l id e s i s m os t co m m on l y u s e d i n n uc l ea r p h a rm a c y p r a c t i c e ? ( A ) g al li u m - 6 7 (
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( E ) t ec h ne t iu m - 9 9m d i s of e n in V i e w A n s we r 4 . T h e a n sw e r i s B [ se e] . 5 . W h ic h o f t h e f o l low i n g r a d i o ph a r ma c eu t i ca l s is u se d in t he d ia g no s is o f ac u t e c h ol e c ys t i t i s ? ( A ) t ec h ne t iu m - 9 9m s u lfu r c o ll o id ( B ) t ec h ne t iu m - 9 9m m e dr o n a te di s o di um ( C ) t ec h ne t iu m -9 9m al bum i n ( D ) t ec h ne t iu m -9 9m e xa m e ta z i m e ( E ) t ec h ne t iu m - 9 9m d i s of e n in V i e w A n s we r 5 . T h e a n sw e r i s E [s e ea n d] . 6 . W h ic h o f t h e f o l low i n g c yc l o t r o n - p r o d uc e d ra di o p h a rm a ce u t ic a ls is us e d fo r a ss es s i ng r eg i on a l m yo c a r d i a l pe r f u si o n as p a r t o f an ex e r ci s e s tr e s s te s t ? 201
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V i e w A n s we r 6 . T h e a n sw e r i s A [ se e] . 7 . G lo m e ru l a r f il t r a t io n an d th e u r i n a r y c o l l e c t i o n s ys t e m ca n b e s t b e e va l u ate d us i n g w h i c h o f th e fo l l ow i ng a g e n ts ? ( A ) t ec h ne t iu m - 9 9m s u lfu r c o ll o id ( B ) t ec h ne t iu m - 9 9m a l bum i n ( C ) t ec h ne t iu m -9 9m s es ta m ib i ( D ) t ec h ne t iu m -9 9m di s of e n in ( E ) t ec h ne t iu m - 9 9m p e n te t a te V i e w A n s we r 7 . T h e a n sw e r i s E [s e e] . D i r ec t i o ns f o r qu e s ti o ns 8 -1 1 : Th e q u es t io ns an d i nc om p le te s ta t em en ts in t hi s se c ti o n c an be c o r r ec tl y a ns we r e d o r c om p le t ed b y on e o r m or e o f t h e su g ge s te d a nswe r s . C h o os e t he an s we r , A- E . 8 . T he de f i n it i o n o f th e o p t i ma l r ad i o ph a r ma c eu t i c al i nc l u de s w hi c h of t h e f o l l ow i ng a t t ri b u te s ? I . s ho r t ha l f - l if e I I . γ p h o to n w i th a 1 00 -3 0 0 k e V e n e rg y I I I . r ap i d l o ca l iz a ti o n i n t a r g e t t i ss u e a n d q u ick c le a r a nc e f r o m n o n tar g e t t is s ue A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 8 . T h e a n sw e r i s E [s e e] . 9 . W h ic h o f t h e f o l low i n g s t a te me n t s a r e t r ue f o r s o d iu m p e rt e c h ne t a te t ec h ne t i um -9 9 m ( I . I t i s us e d t o ra d i ol a be l a ll o th e r I I . Th e m o l yb d e n u m - 9 9 (
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0 . 1 5 k B q /M B q ). I I I . It h as a p h ys i c a l h a lf - l i f e o f 16 h r. A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 9 . T h e a n sw e r i s C [ se ea n d] .P . 46 1
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A m e t a b ol ic t ra pp i ng B p h ag oc y t o s i s C c a pi ll a r y bl oc k a d e D a c ti ve t ra ns p o rt E p as si v e di f f us io n V i e w A n s we r 1 2 . T he a nsw e r i s D [ se e] . 1 3. t ec h ne t i u m -9 9m a lb u mi n a g g r e ga t ed U S P A m e t a b ol ic t ra pp i ng B p h ag oc y t o s i s C c a pi ll a r y bl oc k a d e D a c ti ve t ra ns p o rt E p as si v e di f f us io n V i e w A n s we r 1 3 . T he a nsw e r i s C [ se e] . 1 4. t ec h ne t i u m -9 9m s ul f u r c o l lo id A m e t a b ol ic t ra pp i ng B p h ag oc y t o s i s C c a pi ll a r y bl oc k a d e D a c ti ve t ra ns p o rt E p as si v e di f f us io n V i e w A n s we r 1 4 . T he a nsw e r i s B [ se e] . 1 5. t ec h ne t i u m -9 9m ex a me t az i me A m e t a b ol ic t ra pp i ng B p h ag oc y t o s i s C c a pi ll a r y bl oc k a d e D a c ti ve t ra ns p o rt E p as si v e di f f us io n V i e w A n s we r 1 5 . T he a nsw e r i s E [s e e] . 1 6. f lu o r in e - 1 8 f l ud e ox yg l u c o s e A m e t a b ol ic t ra pp i ng B p h ag oc y t o s i s C c a pi ll a r y bl oc k a d e D a c ti ve t ra ns p o rt E p as si v e di f f us io n
V i e w A n s we r 1 6 . T he a nsw e r i s A [ se e] . P . 46 2
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is D [ s ee I . B . 3. b ]. C u r r e n t c a m e r a t ec h no l og y m os t e f fi c i e n tl y d et ec t s γ r ad ia t io n . α a n d β em is si o ns a r e no t u s e f ul in nu c l e ar m ed ic i ne im ag in g b e ca us e o f th e ir ha r m fu l p a rt ic u l a te e m is s i on s a nd lo w t i s s u e p e ne t r at i on . Al t ho ug h x- r a y e m i ss io ns c a n b e u s e d as i n t h e c as e o f th e m er c ur y d a u gh t er o f t he t ha ll o us c h lo r id e
201
Tl pa r en t , t h ey a r e no t
e f f ic ie n tl y d e te c t e d. A nn ih i la t io n ra d ia ti o n a ss oc i a t e d wi t h po s i t r on de ca y c an be i m ag e d, bu t th is te c h n olo g y is c u r r en t l y l im i te d to a fe w s p ec ia li z e d c e nte r s . 2 . T he an sw e r is C [ s ee I I . A . 1 ] . 99m
Tc h a s b ec om e t he r ad i on u c l id e o f c h oi c e in cu r r e nt nu c l e a r p ha r m a c y p r ac t ic e 99m
s i nc e i ts in t ro d uc ti o n i n th e m i d -1 96 0s .
Tc f u l fil l s a ll of th e re q ui r em en ts o f t he
o p t im al ra d io p ha r m a c e u ti c al , wi t h i ts ph y s ic al ha lf - l i fe of 6 h r , 1 40 ke V γ e n e rg y e m is s i on , re a d y a v a i la bi li t y , c o st , an d a b il it y t o be r a di ol a be le d to a wi d e va r i e t y of b i ol o gi c a ll y a c t i v e c om po u n ds . 3 . T he an sw e r is A [ s ee I I . A . 1 .a ] . 99m
Tc i s o b ta i ne d v ia c om m e r c i a ll y s u p pl ie d , s te ri l e , p yr o ge n -f r e e g en e ra to r
s ys t em s . A g e ne r at o r i s a d e v ic e u s e d t o s ep a r ate a s ho r t h a lf - l if e ra di o nu c li de f r om t h e l o ng e r -l i v e d p ar e nt nu c li de , wh i le r e ta in i ng th e p a re n t t o p r od uc e m o re o f t h e d a u gh t er nu c l i de . In th is wa y , s h o r t - ha lf - l if e n uc l id e s c a n be m a de a v ai la bl e on a c o nt i nu o us b as is a t g re at d is t an c e s f r om th e s it es o f g en e ra t o r p r od uc t ion . 4 . T he an sw e r is B [ s ee I V . A . 2] . Th e
99m
Tc d i ph os ph o na te c o m p o un ds a re th e m os t po pu l a r b on e -i m a g in g a g e nt s
c u r re n tl y u s e d i n n uc l ea r m ed ic i ne im ag in g . Th e y a r e ra pi d l y ta k e n u p b y s k e l et a l b o n e; 50 % o f th e a dm in is t e re d d os e i s a ds o rb e d o n t o b on e h y d r o xy a p a t i te a nd th e r e m ai nd e r i s e xc r e t ed b y t h e k id ne y s . Th e i m a gi ng a d v an t ag es o f t he
99m
T c , c o up le d
wi t h t h e s en s i t i v it y o f b on e ag e nt lo c a li z a t i on i n s k e l et a l b on e h yd r o xya p a t i te , a l lo w f o r de t ec ti o n o f b o ne pa th o lo g y b ef o re e v id e nc e o f pa t ho l og y ca n be s h own b y c o n ven t io n al x- r a y . 5 . T he an sw e r is E [ s e e V I . C . 1 an d 2 ] . 99m
Tc d i s o f en in is an im in o di a c e ti c a ci d d e ri v a t i ve , wh i c h is us ef u l f o r h ep a t ob il i a r y
i m ag in g d u e t o i ts ab i li t y t o be s e le c t i v e l y c le a r ed b y a c a rr i e r- m e d ia t ed h e p at oc y t e p a t h wa y . L ac k o f g al lb l ad d e r v is ua li z a t io n i s a n a b n or m a l fi nd i ng s u gg est i ve o f a c ut e c h ol ec y s ti t is . 6 . T he an sw e r is A [ s ee I I I . A. 1 ]. R e g i on al up t ak e o f th al lo u s c h l o ri de s u pp l y. Th e i nj ec t io n o f
201
201
TI U S P is p r o po r ti o na l t o m y o ca r dia l bl oo d
TI i n c on c e r t wi t h a t rea d m i ll e xe r c is e s t re ss tes t
d e t e rm in es m y o c a r d ia l pe r f us i on at m a xi m u m ca rd i ac ou t pu t wh e n c ar d ia c d em a nd o u ts t r ip s s up pl y a nd t he d i s t r ib u ti o n o f
201
TI is l es s a f te r af f ec t ed b y c ol l at e r al bl o od
s u pp l y wi t h in th e m y o c a rd i um . Re g io ns t ha t d o no t t ak e u p
201
TI a r e i n te rp r e t ed as
a r e as of in f a rc t o r i s c hem i a. I f t he s e f oc al a re as o f de c re as e d u pt ak e s u bs e qu e nt l y
f i ll in wi t h r ed is t ri b ut e d
201
TI , t he y a r e i n te r p re t ed t o be ar e as of isc h em ia , i n
c o nt r as t wi t h a r ea s o f i n fa r c t, wh i c h r em ai n a s d im i ni sh e d a re as o f ac t i vi ty . 7 . T he an sw e r is E [ s e e V I I . B . 1 ] . 99m
Tc p e n te t at e i s c le a red t h ro u gh gl om e ru l ar f il t ra t i on in th e s am e m an ner a s i nu li n
a n d c an be us ed t o d et e rm i ne th e G F R a s we l l as i n t h e e va lu a ti o n o f o bs tr u c ti o n o f va s c ul a r s u p pl y a nd r ena l m o r ph ol o g y . 8 . T he an sw e r is E ( I , II, I I I ) [ s e e I . C ] . Th e o p ti m a l ra di o ph a rm ac e ut ic a l h as a ha l f -l i fe sh o r t e n ou gh t o m i n im i ze r a d ia t io n e xp o s u r e t o th e p a ti en t ye t lo n g e no u gh to al lo w f o r c o ll e c t i on of im ag in g i n f or m at io n . I t s h ou ld in c o r p o ra t e a γ - em it t in g rad i on u cl id e , wh i c h d ec a y s wi t h t h e e m is s i on of a p ho t on e ne r g y b et we e n 10 0 a n d 30 0 k e V , wh ic h i s e f fi ci ent l y d e te ct e d wi t h c u r re n t i ns t ru m e n ta ti o n . Th e r ad io p ha r m a c e ut i c a l s ho u ld lo c a li ze r ap id l y i n t he o r g an s ys t em of in t e re s t a n d b e m et a bo l i zed , e xc r e t e d, o r b ot h fr om t he no n t a rg e t t i ss ue s t o m a xi m i z e c on tr a s t a nd m i ni m i ze r ad ia t io n - ab s o r b ed do s e . 9 . T he an sw e r is C (I , II) [ s e e II . A a n d B ] . S o d iu m p e rt e c h ne t a te
99m
Tc U S P d e c a ys b y is om e r i c t r an s i t io n a nd ha s a p h y s ic al
h a l f- l if e o f 6 h r . Th e em is s i o n o f a γ ph o to n h as th e en e rg y o f 1 4 0 ke V . P.463
1 0 . Th e a n sw e r i s E ( I , II , I I I) [s e e V I . B . 1 ]. 99m
Tc s u lf u r c ol lo i d l oc ali z e s wi t hi n th e r e ti c ul oe nd o t he li a l s y st em ; 80 % -90 % of t he
d o se is p h ag oc y t i z e d b y t h e Ku p ff e r c el ls o f t he liv e r ; 5 % -1 0% , b y th e s ple e n ; a nd t h e b a la nc e , b y t he bo n e m a r ro w. 1 1 . Th e a n sw e r i s E ( I , II , I I I) [s e e V I I I. B ] . A l t h ou gh al l o f th e l is t ed a g en ts ac c u m u l at e i n t he t h y r oi d g l an d , o nl y s o di u m i od id e 123
I p os s e s s es id e al i m ag i ng c h a ra c te r is ti c s an d o r g an i fi c a t io n i n to th yr o id h o rm on e .
W hile th e i m a gi n g p r op er t i es of s o di um pe r t ec hne t a te
99m
Tc U S P a r e g o od , t he
p e r t ec hn e ta t e i on is tr a pp e d o nl y b y t he t h y r oi d an d no t o r g an i fi ed , th us lim i ti n g t he i n f or m at io n pr o v i de d b y th e im ag e . 1 2 . Th e a n sw e r i s D [ s ee I I I. A . 1 ] . Th a l l ou s c hl o ri d e
201
TI US P i s a m on o v a le n t c at i on wi t h di s tr i bu t io n a n al og o us to
+
+
+
p o t ass i um i o n ( K ) . My o c a r di al up t ak e i s b y ac t i ve t r an sp o r t v i a th e Na / K - A TP a s e pump. 1 3 . Th e a n sw e r i s C [ s ee V . A . 1 ] . A f t e r I V ad m i n is t ra t io n of
99m
Tc a l b um i n a gg r eg a te d U S P , 8 0% o f t he r ad io l ab e le d
a l bu m i n p a r ti c l es be c o m e t r ap p ed b y c ap i ll a r y blo c k a de in th e p u lm on a r y c i rc u la ti o n . 1 4 . Th e a n sw e r i s B [ s ee V I . B . 1 ]. A f t e r t h e a dm in is t r at i on o f
99m
Tc s u lf u r c ol l oi d , 80 % - 90 % o f th e d os e i s
p h a go c y ti z e d b y t h e K u pf f e r c el ls o f t he li ve r ; 5 %- 1 0 % , b y th e s pl e en ; an d t h e b a la n ce , b y t he b on e m ar r o w. 1 5 . Th e a n sw e r i s E [s ee I X. A . 1 ]. 99m
Tc e xa m e t a z im e i s u s e d fo r e v al u at i ng br a in pe r f us i on . I t po s s es s e s a l i po p hi li c
p a r ti t io n c o ef f ic ie n t t ha t i s s u ff ic i en t t o d i f fu s e pas s i v e l y ac r os s t he B B B al m os t
c om p le t el y wi t h i n o ne pas s o f t h e c er e b ra l c ir c ul at i o n, an d th a t is s u f fi c i ent l y r e t ai n ed t o p er m i t da t a c o l le c ti on . 1 6 . Th e a n sw e r i s A [ s ee I X. B . 1 ]. 18
F fl u de o xy g l u c os e is us e d i n e v a lu a ti n g ce r eb ra l fu nc t io n b y m ap pi n g th e
d i st r ib u ti o n o f c e re b ra l gl u c o s e m e ta b ol is m . A s an a na lo g of gl uc os e ,
18
F
f l u de o xyg l u c os e is t ra ns p o r t ed in t o t he b ra in b y c a r ri e r -m e di at e d t r an s p or t m ec h an is m s re s p o ns ib l e f o r tr a ns po r t in g g lu c os e a c ro s s th e B B B. B ec au se t he p r e se nc e o f th e f l ou r in e a t om in t he 2 p os it i on pre v e n ts m e t ab o li s m b e y on d th e p h os p ho r y l at i on s t e p, b r a in .
18
F f lu d eo xyg l u c o se be com es m e t ab ol ic a ll y t r ap p ed wi t h i n t he
20 Pharmaceutical Care and Disease State Management P e g g y C . Y a r b o r o ug h
I. INTRODUCTION A. P r a c t i c e o f ph a r ma cy. Th e p r ac t ic e o f p h a rm a c y em b ra ce s a v a r ie t y o f s e t ti ng s , p at i en t p o pu la t io n s , an d s p ec ia li s t a nd g e n er a li st ph a rm ac is t s . C e n t r al to th e pr ac t ic e o f p h a rm ac y, ho we v e r , is th e p ro vi s i on o f cl i ni c a l s e r vic es di r ec t l y to , a n d f o r th e b e ne f it o f, pa t i ent s . B . D e f i ni t i o n. Th e te r m p h a r ma c eu t i ca l c a r e (s o m et im es c a ll e d p h a r ma c is t ca r e ) d es c rib e s s p e ci fi c a c t i vi ti es and se r v i c e s t h ro u gh wh i c h a n in di vi d ua l p h ar m a c i s t “ c o op e ra t es wi t h a pa t ien t an d o t he r p ro f ess i on al s i n de si gn i ng , i m p l em en t in g an d m on i to r in g a t he ra p e ut ic pl a n t ha t wi l l p r o du c e s p ec i fi c t he r a peu t ic ou t co m e s f o r t he pa ti e n t. ”
1
C . P h a rm ac eu t ic al c a r e is in c re as i ng l y be in g a u gm e nt e d b y ac t i v it i es th a t m a y be de s c r ib e d a s f o cu s e d a r ea s o f p r ac t i ce , wh e r e i n t h e p ha r m a ci st i s e n g ag ed in : 1 . D r u g m o ni t o r i ng , fo r a s p ec i fi c d r ug o r f o r t her a p y f o r a s pe c i f ic di s e as e s t a te 2 . D i se a se mo n i to r i n g, f o r a s p e ci fi c d is e as e s ta t e 3 . D r u g t h e r ap y a n d d i se a s e m an a ge me n t / co l lab o r a t i ve p ra c t ic e , b y p ro t oc o l 4 . A p h a rm ac is t m a y i nc o r p o ra t e o ne o r m o r e a re a s o f f oc us e d p r ac ti c e in t o a g e n er a l p r ac ti c e of p ha rm ac y o r m a y s p ec ia l i ze wi t h i n a n a rr o w f i el d o f pr a c ti c e . E xa m p l e s o f h ig h l y s pe c ia l i z ed p ra c ti c e in cl ud e ph a r m a c i s t - di r ec t ed di a bet e s m a na g em en t c li n ic s , h y pe r t e ns io n c li ni c s , a n ti c o ag u la t io n c li n ic s , an d h os p i t al b a se d i n fe c t i ou s d is ea s e s e r v ic es .
II. SCOPE OF PRACTICE WITHIN PHARMACEUTICAL CARE A. R o l e . P h ar m a c e u ti c al c a re ha s e v o l v ed f r om an em p ha si s o n p r e v en t ion o f d r ug r e l at e d p r ob l em s ( ba s i c al l y d r u g m an a ge m en t ) to t he e xp a n de d ro le s o f p h a rm ac is ts in t he t r ia ge o f pa t ie n t s, t r ea t m en t o f r o u ti n e a cu t e il l ne ss e s , m a n ag e me n t o f ch r o n ic d i s ea se s , a nd p r im a r y d i s ea s e p r e ve n t io n . B . F u nc t i o n. Th e p r o v is io n of ph a rm ac e ut ic a l c a re d oe s n ot im pl y t h at t he p h a rm ac is t i s n o l on g e r re s po ns i bl e f o r d is pe n si ng f un c ti on s . I n m an y i ns ta n c e s, h o we ve r , im p le m e n ta t io n o f ph a rm ac eu t ic al ca r e s e r v ic es ne c e ss i ta t es a re d es i gn of t h e p r o fe s s io n al wo r k fl ow, wi t h as s i g nm en t of tec h ni ca l f u nc ti o ns to te c hn i c a l p e r so nn e l u nd e r t h e d ir ec t s u pe r v i s i on an d re s p on s i b il i t y of th e p h a rm ac is t . P.466
Table 20-1. Uniqueness of Pharmaceutical Care
Traditional Characteristic Pharmacy
Clinical Pharmacy
Pharmaceutical Care
Primary focus
Prescription order or OTC request
Physicians or other health professionals
Patient
Continuity
On demand
Discontinuous
Continuous
Strategy
Obey
Find fault or prevention
Anticipate or improve
Orientation
Drug product
Process
Outcomes
OTC, over the counter.
III. UNIQUENESS OF PHARMACEUTICAL CARE. P r o vi si o n o f p h ar m a c eu tic a l c a r e o v e r l ap s so m e wh a t wi t h o t he r as pe c t s o f p h a rm ac y p r a ct ic e ( Ta bl e 2 0 -1 ) . Ho we v e r , p h a rm ac eu t ic al c a r e is no t th e s am e a s th e s e ot h e r a r e as , wh ic h i nc l ud e A. C l i n i c a l p h a rm a c y B . P a t ie n t c o u ns e li n g C . P h a r ma c eu t i ca l s e r vi c e s ; wh e n th e a c ti vi t ie s o f a p ha rm a c y o r ph a rm a c y d e p ar t m e n t a r e p er f o rm ed f o r “ f ac el es s ” p at i en ts o r ch a r ts , t h e ac t i vit y i s o n e o f p h a rm ac y s e r v i c e , no t ph a r m a c e u ti c a l c a re (i . e ., c ha r t o r d ru g p r o fi le r e vi e ws wi t h o u t i n pu t fr om t he pat i e nt o r c a r e gi v e r i s n o t p h a rm ac e ut ic al ca r e ).
IV. ESSENTIAL COMPONENTS OF PHARMACEUTICAL CARE A. P h a r m a c is t - pa t i en t re l a t io n s hi p . The im po r ta n c e of pu t t in g a fa ce and p e r so na l it y wi t h t he c l in ic a l p ic tu r e i s a k e y c o m po n e nt of ph a rm ac e ut ic a l c a r e. A p h a rm ac is t c an ha v e a c a r i ng r el a ti on s hi p wi t h a p a t ie n t b ut no t wi t h a c ha r t o r d ru g p r o fi l e. A ph a rm ac is t c ann o t h a ve e m pa t h y f o r wor d s o n a pa g e o r o n a c om p ut e r s c re e n. P ha r m a c e u ti c a l c a r e is ba se d o n a co ll ab o r a ti v e ef f o rt be t we e n ph a r m a c i s t a n d p a ti e nt . B . P h a r ma c is t ' s w o r k u p o f d r ug t he r a p y ( P W D T ) . Th e p ro vi si o n o f p ha rm ac e ut ic a l 2
c a r e is of t en c e n te r ed a ro u n d a p r oc es s d es c r i bed as t he PW DT. Th e PW D T c o nt a in s t he t ho u gh t p r oc es s es n ec es s a r y f o r p ha r m ac eu t ic al c a r e. Th e PW D T is to o l e ng t h y to be us e d as the c h a r t n ot e fo r ph a rm aci s t i nt e r v e nt i on s; an a bb re vi a t ed f o r m a t k n o wn as a F A R M ( f i nd in g s, as s e ss m e nt , re s ol u ti on s / re c o m m en d at io n , a n d m o ni t o ri ng ) no t e o r a S OA P ( s ub je c ti v e , o b je c t i v e, a s s es s m e n t , a nd pl a n) n o t e is m o r e a pp r op r ia t e f o r a c h a r t n o ta t io n ( Ta bl e 2 0 -2) . N o ne t he l ess , it is h e lpf u l t o th e
p h a rm ac y s tu de n t , o r t o a p ha r m a ci st en t e ri n g a n e w f i e ld of ph a rm ac y p ra c ti c e , to wr i t e o u t c om pl e te PW DTs f o r a v a r ie t y o f p a ti ent s as t r a in in g o r o ri en t a tio n e xe r c i s es . Al th o ug h th e fo r m s an d m e th od s u s e d f o r th e PW D T m a y v a r y, t h e c om p on e nt s a r e e s s en t ial l y t he sa m e . 1 . D a ta c ol l ec t i on . C ol le c t , s y n th es i z e , a nd in t er p r e t r e le v a n t i nf o rm a ti on , s u ch as : a . P at i en t d em o g ra p hi c d a t a: ag e , r a c e , s e x b . P e rt i ne n t m e d ic al in f or m a ti o n ( 1 ) C u r re n t a nd pa s t m ed i c a l h is t o r y ( 2 ) F am il y hi s to r y ( 3 ) S oc ia l h is t o r y ( 4 ) D ie t a r y hi s t o r y ( 5 ) Me d i c a t io n h is t o r y (pr e s c r ip t io n , O TC , so c i al d r u gs ; a l le r gi es ) ( 6 ) P h ys i c a l f i nd in gs ( e.g . , we i gh t , h e ig h t, bl o od p r e s s u re , e d em a) ( 7 ) La b o ra t o r y o r ot h e r te s t r e s u lt s (e . g. , s e ru m d r u g l e v el s , p ot as s i um leve l , se r um c r e at i ni ne as re l e v an t to d r u g t h er a p y ) c . P at ie n t c om pl ai n ts , s y m p to m s , s ig ns P.467
Table 20-2. Components of a FARM Note and a SOAP Note PWDT Component
FARM Note
SOAP Note
The identified or suggestive patient-specific information that gives a basis for or leads to the recognition of a pharmacotherapy problem or indication for pharmacist intervention Findings
Findings (F)
Subjective and objective data incorporated into same section
Desired outcomes Desired end points
Subjective data (S) separated from objective data (O)
Assessment (A)
The pharmacist's clinical judgment based on his or her findings—thus it is no better than the database (the
Drug-related problems Therapeutic selection
findings); the assessment forms the basis for the intervention plan
Resolutions/Recommendation (R)
Monitoring parameters
Plan (P) Monitoring (M)
Follow-up 2 . D e vel o p o r i d en t if y t he C O R E p h a rm a co t h e rap y p l a n
3
a . C = c o nd i t io n or pa t ie n t n e ed . N ot e t h at t hi s m a y in cl u de no nm e di c a l c o nd i ti on s o r n ee ds an d i s t hu s n o t a r ei t e ra t io n o f th e c u r ren t m e di ca l p r o bl em s . b . O = o u t co m e (s ) de s i re d fo r th e c o nd it i on s o r n e e ds . ( 1 ) P a ti e n t o u tc o me s ( PO E MS : p a t ie n t -o r ie n te d e v i d e nc e t ha t m a tt e rs ) . Th e r e a re g e n er a ll y f i v e c at e go r ie s o f pa ti e n t o ut c o m e s : ( a ) Mo r t a l it y ( b ) Mo r b i d it y ( i ) R e la t ed to di s e as e p ro c es s ( i i ) R el a te d to m e di c a t ion / t r ea tm e nt pl a n ( c ) B eh a v i o r ( d ) E c o n om ic ( e ) Q u al i t y o f li fe ( 2 ) T he r a pe u t ic e nd po in t s (s u r ro g at e m a rk e rs ; D O E S : d is e as e -o r ie n te d e v i d e nc e) ( a ) A th e ra p eu t ic e n d p oin t r ep r es e nt s t he ph a rm a c ol o gi c a l o r th e ra p eu t ic e f f ec t t ha t i s e xp e c t e d, ul t im at e l y , to ac h ie ve th e d e si r ed out c om e (s ) . ( b ) Mo r e t h an on e e n d po i n t is us ua l l y n e ed e d t o a ch i e ve a n o ut c om e— f or e xa m p l e, b o t h n ea r - no r m a l g l y c e m i c c on t r ol an d n o rm al i z a ti o n o f b l oo d p r es su r e a re n e ce ss a r y to s i gn i fi c a n tly r e d uc e th e r is k o f e n d -s t ag e re n al di s e as e . c . R = r e gi m en t o ac h ie v e t he de si r e d o ut c o m e ( s ) ( 1 ) T he r a pe u t ic r e gi m en s ( a ) E x is t i ng t he r a p y. F o r e xa m p l e, a p ha r m a c i s t i s a s k ed t o wo r k wi t h a pa t i en t f o r wh o m o ne o r m o r e a g en ts a re al r ea d y p re s c r ib e d f o r th e d is e as e p r oc es s o r p r o bl em . ( i ) E v a l ua t e t he c u r r en t d r u g r e gi m e n f o r i ts p ot en t i al to ac hi e ve d es i r ed e n d p oi n ts a n d t o m ee t th e p a ti e nt ' s i n di v i du a l n ee ds . ( i i ) R e vis e t h e r e gim e n as ap p r op r ia t e. ( b ) I n it i a l t h e ra p y. A p h a r m ac is t is as k e d t o wo rk wi t h a p at i en t wh o s e c o n di t io n wa s n e wl y d i ag n os ed o r i s a s k ed t o d e vel o p a n in i t i a l t r ea t m e n t p la n . ( i ) L is t t he t he r ap e ut ic op t i on s ( d ru g a n d r e gi m en ) m o s t li k e l y t o ac h ie v e t h e d es i re d e n d p oi n ts .
( i i ) S el ec t th e o p ti on be s t s ui t ed fo r th e p a ti e nt ' s m e di c a l , p h ys ic a l ( e .g . , h a n di c a p ), p s yc ho s o c i al ( e. g . , s u p po r t s y s t em ) , m en t al (m o tiv a t i o n, de n ia l , f ea r ) , a n d f i na nc i al we l l - b e in g . P.468
( 2 ) G o a l s et t i n g a nd b eh a vi o r r e g im e ns . Th e pa t i en t i s a n e s s en t ia l p a rt n e r f o r s e t ti ng an d a c h i e v in g i n te r m ed ia t e - a nd s h o rt - t e rm go a ls a n d t he be h a v ior c ha n ge s n e ce ss a r y to ac hi e v e t h os e g o al s . To c o ns t r uc t e ff e c ti v e be ha v i o r re gi m ens , th e p h a rm ac is t p r ac t it i on e r m us t in c o r po r a te th e fo llo wi n g c o nc e pt s : ( a ) I de n ti f y th e t yp e o f g o a l be in g s e t, s u ch as t he f ol l o wi ng : ( i ) S t a r t a ne w p o s i t i v e a c ti o n —f o r e xa m p l e, s t ar t a n e xe r c is e p r o gr a m . ( i i ) I nc r e as e t h e f r eq u enc y o r i n te n si t y of a p os i tive a c ti on — f o r e xa m p le , d r i nk t wo m o r e cu ps o f wa t e r da il y . ( i i i ) S to p o r d ec r e as e the f r eq u en c y o r in t en s i t y o f a d es t ru c ti v e ac ti o n —fo r e xa m p l e , s to p s m ok i ng . ( i v) C o n t i n ue an ac ti o n th a t i s “ p e rf ec t ” — fo r e xa m p le , c on t in u e t o e xe r c is e 3 0 m in a d a y, e ve r y da y . ( b ) S t at e th e b eh a v i o r go a l i n t e rm s t ha t ar e c l ea r , s pe c i fi c , a nd r ea s o na b l e . ( i ) S e t t i me l im i ts — f o r exa m p l e , “ O ve r t h e n e xt 3 we e k s . ” ( i i ) Ta r g et a s pe c i f ic act i o n — fo r e xa m pl e , “ I wi l l wa l k . ” ( i i i ) Se t me as u r e s a nd fr e q u e nc y— f o r e xa m p l e, “ s i x b l oc k s , t h r ee da ys a we e k . ” ( i v) D i vi d e a b i g ta sk int o s e v e r al sm al l o ne s , m a k in g e ac h c ha n ge s m al l r e la t i ve t o t h e c u r re n t p at i en t b e hav i o r . Th e o l d s a y i n g “ I t ' s h a r d b y th e y a rd , bu t a c i nc h b y t h e i nc h ” i s t r ue . d . E = e va l ua t i o n p a ra me t e r s t o a s s es s o u tc om e a c h i e v em en t . ( 1 ) E f f ic a c y p a r a m e t e r s. W hat s h ou l d b e m o n it or e d , h o w o f t en , a n d b y wh o m t o e n su r e t h at t he r ap e ut ic e n d p oi n ts o r p at i en t o u tc om e s a re be i ng ac hi e v ed . ( 2 ) T ox i ci t y p a r a m e t e rs. W hat s h ou l d b e m o n it or e d , h o w o f t en , a n d b y wh o m t o e n su r e t h at ad v e r s e e ff ec t s , al l er g ic re ac t io ns , or t o xi c i t y is n o t o cc u rr i ng . 3 . I de n t i f y t h e P R I M E ph a r m ac o t he r a p y p r o b l e m s o r in d ic a ti on s f o r p har m ac is t 4
5
i n t er ve n t io ns , s o m et im es r ef e r r ed to as d r u g -r e la t e d p r ob le m s . Th e go al is to i d en t i f y a c tu al o r p ot e nt ia l pr o bl em s t h at c o ul d c o m p ro m i se th e d es i r ed pa t i en t o u tc om e s ( Ta b le 20 - 3 ) . a . P = p ha r m ac e u ti c al - ba s e d p r o bl e ms ( 1 ) P a ti en t n o t re c e i v in g a p r es c r ib e d d r ug , d e v ice , o r i nt e r v e nt i on ( 2 ) R o ut in e m o ni t or i ng (la b s , s c r ee ni n gs , e xa m s ) m is si ng
Table 20-3. PRIME Pharmacotherapy Problem Types
P = Pharmaceutical-based problems • •
Patient not receiving a prescribed drug, device, or intervention Routine monitoring (labs, screenings, exams) missing
R = Risks to patient • •
Adverse drug reaction/drug allergy Potential for overlap of adverse effects (must be kept in mind as part of the workup or evaluation of any new complaint or problem reported by patient)
I = Interactions •
Drug-drug, drug-disease, drug-food interactions
M = Mismatch between medications and condition or patient needs • •
No indication for a current drug, device, or intervention Indication for a drug, device, or intervention but none prescribed
E = Efficacy issues • • •
Too much of the correct drug Too little of the correct drug Wrong drug, device, intervention, or regimen prescribed; more efficacious choice possible
Adapted with permission from Canaday BR, Yarborough PC. Documenting pharmaceutical care: Creating a standard. Ann Pharmacother 1994;28:12921296. P.469
b . R = ri s ks t o p a ti e n t ( 1 ) A d ve rs e d r ug r ea c t i on / d r ug al le r g y ( 2 ) P o te n ti al fo r o v e rl a p o f ad v e r se e ff ec t s ; m us t b e k e pt in m i nd as pa r t of t h e wo r k u p o r e v a lu a ti on o f a n y n e w c om pl ai n t o r p ro b le m re po r t ed b y pa ti e nt c . I = in t e r ac t i on s ( 1 ) D r ug - d ru g , d r ug - d is ea s e, d ru g - fo o d, d ru g -l a b i n t er a c t i on s d . M = m i sm a t ch be t we en m e d ic at i on s a nd co nd i ti o n o r pa ti e n t n ee ds ( 1 ) N o i nd ic a ti o n f o r a c ur r e n t d r ug , d e v i c e , o r in te r v e n t io n ( 2 ) I nd ic a ti on f or a d r ug , d e v ic e , o r i n te r v e n ti o n bu t no n e p r es c r i be d ( 3 ) P e rc ei v e d o r ac tu a l ba r r i e rs t o i m p l em en t at i on o f m e di c a t io n o r b e ha v io r r e g im en , s uc h a s f i na nc ia l c o ns t ra i nt s ; li f es t y l e is su e s ; an d i n te ll ec t u al , p h y s ic al , o r e m ot i on al li m i t a ti on s . e . E = e f fi c ac y i s s ue s ( 1 ) To o m uc h o f th e c o r re c t d r ug ( 2 ) To o li t tl e o f t h e c or r ec t dr u g ( 3 ) W ron g d r ug , d e v ic e , in t e r v e nt i on , o r r eg im en p r e s c ri b ed o r m o r e e f fi ca c io us c h oi ce po s s ib l e C . D o c um e n ta t i on o f p ha r m a ce u t ic a l c a re . Fo rm u la t e a F AR M no t e o r S O AP n o t e t o de sc r ib e a n d d oc um en t t he i n t er v e n ti o ns i n te nd e d o r pr o vi de d b y t h e ph a r m a c i st . S o m e h ea l th c a r e f ac i li ti es m a y sp ec i f y on e f o rm at o ve r th e o t he r ; p h ar m ac is t s n ee d t o be co m e p ro f ic ie n t i n ea c h. 1 . F o rm a t o f a F AR M n ot e a . F = f in d i ng s . Th e p at ie n t -s p ec if ic in f o rm at i on th a t g i ves a b as is fo r , o r l e ad s t o , t h e re co g ni t io n o f a ph a rm ac o th e r ap y p r ob le m o r i n d i c a t io n fo r ph a rm ac is t i n t er ve n t io n . W ith in th e F A R M f o r m a t , f in d in gs inc l ud e s ub j ec ti ve an d o b je c ti ve i n f or m at io n ab ou t th e p at i e nt . b . A = a ss e ss m en t . Th e p h a rm ac is t 's e val u at i on o f t he fi n di ng s , i nc lu di n g s t a te m e n ts o f : ( 1 ) A n y ad di t io n al in f or m a t i on th a t i s n ee de d to be s t a ss es s t he p ro bl em to m a k e r e c om m e nd a ti on s ( 2 ) Th e s e v e r it y , p ri o ri t y , o r u rg en c y of t he pr o bl em ( 3 ) Th e s h o rt - t er m a nd lo n g - te rm go a ls of th e i n te r v e n t io n p r op os e d o r p ro vi d e d. ( a ) E xa m p le s o f s h o r t - ter m g o al s : e li m i n at e s ym p t om s , l o we r bl oo d p r ess u r e ( B P ) t o 14 0 /9 0 m m H g wi t hi n 6 we e k s, m a na g e ac u te a s th m a f la r eu p wi t ho u t re q ui r i ng h o sp i ta li z a t io n ( b ) E xa m p l es o f lo n g - te rm g oa l s : p r e ven t re cu r re n ce , m ai n ta i n B P at < 13 0 / 80 m m H g , p re v e n t p r og r es s i o n o f di a be t ic n e r v e d is e as e c . R = r e so l u ti o n (i nc lu di n g p r e v en t io n ) . Th e in t er ve n t i on pl an in c l u de s ac t u a l o r p r o po s e d a c ti o ns b y t h e p h a rm ac is t o r r ec om m e nd a t io ns to o th e r h ea l th c ar e p r o f ess i on al s . Th e r at i ona l e f o r c ho os i ng a s p ec i fi c i n te r ve n ti o n s h o ul d b e s t at e d. I n t e r ven t io n o p ti o ns m a y i nc l ud e t h e f ol l o wi n g: ( 1 ) O bs e r v i ng , re as s e s s in g , o r fo l lo wi n g — no in t er v e n t i on ne ce s s a r y a t th is t im e. I f n o ac ti o n wa s t ak en o r re c om m e nd e d, t he F A R M n o t e s e r v e s a s a re c o r d o f t he e ve n t a n d s ho ul d c on s ti tu t e p a r t o f t h e p at i en t ' s p h a rm ac y ch a r t o r d a ta ba s e. ( 2 ) C o un s e li n g o r e d uc ati n g t h e p at i en t o r c a r eg ive r
6
( 3 ) Ma k i ng r ec om m e nd a ti o ns to t he pa t ie n t o r c a re g i v e r ( 4 ) I nf o rm in g th e p r es c rib e r ( 5 ) Ma k i ng r ec om m e nd a ti o ns to t he pr e s c ri b e r ( 6 ) W it hh o ld i ng m e di c a t io n o r a d vis in g a ga i ns t us e d . M = m o n i to r i n g a nd fo l lo w- u p . Th e pa r am e te rs an d ti m i ng o f f ol lo w- u p m on i to r in g t o as se s s th e e f fi c a c y , s a f e t y , a n d o ut c o m e o f t he i nt e r v e nt i on . Th is p o r tio n of t he F A R M n o t e s h o ul d i nc lu de t he f ol lo wi n g : ( 1 ) Th e pa r am e te r to be f o l lo we d ( e .g . , p ai n , d epr e s s e d m o o d, se r um po ta ss i um l e ve l ) ( 2 ) Th e in t en t o f th e m oni t o ri n g ( e .g . , e f fi c a c y , toxi c i t y , a d ve rs e e ve n t ) ( 3 ) H o w t h e p a ra m e t e r wi l l b e m on i to r ed ( e. g ., p at i e nt in t e r vie w, s e ru m d ru g le v e l , p h ys ic al e xa m in a ti o n) P.470
( 4 ) F re q ue nc y o f m on i to ri n g ( e . g. , we e k l y , m o nt h ly ) ( 5 ) D u ra t io n o f m o ni t or i ng ( e .g . , u n ti l r es o l ved , wh i l e on an t ib i ot ic , un t il re s ol v e d t h e n m o n th l y f or 1 y ea r ) ( 6 ) A n ti c i pa t ed o r d es i red f in d in g ( e . g. , n o p a in , e u gl y c em i a, he a li ng o f les i on ) ( 7 ) D ec is i on po in t to al t er t h e ra p y wh e n o r if ou t c o m e is no t ac hi e v e d ( e .g. , p ai n s ti ll p r e se n t a ft e r 3 da y s , m ild h y p og l y c e m i a m o re th an t wo t im es a we ek ) 2 . F o rm a t o f a S O AP n o t e . Th e S O A P f o rm a t is th e on e u se d m os t o f te n b y m ed ic a l p r a ct i ti o ne rs ; ho we v e r , wh e n u s e d wi t hi n th e p ha r m a c eu t ic al c a r e co n text , t h e c o nt e nt o f t he s e c t i on s m us t be r e v is ed to m a tc h t he ph a rm ac is t ' s l eg a l s c o p e o f p r a ct ic e . a . S = s ub j ec t i ve f in d i ng s . Th e p a ti en t - s p ec i fi c s u bj ec t iv e i nf o rm a ti o n t ha t gi ve s a b a si s f o r, o r l ea ds t o, the r ec o gn i ti on o f a p h ar m a c ot h e ra p y p ro bl em o r i nd i ca t io n f o r ph a rm ac is t i n te r v e n tio n . W ith i n t he S O A P fo rm a t , p at i en t f i nd in g s a re d e li ne a te d i n t o su b je c t i v e a n d o bj ec t i v e da t a . ( 1 ) S ub j ec ti v e da t a a r e op e n t o i n di vi du a l i nt e r pr et a t io n , wh e r e as ob j ec ti v e d a ta a re e a si l y du pl ic a t ed or qu an t i fi e d. E xa m p le s o f s ub je c ti ve f in di n gs i nc l ud e t he p at i en t ' s s t a te m e n t o f c om pl ai n t ( th e c h ie f c om pl a in t ; c c ) an d du r a ti on o r s e ve r i t y of s ym p to m s . ( 2 ) S om e ti m e s , th e d a t a t o be no t ed a re no t c l ea rl y d e li ne a te d a s s ub j ec tiv e o r o b je c ti v e o r t he r e m a y be a p r e po nd e r an c e of one t y p e o f d a ta . In th es e in s ta nc e s, t h e s ub j ec ti v e an d ob je c t i v e da t a m a y b e c om bi ne d as a s i ng l e s e c ti o n, la b el e d “ S / O F i n di ng s .” b . O = o b j ec t i ve f in d in gs . Th e pa ti e n t- s p e c i fi c ob j ec t iv e i nf o rm a ti o n t ha t g i v e s a b a si s f o r, o r l ea ds t o, the r ec o gn i ti on o f a p h ar m a c ot h e ra p y p ro bl em o r i nd i c a t io n f o r ph a rm ac is t i n te r v e n tio n . E xa m pl es o f o bj ec t i ve i nf o rm a ti o n in c l u de la bo r a t or y d a t a, we i g ht , he ig h t , b loo d p re s s u re , a n d p ul s e . c . A = a ss es s me n t . I n th e m e di ca l m od e l, th e as s e ss m e n t s ta t es th e p hy s i ci a n 's wo r k i n g d ia g no s i s a nd / o r p os s i b le e xp l a na t io ns for t h e p at i en t ' s m e d ic al p ro b le m (s ) . I n t he ph a rm ac eu t ic al c ar e m o d el , h o we v e r , di a gn o s i s is no t no r m a ll y wi t h i n t h e p h a rm ac is t ' s s c o pe of p ra c ti c e . In s te ad , th e a s s es s m e nt s ec t io n i nc l ud es t h e
p h a rm ac is t ' s e v a lu a ti o n o f t he s u bj ec t i v e a nd ob je c ti v e f in di n gs i n a m a nne r si m i la r t o t he de s c ri p ti o n o f t h e a s s e s s m e nt in th e F A R M f o rm a t ( s ee I V. C . 1 .b ) . d . P = p l an . In th e m ed ic a l m o d el , th e p la n s t at es t he ph ys ic ia n ' s i nt e nd ed d r ug r e g im en ( s ), s u r gi c a l p r oc e d u re s , a nd / o r di a gn os t ic t es ts . I n th e p ha r m a ceu t ic a l ca r e m o de l , p ha r m a c i s t s m a y n o t h a v e th e a u th o ri t y t o i n it i at e o r al t er d ru g t h er a p y r e g im en s o r o r d e r l ab o rat o r y t es ts . La bo r a to r y o r p r e s c ri p ti v e a ut h or i t y m ay b e g r a n te d o n a s t a te - b y s t at e ba s i s , u nd e r c ol la b o rat i v e p ro t oc ol wi t h s p ec if ic p h ys ic ia n (s ) or wi t h in a s p ec if ic he a lt hc a r e f ac il i t y o r s ys t em . Ac ti o ns i n c l u de d wi t h i n th e p l an s ec t io n s h o ul d b e i d en t if i ed as rec o m m e n de d a c ti on s wh en a p p ro p r ia t e. In t he ph a rm ac e ut ic a l ca r e m od e l, th e pl an is us ua ll y e xp a n d e d t o d e sc r ib e i n fo rm a ti o n i nc lu d e d in t he m o ni t o ri ng an d fo l lo w- u p s e c t i on of th e F A R M n o t e ( se e I V . C . 1. d ) .
V. FOCUSED AREAS OF PRACTICE. Th i s ph r as e re f e rs t o a r ea s o f s p ec ia l t y p r ac t ic e in wh i c h p ha r m a c i s t s a r e i n c re as in g l y b e in g re c o gn i z e d f o r t h ei r th e ra p eu t ic o r m a n ag em e nt e xp e r t is e . As s uc h , p h ar m a c e u ti c al c ar e p ro v i d ed b y th e p h arm ac is t is a u gm en t ed b y a c ti vi t ie s n o t n o r m a ll y p r o v id e d wi t h i n t h e g e ne r al is t ph a rm ac is t r o le . Ca t eg o r ie s o f f oc us e d p r a ct ic e m a y be s t be des c ri b ed b y th e t y p e a n d e xt e n t o f s pe ci a lt y a c t i v it i es . A c t iv it i es fo r ea c h de s c r ip t iv e l ev e l a r e a dd i ti v e to , o r a ug m e n t, t he p re v io u s l ev el — t h a t i s, fo c u s ed dr u g m on i t or i ng in co r p or a te s a nd e xp a n d s t h e ac t i v it i es of p h a rm ac e ut ic al c a r e ; f oc u s ed di s e as e m on i to r i ng i nc o r po r at e s t he ac ti vi t ie s o f p h a rm ac e ut ic al c a r e p lus f oc us ed d ru g m on i to r ing , a n d s o o n . A. D r u g m o n i to r i n g . S pe c ia li z e d m o ni to r i ng fo r a s p ec i fi c d r ug o r d r ug th e r ap y f o r a s p ec if ic di s e a s e s t at e . Exa m p l e s a r e t he f ol lo wi n g : 1 . E x te n si ve p a ti e n t e du c a t io n c o nc er n in g t h e d r u g , t he d ru g m on i to r ing p r oc ess , a n d t h e p ha r m a c i s t ' s a nd p at i en t ' s r es p on s i bi l it ie s fo r fo c u se d d r u g m o n it o r in g . I t m us t be s t r es s e d t o t h e p a t ie n t t ha t fo r th e f o c u s e d d ru g m on i to r in g p r og ra m to be e f f ec t i v e, th e ph a rm ac is t m us t h a v e a c c es s t o i n fo r m at i on c o nc e rn in g a l l th e m e di ca t io ns be i ng ta k e n b y , o r p r es c ri b ed fo r , th e p a ti e nt . P.471
2 . E ac h t im e t h e p at i en t r e t u rn s f o r a r ef il l o f th e m o ni t o re d m ed ic a ti on ( e.g . , fo r h yp e r t en s i on , di ab e te s , h y p e r li p id em ia , c i rc ul a tio n , c a rd i o v asc u la r di s e as e , g l au c om a) : a . P e rf o rm a c om p l ia n ce c he c k ( e xp e c te d v e rs us ac t ua l r e fi l l d at e ) a n d d e t e rm in e w h y th e n e ed ed m e di c at io n o r s u p pl ie s a r e n o t be i ng r e fi ll e d. P h ys ic a l, f in a nc i al , i n t el le c tu al , m e nt a l, o r em o ti o na l i s s ue s m a y b e in v o l v e d , r e qu i ri n g r e fe r ra l to ot h e r h e al t hc a re p ro v i d e rs o r re q ui r i ng ot h e r in n o va ti v e s ol u ti o ns . Tak e t h e r es po n s i bi l it y a n d a p pr o p ri a te ac ti o n to r es o l v e t he s e is su es . b . A sk a b ou t th e o c c u rr en c e a nd f re q ue nc y o f s i de e f fe c t s, es pe ci a ll y t hos e re l at e d t o qu a li t y o f li f e —s uc h as o rt h os t at ic h y po t en s i on , ch an g es i n s e xu a l fu nc t io n , e n e rg y l e v el , e xe r c is e t ol e r an c e , h y po gl yc em i a, hyp e r g l y c e m i a , a nd ab il i t y t o
c o nc en t r at e . Co u ns el the p at i en t a b ou t s t r at e gi es t o m i n im i z e t he s e e ff ect s or c o nt ac t th e p r es c ri b er t o o f f er op t io ns t o r es o l ve t h e p a ti e nt ' s re p or t e d p ro b le m s . 3 . W it h e ac h n e w p r e sc r i p t i o n o r o ve r - t he - co u nt e r ( O TC ) m e d ic a t io n ad d e d t o t he m o ni t o re d d r ug r eg im en , o bs e r v e a n d c o u ns el t he p at i en t c on c e r n in g t h e f o l lo wi n g : a . D r ug s t h at m a y a ff ec t t h e e f fi c ac y o f t he m o ni to r e d d r ug ( d ru g -d is e as e a n d d r ug d r u g i n te r ac ti o ns ) . F o r exa m p l e , wi t h d ia b et e s m e d i c a ti on s : ( 1 ) C e r ta in d ru gs m a y d ir e c tl y c ha ng e b l oo d g lu co s e l e v el s. ( 2 ) C e r ta in d ru gs m a y i nd i r ec tl y c ha n ge bl oo d g lu c os e l e v el s b y i nt e ra c tin g wi t h th e h yp o g l yc em ic ag e nt . b . D r ug s t h at m a y a f fe c t t h e c ou r se o f t he di s e ase f o r t he m o ni t o re d d r u g. F o r e xa m p l e , c e r t ai n d r u gs ad d e d t o a d i ab e te s r e gi m e n m a y a ff ec t th e c om pl ic a ti o ns o f d i ab e te s b y a gg r a v a ti n g n e u ro p at h y a nd ne ph r o pa t h y as a r es u lt of de c rea s ed c i rc u la ti o n . c . D r ug s t ha t m a y af f ec t c om o r bi di t y c o n di t io ns of t h e d is ea s e f o r t he m o nit o r e d d r u g . F o r e xa m p le , c e rt ai n dr u gs ad de d to a d ia be t es r eg im e n m a y a f fe c t c o nc u r re n t h yp e r t en s i on , li pi d a b no rm a li t ie s , an d o t he r c o nd it i o ns th a t oc c u r m o r e f r eq u e nt l y in t h e d i ab e ti c p op u la ti o n. 4 . R em in d a n d e nc ou r a ge p at i en ts t o a dh e re t o s c h ed u l e s f o r r ec om m e n de d l a b o r at o r y t e s t s du r i ng t h e c ou r se o f t he d ru g t he r a p y . E xa m pl es in c l u de p r o t hr om b in ti m e t es ts , l iv e r f u nc ti o n t es ts , e y e exa m i n a t io ns , a n d r e na l fu n c t i on t e s ts . A d he r en c e t o s u c h m on i to r in g pa r am et e rs wi l l a ll o w p r e v e nt i on o r ea r l y d e t ec ti o n a nd t re a tm en t o f c e r ta i n a d v e rs e d r ug e f f ec ts . B . D i s ea s e m on i t o r in g . S p e c i al i z e d m o n it o r in g fo r a s pe ci f ic d is e as e s tat e . D i s ea se - m o n it o ri n g ac t i vi t i es a r e o p ti m a ll y p e r fo rm e d a t r e gu l ar in t e r val s ( e . g ., a t s e t a pp o in tm e nt t im es ) , b u t s ho u ld at le as t be per f o r m e d e ac h t im e th e pa t i en t r e t u rn s f o r re f il l o f a di s e a s e - r el a te d m ed ic a ti o n o r s u p pl y. 1 . A fo cu s e d d is e as e -m on i t or i ng p ro g ra m i s e xt e ns i v e i n ti m e , e f fo r t , a nd p a t ie n t e d uc a ti o n. A t t hi s l e v e l, h o we v e r , t he ph a rm ac is t d o es n o t i ni t ia t e c ha ng es in p h a rm ac ol o gi c a l t h e ra pie s . Re c o m m en d at i on s f or c ha n ge s a r e r el a ye d t o t h e m e di ca l p r o v id e r , wh o t he n di r ec ts th e ph a rm ac ist c on c e r ni n g s p ec i fi c r e gi m en a d ju s tm en ts . 2 . E xa m p le s o f f o c u s e d d i s e as e -m o ni to r i ng ac ti vit i es a re th e fo ll o wi n g : a . E x te n si ve p a ti e n t e du c a t io n c o nc er n in g t h e d i se as e a n d i ts t re a tm ent , t he d i se as e -m o ni to r i ng pr o c e s s , an d t h e p ha r m a ci st ' s an d p a ti e nt ' s re sp o ns ib i li t ie s f o r f o cu se d di s e as e m on i to r in g . Ed uc a ti o n wi l l li k e l y b e ne e de d i ni t ia ll y a n d pe r i od ic a ll y d u r in g th e m on i to r in g p ro g r am . b . F oc us ed m o ni t o ri ng o f a c h r on ic di se as e wo u ld i nc l ud e p a ti en t ed uc a ti on t o e s ta b li sh th e p a ti e nt ' s de s i re d t a rg e ts o r g oa ls an d s t r at e gi es t o a tt a in the m . ( 1 ) E nc ou r a ge an d a s s is t p a ti en t s t o s et lo ng - t e rm go a ls — fo r e xa m pl e , l os e 3 0 l b o r q u i t sm ok in g . ( 2 ) E nc ou r a ge an d a s s is t p a ti en t s t o s et s h o rt - t e rm go a ls th a t a re di r ec t ed t o wa r d m e et i ng th e l o ng - t er m go a ls — f or e xa m p le , l os e 1 l b i n 1 -2 we e k s o r d ec re a s e s m o k i n g b y o ne c i ga r et te p e r d a y . c . As se s s m e n t f o r s ub j ec t i ve e vi d en c e o f i mp r ov e m e nt o r wo r se ni n g o f d i s e as e s y mp to m s .
( 1 ) Th e f re qu e nt o r c on s is t en t occ u r re n c e of c e r tai n s y m p to m s (s uc h a s ast h m a a t t ac ks , h y p og l y c em ia , c h e s t pa i n, di a r rh e a f r om u l ce r a ti ve c o li ti s ) s ho ul d b e b r o ug h t t o t h e a t te n ti on o f t he m e di c a l p r o v id e r . P.472
( 2 ) La ck of s u bj ec t i v e e v i d en c e o f e f fi c a c y (f a il u re o f p ai n c on t r ol , m in im al o r n o i m p ro ve m e n t o f n oc t ur i a ) s ho u ld al so be r ep o r te d t o th e p r es c ri be r . ( 3 ) Th e pa t ie n t 's re p o rt o f da y s of wo r k or sc ho ol m i s s ed o wi n g t o e xa c e rb a t io n o f d i se as e s y m pt om s i s a va l ua b le as se s sm e nt o f d is e as e c on t ro l o r t re a tm en t . d . A ss es s m en t f o r o b j ect i ve e vi d e nc e o r c e r ta i n i n di c e s o f d is e as e c on t rol o r t r e a t m en t . F o r e xa m p l e, a p ha r m a c i s t m a y r e v i e w a n d g ui d e a d i ab e ti c p ati e n t i n i n t er p r et a ti o n o f s el f -m on i t or e d b lo o d g lu c o s e ( SMB G ) r e c o rd s . U si n g t hes e d a ta , t h e p h a rm ac is t c an th e n a d v i s e th e p a ti e nt c o nc er n i ng t he ap pl ic a ti o n o f a p r e sc ri b ed in s u l in ad ju s tm e nt al g o ri t hm . ( 1 ) S om e d a ta m a y be pa t i en t d e ri v e d , s uc h a s SMB G , we i g h t , m e as u re m e n t o f c a lf c i rc um f e re nc e , a nd r ea din g s f r om a p ea k - f lo w m et e r . ( 2 ) S om e d a ta m a y be ph a r m a c i st in i ti a te d , s u c h a s a ph a rm ac y - b as ed lip i d m o ni t o ri ng p ro g ra m , b loo d gl uc os e t e s t in g , a n d b l oo d p r es s u r e m ea s u r em e nt s . I t s h ou l d b e n ot e d t ha t a ph a r m a c y m a y ne e d t o b e C l i n ic a l L a bo r a t o r ie s I m p r o ve me n t Ac t ( C L I A) c e rt i fi e d b ef o re pe r f o rm i ng c e r ta i n wa i ve d o r m o de r a te l y c om p le x l a b o ra t o r y pr o c e d u re s . ( 3 ) S om e d a ta m a y be ob t a in ed t h ro ug h th e p h ys i c ia n ' s o ff ic e ; a c o p y i s fo r wa r d e d t o t he ph a rm ac is t o r br ou g h t i n b y t he pa t ie n t. C . D r u g / di s ea s e m an a ge m e n t b y p r o t o c o l . Th e c om po n en t s o f t hi s f oc us e d p r a ct ic e i nc l ud e t h e f ol l owi n g : 1 . D is ea s e a nd dr u g m oni t o ri n g, in cl u di n g a s ig n ifi c a n t c om po n en t of pa t ien t e d uc a ti o n 2 . D is ea s e a nd qu al i t y - of- l i fe ou t co m e s i de n ti f ie d a n d a g re e d o n b y p at i en t, m ed ic al p r o vi de r , a n d p ha r m a c i s t 3 . A pp l ic at i on of a d r ug -d i s e as e -m a na ge m e n t p ro t oc o l, de v e l op e d as a co l la b o ra t i v e wo r k r e l at io n s h ip be t we e n p ha r m a ci s t an d m ed ic al p ro v i d e r, wh i c h el a bo r at e s s p ec if ic au t ho r i z a ti o ns or l im i ta t io ns fo r th e p h a rm ac is t ' s a ct i vi ti es . C om po n e nt s o f a d r ug - di s e as e -m a na gem e nt p ro t oc ol m a y i nc lud e th e fo ll o wi n g : a . P r oc es s b y wh i c h t he p h y s ic ia n re f e rs t h e p at ie n t to th e p h ar m ac is t b . D r ug s , d e v ic es , m ed ic a l t re a tm en t , t es t s a nd pr o c ed u re s t h at m a y b e pr e s c r ib e d, a d m i ni s te r ed , or o rd e r ed, a s a pp r op r ia t e f o r t h e tr e a tm e nt of t he he al t h p ro b le m a d d re ss e d b y th e p r o to c o l ( 1 ) D r ug in i ti a ti o n, do s a ge a dj us tm e nt an d /o r di s co n t i n ua t io n ( 2 ) S pe c i f ic l a bo r a to r y o rd e r s a nd in t er p r et a ti o n c . Li m i t ed ph y s ic al as s es s m e nt d . I nt e g ra t io n o f t h e p har m ac e ut ic a l c a r e p l an i n to t he t ot a l m e d ic al c a re p l an f o r t h e p a ti e nt e . P r ed e te r m i ne d p l an for e m e r ge n c y s e r v ic es
f . W rit t en c o m m un ic a ti on/ d oc um e nt a ti o n t o /f r om m e di c a l p r o vid e r (e . g. , ch a r t a c c es s a n d n o te en t r y )
VI. CLINICAL SKILLS AND PHARMACIST'S ROLES IN PHARMACEUTICAL CARE. Th e s ki ll s , ac t i v it i es , a nd s e r v ic es in he r e nt in th e p r o v i si on o f p ha r m a c e u tic a l c a r e i n cl ud e th e f o ll o wi n g : A. P a t i e n t a s se s sm e nt 1 . P h ysi c a l a ss es s m e n t 2 . B a r ri e rs to ad he r e nc e 3 . P s yc h os oc ia l i s s ue s B . P a t ie n t e d u ca t i on and c o un s el i n g 1 . I nt e r v ie w s k il ls 2 . C om m u ni c at i on s k i ll s ( e . g ., em pa t h y , l is t en i ng , s pe ak i ng o r wr i t i n g a t t he p a t ie n t 's le v e l o f u n de r s ta n di n g ) P.473
3 . A bi li t y t o m ot i v a te , i ns p i r e 4 . D e vel o p a nd im pl em en t a p a ti en t ed uc a ti on pla n ba s e d o n a n i n it i al e du c at i on a ss e ssm e nt 5 . I de n ti fi c at io n an d r es ol u t io n o f c om pl i an c e ba r ri e r s C . P a t ie n t - sp e ci f i c p har m a c is t ca r e pl a ns 1 . R ec o gn i ti on , p r e v e nt io n , a n d m a n ag em e nt o f d r u g i n te r ac ti o ns 2 . P ha r m a c o l og y a nd th er a p eu t ic s ( in n o va ti v e and c o n v e n ti on a l) 3 . I nt e rp r e ta t io n o f l a bo ra t o r y te s ts 4 . K no wl e d g e o f c o m m u ni t y r es o u rc es , p r o fe s s io na l re f e r ra ls 5 . C om m u ni c at i on an d r ap p o r t wi t h c o m m un i t y m ed i ca l p r o v id e rs D . D r u g - t r ea t m en t p r oto c o ls 1 . D e vel o p a nd m a in t ai n ( u p da t e ) p r ot oc o ls . 2 . F ol lo w p r o t oc ol s a s a p h a rm ac is t c li n ic ia n . 3 . Mo n i t o r a gg r eg a te a dh e r en c e t o t r ea tm e nt p rot o c o ls ( e. g . , d r ug - us e e va l ua t io ns ; D U E s ) , es pe c i al l y f o r a m a na g ed - c a r e o r h e al t h-s y s t em fa ci li t y . E . D o s ag e a d j us t me n t 1 . I de n ti f y pa t ie n ts a t ri s k f or e xa g g e ra t ed o r s u bt h e r ap eu t ic re s po ns e . 2 . A pp l y ph a rm ac ok i ne t ic p ri nc i pl es to de t e rm in e p a ti e nt - s p ec i fi c d os in g . 3 . O r d er an d i n te r p r et r el e v a n t t es ts a t co r r ec t t im e i n te r v a ls to as s e s s do s ag e a d ju s tm en t (e . g. , pl as m a d r u g c o nc e nt r a ti o ns , b loo d gl uc os e l e v e ls , b lo o d p r e s s u re m e as u re m e n ts ) . F . S e le c ti o n o f t he r a peu t i c a l t e r na t i ve s 1 . U se d ru g i n fo rm a ti o n re s ou r c e s e f fe c t i v e l y . 2 . R e vie w a n d c r i ti qu e d ru g li t er a tu r e . 3 . C on s t ru c t c o m p a ra t i ve a na l y se s t o s up p or t the r a pe u ti c d ec is io n s . G . P r e s c r ip t i ve au t h o r ity i n d e s ig n at e d p ra c ti c e s i te s o r p o si ti o ns H . P r e ve n t i ve se r vi c e s
1 . Im m u n i z at i on s 2 . S c r e en i ng s 3 . H ea l th an d we l ln es s ed u c a t io n I . M a n ag e r i al sk i l ls 1 . P la n , d i r e ct , an d im pl e m en t ph a rm ac e ut ic al - c a r e ac ti vi t ie s wi t h i n a var i e t y of p r a ct ic e e n v i r on m e n ts , s u c h as co m m un i t y p h a rm a c y , am bu la t o r y - c a r e se tt i n gs , m a na g ed or c o n t ra c t u al c a r e, ho m e - h ea l th s e r v ice s , l on g - te r m -c ar e fa ci li ti e s, i n pa t ie n t h os pi t al p ra c ti c e , an d o t he r s . 2 . Al l o c a te r es ou r c e s .
VII. PHARMACEUTICAL CARE AS THE MODEL FOR PHARMACY PRACTICE. Th e c on c e p ts , a c ti v i t ie s , a n d s e r vi ce s o f p h a rm ac e ut ic a l ca r e f o rm t he bas is f or p r o vi si on o f c l i ni c a l s er v ic es di r ec t l y to , a n d f o r th e be n ef i t o f , p at i en ts in a l l p h a rm ac y p r ac ti c e s e t ti ng s . Th es e se t t in gs in c l ude h om e -h ea l th , ho s p i ta l , a m bu l at o r y - c a r e, p ri m a ry- c a r e , co n su lt a ti o n, lo ng - t e rm - c a r e, an d c om m un i t y p h a rm ac y p r ac ti c e . W or k f l o w, st a f fi ng p at t e rn s , p r o c e ss es , a n d p ha rm a cy p r o g ra m s m i gh t d i ff e r , b u t t he c o r e a p p ro ac h t o p a ti e nt ca re r em a in s p ha r m a c e u ti ca l c a r e i n a l l s et t in gs . P.474
VIII. DOCUMENTATION OF PHARMACEUTICAL CARE. “ I f it is n ' t d oc um e nt e d, it i s n ' t do n e! ” D oc um en t a ti o n o f p h a rm ac eu t ic al c ar e is i n t eg r al to c o n ti n ui t y of c a r e , d em o ns t ra t io n o f c lin i c i an c o m p e te nc e , c om m u ni c a t io n a m on g h e al t h- c a r e p r o v id e r s , e vid e nc e o f c on t ri bu t i on s t o p a ti en t c a r e, an d r e i m b u rs em en t of p ro f es s i on al s e r v i c e s. A. P h a r m a c eu t i ca l c a r e, i nc lu d in g t h e p ha r m a c eu t ic a l ca r e p l an pr oc e ss ( C O R E , P R I ME , F A R M, o r S O A P ) , i s a s y s te m a t ic m e th o d f o r r ec o rd in g t h e p ha r m ac is t ' s e xa m i n a ti o n o f a p a ti e nt ' s ph a rm ac o th e r ap y a nd s u bs eq u en t i d en t if ic a ti on o f m e di ca t io n - re l at e d p ro b le m s . B . C o m pu t e r so f tw a r e pr o g r a m s, in m os t p ra ct ic e se t t in gs , m ai n ta i n p at ie n t d a ta a n d d r ug - p ro f il e re c o r ds . Th u s af t e r d oc um en t at i on o f t h e i ni ti a l p ha r m a c eu t ic a l c a r e p l an , pa t ie n t d at a o r d rug r e gi m e ns ar e i n cl ud e d i n s u bs eq u en t F A R M ( o r S O A P ) n o t es o n l y i f a c h a ng e oc c u r s t h at is re l e v an t to t h e th e ra p eu t ic i s s ue be in g a d d re ss e d in t he no t e. C . F o rm s t ha t s um m a r i ze p ha r m a c i s t s ' i n te r ve n tio n s us i ng a u n i fi e d c o din g s ys t e m a r e us ef u l f o r p r oc es s i ng r e im b ur s e m e n t o r bi ll i ng f o rm s , b ut t he s e fo r m s a r e no t a d e qu a te do c u m e n ta t io n o f ph a rm ac eu t ic al c a r e. Th e s e fo rm s d o n o t c om m u ni c a t e t o o th e r h ea l th p ro f es s i on a ls th e d e pt h a n d q ua l ity o f p ha r m a c i st in t e r ven ti o ns o r t h e p h a rm ac is t 's pl a n f o r o n go in g ph a rm ac eu t ic al c a re .
IX. PHARMACEUTICAL CARE: AN ONGOING PROCESS. Th e p a t ie n t p ro f i le ( da ta b as e ) i s r e vis e d a nd rea s s e s s ed ea c h ti m e a n ew d r u g is a d d ed to o r d el e te d f r om t h e m ed ic a ti on r eg im e n, a ne w d i s ea s e or c o n di tio n is
d i ag n os ed , or t he pa t ie nt u nd e r go es ot h e r c l i ni cal i nt e r ve nt io n , s uc h a s s u r g e r y . W hen t he pa t ie n t r e tu r ns t o th e p h ar m a c y o r is r ea d m i t te d to th e h e al t h s ys t em f a ci l it y, t he ph a rm ac is t us es t he pa t ie n t p r of il e , PW D T, an d F A R M ( o r S O A P ) n o te s ( m a in t ai ne d i n t h e p a ti ent p ha r m a c y c h a rt o r i n t he m e d ic al c h a rt ) as th e ba s is fo r o n g oi ng ph a rm ac is t - pa t ie n t i n te r ac t io ns .
X. IMPORTANCE OF PHARMACEUTICAL CARE IN TODAY'S PHARMACY PRACTICE A. Th e p o t e nt i al fo r me di c a t io n e r ro r s is g r o wi ng , an d o n e p r of es s i o na l g r o up m u st a ss u m e a p ri m a r y r o le in a d d re ss in g t h is i ss ue , ra t h e r t ha n v a ri ou s g r ou ps o r i n di vi d ua ls m a k i ng f ra gm e n t ed ef f o rt s . Th e ph a rm a c i s t i s t r ai ne d s p ec if ic all y t o a d d re ss th es e th e ra p eu t ic is s u es . B . Th e us e o f pr e s c ri p ti on a nd no n pr e sc ri p ti o n m e d ic a ti on s i s g r o wi n g a nd n o w c o ns ti t u te s t he p ri m a r y th e r ap e ut ic m o da l it y a v a ila b le t o h ea l th c a r e p r ac tit i o ne r s a n d p a ti e nt s . C . Th e n um be r , c om pl e xi t y , a n d p ot e nc y o f p r esc ri p t io n a nd no n p re s c r ip t ion d r ug p r o du c ts a r e i nc r ea s i n g. D . Th e n ee d f o r p h ar m a c e u t ic al c a r e se c u r es an e n d ur i ng r ol e f o r t h e p har m ac is t i n t h e U . S. he a lt hc a r e s y s te m . E v e r y e nc o un t er wi t h p at i en ts , re g a rd le ss of p r ac t ic e s e t ti ng , pr o v i de s p ha r m ac e ut ic a l c a r e . E . P h a rm ac eu t ic al - c a r e a c ti v i t ie s i n te g ra t e p ha rm ac is t s i nt o t h e h ea l th car e s ys t em o f t he fu t u re . P.475
STUDY QUESTIONS D i r e c t i on s : E a c h of t he q u es t io ns , s t at em e nt s , or i nc om p le t e s t a te m en ts c a n b e c o r re c tl y a ns we r e d o r c om p le t ed b y on e o f th e s ug g es t ed an s we r s o r p h r as es . C h o os e th e b e st an s we r . 1 . W hi c h o f th e fo l l ow in g s ta t e me n ts b es t de sc r i b es F AR M ? ( A ) c ul ti v a t io n o f a p ha rm ac is t ' s k no wl e d ge t o be t t e r s e r v e t he pu bl ic ( B ) f in d in gs , a s s es s m en t, r es o lu t io n , m o n it o r in g ( C ) f i nd in gs , as s e s s m e nt, r ec o gn i ti o n, m a na g em en t ( D ) t h e p r oc es s b y wh i c h a n i n di vi du a l p ha r m a ci st i n te r ac ts wi t h a s p e c i fi c p a ti e nt t o a t t ai n p e r ti n en t m ed ic a l in f o rm a ti o n V i e w A n s we r 1 . T h e a n sw e r i s B [ se e] . 2 . An ex am p l e o f an ex p an d ed r ol e o f t h e p ha r m ac i s t i s ( A ) c om m u ni t y le a de r . ( B ) p r ep a ra t io n o f c om p ou n d ed pr es c ri p ti o ns . ( C ) m ai n ta in i ng ad e qu a te i n v en t o r y o f or p ha n d ru g s. ( D ) t r ia g e o f p a ti e nt s . V i e w A n s we r 2 . T h e a n sw e r i s D [ se e] . 3 . W h a t is t h e m os t im p o r ta n t f oc u s o f p ha r m ac e u ti c al c a re? ( A ) p ha r m a c i s t
( B ) p a ti en t ( C ) p r es c ri pt i on ( D ) p a ti en t c h a rt V i e w A n s we r 3 . T h e a n sw e r i s B [ se e] . 4 . W h ic h o f t h e f o l low i n g s t a te me n t s r e g a r d in g ph a r ma c eu t ic a l c a r e i s t ru e ? P h a r ma c e u ti c al ca r e ( A ) u su al l y do es no t o v er l a p i nt o o t h er a re as o f he a t h c a r e . ( B ) a nd c l in ic a l p ha r m a c y a r e s yno n ym o us . ( C ) i m p li es t ha t t h e p ha rm ac is t is n o l o ng e r r es po n si bl e fo r di s p en s i n g f un c ti o ns . ( D ) i s b as ed on s t r a te gi es t o p ro v i d e c on t in uo us p a t ie n t c a r e t o a t t ai n d es i r ed o u tc om e s . V i e w A n s we r 4 . T h e a n sw e r i s D [ se e] . p h a rm ac eu t i c al ca r e 5 . E s se n t ia l c o m po n e nt s of p ha r m ac e u t ic a l c a re i nc l u de ( A ) p a ti en t - ph a rm ac is t rel a t io ns hi p , l eg i bl e p h y si c i a n o r de r s, an d a c c u ra t e d a ta c o ll ec t io n . ( B ) p ha r m a c i s t - p at i en t rel a t io ns hi p a n d wo r k u p o f d r u g t he r ap y . ( C ) a s o f t wa r e p r og r am th a t a c c es s e s m ed ic a ti on h is t o r y a n d p r om pt s t h e p h a rm ac is t c on c e r n in g qu e s t i on s t o a s k th e p a ti en t . ( D ) m ai n te n an c e of pa t ien t m e di ca t io n h is t o r y fo r a t le as t 2 ye a rs an d a foc us on a c ut e i l ln es s . V i e w A n s we r 5 . T h e a n sw e r i s B [ se ea n d] .6 . I n th e C O R E p ha r m ac o t he ra p y p l a n , w h a t d o es t he E st a n d fo r ? ( A ) e du c a t io n o f pa t ie n t o r c a r eg i v e r ( B ) e f fi c a c y i s s u es ( C ) e la b o ra t io n ( D ) e va l ua ti o n p a ra m e t e rs V i e w A n s we r 6 . T h e a n sw e r i s D [ se e] . 7 . T h e m os t i mp o r t an t r ea s o n f o r u s i n g t h e F AR M n o te i s t o ( A ) c ol le c t in f o rm a ti on f or t h e p h y s i c i an . ( B ) d oc um en t p ro bl em - s o l v i ng an d / or in t e r v en t ion s p e r fo r m e d b y t he p har m ac is t . ( C ) k ee p a lo g o f a l l d r ug i nt e r ac ti o ns . ( D ) c r ea t e a u n if o rm m e th o d o f re co r di n g p a ti en t i n f or m at io n . V i e w A n s we r 7 . T h e a n sw e r i s B [ se e] . 8 . W h ic h o f t h e f o l low i n g t o p ic s w o ul d no t be i nc l u de d in t h e a ss e ss m en t po r t io n o f th e F AR M n o t e? ( A ) r ec om m e n da t io ns m ad e to t he pa t ie n t o r c a reg i v e r ( B ) s e v er i t y , p r io r i t y , o r u r g en c y of t he pr o bl em ( C ) s ho r t - te r m a nd lo ng - te r m g o al s o f t he in t e r v ent i o n ( D ) a d di ti o na l i n fo r m a t ion t ha t i s n e ed ed t o b es t a s s e s s t h e p r ob le m V i e w A n s we r 8 . T h e a n sw e r i s A [ se e] . 9 . I m mu n iz a t io n s , s c re e ni n g s, and w e ll n es s e d u ca t i on a re e x am p le s of w h i ch cl i ni c a l s k il l ? ( A ) c om m u ni t y he a lt h o v e r v i e w ( B ) p a ti en t m e di c a ti o n ed u c a t io n a n d c o u ns el in g ( C ) p r e ven t i v e s e r v ic es ( D ) m an a ge r ia l s e r v ic es
V i e w A n s we r 9 . T h e a n sw e r i s C [ se e] . 1 0. T he ph a r m ac i s t' s r ol e in t he s e l ec t i on o f t h e r ap e u tic a l te r n a ti ve s r e qu i r es w h ic h of t h e f o ll ow i n g c l i n ic a l s k i l ls ? ( A ) r e v i e w a nd c r i ti q ue dr u g l i te r a tu r e ( B ) m ot i v a te an d i ns p ir e p a t ie n ts ( C ) p e r fo rm d ru g - us e e va l ua t io ns ( D U E s ) ( D ) k no wl e d g e o f c o m m un i t y r es ou r c e s V i e w A n s we r 1 0 . T he a nsw e r i s A [ se e] . P . 47 6
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee I V . C ] . A F A R M p r o g r es s n o te is u s e d to de sc r ib e a nd doc um e nt t he in t er v e n t io ns i n te n de d o r p ro vi d ed b y th e p h arm ac is t . Th e a c r o n ym F AR M s t a n d s f o r f in d in gs , a s s e s sm e nt , r e s ol u ti on , an d m on i to r ing a nd fo l lo w- u p . 2 . T he an sw e r is D [ s ee I I . A ]. P h a r m a c e u ti c a l c ar e ha s e v o l v e d f r om an em ph as is on p re ve n ti o n o f d r ug- r e l at e d p r o bl em s t o t h e e xp a n d ed r ol e s o f t r ia g e o f p at i en t s , t r ea tm e nt o f r ou t in e a c ut e i l ln es se s , m a n ag em e nt of c hr o ni c d is ea s e s , a nd p r i m a r y di se a s e pr e ve n tio n . 3 . T he an sw e r is B [ s ee I V . A ] . P h a r m a c e u ti c a l c ar e i s ba s ed on a c ol la b or a ti v e e f f o rt be t we e n ph a rm ac is t an d p a t ie n t. 4 . T he an sw e r is D [ s ee I . B ; I X] . Th e t e rm ph a r m ac e ut ic a l c a re de s c r ib es s p ec i fi c a c ti vi t ie s a nd se r v i c e s t hr o u gh wh i c h an in d i v id ua l p h a rm ac is t c o op e ra t es wi t h a p a ti e nt an d o t he r p ro f es s i on al s i n d e si g ni ng , i m p l em en t in g , a n d m o n it o r in g a th e ra pe u t ic p l an th a t wi ll p ro d uc e s p ec if ic t he r ap e ut ic ou t c o m es fo r th e p a ti e nt . The p at i en t p r o fi le ( da t ab as e ) i s r e v i s ed an d t h e p ot e nt i al f o r d r u g- r e la t ed p ro bl em s is re a s s es s e d e ac h t im e a n e w d r u g i s a dd ed t o o r d el e te d f ro m t he m e di c at io n re g im e n, a n e w d is ea s e or c on d it i on i s d i ag no s ed , o r th e p a tie n t u n de r go e s o th e r c li nic a l i nt e r v e nt i on (e . g ., s ur g e r y) . 5 . T he an sw e r is B [ s ee I V . A an d B] . Th e e ss en t ia l c om p on en ts o f p ha r m a c e u ti ca l c ar e a r e t h e p ha r m a ci st - p at ie n t r e l at i on sh i p a nd th e p h ar m ac is t ' s wo r k u p o f d r ug t h e ra p y . 6 . T he an sw e r is D [ s ee I V . B . 2] . Th e a c ro n y m C O R E re f er s to t he c om p on e nt s o f th e ph a rm ac o th e ra p y pl an , wh i ch is p a r t o f th e p ha r m a c i s t 's wo r k u p of d ru g t h e ra p y . C O R E s t a nd s f o r c o n di t io n ( or p a t ie n t n ee d ) , o ut c o m e (d e s i r ed f or t ha t c on d it i on ) , r eg im en ( se le c te d t o a c hi e v e t h a t o u tc om e ), an d e v a l ua t i on pa r am e te r s ( t o as s e ss ou t c o m e ac hi e vem en t ) . 7 . T he an sw e r is B [ s ee I V . C ; V II I ; I X] . Th e F A R M n o t e is th e p ha r m ac is t 's p ro g re s s no t e, d es c ri bi n g a nd do cu m en t i ng th e i n t er ve n t io ns in t en de d o r p r o v i de d b y t he ph a rm ac is t . Th is c on s ti t ut es t he p r o gr es s n o t e i n t he m e di c a l c ha r t ( i n h e al th - s y s t em f ac il it ie s ) o r in th e p h a rm ac y pa t i en t c h a rt ( in c om m u n it y p ha rm ac y o r s i te s wi t h o u t r ea d y ac c es s t o t he m e di c a l c h a rt ) . 8 . T he an sw e r is A [ s ee I V . C ] .
Th e a ss es s m en t p o r ti o n o f t he F A R M n o te s t a te s t h e p h a rm ac is t 's e v al u at io n of t he f i n di ng s . R e c o m m en da t io n s a r e m a d e t o t h e p at ie n t o r c a r eg i v e r t o re s o lve o r p r e ve n t a n ac t ua l o r po te n t ia l p r ob l em i d en t if i ed b y t h e p ha r m a c i s t. Th u s s uc h r e c om m e nd a ti on s wo u ld b e in c l ud e d i n t h e r es ol ut i o n p o rt io n of th e FA R M n o te . 9 . T he an sw e r is C [ s ee V I . H ] . I m m u ni z a t io ns , s c re e ni ng s , a nd he a lt h a n d we l l ne s s ed u c a t io n a r e e xa m pl e s o f c l in ic al s k il ls us ed in a ph a r m a c i s t ' s p r o vis i on of p r e v e n ti ve s e r vic es . 1 0 . Th e a n sw e r i s A [ s ee V I . F] . F o r ef f ec t i v e s e l ec ti o n o f t h e ra p eu t ic a l te r na t i v es , a ph a rm ac is t wo u ld us e c e r ta i n c l in ic al s k il ls , i nc l ud in g u s e o f d r ug in f o rm at i on re s ou r ce s , c o m p a ra t i v e an a l ys e s , a n d re vi e w a n d c ri t iq ue o f d ru g l i te r a tu r e.
21 Drug Information Resources P a u l F. S ou n e y C o n n i e L ee B a r ne s V a l e r ie B . C li n a r d
I. DEFINITION. D r u g in f or m at io n i s c u rr en t , c r i ti c a ll y e xa m i ne d , re l e v a nt da t a a bo u t d r ug s a n d d r ug us e i n a gi v e n p a t ie n t o r s it u at i on . A. C u r r e n t i n f o rm a t io n u s es th e m os t r e c e n t, up- t o - da t e s ou r ce s p os s i ble . B . C r i t i ca l l y e x a m i n e d in f o r m a ti o n s ho ul d m e et t h e f ol l o wi n g c ri t e ri a : 1 . Mo r e t ha n o n e s ou r c e s ho u ld be us ed wh e n a pp r o p ri a te . 2 . Th e e xt e n t o f a g re em e n t o f s o ur c es s ho u ld be d e te r m i n ed ; i f s ou r ce s do n o t a g r ee , g o od ju dg m e nt s ho ul d b e u s e d . 3 . Th e pl au s i b il i t y o f i n for m a ti o n, ba s e d o n c li n ica l c i rc um s t a nc es , s ho u ld b e de t e rm in ed . C . R e l e va n t i n fo r m a ti on m us t b e p r es en t ed in a m an n e r t ha t a p pl i es d i r ec tl y t o th e c ir c um s t an c es u n de r c o ns id e r at ion ( e .g . , p a ti en t pa r am e ter s , t h e r ap eu t ic ob je c ti v e s , al t e rn a ti ve a pp r oa c h es ) .
II. DRUG INFORMATION RESOURCES. Th e r e a re t hr e e s ou rc e s o f d ru g i n fo r m a t io n : j ou rn a ls ( pr im a r y s o u rc es ) , i n de xi n g a nd ab s tr a c t in g s e r v ic es (s ec o nd a r y s o ur c e s ) , a n d t e xt b o ok d a t ab as es ( te r t ia r y s o u rc e s ) . A. P r i m a r y s o u r c e s 1 . B e ne f i ts . J o ur n al a rt ic l es p r o v i de th e m os t c ur r e n t i n fo rm a ti o n a bo u t d r u gs an d , i de al l y , s h ou ld b e t he so u rc e f o r a ns we r i ng t he r ap e ut ic q u es t io ns . J o ur n al s e nab l e p ha r m a c i s ts to : a . K ee p a b r ea s t of p ro f es s i o na l n e ws b . L ea r n h o w a no t he r c l in i c i an ha n dl e d a p a r ti c u la r p ro b le m c . K ee p u p wi t h n e w d e ve l op m en ts in pa t ho p h ys io l og y , d ia g no s t ic ag e nt s, a n d t h e ra pe u ti c r e gi m e ns d . D is t in g ui s h us ef u l f r om us el es s o r e v en ha r m fu l th e r ap y e . E nh a nc e c o m m u ni c a t io n wi t h o t he r he a lt hc a r e p r o f es s i on al s a n d c o ns um e rs f . O b t ai n c on t in u in g e duc a ti o n c re d it s g . S ha r e o p in io ns wi t h oth e r he al t hc a re p ro f es s i on a ls th r o ug h l e tt e rs to t he e d i to r h . P r ep a re f or t he bo a rd c e r ti f ic at i on e xa m in a ti o n i n p h a rm ac ot h e ra p y, n u t ri t io n s u pp o rt , on c o log y , e tc . 2 . L im i t at i o ns . Al t ho u gh p u bl ic a ti on o f a n a r ti cl e i n a we l l - k n o wn , r e s pe c t e d j ou r na l e n ha nc es t he c r e di bi l it y o f i n for m a ti o n c o n ta i ne d i n a n a r t ic le , th is do es no t gu ar a n t ee th a t t he a r ti cl e is a cc u r at e . Ma n y a r ti c l es p o ss es s i na de q ua c i es t ha t be c o m e a pp a re n t as th e ab il i t y to e val u at e d r ug i n f or m at io n i m p r o v es .
3 . R e vi ew a r ti c le s (n a r ra t i ve r e vi ew s , s ys t e m a t i c r e vi ew s , a nd me t a a n a l ys e s ) , a r t i cl e s o f op i n i on , co r r e s po n de n ce , s pe c ia l re p o r t s. A l l m a te r ia l i nc l ud ed in a j o ur n al is n o t c on s i d er e d a p r im a r y r es ou r c e . O r i g i na l c li ni c a l t r i al s a re c o ns i de r ed p ri m a r y l it er a t u re ; ho we v e r , r e v i e w a r t ic le s , a r ti c l es of o pi nio n , c o r re s p o nd en c e, an d s pe ci a l r e po r ts a re no t . B . S e c on d a r y s o u r c e s 1 . B e ne f i ts . In d e xi n g a nd a bs t ra c ti ng s e r v ic e s a re v a l ua bl e to o l s f o r q u ick a n d s el ec t i v e s c r ee n in g o f t he pr im a r y li t e ra t ur e f o r s p ec if ic in f o rm a ti on , d a t a, c i t at i on , a n d a r ti c le s ( Ta bl e 2 1 -1 ) . P.478 I n so m e c as e s , th e s ou rc es p ro vi d e s u f f ic ie n t i nfo r m at i on to s e r ve a s r e f e re nc e s f o r a ns we r i ng d r u g i nf o rm a ti on r eq u es t s .
Table 21-1. Examples of Abstracting and Indexing Services Secondary References
Journals Indexed
Approximate Lag Time
CINAHL*
2,717
ClinAlert
150
1-6 weeks
Current Contents Connect
8000
1-6 weeks
Embase
7000
10 days
Medline/PubMed
5000
1 week
Inpharma
1800
3 weeks
International Pharmaceutical Abstracts
800
3-4 weeks
Iowa Drug Information System
340
30-60 days
Pharmaceutical News Index
—
2-8 weeks
Reactions
1800
—
3 weeks
Science Citation Index *
3700
3 months
Cumulative Index to Nursing and Allied Health Literature
2 . L im i t at i o ns . Ea c h in de xi n g o r ab s t r ac t in g s e r vi c e r e v i e ws a f in it e n u m b e r o f j o ur n al s . Th e re f o r e, r el yi ng on on l y one s e r v i ce c a n g r ea t l y h i nd e r th e t h or o ug h ne s s o f a l it e r at u r e s e a rc h . A no t h e r im p or t an t fa c t t o r e m em be r i s t h e s u bs t a nt i a l d if f e re nc e i n l ag t im e ( i . e. , th e i n te r v a l b e t wee n t h e p u bl ic a ti on o f a n a r tic l e a nd th e c i ta t io n o f t ha t a rt ic l e i n a n i nd e x) a m on g t h e a v a il a bl e s erv i c es . S e v e ra l e xa m p le s a r e gi v e n i n Ta bl e 2 1 -1 . a . S ec on d a r y s ou r c e s u s u a ll y d e sc r i be on l y a r ti c l e s a nd c l in ic al st u di es f r o m j ou r na ls . F re qu e nt ly , r e a de r s r es p on d t o , c ri t ic i z e , a nd ad d n e w i n f or m at io n to pu bl is h ed a r t ic le s a n d st u di es t hr ou g h l e tt e rs . Se r v i c e s s uc h a s Me d l in e / Pu b Me d o r t he I o wa D r ug I nf o rm a ti o n S e r v i c e g en e ra ll y d o i n cl ud e p e r ti n en t l e tt e rs t o t he ed i to r wi t hi n th e s c o pe of co v e r ag e . b . I nd e xi n g an d a bs t r ac tin g s e r vic es a re p ri m a r il y u s e d to lo c a te jo u rn a l a r t ic le s . I n g en e r al , a bs tr a c ts s h ou ld no t be us ed a s p r im a r y s ou r ce s o f i n f or m at io n be c a us e t h ey a r e ge n e ra ll y i nt e r pr e ta t i on s o f a s t ud y a nd m ay b e a m i s i n te r p re t a ti on o f i m p o r ta n t i nf o rm a ti o n. Ph a r m a c i s t s s ho ul d o b ta i n a n d e va l ua t e t he o ri gi n al a r t ic le be c a us e a bs t r ac ts m a y n ot in c l u de en o ugh i n f or m at io n to c r i ti c a ll y ev a l u a te th e s t ud y . C . T e r t ia r y s o u r c e s 1 . B e ne f i ts . a . T ex t b oo ks . G e ne r al re f e r en c e te xt b o o k s c a n p r o vi de ea s y an d c o n ven i en t a c c es s t o a br o a d s pe c t r um of r el a te d t o pi c s . Ba ck g ro u nd i n f or m at io n on dr u gs a n d d is e as es i s o f te n a v a i lab l e . A l th o ug h a te xt b o o k m i gh t a ns we r m an y d r ug- r e l at e d q ue st i on s , t he lim i ta t io ns o f t he se s o u rce s s h ou l d n ot be o v e rl oo k ed . ( 1 ) I t co u ld ta k e s e v e r al y e a r s to pu bl is h a t e xt , so i nf o rm a ti o n a va il ab l e in t e xt b o o k s m i gh t n o t i nc lud e th e m os t re ce n t d e velo p m e n ts i n th e f i el d . O t h e r re s ou rc e s s h o ul d b e us ed to up d a te or s u pp l em e nt in f o rm at i on o b t ai ne d f ro m t e xt b o ok s . ( 2 ) Th e au t ho r o f a t e xt b o o k m i g ht no t ha v e c o ndu c te d a t ho r ou g h s e a rc h o f t h e l i te r a tu r e , s o pe r t in en t da t a c ou ld ha ve b ee n o m it t ed . An au t h or al s o
m i gh t h a v e m is in t e rp r e ted t he p ri m a r y o r s ec on d ar y l i t e ra t ur e . Re f e re nc e c i ta t io ns s h ou l d b e a v a ila b le t o ve r i f y th e val id i t y a n d ac c ur ac y o f th e d a ta . b . D a ta b as e s . C om p ut e r d a ta b as es ar e c on v e n ien t , ea s y to us e, an d r e f e re nc e d . Th e s e r es our c es a re s im i la r to te xt b o o k s , bu t a r e t y p ic a ll y u p d at e d m o r e f r e qu en t l y. C o m p u te r da t ab as es a re e as y t o s e a rc h a n d a r e o f t en us e fu l r e s o u rc es for d r ug m o no g r ap hs , p i ll id e n ti f ic at i on s , d ru g i n t er a ct i on s , an d v a ri o us t h e ra p eu t ic c al c u l at i on s . A d di t io n al l y , c om pu t e r d a t ab as es m a y a dd r es s c l in ic al qu es t io n s . In som e i ns t an c e s , a P D A ve r s i on of th e da t ab as e is a v ai l ab le . E xa m p le s i nc l ud e Cl i ni c a l P h a r m a c o lo g y O n H an d , C l i ni c al Xp e r t, Le xi - C o m p O n - H a nd , a n d e P o c r at es R x. 2 . G e ne r a l c o ns i de r a t i on s wh e n e xa m i n in g a n d u s in g t e xt b o o k s a n d/ o r d a t ab as es as s o u rc es o f d r u g i nf o rm a ti on in cl u de t h e f ol l o wi n g: a . Th e au t ho r , p ub l is he r , o r bo t h: W hat a r e t h e au t h o r 's an d p u bl is he r ' s a r e as of e xp e r t is e? b . Th e y e a r o f p ub l ic at i on ( c o p y r ig h t d a te ) or la s t r e vi si o n d at e ? P.479
c . Th e e d it io n of th e te xt : I s i t t h e m o s t c u r r en t ed i t io n? d . Th e p re s e nc e o f a bi bl i og r a ph y: I f a b i bl io g r aph y i s i nc lu d ed , a r e i m po r t an t s ta t em e nt s a c c u r at e l y re f e re nc ed ? W he n we r e th e re f e re nc es p u bl is h ed ? e . Th e s c o p e o f t h e t e xt bo o k o r d a ta b as e: H o w a c c es si b le is th e i n f or m at io n ? f . A l te r na t i v e re s o u rc es th a t a r e a v a i la bl e (e . g. , pr i m ar y a nd s e co n da r y s o u rc es , o t he r re l e v an t te xt s )
III. INTERNET A. B e n e f i t s . Th e I nt e rn et e xp a n d s t he ab il i t y to se a r ch th e r ap ie s t h at ha ve b e e n r ec en t l y pu bl is h ed o r di s c us s e d i n th e m ed ia . A n I n te r ne t s e ar c h m ay b e r eq ui r e d f o r t he f ol lowi n g : c o m pa n y - s p ec i fi c in f o rm a ti o n, iss u es c u r ren t l y i n th e n e ws , al t e rn a ti v e m e di c i n e, o r U . S . g o ve rnm e nt in f o rm at i on . Th e m os t po pu l a r W eb b ro ws e r s a r e Mo z i l la F ir e fo x a n d Mi c r os o f t I nt e r ne t E xp l o r e r . A v a ri e t y of s ea r c h e ng in es , s o f t wa r e to o ls fo r s e a rc hi n g t he I n t e rn e t, ha v e b ee n d e v el o pe d . G en e ra l s ea r c h en g in e s ( A lt a V is ta , G oo g le , Ya h o o , As k , D o gp il e ) a t te m pt t o i nd e x a s m uc h of t h e I nt e r ne t a s p os s i bl e. B . L i mi t a t io n s 1 . U nl ik e i n fo r m a t io n p ub l is he d i n j o u rn al s a nd te xt b o o k s , in f o rm at i on o b t ai ne d f ro m t he In t e rne t m a y n ot be pe e r re vi ewe d o r e di t ed be f o re r e l ea se . 2 . I nf o rm a ti on r ec ei v e d fr o m t h e I n te r ne t m a y be o n l y as re l ia bl e a s t h e p e r so n wh o p os t ed it a nd t he us e rs wh o r ea d a nd co m m en t on it s c on t ent . A W eb s it e s h ou ld be e v alu a t ed b y i t s s o u rc e (a u tho r ) o f i nf o rm a ti on . Th e n a m e , l oc a ti o n, an d s p on s o rs hi p s ho ul d be di s c lo s ed . Al so , a r ep u ta b le s i t e
wi l l p r o v id e e as y a c c es s t o in f o rm at i on an d t h e ab i li t y t o g i ve f ee d ba c k . P h a r m a c i s t s s ho ul d u s e t r a di t io n al li t e ra t ur e e v a lu a t io n sk i ll s t o d e te rm i ne wh e t h e r in f o rm at i on on W eb s it e i s c le a r , c o nc is e , un b ia se d , r e le v a n t, and r e f e re nc e d . C . U s e . To o b ta in in f o rm a t i on f ro m t he I nt e rn e t , th e us e r m u s t h a ve a n a d d re ss ( re f e r re d t o a s a U R L , o r u ni f or m re s o u rc e l oc at o r ) t o t y p e in t o t he b r o ws e r , wh ic h wi l l t he n f i n d t he s i t e a ut om a ti c a l l y . Ma n y a s s oc i at io n s a nd o r g an i za ti o ns h a v e W eb s i te s t h at a re li nk ed t o ot h e r W eb p ag es . Ta bl e 21 2 p r o vid es a s e l ec ti o n o f W eb s i t es .
IV. STRATEGIES FOR EVALUATING INFORMATION REQUESTS. I t is im po r t an t t o o b ta i n a s m uc h i n fo r m a t io n a s p o s s ib l e a bo u t d ru g i n f or m at io n re q ue s t s b e fo r e be gi n ni ng a l i te r at u re s e a rc h . B o th t im e a nd m o ne y c an be lo s t do i ng a v a s t se a rc h . B el o w a re im p o rt a nt qu es t io ns t o a sk t he in qu i r er o r t o e v a l ua t e b e fo r e a m a nu al or c om pu t e ri z e d s ea r c h . A. C o n ve r s e w it h t he inq u i r e r . Be f or e s p en di n g t i m e s e a rc hi n g f o r i n f or m at io n , t a lk to th e pe r s on wh o is re q ue s t i ng t h e i n fo r m a t io n a n d a c qu i re an y n ec es s a r y ad d i ti on a l i nf o rm a ti o n. 1 . D e te r m i ne t he r ea s on f o r t he in q u i r y. F i n d ou t wh e r e th e i nq u ir e r h ea r d o r r ea d a b ou t th e d r ug . Is he o r s he ta k i n g t he m e d ic a ti on ? If so , wh y? B e c au se th e s e ar c h c a n b e do n e b y th e dr u g o r di s ea se na m e , de t er m i n e i f t h e i n qu i re r ha s a m ed ic a l c o nd i ti on . As ce r t ai ni ng t he r ea s o n fo r th e i nq ui r y h e lp s d e te r m i ne wh a t add i t io na l i n fo r m a t io n s ho ul d be p ro vi de d . F o r e xa m p l e , i f t h e i nq ui r y c o n c e r ns a f o re i gn dr u g, th e in qu i r er m i gh t as k f o r a d o m e st ic eq u i v al e nt . 2 . C l a ri f y t h e d r u g 's i de n t i f ic a t io n a n d a va i l abi l i t y. Ma k e su r e t ha t th e d r u g i n q ue s ti on is a v ai la b le an d do ub l e -c he c k in f o rm a ti o n a bo u t t he d rug , s uc h a s : a . Th e co r r e c t s pe l l in g o f t he dr u g 's na m e b . W het he r i t is a ge n e r ic o r b r a n d n am e d r u g c . W ha t p h a rm ac e u t ic a l c o mp a n y m a n u f ac t u re s t h e d r u g a nd in wh a t c o u n t r y t h e d r u g i s m a nu f ac t u re d d . W het he r th e d r ug is pr e s c r i pt i o n o r n o n p re s cr i p t i o n e . W he t he r th e d r ug is s ti l l u n de r i n ve st i g at i o n an d , i f i t is o n t h e m ar k e t , t h e le n g th o f ti m e o n t he m a rk e t f . Th e d os a ge f o rm of th e d ru g g . Th e pu r p o se of t he d ru g (i . e ., wh a t m e di c a l c on d i ti on o r s ym p t om th e d r u g i s i nt e nd ed t o a ll e v ia t e ; t hi s i n fo r m a t io n h el ps na r r o w t h e s ea rc h i f p r o du c ts wi t h s im il a r n am es a re f ou nd ) P.480
Table 21-2. Selected Web Sites
Site
URL (Web Address)
Agency for Healthcare Research and Quality
www.ahrq.gov
American Association of Colleges of Pharmacy
www.aacp.org
American Cancer Society
www.cancer.org
American Diabetes Association
www.diabetes.org
American Heart Association
www.americanheart.org
American Society of Health-System Pharmacists
www.ashp.org
Centers for Disease Control and Prevention
www.cdc.gov
Clinical Trial Results
www.clinicaltrialresults.org
Clincal Trials
www.clinicaltrials.gov
Drug Infonet
www.druginfonet.com
eMedicine
www.emedicine.com
Healthfinder
www.healthfinder.gov
Health on the Net Foundation
www.hon.ch
Mayo Clinic College of Medicine
www.mayo.edu
Medscape
www.medscape.com
MedWatch
www.fda.gov/medwatch
National Cancer Institute
www.cancer.gov
National Guideline Clearinghouse
www.guideline.gov
National Heart, Lung, and Blood Institute
www.nhlbi.nih.gov
National Institutes of Health
www.nih.gov
National Library of Medicine
www.nlm.nih.gov
Pharmaceutical Research and Manufacturers of America
www.phrma.org
PharmacyOneSource
www.pharmacyonesource.com
Pharmscope
www.pharmscope.com
RxList
www.rxlist.com
RxMed
www.rxmed.com
U.S. Department of Health and Human Services
www.os.dhhs.gov
U.S. Food and Drug Administration
www.fda.gov
WebMD
www.webmd.com
B . To i d e nt i f y o r a s se s s p r o d uc t a va il a b il i t y, c o n s id e r u s i ng t he fo l lo wi ng r e s ou r ce s ( s e e a ls o Ap pe n di x E ) . S o m e o f t h es e r e s ou r c e s a re a v a il ab l e in a n el ec t r on ic fo r m a t o r in a n I n te r ne t / In t r an e t v er s i on . 1 . F or d ru gs m a nu f ac t u re d in th e U ni t e d S t a te s , t h e f ol l o wi n g r es o ur c es a r e a vai la b le : a . T he A m e ri c a n D ru g Ind e x , up d at e d a nn u al l y
b . D r ug F ac ts an d Co mpa r i s o ns , u p da t ed m o nt h ly a n d b o un d a n nu al l y / F ac t s a n d Co m p a r is on 4. 0 (o nli n e ) c . D r ug To p ic s R ed B oo k , p e ri o di c a ll y s up pl em e nte d an d u p da t ed an nu a ll y d . P hy si c i a n 's D es k R e fer e n c e ( P D R ) , u pd a te d a nn u al l y e . A m e r ic an H os pi t al Fo rm u l a r y S e rv ic e ( A H F S ) D r u g In f o r m at i on , s u pp l em en t ed qu a r te r l y a n d u p da t ed an nu a ll y f . Ma r t i n d al e : T he C o mple t e D ru g Re f e re nc e , u pda t e d e ve r y 3 yea r s g . L ex i- D r u gs O nl i ne (L ex i - C o mp O n li n e ) h . C li n ic al P ha r m a c o lo gy i . Th o m s on H ea l th c a r e Se r i es ( Mi c r om ed e x) 2 . F or d ru gs m a nu f ac t u re d in f o re i g n c ou n t r i es , t h e f ol l o wi n g r es o ur c es a r e a vai la b le : a . Ma r t i n da l e: Th e Co mp l e t e D r u g R e fe r e nc e b . I nd ex N o m in u m c . U S P Di c ti on a ry of U ni te d S ta t es Ad o p te d Na m es ( U S A N ) a n d I n t e rn a ti o na l Dr u g N a m es d . L ex i- D r u gs In t er n a ti ona l O nl i ne ( Le x i - C o mp Onl i ne ) 3 . F or i n ve st i g at i o na l dr u g s , t h e f ol l o wi n g r es ou r c es a r e a v a i la bl e : a . Ma r t i n da l e: Th e Co mp l e t e D r u g R e fe r e nc e b . D r ug F ac ts an d Co mpa r i s o ns / Fa c ts a n d C o mpa r i s o n 4 . 0 ( on l in e ) c . Th e Pi nk S he e t p ub li s h e d b y F D C R ep o r ts d . T he N D A Pi p el in e p u bl i s h ed b y F D C Re p o rt s P.481
4 . F or o r ph a n d r u g s— t ha t is , d r ug s t h at a re us ed t o p r e v en t or t re a t a r ar e d i se as e (a f fe c ts < 20 0 ,00 0 pe o pl e i n t h e U n it e d S t a t es , s o t he co s t o f d e ve l op m e n t is no t l ik e l y t o be of fs e t b y s a l es ) a nd f o r wh i c h t h e U . S . F o od a n d D ru g Ad m i ni s tr a ti o n ( F D A ) o ff e rs as si st a nc e a n d f i na nc i al i nc e n ti ve s to s p on so r s u nd e r ta k i n g t he d e v el o pm en t o f th e d r ug s — th e fo ll o wi n g r e s ou r ce s a re a v a il ab l e: a . D r ug F ac ts a n d Co mpa r i s o ns / Fa c ts a n d C o mpa r i s o n 4 . 0 ( on l in e ) b . Th e F D A O ff ic e o f O rp h a n P r od uc t s D e v e lo pm e n t ( O O P D ) c . Th e Na t io n al In s ti tu t es o f H e al t h ( N I H ) O f fi c e o f R a re D is ea s es d . N a ti o na l O rg a ni z a t io n f o r R ar e Di s or d e rs e . Le x i - D r u gs O nl in e (L ex i - C o mp O n li n e ) 5 . F or an u nk n ow n d r u g ( i . e. , on e t h at is i n h a nd b u t n o t i de n ti fi e d ), c h em ic al an a l ys is c a n be p e rf o rm ed o r t h e d ru g c a n b e i de n ti f ie d b y p h ys ic al c h a ra c t e r is ti c s , s uc h a s c ol o r , s p ec i al m a r k in gs , a n d sh a pe . C o n su l t t h e f ol lo wi n g s ou r c es fo r h e lp : a . P D R , D ru g F a c t s a nd C o mp a r is o ns , F ac ts an d C o mp a r is o n 4 .0 ( on li n e ), D r u g To p ic s R e d B oo k , Id e n t -A - D r u g R e fe r e nc e b . I de n ti de x ( Mi c ro m e d ex ) c . Th e m an u fa c tu r e r d . A la bo r a to r y
e . Le x i - C o mp O nl in e (L ex i - D r ug I D ) f . C l in ic al P ha r m a c o l og y P r o du c t I de n ti f ic a ti on 6 . F or a n a t u ra l p ro d uc t, t h e f ol lo wi n g r es ou r ce s a r e a v a i la bl e : a . F ac ts a n d Co m p a ri s o n 4 . 0 ( o nl in e ) b . N a tu r al Me d i c i n es C om p r eh en s i v e D a ta b as e c . N at u r al S ta nd a r ds d . C om p le t e G e r m a n Com m i s s io n E Mo n og r a ph s e . N a tu r al P r od uc ts ( Le xi - C o m p O n li n e )
V. SEARCH STRATEGIES. To d e ve l op an ef f ec t i v e s e a rc h s tr a te g y f o r l oc at in g d ru g i n fo rm a ti o n l i t er a tu r e , t h e f ol lo wi n g ta c ti c s s h ou l d b e f ol lo we d a f te r d e te r m i n in g wh e th e r p r i m a r y o r s ec on da r y s ou r c es a r e d es i re d . A. D e t e r m in e wh e th e r t he q ue s t i on at ha n d is c lin i c a l o r re s ea r c h r e l at ed . D e f i n e t h e q u es t i on as s p ec if ic a ll y as po s s i bl e. A l s o, id e nt i f y a p p ro p ri a te i n de x t e r m s ( a ls o c a l le d k e y wo r d s or de s c r ip t o rs ) wi t h wh i c h t o s ea r c h f or t h e i n fo r m a t io n . B . D e t e rm in e t h e t yp e o f i n f o rm a t io n an d h ow m u c h is ne e de d (i . e. , onl y o n e f ac t , t h e m os t r ec e nt j o ur n al a rt ic l es , r e v i e w a r t ic le s , o r a c om p r eh e ns i v e d at a ba s e s ea r c h ) . C . As c e r t a i n a s m uc h in f o r m a ti o n a s p o ss i b le a b ou t th e d r ug be i ng q u es t io n ed an d t h e i n qui r e r ' s a s so c ia t i o n wi t h it . R em em b e r t ha t d a t a on a d ve r s e d ru g e f fe c ts o r d r u g i n te r ac ti o ns a r e o f te n f ra gm e nt e d a nd i n ad e qu a te l y do c u m e n t ed . S ee I V . A. 2 f o r t h e s pec i fi c d r ug in f o rm at i on th at s h ou l d b e ac q ui r ed . D ete r m in e t h e a ns we r s to the f ol l o wi ng q ue s t i on s: 1 . W ha t i s t he in d ic at i on f o r th e p r es c ri b ed dr u g? 2 . Is th e d r u g 's us e a pp ro v e d o r u na p pr o ve d? Th is in f o rm at i on c a n b e f o un d i n th e f o ll o wi n g re s o u rc es ( r em em be r to c h ec k h ow o f t e n th es e re so u rc es a r e up da t ed t o e ns u re ha v i n g t h e l at es t in f or m a t io n ) . a . Ap p r o ve d u se s o f d r ug s c an b e ch ec k e d i n : ( 1 ) A H F S D ru g I n fo r m a t io n ( 2 ) D r ug F ac ts an d Co mp a r is on s /F ac t s a nd C o mp a r is on 4 .0 (o n li n e) (3) PDR ( 4 ) U S P D r ug In f o r m at i on ( 5 ) D r ug d ex ( Mi c r o m ed ex ) ( 6 ) C li n ic al P ha r m a c o lo gy ( 7 ) D r ug I nf o r m a ti on H a nd b o ok /L ex i - D ru g s O n li n e ( L ex i - C o mp O n li n e ) b . U n ap p r o ve d u s es o f d r u gs c a n b e f ou n d i n: ( 1 ) A H F S D ru g I n fo r m a t io n ( 2 ) D r ug F ac ts an d Co mp a r is on s /F ac t s a nd C o mp a r is on 4 .0 (o n li n e) P.482
( 3 ) Ma r t i n da l e: Th e C o mp l e te D r ug R ef e r en c e ( 4 ) Me d l i ne
( 5 ) D r ug d ex ( Mi c r om ed ex) ( 6 ) I np ha r m a ( 7 ) U S P D r ug In f o r m at i on ( 8 ) C li n ic al P ha r m a c o lo gy ( 9 ) D r ug I nf o r m a ti on H a nd b o ok /L ex i - D ru g s O n li n e ( L ex i - C o mp O n li n e ) 3 . W ha t a r e t h e a ge , s e x, a nd we i g ht o f t he pa t ien t in qu es t io n ? 4 . D oe s t h e p at i en t h a v e a n y o th e r m ed ic al c o nd it i o ns o r r en al o r h ep a ti c d i se as e ? 5 . Is th e p a ti e nt t ak in g an y o t he r m e di c a t io ns ? 6 . W ha t d r ug s h as th e pa t i en t t a k e n d u ri n g t he pa s t 6 m o nt hs , an d wh a t we r e t h e d os a ge s ? 7 . D id t he pa t ie n t e xp e r ie n c e an y s ig ns or s ym p to m s o f a p os s i b le ad v e r s e d r u g r e ac ti o n? I f s o : a . H o w s e v e re wa s th e re a c t i on ? b . W hen d id t he r ea c t i on a p pe a r? c . H as th e p a ti en t (o r any m e m b e r o f t h e p at i en t 's f am il y) e xp e r i en c e d a ny a l le r g ic o r ad v e r s e r ea c t io n s t o m ed ic a ti on s i n t he p as t? d . C o ns ul t t h e f ol l o wi n g r e s ou r c e s f o r m o r e i n fo rm a ti o n: ( 1 ) Me y l e r ' s S id e Ef f ec ts o f D r ug s ( 2 ) A ge ne r a l d ru g re f e ren c e ( e .g . P D R ) ( 3 ) R e ac ti o ns ( 4 ) Me d l i ne e . Th e m a nu f ac tu r e r o f th e d ru g m a y b e a us e fu l s o u rc e f o r m i s s in g i n f or m at io n . Mo s t c om pan i es r eq ue s t f u rt h e r i nf o rm a ti o n r e ga r di n g a s us p ec t ed ad v e r s e dr u g r e a c t i on . 8 . D id t he pa t ie n t e xp e r ie n c e an y s ig ns or s ym p to m s o f a d r u g in t e ra c ti on? I f so : a . W ha t we r e t h e s p e c i fic d ru gs in qu es t io n ? b . W hat we r e t h e r es p ec t i v e do s a g es of th e d r u gs ? c . W ha t wa s t he du r a ti on o f th e ra p y? d . W hat wa s t h e l en g th of t h e c o u rs e o f a dm i ni st ra t i on ? e . W ha t a r e t h e d et a il s of t h e e ve nt s s ec on d ar y to t he su s p ec t ed r ea c t i on? f . C o ns ul t th e f o ll o wi n g re s ou r c e s f o r m or e i n fo rm a ti o n: ( 1 ) A dr u g i nt e r ac ti o ns re f e r en c e — f or e xa m pl e , D r u g In t e ra ct i on Fa c ts , H a n s te n 's D r ug I nt e ra c tio n A na ly s i s a nd Ma n a g em e n t , Ev a lu a ti on s o f D rug I n t e ra ct i on s ( E D I ) ( 2 ) A ge ne r a l d ru g re f e ren c e ( e .g . , P D R ) ( 3 ) R e ac ti o ns ( 4 ) Me d l i ne 9 . W ha t i s t he pa t ie n t 's c u r r e nt m e di c a t io n s t at us ? 1 0 . Do e s t he pa t ie n t h a ve a n y u n de r l yin g d is e as es ? 1 1 . Ho w h a s th e p a ti en t b e e n m a n ag ed s o fa r ? 1 2 . W ha t is th e s t ab il i t y o f t he dr u g? H o w i s c o m p a t ib il i t y of th e d r u g wi t h o t h e r d ru g s ?
W hat a r e t he ad m i n is t ra ti o n t ec h ni q ue s ? W ha t a re a pp r op r i at e c on t ai n er s f o r th e p r o du c t ? R e s ou r ce s a v a il a bl e wi t h t h is i n fo r m a t io n i nc l ud e a . Tr i s s el ' s H an db o ok o n I n je c ta bl e D ru gs b . K in g ' s G u i de to P a re nt e r al A d m ix t u re s c . Tr i ss el ' s St a bi li ty o f Co mp o u nd ed F or m u l at i ons D . E x p lo r e o th e r p o ss ib l e in f o r ma t i on r e so u r ce s i f n ec e ss a r y. F o r e xa m p l e , i t m a y b e u s e fu l to fi n d b ac k g r ou n d m at e r ia l i n te xt b o o k s ( te r ti ar y r e f e re nc e s ) , an d t h en s ea r c h t he jo u rn a l l it e r at u re ( p ri m a r y r e fe r e nc es ) f or m o r e cu r r en t in f or m a t io n.
VI. EVALUATING A CLINICAL STUDY. R e s ou r ce id e nt i fi c a t io n is f ol lo we d b y a c r it ic a l a s s e s s m e n t o f t h e a v a il a bl e i n f or m at io n . Th is s t ep is c r i ti c a l i n d e v el o pi n g a n a p p ro p r ia t e r es p on s e fo r t h e i n qu i re r . P.483
A. E va l u a t e t he o bj e c tive o f t h e s t ud y. D e t e r m i n e t h e a im o f th e re s e a rc h t h a t wa s p e rf o rm e d. 1 . W ha t d id t he r es ea r c he r s i n te n d t o e xa m i ne ? 2 . Is th is go a l s ta t ed c l ea r l y ( i .e . , is t he ob je c ti v e s p ec i fi c )? 3 . W as t h e r es e a rc h l im i te d to a s in gl e o b je c t i v e , o r we r e t he r e m ul t ip le d r u gs or e ff ec t s b ei ng t es t ed ? B . E va l u a te t he s ub j ec ts o f th e s t u d y. D e t e r m in e th e p r o fi l e o f t he st u dy p o p ul at i on b y as s es s i n g t h e fo ll o wi n g i n fo r m a ti o n: 1 . W er e h e al t h y s ub j ec ts o r af f ec t ed pa t ie n ts u s ed i n t he s t u d y? 2 . W er e th e s ub je c ts v olu n t ee r s ? 3 . W ha t we r e t h e c ri t e ri a f o r s el ec t in g th e s ub j ec ts ? 4 . H o w m an y s ub je c ts we r e i n c l ud e d, an d wh a t ar e t he de m o g r ap hi c s of th e s u bj ec ts ( ag e , s e x, a nd ra c e )? 5 . I f a d is e as e wa s b ei ng t r e at e d, di d a n y o f t he su b je c ts h a v e di s e as es o t h e r t ha n t h at in i ti a ll y be i ng t r ea t ed ? W ere an y a d di t io n al t re a tm en t s g i ve n ? W ere th e re an y c o n t r ai nd ic a ti o ns to th e t he r a p y? 6 . W ha t wa s t h e p at i en t s e le c t i on m e th o d a nd wh o wa s e xc l u de d f r om th e s t ud y? 7 . A p a ti e nt s e le c ti o n r ev i e w s h o ul d b e d o ne . You wi l l fi n d t ha t m os t g r o up s o f su bj ec t s a r e h om og ene o us ( i. e ., t he y a ll ha ve c om p a ra bl e c h a ra c t e ri s ti c s ) . I f a di s ea s e s ta t e is st u di ed , pa t ie n ts s h o ul d e xh i b i t s i m i la r s e ve r it y o f s y m pt om s . Re s ea r c h e rs ai m t o e li m i na t e i n te r p at i en t v a ri ab i li ty . B y s e le c ti ng pa t ie n ts wi th s i m i l ar c h a ra c te r is ti c s , r e s e a rc h er s c an a v oi d r e s ul ts th a t a r e c au s e d by i n d i v id ua l d i f fe r en c e s a m on g p a ti e nt s . S t ro n g i n di vi d ua l d i ff e r en c e s c an o bs c u r e t he r es ul t s o f t h e e xp e r i m en t . I f s t ud y in g a g r ou p o f p a ti e nt s wh o e xh i b i t s i gn i fi c a n t i nt e rpa t i en t v a ri a bi li t y is n e ce ss a r y , re s e a rc he r s m a y di v i d e t he pa t ie n ts in t o g r o up s ac c o r d in g t o th e
va r i a bl es li k e l y t o b e as s o c ia t ed wi t h re s p o ns i v ene ss t o t he r a p y . Th i s i s k n o wn as s t r at i fi c a t io n . C . E va l u a te t he a dm i nis t r a t i on o f t h e d r u g t r ea t m e nt . Fo r ea ch d ru g b e in g i n v e s t i ga t ed , d e te rm i ne th e fo ll o wi n g i n fo rm a ti o n: 1 . D e ta i l s o f t re a tm e n t wi t h t h e a ge n t b ei n g s tud i ed : a . D ai l y do s e b . F r eq ue nc y o f a dm i ni s tr a t io n c . H ou r s o f d a y wh e n a dm i ni s t e r ed d . R o ut e o f ad m i ni s tr a ti on e . S ou r c e of d ru g (i . e. , th e s u pp li e r ) f . D o sa ge f or m g . Ti m in g o f d r ug a dm i n is t r at i on in r el a ti on t o f ac t o r s a f fe c t i ng d ru g a b so r p ti on h . Me t h o ds of en s u r i ng c o m pl ia n ce i . To t a l d u ra ti o n o f t r e atm e nt 2 . O t h e r t h e r ap e u ti c m ea s u r es in ad d it i on to th e a g en t b e in g s tu d ie d D . E va l u a te t he se t t i ng o f t h e s t ud y. Tr y t o d e ter m i ne th e e n v i ro nm e n t o f t h e s t ud y a nd th e d a te s o n wh i c h t he t ri al be g an a n d e n de d . A ss es s t he f o l lo wi n g i n fo r m a t io n : 1 . P eo p le wh o m a de th e o b s e r v a t io ns ; v a ri o us p ro f es s i o na ls wh o o ff e r d i f fe r e nt an d u n iq ue pe rs p ec ti v e s b as e d o n t he i r b a c k g r o un ds an d i n te r es t s (W er e t h e s a m e pe o pl e m ak i ng ob s e r v a t io ns th ro u g ho u t t he s t u d y?) 2 . W he t he r th e s tu d y wa s do n e o n a n i np a ti e nt or o u tp a ti e nt ba si s 3 . D es c ri p ti on o f p h ys ic al s e t ti n g ( e .g . , h os p it a l, c l in ic , wa r d ) 4 . Le n gt h o f th e s t ud y ( i .e . , da t es o n wh ic h th e t r ia l be ga n an d e nd e d ) E . E va l u a te t he me t h ods a nd d es i gn o f t h e s t ud y. Th e m et h od s e ct i on o f t h e re se a rc h p a pe r e xp l a i n s h o w t h e r es ea r c h wa s co nd u c t e d. Th e s t ud y d e si g n ( i .e . , r e t ro s p ec t i ve , p ro s p ec t i v e , b li nd , c r os s o ve r ) an d t h e m et h od s u s ed to c o m p l et e t h e s tud y a r e i m p o r ta n t i n j ud gin g wh e t he r P.484 t h e s t ud y a nd th e re s u l ts a r e re li a bl e a nd va li d . Fr o m t h e s tu d y, tr y t o d e t e rm in e a ns we r s to t he f ol l o wi ng q ue s t i on s:
Figure 21-1. Parallel study design.
1 . A r e t he m e t ho ds of as s es s i n g t h e t he r ap e ut ic e f f ec ts c l ea r l y de s c r ib e d? 2 . W er e th e m et h od s s tan d a rd i z e d? a . R e t r os p ec t i ve ve r s us p r o sp e ct i ve ( 1 ) R e t r os p ec t i ve s t ud i es e v al u at e e ve n ts th a t ha ve a l re ad y o cc u r re d t o f i n d so m e c o m m on li nk am o ng th em , r eq ui r e re li an c e o n p at i en t m em o ri es a n d a cc u ra t e m e d ic al r ec o r ds , a nd a re un a bl e t o s ho w c a us e a n d e f fe ct . R e t r os p ec ti v e s t u di es a re us e fu l fo r s t ud y i n g r a re d is ea s e s ( o r e f fe c ts ) an d c a n h el p a he a lt hc a re p ro f es s i o na l d ec i de if en ou g h i n fo r m a t io n e xi s t s t o wa r r a n t p ro s p e c t i v e e xa m i na t io n o f a p ro bl e m . ( 2 ) P r o sp e ct i ve s t u di es f o l lo w i d en t i fi ed pa t ie n ts f o r wa r d in ti m e t o a ns we r a sp ec i fi c q ue s ti on . Th e y c an be ob s er v a t io n al o r e xp e r i m en t al ( i. e . , c l i ni c a l t r i al s ) . b . T r ea t me n t a l l oc a t io n ( 1 ) P a ra l l el s t u d y d es i gn i s a pr o to co l i n wh i c h t wo o r m o re pa t ie n t g r ou ps a r e s t ud i ed c o nc u rr e nt l y . Th e g r ou ps a re t re a te d id e n ti ca ll y e xc e p t fo r on e va r i a bl e , s uc h as a d r ug t h e r ap y ( F ig u re 21 - 1 ) . ( 2 ) C r o ss o ve r de s i g n m a y b e u s ed as a n a d di t ion a l c on t r ol fo r in t er p at i en t a n d i n t ra pa t ie n t v ar i ab il it y ( F i gu r e 2 1 -2 ) . In th is ty p e o f d es ig n , e ac h p a t ie n t g r ou p u nd e r go es e ac h t ype of t re a tm en t . H o we v e r , t h e s eq u en c e in wh i c h th e s u bj ec ts un d e rg o t re a tm en t i s re ve r s e d f o r o n e g r ou p . C r os so v e r d e si g n r ed uc e s t he po s s ib i li t y t ha t th e re s u l ts we re s tr o ng l y in f lu e nc ed b y t h e o r d er in wh i c h t he r apy wa s g i v e n . A n d b ec au s e b ot h g r o up s o f p a ti en ts r e c ei ve bo t h t y p es of t rea t m e n t , a n y d i ff e r en c e s in r es p on si v e n ess be t we e n t h e g r o up s as a r e s u lt o f p a ti e nt se le c ti on wi l l b e u nc o v e r ed . 3 . W er e c o n t r ol me a su re s us ed to r ed uc e va ri a tio n th a t m ig h t i nf lu e nc e th e r e s ul ts ? E xa m pl es o f s uc h c on t r ol m e t ho ds in c l ud e a . C on c ur r e nt c o n tr o ls b . S t ra t i fi c a t io n o r m a tc he d s u bg r ou p s c . A ru n -i n p h as e d . Th e pa t ie n t as hi s o r h e r o wn c o nt r o l ( i .e . , c ros s o v e r de s i g n ) e . I de n ti c a l a nc il l ar y t r e at m en t
4 . W er e c on t r ol s u s e d t o r e d uc e b ia s? E xa m p le s o f s u c h c o nt r o ls i nc l ud e a . B l in d as se s sm e n t, wh i c h m e an s t h at th e p e op l e o bs e r vin g th e p a ti en ts do no t k n o w wh o i s a s ub j ec t an d wh o is a c o n t ro l
Figure 21-2. Crossover study design.
P.485
Table 21-3. Types of Blind Studies Patient Aware of Treatment
Physician Aware of Treatment
Open label (nonblind)
[check mark]
[check mark]
Single-blind
—
[check mark]
Double-blind
—
—
Types of Blinds
b . B l i nd pa t i en t s , wh i c h m ea ns t ha t th e p a ti en t s d o no t k no w wh e t h e r t hey r e c ei v e d t h e s ub s ta nc e b e in g s tud i ed o r a pl ac eb o (d o u ble - b l i nd c om b in es th is p oi n t wi t h p o in t a a bo v e [ V I. E . 4. a ] ) ( Ta b l e 2 1 -3 ) c . R an d om a ll o ca t i on , wh i c h m e an s t h at pa t ie n ts in vo l ve d i n t he st u d y ha ve a n e ve n c h an c e o f b ei ng as s i gn e d t o e it h e r t he g ro up o f s ub je c ts re c e i v i ng th e ac ti v e d r u g o r th e g r ou p re c e i v in g a p la ce b o d . M a t c hi n g d u mm i es , wh i c h a re pl ac e bo s t ha t a r e ph ys ic al l y id en t ic al to t he ac t i ve a g e nt be i ng s t ud i ed e . C o mp a r is o n o f a pl ac e b o o r a t he r ap y t o a r eco g ni z e d s t an d a rd pr ac t ice ( p l ac eb oc o nt r o ll ed )
F . E va l u at e th e an a l ys i s o f th e s t u d y. A f t e r a s se s s i ng s p ec i fi c a re as o f t h e s t ud y s e pa r a te l y , c om pi l e t he in f o rm a ti o n t og e th e r t o de t e rm i ne wh e t he r th e t r ia l is a cc e pt a bl e a n d t he c o nc lu s io ns a re ju s t i fi e d b y de t e rm i ni ng an s we r s t o t he f ol l o wi ng q u es t io ns ( Fi g ur e 2 1 - 3 ): 1 . W er e th e s ub je c ts s ui ta b l y s e le c t e d i n r e la t io n t o t he ai m ( s ) o f t h e s tu dy ? 2 . W er e th e m et h od s o f m e as u re m e n t v a l id in r ela t i on to t he ai m ( s ) o f t h e s t ud y ? 3 . W er e th e m et h od s a de q u at el y s ta n da r di z e d ? 4 . W er e th e m et h od s s u ff i c i e nt l y s e ns i ti ve ? 5 . W as t h e d es ig n a p p rop r i at e ? 6 . W er e e n ou g h s u b je c t s e n r ol le d ? 7 . W as t h e d os ag e a p p rop r i at e ? 8 . W as t h e d u ra t io n o f t re a tm e nt ad e qu a te ? 9 . W er e c a r r y o v e r e f fe c ts a v oi d ed , o r we r e c o m pe n sa t io ns m a de f or t he m ? D i d a wa s h - o u t p e ri od e xi s t ? 1 0 . If no c o n tr o ls we r e us e d, we r e t he y u nn ec es sa r y o r o v e rl oo ke d ? 1 1 . If c o nt r o ls we r e u s e d, we r e t h e y a d eq ua t e ? 1 2 . W as t he c o m p a ra b il ity o f t r ea tm e nt g ro u ps e x a m in e d? 1 3 . A re th e d a ta ad e qu a te f o r as s es s m e n t? 1 4 . If s t a ti s t ic a l t es ts we r e n ot do n e, we r e th e y un n ec es s a r y o r o v e r l oo k ed ? 1 5 . If s t a ti s t ic a l t es ts a re r e po r te d , a ss es s t he fol l o wi n g: a . Is it c l ea r ho w t h e s t a ti s ti c a l t e st s we r e d on e ? b . W ere th e t es t s a pp r opr i a te l y us e d? c . If r es ul t s s h o w n o s ign i f ic an t d i ff e r en ce be t we e n te s t g ro u ps , we r e e n ou g h p a t ie n ts s t ud ie d (i . e. , s ta t is t ic al po we r ) ?
VII. GENERAL GUIDELINES FOR RESPONSES TO DRUG INFORMATION REQUESTS A. D o n o t g ue s s ! B . R e sp o ns es to a m e m be r o f t he pu b li c m u s t t ak e s e ve r a l e th ic a l is s u es in t o a cc o un t . P.486
Figure 21-3. Evaluation of study analysis.
P.487
1 . P at i en t p r i v ac y m us t be p r ot ec t ed . 2 . P r of es s i o na l e t hi c s m u s t b e m ai n ta in e d. 3 . Th e pa ti e n t- p h y s i c i an r e l at i on s h i p ca n no t b e b re a c h e d. 4 . R es p on s e is n o t n ec es s a r y i f t h e i nq ui r e r i n ten d s t o m is us e o r a b us e in f o rm a ti o n t h a t i s p ro v i d ed . Th e i nqu i r e r o f te n a dm i ts i n te n t o r o ff e rs cl ue s t o p o te n tia l ab us e , s uc h a s i n t h e f ol l o wi n g e xa m p l es : a . A p a ti e nt as k s h o w a c e r ta i n d ru g i s d os e d ( i .e . , ho w m uc h th e d r ug c a n be i n c re as ed , wh e n i t c an be i nc r ea se d , wh a t t he m a xi m u m d a il y d os e is ) . Th i s ki n d o f i n qu i r y s i gn a ls th a t t he pa t i en t m ig h t b e a dj us t in g h is o r h e r o wn t he r a p y . b . A pa t ie n t as k s a p ha rm ac is t to id e nt i f y a t ab let t h at is a p re s c r ip t io n p ro d uc t k n o wn f or a h ig h ra t e o f a b us e . C . O r g a ni z e in f o rm at i on b e f o re at t em pt i ng to c o m m u ni c a t e t he r es po ns e to t he i n qu i r er . R es po ns es s h ou l d b e c on c i s e an d s uc c in c t . A n ti c i pa t e a d di ti o na l q u es t io ns . D . Ta i l o r t he r es po ns e to t h e i nq u ir e r ' s b ac kg r ou nd . A ls o, c o ns i de r th e e n vi r o nm en t o f t he pr ac t ic e , i ns ti t u ti on a l p ol ic y a n d p ro c e d u re, a nd f or m u l a r y . E . Te l l t h e i nq u ir e r wh e re t he in f o rm at i on wa s fou n d . E xe r c i se c a u ti on wh e n m ak in g s t a te m e n ts s uc h a s , “ The r e ar e n o re p o rt s i n t he l i te r a tu r e .” F . U se ex t re m e c a u ti o n wh e n m ak in g s t at em e nt s s uc h a s , “ I r e c o m m en d … ” D o no t h e si t at e to re f e r c on s u m e r s t o th ei r ph ys ic ia ns . G . U s e m o re th a n a bs t rac t s t o a ns we r d r ug in f o rm a ti o n q ue s t i on s b ec au s e t he y m i gh t b e ta k e n o u t o f c on t e xt a n d d o n o t i nc lu d e a l l o f t h e d at a a v ai la b le in t he o r i gi n al ar t ic le . H . A l e rt t he in qu i r er o f a p os s i b le de l a y wh e n i t ta k es l o ng e r t h an an t ic ipa t e d t o a n s we r th e q u es ti o n.
I . A sk i f th e i n fo r m a t io n th a t i s p r o v id e d a ns we r s t h e i n qu i re r ' s q u es ti o ns . J . A s k i f th e i nq u i re r wou l d l ik e t o h a v e re p ri n ts o f a rt ic l es o r a wr i t t e n r es p on s e . P.488
STUDY QUESTIONS D i r e c t i on s : E a c h of t he n u m b e re d i t em s o r i nc om p le t e s ta t em en ts in t his se c t i on is f o l lo we d b y an s we r s o r c o m pl e ti on s o f th e s ta t em e n t . S e le c t t he on e l e t ter e d a n s we r o r c o m p l et i on tha t is be s t i n e ac h c as e. 1 . P r i ma r y l i t e r a t u r e i nc l u de s w h ic h o f t he f o llow in g ? ( A ) O r i gi n al c l in ic al t ri a ls ( B ) L e tt e rs to th e Ed i to r ( C ) S ys t em a ti c r e v i e ws ( D ) S p ec ia l re p or t s V i e w A n s we r 1 . T h e a n sw e r i s A [] .2 . W h ic h o f th e f o ll ow i ng s ta t e me n ts i s T R U E r e g a r di n g t e r t ia r y r e s o u r c e s ? ( A ) Te r t i a r y re s o u rc es inc l ud e t e xt b o o k s a n d c o m p u t e r d at a ba se s . ( B ) Te xt b o o k s t y p ic a ll y in c lu d e t he m o s t r ec en t l it e r a tu r e a nd / o r i nf o rm a tio n . ( C ) Te r t i a r y re s ou rc e s do n ot t y p ic al l y in c l ud e a b i bl i og r ap h y. ( D ) Th e c re d en t ia ls of the e di t o r o f a te r ti a r y r es o u r ce ar e no t c on s i d er e d i m p o r ta n t. V i e w A n s we r 2 . T h e a n sw e r i s A [] .3 . W h ic h o f th e f o ll ow i ng s ho u l d N O T b e d o n e w he n d e ve l o pi n g a n e f fe c ti ve s ea r c h s t ra t e g y? ( A ) D e t er m i n e i f t h e q ues t io n i s c li ni c a l o r r es ea rc h - re l at e d ( B ) I d en ti f y a pp r op r i at e s e a rc h t e rm s ( C ) D i s re g ar d o t he r m e dic a ti o ns th e p a ti en t m a y b e ta k i n g ( D ) A sc e r ta i n i f t he in q uir e r is a h ea l th c a r e p r of es si o na l V i e w A n s we r 3 . T h e a n sw e r i s C [] .4 . W h ic h o f th e f o ll ow i ng r e so u r ce s w o ul d be ap p r o p r ia t e fo r i d en t i f yi n g a d r u g ma n u f ac t u r ed i n a fo r e i gn c o un t r y? ( A ) Ma r t i n d al e : Th e C om p l e te D r ug R ef e r en c e ( B ) C l in ic a l P h ar m a c ol ogy ( C ) Tr i s s e l ' s S t ab il i t y of C o m po u nd e d F o rm ul a ti on s (D) AHFS V i e w A n s we r 4 . T h e a n sw e r i s A [] . Ma r t i n da l e : Th e C o mp l e te D r u g R e f e r e nc e Ma r t i n d a le : Th e C o mp l e te D r u g R e f er e n c e, L ex i - D r u gs I n t e r na t i o na l O nl i n e ( Le x i - C om p O n li n e ), D i c tio n a r y o f U n it e d St a t es A d o p t e d N a me s ( U S A N ) a n d I n t e rn a t io n a l D r u g N a m es . C li n i ca l P h a r m ac o l og y , T r i ss e l 's S t a bi l i ty o f Co m po u nd e d Fo r m u la t i on s , A H F S5 . W h i c h o f th e fo l l ow in g r e s o u r ce s w ou l d b e a pp r o p r i a te f o r i d en t i f yi n g t h e c a p su l e w it h t he im p r i nt c o de o f W a ts o n 4 0 5? I F a ct s a n d Co m pa r i s on 4 . 0 ( o nl i n e) I I L ex i D r ug s O n li n e ( Le x i - C om p O n li n e ) I I I M yl e r ' s S i d e E f f e ct s o f D r u g s ( A ) I an d I I on l y ( B ) I an d I I I o n l y
( C ) I I an d I I I o nl y V i e w A n s we r 5 . T h e a n sw e r i s A [] .F a ct s a n d Com p a r is o n 4 . 0 ( O n l i ne )L e x i D r u g s O n l in e (L e xi - C om p O n l in e ). 6 . W h i ch o f t h e f ol l ow i ng r es o u r ces w o ul d be ap p r o p r ia t e fo r d e te r m i ni n g th e a d ve r s e e f f ec t s o f g in k o b il o b a ? I N a t u r al M e d ic i ne s C om p r e he n s i ve Da t a ba se I I F ac t s a n d C o m pa r i son s 4 .0 ( on l i ne ) I I I N a tu r a l St a n da r d s I V C l i n ic a l P h a rm a co l og y ( A ) I an d I I on l y ( B ) I I a n d I I I o nl y ( C ) I , II , an d I I I o nl y ( D ) I I an d I V on l y V i e w A n s we r 6 . T h e a n sw e r i s C [] .F a ct s a n d Com p a r is o n 4 . 0 ( o n li n e ), N a t u r a l Me d i ci n es C o mp r e h e ns i ve D a ta b as e , Na t u r a l S t a nd a r d s, C o m p l et e G e rm a n Co mm i s si o n E Mo n o g r a p hs ,N a t u r a l P ro d uc t s (L e xi C o m p O n li n e ). 7 . W h ic h o f t h e f o l low i n g re s ou rc e s w ou l d b e a p p r op r i at e f o r d e te r m i ni n g i f Le va q u i n i s c o m pa t i bl e o r st a b l e i n D5W ? ( A ) E va l ua t io ns of D r ug In t e r ac ti o ns ( E DI ) ( B ) Tr i s s e l 's H a nd bo ok on I nj ec t ab l e D r u gs ( C ) R e d Bo ok ( D ) I n ph a rm a V i e w A n s we r 7 . T h e a n sw e r i s B [] .T r i ss e l 's H and b o o k o n I n je c t ab l e D r u g s , K i n g 's G u i d e t o Pa r e n te r a l A dm i x tu r e s, T r i ss e l's S t a b i l i ty o f C o m p o un d ed F o rm u l at io n s .8 . Wh i c h o f th e fo l low in g r es o u r ce s c a n be u s e d t o de t e rm i n e u na pp r o ve d u se s o f d r ug s ? ( A ) C l in ic a l P h ar m a c ol ogy (B) PDR ( C ) I n de x N o m i nu m ( D ) K i ng ' s G ui d e t o P a r en t e r al Ad m i xt u r e s V i e w A n s we r 8 . T h e a n sw e r i s A [] . Cl i n ic a l P h a rm a c ol o gy . K i n g 's G ui d e t o P a r e n t e ra l A dm i x tu r e s.9 . W hi c h o f th e fo l l ow in g a r e N O T i mp o r t an t w h en e va l u a t in g a c li n i ca l s tu d y? ( A ) S t ud y o bj e c t i v e ( B ) P a ti e nt de m o g r ap hi c s ( C ) D r u g a dm in is t r a ti on ( D ) N u m b e r o f a u th o rs V i e w A n s we r 9 . T h e a n sw e r i s D [] .1 0 . W hi c h o f t h e f ol l ow i ng s ta t em e n ts i s TRUE? ( A ) P r os p ec ti v e s t u di es e v a l u at e e v e n ts th a t h a ve a lr e ad y o cc u rr e d. ( B ) R e t ro s pe c t i v e s t ud ies a re us e fu l f o r e v a lu a ti ng r a re di s e a s e s . ( C ) A r un - i n p ha s e t y pi c a l l y in c r e as es v a r ia ti o n. ( D ) C r o s s o v e r d es ig n a llo ws p a ti e n ts t o u n de r g o o n l y on e t y p e o f t re a tm en t . V i e w A n s we r 1 0 . T he a nsw e r i s B [] .P . 48 9
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is A [ I I . A. 3 ] . A l l m a te r ia l i nc l ud ed in a j o ur n al is n o t c on si d er e d a p r im a r y r es ou r c e . O ri g in a l c l in ic al t ri a ls a r e c on s i de r e d p r im a r y l i te r a tu r e; ho we v e r , r e v i e w a r t ic le s, a r t ic le s o f o p in i on , c o r re s p o nd e nc e, a nd s p ec ia l re p or t s a r e n o t . 2 . T he an sw e r is A [ I I , II . C ] . Te r t i a r y r es o ur c e s i nc lu de b ot h te xt b o o k s a n d d a ta b as es . In f o rm at i on a vail a bl e i n t e xt b o o k s m a y n ot in c l u de t he m o s t r ec en t d a ta sin c e i t c ou ld t ak e se v e r a l y e a r s t o p u bl is h . A b ib li o gr a ph y an d r ef e re n c e c i ta t io ns s ho u ld be p re se n t i n b o th te xt b o o k s a n d d a ta b as es s o t h at t he r e ad e r m a y r e f er t o a sp e c i f ic re f e re nc e i f d es i re d . A d d i ti on a ll y , t he ar e as of e xp e r t is e fo r th e a u th o r a n d/ o r p u bl is he r s h ou l d b e e va l u at e d wh e n us in g a te r t ia r y r e s o u rc e. 3 . T he an sw e r is C [ V . A, V . C , V II . B , V I I . D ]. O n e sh o ul d d e te r m i ne if t h e q u es ti o n is r el a te d t o a cl in ic a l s c en a r io or is r e s ea r c h r e l at e d t o d e v e lo p a n e f fe c ti v e s e a rc h s t ra t eg y . Ap p r op r i at e i n de x t e r m s s h o ul d b e i d en t i fi ed t o as s i s t i n t he l i te r a tu r e s ea rc h . O th e r m e di c a t io ns , i nc l ud i ng he r b al p r o du c ts , a nd di s e as e s ta t es s h o ul d b e t ak e n i nto c o ns i de r a ti on . Th e b ac k g r ou nd o f t h e i n qu i re r s h ou l d b e de t e rm i ne d s o t ha t th e res p on s e c a n b e t a il o re d to t he s p ec if ic in q ui r e r. 4 . T he an sw e r is A [ I V .B . 2 ] . Ma r t i n d a le : Th e Co mp l ete D r u g R e fe r e nc e is on e r e s o u rc e t h at m a y b e us e d to i d en t i f y a d ru g m an u fa c tu r e d i n a fo r ei g n c o u nt r y. O t h e r r es o u rc es fo r i d en t i f y in g d r u gs m a nu f ac tu r e d i n a f o r ei g n c ou n tr y i nc lu d e Ma r t i n d a le : Th e Co mp l ete D r u g R e f e r en c e , L e x i - D r ug s In t e r na t io na l O nl in e (L ex i- C o mp O n li n e ), an d th e U S P D i c ti o na r y o f Un i te d St a te s Ad o pt e d N a m e s ( U S AN ) a n d I n te r na t io n al D rug N a m e s . C l i ni c al Ph a r m ac o lo gy , Tr i s s e l 's S ta bi l it y o f Co mpo u n de d F o r m ul a ti o ns , a nd A H F S d o no t c on t ai n th is t y pe o f in f o rm at i on . 5 . T he an sw e r is A [ I V .B . 5 ] . F o r an un k n o wn d r ug , the p h ys ic a l c ha r ac te r is t ic s , in cl ud i ng an im p ri nt co d e , m a y b e us ed to id e nt i f y th e dr u g i n ad di t io n t o th e u se o f s e v e ra l r es o u rc es , in c lu di n g F a c ts a n d C o mp a ri s o n 4 .0 ( O n li n e) a nd Le x i D r ugs O n li ne ( Le x i - C o mp O nli n e ). 6 . T he an sw e r is C [ I V .B . 6 ] . F o r a n at u r al pr o du c t, the f ol l o wi ng r es ou r c e s a re a va il ab l e: F ac ts an d Co mp a r is on 4 . 0 (o n li ne ) , Na t u ra l Me di c in es C o mp re h en si ve Da t a b a se , N at u ra l S ta nd ar d s , C o mp l e te G e r m a n C o m m i s s i on E Mo n o g ra ph s , a nd N a tu r a l P r od u ct s ( L ex i- C o mp O n l i ne ) . 7 . T he an sw e r is B [ V . C. 1 2 ] . Th e s t ab il i t y o f a d r ug , th e c om p at i bi li t y o f a dr ug wi t h o th e r d r ug s a nd / or a p p ro p r ia t e c o n ta i ne r s , a n d p r op e r a dm i ni s t r a ti on t ec hn i qu es a re in cl ud ed i n T r i ss el ' s Ha n db o ok o n I nj e c t a bl e D ru gs , Ki n g 's Gu i de t o P a re n te r a l A d m ix t u r es , a n d T r i ss el ' s St a bi li t y o f C omp o u n de d F o r m ul a ti o ns . 8 . T he an sw e r is A [ V . C. 2 . b ].
U n a p p ro v e d u s e s o f d r ug s c an b e f ou n d i n C l in ica l P ha r m a c o lo gy . Th is inf o r m a t io n i s n o t a v a il a bl e i n t h e PD R , I n de x N o m i nu m , o r K i n g 's G u id e t o Pa r e nt e ra l A d m i x tu r es . 9 . T he an sw e r is D [ V I .A , V I . B , V I . C ]. A c r it ic a l as s e s s m e n t o f a v a i la b le in f o rm at i on is im p o rt a nt in de v e l op in g an a p p ro p r ia t e r es p on s e . Th e s t ud y o bj e c t i v e , t he st u d y s u bj e c t s ( v i a d em o gr a p hi c s a n d i nc lu s i o n a nd e xc l us i o n c ri t e ri a ) , a nd d ru g a dm i ni s t r a ti on sh o ul d b e eva l u a te d . 1 0 . Th e a n sw e r i s B [ V I .E ] . R e t r os p ec ti v e s t u di es e va l ua t e e v e n ts th a t h a v e a l r ea d y oc c u r r ed an d a re us e fu l fo r s t ud yi n g r a r e di s ea s e s . P r o s pe c t i v e s t ud ie s f o ll ow i d e n t if i ed pa t ie n ts fo rwa r d i n ti m e t o an s we r a s pe c i f ic q u es t io n . C ro s s o v e r d es ig n a l l o ws f o r e ac h p a ti e nt gr o u p t o u n d er g o e ac h t y p e o f tr ea t m e n t . A r un - in ph as e is a c on t r ol m e as ur e u s ed t o r e du c e va r i a ti o n .
22 Adverse Drug Reaction Reporting B a r b a r a Sz ym u s i a k - M u tn i c k
I. INTRODUCTION. A d ve r s e d ru g re ac t io ns (A D R s ) a re a c au se of s ig n i fi ca n t m o r b id it y a n d m o r ta li t y i n p a t ie n ts i n a l l a re a s o f he a l th c a r e t od a y. Th e re is wi d e v a ri a ti o n i n t he c u r r e nt h e al t hc a re li t e ra t u re , b u t i t h a s b ee n e s t im a te d tha t f ro m o ne t hi r d t o a s h ig h as o n e h a l f o f A D R s a r e b e li e v ed t o b e p r e v en t ab l e. Th e I n s t i tu t e o f Me d ic in e re po r t e d i n J u l y 2 0 06 th a t a n e s t im at e d 1 . 5 m il li o n i nj u ri es oc c u r ea ch y e a r a s a re sul t of m e di ca t io n e r r o rs . B e t we e n 44 , 00 0 t o 9 8 ,0 0 0 p eop l e d ie f ro m m ed ic a ti o n e r r o rs a n n ua ll y . Me d i c at i on er ro r s k il l m o re pe op l e p e r y e a r t ha n b r e as t c an c e r , A I D S , o r m o to r ve hi c l e a c c id e nt s . Th e c os t o f m o rb i di t y and m o r t al i t y o wi n g to d ru g- r e l at e d a d ve r s e e v en t s in ho s pi ta l i z ed pa t ie n ts wa s re cen t l y es t im at e d t o b e a t l ea s t $ 3 .5 b i ll i on an nu a ll y . Th e r e a re a n es t im a te d 3 m i ll io n h o s p i ta l a dm is si o ns e ac h ye a r c a us ed b y th e m is us e o f p h a rm ac e ut ic al s . Th e suf f e r in g t h at pa t ie n ts e xp e r i en ce b e ca us e o f dr u g -r e la t ed e v e n ts c a n no t b e q u an t ifi e d .
II. DEFINITIONS. Th e t e rm s a dv e rs e d r ug r e a c t i on , a dv e rs e d r ug ev e nt , un t o wa r d d r ug r ea c t i o n, d ru g m i s a dv en t u re , s id e e f f ec t , m e d ic at i on er r o rs , m is u s e o f p ha r m a c e u ti ca ls , a n d d r ug r e l at e d p r ob l e m a r e m any t i m es u s e d i n te r ch a nge a bl y b u t d o n ot al wa ys d e sc r ib e t h e s am e s it u at i on . A. Th e N a t i o na l Co o r di na t i ng C ou nc i l f o r Me d i c ati o n Er r o r Re p or t in g a n d P r e ve n ti o n s t a te s “ A m e di c a t io n e r ro r is an y p r e v en t ab l e e ve n t th a t m a y c au s e o r lea d to i n ap p r op r ia t e m ed ic a ti on u s e o r p at i en t h a rm wh i le t he m e di c a t io n i s i n t he c o n t ro l o f t he he al t h c ar e pr o fe s s i on al s , p at i en t , o r c o nsu m e r. S uc h e v e n ts m a y b e r el a te d t o p ro f es s i on a l p ra c ti c e , h e al t h c a re pr o du c ts , p ro c ed u re s , a nd s y s t em s , in c lu di n g p r e sc ri b in g ; o r de r c om m u n ic a ti on ; p ro du c t l ab el in g ; p ac k ag in g ; a nd no m e n c l a tu r e ; c om p ou n di ng ; di s p en s i ng ; di s tr i bu t io n ; a dm in is t ra t i on ; e d uc at i on ; m on i to ri n g ; a nd u s e. ”
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B . Th e U . S . F o od an d D ru g A dm in is t ra t io n ' s ( F D A) d e fi ni t io n o f an ad ve r se d r u g e ve n t i s “ a n y ad v e r s e e ve n t a s s oc i at e d wi t h th e us e o f a d ru g i n h u m a ns , wh e t h e r o r n o t c on s i d e re d d r ug r el at e d , i nc lu d in g t h e f ol l o win g : a n a d v e rs e e v e n t o c c u r ri n g i n t h e c ou r s e o f t he us e o f a d r ug in pr o fe s s io n al p ra c ti c e ; an ad v e r s e e v en t o c c u r ri ng f r o m a d r u g o v e r do s e , wh e t he r ac c i de n ta l o r i n ten t i on al ; an ad v e r se e v ent o c c u rr i ng f r o m d r ug ab us e ; a n a d ve r s e e v e nt oc c u r r in g f r om d ru g wi t hd r a wa l ; a n d a n y s i gn i fi ca n t f ai l ur e o f e xp e c te d p h a rm ac ol o gi c a l ac t io n . ”
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C . Ad ve r s e d r u g r ea c t io n is de f in ed b y th e W orl d H ea l th O r ga n i zat i on (W HO ) a s “ o n e wh ic h i s n o xi o us and u ni n te n de d , a nd wh i c h o cc u rs at do se s n o rm al ly u s ed in m a n f o r t he p ro p h y la xi s , d i ag n os is , o r th e ra p y o f d i s e as e , o r f o r th e m od i fi c at i on of p h ys io l og ic al f un c t i on . ”
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D . Th e W HO de f in es a s id e ef f ec t o f a d ru g a s : ‘ an y u n in t en d ed ef f ec t o f a p h a rm ac e ut ic al p ro d uc t o c c u r ri n g a t d os es no r m a l l y us ed b y a pa t ie n t whi c h is r e l at e d t o t h e p ha r m a c o lo g ic al p ro p e rt i es o f th e d r u g .’
III. TYPES OF ADVERSE DRUG REACTIONS A. T yp e A 1 . Typ e A r ea c t i on s a r e e xt e n s i on s o f t h e d r ug ' s k n o wn ph a rm ac o lo g y and a r e r e s po ns ib l e f o r t he m a jo ri t y o f A D Rs . P.491
2 . Typ e A r ea c t i on s a r e u s ua ll y d os e d e pe n de n t a n d p r ed ic t ab l e b ut c a n b e th e r e s ul t o f c on c om it a nt di s e a s e s t a te s, d ru g - dr u g in t e r ac ti o ns , o r d r u g- f oo d i n t er a ct i on s . 3 . W a ys to m i ni m i z e t y pe A r ea c t i on s i nc lu d e u nd e r s t a nd in g th e p ha r m a c o l og y o f th e d r u g b ei n g p r es c r i be d , m o n i to r in g d r u gs wi t h a nar r o w t h e r ap e ut ic in d e x, an d a vo i di n g p ol y p h a rm ac y wh e n p os s i b le . B . T yp e B 1 . Typ e B r ea c t i on s i nc lud e id io s ync r a ti c r e ac ti o ns , im m u no lo g ic al o r a ll e rg i c r e a ct i on s , an d c a rc in o gen i c / t e ra t og e ni c r ea c ti o ns . 2 . Typ e B r ea c t i on s a r e u s ua ll y n o t t he r es ul t of a k n o wn p ha r m a co l og y of t h e d ru g b u t s ee m t o b e a f un c t i on o f p a ti en t s us c e p ti b il i ty . Th e y a r e r ar e l y p r e di c t a b le , a r e u s ua ll y n o t d os e d ep e nde n t , a nd s e em to c o nc e nt r a t e i n c e r t ai n b o d y s y s te m s su ch a s th e l i v e r, bl o od , s k i n , k i dn e y , a n d n e r v ou s s y s te m . 3 . Typ e B r ea c t i on s a r e u n c o m m on bu t ar e g e ne ra l l y s e ri o us an d c an be li f e t h r e at e ni ng . 4 . E xc e p t f o r i m m ed i at e h y p e r s e ns i ti v i t y r ea c t i ons , t ype B re ac t io ns us ua ll y t a ke 5 d a ys b e f or e th e p a ti en t d e m o ns t r at es h y p er s e n sit i v i t y t o a d r u g. Th e r e is n o m a xi m um t im e f o r t he oc c u r re n ce of a r e ac ti o n, bu t m o st oc c u r wi t hi n 12 we e k s of i n i ti a ti on o f t he r ap y .
IV. RECOGNITION A. D r u g s m us t al wa y s b e c on s i d e re d a s a p os si b le c a us e of di se as e o r s y m p to m s t h a t a r e am o ng a p a ti en t' s l is t o f c om pl a in ts . C om p le t e d r ug hi s t o ri es , inc l ud in g n o n pr es c ri p ti o n d r ug s , m u s t a ls o b e c a rr i ed ou t . B . R e co g ni t io n i s o ft e n s u b je c ti ve , a n d i t i s n ot alwa y s p o s s i bl e t o d em o ns t r a t e s t r on g c au s a l it y b e t we e n t h e d r ug an d t h e o c c ur re n c e . 1 . S e ve ra l f ac t o rs m a y he l p i n a s s es si ng th e de te r m in a ti on o f ca us a li t y . a . D id t he pa t ie n t ac t ua l ly i n g es t t h e d r ug i n qu es t i o n? b . D i d t he on s e t of s y m pt o m s occ u r a f te r t he dr ug wa s t ak en ? c . W ha t is t he ti m e in t e rv a l b et we e n t ak in g t h e dr u g an d t h e o ns et o f s y m p t om s ? d . D i d t he s y m p to m s re s o l v e o r im p ro v e a ft e r t h e d r u g wa s s t o pp e d o r t h e d os e d e c re as e d? e . D id t he s y m p to m s re oc c u r a ft e r t h e d ru g wa s re i n tr o du ce d ? f . D i d d r ug - d ru g i n te r ac t io n s c o n t ri b ut e to th e s y m p to m s ? g . W ere th e d r ug s m ea s u r e d i n “ t o xi c le v e ls ” i n th e pa t ie n t 's s e r um ? h . H as th is r ea c ti on be en p r e v io us l y s e en wi t h us e o f th e d r u g? i . W hat i s t h e p er s o n al exp e r i e n c e o f t he c l in ic i an wi t h p re vi o us u se o f t he d r ug an d r e a c t i on s s e c o n da r y t o th e d ru g?
2 . N om o gr am s h a v e b e en d e v el o pe d t o a i d i n t he a ss es s m en t of c a us al i t y.
V. SURVEILLANCE PROGRAMS. P h a r m a c i s t s a s we l l as al l he al t hc a re p ro f es s i on al s s ho u ld ta ke an ac t i ve r o l e i n m o ni t o ri ng , re p o rt i ng , a nd t r en d in g A D R i nf o rm a tio n . So m e o f t he ac ti v i t ies in v o l v e d i n a co nc u r r en t a n d o ng oi n g A D R s ur ve i ll an c e p rog r a m a t a n i ns ti t u ti on a l le v e l i n cl ud e th e f o ll o wi n g c om p on e nt s : A. P h a r m ac y d ep a rt m en ts s h ou l d t ak e t h e l ea d i n t h e c ol le c ti on o f i nf o rm at i o n a nd s h ou l d s u bm i t a ll r e v ie ws an d re p o rt s t o t h e p ha rm ac y a n d t he r ap e ut ic s c o m m i t te es f o r r e vie w a n d e v a l ua t ion . 1 . E nc ou r a ge al l h ea l th c a r e pr o fe s s i on al s t o b e in v o l v e d i n re po r t in g . 2 . Mo n i t o r p at i en ts wh o a r e us in g h ig h - ri sk ag e nts . 3 . R e vie w p a t i en ts wh o h a v e r ec ei ve d “a n ti do t e ”- t y p e d ru gs . 4 . N o ti f y p re s c r ib e rs of s u s pe c t e d A D R s , a nd en c o u r ag e th o ro u gh do c u m en t a ti o n o f t h e d es c ri p ti o n o f t h e r ea c ti o n as we l l a s t h e o utc om e i n p a ti e nt s ' m ed ic al r ec o rd s . P.492
5 . R ep o r t a pp r o pr i at e l y id e n ti f ie d A D Rs to th e F DA . 6 . D e vel o p t h e us e o f p ha r m ac y c o m p u te r s y s t em s t o t r ack A D R s . B . E va l ua t io n o f th e c aus es o f A D R s s ho u ld be c a r r i ed ou t . A D R r e po r t i nf o r m a t io n s h ou l d b e us e d f o r e du c a t i on al pu r p os es a n d i den t i fi ca t io n o f d r u g us e a nd m e di ca t io n u s e p ro c e s s es t o p re v e n t f u r th e r o c c ur r e nc e s o f s u c h r ea c ti ons . A D R r e p o rt i ng in f o rm at i on s ho u ld be in c or p o ra t ed in to i ns ti t ut i on a l r is k m a n ag e m e n t p r o g ra m s .
VI. REPORTING TO THE FDA. Th r e e o f t he f i v e m a j or c e n t e rs a t th e F D A a re inv o l v e d wi t h e val ua t in g the sa f e t y a n d e f fi c a c y of d ru gs . The l ar g es t c en t e r is t he Ce n t e r f o r D r u g E va l ua t ion a nd R e s ea r ch ( C D E R ) , wh ic h o v e r s e es bo t h p r es cr i pt io n an d n o np r es c r i pt i on —o v e r - t he c o un t e r ( O TC ) — d r u gs . In 2 00 2 , C D E R es t ab l is he d th e Ad ve r se E ve n ts Re p o r ti ng S ys t e m ( A E R S ) , a c om pu t e ri z e d da t a b as e d es ign e d t o s up p o rt t he F D A 's p o st m a r k e t in g s a fe t y p rog r a m f o r d r ug s a nd th e r ap e u ti c b io lo g ic p r o du ct s . A n n ua ll y , t h e A E R S r ec e i v es a b ou t 4 7 0, 0 00 r ep o rt s o f a d v er s e e xp e r i e nc es po ss ib l y a ss o ci at e d wi t h d ru g s . Th e C en t e r f o r B i ol og ic a l E v a l u a ti on an d R es ea r ch ( C B E R ) e n su r es th e s a fe t y an d ef f i c a c y o f bl oo d p r o du c t s , v a cc i ne s , al l er g en ic s , bi o lo g ic al t h e r ap eu t ic s , ge n e t he r ap y , m ed ic al de vi c es a n d t e s ts , xe n o t r a ns pl a nt a ti on p r o du c ts , a nd ba nk e d h um a n t is s u e a n d c e ll u la r p r o d u c ts . Th e C e nt e r f o r F o od S a f e t y an d A p pl i ed N ut r it i o n ( C F S A N ) e s t a bl is h ed t he C F S A N Ad v e r se E ve n ts R e p o r ti ng S y s te m ( C A ER S ) i n 2 0 02 . Th e C A E R S p r o vi de s a m on i to r in g sy s t e m t o i d en t i f y p o te n ti a ll y s e r iou s p r o bl em s s e co n da r y to n on - F D A -a p p ro ve d h e rb s , m i ne r al s , v i t am in s , di e tar y s u pp l em en ts , an d o t he r s u bs t an c e s . A. Th e n a t i on al V ac c i ne Ad ve r s e E ve n t R e p o r tin g S ys t e m ( V A E R S ) i s c o ad m i n is te r ed b y th e FD A a n d t he C e nt e rs fo r D i s ea se C o nt r ol an d P reve n t i on ( C D C ) . Mo r e t h a n 1 0 m i lli o n v acc i ne s a r e g i v en to c hi l dr e n a nd m a n y m i ll ion m o r e
d o se s t o a d ul ts ea c h y e ar . A l th o ug h v acc i ne s p r ote c t m an y p eo p le f ro m d an g e ro us d i se as es , th e y do ha v e th e po t en t ia l t o c au se a dve r s e e f f ec ts . 1 . Th e N at i on al C hi l dh o od V ac c i n e I nj u r y Ac t ( N CV I A ) r eq u i re s h ea l th p ro fe ss i on a ls t o r ep o r t a . A d ve rs e e v e n ts a f te r th e ad m i ni s t ra t io n o f v ac c i ne s sp e c i fi e d i n t he ac t, a s d e sc r ib ed in t he “ R ep o rta b le E v e n ts Ta bl e , ” wi t h in t he sp ec i fi ed t im e p er io d ( a v a i la b le at ww w. v a e r s .h h s . g o v/ o r 1- 8 00 - 82 2 - 79 6 7 ) b . A n y e v en t l is t ed in t he m a n uf ac t u re r ' s p ac ka ge i ns e rt as a co n t ra in d ica t i on to s u bs eq u en t d os e s o f t he v a c c i ne 2 . I n 1 99 0 , V A E R S wa s s e t u p t o re ce i ve a ll r ep or t s o f s us p ec t ed ad v e r s e e v e n ts c a us ed b y an y U . S . l ic e ns e d v a c c i ne ( Fi gu r e 2 2 -1) . 3 . Th e V A E R S d ep e nd s o n v o lu n ta r y r e po r ti n g b y h e al t h p r of es s i o na ls to : a . I de n ti f y r ar e ad v e rs e re a c t i on s n ot de t ec t ed in p r e li ce ns i ng s t ud i es b . Mo n i t o r f o r i nc r ea s e s i n al r ea d y k n o wn r ea c ti on s c . Id e nt i f y ri s k fa c t o rs o r p r e e xi s ti n g c o n di t io ns th a t p r om o te r ea ct i on s d . I de n ti f y pa r t ic ul a r v ac c i ne lo ts wi t h un us u al l y h i gh r a te s o r u nu s ua l t y pe s o f e v e n ts B . M ed W a tc h , t he F D A ' s Me d i c a l P r od u c t s R e po rt i n g P r og r am es t ab li s h e d i n 1 9 93 , i s a vo lu n ta r y s y s te m f o r h e al t hc a re pr o v i de r s ( F ig u r e 2 2 -2 ) . Ho we v e r , m a nu f ac tu r e rs an d d is t r ib u t o rs o f F D A -a pp r o ve d d r u gs , b i ol og ic s , r ad i at i on - e m i t ti ng d e vi ce s, s p ec i al nu t ri t io na l pr o du c ts , d ie t a r y s up pl e m e n ts , i n fa n t f o rm ul as , a n d d e vi ce s a r e m a n da t ed to r e p or t pr o bl em s t o t h e FD A . Th e g oa ls of th e p r og r a m a re t o in c re as e a wa r e n es s of r e po r t in g o f m ed ic a l- p ro d u c t - in du c e d di s e as es a n d t h e i m po r t an c e of r ep o r ti ng , t o c l a ri f y wh a t s h ou l d b e r e p or t ed , to m a ke re p o rti n g a s e a s y a s p os s i b le , a n d t o p r o v i de f ee db a c k t o h e alt h p ro f es s i on a ls . 1 . I mp o r t an c e o f re p o r ti n g a . Th e i n c i de nc e o f A D Rs oc c u r s a t a hi gh r at e i n h e al t h ca r e t o da y. ( 1 ) G e ne r al l y , it is re p or te d th a t 3 % -1 1 % o f a ll hos p it a l a dm is s i on s c an be a t t r ib u ta bl e to A D R s , al th o u gh s om e s t ud ie s r e po r t th e fi gu r e t o b e a s h ig h as 2 9 %. ( 2 ) Th e li k e li h oo d t h at a p a t ie n t wi l l e xp e r ie nc e an A D R wh i l e h os pi t al i z e d i s r e p o rt e d i n t he li t e ra t u re t o be i n a r an g e f r om 5% - 2 5% . P.493
Figure 22-1. VAERS form for reporting possible adverse drug reactions.
P.494
Figure 22-2. Form for reporting possible adverse drug reactions to the FDA Medical Products Reporting Program.
b . P r e ven t io n o f A D Rs is a n i m p o r ta n t s t ra t eg y i n h e al t h c a r e . I t h as be e n e s ti m a t ed t h a t a t l e as t o ne th i r d o f a l l A D R s m a y be p re v e n ta b le . It h as b e en fu r t he r n o t ed t h a t p r e v en t ab l e A D R s te n d t o b e th e m os t c os tly t o t r ea t a n d ca us e th e g r e a te s t d e g re e o f pa t ie n t m o r bi di t y . ( 1 ) F ut u re A D R s c an be p r e v e n te d i n i nd i v i du al pa t i en ts b y c a r ef u l a nd c on s is te n t d o cu m e n ta t io n i n p a ti e nt r e c o r ds . ( 2 ) A pr o g ra m t ha t t ra c k s A D R s c an he lp di s c o v er p r e v io us l y u ni de n ti f ie d t r e n ds . Th e s e tr e nd s c an be us ed wi t h i n t he in s ti t ut i on to d e v e lo p p r og r am s o f p ro s pe c t i v e i n t er ve n t io n P.495 t o p re ve n t r e oc c u r r en c e o f t he re ac t io n i n th e p a ti e n t p op ul a ti o ns th a t a r e a t s im il a r r i sk .
c . R ec og n it i on of p re v i ous l y un d is c o v e r ed A D R s at t r i bu t ab le t o a d r u g is pa r t ic ul a r l y t r u e i n t h e c a s e o f n e wl y m a rk et e d p r od uc t s . ( 1 ) A lt h ou g h c l i ni c a l t r ia ls a re ge n e ra ll y e f fe c t i ve i n as s es si n g e f fi c a c y and r is k t o b e n ef i t r a ti o , i nh e re n t l im i ta t io ns e xi s t i n p r em a rk e ti n g t r ia ls . ( a ) Th e t ri al s a r e u s u al l y r e la t i v el y s ho r t i n d u ra t io n an d d o n o t e f fe c t i ve l y m im ic th e e xp o s u r e p a ti e nt s wo u l d e xp e r i e nc e i f us in g t h e dr u g as a c h r on ic a ll y a dm i n is t er e d a g e nt . ( b ) D r u g- d r ug in t er a c t io ns an d u s e in pa t ie n ts wi th c o nc o m i ta n t d is e as e s ta t es m a y n o t b e te s t e d f o r i n t he s e t r ia ls . ( c ) Th e s m a l l s i z e of t he t r i al s ( us u al l y 10 00 - 3 500 i nd i vid u al s ) is in s u f fi c ie n t to d e t ec t r a r el y oc c u r r in g ad v e r s e r e ac ti o ns . ( d ) R ac i al an d e t hn ic g rou p s m a y n o t b e p a rt ic i pat i n g i n t he sa m e nu m b e rs as r e p r es en t ed in th e ge ne ra l po pu l at i on . d . P r om p t r ec al l i n c as es o f pr o du c t p ro b le m s a r e a c c om pl is h ed wh e n th e Me dW a tc h P r o g r am i s u s e d t o re p ort p r od uc t p r o bl em s o r d evi c e d e fe c ts . 2 . W ha t sh o ul d be r e por t e d ? a . A D R s t ha t ar e s e ri o us , e v e n i f c au s a l it y i s n ot p r o ve n , i nc lu di n g ( 1 ) A pa ti e nt ' s de a th th a t i s s us pe c t e d o f b ei n g a d i r ec t o u tc om e o f a n A DR ( 2 ) A l i fe - t h re a te ni n g e v e n t ( 3 ) A n i ni t ia l o r pr o lo n ged h os pi t al i za ti on ( 4 ) A s i gn if ic a nt , pe r s i s te n t , o r p e rm a ne n t ch a nge o r d is a bi li t y/ in c ap ac i t y ( 5 ) A c o ng en i ta l a n om al y ( i nc lu d in g t h os e o cc u rr in g in a f e tu s ) ( 6 ) O t he r p ro bl e m s t h at a r e n ' t l is t ed i n th e m an u fa c tu r e r ' s p ac k a ge in s e r t a s a k n o wn s i de e ff ec t b . Ma l f u nc t io ni n g m ed ic a l de v i c e s s uc h as he a r t v a l v e s , l a te x g l o ve s , di a ly s i s m ac h in es , a n d v en t il at o rs an d p r o bl em s wi t h nu t ri t i on al p ro d uc ts c . P ro d uc t p r ob l em s t ha t c an r es ul t i n c om p ro m i se d s a fe t y o r q u al it y, i nc lu d in g p r o du c t c o n ta m i n at i on , m is l ab el i ng , u nc l ea r la bel i n g , po o r p ac k a gi n g, po te n c y p r o bl em s , a nd qu es t io n ab l e s ta b il i t y d . C o un t e rf ei t o r s u s p ec te d c o un t e rf e it d ru gs e . A d ve rs e e v e n ts wi t h fo o d , h e rb s , v i t am i n s , c os m e t ic s , o r d ie t a r y s up p le m en ts , a l t ho ug h C A E R S i s t he pr e f e re d re p o rt in g s y s t em f . A d ve rs e e v e n ts o wi n g t o bl o od p ro du c ts , a ll e rge n ic s, ge n e t he r a p y , h um a n t is s u e a n d c el lu l a r p r od uc ts , and xe n o t r a ns pl a nt a ti on p ro d uc ts g . Me d i c at i on er r o rs 3 . C o n fi d en t i al i t y o f b o th t he r ep o r te r an d t h e pa t i en ts wh o s e ca s e s a r e r e p o rt e d a r e s u bs ta n ti a ll y p ro t ec te d b y th e F D A . 4 . R ep o r ti n g o f p r ob l em s wi t h O TC m e d ic at i on s ar e r eq u i re d wh e n t he p rod u ct ha s b e e n m a r k e t ed wi t h a new d r u g a pp li ca t io n ( N D A) , i n c lu di n g d r ug s f o rm e rl y m a rk e te d a s p r es c r i pt i on- o n l y dr u gs . O TC p r od uc t s m a rk e te d wi t ho u t a n ND A d o n o t r e q ui r e re po r t in g , b ut r ep o r ti n g i s st r o ng l y en c o ur a g ed . A pp r o v al of t he FD A i s n o t r e q ui r e d f o r t he m a rk e ti ng o f n on p r esc r i pt io n he rb s , m in e ra ls , vi ta m i ns , di e t ar y s u pp l em en ts , an d o t he r s u bs ta n c e s . B ec au s e t he F D A d oe s n ot ap p r o v e th e se s u bs ta n c e s , ef f ic ac y a nd s a fe t y do no t ha v e to be d em o ns t ra t ed , no r i s i t m a nd a te d t o r ep o r t p ro b le m s to th e F D A .
5 . R ep o r ti n g t o m an u fa c tu r e rs is no t d es c ri b ed in t h e F D A 's gu id e li ne s , a lth o u gh a s ec t io n o f th e Me dW atc h f o rm c a n b e c he c k ed o ff t o i n fo r m t h e F D A th a t a c op y o f t h e re p or t ha s b ee n f o r wa r d ed t o t he m a nu f ac t ure r b y th e re p o rt e r . C . I n f o rm a t io n on p r e vio u s l y r e p o r t e d e ve n t s 1 . Th e F D A W eb s i t e p rov i d e s o n -l in e s a fe t y in f o rm a ti o n a t w w w. f d a . g o v / m e d wa t c h /s a fe t y . h tm g a th e re d f rom ap p r o xi m at e l y 2 5 ,0 0 0 r e p o rt s t h at a r e s u bm it t ed ea c h y e a r . 2 . C li n ic al l y im po r t an t p ro d uc t s a fe t y al e r ts a r e av a i l ab l e vi a a n a u t om at ed e -m a il m es s ag ed e li v e r y s y s t em f r om ww w. f d a . g o v / m e d wa t c h / el is t . ht m . P.496
3 . F D A a l er t s a ls o a pp e ar o n ww w. P h a r m ac is t .c om , a j oi nt v e n tu r e o f t h e A m e ri c an P h a r m a c i s t As s o c i a ti o n a n d t h e N a ti o na l As s o ci at i o n o f B o a rd s o f P h a rm ac y .
VII. American Society of Health-Systems Pharmacists (ASHP) Guidelines d e f in e c r it e ri a fo r c la s s i fy i n g an A D R as s ig n if ic an t . Th e y en c o u r ag e r e por t i ng o f s e r io us or u ne xp e c t ed AD R s t o t h e F D A , t h e m a nu f ac t u re r , o r bo t h.
VIII. Joint Commission on Accreditation of Healthcare Organizations (JCAHO) r e q ui r em e nt s f o r a c c r ed it a t io n d es c ri b e t he ne e d f o r ea ch he a lt hc a r e o rg an i za t io n t o m o ni t o r f o r a d v e rs e e v e nt s in v o l vin g d r u gs a n d de v i c es i n a co n ti nu a l, c o ll a bo r a ti ve f a sh i on .
IX. United States Pharmacopeia (USP). Me d i c a t io n Er r o rs R ep o rt i n g P r og r am a t ww w. u s p . o r g /h q i/ p at i en t Sa f e t y /m e r / a nd th e U S P - I n s t i tu t e f o r Sa f e M e d ic a ti on P r ac ti c es (I S M P ) Me d i c a ti on E r r o rs Rep o r ti n g P r o g r am a t ht t ps : // w w w. i s m p . o rg / o rd e r fo rm s / re por t e r r o rt o I S MP . a s p a re t wo p r o g ra m s i n v o l v ed in c o lle c ti o n o f m ed ic a ti on e r ror d a ta .
X. FURTHER INFORMATION A. I n f o r m a t io n a b ou t t h e Me dW a tc h p r og r am c a n b e ob t ai n ed b y p h on e a t 1 - 8 00 F D A - 1 0 88 an d a t ww w. f d a . g o v / Me d wa t c h / . B . I n fo r m a t io n a b ou t V AE R S c an be ob t ai n ed b y p h o ne at 1 -8 00 - 8 22 - 79 67 a nd at w w w. f d a . g o v / c b e r / v ae r s /v a e r s .h t m . C . I n fo r m a t io n a b ou t re po r t in g to th e C F S A N p r og r a m c a n b e o b ta i ne d b y p h on e a t 3 0 1 -4 3 6 -2 40 5 o r a t ww w . c fs a n. f da . go v . D . F u r th e r i nf o rm a ti o n ab o u t t he F D A ' s r e po r ti n g s y s te m s an d p r og r am s , s uc h a s C D E R , c an be f ou nd on th e F D A 's W eb s i te ( ww w . f d a .g o v) . P.497
STUDY QUESTIONS
D i r e c t i on s : E a c h of t he q u es t io ns , s t at em e nt s , or i nc om p le t e s t a te m en ts c a n b e c o r re c tl y a ns we r e d o r c om p le t ed b y on e o f th e s ug g es t ed an s we r s o r p h r as es . C h o os e th e b e st an s we r . 1 . T he ph r a se “ o n e w h ic h i s n ox i o us an d un i n te n d ed , an d w h ic h o c cur s a t d o s es n o rm a ll y u s e d i n m a n f o r t he p r op h yl a x i s , d ia g no s is , o r t h e r apy o f d i s ea s e, o r fo r t h e m odi f i c a ti o n o f ph ys i o l o g i ca l f u nc t i on ,” d es c r ib e s ( A ) a s i de ef f ec t . ( B ) a n a d v e rs e d r ug r ea c t i o n. ( C ) a n a d v e rs e d r ug e v en t . ( D ) a m e di c a t io n e r r o r. V i e w A n s we r 1 . T h e a n sw e r i s B [ se e] . 2 . T yp e A r e a c ti o n s a r e c h a r ac t e r iz e d b y w h i c h o f t he f o ll ow i n g? ( A ) i di os y n c ra t ic re ac t ion s ( B ) a fu nc t io n o f p a ti e nt s us c ep ti b il i t y ( C ) c au s e d b y d r ug - d ru g i n te r ac t io ns ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 2 . T h e a n sw e r i s C [ se e] . 3 . T h e M ed W a t ch f o rm i s n o t t h e a p p r o p r ia t e f o r m t o r epo r t w h i c h o f th e fo l l ow in g e ve n ts ? ( A ) a vac c i n e e v e nt de s c r i b ed in th e Va c c in e Ad ve r s e E ve n t R e po r t in g S ys t em ( V A E R S ) “ R e po r t ab le E v e n ts Ta b le ” ( B ) a s us p ec te d c ou n t er fe i t d r u g ( C ) a m a lf u nc ti o ni n g v e nt i l at o r ( D ) a d ru g t h at is c o nt ain e d i n a pa ck ag e wi t h u nc l ea r l a be l in g ( E ) N o ne o f t he ab o v e V i e w A n s we r 3 . T h e a n sw e r i s A [ se e] . 4 . P re ve nt a b l e a d ve r se d r ug r e a c t io n s ( AD R s ) ( A ) g en e r al l y di s p la y m ild s y m p t om s . ( B ) a r e a l wa y s ea s i l y re c o g ni z e d . ( C ) a r e p r ob l em s t ha t a re e as il y m e d ic al l y m a nag e d . ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 4 . T h e a n sw e r i s E [s e e] . 5 . R e p o r tin g p r o bl e ms w i t h vi t a mi n s t o t h e F D A i s r e qu i r e d b y l a w i n w h ic h o f t he fo l l ow i ng s it u a t io n s? ( A ) wh e n t he p ro bl em is d i s c o v e re d b y t he co ns um e r ( B ) wh e n s a f et y a nd e ff ic a c y ha ve b ee n p r o v en b y m an u fa c tu r e rs to th e F D A ( C ) wh e n a h e al t hc a re pro f es s i o na l d is c o ve r s t he p r o bl em ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 5 . T h e a n sw e r i s E [s e e] . P . 49 8
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is B [ s ee I I . C ] .
Th i s is th e d e fi ni t io n fr om t he W HO . 2 . T he an sw e r is C [ s ee I I I . A. 2 ] . Typ e A r e ac t io ns c a n b e c a us ed b y dr u g -d r ug in t er a c ti o ns . I di os y n c ra t ic r ea c ti o ns a n d re ac t io ns c a us ed b y p a ti e nt s u s c ep t ib il i t y are g en e ra l l y i n th e c la s s ifi c at i on of Typ e B r e ac t io ns . 3 . T he an sw e r is A [ s ee V I . A . 1] . A l l th e o t he r s a r e r ep o r ta b le on t he Me dW atc h f or m . Th e Na t io n al C hi ld h oo d V a cc i ne In j u r y Ac t r e qu i re s th e u se of a V A E R S fo r m t o re p o rt v ac c i n e - re la t e d i n ju r i es . 4 . T he an sw e r is E [ s e e V I . B . 1] . P r e ve n t ab le A D R s c a n be t he c a us e o f s e ri o us m e d ic al p ro b le m s th a t r equ i r e i n t en si ve m e di c a l c a re . A l t h ou gh s o m e p re v e n tab l e A D Rs m a y ap p ea r obvi o u s o n r e v i e w o f a p a ti en t ' s m ed i c a t io n h is t o r y, t hi s i s no t al wa ys t h e c a s e. 5 . T he an sw e r is E [ s e e V I . B . 4] . Ma r k e t i n g o f t he s e p ro d uc t s d oe s n ot de p en d o n th e m a nu f ac t ur e rs p ro v i ng e f fi c a c y a n d s af e t y of t he pr o du c t s . No la w r e q u ir e s r ep o rt i n g o f s ub s e qu e n t p ro b le m s . Th e s e p r o du c t s d o n o t re q ui r e a n N D A . A l th o ug h i t i s n o t r e qu i re d f o r h e al t hc a r e p r o f ess i on al s t o re p or t pr o b le m s , i t i s e s s en t ia l th a t v ol u nt a r y r ep o r ti ng ta k es p l ac e .
23 Medication Errors R o b e r t C is n e r os
I. MEDICATION ERROR PROBLEM A. Th e 2 0 0 0 I ns t i tu t e o f Me d i c i n e ( I O M) r e p o r t To E r r Is H u m an br o ug h t th e p ro bl em o f e r ro r s in m e di c i n e t o n a t io na l a t t en t io n .
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1 . A n e s t im a te d 4 4 ,0 0 0-9 8 , 00 0 d e a th s p e r ye a r a r e c a us ed b y m e di c a l er r o r s . O f t h o s e d ea t h s, ap p r o xi m a t e l y 7 , 00 0 a r e t h e r es u lt o f m ed ic a ti o n e r ro r s. 2 . A c al l to ac ti o n wa s giv e n t o i m p r o v e p a ti en t sa f e t y . B . I n re c e n t y e a rs , t ra gi c m ed ic a ti o n e r ro r s h a v e fo c us ed a tt e nt io n on c o nc e r ns r e g a rd i ng pa t ie n t s a f et y . 1 . A c h em ot h er a p y m i x u p a t a m a jo r c an c er c e n te r r es ul t ed in t he de a th o f a p a ti en t f r o m a fo u r f o ld o ve r d ose d ai l y fo r 4 d a y s. 2 . A c hi l d ac c i d en t al l y r ec e i v ed an i nt r a ve n o us ra t h e r th a n i n t r am u sc u la r d os e o f l o ng - ac t in g p e ni c i ll i n a nd d ie d . 3 . A c om p ou nd i ng e rr o r re s ul t ed in de a th of a c hi ld wh o r ec e i ved a t r ic yc lic a n t id ep r es s a n t a t a do s e 1 0 ti m es g r ea t e r t h a n th e d os e p r e sc r i b ed b y p h ys ic ia n . 4 . Mi xu p s wi t h h e pa r in v ia l s wh i c h h ad s im i la r p ac k a gi n g , b u t d i f fe r e n t c o n ce n t r a ti o ns , r es ul t ed i n o ve r d o se s c au s i n g s e r io us in ju r y a nd se v e ra l in f an t d e a th s.
II. ERROR DEFINITION. Th e N a t io n al C oo r di n a ti ng C o un ci l f o r Me d ic a ti o n E r r o r R ep o r ti ng a nd P rev e n t i on ( N C C ME R P ) d e f in es a m e d ic a ti on e r ro r as fo ll o ws : “ A m ed ic a ti on e r ro r i s a n y p r e ve n ta bl e e v e n t t h at m a y c au s e o r l ea d to in app r o p ri a te m e di c a t io n u s e o r pa t ie n t h a r m wh i l e t h e m e d ic at i on is in th e c o nt r ol o f t he h e al t h c a re pr o fe s s i on al , p a ti e nt , o r co ns um e r . S uc h e v e n ts m a y b e r e la t ed to p ro fe ss i on a l p ra c ti c e , h e al t h c a re p r o du c ts , p r oc ed u r es , a nd s y s t em s , i nc lu di n g p r es c ri b in g ; o rd e r c om m u nic a ti o n; p r o du c t l ab el i ng , p ac k a gi n g , a nd no m e nc l at u re ; c o m p o u nd in g ; d is pe ns i ng ; d i st r ib u ti o n; a dm i n is t ra t io n ; e d uc at i on ; m on i to r i ng ; an d u se . ”
2
III. TYPES OF ERRORS. Th e f o ll o wi n g c at e go r ie s o f er r o rs ha v e be e n us ed i n n um e ro us r es ea r ch s t ud i es .
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A. W r o n g d r u g e r r o r . A d r u g t h at wa s no t o r d er ed f o r a p a ti e nt wa s ad m in i s t e r ed — f o r e xa m pl e , a p a ti e nt ac c i de n ta ll y r e ce i ved f ur o se m id e 4 0 m g o r al l y. Po s s i bl e c a us es : Th e p ha r m a c i s t a c c i de n ta ll y f i ll ed t he pat i e nt ' s p r es c ri p ti on f o r an a nt i bi o ti c wi t h f u r os em id e ; t h e p har m ac is t re ac h ed fo r t he wr o n g b o tt l e o n t he sh el f a n d d id n o t c he c k th e l a be l c a re fu l l y en ou g h . B . E x t r a d o se e r r o r. A pa t i en t re c e i v es m o r e d os e s o f a d ru g th a n we r e or d e r ed — f o r e xa m pl e , a p a ti e nt wa s s up p os ed t o r ec ei ve a m e d ic at i on wi t h b r e ak fa s t f o r 3 d a ys b u t re c e i v ed i t f o r 5 d a y s . P os si b le c a us e: Th e pa t ie n t 's nu r s e wa s co n f us ed b y t h e m ed ic a ti on di r ec t io n s . C . O m i ss i o n e r r o r . A d os e o f a d ru g wa s n o t a dm i ni s t e r ed as o r d er e d b ut wa s s ki p pe d — fo r e xa m pl e , a p a t ie n t wa s s u p po se d t o r e c ei ve di go xi n 0 . 25 m g o r a ll y i n
t h e m o rn i ng bu t d i d n ot re c ei v e th e d o se . Po s s ib le c a us e : Th e p at i en t ' s nu r s e wa s s o b us y t h at he o r s he for g o t t o a dm i ni st e r t h e d os e . P.500
D . W r o n g d os e o r w r ong s t r en g t h e r r o r . Ei t he r t h e wr o n g d os e o f a m e di c in e o r t h e wr o n g s tr e ng t h i s a dm i ni s t e r ed — fo r e xa m pl e , t h e p a ti en t wa s s up p os ed t o r e c ei ve wa r f a ri n 0 . 5 m g b u t re c e i v e d wa r f a r in 5 m g i ns t ea d . Po ss ib le c au s es : Th e p h a rm ac is t m is r ea d t h e la b el ; th e p h y si ci a n wr o t e t h e o r de r as “ wa r f a ri n . 5 m g .” A n o t he r e xa m pl e : a p a tie n t wa s s up p os ed to r ece i ve ti m o l ol 0. 2 5% bu t wa s g i v e n t i m o l ol 0. 5 %. P os s i bl e c a u s e : Th e p ha r m a c i s t t oo k th e wr o ng p ro d uc t o f f o f t he s h el f , c on f us ed b y th e c o n c e n t ra t io ns . E . W r o ng r o u te e r r o r . A p a ti e nt r ec ei ve s a do s e o f a m ed ic a ti on b y a r o ute t ha t wa s n o t o r d er e d b y t he ph y s ic i an — f or e xa m p le , a pa t ie n t wa s s up p os ed to r ece i ve p r o ch lo r p er a z i ne 10 m g in t r am us c u l a rl y b ut th e d ru g wa s ad m i ni s te r ed i n t ra ve n ou s l y . P os s i b le c a u s e s : Th e nu r s e m is r e ad t he o rd e rs ; th e p h y si c ia n m is t ak en l y wr o t e “ I V” in s t e a d o f “ I M. ” F . W r o ng t im e e r r o r . A p a t ie n t d oe s n ot r ec ei v e a d os e o f m ed ic a ti on a t th e ti m e a t wh i c h it wa s to be a dm i ni s te r e d— f o r e xa m p le , a h o s p i ta li ze d pa ti e n t wi t h d i ab e te s i s s ch e du l ed to r ec ei v e a do s e o f i ns ul i n im m e d ia t ely b e f o re b re ak f as t (a t 7 :0 0 A . M. ) b u t th e d os e i s g i v en 2 hr a f te r b re ak f as t . P os s i b le c a us e : Th e n u rs e wa s b u s y a n d c o ul d n o t g i v e d os e o n t im e . G . W r o n g d o sa g e f o r m e r r o r . A pa ti e n t r ec ei ve s a do s e o f m e d ic in e i n a d o s a g e f o r m t ha t wa s n o t i n te nde d — f or e xa m p le , n ic o ti nic ac id 50 0 m g t a bl e ts we r e o rd e r ed f o r a p at i en t wh o i n s t e ad r e c e i v es ni c o t in ic ac id 50 0 m g s lo w- r e l e as e c ap s u l es . P o ss i bl e c au s e : Th e p har m ac is t d i d n ot c a r e fu ll y c h ec k t he p ro du c t o r was c o n fu s e d b y t h e l ab e l. H . O t h e r . E rr o rs t ha t d o n o t fi t i n to an y o f t h e o the r c a t eg o ri e s .
IV. COMMON ERROR HAZARDS A. D a n g e r o u s a bb r e vi a ti o n s . N um e r ou s c o m m o n a b b re vi a ti on s a nd s ym bo l s h a v e b e e n as s o c i a te d wi t h e r ro r s . D e t ai le d l is ts a re a va i la b le f ro m t he I ns ti t u te f o r Sa f e Me d i c a t io n Pr a c t ic es ( I SMP ) a t h t t p :/ / ww w. j o i n t c o m m is s io n . o rg / S en ti n el E ve n ts / for m s . an d th e J oi n t C o m m i ss i on on A c c re d it a ti o n o f H e al t hc a r e O r ga n i z at i on s ( J C A HO ) a t h t t p :/ / ww w. j o i n t c o m m is s io n . o rg / P at ie n t Sa f e t y / DoN o t U s eL is t / . J C A H O ' s a c c r e di t ed o r g an i za ti o ns a r e re q ui re d to a voi d u s i n g t he p ote n t ia ll y c on f us in g a b br e vi a t io ns on i t s “ D o N ot U s e ” l is t . 1 . U , I U : u n i t ( s ) . Th e le tt e r U c a n e as il y b e m i si nt e r p re t ed as a n um be r ( e. g . , 0 o r 4 ) , an d s e ri ou s h a rm ha s o c c u r re d wi t h i ns ul i n a nd h ep a ri n a s a re s ul t o f th i s c o nf us i on . Fo r e xa m p l e , a p at i en t re ce i ve d 6 6 u nit s of in su l in i n s t e ad of 6 u n i ts . Th e o r d e r, wh i c h wa s wr i t t e n f o r “ 6 U ” o f r e gu la r in su l i n wa s m i s re ad as 66 . The wo r d u n i ts s ho u ld be wr i t t en ou t in fu l l.
2 . Q D , Q . D . , q d , q .d . ( dai l y) . Th e s e c o m m on ab b re vi a t io ns ha v e be e n m is i nt e r pr e te d a s “ Q I D ” o r “ qi d ” (f o ur t im es d a il y) r e su l ti ng in o ve rd os es . Th e wo r d d a il y s ho ul d be wr i t t en ou t in fu l l. 3 . Q . O . D , Q O D , qo d (e ve r y o t h e r d a y) . Th e s e c o m m o n a bb r e v ia t io n s h av e b e en m is i nt e r pr e te d a s Q I D ( fo u r ti m e s d ai l y ) , re s u l ti ng i n o v e r do s e s . Th e wo r d s e v e r y o t h e r d ay s ho u ld be wr i t te n ou t c om pl e te l y. 4 . T r ai l i ng z e r o . W hen a d os e i s o r de r e d a nd fo llo we d wi t h a de c i m a l p oin t an d a ze r o , su c h as 2 . 0 m g o r 2 5 . 0 m g , er r o rs c a n o c c ur . Th e de c i m a l p o in t m a y b e m is se d a n d a n o v e r do s e c a n oc c ur . Fo r e xa m pl e , wa r f a r i n 2 . 0 m g m a y b e m is i nt e r pr e te d a s 2 0 m g. Tr a i l in g ze ro s s ho ul d b e a vo i de d , a nd th e d o s e wr i t t e n wi t h o u t th e a dd i ti o na l z er o — f o r e xa m p le , wa r f a rin 2 m g ( i ns te a d o f 2 . 0 m g ) . 5 . L ac k o f le a di n g z e r o. A d r ug ' s d os e m a y be les s t h an 1 m g , s uc h a s f or d ig o xi n . O f t e n th e d os e i s wr i t t e n wi t h o u t a le ad i ng ze r o: d i go xi n . 2 5 m g i ns te a d of d ig o xi n 0 . 2 5 m g . E r ro r s h a v e o c c u r re d b e c a us e t h e d ec im a l p oi n t is m i s s ed — f or e xa m p l e , wa r f a r i n .5 m g m a y be int e r p re t ed as wa r f a ri n 5 m g . L ea d in g ze ro es s h ou l d b e i n cl ud e d, s o th e d o s e i s wr i t t e n as di go xi n 0 . 25 m g o r wa r f a r in 0. 5 m g. 6 . M S , M S O 4 ( mo r p h in e s u l f a te ) , M g S O 4 ( m ag n es i u m s u l fa t e ). Th e a b b re v i a t io ns f o r m o r ph in e s ul f a te an d m ag n es iu m s ul fa t e a r e q u i te s im i la r a n d c an be c o nf us e d . I t is r ec om m e nd th a t m o rp h in e s ul f a te an d m ag n es i u m s ul f a te be wr i t t en in o ut in f u l l. P.501
B . O t h e r co n f us i n g s ym b o l s , a bb r e vi a t i on s . Th e r e ar e n um e r ou s o th e r h a za r do u s s ym b ol s a nd ab b re v i a ti on s th a t sh o ul d b e u s e d wi t h c au t io n wh e n wr i t i n g p r e sc ri p ti o n o r de r s a nd c a r e f ul l y e xa m in ed wh e n fi l li n g p re sc r ip t io ns . E xa m p le s i n cl ud e th e f o ll o wi n g : 1 . cc . S t an d s f o r c u b ic c e n t im et e rs an d i s o f te n us e d i ns te a d o f m L. Th i s h a s b ee n m is i nt e r pr e te d a s a 0 ( z er o ) ; us e m L . 2 . µ g . U s ed fo r m ic r o gr am s —f o r e xa m p l e, le v o t hy r o xi n e 2 5 0 µg da i l y . Th e a b b re vi a ti o n h as b e en m i s ta k e n fo r m g , a nd o ve rd o s e s h a v e o c c u rr e d; bet t e r to us e m cg o r t o wr i t e o ut th e wo r d m ic r og r a m s . 3 . < , > . S ym b ol s f o r l es s t h an ( < ) a nd g re a te r th an ( > ) h a v e b e en m is t ak en f o r e ac h o t h e r o r m is in t er p r et e d as nu m b e rs . B et t e r t o wr i t e o ut t he wo r d s l ess t han o r g r e a te r th an . 4 . H C T . Th is a b br e v i at i on f o r “ h y d r oc or t is on e ” h as be e n m i s i n te r p r et e d as h yd r o ch lo r o th i a z id e . B e tte r t o wr i t e t he wo r d ou t c om p le t el y . 5 . H C l . Th e a bb r e v ia t io n f o r “h yd r oc h lo r ic a c i d ” ha s b e en m is i nt e r p re t ed as K C l ( p o t ass i um c hl o ri d e ). B et t e r to wr i t e o u t t he wo r ds c o m p le t el y . C . S o u nd - a - li k e o r l oo k- a - l i ke d r ug na m es . A de t a il ed li s t o f c o n f us in g d r u g n am es c a n b e f ou n d i n t he 2 00 4 U n i te d S ta t es Ph a r m ac op e ia pu b li c a t io n “ U S P Q u a li t y R e vi e w” ( w w w. u s p . o r g/ pd f / E N / pa t ie n tS a f et y / q r 792 0 0 4- 0 4 -0 1 .p d f ). A no t her l is t i s a va i la b le f ro m I S MP ( w w w. i s m p .o r g / To ol s / c o n fu s e d d ru g na m e s .p d f) . 1 . E xa m p le s i nc lu d e t he f o l lo wi n g : a . Am i t ri p t y li n e a nd am ino p h y ll i ne
b . C is p la t in an d c ar b op la t i n c . K - Du r an d C ar d u ra 2 . To a v o id th es e p r o bl em s , t he I S MP o f f e rs s e ve r a l s ug ge s ti on s , i nc lu din g th e u se o f co m p u te r i z ed r em in d er s , n am e - al e r t s t ic ke r s , a n d i nd e pe n de n t ch e c ks ; o p en in g t h e b o t tl e i n f r on t of th e p a t ie n t, wh o c a n c on f i rm t h e a pp e a ra nc e ; a nd r ep o r ti n g e r r o rs . D . H i g h - r is k d r u g s. C e rta i n p o t en t d r ug s h a ve be e n i m p li c a t ed in m a n y se r i ou s a n d t r a gi c m e d ic at i on er ro r s . Th e s e h a v e b ee n c al l e d hi g h -r is k o r hi gh - al er t d r ug s . A l is t o f s uc h m ed ic a ti o ns c a n b e f o un d a t w w w. i s m p .o r g / To ol s / h ig ha l e rt m ed ic a ti on s .p d f. E xa m pl es in c l u de th e f o ll owi n g : 1 . B l oo d - mo d i f yi n g a g en t s su c h a s h e pa r i n a nd w a r f a r i n. E r ro r s h a v e r e s ul t ed in s e r io us in ju r y o r d e at h fro m h em o r rh a gi n g as a r es u lt o f o v e rd o se (p a ti e nt r e ce i vi ng 1 0 m g i ns t ea d o f 1 m g ) or f r om bl o od c l ot s a s a re s ul t o f un de r d os e ( p at ie n t r e c ei vi ng 0 .5 m g i ns t ea d o f 5 m g ) . 2 . N a r co t i cs an d s e da t ive s . C e n tr a l n e r v ou s s y st e m d ep r es s i o n a nd r es pi r a to r y a r r es t ha v e r es ul t ed f rom e r ro r s wi t h th e se dr u gs , s uc h a s d ia z e p am 25 m g g i v e n i n t ra ve n ou s l y i ns t ea d o f 2 . 5 m g . 3 . N e u ro m us c u la r pa r a lyz i n g a g e n ts su c h a s su c c in yl c h o l i n e a n d ve cu r o n i um . A c ci d en t al us e o r i n ad v er t e n t us e b e f or e a d eq u ate v e n ti l at i on p ro c e du r es we r e s t a rt e d h a v e r es u lt e d i n r e s pi r at o r y a r re s t an d d ea t h . 4 . C h em o t he r a p y d r u g s . Th e s e d ru g s a re as s o cia t e d wi t h po t en t ad ve r s e e f f ec ts , a f f ec t in g n um e ro us bo d y s y s te m s , s uc h a s t he im m u ne , n e u ro lo g ic , a nd clo t t in g s ys t em s . D ea t hs ha v e oc c u r re d a s a r es ul t o f e r r or s wi t h th es e p r od u c t s. Fo r e xa m p l e , v i nc r is t in e wa s a c c id e nt a ll y g i ven to a c h i ld in s te ad o f v i n bl as t ine , r e s ul ti n g i n d ea t h . C o nf us i on o v e r t he do s i n g o f cy c l o ph os p ha m i d e r es ul t ed i n a f a t al fo u r fo l d o v e r do s e .
V. SEVERAL SAFETY TECHNIQUES OBSERVED IN COMMUNITY PHARMACIES 4 A. K e e p wo r k p ro c e du r es o rg a ni ze d a n d s i m p li f ied . B . D o n ' t wo r k o n s e v er a l p r es c ri p ti on s a t o nc e , j us t on e a t a ti m e . P.502
C . Ma n a g e i n t er r u pt i on s , d o n ' t b e p r ess u r ed to r us h . D . S m el l c he c k . E . B a r c od e c he c k . F . U se a m ag ni f y i ng gl as s wh e n ne ed e d. G . E n h an c e th e d e s i gn of t h e f ac il i t y .
VI. ROOT CAUSE AN ALYSIS (RCA). Th i s is a s t r uc t u re d p r oc e s s f o r id e nt i f y in g d i r ec t a n d i nd i r ec t f ac t o rs th a t c o nt r i bu t ed to a m ed ic a tio n e rr o r . A f ra m e wo r k f or c on d uc ti n g a n R C A is ava i l ab l e a t h t t p :/ / ww w. j o i n t c o m m is s io n . o rg / S en ti n el E ve n ts / for m s . S ee “ F ra m e wo r k F or C o n d uc ti n g a Ro o t Ca us e A n al y s is . ”
A. I m p o r ta n t q ue s ti on s to as k : 1 . W ha t h a pp en e d a nd wh y ? 2 . W ha t we r e t h e c o n t ri bu t i ng fa c to rs ? a . A ge ? Ho u rs wo r k ed ? S t a f fi n g? b . W ork l o ad ? St r es s ? C on f us i ng na m e s? Lo ca t io n o n s he l f? c . In a de qu a te in f o rm a ti on ? C om m u ni c a t io n ? d . I na d eq ua t e e qu i pm en t? e . W or kp l ac e a tm os p he re c o n du ci ve t o s a f et y ? f . I na d eq u at e t r a in in g o f p h a rm ac is t o r te c h n ic ia n? B . L a te n t de f ec t . A w eak n e ss i n a s ys t e m t ha t d o es no t i m m ed i at e l y res u lt in an e r r o r b u t, un d e r t he r ig h t s e t o f ci r c u m s t an ce s , c an c o n t ri b ut e t o a m i st ak e. F o r e xa m p l e : 1 . S t oc k in g lo ok - al ik e o r s ou n d -a li k e d ru gs ne xt t o e ac h o th e r , c on t ri b ut i ng t o a p h a rm ac is t i nc o r re c tl y f ill i ng a p r es cr i pt i on . 2 . I na d eq u a te t r ai n i ng o f em pl o ye es , c on t r ib u tin g to an e r ro r i n wh i c h an a u t om at e d d is pe ns i ng m a c hi n e wa s us ed im p ro pe r l y a n d a p at i en t re c e i ve d th e wr o n g m ed ic a ti o n.
VII. NATIONAL SAFETY EFFORTS A. J C A H O ' s N a t io n al P ati e n t S a fe t y G o al s f o r Ac cr e d it e d O rg a ni za t io ns c an b e f o u nd at h tt p :/ / ww w. j o i n tc om m i s s io n .o r g / Pa t ie n t Sa f e t y/ N at i on al P a ti e nt S a fe t yG o a ls / . H o s pi t al go a ls i nc l ud e : 1 . Im p ro v e t he ac c u r ac y o f pa t ie n t i de n ti f ic at i on . H a v e t wo m ea ns o f i de n ti f yi n g t he p a t ie n t o th e r t h an r oo m n u m b e r . 2 . Im p ro v e c o m m un ic a ti on am o ng c a r eg i ve rs . Ve ri f y a nd r ea d b ac k t e le pho n e a n d o r a l o r de r s . 3 . C r ea t e a l is t of “ do not u s e ” a b b re vi a ti on s . S t an d a rd i z e th e a bb r e vi at i on s u s e d , a n d p r oh i bi t th e u s e of th o s e th a t a r e p r on e t o co n f us io n a n d m i si n te r p ret a t io n . 4 . Im p ro v e t he s a fe us e o f m e di c i n es . a . Li m i t th e n um b er o f d if f e r en t c on c en t ra t io ns a va i la b le pe r dr u g p r od uc t ; s t an d a rd i z e . b . D e ve lo p m et h od s o f id e n ti f y i ng an d re v i e wi n g s o un d -a l ik e a nd lo ok - al ike d r ug s , p r e ve n ti ng e r ro r s wi t h t he m . c . Al l m ed ic a ti o ns a n d c o n t ai ne r s s ho ul d b e p r o pe r l y la b el e d. d . R e du c e th e l ik e li ho o d o f pa t ie n t h a rm a s s oc i ate d wi t h th e u s e of an t ic oa g ul a ti o n t h e r ap y. 5 . R ed u c e th e ri s k o f i n fe c ti o ns . a . C om pl y wi t h a ll C en t er s fo r D is ea s e C o nt r ol an d P re ve n t io n ( C D C ) r e c om m e nd a ti on s f o r h an d wa s hi n g a nd h ygi e ne . b . Th o r ou g hl y i n v es ti g ate a ll s e ri o us ad v e r se e ve n ts an d d e at h s as so c i a te d wi t h i n f ec ti o n ac q ui r ed in a he a l th c a r e s et t in g . P.503
Figure 23-1. The medication error form used by the United States Pharmacopeia. [Reprinted with permission of the United States Pharmacopeia.]
P.504
6 . K ee p a c c u ra t e p a ti en t m ed ic a ti o n r ec o r ds a n d h i s t o ri e s t h ro ug h ou t th e c o nt i nu um o f ca r e. a . E ns u re th a t a pa t ie n t 's m e di c a t io n re co r ds a re c om pl e te an d a c c u ra t e wh e n h e o r s h e is r ef e r r ed or t ra n s f er r e d wi t hi n o r be t we e n o rg a ni za t io n s . b . P r op e r c om m u ni c a t io n o f ac c u r at e p a ti e nt m e dic a ti o n i nf o rm a ti o n is c r i tic a l f o r e ve r yo n e i n v ol v e d in th e p a ti e nt ' s c a re . B . T h e F iv e Mi l l i on Li v e s C a mp a ig n i n it ia t e d b y the I ns t it u te fo r H ea l th ca r e I m p ro ve m e n t c an be fo un d at h tt p :/ / ww w. i h i . o r g /IH I / P r o g ra m s / C am pa ig n . 1 . P u rp os e : “ To p r ot ec t p a t ie n ts fr om f i ve mi l l ion i n ci d en t s o f me d ic a l h a r m o v e r t h e n e xt t wo y e a r s ( D ec em b e r, 20 0 6- D e ce m b e r , 20 0 8 ) .” 2 . Twe l v e i n t er v e n ti o ns we r e i d en t i fi ed an d c an b e fo u nd de s c r ib e d in m o r e de t ai l a t t h e we b s i t e a bo v e . Th e in t e r v e nt i on s i nc lu de d : a . P r e v en t in g a d ve r s e dr u g e ve n ts t h ro ug h m e di c a t io n r ec o nc i l ia t i on . b . P r e ven t in g s u r g ic a l si t e i nf e c ti o ns b y ap p r op r i a t e c a r e a nd an i t b io ti c u se . c . Fo cu s o n p r e v en t in g ha r m f r om h ig h r is k m e dic a t i on s s uc h a s a nt ic o ag u la n ts , s e da t i ves , n a rc o ti c s , a nd i ns u li n . d . R e du c e M e t hi c i ll i n - Re s i s ta n t St a ph y l oc o cc us a u re u s (M S R A) i n f ec ti o n s t h r o ug h a pp r o p ri at e e vi d e n c e -b a se d p r a c ti c es . C . Th e I O M i n J ul y 2 00 6 r e l ea s e d i t s r ep o r t “ P r e ve n t in g Me d ic a ti o n E r r o rs. ” S e v e r al r e c om m e nd a ti on s we r e m a de to im p ro ve pa t ie n t s a fe t y i nc lu di n g: en h an c in g r ol e o f p a t ie n t i n m e d ic at i on m an a g em en t , im p r o v in g p a ti e n t e du c a t io n , a nd in c rea s in g t h e u s e o f t ec h no lo g y , s u c h a s e - p re s c r ib i ng . Th is rep o r t c an be ac c e ss ed at w w w. i o m . e du . D . M ed i ca t i on e r r o r re po r t i n g . Th e r ep o r ti n g o f m e di ca t io n e r r o rs p r o v i de s c r it ic a l s a fe t y f ee d ba c k . F i gu r e 2 3 - 1 s ho ws t h e f o rm u sed i n t he U ni t ed S t at es P h a r m a c o pe i a 's e rr o r rep o r ti n g p r og r am . E rr o rs c a n b e s ub m i t te d a n on y m o us l y v ia t h e In t er n et , b y te le p ho ne , o r b y m a il .
E . Th e “ S o rr y W ork s C o al i ti o n ” ( ww w. s o r r y wo r k s .n e t ) i s a n o r ga ni z a t io n of v a r i ou s i n di vi d ua ls ( he al t hc a re pr o f es s i o na ls , l a wye r s , i ns u r an c e e xe c u ti ve s , c o nc e r ne d c i ti ze ns , et c .) wh o p ro m o t e th e n ec es si t y o f d is cl o s u r e a nd a po l o g y f o l lo wi n g e r r o r . Th e c o al i ti o n p r o v id e s t r ai n in g a nd ed uc a tio n p ro g ra m s . F . Th e In s ti t ut e f o r Sa f e Me d i c a t io n Pr a c t ic es ( ww w. i s m p .o r g ) f oc us es i ts e f f or t s o n m e d ic a t io n e r r o r p r e ven t i o n a n d p a ti e n t s a fe ty. Th e I S MP p u b l is he s fo u r di f fe r en t s a fe t y n e ws le t te r s , p ro v id e s c o n su l ti ng s e r v ic e s , a n d p r es en t s n um e ro us e d uc a ti o na l p r og r am s , s e r v i c es , a nd ac t i vit i es . G . Th e N a t io na l Pa t ie n t S a f e t y Fo u nd a ti on ( ww w. n p sf . o rg ) r ep r es en t s s tak e h ol d e r s f r o m a b r o ad a r r a y o f d i s c i pl i ne s , i nc lu d in g p a ti e n ts a n d f am il i es . Th e NP S F m is si o n is f oc us ed on imp r o vi n g p at i e nt sa f e t y. I t p ro v i d es n u m e r ou s r eso u r c e s , p u bl ic a ti o ns , a n d ac t i v it ie s d i r ec te d a t i m p r o vi ng t h e c a re of p at ie n ts . P.505
STUDY QUESTIONS D i r e c t i on s : E a c h of t he q u es t io ns , s t at em e nt s , or i nc om p le t e s t a te m en ts c a n b e c o r re c tl y a ns we r e d o r c om p le t ed b y on e o f th e s ug g es t ed an s we r s o r p h r as es . C h o os e th e b e st an s we r . 1 . A m a j o r re s ul t i n t h e 2 0 00 I ns t i tu t e o f M e d ici n e ( I OM ) r ep o r t is t ha t ( A ) p ha r m a c i s t s a r e n o t b l am e d f o r t he m a jo r i t y of m ed ic al e r ro r s. ( B ) s ur g eo ns m a k e m o r e m is t ak es th an an y o t he r h e al t h p r of es s i o na l . ( C ) p h ar m a c i s ts m ak e m o r e m is t ak es th a n a n y o th e r he al t h p r of es s i o na l . ( D ) t h e re is n o w m o re em p ha s i s o n e r r or p re v e nt i o n. V i e w A n s we r 1 . T h e c o r re c t an s w e r i s D [s e e] . 2 . A p h a r m a c is t is p r es e nt e d a p r es c r i p ti o n f o r 25 0 m c g o f l e vo t h yr o x i n e . W h i c h o f th e fo l l ow in g d o s ag e s w o ul d be eq u i va l en t t o t h a t am o un t ? (A) 2.5 mg ( B ) 0 . 25 gm ( C ) 0 . 25 m g (D) 25 gm V i e w A n s we r 2 . T h e c o r re c t an s w e r i s C [s e e] . 3 . A p r e s c r i p t i on is w ri t t en f o r w a r f a r i n 1 .0 mg . The c om m un i t y p h a r m a c is t a cc i de n t al l y d i s p e n se s 10 mg . T h e pa t i en t de ve l o ps se ve r e b l ee d in g w i th i n 3 d a ys a n d n e a r l y d i e s . W h i c h o f t h e f ol l ow i ng i s t h e m os t a cc u r a te as se s sm e n t o f t h is p re s c r ip t i on ? ( A ) A t ra i li ng z e r o i s p res e nt in t hi s p re s c r ip t io n a n d c ou l d h a v e c o n t ri b ute d to t he p h a rm ac is t ' s e r ro r . ( B ) Th i s i s a n e xa m p le of a l e ad i ng ze r o, wh i c h co n t ri b u te d t o t h e e r r or an d th e p a t ie n t t r ag e d y . ( C ) S o un d - al ik e m ed ic a tio n s c o n t ri b ut e d t o t h is er r o r . ( D ) Th i s d o es n o t q ua l if y a s a n e r r o r b as ed on the N a ti o na l Co o r di na t in g C o u nc i l f o r Me d i c a t io n Er r o r Re p o rt in g an d P re ve n ti on ( N C CME R P ) d e f i n i ti on . V i e w A n s we r 3 . T h e c o r re c t an s w e r i s A [s e e] . 4 . A h o s p i t a l p h a rm a c y b e g i ns s to ck i n g n ew int r a ve n o u s m i ni - b ag s o f a n eu r o mu s cu l a r - bl o cki n g ag e n t.
T h e pa ck a g in g is si m ila r t o a c om m on l y u s e d i n t r a ve n o us an t i bi o t ic . T h e a d d i t io n o f t he new m i ni - b a gs w a s n o t w id e l y c o m m un i ca t e d t o a l l p e rs o n ne l . O n e w e e ke n d, se ve r a l d o s es o f t h i s n ew p r o du c t w e r e a cc i de n t al l y d i s p en s ed i n p la c e o f th e in t e nd ed d o se s o f an t i bi o t i c. Se ve r a l p at i e nt s s u f f e red r e s p i r at o r y a r r e s t a n d o n e of t he p a ti e n ts e ven t u a l l y d i e d . W ha t w o uld a r oo t c a u se an a l ys i s o f t h i s e r r o r f i n d? ( A ) Th e o nl y c a us e o f th is e r ro r wa s a ph a rm ac is t wh o wa s n o t p a y in g a t t en t i on . Th e p h a rm ac is t s ho u ld be di s m is s e d . ( B ) P o o r c o m m un ic a ti o n p r a c t ic es is a la t e nt de f ec t in th is ph a rm ac y s ys t em an d s i gn i fi ca n tl y c o n t ri b ut e d t o t he er r o r . ( C ) Th e p ha r m a c y te c h nic i an s a r e t o b la m e f or t hi s e r r o r, no t th e p h a rm ac i s t , b e ca us e th e t ec h ni c i an s o b t ai ne d th e m in i -b a gs fro m s t ock an d p l ac ed t he l a be ls on t h e b a gs . Th e p ha r m a c i s t c he c k ed on l y th e te ch nic i an ' s wo r k . Th e te c h n ic ia n s h ou l d b e di sm is s e d. ( D ) Th i s i s a n e xa m p le of a n e xt r a d os e e r r o r. V i e w A n s we r 4 . T h e c o r re c t an s w e r i s B [s e e] . 5 . W h a t d o t he f ol l ow i ng a b b r e vi a t io n s M S, M S O 4 a n d M g S O 4 h a ve i n c om m o n? ( A ) c om m o n a bb r e v ia t io ns f or m o r ph i ne s u lf a te ( B ) c om m o n a bb r e v ia t io ns f or m a g ne s i um s u lf a te ( C ) s ho u ld no t b e u s e d in J C A H O - ac cr e di t ed in sti t u ti o ns ( D ) a p pr o v e d a bb r e v i at i on s i n m os t h os p it a ls V i e w A n s we r 5 . T h e c o r re c t an s w e r i s C [s e e] . 6 . A m a j o r e r r o r in a h o spi t a l p h a r ma c y r e s u l t e d i n a t o t a l p a r e nt e r a l n u t r it i on s o lu t i on b ei n g m i st a ke n f o r a c a r d i op l eg i c s o lu t i o n fo r c o r o na r y b yp a s s s u rg e r y. W h i c h o f t h e f o ll ow i ng i s t r u e r e ga r d i ng t he r o o t c a u se an a l ys i s t h a t w as d o ne a t t h e h os p i ta l a f t e r t he error? ( A ) Th e p ri m a r y o bj ec t i ve is t o f in d o u t wh i c h p ha r m ac is t m ad e t h e m i s t ak e th a t a l lo we d t hi s t o ta k e pl ac e . ( B ) Th e r es ul t of th e a n al y s is wo u l d b e t h e a dm iss i on th a t a n e r r o r h ad tak e n p la ce . ( C ) A l l f ac t o rs th a t c o u ld h a v e c o nt r ib u te d to th is e r r o r wo u ld be id e nt i fi ed a n d a n al yze d . ( D ) A r oo t c a us e a na l y s is wo u l d b e i na p p ro p ri a te i n t h is c as e . V i e w A n s we r 6 . T h e c o r re c t an s w e r i s C [s e e] . P .5 0 6
ANSWERS AND EXPLANATIONS 1 . T he co r r e c t a nsw e r is D [s e e I . A .2 ] . Th e I O M r e p o r t r e v ea l ed a l ar m i n g d a ta on de a th s r e la t e d t o m e d ic al e rr o rs . Th e r e p o rt co n t ri bu t ed t o i nc re a s e d e f fo r t s t o im p r o v e p a t ie n t sa f e t y . 2 . T he co r r e c t a nsw e r is C [s e e I I I. D ] . A l t h ou gh t hi s m a y s ee m t o be an el em e nt a r y qu es t io n a n d a ns we r , a wr on g do s e e r r o r s uc h a s t hi s c ou ld e a s i l y le ad t o a s e ri o us i n j u r y or de a th t o a p a ti en t . 3 . T he co r r e c t a nsw e r is A [ s e e I V . A .4 ] .
W arf a ri n 1 . 0 m g . i s a n exa m p l e of a t r ai l in g z e ro . J C A H O h as i nc l ud ed t his in it s “ Do N o t U se ” li s t of a bb r e v iat i o ns . Ho we ve r , i n t he c om m u n it y s et t in g , i t i s a pr a c ti c e t h a t c an s t il l b e f r e qu en tl y s ee n o n p r es c ri p ti o ns . W hen a t r ai l in g z er o i s o b s e r ve d , m uc h c a ut io n s h ou ld be e xe r c i s ed in in t er p r et i ng t h e p r es c ri p ti on . 4 . T he co r r e c t a nsw e r is B [s e e V I . A .2 ] . P o o r c om m u n ic at i on wa s a m a jo r c o nt r i bu t in g f act o r to t hi s t r ag ic s e r ie s of e r r or s . Th e d r u g wa s a h ig h - ri s k d r u g a nd ha d s im il a r p ac k a g in g a s a no t he r c o m m o nl y us e d d r u g . Th e s e a re t wo m a jo r in g r ed ie n ts fo r th e s e ri o us e rr o r t h at t oo k p la c e . Th i s d o es no t a b s o l v e t h e t ec h n ic ia n a n d p ha r m a c i s t to t a ll y f r om a n y bl am e b ut e m ph as i z es t he s i gn i fi c an t r ol e t h at f ai lu r e o f c om m u n ic at i on pl a ye d wi t hi n th is p h a rm ac y s y s t em . Th e s y s t e m wa s as m u ch or m o r e to bl am e t h an an y i nd i v i du a ls . F i r in g th e i nd i v i du al s d oe s n o t r e pa i r t h e p r ob lem o f p oo r c om m u n ic at i on i n t he s ys t em b u t o nl y s et s t h e s t ag e fo r a si m i la r m is t ak e to oc c u r a g ai n . 5 . T he co r r e c t a nsw e r is C [s e e I V . A .6 ] . Th e s e a b b re v i a ti on s a r e i n c l ud e d i n J C A H O ' s “ Do N o t Us e ” l is t . Er r o rs r esu l t in g i n s e r io us ha r m h a v e oc c u rr e d af t e r m i x u p s wi t h m o r p hi n e a nd m a gn es i um . 6 . T he co r r e c t a nsw e r is C [s e e V I . A .2 ] . A r o o t c a us e a n al y s is is n o t i n te n de d t o fo c u s o n b l am e b u t o n a ll fa c to rs th a t c ou l d h a ve be e n r el a te d to th is e r r o r. F ac to r s m i g ht ha ve i nc lu de d t ra in i ng of pha r m ac is t a n d t ec h ni c i a ns , t h e ac tu a l d r ug o rd e r , a nd th e la b el . Th e c on t r ib u ti o n o f s uc h f a c to r s m i g ht no t b e d is c o v e r e d i f t h e f oc us is o n o n l y id en t i f y in g wh ic h p ha r m ac is t, t e ch n ic ia n , o r o t he r p ro fe s s i on a l is to bl am e .
24 Clinical Toxicology J o h n J . Po n zi l l o
I. OVERVIEW A . Th i s c ha p te r is i n te n de d to p ro v i d e t he r ea d er wi t h a n o v e r vi e w o f th e m a na g em en t o f v a ri o us to xi c e xp o s u r es . Em er g en c y m e di c al s e r v ic es ( E MS ) s h o u ld be im m e dia t e l y c on t ac t ed to p ro vi de a d v an c e d l i fe s u pp o r t fo r p a t ie n ts wi t h u ns t ab l e v i ta l s i gn s r es u lt i ng f ro m a p o is o ni ng e xp o s u r e . I n a d di t io n , t h es e p at i en ts s h ou l d b e r e fe r r ed to a ho s pi t al fo r fo l lo w- u p . A n a t io n wi d e t o ll - f re e p o is o n c e nt e r n um b e r b ec am e a v a il ab l e. Th i s n um be r, 8 0 0 -2 2 2 -1 22 2 i s a v a il a ble 2 4 h r /d a y an d s ho u ld be u s e d b y h ea lt h ca r e p r o f es s i on al s a n d t he gen e r al pu b li c wh e n de a li ng wi t h e xp o s ur e s t o p o t en t ia ll y t o xi c su bs t anc es . B . D e f in it i on s 1 . C li n ic al to xi c o l og y . F oc us e s o n t he ef f ec ts o f s u b st a nc es in pa ti e n ts c a us ed b y ac c i de n ta l p ois o ni n gs o r in t en t io na l o v e r d os es of m e di ca t io ns , d r u gs of ab us e , h ou s eh ol d pr o du c ts , o r va ri o us ot h e r c he m i c a ls 2 . I nt o xi c a ti o n. To xi c i t y a s s o c i at e d wi t h a n y c hem ic a l su bs t an c e 3 . P oi s o n in g . A c l in ic al to xi c i t y s ec on d ar y t o a c c i d e n ta l e xp o s u r e 4 . O v e r d os e. A n i nt e nt i on a l e xp o s u re wi t h th e i n te n t o f c a us in g s el f -i n ju r y o r d ea t h C . E p id em i ol og y . I n 2 004 , m o r e t ha n 2 . 4 m il li o n a c c i de n ta l a n d i nt e nt i ona l p o is o ni ng s we r e r e po r t ed t o t h e A m e r ic an A ss oc ia t i on of P oi s o n Co n t ro l C e n t e rs ( A A P C C ). Th e m a j o ri t y o f p oi s o n e xp o s u re s (8 4 .1 % ) we r e a c c i de n ta l . H o we v e r , 1 18 3 of t he s e e xp o s u r es r es u lt e d i n d ea t h. Mo r e i n f or m at io n c a n b e f ou n d a t th e A A P C C 's W eb s i te ( ww w. a a p c c .o r g ) . D . I n fo r m a t io n re s o u rc es 1 . C om p ut e ri ze d d a ta b as e s a . P oi si n de x i s a c om pu te r i z e d C D - R O M d a t ab as e t ha t i s u p da t ed qu a r te rl y a n d i s a p r im a r y r es ou r ce f o r p oi s o n c on t r ol c e nte r s . 2 . P r in t ed pu bl ic a ti o ns . Te xt b o o k s an d m an u al s p r o v i de us e fu l i n fo rm a ti on r e g a rd i ng th e a s s es s m en t an d tr e at m e n t o f p a ti en t s e xp o s e d t o v a r i ou s s u bs ta n c e s , al t ho u gh the i r u s ef u ln es s is li m i t ed b y t h e l ag t im e o f i n f or m at io n pu bl is h ed in t h e p r im a r y li t er a tu r e re a c h in g u p da t ed ed i ti on s . a . E ll e nh o rn MJ , e d. Me d i ca l To xi c o lo g y: Di a gn os is an d Tr e at m en t o f H u m an P oi s o n in gs , 2 n d e d . Ne w Yo r k , E l s e v i e r Sc i en c e , 1 9 97 . b . F ra u nf e ld e r F T, F r au nf e l de r FW . D ru g - In d uc ed O c u la r Si d e E f f ec ts , 5 t h e d . L i tt l e R o ck : B u t te r wo r t h - H ei n em an n , 2 00 1 . c . F ra un f el d e r, F ra u nf e lde r a nd W ile y . C l in ic al O c u l a r To xi c o l o g y . Ma r c h 2 0 0 8 6 th ed i ti o n S au n der s d . G o ld f r an k L , e d. To xi c o l og ic E m e r ge nc i es . 8 t h e d . Ne w Yo r k : Mc G r a w H i l l , 2 00 6 . e . G r a nt W M. To xi c o lo g y o f th e E ye, 4 th ed . Sp r in g f ie ld , IL : C ha r le s C Th o m as , 19 95 .
f . H a dd a d a nd W inc h es te r ' s C li ni c a l Ma n a ge m e nt o f Po is on i ng an d D ru g O ve r d o s e S ha n no n MO , B o r r o w SW , B ur n s M 4 t h E d i ti o n 2 00 7 W B S au nde r s g . H ed g es J R , H en d er s on R G , e ds . Te r r o r is m a nd c ri t ic al c a r e: c h em ic al , b i ol o gi c a l , r a di ol o gi c , and n uc le a r we a po ns . C ri t C a r e C li n 2 0 05 ; 21 ( 4 ). h . H ol s te g e C P , R us y n iak D E , e ds . Me d i c a l To xi c o l og y. Me d C l i n N o r th Am 2 0 0 5; 8 (6 ) . i . Le ik i n J B, P al o uc ek FP . P o is on i ng an d To xi c o lo g y C o m p en d iu m , 3 rd ed. H u d so n , O H : L e xi - C o m p , 2 0 02 . j . O ls o n K R , ed . , wi t h , An d e rs on I B , B e no wi t z N L , B l an c P D , et al . P o i s o ni n g a nd D r ug O v er d o s e , 5 t h e d . S t am fo r d , C T, A p p l e to n & La n ge , 2 0 0 6. P.508
3 . I nt e rn e t
1
a . C en t e rs fo r D is ea s e Co n t r ol an d P r e v e nt i on ( CD C ) a t ww w. c d c . go v b . U . S . F oo d a n d D r u g Ad m in is t r at io n ( F D A) a t ww w. f d a . g o v c . N at i on al Li b r ar y o f Me d i ci ne a t w w w. n l m .n i h. g ov d . N a ti on a l I ns t it u te fo r O c c up a ti o na l Sa f et y a nd H e a lt h ( N I O S H ) a t w w w. c d c . go v/ n i os h e . Am e r ic an S oc ie t y o f He a l th - S y s te m P h a rm ac is ts a t ww w. a s h p . o r g f . Ma t e r i al S af e t y D at a Sh e e ts a t ww w. m s d ss e ar c h . c o m g . U . S . E n v i r on m e n ta l Pro t ec t io n Ag e nc y ( E P A ) at w w w. e p a . go v h . C he m i c al Ab s t ra ct s Se r v i c e a t w w w. c a s .o r g 4 . P oi s o n c on t r ol c e nt e rs a c c r ed i te d b y t h e A A P CC p r o v i de in f o rm at i on to t h e g e ne r al pu b li c a nd he a l th c a r e p r o v id e rs . Th es e c en t e rs ar e th e m os t r e l ia b le an d u p -t o - da t e s o u r ce s o f i nf o rm a ti o n; t hu s th e AA P C C ' s ph o ne n u m b e r ( 8 00 - 2 22 - 12 2 2) s h ou l d b e r ea d il y a va il ab l e .
II. GENERAL MANAGEMENT A . S u pp o r ti v e c a r e a nd A B C s . E v al u a ti ng an d s up p o r ti ng t he vi ta l f u nc ti on s ( a i r wa y , b r ea t hi n g, an d c i r c ul at i on [ A B Cs ] ) a r e t he m a n da t o r y fi rs t s t ep s in t h e i n it i al m a na ge m e n t of d r ug in g es ti o ns . A f t er th e pa t ie n t is st a bi li z e d , t h e s pe c i f ic is s u e (s ) o f po i so n m an a ge m e n t s h o uld b e a dd r es s e d .
2
B . Tr e a t m e n t f o r p at i en ts wi t h d ep r es s e d m e nt al s t a t us in c l ud es t he f o l lo wi n g : 1 . To r ul e o u t o r tr e at h yp o gl y c em i a, 50 m L of 50% d e xt r o s e in ad u lt s a nd 1 m L /k g i n c hi ld r e n, in t r a ve n o us l y (I V ) 2 . Th i am in e 1 0 0 m g I V pu s h ( g lu c o s e c a n p r ec ip it a t e t h e W ern ic ke K o r s ak of f s y n d ro m e in t hi a m i ne - d ef ic i en t p a ti e nt s) 3 . N al o xo n e ( N a rc an ) 0.4 - 2 m g I V pu sh , if op i at e i n ge s t i on is s us pe c te d C . O b t ai n in g a hi s t o r y o f e xp o s u r e 1 . I de n ti f y th e s u bs ta nc e( s ) in ge s te d , t he r ou t e o f e xp o s u r e, t he qu an t i t y i n ge s te d , t he am ou n t o f t i m e s i nc e i ng es t io n , s ign s a n d s ym p t om s o f
o ve r d os e , a nd an y a s s oc i a t ed il ln es s o r i n ju r y . Co r r o bo r a te hi st o r y an d o t h e r p h ys ic a l e v i de nc e ( e . g ., pi l l co n ta i ne r s) f rom p re h os pi t al pr o v i de r s . 2 . N eu r o lo gi c a l e xa m i n a ti o n e v a lu a t es a n y se i zu re s , a l te r at i on s i n c o ns ci ou s n es s , c o n fu s i on , a ta xi a , s l u r re d s pe ec h, t r em o r, he a da c h e , o r s yn c op e . 3 . C a rd i op ul m o n a r y e xa m i na t io n e v a lu a t es a n y sy n c o p e , pa lp i ta t io ns , c o ug h , c he s t pa i n, s h o rtn e s s o f b re a th , o r bu r ni ng o r i r r it a ti o n o f t h e u ppe r a i r wa y. 4 . G as t r oi n te s ti na l ( G I) exa m i n a t io n e v a l ua t es a ny a b d om in a l p ai n , n au sea , vo m i ti n g, di a r rh e a, o r d iff i c u l t y i n s wa l l o wi n g. 5 . P as t m ed ic a l hi s to r y s h o ul d i nc l ud e a . Me d i c a t io ns , in c l ud i ng n o np r es c ri p ti on ( o ve r- t he - c ou n te r [ O TC ] ) s u bs ta n c e s b . U se of he r b al m e di c a ti o ns c . Al c oh ol o r d r ug ab us e d . P s yc h ia t ri c h is t o r y e . A ll e rg i es f . O cc u pa t io na l o r ho b b y e xp o s u r es g . Tr a ve l h . P r io r i n ge s t i on s i . S oc ia l h is t o r y wi t h p o te n t ia l f o r d om es t ic vio l en c e o r n e gl ec t j . La s t n or m a l m en s t ru al p e r io d o r p re gn a nc y P.509
D . R o u ti n e l ab o ra t o r y a s s es s m e nt 1 . C om pl e te bl o od c e ll (C B C ) c ou n t 2 . S e ru m e le c t r o l y te s 3 . B lo o d u re a n i t ro g en (B U N ) ; s er um c re a ti ni n e (S C r ) 4 . B lo o d g lu c o s e 5 . U r in a l ys is 6 . E le ct r oc a r di og r am ( EC G ) 7 . C he s t r o en t ge no g r am a n d /o r k i dn e ys , u re t e rs , a n d b la d de r ( K U B ) x- r a y E . To xi c o l o g y l a bo r a to r y t e s ts 1 . A d van t ag es a . C on f i rm or de t e rm in e t h e p r es e nc e o f a pa r ti cul a r a g en t b . P r ed ic t th e a n ti c i pa t ed t o xi c ef f ec ts o r se v e r i ty o f e xp o s u re to s o m e p o is o ns c . C on f i rm o r di s t i ng ui s h d i ff e r en t ia l o r c o nt r ib u tin g di ag n os is d . O cc as i on al l y he l p g uid e th e r ap y 2 . D is ad v a n t ag es a . Th e se te s ts c an n ot p ro v i d e a s p ec if ic di a gn os is f or al l p a ti e nt s . b . A ll po s s ib l e i nt o xi c a tin g ag e nt s c an no t be s c re e n ed . c . In c r i ti c a l l y i ll pa t ie n ts , s up po r t i v e t r ea t m e n t is n e ed e d b ef o re la b o ra t o ry r e s ul ts of t he to xi c o l og y s c re e n a r e a va il ab l e.
d . La b o ra t or y d r ug - d et ec t i o n a bi li t ie s d if f e r . e . I n g en e ra l , o nl y a q u al i t at i v e d e te r m i na t io n o f a s u bs t a nc e o r s ub s t a nc e s i s n ec es s ar y ; h o we v e r , qu a n ti t at i ve l e v e ls o f th e fo l lo wi n g d ru gs a re n e ce ss a r y to gu id e th e rap y : ( 1 ) A ce t am in op h en ( 2 ) A m i no g l yc os i de s ( 3 ) A rs e ni c ( 4 ) C a rb am a z e pi n e ( Te gr e t ol ) ( 5 ) C a rb o xy h e m o gl o bi n ( 6 ) C y c lo s p o ri n e ( 7 ) D ig o xi n ( L an o xi n ) ( 8 ) E t ha no l ( 9 ) E t h y le ne gl y c ol ( 1 0 ) Ir o n ( 1 1 ) L e ad ( 1 2 ) L i th i um ( Es k a li t h ) ( 1 3 ) Me r c u r y ( 1 4 ) Me t h an o l ( 1 5 ) Me t h em o gl ob i n ( 1 6 ) Me t h o t re xa t e ( 1 7 ) Ph e no b ar b it a l ( 1 8 ) Ph e n y to i n ( D i la n ti n ) ( 1 9 ) Sa l ic y l at es ( 2 0 ) Ta c r o li m u s ( 2 1 ) Th eo p h y ll in e ( 2 2 ) Va l pr o ic ac id ( D ep ak e ne ) ( 2 3 ) Va nc om y c i n F . S ki n d ec o nt am i na ti o n s h ou l d b e p er f o rm ed wh e n pe r c u t an e ou s a b so r p ti on o f a s ub s ta nc e m a y r e s u l t in s ys t em ic t o xi c i t y o r wh e n t he c o nt am i na t in g s ub s ta nc e m a y pr o du c e lo c a l to xi c e f f ec ts ( e. g . , ac i d b ur n s ). Th e p a ti e nt ' s c lo t hi n g is r e m o v ed , a n d t he a re as a r e i r r ig a t ed wi t h c op i ous q u a nt i ti es of wa t e r . Ne u tr a l i z at i on sh ou l d n ot be a t t em p te d . F o r e xa m p le , n e u t ra li z i n g ac i d b u rn s wi t h s od i um b ic a r bo na t e wi l l p r od uc e a n e xo t h e r m ic c h em ic al r ea c t i on , t h e reb y e xa c e r b at i ng th e p a tie n t ' s co n di t io n . G . G a s t ri c d ec on t am in a tio n m a y be a tt em p te d wh e n s u pp o r ti v e c a r e is b e g un . G I d ec on t am in a tio n in v o l v es r em o v al of th e i n ge s ta n t wi t h em es is o r l a va g e, th e u s e o f ac t i v at e d c ha r co a l p ot e nt i al l y to b in d a n y in g es ta n ts , an d t h e u se o f c a t ha r t ic s t o ha s te n e xc r e t i on an d th e re b y l im it ab so r p ti o n. P.510
1 . Em e s i s a . C on t r ai n di c a t io ns ( 1 ) C hi l d re n y ou n ge r th an 6 m on t hs of ag e ( 2 ) P a ti en t s wi t h c e n tr a l n e r v o us s y s t em ( C N S ) de p r es s i on o r s ei zu r es
( 3 ) P a ti en t s wh o h a v e i ng e s t e d a s t r on g a c i d , a lka l i , o r a s h a rp ob je c t ( 4 ) P a ti en t s wi t h c o m p r om is e d a i r wa y p r ot ec t i v e r e f le xe s ( i nc lu d in g c om a a n d c on v u ls i on s ) ( 5 ) P a ti en t s wh o h a v e i ng e s t e d s om e t y p es of h yd r o c a r bo ns o r p et r o le um d i st i ll a te s ( 6 ) P a ti en t s wh o h a v e i ng e s t e d s ub s t a nc es wi t h a n e xt r e m e l y r ap i d o ns et o f a c ti o n ( 7 ) P a ti en t s wi t h em es is a f t e r t he in g es ti o n b . S yr u p o f i pe c a c . O wi n g t o c on c e r ns of s a f et y , e f f ic ac y a nd th e d e la y o f a n t id o te ad m i ni s t ra ti o n , s y r u p o f i p ec ac is n o l o ng e r re co m m e nd ed f or g e n er a l us e . I p ec ac m a y b e a dm i ni s t e r ed wi t h in 3 0 m i n o f a n i ng es t io n an d 3
o n l y on th e a d v ic e of a po i s o n c on t r ol c e nt e r . Th e r e i s n o c on t r ai nd ic a ti on t o t he us e o f i pe c a c s y r up : an d Th e re is s u bs ta n tia l ri sk of s e r io us t o xi c it y t o t he vic t im : a nd Th e r e i s n o a l te r n at i v e t h e ra p y a v a i la b le o r e f fe c t i v e t o d e c re as e g as t r oi n te s t i nal a bs o rp t io n ( e .g . , a c ti v at e d c ha r c o a l ); an d Th e re wi l l b e a de la y o f g r e at e r t h an 1 h ou r be f o re th e pa t i en t wi l l a r ri v e a t a n e m e rg en c y m e di c a l f ac i lit y a n d i pe c a c s y r u p ca n b e ad m i ni s te r ed wi t h in 30 9 0 m i nu t es o f th e i n ge s t io n ; a n d I pe ca c s y r u p a dm i ni s t r a ti on wi l l n o t a d ve r s e l y af f ec t m o re def i n it i v e t r e at m e n t t h at m ig h t b e p r o v i de d a t th e h o sp i ta l . ( 1 ) Me c h a ni s m o f a c ti on . Th e o ns e t o f e m e s i s us u a ll y o cc u rs wi t hi n 3 0 m in a f t e r s y r up o f i pe c a c . Th e e f fe c t s l as t f o r a p pr o xi m a te l y 2 h r a n d p r od uc e a p p ro xi m a t el y t h r ee ep is o d es of em es is in 60 m i n. ( 2 ) D os a ge s . P at i en ts 6 -1 2 m o nt hs o f a ge , 5 - 1 0 m L ; p a ti en t s 1 -1 2 y e ar s o f a g e , 1 5 m L ; pa t ie n ts o l de r t ha n a g e 1 2 ye a rs , 3 0 m L . E ac h d os e o f s y r u p o f i p ec ac s h ou l d b e f ol l o wed wi t h 12 0 - 24 0 m L o f wat e r . Th e p a ti en t s h ou ld be u p r ig h t t o a v o i d ac c i d en ta l as pi r a ti on an d s ho u ld b e s u pe r v i s e d . ( 3 ) A d ve rs e e f fe c t s . D i a rr h e a , l et h ar g y / d ro ws i n ess , an d p r ol o ng ed ( > 1 h r) e m es is 2 . G as t r ic l a v a ge a . U se . G as t ri c l a v ag e i s i n f re q ue n tl y us e d i n p at ie n ts wh o a re no t al e rt o r h a ve a d im in is h ed ga g re f l e x. Th i s p r oc ed u r e sho u ld al s o b e co ns i de r ed i n p a t ie n ts wh o ar e s ee n ea r l y a ft e r m as s i v e in ge s ti o ns . Th is pr oc e du r e i s c o nt r a in di c a t ed in pa t ie nt s wh o ha v e in g es te d a c id s , a lk al is , or h yd r o ca r bo ns . In ad d it i on , pa t ie n ts s h ou ld no t r ec e i v e g as t ri c l a vag e i f the y a r e at r is k f or G I pe r fo r at i o n o r i f t h e y ar e c om b at i v e . b . P r oc ed u re . P at i en ts ar e pl a c e d i n t h e l ef t l a te ra l de cu bi t us po si t io n . L a va g e is pe r f o rm ed af t er a c u f fe d e n do t ra c h e al tu b e i s i n p la ce to p ro t ec t t h e a i r wa y . A f t e r as p ir a tio n of t he ga s t r ic c o nt e nts , 25 0 -3 0 0 m L o f t ap wa t e r o r sa li n e i s in s ti ll e d a nd t h e n as p i ra t ed . Th e s eq u e n c e s h ou l d b e r e pe a te d u n t il th e re t u rn i s c on t inu o us l y c l ea r fo r at le as t 2 L . 3 . A ct i va te d c ha r c o a l a ds o r bs a lm os t al l c om m o nl y i n ge s t e d d r ug s a nd c h em ic al s a nd is us ua ll y a dm i ni s t e r ed to m o s t o ve r d os e p a ti en t s as qu ic k ly a s p os s i b le . C om m o nl y in g es t ed s u bs t an c e s n ot a d s o r be d i nc l ud e e t ha n ol ,
i r o n, li t hi um , c y a n id e , e th y l e n e gl y c o l, le a d, m e rc u r y, m e t h an ol , o r g an ic s o l ven ts , po t as s i um , s t ron g ac id s, an d s t r on g a lk a l is . a . D os a ge . Ac ti v a t ed c ha r c oa l ( A c ti do se wi t h s o rb i t ol ) i s a v a il a bl e a s a c o ll oi d al di s p e rs io n wi t h wa t e r o r s o r bi t ol . I n a d u lt s , t h e d os e o f a ct i va t ed c h a rc oa l i s 2 5 -1 00 g ; t he d os e i n c hi l d re n 1 - 12 y ea r s o f a g e is 2 5- 5 0 g ; t he d o se in c h il d re n u p to 1 y e a r o f a ge is 1 g /k g. C on s ti p at i on ha s n ot be e n o b se r v e d a f te r th e a d m i ni s t ra t io n o f a s i ng l e d os e o f ac ti va t ed ch a rc oa l . Mu l t i p l e d os es of an y c ath a r ti c s sh ou l d b e a vo id ed b ec au se t he y c a n c au se e l ec t r ol y t e i m b a la nc es an d / o r d eh y d r a ti on . To xi c i n ge s ti on s wi t h d r ug s h a vi n g a n e nt e ro h ep a ti c c i rc u la ti o n ( e .g . , c a rb am a z e p i ne , t h eo p h y ll in e , p h e no ba r b it al , t ri c yc l ic an t i de p re ss an t s, ph e no t hia z i n es , d i gi t al is ) ge ne r a ll y r e q ui r e t h at t he c h a rc oa l b e re a dm in is t er e d e v e r y 6 h r t o p r e ven t r e a bs o rp t io n d u ri n g r ec i rc u la t io n . b . A d ve rs e e f fe c t s . C h a rc o al as pi r a ti on an d e m pye m a h a v e be en r ep o r ted i n t h e l i te r a tu r e . A s s u c h , c h a r c o al s h ou l d b e wi t h h el d if pa t ie n ts a r e v om i ti ng . B o we l o bs t r uc ti o n m a y P.511 o cc u r wi t h m ul t ip le do s es o f ac t i va te d c ha r c o al an d / o r p at i en ts wh o a re r e c ei vi ng c o nc om i ta n t t he r a p y wi t h n e u ro m u sc ul ar - b l ock i ng d ru gs .
4
H . W hol e -b o we l ir r i ga t ion h as b e en s h o wn t o b e e f f e c t i v e u nd e r c er t ai n c o nd i ti on s , p a rt ic u la r l y wh e n a c t i v a te d c h ar c o a l la c k s e f fi c a c y . An is os m ot i c c a th a r ti c s ol ut i on s u c h as po l y e th y l e ne gl yc ol ( Go L YTE L Y, C o l y t e ) i s u s ed . Th e d os a ge is 1 - 2 L / h r gi v e n o ra ll y o r b y n as o gas t r ic tu be un t il t he re c ta l e f f lu e nt is c l ea r . I . F o rc ed di u re s i s a nd u ri n a r y p H m a n ip ul a ti o n m a y b e u s ed to en h an c e th e e l im in a ti o n o f s ub s t a nc es , wh o s e el im in a ti o n is pr i m ar i l y re n al , i f t h e s u bs ta n c e ha s a re la t i v ely s m al l vol um e o f d is t r ibu t i on wi t h l i tt l e p r ot e in b i nd i ng . H o we v e r , t h e u s e o f t h es e m e t ho ds is ass oc i at e d wi t h f lu id an d e l ec t r ol y t e d is t u rb an c es . 1 . A lk al i ne di u re s i s p r om o t es t he io ni z a t io n o f we a k a c i ds , th e r eb y p r e ve n ti ng t he i r r e ab s o rp t i on b y th e k id ne y , wh i c h f ac il i ta t es th e e xc r e t i on o f su ch we a k a c i ds . Th is p r oc e du r e h as be en us ed i n t he m a na g em en t o f p a t ie n ts wh o ha v e in ge s te d lo ng - ac t in g b a r bi t ur a te s s uc h a s p he n ob a rb i tal o r sa li c y li c a c i d . P a ti e nts a re gi ve n 5 0 - 10 0 m E q o f s o di um bi c a r b on a te I V p u sh , fo ll o we d b y a c o n tin u o us i n fu s i o n o f 5 0 -1 0 0 m E q o f s od i um b i ca r bo n at e i n 1 L o f 0 . 25 % - 0 .4 5% no r m a l s al i ne , m a i n ta i ni ng a u r in e p H o f 7 . 3 - 8. 5 . U r i ne ou t pu t s hou l d b e 5 - 7 m L/ k g / h r. C om p li c a t io ns in cl ud e m e ta b ol ic al k a lo s i s , h y pe r n a tr em i a, h y p er os m o l ar i t y , an d fl ui d o v e r l oa d . J . D ia l ys i s . I n p at i en ts wh o fa i l t o r es p on d t o th e m e as u re s o f d e co n ta m i n at i on al r ea d y o u tl i ne d , h em od ia l y si s , a n d t o a le s s e r e xt e n t p e r it o ne a l d ia l y s i s , m a y e n h an c e dr u g e li m i n at i on . S ub s ta nc es th a t a r e r e m o ved b y h em o di a l ys is ge n e ra ll y a r e wa t e r so lu b le , ha v e a s m al l vol um e o f di s tr i bu t io n (< 0. 5 L / k g ) , ha v e a l o w m ol ec ul a r we i g h t (< 50 0 d a lt o ns ) , a n d a r e n o t s i g ni f ic an t l y b o u nd to pl as m a p ro t ei ns . H em od i al y s is u s u a ll y is
i n di ca t ed f o r li f e -t h r ea t en i ng in g es ti o ns of et h y l e n e gl y c ol , m e th an o l, o r p a r aq u at . Th is te c hn iq u e a ls o h as be e n u s e d t o en h a nc e t he el im i na ti o n of e t h an ol , th e op h y l li ne , l i th i um , s al ic y l a te s , a nd lo n g - ac t in g b a rb i tu r a te s . K . H e m o pe r f us io n i s a tec h ni q ue i n wh i c h an t ic oag u l a t ed bl o od is pa s s ed t h r o ug h ( p e rf us e d ) a c olu m n c o n ta i ni n g ac t i vat e d c h a r c o a l o r re s i n p a r ti c l e s . Th is m e t ho d o f e l im in a ti on c l ea r s s ub s ta n c e s f r om th e b l oo d m or e r a p id l y t ha n h em od i al y s is , bu t i t d o es no t c o rr e c t f l ui d a n d e le c t r ol y t e a b n or m a l it i es , a s d oe s he m od i al y s is . H e m o pe r f us i on , a l th o ug h m o re e f f ec t i v e i n r em o v in g phe n o ba r bi t al , p h en y t o in , c a r b am a z e pi ne , m e th o t re xa t e , a nd th e oph y l l in e th an he m od ia l y s is , i s l es s e f fe ct i ve i n r e m o vin g e t ha no l o r m e th a n ol . Co m p l ic at i on s o f h e m o p er f us io n i nc l ud e t h r om b oc y t op e ni a , l eu k op e ni a , h yp oc a lc em ia , h y p o gl y c em i a, an d h yp o t en s i o n.
III. MANAGEMENT OF SPECIFIC INGESTIONS A . A ce t am in o ph e n ( Ty l e n o l ) is a n a nt i p y re t ic - an al g e s ic th a t c an p ro du c e f a t al he p at o to xi c i t y i n u nt r e a te d p a ti e nt s t h ro u gh t h e g e ne r a ti on o f a t o xi c m e ta b ol i te . 1 . A va il a bl e d os ag e fo r m s . Ac e ta m i n op he n i s a v ai l ab l e i n a v a ri e t y o f O TC a n d p r es c ri p ti on d ru g p ro d uc ts . 2 . To xi c o k in e ti c s . A c et am i no p he n i s we l l ab s o r be d f ro m t he G I t ra c t an d h a s a h a lf - li f e b e t we e n 2 a n d 3 h r . L e ss t h an 5% i s e xc r e t e d u nc ha n ge d in t h e u r i ne ; t h e r em a in de r i s m e ta bo l i zed in th e l i v e r b y t he c y to c hr om e P4 50 s ys t em . 3 . C li n ic al p re s e n ta t io n a . P ha se I (1 2 -2 4 h r po s ti n ge s ti on ) . N au s e a , v o m it i n g, an o r e xi a , a n d d i ap h o re s i s b . P ha se I I ( 1 -4 da y s pos t in g es ti o n ). As y m p to m at i c c . P ha se II I (2 - 3 d a y s i n u n t r ea t ed pa t ie n ts ) . N a us e a, ab d om in a l p ai n , p r o g re ss i v e e v i de nc e of h e p at ic fa i lu r e , c o m a , a nd d ea t h P.512
4 . La b o ra t or y d a ta a . S e ru m ac e ta m i n op h en l e v e ls . P a ti e nt s wi t h l e ve l s g r ea t er t ha n 1 5 0, 70 , o r 4 0 m g /m L at 4, 8 , o r 12 h r a f te r in g es ti o n r e qu ir e a nt i do t al th e ra p y wi t h N - a c et yl - L -c y s te i ne ( N AC ) a c c o rd i ng to th e R um a c k - Ma t t h e ws n om og r am . b . B as el i ne li v e r fu nc t io n t e s t s s ho ul d b e d o ne in a l l p a ti en t s. c . R en al f un c t i on te s ts , in c lu di n g a B U N a n d S C r , s ho u ld be do n e. d . C oa g ul a ti o n s t u di es inc l ud e p r o th r om bi n t im e (P T) , p a r t ia l t h ro m b o pl as ti n t i m e ( P TT) , a n d b le e di ng t im e . 5 . Tr e a tm en t a . A du l t p at i en ts wh o h av e i n ge st e d > 10 g o r c hil d r en wh o ha v e i ng es t ed > 2 0 0 m g/ k g r eq u i re t re a tm e nt . El d e rl y a nd al co h ol i c p at i en ts ha v e an i n c re as ed s u s c ep t ib i li t y to ac e ta m i n op h en he p at ot o xi c i t y.
b . Th e re c o m m e nd ed t rea t m e n t i s G I de c o n ta m i na t i on wi t h a c ti va t ed c h a rc oa l . c . A nt id o ta l th e ra p y wi t h N A C i s i nd ic a te d fo r pa t ie n ts wi t h to xi c b lo o d l e ve ls of ac e ta m i no p he n . ( 1 ) N A C do s a g e is 14 0 m g /k g a s a l o ad in g d o se f o ll o we d b y 7 0 m g /k g e v e r y 4 h r f o r a to t al o f 1 7 d os e s . N A C is ad m i n is te r e d e i t he r or a ll y o r via a n a so g as t ri c t ub e . N A C (Mu c o m ys t ) 2 0 % c o n ta i ns 2 0 0 m g / m L . Ea ch do s e m us t be di lu t ed 1 :3 in ei th e r c o la or f ru i t j ui c e t o m as k t h e u np l ea sa n t t as t e a n d sm e ll . Th e d os e o f N A C s h ou ld be r ep e at e d i f th e p a ti en t vom i ts wi th i n 3 0 m i n o f a dm in is t r at i on . P a t ie n ts wi t h s e v e re nau s ea s e co nd a r y t o N A C m a y be p re t r ea t ed wi t h IV m et o cl op r am i de ( R eg la n ) 10 m g e v e r y 6 h r . Me t o c l o p ra m i de ac ts as a n an t ie m e t ic wh i le in c rea s i n g t h e r a te of N A C a b so r p ti on . ( 2 ) I V N A C ( A c e t ad o te ) ( a ) Lo a di n g d os e: 15 0 m g / k g o v e r 6 0 m in ( b ) Ma i n t en a nc e d os e : 50 m g / k g o ve r 4 h r fo l lo we d b y 1 0 0 m g/ k g o ve r 1 6 h r ( c ) A na ph y l ac t oi d re ac t ion s a r e o bs e r ve d i n a pp r oxi m a t e l y 20 % o f pa t ie n ts. C a u t io n s ho u ld be e xe r c is e d i n p at i en ts wi t h a h is t o r y o f a s t hm a . B . A lc o ho ls
5
1 . E th yl e ne gl y c ol a . A va il a bl e f o rm s . E th y le n e g l y c o l c om m o nl y i s u s ed in an t if r e e z e a nd wi n d s h ie ld de ic i ng s o lu t io n s . Th i s f o rm i s s om et im e s c o lo r l es s an d h a s a s we e t t as te . b . To xi c o k in e ti c s . E t h y len e gl y c ol is h e pa t ic al l y m e ta b ol i z e d b y al co h ol d e h yd ro g en as e to gl y c ola l de h y d e , wh i c h is m e t ab o li z e d b y a l de h yde d e h yd ro g en as e to gl y c ol ic ac id . G l y c o li c a c i d i s c o n ve r t ed to gl y o xy l i c a cid , wh o s e m o s t t o xi c m et a bo l i te is o xa l i c a c i d . c . C li ni c a l p r es e nt a ti o n ( 1 ) S t ag e I ( 0. 5 -1 2 h r s po s ti n ge s t i on ) . At a xi a , n ys t ag m u s , n au s e a a n d vo m i ti n g, de c re as e d d eep t en d on r ef l e xe s , a nd se v e r e ac id os is (m o re s e ve r e o v e r do s e s : h y p oc a l c e m i c t e ta n y an d s ei zur e s , c er e b ra l e de m a , c om a , a nd d ea t h) ( 2 ) S t ag e I I (1 2 -2 4 h r s po s ti n ge s t i on ) . Tac h yp nea , c y an os is , ta c h yc a rd ia , p u lm o na r y ed em a , a n d pn e um o ni ti s ( 3 ) S t ag e I I I ( 2 4 -7 2 h r s po s ti n ge s t i on ) . F l an k p ai n a n d c o s to v e r t eb r al an g le t e n de r ne s s ; o l ig u ri c r e nal f ai l ur e d . La b o ra t or y d a ta m a y re v e a l s e v e re m e ta b ol ic ac i do s i s , h y p oc al c e m i a , a n d c al c i um o xa l a te c r y s t a ls in th e ur i na l y si s . e . Tr e a tm en t ( 1 ) G as t r ic l a v a ge is pe r fo r m ed wi t h in 30 m i n o f in g es t io n . ( 2 ) I V e t ha n ol ( Et O H ) is u s ed in s i tu a ti o ns i n wh ic h fo m e pi z o l e is no t a va i la b le . ( a ) I nd ic a ti on s i nc lu d e an e th y l e ne gl yc ol le v e l > 2 0 m g /d L , su s p ic i on of i n ge s ti on p en di n g l e v el , o r a n a ni on ga p m e ta bo l ic ac id os is wi t h a h is to r y o f i n ge s ti on , r eg a rd l es s o f th e le v e l .
( b ) E t O H do s a g e ( i ) A n E t O H le v e l o f at lea s t 1 00 m g / dL s h ou l d b e m ai n ta i ne d . ( i i ) L o ad in g d o s e i s 7 . 5 -1 0 m L /k g o f a 10 % e t ha no l in de xt r o s e 5 % i n wa te r ( D 5 W ) o v e r 1 h r , fo ll o we d b y a m ai n te na n ce i n f us i on of 1 .4 m L /k g /h r . ( i i i ) I nf us i on r at es m a y ne e d t o b e i nc r e as ed in pa t i en ts r ec ei v i n g h e m o d ia l y s i s . P.513
( 3 ) F om ep i z ol e ( An t i z ol ) i s a po t en t in hi b it o r o f a lc o ho l d e h y dr o ge n as e t ha t c a n p r e v en t th e f o rm a ti on o f t h e t o xi c m e ta b ol it es o f e it h er m e t ha n ol o r e t h yl en e g l y c o l . ( a ) A dm in is t e r a l o ad in g d o s e of 15 m g /k g (u p t o 1 g ) i n 1 0 0 m L of D 5 W o r 0 . 9 % so d iu m c h l o ri de ( Na C l ) in f us ed o v e r 3 0 m i n. ( b ) Ma i n t en a nc e d os es : 1 0 m g /k g e v e r y 1 4 h r f o r 4 do se s , t he n i nc r e as e to 1 5 m g /k g (t o o f fs e t a ut o in d uc t io n p h en om en o n ) un t i l m e t ha n ol or e th y l e ne g l yc ol le v e ls a re < 2 0 m g / d L. ( 4 ) P yr i do xi n e ( 10 0 m g IV e v e r y d a y ) a n d t hi am i ne ( 1 00 m g I V e v e r y da y ) a r e c o fa c to rs t ha t m a y c o n v e r t g l y o xy l i c ac id t o no n o xa l a t e m e t ab o li t es . ( 5 ) S od i um b ic a r bo na t e is us ed as ne e de d t o c o r re c t t h e ac i do s i s . ( 6 ) H em o di al y s is . Et O H in f us i on m us t be c o nt i nue d , a n d t he r at e of a d m i ni s t ra ti o n m a y n e ed t o be i n c r e as ed . In d ic at io n s i nc lu d e e th y l e ne g l yc ol le v e l > 50 m g / dL , c o ng es t i v e h ea r t fa il u r e, r e n al f ai lu r e , a nd s e v e r e a c id os is . 2 . Me t h a no l a . A va il a bl e f o rm s i nc lu de g as - li ne an t i fr e e z e, wi n d sh i el d wa s h e r , a nd s om e s t e rn o . b . To xi c o k in e ti c s . A lc o hol d eh y d r og e na s e co n v e r ts m e t ha no l to f o r m a l de h y de , wh i c h is th e n c on ve r t ed to f or m i c a c id . c . C li ni c a l p r es e nt a ti o n ( 1 ) S t ag e I . Eu p ho r ia , gre g a ri o us ne ss , a n d m u s c le we a k ne s s fo r 6 -3 6 h r , d e p en di n g o n t he r at e o f f o rm a ti o n o f f o rm ic ac id ( 2 ) S t ag e I I . V o m i ti n g, up p e r a bd om i na l p ai n , d iar r h e a, di z z i n e s s , h e a da c h e , r es t le s s ne s s , d y s p ne a , b lu r r ed v i s i on , p h o to p ho bi a , b li n dn es s, c om a , c e re b ra l e d em a, c a r d ia c a nd r es pi r a to r y de p r es si on , s e i z u re s, an d d e a th d . La b o ra t or y d a ta in c l ud e s e v e r e m e t ab o li c ac i do s i s , h y p e rg l y c e m i a , a nd h yp e r am y l as em i a. e . Tr e a tm en t ( 1 ) G as t r ic l a v a ge . C ha rc o al ha s n ot be e n s ho wn t o ab so r b a lc oh o ls . ( 2 ) I V Et O H ( us e d i n s i t ua t i on s i n wh i c h f om e pi zol e is n o t a v a il a bl e ) ( a ) I nd ic a ti on s i nc lu d e an y p e ak m e th a no l l e v el > 2 0 m g /d L , a s us pi c i o us i n ge s ti on wi t h a p os it i v e h i s t o r y , o r an y s y m p t om a t ic pa t ie n t wi t h a n a ni on g a p a ci d os is . ( b ) A dm in is t r at i on is th e s am e a s p e r e t h y le ne glyc o l (s ee I II . B .1 ) .
( 3 ) F ol ic ac id ad m i ni s te re d at 1 m g/ k g (m a xi m um 5 0 m g ) I V e v er y 4 h r f o r 6 d o se s i nc r ea s e s t h e m e ta b ol is m o f fo rm a te . ( 4 ) F om ep i z ol e ( An t i z ol ) ( s e e I I I. B . 1. e . (3 ) ) ( 5 ) S od i um b ic a r bo na t e is us ed f o r s e ve r e a c i d osi s . ( 6 ) H em o di al y s is is u s e d f o r m e th an o l l e v el s > 50 m g /d L , se v e r e a n d r e s is ta n t a c i do s i s , r en a l f a i lu r e, o r v is ua l s y m p t om s . 6
7
C . A n t ic oa gu l an ts , ,
8
an d
9
1 . H ep a r in / L o w Mo l e c u la r W eigh t H ep a ri n (L MW H ) a . A va il a bl e d os ag e fo r m s in c l u de pa r en t e ra l d os a g e f o rm s f o r I V an d s u bc ut a ne o us a dm i ni s t r at i o n. b . To xi c o k in e ti c s . He pa r in h as a ha l f -l i fe of 1 -1 . 5 h r a nd is p r im a ri l y m e ta b ol i z e d in t he li v e r . Th e n e we r L MW H s —e noxa p a r i n ( Lo v e n o x) , d a l te pa r i n ( F r ag m i n ), ti nz a p a r in ( In n oh e p )— h a ve a l o n ge r ha l f- l if e , e s pe ci a ll y in p at ie n ts wi th r e na l f ai l u re . c . C li ni c a l p r es e nt a ti o n. L o ok fo r an y s ig ns o r s ym p to m s of bl e ed in g o r b r u is in g . d . La b o ra t or y d a ta . O bt ai n P TT, b l ee d in g t im e , an d pl a te le t c o un ts . e . Tr e a tm en t ( 1 ) S t op pi n g h ep a ri n a dm i ni s t r a ti on f o r 1 -2 h r a nd r es t a rt i ng th e r ap y a t a r e d uc ed do s e c a n re v e r s e m i l d o v e r -a n ti co a gu l at io n . P.514
( 2 ) S e ve re o v e rd os es m a y r e q ui r e t he ad m i n is t rat i o n o f p r ot am i ne . ( a ) P r ot am i ne c om b in es wi t h h e pa r in an d n e ut r a liz e s i t: 1 m g p ro t am in e n e u t ra li z e s 1 00 U he p ar in . ( b ) P r ot am i ne s h ou l d b e a d m i ni s te r ed s l o wl y, i nt ra v e n o us l y o ve r 10 m i n. Th e m a xi m um do s e of p ro t am i ne is 5 0 m g i n a n y 1 0 - m i n p e ri o d. ( c ) C on s i d er a bl e c on t r o ve r s y e xi s ts ab o ut t he m et h o d o f r e v e rs i ng th e o v er a n t ic oa g ul a ti on wi t h L MW Hs . So m e s o u rc es re c o m m e nd th e a d m i ni st r a tio n o f p ro t am in e t o n e ut r a li z e p a rt of t he ef f ec ts of t he s e a nt ic o ag u la n ts , wh e r e a s c as e r e po r ts r ep o r t ed s uc c e ss es wi t h rec om b in a nt fa c to r V II ( N o vo S e v e n ) . ( d ) Th e s e o v e rd os es s h ou l d b e re f er r e d t o a he m a t o l o gi s t a nd / o r t he po is o n c o nt r o l c e n te r . 2 . W ar f a ri n ( Co um a di n ) a . A va il a bl e d os ag e fo r m s in c l u de o ra l t a bl e ts a nd a s ol u ti o n f o r p a re n te ra l a d m i ni s t ra ti o n . b . To xi c o k in e ti c s . W ar fa ri n is we l l a bs o rb ed a ft e r o r a l a dm in is t r at i on . It s m e an ha l f -l if e i s 3 5 h r ; pr o t ei n bi nd i ng is 9 9 %, wi t h a 5 - da y d u ra t io n o f a c ti vi t y. V it am i n K - de p end e n t c l o t ti ng f ac to r s b eg in t o d ec li n e 6 h r af t e r a d m i ni s t ra ti o n , b ut th e r ap e u ti c a nt ic o ag u la t io n m a y r e q ui r e s e v er a l d a ys . c . C li ni c a l p r es e nt a ti o n in c lu d es m in o r b le e di n g, b r u is in g , h em a tu r ia , e p is t a xi s , a nd c o nj u nc t i va l he m o r r ha g e. Mo r e s e ri o u s bl ee d in g i nc l ud es GI , i n t ra c ra n ia l , r e t ro pe r i to ne a l , a nd wo u n d s i t e .
d . La b o ra t or y d a ta in c l ud e P T, in t e rn a ti o na l n o rm a l i ze d ra ti o ( I N R ), an d b l ee d in g t im e . e . Tr e a tm en t ( 1 ) I f P T o r I N R i s s li gh t ly e l e v a te d , wi t hh ol d wa r fa r i n f o r 2 4 -4 8 h r ; th en r e i ns ti t u te th e r ap y wi t h a r e d uc ed do sa g e. ( 2 ) I f P T o r I N R i s e le v a te d an d b l ee di n g, ad m i n is t e r 1 0 m g o f p h y to n ad i on e ( vi t a m i n K) o v e r 3 0 m in . P a t i en ts wh o a re bl e ed ing m a y r e qu i re t he a d m i ni s t ra ti o n o f b lo o d pr o d uc ts t ha t c on t ai n c lo t ti n g f ac t o rs . ( 3 ) F or m i ld o v e r -a n ti c o ag u la t io n , f o ll o w A m er ic an C o ll e ge of C he s t P h ys ic i an s ( A C C P ) gu i de l in es . ( 4 ) F or pa t ie n ts wi t h l i fe t h r e at e ni ng bl e ed in g or in t r ac r an i al he m o r r ha g e, t h e Am e ri c a n Co l le ge o f C h e s t P h y s i c i a ns re co m m e nd s t he us e o f p r o t hr om b in c o m p le x c o n c en t r at es o r r ec om b in an t f ac to r V II a to i m m e di a te l y r e v er s e t he I N R . D . A n t id ep r es s a n ts 1 . Tr i c ycl ic an t id ep r es s an t s ( TC A s ) a . A va il a bl e f o rm s i nc lu de am i t ri p t y li ne ( E la v i l ), no r t r ip t y l in e ( A v en t y l ) , i m ip r am in e ( To f ra ni l ) , d es i p ra m i ne ( N o rp r am in ) , do xe p i n ( S in e qu an ) , p r o t ri p t y li n e ( V i v ac t il ) , an d c l om ip r am in e ( An a f ran i l ). b . To xi c o k in e ti c s . Th e c om p ou n ds a r e h e pa t ic al l y m e ta bo l i z ed , u n de r go e n t e ro he p at ic r ec i rc ul a tio n , a r e h i gh l y bo un d to p l as m a p ro t ei ns , a n d h av e a n el im in a ti o n h al f -l i fe o f a p p ro xi m a t el y 2 4 h r . c . C li ni c a l p r es e nt a ti o n. A n t ic h ol in e r gi c e ff ec t s i nc l ud e m y d r ia s i s , il e us , u r i na r y r e te n ti o n, an d h y p e r p y r e xi a . C ar d io p ul m on a r y t o xi c it y e xh i b i ts t a ch yc a rd i as , c on d uc ti o n b l oc k s , h y p ot e ns io n , a nd p ul m o n ar y e de m a. C NS m a ni f es ta t io ns r an g e f r om ag i ta t io n a n d co n fu s i on t o h al l uc in a ti on s , s e i zu re s , an d c om a . d . La b o ra t or y d a ta . Bl o od l e v el m o ni t o ri ng do es n o t c o r re la t e we ll wi t h c l in ic al s i gn s a n d s y m p to m s o f t o xi c it y . S om e a ut h o rs s u gg es t th a t e l ec t r oc ar d io g ra p hi c m on i t or i ng is a b et t e r g ui de t o as s es si n g t he s e v e r i ty o f in g es ti o n. e . Tr e a tm en t ( 1 ) G I de c o n ta m i n at io n . S y r u p o f i pe ca c is n ot r ec om m e n de d b ec a us e p a t ie n ts m a y qu ic k l y b ec o m e c o m a t os e , i nc r ea s i ng t he r is k o f as p i ra t io n . A c t i v a te d c ha r c o al is gi v e n e v e r y 6 h r. ( 2 ) A lk al i ni z a t io n wi t h s od i um bi c a r bo n at e 1 - 2 m Eq / k g t o m a i nt a in an a r t e ri a l p H o f 7. 4 5 -7 . 55 d e c re as es th e fr e e f r ac t io n of t he ab s o r be d to xi n s , wh i l e r e v e rs in g s om e o f t h e c a rd i ac a b no r m a li t ies . ( 3 ) P he n y t oi n ( Di l an t in ) a n d /o r be n z o di a z ep i ne s m a y be r eq u ir e d t o c on t ro l s e i zu re s . P he n y t oi n m us t b e a dm in is t e re d a t a r at e no t e xc e ed in g 25 m g /m in be c a u s e of h y po te n s i v e s i de ef f ec ts . ( Fo sp h e n y to i n [ C e re b yx] m a y b e us ed be c a us e i t ha s a l o we r in ci de nc e of h ypo t e n s io n t h an ph e n yto i n.) P.515
( 4 ) P h ys o s t i gm in e 2 m g IV o v e r 1 m i n m a y be us ed t o r e v e rs e s e v e re a n t ic ho li n e rg ic to xi c i t y owi n g t o th es e d r ug s . B ec a u s e th is an t id o te m a y c a us e a s ys t ol e , t h e us e o f t hi s a nt i do t e f o r TC A o v e r d os es is d e cl in i ng . 2 . S el ec t i v e s er o to n in r eu p t ak e i nh i bi to r s ( S S R I s ) a . A va il a bl e f o rm s ( n on t ri c y c l ic ag e nt s ) i nc lu d e f l u o xe t i n e ( Pr o za c ) , s e r t ra li n e ( Z ol o ft ) , a n d pa r o xe t i n e ( P a xi l ) . b . To xi c o k in e ti c s . S S R I s a r e we l l a bs o rb ed a ft e r o r a l a dm in is t r at i on . Pe ak l e ve ls oc c u r wi t hi n 2 - 6 hs . S S R Is a r e h e pa t ic al l y m e ta b ol i z e d wi t h a h al f l i f e b et we e n 8 a nd 30 h r. c . C li ni c a l p r es e nt a ti o n in c lu d es m il d s y m pt om a to l o g y . P a ti e nt s m a y b e co m e ag i ta t ed , d r o ws y , o r c on f us e d. S ei zu r es a n d c a rd io v a sc u la r to xi c it y a r e ra r e . d . La b o ra t or y d a ta . E C G m on i to r in g i s re c o m m end e d . B l oo d l e v el m o ni t o rin g i s n o t r ec o m m en de d . e . Tr e a tm en t in c l ud es g as t r ic l a va ge an d s up p o rt ive t r e at m en t . S om e t o xi c o l og is ts m a y r ec om m e nd th e u s e o f c yp ro h ep t a di ne ( P e ri ac t in ) to m a na g e t he s e r ot o ni n s yn d r om e , wh i c h m a y m an if e s t as a r es u lt o f t he s e i n ge s ti on s . E . B e n z od i a z ep in e s 1 . A va il a bl e f o rm s i nc lu de c h l o rd ia ze p o xi d e (L ib r iu m ) , d ia z e p am ( Va li um ) , f l u ra ze p am ( D al m a ne ) , m i da z o l am (V e rs e d ), lo ra ze p am ( A ti v a n ) , a lp r a zo l am ( Xa n a x) , a n d t ri a z o la m (H a l c i o n) . 2 . To xi c o k in e ti c s . Th es e d r u gs ar e he pa t ic al l y m et a b ol i z ed . 3 . C li n ic al p re s e n ta t io n in c lu d es d r o ws i ne s s , a t axi a , a n d c on f us io n . F a t al i ti es a re ra r e . 4 . La b o ra t or y d a ta . D ru g l e v e l m o n it o ri n g is no t in d ic a te d . 5 . Tr e a tm en t a . S up p o rt i v e t r e at m e n t in c lu d es g as t r ic e m p t yi ng, a c t i v a te d c ha r c o a l, an d a ca t ha r t ic . b . Fl um a z e ni l ( Ro m a z i c on ) is gi ve n 0 . 2 m g I V o ver 3 0 s ec ; re pe a t d os es of 0 . 5 m g o v e r 30 s ec a t 1 -m i n i nt e r v al s f o r a m a xi m um cu m u la t i v e d os e o f 5 mg. ( 1 ) Fl u m a z e ni l h as a s hor t e li m i na t io n h a lf - li f e . ( 2 ) C a re f ul ob s e r v a t io n fo r r es ed a ti o n is ne c es s ar y , e s pe c i al l y fo r i n ge s ti on s o f l o ng - ac t in g b e n z od i a zep in es . ( 3 ) Fl u m a z e ni l i s c on t ra in d ic a te d i n m i xe d o v e rdo s e p at i en ts ( pa r t ic ul a rl y i n vo l vin g t ri c yc l ic a n ti d ep r e s s an ts ) in wh o m s ei z u r e s a re li k e l y . F . β - ad r e ne r gi c a n ta go n is t s 1 . A va il a bl e d os ag e fo r m s . C la s s e xa m p l es in c l ude p r op r an o lo l ( I nd e r al ) , m e to p r ol ol ( Lo p re s s o r ), a n d a t en o lo l ( Te n o rm i n) . O r a l an d p a re n te r al d o sa g e f o rm s a re a v ai l ab l e . 2 . To xi c o k in e ti c s . A l l o f th e m em b e rs wi t hi n th is c l a s s d i f fe r i n re g ar d to r e n al ve rs u s h ep a ti c e lim i na t io n , l ip id so lu b il i t y, a n d p r ot e in bi nd i ng . P a t i en ts m a y b ec om e t oxi c o wi n g t o c ha n ge s i n o r g an f un c t i on .
3 . C li n ic al p re s e n ta t io n in c lu d es h yp o te ns i on , b ra d y c a rd ia , an d a t r io ve n t ri c u l a r b lo c k . B ro n c h os p as m m a y oc c ur , p a r ti c ul a rl y wi t h n o nc a rd i os el ec t i v e a ge n ts . 4 . La b o ra t or y d a ta in c l ud e s e r um e l ec t ro l y t es a nd b lo od gl u co s e (p a ti e nts m a y be c om e h y p og l y c e m i c ) . 5 . Tr e a tm en t a . G I de c o n ta m i na t io n i nc l ud es ga s tr ic la va g e a nd ac t i v a te d c ha r c o al . b . G l uc ag o n is gi v e n 5 0 -1 5 0 µg / k g as a lo a di ng do s e o v e r 1 m i n , f ol lo we d b y a co n ti nu o us i n f us io n o f 1- 5 m g /h r . c . E pi ne p h ri ne s h ou l d b e u s e d c a ut io u s l y in β - bl oc k e r o ve rd os es . U n o p po s e d α - re c e p to r s ti m ul a ti on in t he fa c e o f c o m pl e te β - re c ep t or bl oc k m a y le a d t o p r of o un d h y p e r t en s i on . d . C al ci um s a l ts (s ee C al c iu m C h an n el A nt a go ni s t s ) e . H ig h D os e I ns ul i n D e xt r o s e (s e e C a lc iu m Ch ann e l An t ag on is t s ) G . C a lc i um c h an ne l a n tag o ni s ts 1 . A va il a bl e f o rm s i nc lu de v e r a pa m i l ( C a la n ) , d il t i a z e m ( Ca r d i zem ) , a nd the d i h yd ro p y r i di ne c l as s ( n if e d ip in e d e r i v at i ves [ P roc a r di a ]) . P.516
2 . To xi c o k in e ti c s . On s e t o f ac t io n i s a pp r o xi m a te ly 3 0 m i n , wh e r e as th e d u r a ti on is 6- 8 h r . Se v e ra l c om p ou n ds a r e a v a i lab l e a s su s ta in e d - re le as e d o sa g e f o rm s , wh i c h m ay c o n t ri bu t e t o p r ol o ng ed t o xi c i t y. 3 . C li n ic al p re s e n ta t io n . H y p o t e ns io n i s c om m o n t o al l c la s s es . B ra d yc a r di a a n d a t r io v e n tr ic u la r bl oc k a re m o r e c o m m o nl y see n wi t h i n ge s t i on s o f ve r a p am il o r d il t ia z e m . Pu l m o n ar y e de m a a nd s e izu r e s ( v e ra pa m i l ) h a ve b e e n r ep o r te d . 4 . La b o ra t or y d a ta in c l ud e E C G an d s e ru m e le c tr o l y t es . 5 . Tr e a tm en t a . G I de c o n ta m i na t io n i nc l ud es ga s tr ic la va g e, ac t i v a t ed c h a rc oa l , a nd wh o l e - b o we l i r r ig a ti o n ( es p ec ia ll y f o r i n ge st i on s wi t h s us t ai n ed - r el ea se p r o du c ts ) . b . C al ci um . C al c i um c h lor i d e 1 0% ( 10 - 20 m L ) I V p u sh is g i v e n f o r t h e m a na g em en t o f h y po t en s i o n , b r ad y c a rd ia , o r he a rt b l o c k . c . G lu ca g on do s a g e is t he s a m e as fo r β - bl oc k e r o v e r d os e . d . C om bi n ed in s u l in an d d e xt r o s e a dm i ni s t r a ti o n h a s b ee n u s e d i n s el ec t ed c as e s. Th is s h ou l d b e u s e d on l y in c o ns ul t at i on wi t h a po is o n c o n t ro l c e nt e r . e . P ho sp h od i es te r as e I nh i bi t o rs . I n am r in on e o r m i lr i no n e. H . C o ca i ne 1 . A va il a bl e f o rm s i nc lu de a lk al oi d o b ta i ne d f r om E r y t h r o xy l o n c oc a. 2 . To xi c o k in e ti c s . Co c a in e is we l l a bs o rb e d a ft e r o r al , in ha l at i on a l, i n t ra n as al , an d I V ad m i nis t r at i on . C oc ai ne is m e tab o li z e d i n th e l i v e r a nd e xc r e t e d i n t h e u r in e .
3 . C li n ic al p re s e n ta t io n in c lu d es C N S a nd s ym p ath e t ic s t im ul a ti on ( e. g . , h yp e r t en s i on , ta c h y p n ea, t ac h y c a r d ia , n a us ea , vo m it i ng , s ei z u r es ) . De a th m a y r es ul t f ro m r es pi r a to r y f a il u re , m yo c a r d ia l i nf a r ct i on , o r c a r di ac a rr e st . 4 . La b o ra t or y d a ta in c l ud e c oc a in e a n d c o ca i ne m e ta b ol i te u ri ne sc re e ns. 5 . Tr e a tm en t is s up p o rt i ve : be n z o di a z e pi ne s f o r se d a ti on s e i z u re t re a tm e nt , L a b et al o l ( N o rm o d y ne ) fo r h y p er t e ns io n . I . C o r ro s i v e s 1 . A va il a bl e f o rm s i nc lu de s tr o ng ac id s o r a lk a li s . 2 . To xi c o k in e ti c s . Co r r os i v e s a r e we l l a bs o rb ed af t e r o r a l a nd in ha l at i on al a d m i ni s t ra ti o n . 3 . C li n ic al p re s e n ta t io n . Th e s e c om p ou nd s p r od uc e b u r ns o n c on t ac t . 4 . La b o ra t or y d a ta . A rt e ri a l b lo o d g as es ( A B Gs ) , c h es t ra di o g ra ph s , a nd at l e as t 6 h r o f o bs e r v a ti on a r e re qu i r ed fo r in ha l at i o n e xp o s u r e . 5 . Tr e a tm en t is d ec o nt am i na t io n . E xp o s e d sk in m us t be ir r i ga t ed wi t h wa t e r . N e u t r al i z a ti on s h o ul d b e a v o i d ed be c a us e t h es e re a c t i on s a r e e xo t h e rm ic a n d wi ll p ro d uc e f u rt h e r t i s s ue da m a g e . J . C ya ni d e 1 . A va il a bl e f o rm s i nc lu de i nd us t r ia l c he m i ca ls and so m e na i l -p ol is h r e m o ve rs . 2 . To xi c o k in e ti c s . Th e d ru g is ra p id l y ab s o r be d a ft e r o ra l o r i n ha l at io n e xp o s u r e . 3 . C li n ic al p re s e n ta t io n in c lu d es h e ad ac h e, d ys pn e a , n au s e a , v o m it in g , a t a xi a , c o m a , s ei z u r es , a n d d e at h . 4 . La b o ra t or y d a ta in c l ud e c y a n id e l e ve ls , A B G s , e le c tr o l yte s , a nd an E CG . 5 . Tr e a tm en t . a . C ya ni d e a n ti do t e k it ( 1 ) A m yl ni t r it e Pe a r ls a re c ru s h e d a nd he l d u nd er t h e p at i en t ' s n os t ri ls . ( 2 ) S od i um n i t ri t e 1 0 m L I V p us h . C o n v e rt s h em og l ob i n t o m et h em og l ob in, wh i c h bi n ds th e c y a ni de i o n . ( 3 ) S od i um th io s u l fa t e 50 m L o f a 2 5 % s o l ut i on IV p us h . Ma y b e re p ea t ed i f t h e r e is no r es po ns e . P.517
b . O xyg e n c . S od iu m b ic a rb o na t e. A s ne e de d f o r s e ve re ac id o s i s d . H yd r o xy c o b a la m i n ( C y a n ok i t ) ( 1 ) A du l t d os e i s 5 g r am s I V o v e r 15 m i nu t es . Dos e m a y be r ep ea t ed f o r a t o t al do s e o f 1 0 g r am s . N o d at a ar e a va i la bl e fo r p e di a t ri c d os in g .
7
K . D i go xi n ( L a no xi n ) 1 . A va il a bl e d os ag e fo r m s in c l u de o ra l a nd pa r e nte r a l. 2 . To xi c o k in e ti c s . Di go xi n is we l l a bs o r be d , is p ri m a r il y r en a ll y e li m i na t ed, a n d h as a h al f - li f e o f 3 6 -4 8 h r. I ts v ol um e o f di s t ri b u ti on is 7- 1 0 L /k g . E q u il i br a ti o n b et we e n s er u m l e ve l a nd m y o ca r d ial b i n di n g r e qu i re s 6 - 8 h r .
3 . C li n ic al p re s e n ta t io n in c lu d es c on f us io n , a no re xi a , n a us ea , a n d vom it in g i n m i ld c as es . In m o r e s e v e r e c as es , c a r di ac d ysr h y t h m i as a re s e en . 4 . La b o ra t or y d a ta in c l ud e s e r um d i go xi n l e v el s , e l ec t r ol y t es , p a r ti c u l a rl y s e r um p o ta s s iu m l e v el s , a n d a n E C G . 5 . Tr e a tm en t a . D ec o nt am i na t io n wi t h a c ti v a t ed c h a rc oa l i s r e c o m m e nd e d. b . S up p o rt i v e t h e ra p y inc l ud es m a na g in g h yp e rk a l em i a o r h y p ok al em i a an d i n o tr o pi c s up po r t a s n e ed e d . c . D ig o xi n - s p ec i fi c F a b an t i bo di es ( D ig i bi nd ) . To d e t e rm in e t h e d os ag e , us e t h e fo ll o wi n g f o rm u la
E a c h vi a l c o n ta i ns 4 0 m g o f d ig o xi n a nt i bo di e s (D i g i bi nd ) an d s ho u ld be r e c on s t i tu t ed wi t h 4 m L o f s t e ri l e wa t e r . L . E le ct r o l y te s 1 . Ma g n es i um a . A va il a bl e d os ag e fo r m s in c l u de o ra l , r ec t al , a nd p a re n te r al . Ma g n es iu m c o nt a in in g c a th a r ti c s (e .g . , m a gn es iu m c it r a te ) ha v e b ee n re p or t ed t o p r o du c e h y p er m a g ne s e m i a in pa t ie n ts re ce i vi ng re p e ti t i v e d os es wi t h a c ti va t ed c h a rc oa l . b . To xi c o k in e ti c s . Ma g nes i um i s f o un d i n tr ac e ll ula r l y a nd is re na l l y e l im in a te d . c . C li ni c a l p r es e nt a ti o n ( 1 ) Mi l d : D ee p t e nd o n r ef l e xe s m a y b e d ep r es s e d; l et h a rg y a nd we a kn e s s ( 2 ) S e ve re : R es pi r at o r y p a r al y s is an d h e ar t bl oc k ; pr o lo n ge d P R, Q R S , an d Q T i n t e r v a ls d . La b o ra t or y d a ta ( 1 ) Mi l d : > 4 m E q/ L ( 2 ) S e ve re : > 1 0 m Eq / L e . Tr e a tm en t is 1 0 % c a lc i u m c h l o ri de 10 - 2 0 m L to t e m p o ra r il y a n ta go n i z e t h e c a rd i ac e f f ec ts o f m ag n es i um . I n s e v e re c as es , he m o di a l ys is m a y b e r e q ui r e d. 2 . P ot a s s iu m a . A va il a bl e d os ag e fo r m s a re o ra l a nd pa r e nt e r al. b . To xi c o k in e ti c s . P o ta s s i u m is p ri m a r il y a n i nt r ac e l lu l a r c a t io n . C h an g es in a c id - ba s e ba l an c e p ro d uc e s hi f ts in se r um p o ta ss i u m va l ue s ( e .g . , a 0. 1 - U i n c re as e i n s e ru m p H p ro d uc es a 0 . 1- 0 .7 m Eq / L d e c re as e i n s e ru m p o t ass i um v al u es ) . c . C li ni c a l p r es e nt a ti o n in c lu d es c a rd ia c i r r it a bi l i ty a n d p e r ip he r a l we a k nes s wi t h m in o r i nc r ea s es . C ar d i ac d ys r h y t hm ia s , in c l ud i ng b ra d y ca r d ia , m a y p r o g re ss to as y s to l e. d . La b o ra t or y d a ta . E C G d a ta in c l u de pe ak e d T wa v e s a n d p r ol o ng a ti on o f t h e Q R S c om pl e x. P.518
e . Tr e a tm en t ( 1 ) C al c i u m . A dm in is t er c a lc iu m ch l o ri de 10 % 1 0- 2 0 m L t o a n ta g on i z e th e c a r di ac ef f ec ts of h y p er k a l em ia . ( 2 ) S od i um b ic a r bo na t e . 1 - 2 m E q /k g I V i n c r e as es s e ru m p H an d c au s e s an i n t ra c el lu l ar s h i ft of p ot as s i um . ( 3 ) G l uc os e a nd in s u l in . 5 0 m L o f 50 % d e xt r o s e an d 5 -1 0 U o f r e gu l ar i n su li n a r e a dm i ni s t e r ed v i a I V p u s h to s h if t po t as s i um fr om t he e xt r a c e l lu la r fl u id in t o t he c e l ls . ( 4 ) C a ti on e xc h a ng e re s in s b i nd po t as s i um i n e xc h a n ge fo r an o th e r c at i on ( s o di um ) . So di um po l y s ty r e n e s u lf o na t e ( K a ye xa l a t e ) i s g i v en 15 g/ 6 0 m L wi t h 2 3 .5 % s o rb i to l i n d os es 15 - 3 0 g b y m ou t h e ve r y 3 - 4 h r as n e ed ed u nti l t h e h yp e rk a le m i a re s o l ve s . Al te r n at i ve l y, 5 0 g of s od i um p o l ys t yr e ne s u lf o na t e c a n b e gi v e n re c ta l l y i n 2 0 0 m L o f s o d iu m c hl o r id e a s a re t en t ion e n em a . ( 5 ) H em o di al y s is is re s e rv e d f o r l if e - th r ea t en i ng h yp e r k al em ia t ha t d o es no t r e s po nd t o t he ab o v e m ea s u re s . M. I r o n ( F e ) 1 . A va il a bl e d os ag e fo r m s . N um e ro us O TC p r o duc t s a r e a v a il ab l e. To xi c i ty i s b as e d o n t he am o un t o f el em e nt a l i ro n i n ge s ted : su l fa t e sa l t 2 0% e l em e nt al F e; fu m ar a te s a l t 3 3 % e le m e n ta l F e ; a nd g lu c o n at e s al t 1 2 % e l em e nt al F e. 2 . To xi c o k in e ti c s . I r on is a bs o r be d i n t h e d uo d enu m a n d j ej un u m . 3 . C li n ic al p re s e n ta t io n a . P ha se I . N a us ea , v om i t i ng , d i ar r h ea , G I b le e din g , h y p o te n si on b . P ha se I I. C li n ic al im p ro v e m en t s e en 6- 2 4 h r p os t in g es ti o n c . P ha se II I . Me t a bo l ic ac i do s i s , r en a l a nd he pa t ic f ai lu r e , s e ps is , p u lm o na r y ed em a , a n d de a t h 4 . La b o ra t or y d a ta in c l ud e s e r um F e l e v e ls , t o ta l i r on - b in di n g c ap ac i t y ( TI B C ; i s c on t r o v e rs ia l ), A B G s , li ve r fu nc t io n t e s ts ( LF Ts ) , he m o gl o bi n , an d h e m a t oc r it . R ad io l og ic al e v a l u at io n of th e a b do m e n no t es th e p r es en c e o f r a d io p aq u e pi l ls . 5 . Tr e a tm en t a . D ec o nt am i na t io n . F o r i n ge s ti on s > 40 m g /k g . Ga s t ri c l a vag e u si n g s o di um bi c a r bo n at e i s o f q u es ti o na b le ef f ic ac y. W hole - bo we l i r ri g at i on is u s ed fo r la r ge in g es ti o ns . b . S up p o rt i v e t r e at m e n t c . D ef e r o xa m in e ( De s f e ra l ) i s u s e d t o c h el at e i r on . A dm in is t e r 2 5 -5 0 m g/k g u p to a d os e o f 1 g , a nd o b s e r v e fo r a r e d c o l o r in t he u ri n e. Th e n a d m i ni s te r at a r a te of 15 m g / k g / h r u p t o a m a xi m um do s e o f 6 g / da y . C o n t in u e u nt i l s e r um ir on is wi t h in t he th e ra p eu t ic r an g e. N . I so n ia z i d (I N H ) 1 . A va il a bl e d os ag e fo r m s in c l u de o ra l a nd pa r e nte r a l.
2 . To xi c o k in e ti c s . I N H is we l l a bs o rb ed o ra l l y . P ea k l e ve ls a r e wi t hi n 1 - 2 h r p o st i ng es t io n . I s o ni a z i d is he p at ic a ll y m e t ab o li zed . 3 . C li n ic al p re s e n ta t io n in c lu d es n a us ea , v om i ti ng , sl u r re d s pe ec h , a ta xi a , g e n er a li z e d t o ni c -c lo ni c s e i z u re s, an d c om a . 4 . La b o ra t or y d a ta in c l ud e s e v e r e l ac ti c a ci do s i s , h y p og l y c em i a , m il d h yp e r ka le m i a , a nd le u k oc y t o s i s . 5 . Tr e a tm en t a . D ec o nt am i na t io n . A v oi d em es is b ec a us e p a ti en t s a r e a t h ig h ri s k fo r d e ve l op in g s ei z u r es ; fo r s e v e r e i ng es t io ns us e a c t i v a t ed c h a rc oa l g as t r ic l a va g e. b . P yr i do xi n e , wh i c h r e ve r s es I N H -i nd uc e d s ei z ur e s , is gi ve n i n g r am do s e s e q ui va l en t to th e a m o u nt o f i s on ia zi d i n ge st e d. Py r i d o xi n e is m i xe d as a 1 0 % s ol u ti on in D 5W a nd i nf us e d o ve r 3 0 - 60 m i n. c . S od iu m b ic a rb o na t e c o r r ec t s t he ac id os is . P.519
O . L e ad 1 . A va il a bl e f o rm s i nc lu de l ea d -c on t ai n in g p ai n t or g as o li ne f um e i nh al a ti on . 2 . To xi c o k in e ti c s . L ea d ha s s lo w d i s t ri bu t io n , wi t h a ha l f -l i fe of a p p ro xi m a t el y 2 m o nt hs . 3 . C li n ic al p re s e n ta t io n in c lu d es n a us ea , v om i ti ng , ab d om in al p ai n, p e r ip h e ra l n eu r o pa t hi es , c on v u ls i on s , a nd c om a . 4 . La b o ra t or y d a ta in c l ud e an em i a a nd an el e v a te d b l oo d - le ad le ve l . 5 . Tr e a tm en t a . E de t at e c a lc iu m d is odi u m ( c a lc i um d is o di um Ve r s e n a te ) i s g i ve n 5 0- 7 5 m g /k g /d a y in t r am us c u la rl y ( I M) o r vi a sl o w I V in 4 d i v id ed d os es . b . D im e rc ap r o l ( B A L ) is g i v e n 4 m g /k g I M e v e r y 4 h r f o r 3 - 5 d a y s. P . L it h iu m ( E s k al i th ) 1 . A va il a bl e d os ag e fo r m s in c l u de li qu i d, c a ps u les , an d t a bl e ts (i m m ed ia te a n d s us t ai ne d re le a s e ) . 2 . To xi c o k in e ti c s . L it h ium is we l l a bs o rb e d a f te r o r a l a dm in is t r at i on . It is n o t a p p re c i ab l y bo u nd t o p l as m a p r o te i ns a n d h as a s m a ll v o lu m e of d i st r ib u ti o n ( V d ) o f 0 . 5 L /k g . El im in a ti o n is r en al , wi t h a ha l f -l i fe of 14 - 2 4 h r . 3 . C li n ic al p re s e n ta t io n a . Mi l d : Po l y u r ia , b l ur r e d v i s io n , we ak n es s , s l ur r ed s p e ec h , a ta xi a t r em o r , a n d m y o c l on ic je r k s b . S e ve re : D el i ri um , c om a , s e i z u re s , a nd h y pe r t he r m ia 4 . La b o ra t or y d a ta a . Th e r ap e ut ic r an ge : 0.6 - 1 . 2 m Eq / L b . Mi l d to xi c i t y : 1 .5 - 2. 5 m E q /L c . Mo d e r a te to xi c i t y : 2. 5 -3 m Eq / L d . S e ve re to xi c i t y : > 3 m E q / L 5 . Tr e a tm en t
a . S up p o rt i v e c a re , i nc l ud i ng ba s i c l i fe s u pp o r t an d fl u id an d e le c t ro l y t e r e p la ce m e n t b . D ec o nt am i na t io n ( 1 ) S yr u p o f i pe c a c n o t re c om m e nd e d ( 2 ) A ct i v a te d c ha r c o a l i ne f f ec t i v e ( 3 ) S od i um p o l ys t y r e ne s u l f on a te ha s b ee n e f f ec tiv e i n e xp e r i m en t al m o de ls . N ee d t o m on i to r p o ta s s iu m l e v el s . ( 4 ) W hole - b o we l i r r ig a ti on f o r l a rg e i ng es t io ns , es p e c i al l y t ho se in v o l v i ng s us t ai n ed - r el e as e p r od uc t s ( 5 ) H em o di al y s is fo r s e ve r e l y s y m p to m a t ic p a ti e nt s wi t h a cu t e e xp o s u re l e ve ls > 2 . 5 m Eq / L o r c hr o n ic l e ve ls > 1 .5 m Eq / L. N o t e : L it h iu m l e v el s m ay r i s e a ft e r d i al y s is o wi n g t o a r e bo u nd ef f ec t . Q . O p i a te s 1 . A va il a bl e d os ag e fo r m s in c l u de o ra l i m m ed ia t e- r e l ea s e an d s us t ai ne d r e l ea se p re p ar a ti o ns as we l l a s p a re n te r al ag e nts . 2 . To xi c o k in e ti c s . S om e a g e nt s h a v e p r ol o ng ed el i m i na t io n h a lf - li v e s (e . g., h e r oi n , m et h ad on e ) . 3 . C li n ic al p re s e n ta t io n in c lu d es re s p i ra t o r y d e p re s s i on an d a de c re as e d l e ve l o f c on s c io u s n es s . R a r e ef f ec ts in c l u de h y po t e ns io n , b r ad y c a rd ia , an d p u lm o na r y ed em a . Se i z ur e s h a ve b e en r ep o rt e d in p at i en ts wi t h r en al d ys f un c ti o n in in d i v id u als wh o a re r ec ei v i n g m e pe r i di n e o wi n g t o th e a cc u m u la t io n o f th e m eta b ol i te no r m e p e ri di n e. 4 . La b o ra t or y d a ta in c l ud e ba s e li n e A B G s a n d t oxi c o l o g y s c re e ns . 5 . Tr e a tm en t a . N al o xo n e is gi v e n 0 . 4-2 m g e v e r y 5 m i n u p t o 10 m g an d 0 . 03 - 0 .1 m g /k g i n pe di a t ri c p a ti en t s . N alo xo n e h as a ver y s ho r t ha l f -l i fe , an d r e se da t io n is a co nc e r n i n p at i en ts o ve r d os in g o n l o ng - ac t in g o p i o i ds o r s u s t a in ed r e l ea se do s a g e f o rm s . P.520
b . N al m e f en e ( Re v e x) h a s a h al f - li f e o f 4 - 8 h r . I nit i a l d os ag es a re 0. 5 m g /7 0 k g . A f ol lo w- u p d os e 2 - 5 m i n l at e r i s 1 m g /7 0 k g. R . O r g a no p ho s p ha t es 1 . Th e r e a r e a v a ri e t y o f a v a i la b le fo r m s ; t h e y ar e u s u a ll y p es ti ci d es o r c h em ic al wa r f a r e a ge n ts . 2 . To xi c o k in e ti c s . O rg a no p h os ph a te s a r e a bs o rbe d th r o ug h t h e l un gs , s kin , G I t r ac t , a n d c o n ju nc t i v a. 3 . C li n ic al p re s e n ta t io n in c lu d es e xc e s s i v e c h ol i ne r g ic s t im ul a ti o n. 4 . La b o ra t or y d a ta in c l ud e r ed bl oo d c el l a c e t y l c h o li n es te r as e a c ti v i t y. 5 . Tr e a tm en t a . D ec o nt am i na t io n b . A t ro p in e i s g i v en 0. 5 -2 m g I V t o re ve r s e th e pe r i ph e r al m us c a r in ic e f f ec ts .
c . P ra l id o xi m e (2 - P A M; P r o t op a m ) is gi v e n 1 g IV o v e r 2 m i n a n d r e pe a te d i n 20 m i n as ne e de d . S . S a li c y la t es 1 . A va il a bl e d os ag e fo r m s in c l u de a v a r i et y o f O TC p r o du ct s : o r al , re ct a l, a n d t o pi c a l . 2 . To xi c o k in e ti c s . S a li c y la t es a re we l l a bs o r be d af t e r o r a l a dm in is t ra t io n . Th e h a lf - li f e i s 6 -1 2 h r a t l o we r d os es . I n o ve r d os e si t ua t io ns , th e h a lf - li f e m a y be p ro l on ge d to m o re t ha n 2 0 h r . 3 . C li n ic al p re s e n ta t io n in c lu d es n a us ea , v om i ti ng , ti n ni t us , a n d m a l ai s e ( m il d to xi c i t y ) . L e th a r g y , c on v u ls i on s , co m a , a n d m e ta b ol ic ac id os is ap p ea r i n m o r e s e v e r e o v e r d os es . P ot e nt ia l c om pl ic a ti o ns f ro m t h e ra pe u ti c a nd t o xi c d os es in c l u de G I b le e di n g, in c re as e d P T, he p a ti c t o xi c i t y, p a nc r ea t i ti s , an d p r o te inu r i a. 4 . La b o ra t or y d a ta fo r the f ol l o wi ng 6 -h r po s t i ng es t io n l e v e ls a r e : a . 40 - 6 0 m g / dL : ti nn i tu s b . 60 - 9 5 m g / dL : m o de r ate t o xi c i t y c . Mo r e t ha n 9 5 m g/ d L: s e v e r e to xi c i t y d . W it h t h e p r es en c e of a c id em i a a nd ac id u ri a , ev a l u a te A B G s . e . I n a dd i ti on , l a bo r a to r y e v a l ua t io n m a y s h o w l eu k oc yt os is , t h r om b oc y t op e ni a , i nc r ea s ed o r d ec r ea s e d s e rum gl uc os e a n d s od iu m , h yp o ka l em ia , a n d i nc r eas e d s e r um B U N , c r ea t in in e , a n d k e t on e s. 5 . Tr e a tm en t a . D ec o nt am i na t io n . R e pe t i ti v e do s e s o f a c ti v a t ed c h a rc o al e v e r y 6 h r, wi t h 1 d os e o f c at h a rt ic fo r pa t i en ts wh o in g es t ed > 15 0 m g /k g . W hol e- b o we l i r r i ga t io n f o r l a rg e i n ge s ti o ns . b . A lk al i ne di u re s i s is giv e n as n ot e d in d ec on t am i na t io n s ec ti o n t o e nh an c e s a li c yla t e e xc r e t io n . Thi s i s i nd ic a te d fo r l e ve ls > 4 0 m g /d L . c . H em od i al y s is i s u s e d fo r s e v e r e i n to xi c a t io ns wh e n s e ru m l e v el s a r e > 1 0 0 m g/ d L. Th i s m e t ho d o f de c o n ta m i n at i on is m u c h b et t e r t h an re p et i ti v e d o se s o f a c t i v a te d c h ar c o a l . d . Fl u id an d e l ec t ro l y t e re p la c em en t i s a dm in is t e re d as n e ed e d. e . V it am i n K ( A qu am e phy t o n ) an d f r es h fr o z e n p la s m a a r e u s e d to c o r re c t a n y co a gu l op a th y . T. S n a k e bi t es 1 . Typ e s . Th e r e a r e n um e r o us s p ec ie s o f s na ke s f o u nd wo r l d wi d e . Th e ve n o m o us s n ak es fo u nd i n N o rt h Am e ri ca in c l ud e t h e f ol l o wi n g: r at t le s n a ke , c o t to nm ou t h , c o p pe r he ad , an d c o ra l . B ec a us e p at i e nt s m a y b e e xp o s e d to m o r e e xo t i c s na k e s , a he r p e to lo g is t s ho ul d b e c o n su l te d f o r a m o r e d e f in i ti v e id en t i fi c a ti o n . 2 . To xi c o k in e ti c s . On s e t o f s ym p to m a t ol o g y d e pen d s o n t he sp ec i es o f s n ak e a nd t he pa t ie n t 's u n d er l y i ng m e di ca l c on d it i o n. 3 . C li n ic al p re s e n ta t io n in c lu d es n a us ea ; v om i ti ng ; di a r rh e a; s ync op e ; t a ch yc a rd i a; an d c ol d , c la m m y s k i n. Lo c a l fi nd i ngs in c l u de pa i n, ed em a , an d e r y t h em a . Mo r e s e v e re en v e n om a ti o ns c an le a d to se v e r e ti ss ue in ju r y , c om p a rt m e n t s y n d ro m e , a n d s ho ck .
P.521
4 . La b o ra t or y d a ta a . C B C an d p l at el e t c oun t b . C oa g ul a ti o n p ro f il e c . Fi b ri n d e g ra da t io n p r od u c t s d . E le ct r o l y te s e . B U N , S C r, an d u r i na l ys is 5 . Tr e a tm en t a . S up p o rt i v e . Mo v e t h e p a t ie n t a wa y f r o m s tr ik i ng d is ta nc e o f th e s na k e . I d e al l y, t h e p a ti en t s h ou ld b e t r an sp o r te d t o a m ed i ca l f ac i li t y as s o on as p o ss ib l e. C on s tr ic t i v e c lo t h in g , r in g s , wa t c he s, et c . s ho u ld be r em o ved . Te t a n us im m u ni z a t io n s ho u ld be as s e s s ed , an d s u r g ic al in t e r v en t io n m a y b e n e ce ss a r y fo r s e v e r e c as es . b . A nt i v e no m s ( 1 ) A n ti v e ni n ( C ro t al id a e) p ol y v a l e n t is a h o rs e -de r i v e d p r od uc t th a t h as b e e n r ep o r te d t o pr o du c e a ll e rg ic r ea c t i on s. F or m i ld bi t es , t he r e c om m e nd e d d os e is 5 -1 0 v i al s; m o de r a te , 10 - 20 ; an d s e v e re e n ve n om at i on s m a y r e qui r e 2 0 or m o r e vi a ls . ( 2 ) C r o ta li d ae po l y v a l en t i m m un e Fa b i s a p o l yv a le n t a n ti v e n in m a de f ro m s h ee p s ou r c e s . Th e in i tia l do s e is 4 - 6 v ia ls di l ute d in 25 0 m L o f 0 . 9% n o r m a l s al in e ( N S ) a dm in i s t e r ed o ve r 1 h r . Ad di t io n al do s es m a y be r e q ui r e d f o r s e v e r e e n v en o m a t io ns . U . Th e o ph y l l in e 1 . A va il a bl e d os ag e fo r m s in c l u de li qu i d, s u s t a in ed - r e le as e t a bl e ts a n d c a ps ul es as we l l a s p a ren t e r al fo r m s . 2 . To xi c o k in e ti c s . W ell ab s o rb ed o ra l l y wi t h a V d o f ap p r o xi m at e l y 0 . 5 L /kg . Th e o p h y ll i ne is h e pa t ic all y m e ta bo l i z ed an d h as a h a lf - li f e o f 4 - 8 h r . Th e o p h y ll i ne c l ea r an c e d e p en ds hi gh l y on ag e , c o nc o m it a nt di s ea s e s t a te s , a n d i n te r ac t in g d r ug s . 3 . C li n ic al p re s e n ta t io n in c lu d es n a us ea , v om i ti ng , se i zu re s , a nd c a r di ac d ys r h yt hm ia s . C h r on ic toxi c i t y c a r ri es a p oo r e r p ro g n os is t h an ac u te t o xi c i t y. 4 . La b o ra t or y d a ta . Th e ra p e ut ic th e op h yl li ne le v el s a r e 5 - 20 µ g /m L . H yp e r g l y c e m i a a n d h y p ok a le m i a a r e s ee n wi t h ac u t e i n ge st i on s . O t he r u s ef u l l ab o ra t o r y te s t s i nc l ud e s e ru m e le c t r o l y te s , B U N , c r e at i ni n e, he p at ic f u nc t io n , a nd E C G m o ni to r i ng . 5 . Tr e a tm en t a . S up p o rt i v e t h e ra p y inc l ud es m a in t ai ni n g a n a ir wa y a n d t r ea t in g s ei z u re s a n d d ys r h y th m i as as th ey o c c u r . b . D ec o nt am i na t io n . S y r u p of ip ec ac no t r ec om m e n d ed . c . Ac t i vat e d c ha rc o al ( rep e t it i v e d os es ) t o e nh anc e e l im in a ti on . W ho le b o we l i r ri g at io n fo r m as s i v e i ng es t io ns ( es pe ci al ly wi t h s us t ai n ed - r el e as e p r o du c ts ) . C h a rc oa l h em o p e r fu s i on is us ed in uns t ab l e p at i en ts wh o a re in
s t a tu s e pi le p ti c u s . H em od i al y s is is u s e d wh e n h em o p e r f us io n i s u n a va il ab l e. d . β - ad r e ne r gi c a nt a go n is t s ( e .g . , e sm ol ol , B re vib l oc ) ar e u s ed to t re a t t he h yp o t en s i o n, ta c h yc a r di a, a nd d y s rh yt hm i as c au se d b y e l e v at e d c y cl ic a d e no s i ne m o no p ho s p h at e le v e ls .
IV. REFERENCES A . A m e r ic a n A c a d em y o f C l i ni c a l To xi c o lo g y an d E u r o pe a n A ss oc ia t io n o f P o i so ns C en t r es a n d C l in i c a l To xi c o lo gi s ts . P o s i ti o n s ta t em en t : Si n gl e -d os e a c ti va t ed c h a rc oa l . Cl in To xi c o l 1 9 97 ; 3 5 :7 2 1 -7 41 . B . A m e r ic a n A c a d em y o f C l i ni c a l To xi c o lo g y an d E u r o pe a n A ss oc ia t io n o f P o i so ns C en t r es a n d C l in i c a l To xi c o lo gi s ts . P o s i ti o n s ta t em en t : S y r up of i p ec ac . Cl i n To xi c o l 19 97 ; 3 5: 6 99 - 70 9 . C . A m er ic a n C o ll e ge of E m e r ge nc y P h y s i c i a ns . C l i ni c al p o li c y fo r th e i nit i a l a p p ro ac h to pa t ie n ts p r es e nt i ng wi t h a c ut e t o xi c in g es t io n o r de r m a l o r i n ha l at i on e xp o s u r e . A n n E m e rg Me d 1 99 9 ; 3 3: 7 35 - 7 62 . P.522
D . A m er ic a n C o ll e ge of E m e r ge nc y P h y s i c i a ns . C l i ni c al p o li c y fo r th e i nit i a l a p p ro ac h to pa t ie n ts p r es e nt i ng wi t h a c ut e t o xi c in g es t io n o r de r m a l o r i n ha l at i on e xp o s u r e . A n n E m e rg Me d A p ri l 1 9 95 ; 25 : 2 7 0 - 58 5 . E . A m e r ic a n H e a rt As s oc i a t io n . To xi c o l o g y i n E CC . C i r c u la t io n [S p ec ia l i ss u e] 20 0 5; 1 12 : I V1 26 - IV 1 3 2 . A v a i la bl e a t ww w. c i rc u la ti o na h a. o r g. F . A ns el l J , Hi r s h J , H y l ek E , e t a l . P h a rm ac ol o g y a n d m a n ag em e nt o f t he vi t a m i n K a nt a go n is ts . Am e r ic an C ol le g e o f Ch est P h ys ic ia ns E v i de nc e B a s ed C li ni c al P ra c ti c e G u i d el i ne s ( 8 th E di ti o n ). C h e st 20 0 8; 1 33 : 16 0s 1 9 8s . G . B o n d R C . Th e ro l e o f a c ti v a t ed ch a rc oa l a n d ga s t ri c em p t yi ng i n g a st r o in t es ti n al de c o n tam i na t io n : A s t a te - o f- t he -a r t r e v ie w. A n n Em e rg Me d 2 0 0 2; 3 9: 2 73 - 28 5 . H . G o l d B S , D ar t R C , Bar i s h R A . Bi t es of v e no m ou s s na k es . N e w E n g l J Me d 2 0 0 2 ;3 4 7: 3 47 - 35 6 . I . H i rs h J , Ba ue r K A , D on a t i MB , e t a l. P a re n te r al a nt ic o ag ul a nt s . A m e r ica n C o l l eg e o f Ch es t P h ys ic ia n s E v i d en c e - B as ed C li ni c al P ra c ti c e G ui d el i ne s ( 8 t h Ed i ti on ) . C he s t 20 08 ; 1 33 : 14 1s - 1 59 s . J . Sc h ul m a n S, B e y th R J , K e a ro n C, e t a l. H em o rr h a gi c c om pl ic a ti on s o f a n t ic oa g ul an t an d t h ro m b o l y t ic tr e at m e n t . A m e r ica n C ol l eg e o f Ch es t P h ys ic i an s E v i d en c e - B as e d C l in ic a l P r ac t ic e G u id e li n es (8 t h E d it i on ) . Che s t 2 0 0 8; 1 33 : 25 7s - 29 8s . K . L it o vi t z TL , Kl e in - Sc hwa r t z , R o d g e rs G C , e t al. 2 00 1 a n nu a l r ep o r t o f th e A m e ri c an As s o c i a ti o n o f P o i s o n Co n t ro l Ce n te r s To xi c E xp o s u r e S u r ve i ll a nc e S y s t em . A m J Em e rg Me d 2 00 2 ; 20 : 1- 6 2 .
L . Me g a r b an e B, B o rr o n SW , B au d F J . C u r r en t rec om m e n da t io ns f or t he t r e a tm en t o f s e v e r e t o xi c a lc o ho l p oi s on in gs . In t en s i v e C a r e Me d 2 0 0 5; 3 1: 1 89 - 19 5 . M. Mo k h l e s i B , L ei k e n J B , Mu r r a y P , e t a l . A d ul t t o xi c o l og y i n c ri t ic al c a re p a r t 1 : G en e ra l a p p ro ac h t o t h e i nt o xi c a te d p a ti en t . C he st 20 0 3; 1 23 : 57 7 592. N . Mo k h l es i B, Le ik e n J B , Mu r r a y P , e t a l . A d ul t t o xi c o l og y i n c ri t ic al c a re p a r t 2 : G en e ra l a p p ro ac h t o t h e i nt o xi c a te d p a ti en t . C he st 20 0 3; 1 23 : 89 7 922. O . P a l ou c e k F . An t id o ta l f l um a z en i l us e — Th e p r ot a m i n e o f t h e 9 0s . C r i t C a r e Me d 1 99 9 ;2 7 :1 0 - 11. P . P a t ro n o C , B ai ge n t C , H i r s h J , R o th G . An t ip lat e l et D r ug s . A m e r ic an C o l l eg e o f Ch es t P h ys ic ia n s E v i d en c e - B as ed C li ni c al P ra c ti c e G ui d el i ne s ( 8 t h Ed i ti on ) . C he s t 20 08 ; 1 33 : 19 9s - 2 33 s . P.523
STUDY QUESTIONS D i r e ct i on s : E ac h o f t h e qu e s t i on s , s t a te m e n ts , o r i n c o m p l et e s ta t em e nt s c a n b e c or r ec t l y a n s we re d o r c o m p l et e d b y on e o f t he s u gg es t ed an s we rs o r p h r as es . Ch o os e t h e b es t a ns we r . 1 . A p h ys i c i a n r ec e i ve s a ca l l f ro m th e pa r e n t o f a 2 - ye a r - o l d c hi l d w h o h a s in g es t ed a n u nk n ow n q u a nt i t y o f m o r p h ine c on t r o l le d - r el e as e t a b l e ts an d is now u n co n s ci o u s. T he ph ys i c i an ' s in i t ia l r e c o mm e nd a t io n is t o ( A ) c al l em e r ge nc y m ed ic a l se r v i c e s ( E MS ) a n d h a ve th e c hi l d t ak e n t o t he ho s p i ta l e m e r ge nc y d e p a rt m e n t . ( B ) a dm in is t e r 1 g / k g of a c ti va t ed ch a rc oa l wi t h s o r b it o l. ( C ) a dm i ni s t e r s y r u p o f ip e c a c 1 5 m L b y m o u th to i nd uc e vom it i ng . ( D ) s ug g es t t h at th e c hi ld r ec e i ve em e r ge nc y h em o di al y s is . ( E ) s ug ge s t t ha t th e c hi ld r ec e i v e ac i d d iu r es is wi t h a m m on i um c h lo r id e . V i e w A n s we r 1 . T h e a ns we r is A [ se e I. A ] . 2. A g r a nd f a t h e r a r r i ve s a t yo u r p h a r m a c y a s k i n g to p u r ch a se a b o t tl e of s yr u p o f i p e ca c to ke e p i n h is h om e i n th e e ve nt o f a p o is o ni n g w he n gr a n d c hi l d r en a re vi s i t i n g . W ha t sh o u ld yo u t e ll h im ? ( A ) A dm i ni s t e r 1 5 m L o f s yr u p o f i p ec ac at th e fi rs t s i gn of an i n ge s ti on . ( B ) S y r u p o f i p ec ac is n o l o ng e r r ec om m en de d b y t h e A m er ic a n A s s o c i a ti o n o f P o is on Co n t r ol C en t e rs a n d t he Am e r i c an Ac a de m y o f P e d ia t r ic s . ( C ) P r o v i de hi m wi t h t he t o l l- f r ee nu m b e r f o r t h e p o is o n c o n t ro l c e nt e r . ( D ) B o t h B an d C .
V i e w A n s we r 2 . T h e a ns we r is D [ se e II . G . 1 .a ] .3 . An u n co n sc i o us p a t i en t is b r ou g h t i n t o t h e em e r ge n c y d e p a r t me n t . Th e p a t ie n t i s gi ve n 5 0 m L of 50 % d e x t r o s e i n w a t e r , t h ia m in e 1 0 0 m g IV , f ol l ow ed b y n a l ox o n e 1 m g , a t w hi ch p o in t he aw ak e ns . Thi s p at i e nt m os t li k el y h a s o ve r d o s e d o n w hi c h o f t h e f ol l ow i ng su b s ta n ce s ? ( A ) m et h an ol ( B ) a m i t ri p t y li n e ( C ) c oc ai n e ( D ) h al o pe r id o l ( E ) h e ro in V i e w A n s we r 3 . T h e a ns we r is E [ se e II I . Q .5 ] . 4. C on t r a i n di c a ti o ns t o t h e ad m in i s t ra t i o n o f syr u p o f i p e c ac i nc l ud e w h ic h of t h e f o ll ow i n g? ( A ) a n u nc on s c i ou s p at i en t ( B ) a pa ti e nt wh o is e xp er i e nc in g a ge n e ra li ze d ton i c -c lo ni c s ei z u r e ( C ) a pa t ie n t wh o h as ing e s t e d a c a us ti c s ub st a nc e ( D ) A l l o f t h e a bo v e ( E ) N o ne o f t he ab o v e V i e w A n s we r 4 . T h e a ns we r is D [ se e II . G . 1 ]. t he a ns we r t o qu es t io n 2 5 . An u nc o n sc i ou s pa ti e n t is b ro u g h t t o th e em e r g en c y d e p a r tm e n t w i t h a h is to r y o f a n u n k now n d r ug o ve r d o se . Wh i ch o f th e f o l l ow i ng ac t i on s sh o uld t h e p h ys i c i a n p e r f o rm ? ( A ) a dm in is t e r 5 0 m L o f 5 0 % d e xt r o s e, t hi am in e 1 0 0 m g I V pu sh , a n d n al o xo n e 0 .4 m g IV p u s h ( B ) p r ot ec t th e p a ti e nt ' s a i r wa y a n d e ns u re t ha t vi t a l s i g ns a r e s ta b le ( C ) o r de r th e fo ll o wi n g l ab o r a to r y t es ts : c om pl e te b l oo d c o un t ( C B C ) , e le c t r o l y te s , a nd a t o xi c ol o g y s c re en ( D ) A l l o f t h e a bo v e V i e w A n s we r 5 . T h e a ns we r is D [ se e II ] . 6. A p a t i en t w h o o ve r do s es o n ac e t am i no p h en is ad m i t t ed t o t h e h o sp i t al f o r a n t id o ta l t he r a p y w it h N - a c e t yl - L - c ys t e i n e ( NAC ) . T h e p a ti e n t h as t he f o l low i n g m ed i ca t i o n o r d e r s : N AC 1 4 0 m g / kg l o a d in g do s e f o ll ow e d b y 7 0 m g / kg f o r a t ot a l o f 1 7 do s es , r an i t i di n e 5 0 m g IV e ve r y 8 h r , p r o chl o r p e r az i ne 10 m g I M e ve r y 6 h r a s n ee d ed f or n a u se a , t h ia m in e 1 0 0 m g IV e ve r y d a y f o r 3 d o s es , an d Da r vo c e t N -1 0 0 1 - 2 t a b le t s e ve r y 4 h r a s n e ed e d f o r h e a da c he . Wh a t i s th e b e s t c o u rs e of a ct i o n? ( A ) C a ll t he ph y s ic ia n t o i n c re as e t h e d os ag e o f ra n i ti di n e t o 5 0 m g IV every 6 hr. ( B ) C a ll t he ph y s ic ia n t o h a ve th e D ar vo c et N - 10 0 d is co n ti n ue d . ( C ) C a l l t he ph y s ic ia n t o i n i ti a te he m o di a l ys is t he r a p y. ( D ) H a v e t he pa t ie n t p rop h y l ac t ic al l y in t ub a te d t o p r o te c t t he ai r wa y. ( E ) A dm i ni s t e r e t ha n ol 10 % at a l oa d in g d os e o f 7 . 5 m L /k g o v e r 1 h r, f o l lo we d b y a c on ti n uo us i n fu si o n o f 1 . 4 m L /k g / hr f o r 4 8 h r . V i e w A n s we r 6 . T h e a ns we r is B [ se e II I . A ]. O TC P . 5 2 4
7 . E t h yl a l c o h o l ( E t O H ) i s a dm i ni s t e re d to pa t ie n t s w ho ha ve i n ge s t ed e i t h e r e t h yl e n e g l yc o l o r m e th a n ol be c au s e E tO H ( A ) h el ps s e da t e p a ti en ts . ( B ) i nc r ea s e s t h e m e t abo l is m o f e t h y le ne gl y c ol a n d m et h an o l. ( C ) b lo c k s t h e f o rm at i on o f t he to xi c m et a bo li t es o f e th y l en e g l y co l a n d m et h an o l. ( D ) i nc r ea s e s t h e r e na l cl e a ra nc e o f et h yl en e g l yc o l a nd m e th a no l . ( E ) is n ot an an t id o te fo r e t h y le n e g l yc o l o r m e tha n ol o ve rd os e s. V i e w A n s we r 7 . T h e a ns we r is C [ se e II I . B ] .8 . A p a ti e n t w i th r e na l f a i l u r e i s i n ad ve r t e n t l y g i ve n 3 d o se s o f p ot a ss i u m c h lo r i d e 4 0 m Eq IV i n 1 00 m L o f 0. 9 % s o d iu m ch l o r i de o ve r a 3 -h r p e r i od . Th i s e r r o r is i m m ed i a te l y d i s c o ve r e d a n d a ST AT s e r u m p ot a s s iu m l e ve l is 8. 0 m E q /L . Th e pa t ie n t is br a d yc a r d i c w i t h a ma r ke d l y p r o l o n g ed Q R S c o m pl e x. T he pa t i en t sh o u l d r e ce i ve w h i ch o f t h e f ol l ow i ng ? ( A ) c al c i um c h lo r id e 1 0 % 1 0 m L I V pu sh ( B ) s od iu m b ic a rb o na t e 5 0 m E q IV pu s h ( C ) i ns ul i n 1 0 U a nd 50% d e xt r o se 50 m L I V p us h ( D ) s od i um p o l ys t y r e ne s u l f on a te 30 g b y m o u th ev e r y 3 h r fo r 4 doses ( E ) N o ne o f t he ab o v e V i e w A n s we r 8 . T h e a ns we r is A [ se e II I .L . 2 ]. 9 . Pa re n t e r al ca l c iu m i s u s e d a s a n a n t id o t e f o r w h ic h o f t he f ol l ow i ng s i t u a ti o ns ? ( A ) v e r a pa m i l o v e r do s es ( B ) h y p e rk al em i a ( C ) c oc ai n e i nt o xi c a ti o n ( D ) v e r a pa m i l o v e r d os es a n d h y p e rk al em ia V i e w A n s we r 9 . T h e a ns we r is D [ se e II I . G I II . L .2 ] . 10 . A 6 5 - ye a r - o l d w o ma n w i th n o rm a l r e na l f u nc t i on is a dm i ni s te r e d a 0 .2 5 m g d o se o f d i g o xi n I V p us h . A s e r um l e ve l o b t ai n ed 1 h r af t e r d r u g a dm i n is t r a ti on i s 5 n g /m L . Y o u r re c omm e n da t i on t o t h e p h ys i c i a n i s w hi c h o f t he f o l l ow i ng ? ( A ) A dm i ni s t e r 2 v i al s o f d i go xi n i m m u ne an ti b od ie s S TA T. ( B ) A dm i ni s t e r re p et i ti v e d os es o f ac t i v a te d c ha rc o al . ( C ) C a l l a n e ph r ol o gi s t , a n d p u t t he pa t ie n t o n he m od i al y s is . ( D ) R e p ea t th e s er um dig o xi n l e vel 6 -8 h r a f te r th e do se , a n d r e a s s es s t he pa t ie n t. V i e w A n s we r 1 0 . T he an s w e r is D [ se e I II . K ] .1 1 . A 1 6 - ye a r - o l d w o ma n i s r e po r t e d t o ha ve o ver d o s e d o n 4 0 s u st a i ne d- r e l e as e th e op h yl l i n e t a b l e ts . Sh e is t r an s po rt e d t o t h e e me r g en c y d e p a r t me n t , w h e r e g as t ri c l a va g e w as pe r f o r me d a n d s h e w as gi ve n o ne d o s e o f ac t i va t ed c h a r co a l . An i n i t ia l t heo p h yl l i n e l e ve l i s 4 2 µg/ m L , b u t a fo l l ow - up le ve l i n t h e i n te n si ve c a re un i t ( I C U ) i s 9 5 µ g/ m L . Wh a t is t he m os t a p p r o p r ia t e c o u rs e o f th e r a p y? ( A ) c ha rc o al he m o p e rf usi o n a nd m u l ti pl e - do s e ac t i v a t ed c h a rc oa l ( B ) s y r up o f i pe c a c a dm in i s t r a ti o n
( C ) f o rc e d a lk al in e d i u res is ( D ) n as o ga s t r ic ad m i ni s tr a t io n of s o di um - po l ys t yre n e s ul f on a te V i e w A n s we r 1 1 . T he an s w e r is A [ se e II I . T] . 1 2. A 2 3 - ye a r - o l d m a n is a d m i t te d to t he i nt e ns ive c a r e un i t (I C U ) a f te r i n g es t i n g 2 0 a c e ta m i no p he n ta b le t s 5 0 0 m g w i t h a s ix - pa c k o f b ee r . H e w a s in i t ia l ly aw ak e a n d a le r t i n t h e e m e r ge n c y d e p a r t m e n t a n d w as g i ve n o ne d ose o f a c ti va t e d c h a rc o al . H i s i ni t i a l a ce t am i n op he n l e ve l t ak e n a p p r o xi m at e l y 2 h r a f t er i n g es t i on i s 9 0 µ g /m L . W h a t w o u l d b e t h e m os t a p p r o p r ia t e c o u rs e o f ac t i o n? ( A ) A dm i ni s t e r re p ea t ed d o s e s o f a c t i v a te d c h ar co a l a nd s o r bi t ol . ( B ) A dm i ni s t e r s y r u p o f ip e c a c. ( C ) A d m i ni s te r a lo a di n g d o s e of N - ac e t yl -L -c y s t ein e ( N A C ) , a nd r e p ea t th e a c e t am in o ph en l e vel in 4 h r . ( D ) D i s c ha r g e t he pa t ie nt t o h om e . V i e w A n s we r 1 2 . T he an s w e r is C [ se e I II . A ] .m g1 3 . An o ve r d o s e vi c t i m p r es e nt s to t he e m e r ge n c y d e p a r t m e n t w i t h a n e l e va te d he a r t r a t e , de c r ea se d bl o o d p r e s su r e , d i l at e d p u p ils , a nd le t h a rg y. U p o n a r r i va l t o th e in t e ns i ve c a r e u n i t (I C U ) , s h e h as a ge n e ra l iz e d t o ni c c l o n ic se iz u r e th a t i s t re a t e d w i t h I V d ia ze p am a n d fo s ph e n yt o i n . W h ic h o f t h e f o l low i n g i s th e m o s t l i ke l y i n t o x i ca n t ? ( A ) e t h y l al c oh ol ( B ) m et h an ol ( C ) a c e t am in o ph en ( D ) o xy c o d o n e ( E ) a m i t ri p t y li n e V i e w A n s we r 1 3 . T he an s w e r is E [ se e II I . D ] . P. 5 25
ANSWERS AND EXPLANATIONS 1 . Th e an s we r is A [ s e e I. A ] . P a t i en ts wi t h un s t a bl e v it a l s ig ns s h ou l d b e t ak en t o a n e m e r ge nc y d e p ar t m e n t f o r im m e d ia te t r ea tm e nt . 2 . Th e an s we r is D [ s e e I I . G . 1 .a ] . I n d uc ed v o m i ti n g is no lon g e r a n a cc ep t ab l e o pt i on o f m an ag i ng po is o ni ngs a t ho m e be c au s e it is a re l a ti v e l y in e ff ec t i ve m et ho d of r em o v in g t o xi n s and r e s ul ts in a d el a y in ad m i n is t er i ng an t id o ta l t h e ra p y . I t i s i m p o rt a nt t o c o un ci l p a ti e nt s o n p oi s on p r e v en t io n a nd t o g i ve p a r en t s a nd ot h e r f r ie nds a n d re la t i v es th e t o ll - f ree n um be r fo r th e p o is on c o nt r o l c e n te r . Pa r e nt s s h ou l d al s o k n o w b a s i c fi r s t a id an d c a rd io p ul m on a r y r es us c i t at i on ( C P R ). 3 . Th e an s we r is E [ s e e II I . Q . 5 ]. N a l o xo n e r e v er s es t h e ef f e c t s o f o pi o id r ec ep t o r a g o ni s t s, su c h as he r oi n, m o r ph in e , a nd p ro p o xy p h e n e. 4 . Th e an s we r is D [ s e e I I . G . 1 ].
C o n t r ai nd ic a ti o ns to ip ec a c i nc l ud e t h e t h re e Cs : c a us ti c s , c on s c i ou s , an d c o n vul si o ns ; s ee al s o the a ns we r t o q ue s ti on 2 . Th e u se o f s y r up of ip ec a c i s re se r v e d f o r ra r e c ir c um s ta nc es an d o n l y u n de r t h e d i re c t i on of t he p o is o n c o n t ro l c en t e r a nd / o r a ph ys ic ia n . Th es e a r e ne w r e c om m e nd a ti o ns a n d m an y p a re n ts , r e la t iv e s , an d f r ie n ds m a y hav e t h is pr o du c t i n t he i r m e di ci n e c a b in e ts . 5 . Th e an s we r is D [ s e e I I ] . Th e m an a ge m e n t o f u nc o n s c io us o ve rd os e p a ti en t s i n v ol ve s a g gr es s i v e s u pp o r t o f v i t al s i gn s a nd t he ad m i n is t ra t io n o f em p i ri c a nt id o t al th e ra p y, wh i l e o bt ai n in g v a ri o us la b o ra t o r y te st s t o d e te rm i ne th e n a tu r e o f th e o ve r d os e . 6 . Th e an s we r is B [ s e e II I . A ] . D a r vo c et N - 10 0 i s a n a c e t am i no p he n -c on t ai n in g p r o du c t t ha t s h ou ld no t b e g i ve n t o a pa t ie n t wi t h do c um en t ed ac e ta m i no p he n to xi c i t y . B e a wa r e p a r ti c ul a rl y o f O TC p r odu c ts c o nt a in in g a c et am i no p h en . 7 . Th e an s we r is C [ s e e I I I . B ]. E t h a no l s at u r at es al c o h ol d eh y d r og e na s e an d p r ev e n t s t h e f o rm at i on of t he t o xi c m et a bo li t es of ei t he r e th y l e ne gl yc ol or m e th a n ol , h o we v e r t hi s a n t id o te is fa ll i ng ou t o f f a v o r o wi n g t o i ts ad v e r s e m e t ab o li c a nd c e nt r a l n e r vo us s y s t em e f f ec ts . F o m e p i zol e (A n ti z o l ) , a sp e c i f ic i n hi bi t o r o f a lc oho l d e h yd ro g en as e , i s b ec om i ng th e p r e fe r r ed an t ido t e fo r m e th an o l o r e t h y le n e g l yc ol o v e rd os es . E th ano l m a y be us e d in s i t ua t io n s i n wh i c h f om e pi zo le i s n o t a va i la bl e . 8 . Th e an s we r is A [ s e e II I . L .2 ] . A l l o f th e s el ec t io ns a re u s ed to m a n ag e h y p e rk al e m i a . A l th o ug h , in a n u n st a bl e p a ti e nt , th e c a rd i ac ef f ec ts o f h y p er k al em i a m u s t f i rs t b e r e ve rs ed wi t h i n t ra v e n ou s c a lc i um . 9 . Th e an s we r is D [ s e e I I I . G ; II I .L . 2 ]. P a r e nt e r al c a lc iu m is us e d to r e v e rs e t he c a r di ac e f f ec ts of c a lc iu m c h a nne l b l oc ke r o v e ru s e an d h y pe r k al em ia . 1 0 . Th e a ns we r i s D [s e e I I I . K] . Th e p l as m a - ti s s ue di s tr ib u t io n p h as e f o r d ig o xi n i s 6 - 8 h r p o st a dm in is t r at i on . Sa m p l in g d i go xi n l e ve ls s oo ne r m a y g i v e a fa ls el y e l e va te d l e v e l. O nl y s y m p t om a ti c p a ti en t s sh o ul d r e c e i v e d i go xi n i m m un e a n t ib od i es . He m o d ia l y s i s i s o f n o v al u e i n m a n ag in g di go xi n o v e r d os es . 1 1 . Th e a ns we r i s A [s ee I I I . T] . L a r ge in g es ti o ns o f s us ta i ne d - r el ea se p ro d uc ts m a y ac t a s d r ug r es e r voir s , n e ce ss it a ti n g a gg r es s i v e m ea s u r es t o r em o ve t h e t o xi n . P.526
1 2 . Th e a ns we r i s C [s e e I I I . A] . L a r ge ac e ta m i no p he n i ng e s t i on s ( > 1 4 0 m g/ k g ) m a y be f at a l i f u n r ec og n i z ed . Th e Ru m ac k - Ma t t h e w n om og r am re q ui r es a 4 - h r l e v el to
a cc u r at e l y a s s es s t he p ot e n ti a l f o r t o xi c i t y . I f t h e 4 - h r l e v e l is in t he to xi c r a n ge , th e f u ll c o u rs e o f N A C t h e ra p y s h o ul d b e ad m in is t e re d . 1 3 . Th e a ns we r i s E [s ee I I I . D ]. Tr i c yc l ic a n ti d ep r es s a n t o v e r d os es wi l l p r od uc e se i zu r es , h y p o te ns i on , m yd r i as is , h y p o te ns io n , a n d v en t r ic ul a r d y s rh y t hm i as . Th e ca r di a c a nd CN S e f f ec ts o f t r ic y c l ic an t id ep r e s s an t to xi c i t y wi l l re sp o n d t o b ic a rb on a te t h e r ap y. O p ia t es s uc h a s o xy c o d o n e wi ll p ro d uc e m i os is .
25 Federal Pharmacy Law R o b e r t C . P a vl a n J r . J a m es A. B o yd
I. FEDERAL CONTROLLED SUBSTANCES ACT A. S c h e d u le s of c on t r o ll e d su b s ta nc e s . C e r ta in d r u gs h a v e a po t en t ia l fo r a bu se t h a t l ea ds t o p h ys ic a l o r p s y c ho lo g ic al de pe n de nc e . As a r es ul t , t h e U . S . f e d e ra l g o ve r nm e nt ha s p la c e d th e s e d ru gs in t o sc he d ule s (I , II , I II , IV , an d V) an d r ef e rs to t h em as c o nt r o ll ed s u bs ta n c e s . Th e A tt o r ne y G e ne r a l o f t h e U n it e d S t a te s h as t he a u t ho r i t y t o a d d o r re m ov e a d ru g o r s u bs t an c e fr o m o n e o f t he f ed e ra l s c h ed u le s , o r t o t r an s fe r a d ru g f r om on e fe de r a l sc he d ul e to a no t he r . Th e f ed e r al s c h ed u le s a r e up da t ed an d p u bl is he d an n ua ll y b y t he fe d e ra l g o v e r nm en t . 1 . S ch e d ul e I ( C I ; C - I ) Sc h ed u le I d r ug s m a y n o t b e k e pt in a p ha r m a c y no r d i sp e ns ed pu r s u an t to a p r e s c ri p ti o n ( e xc e p t f o r p r o pe r l y r eg is t e re d f ac il it i es f or i n ve st i ga t i v e o r re s e a rc h p u r po se s ). A c on t r ol l ed s u bs ta n c e an al o gu e o f a d r u g i n a n y f ed e r al s c h e du l e, c om m o n l y re f e r re d t o a s a “ d e s i gn e r d r ug , ” i s c on sid e r ed a s ch e du l e I s u bs ta nc e to t h e e xt e n t i nt e nd ed f o r hu m an c o ns um p ti on . R equ i r ed f i n di ng s b y t he go v e r nm e n t fo r p l ac em en t of a d ru g in t o sc he d ul e I in cl u de : a . Th e dr u g o r o t he r s u bs t an c e h as a hi g h p ot e nti a l f o r a bu s e. b . Th e d ru g o r o t he r s u bs t an c e h as n o c u r re n tl y a c c e pt e d m ed ic al us e i n t r e a tm en t i n th e Un i te d S ta t es . c . Th e re is a l ac k o f ac c e p t ed s a fe t y f o r us e of th e d ru g o r o t he r su bs t anc e u n de r m e di ca l s up e r v is io n . 2 . S ch e d ul e I I ( C II ; C - I I ). R e qu i r ed fi n di ng s f o r p la c em en t o f a d r ug in t o s c h ed u le II i n cl ud e : a . Th e dr u g o r o t he r s u bs t an c e h as a hi g h p ot e nti a l f o r a bu s e. b . Th e d ru g o r o t he r s u bs t an c e h as a c u r r en t l y ac ce p te d m e di c a l u se in tr e a tm e nt in t h e Un i te d S ta t es o r a c ur r e n tl y a c c ep t ed m e di ca l u s e wi t h s e v e r e r es t r ic tio n s . c . A bu se of th e d r u g o r ot h e r s ub s ta nc e m a y l e ad t o s e v e r e ps y c ho l og ic al o r p h ys ic al de p en de n c e . 3 . S ch e d ul e I I I ( CI I I ; C - II I ) . R eq ui r e d f in d in gs fo r p l ac em en t o f a d r ug i n to s c h ed u le I I I in cl ud e : a . Th e dr u g o r o t he r s u bs t an c e h as a po t en t ia l f or a b us e l es s t ha n t h e d rug s o r o t h e r su bs t an c e s i n s c h ed u le s I an d II . b . Th e d ru g o r o t he r s u bs t an c e h as a c u r r en t l y ac ce p te d m e di c a l u se in tr e a tm e nt in t h e Un i te d S ta t es . c . A bu se of th e d r u g o r ot h e r s ub s ta nc e m a y l e ad t o m o de r at e o r lo w p h ys i c al d e p en de nc e o r hi g h ps y c h o lo g ic al de p en de n c e . 4 . S ch e d ul e I V ( C I V ; C - IV ) . R e qu i re d fi nd i ng s f o r p l ac em en t o f a d r ug i n to s c h ed u le I V i nc lu d e: a . Th e dr u g o r o t he r s u bs t an c e h as a lo w p o t en t ia l fo r ab us e re la t i v e t o th e d ru gs o r o t h e r su bs t an c e s i n s c h ed u le I II . b . Th e d ru g o r o t he r s u bs t an c e h as a c u r r en t l y ac ce p te d m e di c a l u se in tr e a tm e nt in t h e Un i te d S ta t es .
c . A bu se of th e d r u g o r ot h e r s ub s ta nc e m a y l e ad t o l im i te d p h ys i c al de pen d e nc e o r p s yc ho lo g ic al de pe n de nc e re l at i v e t o th e d r ug s o r o th e r s ub s t a nc es in s c h ed u le II I . 5 . S ch e d ul e V ( C V ; C - V ) . R e qu i r ed fi n di ng s f o r p la c em en t o f a d r ug in t o s c h ed u le V i n cl ud e : a . Th e dr u g o r o t he r s u bs t an c e h as a lo w p o t en t ia l fo r ab us e re la t i v e t o th e d ru gs o r o t h e r su bs t an c e s i n s c h ed u le I V . b . Th e d ru g o r o t he r s u bs t an c e h as a c u r r en t l y ac ce p te d m e di c a l u se in tr e a tm e nt in t h e Un i te d S ta t es . c . A bu se of th e d r u g o r ot h e r s ub s ta nc e m a y l e ad t o l im i te d p h ys i c al de pen d e nc e o r p s yc ho lo g ic al de pe n de nc e re l at i v e t o th e d r ug s o r o th e r s ub s t a nc es in s c h ed u le I V. P.528
B . R e g is t r a t io n r eq u i r em e n t s. Th is Ac t r eg ul a tes t he us e o f c on t ro l le d su b s t a nc es b y r e q ui r in g a ll en t i ti es th a t l a wf u l l y h a nd l e t he m t o r eg is t e r wi t h t he fe d era l g o ve r nm e nt , s pe c i f ic al l y , t h e D ru g E n fo r c e m e n t Ad m in is t r at io n ( D E A ). 1 . E n ti t i es t ha t mu s t reg i s t e r a . M a n u fa c tu r e r s a n d w h o l es a l e rs of c o n tr o ll e d s u bs ta n c e s m u s t r eg is t er wi t h t he D E A i n it ia l l y a n d r e r eg is te r e v e r y y e a r t he r e af t e r. b . D i sp e ns e r s ( p r ac ti t ion e r s a nd ph a rm ac ie s ) o f c o nt r o ll ed s u bs t an ce s m u s t r e g is t er wi t h th e D E A i nit i a ll y a nd re r e gi s t e r e v e ry 3 y e a r s t he r ea f t e r. P har m ac is t s, p h a rm ac y i nt e r ns , p ha r m a c y t ec hn ic i an s, an d a l l o t h e r em p lo y e es o r a ge nt s of a p h a rm ac y d o n ot ha v e t o r e gi s te r , p r o vid i ng th e ph a r m a c y i s p r op e rl y r e gis t e re d a n d t h e e m p l o y ee o r a ge n t is a c ti ng in t he us ua l c ou rs e o f em pl o y m e n t o r b us i n es s . c . Al l o t he r en t it i es th a t la wf u l l y h an d le an y c o n t ro l le d s ub s ta nc e m us t reg i s t e r wi t h t h e D E A , in c l u di n g r es e ar c h er s , cl i ni c s a n d l ab o ra t o ri e s, an d t e ac hi n g i ns t i t ut i on s. 2 . S ep a r a te r e gi s t r at i on f o r se p a ra t e a c t i vi t ies . E v e r y en t i t y t h a t e ng ag e s i n o ne o f t he fo ll o wi n g a c ti v i t ie s m us t re gi s te r wi t h t h e D E A . A se pa r a te r eg is t r at io n is r e q ui r e d f o r e ac h ac t i v i t y, wi t h ce r t ai n e xc e p t io ns ( e . g. , a m a n uf ac t u re r of a s ch e du l e o f a c o nt r ol l ed s u bs ta n ce is a ll o we d t o d i s t r ib u t e t ha t s c h e du le wi t h o u t b e in g re g is te r e d as a d is t r i bu t o r ). a . Ma n u f ac t u ri ng c o n tr o lle d s u bs t an ce s b . D is t r ib u ti ng c o n t ro ll e d s ub s ta nc es c . D is pe ns i ng c o nt r ol l ed s u bs ta n c e s l is te d i n s che d ul e s I I - V ( e .g . , p r ac ti t io n e rs , p h a rm ac ie s ) d . C o nd uc t in g re s e a rc h wi t h c on t r ol l ed s u bs ta nce s l is t ed in sc he du l es II -V e . C on d uc t in g i ns t ru c ti ona l ac ti vi t ie s wi t h c o n t ro lle d s u bs t an ce s l is te d i n s c h ed u le s II-V f . C o nd uc t in g a na r c o t ic t r e a tm en t p r o g ra m us i ng a n y na r c o t ic dr u g l is te d i n s ch e du l es II , II I , I V , o r V g . C o nd uc t in g re s e a rc h a n d i ns t r uc ti o na l a c t i v i tie s wi t h c on t r ol le d s ub s tan c es l is t ed i n s ch e du l e I h . C on d uc t in g c he m i c a l a n al y s is wi t h c o nt r ol l ed s u b s ta n c e s l is te d i n a n y s ch e du l e i . Im p o rt i ng c o nt r ol l ed s u b s t a nc es j . E xp o r t i ng c o n tr o ll e d s u b s t a nc es
k . P a rt ic i pa t in g i n m ai n te n a nc e o r d e to xi f i c at i on t r e a tm en t a n d m i xi n g , p re p a ri n g, p a ck ag i ng , o r c h an g in g th e do s a g e f o rm o f a n arc o ti c d r ug li s t e d i n s c h ed u le s I I , I I I , I V , o r V f or us e i n m ai n te n a nc e o r d e to xi f i c at i on t r e a tm en t b y a n ot h er na rc o ti c t r e a tm en t p r o g ra m . 3 . S ep a r a te r e gi s t r at i on s f o r s e pa r a t e l oc a t ion s . Ea c h p ri nc i pa l p la c e o f bu si n es s o f a r e gi s t r a nt ha v i n g m or e t ha n o n e l oc at i on m us t h a v e i ts o wn r eg is t r at i on c e r ti f ic at e . Ea c h ph a rm ac y , c h a in ph a rm ac y, an d h os p it a l t ha t di s p en s e s c o nt r o ll ed s u bs ta n c e s m u s t h a v e i ts o wn r eg is t r at i on c e r ti f ic a te . R eg is t r at i on is n o t r e q ui r e d f o r an of f ic e t h at is us ed b y a re g is t ra n t wh e re c on t r ol l ed s u bs t an ce s a r e n e i th e r s t o re d n o r d is p en s e d . a . Wa r e h ou s es . A wa r eho u s e wh e r e c on t r ol le d s u b st a nc es ar e s t o re d b y o r o n b e h al f o f a r eg is t r an t i s n o t re q ui r ed to r eg is t e r un l es s o ne of t he fo l lo wi ng oc cu r s : ( 1 ) C o nt r ol l ed s u bs ta n c es a re di r ec t l y d is t r ib u te d f r om t he wa r e ho u s e to a r e g is t er e d l oc at i on di f fe re n t th an t he lo c a t io n f r om wh i c h t he s u bs t an ce s we r e s h ip p ed . ( 2 ) C o nt r ol l ed s u bs ta n c es a re di r ec t l y d is t r ib u te d f r om t he wa r e ho u s e to a p e rs o n o r e n t it y n o t r eq u i re d t o re gi s te r un d er t he Ac t . 4 . R e gi s t r a ti o n p r o ce d ur e . A pp l ic at i on s t o b ec om e re g is te r ed m u s t be s u b m i t te d to t h e D E A o n t h e a pp r op r ia t e fo rm wi t h th e re q ui r ed f ee , i n f or m a t io n , a nd si g na t u re o f o n e o f th e f o ll o wi n g: a . Th e i n di v i d ua l wh o o wn s a n d o pe r a te s t he en t it y , i f d o in g b us i ne s s a s a n i n di vi d ua l b . A pa r tn e r o f th e a p pl ic a nt , if a p a rt n e rs hi p c . A n o ff ic e r o f th e a p pl ic a nt , if a c o r p o ra t io n , c or p o r at e d i v is i on , a s s oc i at i o n, t ru s t, o r o th e r e n ti t y d . O n e o r m o re in d i v id ual s wh o h a ve be en g ra n ted a p o we r o f a t to r ne y b y a n a p pl ic a nt . A p ow e r o f a tt o r n e y a l l o ws o n e to la wf u l l y a c t i n pl a ce of an o th e r . Th e p o we r o f a t t or n e y m us t be s i g ne d b y o ne o f t he ind i v i du a ls l is t ed ab o ve in a - c a n d b y t h e i nd i v i du al r ec ei v i ng t he po we r o f at t o rn e y . Th e p o we r o f a t to r ne y r em a in s va l i d u n ti l r e v o k e d b y t he a pp li c a n t . P.529
5 . R e gi s t r a ti o n a c ti o n by t h e D E A. I f a n a pp li c a ti o n i s co m p l et e , i t wi ll be a c c ep t e d f o r fi l in g . I f i t i s d ef ec t i ve , t he D E A wi ll r e tu r n t he a pp li c a t io n wi t h a s t a te m en t i n di ca t in g th e re as on f or i t s n on ac ce p ta nc e . Th e a p pl ic a ti o n m a y b e c o r rec t ed an d r e s ub m i t te d a t a n y t im e. a . I ss u an c e o f c e r t i fi c at e o f re g i st r a t i on . A c ert i f ic at e o f r eg is t ra t io n wi ll b e i ss u ed b y th e D E A wh e n i t de t e rm in es th a t t h e r eg i s t r a ti o n is r eq ui r e d b y l a w i n o r d e r t o c on d uc t s uc h ac t i v i t y ( e .g . , m a n uf a c t u ri ng , di s tr i bu t in g , o r d is p ens i ng a c o nt r o ll ed s u bs t an c e ) . Th e c e r ti f ic at e m us t b e c on s pi c u o us l y m ai n ta i ne d a n d re ad i l y r e t r ie va b le at t he re g is t er e d l o c a t io n . b . D e ni a l o f r eg i s t ra t i on . I f t h e D E A de t e rm in es t h a t a re gi s tr a ti o n is no t r e q ui r ed b y l a w, i t wi l l is s u e a n Or d e r To S ho w C a u s e wh y t h e r e gi st r a ti o n s h o ul d n o t b e d e ni e d. Th e ap pl ic a nt m a y r e q ue st a h ea r i ng an d e xp l a i n wh y t h e ce r t if ic at e o f
r e g is t ra t io n s ho u ld be is s u ed . A ft e r t h e h ea r in g , t h e D E A m a y d e n y th e ap p li c a t io n o r is su e t h e c er t i fi c a t e. 6 . M o d i fi c a ti o n o f r eg i st r a t i o n . A re g is t ra n t m a y s ub m i t a l et t e r o f r e qu es t to th e D E A s ee k i n g t o m od i f y i ts r eg is t r at i on . A m o d if ica t i on m a y be s o u gh t wh en t he r e i s a ch a ng e i n t h e n am e o r a d d re s s th a t a pp e a rs o n t h e c e rt i fi c a t e , o r wh e n th e p h a rm ac y s e e k s D E A a pp r o v a l t o d is p en se ad di t io n al c o n t ro ll e d s u bs t an c e s [i f i n i ti al l y au t ho r i z e d t o o nly d i s p e ns e a pa r ti c u l a r s c h ed u le (s ) o f c o n t ro ll e d s u bs ta n c e s ] . 7 . T r an s f e r o f re g i s t ra t io n . A re gi s tr a ti o n t o d is pe n s e c o n tr o ll ed s u bs t an ce s m a y n o t b e tr a ns f er r e d t o a n y o t he r pe r s o n o r en t it y exc e p t wh e n t he o wn e rs h ip o f a p h a rm ac y is be i ng t ra ns fe r r e d f r om on e e n ti t y to a n o th e r . I n s uc h a c as e , c o nt r o ll ed s u bs ta n c e s i n s c he d ul es I I - V m us t b e p r o pe r l y dis p os ed o f o r t r an s fe r r ed t o t he ne w e n t it y. 8 . S us p e ns i on o r re vo ca t i o n o f r eg i s t ra t i on . Th e D E A m a y s us p en d o r r e v o k e a n y r e g is t ra t io n . Th e D E A m u s t f i rs t i s s ue an O r d er To S h o w C a u s e ( up o n t he r e g is t ra n t ) wh y t h e r eg is t r a t io n s ho u ld no t b e re v o k ed o r s u sp e nd e d. Th e r e g is t ra n t m a y r eq u es t a he a ri n g t o e xp l a i n wh y t h e r eg is t r at i o n s h o ul d n o t b e s u s pen d e d o r r e v o k ed . Af t e r a he a ri n g, t h e D E A m a y s us pe nd , re vo k e, o r t ak e n o a c ti on o n th e r e g is t ra t io n . a . O r d e r o f su s pe n s io n o r r e vo c a t io n . Af t e r a reg i st r a nt ha s r ec e i v ed an o r d e r s us p en d in g o r re v o k i n g it s re g is t ra t io n , i t m us t t ak e th e f o ll o wi n g ac t io n : ( 1 ) Im m e d ia t el y d el i v e r i ts c e r ti f ic a te of r eg is t r at io n an d a n y D E A 2 2 2 o r de r f o rm s in i t s p os s e s s io n t o th e n ear e s t o f fi c e of t he D E A ( 2 ) A s i ns t ru c t e d b y t he D E A , e it h e r: ( a ) de l i v e r a ll c o nt r ol l ed s u bs ta n c e s i n i ts p o ss es s i o n to t he ne a re s t o ff ic e o f th e D E A o r to au t ho r i z e d a ge n ts o f t he D E A o r ( b ) pl a c e al l c on t ro l le d s u b s t a nc es in i t s p os s e ss i o n u nd e r s ea l . b . I mm i ne n t d a n ge r t o p u b l ic he a l th o r s a f e t y. Th e D E A m a y s e r v e on a r e gi st r an t a n o rd e r o f i m m ed ia t e s us p en s i o n wh e n it fi n ds tha t t he r e is an i mm i ne n t d a n ge r t o t h e pu b li c he a l th o r s afe t y. Th e i m m e d ia t e s u s pe n s i o n r em ai ns in e ff ec t u n t il th e c o nc lu s i o n o f a ll p ro c e edi n gs , e i th e r a dm i ni s t r a ti v e p r oc ee di n gs b y t h e D EA o r j u di ci a l p r oc ee di n gs . Af te r r ec ei vi n g a n o r de r of i m m e d ia t e s u s pe ns io n , t he r e g is t ra n t m us t t ak e t h e s am e a c ti on as ou t li ne d a b o v e u n de r I B 8 a . 9 . E xe m p ti o ns f r o m r e gi s t r a t io n . Ce r t ai n i nd i v i du a ls a re e xe m pt f ro m r eg i s t r a ti o n u n d er t he Ac t . Th e f ol l owi n g a r e e xe m p t : a . M i l i ta r y o f f i c i a l s. Mi l it a r y o f fi ci al s , i nc lu di n g Pu b li c He a lt h Se r v i c e an d B u r ea u of P r i so n s o ff ic i al s , wh o a re a ut h o ri z e d t o p r es c ri be, d is pe ns e , o r ad m i ni s te r, b u t n ot t o p ro cu r e o r pu rc h as e , c o nt r o ll ed s u bs t an c e s i n t h e c ou r s e o f t he i r o f fi c ia l du t ie s, a r e e xe m pt f ro m r e gi s t e ri n g wi t h t he D E A . Th e i nd i v i du a l m u s t, ho we v e r , o b t ai n a r e g is t ra t io n fo r s uc h a c t iv i t i es c o nd u ct e d d ur i ng a n y s e p a ra t e p r i v at e p r ac t ic e . b . L aw -e n f o rc e me n t o f fi c i a ls . F e de r al an d s t at e l a w- e n f or c em en t p e rs o nn e l a c t i ng i n th e c ou r s e o f e nf o rc ing a n y l a w r e l at i ng to c o nt r o ll e d s ub st a nc es a r e exe m p t f r om r e g is t ra t io n .
c . C i vi l d e f en s e o f f ic i als . C i v il de f en se an d di s as t e r -r e li e f o r ga ni z a t io n of f i ci al s a r e e xe m p t f r om re gi s tr a ti o n i n o r d er t o m a i nt a in an d d is p en s e co n tr o ll ed su bs t an c e s d u r in g tim e s o f p r oc la im e d em e rg en c i e s o r d is as t e r s . d . Ag e n t s a n d e m pl o ye e s o f r e g is t r a n ts . Ag e nts an d e m p l o y ee s , wh i l e a c ti n g l a wf u l l y in th e u s u a l c o u rs e o f th e ir bu s i n es s o r em p lo y m en t , a r e e xe m p t fr o m r e g is t ra t io n wh e n t h e b us i ne s s o r em pl o y m e n t i s c o nd uc t ed on be h al f o f a p e rs o n ( o r bu si n es s ) wh o is r eg is t e re d u n de r th e Ac t . D el i v e r y p er s o n ne l (e . g. , Un i t ed P a r c el Se r v i c e , Fe d er a l E xp r e s s ) a re th e re f o re no t r eq u ir e d t o r e gi s t e r . Li k e wi se , p h a rm ac is ts wo r k in g fo r a r e gi s t e re d p h a rm ac y ar e n ot r eq ui r e d t o r e gi s t er . P.530
1 0 . Te r m in a t io n of r e gis t r a t i on . Th e re gi s tr a ti on o f a n y pe r s o n o r e n ti t y wi l l t e r m i n at e wh e n t he pe r s o n di es , c ea s es l e ga l e xi s t en ce ( e .g . , c o r p o ra t e di s s o lu t io n , p a r t ne rs h ip di s s ol u ti o n) , o r di s c o nt i nu es bu si n es s o r p ro f es s i on al p ra c ti c e . Th e D E A m us t be no t if i ed pr om p tly wh e n a n y o f t h es e oc c u r s . I n s uc h a c as e , a ll c o n t r ol le d s u bs ta n c e s i n s c he d ul es I I - V m us t b e p r o pe r l y dis p os ed o f. C . R e q u i re d in ve n t o r ies . Th e Ac t re q ui r es a l l ph a r m a c i es an d h os p it a ls ( e v e r y s e pa r a te l y r eg is t er e d l oc a t i on ) to c o nd uc t an in it i a l in v e n to r y a nd bi en n ia l i n ve nt o r y o f al l c on t r ol le d s u bs ta nc es in s c he d ul es II , II I , IV , a nd V . 1 . I ni t i al i n ve n to r y. Th e i n it i al i n ve n to r y m u s t be t a ke n o n t h e d at e th e en t i t y c om m e n c e s b us in es s a nd b eg in s d is p en s i ng c o n tr o l le d s ub s ta nc es . If th e e n t it y h as n o c o nt r o ll ed s u bs t an c e s o n h a nd , a r ec o rd of t his f ac t m us t b e m ai nt a in ed as i ts i n i ti al in v e n to r y . 2 . B i en n ia l in ve n t o r y. T h e bi en n ia l i n v e nt o r y m us t be ta k e n a t le as t e ve ry 2 y e a r s f r o m t he da t e o f th e i ni t ia l in v e n to r y. a . B i en n ia l da t e . Th e bie n ni a l d at e m a y be an y d a t e t ha t is wi t hi n 2 ye a rs o f t he p r e vi ou s b ie n ni al ( o r i ni t ia l ) d a t e. Th is da t e d oe s n o t ha v e t o b e r e po r te d t o t he D E A i f i t i s d i ff e r en t t h an t h e b ie n ni al da t e t h at wo u ld o th e r wi s e a pp l y (i . e. , o n t he e xa c t d a y 2 y e a rs a ft e r th e p re v i ou s i n v e nt o r y ) . 3 . I n ve n to r y p r o c e d u r es a . A ll in v e n to r ie s m us t be m a i nt a in ed in a w r i t ten , t yp ew r i t t en , or p r i nt ed f o r m a nd b e c o nd uc t ed a t e it h er th e op e ni ng o f b us in es s o r t he c l os e o f b us i ne s s o n th e i n ve n to r y d at e ( wh ic h m u s t b e n o te d o n t h e i n v en t o r y) . b . S e pa r a te i n ve n to r y r e c o r d f o r sc h ed u l e I I co n t r o l le d s u b st a nc e s. B e c au se al l r e c or d s f o r s c he d ul e I I c o n t r ol le d s ub s ta nc es m us t be m a in t ai ne d s ep a r ate l y f r om o t h e r r ec o rd s , s c he d ul e II i n v en t o ri es m u s t be m ai n t ai ne d s e pa r at e l y fr om o t h e r c o nt r o ll ed - s u bs t an c e in v e n t o ri es . 4 . I n ve n to r y c o n t e n t . A ll i n v en t o r y re c o r ds m us t c o nt a in th e fo ll o wi n g : a . D a te th e i n v e nt o r y is ta k en b . E ac h f i ni s h ed f o rm o f t h e s ub s ta nc e (d os a ge fo r m a n d s tr e ng t h ) c . N um be r of un i ts or v o lu m e o f e ac h f i ni s h ed f o rm in ea ch c o m m e rc ia l c on t a in e r ( e . g ., 10 0 - ta b le t b o tt l e ). F o r op e ne d c om m e rc i al c o nt a in e rs , i n ve nt o r y m us t be ta ke n a s fo ll o ws : ( 1 ) F or s c he d ul e I I c on t ro l le d s ub s ta nc es , an e xa c t c o un t o r m e as u re m us t b e t ak e n.
( 2 ) F or s c he d ul e I I I , I V , a n d V c o n t ro ll e d s ub s t a nc es , an es ti m a t ed c o u nt o r m e as u re m a y be t ak en , e xc e p t t ha t a n e xa c t c o un t m u s t be t ak en if th e c o n t ai ne r h o ld s m o re th a n 1 00 0 t ab l e ts o r c a ps ul es . d . F o r e ac h c o n t ro ll e d s u b s t a nc e m ai n ta in e d f o r e xt e m p o r an e ou s c o m p o un d in g , o r f o r s u bs t an c e s t ha t ar e da m ag e d, de f ec ti ve , o r im p u r e a nd a wa i ti n g d is po s a l : ( 1 ) N am e o f th e s ub s t a nc e ( 2 ) To t a l q ua n ti t y to t he n e a re s t m e t r ic u n it we i gh t o r t he t ot a l n um be r of u n i ts o f f i n is he d f o rm ( 3 ) R e as on th e s ub s ta nc e is be i ng m a in t ai ne d a nd wh e t h e r i t is c a p ab le of u s e in t h e m an u fa c tu r e o f a n y c o n t r ol le d s ub s ta nc e i n f in i sh e d f o rm 5 . I n ve n to r y r e c o r d m ain t e n an c e. E v e r y in v e n tor y r e c o rd m us t be m a in t ai n ed a t t h e re g is te r ed lo c a t io n (e . g . , p ha rm a c y , h os pi t al ) f o r a t le as t 2 ye a rs f ro m t h e d a te o f t he i n v e n to r y . a . S c h ed u le I I in v e n t or i es m u s t be m a in t ai n ed s ep a r a te l y f ro m a ll ot h er r ec o r ds o f t h e p h a rm ac y . b . S ch e du le I II - V in v e n tor y r e c o rd s m u s t b e m a i nta i ne d e i th e r s ep a r at e l y fr o m a ll o t h e r r ec o rd s o f t h e p ha rm ac y o r i n s uc h a m a nn er t h at t he re q ui r ed in f o rm a ti o n is r e a di l y r et r i e v ab le f ro m o r d in a r y bu s i n ess r ec o rds o f t he ph a rm ac y . “ R e ad i l y r e t r ie va b le ” m e an s t ha t th e in v e n to r y r ec o rd s c an b e s ep a r at e d o ut f ro m al l ot h er r e c or d s in a re as on a bl e ti m e. 6 . P e r pe t ua l in ve n t o r i es . Th e Ac t d o es n o t re qui r e a di s pe ns e r r e gi st r a nt ( e .g . , p h a rm ac y , ho s p i ta l ) t o m a i n ta in a p e rp e tu a l i n vent o r y o f a n y c o nt r o ll ed sub s ta nc e . 7 . N ew l y c o n t r o l l e d s u bs t a n ce s o r c ha n ge s i n s c h ed u l in g of a s u bs t an c e . A n i n ve n to r y o f a s u bs ta nc e m us t b e t a ke n wh e n, b y o r d er o f t he D E A , i t b eco m es a n e wl y c o n tr o ll ed s u bs t anc e o r it s h i ft s i nt o a n o the r sc he d ul e . Th e in ve n tor y o f t ha t p a r ti c ul a r c o n t ro l le d s ubs t an c e m u st be t ak en on t h e e f fe c t i v e da t e o f t he c ha n ge . A c om p le t e i n v en t o r y o f al l c on t r ol l ed s u bs ta nc es is n o t r e qu i re d , n o r is a n in v e n t o r y r e q ui r e d wh e n a s u b s t a nc e m o v es f ro m a c o nt r ol le d - s u bs t an c e s c he du l e to a n o n fe d er a l s c h ed ul e . P.531
8 . T r an s f e r o f b u s in e ss a c t i vi t y. A n i n ve n t o r y of c on t ro l le d s ub s ta nc es II - V m u s t b e ta ke n a t th e tim e a ph a r m a c y o r ho s p i ta l u n de r g oe s a c h an g e i n o wn er s h ip . Th e i n ve n to r y m u s t b e t ak en o n th e d a te o f t r an s f e r an d s e r ves as th e fi na l i nve n t o r y o f t h e tr a ns fe r o r a n d t he in it i a l i n v en t or y o f th e t r ans f e re e . 9 . I n ve n to r y r e c o r d s u bm i s si o n . Th e Ac t do es no t r eq u ir e th e s ub m i s s ion o f i n ve n to r y r ec o rd s t o a n yo n e , i nc lu di n g t h e D E A . Th e r e co r ds m us t be m a in t a in ed a t t h e re g is te r ed lo c a t io n fo r in s pe c t i on an d c op y i ng b y au t ho r i z e d a ge n ts of t h e D E A . D . O b t a i ni n g c o n t ro l l ed s u bs t a nc e s. S c h ed u le II c on t ro l le d s ub s ta nc es m us t be o b t ai ne d f ro m a s up p li e r ( wh o l e s al e r, m a nu f ac t u re r ) b y us in g D E A F o rm 22 2 . Th e A c t do es no t re q ui r e t he u s e o f a n y s p ec ia l f o rm to o bt a in c o nt r o ll ed s u bs ta n ce s i n s ch e du l es II I - V . 1 . D E A F o r m 22 2 . O n l y e n t it i es t h a t a re r eg is t e re d to di s p e ns e o r h a nd l e s ch ed u le I I co n t ro ll e d s u b s t a nc es m a y ob t ai n Fo rm 22 2 . The f o rm s a re se r ia ll y n um b e r ed an d
i ss u ed b y th e D E A wi t h th e na m e , a d d re ss , r e gi s tr a t io n nu m b e r, au t ho r i z ed ac t i v i t y, a n d sc h ed u le s o f t h e r egi s t ra n t. E ac h f o rm c o nt a in s a n o r i gi na l , d up l ic at e , a n d t r i pl ic a te c o p y ( C op y 1 , C o p y 2 , a n d C o p y 3 , r es p e c t i v e l y ) . a . E xe c u ti o n o f Fo r m 22 2 . Fo rm 22 2 m a y be e xe c ut e d o nl y o n b eh a lf o f t h e r e g is t ra n t n am e d o n t he f o r m a nd on l y if t he re g is t r at i on ha s n o t e xp i r e d n o r be en r e v o k ed o r s u s p e nd e d. Th e fo r m m u s t b e p r ep a red i n t r ip li c a t e a s p r o v id ed b y t he D E A b y u s e of a t y p e wr i te r , pe n , o r i n de li b le pe nc i l i n t he fo l lo wi n g m a nne r : ( 1 ) O n l y o n e i te m m a y be o r de r ed on ea c h o f t he 1 0 n um b e re d l in es on t he f o rm . Th e t o t al n u m b e r o f i t em s o rd e re d m us t b e n o t ed o n th e f o rm in th e s pa c e p r o vi de d . ( 2 ) O n e i te m m a y c on s i s t o f o n e o r m o re c om m e rc i al or b ul k c o n ta i ne rs o f a p ro d uc t. A s ep a r at e i t em m us t b e m ad e fo r d i f fe r en t c om m e rc i al or bu lk c o n ta in e rs o f a p r o du c t. Fo r ea c h i te m , th e fo r m m u s t co n ta i n t he f o ll o wi n g i n fo r m a ti o n: ( a ) N am e o f th e a r ti c l e or d e r ed ( b ) F in is he d or bu lk f or m o f th e p r od u c t ( do sa ge fo r m a n d s tr e ng t h ) ( c ) N um b er o f u ni ts o r v o l um e i n e ac h c om m e rc ia l or b ul k c o n ta i ne r (e . g ., 1 00 - t ab l et b o t tl e ) ( d ) N um b e r o f c o m m e rc ia l or b ul k co n ta i ne rs o rde r e d ( e ) I f t he a r ti c l e is no t in p u r e f o rm , t h e n am e a nd q ua n ti t y pe r un i t o f t h e c on t r ol l ed s u bs ta n c e s c o n ta i ne d i n t h e a r t ic le . ( 3 ) Th e s u pp li e r ' s n am e a n d a d dr es s m us t b e i nc l u de d o n th e f o rm . O nl y o n e s u pp li e r m a y be li s t e d on a n y o n e f o rm . ( 4 ) E ac h f o rm m us t in c l ud e th e d a te o f t he o rd e r , a n d n o f o rm i s val id m o re t ha n 6 0 d a ys a f t e r i ts e xe c u t io n b y t h e p u rc ha se r . ( 5 ) Th e fo r m m u s t b e s i gn e d e i th e r b y t he pe r so n wh o s ig n ed t he m os t rec e nt a p pl ic a ti o n f o r r e gi s t r a tio n o r r e re g is t ra t io n , o r by a p e rs on au t ho r i z e d t o o b t ai n a n d e xe c u t e or d e r f o rm s b y a p ow e r o f a t t o rn e y. ( a ) A n y pu r c h as e r m a y au t h o ri z e on e o r m o re in di vi d ua l s ( do es no t ha v e to b e a n a t t o rn e y - a t -l a w) , wh e t h er o r no t l oc a te d a t th e reg i s t e r ed lo c a t io n , t o o bt ai n an d e xe c u t e 22 2 F o rm s b y exe c u t i n g a p o we r o f a t to rn e y f o r t he in d i v id u al (s ) . ( b ) Th e po we r o f a t t or n ey m u s t be s i gn e d b y t he p e r so n wh o s ig n ed th e m o s t r e c e n t a p pl ic a ti o n f o r r e gi s t r a tio n o r r e re g is t ra t io n a n d b y t h e i nd i vi du al ( s ) r ec e ivi n g th e p o we r o f a t t or n e y . Th is fo r m m us t b e s im il a r o r i de n t ic al to t he D E A ' s “ P owe r o f A t t o r ne y f o r D E A O r d e r F o r m s . ” ( c ) O nc e pr o pe r l y e xe c ute d , th e i nd i vi du al r ec ei vin g th e p o we r o f a t to r ne y m a y o b t ai n a n d s i g n D E A Fo rm 22 2 to th e s am e e xt e n t a s t he in d i vid ua l wh o s ig n e d t he m os t re c en t a p pl ic a ti on fo r r eg is t r at i on o r r e re g is t r a t io n . ( d ) Th e po we r o f a t t or n ey m u s t be fi l ed wi t h th e e xe c u t e d 2 22 F or m s of th e p u r ch as e r a nd be r et a ine d fo r th e s am e p e ri o d as an y o r de r fo r m b ea r in g t h e s i gn a tu r e o f t h e a t to r ne y [ s ee I. D . 1 .a ( 8) ] . Th e p owe r o f a t to r ne y d o es n o t h a v e to b e s u bm it t ed t o t he D E A. ( 6 ) C o pi es 1 a nd 2 m u s t b e s u bm it t ed t o t he su ppl i e r. C o p y 3 m u st be r et ai n ed b y t h e p u rc h as e r. ( 7 ) W hen t h e o rd e r ed s c h e d ul e I I c on t r ol l ed s u bs t a nc es a re r ec ei v e d b y th e p h a rm ac y , t he fo ll o wi n g in f o rm a ti o n m u s t b e r ec or d e d o n t h e r e ta in e d C o py 3 : ( a ) N um b er o f c o m m e rc ia l or b ul k co n ta i ne rs f u rn i s h e d o n e ac h i te m ( o r li n e )
( b ) D a te on wh i c h t he c on t a in e rs ar e re c e i v e d b y t h e p h a rm ac y ( 8 ) D E A 22 2 F o rm s m u s t b e m ai n ta i ne d a t th e r eg i s t e r ed lo c a t io n ( p ha r m a c y o r h o sp i ta l ) f o r a t l e as t 2 ye a r s f r om th ei r e xe c u ti on. Th e t im e o f e xe c u t io n wo u l d b e t h e d a te t he la s t en t r y wa s m ad e o n C op y 3 . P.532
b . C a nc e ll a t io n b y p u r c h a s e r. A pu r c h as e r m a y c a nc el al l o r pa r t o f a n or d e r b y n o t if yi n g t he s u pp l ie r i n wr i t i n g . Th e su p pl i er m us t in di ca t e t h e c a nc e ll a tio n on C o p i es 1 an d 2 b y dr a wi n g a l in e t h r ou gh t he c an c el e d i te m s a n d p r in t ing t he wo r d “ c a nc el ed ” in th e s p ac e p r o v i de d fo r n u m b e r o f i te m s s h ip p ed . Li ke wi s e , a s u p pl ie r m a y vo id al l o r pa r t o f an o r de r b y n o ti f yi ng th e p u r c h as e r i n wr i ti n g a nd p r i nt i ng th e wo r d “ c a nc el ed ” in th e s p a c e p ro vi de d fo r nu m b er o f i t em s s h i pp ed . c . M a in t e na n ce o f D E A F o r m 22 2 . E xe c u t ed C o py 3 f o rm s a nd C op i es 1 a n d 2 of e a ch un ac c e p te d o r de f ec t i v e f o rm an d t h e s ta t em e nt o f r e fu s a l f r om th e s u pp li e r m us t be m a in t ai ne d b y th e pu r c h as e r . Th e y m us t b e k ep t s e pa r a te f ro m al l ot h er r e c or d s a nd be a v ai la b le f o r i ns p ec ti o n f o r a t l eas t 2 y e a rs . Al l f o rm s m us t b e m a in t ai ne d a t th e re g is ter e d l o c a t io n p r ep r in t ed on t he f or m , a nd no t a t a c e nt r a l l o ca t io n . d . L os s o r t h ef t o f D E A F o r m 22 2 . A n y us ed o r un u s e d f o rm s t o le n f r om or l os t b y a p u rc ha s e r or s u p pl ie r m us t be r ep o rt e d im m e d ia t e l y to th e D E A. S uc h no t i fi ca t io n m us t in c l ud e th e s e ri al nu m be r of ea c h f or m l os t o r st o le n . 2 . O b t ai n i ng sc h ed u l e II I - V co n t r o ll e d s u bs t a nc e s . Th e r e i s n o s pe ci al f o r m f o r o b t ai ni n g s c h ed ul e II I - V c o nt r o ll ed s u bs t an ce s . Ea c h r e gi st r a nt m us t , h o we ve r , m a in t ai n a c om p le t e a nd a c c u ra t e r ec o r d o f r ec e ip t f or ea c h s u ch s u bs t anc e . Th e r e c or d m us t b e m ai n ta i ne d at ei t he r th e re g is te r ed l oc at i on of t he ph a rm ac y o r h o sp i ta l , o r a t a c e n t ra l lo c at i on , fo r 2 ye a rs . I f a c e nt r a l l oc at i on is u se d , t h e p h a rm ac y m u s t f i rs t n o ti fy t h e D E A , i nd ic a ti n g i ts i n t en t io n t o k ee p c en t r al r e c or d s . C e n t r al re c or ds m a y t hen b e m a i nt a in e d u nl es s th e D E A d e ni es th e re q ues t to k e ep s uc h re c o r ds . An in v o ic e o r pa c k in g s li p wi l l s u f fi c e a s a r ec or d o f r ec ei p t, p r o v id i ng t h e fo ll o wi n g i n fo r m a ti o n i s i nc lu d ed : a . N am e o f th e c on t r ol led s u bs t a nc e b . F in is he d fo r m o f t he s u b s t a nc e ( d os ag e f o rm an d s t r en g th ) c . N um be r of un i ts or v o lu m e o f t h e f in is h ed fo r m i n ea ch c om m er ci a l co n ta i ne r ( e . g ., 10 0 - ta b le t b o tt l e ) d . N um b e r o f c o m m e rc ial c o n ta i ne r s o f e ac h s uc h f in is h ed fo r m r ec e i v ed f r o m o th e r p e r so ns e . D a te of ac t ua l r ec e ip t o f ea c h co m m e rc ia l c on ta i ne r f . N a m e , a d dr e s s , a nd r eg i s t r a ti o n n um be r o f th e p e r s o n f r om wh o m t h e co n t ai ne r s we r e r e c ei v e d E . S t o r a ge o f c on t r o l led s u bs t an c es . Al l c on t ro l le d s ub s ta nc es in s c hed u le s I I - V m us t be s t o re d i n o n e o f t h e fo ll o wi n g wa ys : 1 . I n a s ec u re l y lo c k ed , s u bs ta n ti a ll y c o n s t r uc t ed c ab i ne t 2 . D is pe r s e d th r ou g ho u t t h e s t oc k o f u ns c h ed u le d p r es c ri p ti on m e di c at io n t o p re ve n t a n y t he f t o r di v e r s i on
F . T he f t o r s i gn i f ic a n t lo s s o f sc h ed u l e I I - V c on t r o l l ed su b s ta n ce s . E v e r y r e g is t ra n t m us t p r om pt l y n o t if y t h e r eg i on a l o ff ic e o f th e D E A o f t h e t he f t o r s i gn i fi ca n t l os s o f a n y c on t r ol l ed s u bs t an ce in s che d ul e s I I - V. Th i s r ep o r t m us t be d o n e us i ng D E A F o r m 10 6 . G . D i s p os a l o f c o n t r ol le d su b s ta n ce s . E v e r y d is p os al of a c on t r ol le d s ub s ta nc e m us t be ac c om p li s h e d by s u bm i tt i ng D E A F o r m 4 1 to t he D E A (e xc e p t for d is p os al s p u r su an t to a v al id p re s c r i p ti o n, di sc us s e d b e lo w) . Th e f o rm m us t l is t th e c o nt r o ll ed s u bs ta n c e s e a rm ar k e d fo r di s po s a l . Th e D E A wi ll a ut h o ri z e th e d is p os al a n d i ns t r uc t t h e re g is t ra n t t o d is po s e o f th e c on t r ol le d s u bs tan c es i n o n e o f t h e f ol l o wi n g wa ys : 1 . B y t he t ra ns f e r t o a pe r s on or e nt i t y re g is te r ed wi t h t he D E A a n d a ut ho r i ze d t o p o ss es s t he s u bs t an c e . S c h ed ul e II co n tr o ll e d s ub s ta nc e s m u s t b e t r an sfe r r e d b y u s e o f t h e t r an s f e r ee ' s (a n o th e r p ha r m a c y o r h os p i t al , o r th e wh o le s a l er or m a nu f ac tu r e r ) D E A F o rm 2 2 2. A wr i t t en re c or d o f t h e tr a ns fe r o f sc he d ul e I I I - V c o nt r o ll ed s u bs t an c e s m u s t b e k ep t fo r a t le as t 2 y e a r s a nd in c l u de th e fol l o wi n g i n f or m at io n : a . N am e o f th e c on t r ol led s u bs t a nc e b . F in is he d fo r m o f t he s u b s t a nc e ( d os ag e f o rm an d s t r en g th ) c . N um be r of un i ts or v o lu m e o f t h e f in is h ed fo r m i n ea ch c om m er ci a l co n ta i ne r ( e . g ., 10 0 - ta b le t b o tt l e ) d . N um b e r o f c o m m e rc ial c o n ta i ne r s o f e ac h f i ni s h e d f o rm t ra ns f e r re d e . D a te of t he t ra ns f e r f . N a m e , a d dr e s s , a nd r eg i s t r a ti o n n um be r o f th e t r a ns f e re e P.533
2 . B y t he de li v e r y t o a n a g e nt of t he D E A o r to the n ea r es t o f fi c e o f t he DE A 3 . B y t he de s t r uc t io n i n th e p re se nc e o f a n a g en t o f t he D E A o r ot h er au t ho r i z e d p e r so n 4 . B y a n y o t he r m e an s th a t th e D E A d et e rm in es t o en s u r e t h a t t he s u bs ta n c e do es n o t b ec om e a v ai la b le to u n a ut h or i z e d p e rs on s o r e n t it i es H . R e g u la r d is p os a ls o f c o n t r ol l ed s ub s ta n ce s . I f a r e gi s t r an t ( us ua ll y a h os p it a l ) r e g ul a rl y d is p os es o f c on t r ol l ed s u bs t an ce s i n sc h e d ul es II - V th e D E A m ay a u t ho r i ze d i sp os a ls wi t ho u t p r io r ap p r o v al in ea c h in s ta nc e. I f th e D E A g ra n ts th is au t h o ri t y , t h e re g is t ra n t m u s t k e e p r e c or d s o f e ac h d is po sa l a n d f il e p e ri o di c r e po r ts t o th e r e g io n al of f ic e o f t h e D EA s um m a r i z in g t h e d is pos a l s . Th e D E A m a y pl a c e a dd i ti on a l c o nd i ti on s o n s uc h d is pos a l, in cl u di ng t he m e th od o f d is po s a l a n d t he f r eq u e nc y an d d e t ai l o f re p or t s . I . D i sp o sa l o f c on t r o l led s u bs t an c es p u rs u an t t o a va l id p r es c r ip t i on 1 . P e rs o n s w h o m a y i s s u e p r es c r ip t i o ns f o r c on t r o l l ed su b s ta n ce s . A c o nt r o ll ed s u bs ta n c e pr e s c ri p ti o n m a y be is s u e d o nl y b y a p r a c t i ti o ne r wh o i s g r an te d s uc h a u t ho r i t y b y t h e s t a te in wh i c h th a t p r ac t it i on e r is l ic e ns ed . Al t ho u gh th e A c t i s f e d e ra l l eg is l at i on , e ac h s t a te de t er m i n es wh o wi ll b e a ut h o ri ze d t o d is p ens e c o nt r o ll ed s u bs t an c e s . M o s t s ta t es al lo w t h e fo l lowi n g i n di v i du a ls to pr es c r i b e: p h ys ic ia ns , de n ti s t s , po di a t ri s ts , a nd v e t e ri na r ia ns . S om e s t a te s a ll o w t h e f o ll o wi n g i n di vi d ua ls , re f e r re d t o as m i dl e v e l p r ac ti t io n er s , t o p re s c r ib e (u su al l y wi t h c e r t ai n
r e s t ri ct i on s ): ph y s ic ia n ' s a s s is t an ts , nu r se pr ac t i ti o ne r s , c e r t if i ed nu r se m id wi v e s , p s yc hi at r ic nu r s e s , m e n ta l he al t h c li ni c a l s pe ci a li s t s. A ll pr e s c ri b e rs m us t b e r e g is t er e d wi t h t he D E A o r e xe m p te d fr om r eg is t ra t i on (s e e I . B .9 ) . P ra c t iti o n e r m e an s a p h y s ic ia n , d en t is t , v et e r in a ri a n, o r o th e r p e rs o n l ic en s e d (m id - lev e l p r a ct i ti o ne rs ) b y th e s ta te t o p r es c r i be c o nt r o ll ed s ub s ta nc es , a n d p h a rm a c y , h o sp i ta l , o r o t he r in s t i tu ti o n l ic en se d to di s t r i bu t e c on t r ol l ed s u bs ta nc es . In d i vi d u al P r a c t i t io n e r m ea ns a p hy s i c i a n, de n ti s t, v e t er i nar i a n, o r o t he r p e rs o n l ic en s ed ( m i d- l e v el p ra c t i ti o ne rs ) b y t h e s ta t e t o p r es c ri be c on t r ol l ed s u bs ta nc es . It i s wo r t h n o t in g t h at t he te r m “ in d iv i d u al p ra c ti ti o ne r ” is i nc l u de d i n th e d e fi ni t io n o f “ p r ac t i ti on e r . ” P r es c ri bi ng a ut h o ri t y g ra n te d b y s ta t es is li m i te d to p ro f es si o na ls wi t h i n th e “i n di v i du a l p r ac t i ti on e r ” c at e go r y . Th e s t a te m e n t l ik e “ p ra c ti ti o ne r wh o is g r a n te d p r es c r i bi n g a ut ho r i t y ” m e an s t he “ in di v i du a l p r ac t it io n e r ” wh o h as b e en g r a n te d p r es c r i bi n g a ut ho r i t y b y th e s ta t e b ec a use t he in d i v id ua l p r ac t it i on e r i s i n cl ud e d i n t he d ef in i ti o n o f pr ac t i ti on e r . “ P h ar m a c y” is d ef in e d a s a “p r ac ti t i on e r ” b u t , o f c ou r s e , d o es no t h a v e p re sc r ib in g a u th o r ity . a . D E A n u m be r s an d a ut h e n t ic i t y. A f t e r r e g is te ri n g wi t h t he D E A , a ll r eg is t r an t s a r e ass i gn ed a D E A n um b e r b y t h e D E A . A p r ac t iti o ne r ' s D E A n um be r c o ns is t s o f n i ne ch a ra c te r s . Th e fi rs t t wo c ha r ac t e rs a r e l e tte r s . Th e f ir s t l et t e r wi l l be e it h e r A o r B . Th e s ec on d l e tt e r wi l l b e t h e f i rs t l e tt e r o f th e p ra c t i ti o ne r ' s l as t n am e . Th e n e xt s i x c h a r ac te r s a r e ra n d om l y c ho s e n n um b e rs . Th e l as t c h ar ac t e r is a n um b e r o f t en r ef e r re d to as th e “c h ec k di g it . ” Fo r e xa m ple , D r . He n r y J o ne s m a y h a v e a D E A n um b e r o f A J 4 35 77 8 2 . ( 1 ) Au t h e n t ic a t io n of DE A n u m b e r . Th e D E A ass i gn s D E A nu m b e rs wi t h a q ui ck m e th o d o f v e ri fi c a t io n b ui l t i n to th e n um b e r. Th is a l lo ws a di s p e ns in g p h arm ac is t to m ak e a c u r s o r y r e v ie w o f t h e n um be r fo r au t he n tic i t y . F o r e xa m p l e, us in g t h e a b o v e D E A n um b e r, th e p r ac t i tio n e r 's la s t n am e m u s t s ta r t wi t h a J . A ls o, t he fo ll o wi n g q u ic k c a lc u la t io n c an be m a de to ve r if y t h at t he “c h ec k di g it ” is c o r re c t: ( a ) Th e di gi t s in p os it io ns 1 , 3 , a nd 5 a r e a dd e d to g e th e r t o re ac h a nu m be r . In t he a b o ve e xa m p l e, t ha t wo ul d be 4 + 5 + 7 = 1 6 . ( b ) Th e di gi t s i n p os it i ons 2 , 4 , a nd 6 a r e a dd e d to g e th e r , t he n m ul t ip li e d b y 2 . In t h e a b o v e e xa m p le , th a t wo u l d b e ( 3 + 7 + 8) × 2 = 3 6. ( c ) Th e s e nu m b e rs ab o ve a r e a dd ed t og e th e r : 1 6 + 36 = 5 2 . Th e f a r- r i gh t d i gi t b e co m e s t h e c h ec k d ig i t . Th e c he c k d i gi t m us t t he r e f or e b e a 2 . I f t h e c h ec k d ig i t i s a n yt h in g o t he r th a n a 2 , t h e n um b e r m a y n o t b e a v a l i d D E A nu m b e r . I n s uc h a c as e , t h e D E A s h ou l d b e n o ti f ie d i n o r de r t o ve r i fy t h e nu m b e r . ( 2 ) M i d le ve l p r ac t i t io n er D E A n u m b e r s . Mi d l e v el p ra c ti t io ne r D E A n u m be r s a r e s im i la r to p ra c t i ti on e r D EA n um b e rs e xc e p t fo r the f i rs t c ha r ac t er . In s te ad o f th e l e t te r A o r B , m i d le v e l p ra c ti t io n e rs h a v e th e l e tt er M a s t h e f i rs t c ha r ac t er i n t h ei r D E A n um b e r. Th e m a th em a ti c a l m e th od f or v e r i f yi n g t h e a ut h en t ic it y o f t he n um be r i s th e s am e. ( 3 ) D E A n u m be r s f o r p ra c t i t io n e rs a nd mi d le ve l p r a c ti t i on e r s w ho a re e m p lo ye e s o f i ns t i t ut i on s . P ra c ti ti o ne r s a nd m id l e v el p ra c ti ti o ne r s wh o i s s u e p r e sc ri p ti o ns i n th e P.534
c o u rs e o f t h ei r e m p l o ym e n t wi t h a n i ns t it u ti o n m a y i s s ue p re s c r ip t io ns f or a ll c o nt r o ll ed s u bs t an c e s u nd e r th e i ns t it u ti o n 's D E A r e gi s t ra t io n . Th e p ra c t i tio n e r 's o r m i d -l e vel p ra c t i ti o ne r ' s “D E A n um b e r” wi l l b e a s p e ci f ic i n te r n al c o de num b e r is s u e d b y t h e i ns t it u ti o n. Th e c od e nu m b e r m us t c on s i st o f nu m b e rs , l e t te r s , o r a c om b in a ti o n o f n um be r s a n d l e tt e rs an d m us t b e a su f f i x t o th e i ns t it u ti o n 's D E A n u m b e r , p re c ed ed b y a hy p h e n (e . g. , A P0 1 23 4 56 -1 0 o r A P 01 2 34 5 6 -A 1 2 ). 2 . P u r po s e o f is s ua n ce o f c on t r o l le d - su b s ta n ce p r es c r i p ti o ns . A c on t ro l le d s u bs ta n c e pr e s c ri p ti o n m a y be is s u e d o nl y i n g oo d fa i th f or a l eg i ti m a t e m e di c a l p u r po s e b y a p r ac ti t io n er a c ti ng in t he us ua l c ou rs e o f hi s o r h e r p r of es sio n al p r a ct ic e . Th e p ra c ti ti o ner a n d t he di s p e ns in g p h ar m ac is t h a v e th e re s p o ns i bi li t y t o e n su r e t h at a p r es c r i pt i on is p ro p er l y is su e d a nd d i s p e ns ed ( re f e r re d t o as c o r re s po nd i ng r es po ns ibi l it y o f th e p ha r m a ci s t) . a . L eg i t im a te me d i ca l pu r p o s e. Le g it im a te m e dic a l p u rp os e a n d g oo d f a it h a re p r e r eq u is it es fo r al l c on tr o l le d -s u bs ta nc e p r es c rip t i on s . W it h r e sp ec t t o a p h a rm ac is t , t h es e r eq u i re m en ts wi l l b e a p pa r e nt f r o m a n o bj ec t i ve p oi n t of v i e w. A s a g en e ra l ru l e, if , f ro m a ll t he s u r r ou nd i ng fa c ts an d c i rc um s ta nc es , a r eas o na b l y p r u de n t p ha r m a c i s t wo u ld f o rm th e o pi n io n t h at a p r es c ri p ti on wa s is su ed f o r a l e gi t im a te m e di c a l p u rp os e , t h en th e p h a rm ac is t h a s f ul f il l ed hi s o r h e r r e s po ns ib i li t y un d e r t he A c t , a n d t he p re s c r ip ti o n m a y be le ga l l y d is p en s ed . b . U s ua l c o u r se o f p r o fe s s io n a l p r ac t i ce . A p ra c t i t io n e r -p a t ie n t re l a tio n s h ip fo r t h e p u r po s e of t re a ti n g an d c a r in g f o r t h e p at i en t m us t be p re se n t. U su al l y, s uc h a r e l at i on sh i p i nc lu de s t h e t a k i ng an d re c o r di n g o f a n ap p ro p r ia t e m e d ic al hi s to r y, an d a n ap p ro p r ia t e p h ys ic a l e xa m . Th i s l im i ts a p ra c ti t i on e r 's ab i li t y to p re s c r ib e ou ts i de h i s o r h e r c ou r s e of p ro fe s s i on a l p ra c ti c e ( e. g ., a v e t e r in a ri a n m a y n o t p re sc r i be a c o nt r o ll ed s u bs t an c e fo r a h um an ) . Th e n ot i on of “ u s ua l c ou r se of p ra ct ic e” b ec om es m o r e u nc le a r wi t h r es p ec t to m e di c a l d oc t o rs wh o s p ec i al i z e . S uc h s pe cia l is ts o ft e n i ss u e p r es c r i pt i on s “ ou t s i d e ” t h ei r s pe c i a lt y. G e ne r a ll y , al l c on t r ol l ed - s u bs t an c e p r e sc ri p ti o ns f ro m m e d ic a l do c t o rs a re de em e d t o b e “i n t h e us u al c o u rs e o f p r o f ess i on al p ra c ti c e ” a s l o ng as i t i s i ss ue d f o r a h um a n, r eg a r dl es s o f w h e t he r th e p r o bl em be i ng t re a te d i s wi t h i n th e d oc t o r 's sp ec ia l t y . c . R es t r i c ti o ns o n i ss ua n c e o f a c on t r o ll e d -s ub s t a nc e p r e sc r i p t io n ( 1 ) A pr es c ri p ti o n m a y no t be is s u ed b y a p r ac ti t io n e r i n o r de r fo r th a t p r ac t i ti on e r t o o b t ai n c on t r ol le d s ub s tan c es fo r th e p u rp o s e of g e n e ra l di s pe n s in g to hi s o r he r p a t ie n ts . ( 2 ) A pr es c ri p ti o n m a y no t be is s u ed f o r t he di s pe n s i n g o f c o n t ro l le d s ubs t an c e s f o r d e t o xi f i ca t i on o r m a i nt en a nc e t r e at m e n t . A dm in is t r at i on an d d i re c t d is pen s in g o f c o nt r o ll ed s u bs t an c e s a re a ll o we d on l y wh e n c ond u c t e d i n p r op e rl y r e gi s te r e d t r e a tm en t p r o g ra m s . A pr e s c r ip t io n fo r m e t ha d on e is v a li d o nl y wh e n is su e d a s a n a n al g es ic i n c as es o f s ev e r e p ai n . Me t h a d on e m a y b e d is p en se d i n a ho s p i t al to m a in t ai n a pa t ie n t 's ad dic t io n a s l on g a s t h e p at ie n t i s a dm i tt e d a nd be ing t r ea t ed f o r s om e ot h er m e di c a l c o n di t io n a n d is n ot ad m in i s t e r ed m e th a do n e s o l el y f o r d e t o xi f ic a ti o n p u rp os es . Th e 4 0m g ta bl e ts of m e th a d on e a r e o nl y a v a il a ble t o f a ci l it i es a u th o ri z e d fo r de t o xi f i ca t io n a n d m a i nt e n a nc e t r e at m e n t o f o p io id a dd ic t io n a n d h os p it a ls . Th e o th e r s t r en g th s ( 5m g a n d 1 0m g f o rm ul a ti o ns ) i nd ic a te d f o r th e
t r e a tm en t o f pa in a re a va i la b le to al l a u th o ri z e d r e g is t ra n ts , i nc l ud in g re ta i l p h a rm ac ie s . 3 . M a n ne r o f i s su a nc e o f a c o n t r ol l ed - s ub s t anc e p re s c r ip t i on . Sc h ed ul e II c o nt r o ll ed - s u bs t an c e p res c ri p ti o ns m us t b e wr i t ten wi t h in k o r i n de l ib le pen c il or t yp e wr i t t e n ( e xc e p t i n c as es o f o r al e m er g en c y s c h ed u le II p re sc r ip t io ns ) . S c he d ul e I I I - V c o nt r ol l ed - s u bs t an c e p r es c r ip t io n s m a y b e or a l l y o r d e re d b y t he p ra c t i t io n er . P r e sc r ip t io ns m a y b e p r ep a r ed b y ei t he r th e p r ac ti t i on e r o r a n a g en t o f th e p r a ct i ti o ne r , a nd c o m m un i c a t ed to t he ph a rm ac y b y t h e p r ac ti t io n e r o r t h e a g en t . A u t h or i z a ti o n f o r t h e p res c ri p ti o n ( o r r e fi l l) m u s t , h o we v e r , o r ig in a te wi t h th e p r a ct i ti o ne r . B o t h t he p ra c ti t io n e r a nd di sp en si ng p ha r m a ci s t a re r es po ns i bl e f o r t h e c om p le t en es s o f t h e p r es c ri p ti o n. A ll pr es c ri p ti on s fo r c o nt r ol l ed s u bs ta nc es m u st i n cl ud e th e f o ll o wi n g i nf or m a ti o n: a . F ul l n am e a nd ad d r es s o f t he pa t ie n t b . D a te th e pr es c ri p ti o n is is s u ed a nd s i gn ed ( one a nd th e s am e ) c . D r ug na m e , d os a ge for m an d s t re n gt h d . Q u an t it y o f d r u g p r es c r i b ed e . D i re c ti on s f o r u s e f . N a m e , a d dr e s s , a nd DE A r e gi s tr a ti o n n um be r of t h e p ra c ti t io ne r P.535
g . Th e s i gn a tu r e o f t h e pr a c ti t io n er ( no p re p ri n te d o r s t am p ed s i gn a tu r es ) a s h e o r s h e wo u l d s ig n a n y le g al d oc um e nt ( al l s ch ed u le I I co n t ro ll e d -s ub s t a nc e p r e sc ri p ti o ns m us t b e m a n u al l y s ig n ed b y th e p ra c ti t io n e r) 4 . E me r g e nc y d i s p e ns in g o f s c he d ul e II co n t ro l l e d s ub s t an c es a . A n o r al s c h e du l e I I c on t r ol l ed - s u bs t an c e p re s cr i p ti o n m a y b e re c e i v e d fr o m a p r a ct i ti o ne r i n a n e m e r ge n c y s i tu a ti on . A n em e r ge n c y p r es c ri p ti o n m u s t in c lu d e al l o f t he i n f or m a t io n re q ui re d fo r an y c on t ro l le d -s ubs t an c e p re s c r ip t io n . A n em e r ge nc y s i tu a ti o n e xi s t s wh e n al l t h r e e o f th e f o ll o wi n g f ac t o rs ar e p r es e nt : ( 1 ) Th e im m e di a te ad m i ni s t ra t io n o f th e c on t r ol led s u bs t a nc e is ne ce s s a ry f o r p r o pe r t re a tm en t of th e pa t i en t . ( 2 ) N o a p pr o p ri a te al t er na t i v e tr e at m e n t i s a v a il ab l e , i nc lu di n g a dm in is t r at i o n o f a c o nt r o ll ed s u bs t an c e th at i s n ot in s ch e du l e I I . ( 3 ) I t is no t r ea s o na b l y po s s i bl e f o r t h e p r ac ti t io ne r t o p r o v id e a wr i t t en p re s c r i pt i on t o be p re s e n te d to th e pe r s on di sp en s i n g t h e c on t r ol l ed s u bs t an ce be f o re t he d i sp e ns in g . b . P r o pe r d is p en s i ng . Th e qu a nt i t y p r es c ri b ed an d di s p e ns ed m us t be lim i te d to t h e a m o u nt ne c es s a r y to a d eq u at e l y t r e at t he pa ti e n t d u ri ng t he em er g en c y p e r i od . I f t he p ra c t i ti o ne r i s n o t k n o wn t o t he ph a rm ac is t, t h e p ha rm a c i st m us t m a k e a r e a so na b le go o d- f ai t h e ff o r t to de t er m i n e t ha t th e o r al a ut h or i z a ti o n c a m e f r o m a r e g is t er e d p r ac ti t io n er . ( 1 ) D e li ve r y o f w r i tt e n p r e s c r ip t i on . Th e p r ac t it i o ne r wh o au t ho r i zes the e m e rg en c y p re s c r ip ti o n m us t , wi t hi n 7 da ys of t he o r al au t ho r i zat i on , d e liv e r a wr i t t e n p re s c r ip t io n t o t he d is pe ns i ng ph a rm ac is t . Th e p r es c r i pt i on m us t c o n t ai n t h e i n f or m at io n re q ui r ed o f al l c o nt r ol l ed - s u bs t an c e pr e s c r ip t io ns , ha v e wr i t t en o n i ts
f a ce t he wo r d s “ A u th o ri z a t i on fo r Em e r ge nc y D isp e ns i ng , ” a nd t he da t e of t h e o ra l a u t ho r i z a ti on . Th e p r es c r i p ti o n m a y b e d e li ve r ed i n pe r s o n o r b y m ai l ; i f de l i v e re d b y m ai l , i t m us t b e p os tm a rk e d wi t h i n t he 7 -d a y p e r io d . Up on r ec ei p t , t he d is p en s i n g p h a rm ac is t m us t a t ta c h it t o t h e o r al em er g en c y p r e s c ri p ti o n, wh i c h wa s p r e v i ou s l y r e d uc ed t o wr i t i n g. ( 2 ) F ai l u r e t o d e l i ve r a w r i t t en p r es c r ip t i on . I f a p r ac ti t io n er f ai ls to de li ve r t he wr i t t e n p re s c r ip t io n a s r eq u i re d , t h e d is pe ns in g ph a r m a c i s t m u s t no t if y t he r e gi on a l o f f ic e o f t h e D E A . Fa il u re b y t he ph a rm ac is t t o no t i f y th e D E A s e r v e s t o vo i d t h e p h a rm ac is t ' s a ut h o ri t y to d is p en s e an o ra l e m e r ge n c y s c h e du le I I p r es c r ip t i on . Th e p h a rm ac is t wi l l b e d ee m e d to ha v e un l a wf u ll y d isp e n s e d a s ch ed u le I I con t r ol l ed s u bs ta n c e . 5 . F ac s im i le p r es c r ip t io n s . Pr e s c ri p ti o ns fo r c on t r ol l ed s u bs t an ce s I I I, IV a n d V ( a n d n on f ed e r al c o nt r ol le d s u bs t an c e s su c h as pe n ic il l in an d f u r os em id e ) m a y be d e li v e r e d t o t h e d is pe ns in g ph a rm ac y v i a fa cs im ile m a ch i ne . A f ac s i m i l e pr e sc r ip t io n i s d e em ed to be t he wr i t te n , s ig n ed p re sc r ip ti o n fr o m t h e p r es c r i be r s o l on g as i t c o nt a in s t he in f o rm a ti on r e q ui r e d o f a ll p re sc ri p ti o n s u nd e r f e de r al la w. T h e p r e sc ri p ti o n m u s t b e s e nt d i re c t l y f ro m t h e p r es c ri b e r o r h is au t ho r i z e d a ge n t to th e p h a rm ac y . a . S ch e d ul e I I co n t r o ll ed s u bs t an c es . P re s c r ip ti o ns fo r s c he du l e I I c on t ro l le d s u bs ta n c e s m a y b e s en t v i a f ac s i m i le t o a d is p ens i ng ph a rm ac y t o f ac i li t at e d i sp e ns in g o f t h e p r es c r ip t i on . N o d r u g m a y b e r e l e as e d t o t h e p at i en t un t i l t he o r i gi n al , s ig n ed pr e s c ri p ti o n i s p r es en t ed to t he d is p en s i n g p ha r m a c i s t . A s c h e du l e I I co n t ro ll e d -s ub s t a nc e fa c s im i le p re sc ri p ti o n w i ll s e r ve as t h e o r ig in a l, s i g ne d p r e sc ri p ti o n i n t he f ol lo wi n g s it u at i on s : ( 1 ) I nj e c ta b le h om e -h e al t h p r es c r ip t i o ns . A f ac s im i le s c h e du l e I I n a rc o ti c p r e sc ri p ti o n c al li n g f o r th e c om p ou n di ng o f a s olu t i on fo r di r ec t a dm i ni st ra t i on to a p a t ie n t i n a p r i v a te r es ide n c e , l o ng - t er m -c a re fa ci l it y , o r h os p ic e se t t in g m a y s e r v e a s th e o r ig i na l p r es c r i pt io n . Th e e xc e p t io n a p pl ies so lo ng as th e s ol u ti o n wi l l b e a d m i ni s te r ed b y m e an s of p a re n te r al , in t ra v e n ou s , i nt r am us c ul a r, s u bc u tan e o us , o r i n t ra s pi na l i n fu s i o n. ( 2 ) L on g - t e rm - ca r e fa c il i t y p r e s c r i p t i on s . A n y fa c s im i le s ch e du l e I I p r esc r i pt io n i ss u ed fo r a r es i de n t o f a l on g - te rm - c a r e f ac i li t y m a y se r ve as th e o r ig in al , s i gn e d p r e sc ri p ti o n. ( 3 ) H o sp i ce pa t i e nt p r es c r i p t io n s. A n y fa c s im ile s c he d ul e I I na r c o t ic p re s c r i pt i on i ss u ed fo r a p a ti en t en r ol l ed in a h os pi c e - c a r e p ro g r am c e r ti f ie d a nd / o r pa i d f o r b y Me d i c a r e u nd e r Ti tl e XV II I o r l ic en s e d b y s ta t e l aw m a y s e r v e a s t h e o ri g in a l p r e sc ri p ti o n. Th e pr e s c rib e r , o r hi s a ge n t, mu s t no t e o n th e p r es cr i pt i on th a t th e p a t ie n t is a h os pi c e pa t ie n t . P.536
6 . E le c t r o ni c d a t a t r a nsm i s si o n p r e sc r i p t io n s fo r n o n -c o n t r ol l ed s ub st a n c es : P r e sc r ip t io n i n fo r m a t io n t h a t i s t r an sm it t ed di r ec tl y f r om a p r ac ti t io n e r t o a p h a rm ac y b y el ec t r on ic m e an s s uc h as v i a t h e I nt e r n et is re f e r re d t o a s el e ct r o ni c d a t a t r an s m is s i on p re s c ri p t io n . E le c t ro ni c s ig na t ur e s a r e re c o gn i z e d a s leg a ll y
a cc e pt a bl e s ig n at u r es o f p r ac t it i on e rs . L e ge n d d ru g s , e xc e p t f o r c on t ro l led s u bs ta n c e s , m a y b e t r ans m i t t ed to ph a rm ac i es v ia t he I nt e rn e t i f a ll o we d b y s t at e l a w. A s ta t e m a y a ll o w a p r a c t i ti o ne r a n d p ha r m a cy t o m a i nt a in th e p r es c rip t i on i n f or m at io n i n e l ec t ro n ic f o r m wi t h o u t r ed uc i ng it to wr i t i n g, s o l o ng as th ey c o m p l y wi t h s t at e m an d at e d s afe g u ar ds . a . E le c t r o ni c d a t a t r a nsm i s si o n p r e sc r i p t io n s fo r c o n t ro l l ed su b s ta n ce s : Th e D E A d o es n o t y et r ec og ni z e e le ct r o ni c d at a t r a ns m is si o n p r es c r i pt io n s as a m e a ns o f co m m un ic a ti ng p re s c ri p t io n i n fo rm a ti o n f o r a ny c o n t ro ll e d s u bs t an c e . Th e r e f o re , p r e sc ri p ti o n i nf o rm a ti o n f o r c o nt r o ll ed s u bs t an c es m a y n ot be co m m un ic at e d fr om a p r a ct i ti o ne r to a p ha r m ac y b y e le c t r o ni c m e a ns . 7 . P e rs o n s w h o m a y d i s p e ns e c o n t r ol l ed - s ub st a n c e p r es c r i p ti o ns . A p h a r ma c is t a c ti n g i n t he us ua l c ou r s e o f h is or he r p ro f es s i on a l p r ac t ic e i n a D E A -r eg i s t e r ed p h a rm ac y ( o r h os pi t al o r o t he r r eg is t er e d f ac il i t y ) m a y di s p en s e a c on t r ol le d s u bs ta n c e pu r s u an t to a p r e s c ri p ti o n. A ph a r ma cy i n t e r n a c ti n g u nd e r t he d ir e c t s u pe r v i s i on o f h is p r ec ep t o r i n a D E A - re g is te r e d f a ci l it y m a y a ls o d is p en s e a c o nt r o ll ed s u bs t an c e pu rs u an t to a p r es c r ip t io n . 8 . D i sp e ns i n g p r o ce d u re s o f c o nt r o l le d s u b st an c e s p u r su a n t t o a p r es c r i p t io n . O n c e a c o n tr o ll ed - s u bs ta n c e p re s c r ip t io n h as bee n l a wf u l l y is s u ed b y a pr a c ti t io n er a n d p r es en t e d t o a p h a rm ac is t , i t m a y be di s p e ns e d i n ac c or d an c e wi t h th e f o l lo wi n g : a . P r es e n ta t i on t o th e ph a r m ac i s t. S c h ed u le s I I I a n d I V c o nt r ol l ed - s u bs ta n c e p r e sc ri p ti o ns ar e v al i d f or 6 m o nt h s f r om t h e d at e o f i s s u an c e b y th e p r ac ti t i on e r. S c h ed ul e II c o n tr o ll e d- s ub s ta nc e pr es c ri p ti o ns h av e n o ti m e li m i t f o r p r es en t a ti o n u n d er t he Ac t , a l th ou g h th e y a r e o ft e n r ec o gn i z e d t o be va li d f o r u p t o 6 m o n t hs . S c h ed ul e V c on t r ol le d -s u b s t a nc e p r es c r i pt i on s al s o h a v e n o s et ti m e li m it f o r p r e se n ta t io n u nd e r th e Ac t . Re g a rd le s s of wh i c h s c h e du l e o f c on t ro l le d s u b st a nc e i s i n vo l ve d, th e g o od - f ai t h a n d “l eg i ti m a t e m ed ic al p u r po s e ” li m i t at i on wi l l al wa y s a p pl y a n d m a y s e r v e t o o t he r wi s e l im it th e v al i di t y o f a p r e sc ri p ti o n. b . I n fo r m a ti o n t h a t m ust b e r ec o r de d on t he p re s c r ip t i o n b y t h e d i s p en s i n g p h a r ma c is t . U n d e r t h e A c t, a f il l ed pre s c r i pt i on is c on si d e re d t o be a l a wf u l r e c o r d o f d i s p os i ti on f o r a c o n t ro l le d s ub s t a nc e . A s a re s u l t, e v e r y p r es c ri p ti o n f o r a c on t r ol le d s ub s ta nc e m us t c o nt a in c e r ta i n i nf or m a ti o n. S om e o f t h e i nfo r m at i on wi l l a l re ad y b e c o nt a in e d i n th e p r es c ri p ti on , al t hou g h t h e d is pe ns i ng ph a rm a c is t is re sp o ns ib le f or e ns u r in g t h a t a ll of t he fo l lo wi n g in f o rm a ti o n is r ec o rd ed (u s ua ll y o n t h e f ac e o f the p r e sc ri p ti o n ): ( 1 ) N am e o f th e c on t r ol led s u bs t a nc e ( 2 ) Fi n is he d fo rm o f t he c o nt r o ll ed su bs t an c e ( dos a ge fo r m a nd s t r en g t h) ( 3 ) N am e a n d a dd r es s o f t h e p e rs on t o wh o m i t wa s d is p en s e d ( 4 ) D a te of di s p e ns in g ( 5 ) N um b er o f u ni ts o r v o l um e d is p en s e d ( q ua n tit y ) ( 6 ) W rit t en or t y p e wr i t ten n am e o r i n it ia ls o f t he i n di v i d ua l wh o d is p en s ed t he c o nt r o ll ed s u bs t an c e ( 7 ) S e ri al nu m b e r o f th e p r e s c ri p ti o n
c . R eq u i r ed i nf o r m at i o n o n p re s c r ip t i on l ab e ls . E v e r y p r es c ri p ti o n la b el f o r a c o nt r o ll ed s u bs t an c e m us t in c l ud e th e f o ll o wi n g in f o rm a ti o n: ( 1 ) N am e a n d a dd r es s o f t h e p ha r m a c y ( 2 ) S e ri al nu m b e r a s s ig ne d to t he pr e s c ri p ti o n ( 3 ) D a te of t he in i ti al fi l lin g of t he pr e sc ri p ti o n ( f or r e f il ls , t h e d at e o r i gi na ll y f i ll e d) ( 4 ) N am e o f th e p a ti en t ( 5 ) N am e o f th e p r es c r i bin g p ra c t i ti o ne r ( 6 ) D i re c ti on s f o r u s e , an d c a ut i on a r y s t a te m e n ts , if an y ( 7 ) F or s c he d ul e I I , I I I , an d I V c on t ro l le d s ub st a nc es , th e fe de r a l c ri m e t ra n s f e r wa r n i n g m us t a p pe a r o n t h e c on t ai n e r: “ C au t io n : F e d e ra l l a w p r oh i bi ts th e t r a ns fe r o f t hi s d ru g to an y p e rs on o th e r t h an th e pa ti e nt fo r wh o m i t wa s p r es c ri b ed . ” d . Al l ow a b l e q ua n t i ti e s t h a t ma y b e d i s pe n se d . Th e A c t co n ta i ns n o l im it a t io n c o nc e rn in g th e q u an ti t y o f a c on t ro l le d s ub s ta nc e t ha t m a y be di s p e ns ed p u rs u an t t o a p r esc r ip t io n . Al l q ua n tit i es a re , o f c o u rs e, li m i te d to t he go od - f ai t h a nd “ l e gi t im at e m e di ca l p u rp os e ” s t an dar d s . e . F il i n g c on t r o l le d s u bs t a n ce p re s c r ip t i on s . W rit te n c on t r ol le d -s u bs ta n c e p r e sc ri p ti o ns m us t b e m a i n ta in e d a t t h e p ha r m a c y f o r a p e ri o d o f 2 y e ar s f r o m t he d a t e o f t h e o ri g in al P.537 d i sp e ns in g o r l as t re f il l , wh i c h e ve r i s l at e r . Th e y m us t be a v ai la b le fo r in sp e c t i on a n d c op y i n g b y em pl o y ee s a n d a ge n ts of th e D EA a n d b e f il e d s eg r e ga te d f ro m a ll o t h e r r ec o rd s i n o ne o f th e fo l lo wi n g wa y s ( st a te l a w u s ua l l y d ic t at e s t he m e th o d t o b e us ed ) : ( 1 ) U si n g t h r ee se p a ra te f i le s a s f o ll o ws : ( a ) O n e f il e fo r s c h e du le I I c o nt r o ll ed - s u bs t an c e p r e s c ri p ti o ns ( b ) O n e f il e fo r s c h e du le I I I , I V , a n d V c o n tr o ll ed -s u bs ta n c e pr e sc ri p ti o ns ( c ) O n e f il e fo r u ns c he dul e d p r es c r i pt i on d ru gs ( 2 ) U si n g tw o se p a ra t e fi l e s a s f ol l o ws : ( a ) O n e f il e fo r a l l c o n t rol l ed - s u bs t an c e p re s c r ip t io n s ( I I - V ), as l o ng as s c h e d ul e I I I , I V , an d V p r es c r i pt i on s ha v e t he le t t er “ C ” s t am ped i n r e d in k i n t h e l o we r -r i g ht c o r ne r n o l e s s t h an 1 i nc h h ig h ( b ) O n e f il e fo r un s c he du l ed p re s c r ip t io n d r ug s ( 3 ) U si n g tw o se p a ra t e fi l e s a s f ol l o ws : ( a ) O n e f il e fo r s c h e du le I I c o nt r o ll ed - s u bs t an c e p r e s c ri p ti o ns ( b ) O n e f il e fo r al l o th e r c o nt r o ll ed s u bs t an c e s ( I II - V ) a nd un s c he d ul ed p re s c r i pt i on d r u gs , a s l on g a s s c h edu l e I I I , I V , a nd V pr e s c rip t i on s h a v e t he le t t e r “ C” s ta m p e d i n re d i n k in t he lo we r - r ig h t c o rn e r n o l es s t ha n 1 i nc h h i gh ( 4 ) I n e it h er ( 2 ) o r (3 ) a bo v e , i f a p h ar m a c y ut i li z e s a n e l ec t ro n ic re co r d -k e e pi n g s ys t em fo r p r es c ri p ti o ns ( i . e ., c o m p u te r i zed r ec o rd s ) , wh i c h p e rm it s i de n tif i c a t io n b y p r e sc ri p ti o n n um be r an d r e t r ie v a l o f or i gi n al d o c um e nt s b y p r esc r i be r ' s n am e , p a t ie n t 's na m e , d r u g d is p e ns e d, an d d a te fi l le d , th e n t h e r e qu i re m e n t t o m a rk th e h a r d c op y p r es c r i pt io n wi t h a r ed “ C ” i s wa i ve d . f . R e f i ll d is p en s in g of co n t r o l le d s u b st a nc e s. P r e sc r ip t io ns f or sc he d ule I I c o nt r o ll ed s u bs t an c e s m a y n o t b e r e fi l le d . P r es c ri p t io ns fo r s ch e du l es II I a n d I V
c o nt r o ll ed s u bs t an c e s m a y b e re f il le d up to fi ve ti m es wi t hi n 6 m o n th s f r om t he da t e o f is su e o f t h e p r es c r i pt io n . Sc he d ul e V c o n t ro ll ed - s ub s t a nc e p r es c r i pt i ons ha v e n o l i m i t at io n s f o r r e fi ll i ng un d e r t h e A ct ; ho we v e r , on c e a ga i n, th e g o od - f ai th a nd “ l e gi t im at e m ed ic a l p u rpo s e ” li m i t a ti on s a p pl y h er e , as we l l a s t o a ll c o nt ro l le d s u bs ta n c e re f il ls . ( 1 ) R e fi ll in f o rm at i on m ay b e m a in t ai n ed ei t he r m a n u al l y o r b y us e o f a c om p ut e r . Th e A c t re qu i r es t h at t he i n fo r m a t io n b e m ai n ta ine d on e wa y o r th e o t he r , b u t n o t b o t h wa y s . I f c o mp u t e r iz e d re f i ll r e co r d s a r e m a i n ta in e d, t he s y s t em m u s t h a v e c e r ta i n ca p ab il i ti es an d th e di s p e ns in g p ha r m a c i s t m us t f ol l o w c er t ai n p r oc e du r es . ( a ) Th e c om p ut e r m us t be a bl e t o p r o v i de on - li n e r e t r ie va l o f t h e o r ig in a l p r e s c ri p ti o n i nf o rm a ti o n, p r o v i de on - li n e r e tr i e val o f th e re f il l h is to r y , a ref i ll - b y - r e fi ll a u di t t ra il , an d a n a u xi l i ar y p r o ce d ur e i n th os e c a s es wh e r e th e s y s te m e xp e r ie nc es d o wn t i m e . ( b ) Th e s y s t em m us t a ls o a ll o w t h e p ha r m a ci st wh o r ef il ls a p r es cr i pt i on to d o cu m e n t t h at th e i n fo r m a t i on he o r sh e e n te r e d in t o th e c om pu t e r is c o r re c t . ( 2 ) W hen d is pe ns i ng a re f i ll , t h e p ha r m a c i s t m u s t r ec o r d, on t he ba c k o f th e o ri gi n al p r e sc ri p ti o n o r b y c om put e r , th e f o ll o wi n g i nf o rm at i o n: ( a ) D a te of t he re f il l ( b ) N am e o r in i ti al s o f t he r e fi ll i ng ph a rm ac is t ( c ) A m o un t of th e m e di c a t i on di sp e ns ed (i f th e am o un t i s o m i t te d , t he r e fi l l wi l l be d e em e d t o h a v e b ee n fo r t h e f ul l fa c e am ou n t p r es c ri b ed b y th e p r ac ti t io ne r ) g . M u l t i pl e s c he d u le II p r e s c r ip t i on s p re s c ri b ed o n th e s a me da y t o b e f i l le d s e q ue n t ia l l y. Th e r e f il l o f a p r es c r i pt i on fo r a c on t r ol l ed s u bs t an c e li s t e d i n s ch e du l e I I i s p r oh ib i te d . H o we ve r , a n i n di v i du a l p r a c t i ti o ne r m a y iss u e m u l t ip le p r e sc ri p ti o ns au t ho r i z in g t h e p a ti en t to r ec ei ve a t o t al of u p t o a 9 0 - da y s u p pl y o f a s ch e du l e I I c on t r ol le d s ub s ta nc e pr o v i di n g e ac h p r e s c ri p ti o n is is su e d f o r a l e gi t im a te m e di c a l p u rp os e b y a n i nd i v i du a l p ra c ti t i on e r a c t in g i n th e u s u al c o u rs e o f p r o f ess i on al p ra c ti c e . The i nd i v id u al p ra c t i ti o ne r p r o v i de s wr i t te n i ns t r uc tio n s o n e a ch p re s c r ip t io n ( o th e r t h a n t he f ir s t p r es c r ip t ion , if t he p re s c ri b in g p r ac t i t io n er i n t en ds fo r th a t p r es c r i pti o n t o b e fi ll e d im m e di a te l y) in d ic a ti ng t he ea r li es t da t e o n wh i c h a p ha r m a c y m a y fil l ea c h p re sc ri p ti o n. h . P a r ti a l d i sp e ns i n g o f c o n t r ol l ed s ub s ta n ce s . Th e A c t d oe s n ot p ro h ibi t th e p a r ti a l d is pe ns i ng of c o nt r o ll e d s ub st a nc es i n s c he d ul e s I I I a nd I V, p ro v i de d th a t e a ch pa r t ia l f il l in g i s r ec o r d ed in t he s am e m an ne r as r ef i ll s , th e to t al qua n t it y d i sp e ns ed in al l p a rt i al fil l in gs do es n ot e xc e ed th e to t al qu a nt i t y pr e s c ri be d , a n d n o p a r ti a l f il l in g o c c u rs a f t er 6 m o nt h s f r om t h e d at e o f i s s u an c e of t he pr e sc r i p ti o n. L i ke wi s e , a ll pa r t ia l f il l ing s o f a s c he d ul e V p r es c r i p ti o n m u s t n ot e xc e e d th e to t al q u a nt i t y p r es c ri b ed . ( 1 ) P a r t ia l d i s pe n si n g of a sc h ed u l e I I c o n t ro l le d su b s ta n ce . Th e p a r tia l d i sp e ns in g o f a s c he du l e I I p re sc ri p ti o n is al l o wed i f t he p ha rm ac is t is u na b le t o s u pp l y th e fu ll P.538 q u a nt i t y o r th e p r es c ri p tio n is fo r a t er m i n al l y il l p a t ie n t o r a pa t ie n t i n a lo n g -
t e r m c a re fa c i l it y ( L TC F ) . U n d e r n o o th e r c i rc um s ta n c e m a y a s c h ed u le I I p r e sc ri p ti o n b e p a rt i al l y d i s p e ns ed . ( a ) I na d eq u a te su p p l y. I n c a s e s o f a n i na d eq u ate s u p pl y , t he di s p e ns in g p h a rm ac is t m us t n o te on t h e f ac e o f th e p r es c ri p ti o n t h e am o un t d is p en s ed . Th e r e m ai ni n g b al an c e o f t he s c h ed u le I I p r esc r ip t io n m us t be di sp e ns ed wi t h in 7 2 h ou r s o f t he fi r s t pa r t ia l f il l in g . I f , fo r a n y r ea s o n , t h e ba l an c e is no t d is p en se d wi t h i n th e 7 2 - ho u r p e ri o d, t he ph a rm ac is t m us t no t if y t he p re s c r i bi ng p ra c ti ti o ne r of t h is f ac t. Th e p h a rm ac is t m a y n o t d i s p e ns e a n y fu r th e r a m o u n ts p u rs u an t to th is p re s c r i pt i on b e yo n d t he 72 - h ou r p e r io d . ( b ) T e rm i na l l y i l l a n d pa t i e n ts in L T CF s . I t i s th e ph a rm ac is t ' s r es p on s ib i li t y t o e n su r e t h at a p a ti en t has a m ed ic al di a gn os is doc um e nt i ng a t e rm in a l il l ne s s o r t h at t h e p a ti e nt is i n an L TC F. B e fo r e a n y pa r t ia l d is pe n s i n g, th e p h a rm ac is t m us t re c or d o n th e p r es c ri p ti on wh e th e r th e p a ti e nt is “t e rm i na l l y il l ” o r a n “L TC F p a tie n t . ” A n y p a r ti a l d is pe ns i ng wi t h out o ne o f t he s e no t a ti on s s h al l b e d e em ed to be a d i sp e ns in g i n v io la t io n o f t h e A c t. Th e to t al am oun t o f t he s c he du l e I I s ubs t an c e d i sp e ns ed in al l p a rt i al fil l in gs m u s t no t e xc e ed the t o ta l q ua n ti t y p re s c r ib ed . S c h ed ul e II p re s c r ip t io ns f o r a t er m i n al l y il l p a ti en t o r a p a ti e nt in an L TC F a r e v a l id u p to 60 da y s f ro m t he da t e o f i s s u an c e of t he pre s c r i pt i on b y t h e p r ac ti t io n e r . A ll o f t h e fo ll o wi n g i n fo r m a ti o n m us t b e re c o r de d , e i th er m an u al l y on th e b ac k of t h e p r e sc ri p ti o n o r v ia c o m pu t e r ( wi t h si m i l ar c a p ab ili t i es re q ui r ed fo r c om p u te r i ze d r e f il l re c o r d k ee p in g ), wh e n pa r t ia ll y d is pe ns i ng a s c h ed u le I I p r es c r ip t io n f o r a t e r m i n al l y i l l p at i en t o r a p a ti e nt in an L TC F : ( i ) D a te o f t he pa r t ia l f il l in g ( i i ) Q u an t it y o f d r ug di s pe n s e d ( i i i ) R em ai ni n g q ua n ti t y a u t ho r i z ed t o b e d is pe ns e d ( i v) I d e nt i fi c a t io n o f th e d i s p e ns in g p ha r m a c i s t i . T r an s f e r o f r e fi l l i n f or m a t i on f o r a co n t r o ll ed - s u bs t a nc e p r e sc r i p t io n . R ef i ll i n f or m at io n c o nc e rn in g s c h ed u le s I I I, I V , a nd V c o n t r ol le d s ub s ta nc es m ay b e t r a ns f e r re d t o a n ot h er pha r m ac y on l y on ce ( if al l owe d b y s t at e l a w) . P h a rm ac i es e l ec t r on ic al l y s h a ri n g a re a l ti m e , o n -l i ne da t ab as e ( s u ch as c h ai n p ha r m ac i es ) m a y t r a ns f e r r e fi ll in f o rm at i on f o r th es e c on t r ol le d s ubs t an c e s u p t o th e m a xi m u m n u m b e r o f re f il ls pe rm i t te d b y l a w a n d t h e p re sc ri b e r 's au t ho r i za ti o n. Th e c om m u n ic at i on m u s t be m a de di r ec t l y b e t we e n two l i c en se d p h a rm ac is ts . B o th t he o r i gi n al pr es c ri p ti o n a nd t h e tr a ns fe r r e d p re s c r ip t io n m us t be m a in t ai ne d fo r 2 yea r s f r o m t he da t e o f th e l as t r e f il l . Ce r t ai n i nf o rm a ti on m u s t b e r ec o rd e d a s f ol l o ws : ( 1 ) Th e t r an s fe r r i n g p ha r m a ci s t m us t : ( a ) W rit e t h e wo r d “ v o id ” o n th e f ac e o f th e o r ig i na l pr e sc ri p ti o n ( b ) O n th e b ac k o f t h e p re s c r i pt i on , re c o r d t h e n am e , a dd r es s , a nd D E A re g is t r at i on n u m b e r o f t h e p ha r m a c y t o wh i c h i t wa s t r an sf e r re d an d t h e n am e o f t h e p h a rm ac is t r e c ei vi ng t he in f or m a t io n ( c ) R ec o rd t he da t e o f t he t r an s f e r a n d t he na m e o f t he t ra ns f e rr i ng ph a rm a c is t ( 2 ) Th e r ec e i vi n g p ha r m a c is t m us t : ( a ) W rit e t h e wo r d “ t ra n s f e r ” on th e f a c e of th e tra n sf e r re d pr es c ri p ti o n ( b ) R ec o r d a ll of th e i n for m a ti o n r eq u i re d f o r a n y c o nt r o ll ed - s u bs t an c e p res c ri p ti o n ( s e e I . I. 3 ) , a nd in c l u de th e fo l lo wi n g :
( i ) D a te o f is s u a nc e o f t he o ri g in a l p re sc r ip t io n ( i i ) O r ig i na l n um b er o f r ef i ll s a u th o ri z e d on th e o ri g i n a l p r es c r ip t io n ( i i i ) D at e t h e p r es c r i pt i on wa s in i ti a ll y d is pe ns e d ( i v) N u m be r of v a li d re f ill s re m a i ni ng an d th e d a te o f t h e l as t r e fi ll ( v) P h a r m a c y ' s n am e , a dd r e s s , D EA r eg is t r at i on n u m b e r , a nd o ri gi n al pr es c ri p ti o n n u m b e r f r om wh i c h th e pr e s c r ip t io n i n fo r m a t io n wa s tr a ns f er r e d ( vi ) N a m e o f t h e t r an s f e rr i n g p ha r m a ci s t J . D i sp o sa l of c on t r o l led s u bs t an c es t o a pa t i en t w i t h ou t a p r e sc r i p t ion . C o n t r ol le d s ub s ta nc es t ha t a re no t p r es c ri p ti o n ( or l eg e nd ) d ru gs un d er f ed e r al la w m a y be di s p e ns ed t o a pa t i en t a t re t ai l wi t ho u t a p r e sc ri p ti o n. Th e s e d ru gs do no t h a v e on th e m a nu f ac tu r er ' s l ab el t he fe d er a l s ta te m en t : “ C a u ti on : Fe d er a l l a w p r o hi b it s d is pe ns i ng wi t ho u t a p re sc r ip t io n . ” Th e s u bs ta n c e s m a y b e d is pe n se d wi t h o u t a p re s c r ip t io n i n a c c o r da nc e wi t h t h e f ol lowi n g : P.539
1 . Th e di s p en s i n g m u s t b e m a de on l y b y a li ce n s e d ph a rm ac is t . Th e ac t ua l c as h t r a ns f e r o r d el i v e r y m a y b e m a de b y a n on ph a rm a c is t . 2 . N o t m o r e t h an 8 o z o f a n y s u b st a nc e c o n ta i ni ng o pi um , 4 o z of an y o t he r c o nt r o ll ed s u bs t an c e , 4 8 d os a ge un i ts o f an y s u bs t an c e c o n ta i ni ng op i um , o r 24 d o sa g e u ni ts of a n y o t her c on t r ol le d s ub s ta nc e m a y b e d is p en s e d to th e s a m e p u r ch as e r i n a n y 48 - ho ur p e ri o d. 3 . Th e pu rc h as e r is a t l ea s t 1 8 y ea r s o ld . 4 . A n y pu rc h as e r n ot k no wn t o t he ph a rm ac is t m u s t f u rn is h s ui t a bl e i de n ti f ic a ti o n. 5 . A b o un d re c o r d b o ok m us t be m a in t ai ne d fo r 2 y e a r s f r om th e d a te o f th e la s t e n t r y. Th e f o ll o wi n g i nf o rm a ti o n m u s t b e r ec o rd e d f o r e ac h p u rc h as e : a . N am e a n d a dd r es s o f t h e p u rc h as e r b . N am e a n d q ua n ti t y o f c o nt r o ll ed su bs t an c e pu rc h as ed c . D at e o f ea c h pu r c h as e d . N am e o r in i ti al s o f t h e p h a rm ac is t wh o d is p en se d th e s ub s ta nc e t o th e p u r ch as e r 6 . A ll di s p e ns in g o f a c on t r ol l ed s u bs t an c e wi t h ou t a p r es cr i pt i on m us t be d o ne in g o o d f ai t h a nd no t to e va d e t h e p r o v is io ns of t he A c t . K . S e c u ri t y c o n s i d e ra t io n s 1 . C o n t ro l l ed - s ub s ta n ce s ea l s. Ma n u f ac t u re r s m us t pa c k ag e c e rt a in c on t r ol l ed s u bs ta n c e s i n a c on t ai n er wi t h a s ec u re l y a ff i xe d s e al to r e v ea l a n y t am per i n g. E ve r y b o t tl e , m ul t ip le - d os e v ia l , o r o t he r c o m m erc i al c o nt a in e r o f a n y c o nt r o ll e d s u bs ta n c e li s t e d in s c hed u le I I, o r o f a n y na r co t ic co n t ro ll e d su bs t an c e lis t ed in s ch e du l e I I I o r I V , m us t b e pa c k ag e d wi t h s u c h a s ea l . 2 . F el o n y c o n vi c t i o n s . N o D E A r eg is t r an t m a y em p lo y a n i nd i vid u al wh o h a s ac c ess t o co n tr o ll e d s u bs t an c e s i f th a t i nd i v id u al ha d p re v i o us l y be e n c o n vic t ed o f a f el o n y o f f en se r el a te d t o c o nt r ol l ed s u bs t an ce s . 3 . M a n u fa c tu r e r ' s l a be l . E v e r y c om m e r c i al c o n tai n e r o f a c o nt r o ll ed s u bs ta n ce m us t ha v e on it s l ab e l t he s y m b ol de s i g na t in g t h e s c h ed u le in wh i c h t he c o n t r ol le d s u bs ta n c e is l is t ed . Th e s y m b ol m us t a p pe a r i n th e up p er - r ig h t c o rn e r o f t h e l a be l o r b e o ve rp r in t ed on t he l ab e l .
L . R e co r d ma i n te n an c e. A l l re c o r ds re q ui r ed t o be m a i nt a in ed u nd e r t he A c t m us t b e k e pt b y th e re g is t ra n t f o r 2 y e a rs . Th e r ec o r ds m a y be m a in t ai ne d a t a c e nt r a l l o ca t io n (e . g. , a t a c h a in p h a rm ac y ' s re g io na l o f f ic e ) a f te r no t if y i n g t h e DE A . H o we ve r , e xe c u t e d D E A 2 2 2 F o rm s ( C o p y 3) , al l c o nt r o ll ed - s u bs t an c e p res c ri p ti o ns , a n d a ll in v e n to r i es m us t b e m a in t ai ne d at th e p h ar m ac y , n ot c e nt r a ll y . A ll s c h e du l e I I co n t ro ll e d -s ub s t a nc e re c o rd s m u s t b e m a i nt a ine d s e pa r a te l y an d re ad i ly r e t r ie va b le f ro m a ll ot h e r r e c o r ds . M . D E A i n s pe c t io n s. I ns p ec ti o ns b y t h e D E A o f a n y r e gi s t e r ed fa c i li t y m a y b e c o nd uc t ed on l y in a r e as o n a bl e m an ne r an d d u ri ng r e gu la r bu s i n es s ho u rs . I n sp ec t io n m a y be c o nd uc t ed a ft e r o b ta in i ng co ns e n t o f th e re gi s t ra n t o r af t e r th e D E A h as ob t ai n ed an adm i ni s t r a ti v e wa r r a n t f r om a j u d ge . An ap p li c a t io n f o r an a d m i ni s t ra ti v e wa r r a n t m u s t s ta t e wi t h sp ec i fi c i t y t h e n a tu r e , e xt e n t , a n d au t h o ri t y to c o nd uc t th e re qu es t e d ins p ec ti o n. Th e s co p e o f an a dm in is t r at i v e i ns p ec tio n e xt e n d s to an y r ec o r ds re q ui r e d u nd e r t h e A c t , eq u ip m en t a n d c o n ta i ne r s u se d i n t h e h a nd li n g o f c on t r ol led s u bs t a nc es , a nd t he ve r i fi ca t io n o f c om p li an c e wi t h a n y r e q ui r em e nt of t he Ac t . If r ec o r ds a r e re m o v e d f ro m th e r e gi st r a nt b y th e D E A , a r e c ei p t g i v en to th e re g is t r a n t wi l l li st th e i t em s t ak e n. N . L o n g- t e r m -c a r e f ac i li t i e s ( L T C Fs ) . An L TC F is de f in e d as a n u rs in g ho m e, r e t i re m e n t c a re , m en t al c a r e, o r o th e r f ac i li t y o r in s ti t u ti on t ha t p r o v id e s ext e n d e d h e al t h c a re to r es id e nt pa t i en ts . L TC F s a re no t no r m al l y re g is te r e d wi t h th e D E A , a l t ho ug h th e y of t en m a int a i n c o n t ro ll e d s ub s t a nc e s th a t a re di s pe ns ed t o a p at i en t b y p r es c ri p ti o n f r om a pha r m ac y. Th e y a re no t req u i re d to be re g is te r e d wi t h t h e D E A b ec a us e t h e c o n t ro ll e d s ub s t a nc e i s di s pe ns e d to t he ul ti m at e u se r ( th e p a t ie n t ) a nd is n o t is s ued b y o r t h ro u gh th e L TC F . W hen d is p os in g o f c on t r ol l ed s u bs ta n c e s , L TC F s m u s t c on t ac t th e n ea r es t D EA D i ve r s i o n F ie ld O f f ic e f o r di s p os a l i n st r uc t io ns . P.540
1 . E me r g e nc y k i t s f o r LT C F s . An L TC F m a y m a in t a in c o nt r o ll ed s u bs t anc es in e m e rg en c y k i ts s o l o ng as s t a te la w s p ec i fi c a ll y ap p r o ves of s u ch us e a nd t h e s ta t e s e ts fo r t h p r oc ed u re s t ha t r eq u ir e th e f o ll o wi n g: a . S o u rc e o f su p p l y: Th e L TC F m u s t o bt a in c o ntr o l le d s ub s ta nc es fo r th e e m e rg en c y k i ts f ro m a DE A - r e g is te r ed h os pi t al /c li n i c , p h a rm ac y, or p ra c ti ti o ne r . b . S ec u r i t y s a f e g u a r d s : A c c e s s to ea ch em e rg en c y k i t i n t h e L TC F m u s t b e r e s t ri ct e d, an d th e t y p e a n d q u an t it y o f c on t r ol led s u bs t a nc es t h a t m a y be p la c e d i n t h e e m e r g en c y k i t m u s t b e s p ec if ic a ll y l im it e d. c . P r op e r co n t r o l, ac c ou n t a bi l i t y, a n d r e c o r d ke e p in g : Th e L TC F a nd th e p r o vi di n g D E A - r eg is t e red h os pi t al /c l in ic , p h a rm ac y , o r p r ac t it i on e r m u s t m a in t ai n c om p le t e a nd ac c u r at e re c o rd s o f t h e co n t ro ll e d s u bs ta n c e s p la c e d i n t h e e m e rg en c y k i t , i nc lu di n g t h e d is p os it i on of t he se c o nt r o ll ed su bs t an c e s, as we l l a s t a ke pe r i od ic ph y s ic al inv e n t o r ie s o f t h e d ru gs . d . Ad m i n i st r a t i on o f c on t r o l l ed su b s ta n ce s . I n e m e r g en c y m ed ic a l s i t ua t i on s wh e n m ed ic a ti o n is ne e de d f ro m t he em e rg e nc y ki t , o n l y L TC F p e rs o nn el wh o a r e a u t ho r i z ed b y an in di v i du a l p r ac t it io n e r ca n a dm in i st e r t h e co n t ro l le d s ubs t an c e s .
e . P r o hi b i te d ac t i vi t i es : P r o hi b it e d ac t i vi ti es c a n r e s u l t i n t he st a te r e v oc a t i on , d e ni a l, o r s us pe ns io n o f h a v i n g em e rg e nc y k i t s c o n t ai ni n g c on t ro l le d s ubs t an ce s i n a n L TC F . O . V i o l at i o ns u nd e r th e Ac t . P e n al t ie s f o r v i o la ti o ns of t he Fe d er a l C o n tro l le d S u b st a nc es Ac t d e pe n d o n th e s ch e du le o f co n t ro l le d s ub s ta nc e i n v o l v ed, t h e u n la wf u l ac t , a n d t h e k now le d ge a nd i nt e n t o f th e vi o l a to r . It wi l l a ls o de p e nd on wh e t h e r it is a f ir s t o f fe ns e o r a s ub se qu e nt o ff e ns e . 1 . C i vi l pe n al t y. G e n e r al l y , ea c h vi ol a ti o n o f t h e A c t m a y s u bj ec t an in di v id u al t o a c i v i l p en al t y ( f in e ) o f u p t o $1 0 ,0 0 0. Th e go ve r nm e n t m us t p r o v e t h at t he vi o la t o r wa s n e gl i ge n t wi t h r es pec t to c o m p li a nc e u nd e r th e Ac t , a s o pp os e d t o m e r e m is t ak e o r i n ad v e r t en c e . 2 . I mp r i so n me n t . I f a n in d i v id u al k n o wi n gl y a nd i n t en t io na l l y v io l a t es t he A c t , h e o r s h e m a y b e s en t en c e d to a t er m o f y ea r s, in ad d iti o n t o a ci v i l p en a lt y .
II. FEDERAL FOOD, DRUG, AND COSMETIC ACT (FDCA). I n 19 3 7, s u l fa ni l am id e e li xi r c o n ta i ni ng de a dl y d ie t h y l en e g l y co l (a u to m ob i le a n t if r e e z e) wa s m a nu f ac t u r e d wi t h o ut an y s af e t y d a t a. Th e r e we r e n um e ro u s d ea t hs a ss o ci at e d wi t h i ts u s e, wh i c h p ro m p t ed th e fe der a l g o ve r nm en t to pa s s th e 19 3 8 F D C A . Th e F D C A re q ui re s th a t a ll ne w d r u g p r odu c ts in t en de d fo r us e as l a be l ed b y t h e m an u fa c tu r e r i n t he U n i t ed S ta t es m us t be pro ve n to t he fe d e ra l g o v er n m en t t o b e s a fe an d e f f ec ti v e . Su c h p r oo f i s s ub m i t te d t o t h e F o od an d D ru g Ad m in i st r a ti o n ( F D A ) b y us e o f a N e w D r u g Ap p li c a t io n ( N D A ). A. D e f i n i t i o n. U nd e r t h e F D C A , t he te r m “ d ru g ” is de f in e d as in c l u di n g a ll o f th e f o l lo wi n g : 1 . A r ti cl es r ec og n i z ed in t h e o f fi ci a l U n i te d S t a te s P h a r m ac o pe ia ( U S P ) , o ff i c i a l H o m e o p at h ic Ph a r m ac o po e ia o f t he U ni t ed S t at es, o r o f f ic ia l N a t io na l Fo rm u l a r y , o r a n y su p pl em e nt t o t he s e 2 . A r ti cl es in t en d ed fo r us e i n th e d ia g no si s , cu r e, m i t ig a ti o n, t re a tm e nt , or p r e ve n ti on o f d is ea s e in m a n o r o t he r an im al s 3 . A r ti cl es ( ot h e r t ha n f oo d ) i n t en de d to af f ec t t he s tr u ct u re o r a n y fu nc t io n of t he b o d y of m a n o r ot h er an im a ls 4 . A r ti cl es in t en d ed fo r us e a s a c om p on e nt o f a ny a r t ic l e sp e c i fi e d i n 1 , 2, o r 3 a b o ve B . L e ge n d d r u gs . Le g end d r ug s a r e t ho se m e di c a t i on s t ha t ha ve on th e i r l a be l f r om t h e m an u fa c tu r e r t he f ol lo wi n g f ed e ra l l y re q ui r ed s t a te m e n t: “ R x o nl y. ” S uc h m e di ca t io ns m a y b e d is pe n s e d d i re c tl y t o t h e p at ie n t b y m ea ns of a val id wr i t t e n o r o r a l p r es c r i pt i on f ro m a p r a c t i ti o ne r o r b y a v a li d r e f il l a u th o ri za t io n o f e i th e r . B y l a w, t h es e m ed ic a ti o ns m us t be a r a l a be l wi t h ad e q u a t e d ir ec t io ns f o r us e , wh i c h c a n o nl y b e g i v en b y a lic e ns ed p ra c t i ti o ne r an d , t h e r ef o re , th e re q ui r em en t o f a p r e sc ri p ti o n. A dr u g, in t en d e d f o r us e b y h um an s , i s c on s i de r e d a l e ge nd d r u g ( a nd h a ve th e a b o v e c au t io n o n it s l ab e l) i f a n y o f th e f o ll o wi n g a p pl y : 1 . B ec au s e o f t he d ru g ' s t o xi c i t y o r o th e r p o te n tia l fo r a h a rm fu l e f fe c t, or i ts m e t ho d o f us e , o r c ol la t e ra l m eas u r es n ec es s ar y t o i t s us e , it is no t sa f e f o r u s e e x c ep t u n d e r th e s u pe r vi s i o n o f a p r ac ti t io n e r li c en s e d b y l a w t o a dm i ni st e r s uc h d r ug . P.541
2 . Th e dr u g is a n ew d r ug f o r wh ic h a n a p pr o v e d N D A l im i ts it s u s e to th e p r o f ess i on al s u p er v i s i o n o f a p r ac ti t io n e r li c en se d b y l a w t o a dm i ni st e r s uc h d r ug . A n e w d r u g i s b r oa dl y d e fin e d a s b ei n g o ne th a t g en e r al l y is no t re c o gn i z e d a m o n g e xp e r t s as s a fe an d e f f ec t i v e f o r u s e un d er t he c o n di t io ns p re sc r ib e d, r e c om m e nd e d, o r s u g ges t ed in t he la be l in g . I t i s a l s o d e fi n ed as b e in g a d r u g t h at , a s a r es ul t o f in v e s t i ga t io n s t o d e te r m i ne it s s af et y a n d e f fe c ti ve ne s s fo r u s e u nd e r s uc h c o nd i ti on s , h as b ec o m e s o r ec og n i z ed bu t th a t h as no t , o t he r th a n in t he i n ve st i ga t io ns , b e en us ed t o a m a te r ia l e xt e n t o r f o r a m a t e ri a l t im e u nd e r s uc h c o nd i ti on s . F in a ll y , a n ew d r u g m a y r e su l t f r om a c ha n ge in th e d o s a ge f or m , l a be l in g , i nd ic a ti on s , o r a n y o th e r c ha n ge in a d ru g p ro du c t t ha t i s a l re a dy b e i ng m a rk e te d . Th e ul t im a te de c is io n o f wh e t he r a d rug is a n e w d r ug li es wi t h t h e F D A b e ca us e o f i t s e xp e r t is e i n re s ol vi ng t ec hn ic al and s c ie n ti f ic qu es t io ns . a . N D A. E v e r y n e w d r u g m a rk e te d i n t h e U n i te d St a t es m us t be s a fe an d ef f e c t i v e f o r it s i n te nd e d us e as l ab e le d b y t h e m a n uf a c t u re r . P r oo f o f s a fe t y an d e f f ec t i v en es s m u s t b e s ub m it t ed t o t he F D A b y t he m a n uf ac t u re r vi a t he ND A . W hen a n e w c he m i c a l e n ti t y ( NC E ) i s i de n ti f ie d b y a m an u f ac tu r e r , t he m a nu f ac tu r e r m us t o b t ai n a n I n v es t ig a ti o na l N e w D r u g A p pl ic at i on ( IN D ) b e fo r e c on d uc ti n g pr e c li ni c a l a n im al t es ts an d c li ni c a l h u m a n i n ves t ig a ti o ns . b . I N D . Be c a us e a n N C E h as no t y e t b ee n a p p ro v e d b y th e F D A as a s a f e a n d e f f ec t i v e d ru g , a m a nu f ac t u re r is re q ui r ed to f il e a n I N D wi t h t h e F D A . The I N D a l lo ws a m a nu f ac t ur e r t o c on d uc t re s e a rc h wi t h th e N C E an d e xe m p ts t he d r u g f r om c e r ta i n p ro h ib i ti on s o f the F D C A in or d e r t o f ac i li ta t e c li n ic al in ve s t i ga t io ns ; th us , I N D s a re s om e ti m e s re f er r e d to as a n In v e s t i ga t io n al N e w D r u g E xe m p ti on . G e n e r al l y , c li n ic al in v e s ti g a ti on o f a n N C E is di v i d e d i n to th r e e p ha s e s, wi t h e ac h p h as e i n v o l v in g a gr e at er n um b er o f h um an s u bj ec t s. ( 1 ) P ha s e 1 . A p ha s e 1 in v e s ti g at i on is th e i ni t ia l i n t ro d uc ti o n o f a n i n v es ti g a ti on a l n e w d r u g i n to hu m a ns to d e te r m i n e t he m e ta b ol is m , ph a rm ac ol o g y , s id e ef f e c t s, m ec h an is m o f a c t i on , a nd e a rl y e v i de nc e o n e f fec t i v en es s . ( 2 ) P ha s e 2 . A p ha s e 2 in v e s ti g at i on in c l u de s t he we l l - c on t ro l l e d , c l os e l y m o ni t o re d c l in ic al s t u di es in o rd e r to e v a lu a te th e e f f ec ti v e ne s s o f t he d ru g f o r a pa r ti c ul a r i n di ca t io n a n d t o f u r th e r d e t e rm in e s id e e f fe c ts an d ri s k s . ( 3 ) P ha s e 3 . A p ha s e 3 in v e s ti g at i on in c l u de s e xp a n de d c li ni c a l t r i al s t o g a t he r a d di t io n al in f o rm at i on c on c e rn in g s a fe t y, ef f ec ti ve n es s, a nd th e o v e r al l be n e fi t - ri s k r e l at i on sh i p as s o c i a te d wi t h t h e d r ug ' s u s e . Th is p h as e a ls o i nc lu d es g a th e r in g i n f or m at io n to p ro v i de an a d eq u at e b as is f or ph y s i c ia n l ab e li n g. c . T re a t me n t I N D s (o r t re a t me n t p ro t o co l s ). Th e F D A m a y al l o w a tr e atm e nt I N D , wh i c h al l o ws a r es ea r c he r ( ph y s ic ia n ) to us e a n in v e s ti g at i on a l d ru g a s t re a tm e nt in s e r io us an d l i fe - th r e at e ni n g d is ea s es wh e r e n o co m p a r ab l e o r s a ti s f ac t o ry a l t er n a ti v e dr u g o r o t he r t h e r ap y is a v ai l ab le . C . O ve r - t h e - c ou n t e r ( O TC ) m e d i ca t i o ns . Ce r t ain m e d ic at i on s m a y b e d is p en s e d O TC a t r e t ai l d is t r ib u to r s wi t h o u t a pr e sc ri p ti o n. Th e fe d e ra l g o v e rn m e n t ha s d e t e rm in ed t ha t t h es e m e d ic a ti on s m a y be s a fe l y a n d p r op e rl y s el f -a dm i nis t e re d wi t h o u t th e s up e r v is io n of a pr ac t i ti on e r l ic e ns ed b y l a w t o ad m i ni s te r (o r p r e sc ri b e )
s uc h a d ru g . Ge n e ra ll y , th e s e m e di ca t io ns a re not h ab i t -f o rm i ng an d h a v e a lo w t o xi c i t y o r o t he r po t en t ial f o r a h a rm f ul ef f ec t . The s e m e d ic at i on s d o n o t h a v e th e f e d e ra l s ta t em en t “ Rx o nl y ” o n t h ei r la be l (s ee I I.B ) . 1 . O TC p r e pa r a ti o ns m us t ha v e ad e qu a t e d i r ec ti o n s f o r u s e on th e i r l abe l , a n d t he p r o du c t m u s t c o m p l y wi t h t he ap p li ca bl e F D A m on o g ra p h. Th e F D C A r e qui r e s al l d r u gs m a rk e te d i n t h e U n i t ed S ta t es to be ge n era l l y re c og ni z e d a s s af e an d e f f ec t i v e. As a r e s u l t, it c o n v en e d r e v i e w p an el s t o r e vie w O TC d r u g e f fec t i v en es s a n d c r ea t e m o n og r ap h s fo r e ac h t he r a pe u ti c c l ass o f O TC d r u gs . Th is r e vi e w i s r e f e r re d t o a s t h e D r u g -E f f ic a c y (o r E ff ec t i v en es s ) S tu d y Im p le m e n ta t io n ( D E S I ) . A ll O TC d r u g s m us t c om pl y wi t h t h e a pp l ic ab l e d ru g m o no g ra p h o r b e c on s i de r e d m is b r an de d (s ee I I. I ) a nd s u b je ct t o F D A re g ul a to r y a c ti on . 2 . O TC p r e pa r a ti o ns m us t ha v e th e fo ll o wi n g i n fo r m at i on on it s l ab el : a . I de n ti t y , i n b o ld fa c e , o f t he O TC p r o du ct on t he p ri n ci pa l d is p la y p an el b . A de q ua t e d i re c t i on s fo r us e c . In g re d ie n ts (i nc l ud in g i n e rt o r i na c ti v e in g re d i en t s ) i n t he p ro d uc t d . N e t q ua n ti t y o f c o n te nt s e . E xp i r a t io n d a te of t he p r o du c t f . L ot nu m b e r o f th e p r odu c t g . N am e a n d p la c e of bus i ne s s o f th e m an u fa c tu re r , pa ck e r, o r d is t ri b ut o r P.542
h . D is cl os u re o f c e r t ai n c o nt e nt s a n d t he de cl a rat i o n o f c er t ai n wa r n in gs , i n cl ud i ng h a bi t - f or m i n g i ng r ed i en ts a n d wa r n i ng s , p r eg na n cy / n u r si n g wa r n i ng s , a nd a s pi r in wa r n i n g s 3 . P r es c r i p ti o n d r u g c on ve r s i o n to O TC . A l eg en d d ru g wi ll c o n ve r t t o an O TC d r u g wh e n t he F D A f i nd s t h a t t he p re s c r ip t io n -o n ly l i m i t at i on is n o t n ec es s a r y f o r t h e p r o te c t i on of t he pu bl i c h ea l th b y re as o n o f t he d r ug ' s t o xi c i t y or o th e r p o te n ti a l f o r ha r m f u l e ff e c t , th e m e t h od of i ts u s e , or t he co l la t e ra l m ea s u r es ne c es sa r y t o i ts u s e. Th e F D A m u s t a ls o f i n d t ha t th e d r ug is s a fe a n d e f fe c t i v e fo r u s e in s e lf m e di ca t io n a s d i re c t e d in p r op os ed la b el i ng . 4 . M i s ce l la n eo u s re g u la t i o ns f o r O T Cs . a . I pe c ac s yr u p . A l t h oug h ip ec ac s y ru p c a n o nl y b e d is p en se d p u rs u a n t to a p r e sc ri p ti o n, t he F D A b eli e v e s t ha t it s h ou l d b e r ea d il y a v a il a bl e O TC a s an e m e rg en c y t re a tm en t em e t ic f or us e i n p oi s o n in gs . Th e F D A al l o ws th e OTC s a l e o f i p ec ac s y r u p i n 1 f lu id ou n c e c o n ta in e rs s o th a t it wi l l be r ea di l y a v a il ab l e i n t h e h o us e ho ld f or em e rg e nc y t r e a tm e nt of po is o ni n gs , un de r m e di c a l s up e r vis i on , a n d t h a t t h e d ru g b e ap p ro p ria t e l y p ac k ag ed an d l a be le d fo r th is pu r p os e. b . P r e gn a nc y- n u r s i n g w a r ni n g . A l l O TC d r u gs i n t en de d fo r s y s t em ic a bs o r pt i on m us t c o nt a in a wa r n i ng th a t i f th e u s e r is p r e gn an t o r n u rs in g a ba b y , s he s ho u ld f i r s t s e ek th e a d v ic e o f a h e al t h p r of es s i o na l b e for e us i ng th e p r od u c t . E xc e pt i on s t o t hi s la b el i ng re q ui r em e n t e xi s t wh e n an O TC i s i n t en d ed to be n ef i t t h e f e t us o r n u r si ng in f an t , a n d f o r O TC d r u g s t h at a re la be l ed e xc l us i v e l y fo r pe di a t ric us e . c . As p i r i n w a r n i ng s . Al l O TC a s p i ri n c on t ai n in g p r e pa r a ti o ns m us t h a ve a wa r n i ng t o ke ep ou t of c h il d r en ' s r e a c h an d t o c on t ac t a ph ys ic i an im m e di a te l y in c as e o f
a cc i de n ta l o v e r d os e. O ra l or r ec t al O TC a s p i ri n c o nt a in in g pr e pa r a ti on s m us t al s o h a ve a wa r n i n g c o nc e r nin g R e y e 's s y nd r om e i n ch i ld r e n a nd te e na g er s . d . C h em i ca l s a n d p r ec ur s o r s . I t wa s di s c o v e re d t h a t co m b i na t io n d r ug pr o d uc ts c o nt a in in g ep he d r in e , ps e u d oe ph e d ri ne , or ph e n yl p r o p a no la m i n e a r e t he pr e c ur s or m a te r i al s us e d b y il l eg al m e th am ph e ta m i n e l ab o ra t o ri e s . Th e C om pr e he ns i v e Me t h a m p he t am in e Co n t ro l Ac t o f 19 9 6 r eq u i re s al l re t ai l d is t r ib u to r s o f t he s e O TC p r o du c ts to fu l fi ll c e r ta i n o b li ga t io ns . A re t ai l d is tr i b ut o r i nc l ud es a g r oc e ry s t o r e, g e n er a l m e r c h a nd is e s tor e , a p ha r m a c y, o r an y ot h e r e n ti t y o r p e rs on wh o s el ls t h es e i t em s t o c us to m e rs f or pe r s o n al us e. F or re g ul a te d t ra ns ac t io ns , a r e t ai l e r m us t m a in t ai n a re c or d of t h es e t r an s a c t i on s f o r a p e ri od o f 2 y ea r s , m u st o b ta i n p r o o f o f i de n ti t y f ro m c us t om e rs , a n d m u s t r ep o rt s us pi c i ou s re gu l at e d s al e s i m m e di a te l y to t he D E A . Th e r e co r d m us t b e m ai nt a i ne d s ep a ra t el y f r om oth e r r e c or d s o f c o n t ro l le d s ubs t an c e s , a nd th e D E A s ug g es ts t ha t th e r ec o r d be m a d e i n a b ou n d l og bo ok s im i la r t o th e re c o r d k ep t f o r the s a l e o f O TC c o n t ro l le d s u bs ta n c e s ( s e e I J ) . Th e f o ll o wi n g s in gl e t ra ns ac ti o ns of t he se p ro du c ts i n t h e a m ou n ts s t at e d a r e c o ns i d e re d to be “ re g ul a te d tr a n s a c t i on s . ” ( 1 ) P he n yl p r o p a n o la m in e ( P P A) . P P A is n o l o ng e r i n an y O TC d r u g p r od u ct . ( 2 ) P se u d oe p he d r i ne . Sa l es of c o m b in a ti o n p r odu c ts c o nt a in in g m o re t han 2 4 g o f p s eu d oe ph e d ri ne . B li s t e r- p a c k s al es o f t he se p rod u c t s e xc e e d in g 2 4 g a re n o t r e g ul a te d s al es . ( 3 ) E p he d r i ne . Sa le s o f c om b in a ti o n p ro d uc ts c on t a in in g m o re t ha n 2 4 g o f e p h ed r in e a n d a l l s i n gl e- e n ti t y e ph e dr i ne p ro du c t s re g a rd le ss of t he am ou n t o f e p h ed r in e (m or e th a n z er o g ra m s ) . D . G e n e r ic d r ug s 1 . D e f in i t io n . Th e g en e ri c n a m e o f a d ru g ha s b ee n de f in e d as it s c he m i c a l na m e , a c om m o n n a m e , o r an of f ic i al na m e us ed in an of f ic i al c om p en d iu m . A m anu f ac t u re r s e ek in g a p pr o v a l f r om the F D A fo r a d ru g th a t h as al r e ad y b ee n p r o ven t o b e s a fe a n d e f fe c ti v e m a y f il e a n A b b re v i a t ed N e w D r u g A p p l i c a t io n ( A N D A ). 2 . AN D A. A f i l i ng o f a n AN D A a l lo ws t h e a pp r o v al o f a d ru g fo r wh i c h e xh au s ti ve s a fe t y a nd ef f ic ac y s tu die s h a v e al r ea d y be e n p er f o r m e d . A d ru g i s c o ns id e r ed t o b e t h e s am e a s a n a pp r o v ed d r ug wh e n t h e t wo a r e i d en t ic al in ac t i v e i ng r edi e n t( s ) , d o sa g e f o rm , s t re ng t h , ro u t e o f a dm in is t r at i on , i nd i c a t io ns , a n d co n di t io ns o f us e. R i g o ro u s a ni m a l a nd hum a n d at a to de t e rm i n e s a f e t y an d e f fe c ti v e ne s s a r e no t r e q ui r e d in t he A N D A . Ho we v e r , i n fo r m a t io n s howi n g t h at t he ge n er ic ve rs i on of t he d r u g i s b io a v ai l ab le an d b i oe q ui v a l en t t o th e p io ne e r (o r i gi na l ) d r ug is ne c e s s a r y. S u c h a pp r o v ed d ru gs a re l is te d b y t h e F D A i n the “ A pp r o v e d D r u g P r o duc t s wi t h Th e r a p eu t ic E qu i v al e nc e E v a l u at i on s , ” c om m o n l y r e f e rr e d t o a s t he F D A O r a n g e B o o k ( b ec au s e it c o m e s f r o m t he F D A i n a n o r a ng e bi nd e r ) . P.543
E . P r o p r ie t a r y d r u g s . T h e p ro p ri e ta r y n a m e o f a d r u g is th e n am e gi v e n b y t h e m a nu f ac tu r e r t o d es i gn a te t he d ru g ' s s o u rc e o f m a n u fa c t u r e a nd to di f f er en t i at e i t f r o m t he s a m e o r c h em ic a l l y s im i la r d r u gs fr om o th e r m a nu f ac tu r e rs . An o th e r na m e f o r th e p r o pr i et a r y na m e o f a d r ug is i t s t r ad e n am e .
F . E s ta b l is h ed na m es fo r d r u g s. Th e F D C A a uth o r i z es th e Co m m is s i o ne r o f t he F D A t o d es i gn a te an of f ic i al na m e fo r an y d r ug if h e d e te r m i n es t h a t su c h a c ti on is n e ce ss a r y o r de s i r a bl e in t he in t e re st o f us e fu l ne s s an d s im pl ic i t y . Th e FD C A a l s o r e q ui r es th a t a d ru g 's es t a b li s h ed n am e a pp ea r on t he la b el an d l ab e li n g o f t he d r u g . A d ru g 's es t ab li s h ed n a m e is de f in e d as f ol lo ws : 1 . I t m a y b e a n o f f i ci a l n a m e d es ig n at e d b y th e C o m m i s s io ne r of F oo d an d D r ug s . F o r N C E s , th e n am e s h ou l d b e s im pl e a n d us e fu l. I n t h is re g ar d , t h e F D A r e c og ni z e s t h e U . S . Ad op t e d N a m e s C o un c i l ( U SA N ) i n d e ri vi n g n am es for N C E s . Th e U S A N n am e i s c o ns id e r ed t o b e a n o f fi c i al na m e r ec o gn i z e d in a n o ffi c ia l c om p en d iu m . Th e F D A m a y u s e a no t he r n am e i f th e U S A N o r co m m on o r u s ua l n a m e is u n du l y c o m p le x, m is le a di ng , o r is no t u s e f u l f o r a n y o t he r r ea s o n. 2 . I f n o o f fi c i al na m e ha s b e en de s i g na t ed fo r th e d r u g a nd th e d r u g is an a r t ic le r e c og ni z e d i n a n o f f ic ia l c om p en d iu m , th e n t h e o ff i c i al t i tl e c o nt a in ed in th e c om p en d iu m m a y b e t h e e s ta b li sh e d n am e. 3 . I f n ei t he r of th e a b o v e t wo a p pl y , t he n th e c o mm o n o r us u a l n am e o f th e d ru g m a y be i ts e s ta bl is h ed na m e. G . D i s p en s in g a p r es c r ip t i o n d r u g . A p re s c r ip t io n d ru g m a y b e d is p en se d on l y b y a p r ac ti t io n er o r b y a p ha r m ac is t p u rs ua n t t o a wr i t t en o r o ra l p r es c ri p ti on o f a p r a ct i ti o ne r , o r a r e fi ll of e i th e r . Th e p re s c r ip t io n l a be l o n th e c on t ai n er dis p en se d to t h e p a ti e nt m u s t c o n ta in c e r ta i n i nf o rm a ti on , or i t wi l l b e c on s i d er e d m i sb ra n d ed an d d i sp e ns ed in v i ol a ti on o f t h e F D C A . Th is in f o rm ati o n i s m i n im al un de r th e F D C A a nd i s u su a ll y s u p pl em e nt e d b y s t at e l a ws , wh i c h r equ i r e m or e i n fo r m a t io n . So l on g a s t h is in f o rm at i on is i n En gl i s h , t h e d is pe ns i ng ph a rm ac is t wi l l b e i n c om pl ian c e wi t h t h e F D C A. I f a n y o f th e re q ui r e d i nf o rm a ti o n is in a n o th e r l an g ua g e, th e n a l l o f t h e r e q ui r e d in f o rm a ti on m u s t b e i n t h at la n gu ag e . The p r esc r ip t io n m us t a ls o b e p a ck ag e d i n a c hi l d- r es is t a n t c on t ai ne r as re q ui r ed u nd e r t h e P oi s on P re v e n t io n P a ck a gi n g A c t (s e e I I I ). Th e f o ll o wi n g i n fo r m a ti on m u s t a pp e ar on e v e r y p r e s c ri p ti o n l a be l : 1 . N am e a n d a dd r es s o f t h e p h a rm ac y 2 . S e ri al nu m b e r o f th e pr e s c r ip t io n 3 . D a te th e p r es c ri p ti on is f il le d o r th e d a te o f t he p r es c ri p ti on 4 . N am e o f th e p r es c r i ber 5 . N am e o f th e p a ti en t (if s ta t ed in th e p r es c ri p tio n ) 6 . D i re c ti on s f o r u s e an d a n y c a u ti on a r y s t a te m en t s c on t ai ne d i n th e p r es c r i pt io n H . D r u g r ec a l l. Th e F D CA a ll o ws t he F D A t o i n it ia t e re g ul a to r y ac t io ns to e ns u r e t h a t u ns a fe , u n fi t , o r i n eff e c ti v e pr o du c ts d o n o t re a c h th e m a rk e t, o r t o p ro m pt l y r e m o ve t ho s e p ro d uc ts th a t d o re ac h th e m ar k etp l ac e . Th e en f o rc em en t a c ti o ns th a t m a y be in i ti a te d i nc l ud e t h e re l ea s e of in f o rm at i on t o t h e g en e ra l p u bl ic an d / o r p r o f ess i on al g ro u ps ; a dm i ni s t r a ti ve ac ti o ns a n d i n s p ec t io ns ; th e i ns t it u tio n of r ec al l ; o r se i zu re , in ju nc t io n , o r c r im in al p ro s e c u t io n . 1 . V o lu n t a r y a c t i o n o f th e ma n u fa c t u re r . A ft e r s e v e r al un s u cc es s f u l a tte m pt s b y t h e F D A t o r ec e i v e c o u r t- o r d e re d r e c a ll s , t he F DA r e c o g ni z e s t ha t re c a l ls a r e vo l u n ta r y ac t io ns o f t he m a nu f ac tu r e rs an d d is t r ib u t o rs . A s a r es ul t , a re c a l l m a y b e u n d er t ak en a t a n y ti m e , o r u po n r e qu es t of th e FD A . I f th e F D A is u n s u cc e s s f ul in p e r su ad i ng a c om pa n y to r ec a ll a p ro d uc t , o r whe n th e F D A d et e rm in e s th a t a r ec al l
i s o r wi l l b e i ne f f ec ti v e , it m a y s ee k a c o u rt o rd e r c on d em ni n g t he p ro d uc t a n d a l lo wi n g th e pr o du c t ' s s ei z u r e . 2 . D r u g re c al l c l as s i f ica t i o n . A f te r th e F D A h as e va l ua t ed th e p r o bl em ( s ) a ss o ci at e d wi t h t he p ro du c t a nd a ft e r t h e d eg r ee o f he a lt h h a z a r d h as b e en d e t e rm in ed , th e F D A wi l l a s s ig n th e r e c a ll on e o f t h e fo ll o wi n g c la ss if ic a tio n s : a . C l as s I — a s it u at i on in wh i c h th e re is a r ea s ona b le p ro b ab il i t y th a t t h e u s e o f o r e xp o s u r e t o a v i ol a ti v e pr o d uc t wi l l c a us e s e ri o us a d v e rs e h e al t h co ns e que n c e s o r d e a th P.544
b . C l as s I I — a s it u at i on in wh i c h u se of o r e xp o s ur e t o a v io l at i ve p r o du ct m a y c a us e t e m p o r ar y o r m e di c a ll y re v e r s ib le ad ve r s e he a lt h c o n se q ue nc es o r wh e re t h e p r o ba b il i t y o f s e ri o us h ea l t h c o ns e qu e nc es i s r em o te c . C la s s I I I —a s i tu a ti o n in wh i c h u se of o r e xp o s ur e t o a v io l at i ve p r o du ct i s n o t l i ke l y to c a us e a d v e rs e he a l th c o ns eq u en c e s 3 . R ec a l l p r o ce d u re . A re c al l s t ra t eg y wi l l be de v e l op e d t h at wi l l c on s i d er t h e d ep t h o f t he re c a l l ( c o ns um e r le v e l , re t ai l l e v el , wh o l es a l e l e v el ) , th e n e ed fo r pu b li c wa r n i n g s , an d t h e e xt e n t o f ef f ec ti v e n es s c h ec k s f o r th e re ca l l. E ve r y r ec al l in g c om p an y i s r es po n s i bl e fo r n ot i f y in g e ac h o f i t s af f e c t e d d ir ec t acc o un t s by f i r s tc l as s m a il , m a il g ra m , o r t e l eg r am . Pu bl ic no t i fi c a ti o n i s m a d e b y t he F D A v i a t he we e k l y F D A E nf o rc e m e nt R e p o rt , wh i ch pu bl is h es e ac h re ca l l ac c o r d in g t o i t s c l as s i fi c a t io n . I . Ad u l t e r a ti o n a n d m i sb r a n d in g . A m i s b r a nd ing o r a d ul t er a ti o n o f a dr ug is p r o hi b it e d b y t he F D C A . A l t h ou gh t he m is b r an di ng a nd ad u lt e ra t io n p r o v isi o ns a re m a in l y c o nc e rn e d wi t h the m a n uf ac t u ri n g o f a dr ug , a p ha r m a c i s t m a y a ls o m i sb r a nd o r a du l te r at e a d ru g . The p u r po se of t he m is b ra n di n g a nd a du lt e r at i on s t a tu t es is to p r o t ec t t he p ub li c h ea l th o f c o ns um e rs wh o a re lar g e l y un ab l e t o p r ot e ct th e m s el v e s wh e r e d r ug s a r e i n v ol v ed . Th e ad ul t e ra t io n a n d m is b r an di n g s ta t ut es a re c r im in al in n a t u re an d m a y s ub j ec t a p ha r m a c i s t t o c ri m i na l p r o ce ed i ng s i n f ed e r al c o u r t , i n a d di t io n to ad m i ni s tr a ti v e p r oc ee di n gs . 1 . Ad u l t e r a ti o n . I n g en er a l , t h e t e rm a d ul t e ra t io n r e f e rs t o a c h a ng e o r var i a ti o n f r o m o f fi c i al f or m u l a r y s ta n d ar ds o r f r om th e m anu f ac t u re r ' s s ta n da r ds . A d r u g i s c o ns id e re d a d ul t e ra t ed if a n y o f t he f ol lo wi n g c o nd i t io ns oc c u r : a . I f t he d ru g c on s i s ts i n wh o l e o r i n p ar t of an y fi l t h y , p ut r i d, o r d ec om pos e d s u bs ta n c e b . I f t h e d ru g h a s b ee n pr e p a re d , p ac k e d , o r h el d u n de r un s a ni t a r y c o nd i tio n s wh e r e i t m a y h a v e b ee n c on t am i n a te d wi t h f il t h o r re n der e d i n ju r io us t o h ea l th c . If t he d ru g 's c o n ta in e r i s c om po s e d , i n wh o l e or i n p a r t, of an y p oi s on ou s o r d e le t e ri o us s ub s ta nc e t ha t m a y r e nd e r t he co n ten t s i nj u ri o us to he a lt h d . I f t h e d ru g c o nt ai n s , fo r p ur p os es of c o lo r in g on l y, a c ol o r a dd i ti v e th a t i s u ns a fe wi t h i n th e m ea n in g o f the F D C A e . I f t he d ru g i s a ne w a n i m a l d r ug , or an an im a l f e e d co n ta i ni n g a n e w an i m a l d r ug , t h a t i s u ns af e wi t hi n th e m e an i ng of th e F D C A
f . I f t h e d r ug is p u r po r ted t o b e a dr u g t h at is re c o g ni ze d i n an of f ic ia l c om p en d iu m , a n d i ts s t r en g t h di f f e rs f ro m , o r i t s q ua li t y o r p u ri ty f a l ls be lo w, t h e s t an dar d se t f o r t h i n t he c o m p e nd iu m , u n le s s th e d e v ia t io n i s p l ai n l y a n d s pe c i fi c al l y st a t ed on i t s l ab e l g . I f t h e d ru g i s n o t a c om p ou n d r ec o gn i zed b y na m e i n a n o f fi ci al co m p en d iu m ; i f i t s s t re ng t h d i ff e rs f ro m , o r i ts p u r it y o r q u al i t y f a ll s b e lo w, t h a t wh i c h i t p ur p o r ts o r i s re p re s e n t ed to po s s es s h . I f t he d ru g h as be e n m i xe d o r p ac k e d wi t h a no t h e r s u bs t an ce s o as to r e d uc e t he d r u g 's qu a li t y o r s t re ng th i . I f t h e d ru g h a s b ee n s u b s t i tu t ed , wh o ll y o r pa r ti a ll y, wi t h an o th e r s ub s ta n c e j . I f t h e d ru g i s a n O TC d r u g a nd i t is no t p a c k age d in th e re q ui r ed ta m p er - r e si st a n t p a ck ag i ng or p ro p e rl y l ab e le d i n c o nf o rm i t y wi t h t h e ta m p e r - re s i s t a nt r egu l a ti on s (see IV) k . I f t he d ru g (o r m e di c a l d e v ic e ) i s a n o ph t ha lm ic p r e pa r at i on of f e re d o r in t e nd e d f o r op h th a lm ic u s e t ha t is no t s t e ri le 2 . M i s b ra n d in g . I n g e ner a l , t h e t e rm m is b ra n di ng m e a ns th a t a d r u g is s o l d o r d i sp e ns ed wi t h a la b el or l a be li n g t ha t is i n v io l a t io n of t he F D C A . L ab el is d e fi n ed a s b e in g a di s p l a y o f wr it t e n , p ri n te d , o r g r a ph ic m a t te r u p on th e i m m e di at e c o nt a in e r o f a n y a rt ic l e (o r d ru g ) . L ab e li ng is m o re b r oa dl y d e fi ne d to in clu d e t h e l a be l a s we ll as ot h e r wr i t t e n , p ri n te d , o r g r a ph ic m a t te r u p on an y a r ti cl e or a n y of i t s c on t ai ne r s o r wr a p pe rs , or ac co m p a n y in g t h e a r t ic le ( o r d r ug ) . A d ru g is c o ns id e re d m is b ra n de d if a n y of th e fo ll o wi n g c on d i ti on s o c c u r: a . I f t he la b el in g i s f a ls e o r m is l ea di n g i n a n y pa rt i c u l ar b . I f t h e d ru g i s a n i m i t ati o n o f a n ot h e r d ru g , o r i f i t i s o f fe r e d f o r s a l e u nde r t he n a m e of an o th e r d r u g c . If t he d ru g i s c o m p os ed wh o l l y o r p a rt l y of in s ul i n a nd i t is no t p r o pe r l y b a tc h c e r ti f ie d u n de r th e F D C A d . I f t h e d ru g i s c om po s ed wh o l l y o r p a rt l y of an an t i bi o ti c a nd it is n o t p r op e r l y b a tc h c e r ti fi e d u nd e r t h e F D C A e . I f t he d ru g i s d is pe ns ed b y a n am e t h at is re c og n i ze d in a n o ff ic i al c om p e n di um a n d i t i s e it h e r n ot pa c k ag e d o r no t l a be le d i n c onf o r m i t y wi t h th e o f fi c i a l c om p en d iu m P.545
f . I f t h e d r ug is d e te r m i ne d b y th e f e de r al go v e r nm e nt t o b e li a bl e t o de t er i o r at i on a n d i t i s n o t p ac k a ge d i n a p ro p er f or m a n d m a n ne r , an d t h e l ab e l f ai ls to b e a r a s t a te m e n t o f p r op e r p r ec a u t io ns g . I f t h e d ru g i s d is pe n s e d in a n on - c h il d - re s i s tan t c o n ta in e r , wh e n a c hi ld - r es is t an t c o nt a in e r i s o th e r wi s e r eq u i re d (s ee I II ) h . I f t he m a nu f ac t u re r fa il s to pl ac e o n t h e l ab el an y o f th e f o ll o wi n g : ( 1 ) F ac t t ha t c e r ta i n d rug s m a y be ha b it fo r m i n g ( 2 ) N am e o f e a c h ac ti v e i n g re d ie n t ( 3 ) N am e a n d p la c e of bu s in es s o f t h e m a n uf a ctu r e r , p ac k e r , o r di s t r ib u to r
i . I f a ph a rm ac is t f a il s t o p l ac e o n a p r es c ri p ti o n c o nt a in e r l ab e l a n y o f the f o l lo wi n g : ( 1 ) N am e a n d a dd r es s o f t h e p ha r m a c y ( 2 ) S e ri al nu m b e r o f th e p r e s c ri p ti o n ( 3 ) D a te of f il li n g t he p res c ri p ti o n o r t h e d at e o f th e p re s c ri p ti o n ( 4 ) N am e o f th e p r es c r i be r ( 5 ) N am e o f th e p a ti en t ( 6 ) D i re c ti on s f o r u s e and a n y c a ut io n a r y s t at em e n ts c o n ta in e d i n t he p res c ri p ti o n j . I f a n o r al c o nt r ac e pt i ve is di s p e ns ed wi t h ou t the r e qu i re d p a ti e nt pa c k ag e in s e r t k . I f a n i nt r a ut e ri n e d e v ic e th a t m u s t b e d is pe ns e d wi t h a pa t ie n t p ac k a ge i ns e rt is d i sp e ns ed wi t h ou t th e i ns e r t l . I f a n e s t r o ge n p r od uc t i s d is p en s e d wi t ho u t t h e r e q ui r e d p at i en t p ac k a g e i ns e r t m . I f a p r o ge s t o ge n -c on ta i ni n g p r od uc t i s d is pe ns e d wi t h ou t th e re qu i r ed p a t ie n t p a ck ag e i ns e r t n . I f a l e ge n d d r ug is d is p e ns e d ( o r r e fi l le d ) wi t ho u t a p re s c r ip t io n (o r re fi l l a u t ho r i z a ti on ) of a l ic en s e d p ra ct i ti o ne r , i t i s d eem e d t o b e m is b ra nd e d by t h e d i sp e ns in g p ha r m a c i s t o . I f t h e d ru g i s a n O TC d r u g a nd i t is no t p a c k age d in ta m p e r - re s i s ta n t pa c k a gi n g o r p ro p e rl y l ab el e d i n c on f o rm i t y wi t h t h e t am pe r -r e s is ta n t r e gu la t io ns ( see I V ) p . I f t h e d ru g i s a n O TC d r u g a nd i t is no t p r o pe r ly l a b el ed in c o n fo r m i t y wi t h t h e l a be l in g re qu i r em en ts o f t h e F D C A q . I f t he d ru g (o r m e di c a l d e v ic e ) i s a n o ph t ha lm ic p r e pa r at i on of f e re d o r in t e nd e d f o r op h th a lm ic u s e t ha t is no t s t e ri le 3 . V i ol a t io n s u n de r t he Ac t . A n y m is b ra n di n g o r a d ul t e ra t io n o f a d ru g m a y s ub j ec t t h e i n di v i du a l ( e .g . , a pha r m ac is t ) t o i m p r is on m en t , a f in e , o r b o th . A p har m ac y a nd p h a rm ac is t wi l l b e e xe m p t f ro m c ri m i n al s a nc ti o ns i n ei t he r of t he fo ll o wi ng c a se s : a . C e r ta i n c a se s o f g ood f a i th . W he n a du l te r at ed o r m is b ra nd e d p r od uc ts a re r e c ei ve d f r om a m a n uf a c t u r e r o r wh o le s a l e r i n g oo d fa i th b y th e p h a rm ac y, t h e p h a rm ac y m a y n o t b e h el d re s po ns ib l e i n c e r t ai n s i tu a ti o ns . Thi s e xe m p t ion a pp li es o n l y if it is a f i rs t v io la t io n an d , i f r e qu es t ed , th e p h a rm ac y o r p ha r m a ci st f u r ni s h es t o t he go v e r nm en t th e na m e a nd ad d re ss of t he p e r s o n f r om wh o m t h e d ru g wa s r e c ei ve d a nd c o p ie s o f al l do c u m e n ts p e r ta i ni ng to i ts de li ve r y . b . R e ce i p t o f d r u g w i th a s i gn e d, w r i t t en g ua r an t y. A p h a r m a c y an d p ha r m ac is t wi l l b e e xe m p t fr o m m i s br a n di n g a nd ad u lt e ra t io n v i o l at i on s wh e n a si g ned , wr i t t en g u a ra n t y is re c e i v e d f r om t he wh o le s al e r o r m anu f ac t u re r . Th e g ua r a nt y m us t c o nt a in th e n am e a n d a dd r e s s o f th e p e rs o n r es idi n g i n t h e U n it e d S t a te s fr o m wh o m t h e d ru g wa s re c e iv e d i n g oo d f a it h a n d a st a t em en t th a t t he d ru g i s n o t a d ul t e ra t ed o r m i s b r a nde d . 4 . S ei z u re s . A n y a du lt e ra t e d o r m is b ra n de d d r ug wi l l b e su b je ct t o c o n dem n at i on a n d s ei z u r e b y t he U . S . g o v e r nm e nt af t e r a h e a rin g in an y d is t ri c t c o u r t of t h e U n i t ed S ta t es (o r t er r i to ry ) wi t h p r o pe r ju r is di c t i on . A s ei zu r e m a y be do ne wi t h o ut a h e a ri n g i f t h e f ed e ra l g ov e r n m en t h as p ro b ab le c a u s e to be l ie v e th a t t h e v i o l a ti on wo u l d b e d an ge r o us to he a l th o r t ha t th e l ab e li ng o f th e m is b ra nd e d a r ti c le is f r a u du le n t o r wo u ld be m a t e ri a ll y m i s l e ad i ng to the i nj u r y or da m a g e o f t he p u r ch as e r o r c o ns um er .
5 . I n ve st i g at i o ns an d ins p e c ti o ns a . Th e U . S. S ec r et a r y o f H e a l th an d Hu m a n Se r vic es ha s t h e a ut h o ri t y t o c o nd uc t e xa m i n a ti o ns a n d i ns pe c t i o ns th r ou g h f ed e r al e m p l o y e es a n d b y o ff ic e rs a n d e m pl o ye es o f an y s t a t e, t e r r i to r y, or p ol it ic a l su bd i v i s i on du l y co m m is s i one d b y th e U . S . S ec r e ta r y o f H e al t h a n d H u m a n S e r v ic es as a n of f ic e r o f t h e U . S . Dep a r tm e nt o f H ea l th an d H um an S er v i c es . b . S c op e o f i n ves t i ga t io n . A n i n v es ti g at o r m a y e n t e r a p h ar m ac y o r o the r e s ta b li sh m e n t wh e r e ad ul t e ra t e d o r m is br a nd e d dr u g s a re h el d a nd in sp ec t a ll d r u gs , m a te r ia ls , c on t ai ne r s , a nd la b el in g . Th e ins p ec ti o n d oe s n o t e xt e nd t o f i n an ci al da t a , s a l es d a ta o th e r P.546 t h a n sh i pm en t d a ta , p ri c in g da t a, pe r s o n ne l d a ta , a n d o th e r re c o r ds th a t ha v e n o b e a ri n g o n a du l te r a ti on a n d m is b ra nd i ng . Th e i nve s t ig a to r m u st p re s e n t a p p ro p r ia t e c r e de n ti al s a nd a wr i t te n n o ti c e t o t he o wn e r , o per a t o r , o r a ge n t i n c ha r ge t h a t h e o r s h e is au t ho r i z e d t o c ond u c t an in v e s ti ga t io n . The i ns pe ct i on m u s t be don e at r e a so na b le ti m e s , wi t h i n r e a s o na b le li m i ts , an d i n a r ea so n ab le m a n ne r . 6 . C u r r e nt G o o d M a n u fa c t u r in g P r ac t i ce (c G M P ) . U n de r th e F D C A , a dr u g i s c o ns id e re d a d ul t e ra t ed if i t i s n o t m a n uf ac t u re d “i n c o n fo r m i t y wi t h c u r r en t G o o d Ma n u f a c tu r i ng P ra c ti c e . ” F D A r eg u la t io ns s t a te wi t h p a r ti cu la r i t y th e m in im um c G MP s f o r m e t ho ds to be us e d i n, an d th e f ac i li tie s o r c o n tr o ls to be us ed f o r , t h e m a nu f ac tu r e , p r oc es s i ng, p ac k i ng , or h ol di n g o f a d r u g. Th e c G MP s e n s u re t ha t a d r u g m ee ts t he re q ui r em e n ts o f t he F D C A a s t o s a f e t y an d h as th e i d en t ity a n d s t r en g th an d m ee t s t he qu a li t y a nd pu r i t y c ha r ac te r i st ic s t ha t it pu r p or t s. J . R e gi s t r a ti o n o f p ro du c e r s o f d ru g s 1 . Ma n u f ac t u re rs an d bus i ne s s es th a t d is t ri b ut e a d r ug m a nu f ac tu r e d b y a n o th e r b u t s o ld un d er t he i r o wn l abe l or t r ad e n am e m us t r eg i s t e r t h ei r es ta b li s h m e nt wi t h t he F D A . Th e y a ls o m u s t s ub m it a l is t o f e ve r y d r ug ( p r es c ri p ti o n a nd O TC ) in c om m e r c i a l d is t ri bu t io n , wi t h u p da t es e ver y J un e a n d De ce m b e r . 2 . P ha r m a c i es p ro p er l y lic e ns ed b y s t at e l a w t h a t d o no t m an u fa c tu r e o r po s s e ss d r u gs fo r s a le ot h e r t ha n i n t h e r e gu l ar c o u rs e o f t h e p r ac t ic e o f p h ar m a c y a r e n o t r e q ui r e d t o r e gi s t e r wi t h t h e F D A. A p h a rm ac y eng a g ed i n m a nu f ac tu r in g o r p r o ce s s in g a c t i v i ti es t ha t a r e c on s i d e re d b e y on d th e no r m a l p r ac ti c e o f p ha r m ac y m us t re g is t er wi t h th e FD A a n d su p pl y a l is t of ev e r y d r u g i n c om m e rc i al d i st r ib u ti o n. a . S co p e o f ph a r ma c y p r a c t i ce . A p ha r m a c y or p h a rm ac is t m a y no t m anu f ac t u re d r u g p r od uc t s . Th e y m a y o n l y c om po u nd d ru g p r ep a r a ti on s p u rs ua n t t o a va l id p r e sc ri p ti o n o f a p ra c t i tio n e r f o r a pa r ti c ul a r p at ie n t . L a rg e -s c a l e m a n uf ac t u ri n g o f d r u g p r od uc t s b y a p ha rm ac y o r ph a rm ac is t i s ou t si d e t he s c op e o f p h a rm ac y p r a ct ic e a n d r e qu i re s p ro p e r r e gi s t r a ti o n wi t h t he F D A an d c om pl ia nc e wi t h c G MP s . K . P a ck a ge i ns e r t s. Th e f e de r a l g o ver n m e n t h as d e t e rm in ed t ha t p r es c ri pt i o n m e di ca t io n i n fo r m a t io n ne e ds to be di s s em i na t ed t o he al t h p r of es s i o na ls a n d , i n t he c as e o f c e r ta i n d ru g s , to t h e p a ti en t . 1 . M a n u fa c tu r e r ' s i n se rt . A n a m e n dm en t to th e F D C A r e qu i re d th a t a ll m a nu f ac tu r e rs p ro v i d e “ fu l l d is c l os u re ” c o nc e rn i ng p r esc r ip t io n m e di ca ti on t ha t th e y
m a rk e t. F ul l d is c l os u re is ac c o m p li s he d b y m e a ns o f a p ac k a g e i ns e rt t hat i s e n cl os e d wi t h e v e r y c om m e rc i al c o nt a in e r o f a d ru g p ro du c t. Th e i n s e r t s h o ul d c o nt a in es s e n ti al s c i e n ti fi c i n fo r m a t io n n e ed ed f or t h e s af e a n d e f fe ct i ve us e o f th e d r u g a nd s h o ul d b e i nf o rm a ti v e an d a c c u ra t e . I t m us t no t b e p r om o ti o na l i n to n e, f a ls e , o r m is le a di n g. 2 . P a ti e n t p ac k ag e in s er t . Th e F D A h as de t e rm in e d t h at , be c a us e o f c e rt a i n s i d e e f f ec ts as s o c i a te d wi t h th e us e o f p a r ti c u la r d ru g p r o du c t s , p at i en t p ac k ag e in s e r ts m us t be di s p e ns ed to the p at i en t a t th e t im e o f di s pe ns i ng th e m ed ic a ti o ns . Th e f o l lo wi n g p r o du c t s m us t b e di s p e ns ed wi t h a pa t ie n t p ac k ag e i ns e rt , wh i ch is s u pp li e d wi t h t he p ro du c t f r om th e m an u fa c tu r e r: a . O r a l c o n t ra c ep t i ve s . H o s pi t al in p at i en ts o r L TC F p a ti en t s m a y r e ce i ve t h e i ns e r t b e f o re ad m i ni s tr a ti o n o f t h e fi rs t or a l co n t ra c e p tive a n d e v e r y 30 da y s the r e a ft e r , as l o ng as th e th e ra p y c o n tin u es . b . I n t ra u t e ri n e d e vi c es f o r hu m a n u s e in co n tr a c e p t io n . E v e r y p r ac ti t io n er d i sp e ns in g s uc h a d e v ic e m u s t p r o v id e t h e p at i en t wi t h an in f or m a t i v e i ns e r t. c . E st r o g en an d es t r o ge n - c on t a in i n g p r o du c t s. H o sp i ta l i np a ti e nt s o r LTC F p a t ie n ts m a y r ec ei v e th e i ns e r t b ef o r e a dm in is t r at i o n o f t h e f i rs t es t r og e n d o s e an d e ve r y 3 0 d a y s t h e re a ft e r, a s l on g a s t he t he r ap y c o nt i nu es . d . P r o ge s t at i o na l d ru g p r o d u c ts . Ho s p i ta l i n pa ti e n ts o r L TC F pa t ie n ts m a y r e c e i v e t h e i ns e r t b ef o r e a dm in is t r a t io n o f th e f i rs t p r o ge s t a t io n al dr u g p r od uc t a nd e v e r y 30 d a ys th e re a f te r , a s l on g a s th e t h er a p y c o nt i nu es. e . I so p r o te r e n ol i nh a la ti o n p r od u c ts re q ui r e t he f ol l o wi ng wa r n i ng st a tem e nt on t h e i m m ed i at e c on t ai n e r l a be l o f s uc h a p ro d uc t : “W ar ni n g: D o n o t e xc e e d t h e d os e p r e sc ri b ed b y y o u r p h ys ic i an . If di f fi c u l t y pe rs is t s , c on t ac t you r p h y s ic ia n i m m e di a te l y . ” P.547
f . M is ce l l an e ou s d ru g pr o d u c ts . C e rt a in dr u g p ro d uc ts we r e a pp r o ved b y t h e F D A wi t h t h e p r o v is io n th a t t he y m us t b e d is p en s e d a lo n g wi t h a p a ti e nt pa c k ag e in s e r t t h a t i nc lu d es a pa r t ic ul a r wa r n i n g o r s t at em e nt o f b e n ef i ts a n d r is k s ass oc ia t e d wi t h t h e u se o f t he d ru g . F o r e xa m p l e , is o t re t in o in wa s ap p r o v ed fo r di s p e ns ing wi t h an i n se r t wa r ni n g a bo u t s er io u s f e ta l h a rm wh e n a dm i ni s t e r ed to p re gn a nt wo m en . L . M e d ic a t io n G u id e s 1 . Th e “ Me d ic a ti o n G u i de ” bi l l wa s s i g ne d i n to law i n A u g us t 1 99 6 . B y 2 00 6 , 9 5 % o f p a t ie n ts re c e i v i ng a n e w p r e s c ri p ti o n we r e t o r e cei v e wr i t t e n i nf o rm a ti o n i n n o n t e ch n ic al la n gu ag e a n d in a u n if o rm fo r m a t . “ Me di c at i on G ui d es ” o r “ Me d G u i d es ” s h ou l d n ot be c o n fu s e d wi t h t h e p a ti en t le a fl e ts g e n er a te d b y m os t p ha rm ac y c om p ut e r s o ft wa r e p ro g ra m s . P at i en t l ea f le t s a r e t y p i ca ll y p a rt o f t he ph ar m ac y s o f t wa r e p ac k a g e t o p r oc es s p r es c ri p ti on s a nd ar e wr i t t e n a nd up d at e d by a s ou r ce o t h e r t ha n t h e m an u fa c tu r e r o r F D A . Th e la n gu ag e of Me d i c a t io n G ui d es i s a p p ro v e d b y t h e F D A wh i l e p at i en t l e af l et s a r e n ot ap p r o v ed b y t he F D A. Th e m a nu fa c tu r e rs m us t m ak e Me d ic a ti o n G u i de s a v a il a bl e e l ec t ro nic a ll y t o p ha r m a c i es . 2 . Th e l e gi s l a ti o n h as c re a t ed s i gn i fi ca n t co n fu s io n an d c on t r o ve rs y wi t h in t he p h a rm ac y a nd he a lt h c a re c o m m un i ti es . Ma n y p ha r m ac i s ts ass um e th a t th e pa t ie n t
l e a fl e t s a t is fi e s t he Me d G u i d e r e qu i re m e n t , b ut s i n c e th e l a ng u ag e wa s n ' t a p p ro ve d b y t h e F D A , th e a g en c y (F D A ) s a ys th e t wo a re no t su bs t it u ta b le . I t is n o t c le a r i f o n e m an u fa c tu r e r 's Me d G u i d e c an be gi ve n t o t he p at i en t wh e n a no t he r m a nu f ac tu r e r ' s e qu i v al en t ge n e ri c p ro d uc t i s d is p e n s e d. E ac h m an u fa ct ur e r is to m ak e th e Me d ic a ti o n G u id e s a v a il a bl e t o p h ar m ac i es . I f a ph a rm ac y g a ve t h e wr o ng m a nu f ac tu r e r ' s Me d G u i de f o r a g e ne r ic p ro du c t, a ss u m i ng th e m a nu f ac tur e r ' s n am e i s o n th e d oc um e nt , te c hn i c a ll y t h is c ou l d b e c o ns t r ue d a s a l a be l in g v io la t i on . P r o f es si o na l p ha r m a c y or g a ni z a t io ns an d o t he r int e r es t ed pa r t ie s ( i .e . , p h a rm ac e ut ic al m a n uf ac tu r e rs ) a re wo r k in g wi t h th e F D A t o c la r i f y t h es e r e q ui r em e nt s . M . P r es c r ip t i o n d r u g s am p l es 1 . A n a me n dm e n t t o t h e F D C A ( P r es cr i pt i on D r ug Ma r k e t in g Ac t ) s e ver e ly r e s t ri c te d t h e d is t r ib u ti o n o f d r ug s a m pl es b y m a nu f ac tu r e rs . U nd e r t h e F D C A , n o pe r s on m a y s e ll , p u rc h as e, o r t r ad e , o r o ff e r t o s el l , p u rc ha s e, o r tr a de an y d r ug s a m pl e . S a m pl es m a y on l y be di s t r i bu t e d u po n wr i t te n re qu e s t o f a p r ac t it i on e r . Ma n u f a c tu r e rs m u s t m a in t a in r ec or d s o f e v e r y s am p le di s t r ib u ti o n f o r a pe r i od o f t h r e e ye a rs . Ph a rm ac i es m a y no t re c e i v e s am pl es f ro m a m a nu f ac tu r e r exc e p t i n c e r ta i n si t ua t io ns in wh i c h a p r ac t it i on e r r e qu es t s s t or a ge of hi s o r he r s am p le s i n t h e p h a rm ac y . 2 . I mp o r t a ti o n u n de r t he F D C A. Th e P r e s c ri p ti on D r u g Ma r k e t in g Ac t p ro h ib i ts th e i m po r t o f p r es c ri p ti on d ru g s o nc e e xp o r t e d. Im p or t a t io n i s a ll o we d af t e r no t i fi c a t io n a n d a p pr o v a l o f t h e F D A a n d i n c a se s o f a n e m e rg e nc y . N . M ed i ca l de vi c e s. A n a m en dm e nt to t he F D C A i n 1 9 76 ( Me d i c a l De v i c e A m e nd m e n ts ) re q ui r ed a d e v ic e m an u f ac tu r e r t o p r o v i de r ea so n ab le as sur a n c e of t h e s a fe t y an d e f f ec ti v e ne s s o f t he de vi ce . Th e am e nd m e n t r e qu i re d th e F D A t o c a te g o ri z e ea c h de v i c e on t he m a r ke t i n 1 9 76 i n to o n e o f t h re e c la s s es : C la ss I , C l a ss II , or C la s s I II , d ep e n di ng on ea c h de vi c e 's s a f et y a nd e ff ec t i ven es s . G e n e r al l y , C la s s I d e v ic e s a r e t h os e t h at ha v e a r e as o na bl e a s s u ra n c e of s af e t y a n d e f fe c ti v e ne s s . C la s s I I de v i c e s a r e t ho se t ha t d o n o t h a ve t h e r e as on ab l e a ss u r an c e of s a f et y a nd e f f ec t i ven es s, bu t th e r e is su f fi c i e nt in f o rm at i on ab o u t t he d e vi ce to es t ab li s h s p ec ia l c o nt r o ls t o e n su r e i ts s a fe t y a nd ef f ec t i v en es s ( a n d m a y b e m a rk e te d wi t h s uc h c o n t r ol s ) . C la s s I I I d e vic es a re th o se fo r wh i c h in fo r m at i on i s n o t s u ff ic i en t t o p r o v i de r e a s o na b le as su r an c e o f t h ei r s a fe t y a nd ef f ec t i ve n es s . C l a ss II I de v i c e s m a y b e m a rk et e d o nl y i f t h e y a re p r o v en to be su bs t an t ia l l y e q ui va l en t to a d e v ic e on t he m a r k e t b e fo r e 1 976 , b y ap p ro va l o f a p re m a r k et a p pl ic a ti o n, o r b y r ec la s s i fi c a t io n i n to C la s s I o r I I . 1 . M e d ic a l d e vi ce t r ac ki n g . Ma n u fa c tu r e rs o f m e d ic al de v i c es wh os e fa ilu r e wo u ld b e r ea so na b l y l ik e l y to ha v e a s e ri o us a d ve rs e he a l th c o ns eq u en ce m u s t t r a c k th e d e vi ce do wn t h e c ha in o f d is t r ib u ti on t o t he pa t ien t . Su c h t r ac k i ng al lo ws t h e m a nu f ac tu r e r t o ta k e app r o p ri a te ac ti o n wi t h r es p e c t t o r ec al ls , de f ec ts , o r o th e r r e l e van t in f or m a t io n c onc e r ni ng t he de v i c e . E v e ry f i n al di s tr i bu t o r s u ch as a p h a rm ac y , ho s p i ta l , o r ho m e h ea l th - c a r e c om pa ny m u s t r ep o r t ce r t ai n i n fo r m at i on to t h e m an u fa c tu r e r. Tr a c k in g in f o rm at i on m us t b e m a in t ai ne d b y t h e m a n ufa c tu r e r a n d d i st r ib u t or f or t he us ef u l l i f e o f t he de vi c e a nd be a v a i la b le fo r in sp ec t io n b y F D A p e r so nn e l.
P.548
2 . M a n u fa c tu r e r ' s r e p o rt s . E v e r y de v i c e m a nu f ac t u re r m us t re p o rt t o t he F D A i n f or m at io n , wh e n r ec e i ve d o r m a d e a wa r e of , tha t r ea s o n ab l y s u gg es t s th a t o n e o f i t s m ar k e t e d d e v ic es m ay h a v e ca us e d o r c on t r ibu t e d t o a de a th o r s e r io us in j ur y. L i ke wi s e , h os pi t al s a nd o t h e r m e d ic al s e r vic e f ac i l i ti e s m u s t p ro v i d e r e po r t s o n a d ve r s e r ea c t i on s t o , o r m a lf u nc ti o ni ng o f, m e di c a l de vi ce s . 3 . Ad u l t e r a ti o n a n d m isb r a n d in g . Me d ic a l d e v ic e s m a y be ad u lt e ra t ed o r m is b r an de d i n th e s am e wa y t h a t d r ug s a r e a du l te r a t ed or m i sb r an d ed (s e e I I. I ) .
III. POISON PREVENTION PACKAGING ACT (PPPA). Th e P P P A o f 1 97 0 re q ui re s th a t d ru g s f o r h um an u s e i n a n o r al do s a ge f or m m us t b e pa ck ag e d f o r t he c o ns um e r i n s pe ci a l p ack a gin g . Al l s uc h f e de r al c o ntr o l le d s u bs ta n c e s a nd d ru gs dis p en s e d p u rs u an t t o a p re sc r i pt i on m us t be di sp en s ed to t h e c on s um er in s p ec ia l p a c k ag i ng . Sp e ci a l p a cka g i n g, r ef e r re d to as c h il d r e s i s ta n t c on t ai n er s , is d e f in ed as a co n t ai ne r tha t is de s i gn e d t o b e s ig ni f ic a nt l y d i f fi cu l t f o r c hi ld r en u nde r 5 y ea r s o f a ge t o g ai n a c c es s t o wi t hi n a r ea s on a bl e ti m e . Th e c on t ai n e r m u s t n ot be t oo di f fi c ul t f o r n o rm al a d ul t s ( o ne s wi t h no o v er t p h ys i ca l o r m e n ta l h a nd ic ap s ) t o u s e p r op e rl y a nd do es no t i n c l u de pa c k ag i ng th at a ll s u ch c h il d re n c an n ot ga i n ac c e s s wi t h in a re as on a bl e ti m e. Th e C on s u m e r P ro du c ts S a f e t y C om m is s i o n is r es p on s i b le fo r in t er p r et i ng , es t ab li sh i ng r ul es an d r e g ul a ti on s f o r , a n d e nf o rc i ng th e p ro v i s io ns of t he P P P A . A. E x c e p t i on s . Th e f ol lowi n g m ed ic a ti o ns a r e e x e m pt f ro m t h e s p ec i al pac ka g in g r e q ui r em e nt s : 1 . S ub l in gu a l d os ag e f o rm s o f n i t ro gl yc e ri n ; o t her d os a ge fo r m s i n te n de d f o r o ra l a d m i ni s t ra ti o n , s u c h as n i t ro g l y ce r in s u s t ai n ed - re l ea s e p re p a ra t io ns , m us t be p a ck ag e d i n c h i ld - r es is tan t c o n ta in e rs 2 . S ub l in gu a l a nd c h e wab l e f o rm s o f i s o s o r bi d e di n i tr a te in do s ag e s t re ngt h s o f 1 0 m g o r le s s 3 . E r yt h ro m y c i n e t h y ls uc c i na t e g r an ul es f or o ra l s us p en s i o n a nd o ra l s usp e ns i on s i n p a ck ag es c o n ta in i ng no t m o r e t ha n 8 g o f t h e e qui va l en t of e r y th r om y c in 4 . C yc li c a ll y a dm in is t e red o r al c o nt r ac e pt i v es in m a n u f ac tu r e rs ' m n em o nic (m em o r y a i d ) d is pe ns e r p ac k a g es t h a t r el y s ol el y o n t h e ac t i v i t y o f o n e o r m o re p ro g es t og e n o r es t r og e n s u bs t an c e s 5 . A nh yd r o us c ho l es t y r am i ne in po wd e r f o rm 6 . A ll un i t -d os e f o rm s o f p o t as s i um s u pp le m e n ts , i n cl ud i ng in d i vid ua l l y wr a p p ed e f f e r ves c e n t t ab l et s , u ni t- d o s e vi al s o f l iq u id po t as s i um , an d p o wd e r ed po ta s s i um i n u n i t- d os e p ac k a g es , c ont a i ni ng no t m o r e t ha n 5 0 m E q o f p o ta ss iu m p e r un i t d os e 7 . S od i um f l uo r id e d r u g p r e pa r a ti o ns , i nc lu d in g l iq u i d an d ta bl e t f o rm s, con t a in in g n o m o r e t ha n 2 6 4 m g o f s o di um fl u o ri de pe r pa ck a g e a n d c o n ta i ni ng no o th e r p r e sc ri p ti o n m e d ic a ti on 8 . B et a m e t ha s o ne t ab le ts pa c k a ge d i n m an u fa c t ur e r s ' d is p en s e r pa ck ag es , c o nt a in in g no m o re t ha n 1 2 . 6 m g be t am e th as o ne
9 . P an c re li p as e p r ep a ra ti o ns in ta b le t , c ap s u le , or p o wd e r fo r m a nd c o nt a in i ng no o t h e r p re s c r ip t io n m ed ic a t i on 1 0 . P re d ni s o ne in t ab le t f o r m , wh e n di sp en s ed i n p ac ka g es c o nt a in in g n o m o r e t ha n 1 0 5 m g o f t h e d r ug , a n d c o nt a in in g no ot h er p re s c r i pt io n m e di c a t io n 1 1 . Me b e nd a z o le in ta b le t f or m i n p ac k a g es c on ta i ni n g n ot m o r e t h an 60 0 m g o f t h e d r u g a nd no o th e r p r es c ri p t io n m ed ic a ti on 1 2 . Me t h y l p re d ni s o lo n e in t ab l et f or m i n p ac k a g es co n ta in i ng no t m o re t ha n 84 m g o f t he dr u g a nd no o th e r p r e s c ri p ti o n m e d ic a ti on 1 3 . Co l es ti p ol in po wd e r f o r m i n p ac k a ge s c on t ain i ng n o t m o r e t ha n 5 g of t h e d ru g a n d n o o t he r pr e s c ri p ti on m e d ic at i on 1 4 . E r yth r om y c in e th y l s uc c i n at e ta bl e ts in pa c k age s c on t ai n in g n o m o re tha n th e e q ui va l en t of 16 g e r y t h ro m y c i n P.549
1 5 . Co n ju g at e d es t r og e n t a bl e ts U S P , wh e n di s pe n s e d i n m ne m o n ic p ac ka g es c o nt a in in g no t m o re th a n 3 2 m g o f t h e d r ug an d no o th e r p r es c ri p ti on m e dic a ti o n 1 6 . No r e th i nd r on e a c e t a te t ab l et s U S P, wh e n d is p e ns e d i n m n em o ni c p ac k a ge s c o nt a in in g no t m o re th a n 5 0 m g o f t h e d r ug an d no o th e r p r es c ri p ti on m e dic a ti o n 1 7 . Me d r o xy p r o g e s t e r one ac e ta t e t a bl e ts B . R e q ue s t s f o r a n on -c h i l d - re s is t a nt c on t a ine r . A pr e s c ri b in g p r ac t it io n e r m a y m ak e a r eq u es t i n t h e p re s c r i pt i on th a t t he m e di ca t i on be di s p e ns ed in a n o n -c hi l d r e s is ta n t c on t ai ne r . A p ra c ti t io n e r m a y n ot , ho we v e r , m a k e a b l an k e t re q ue s t t h at al l p r e sc ri p ti o ns i s s u ed b y hi m o r he r be di s p en s ed in n on - c h il d - re s i s ta n t c o nt a i ne r s . Th e p u rc h as e r, o r p at i ent , m a y a ls o m ak e a re q ue s t t h at th e m e di ca ti o n be d i sp e ns ed in a n on - c h il d- r e s i s ta n t co n ta i ne r . Th e r e q ue s t of t he pu r ch as er , o r p a t ie n t, do es no t ( un de r t h e P P P A) ha ve t o b e i n wr i t i n g . Th e p u rc ha s e r , or p a ti e nt , m a y m a k e a b la nk e t r e qu e s t t ha t n o ne of hi s o r h e r m e di c a t io ns be di s pe n s e d i n a c h il d - re s i s t a nt c o n ta in e r . A d is pe ns i ng ph a rm ac is t m a y n e v e r m ak e t h e d ec is i on to u s e n on - c h il d - re s i s ta n t c o n t ai ne r s . C . R e u se o f c h il d - r es i st a n t co n t ai n e rs . R eu s e o f c h il d - re s i s ta n t c o n ta i ne r s a r e p r o hi b it e d b y r eg u la t io n o f t he fe d er a l C o ns um e r P r o d uc ts S af e t y C om m is s i on . H o we ve r , t h e Co m m is s i on h as i n di ca t ed th a t g la s s c o n ta in e rs m a y b e r e us e d as l o ng as a n e w s af e t y c l os u r e is us ed . D . M an u f ac t u r e r' s pa cka g i n g. P ac ka gi n g f r om th e m a nu f ac t ur e r t h at is in t e nd e d t o b e di sp e ns ed di r ec tl y t o t h e p a ti e nt m u st be in c hi l d - re s i s t a nt pa c k a gi ng . B u l k p a ck ag i ng in t en de d to be r e pa c k ag e d b y th e ph ar m ac i s t fo r ea c h pr e sc ri pt i o n d oe s n o t h a ve to be in s p ec ia l p ac k a g in g f r om t he m a nu f ac t u re r . Un i t p ac ka g ing f r om th e m a nu f ac tu r e r t h at wi l l b e d is p en se d d i re c tl y t o t he co ns u m e r , o r p a ti e nt , m us t c om p l y wi t h t h e c h i ld - r es i s ta n t r e qu i re m e n ts of t he P P P A (u n le ss s p ec if ic a l l y e xe m p t e d; s e e I I I . A ). E . E x em p t io n s f o r ea s y a c ce s s. S pe c i al pa c k a gi n g i s n ot r eq u ir e d i n c a s e s wh e r e O TC m e d ic a ti o n n ee ds to b e r e ad il y a v a il a bl e t o t h e e l de r l y or ha n di c a p pe d p e r so ns . A m an u fa c t u re r m a y s u pp l y a s i n gl e s i ze o f a dr u g p r od uc t i n n on - c hi ld r e s is ta n t p ac k a gi n g, as lo n g a s i t a ls o s up pl i es th e m e di c a t io n i n p ac k a ge s th a t us e
t h e s pe ci a l p ac k a gi n g. Ad d i ti on a ll y , t he pa c k ag e m u s t be c o ns pi cu o us l y la b el e d wi t h t h e s t at em e nt : “ Th is pa c k a ge fo r ho us e ho l ds wi t ho u t you n g c hi ld r en . ” Fo r t h os e p a ck ag es t oo s m a l l f o r th i s s ta t em en t , t h e st a tem e nt “ P ac k a ge no t c h il d -r e s is ta n t ” m a y be us e d. F . H o sp i t al s a n d i n s ti t ut i o n s . Th e s p ec ia l p ac k ag i ng r eq u ir e m e n ts o f th e P P P A a p pl y t o h o us eh o ld s u bs ta n c e s . H o us eh ol d s u bs ta n ce is d e fi n ed as “a n y s u bs ta n c e wh i c h is c us t om a ri l y p rod u c e d o r di s t r ib u te d fo r s a le fo r c o ns um p ti on o r u s e, o r c us t om a ri l y s t o re d , b y i nd i v i du a ls i n o r ab o ut t he h o us e ho ld … . ” As l o ng as t h e m e di ca t io n i s a dm in is t e re d b y i ns t i tu t io na l p e rs on n el an d i s n o t d i re ct l y di s pe ns e d t o t he c o ns um e r ( pa t ie n t) , c h i ld - r es is ta n t c on t ai ne r s a r e n o t r e qu i re d . G . M i sc e ll a ne o us p r od uc t s r eq u i r in g sp e ci a l pa c k ag i ng . Th e P P P A r equ i r es th a t c e r ta i n h ou s e h ol d s ub s ta n c e s b e d is t ri b ut e d t o th e c o ns um e r i n sp e c i al pa c k a gi n g. E xa m p l e s o f t h es e s u bs ta n c e s i nc lu d e f u rn i tu r e po l i s h c on t ai ni n g p e tr o le um d i st i ll a te s , d ra in pi p e c l ea n e rs , t u r pe n ti ne , pa in t s o l v en ts , an d l ig h te r fl u id .
IV. ANTI-TAMPERING ACT. Th e U . S . C on g r es s pa s s e d th e An t i - Tam p e ri ng Ac t in 19 84 du e to a n um be r o f d e a th s t ha t oc c u r r ed i n th e ea r l y 19 80 s f r om O TC m e di c a ti o n c ap su le s co n t am in a te d wi t h c ya ni d e . A. V i o l a t i o ns . Un l a wf u l a c ts in vo l vin g a co ns um e r p ro d uc t c an be b ro k en d o wn in t o o n e o f th e f o ll o wi n g l is ted v i o la t io ns . Th e t e rm c on s u m e r p r od uc t i nc l ud es a n y f oo d , d r u g , d e v ic e, o r c o s m e tic , as we l l as an y a r ti c l e , p r o du c t , o r c o m m od i t y th a t i s c us t om a ri l y us ed b y in div i d u al s f o r p u rp o s e s o f pe r s on al c a r e o r to pe r fo rm s e r v i c e s o r d in a ri l y do n e wi t hi n a h o us e ho ld . 1 . T am pe r i n g . A n y in d i v id u al wh o t am pe r s o r a t t em p ts to ta m pe r wi t h a n y c o ns um e r p r o du c t t ha t af f ec ts in t e rs t a te or f o re ig n c om m e r ce , o r i ts la be l in g o r c o nta i ne r , m a y b e in vi ol a ti on o f t he s t a tu t e . A vi ol a ti o n oc c ur s wh e n t h e i nd i vid u al ac ts (o r t h r e at e ns t o ac t ) wi t h r ec k l es s d is r eg a r d f o r t he r i s k th a t a no t h er pe r s o n wi l l b e p l ac e d in d an ge r of de a th o r b o di l y i n ju r y . P.550 A n y i n di v i du a l wh o t ai n ts a n y c o ns um e r p r od uc t or c au s e s i ts la b el in g o r c o n t ai ne r t o be m a t er i al l y fa ls e o r m is l ea di n g is in v i ol a ti o n o f th e s ta t u te if do n e wi t h in t en t to c a us e s er i ou s i nj u r y to th e bu s i n ess o f a no t he r . 2 . F al s e c om m un i ca t i on s . Kn o wi n g l y c om m u ni c a t i ng fa ls e i n fo r m a t io n t ha t a c o ns um e r p r od uc t h as be e n t a in t ed m a y be a v iol a t io n . I f s uc h t ai n ti n g, ha d it o cc u r r ed , wo u ld c r e at e a r i s k o f de a th o r b od il y in j u r y to an o th e r p e rs on , t h e n t he f a ls e c om m u ni c at io n i s de e m e d a v i ol a ti o n. 3 . C o ns p i r ac y. A n a g re em e nt be t we e n t wo o r m or e p er s o n s t o d o ( o r f u r th e r ) e i th e r o f t he ab o v e a c t s i s c o ns i d e re d a v i ol a ti o n. B . O TC t a m p e r - r es i s ta nt p a ck a gi n g . C e r ta i n O TC p r o du ct s m us t b e p ac ka g e d, b y F D A r e gu l at io n , i n t am p er - r e s i s t a n t p ac k a gi ng . E xa m pl es in c l u de c o nt ac t le n s s o lu t io ns an d o t he r op h th a lm ic s o lu t io ns . A t a mpe r - r e s is t a n t p ac k ag e i s o n e h a vi n g o ne or m o r e i nd ic a t o rs o r b a rr i e rs t o e n t r y t h a t, if b re ac h ed o r m i s s i ng , c an r e a so na b l y b e e xp e c t e d t o p ro v i d e v i s i b le e v id enc e to c o ns um e rs th a t t am p e ri ng ha s
o cc u r r ed . To re d uc e t am p e r in g , t h e p ac k a ge m ust h a v e o n e o f t h e f ol l o win g c h a ra ct e ri s ti c s : 1 . B e d is ti nc t i v e b y d es ig n s o th a t t he p ro d uc t c a n n ot be du p li ca t ed b y co m m o nl y a va i la b le m a te r i al s o r p ro c es s e s o r 2 . U se on e o r m o r e in d ic a t o rs o r b a rr i e rs t o e n t r y t h a t em p lo y a n i de n ti f y in g c h a ra ct e ri s ti c C . O TC t a m p e r - r es i s ta nt l a be l i ng . Th e O TC p r od u ct m u st be la b el ed wi t h a p r o m i ne n tl y p la c e d s t at em e nt al e r ti n g c o ns um e rs t o th e s pe c i f ic ta m p e r - re s is ta n t f e a tu r e o f th e p ac k a g e. Th e s t at em e nt m u s t be pl a ce d s o t ha t it wi l l b e un a f fe c te d i f t h e ta m p e r - re s i s t a nt fe a tu r e i s b r ea c he d o r m is sin g . D . M ed i ca l de vi c e s a nd c o sm e t ic s . C e r ta i n m e di c al de vi ce s a nd c o sm et ic s m us t b e p a ck ag e d i n t am pe r - r es is t an t pa c k ag i ng . Th e p ac ka g i n g re qu i r em en ts a re s i m i l ar t o t h e re q ui r em en t s o ut li n ed a bo v e fo r O TC d r u g p ro d uc ts .
V. MAILING PRESCRIPTION MEDICATION A. A l l p r es c r i pt i on m e di c a t i on , i nc l ud in g c o nt r ol l ed s u bs t a nc es a n d n a rc oti cs in s ch e du l es II - V , m a y b e m a il ed f ro m a ph y s ic ia n , o r ph a rm ac is t p u rs u an t t o a p r e sc ri p ti o n, t o t he pa t ien t . Fl am m a bl e s u bs ta nc es ( e. g . , ac e to n e ) a nd al co h ol ic b e ve r ag e s m a y n o t b e s e n t to a p at i en t t h r ou gh th e U . S . m a i l. B . Th e m e d ic at i on m us t b e pl ac e d i n a p l ai n o ut er c on t ai n er o r b e s ec u re ly o ve r wr a p p e d i n p la in p ap e r . Th e re m us t be no m a r k in gs of an y k in d o n t he o ut s i d e wr a p p e r o r c o n t ai ne r th at wo u l d i n di c a t e t he na t ur e o f t he co n te n ts .
VI. OMNIBUS BUDGET RECONCILIATION ACT OF 1990 (OBRA ′90). U n d e r t h e C o ns t it u ti on of t h e U n it e d S t at es , th e fe d e ra l g o v e r nm en t h as no p o we r o r a u t ho r i t y t o d i r ec tl y r e gul a t e t he p ra ct ic e o f ph a rm ac y . S uc h p o we r r es t s wi t h e ac h s t a te . Th e f ed e r al go v e rn m en t c an , ho we v e r , i ndi r e c t l y r eg ul a te , or a ff ec t, t h e p r a ct ic e o f p h a rm ac y b y a t t ac hi n g co n di t io ns of pa r t ic ip a ti o n a nd r ei m b u rs e m en t fo r f e d e ra ll y f u nd ed p ro g ram s . A. M e d i ca i d p r e sc r i p t ion s . W it h r es p ec t t o p r es c r i pt io n s d is pe ns e d t o M e d ic ai d p a t ie n ts (p a id in pa r t b y t h e fe de r a l g o v er n m e n t a l on g wi t h t h e s ta t e g o ve r n m e n t) , t h e fe de r a l g o v er n m e n t h a s a t ta c h e d c e r t ai n c ond i t i o ns fo r r ei m b u rs em ent . S uc h c o nd i ti on s we r e d e em ed n e c e s s a r y to s t em th e a lwa y s i n c re a s i ng c o s t of th e Me d i c a i d p ro g r am s . It wa s b e li e ve d t ha t i m p r o v ed m e d ic at i on c om p li a nc e b y Me d i c a i d r ec ip i en ts wo u ld , in th e l o ng r un , re d uce t he co s t o f t he p ro g ram s b y r e d uc in g s ub s eq ue n t h os p i t al i z a ti on s a nd o th e r s u b s e q ue n t u ti li z a t i on of h e al t h c a r e. As a r e s u l t, ph a rm a c is ts a re re q ui r ed t o d o t h e f ol l o wi n g i n t he c o u rs e o f d i sp e ns in g a Me d i c a id p re s c r i pt i on : 1 . Ma k e a r e as on ab l e g oo d - f ai t h e ff o r t t o o b ta in a n d m ai n ta in a h is t o r y o f t h e p a t ie n t, in c l u di ng a m ed ic a ti o n h is to r y P.551
2 . C on d uc t a r e v ie w o f ev e r y p r e s c r ip t io n f o r a p pr o p r ia t en es s a nd t o s c r ee n fo r p o t en t ia l d r ug t he r ap y p ro b le m s 3 . Ma k e an of f e r t o c ou ns e l e ac h Me d i c ai d re c i pie n t c on c er n in g t h e d r ug ( i f th e o f f er i s a cc ep t e d, th e c ou n s e lin g m us t in c l ud e th e d r ug' s p r op e r a dm in is t r at i on , c om m o n a d ve r s e o r s e v e r e s id e ef f e c t s , t ec hn i qu es fo r s e lf - m on i to r in g , a nd p ro p er s t o ra g e) B . M an u f ac t u r e r' s be s t p r i c e . O B R A ′ 9 0 r e qu i res m a nu f ac t u re r s t ha t wi s h t o p a r ti c i p a te i n th e Me d ic ai d pr o g ra m t o o f fe r th e fe d e ra l g o v e r nm en t th ei r b e s t p ri ce f o r p re sc r ip ti o n d r ug s . Be s t p r ic e is de f in e d a s t he l o we s t p ri c e a t wh i c h an y p u r ch as e r i s p ur c ha s i ng t h a t d r ug p ro du c t.
VII. HEALTH INSURANCE PORTABILITY AND ACCOUNTABILITY ACT OF 1996 (HIPAA). H I P A A is f ed e ra l l e gi s l a ti o n t h at r eq u ir es al l h e al t h - c a r e p r o v id e rs , i nc l ud in g p h a rm ac ie s , t o p r ot ec t pa t i en t i n fo r m a t io n f r om un a u th o ri ze d u s e a nd di s c l os u re s . Th i s is re f e r re d t o a s t h e P r i v a c y R ul e a nd wa s es t ab l is he d a s a re s u l t o f t h e g o ve r nm e nt ' s re c o g ni ti on t ha t i n di vi d ua ll y i de n ti fi a bl e h e al t h i nf o rm a ti o n is r ea d il y a va i la b le du e t o he al t h -c a r e pl an s , h ea l th -c a r e c le a r in g ho us es , th i rd - p ar ty b i l li ng p r a ct ic es , c li n ic al r es ea rc h tr i al s , an d th e t r a nsm is s i o n o f h ea l th in f o rm at io n in e l ec t r on ic fo r m . P r ot ec t ed h ea l th in f o rm at io n ( P HI ) m u s t b e co n fi d en t ia ll y m a in t ai ne d b y a he a lt h -c a r e pr o v i de r to p re ve n t an y u n au t ho r i z e d us e o r di s c l os u re . O t h e r c o v e r ed en t it i es , s u c h as O r g an i ze d H e al t h C a r e A rr a ng em e nt s , H M O ' s a n d i n su r an c e pl a ns , m us t a ls o fo ll o w t h e Pr i vac y R u le . A. D e f i n i t i o ns . Un d e r t he P r i v ac y R u le , c e r ta in te r m s ha ve s p ec i fi c m e a ni n gs . 1 . “ Co ve r e d en t i t y” m e a n s : a . a h ea l th pl a n ( e .g . , g ro u p h e al t h in s ur a nc e, M e d ic ai d , Me d ic a re ) . b . a h e al th - c a r e c le a ri n gh o us e (e . g. , bi ll in g s e r v ic e c om p an ie s a nd co m pa n ie s t h at p r o ce s s h e al t h i nf o rm a tio n r ec ei v e d f r om an o th er e n ti t y ) . c . a h ea l th -c a r e p r o v id e r wh o t r a ns m i ts an y h ea l th i nf o rm a ti o n in el ec t r on ic f or m i n c o nn ec t io n wi t h a t ra ns ac t io n c o v e re d b y H I P A A . “ H e a lt h c a re ” is d e fi n ed a s i n cl ud i ng th e s al e or di s p e ns i ng of a d r ug , d e vic e , eq u ip m e n t, o r o th e r i te m i n a cc o r da nc e wi t h a pr es c r i p ti o n. 2 . “I n d i vi du a l l y i d e n t i f ia b l e h e al t h i n f o rm a t io n” is in f or m a t io n c r ea t ed o r r ec ei v e d b y a co v e r ed en t i t y t h a t r e l at e s t o t he pa s t, p re se n t , o r fu t ur e ph y s ic al or m en t al h e al t h o r c o nd i ti on o f a n i n di v i du a l; t he pr o v i si on o f he al t h c ar e to an in divi d u al ; o r a n y p a y m e n t f o r a n y p r ov i s i on of an y h ea l th c a r e, a n d t ha t i d en t if i es th e in d i v id u al o r t h at p ro v i d es a r ea s on a bl e b a si s t o i de n ti f y t he i nd i vid u al . Th e i t em s lis t ed be l o w a r e de em ed s u f fi c i e nt t o i d en t i f y a n i n di vi du a l: a . N am e b . A dd r es s , i nc lu di n g a ll g e o gr a ph ic s u bd i v is i on s s m a l le r th a n a s ta t e (e . g. , s t r e et a d d re ss , c i t y , c ou n t y , z ip c o d e ) c . D at es ( e xc e p t y e a r ) , in c lu di n g b i rt h d a te s , a dm is s i o n d at es , di s c ha r ge d a te s , d a t es o f de a th d . Te l ep h on e n um b e rs e . F a x n um b e rs f . E - m a il ad d r es s e s
g . S oc ia l Se c u r i t y n um be r s h . Me d i c a l re c o r d n um b er s i . H e al t h p la n b en e fi c i a ry n u m b e rs j . A cc ou n t n um be r s k . C e r ti fi c a t e /l ic en s e n um b e rs l . V eh ic l e i de n ti f ie r s a nd s e ri al n um be rs , in cl ud i ng l ic en s e pl a te nu m b e rs m . D e vic e i de n ti f ie r s n . W eb un i v e rs al r es ou rc e l oc a te r s ( U R L s ) o . I nt e r ne t p r o to c o l (I P ) a d d re s s nu m b e rs p . B io m e t r ic i d en t if i e rs , in c lu di n g f in g e rp r in t s a nd vo i ce p ri n ts q . F ul l f ac e p h ot o gr a ph ic i m a g es a n d a n y c om p a ra b le im ag e s r . A n y o th e r u n iq ue id e nti f y i n g n um be r , c ha r ac t is ti c , o r c od e , e xc e p t fo r c od e s a ss i gn e d t o r e id en t i f y i n fo r m at i on th a t h as be en de - i de n ti f ie d s . N am es o f an y r e la t i v e, e m p l o y e r, o r h ou s e h ol d m em b e r o f t h e in d i v id u al P.552
3 . “ P ro t e ct e d h e al t h i n fo r m a t io n ” ( P H I ) i s a ll ind i v i du a ll y i de n ti f ia bl e h ea l t h i n f or m at io n th a t is t ra ns m i tt e d o r m ai n ta i ne d i n an y f o r m o r m ed i um , e le c t r o ni c al l y o r o th e r wi s e. 4 . “ No t i ce o f p r i va c y p r a c t i ce s f o r p r o te c te d he a l t h i n f o rm a t io n .” An in d i vid u al h a s t he r ig h t t o a d eq ua te n ot ic e o f th e u s e s a nd d i sc lo s u r es of P H I t h at m a y be m a de b y th e c o v e re d e n ti t y , a nd of th e i n di vi d ua l 's r ig h ts a n d t h e co v e r e d e n t it y' s l e ga l d u ti es wi t h r es pe c t t o P H I. G e ne r al l y , th e no t ic e m us t c on t ai n i n fo rm a ti o n d e sc r ib in g th e i nd i v i du al ' s r ig h ts u n de r th e P ri v a c y R u l e a n d t h e c o ve r e d e n t it y ' s r e s po ns ib i li t ie s . a . H ea d e r . E v e r y n o ti c e m us t c o nt a in th e fo ll o wi ng s ta t em en t a s a he ad e r o r b e o t h e r wi s e p ro m i ne n tl y d is p la y e d : “ TH I S N O TI C E D E S C R I B E S H OW ME D IC A L I N F O R MA TI O N A B O U T YO U MA Y B E U S E D A N D D I S C L O S E D A N D H O W YO U C A N G E T A C C E S S TO TH I S I N F O R MA TI O N . P L E A S E R E V I EW I T C A R E F U L L Y. ” b . I nd i vi d u al ' s ri g h ts . An i nd i v id u al ha s t h e r ig h t t o re q ue s t r es t ri c ti on s on c e r t ai n u s es a n d d is c l os u re s o f P H I , t he r ig h t t o r ec e i v e c o nf i de n ti al co m m un ic a tio n s o f P HI b y a l te r n at i v e m ea ns o r a t al t e rn a ti ve lo c a t io ns , th e ri g h t t o i ns pe c t a nd c o p y h is P H I , t he r ig h t t o am e nd h i s P H I , t h e r i gh t t o re cei v e a n ac c ou n ti ng o f di s c l o s u r es of P H I , a nd th e ri gh t to ob ta i n a pa p er c o p y of t he n o t ic e f r om th e c o ve re d e n t it y . c . C o ve r ed e nt i t y' s r e sp o n s ib i l it i e s. Th e n o ti c e m u s t i nc lu de a s ta t em e n t th a t t he c o ve r ed en t it y i s r eq u i red b y la w t o m a i nt a in th e p r i va c y o f P H I, a s ta t em e n t o f i t s l e ga l d u ti es an d pr i v ac y p r a c t ic es wi t h re s pe ct to P H I , a s ta t em en t th a t i t m us t a b id e b y t h e n ot ic e c u r ren t l y in ef f ec t , a nd a s ta te m en t th a t i t r es e r v es t he r ig h t t o c h an g e t he te r m s of it s no t ic e a n d h o w i t wi ll p ro v i d e i nd i vi du a ls wi t h a re v i s ed n o t ic e. d . M i s ce l la n e ou s c o n ten t s o f n o t ic e . Th e no t ic e m u s t c o n ta i n a s t at em e n t th a t i n di vi d ua ls m a y c o m p l ain t o t h e c o ve r e d e nt i t y an d to t he U . S. D e pa r tm en t o f H e al t h a n d Hu m a n Se r v i c e s i f th e y b el ie v e t he i r p r i vac y r i gh t s h a ve b ee n vio l at ed . Th e
n o t ic e m u s t s ta t e a d a te o n wh i ch it be c om es e f f ec t i ve . Th e ef f ec t i v e d at e m us t be n o la t e r t ha n t h e d at e o f t h e fi rs t s e r vic e d e li v e r y . e . P os t i n g o f n o t ic e . A p h a rm ac y m u s t p os t t h e n o t ic e i n a c le a r a n d p rom i ne n t l o ca t io n wh e re i t is r ea s o n a bl e t o e xp e c t i n di vi du a ls to be ab l e t o r e ad th e no t ic e. f . W r i t te n ac k now l e dg me n t o f n o t ic e . E v e r y c o ve r e d e n ti t y m u s t ob t ai n a wr i t t e n a ck n o wl e dg m e n t o f re c e ip t o f t he no t ic e b y t he ind i v i du a l. I f o ne is no t o b ta i ne d , t h e c o ve r ed en t it y m us t d oc u m en t i t s g oo d -f a it h e f f or t s to ob t ai n t h e ac kn o wl e d gm e nt a n d t h e r e as on wh y i t wa s no t ob t ai ne d . g . E xc e p ti o n s f o r in m ate s . A p e rs on in ca r c e r a ted i n o r o t he r wi s e c on f in ed t o a c o r re c ti on a l i ns ti t u ti on do e s n ot ha ve a ri gh t to no t ic e u n de r th e P ri v a c y R u l e , a nd t h e n o ti c e r eq u ir em e nt s d o no t a p pl y t o a c o r re c ti o na l i ns t i tu t io n t h at is a c o ve r ed e n t it y. 5 . “ Au t h o r iz a ti o n” fo r a c o v e re d e n ti t y t o us e or d is cl os e P H I: a p a ti en t m us t gi v e wr i t t e n au t ho r i z a ti on b efo r e a c o v e r e d e nt i t y , i nc l u d in g p h a rm ac ie s a nd ph a r m a c i s t s , m a y us e o r di s c lo s e P H I . N o p a ti e n t c on s en t o r a u t h o r iz a ti o n i s n ec es sa r y wh e n P H I u se an d d is c l os u re is f or t r ea t m en t , p a ym e n t , o r he a l th - c a re o pe r a ti o n s . Th i s a l lo ws a he a lt h -c a re p rov i d e r to c o ns ul t wi t h o t he r c o v e r e d e nt i ti es ( i. e ., o t h e r h e al t h -c a re p ro v i d er s ) t o p r o v i de pr o pe r pa t ie n t c a r e wi t h ou t b e in g u nd u l y h i nd e re d b y t h e Pr i v ac y R u l e. Fo r u s es a n d d is c l os u re s t h at r e qu i re an au t ho r i z a ti on , t he w r i t t en au t h o r iz a ti o n m u s t b e wr i t te n i n p la i n l an g u ag e , a nd a s ig n e d co p y m u s t b e p ro vi de d to th e i n di v id u al . Th e s ig n ed au t ho r iz a t i o n m u s t b e m a i nt a ine d b y th e c o ve r ed en t it y f o r 6 ye a r s f r om th e d a te of it s c r ea t i on o r t he da t e wh e n i t wa s l as t i n ef f ec t , wh i c he v e r is l at e r . Th e wr i t te n a u th o ri z a t i on m us t at le as t c o nt ai n th e f o l lo wi n g c o re el em e nt s a n d s ta t em e nt s : a . A d e s c ri p ti o n o f t h e i nf o r m a t io n t o b e u s ed or d i s c lo se d t h at id e nt i fi es t h e i n f or m at io n i n a s p ec i fi c a n d m ea n in g fu l f as h io n . b . Th e na m e o r o th e r s pe c if ic id e nt i fi ca t io n o f the p e rs on ( s ) , or c l as s o f p e r so ns , a u t ho r i z ed t o m a k e t he re q u es te d u se o r d is c l os ur e . c . Th e n am e o r ot h e r s pe c if ic id e nt i fi ca t io n o f the p e rs on ( s ) , or c l as s o f p e r s o ns , to wh o m t h e c o v e r e d e nt i t y m a y m ak e th e r e qu es t ed us e o r di s c lo su r e . d . A de s c r ip ti o n o f e ac h p u r po s e o f t he r eq u es ted us e o r di s c lo su r e . e . A n e xp i r a t io n d a te o r a n e xp i r a ti on e v en t th a t r e l at e s t o t he in d i v id u al o r t he p u r po s e o f t he us e o r d is c l os u re . f . S i gn a tu r e o f t h e i nd i v id u al an d da t e. I f si g ne d b y a pe r s o n al r ep r es en t at i ve , i t m us t al s o in c l ud e a de s c r i p ti o n o f s uc h r e p re s e n ta t i ve ' s a ut h o ri t y t o ac t for t h e i n di vi d ua l . g . Th e wr i t t en au t ho r i z a ti o n m us t c on t ai n t h e f ol lo wi n g st a t em en ts : ( 1 ) Th e in di v i d ua l 's r ig h t t o re v o k e t he au t ho r i z a ti o n i n wr i ti n g a lo n g wi t h t h e e xc e p t i on s t o t h e r i gh t t o r e v o k e an d a de s c r ip t ion o f h o w t h e i nd i v id u al m a y r e vo k e t h e a u th o r i z at i on . P.553
( 2 ) Th e ab il i t y o r in a bi li ty t o c o n di t io n t r ea t m e n t, p a y m e n t , e n ro ll m e n t, o r e l ig ib i li t y f o r be n ef i ts o n th e a u th or i z a t io n , b y s ta t in g e i th er t h at t he c o ve r ed en t it y c a nn o t
r e q ui r e a u th o ri z a t io n , o r t h a t i f t h e co v e r e d e nt i t y c an r eq u ir e a u th o r i z at i on , t he c o ns eq u en c e s t o t h e i nd iv i d u al o f h is o r he r re f us a l to s i gn t he au t ho r i z at io n . ( 3 ) Th e po t en t ia l f o r t h e d i s c lo s e d i n fo r m a t io n t o b e r ed is c l os ed b y th e rec i pi en t an d n o lo ng e r b e p r o te c te d by t h e P ri v a c y R ul e . 6 . “M in i m um ne c es sa r y. ” W he n us i ng or di s c lo si n g P HI o r wh e n r eq u es tin g P H I f r o m a no t he r c o v e r ed ent i t y , a co v e r e d e nt i t y m us t m ak e re as o na bl e e f f o rt s to li m i t P H I t o t h e m i ni m um ne ce s s a r y t o a c c o m p li s h t he i nt e nd e d p ur p os e o f t he us e , d i sc lo su r e , o r re qu es t . Th e m i ni m u m n ec es s a r y ru l e d o es n ot a pp l y t o d i s c l os u r es o r r eq u es ts b y a h ea lt h -c a r e pr o v i de r fo r t re a tm ent , us es o r d isc l os u re s m a d e p u r su an t to an au t ho r i z at i o n, an d u s e s o r di s c lo su r e s t ha t a r e re q ui r ed b y l a w. “ R e q ui r e d b y la w” m e an s a m a nd a te in a l a w t h at c om p el s a n e n ti t y to m a k e a u s e o r di sc l os ur e of P H I . I t in c lu d es a c o ve r ed en t it y ' s co m p li a nc e wi t h s t a te a n d f e de r al l a ws a nd r eg ul a ti o ns th at r e qu i re t he pr o du c ti on o f in f o rm at i on ; c ou r t o r de r s a n d c o u rt - o rd e r ed wa r r a nt s , s u bp o en as o r s u m m on s is s u e d b y a c ou r t , a go v er n m en t al o r t r ib al in s p ec t o r g en e ra l , o r an ad m i ni s t ra t i ve bo d y a ut h o ri z e d t o re q ui re t he p r o du c ti on o f i nf o rm a ti on a n d Me d i c a re c o nd i ti ons o f p ar t ic ip a ti o n wi t h r es p ec t t o h e al t h -c a re p ro v i d er s p ar t i c i pa t in g i n th e p r og r am . 7 . “ Bu s i ne ss as s oc i a tes . ” A b us in es s as so c i a t e o f a c o ve r e d e nt i t y i s a p e r s o n o r b u si n es s t ha t p e r fo rm s a f u nc t io n o r a c ti vi t y on be h al f of t he c o v e r ed en t it y , s uc h a s c l ai m s p r oc es s i n g, bi l li ng , u ti li z a t io n re vi e w, q ua l i t y as s u r an c e , et c . , an d t h a t r e q ui r es th e u s e o r d is c lo s u re of in d i v id ua l l y i d en t i fi a bl e h ea l th in f o rm at io n . A b u si n es s as s o c i a te wo u ld a ls o i nc lu d e p er so n s wh o p ro v i de s e r vi ce s t o t he c o v e r e d e n t it y, a nd t he s e r v ic e i nv o l v e s d is cl o su r e o f i nd iv i d u al l y id e nt i fi a bl e h e alt h i n f or m at io n , s uc h a s l ega l , a c tu a ri al , acc o un t in g , c on s u l ti n g, da t a a gg r e ga t i on , m a na g em en t , a dm in is t r at i v e , ac c r e di ta t io n , o r fi na n ci al se r v i c e s. E xc l u ded f r om th e d e f in i ti on o f b us in es s as s oc i at es a re m e m b e rs of t h e wo r k f o rc e o f th e c o ve r e d e n t it y, a nd fu nc t io ns o r s e r v i c es th a t d o n ot r eq uir e di sc l os ur e of in di v i d ua l l y i d en t i fi ab l e h ea l th in f or m a t i on . a . B u si n es s a s so c ia t e c o n t r ac t s . E v e r y b us in es s a ss oc ia t e m us t e nt e r in t o a n a g r ee m e n t wi t h t he c o v er e d en t it y t o e ns u re c o m p l ia nc e wi t h t h e P r i v ac y R u l e . G e n e r al l y , th e a g re em e nt m us t e st a bl is h t h e r eq ui r e d u s e s a nd di sc lo s u r es o f P H I b y t h e b us in e s s a s s oc ia te a nd r eq ui r e t h e r e tu r n o r d es t ru ct i on of P H I a t te r m in a ti on o f t he c o nt r ac t . B . Ad d i t i o n al r e sp o ns ib i l i t ie s o f co ve r e d en t i ti e s . E v e r y c o v e re d e n ti t y m us t c r e at e p o li c i es an d p r oc e d u re s f o r c om pl i an c e wi t h t he P ri v a c y R ul e , m u st d es ig n at e a p ri va c y o ff ic ia l re s p o ns i bl e f o r c r ea t in g s uc h po l ic ie s a nd p ro ce d u re s , m us t d e si g na t e a c on t ac t p e rs o n o r o ff ic e th a t is r es pon s ib le f o r r ec ei v i n g co m p l ai n ts an d t h a t i s a bl e t o p r o v id e fur t h e r i n fo rm a ti o n a bo u t m a t te rs co v e r e d b y th e no t ic e , a nd m us t t ra in al l m em be r s of i ts wo r k fo r c e wi t h re s pe c t t o t h e P r i v ac y R u le . E v e r y d e si g na ti o n m us t b e m ain t a in ed b y th e c o ve re d en t i t y fo r 6 ye a rs f ro m t h e d a te it l a st wa s in ef f ec t . L as tl y , e v e r y c o ve r e d e nt i t y m u s t h a v e a n d a pp l y ap p ro p r ia t e s a nc ti o ns ag ai ns t m em be r s o f i t s wo r k f o rc e wh o f a i l t o c o m pl y wi t h th e P ri va c y Rule. C . S t a t e l aw p r i va c y r u l e s . Th e f e de r al P ri va c y R u l e i s i nt e nd e d as t he m i ni m u m r e q ui r em e nt fo r p ri v a c y s t a n da r ds . I f a s ta t e l a w is m o r e s t ri ng e nt , th e n a c o v e r ed
e n t it y m us t f ol l o w t h at s ta t e ' s p r i v ac y s t a nd a rd s . I f a s ta t e p r i vac y l a w is n o t a s s t r in g en t , t he f ed e ra l P riv a c y R u l e p re e m p ts an y c o nt r a r y s t a te la w a n d a c o v e r ed e n t it y m us t a bi d e b y t he f e d e ra l P r i vac y R u l e. D . P e n al t i es f o r vi o l a t io n o f th e P ri va c y R u l e . A n y p e rs o n wh o vi o la t es t h e P r i va c y R ul e m a y no t b e f i ne d m o re th a n $ 10 0 f or e ac h v io l at i on up to a to t a l o f $ 2 5 ,0 0 0 p er c a le n da r y ea r f o r a ll vi ol at i on s o f a n i d en t ic al re q ui r em e nt . Ad d i ti on a l p e n al ti es m a y b e im p os ed f o r t he f ol lo wi n g w r o ng f u l di s cl o su r e of in d i v id u al l y i d en t i fi ab l e h ea l th in f or m a t i on : 1 . W ron gf u l o bt a in m e n t o r di s c l os ur e of P H I : f in ed n ot m o r e t ha n $5 0 ,0 00, i m p ri so ne d n o t m or e th an 1 y ea r , o r bo t h . 2 . W ron gf u l o bt a in m e n t o r di s c l os ur e of P H I u nde r f al se p re t en s e s : f in ed n o t m or e t h a n $ 10 0 ,0 0 0, im p ri s o ne d no t m o re th a n 5 y e ars , or bo t h . 3 . W ron gf u l o bt a in m e n t o r di s c l os ur e of P H I c om m i tt e d wi t h i nt e nt to se ll , t r a ns fe r , o r us e s am e f o r c om m e rc i al ad v a n ta g e, pe r so n al g a in , o r m a li ci ou s h a rm : f i ne d n o t m o r e t ha n $ 2 50 , 00 0 , im pr i s on ed no t m o r e t ha n 10 ye a rs , or bo t h . P.554
VIII. NARCOTIC TREATMENT PROGRAMS. Me t h a d o n e us e i s c ur r e nt l y a ll o we d as p a r t o f a to t a l t r ea tm e nt p ro g r am fo r n ar co t ic a d di c ti on . R eg u la t io ns c o n c e r ni n g m e t ha d on e tr ea t m e n t p r og r am s h a ve be e n j oi n tl y e s ta b li sh e d b y th e D E A a n d F D A . N a rc ot ic - de p en d e nt in di v i d ua ls a re th os e wh o p h ys io l og ic al l y ne e d h e ro i n o r a m o r ph i ne - li k e d ru g to p re v e n t t h e o ns et o f s i gn s o f wi t h d r a wa l . A. D e f i n i t i o n. A n a rc o ti c t r e at m e n t p r og r am is a n o r g an i za ti on t ha t a dm i nis t e rs or d i sp e ns es a na r c o t ic d r ug t o a na rc o ti c a d di c t fo r m ai n te n an c e o r d et o xi f ic a ti o n t r e a tm en t , a nd p ro v i d es , wh e n a pp r o pr i at e o r ne ce s s a r y , a c o m p r e he ns i v e r a n ge of m e di ca l a n d r eh a bi li t a ti v e s e r v i ce s . Th e p ro g ra m m u s t be : 1 . A pp r o v e d b y t he F D A 2 . A pp r o v e d b y t he ap p ro p r ia t e s ta t e a ge nc y, usu a ll y t h e s ta t e 's D ep a r tm e n t o f P u b li c He al t h o r eq ui v a le n t 3 . R eg is t e re d u n de r th e F e d e ra l C o n tr o ll e d S u bs ta n ce s A c t wi t h t he D E A to us e a n a r co t ic d r u g f o r t he t re at m en t of na r c o t ic a d di c t io n B . D e t o xi f i ca t i on t r ea tm e n t i s d ef i ne d a s d is pen s in g o f n a rc o ti c d r ug s in d e c re as in g d o s e s t o a n in d i v id u al to al l e v ia t e a d ve r s e p h ys i ol og ic a l o r p s yc h ol o gi ca l e f f ec ts in c i d en t to wi t h dra wa l o f n a rc o ti c d r ug us e . D e to xi f i c at i on is fo r a p e r io d n o t i n e xc es s o f 1 8 0 d a y s . C . M ai n t en a nc e t re a t men t is t he di s p en s i n g o f a n a r co t ic d r u g, at r el a ti vel y s t ab le d o sa g e l e v el s , in th e t rea t m e n t o f a n i n di v i du a l fo r d ep en d en c e on he r o in o r ot h e r m o r ph in e - li k e dr u g. D . R e q u i re m en t s t o adm i t pa t i en t s i n t o a p r ogr a m . In ge n er a l, f or a p at i e nt to b e a d m i t te d i n to a c om pr e he n s i v e m a in t en a nc e p r ogr a m , t he f ol lo wi n g r eq ui re m en ts m us t be m e t :
1 . A p r o g ra m p h ys ic i an m us t de t e rm i n e t h at th e p e r s o n i s c u r r en t l y ph ys io l og ic a ll y d e p en de n t o n a na r c o t ic d r u g a nd be c am e p h ys i olo g ic al l y de p en d en t a t lea s t 1 y e a r b e f o re ad m i s s io n t o th e p r o g ra m . 2 . Th e pa ti e n t m u s t ha v e v o l u nt a r il y c h os e n t o p ar t i c i pa t e i n t h e p r og r am a n d m us t s i gn a “ C o ns en t to Me t ha d o ne Tr e a tm en t ” (p r o v id e d b y t he F D A ) a f te r bei n g c le a rl y a n d a d eq ua t el y i n fo rm e d a b ou t th e u se of m e t ha do n e . E . T ak e - ho m e m e th a don e . Ta k e - ho m e m e t ha d on e m a y be gi v e n on l y to p a t ie n ts wh o , i n th e c li ni c a l j u dgm e nt o f t he p ro g ra m p h ys ic i an , a r e re s p o ns ib le in h an dl i ng n a r co t ic d r u gs . Th e pa t ien t m u s t co m e to th e c li n ic f or ob s er va t io n d a il y o r a t l e as t 6 d a ys a we ek . O v e r ti m e , t he pr o g ra m p h ys ic i an m a y re d uc e c li ni c a l o bse r va t i on s t o on ce we e k l y . Me t h a d on e fo r ta ke - h om e us e m us t be di sp en s ed s im il a r l y t o th e d i sp e ns in g o f a n y s c he du l e I I c o nt r ol l ed s u bs t anc e a n d i nc lu d e t he t re a tm e nt c e nt e r ' s n am e, ad d r es s , a n d t e le p ho ne nu m b e r on i ts l a be l . P.555
STUDY QUESTIONS D i r e c t i on s : E a c h of t he n u m b e re d i t em s o r i nc om p le t e s ta t em en ts in t his se c t i on is f o l lo we d b y an s we r s o r by c o m p le t io ns o f t he s t a te m en t . Se le c t t he o ne l et t e r ed a n s we r o r c o m p l et i on tha t is be s t i n e ac h c as e. 1 . Al l o f t he f ol l ow i ng pr e s c r i pt i o n m ed i ca t i o ns m a y b e d e l i ve r e d b y m a i l t o t he p a t i en t vi a th e U . S. P ost a l S e r vi ce E X C E P T ( A ) p r oc ai n am id e ( B ) a m p ic il li n ( C ) h yd r om o rp h on e ( D ) d ia ze p am ( E ) a ll of t he ab o v e m a y b e de li v e r e d b y m a il V i e w A n s we r 1 . T h e a n sw e r i s E [] . 2 . W h ic h of th e f o ll ow i ng n a rc o t ic dr u g s h a s b e en a pp r o ve d b y t h e F D A f o r u se i n t h e t re a t me n t of n a rc o t ic add i c t i on ? ( A ) Mo r p h i n e ( B ) C o de i ne ( C ) Me t h a d o ne ( D ) H yd r o c o d on e ( E ) N o ne o f t he ab o v e V i e w A n s we r 2 . T h e a n sw e r i s C [] .3 . F o r t he U .S . g o ve r n me n t to p la ce a d r u g i nt o sc h ed u le I II , w h ic h of t h e f o ll ow i n g fi n d i ng s m u s t b e m a de c o n ce r n i ng t he d r u g? ( A ) Th e d ru g o r ot h e r s ub s ta nc e ha s a h i gh po t en t i al fo r ab us e . ( B ) A b us e o f t h e d r ug or o t h e r s u bs t an c e m a y l ead t o l im it e d p h y s i c a l d epe n d en ce o r ps yc ho l og ic al d ep en de n c e r el a ti v e to th e dr u gs o r o th e r s ub s ta nc es in s ch e du l e IV. ( C ) Th e d r ug or o th e r s ub s ta nc e ha s n o c u r r en t l y a c c ep t e d m e d ic al us e i n t r e at m e n t i n th e Un i te d S ta t es .
( D ) A b us e o f th e d r ug o r o t h e r su bs t an c e m a y l ead t o m od e ra t e o r l o w p h ys ic a l d e p en de nc e o r hi g h ps y c h o lo g ic al de p en de n c e . ( E ) Th e r e i s a l a c k o f a c c e pt e d s af e t y fo r u s e o f t h e d r u g o r o t he r s u bs tan c e u nd e r m e di ca l s up e r v is io n . V i e w A n s we r 3 . T h e a n sw e r i s D [] .4 . Un d e r th e F e d e ra l C o nt r o l le d S u b s t an c es Ac t , al l o f th e f o ll ow i ng i t em s m ust a p pe a r on a c o nt r o l led s u b s ta n ce p re s c r ip t i on l a b el E X C E P T t h e ( A ) n am e , a dd r es s , an d D E A n um b e r o f t he ph a rm ac y . ( B ) n am e o f t h e p at i en t . ( C ) n am e o f th e p r es c r i bin g p ra ct i ti o ne r . ( D ) s e ri al nu m b e r a s s ig ne d to t he pr e sc ri p ti o n. ( E ) d a te of th e i n it i al fi ll in g of t he pr e s c ri p ti o n. V i e w A n s we r 4 . T h e a n sw e r i s A [ an d] .5 . U nd e r t h e Fe d e ra l C o nt r o l le d S u b s t an c es Ac t , al l o f th e f o ll ow i ng e nt i t i es mu s t r eg i s te r w i t h th e DE A EXCEPT ( A ) p r es c r i be r s o f c o n t rol l ed s u bs t an c e s . ( B ) p ha r m a c i s t s wh o d is p e ns e c on t r ol le d s u bs tan c es . ( C ) d is t ri b u to rs o f c o n t rol l ed s u bs t an c e s . ( D ) i m p o r te rs o f c o n t ro lle d s u bs t an c e s. ( E ) u ni ve r s i t ie s c o n du c tin g in s t r uc t io n al ac ti v i t ies wi t h c o nt r o ll ed su bs t anc es li s te d i n s ch e du l es I I - V . V i e w A n s we r 5 . T h e a n sw e r i s B [ an d] .6 . U nd e r t h e Fe d e ra l C o nt r o l le d S u b s t an c es Ac t , w h ic h o f t h e f o l low i n g s t a te me n t s c o nc e r n in g th e e me r g e nc y d i s pe n s in g of a s c he d ul e I I c o nt r o l le d su b s ta nc e is t r u e? ( A ) Th e p ra c ti ti o ne r wh o a u t ho r i z es th e o r al p re sc r i p ti o n m u s t, wi t h in 7 d ay s , d el i v e r a wr i t t e n p r es c r i pt i on to t h e d is p en s i n g p ha r m a c is t . ( B ) Th e q ua n ti t y p re s c r ibe d an d d is p en se d m us t be l im it e d t o t he am o un t ne c es sa r y t o ad e qu a te l y t re a t t h e pa t i en t d u ri n g t h e em e rg en c y pe r i od . ( C ) I t i s n o t r e as on a bl y po s s i bl e f o r t h e p r ac ti t io ne r t o p r o v id e a wr i t t en p re s c r i pt i on t o be p re s e n te d to th e pe r s on di s p en si n g t h e con t r ol l ed su bs t an c e be f o re t he d i sp e ns in g . ( D ) N o ap p r op r ia t e a lt e rn a t i v e t r ea tm e nt is a v ai la b le , in cl ud i ng ad m i n is t ra t i on of a c o nt r o ll ed s u bs t an c e th at i s n ot in s ch e du l e I I . ( E ) A l l o f t h e a bo v e s t a te m en ts a re t ru e . V i e w A n s we r 6 . T h e a n sw e r i s E [] . 7 . Un d e r t h e F e d e ra l C o nt r o l le d S u b s t an c es Ac t , t he c r im e t r an s f e r w a r n i ng , “ C a u t i o n : F ed e r al l aw p ro h i b i ts t he t r a n s f e r o f th i s d r u g t o a n y p e r s o n o th e r t ha n th e pa t i e nt f o r w ho m i t w a s p r e s c r ib e d, ” m u st a pp ea r o n th e p r e sc r i p t io n c o n t ai n e r l a be l of a ll co n t r o l le d s u b s ta n ce s E X C E PT ( A ) sc h ed ul e II c o n tr o ll ed s u bs t a nc es . ( B ) sc h ed ul e II I c o nt r ol l ed s u bs t a nc es . ( C ) sc h ed u le I V c o n t ro l led s u bs t a nc es . ( D ) sc h ed u le V c on t r ol led s u bs t a nc es . V i e w A n s we r 7 . T h e a n sw e r i s D [] .P . 55 6
8 . W hi c h o f th e fo l l ow in g s ta t e me n ts c on c e rn in g d r u g r e ca l l c l as s if i ca t i o n i s true? ( A ) A C la s s I r e c a ll is a s i tu a ti o n i n wh i c h us e of , o r e xp o su r e t o , a v i ol a tiv e p r o du ct i s n o t l ik el y t o c au s e ad v e r s e h ea l th c o ns eq u en ces . ( B ) A C la s s I r e c a ll is a s i tu a ti o n i n wh i c h us e of , o r e xp o su r e t o , a v i ol a tiv e p r o du ct m a y ca us e t em p o ra r y o r m e di c a ll y r e v e r s i bl e a d ve r s e h ea l th c o ns eq u en c es o r i n wh i c h th e pr o ba b il it y o f s e r io us he al t h c on se q uen c e s i s re m o t e. ( C ) A C l as s I re c a ll is a s i tu a ti o n i n wh i c h t he r e is a r e as on a bl e p r ob a bi li ty t h a t t h e u s e o f , o r e xp o s u r e t o, a v i o l at i ve p r o du c t wi l l c au s e se r i ou s a d v e rs e h eal t h c o ns eq u en c e s o r d e at h . ( D ) A C l as s I I r ec a ll is a s i tu a ti o n i n wh i c h us e of , o r e xp o s u r e t o , a vi ol a tive p r o du c t is no t l ik e l y to c a u s e ad v e r se he a lt h c ons e qu e nc es . ( E ) A C la s s I II r ec al l i s a s i tu a ti on in wh i c h t he r e i s a r ea s o n ab le p ro b ab il it y t h a t t he u s e o f , o r e xp o s u r e t o, a v i o l at i ve p r o du c t wi l l c au s e s e r i ou s a d ve rs e h eal t h c o ns eq u en c e s o r d e at h . V i e w A n s we r 8 . T h e a n sw e r i s C [ an d] .9 . U nd e r t h e Fe d e ra l Fo o d , D r u g, a n d C os m et i c Ac t , a l l of t h e fo l l ow in g s t a te m en t s a re c on s id e r ed a m is b r a n di n g o f a d ru g E X C E PT i f ( A ) t h e la b el i ng is f a ls e o r m i s l e ad in g i n a n y pa r ti c ul a r. ( B ) a n o r al c o nt r ac e pt i v e i s d is pe ns e d wi t h o u t t he r e q ui r ed pa t ie n t p ac ka ge i ns e rt . ( C ) t h e d r ug is a n i m i t at io n of an o th e r d r u g, o r i f i t is o f f e re d f o r s al e u nde r t he n a m e of an o th e r d r u g. ( D ) t h e d r ug c o ns is ts in wh o l e o r i n p a rt o f a n y fil t h y , pu t ri d , o r d e c o m p os e d s u bs ta n c e . V i e w A n s we r 9 . T h e a n sw e r i s D [] .1 0 . Al l o f t he f o l l ow in g o ra l m e d ic a tio n s a r e ex e mp t f r om ch i l d - re s i s ta n t p a ck a gi n g E XC E P T ( A ) a nh y d r o us c ho l es t y ra m in e i n p o wd e r fo r m ( B ) n it r o gl y c e ri n p r ep a rat i o ns i n s us t ai ne d re l ea s e f o rm ( C ) c ycl ic a ll y a dm in is t e re d o ra l c on t ra c ep ti v e s i n m an u fa c tu r e rs ' m n em oni c ( m em o r y - ai d ) d is p en s e r p a c k ag es t ha t re l y s o le l y u p on th e a c ti vi t y o f o ne o r m o r e p r o ge s to ge n or es t ro g en s ub s ta nc es ( D ) p a nc re l ip as e p r ep a r at i o ns i n t a bl e t, ca ps u le , o r p o wd e r f o rm th a t c on ta i n n o o t h e r p re s c r ip t io n m ed ic a t i on V i e w A n s we r 1 0 . T he a nsw e r i s B [] .P . 55 7
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is E [ V ] . N a r c ot ic s a nd c o n t ro ll e d s u bs ta n ce s i n sc he d ul es I I - V m a y be de l i v er e d t o t h e p a t ie n t b y m a il . Th e U. S . P o s ta l S e r vic e n o l o ng er p r oh i bi ts t he m a il in g o f n a rc o ti c s b y a ph y s ic i an or ph a rm a c is t ( p u rs ua n t t o a pr e sc r i pt io n ) to th e p a ti e nt . 2 . T he an sw e r is C [ V I I I; V I I I. A ; I. I . 2. c .( 2 ) ].
Me t h a d o n e is ap p r o v ed b y t h e F D A fo r us e i n t he t r ea tm e nt o f n a rc ot ic ad d ic t io n . O n l y a p ro pe r l y r eg is t e red n a rc ot ic t re a tm en t pr og r a m m a y d is pe ns e m e tha d o ne fo r m a in t en a nc e o r d e to xi f i c a t i on t re a tm en t . Ph a rm ac i es th a t a re n ot s o re g is t e r e d m a y o n l y di sp e ns e m e t ha d one f o r s e ve r e p a in . 3 . T he an sw e r is D [ I . A .3 ] . To p l ac e a d ru g i n to s c he d ul e II I , t h e U . S . g o v e rn m en t m us t m ak e t h e f oll o wi n g f i n di ng s c on c e r ni n g t he d r u g : ( 1 ) i t h as a p ot e nt ia l fo r ab us e l es s t h an the d r ug s o r o t h e r su bs t an c e s i n s c h ed u le s I an d II ; (2 ) it ha s a cu r r en t l y acc e pt e d m ed i c a l u se i n t re a tm en t i n th e Un i ted S t at e s ; an d (3 ) a b us e o f t he dr u g m a y l e ad to m o de r a te or l o w p h ys ic al de p en d en c e o r hi g h ps y c ho l og ic al dep e n de nc e . 4 . T he an sw e r is A [ I . I .8. c . (1 ) , (2 ) , (3 ) , (4 ) , (5 ) , (6 ) a nd (7 ) ] . A p h ar m ac y ' s D E A n um be r is no t re q ui r ed to a ppe a r on th e m ed ic a ti o n c on t a in e r l a be l d is p en s e d to th e pa t i en t . 5 . T he an sw e r is B [ I . B .2 . a , b , c , d , e , f, g , h , i , j a n d k ; I . B .9 . d] . A g e n ts a n d em p lo y e es of D E A r eg is t r an ts , s uc h a s p h a rm ac is ts , a r e e xe m p t f r om r e g is t er i ng wi t h th e D E A. P h a rm ac i es , n ot t he in div i d u al ph a rm ac is t s, m u s t r e gi s te r wi t h t h e D E A. 6 . T he an sw e r is E [ I . I. 4. a , b] . E m e r ge nc y d is pe ns i ng of a n o r al s c h e du l e I I c on tr o l le d -s u bs ta nc e p r es c rip t i on m us t b e do n e i n s t r ic t c om p li an c e wi t h t he la w. B e f o re d i sp e ns in g s uc h a p r es c ri p t io n , t he p h a rm ac is t m us t m ak e t he t h re s h o ld de t er m i n at i on t ha t AL L th r ee f ac to r s t h a t d e fi ne a n em e rg en c y s i tu a ti o n (s e e I . I. 4 .a ) a re p re se n t. I f a n y o n e o f t h e t h re e f ac t o rs i s a b se n t, t he p re s c ri p ti o n is no t fo r an em e rg en c y s i t u at i on , a n d a wr i t te n p re s c r i pt i on m us t be p re s e n te d t o t h e p h a rm ac is t . 7 . T he an sw e r is D [ I . I .8. c . (7 ) ] . Th e f e de r a l c ri m e t ra ns fe r wa r n i ng la b el is n o t r eq u i re d to ap pe a r o n t h e p r e sc ri p ti o n c on t ai ne r lab e l o f s c h ed u le V c on t r oll e d s ub st a nc es . 8 . T he an sw e r is C [ I I . H. 2 . a , b a n d c ]. A C l as s I r ec al l i s a s it ua t i on in wh i c h th e r e is a r e a s o na b le p ro ba b il i t y tha t t he us e o f , or e xp o s ur e to , a v i ola t i v e p r o du ct wi l l c au s e s e r io us ad v e r se he al t h c o ns eq u en c e s o r d e at h . 9 . T he an sw e r is D [ I I . I.1 , 2 ]. Th e F e de r al F oo d , D r u g, a n d C o s m et ic Ac t s t a te s t h a t a d r ug is c o ns id e red a d ul t e ra t ed i f i t c o ns is t s i n wh o l e o r i n p a rt o f a n y f i lt h y , pu t ri d , o r de c o m po s ed s u bs ta n c e . Th e t e rm s “ m i s b ra nd i ng ” an d “ a du l te ra t i on ” ar e o f t en re f e r re d t o in l i t er a tu r e a n d c a s e la w a s be i ng th e s am e o r s im il a r v io l at i on s u nd e r t h e la w. H o we ve r , t h e Ac t s et s f or t h s p ec if ic in s ta nc es of a d ul t e ra t io n a n d sp ec i fi c i ns t an c e s o f m i sb r an d in g . 1 0 . Th e a n sw e r i s B [ I II .A . 1 ] . O n l y s ub li n gu a l d os ag e fo r m s of ni t r og l y c e r i n a re e xe m p t f ro m ch i ld - r es is ta n t p a ck ag i ng .
26 Reviewing and Dispensing Prescription and Medication Orders T o d d A. B r ow n
I. DEFINITIONS A. P r e s c r i p t i on s a r e o rd e r s f o r m e d ic at i on s, non d r ug p ro d uc ts , a n d se r v i c es th a t a r e wr i t t en b y a li c e ns e d p r ac t it i on e r o r m id l e v el p r a c t i ti o ne r wh o i s a u th or i ze d b y s t a te la w t o p re s c r ib e (s e e A pp en d i x A ) . P ha r m ac is t s a r e in c re as i ng l y be in g gi ve n p r e sc ri b in g p r i v il e ge s b y e n ac tm en t of s t a te co l la b o r a ti ve d r u g t h e r ap y m a n ag e me n t ( C D T M) l e g i s l a ti on . Th is al l o ws p ha r m ac is ts to c h an g e t he d o s e of e xi s t i n g m e d ic at i on s o r or d e r n e w m e di ca t io n u nde r es t ab l is he d p r ot o co ls o r g u id e li n es a g re e d o n b y t h e p h a rm ac is t a nd ph ys i c ia n . P r ac t it i on e rs m a y p r e s c ri b e o n l y m e di c a t io ns th a t a re wi t h i n t he i r s c o pe o f p ra c ti c e . P re sc r ip t io ns m ay b e wr i t t e n , p r es e nt e d o r al l y ( b y t e le p ho ne ) , o r p re s en t e d e le ct r o ni ca ll y ( i .e . , vi a f a x o r c om p ut e r n e t wo r k ) t o t h e p h a rm ac is t . Th e r eq ui r em e nt s o f t h e p r es cr i pt i on f o rm i n cl ud e s ec u ri t y f ea t u re s a n d t am pe r - r es is t an t c ha r a c t e ri s ti cs a n d v a r y wi t h s t a te r e g ul a ti o ns . Th e p re s c r ipt i o n s e r ve s a s a veh ic l e f o r c om m un ic a ti on f ro m th e p r e sc ri b e r t o t h e p ha rm ac is t ab ou t th e n e ed s o f th e pa t ie n t. Th e fo ll o wi n g i n f or m at io n s h ou ld be inc l ud e d o n a p r es c ri p ti on : 1 . P a ti e n t i n f o rm a t io n , in c lu di n g f ul l n am e a n d ad d r es s 2 . D a te on wh i c h t he p res c ri p ti o n wa s is s u e d 3 . N am e a n d d o sa g e f o rm o f th e p r o d uc t . Th e na m e c a n b e an y o f t he f ol l o wi n g: a . P r op r ie t a r y (b r an d ) b . N o np r op r ie t a r y (g e ne ri c ) c . C he m i c a l 4 . P r o du c t s t r e ng t h . The s tr e ng t h o f t h e p r od uc t i s n o t r eq u i re d i f o n l y on e s t r en g th i s c om m e r c i al l y a v ai l ab le o r i f th e p r od uc t c o nt a in s a c o m b in a ti o n o f a c t i ve i n g re d ie n ts . I t i s a d v is a bl e to in cl u de th e s t re n gt h t o re d uc e t h e ch a nc e o f m is i nt e r pr e ti n g t he p re s c r i p ti o n. I f t h e d os e is to b e c a lc ul a te d b y t h e p har m ac is t , t h e n t he ph a rm ac is t c a n d e c i d e t he s t r en g th o f t he p r od uc t d is p en s e d a f ter c a lc ul a ti ng t he pa t ie n t 's d o s e . 5 . Q u a nt i t y t o b e d i s pen s e d. Th i s s h o ul d i nc lu de t he am ou n t a nd t he un it s of m e as u re ( e. g ., g ra m s , ou n c e s , t ab le t s ). I f t he am o un t i s n o t sp ec i fi e d, th e di r ec t io ns s h ou l d s p ec i f y th e d os e to b e t ak en an d th e d u ra ti o n o f t h e ra p y so th a t t he p h a rm ac is t c an c a lc ul a te t h e q ua n ti t y r eq u i re d f o r t h e p a ti en t . 6 . D i r ec t i on s fo r t h e p ha r m a ci s t . D i r ec ti o ns m ay b e r eq u ir e d f o r : a . P r ep a ra t io n (e . g. , c om p o u nd in g ) b . L ab el i ng (i . e ., in f o rm at i o n t o b e p u t o n t he p res c ri p ti o n l ab el ) 7 . D i r ec t i on s fo r t h e p at i e n t . Th e se s h o ul d i nc lud e e xp l ic i t i ns t ru c t i on s on t he q u a nt i t y , s c h ed ul e , a n d d u r a ti on f or p ro p er us e . “ A s D i re ct e d ” s h o ul d b e a v o i d ed . I f t h e d i r ec ti o ns v a r y , a m in i m u m a nd m a xi m u m d os e c an b e us e d. 8 . R e f il l in f o r ma t i on . If r e f il l i n fo r m a t io n i s n ot s u p pl i ed , i t is g e ne r al l y as s u m ed t h a t n o r e fi l ls a r e a u th o riz e d . “ As ne e de d ” (p r o r e n a ta [ pr n ] ) r e fi l ls a r e u su a ll y
i n t er p r et e d as al l o wi n g fo r r e fi ll s f o r 1 y e ar u nl es s la ws o r re g ul a ti o ns re s t r i ct t he a m ou n t o r t im e p e r io d i n wh i c h a p re s c r ip t io n i s va l id . 9 . P r es c r i be r i n fo r m a tio n . Th is s h ou l d i nc lu de th e na m e , o f f ic e a dd r es s, s ig n at u r e o f t he pr es c ri b e r, th e D ru g E nf o rc em e nt A dm in is tr a t io n ( D E A ) n um be r ( fo r c on t r ol l ed s u bs ta n c e s o nl y ) a nd the N a ti o na l P ro vi de r Id e nti f i er ( N P I ) n um be r . P.559
B . M ed i ca t i on o r de r s are o r de rs f o r m e d ic at i on s b y a n i n di v i d ua l a u th o ri ze d to p r e sc ri b e a nd a re in t en de d fo r us e b y p at i en ts wh i l e in an in s ti t ut io n al s et t i ng . Th e y m a y be wr i t t e n, p re s e n ted o r al l y (b y t e le ph o ne ) , o r p re s e n t ed el ec t ro n ic all y ( i . e. , v i a f a x o r c om p ut e r n e t wo r k ) t o th e p h ar m a c i s t. Th e m e di c a t io n o r de r ge n e ra ll y i nc l ud es 1 . P a ti e n t i n f o rm a t io n (e . g . , f ul l n am e , i de n ti f ic at i o n n um be r ) 2 . D a te a nd t im e t h e o r de r wa s wr i t t e n 3 . N am e of t he p r o du c t . Th e n am e c an be an y o f t h e f ol l o wi n g: a . P r op r ie t a r y (b r an d ) b . N o np r op r ie t a r y (g e ne ri c ) c . C he m i c a l 4 . P r o du c t s t r e ng t h , d os a g e, a nd r o ut e of a dmi n i s t r at i o n. Th e s t r en g th o f th e p r o du c t is no t re q ui r ed i f o n l y o n e s tr e ng t h i s com m e r c i a ll y a v a il ab l e o r if t h e p r o du c t c o n ta i ns a c o m bi n a ti on o f ac t i ve i ng r e di en t s . I t i s a d vis ab l e t o i ncl u de t he s t r en g th to r ed uc e th e c h a nc e o f m is in t e rp r e ti ng t h e o r d er . Th e p h a rm ac is t m a y d e ci d e t he s t r en g th o f t he p r od uc t d is p en s e d a f ter c al c u l at i ng th e p a ti e nt ' s do se . Th e d os a ge an d ro u te of a dm i ni s t r a ti o n sh o ul d be i n c lu de d to r ed uc e t h e c h an ce o f m is i nt e r pr e ti n g t he o rd e r a n d t o a ll o w f o r c o r re c t a d m i ni s t ra ti o n t o t h e p at ie n t . 5 . P r es c r i be r ' s s i gn a t u re . I f t he o rd e r wa s t ak e n v e r b a ll y, th e n am e of the p e rs on t r a ns c ri bi n g t he o rd e r s ho u ld be in cl u de d . 6 . D i r ec t i on s fo r t h e p ha r m a ci s t . Th e se c a n b e u s ed fo r : a . P r ep a ra t io n (e . g. , c om p o u nd in g ) b . L ab el i ng (i . e ., in f o rm at i o n t o b e p u t o n t he la be l ) 7 . I ns t r u c ti o ns f o r a d min i s t r a ti o n , i nc lu di n g q uan t i t y, ro u te of ad m i n is t rat i o n, s ch e du l e, an d d u r at io n of u s e
II. UNDERSTANDING THE PRESCRIPTION OR MEDICATION ORDER AND EVALUATING ITS APPROPRIATENESS A. U n d e r s t a n di n g t h e or d e r . A c om pl e te un d e rs t a n di ng o f a ll in f or m a t io n c on t ai n ed i n a p r es c r ip t io n o r m e dic a ti o n o r de r i s r e qu i re d . E a c h p ie ce of in f o rm at i on sh o ul d b e ap p ro p r ia t e a nd c o ns is t en t wi t h th e r em a in i ng i n f or m at io n (i . e. , th e i ns tr u c ti o ns f o r us e s ho ul d b e a p p ro pr i a te f o r t he m e di ca t io n b e in g o r d e re d ). Th e ph a rm ac is t s h ou l d r ea d th e e n ti r e p re s c r i pt i on or m e di c at io n o r d e r c a r e fu l l y t o de t er m i n e t h e p r e sc ri b e r 's in t en t b y i n te r p r et i ng th e fo ll o wi n g i nf o r m a t io n : 1 . Th e na m e an d a dd r es s o f b ot h t h e p a ti en t an d t h e p r es cr i be r 2 . Th e pa ti e n t 's di s e as e o r c o n di t io n r e qu i ri n g t r ea t m e n t
3 . Th e re as o n t h e o rd e r is in d ic at e d, r el a ti v e to t he m e d ic al ne e d o f t he pat i e nt ( e . g ., an an t ib ac t e ri a l f o r a n i n fe c ti on ) 4 . Th e na m e of th e p r o du c t , t he qu a nt i t y pr es c ri be d , a n d i ns t ru c ti on s f o r u s e 5 . A ll te r m i n ol og y , i nc lu di n g u ni t s o f m ea s u r e ( a po t h ec a r y , m et r ic , o r E ng li s h ) a nd L a t in ab b re v i a ti o ns (s ee A p p en d i x A f o r c om m o n a b b re v i a ti o ns ) B . E va l u a t in g th e a p p r op r i a t en e ss . C om pl e te inf o r m a t io n i s r e qu i re d o n t h e p r e sc ri p ti o n o r m ed ic a ti on o r de r to pr o vi de t he nec es s ar y i n fo rm a ti o n t o a ll o w t h e p h a rm ac is t to e v al ua t e th e ap p ro p r ia t en es s o f t he o r de r . W hen th e o r d er i s i n co m p l et e , t he ph a rm ac i s t m us t o bt a in th e re q uir e d i n f or m a t io n fr om ei t he r t he p a t ie n t o r t h e p r es c r i be r . Th e f ol l o wi n g s h o ul d b e c on s i d e re d d u ri n g a n e va l ua t io n : 1 . Th e pa ti e n t 's di s e as e o r c o n di t io n r e qu i ri n g t r ea t m e n t 2 . Th e pa ti e n t 's al le r gi e s o r h y pe r se ns i ti v i t ie s 3 . Th e ph a rm ac ol o gi c a l o r bi o lo g ic al ac ti o n o f t he p r esc r ib e d p r od uc t 4 . Th e pr es c ri b ed r ou t e o f ad m i n is t ra t io n 5 . W he t he r th e p r es c r i bed p r od uc t m ig h t r es u lt in a d ru g -d r u g, d ru g -d is e as e , o r d r u g -f o od in t e ra c t i on P.560
6 . W he t he r th e d os e , d os a ge fo r m , a nd do sa ge re g im e n a re s a f e a nd li kel y t o m e et t h e n e ed s o f t h e p at i en t 7 . W he t he r th e p a ti en t wi l l h a v e a n y di f fi cu l ti es ad h e ri n g t o t h e r eg im e n an d th e p o t en t ia l i m p ac t o n th e th e r ap e ut ic ou t c o m e de sir e d 8 . W he t he r th e t o ta l q u an t i t y of m e di c a t io n p r es c r i b ed is s u ff ic i en t to al low p r o p e r c om p le t io n o f a c o u rs e of t h er a p y 9 . W he t he r a ph y s ic al o r c he m i c a l i nc om p at i bi li t y m ig h t r es u lt ( i. e . , i f t he p r o du c t r e q ui r es e xt e m po r an e ous c o m p o un di n g ) 1 0 . W he th e r a l ic e ns ed pr a c ti t io n er , ac ti n g i n t he c o u rs e a nd s c op e o f p r ac t ic e , i ss u ed th e p r es c ri p ti o n in g oo d f a it h , f o r a le gi t i m a te m e di c a l p u r po se C . D i s co ve r i n g in a pp r op r i a t e p r e sc r i p ti o n s o r m e d ic a t io n o rd e r s . P h ar m ac is t s a r e re q ui r ed t o r e v ie w m e d ic a ti on p ro f il es t o e ns u r e th e a p pr o p ri a te ne s s o f p r e sc ri p ti o ns or m e di c a t io n o rd e rs . Th is i s c om m o n l y c a ll ed d ru g u t il i z a tio n r e vie w ( D U R ) . P h a rm ac is ts s h ou l d n o t f il l o r pr oc e ss p re s c r i pt i on s o r m ed ic a ti on o r de rs t h a t t h e y h a v e c on c er ns wi t h o r th a t a r e c on si de re d in ap p r op r ia t e b u t, r ath e r , s ho u ld c o nt ac t th e p r es c ri b er . Th e p ro c e s s o f c a ll in g a pr e sc r ib e r to di s c us s c o nc e r n s i d en t i fi ed du r i ng a D U R is c o m m on l y c a ll e d t h e rap e u t ic i n te r ve n t i on . 1 . W he n p e rf o rm i ng a t he r a pe u ti c i n te r ve nt i on , th e fo l lo wi n g i n fo r m a t io n s h ou l d b e p r o vi de d : a . A b r i ef de s c r ip t io n o f th e p ro bl em b . A re f e re nc e s o ur c e t ha t do c u m e n ts th e p r o bl em c . A d es c ri p ti on o f t he c li n ic al s i gn i fi c a nc e o f th e p r o bl em d . A s u gg es t io n o f a s o lut i o n t o t h e p ro b le m 2 . Th e fo ll o wi n g re s o l ut io n s a r e p os s i bl e t o s ol ve t h e p r ob l em o r c o nc e rn : a . Th e pr es c ri p ti o n o r m e d ic a ti on o rd e r wi l l b e d is p e n se d a s wr i t te n . b . Th e p re s c ri p ti o n o r m e d ic a ti on o rd e r wi l l n ot be d is pe ns e d.
c . Th e p r es c ri p ti on o r m e d ic a ti on o rd e r wi l l b e a lt e r e d a nd di s p en s ed . 3 . D oc um e nt a ti o n o f t he r e s ul ts of a t h e ra pe u ti c in t e r v e nt i on ar e re q ui r ed i f th e p r e sc ri p ti o n o r m ed ic a ti on o r de r i s c ha n ge d . Th e n a m e of t he pr e s c ri b e r, d a t e o f c om m u n ic at i on , i s s u es di s c us s ed , a n d r es ol u ti o n s h o u l d b e i nc lu de d i n the d o cu m e n ta t io n . Th i s i n for m a ti o n sh o ul d b e k ep t fo r t he s a m e ti m e pe r io d a s th e p r e sc ri p ti o n o r m ed ic a ti on o r de r . 4 . I f t he ph a rm ac is t fe e ls t h a t, in hi s o r h e r p r o fe s s i on al ju d gm en t , a n o r der i s i n ap p r op r ia t e a nd c o ul d h a r m t he pa t ie n t, t he pha r m ac is t s ho ul d n o t p r oce s s t he o r d e r. Th e ph a rm ac is t m a y a ls o b e re q ui r ed t o e xp l ai n th e s it u at i on to th e p a ti e nt . I f , af t e r a th e ra p eu t ic i n te r v e n t io n , t he ph a rm ac is t b el i e ves th e o r de r is s t il l i n ap p r op r ia t e , t he gu i de li n es of t he in st i tu t io n a n d p r of es s i o na l j ud gm e nt s h ou l d b e f o l lo we d .
III. PROCESSING PRESCRIPTIONS AND MEDICATION ORDERS r e q ui r es th a t t h e p ha r m ac is t fo ll o w a p p ro p ri a te gu i de l in es . An en vi r o nm en t t ha t l i m i ts di s t r ac t io ns an d d is r u pt i on s d u ri ng th e s e ac t i v i ti es wi l l a s s is t i n i nc r e a si ng t he a cc u r ac y o f t hi s p r oc es s . A u t om a ti on an d th e u se o f ph a rm ac y t ec hn ic i an s a l lo w t h e p h a rm ac is t to o v er s ee the s e f un c ti on s b u t s p e nd l e s s ti m e pe r fo r m i n g t hes e a c ti vi t ie s . Th e ti m e s a v ed a ll o ws th e p h a rm ac is t g r e a te r ti m e fo r pa t ie n t- fo c us ed a c ti vi t ie s , s u c h as c o un s e l in g a n d p at i en t e d uc a tio n . A. T h e f o l low i n g i n fo rm a t i on s h ou l d b e r ec o rd e d o n th e p r es cr i pt i on : 1 . Th e pr es c ri p ti o n n um be r ( f or in i ti a l f il li n g ) 2 . Th e or i gi na l d a te o f f ill i ng 3 . Th e pr o du c t a nd qu ant i t y di s pe ns ed 4 . Th e ph a rm ac is t ' s i ni tia l s B . P r o d uc t se l ec t i o n. Ge n e ri c s ub s t i tu t io n s t at u te s , a s we l l as fo rm u la r y a n d t h e r ap eu t ic s u bs ti t u ti on p o li c i es , m i gh t p r o vi de di r e c t io n i n p r o du ct se le c ti o n . C . P r o d uc t p r ep a r a ti o n f o r us e b y t he pa t ie n t. Th e fo l lo wi n g m ig h t b e n ec es s ar y f o r p r e pa r a ti o n: P.561
1 . O b ta i ni ng t he p ro pe r a m ou n t o f m ed ic a ti on t o b e di s p e ns ed 2 . R ec o ns ti t ut i on ( th e a dd i t io n o f l i qu id to m a k e a s ol u ti o n o r s us pe ns i on ) 3 . E xt e m p or a ne o us c om p o u nd in g (s ee C ha p te r 5) 4 . A s s em bl y o f t h e m e d ic a ti o n d el i v e r y un i t D . S e l ec t i on o f t h e p r op e r p ac ka g e o r c on t a ine r is r eq u i re d t o e ns u r e p r o du c t s t ab i li t y, to p ro m o t e p at ie n t c om pl i an c e , a n d t o c o m pl y wi t h le g al r eq ui r em e nt s . Th i s i n f or m at io n i s c om m o nl y f o u nd in th e Un i te d S ta te s Ph a r m ac o pe ia ( U S P ) . E . L a be l in g t he p re s c r ib e d p ro d u ct 1 . Th e p re s c ri p t i on la be l t y p ic al l y c o nt a in s t he f o l lo wi n g i n fo r m a t io n : a . N am e a n d a dd r es s o f t h e p h a rm ac y b . P a ti en t ' s n am e c . O r ig i na l d at e of fi l li ng
d . P r es c r i pt i on nu m b e r e . D i re c ti on s f o r u s e f . P r o du c t ' s b r a nd na m e o r g en e ri c n am e a nd m an u f ac tu r e r g . P r od uc t s t r en g th (i f av a i l ab l e i n m o r e t h an one s tr e ng t h ) h . Q u an t it y o f m ed ic a ti on d is pe ns e d i . P r es c r i be r ' s n am e j . E xp i r a t io n d a te o f t he m e di c a t io n k . P ha r m a c i s t ' s i n it i al s 2 . U n i t -d o se pa c ka g es c o nt a in on e d os e o r on e u n i t o f m ed ic a ti on . Fo r a m e di ca t io n o r de r th a t i s d i s p e ns ed in un i t - do s e p a c ka g es , th e l ab e l s h ou l d i de n ti f y t h e p r o du c t ' s b r a nd or ge n e ri c n am e , s tr e ng t h, lot n um be r , a n d e xp i r a t io n d a te . 3 . Au x i l ia r y a n d c a u ti on a r y l a b e l s . To e ns u re p r o pe r m e di c a t io n u s e , s t o r a ge , a n d c om p li a nc e wi t h ap p li c ab l e s ta t u te s , an d to re i nfo r c e i nf o rm a ti on p ro vi d ed d u ri ng c o un se l in g , a u xi l ia r y a nd/ o r c a ut i on a r y la be ls sh ou l d b e a f fi xe d wh e n a pp ro p r ia t e ( s e e A p pe nd i x A ) . 4 . F or m e di c a t io n i n s c he d ul e s I I -I V (s e e C h ap t er 2 5 ) , a f e de r al t r an s f e r wa r n i n g i s r e q ui r e d. F . R e co r d ke e pi n g a n d c o n f id e n ti a l i t y. Th e p h ar m ac is t i s re qu i r ed to m ai n t ai n p r e s c r ip t i on f i le s a n d re c o r ds in ac c o r da n ce wi t h s t a nd a rd s o f s ou n d p ra c ti c e an d s t a tu t or y r e qu i r em en ts . Th e i m p l em en t at i on of t he H e al t h ca r e In s u ra n ce P o r t a b i li t y a n d Ac c o u nt a b i l it y Ac t ( H I P A A ) h as p u t a dd i ti o na l r e qu i re m en t s o n a ll h e al t h p r o fe s s io na ls wh o h a v e a cc es s t o h e al t h inf o r m a t io n (s ee C ha p te r 25 ) . Th e r e c or d s in c l u de a p a t ie nt p r o f i le , c on t ai n in g p a tie n t d em o g ra ph ic in f o rm at i o n a nd a c om p le t e c h r o no lo g ic al re c o rd of al l m ed ic a ti o n us e a n d s er v i c e s p r o v id e d i n t h e d e li v e r y o f p h ar m ac eu t ic a l c a r e. 1 . Th e pa ti e n t p ro f il e s ho u ld c o n ta i n t he fo l lo wi n g p a ti e n t i n f o rm a t io n : a . P at i en t ' s n am e b . P a ti en t ' s a dd r es s (o r r o o m n um be r i n i ns t i tu t ion a l s et t in gs ) c . A n y k no wn a l le r gi es , s e n s i t i v it i es , o r h is t o r y of i d io s y nc r a ti c r e ac ti o ns to p r e v io us m e di ca t io ns d . B i rt h d a te ( i. e . , t o a s s e s s t he ap p ro p r ia t en es s o f t he do se ) e . C li n ic al c o nd i ti on ( s ) ( to h el p a s s es s t he ap p r op r i at e ne ss of t he m e di c at i o n a nd to p r e ve n t d r ug - di s e as e i n te r a c t i on s ) f . W eig ht ( to as s e s s th e a p p ro p r ia t en es s o f t h e do s e ) g . O cc u pa t io n ( t o d e te c t c o nd i ti on s a ss oc ia t ed wi t h a p a rt ic u la r oc c u pa t ion a nd to h e lp de t e rm in e i f th e p a ti e n t wi l l be ab le t o co m p l y wi t h t h e re gi m en ) h . N on p r es c r i pt i on m e di c a t i on us e ( t o p r e v en t d r ug - d r ug an d d r u g- d is ea s e i n t er a ct i on s , to as s e s s m e d ic a ti on e ff ec t i v en e s s , a n d t o d e te c t p oss i bl e ad v e r s e e f f ec ts ) 2 . I n a dd i ti on , th e p a ti e nt p r of i le s h ou l d c o n ta i n th e fo l lo wi n g i n fo r m a t io n f r o m e ac h p r e sc ri p ti o n o r m ed ic a ti on o r de r : a . N am e o f th e m ed ic a tio n b . Me d i c at i on s t r en g th c . D os ag e f o rm d . Q u an t it y d is p en s e d
P.562
e . D i re c ti on s f o r u s e f . P r es c ri p ti on nu m b e r g . D is p en s i ng d at e h . N um b er o f r e fi ll s a u tho r i z e d a nd r em ai n in g i . P r es c r i be r ' s n am e j . P ha r m a c i s t 's in i ti al s
IV. DISPENSING MEDICATION AND COUNSELING. Th e d is p en s i n g o f m e d ic a t i on r eq ui r es th a t t h e ph a r m a c i s t v e r if y t h at pa t ie n ts ha ve t h e n ec e s s ar y k no wl e d ge a nd ab il i t y to ad h e re to t he p re s c r ib e d t r ea tm en t . Th is wi l l i n c re as e t h e l ik el ih o od of o b ta in i ng th e d es i r ed ou t c o m e s . A. C o u n s e l in g pa t i en t s . Th e p ha r m a ci s t sh o ul d e v a l u at e t h e p at i en t ' s u n d er s ta nd i ng of ea c h m e d ic a ti on a nd s u pp l y ad di t i o n al in f o rm at i on wh e n t h e p a t ie n t 's in f o rm at i on i s in c o rr e c t o r i ns uf f ic ie n t. Th e p h a rm ac is t m i g ht n ee d to a d vi se pa t ie n ts re g a rd ing t he p ro p er do s ag e , a pp e a ra nc e , a n d n am e o f th e m e di ca t io n . I n fo rm a ti o n a b o ut th e ro u te o f a dm i ni s t ra t io n , i ns t ru c t i on s f o r u se , d u r a ti on o f us e , a nd t he r e a s o n t h e p r od uc t wa s p r e s c ri b ed m a y a ls o b e n e e de d . I n a d di t io n , t h e f ol l o wi ng t op i c s m ig h t a ls o b e a pp r op r i at e du r in g t h e co u ns eli n g s es si o n: 1 . S pe c ia l p r oc e du r e s. A s ap p r op r ia t e, t he ph a rm ac is t s h ou ld a d v is e p ati e n ts o n h o w t o t ak e t he m e di c at io n ( e. g ., on an em p t y s to m ac h, wi t h pl e nt y o f wat e r ) an d i n st r uc t th em on fo o ds to a v o i d wh i l e t ak i ng th e m e d ic a ti on ( e .g . , a lc oh o li c b e ve r ag e s , da i r y pr o du c ts ) . 2 . P o te n t ia l ad ve r s e e f fe c t s . Th e ph a rm ac is t s ho u ld en s ur e th a t p at i en ts a r e a wa r e o f t he po s s ib le ad v e r s e e f f ec ts as so c i a te d wi t h th e m e di ca t io n . P a ti e nt s s h ou l d u n d er s ta nd t he fo l lo wi n g: a . Th e f r eq u en c y o f a n a d v e r s e ef f ec t . Th i s wi ll h e lp pa t ie n ts r ec og ni z e c om m o n a d ve r s e ef f ec ts an d n o t b e o v e rl y c o nc e r ne d wi t h t h os e t h at a re r ar e . b . Th e se ve r i t y o f a n a dv e r s e e f f ec t. Th i s wi l l hel p pa t ie n ts fo cu s o n t ho s e a d v e rs e e f f ec ts t ha t a r e s e v e re an d no t th os e t h at a re in c o n s e q ue n ti al . c . W ha t ac t io n s h ou ld be t a k e n t o m a na g e o r m i ni m i z e th e a d ve rs e e f fe c t. Th i s wi l l h e lp pa t ie n ts de a l wi t h po s s i bl e a d ve rs e e f fe c ts in t he ap p r op r ia t e m a n ner . 3 . P r o pe r s to r a g e. Th e p h a rm ac is t s ho u ld c o un s e l pa t ie n ts o n h o w t o s t or e m e di ca t io ns p ro pe r l y t o e n s u r e s ta b il i t y a n d p ot en c y . 4 . O ve r - t h e -c o u n te r ( OTC ) p r o d u c t s. Th e ph a rm ac is t s h ou ld in s t ru c t pat i e nt s a bo u t t h e u se o f O TC p r o d uc ts t h a t m i g ht o r m i g ht no t b e ap p ro p r ia t e wh e n ta kin g a p r e sc ri b ed p ro d uc t. B . C o u n se l in g he a l th pr o f e s si o na l s . H e al t h p r of e ss io n al s ( i .e . , i n a n i ns t i t ut i on a l s e t ti ng ) m a y a dm in is t er m e di c a t io ns to pa t ie n ts . I n t he se c as es , th e p h a rm ac is t s h ou l d e ns ur e th a t t he he a l th p ro f es s i on al ha s s u f f ic ie n t k no wl e d ge t o ad m in is t e r t h e p r o du c t . In f o rm at i on t h a t h ea l th p ro f es s i on a ls wo u l d ne e d t o a dm in is t er m e di ca t io ns s a f el y a nd ef f e c t i v e l y i nc l ud e t h e f ol l o wi n g :
1 . Th e c h oi c e of a p a rt ic u l a r p r od uc t 2 . Th e pr o pe r do s a g e, do s ag e re gi m e n , a n d r ou te o f a dm in is t r at i on 3 . Th e c os t of th e p r es c ri b ed p ro d uc t a nd t he c ost s as s oc i at e d wi t h i ts u s e ( i .e . , a d m i ni s t ra ti o n c os ts an d c os ts o f t r ea t in g p os si ble a d ve rs e e f fe c t s ) 4 . Th e a v ai la b il i t y o f c om m e r c i a ll y m a d e p ro d uc ts 5 . P ot e nt i al ad v e r s e ef f ec t s 6 . D r ug in t e ra c t i on s 7 . P h ysi c a l i nc om pa t ib i li ti e s 8 . S af e h a nd l in g a nd di s p o s a l p r oc ed u r es 9 . N u t ri ti o na l i n te r ac t io ns o r r e qu i re m e n ts 1 0 . D ru g i n te r f e re nc e wi th l ab o ra t o r y te st s
V. PATIENT MONITORING. Th e p r o v is i on of ph a rm ac e ut ic a l c a r e re q ui r es a p h a r ma c eu t i ca l c a r e p la n (s e e C h a p te r 20 ) . Mo n i to r in g a p at i en t ' s n ee d f o r m ed ic a ti o n a nd th e e f f ec t o f th e m e di ca t io n P.563 o n th e p a ti e nt m a xi m i z e s t h e e f fe c t i ve ne s s of t he m e di c a t io ns be i ng ta k e n . U n d es i r ed ou tc om es as s o c ia t ed wi t h d r u g t he r a py a r e f re q ue n tl y c a l le d dr u g therapy problems. A. P h a r m a c eu t i ca l c a r e p l a n. To in c re as e th e f re q u en c y a n d b en e fi ts o f d e s i r ed o u tc om e s , a p ha r m a c e u ti c al c a r e p la n s ho ul d i nc lu d e t h e f ol l o wi n g: 1 . As s e ss m en t . A r e v i ew o f t h e m ed ic a l c o n di t ion s a n d s ym p t om s t o d et er m i ne th e n e e d f o r m e d ic at i on 2 . P la n . A d ec is io n o f a n a p p ro p ri a te d ru g t h e ra py b a s e d on th e a s s es s m e n t o f th e p a t ie n t 3 . M o n i to r i n g. A re v i e w o f t he ou tc om es o f d ru g t h e r ap y ( i .e . , g oa ls an d e n d p oi n ts ) t o de t e rm in e i f th e p a ti en t is ob t ai ni n g t he de s i r ed o ut co m e s B . D r u g t he r a p y p r o b l e m s a re e v id en c e o f l es s -t h a n -o p ti m a l d r ug th e r apy . D e t e ct io n of d ru g - re la t ed p r o bl em s r eq u i re s a n as s e s sm e nt of t he ne e d f o r a ch an g e i n dr u g t h er a p y . Po s s ib le p r o bl em s i nc lu de 1 . U n ne c es sa r y d r u g t h e r a p y. Th e m e di c a t io n c a n n ot be as so c i a te d wi t h a m e di c a l c o nd i ti on o r t h e p re s en c e o f a c o nd i ti on in wh i c h n o nd r ug t he r ap y i s m o re a p p ro p r ia t e. 2 . W r on g d ru g . Th e d r ug is no t i n di c a t ed f or t he c on d it i on o r is no t d e li v e r i ng t he d e si r ed ou t c o m e s , o r a m o r e e ff e c t i v e d r ug is a va i la b le . 3 . D o se t oo l ow . I nc o r rec t do s e , fr e qu e nc y, ad m in i s t r a ti o n, o r d ur a ti o n o f t h e r ap y r e s ul ts in an in s u f fi c i e nt d o s e of d ru g to th e p a ti en t . 4 . Ad ve r s e d r u g r e ac t i on . A n a ll e r gi c r ea c ti on , dr u g i n t er ac t io n , o r a n und e s i r ab l e e f f ec t o c c u rs f ro m a m edi c at i on . 5 . D o se t oo h ig h . I nc o r re c t d os e , f r eq u en c y , o r du r a ti o n , r es ul t s i n m o r e m e di c a t io n t h a n is r eq u ir e d.
6 . I na p p r op r i a te ad h e r en c e . Th e p at ie n t i s n ot ta k in g t h e o pt im a l am o unt o f m e di ca t io n o wi n g to c o s t, a dm in is t r at i on di f fi c u l ti e s , a l te r na t i v e h ea l th be li e fs , or a l a ck o f un de r s ta nd i ng of t h e n e ed fo r th e m e di c a tio n . 7 . N ee d ad d i ti o n al d r ug t h e r ap y. O wi n g t o a n un d e r tr e at e d c on di t io n , s yn e r gi s m wi t h c on c ur r e nt d ru g t h er a p y o r p r op h y l ac ti c t h e ra p y is r eq u ir e d. P.564
STUDY QUESTIONS D i r e c t i on s : E a c h of t he q u es t io ns , s t at em e nt s , or i nc om p le t e s t a te m en ts c a n b e c o r re c tl y a ns we r e d o r c om p le t ed b y on e o f th e s ug g es t ed an s we r s o r p h r as es . C h o os e th e b e st an s we r . 1 . M e d ic a t io n o rd e r s d if f e r f r o m p r es c r i p ti o ns i n w h i ch o f t h e f o l low i ng w a ys ? They ( A ) a r e i nt e nd e d f o r am bu l a to r y us e . ( B ) c on t ai n o nl y t h e g ene r i c n am e o f t he m e di c ati o n . ( C ) a r e i n te nd e d f o r i ns tit u t io n al us e. ( D ) m a y b e t ra ns m i t te d el e c t r o ni ca ll y. ( E ) c on t ai n t h e q ua n ti t y o f m e di ca t io n to be di spe n s e d . V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . I f a t h er a p e u ti c in t e r ve n t io n is n e c es s a r y, a l l o f t he f ol l ow i n g i n f o rm a t io n s ho u l d b e c o mm u n ic a te d t o t h e p r e s c r ib e r e x ce p t ( A ) a de c l a ra t io n t h at “ a m is t ak e wa s m ad e .” ( B ) a br i ef de s c r ip t io n o f t h e p r ob l em . ( C ) a r ef e re n c e s o ur c e th a t d oc um e n ts t h e p r ob le m . ( D ) a n a l te r na t i v e o r s u gg e s t i on to r es ol ve t he pro b le m . ( E ) a de s c ri p ti o n o f t h e c l i ni c a l s ig n if ic a nc e o f t h e p r o bl em . V i e w A n s we r 2 . T h e a n sw e r i s A [ se e] . 3 . T h e f o ll ow in g i n f o r ma t i on sh ou l d b e r ec o r d ed o n a p re s cr i p t i o n e xc e p t t h e ( A ) p r es c r i pt i on nu m b e r . ( B ) d a te of fi l li ng . ( C ) e xp i r a t io n d a te . ( D ) p r od uc t an d q u an ti t y d i s p e ns ed . ( E ) p ha r m a c i s t ' s i n it i al s . V i e w A n s we r 3 . T h e a n sw e r i s C [ se e] . 4 . A p r e sc r i p t i on la b e l u su a l l y c o n t ai n s a l l o f th e fo l l ow i ng e xc ep t t he ( A ) q ua n ti t y di s pe ns ed . ( B ) l ot nu m be r . ( C ) p a ti en t ' s d i ag no s i s . ( D ) e xp i r a t io n d a te . ( E ) p r es c r i be r ' s n am e . V i e w A n s we r 4 . T h e a n sw e r i s C [ se e] . 5 . Au x i li ar y a n d c a u t i on a r y l a b e ls s h o u ld be u se d fo r a ll o f t h e f o l low i n g p u r p ose s ex c ep t t o ( A ) s ub s t i tu t e f o r v e r b al c o ns ul t at i on .
( B ) e ns u re p ro p er us ag e. ( C ) i n fo r m o f s to r ag e re qu i r em en t s. ( D ) c om pl y wi t h r eg u la t or y r e q ui r em e nt s . ( E ) wa r n a ga i ns t t h e c o nc om i ta n t u s e of c e r ta i n dr u g s o r f o od s. V i e w A n s we r 5 . T h e a n sw e r i s A [ se e] . 6 . T h e f o ll ow in g i t e ms a re es s ent i a l f o r a pa t i en t p ro f i l e s ys t e m ex ce p t ( A ) t h e p at ie n t ' s n am e. ( B ) t h e p re s c r ib e r ' s D r u g E n f o rc em en t Ad m i n is t rat i o n ( D E A ) re g is t ra t io n nu m be r . ( C ) t h e p at i en t ' s a ll e rg i es . ( D ) t h e p at i en t ' s b i rt h d at e . ( E ) i ns t ru c ti on s f o r m ed ic a ti o n us e . V i e w A n s we r 6 . T h e a n sw e r i s B [ se ea n d] .7 . T h e f o l l ow in g a r e d r ug t he ra p y p r o b l em s e x ce p t ( A ) a n a d v e rs e e f fe c t f r om a m ed ic a ti on . ( B ) s ym p t om s c a us e d b y u n de r t re a tm e nt . ( C ) a d ru g -d r ug in t e ra c tio n . ( D ) a n u n di ag n os ed c o nd i t io n . ( E ) a n a ll e rg ic r ea c ti on to a m ed ic a ti o n. V i e w A n s we r 7 . T h e a n sw e r i s D [ se e] . P . 56 5
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C [ s ee I . B ] . Me d i c a t io n o r de r s a r e wr i t t en fo r t he c a r e o f i np a ti e n ts . B o th m e di c at i on ord e r s a nd p r e sc ri p ti o ns m a y c o n ta in t he b ra n d o r g e ne r ic na m e o f t h e d ru g an d m a y b e t r a ns m i t te d e l ec t ro n ic al ly . O n l y p r es cr i pt i on s c ont a i n t he qu a nt i t y of m e dic a ti o n t o b e di sp e ns ed . 2 . T he an sw e r is A [ s ee I I . C .1 ] . I n f o rm at i on p ro v i de d to th e p re s c ri b e r d u ri ng a t he r a pe u ti c i n te r v e nt i on s ho u ld i n cl ud e a d es c r ip t io n o f th e p ro bl em , re f e re nc e s o u r c e , d es c ri p ti o n o f t he c li n ic al s i gn i fi ca nc e , a nd an al t er n a ti v e . In f o rm in g t h e p re s c r i be r th a t a m is t ak e wa s m a de d o es no t e n c o u ra g e c o op e r a ti on an d re s o l ut i on o f t h e pr o bl em . 3 . T he an sw e r is C [ s ee I I I . A] . Th e p r es c ri p ti on nu m be r, d a te of fi l li ng , pr o du c t a n d q u an t it y d is pe ns e d, a n d p h a rm ac is t ' s i ni t ia ls s h ou l d b e re c o r de d o n th e pr e sc r ip t io n . Th e e xp i r a tio n da t e o f t h e p r o du c t be i ng di s p e ns e d is no t re q ui r ed . 4 . T he an sw e r is C [ s ee I I I . E. 1 ] . Th e q u an t it y o f m ed ic a tio n di s p e ns ed , l o t n um ber , e xp i r a t io n d a te of th e p r o du c t, a n d p r es c ri be r ' s n am e a re us u al l y in cl u de d o n t he l ab el . Th e p a ti e nt ' s d i ag n os is , a l t ho ug h l is t ed in t he pa ti e n t 's p ro f il e, is no t i nc l ud e d o n t h e p r es c r i pt i on la b el . 5 . T he an sw e r is A [ s ee I I I . E. 3 ; I V . A .1 ] . A u xi l i a r y a nd c a u ti on a r y l a be ls a re an ad j un c t t o, n o t a r ep l ac em en t fo r , ve r b al c o ns ul t at i on . Ap p r op r ia te us es f o r s u c h la b el s i nc l ud e e ns u ri n g p r op e r u se , s t o ra g e
r e q ui r em e nt s , a nd c om p li a nc e wi t h s ta t ut o r y r eq ui r e m e n ts , a nd wa r n i ng ag a in s t f oo d a n d d r ug in t e ra c t i on s . 6 . T he an sw e r is B [ s ee I I I . F. 1 a n d 2 ]. Th e p a ti e nt ' s n am e i s r eq u i re d to i d en t if y e ac h pa t i en t . O f t e n, th e a d d re ss o r r o om n u m b e r i s r eq u i re d t o i de n t if y p a ti en t s wi t h s i m i la r n am es . Th e p at ie n t ' s a l le r g ie s , b i r th d at e , a nd in s t r uc t ion s fo r u s e a re r eq u ir e d to p r e v en t d r u g al l e rg ie s a n d t o a ss e ss t h e a pp r o pr i at e ne s s o f t he p re s c r ip t io n or m ed ic a ti o n o rd e r . 7 . T he an sw e r is D [ s ee V . B ] . A d ve r s e e ff e c t s , un d e rt re a t ed c o nd i ti o ns , a ll e rg ic r ea c ti on s , a nd dr u g -d ru g i n t er a ct i on s a re al l d r u g t h e r ap y p r ob le m s . An und i ag n os ed co nd i ti o n m a y l e ad to a d r u g - re la t ed p ro b le m o nc e d i ag n os ed ; h o we v e r , d i ag n os is i s re qu i r ed be fo r e th e n e e d f o r m e d ic at i on c a n b e as s e ss ed .
27 Sterile Products J o h n F a ni k os
I. INTRODUCTION. Th e U n i te d S ta t es Ph a rm ac o pe i a a nd Th e Na t ion a l F o rm ul a r y ( U S P ) p u bl i s h ed p r a ct ic e s t an da r ds f or c om p ou n di ng st e ri l e p r ep a ra t i on s a f te r c as e re po r t s o f pa ti e n t h a r m a nd fa t al i t y . Th e p ro c ed u re s a n d r eq u i re m en t s o u tl in e d i n U S P C hap t e r 7 9 7 a r e i n t en de d to pr e v e n t p a t ie n t h a rm re s u l ti ng f ro m i n g re di e nt e r ro r s a nd m ic r ob i al c o nt am i na t io n . Th e c h apt e r in c l u de s c o m p o un d ing p e rs on ne l re sp o ns ib il i ti e s , t r a in i ng an d e v a l ua t io n re q ui r em e nt s , m e d ic at i on p r e pa r at i on s t e ri l it y a nd a c c u ra c y v e r i f ic a ti o n, c l as s i fi c a t ion o f m ic ro b ia l c on t am in a t i o n r is k , an d e q ui pm e nt a n d e n vi r on m e n ta l q u al i t y a nd c o n t ro l . W hil e t he se s ta n d ar ds ap p l y to al l f ac i li t i es ( h o sp i ta ls , n u rs in g h o m es , ph a rm ac ie s ) a nd al l p ra c ti t io n e rs (p h y si c i a ns , n u r s e s , t e ch n ic ia ns ) , t h e y ar e e s p e c i al l y im po r t an t fo r pha r m ac is ts wh o a re m os t o f t en i n vo l ve d wi t h s t e ri l e m e di c at i on p re pa r a ti o n. S in c e t he s t a nd a rd s r e qu i re s u bs ta n ti a l i n ve st m e n t i n l ab o r , e qu ip m en t , a nd s u p pl ie s , r egu l a to r y a ge nc ie s (F o od an d D r ug A d m in is t ra t io n , J oi n t C om m i s s io n o n Ac c re di t a tio n of H e al th C a re O r g ani za t i on s , U . S . st a te b oa r ds o f ph ar m ac y ) a r e e xp e c ti n g im p l em e nt a ti on b y J a nu a r y 2 0 06 , wi t h e vi d e nc e o f l on g t e rm c om p li an c e a nd ro u ti n e m on i t o r i ng th e r ea f te r .
II. DEFINITIONS A. S t e r i l i t y, a n a bs ol u te t e rm , m e an s t he ab s en c e o f l i v in g m ic r oo r ga n is m s . 1 . M i c r o be i s a m ic r os c op i c o r ga ni s m s s u c h as a b a ct e r ia , f u ng us , pr o ta zoa o r v i ru s 2 . P yr o g e n s a re m e ta b ol i c b y- p ro d uc ts of li v e o r d e a d m i c ro o rg a ni sm s t ha t c a us e a p yr e t ic r es po ns e (i . e. , a f e v e r ) up o n in j ec ti o n. 3 . S t e ri l e p r o d uc t s a r e p h a rm ac e ut ic al do s ag e fo r m s th a t a r e s te r il e . This in c l u de s p r o du c ts l ik e p a r en t er a l p r e pa r a ti o ns , i r ri g at i ng s o l u ti on s , a nd op h th a lm i c p r e pa r a ti o ns (s ee C ha p te r 2 9) . S te r il e p r o du ct co m po u nd in g re q ui r es c lea n e r f a ci l it i es , p e rs on n el t ra ini n g a nd t es ti n g, an d a s ou n d k no wl e d g e o f s te r il i za t i on an d s t ab i li t y p ri nc ip l es an d pr a c ti c e s . 4 . As e p t i c m an i pu l a ti on s r ef e rs to t he te ch n iq ue s a n d p r oc ed u re s u s e d d u r in g c om p ou n di ng t ha t m ai n ta i n t h e s te r il i t y o f ph a rm a c eu t ic al do s a g e f o rm s . 5 . C o mp o u nd e d S t e r il e P r e p a r a ti o n s ( C S P s ) in c l u de ; a . P r ep a ra t io ns , wh e n p re p a re d a c c o rd i ng to m a nu f ac t u re r in s t r uc t io ns , e x p o se a s t e ri le a ge n t t o p ot e nt i al m ic r ob i al c o nt am i na t io n. b . P r ep a r at io n s m a d e f r om no ns t e ri l e i ng r ed i en ts t h a t m us t b e s te r il e b e for e p at i en t a d m i ni s t ra ti o n . c . S te r il e o r no ns t e ri le bio l og ic a ls ( v ac ci ne s , im m u n e g lo b ul i ns ) , d ia gn o st ic s , m e di ca t io ns , n u t ri t io n al s , a nd r ad i op ha r m a c e u ti ca l s t ha t m us t be s t e ri le pr i o r to a d m i ni s t ra ti o n o r u s e as a n ir r i ga t io n , b at h , im p lan t , i n ha l at i on , i nj e c t i on , o r f o r us e i n th e e y e o r e a r. 6 . M i c r o bi a l C o n ta m i nat i o n R is k L e ve l s a r e as s i gn e d ac co r di n g t o t h e p r o ba b il i t y o f co n ta m i na t in g a p re p ar a t io n wi t h m ic r ob ia l o r ga n is m s , e nd o t o xi n s , o r wi t h f o r ei gn c h em ic al o r p h ys ic a l p a rti c ul a te m a t te r .
a . L ow Ri s k L e ve l C S Ps a r e c om po u nd e d b y as ep t ic a ll y t r an s f e r ri n g a s ing l e s te r il e d o sa g e f o rm fr om a s te r il e am pu le , v i al , b o tt l e, or b a g us i ng s t e ri le ne e dle s a n d s yr i n ge s t o a fi n al s t e ri le c on t ai n e r o r d e vic e f o r p a t ie n t a dm in is t r at io n . b . M e d iu m R is k L e ve l CS P s a re c o m p o un de d b y a s ep t ic al l y t ra ns f e r ri ng m u lt i pl e s t e ri le d os ag e f o rm s f r om s t e ri l e am p ul es , via ls , b o t tl es , o r ba gs us in g s te r i le n e e dl es an d s y r i ng es to a s i n gl e f i na l s te r il e c on ta i ne r o r d e v ic e f o r a dm ini s t ra t io n t o m u l ti pl e p a ti e nt s o r to o n e p at i en t o n m ul t ip l e o c c a s i on s . c . H i gh R is k Le ve l C S Ps a r e c o m p o un d ed f ro m n o ns t e ri le in g r ed ie n ts and t e r m i n al l y s t e ri li z e d p r io r t o pa ti e n t a dm in is t ra t i o n o r s t e ri l e i ng r ed i en ts tha t a re c om p ou n de d u n de r i n fe r io r ai r qu a li t y co nd i ti o ns . P.567
d . I mm e di a te - u se C S P s a r e c om po u nd e d i n em er g e nc y si t ua t io ns o r wh e r e i m m e di a te pa t ie n t a dm ini s t ra t io n i s m a n da t ed to a v o i d o r ha rm t ha t m a y re s ul t fr om d e la ys in t re a tm en t . 7 . C o mp o u nd e d P a r en te r a l P r ep a r a ti o ns a re ph a r m a ce u ti c a l d os a ge for m s t ha t a re i n je c te d t h r ou gh on e o r m o r e l a yer s o f s ki n . B eca u s e th e p a r en t e ra l r o ute b y p as se s t h e p r o te c t i v e ba r r ie rs o f t h e b od y , p a re n te r al p rep a r a ti on s m us t b e s te r il e. Th e p H o f a s ol u ti on m a y m a r k ed l y i nf l ue nc e t h e s ta bi l ity a n d c om p at i bi li t y o f p ar e n t er a l p r e pa r a ti o ns (s ee V . B ). B . D e s ig n an d fu n c ti o n o f s t e ri l e c o mp o un d i ng a r e as 1 . C l ea n r o om s a r e a r eas s p ec ia l l y c o ns t ru c t e d an d m a in t ai ne d to r ed uc e t h e p r o ba b il i t y o f en v i r on m en t a l c o n ta m i n at i on of s t er i l e p r od uc ts du r i ng th e m a nu f ac tu r i ng p ro c e s s . E n g in e e ri ng co n t ro ls to re d uc e t h e p ot e n ti al fo r ai r b o rn e c o nt am i na t io n i nc l ud e a ir f l o w t h r ou g h hi g h -e f fi c i en c y pa r t ic ul a te - ai r ( H E PA ) f i lt e rs , u s e o f h o ri z o n ta l f l o w c le a n b e nc he s, ve r ti ca l fl ow c l e a n b en c h es , bi ol o gic a l s a f e t y c a bi n et s , an d b a r ri e r i s o la t o rs . C le an r oo m a r e t ra d i ti on a ll y d es ig n ed in m u l t ic om p a rt m e n ts or pa r t it i on e d wo r k a r ea s f o r as e p ti c p r oc es si n g ( F ig u re 27 -1 ) . a . An t e - a r ea p ro v i d es a c l ea n a r ea f or pe r so n al h y g i e ne an d f o r d on n in g p e r so na l p r o t ec ti v e eq u ip m e n t s uc h a s h ai r co v e r s, gl o v es , g o wn s , o r f u ll c l ea n ro om a tt i re ( F i gu r e 2 7 - 2) . S up pl i es ar e r em o v e d f r om s hi p pi ng c a r t on s a nd de c o n t am in a t ed wi t h a d is en f ec ti n g a ge n t. Th e a r ea s h ou ld p ro v i d e a t l e as t a n I n te r na t io n al Or g a ni z a t io n f o r S ta n da r di z a t io n (I S O ) C l as s 8 or be t t e r wo r k e n v i r on m e n t . b . B u f fe r a r ea c o n ta in s th e wo r k s u r fa ce s f o r t he s t ag i ng of su pp l ie s a nd e q ui p m e n t u s ed in C S P p r e pa r at i on. I t s ho u ld p ro vi de a t l eas t an I S O Cl as s 7 wo r k e n vi r on m e n t . Th e bu f f er a r e a s ho ul d c o nt ai n n o s i n k s o r d ra in s a n d b e f r ee o f o b je c ts th a t s h e d p a rt ic le s (c a rd b oa r d, pa p e r, c ot t o n , e tc . ) . Tr a f f ic fl o w i n a n d o ut is m i ni m i ze d a n d r es t ri c te d t o qu al i fi e d c o m p o un di ng p e rs on ne l . c . P r im a r y e n g i n e e r i n g c o n t r o l is th e ro om t ha t p r o v i de s t h e I S O C la ss 5 e n vi r on m e n t f o r C S P p r ep a r a ti on . d . D i r ec t co m p ou n d in g a r e a i s t h e c ri t ic al ar e a wi t h t h e p r im a r y e n gi n eer i n g c o nt r o l wh e r e c om p ou n din g is p e r fo r m e d a n d c ri t ic a l s i t es ar e e xp o s e d t o H E P A f i l te r ed ai r .
e . H E P A F i l t e rs a re us ed t o c le an s e t he ai r en t er i n g t h e r oo m . Th e s e fi l te r s re m o v e a l l a i rb o rn e p a r ti c l es 0 .3 m m o r l a rg e r , wi t h an e ff i c i e nc y o f 9 9. 9 7% . Th e re f e r en c e s t an d a rd s f o r H E P A - f il t er e d ro om s h as ch an g ed to a m e tr ic ba s ed s ys t em ( Ta b l e 2 7 1 ) . H E P A - fi l te r ed r oo m s a r e c l ass i fi e d as I S O C las s 3 th r o ug h 8 . An I S O C l a s s 8 r o o m co n ta i ns n o m o re th a n 3 , 52 0 ,0 0 0 p ar t ic le s o f 0 .5 µm o r l a rg e r p e r c u b ic m e te r o f ai r .
Figure 27-1. Clean room design.
P.568
Figure 27-2. Clean room attire.
f . P o si t i ve - p r es s u re a i rf l ow is us ed t o p r e v en t c o n t am in a te d a i r f r om fl owi n g i n to t h e c le a n r o om . I n o r de r t o ac hi e ve th is , th e a i r pr e s s u r e in si d e t h e cl e an r o o m m u s t b e g re a te r th an t he p re s s u r e o ut s i d e t he r oo m , s o t ha t wh e n a do o r o r wi n d o w t o th e c l ea n ro om is o p en e d, the a ir f lo w i s ou t wa r d . g . C o u nt e r s i n t h e c l e an r o om a re m a de of s t a in le s s s t e el o r o th e r n on p or o u s , e a si l y c l ea n ed m a te r ia l .
h . Wa l l s, f l oo r s , a n d c ei l i n gs do no t ha ve c r ac k s o r c re vi c e s a n d h a v e ro u n de d c o r ne r s. A ll s u r fa c e s s hou l d a ls o b e n o np o ro us an d wa s ha b le to en a bl e re g ul a r d i si n fe ct i on . If wa l ls o r f lo o r s a re p ai nt e d, a n e pox y p a i n t i s us e d. i . Ai r f l ow . A s wi t h t he HE P A f i lt e rs us ed in c l ea n r o om s, t he ai r fl o w m o v es wi t h a u n i fo r m v e l oc it y a lo n g pa r a ll e l li n es . Th e v e l oc ity o f t he ai r f lo w i s 2 7 m e te r s (9 0 f e e t ) p e r m i n ut e .
Table 27-1. International Organization of Standardization (ISO) Classification of Particulate Matter in Room Air Class Name ISO Class
Particle Count Number of Particles of 0.5 µm or larger ISO (Particles per U.S. Federal Standard* cubic meter) (Particles per cubic foot)
U.S. Federal Standard*
3
Class 1
35.2
1
4
Class 10
352
10
5
Class 100
3520
100
6
Class 1000
35,200
1,000
7
Class 10,000
352,000
10,000
8
Class 100,000
3,520,000
100,000
*
Federal Standard No. 209E, General Services Administration, Washington DC, 20407 P.569
j . C r i t ic a l s i t e is an y o pe n in g p r o vi di ng a d i re c t p a t h b et we e n a s te r il e p ro d uc t a n d t h e e n vi r on m e n t o r a n y s u r f ac e c om in g i n d i re c t c o n t ac t wi t h t he st e ri l e p ro d uc t a n d t h e e n vi r on m e n t. La m i n ar f l o w wo r k b en ch es a re u s ed to p ro v i d e a n a de qu a t e c r i ti ca l s it e e n v i r on m e n t. U S P C h ap t e r 7 97 r eq u ire s s t e ri le p re pa r a ti o n c om p ou n di ng b e pe r f or m e d i n a t le as t a I S O C la s s 5 q ua li t y a ir e n vi r on m e n t. 2 . L am i na r f low w o r k be n c he s (L F W B ) a r e g ene r a ll y u s e d i n c on ju nc t ion wi t h c l ea n r o o m s a n d a r e s p ec i al l y d e s i g ne d t o c r ea t e a n as e p t ic e n v i r on m e n t f o r t he p r e pa r a ti o n o f s te r il e p r od u c t s . A n I S O C l as s 5 en v i r o nm en t e xi s ts in s i de a c e r t if i ed h o r i zon t al o r v e r t ic al LFW B.
a . H E P A f i l t e r re q u i re me n t . L ik e c le a n r o om s , lam i na r fl o w wo r k b en ch es u s e H E P A f i lt e rs , b u t t h e b enc h es u s e a h i gh e r -e f fi c i en c y ai r fi l te r th a n d o c l ea n r oo m s . b . T yp e s o f l a mi n a r fl ow w o r k b e nc h es ( 1 ) H o r iz o n ta l l am i na r flo w h o o ds ( Fi g u re 27 - 3 ) we r e t h e fi rs t ho od s u sed i n p h a rm ac ie s f o r t h e p r epa r a ti o n o f s te r i le pr o du c ts . Ai r f lo w i n ho r i z o nt a l ho o ds m o ve s ac r os s t he s u r f ac e o f t h e wo r k a re a , f lo wi n g fi r st t hr o ug h a p re f il t er a n d t he n t h r o ug h t h e H E P A fi l te r . Th e m aj o r d is a d v an t ag e o f t he ho r i z on t al ho o d is t h a t i t o f f e rs n o p r o te c ti on t o t he o pe r a to r , wh ic h i s e s pe c ia ll y s ig ni f ic an t wh e n a n t in eo p la s ti c a ge n ts a re b ei ng p re p a re d ( s ee V II . D . ) . ( 2 ) V e r t ic a l la m i n a r f lo w h o od s ( F ig u re 27 - 4 ) p r ov i d e t wo m a jo r a d van t a ge s o v e r h o r i zon t al fl o w h o od s . ( a ) Th e ai r fl o w i s v e rt ic al , fl o wi n g d o wn o n t h e wo r k s pa c e . Th is ai r f lo w p a t t e rn p r o t ec ts th e o p er a to r aga i ns t p o te n ti a l h a z a rd s f ro m th e p r od uc t s b ei ng p re p a re d . ( b ) A po r ti o n o f t h e H E PA - f i l te r ed ai r is re c i r c u lat e d a s e c o n d t im e t h ro u gh t he H E P A f i lt e r . Th e r em ai n de r o f t he f il t er e d a i r is r em o v e d t h ro u gh an e xh a us t fi l te r , wh i c h m a y b e v e n te d to th e ou ts i de to p ro t ec t t h e o p e ra t or f ro m c h ro ni c , c o nc en t r at e d e xp o s u re to h a z a rd ou s m at e r ia ls . 3 . B i ol o g ic a l S a f et y C a b i n e ts ( B S Cs ) a re v e r ti ca l fl o w h o od s wi t h f ou r m a j o r t yp es a va i la b le . Th e y a re di f fer e n ti a t ed b y t h e a m o un t o f ai r r ec ir cu l at e d i n t he c a bi n et , wh e t h e r th is ai r is v en t ed t o t h e r oo m o r ou ts i de , a n d wh e t h e r c o n ta m i n ate d du c t s a r e un de r po s i t i v e o r n eg a t i v e p r es s u r e. a . T yp e A c a b i n et s re c i rc u la t e 7 0% of c a bi n et ai r t h r ou g h H E P A fi l te r s b ac k i n to th e c a bi n et , th e r em a in d er is d is c h a r ge d t h r ou gh a HE P A f i lt e r i n to th e c le a nro o m , c o nt am i na t ed du c ts a r e u n d er po s i t i v e p r es s u r e. b . T yp e B 1 c a b i ne t s r e c i r c ul at e 30 % o f c ab i ne t ai r t h ro ug h H E P A f il t e rs ba c k in t o t h e c ab i ne t , t h e r em ai n de r is di sc ha r g ed th r ou g h H E P A f i lt e rs to t he ou ts id e e n vi r on m e n t , c o n ta m i n ate d du c t s a r e u nd e r n e gat i v e p re ss u re . c . T yp e B 2 c a b in e t s d is c h a rg ed al l c ab i ne t a i r t hr o u gh H E P A fi l te rs t o t he o u ts id e e n vi r on m e n t wi t h c o n ta m i n a te d d uc ts un d e r n eg a ti v e p r es s u r e.
Figure 27-3. Horizontal laminar flow hood. (Photo taken by William Salkin.)
P.570
Figure 27-4. Vertical laminar flow hood. (Photo taken by William Salkin.)
d . T yp e B 3 c a b i ne t s r e c i r c ul at e 70 % o f c ab i ne t ai r t h ro ug h H E P A f il t e rs ba c k in t o t h e c ab i ne t , 3 0% is di s c h a r ge d th r ou g h H E P A fi l te r s t o th e o u ts id e , a nd c o nt am i na t ed du c ts a r e u n d er ne g at i v e p r es s u r e . 4 . C o mp o u nd i ng as e p tic i s ol a t o r ( C AI ) p r o vi de a I S O C la ss 5 e n v i ro nm en t f or p r o du c t p r ep a ra t io n , wi t h a s e p ti c m an ip u la t io ns oc c u r r in g i ns i de a c l o s e d , p r e ss u ri z e d e n v i ro nm e nt a c c es s i bl e on l y v i a se a le d gl o ves th a t re ac h i n to t h e wo r k a r e a ( F ig u r e 2 7- 5 ) . C o mp o u n di n g a s ep t i c c on t ai n m en t i so l a to r s p r o te c t wo r k e r s f r o m e xp o s u re to un d es i ra b le o r h a z a rd o us d r u gs d u r in g th e c om po u nd in g a n d m a te r i al t ra ns f er p ro c e s s e s . I s o l at o rs us e u ni d ir ec t io n al P.571 o r t u rb ul e nt ai r f lo w t o r em o v e c o nt am i na n ts f r om t h e u ni t . I t us es p os i ti v e a i r p r e ss u re to k e ep e xt e r n al a ir b o rn e p a r ti c l es ou t of t h e is ol a t or . Th is te c h no l og y r e p r es en t s a n ac c e p ta b le a lt e r na ti ve t o L FW Bs in a c le a n r o om s f or as e pt i c p r o ce ss in g .
Figure 27-5. Barrier isolator.
3 . I ns p ec t i on an d ce r t i fi c a t io n . Cl e an ro o m s , LFW Bs , B S C s, an d ba r r ier i so la t o rs a r e i n sp ec t ed an d c e rt i fie d wh e n th e y ar e fi r s t ins t al l ed , a t l e as t e v e r y 6 m o nt hs t h e r ea f te r , a n d, in th e c as e o f LFW B, B S C s , a nd is o la t o rs , wh e n m o v e d t o a ne w l o ca t io n . a . I ns p ec t i on s s ho u ld be c o n du c te d b y N a ti o na l S a n i ta t io n F o un da t io n ( NS F ) a cc r e di t ed an d c e rt i fi e d te c hn ic i an s wi t h e xp e r t ise a nd t ra i ni ng in co n ta m in a t io n c o nt r o l t ec hn o lo gi es . E qu i pm e nt us ed fo r t es ti n g h a s a pp r op r i at e t o le r an ce f o r t he s p ec if i ed te s ti ng an d i s c a l ib r a te d t o N at i on al I ns ti t u te of S t an da r ds an d Te c hn o lo g y ( N I S T) t r a c e a bl e s ta n da rd s . b . T es t i ng is pe r fo r m e d p e r re l e van t i n du st r y s tan d a rd s a nd a t m i n im um in c lu d es : ( 1 ) H E P A fi l te r i n te g r it y te s ti n g ( 2 ) A i rf l o w t es t in g : D o wn f l o w a n d i nf l o w wh e r e app r o p ri a te ( 3 ) P a rt ic u la t e m o n it o ri ng ( 4 ) P r es s u r i z at i on m o ni to r i ng (c l ea n ro om s a n d ba r r i e r is ol a t or s ) e ns u re s t h a t n o p a r ti c l e l a r ge r th a n 0 .3 m m p as se s t h ro u gh th e H E P A f i lt e r . I n a dd i ti o n, a n a n em om e te r is u s e d to de t e rm i ne ai r fl o w ve l o ci t y, a nd a p a rt ic l e c o u n te r is us ed t o d e t e rm in e t h e p ar t ic le c ou n t .
III. QUALITY CONTROL AND QUALITY ASSURANCE A. D e f i n i t i o ns 1 . Q u a li t y c o n t r o l i s t h e d a y - t o -d a y as s e ss m e nt o f al l s te r i le c om p ou n di ng o p e ra t io ns . Th is in c l u des r ec ei p t o f ra w m a te r i als , pr e pa r a ti on , s t o ra g e, d i s t r ib u ti o n, p a t ie n t a dm in is t r at io n , an d an al yt i c t es t in g o f t h e f i ni s h e d p r od uc t . 2 . Q u a li t y a s s u r a nc e , an o v e rs i gh t f u nc t io n , i n vo l v e s t he au d it i ng of qu al i t y c o n tr o l p r o ce du r es an d s y s te m s , wi t h s ug g es ti o ns f o r c han g es as ne ed e d. B . T e st i n g p r o ce d u r es . V a r i ou s t y p es of t es ts a re us e d t o e ns u re t ha t a l l s t er i le p r o du c ts a r e f r e e o f m i c ro b ia l c on t am in a ti o n, p yro g e ns , a nd pa r t ic ul a te m a t t e r. 1 . C l a ri t y t e s t i n g i s u s ed t o c he c k s t e ri le p ro du c t s fo r pa r ti c ul at e m a tt e r a n d l ea k s . B e f o re di s pe ns in g a pa re n t e ra l s ol u ti on , ph a rm ac y p e rs on n el s h ou l d ch ec k i t f o r p a r ti c ul a te s b y s wi r li n g th e s o lu t io n a n d l oo k i ng a t it ag a in s t b ot h l ig h t an d da r k b a ck g ro u nd s , us in g a c l ar i t y t es t in g l am p o r o t he r s t an da r d l i gh t s ou r c e . 2 . C o mp o u nd Ac c u r ac y C h e ck i n g is a d ou b le ch e c k o f th e u s e d d r u g p ro d uc ts a nd s u pp li e s b y a p e rs on ot he r t ha n t h e c om po un d e r. Th i s i n cl ud es an in sp ec ti o n o f t h e l a be l a n d s y r in g es u s ed t o m e as u re t he ad di t i v es . 3 . B e yo n d U s e D a t i ng re p r es en t s t he da t e a nd ti m e b e y on d wh ic h a p ro du c t s ho ul d n o t b e a dm i ni s t e r ed be c a u s e of po t en c y, s t e ri li t y, o r s t or a ge co nc e rn s . Be y o n d u se d a t in g s ho u ld be as s i gn ed i n ac c o r d an c e wi t h th e m a n u fa c tu r e r 's p ro du c t la b el i ng . 4 . E n d p r o du c t T e s ti n g i s s t er i li t y an d p yr o g en te s ti n g wh i c h s ho ul d b e pe r f o rm ed o n al l h ig h ri s k C S Ps th at a r e p r ep a re d i n b a tc hes o f 2 5 u ni ts o r m o r e , m u l t id os e vi a l s, o r p r ep a ra t io ns wh e r e i n g re di e n ts a r e e xp o s e d l on g er t ha n 6 - 12 hou r s p r io r to s t e ri li za t io n . a . S t e ri l i t y t e s t i n g e ns ur e s t h at t he p ro c e s s u sed t o s te r il i z e th e p r od uc t wa s s uc c ess f ul . Th e m em b r an e s te r i l iz a ti o n m e th o d i s o f te n u se d to c o nd uc t s t er i li t y t e s ti ng . Te s t s a m p l es a re p as s e d t h ro u gh m em b ra n e f i lt e rs , a n d a n u t ri e nt m ed iu m
i s th en ad d ed to p ro m o t e m ic r ob i al g r o wt h . A ft e r a n in cu b at i on pe r io d , m ic r o bi al g r o wt h is de t e rm in e d. b . P yr o g e n t e s ti n g c an b e ac c o m p li s h e d b y m e an s o f qu al i ta t i v e f e v e r res p on s e t e s ti ng in r ab b it s o r b y in v i t r o l im ul us l ys a te t es t i n g. C om m e r ci al la b or a to r i es ar e a va i la b le to pe r f o rm th es e t es ts . Pe r so n ne l h a nd lin g s t e ri l e p ro d uc ts c a n at t e m p t t o a vo i d p r ob l em s wi t h p y r og e ns b y pu rc h as in g p y r og e n - fr e e wa t e r an d s o di um c h lo r id e fo r i n je c t i on f rom r ep u ta b le m a nu f ac tu r er s an d b y u s i ng p ro p er ha n dl i ng a n d s to r a ge p ro c e du r es . C . E n vi r o n me n t al T es t in g in c l u de s a i r a nd s u r fac e s am pl i ng to m e as u re m ic r o bi ol o g y c on d it i on s o f t he c l ea n ro om an d a s s es s es t h e e f fe ct i v e ne ss o f c l ea ni n g a nd s a ni t i z in g pr o c ed u re s . P.572
1 . V ia b l e Ai r s a m pl i n g in c lu d es v ol um e t ri c a i r col l ec t io n i n t h e c o n t ro ll e d e n vi r on m e n t a nd e v a lu a ti o n o f a i rb o r ne m ic r o or ga n is m s o r c o ll ec t io n o f ai r b o rn e o r g an is m s b y e xp o s i ng s t e r il e n u t ri e nt pl a te s c ont a i ni ng t r yp ti c s o y b r o th ( TS B ) o r a g a r ( TS A ) f o r a s u i ta bl e t im e f ra m e . 2 . N o n - vi ab l e Ai r S a m p li n g is i n te n de d t o e v a l uat e t he eq ui pm e nt t ha t i s u s ed to c r e at e c le a n a ir . To t a l Pa r t i c le C o un t s ( Ta bl e 27 - 1 ) s ho u ld be wi t h in es ta b li s h e d I S O c la s s i fi c a ti o ns fo r a g i v e n c om po u nd in g a r e a. 3 . S u r fa c e s am p l in g u t ili z e s TS A pl a te s c al le d rep l ic a te o rg an is m d e te ct io n an d c o un t in g ( R O D A C ) p l at es t o c a p tu r e m ic r oo r ga n is m . B o t h a i r a nd s u r f ac e s am p li ng pl a te s a r e c ol le c te d an d i nc u ba t ed . Th e nu m be r of d i sc r et e c ol o ni es of o rg an i s m s , c o lo n y fo r m i n g u ni t s ( C F U s ), a re c o un t ed a n d r e p o rt e d. D . P r a c t ic a l q ua l i t y a s s u r a n ce p r o g ra m s f o r n on c om m e rc i al s t e ri le p ro du c ts i n cl ud e t ra in i ng , m on i to r in g th e m an u fa c tu r in g p ro c es s , pe r s o n ne l c om pe te n c y a ss e ssm e nt , qu al i t y c o ntr o l c h eck , an d d oc um e nta t i on . 1 . T r ai n i ng o f p h a rm a cis t s an d te c hn i c ia n s i n p r o pe r as ep t ic te c h n iq ues an d p r a ct ic es is th e s in g le m o s t i m p o rt a nt as p ec t o f an e f fe c t i ve q u al i t y a ss u ra n ce p r o g ra m . Tr a i ni n g s h o uld im p a rt a t ho r o ug h u n de r s ta n di ng o f d ep a r tm ent a l p o li ci es a n d p r oc ed u r es . 2 . B y m on i t o r in g th e ma n u f ac t u r in g p r oc es s , a s u p e r v is o r c a n c he c k ad h e re nc e to e s ta b li sh e d p ol ic ie s a nd p r o c e du r es an d ta ke c o rr e c ti ve ac ti o n a s n ec es s a r y . 3 . A f te r t ra in i ng is c om ple t e d c om p e te n c y a s s e ss m e n t t h ro ug h p e r fo r m an c e e va l u at io n an d r e - e v al uat i o n is r eq ui r e d f o r r o ut i n e t as k s l ik e h a nd wa s h ing , g o wn i n g , g lo v i ng , an d a s e p t ic m an i pu la t io n s. E val u a ti on s s ho u ld oc c u r a nn u al l y f o r p e r so nn e l c o m po un d in g lo w a n d m e di um r is k C S Ps an d s em i -a n nu al y f o r hi g h r is k CSPs. E . P r o c es s va li d a ti o n pr o v i d es a m e c h a ni s m fo r e ns u r in g p r oc es s e s c o ns is t en t l y r e s ul t i n s te r i le pr o du c t s o f ac c e pt a bl e q u al it y . Th i s s h o ul d i nc l ud e a wr i t te n p r o ce du r e to fo ll o w a s we l l a s e va lu a ti on o f as e pt i c t ec h ni qu e th r ou g h p ro c es s s im u la t io n .
F . P r o ce s s s im u la t i o n te s t i ng o r Pe r s o nn e l E va l u a ti o n d u pl ic at e s st e r il e c om p ou n di ng o f l o w, m ed i um , a n d h ig h ri s k l e v e l C S P s un de r m o s t s t r es s f u l c o nd i ti on s e xc e p t th a t an a pp r op r i at e g r o wt h m ed i a ( S o yb ea n - C as ei n Di ge s t Me d i u m ) is u s e d i n p l ac e o f th e d r ug p ro d uc ts . Aft e r p re pa r a ti o n a nd in cub a t io n o f t h e fi na l p r o du c t , n o g r owt h i n d ic at e s p ro p e r as ep t ic t ec hn iq u es we r e fo llo we d . G . Q u a l i t y c o n t r o l c he c k i ng in cl ud e s m o n it o ri n g t h e s t er i li t y o f a s am pl e o f m a nu f ac tu r e d p r od uc ts . Th e m em b ra n e s te r il i z a tio n m e th o d is p ra c ti c a ll y e m pl o y e d u s in g a c om m er c i a ll y a va i la b le fi l te r an d t r y p t ic as e s o y b ro t h m e d ia . H . D o c um e n ta t i on o f t r ai n in g p r oc e du r es , q u al i t y c on t r ol r es ul ts , l a m i na r f l o w h o od c e r ti f ic at i on , a n d p r od uc ti o n r e c o r ds ar e re q ui r ed b y va r i o us a g en c i es an d o r g an i za ti o ns .
IV. STERILIZATION METHODS AND EQUIPMENT. S t e r il i za ti o n is pe r f o rm ed t o d es t ro y o r re m o ve al l m ic r oo r g an is m s i n o r on a p r o du c t. S te r il i z a ti o n c an b e ac h ie v e d t h r ou g h t he r m al , c he m i ca l , r a di oa ct i v e , or m ec h an ic a l m e t ho ds . A. T h e r m a l s t e r il i z a t i on i n v o l v es th e u s e of ei t he r m o is t o r d r y h e at . 1 . M o i s t- h ea t s te r i l iz a tio n is th e m o s t w i d e l y u s e d a n d r e li ab l e s t e r il i z at i o n m e th o d. a . Mi c r o o rg an is m s a re de s t ro y e d b y c e ll u la r p r ot e i n c o a gu l a ti o n. b . Th e ob je c ts to be s t e ri l i z ed a re e xp o s e d to s a tu r a t ed s t ea m u nd e r 1 atm os p he r e p r e ss u re at a m i n im um te m pe r a tu r e o f 1 2 1° C f o r a t le as t 20 - 60 m i nu t es . c . A n a u to c la ve is c o m m o n l y us ed fo r m o is t -h e at s t e ri li za t io n . d . B ec a us e i t d oe s n ot re q ui r e a s h ig h a t em pe r at u r e , m o is t - he a t s te r il i zat i o n c a us es le s s p r o du c t a nd e q ui p me n t d a ma g e c om p a re d t o d r y - h ea t s t e ri li za t i on . P.573
2 . D r y- h e a t s t e r il iz a t io n i s a pp r o pr i at e fo r m a te r ia l s t ha t c a nn o t wi t h s ta nd m oi s th e a t s te r il i z a ti o n. O bj e c ts a re s u bj ec t ed t o a t em p e r a tu r e o f a t l e as t 1 60 °C f o r 12 0 m i n u te s (i f h i gh e r t em p er a t u re s c an be us ed , l e s s e xp o s ur e ti m e is re qu i re d ) . B . C h e mi c al ( ga s ) s t e r i li z a ti o n i s us e d t o s te r i liz e s u r fa ce s a nd po r ou s m a te r i al s ( e . g ., su r gi c a l d r es s i n gs ) t h a t o th e r s te r il i za ti o n m e th o ds m a y da m a g e. 1 . I n t hi s m e t ho d , e t h yl e n e ox i d e is us ed ge n e ral l y i n co m b i na t io n wi t h he a t a n d m o is tu r e . 2 . R es i d ua l ga s m us t b e a l lo we d t o d iss i pa t e a f te r st e r il i za ti on an d b e fo re us e o f t h e s t er i le p ro du c t. C . R a d i oa c ti ve s t e ri l iz at i o n i s s ui t ab le f o r t he ind u st r i al s t e ri li za t io n o f co n t en ts in s e al e d p ac k a ge s t ha t c an n o t b e e xp o s ed t o h ea t ( e . g ., p re p ac k a ge d s u rg ic a l c om p on e nt s , s o m e op h tha l m i c o in tm e nt s ). 1 . Th i s t ec hn i qu e i n v ol v es ei t he r el e c t ro m ag n e tic o r p a r t ic u l at e r ad i a ti on . 2 . A c c el e ra t ed d ru g d ec o m po s i t io n s om et im e s r es u lt s . D . M ec h an i ca l st e r i li z a ti o n ( f il t r a t io n ) re m o v e s b u t d o es n o t d es t r o y m ic r o or g an is m s an d c la ri f i es s ol u ti o ns b y e li m i n at i n g p a rt ic ul a t e m a t te r . Fo r s o lu t io ns r en de r e d u ns tab l e b y t he r m a l , c h e m i c a l, o r ra d ia t io n s te r il i z a ti on , fi l t ra t io n
i s th e p r ef e r re d m e th o d. A d e pt h f i lt e r o r s c re e n fi l t er m a y b e us e d. P e rs on n el s h ou l d e ns ur e th e f i lt e r u s ed ei t he r du r in g c om po u n di ng o r a dm in is t r at i on is c h em ic al l y an d p h y s i c a l ly c o m p a ti bl e wi t h t h e C SP a t th e t em p e ra t ur e a n d p r es s u r e c o nd i ti on s u s e d . 1 . D e pt h f il t e r s us u al l y c o ns is t o f fr i t te d g la s s or u n gl a z e d p or c el ai n (i . e. , s u bs ta n c e s t ha t t ra p p a rti c le s i n ch a nn e ls ) . 2 . S c re e n ( m em b r a ne ) fi l t e r s a r e f il m s m e as u ri ng 1 - 20 0 m m t hi c k m ad e o f c e ll ul os e e s te r s , m i c r o fi la m en ts , po l y ca r bo n at e , s y n t he t ic po l y m e r s , s i l v er , o r s t ai n le ss s t ee l . a . A m e sh o f m i ll i on s o f m ic r oc a pi ll a r y po r es of id e n ti c a l s i z e f il t e r t he s ol u t io n b y a p r o ce s s o f ph y s ic al s i e v in g . b . F low r a t e . B ec a us e po r e s m a k e up 70 % to 85% o f t h e s u r f ac e, s c r ee n f i lt e rs h a ve a h ig h er f lo w r a t e th a n d e pt h f i lt e rs . c . T yp e s o f s c re e n f i l ter s ( 1 ) P a r t ic u la t e f i l te r s rem o v e p a r ti c l es o f gl a s s , p l as t ic , r u bb e r , a nd ot h er c o nt am i na n ts . ( a ) O t h e r u s es . Th es e f il t e rs al so a re us ed to r ed u c e th e ri sk of ph l eb i ti s a ss o ci at e d wi t h a dm in is tr a t io n of r ec on st i tu t ed po wd e r s . Fi lt r a ti o n r em o ve s a n y u n di ss o l v ed po wd e r pa r t ic l es th a t m a y c au s e ve no u s i nf l am m a ti o n. ( b ) Th e po r e si z e o f s tan d a rd pa r t ic ul a te fi l te r s ra n g es f r om 0 .4 5 -5 m m . S p e ci al p a r ti c ul a te fi l te r s a re r equ i r ed t o f il t er bl o od , e m ul s io ns ( e. g ., f at em ul s i o ns ) , o r c o ll oi d al di s p e rs io ns o r s u s pe ns i on s b ec au se t hes e p r e pa r a ti on s h a ve a la r g e r p a r ti c l e s i z e . ( 2 ) M i c r o bi a l f i l te r s , wi th a p o r e s i z e o f 0 .2 2 m m o r s m a l le r , e ns u r e co m pl e t e m ic r o bi al r em o v al an d s te r i li z a t io n . Th i s i s r e fe r re d to as c o ld s t e ri li z a t ion . ( 3 ) F in a l f i l te r s , wh ic h m a y be ei t he r pa r t ic ul a te o r m ic r o bi al , ar e o f t en in c lu d ed as p a r t o f th e t u bi ng us e d in d r ug ad m i ni s tr a ti o n. Th e y a r e r e fe r r ed to as in- l i ne fi l te r s a n d a r e u s e d t o re m o v e p a r ti c ul a te s o r m ic r oo r gan i s m s f ro m a n i n t ra v e nou s (I V ) s o lu t io n d u ri n g i nf us i on .
V. PACKAGING OF PARENTERAL PRODUCTS. P a r e nt e r al p re pa r a ti o ns a n d o t he r s t e ri le p ro d uc ts m u st be pa c k a ge d i n a wa y t h a t m a in t ai ns p ro du c t s te r il i ty u n t il th e ti m e of us e a nd p r e v en ts co n ta m i na t ion o f c o nt e nt s d u ri n g o pe ni n g . A. T yp e s o f co n t ai n e r s 1 . Am p u l es , th e o ld e s t ty p e o f p a re n te r al p ro d uc t c on t ai ne r s , a re m a de en t i re l y o f g l a ss . a . I nt e nd ed f or s in g le us e on l y, a m p ul es a re ope n e d b y b re ak i ng th e g l as s a t a s co r e l i ne on th e n ec k . b . D i sa d va n t ag e s. B ec au s e g la s s pa r ti c l es m a y b e co m e di s l o dg ed du r i n g a m p u le o p e ni ng , th e p r od uc t m us t be fi l te r ed be f o re it is a d m i ni s te r ed . Th e ir un s ui t a bi li t y f o r m u lt i pl e -d os e P.574
u s e, t he ne ed t o f il t e r s ol u t io ns be f o re us e, an d ot h e r s af e t y c o ns id e r at io ns ha v e m a rk e dl y r e du c e d t h e am p ul e a s a p a c k ag e f o rm .
Figure 27-6. Syringes and vials. (Photo taken by William Salkin.)
2 . V ia l s a r e g la s s or pl as t ic c o nt a in e rs c l os ed wi t h a r u bb e r s to p pe r an d s e al e d wi t h a n al um in u m c ri m p ( Fi gur e 2 7- 6 ) . a . V ia ls ha v e s e v e r al adva n t a g e s o v e r a m p ul e s . ( 1 ) V ia ls c a n b e d es ig n ed t o h ol d m ul t ip l e d os es ( i f p re pa r e d wi t h a b ac t er i o s t a ti c a g e nt ) . ( 2 ) Th e dr u g p r od uc t i s ea s ie r to r em o v e f r om v ia ls t ha n f r om am pu l es . ( 3 ) V ia ls el im in a t e t he r is k o f g l ass pa r t ic le c o nta m in a ti on du r i ng op e ni ng . b . H o we v e r , v i al s a ls o ha v e c e r t ai n d i sa d va n t age s . ( 1 ) Th e ru b be r s t op p e r c a n be c o m e co r e d , c au s in g a s m al l b i t o f ru bb e r to e nt e r t h e s o lu t io n . ( 2 ) Mu l t i pl e wi t hd r a wa l s ( a s wi t h m ul ti p le - do s e via l s ) c a n re su l t i n m i c ro bia l c o nt am i na t io n . c . S om e d ru g s t ha t a r e un s ta b le in s o lu t io n a r e pa c k a ge d i n via ls un r ec o ns t i tu t ed a n d m us t b e re c on s t i tu te d wi t h a d il ue n t b e fo r e u s e. S t er i le wa t e r o r s t e ri l e s od iu m c h lo r id e fo r i n je c t i on a re t h e m os t c om m o nl y us ed d r ug di lu e nt s . ( 1 ) To ac c e l e ra t e t he di s s o lu t io n ra t e a nd pe rm i t r a p i d r ec on s ti tu t io n , m any p o wd e r s a r e l y o p hi l i z ed ( f re e z e dr i e d ). ( 2 ) S om e o f t h es e d r ug s c om e i n v ia ls t ha t c on t ain a d o ub l e c h am b e r. ( a ) Th e to p c ha m b e r , c on t a in in g s t e ri le wa t e r fo r i n je ct i on , i s s ep a ra t ed fr o m t h e u n r ec on s ti t ut e d d r ug b y a r u bb e r c l o s u r e. ( b ) To d is lo d ge th e i n ne r c lo s u r e a n d m i x t h e c o nt e n ts of th e c om p ar t m e n ts , e xt e r n a l pr e s s ur e i s a pp li e d t o t h e o u te r ru b be r c l o s u re . Th is s y s te m e li m in a t es th e n e e d t o e nt e r t h e v ia l t wi c e , t h er e b y re d uc in g t h e r i sk of m i c ro bi a l co n ta m in a t io n . 3 . S om e d r ug s c om e i n v i a ls th a t m a y b e a t ta c hed t o a n d il u en t c on t ai n ing b ag fo r r e c on s t i tu t io n a n d a dm ini s t ra t io n ( AD D - V a n t ag e b y A b b ot t ) (F i gu r e 2 7 -7 ) . P r e m ea s u r ed d ru g a n d di l ue n t m a y a ls o b e s t o red i n se p a ra t e c o m p a r tm en t s wi t hi n a d el i ve r y s y s t em t h en c o m bi n ed at th e p o in t o f u s e. ( D up l e x b y B . B r aun ) .
a . Th e A D D - Va n ta g e v ia l i s s c r e we d in t o t he to p o f an A D D - V an t ag e d i lu en t ba g , a n d t h e r u bb e r d ia p hr a gm is di s l od g ed f ro m t he v i a l , a l lo wi n g th e d li u en t s ol u ti o n t o d i ss ol ve th e d r u g. b . Th e r ec on s t i tu t ed A DD - V a n t ag e v ia l a nd I V ba g a re re a d y fo r ad m i ni s t r a t io n wh e n h u n g. c . Th e Du p le x s y s t em s ha s t wo - c o m p a r tm en ts wh e r e a se a l is b ro k e n a n d d r u g a nd d i lu e nt a re m i xe d t o f o rm a s o lu t io n . Th e r ec on s ti tu t e d d r ug is re ad y f o r p at i e nt a d m i ni s t ra ti o n . 4 . P r e fi l l ed s yr i n g e s a nd c a r t r id g es a re de s i gne d fo r m a xi m u m c o n v e nie n c e (s e e F i g ur e 2 7 - 6 ). a . P r e fi l l ed s yr i n g e s . D r u g s a dm in is t er e d i n a n e m e rg en c y ( e. g ., a t ro pi ne , e p in e ph r in e ) a r e a v a i la ble f o r im m e d ia t e i nj ec t io n wh e n p ac k a ge d i n p r e fi lle d s yr i n ge s . P.575
Figure 27-7. Left, Abbott ADDVantage System. Center, B. Braun Duplex System. Right, prefilled antibiotic piggyback dose. (Photograph by William Salkin.)
b . P r e f il l ed ca r t r i d ge s a r e re a d y - to - us e p a r en t er a l p a c k ag es th a t o f fe r im p r o v ed s t e ri li t y a nd ac c u r ac y . Th e y c o n s i s t of a p la s ti c c a r t r id g e h ol d er an d a p ref i ll e d m e di ca t io n c a rt r id g e wi t h a n e ed l e a tt ac h ed . Th e m ed ic a ti o n is p re m i xe d a n d p r e m e as u re d . Na r c o t ic s s uc h a s , m e p e ri di n e ( D em e r ol ) a n d h y d r om o rp hon e ( D i l au d id ) ar e c om m o n l y a v a i la bl e i n p r e fi ll e d c art r i dg e s. 5 . I n fu s io n so l u ti o ns a re d i v id ed in t o t wo c a te go r i es : s m al l - vo l um e pa re n t e r al s ( S V P s ) , t h os e h a v in g a vo l um e l es s t ha n 1 0 0 m L; a n d l a r ge - vo l u me pa r en t e r a ls ( L V P s ), t ho s e ha v i n g a vo l um e o f 1 0 0 m L o r g r eat e r . In f us io n s ol u ti on s a re us e d f o r t h e i n te r m i t te n t o r c on t inu o us in f us io n o f fl ui ds o r d r u gs (s ee V I .B ) . B . P a ck a g in g m a t e ri a ls. Ma t e r i a ls u s e d to pa c ka g e p a re n te r a l p ro d uc ts i n c l ud e g l as s a nd pl as t ic p o l y m er s . P.576
1 . G l as s , t h e o ri g in a l p ar e n t er a l p ac k a gi n g m a t e ri a l , h as s u p e r io r c la r i t y, f a c i l it a ti n g i n sp ec t io n f o r p a r ti c u la t e m a tt e r . C om p a re d t o p l as t ic , g l as s le s s f re qu e nt ly i n t er a ct s wi t h t he p re pa ra t i on it c o n ta in s . 2 . P la s t ic p ol ym e r s u s ed f o r p a re n te r al pa c k ag in g in c l ud e po l y v i n y lc hl o ri d e ( P V C ) a n d p ol y o l e fi n. a . P V C i s f l e xi b le an d n on r i gi d . b . P o l yo l e f i n i s s e m i r ig id ; un l ik e P V C , i t c a n b e s t o re d u p ri g ht . c . B ot h t y p e s o f p la s t ic of f e r s e ve ra l a d va n t ag e s o v e r g la s s , i nc lu d in g d u ra b il i t y, e a si e r s to r a ge an d d is pos a l, r ed uc e d we i g h t, an d i m p r o v e d s a f e t y .
VI. PARENTERAL ADMINISTRATION ROUTES. P a r e nt e r al p re pa r a ti o ns m a y be gi ve n b y a v a r ie ty o f a dm in is t ra t io n ro u tes . A. S u b c u t a ne o us ( S C or S Q ) a dm i ni s t r a ti on r e fer s to in j ec ti o n i nt o th e s u bc ut a ne o us ti s s ue be ne a t h t he s k in la y e r s, us ua l l y of th e ab do m e n , a r m , o r th ig h . I n su l in is a n e xa m p l e o f a s u bc u t an eo us l y ad m i n is t e re d d r u g. B . I n t r am u sc u la r ( I M) a d m in is t r at io n m e an s i nj ec t io n i n to a m us c l e m a ss . Th e m i d d e l to id a re a a n d g lu t eu s m e di us a re c om m o n i n jec t io n s i te s . 1 . N o m o re th a n 5 m L o f a s o l ut i on s h ou l d b e i nj ec t ed b y th is r ou t e. 2 . D r ug s i n te nd e d f o r p ro l on g ed o r d el a y e d a bs or p t io n s uc h a s m e d ro xy p r o g e s te r on e ( De p o - P ro ve r a ) a nd m e t h y lp r e dn i s o lo n e ( D e po - Me d r o l ) c om m o n l y a r e a dm i ni s t e re d in t r am us c u la r l y . C . I n t r a ve no u s ( I V ) a dm i n is t ra t io n i s t h e m o s t im p o r t an t a n d m o s t co m m on p a r en t e ra l a dm i ni s t r a ti on r o u te . It al l o ws a n i m m ed i a te th e r ap eu t ic ef f ec t b y d e li v e r i ng th e d r u g d ir ec t l y i nt o th e c i rc ul a ti on . Ho we v e r , t h is ro u te p re c l ud e s r ec a ll o f an in a d v e rt e nt d ru g ov e r d o s e . An t ib i ot ic s, c a rd i ac m e di ca t io ns , a n d m a n y o th e r d r u gs ar e gi v e n i nt r a v e no u s l y . D . I n t r ad e r ma l ( I D ) a dm i n is t ra t io n i n v o l v es in je c ti o n i n to th e m os t s up e r fic i al s k i n l a ye r . Be c a us e t h is ro u te c an de l i v e r o nl y a l im i ted d r ug v o lu m e , i ts us e ge n e ra l l y i s r e s t ri ct e d t o s k i n t es ts an d c e r ta i n v a c c in es . E . I n t r a- a r t e r ia l (I A) a dm i ni s t r a ti on is in je c ti on d i r ec tl y i n to an a rt e r y . It d e li v e r s a h i gh d ru g c on c en t ra t io n t o t he ta r ge t s i te wi t h li t tl e di lu t io n b y t h e ci r c u la ti o n . G e n e r al l y , th is ro u te is us e d o nl y f o r r a di op a qu e m a te r i al s , th r om b ol y t ic ag e n ts , a nd s om e a n ti n eo p la s t ic ag en t s . F . I n t ra c a rd i ac ( I C ) a dm i n is t ra t io n i s i nj ec t io n o f a d r ug di r ec tl y i n to th e he a r t . G . H yp o d e r m o c l ys i s r e f e r s t o i n je ct i on of la r g e vo l u m e s o f a s o lu t io n i n to s u bc ut a ne o us ti s s ue to pr o v i d e a c o nt i nu ou s , a bun d a nt d ru g s up pl y . Th i s ro u t e o cc a si on a ll y is us ed f or a n t ib io t ic ad m i ni s tr a ti o n i n c h il d re n . H . I n t r as p i na l a dm i ni s t ra t i on r ef e rs to in j ec ti o n in t o th e s pi na l c ol um n . Lo c al a n es t he t ic s ( e .g . , l id oc a in e , b u pi va c a i ne ) a r e fr eq u e nt l y ad m i ni s te r ed v i a t h is ro u te d u r in g s u rg ic a l p ro c ed u re s . I . I n t ra - a r t ic u la r a dm in is t r at i on m e an s i nj ec t io n i n t o a j o in t s pa ce . C o rt ic o s te r o id s ( e . g ., m e t h y lp r ed n is ol one , h y d ro c o r t is on e ) u se thi s ro u te fo r th e t re a tm en t o f a r t h ri t is . J . I n t ra s yn o vi a l a dm in is t r a t io n re f er s t o i n je c t i on i n to th e j o in t fl ui d .
K . I n t r a th e ca l (I T ) a dm in i s t r a ti o n is in je c ti on in to t he s p in a l f lu i d; it s o m e t im es is u s ed fo r an t ib i ot ic s a nd c a nc e r ch em o th e r ap y . L . E p id u r a l ( E D ) ad m i nis t r at i on r ef e rs to t he in jec t io n o f m e di c a t io ns , u sua l l y lo c a l a n es t he t ic s a nd / or na r c ot i c s ne a r o r o u ts id e th e d u r a m at e r o f th e c en t ra l n e r vo us s ys t em . Th is ro u te is f r eq u e nt l y us ed du r in g c hi ld b i rt h . P.577
VII. PARENTERAL PREPARATIONS A. I V a d m ix t u r es . Th es e p r e pa r at i on s c on s i st of o n e o r m o re s t e r il e d r ug p r o du c ts a d d ed to an I V f l ui d, ge ne r a ll y d e xt r o s e o r s od ium c h lo r i de s o lu t io n a lo ne o r i n c om b in a ti o n. I V a dm i xt u re s a r e u s e d fo r d r u gs i n te n d ed fo r c o nt i nu ou s i n fu s io n . D r u g s t ha t m a y c a us e i r ri t a ti o n o r t o xi c i t y wh e n gi v e n as a r ap i d d ir ec t I V i n je c ti on a r e al so pr e pa r e d as I V a d m i xt u r e s . B . I V f lu i d s a nd e le c t r ol yt e s 1 . F lu i ds us e d i n t he p rep a r a ti on an d a dm i ni st r a tio n of pa r e nt e ra l p r o du c ts in cl u de s t e ri le wa t e r an d s od i um c hl o ri d e , d e xt r o s e , a n d R i n g er ' s s ol u ti o ns , a ll o f wh i c h h a ve m u lt i pl e u s e s . Th e s e f lu i ds s e r ve a s v e h ic les in I V a dm i xt u r e s , p ro vid i ng a m e an s f o r r ec o ns ti t u ti ng s t e ri le p o wd e rs . Th e y s er v e a s t h e b as is f o r c o r re c ti n g b o d y fl u id an d e l ec t ro l y te d is tu r b an c e s a nd p ro vid e a c a l o ri c s o u rc e i n p ar e n t er a l n u t ri t io n . a . D ex t r o se ( D - g lu c os e ) s o l u ti o ns a re th e m os t f r e q ue n tl y us e d g lu c o s e s o lu t io ns i n pa r en t e ra l p r ep a r at i ons . ( 1 ) U s es . G en e ra l l y , a s o l u ti on o f d e xt r o s e 5% in wa t e r ( d 5 w) is us ed as a v e h ic le in I V a dm i xt u r es . D 5W m a y a ls o s e r v e a s a h y d r a ti ng s o l ut i on . In hi gh e r c o nc en t r at i on s ( e .g . , a 10 % s o lu t io n i n wa t e r) , dext r o s e p r o v id es a s ou rc e o f c a r bo h yd ra t es in pa r en t er a l n u t ri t io n s ol u ti o ns . ( 2 ) C o ns i de r a t i on s . B ec a u s e th e p H o f D 5W ra ng e s f r om 3. 5 -6 . 5 , i ns ta b il i t y m a y r e s ul t i f i t i s c om bi n ed wi t h a n a c i d -s e ns it i v e d r ug . ( a ) D e xt r o s e c o n c e n tr a tio n s g r ea t e r t ha n 1 5 % m u s t b e a dm in is t e re d th r ou g h a c e nt r a l v e i n. ( b ) D e xt r o s e s ol u ti on s s h o ul d b e us ed c a ut i ou sl y i n p a ti e nt s wi t h d ia be t es m e ll i tu s . b . S o di u m c h lo r i d e us ua l l y is g i v e n as a 0 . 9% s o l u ti on . B ec au s e it is i s ot o n ic wi t h b l oo d , t h is s ol u ti o n is c al l ed no r m a l s al i ne s o lu t i o n ( N S S ) . A s o lu t io n o f 0. 4 5 % s o di um c h lo r id e i s t e rm ed h al f - no rm a l sa l in e . A s o l u ti on o f 0 .2 2 5% s o di um c h lo r i de i s te rm e d q ua r t e rn o rm al s a li ne . ( 1 ) S o di u m c h lo r i d e f o r i n j ec t i on , wh i ch is a so lu t i on of 0 .9 % s od iu m c hlo r i de , i s u s ed as a v e h ic le i n I V ad m i xt u r es an d fo r fl ui d an d el ec t r ol yt e re pl ac e m en t . In s m a l le r v o lu m e s , it is s u it a b le fo r th e re c o ns t i tu tio n of v a r io us m e di ca t io ns . ( 2 ) B a ct e r i os t a ti c s o d ium c hl o r i de f o r i n j ec t i on, wh i c h i s a ls o a 0 . 9% s ol u t io n , is i n t en de d s o le l y fo r m u lt ip l e r e c o ns t it u ti o ns . I t c on t a in s a n a ge n t t ha t in hib i ts b a ct e r ia l g r o wt h (e . g ., be n z y l a lc oh o l, p ro p y lp a ra b e n, m e th y l p a ra b en ) , wh i ch al lo ws f o r it s u s e in m u lt i pl e -d os e p r e pa r a ti on s .
c . Wa t e r s a re us e d f o r re c on s t i tu t io n a n d f o r d il ut i o n o f s uc h I V s ol u ti o ns a s d e xt r o s e a n d s o d iu m c hlo r i de . W at e rs s ui t ab l e f or p a re n te r a l p re p a ra t io ns i nc l ud e s t e ri le wa t e r fo r in je c ti on a n d b ac te r i os ta t ic wa t e r f o r i n je ct i on . d . R i n ge r ' s s o lu t i on s , wh i c h a re ap p ro p r ia t e f or f l ui d a nd el e c t r ol yt e rep l ac em e nt , c om m o n l y a r e a dm i ni s t e re d to po s ts u rg ic al pa t ie nt s . ( 1 ) L ac t a te d R in g e r 's inj e c t io n (i . e ., H a rt m a n n 's s ol u ti o n, R in g e r 's la ct a te so l ut i on ) c o nt a in s s od iu m l ac t at e , s o di um c h lo r id e , p o ta s s iu m c hl o r id e , a nd c a lc iu m c hl o ri d e . F r e q ue n tl y , it is c om b in ed wi t h de xt r o s e (e . g ., as 5 % de xt r o s e i n l ac t a te d R i n g er ' s i n je c ti on ) . ( 2 ) R i ng e r ' s i n je c t io n d if f e rs f ro m l ac t at e d R i ng er ' s i nj ec ti o n i n t ha t it doe s n o t c o nt a in s o di um la c t a te an d ha s sl i gh t l y d i f fe r en t c o nc en t r at i on s o f s od ium ch lo r i de a n d c al c i um c h lo r id e . L ik e l ac ta t ed R in g e r 's in je c ti o n , i t m a y b e c om bi n ed i n s o lu t io n wi t h d e xt r o s e . 2 . E le c t r o l yt e p r e p a r a t io n s . W ith io ns p re se n t in b ot h i n t ra c e l lu la r an d e xt r a c e l lu la r fl u id , e l ec t ro l y t es a re cr uc i al fo r v a ri o us bi ol o gi ca l p r oc es ses . S ur g ic al a n d m ed ic a l p at i en ts wh o c a n no t ta k e fo o d b y m o u t h o r wh o n e ed nu t r it io n al s u pp l em en t at i on re q ui r e t h e a d di t io n o f e l ec t ro l y te s i n h yd r a ti n g s o l ut i on s o r p a r en t e ra l n u t ri t io n s ol u ti o ns . a . C a t io n s a r e p os it i v e l y c ha r g ed el ec t r ol y t es . ( 1 ) S o di u m is t he c h ie f e xt r a c e l lu la r c a ti o n. ( a ) I mp o r t an c e. S od i um p l a y s a k e y r ol e i n i nt e rst i t ia l o sm ot ic p re s s u re , tis s u e h yd r a t io n , ac i d- b as e b ala n c e , n e r v e - im pu ls e t r ans m i s s io n , a nd m u s c le c on t r ac t io n . ( b ) P a r en t e r al so d i um pr e p a r a ti o n s i nc lu de s o diu m c hl o r id e , so d iu m ac et a t e , a nd s o di um ph os p ha t e. P.578
( 2 ) P o ta s si u m is t he c h ie f in t r ac el lu l a r c a t io n . ( a ) I mp o r t an c e. P ot a s s iu m p a r ti ci p at es in c a r boh y d r a t e m e t ab o li s m , p r ote i n s yn t he s i s , m u s c l e c o n t rac t io n (e sp ec i al l y of ca r dia c m us c l e ) , a nd ne u ro m u sc u la r e xc i t a b il i t y . ( b ) P a r en t e r al p ot a ss i um p r e pa r a t io n s i nc lu d e p o t ass i um a c et a te , p o tas si um c h lo r id e , a nd po t as s i um p h os p ha t e. ( 3 ) C a lc i um ( a ) I mp o r t an c e. C al c i um i s e s s en t ia l t o n e r ve -i m p u ls e t r a nsm is s i o n , m u sc l e c o nt r ac t io n , c ar d ia c f un c t i o n, bo n e f o rm at i on , a nd ca p il la r y a nd ce ll m e m b r a ne p e r m e ab i li t y . ( b ) P a r en t e r al ca l c iu m p r e p a r at i o ns in cl u de c a lc i um c hl o r id e , c a lc i um g lu c on a te , a n d c al c i um gl uc e pt a te . ( 4 ) M a g ne s iu m ( a ) I mp o r t an c e. Ma g n es i u m p la ys a vi t al pa r t i n e n zy m e ac ti v i t ie s , ne u r om us c ul a r t r a ns m i s s io n , a nd m u s c le e xc i t ab i li t y. ( b ) P a r en t e r al p r ep a r a tio n . Ma g n es i um i s g i v en p a r en t e ra ll y a s m ag ne s iu m s ul f a te . b . An i o n s a r e n eg a ti v e l y c ha r g ed el ec t r ol y t es . ( 1 ) C h lo r i d e is t he m a jo r e xt r a c e ll u la r a n io n .
( a ) I mp o r t an c e. A lo n g wi t h s od i um , i t re gu l at es in t e rs t it i al osm o ti c p r es su r e an d h e lp s t o c on t r ol bl o od pH . ( b ) P a r en t e r al ch l o r i de p r e p a r at i o ns in cl u de c a lc i um c hl o r id e , p ot as s i um c hl o ri d e , a n d s od i um c hl o ri d e. ( 2 ) P h os p ha t e i s t he m aj o r i n t ra c e l lu la r an i on . ( a ) I mp o r t an c e. P ho s p ha t e i s c ri t ic al t o v a r io u s e n z ym e ac ti v i t ie s . I t a ls o i n fl u en c e s c a lc iu m l e v el s a nd ac ts a s a bu f f er t o p r e ven t m a r k ed c h an g es i n a ci d -ba s e b a la n ce . ( b ) P a r en t e r al p ho s ph at e p r ep a r a t io n s i nc lu de p o t ass i um p h os ph a te and s o d iu m p h os p ha t e. ( 3 ) Ac e t a t e ( a ) I mp o r t an c e. A c e t at e i s a bi ca r bo n at e p r ec u rso r t ha t m a y be us ed to pr o vi d e a l ka li t o as s i s t i n t he p res e r v a ti o n o f p la s m a p H . ( b ) P a r en t e r al ac e t at e pr e p a r a ti o n s i nc lu de po ta ss i um a c et a te an d s od iu m a c et a te . C . P a r e n te r a l a n ti b i o ti c p r e p a ra t i on s a r e a v a i lab l e a s s te r il e u n re c o n st i tu t e d p o wd e r s , wh i c h m us t b e r e c on s t i tu t ed wi t h s t e ri le wa t e r , n or m a l s al i ne , o r d 5 w, o r a s a st e ri l e, r ea d y- t o -u s e l iq ui d p a r en t er a l. 1 . Ad m i n is t r a t io n me t ho d s . Pa r en t e ra l a n ti bi o tic s m a y b e g i v e n i nt e rm i tt e n tl y b y d i r ec t I V in j ec ti o n, s h o rt -t e r m i nf us i on , i n t ra m u s c u l a r i nj ec t io n , o r i n t ra t hec a l i n je c ti on . 2 . U se s . Pa r en t e ra l a n tib i o ti c s a r e u se d to t re a t i n f ec ti o ns th a t a re s e r io us an d r e q ui r e h ig h an ti b io t ic b lo o d l e v el s o r wh e n t h e ga s t ro i nt es t in a l t r ac t i s c o nt r a in di c a t ed , s uc h a s i n i l eu s. 3 . D o si n g f r e q ue n ci e s o f pa r e nt e ra l a n ti b io t ic s va r y f r o m o nc e d ai l y t o as o ft e n as e ve r y 2 ho u rs , d e pe n di ng o n t he ki ne t ic s o f t h e dr u g , s e ri ou s ne s s o f th e in f ec t io n , t h e s i te of in f ec ti o n, an d t h e p a ti en t ' s d is ea s e o r o r g an st a tu s ( e .g . , re n al d i s e as e ) . D . P a r e n te r a l a n ti n e op la s t i c a ge n t s. S tu d ie s s ug g es t th a t t he s e m e di c a ti o ns m a y b e to xi c t o t h e p e rs on n el wh o p r e pa r e a nd ad m i n is t e r t he m . Th e e vid e nc e i s n o t c o nc lu s i v e , wh i c h ne c e s s i ta t es s p ec ia l p r ec au t ion s to en s u r e s af e t y an d m i ni m i z e r i sk s. I n r es p on s e to c o nc e r ns , t h e O cc u pa t io n al S a f e t y an d He al t h Ad m i ni s t ra t io n ( O S H A ) h as pu b li s h e d a t e c h n ic al m a nu a l, “ C on t ro l li n g O c c u pa t io n al E xp o s u r e t o H a za r d o us D ru gs . ” E v e ry f a c il it y m us t h a ve a wr i t t e n p la n th a t i nc lu de s d ru g p r e pa r a ti o n p re c au ti o ns , s t or a ge , t ra ns po r t , p e rso n al p ro t ec t i v e e qu ip m en t ( gl o ves , g o wn s , m a s k s ) , wo r k e q ui p m e n t, wa s t e d is po s a l , s p il l m an ag e m e n t, an d pe r s on ne l m e di ca l s u r v ei ll a nc e, 1 . Ad m i n is t r a t io n me t ho d s . Pa r en t e ra l a n ti ne o pl a s t ic s m a y b e g i v e n b y d i r ec t I V i n je c ti on , s h o rt - t er m i n fus i on , o r lo n g- t e rm i n fu s i o n . So m e a re ad m i n is te re d b y a n o n - IV r ou t e , s u c h as the s u bc u t an eo us , in t ra m us c u l a r, in t r a- a r te r ia l , o r in t r a th ec a l r o u t es . 2 . S a fe an t i ne o p la s t ic h a n d li n g g u i de l in e s. A ll p h a rm ac y an d n u rs i ng pe r s on ne l wh o p r e p ar e o r ad m i n is te r a nt i ne op l as ti cs s h ou ld r e c e i v e s pe ci a l t r ai ni n g i n th e f o l lo wi n g g u id e li ne s t o re d uc e t h e r is k o f e xp o s ur e t o t he se d ru gs . a . A ve r t ic a l l a mi n a r fl ow ho o d s ho u ld be us ed d u r in g d r u g p re p a ra t io n , wi t h e xh a u s t di r ec te d to th e ou t s i d e.
P.579
b . A ll s y ri n ge s a nd I V t ub i ng s h o ul d h a v e L u e r -Lo k f i t ti n gs (s e e I X. B . 4 . a) . c . C l ot h i ng . Pe r s o n ne l s h o ul d we a r p e rs o na l p r o te c ti v e eq u ip m e n t i nc lu d in g c l os ed f r o n t c u f f ed s u r gi c a l g o wn s a n d d ou b le - la ye r e d lat e x s u r g eo n ' s g lo v e s . d . N e ga t i ve - p r es s u re t ec h n i qu e s ho u ld be us ed d u r in g wi t hd r a wa l of m ed i c a t io n f r o m vi a ls . Th is wi l l p re v e n t p r es s u r e f r om bu i ld ing u p i ns id e t h e v i a l a nd c a us in g t h e d r u g t o s pr a y a ro u nd t h e n ee d le . e . F in a l d o sa g e a dj u s tm e n t s ho u ld be m a de in to t he v i al , am pu le , or di re c tl y i n to a n ab so r be n t g a u z e p ad . f . P r i m in g e q u ip m en t . Sp e c i al ca r e s ho ul d b e tak e n wh e n I V a dm i ni st r a tio n s e ts a r e pr im e d. Th e I V t ub i ng s h o ul d b e p r im ed be f o re a dd in g th e d r ug , or t he t u bi n g c a n b e p r im ed wi t h d r u g-f r e e f l ui d b e fo r e c on ne c ti n g i t t o th e c he m o t he r apy d r u g c o nt a in e r . I f t h es e a r e no t a v ai l ab le , p rim e th e t ub i ng in t o s te r il e g a u z e i n a s e al a bl e p la s ti c b ag . g . P r op e r p r oc ed u r es s ho u ld be f ol lo we d f o r d i spo s a l o f m at e r ia ls us ed in t h e p r e pa r a ti o n a nd ad m i ni s tr a t io n of an t in e op la s ti cs . ( 1 ) N e ed l es s h ou l d n ot be c l i pp ed o r r ec a pp e d. ( 2 ) P r e pa r a t io n s s ho ul d b e d is ca r d ed in c o nt a ine r s t h at a re pu nc t u re - p roo f , l e ak p r o o f, an d p r op e r l y l a be le d . ( 3 ) H az a r d ou s w as t e. Th e r e i s n o c o m p l et e l y a c c e pt a bl e m et h od fo r di s po s in g o f h a za r do u s wa s t e . H i gh - te m pe r a tu r e i nc in e ra t io n m a y be t he p re f er r e d m et h o d. Th e s e m a te r ia ls m a y a ls o b e b u ri ed in an E P A -l ic e n s e d h a z a r do us wa s t e d u m p o r c h em ic al l y de ac t i v a te d . h . A f te r re m o v a l o f gl o v es , pe r s o nn e l sh o ul d w ash h a nd s t h o ro u gh l y. i . P e rs on n el an d e q ui pm e n t i n v o l ved in th e p r e par a t io n an d a dm in is t r at i on o f a n t in eo p la s ti c a ge n ts s ho u ld be m on i t o re d ro u tin e l y . 3 . P a ti e n t p r o bl e ms . In fu s io n p hl e bi t is a n d e xt r a va s a ti o n a r e t he m o s t s er i o us p r o bl em s t h at m a y oc c u r d u ri n g t h e a dm in is t ra t ion o f p a re n te r al an t in e op la s ti cs . a . I n fu s io n ph l eb i t is ( inf l am m a t io n o f a v e i n) is c h a ra ct e ri z e d b y p a in , swe l l i n g, h e a t se n s a ti o n, a nd re d ne s s a t t he in f us io n s i te . D r u g di lu t io n a n d f il t r at i on c a n e l im in a te o r m i n im i z e t he r is k o f p hl e bi t is . b . E x t ra va s a t io n (i n fi l t ra t i on of a d r ug in t o su b c u t a ne o us t is s ue s s u r r oun d in g th e ve i n ) i s e s p ec i al l y ha r m fu l wh e n a n ti n eo pl as t ic s wi t h v e s ic a nt p ro pe r t ie s a r e a d m i ni s te r ed . Me a s u re s m us t be ta ke n i m m ed i at el y i f e xt r a va s a t io n o cc u rs . ( 1 ) D e pe nd i ng on th e d ru g in v o l v e d, em e rg e nc y m e as u re s m a y i nc lu d e s to p pi n g t h e i n f us io n , i nj ec t in g h y d r oc o r ti s o n e o r a n ot h er an t i- i n fl am m at o r y ag en t di r ec t l y in t o t h e a f f ec te d a r e a, in je c tin g an an t id o te ( if a v ai l abl e ) , a n d a pp l yin g a co ld c om p r es s ( t o fa ci l it a te a d r ug - an t ido t e re ac t io n ) . ( 2 ) A wa r m c om p re s s m ay t h e n b e a pp l ie d t o i nc re a s e th e fl o w o f b l oo d , an d th us t h e ves ic a nt , a wa y f r o m d a m a g ed ti ss ue . E . P a r e nt e r a l b i ot e ch n ol o g y p r o d u c t s a r e c re a te d b y th e a pp l ic at i on of r e c om bi na n t t ec h no l og y t o t he ge ne r a ti o n o f t he ra p e ut ic ag e nt s, su c h as m o no cl o na l a n t ib od i es , v a ri ou s v ac c in e s , an d c ol o n y -s t im ul a tin g fa c to r s .
1 . U se s of th es e a g en t s i n c l ud e c a nc er t he r ap y , in f ec t io ns , t ra ns p la n t r ej ec t io n , r h e um a to id a rt h r it is , i n fla m m a to r y b o we l d is e as e, r es p i ra t or y d is e as es , an d m a la r ia a s we l l as v a c c in es ag a in s t c an ce r , H IV in f ec t io n, a nd he p at i ti s B . 2 . C h a ra c te r i s t ic s . P r o te i n a nd p ep ti d e b io t ec hno l og y d r ug s h a v e a s h o rte r h al f l i f e, of t en r eq u ir e s p ec ial s to r ag e s uc h a s r e f ri ger a t io n or f re e z i ng , a n d m u s t n o t b e s h ak en v i go r o us l y t o a v o i d de s t r o y i ng th e p r o te in m ol ec u le s . 3 . Ad m i n is t r a t io n . Ma n y b i ot ec h no l og y p ro d uc ts r e q ui r e re c o ns t it u ti o n wi t h s te r il e wa t e r o r no r m a l s al in e an d m a y be p ar e nt e r al l y ad m i n is t e re d b y d ir e ct I V i n je c ti on o r in f us i on , o r b y i n t ra m u s c u la r or s u bc u ta n eo us i n je c t i on .
VIII. IRRIGATING SOLUTIONS. A l t h ou gh t he s e s t e ri l e p ro d uc ts a re m a nu f ac t u re d b y t h e sa m e s t a nd a rd s u s ed to p r o ce s s I V p re p a ra t io ns , t h e y ar e no t in t e nd e d fo r i n f us i o n i n to t he ve no u s s ys t e m . L ab e li ng di f f er en c es b e t we e n i r r ig a ti on s o lu t io ns an d i nj e c t i on s a r e s p ec if i ed in th e Un i te d St a t es P ha r m a c o pe i a ( U SP ) a nd r e fl ec t d i ff e r en c es in a cc e pt a bl e p a r ti c u la t e m a t t e r l e v el s , v o lu m e o f s o l u ti on a v ai l ab l e f o r us e , a n d t he c o nt a in e r d es ig n . P.580
A. T o p i c a l a dm i n is t r a tio n . I r ri ga t in g s ol u ti o ns fo r t op ic a l us e a r e p ac kag e d i n p o ur b o t tl es s o th a t t h e y c an b e ap pl i ed di r ec t l y o n to th e de s i r ed a re a . Th e s e so l u ti on s a r e i n t en de d fo r s uc h p ur p o s e s as i r ri ga t in g wo un d s , m o is t en in g d r es si n gs , an d c l ea ni n g s ur g ic al in s t r um e n ts . B . I n f us i o n o f i r r i g a ti n g s o l u ti o ns . Th is p ro c e dur e , us in g a n a dm i ni s t r a tio n s e t a t t ac he d to a F ol e y c a t he t e r , is c o m m on l y us ed fo r m a n y s u r gi c a l p a ti e nts . S u r g eo ns pe r f o rm in g u r ol o gi c a l p r oc e du r es of t en u s e i r ri g at i ng s o lu t io ns to p e rf us e t i ss ue s i n o r de r to m a in ta i n t h e i nt e g ri t y of t he s u r g ic al fi e ld , re m o ve bl oo d , a n d p r o vi de a c le a r f ie l d o f v ie w. To d e c r ea se th e ri s k o f i n fe c ti o n, 1 m L o f N eo s po r in G . U . I r r ig a nt , an an t ib io ti c p r e pa r at i on , o f t en is ad d e d t o t he s e so l ut io n s. C . D i a l ys i s . D i a l y s a t es a r e i r r ig a ti n g s ol u ti on s us e d i n t he di a l ys is o f p ati e n ts wi t h s uc h d is o r de r s as r en a l fa i lu r e , p oi s o n in g , a nd ele c t ro l y t e d is tu r b an c e s . Th e s e p r o du c ts re m o v e wa s t e m a te r i al s, s e r um e l ec t ro ly t e s , a n d t o xi c pr o du c ts f r o m t he b o d y. 1 . I n p e r it o n ea l d i a l ys i s , a h y pe r to n ic di al y s a te is in f us ed di r ec t l y i n to t he p e r it o ne a l c a v i t y v i a a s u r g ic al l y im pl a nt e d c a t het e r . Th e d ia l ys a t e , wh i c h c on t ai ns d e xt r o s e a n d e le c t r o l y tes , re m o ve s h a rm f ul s u bs t a nc es b y os m o s i s a nd di f f us io n . A f t e r a s p ec i fi ed pe r i od o f ti m e, th e s ol u ti o n is dr a i ne d . A n ti b io t ics an d he p a ri n m a y b e ad d ed to th e d i al y s a te . 2 . I n h em o di a l ys i s , t h e p a t ie n t 's bl o od i s t r a ns fus e d t h ro u gh a d ia l y z i ng m em b r an e u n i t t ha t re m o v e s t h e h ar m f ul s u bs t an c e s f r om the p at i en t ' s v a sc u la r s ys te m . A f t e r p a ss in g t h r ou g h t he di aly z e r , t h e b lo o d r e en t e rs t h e b o d y th r ou g h a v ei n .
IX. NEEDLES AND SYRINGES
A. H yp o d e r m i c ne e dl e s a r e s ta i nl es s -s te e l o r a lu m in um de v i c e s t h at pe ne t r a te th e s ki n fo r th e p u rp os e o f ad m in is t e ri ng o r t r an sf e r rin g a p a re n te r al p ro du c t (F i g ur e 2 7 8). 1 . N ee d l e g au g e i s t he o u ts i de di am e te r of th e ne e dl e s h af t ; t h e l ar g e r t he n um be r , t h e s m a ll e r t h e d ia m e t e r. G a u g es i n c om m o n u s e r a n ge f ro m 1 3 (l a rg es t d ia m et e r ) t o 27 . Su b c u t an eo u s in j ec t io ns us u al l y re q ui r e a 2 4 - ga u ge o r 2 5 -g au g e ne e dl e . I n t r am us c u la r in je c ti on s r e q ui r e a ne e dl e wi t h a ga u g e b et we e n 19 an d 2 2. N e ed l es b e t we e n 1 8 g a ug e a n d 20 g au g e a re co m m on l y us e d f o r c om po un d in g p a re n t e ra ls . 2 . B e ve l s a re s l an t in g ed g es c u t i n to ne e dl e t ip s t o fa c i li t a te in je c ti on t hro u g h t i ss ue o r r u bb e r v ia l c lo s u r e s . a . R e gu l a r -b e ve l ne e dl es a r e t he m o s t c om m on ly u s ed t y p e, an d th e y a re s u i ta b le f o r s u bc u ta ne o us a n d i ntr a m us c u la r i n je c t i on s a nd h y p od e rm oc l y si s. b . S h o r t -b e ve l n e ed l es a r e us ed wh e n o n l y s ha l lo w p e n e t ra t io n i s r e qu i red ( as in I V i nj ec t io ns ) . c . In t r a de r m a l- b e ve l n ee d l es a re de s i g ne d f o r in t r a de rm a l i nj ec t io ns and h a v e t he m os t be v e le d ed ge s .
Figure 27-8. Needles. Top, 20 gauge-3½ inch. Left to right, 18 gauge-1½ inch, 20 gauge-1 inch, 23 gauge-1 inch, 25 gauge-5/8 inch, and 27 gauge-½ inch.
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Figure 27-9. Syringes. Left to right, 60 mL catheter tip, 60 mL, 30 mL, 10 mL, 5 mL, 3 mL, and 1 mL.
3 . N ee d l e l en g t hs r an g e f r om ¼ i nc h t o 6 in c h es . C h o ic e o f n e ed le le n gt h d e pe n ds o n th e d es i r ed pe ne t r a tio n . a . F or c om p ou n d in g par e n t e r al p r ep a r a ti o n s, 1 ½ - in ch - lo n g n ee dl e s a re c o m m on l y u s ed . b . I n t ra d e rm a l a n d s u bc u t a ne o us i nj e c ti o ns ne c es s i ta t e a s h o rt ne e dle l en g th , u s ua ll y ¼ i n c h to 5/ 8 i nc h . c . In t r a sp i n al i nj e ct i o n r e q ui r es a n ee d le le ng t h o f 3½ i nc h es . d . I V i n f us i o n r e qu i re s ne e dl e s t ha t ra n ge in le ngt h f ro m 1 ¼ i nc he s t o 2 ½ i n ch es . B . S yr i n g e s a r e d e v ic es f o r i n je ct i ng , wi t hd r a wi ng , o r i ns ti l l i ng fl u id s . S yr i n ge s c o ns is t o f a gl as s o r p l as t ic ba r r el wi t h a ti g h t- f itt i n g p lu ng e r a t on e e nd ; a s m al l o p e ni ng a t t he ot h e r e nd a c c om m o d at es th e he ad o f a n ee dl e (F i gu r e 2 7 -9) . 1 . Th e Lu e r s yr i n g e , t h e f i rs t s y r i ng e de v e lo p ed , h a s a u n i v e rs al ne e dl e at t a ch m e n t a cc o m m od a ti ng al l n e ed le s i z e s . 2 . S yr i n g e vo l u m es ra ng e f ro m 0 .3 t o 6 0 m L . Ins u li n s y r i ng es ha ve un i t g r a da t io ns ( 1 0 0 u ni t s / m L ) r at h er t han v o l um e g r ad a ti on s . 3 . C a li b r a ti o n s a r e in t he m e t r ic s ys te m , a nd va ry i n s p ec i fi c i t y de p en di ng o n s yr i n ge s i z e . Th e s m al l er t h e s y r in g e, t he s m a l ler t h e m e a su r em en t s c a l e. 4 . S yr i n g e t i ps c o m e in s e v e r al t y pe s . a . L ue r - L ok t ip s a r e th re a d ed to en su r e t h at t he n e ed le f it s t ig h tl y i n t h e s y r i ng e . A n t i ne op l as ti c a ge n ts s ho u ld be a dm i n is t er e d wi t h s yr in g es o f th is t y pe ( se e V II . D . ) . b . L ue r - S l i p t i ps a re un th r e ad e d so t ha t th e s yr ing e an d n e ed le do no t lo c k in t o p l ac e . B ec a us e o f t h is , th e ne e dl e m a y b ec om e di s lo dg e d. c . E cc e nt r i c ti p s, wh i c h a r e s e t o f f ce n te r , a l lo w t h e n e ed l e t o r em a in pa ra l le l to t h e i n je c t i on s i te an d m in i m i z e ve no us i rr i ta t io n . d . C a t he t e r ti p s a r e us ed f o r wo u n d i r r ig a ti o n a nd a dm in is t r at i on o f en t e ra l f e e di ng s . Th e y a r e n o t int e n de d f o r i n je c t i on s.
X. INTRAVENOUS DRUG DELIVERY A. I n j e c t io n si t e s
1 . P e r ip h e ra l ve i n i n je ct i o n i s p r e fe r r ed fo r d ru gs t ha t d o n o t i r ri t a te th e ve i n s, a d m i ni s t ra ti o n o f i s o t on ic s o lu t io ns , an d p a ti en t s wh o r e q ui r e o nl y s ho r t - te r m I V t h e r ap y. G e ne r al l y , th e do r s al fo r ea r m s ur f ac e i s c h os en f or v e ni p un c t u r e. 2 . C e nt r a l ve in i nj e c ti on is p re f e r re d f o r a dm i nis t r at i on of i r ri t at i ng dr u gs o r h yp e r t on ic s o lu t io ns , p a ti e n ts re q ui r in g l on g - te r m I V t he r ap y, a nd s i tu a ti on s i n wh ic h a p e ri ph e r al l i ne c a nn o t b e m a in t ai ne d . L a rg e vein s i n th e t h or a c i c c a vi t y, s uc h a s t h e s ub c l a v i an v e in , ar e u s ed . P.582
B . I n f us i o n m et h o ds 1 . C o n ti n u ou s - d ri p in f us i o n i s t he sl o w, p ri m ar y - l i ne in f us io n o f a n I V p re p a ra t io n t o m a in t ai n a t he r ap e ut ic d r u g l e v el or p ro vi d e f lui d an d e le c t ro l yt e r ep l ace m en t . a . F low r a t es m us t be c a r e f ul l y m o ni t or e d. G e ner a l l y , t h es e r a te s a r e e xp r e s s ed as vo l u m e pe r un i t o f t im e (e . g . , m L / h r, d ro ps /m i n ) an d s om e ti m e s a s m g / m i n f o r c e r ta i n d ru g s . b . Ad m i n i st r a t i on . D ru gs wi t h a n a rr o w t h e ra p eut i c i nd e x s u c h as o xy t o c i n ( P i t oc in ) , h e pa r in , an d pr e s s o r a g en ts s u ch as no r e pi n ep h ri n e ( L e v o- P h ed ) a nd p h e n yle ph r i ne ( N eo - S y ne p h ri n e ) t y p ic al l y a re adm i ni s t e r ed b y t h is m e th od . 2 . I n te r m i tt e n t i n f us i on a l lo ws d r ug ad m i ni s t ra tio n at s p ec i fi c i nt e r val s (e . g . , e v e r y 4 h ou r s) a nd i s m os t o f ten us e d f o r a n ti bi o ti c s . a . T h re e d i f f e re n t te c hni q u es m a y b e u s e d . ( 1 ) D i r ec t ( bo l u s) i nj e c ti o n r ap id l y de l i v er s s m a ll v o l um es o f an un di l ut ed d r u g . Th i s m e t ho d i s us e d t o : ( a ) A ch ie v e an im m e di a te e f fe c t ( as i n a n e m e r ge n c y ) ( b ) A dm in is t e r d r ug s t ha t c an n ot be di l ut e d ( c ) A ch ie v e a t h er a pe u tic s e r um dr u g l e v el qu ic k ly ( 2 ) Ad d i t i ve se t i nf u s ion , us i ng a v o l um e- c on t rol d e v ic e, is ap p ro p ri a te fo r t he i n t er m i t t en t d e li v e r y o f s m a ll am ou n ts o f I V s o l ut io n s o r d i lu t ed m e di c a t ion s . Th e f l u id c h am be r is a t ta c hed t o a n i nd e pe n de n t f lu i d s up p l y o r pl ac e d d ir e c t ly u n d e r t he e s ta b li sh e d p ri m a r y I V lin e . ( 3 ) Th e pi g g yb a c k m e t ho d is us ed wh e n a d ru g c a nn o t b e m i xe d wi t h t h e p r im a r y s o lu t io n . A s p ec ia l c ou p li n g f o r t h e p r im ar y I V tub i ng pe r m i t s i nf us i on of a s u pp l em en t ar y s ec on d a ry s o lu t io n th r ou g h t he p ri m a r y s y s te m . ( a ) Th i s m e t ho d e l im in a te s th e n ee d fo r a s e c o n d ve n i pu nc t u re o r f u rt h er d i lu t io n o f t h e s up p le m e n ta r y p r ep ar a t io n . ( b ) Ad m i x t u re s i n wh i c h t h e v eh ic le is ad de d to th e d ru g a r e k no wn a s m a nu f ac tu r e rs ' p ig g y ba c k s . A dm i xt u r e s i n wh i c h a s p ec i al d ru g v ia l i s a tta c he d t o a s p ec ia l I V ba g a r e k no wn as t he A D D - V an t ag e s ys t e m ( s e e F i gu r e 2 7 -7 ) . b . I n so m e c a s e s , i n te rm i t t e nt i n fu s io n in j ec t io n d e vi ce s a r e u s e d . A ls o c al l ed s ca l p - vei n , h ep a ri n -l o c k , o r bu t te r f l y i n fu s i o n s ets , th es e d e v ic es p er m i t in t e rm i tt e nt d e li v e r y wh i l e e l im in a ti ng t he ne e d f o r m ul ti p le ve n ip u nc t ur es o r p r ol o ng ed v e n ou s a cc e ss wi t h a c o nt i nu ous in f us io n . To p r e v e nt c lo t t in g i n t h e c an nu l a, di lu t e h e pa r in s o lu t io n o r N S S m a y b e a d d ed . Be n ef i ts o f in t erm i tt e n t in f us io n i n je c t i on d e vic es i n cl ud e th e f o ll o wi n g :
( 1 ) Th i s m e t ho d i s e s p ec i a ll y s ui t ab le f or pa t ie n ts wh o d o no t re qu i r e, o r wo u ld be j e op a r di z e d b y , ad m i n is tr a t io n of la r ge am ou n ts o f I V f l ui ds (e . g ., t ho s e wi t h c o ng es t i v e h ea r t fa il u r e). ( 2 ) B ec au s e in t e rm it t en t i n f us io n i nj ec t io n d e vi ces do no t re q ui r e c on t in uo u s a t t ac hm en t to an I V b o tt le o r b a g a nd po le , th e y p e r m i t g r ea t e r p at i en t am b ul a ti on . C . P u m ps an d c o n t ro l l er s a r e t he el ec t r on ic de v i c es u s e d to ad m i ni s te r p a r en t e ra l i n f us io ns wh e n th e u s e of g r a v it y f l o w a lo n e m i g ht l ea d t o i n ac c u r at e do sin g o r r is k p a t ie n t s a f e t y . P um p s a nd c o n t ro l le rs a re us ed t o a dm i ni s t e r p a re n te r a l nu t r i ti on , c h em ot h e ra p y , c a rd i ac m e di c a t io ns , a n d b lo o d p r o du c ts . 1 . P um p s a r e u s e d t o d el i v e r I V i nf us i on s wi t h ac c u r ac y an d s a fe t y . a . Two t yp e s o f me c ha ni s m s a r e us e d i n i nf us i on p um ps . ( 1 ) P i st o n -c yl i n d e r m ech a n is m s u s e a p is to n i n a c yli n de r or a s y r i ng e -l ik e a p p ar a tu s t o p um p th e de s i re d vol um e o f f l ui d . ( 2 ) L in e a r p e r is t a l ti c me c h an i sm s u s e e xt e r n al p r e ss u re to e xp e l t h e f lu id o ut o f t h e p um p in g c ha m b e r . b . T yp e s o f p u m ps ( 1 ) V o lu m et r i c p u m ps ar e us e d f o r i nt e rm i tt e nt in f us i on of m e di ca t io ns su c h as a n t ib io t ic s . Th e y a re al s o us e d f o r c on t in uo us in fu s io n o f IV f lu id , pa r en t er a l n u t ri t io n , a n ti c o a gu la n ts , a n d a nt i - as th m a m e di cat i o ns . ( 2 ) S yr i n g e p u mp s a r e u s ed to ad m i n is te r in t e rm i tt e n t o r c on t in uo u s in fu s io ns of m e di ca t io ns ( e. g ., a nt ib io t ic s , o pi a te s) in c o nc e nt r a t ed fo r m . ( 3 ) M o b i le in f u si o n p um p s a r e s m a ll in f us io n de v i c es d e si gn e d f o r am bu l a to r y a nd h o m e pa t ie n ts a n d u s e d f o r ad m i ni s te r in g c he m oth e r a p y a nd o pi at e m e di c a t i on s. ( 4 ) I mp l an t a bl e pu m ps a r e i n f us io n d e v ic es s u rg i ca ll y p la ce d un de r th e s ki n to p r o vi de a c on t in uo u s r ele a s e of m e di c at io n , t yp ic a l l y an op ia t e . Th e r es e rv o i r in t he p u m p is re f il le d b y i nj ec ti n g t h e m e d ic at i on th r o ug h a l at e x d i a ph r ag m i n th e pu m p . P.583
( 5 ) P a ti e n t -c o n t ro l l ed an a l ge s i c p um p s a r e us ed t o a dm in is t e r n a rc ot ic s i n t er m i t t en t l y o r on de m an d b y th e p a ti en t wi t h in th e pa t ie n t -s pe c i f ic p a r am e te r s, wh i c h a re o rd e re d b y t h e p h y s i c i a n a nd p ro g ra m m e d i nt o th e p um p . c . B en e f i ts . De s p i te t he ir e xt r a c os ts an d th e t r ain i ng r eq u ir e d b y p er s on ne l , p um ps p r o vi de a n um be r o f im po r t a nt be n ef i ts . Th e y m ain t a in a c o ns t an t , a c c u ra te f lo w r a t e a n d c a n d e te c t i nf il tr a t io n s , oc cl us io ns , an d a i r . Pu m p s a ls o m a y d ec r e a s e th e a m ou n t o f t im e a nu r s e s p e n ds d is p en s i ng m e di c a t i on . Ne we r d e vi ce s a re e q ui pp e d wi t h “ d r ug li b r ar i es ” t h a t h a v e p re sp ec i fi e d hi g h a n d lo w d o s e in f us io n l im it s wh i c h m a y f ac il i ta t e m e d ic at i on a dm i ni s t r a ti o n a nd re d uc e e r r o rs . 2 . C o n t ro l l e rs , u n li k e pum ps , e xe r t no pu m p i ng pr e ss u r e o n t he I V f lu i d. R a t h e r, t h e y r el y o n g r a v it y a nd c o nt r o l t he in f us io n b y c o u n ti ng d ro ps el ec t r on ic a l l y , o r th e y i n f us e t he f lu id m e c h an ic a l l y an d e le c t ro ni c a l l y (e . g . , v ol um e t ri c c o n t ro ll e rs ) . In c o m pa r i s on t o p u mp s , th e fo l lo wi n g ar e c ha r ac te r i s t ic s o f c on t r ol le r s: a . Th e y a re le s s c om p lex a n d g e ne r al l y le s s e xp e n s i v e . b . Th e y ac h ie v e r ea s o n ab l e a c c u ra c y.
c . Th e y a re v e r y us e fu l fo r u nc om pl ic a te d i n fu s i on t he r a p y b u t c an no t be u s ed fo r a r t e ri a l d r ug i n f us io n o r fo r in f us i on i n t o sm al l v ein s . D . I V i nc o mp a t ib i l it i es . W hen t wo o r m o re d ru gs m us t b e a dm i ni st e r ed thr o u gh a s i ng le I V l in e or gi v e n i n a s i ng l e s o l ut i on , a n u n d e s i r ab l e r e ac ti o n c a n oc c u r . A l t h ou gh s u c h in c o m p a tib i li t ie s a r e r e la t i v el y r a re , t he i r co ns e qu e nc es c a n be d e a dl y. A p a ti e nt wh o r ec e i v es a p re p a ra t io n i n wh i c h an in c o m p a ti b il i t y h a s o cc u r r ed c o ul d e xp e r i e nc e to xi c i t y o r a n i nc om ple t e th e ra p eu t ic e f f ec t. 1 . T yp e s o f i n co m pa t i b il i t i es a . A ph ys i c a l i nc o mp a t ib i l i t y o c c u r s wh e n a d r ug c o m b i na t io n p r od u c e s a v i s i b le c h an g e i n t he ap p ea r an c e o f a s o lu t io n . Th e s o lu ti o n s ho ul d ne v e r b e a d m i n is t er e d t o a p a ti en t . ( 1 ) A n e xa m p le of ph y s ic a l i nc om pa t ib il i t y is t h e e v o l u ti on o f ca r b on di o xi d e wh e n s o di um bi c a r bo n at e an d h y d r o c h lo r ic ac id a re adm i xe d . ( 2 ) V a ri ou s t yp e s o f ph y s ic a l i nc om pa t ib il i ti es m a y o c c u r : ( a ) V is ib l e c o l or c h a ng e o r d ar k e n in g ( b ) F o rm at i on of p re c i pi ta t e , wh ic h m a y re s u l t f r om t he c om b in a ti on o f p ho s ph a te a n d c al c i um . b . A ch e mi c al i nc o mp a ti b i l i t y r e f l e c ts th e c he m ic a l d eg r ad a ti o n o f o ne or m o re of t h e a dm i xe d d r ug s , r es ult i n g i n t o xi c it y o r th e ra pe u t ic i n ac ti v i t y . ( 1 ) Th e de g ra d at i on is no t al wa ys vi s ib l e. N o n vis i b l e c he m ic a l i n co m pat i b i l i t y m a y be de t ec t ed on l y b y a n al y t ic a l m e t ho ds . ( 2 ) C h em ic al i n c o m p a ti bil i t y oc c u r s in s e ve r al va r i e t i es . ( a ) C o mp l ex a t io n i s a re a c t i on be t we e n p r o du c ts t ha t i n ac ti v a t es th em . F o r e xa m p l e , t he c o m b i na ti on o f c al ci um an d t e t ra c yc l in e l ea ds t o f o rm at i on o f a c om p le x t h a t in ac t i v at es t e t r ac y c li ne . ( b ) O x i da t i on oc c u r s wh e n on e d r ug lo se s e le c t ro n s t o t h e o th e r , r es u lt i ng i n a c o lo r c h an ge a nd th e ra pe u t ic i n ac ti vi t y . ( c ) R e du c t io n ta k e s p lac e wh e n o ne d ru g g a in s e l ec t r on s f r om th e o t he r . ( d ) P h o to l ys i s ( c h em ic al d ec om po si t io n c au s e d b y l i gh t ) c an le a d t o h y d ro l y s is o r o xi d a t i on , wi t h re s u l ti n g d i s c ol o ra t io n . c . A th e r ap e u ti c in c omp a t i b il i t y o c c u r s wh e n two o r m o re d ru gs , IV f lu id s , o r b o th a r e c om b in ed an d th e res u lt is a r es po n s e ot h er th a n t h at in t en d ed . An e xa m pl e o f a t h e r ap eu t ic in c o m p a ti bi l it y i s t h e r e du ce d b ac t e ric i da l a ct i vi t y of pe n ic il li n G wh e n g i ve n a f te r te t r ac y c li ne . B e c au s e te t r ac y c li ne is a b ac te r i os ta t ic ag en t , i t s lo ws b a ct e r ia l g r o wt h ; p e ni c i lli n , o n t h e o t he r h a nd , i s m os t ef f ec ti v e a ga in s t r ap i dl y p r o li f e ra t in g b ac t e ri a . 2 . F ac t o r s a f fe c t in g I V c o m pa t i bi l i t y a . p H . I nc om p at i bi li t y is m o r e li k el y t o oc c ur wh e n t he c o m p o ne n ts o f a n IV s ol u ti o n d i f fe r s i gn i fi c a n tl y i n p H . Th i s i n c r e as ed r is k is exp l a i n e d b y t he c h em ic al r e ac t io n b e t we e n a n a c i d a n d a ba s e, wh i c h yi e ld s a s al t a n d wa t e r; t he s a lt m a y b e an i n so lu b le p re c i pi t a te . b . T em p e ra t u r e. G e ne r al l y , in c re as e d s t o r ag e t em p e ra t ur e s p ee ds d ru g d e g ra d at i on . To pr es e r ve d r ug s t ab i li t y , d r u gs s ho u ld be s t o r ed in a r e f ri ge r a t or o r f r e e ze r , as ap p r op r ia t e.
c . D eg r e e o f di l u t io n . G e n e ra l l y , t h e m o r e d il u ted t he d ru gs a re in a so l ut i o n, th e l e ss c ha n c e th e re is fo r a n io n i n te r ac t io n l ea d ing t o i nc om pa t ib i li t y . P.584
d . L en g t h o f ti m e i n s o lu t i o n . Th e ch an ce f o r a r e a c t i on re s ul ti n g i n i nc om p at i bi li t y i n c re as es wi t h th e l en g th o f ti m e th a t d r ug s a r e i n c on t ac t wi t h e ac h o t he r . e . O r d e r o f mi x i ng . D rug s th a t a re in c om pa t ib le i n c om b in a ti on , s uc h a s c a lc iu m a n d p h os ph a te , s ho u ld no t be ad d ed c o ns ec u ti v e ly wh e n a n I V a dm i xt u r e is be i ng p r e pa r e d. Th is k e e ps t h es e s ub s ta nc es f ro m p oo l in g , o r fo r m i n g a l a y e r o n t h e t o p o f t he I V f lu i d, an d , t he re f o r e, de c re as es t he c h an c e o f a n i nc om p at ib i li t y. Th o r o ug h m i xi n g af t e r e ac h a dd i ti on is al so es se n ti al . 3 . P r e ve n ti n g o r m in i m iz i n g i n co m pa t i bi l i t ie s . To r e d uc e t h e c ha nc e f or a n i n co m p a ti bi l it y , t he fo l lowi n g s te p s sh o ul d b e t ak e n : a . E ac h d r ug s h ou l d b e m i xe d t ho r o ug hl y a f te r it i s a dd e d t o t h e p r ep a ra ti o n . b . S ol u ti o ns s ho u ld be ad m in is t e re d p r om pt l y a fte r t he y a r e m i xe d t o m i nim i z e th e t i m e a vai l ab le f or a p o ten t i al re a ct io n to oc c u r . c . Th e n um b e r o f d r ug s m i xe d t og e th e r i n a n I V s o lu t io n s ho u ld be k e pt to a m i ni m u m . d . I f a pr es c ri p ti o n c a l ls f o r un f am il ia r d ru gs o r IV f l ui ds , c om p at ib i li t y r efe r e nc es s h ou l d b e c o ns u lt e d. E . H a za r d s o f pa r e n te r al d r u g t h e r ap y. A wi d e r a n g e o f p r ob le m s c a n oc c u r wi t h p a r en t e ra l d r ug ad m i n is tr a t io n . 1 . P h ys i c a l h az a r d s a . P h le b i ti s , wh i c h i s g en e r al l y a m i n o r c o m p l ic at i o n, m a y r es ul t f ro m v e in i nj u r y or i r r i ta t io n . P h le bi t is c a n be m i n im i zed o r p re ve n t ed t h ro u gh pr o pe r I V i ns er t i on t e ch n iq u e, di lu t io n o f ir r it a t in g d r u gs , a nd a d ec re a s e d i n fu si o n r a te . b . T h r om b os i s, t he fo r m a t i on of a b lo o d c l o t i n a ve i n o r a rt e r y. c . E xt r a va s a ti o n m a y o c c u r wi t h a dm in is t r at i on of d r ug s wi t h v e s i c a n t p r op e r ti e s ( s e e V I I . D. 3 .b ) . d . I r r i ta t i o n a t t h e in j ec ti o n s it e c an be r ed uc e d b y v a r y i n g th e i nj ec t io n s i te an d a p pl yi n g a m oi s tu r i z in g lo t i on to t he ar e a. e . P ai n f ro m i nf us i on is m os t c om m o n wi t h p e ri ph e r al I V a dm in is t r at i on of a hi gh l y c o nc en t r at e d p r ep a ra t ion . S wi t c hi ng t o c e n t ra l ve i n i n fu si on an d / or di l ut in g th e d r u g m i gh t a l le v i a te th e p r o ble m . f . Ai r e m b o li s m, po t en t ia l l y fa t al , c a n r es ul t f rom en t r y o f a ir in t o t h e I V t u bi n g. g . I n fe c t io n , a pa r ti c u l a r d a ng e r wi t h ce n t ra l I V lin e s , m a y s te m f r om c on ta m in a ti on d u r in g IV li n e i ns e rt i on or t u bi n g ch a ng es . In f ec ti o n m a y be lo c al o r ge n e ra l i z ed ( s e pt ic em i a) . Th e i n fe c tio n ri s k c a n b e m in im i zed b y f o ll o wi n g es t ab l is he d p r o to co ls f o r th e c a re o f c e n t ra l l ine s . h . Al l e r g i c r e ac t i on s c an r es u lt f ro m h y p e rs en s i ti v i t y t o a n I V s o lu t io n o r a d di t i v e . i . C e n t ra l c a t he t e r m i s pl a c em e n t m a y l ea d t o a ir e m b o li s m o r pn eu m ot ho r a x. To e n su r e t h at t he c a th e te r h a s p as se d i n to th e s ub cl a vi an v e in a nd ad va nc ed t o t h e l e ve l o f t h e v en a c a v a, th e pl ac em e nt s h ou l d a l wa y s be ve r i fi ed r ad io l og ic a ll y .
j . H yp o t h e r m i a , p os s i bly r e s ul t in g i n s ho c k an d c a r di ac ar r es t , m i g h t s tem f ro m a d m i ni s t ra ti o n o f a c o ld IV s ol u ti o n. Th is p ro b le m c a n b e p r e v en t ed b y al lowi n g p a r en t e ra l p r od u c t s t o r ea c h r o om te m p e ra t u re . k . N e u ro t o xi c i t y m a y b e a s e r io us c o m p li ca t io n of i nt r a th ec a l o r i n t ra sp ina l a d m i ni s t ra ti o n o f d r ug s c o n t ai ni n g p r es e r vat i v es . P r e s er v a t i v e - fr e e d r ug s s h ou l d b e u s ed in th es e c i rc um s t a nc es . 2 . M e c ha n ic a l h az a r ds a . I n fu s io n pu m p o r c on t r o l l e r f a i lu r e c an le a d t o ru n a wa y i n fu s i on , fl u id o v e r lo ad , o r in c or r ec t do s a ge s . b . I V tu b i ng c a n b ec om e k in k e d , s pl i t, o r c ra c k ed. I t a ls o m a y p ro du c e pa rt i cu l at es , a l lo w c o n ta m i n at i on , o r in t e r fe r e wi t h t he in f us io n. c . P a r ti c ul a t e m at t e r m a y b e p r es e nt in a p a re nt e r al p ro d uc t a nd c a n c au s e e m bo li s m . d . G l a ss co n t ai n e rs m ay b r e ak , c a us in g i nj u r y . e . R u bb e r vi a l c l os u r es m a y in t er a c t wi t h th e e nc l os ed p ro du c t. 3 . T he r a pe u t ic ha z a rd s a . D r u g i n s ta b il i t y m a y l e ad t o t he r a pe u ti c i ne f fe c ti v e n es s . b . I nc o mp a t ib i l i t y m a y r e s ul t i n t o xi c i t y o r r e du ce d th e r ap eu t ic ef f ec t i vene ss . c . La b el i n g e r r o r s c an c a u s e ad m i n is t ra t io n o f an i nc o rr ec t d ru g o r i m p r op e r d o sa g e. d . D r u g o ve r d o se c a n be c a us e d b y r un a wa y I V i n f us io n , f ai l ur e o f an in fu s io n p u m p o r c o n t ro ll e r , o r n ur s i ng or ph a rm ac y e r r o rs. P.585
e . P r es e r va t i ve an d so lu b i l iz i ng ag e n t t o x ic i t y c an be a s e ri ou s c om pl ic a ti o n, e s pe ci a ll y in c h il d r en . Fo r e xa m p le , p r em a tu r e in f a nt s r e c e i v in g p a r en t era l pr o du c ts c o nt a in in g be n z y l al c o hol c a n d e v e lo p a fa t al ac id o t ic to xi c s y nd r om e , whi c h is r e f e r re d t o a s t h e g as pi ng s y nd r om e . Ra pi d ad m in i st r a ti o n o f p he n yt oi n (D i l a nt in ) a n d d ia z e p am ( Va l iu m ) bo t h u t il i z e p r o p yle ne gl y c o l as a s ol ub i li zi ng a gen t , ha s b e e n as s o c i a te d wi t h c a rd i o v as cu l ar co ll a ps e . P.586
STUDY QUESTIONS D i r e c t i on s : E a c h of t he n u m b e re d i t em s o r i nc om p le t e s ta t em en ts in t his s e c t i on is f o l lo we d b y an s we r s o r by c o m p le t io ns o f t he s t a te m en t . Se le c t t he o ne l et t e r ed a n s we r o r c o m p l et i on tha t is be s t i n e ac h c as e. 1 . P a re n t e ra l p r od u c ts w i t h a n o sm o t i c p r es s ur e l e ss t ha n th a t o f bl oo d o r 0 . 9 % s o d i um ch l o r id e a r e r e fe r r e d t o a s ( A ) I so t on ic s o lu t io ns ( B ) H yp e r t on ic s o lu t io ns ( C ) H yp o t on ic s o lu t io ns ( D ) I so - os m o t ic s o lu t io ns
( E ) N e u tr a l s ol ut i on s V i e w A n s we r 1 . T h e a n sw e r i s C [ V II . B . b,] . 2. As e p t i c t e ch n i qu e s h ou l d b e u s e d i n th e p r e p a ra t i on o f a ll o f t h e f o l low i n g m e d ic a t io n s w it h t he ex c e p ti o n of; ( A ) N e om y c in i rr i ga t io n s o l u ti on ( B ) G a nc ic l o v i r ( C y t o v e ne ) in t r ao c u l a r i nj ec t io n ( C ) P h y t o na di o ne ( A qu am e ph y t o n ) s u bc u t an eo us i n je ct i on ( D ) A m pi c i ll i n ( P r in ic ip e n) I V ad m i xt u r e p ig g y b ack ( E ) B ac i t ra c i n o i nt m e n t V i e w A n s we r 2 . T h e a n sw e r i s E [] . 3 . W h ic h ne ed l e ha s th e s m al l es t d i a me t e r ? ( A ) 2 5 g au g e, 3¾ in c h es ( B ) 2 4 g au g e, 3½ in c h es ( C ) 2 2 g a ug e , 3 ½ in c h es ( D ) 2 0 g a ug e , 3 3/ 8 i nc h es ( E ) 2 6 g au g e, 35 / 8 i nc hes V i e w A n s we r 3 . T h e a n sw e r i s E [] . 4 . I n t r a -a r t i cu l a r in j ec t i o n r e f e rs t o i n j e ct i o n i n to t h e ( A ) Mu s c l e m a s s ( B ) S u bc u ta ne o us ti s s ue ( C ) S p in a l f lu i d ( D ) S u pe r f ic ia l s k i n l a y e r ( E ) J oi n t s p ac e V i e w A n s we r 4 . T h e a n sw e r i s E [I V . 1] . 5 . Ad va n ta g e s o f th e in t r a ve n ous r o u t e in c lu d e ( A ) E as e of r em o v al of th e do s e ( B ) A de p ot e ff ec t ( C ) L o w i nc i de nc e o f p h le b i ti s ( D ) R a p id on s e t o f ac ti on ( E ) A lo c a l i z ed ef f ec t V i e w A n s we r 5 . T h e a n sw e r i s D [] .6 . A c e nt r a l ve i n , e i t he r s ub c la vi a n or i n t e r na l ju g u la r , ma y b e c on s i de r e d a s u i ta b l e r o u t e fo r I V a d mi n is t r at i o n in w h ic h of t h e f o ll ow i n g s i t u a ti o ns ? ( A ) W hen a n i r r i ta t in g d ru g is g i ve n ( B ) W hen h y p e r to n ic d r ug s a r e g i v e n ( C ) F o r l on g - te r m t he r a py ( D ) F o r a dm i ni s t e ri n g d ext r o s e 3 5% as pa r en t e ral n ut r i ti on ( E ) A l l o f t h e a bo v e V i e w A n s we r 6 . T h e a n sw e r i s E [] . 7 . T o p r e p a re a t o ta l pa r e n te r a l n u t r i t i on ( T P N ) t h a t r e qu i r e s 1 0 m E q o f c a lc i um g l uc o na t e a n d 1 5 mM o f p o t a ss i um p ho s ph a t e, th e ap p r o p r ia t e a c ti o n to t a ke w o u ld be w h i ch o f t h e f o l l ow i ng ? ( A ) A d d t he c a lc iu m f i rs t , a d d t he o th e r a dd i ti v e s , t h en ad d th e p ho s ph a te l a s t , t h o r ou gh l y m i xi n g t he s ol u t io n a f te r ad di t io n . ( B ) A d d t he c a lc iu m g lu c o n a te an d p o ta s s iu m p ho s ph a te c o ns ec u ti ve l y.
( C ) N o t c om b in e t h e a gen t s t o ge t he r bu t g i v e t h em as a s e p a ra t e i nf us i on. ( D ) N o n e o f t h e a bo v e . V i e w A n s we r 7 . T h e a n sw e r i s A [] .8 . W h ic h ne ed l e ga u ge w o u ld be m os t l i k e l y u s e d a s a s u b cu ta n e ou s in j ec t i on o f e p oe t i n ? ( A ) 2 5 g au g e, 5 /8 in c h ( B ) 1 6 g au g e, 1 i nc h ( C ) 1 8 g a ug e , 1½ in c h es ( D ) 2 2 g a ug e , 1½ in c h es ( E ) N o ne o f t he ab o v e V i e w A n s we r 8 . T h e a n sw e r i s A [] 9 . Wh i ch o f the f o l low i n g d r u gs s ho ul d N O T b e p re p a r ed i n a ho r i z on t a l l a mi n a r f l ow h o o d ? ( A ) A m p ic i ll in ( P ri n c i pe n) ( B ) D o pa m i n e ( C ) C i sp l at i n ( P la t in o l) ( D ) N i t r og l y c e r in ( E ) B r e t y li um to s y l at e ( Br e t y l ol ) V i e w A n s we r 9 . T h e a n sw e r i s C [] .P . 58 7
1 0 . Al l o f t h e f o l low i n g s t a t em e n ts ab o u t d 5w a r e t r ue E X C E P T ( A ) I ts p H ra ng e i s 3 . 5- 6 .5 . ( B ) I t i s h y p e rt o ni c . ( C ) I t i s a 5% s o lu t io n o f D - g l uc os e. ( D ) I t s h ou ld be us e d wi t h c a u ti o n i n d ia b et ic pa t i e n ts . ( E ) I t i s o f te n u s e d i n I V a d m i xt u r e s . V i e w A n s we r 1 0 . T he a nsw e r i s B [] .1 1 . Al l o f t he f o l l ow in g a r e po t e n ti a l h a za r d s o f pa r e n te r a l th e r a p y E X C E P T ( A ) H yp o t he r m i a ( B ) P h le bi t is ( C ) E xt r a v a s a t io n ( D ) A l le r gi c re ac t io ns ( E ) I le u s V i e w A n s we r 1 1 . T he a nsw e r i s E [] . 1 2. P r o ce d u re s f o r t h e s a fe ha n d li ng o f a n t i ne o p la s t ic ag e n ts in c l u de al l o f t h e f o ll ow i n g E X C E P T ( A ) U s e o f L ue r - Lo k s y r in g e f i tt i ng s . ( B ) W ear i ng do ub l e -l a y er e d l a t e x g l o v es . ( C ) U s e o f n e ga t i v e- p r es s u r e t ec hn i qu e wh e n m ed i c a t io n i s b ei ng wi t h d rawn f r o m vi a l s. ( D ) W ear i ng c l os ed - f r on t, s ur g ic al - t y p e g o wn s wi th c u f fs . ( E ) U s e o f h o ri z o n ta l l am i n a r f lo w h o o d . V i e w A n s we r 1 2 . T he a nsw e r i s E [] . 1 3. I n p r e pa r in g a n i n t ra s p in a l d o se o f b u p i va ca i n e, t he be s t po r e s iz e f i l te r f o r c o l d s t e r i l iz at i o n w o u l d b e ( A ) 8 -m m f il t e r ( B ) 5 - µ m f il t e r ( C ) 0 . 45 - µ m f il t e r
( D ) 0 . 22 - µ m f il t e r ( E ) N o ne o f t he ab o v e V i e w A n s we r 1 3 . T he a nsw e r i s D [] .1 4 . P r o ce s s s i m ul a t i on ( A ) I s a m e th od o f q ua li ty a s s u r an c e . ( B ) E va l ua t es th e a d eq ua c y o f a p r ac t it i on e r 's ase p t ic te ch ni q ue . ( C ) R e q ui r es th e u s e of a m i c ro b ia l g r o wt h m e diu m . ( D ) I s c a rr i ed ou t i n a m a n n er id e nt ic a l t o n o rm al s t er i le ad m i xt u r e p ro d uc t i o n u nd e r r o u ti n e o pe r a ti n g c o n di t io n s . ( E ) A l l o f t h e a bo v e . V i e w A n s we r 1 4 . T he a nsw e r i s E [] . F o r q u es t i o ns 1 5 -1 8 : Th e ph a rm ac is t r e c ei ve s a p r es c ri p ti on fo r h y d ro m or p ho n e ( D il a ud i d ) i nj ec t io n t o b e c om po u n de d t o a so l ut i on of 15 m g pe r m L . Di la u di d i s co m m e rc i a ll y a v a il a bl e i n a n a m pu l e b u t t he c o nc en t r at i on is 1 0 m g pe r m L . Th e p h y si c i a n wo u l d l ik e a m o r e c o nc e nt ra t e d s o lu t io n p r ep a r ed s o th at 5 0 m ls c an be in s ti ll e d i n t o t he ti t an i um re se v o i r o f a Me d t r o n i c i nf us i on pu m p. Th e h yd ro m or p ho n e s o lu t i on wi l l b e c on t in u ou s ly i n f us ed , i n t ra t h ec al l y , o v e r ap p roxi m a t e l y 30 da y s , fo r a pa t i en t wi t h c hr o ni c b ac k p a in , u n co n t ro ll e d wi t h o ra l n ar c o ti c s . Th e p ha r m a ci st c h ec ks h is in v e n to r y a nd f i nd s a b o t tl e o f H y d r om or p ho n e p o wd e r , U S P . H e p r oc ee d s t o we i gh ou t e n ou gh p o wd e r fo r a 6 0 m L p re p a ra ti o n. Th e we i g h in g s te p i s c he c ke d b y a c o ll e ag u e p ha r m a c is t . 1 5 . Ac c o r di n g to U S P Ch a p t e r 7 97 t h is st e r i le p r e p a r at i o n w o u l d b e co n s i de r e d a ( A ) H i gh r is k le v e l C S P ( B ) Me d i u m r is k l e v el C SP (C) Low risk level CSP ( D ) N o n e o f t h es e V i e w A n s we r 1 5 . T he a nsw e r i s A [] .1 6 . W ha t w o ul d b e a n a p p ro p r i a te e n vi r o n m en t f o r t h e a se p t i c m an i p ul a t io n s r eq u i r e d f o r t hi s p r e p a ra ti o n . ( A ) P h a rm ac y wo r k b en c h o r c o un t e r i n am b ie n t r oo m a i r ( B ) I ns i de an An t e ro om , wi t h I S O C l as s 8 q u al i t y a i r ( C ) I ns i de a B a r ri e r I s o l at o r wi t h I S O Cl as s 5 q u ali t y a i r ( D ) A h or i z o n ta l l am in a r f l o w wo r k b e nc h b en ch , ne wl y i n s ta l le d , wi t h no c e r ti f ic at i on , b u t m an u fac t u re r gu a re n te e d t o b e IS O 5 C l ass ai r qu a li t y. V i e w A n s we r 1 6 . T he a nsw e r i s C [] .P . 58 8
1 7 . Th e p h a rm a ci s t b e gi n s t o g a th e r h i s s u pp l ie s f o r t h i s p r ep a r a t io n . T h es e s h o u ld i nc l ud e : ( A ) Mi l l i po r e 0 . 45 m i c r o n H V F il t e r wi t h st e r il e wat e r fo r in j ec ti o n ( B ) Mi l l i po r e 0 . 22 m i c r o n G S F i lt e r wi t h s od iu m c h l o ri d e 0 .9 % ( C ) B e c t i n- D i c k in s o n 1 6 g a u ge , 5 m ic r o n f il t e r n ee d l wi t h s od i um c hl o ri d e 0 . 9 % ( D ) Mi l l i p o re A A 0 . 8 m i c ro n Fi l te r wi t h d e xt r o s e 5% i n wa t e r V i e w A n s we r 1 7 . T he a nsw e r i s B [] .1 8 . Af t e r t h e s o l u t io n w as p re p a r ed t h e a p p r o p r ia t e q u al i t y a s s u r a n ce o r do u b le ch e ck b y a n o t h e r p ha r m ac i st w ou l d i n c l ud e :
( A ) I ns p ec ti o n o f t he p owd e r a n d t h e l ab el t o e ns u r e h yd r om or p ho n e wa s t h e p r e pa r e d i ng r ed i en t a n d t h a t t h e l ab el c o n ta in e d a b e yon d u se da t e a nd th e 15 m g p e r m L c on c e n t ra t io n . ( B ) S e nd i ng a s o l ut i on s a m pl e o r al iq u ot to a m ic r o b io l og y l ab to t es t f o r th e p r e se nc e o f b ac t e ri a a n d p y r o g en s p r io r to di s p ens i ng . ( C ) C h ec k t o e ns u r e a c o r r ec t s t e ri li z i n g f il t e r wa s u t il i z e d. ( D ) V i su al in s p ec t io n to e n s u r e t h e f in a l ac q ue o us so lu t io n h a d n o vi si b le p a r ti c i p a te s . ( E ) A l l o f t h e a bo v e . V i e w A n s we r 1 8 . T he a nsw e r i s E [] . P . 58 9
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C [ V I I .B . b , X. A ] . H yp o t o ni c s ol u ti on s h a ve a n os m o t ic p re ss u re l es s t h an th a t o f b l oo d ( o r 0 . 9 % s a li ne ) , wh e r ea s h y p e r ton i c s o l ut i on s h a ve a n o s m o ti c p r es s u r e g r ea t e r th a n t h at o f b l oo d , a n d is o to n ic o r is o - o s m ot ic so lu t io ns ha ve a n o s m o ti c p r ess u r e e qu a l t o t h a t o f bl o od . 2 . T he an sw e r is E [ I I . A.5 ] . I r r i ga t io n s ol u ti o ns , o ph th a lm ic p re pa r a ti o ns a n d p a r en t e ra l p r od u c t s, an d s u bc ut a ne o us a n d I V m ed i c a t io ns s h ou l d b e p re pa r e d u s i ng as e pt ic te c h ni q ue . S i n ce B ac it r ac in oi n tm ent i s a pp li e d t o t h e s k in an d do es no t b yp a s s th e b o d y' s p r o t ec ti v e ba r r ie r s , i ts p re p a ra t io n wo u ld no t b e he l d t o t h e s am e r e qu i re m e n ts . 3 . T he an sw e r is E [ I X. A . 1 ] . Th e g a ug e s i z e r e fe r s t o t h e o u te r d i am et e r o f the n ee dl e . Th e l o we r th e g a u ge s i z e n u m b e r , t he la r ge r t he ne e dl e . 4 . T he an sw e r is E [ I V .1] . I n t r a -a r ti c u l a r i nj ec t io n re f e rs to an in j ec ti o n i nt o t h e j oi n t s pa ce . Th is a d m i ni s t ra ti o n r o ut e g e ne r a ll y is us e d f o r c e r t ai n t y p e s o f c or t ic os t e ro id s t o r ed uc e i n f la m m at i on as s oc i at e d wi t h i n ju r y o r r h eu m a t oi d a r t h ri ti s . 5 . T he an sw e r is D [ V I .C ] . Th e I V r ou t e o f d r ug adm i ni s t r a ti on al l o ws fo r rap i d o ns e t o f a c t i on an d , th e r e fo r e, i m m e di a te th e r ap eu t ic eff e c t. Th e r e c a n b e n o rec a ll of th e ad m i ni s te r ed d o se , a n d p h le b it is , or in f la m m a ti on o f a v e in , c an oc cu r . I n a d di t io n , a d e po t e f f ec t ( i . e ., a cc u m u la t io n a n d s to r age o f t h e d ru g fo r di s t r ib ut i o n) c a n no t b e a c h i e v ed b y a d m i ni s te r in g a d ru g i n t ra v e n o us l y. De li v e r i ng a d r u g i n tr a v e no us l y r es ul ts in a s ys t em ic ra t he r th a n a l oc a li z e d e f fe c t. 6 . T he an sw e r is E [ X. A . 2 ] . I r r i t at in g dr u gs , h y p e r to ni c d r u gs , l on g - te r m t he r ap y , a nd de xt r o s e 35 % a re b es t g i ve n b y c en t ra l IV ad m in i s t r a ti o n. P er i ph e ra l v ein i nj ec t io n i s us e d f o r p o st o pe r a ti v e h y d ra t io n , a d m i ni s t ra ti o n o f n o ni r ri ta t i ng d ru gs , o r is ot o ni c so l u ti on s a n d f o r s ho r t - te r m I V th er a p y . 7 . T he an sw e r is A [ X. D . 2 . e ].
P h y s ic a l i nc om pa t ib il i ti es oc c u r wh e n t wo o r m o re p r od uc ts a re c o m b in e d a n d p r o du c e a c ha n ge in th e a p p ea r an ce o f t he s o lu t io n , s uc h a s t he f or m at ion o f a p r e ci pi t a te . Ca lc i um a n d p h os p ha t e so l ut i on s wh e n d ir e ct l y c o m b in e d o r ad d e d c o ns ec u ti v e l y to a s ol ut io n wi l l f o rm a wh i t e p r ec i p i ta t e. B y al t e ri n g t he o rd e r of m i xi n g , th e y c a n b e s a f ely a d d ed to TP N s ol u ti o ns . 8 . T he an sw e r is A [ I X. A . 3 . b. ] S i n ce s u bc ut a ne o us i n jec t io n d o es n o t re qu i r e pe n e t ra t io n t h ro u gh se v e ra l s k i n l a ye r s o r m us c l e t is s u e , a s h o r t n ee d le wi t h a na rr o w d i a m e t e r is us ed . A 1 6 - or 18 g a u ge ne ed l e is m o s t c om m o n l y u s e d i n th e p h arm ac y f o r p r ep a r in g p a ren t e r al s o lu t io ns . A 2 2 -g a ug e n ee d le wo u l d b e u s e d f o r in t r am us c u l a r in j ec ti o n. 9 . T he an sw e r is C [ I I . B. 2 . b .1 ] . C i s P la t in is a n a n ti n eo pla s ti c a ge n t a nd , c o ns equ e n tl y , sh ou l d b e p r ep a re d on l y in a ve r t i ca l l am in a r fl o w h ood b ec au s e o f t he po t en t ia l ha z a r d o f t h es e t o xi c a g e nt s t o t h e o p e ra t or . 1 0 . Th e a n sw e r i s B [ V I I. B . 1 .a ] . d 5 w ( d e xt r o s e [ D -g lu c o s e ] 5% in wa t e r ) i s a ci di c , i t s p H ra n ge s f r om 3 . 5 -6. 5 , an d i t i s i so t on ic . It is of t en us e d in I V a dm i xt u r es an d s h ou l d b e us e d wi t h c a u ti o n i n d i ab e ti c p a ti en t s . 1 1 . Th e a n sw e r i s E [ V II. D . 2 . , X. E ] . P a r e nt e r al th e r ap y is of te n a t r ea tm e nt f o r il e us . H yp o t h e rm ia , p h le bi t is , e xt r a va s a t io n , a nd al l e rgi c re ac t io ns c a n b e h a z ar d s o f p a r en t e ra l t h er a p y. P.590
1 2 . Th e a n sw e r i s E [ V II. D . 2 ] . I n o rd e r t o p r e v e nt d ru g e xp o s u r e , a ve rt ic a l f lo w l am i na r h o od ( no t h o r i zo n t al ) s h ou l d b e us e d wh e n an a n t in eo p la s ti c a ge n t is pr e p a re d . Th e o th e r p r ec au t i on s m e nt i on e d in t he qu es t ion a r e im p or t an t s a fe t y m e a s u r es fo r ha n dl in g p a re n t e ra l a n t in eo p la s ti c s . A l l p ha rm ac y a n d n ur s i n g p e rs on n el wh o h an dl e th es e to xi c s u bs ta n c e s s h o ul d re c e iv e s pe c i a l t r ai n in g . 1 3 . Th e a n sw e r i s D [ I V .D . 2 . c . 2 ] . S i n ce in t ra s pi na l a n d e pid u r al do s e s o f b u pi v a c a in e a re f re qu e nt l y p re p a re d f ro m n o ns t e ri le po wd e r s , c ol d s t er i li z a t io n , ac c o m p l is he d b y fi lt r a ti o n, is a si m pl e m e th o d o f en su r i ng c om p le t e m ic r o bi al r em o v al . Th e f il t er s li s t e d 8 m m t o 0 . 45 µm wi l l r e m o ve o nl y p a rt ic u la t e m a t te r . A 0 .2 2 µ M f i l te r e n s u r es th e re m o va l o f m ic r o or g an is m s . 1 4 . Th e a n sw e r i s E [ II I .F ] . P r o c ess s i m u la t io n i s o ne p a rt of an o ve ra l l q ua lit y a s s u r an ce p ro g ra m . I t r e q ui r es d u pl ic a ti n g s te r il e p r o duc t pr e pa r a ti on us in g a g ro wt h m e di um i n p l ac e o f a c tu a l p r o du c ts . I t s e r v es to e va l ua t e t h e as e pt ic t ec hn iq u e o f th e i nd i vi du al pe r fo r m in g a ll t h e n ec e s s ar y s te ps o f s t e r il e p r o du c t p re p ar a ti on . 1 5 . Th e a n sw e r i s A [ I I.A . 6 . c] . Th e h yd r om o r ph on e p r e pa r a ti o n i s a h i gh ri sk le ve l C S P b ec a us e i t i s m ad e f ro m n o n -s t er i le po wd e r . 1 6 . Th e a n sw e r i s C [ I I.B . 4 ] .
U S P C h a pt e r 7 9 7 r e qu i re s a n I S O Cl as s 5 a i r q ua l i t y e n v i r om en t f o r t h is p r e pa r a ti o n. A Ba r r ie r Is o l a to r wi t h in a cl e an r oom c r e at e s a n I S O C la s s 5 e n vi r on m e n t . A m b i en t roo m a i r i s u na cc ep t ab l e fo r a n y p r e pa r at i on . An An t e r oo m is g e n er a ll y a n a r ea of r el at i v e l y hi g h p e rs on ne l a nd s u p pl y t r af f ic . W hil e a ir q u al it y m a y be ac c e p ta b le , i t d oe s n o t p r o v id e a n a c c e pta b l e c ri ti c al s i te of as ep ti c m a ni p ul at i on s . A ll ne w l am i na r fl o w wo r k b en c h e d s h o u ld be te s te d f o r a i r ve l o ci t y a n d f i lt e r i n te g ri t y p ri o r to us e . 1 7 . Th e a n sw e r i s B [ I V .D . 2 . c (2 ) ] . Th e h yd r om o r ph on e re q ui r e s s t e r il i z a ti on p ri o r t o i n t ra t h ec al ad m i ni s tr a ti on . Th i s is b e st ac hi e v e d wi t h a 0 . 22 m i c ro n f i lt e r . S o di um c h l o ri d e 0 .9 % i s t he so l ut io n m os t s im i la r to th e C N S f l ui d a n d wo u ld be a b et t e r cho i c e o ve r s te r il e wa t e r o f d e xt r o s e 5 % in je c ti on . 1 8 . Th e a n sw e r i s E [ II I .B ] . E a c h s te p i n s te r il e c om p o u nd in g s ho u ld ha ve an a ss oc ia t e d q ua li t y as s u ra n ce d o u bl e c he c k . I ns p ec ti o n o f th e i ni t ia l i n g re di e nt s , r e vi e w o f s up p li es , m oni t o ri n g o f a s ep t ic te c h ni q ue , an d exa m i n a t io n o f th e f i na l p ro d uc t c r ea t es m u lt i pl e o p p or t un i ti es t o i nt e rc ept a n e r r or an d m ak e n ec e s s a r y c o r r ec ti o ns . Hi g h r i s k le ve ls C S P s sh ou l d b e u s e d wi th i n 2 4 h o ur s i n t h e a bs en c e o f s te r il i t y te s ti ng . Gi ve n th is p r o du c t wi l l be ad m i ni s ter e d o v er 3 0 d a ys , a st e r il i t y an d p y r o g en te s t wo u l d b e a p p ro p r ia t e.
28 Parapharmaceuticals, Diagnostic Aids, and Medical Devices J e n n y A. V a n Am b u r g h T o d d A. B r ow n
I. AMBULATORY AIDS A. C a n e s . Th es e s im pl e a m bu l at o r y ai ds p ro v i de b a la n c e an d a ll o w f o r the t r an s f e r o f we i g ht o ff a we ak e ne d l e g. 1 . H e ig h t . Th e h ei gh t o f t h e c an e m us t b e a d ju ste d to t he in di vi d ua l p a ti en t . A c an e t h a t i s c o r r ec t l y f i t te d a llo ws f o r m a xi m um we i g ht t r a ns fe r wi t h ou t al lo wi n g t he p a t ie n t t o l oc k t he el b o w. Th e c o r r ec t h e ig h t s h ou l d p r o v id e a 25 - d eg r ee a n gl e a t t h e e l bo w, o r t he to p o f th e c a ne s h ou l d c o m e t o t h e c r ea s e o f t he wr i s t wh i le p a t ie n t is s t a nd in g e r ec t . 2 . T yp e s o f c a ne s . C a ne s m a y be m a de of wo o d o r m e ta l . a . W oo d en ca n es c o m e i n v a r y i ng th ic k n es s e s . Th e th ic k e r on es a re in t end e d f o r m a le s, an d th e t h in ne r on e s a r e f o r f em al es . Th ey m a y b e c u t to th e c o r rec t he ig h t f o r th e p a ti e nt . b . M e t a l c an e s a re us u al l y a dj us t ab le in he i gh t to f it t he in di v i d ua l p a ti e nt . c . Fo l d in g c a ne s wi l l f old t o a ll o w f o r e a s y t r a nsp o r t o r s t o ra g e wh e n no t i n u s e . d . A qu a d c a ne i s a m e ta l c a ne th a t h as a q ua d ra n g ul a r b as e wi t h f ou r leg s . Th is a l lo ws f o r g r e at e r we ig h t t r a ns fe r . Th e b as e o f the q ua d c an e c om es in t wo si ze s . Th e l a rg e r b as e p r o v i de s g r e at e r s ta b il i t y b u t is m o r e d if f ic ul t to m a ni pu la t e b e ca us e o f th e s i z e a nd we i g h t . e . S ea t ca n es c o nt a in an a r ea th a t c an be fo l ded d o wn an d u s e d to s i t on . Th e y a re u s ef u l f o r i nd i v i du al s who c a n no t wa l k l on g d is t an c es wi t h ou t re s t i ng . B . C r u t c he s m a y be us ed b y pa t ie n ts wi t h te m p or a r y d is ab i li t ie s ( e .g . , s pr a i ns , f r a ct u r es ) o r b y th os e wit h c h r on ic c o nd i ti o ns . 1 . U se . C r ut c h es a re us e d to t ak e a ll th e we i gh t o f f an i n ju r e d o r we ak e ne d le g . Th e c r u tc he s a r e u s e d i n p lac e o f th e l e g. C r ut c h s i z e s ra n ge f ro m t od d le r to a d ul t . A c ce s s o ri es t ha t a r e u s ed wi t h a c r ut c h in cl u de a t i p t o p r e v en t s l ip pi n g, h a n dg r ip c us h io n , a nd a rm p a d ( f or a xi l l a r y c r u tc h ) . 2 . T yp e s o f c r u t ch e s a . A n a xi l l a r y c r u t c h , t he m os t co m mo n l y u s e d c r u tc h , is t y pi ca l l y u s e d f o r t e m p o r ar y d is a bi li t ie s . Th e to p o f th e c r ut c h sh ou l d b e 2 in c h es be l o w t he a xi l l a t o p r e ve n t “ c ru tc h p a r al y s is ” ( i . e. , i n ju r y t o t he a xi l l ar y n e r v e s, bl o od ve s s el s, a n d l ym p h n od es ) . Th e h ei g ht o f t h e h an d gr i p s ho ul d b e s e t s o t ha t th e e l bo w f o r m s a 2 5 - de g r ee an gl e . b . A f o re a r m c r u tc h (a ls o c a l le d a C an a d ia n o r L o f s t r an d c r u tc h) r em ain s i n p o si t io n b y a t ta c h in g to th e fo r e ar m b y a c ol l a r o r c u ff . It is c om m o n l y u s ed b y p a t ie n ts wh o ne ed c r u tc h e s o n a l o ng - t er m b as is. c . A q u ad c r u tc h i s a fo re a r m c ru tc h wi t h a qu a dra n g ul a r b as e t ha t ha s f ou r le g s. Th e b as e i s a t ta c h e d t o th e c r u tc h wi t h a f l e xi b l e r u b be r m o un t . Th is a l lo ws f or m o r e s t ab i li t y an d c on s ta n t c on t ac t wi t h th e g r ou n d.
d . A pl a t f o rm c r ut c h c on t a in s a re c t a ng u la r ar ea i n wh i c h t o p la ce t he fo r e a rm . Th e c r u tc h m a y b e h e ld b y a h a n dg r ip o r s e cu r e d b y a b e lt th a t wr a ps a ro un d th e f o r e ar m . I t i s c o m m on l y u s ed b y pa ti e nt s wh o d o n o t h a ve e n ou g h h an d s tr e n g th an d c o nt r o l f o r a f o r ea r m c rut c h . C . S e a t l i f t c h ai r s a r e e le c t ri c -p o we r e d c ha i rs tha t r ai se th e p a ti e nt f ro m a s i t ti n g t o a s ta nd i ng po s i t io n . P.592
D . W a lk e r s a r e l ig h t we igh t r ec ta n gu l ar - s h a pe d de v i c es th a t a r e m a d e o f m e ta l t u b in g a n d h a v e f ou r wi de l y p la ce d l e gs . 1 . U se . W alk e rs a re us ed b y pa t ie n ts wh o ne e d m o r e s up p o r t t h an a can e o r c ru tc h o r wh o h a v e t r ou b le wi t h b a la nc e d u ri n g am b ul a tio n . Th e u se re q ui r es r eas o na b l y g o o d a rm , h a nd , a n d wr i s t fu nc t io n . Th e pa t ie n t h o ld s o n t o th e wa lk e r an d ta k e s a s t ep , th e n m o v e s t h e wa l k e r a n d t ak es an o th e r s te p . 2 . T yp e s o f w al k e rs . W a l k e r s c o m e in t wo si z e s : a d ul t an d c h i ld . W alk er s m a y b e a d ju s ta bl e i n h e ig h t. S om e wa l k e rs wi l l fo ld t o m a k e s to r ag e o r t ra ns p o rt in g ea s i e r . W alke rs c a n h a v e wh e els on t he f ro n t l eg s t o a llo w t h e us e r t o m o ve t h e wa l k e r b y r a i si ng t he ba c k l e gs a nd r ol l in g i t i ns t ea d o f ha v i n g t o p ic k i t u p . P a ti e nts wi t h lo s s o f a rm , wr i s t , o r ha n d f un c ti o n o n o ne s i de m i gh t u se a h e miw a l ke r o r a s i d e w a lk e r . a . A he m iw al ke r is s i m i la r t o a s t an d ar d wa l k e r exc e p t t h at it h as o n e h and l e i n t h e c e nt e r o f th e wa lk e r f o r m a ni p ul at i on . b . A si d e w a l ke r is pl ac e d to t he s i de of th e pa tie n t i ns t ea d o f in f ro n t o f t h e p a t ie n t. c . A re c ip r o c al w a lk e r c o n t ai ns t wo hi n ge s , o ne o n ea ch s i de of t he wa l k e r . Th is a l lo ws t h e u s e r to s wi n g e a c h s i de al t e rn a te l y du ri n g a m b ul a ti o n. d . A r o ll a t o r is a wa lk e r wi t h wh e e l s o n a ll fo u r l eg s . Th e m o v e m e n t i s c o nt r o ll e d b y h a n d b ra k e s . E . W h ee l ch a i rs . Ma n y d if f e r en t t y pe s o f wh e el c ha i r s a re a v ai l ab l e. Th e pa t i en t ' s d i sa bi l it i es , s i z e, we i g ht , a n d ac t i v i ti es ar e th e m a i n c on si d er a ti o ns i n wh e e lc h ai r s e le ct i on . Th e f o ll o wi n g o p t io ns s h ou l d b e c o ns i de r e d wh e n se l ec ti n g a wh e el c ha i r. 1 . S ea t si z e . Th e s t an dar d c h a ir is 18 in c h es wi de a nd 16 in ch es de e p. A n a r r o w wh e e l c ha i r is 16 in c he s wi d e . W hee lc ha i rs ar e av a i l ab l e i n wi d t h s u p t o 48 i nc he s . Th e c ha i r s ho u ld be 2 i nc h es wi d e r t ha n th e wi d es t pa r t o f th e p a ti en t ' s bo d y ( u s ua ll y a r ou n d t he bu t to c k s o r th i gh s) . 2 . Ar m s c a n b e fi xe d o r d e t ac ha b le to al l o w t he p a t ie n t t o t r an s fe r on and o f f t he c h ai r . Ha l fl e ng t h a rm s ( as op p os ed t o f ul l l en g th ) a l lo w t h e us e t o g e t c l os e r t o a t a b le o r wo r k s u r fa c e . Va r i ou s t y p es o f p ad di n g a n d a dj u s t m e n ts i n th e ar m po s i t io n c a n as s i s t t he pa t ie n t i n o b t ai ni n g a p o si ti o n t ha t i s c om f or t a bl e a nd ke ep in g th e a r m s on t he ar m r e s t s . 3 . T i re s c an be ha r d ru bb e r or pn e um a ti c ( i. e . , a ir f i ll ed ) wh i ch al l o ws th e c ha i r t o t r a ns ve r s e r ou g he r s u rf ac es . 4 . W he e ls c a n b e r e in f orc e d wi t h s p ok es o r ca n be co m p o s i te b as ed .
5 . L eg r es t s c an be of dif f e r en t s i zes an d a r e a v ai l ab l e wi t h pa d di n g. S om e h a ve a d ju s ta bl e el e v a ti on t o ai d in he al i ng an ac ut e i n j u r y . 6 . F oo t r e s ts c a n b e o f di f f e re n t s i ze s a n d a re a va i la b le wi t h o r wi t h ou t he e l l oo ps t o k e ep th e fo o t o n t he f oo tr e s t. 7 . C as t e r s ( i .e . , f ro n t w h e e ls ) c a n b e h a rd r ub be r o r p ne um a ti c . 8 . C a l f r e s ts c a n b e o f di f f e re n t si ze s a n d a re a va i la b le wi t h p a dd i ng . 9 . S ea t up h o ls t e r y h o l d s t he pa t ie n t i n t he c h ai r. S e at s c om e i n a va ri e t y o f m a te r i al s t o ac c om m o da te p at i en ts ' n ee ds . 1 0 . Ba c k u p ho l s te r y s u p p o r ts t h e p a ti en t ' s b ac k wh i l e he o r s h e i s s it t ing i n t he c h ai r . Th e m a t e ri a l in t he s e a t a nd ba c k a re us ua l l y th e s am e . 1 1 . C r os s b r a ce s a d d s ta b il i t y an d d u ra b il i t y t o th e c h ai r . 1 2 . W e i gh t . St a nd a rd wh e e lc h ai rs we i g h 3 5 -5 0 l b. L ig h t we i gh t wh e el c h a i rs ( 25 - 35 l b . ) a r e a v a il a bl e f o r t h os e wh o ar e u n ab l e t o m an i pu l at e a st a nd a rd c h ai r a n d f o r e a se of t ra n s p o rt . F . S p o r ts ch a i r s a re wh e e lc h ai rs t ha t a r e l ig h t we i gh t an d d u ra b le . Th e y a r e d e si g ne d f o r p eo p le wh o a r e v e r y a c ti v e . G . P ow e r e d w he e lc h ai rs a r e d es ig ne d fo r pe op le wh o c an no t wh e e l t hem s e l v e s. Th i s t yp e o f wh e e lc h ai r is po we r e d b y an el ec t ri c m o to r a n d b at t e r y. P.593
II. BATHROOM EQUIPMENT. Th i s eq u ip m e n t is us ed fo r p at i en ts wh o c a nn o t ge t t o t he ba t h ro om o r f o r p a ti e nt s wh o n e e d as s i s ta nc e u s in g th e to il e t o r b a th t ub . A. E l e va t e d t o il e t s e at s a r e u s e d t o i n cr e as e t he h e ig h t a t wh ic h t h e p at ie n t s i ts o ve r t he to i le t . Th is a s s is t s p at i en ts wi t h li m i te d m o bi li t y i n g et t in g o n a nd o f f t he t o i le t . A d di t io na l s up p o rt c an be p ro v i d ed wi t h to il e t sa f e t y r a i l s . Th e s e ra i ls al lo w t h e p a ti e nt t o t r an s f e r we i gh t f ro m t he f ee t t o th e h a nd s, an d th e y he l p p re ve n t th e p a t ie n t f r om fa ll i ng wh e n g e t ti ng on o r o f f t he to i le t . B . C o m mo d es a re po r t ab l e t o il e ts t h at a re us ed b y p a ti e nt s wh o c an n ot ge t t o t he b a t h ro om . Co m m od e s c on t a in a f r am e ( wi t h o r wi t h o u t a b ac k re s t) , a se a t , a n d a b u ck et . S om e a r e a dj us ta b le in he i gh t a n d h a v e a r m s th a t d r op t o f ac il i tat e t ra ns f e r t o an d fr om t he c om m o de . F ol di n g c o m m od es a re a v a il ab l e t o m ak e s to ra g e e as i er . C . T h r ee - i n -o n e c o mm od e s fu nc t io n a s co m b i nat i o n c o m m od e , e le va t e d t o i le t s ea t , a n d t o il e t s a f e t y ra il s . Th e s e a re be n ef ic ia l fo r pa t i en ts r eq u ir i ng v a r y i ng a s s is t an c e d u r in g re c u p er a ti o n. D . B a t h b e nc h es a re s ea t s wi t h o r wi t ho u t a b a ck t ha t f i t i n t h e b at h tu b an d al lo w t h e p a ti e nt t o s i t wh i le tak i ng a sh o we r . E . T r a ns f e r b e nc h es a re p la c e d o v e r th e o u ts ide o f t h e b at h tu b . Th e y a re a v a il ab l e wi t h o r wi t h ou t a b ac k . A t r a ns fe r be nc h a ss is ts th e pa t ie n t i n g et t in g i n to t h e b a t ht u b a nd s e r v es as a b a t h b en c h wh i l e t he pa ti e n t t ak es a sh o we r . F . G r a b b a r s a r e b a rs tha t ei t he r at t ac h t o th e wa l l a r ou n d t he ba t h tu b o r t o th e b a t ht u b i ts el f to as s i s t pa t i en ts in ge t ti n g o n a nd o u t o f th e b a th t ub .
III. BLOOD PRESSURE MONITORS.
P a t i en ts wi t h h y pe r t en s io n us e t hi s e qu i pm en t to m on i to r bl o od pr es s ur e s o th a t a p p ro p r ia t e t he r ap e ut ic d e c i s i o ns c an be m a de . A p a ti e nt ' s b l oo d p r es su re m e as u re d a t h om e i s t y pi c al l y 5 m m H g l o we r th an wh e n m e as u re d a t th e o f f ic e .
1
Th e t yp e of m o ni t o r t ha t i s re c o m m en d ed s h ou l d b e de t e rm in ed b y th e p a ti e n t 's a b il i t y to us e t h e p ro d uc t c o r re c t l y . It em s t o c on s id e r wh e n a ss is ti n g a p a tie n t i n t h e s e le ct i on of a b lo o d p r es s u r e m o n it o r : e as e o f u s e ( e .g . a u to m a t ic in f la t ion ) , us e o f t h e m on i to r wi t h o n e h and ( h as D - ri ng cu f f ), t he si ze o f t h e d is pl a y m o ni t or ( v i s ua ll y i m pa i re d p a ti e nt s ), bl o od p r es s u r e c uf f s i ze , a nd th e c a pa b il it y t o s t or e re ad i ng s . Typ e s o f m on i to r s i nc lu de t he f ol lo wi n g : A. M e r c u r y s p h yg m o m a n o m e te r . Th is t y pe o f m o n i to r i s t h e m os t ac c u ra t e an d d o es no t n e ed c a li b ra t ion . Me r c u r y in a g r ad u at ed c o l um n r is es in r es po ns e to p r e ss u re ap pl i ed to t he c u f f . Th e b lo o d p re s s u re is de t e rm in e d b y m e as u rin g th e l e ng t h o f th e m er c ur y c olu m n wh i l e l is t en in g fo r th e K or o tk o ff s o u nd s i n th e s t e th os c o p e. Me r c u r y m o n i to r s a re us u al l y n o t us e d as a h om e d e v ic e b ec a us e o f t h e ir la r g e s i z e , th e n e ed f o r us e o f a s te t ho s c ope , an d th e p o te n ti al f or m e rc u r y s p il l . O wi n g t o t he r is k of m er c u r y e xp o s u re , th is t y p e o f s p h y gm om a no m et e r is b e in g p h as ed ou t of he a lt h c a r e f a c i li t ie s . B . F i n ge r mo n i t o rs . Th es e d e te c t b lo od p re ss u re b y c om p re ss in g t h e f in ge r a nd c o n ve rt i ng bl oo d v es s e l m o v em e nt in t o b lo o d p r es s u r e b y o s c il lo m e t r ic tec h no l og y. Ma n y e n v i r o n m e n ta l c ond i t io ns an d m ed ic a ti o ns c a n i nt e r fe r e wi t h t he r es u lt s o f t h es e m on i to r s . F in ge r blo o d p r es s u r e m on i to r s ar e l ea s t a cc u r a te an d no t r e c om m e nd e d f o r h om e m o ni t o ri ng . C . An e r o i d sp h yg m o m an o m e te r . Th is is s im il a r t o a m er c ur y s ph y g m o m an o m e t e r, e xc e p t t ha t i ns t ea d o f a c o lu m n of m e r c u r y , it has a d ia l t o be re a d. A ne ro i d m od el s h a ve th e a d v a n ta ge o f be i ng l es s e x pe n si ve t han m e r c u r y m o d el s ; ho we v e r , t he y d o r eq ui r e re gu l a r c a l ib ra t i on in a h ea l th ca r e p r ov i d e r ' s o f fi c e wi t h a m e rc u r y s p h ygm om an om e te r t o en s u re pr o pe r r es ul ts . The s e t y p es of m o ni t o rs are p o rt a bl e a n d l ig h t we i gh t , h o we v e r . Mo s t r e qu i re m a nu a l i nfl a t io n o f t h e c uf f , b u t a s e p a ra t e s t e th os c o p e is no t re q ui re d . P.594
D . E l e ct r o n ic o r d i g i ta l m o n i to r . Th is t y p e o f m o n i to r de t ec ts bl oo d p r es s u r e b y u s in g a m ic r o ph on e or by o s c i ll om e t ri c t ec h no lo gy , wh i c h c o n v e rt s m o v em e nt o f ve s s el s in t o b lo o d p r es s u r e . Th is t ype is e as i e r to us e th an a m e rc ur y o r a n e ro i d s p h ygm om an om e te r as m os t of f e r a ut om a ti c i n fla t i on an d d e fl a ti on an d th e r e i s n ot a n ee d f o r a s e pa r a te s te t h os c o pe . Th es e m od e ls a re m o r e e xp e ns i ve , c a n p ro v i de i n ac cu r a te r ea di n gs i f the p at i en t m o ves wh i l e t he b lo od p re ss u re is be ing p e r f or m e d , a n d r eq u i re s f r e q ue n t c a l ib r at i on ag a in s t a m e rc u r y s p h y gm om a n om e te r ; b u t th e y re p r es en t a n a l te r n a ti v e fo r pa t ie n ts wh o c an n ot us e a s p h ygm om a n om e te r . S o m e o f t h es e m o n it o rs c om e wi t h a wr i s t c uf f wh i c h m a y be us e fu l i n o v e r we i g h t o r o b es e p a ti e nt s f o r wh om t h e r e gu l ar si ze a rm b l oo d p re s s u re c u ff is to o s m a ll . P a t i en ts wi t h v e r y la r ge o r v e r y s m al l u p pe r ar m s m a y ne ed t o p u rc ha se a s pe c i a l c u f f i n o rd e r t o ob t ai n a n a c c u ra t e r e ad i ng .
IV. HEAT AND COLD THERAPY. F o r m us c ul os k e le t al di s or d e rs ( e .g . , s p r a in s , st r ain s , a r th r i ti s ), t re a tm en t m a y i n cl ud e th e a p pl ic a ti on of h ea t or c o ld t o sp ec i fi c a r e as of th e bo d y . A. H e a t c an be ap p li ed in a d r y o r m oi s t f o rm . D r y h e a t i s l es s e f fe c t i v e th a n m oi st h e a t b ut is to l er a te d b e t te r ; th us i ts c li n ic al ef f ec ti v e n es s is s i m i la r . M o is t h e at ha s a n ad va n ta g e o f n o t c a us i ng as m uc h p e rs pi r a ti on a nd is o f t en re c om m e nd e d . Th e a p pl ic a ti o n o f h e at p ro duc es v a so d il a ti on an d m us c l e re l a xa t i on . Th is fa c il i t at es p a in r el i ef an d h e al in g . P r o d uc ts th a t c an de li v e r h e at in c l u de th e fo ll o wi n g : 1 . A ho t w a te r b o tt l e , a r u b be r c o n ta in e r , sh o ul d b e h a lf fi l le d wi t h h ot wa t e r . Th e r e m ai ni n g a ir is s q ue e z ed o ut o f t he c o n ta in e r , wh i ch is th en c a pp e d . Th is r es ul t s in a f le xi b l e c o nt a in e r t h at c a n b e s ha pe d to th e a r ea o f t h e b od y f o r wh i c h i t i s b ei n g u s ed to p ro v i d e d r y he a t. 2 . A he a ti n g p a d i s a n el e c t r ic al l y p o we r ed pa d th a t c an p ro d uc e m o is t o r d r y h ea t . Mo i s t h ea t is s up p li ed b y i ns e r ti n g a we t s p on ge in a p oc k et th a t i s n e xt t o t h e p ad . P a t i en ts s h ou l d b e i ns t ruc t ed t o p la ce th e p a d o n t o p o f th e b o d y i ns t ea d of l yi ng on t h e p a d t o p r e v en t bu r nin g . 3 . A m o i st - h ea t pa c k ( a ls o c al l ed a h y d r oc ol la t o r) c on t ai ns s i li ca be a d s , wh i c h a b so r b h ea t wh e n p l ac ed i n b o il in g wa t e r . Th e hea t e d p ac k is wr a p p ed i n a t o we l a n d a p pl ie d t o th e b o d y to p r o v id e m oi st he a t . A m o is t -h e at pa c k m us t be k ep t m o is t t o r et a in it s a bs o rb e nt p ro p e r ti es . Th e p ac k sh o uld b e wr a p p e d i n pl a st ic a n d s to r e d i n th e re f r ig e ra t o r i f us e i s a n ti c i p at e d o r i n t h e f re e z e r if lo n g- t e rm s t o ra ge is r e q ui r e d. 4 . A ge l p a ck p ro v i d es dr y h e a t a f te r i t is h e at e d i n bo il i ng wa t e r o r in th e m ic r o wa v e . I t is r eu s a b le b y r e pe a ti n g t he he a ti ng p r oc es s . 5 . C h em i ca l h o t pa ck s p r o v i de d r y he a t b y m i xi n g c h em ic al s f r om t wo c om p a rt m e n ts . Th e c hem ic a ls u n de r go an e xo t he r m ic re ac t io n . S om e p ac k s a re r e u sa bl e b y r e he a ti n g i n b o il i ng wa t e r o r in th e m i c r o wa v e . 6 . P a ra f f i n b a th s pr o v i de m o is t he a t b y c o v e r in g t h e b od y wi t h h ea t ed par a f f in . O n c e t h e wa x c o o ls a n d h a r de ns , it is re m o v e d . Th i s m e t ho d i s c om m o nl y u s ed fo r p a t ie n ts wi t h a r t hr i ti s i n t h e h a nd s a nd fi n ge r s. B . C o l d a p pl ic a ti on is i nd i c a t ed m a in l y as a c ut e th e r ap y t o d ec r e as e ci r c ul a t io n t o a l o ca l a r ea an d to pr o v i de p a in r el ie f . Co l d is c o nt ra i nd ic a te d i n p a ti e nt s wi th c i rc u la t or y s ta s i s o r l a c er a t e d t is s u e. P r od uc t s t ha t ca n d el i ve r c ol d i nc l ud e th e f o l lo wi n g : 1 . A n i ce b ag is a f le xi b le p la s t ic c o n ta in e r d es i gn e d t o h o ld i c e. Th e ba g i s t h en a p pl i ed to t he bo d y . 2 . A ge l p a ck c a n b e u s e d to ap p l y c ol d b y f r e e zi n g a nd t he n a p pl yi ng t o t h e b o d y. 3 . C h em i ca l p a ck s c an b e us ed to ap p l y c o ld . Ch e m i c a ls f ro m t wo c om pa r t m e n ts a r e m i xe d t og e th e r , r es ul t i ng in a c h em ic a l r ea c tio n th a t p r od uc es co ld . Th e se p a ck s a re us e d o nc e a nd t h en di s p os e d o f . P.595
V. DIAGNOSTIC AIDS
A. S e l f - c a r e t e s ts or k its a r e us e d as s c r ee ni n g t e s ts o r fo r m o ni t o ri ng . Ma n y f a c to r s c a n a f fe c t t he ac c u r ac y o f t he te s ts . Th e m os t c om m o n fa c t o rs a re p at i en ts n o t fo ll o wi n g d i re c ti on s a n d p a ti e nt s h a vin g p o o r t e c h ni q ue . Ph a rm ac is t s s h ou l d b e p r e pa r e d t o c ou ns el pa t ie n ts on t he s e le ct i on of a t es t , o n t h e p ro p e r us e, a nd on i n t er p r et a ti o n o f r es u lt s . P h a r m a c i s t s s ho ul d re f e r p a ti e nt s t o t h e a pp r o pr ia t e h e al t hc a re p ro v i d e r i f n ec es s ar y. B . T yp e s o f t es t s 1 . U r i ne t es t s a . Th e u ri n e g l uc o se t es t d et ec t s su g ar in t he ur i n e. P a ti en t s wi t h di a be te s c an us e t h is t o e v a lu a te gl uc os e c o nt r o l. B lo od gl uc o s e m o n i to r in g i s p r ef e r re d , h owe v e r , b e ca us e i t i s m o re ac c u ra t e a n d g i v es a b et t e r de sc r i pt i on of c u r r en t g l y ce m ia . b . Th e ke t o ne t es t d e tec t s t he p re s e nc e o f k e ton e s i n t he u ri n e. Th is is u s ed b y p a t ie n ts wi t h d ia b et e s as a n i n di c a t o r o f se v e r e l y u n co n t ro ll e d d ia b et es . c . O vu l a t io n p re d ic t i o n t e s t s p r ed ic t wh e n o v u lat i o n oc c u r s t o i nc r ea s e th e c h an ce o f co nc e pt io n . ( 1 ) Th e s e te s ts d e te c t t he p r es en c e of l u te i ni z ing h o r mo n e ( L H ) i n th e ur i n e. I ts p r e se nc e m ea ns t ha t o v u l a ti on sh o ul d o c c ur wi t hi n 2 0 - 48 h r. ( 2 ) Th e te s t is pe r f or m e d d a il y u nt i l a p os i ti v e r es u l t i s o bt a in e d. Ma n y k i ts r e c om m e nd no t u s i n g t he f i rs t m or n in g u r in e a s th e L H s ur g e t y p ic al l y st ar t s i n th e m o r ni ng an d m a y no t b e d e t ec ta b le un t il la t er in th e da y . Th e r ef o r e, it is r e c om m e nd e d t o t es t b e twe e n 1 0 A. M. a n d 8 P . M . ( 3 ) Th e da y o n wh i c h t h e p a ti e nt be g in s t es t in g de p e nd s o n t he le n gt h a nd r e gu la r i t y o f he r m e ns t ru a l c y c l e . Pa t i en ts wi t h m e ns t ru a l c yc l es o f c o ns is te n t l en g th m a y n e e d t o t es t o n l y fo r 4 da y s , wh e r ea s t h os e wi t h m e ns t ru a l c yc l es th a t c ha n g e in l e ng t h m a y n e ed to t es t fo r 8 o r 9 d a ys . ( 4 ) F al s e - po s i t i v e r es u lt s c an oc cu r if th e p a ti e nt i s ta ki ng f er t il i t y m e di ca ti o ns ( e. g ., c l om ip h en e ), o ra l c on t r ac e pt i v es , o r h or m o n e - rep l ac em e nt th e r ap y o r i f th e pa t ie n t h a s p ol y c y s ti c o v a r y s y nd r o m e or im pa i r ed li v e r o r k i d ne y f un c ti on . d . P r e gn a nc y t e s t s de t ec t pr e gn a nc y b y th e p r ese n c e in th e u r i ne of h uma n c h o r i on i c g o na d o t r op i n ( h C G ) , wh i ch is s ec r e ted a f te r fe r ti l i z at i on . Ma ny p r e gn a nc y t es t k it s c an d e t ec t h C G 1 d a y a ft e r m is s e d m en s es . ( 1 ) F al s e - po s i t i v e r es u lt s c an oc cu r if th e p a ti e nt t a k e s t h e t es t t o o e a rl y , i s ta k i ng f e r t il i t y m ed ic a ti o ns (e . g., h C G ) , or ha s o v a r ia n c y s t s . ( 2 ) I f a p a ti e nt us es a h ou s eh o ld c o nt a in e r o r a wa xe d c u p t o c ol le c t u r in e, i t m a y a f f ec t t h e t es t re s u l ts . ( 3 ) P a ti en t s s h o ul d b e r ef e r r ed t o t he ap p r op r ia t e h e al t hc a re pr o vi de r if t he y r e c e i ve a p os it i v e re s u l t o r t wo ne g a ti v e r es ul ts 7 d a y s ap a r t a n d h a ve n ot ha d m e n se s . e . Th e u ri n a r y b a c t e r i a t e s t d e te c ts th e p r es en c e o f n it r i te in th e u r i ne . Th e p r e se nc e o f n i t ri t e is us ed as an in d ic at o r o f a u r in a r y t r a c t i n f ec t i o n ( U TI ) b e ca us e th e m os t c om m o n ba c t e r ia ass oc i at e d w i t h U TI s a r e g r am -n e ga t iv e b a ct e r ia , wh ic h c on v e r t n i t ra t e t o n i t ri t e. ( 1 ) B ec au s e t hi s t es t i s n o t s pe ci f ic fo r ba c t e r ia , f a ls e r es u lt s c an oc c u r . ( 2 ) Th i s t es t i s us e d b y pa t i en ts wh o h a ve r ec u r ren t o r c h r o ni c U TI s o r m an y r i s k f a c to r s. R is k f ac to r s i nc lu d e p r e v io us U TI s , d i abe t es , ur i na r y t r ac t a bn o rm a li t ie s ,
e n la r g ed p ro s t r a te , a n d b e h a v io r al ri s k fa c to r s ( e. g . , f r e qu en t s e xu a l ac ti v i t y , d e la ye d ur i na t io n , t he us e o f s pe r m i ci de s o r d i aph r a gm s ). ( 3 ) F al s e po s i t i v es c an re s ul t fr om m e di c at io n s (e . g . , p he na z o p y r i di ne ) th e pa t ie n t m a y be t ak in g o r f ro m m e n s t r u al bl oo d i n th e u r in e , d e pe n di ng on t he te st u se d . I n a d di t io n , a fa ls e n e ga t i ve m a y b e d e te c t e d i f t h e p a t ie n t is t ak in g h ig h d os es o f vi t a m i n C , a dh e re s t o a s t r ic t v eg e ta r ia n d i et , or h a s f r eq u en t u r in a ti o n. f . Th e r e a r e a v a r ie t y of F D A a pp r o v e d u r i ne d r ug t e s ts a v ai la b le fo r us e a t ho m e . S u b st a nc es th a t m a y b e d e t ec te d i n th e u r in e i nc lu d e : am p he t am in e , m e th am p he t am in e , e c s tas y , m a r ij u an a , c oc ai ne , p h e nc y c l i di ne , op ia t es , b e n zo di a z ep i ne , b a r bi t ura t es , m e th a do n e, t ri c y c l ic an t id e p re s s an ts , an d ox yc o d o ne . Mo s t u r i ne d ru g t es t s r eq u i re t wo s te ps : s cr e en in g ( at ho m e ) an d c on f i rm a ti o n ( l a bo r a to r y ) . ( 1 ) Th e fi r s t s t e p r eq u i res t he c o ll ec t io n o f u r in e in t he p ro vi d ed c o ll ec t io n c up an d r e v i e wi n g th e re s u l ts a s c o lo r ba nd s o n t h e d e v ice a t h om e . Th e c o lo r ban d s a r e s im i la r to r es ul ts ob t ai n ed o n a h om e p r e gn a nc y te s t . I f n o d r ug is de t ec ted , a n e g at i ve re s u l t wi l l ap pea r . P.596
( 2 ) A pr e li m i na r y p os i ti v e r es u lt in di c at es th e ur in e s am p le m a y c o n ta i n th e d ru g b u t a co n fi r m a t io n i s n ee d ed. To o b ta in c o n fi r m a t io n t e s ti ng , i t is n ec e s s ar y to s e n d t he u r i ne s a m p le t ha t wa s u s e d to pe r f o rm th e f i rs t s te p to t he dr u g t es t m an uf a c tu r e r 's c o nt r ac t ed la b o ra t or y . Th e r es ul ts a re a v ai la b le fr o m t h e l ab o ra t o r y 7 t o 10 b us in es s d a ys a f t e r t he s p ec im en i s m ai l ed an d a r e a no n ym o us a s t h e y a r e tr ac k ed b y a p e r so na l i d en t if ic a ti o n nu m be r . 2 . B l oo d te s t s a . Th e ch o le s t e ro l te s t d e t e rm in es a p at i en t ' s t ot a l c ho l es te r o l ( TC ) , l o w- d e ns i t y l i po p r ot e in (L D L ) , h ig h - de n s i t y li p op r o te in ( H D L ) a n d /o r t ri gl y c e ri d es . ( 1 ) S om e t es t s p ro v i d e th e pa t ie n t o nl y wi t h a TC l e ve l, wh e r e as o t he r s p ro vi d e a f u l l li p id p ro f il e ( TC , L D L, H D L , a n d/ o r tr i gl y c e ri de s ) . ( 2 ) S om e c ho le s te r ol k i ts a r e a s i ng l e- us e te s t in wh i c h pa t ie n t a pp l ie s a bl o od s am p le on t o a c ol l ec ti n g c a r d, wh i ch is m a il ed t o a l ab o ra t o r y fo r e v al ua t io n . O th e r s i ng le u s e te s t s c an be pe r f o rm ed an d e v al ua t ed b y t h e p a ti en t at ho m e . Th e m e as u re m e n t o f t h e am ou n t o f c h ol es t e ro l is d et er m i ne d b y a c ol o r c ha r t , wh i c h is p r o vi de d wi t h t h e t es t . ( 3 ) R e ga r dl es s o f t h e t es t u s e d , t he pa t ie n t p la c es a l a rg e d r op o f b lo od on t o th e t e s t ca r d o r c as s e t t e. S om e o f th e t e s t s r e qu i re th e pa t ie n t t o f as t —m e ani n g n o th in g t o ea t or d ri nk e xc e p t wa t e r fo r 12 - 14 h r b e fo r e co l le c ti ng t he bl oo d . ( 4 ) Th e s e te s ts c an be us e fu l fo r p a ti e nt s wh o wan t t o m o n it o r t h ei r th e ra py. Th e y a r e al so us ef u l as s c r een i ng t es ts . Pa t ie n ts wh o t e s t b or d e rl in e o r hi g he r f o r hi g h c h ol es t e ro l s ho ul d b e re fe r r e d t o t h e a pp r op r i at e h e al t hc a re p ro v i d e r. b . Th e bl o o d g l uc o se t es t m e as u r es t h e c on c e n tr a t io n of gl uc os e i n t h e bl o od . P a t i en ts wi t h di ab e te s us e th is in f or m a t io n , a lo ng wi t h di e t , e xe r c is e , a nd m e di ca t io n , t o k ee p g lu c o s e l e v el s wi t h i n a ta r get r a ng e .
( 1 ) O t he r te s ts a r e d es i gn e d t o b e u s e d wi t h b l o od g l uc o se me t e r s, wh i c h r e ad th e t e s t a nd di s p la y t h e ac t ua l bl oo d g l uc os e v al ue . S o m e b lo od gl uc o se m e te r s c on t ai n o p t ic al un i ts th a t m e as u re t he c o lo r c h an g e c a u se d b y g l uc os e ; o th e rs m e a s u r e t h e e l ec t ri c c ha r g e p ro d uc ed b y g lu c o s e. Th e re s u l t is t he n c al ib r a te d t o pr o vid e wh o l e b l oo d o r pl as m a gl uc o s e c on c e n t ra t io n . W hol e b lo o d i s a pp r o xi m a te l y 15% l o we r t h a n p la s m a g lu c o s e , wh i c h is wh a t is m ea su r e d in t he s t a nd a rd la b o ra t ory t e s ts . Ma n y o f t h e n e w g l uc om e t e rs p ro v i d e r es ul t s as th e “ pl as m a eq ui v a l en t , ” m e an i ng t h e y t es t wh ol e b l oo d b ut u s e an in t er n al al g or i thm t o c a lc u la t e t he pl as m a g lu c o se . ( 2 ) P a ti en t s us i ng bl oo d g l uc os e t e s t s m u s t p e rf or m th e te s t s p r op e rl y a nd u n d er s ta nd t he ap p ro p r ia t e a c ti on s t o ta k e wh e n t h e r es u lt i ng va lu es a re o u ts i de th e d e si r ed r an g e. c . O t he r ho m e b l oo d tes t k i ts ar e a v a i la b le th a t p r o v i de re s ul ts at t he tim e o f t e s ti ng in t he ho m e or t he c o l le c t e d s p e ci m e n i s s e nt t o a l a bo r at o r y f or re s ul ts . Th e s e h om e te s t i ng k i ts i n c l ud e H I V, he p at i ti s C vi r u s ( H C V ), gl y c os yl a ted h e m o g lo bi n A1 c ( A 1c ) , an e m i a , p r os t ra t e sp ec i fi c a n ti g en ( P S A ), an d th y ro i d . I f t h e s p ec im en is m ai l ed a wa y f o r p r oc es s i n g, t he re s ul t s c an be ob t ai ne d b y ca l li n g a t o l l- f r ee nu m b e r . d . Th e r e a r e a v a ri e t y of p o i n t -o f - ca r e te s t in g (P O C T ) d e vic es t ha t a r e a v a i la b le f o r us e i n p ha r m a c i es . Be c au s e a m aj o ri t y o f t hem m e e ts th e Cl in ic a l L abo r a t or y I m p ro ve m e n ts Am e nd m en t s ( C L I A ) - wa i ve d r e qu i re m en ts , ph a rm ac ie s a r e a b le t o o f f e r t he s e s e r v i c e s t o t he i r p a ti e nt s . W hen s el ec ti n g a P O C T d e vic e fo r us e m ak e s u r e t o r es e a rc h t he de v ic e s pe ci f ic a ti on s , p o rt a bi l it y , t es t in g p r oc ed u r e, a n d c os t . E xa m p l e s o f p oi n t -o f -c a re t es ts t ha t a r e a va il a bl e i n s el ec t ph a rm ac ie s i ncl u de : e l ec t r on ic pe ak fl o w m e te r s , p o rt a bl e s pi r om e tr y , H I V r ap i d t es t , r a pi d St re p te s ti ng , c o ag u la ti o n a na l y z e r s , os t eo p o ro s i s s c r ee n in g wit h qu a nt i ta t i v e u l tr as o und o r p e r ip h e ra l d ua l -e n e rg y ab s o rp t io m e t r y, a n d b lo o d t e st s t h at m e as u re A 1c , f r u ct o sa m i ne , k e to n es , ur i n a r y m ic r oa l bu m i n , a lan i n e am in o t ra ns f e ra s e s , a n d l ip i d p r o fi l es . 3 . F ec a l o cc u l t b l oo d tes t s de t ec t t h e p re se n c e o f bl o od in th e s t oo l a s a s c re e ni ng t es t f o r c ol o rec t al c a nc e r . P a ti en t s d r op a p a d i nt o th e t o il et a fte r d e f ec at i on . Th e p ad wi l l c h an g e co l or i f b lo od is p r e se n t. P at i en ts s h o ul d e a t h i gh f i b er f oo ds du r in g th e t es t in g p e r io d a nd a re in s tr u c te d t o te s t t hr e e c on se c ut i v e s t oo l s am pl es . P at i en ts wi t h a po si t i v e r e su l t s h ou l d b e re f er r e d t o t h e a pp r o p ri a te h e al t hc a re p ro v i d e r. C e rta i n c on di t io n s ( ga s tr o in te s ti n al bl ee d , n os e bl ee d, m e ns t ru a ti o n) , fo o ds ( red m e a t ), m e di c at io n s ( non s te r o id al an t i -i n fl am m a to r y d r ug s [ N S A I D s ] ), an d to il e t -b owl c l e an e rs c a n p r od uc e f a ls e - po s i t i ve r es ul t s . 4 . F e r ti l i t y m i c r o s c o pes a ll o w wo m e n to de t er m i n e t h ei r m os t fe r ti l e t im e o f t h e m o nt h . A wo m a n p la c e s s a li v a on a v i e wi n g s li d e o r pl a te , a l lo ws t he s a liv a t o dr y f o r 5 -7 m i n, an d P.597 t h e n vi e ws i t u nd e r a m ic r o s c o pe . Th e a pp e a ra nce o f a fe r ni n g p at t e rn m ea n s o vu l a ti on h as o c c u r re d . E s t r og e n l e v el s r is e a nd p e ak wi t h o v ul a ti on , c a us i ng an i n c re as e i n s al t l e v e ls i n t h e s al i v a , r es ul t in g i n a f e r nl ik e p a tt e r n i n d ri e d s a li v a . S i m pl e d o ts o r a b ub bl e lik e a p pe a ra n c e is f o un d d u r in g a no n fe r t il e p e ri od . A
wo m a n s h ou l d b e a d v is ed t o a v o id s m ok in g , e at in g , o r d ri nk in g fo r 2 h r be f o r e t e s ti ng . Po l y c y s ti c o v a r y s y n d ro m e an d p e r im en op a us e c an ca us e f a ls e -po s it i ve r e s ul ts .
VI. HOSPITAL BEDS AND ACCESSORIES. H o s pi t al be ds a re us ed by p a t ie n ts wh o a re c o nf in e d t o b e d f o r l on g p e ri od s o f ti m e o r wh o r e qu i re el e v a ti o n o f t he he ad o r f e et as p ar t o f t h ei r tr e at m e n t . H o s p i t al be ds m a y be m a n ua ll y o r e l ec t r i c a ll y o p er a te d . A. T yp e s o f h os p i ta l b ed s 1 . A m a n ua l h os p it a l b ed h as n o e l ec t ri c a l l y p o we r e d m ot o rs ; th e h ea d , fo o t , a nd b e d h ei g h t a re ad j us te d m a nu a ll y . 2 . A s e mi e le c t r i c h os pi ta l be d c on t ai ns t wo e le ctr i c m ot o rs t ha t ra is e t h e h e a d a nd f o o t o f t h e b ed . Th e p a tie n t c an us u al l y a d ju s t t he h ea d a n d f oo t p o s i ti o n wi t h a h a n dh el d c on t r ol . Th e h ei g h t o f t h e b ed is a d ju st ed m a n ua ll y . Th e se m i el ec t r ic b e d c a n us u al l y be ad j us te d m a nu a ll y in ca s e of lo s s o f el ec t r ic it y. 3 . A fu l l y e l e c t r i c ho s p i ta l be d c on t ai ns th r e e m ot o r s t ha t c a n c h a ng e th e h e ig h t o f t h e b e d as we l l a s ra is e t h e h e ad an d f o ot v i a e lec t r ic al l y po we r e d m o to r s. Th e f ul l y e l ec t ri c h os p it a l b ed c a n u s u a ll y b e a dj us t ed m a nu a ll y i n c as e o f l os s o f el e c t r ic i t y. B . Ac c e s s o ri e s 1 . B e d r a i ls k e ep th e p at i e nt in th e b e d a nd al l ow t h e p a ti en t to c h an g e p o si t io ns . 2 . A t ra p ez e i s a tr i an g ul a r -s h ap e d o bj ec t t h a t ha n gs ab o ve th e p a ti en t an d is u s e d t o ch an g e t he p at ie n t ' s po s it i on . 3 . Al t e r n a t in g p re s su r e p a ds a re us ed b y pa t ien t s t o p r e ve nt de cu b it us u l ce r s ( i .e . , b e d s o re s ). As a p r e v en ti v e m e as u r e, t he se pa ds i n fl a te , th us c h an g in g t he a r ea s o f t h e b o d y th a t r ec e i v e p res s u r e .
VII. INCONTINENCE AND INCONTINENCE PRODUCTS A. U r i n a r y i n c o n t i n e nce is a c on di t io n i n wh ic h i n v o lu n ta r y u r in e l os s is a s o c i a l o r h yg i e ni c p ro b le m a nd is o b je c ti ve l y de m o ns t r ab l e. I nc o nt i ne nc e i s a c om m o n p r o bl em in t he el de r l y . Ty p e s o f in c o n ti ne n c e in c lu d e 1 . U r g e i nc on t in e nc e, wh i c h is u nc o nt r o ll ed co n tr a c ti o ns o f th e b la d de r 2 . S t r es s i nc o nt i ne nc e , a we a k ne ss of t he s p hi nc t e r t ha t c a us es l e ak ag e wh e n i n t ra - a bd om i na l p r es s u r e i nc r e as es (e . g. , wh i le lau g hi n g, co u gh in g , s ne e z in g ) an d i s c om m o n i n p r e gn a nc y 3 . O ve r f l ow in c o n ti n en c e , wh i c h is c a us ed b y obs t r uc ti o n o f u r in e fl o w f ro m th e b l ad d e r a nd is c om m o n in e ld e rl y m en as a r es ul t o f pr os t a te en la r g em en t 4 . F un c t io n al i nc o n ti n en c e , wh ic h i s r el a te d to p h y s ic al o r ps yc h ol og ic al p ro b le m s t h a t i m p ai r th e p a ti e nt ' s a b il i t y to ge t to th e b a th ro o m 5 . T r an s ie n t in c on t i ne nc e , wh ic h i s c au s e d b y m e di c a t io ns , u r i na r y t r ac t i nf e c t io n s , o r m e n ta l i m p ai r m e n t 6 . M i x ed i nc o n ti n en c e, wh i c h is a co m b i na t io n of m or e th an on e t y pe of i n co n ti ne n c e B . I n co n t i ne n ce p r od u ct s 1 . S h ie l ds a re di s p os a ble , ab s o r b en t p a ds th a t ar e pl a c e d i n t h e u nd e r wea r a nd h e ld wi t h an ad h es i v e s tri p on th e b ac k o f th e p ad. Th e s e p ad s a r e us e d f or l ig h t i n co n ti ne n c e pr o bl em s .
2 . U n de r g a r me n ts a re di s po s a b le ab so r be n t g a rm e nt s t h at a re wo r n un de r t he u n d er we a r a nd he l d i n pla c e wi t h el a st ic s t r ap s t ha t go a ro u nd th e h i ps . Th e y a r e d e si g ne d f o r m od e ra t e i nc o nt i ne nc e p r o bl em s . P.598
3 . B r i e fs lo ok li k e ad ul t -s i z e d i ap e rs th a t a r e k e pt i n p la c e wi t h ad he si ve s t r ip s . Th e y a r e de s i g ne d f o r he a v y i nc o n ti ne nc e p r o bl em s . 4 . P u ll - u p p a nt s a r e a bs o r b an t di sp os a bl e g a rm en t s t h at lo ok li k e un d e r we a r an d a r e us ed fo r he a v y i nc ont i n en c e p ro bl em s . 5 . U n de r p a ds ar e a b s o rb e n t p ad s t o b e p la c ed on t he be d u n de r ne a t h a p a t ie n t wi t h i n co n ti ne n c e . Th es e p ads c o n ta in a b a r ri e r t o p r ot e c t t he be d di ng . 6 . Wa t e r p r oo f sh e e ts a re p la s t ic o r vi n yl s h ee ts t h a t p r ot ec t th e m a tt r es s . Th e y m a y be li n ed wi t h a s o f t m a te r i al to p re ve n t f r ic tio n ag ai n st th e s k i n . 7 . I nc o n ti n en c e s ys t e m s a r e g ar m e n ts th a t l oo k l ik e u n de r we a r bu t ha v e a po uc h o r p ock e t d es ig n ed fo r a d i s p os a bl e o r re us a bl e pa d .
VIII. ORTHOPEDIC BRACES AND SURGICAL FITTINGS. Th e s e p r o du c t s p r om o te p r o pe r bo d y al i gn m e n t an d s u pp o r t i nj u re d a r ea s . P h a r m a c i s t s s ho ul d h a v e a d di t io na l tr a in i ng be f ore a t te m p t in g t o f i t a n o r th o p ed ic d e vi ce . A. Ab d o m i n al su p p o r ts a r e el as t ic a n d a re us e d t o s u pp o r t a nd ho l d s u r gi c al d r e ss in gs in pl ac e . A b dom i na l s up p or t s co m e in d i f fe r e nt wi d t hs . B . Ar m s l i n gs a re us ed t o p ro v i d e co m fo r t a nd su p p or t du r in g re c u p er a tio n f ro m f r a ct u r es , s pr a in s , a nd s u r g e r y . Th e e lb o w s ho u ld f o rm a 90 - d eg r ee an g le i n a n a rm s l in g t o a l lo w f o r p ro pe r c i rc u la ti o n . C . B a c k s up p o r t s a re wo r n b y p a ti e nt s t o p r o vide s u p po r t o r p ro m o t e p r op e r a l ig nm e nt . S uc h s u p po r ts a re na m e d a f t er t he are a of t he s p in e o n wh ic h i t i s wo r n . 1 . A s a c ra l be l t (a ls o c al l ed sa c r a l c in c h o r s a cr o i l i ac be l t ) s up p o rt s t he l o we r b a ck . 2 . A lu m bo s ac r a l s u pp or t s up p o rt s t h e l o we r and m i d dl e b ac k . 3 . A th o r a co l um b a r s u pp o r t s u p po r ts th e m id d le a n d h ig h er a re as o f t he b a c k . D . C e r vi c a l c o ll a r s s upp o r t o r li m i t t h e r a ng e o f m o ti on o f t he ne c k . Ce rv i c a l c o l la r s s h ou l d b e o f s u f f ic ie n t l en g t h s o t ha t th e p a ti en t c a n a dj us t th e d e gr e e o f c om p r es s i on . Th e wi d th o f t he c e r v ic al co ll a r s hou l d e qu a l t he m e as u re m e n t fr om t h e c hi n to th e s t er n um wh e n t h e p a ti en t i s s ta nd i ng s t r a ig h t, lo ok i ng ahe a d . 1 . S o f t o r fo a m c e r v i c a l c o ll a rs pr o vi de m i ld s u ppo r t an d re m i nd t he we a re r t o k e e p t h e n ec k s t ra i gh t . 2 . H a r d o r r ig i d c e r v ic al c ol l ar s p r o v id e m o re sup p o r t a nd li m i t m o v em ent t o a g r e a te r d e g re e . 3 . A P hi l ad e l ph i a o r e x tr i c a t i on c o ll a r is us e d t o i m m ob i li z e th e n ec k a nd i s c om m o n l y u s ed in em er ge n c y s i tu a ti on s . E . C l a vi c le su p p o r ts a re us e d a s ai d s f o r t he r ed u c t i on an d s ta b il i za ti o n o f th e c l a vic le (i . e ., c o ll a r bo ne ). Th e s e s u p po r ts a re s om e ti m e s c al le d fi g u r e -e ig h t s t ra p s b e ca us e o f th ei r ap p ea r an c e.
F . K n ee b r ac es ( al s o c al l ed k ne e c a ge s ) a r e us e d to s u pp o r t t h e kn e e. S o m e b r a ce s h a v e m e t al s t a y s o n th e s id e to pr e ve n t t he l at e r al m o v em e nt of t he k n e e. Th o s e wi t h m et a l s ta y s m a y al s o ha v e h in ge s t o a l lo w f o r m o v e m e n t o f t he kn e e. S o m e kn e e b r ac es h a v e a c u t - ou t h o le an d p a dd in g a ro un d th e p a te ll a (i .e . , k n ee c a p ) t o p r e v en t i t s m o v em e nt . G . K n e e i m mo b i li z e r s pr e v e n t a n y m o t io n o f t h e k n ee an d a r e u se d f o r s ev e r e i n ju r i es a n d f r ac tu r es . Th e y a r e a v a il ab l e i n d if f er e n t l e ng t hs a n d a r e a dju s ta b le in size. H . N i g h t ti m e a nk l e b r a ce k e e ps th e a nk l e a t a 90 - d eg r e e a ng le wh i l e s l ee p in g . I t c a n b e u s e d i n t h e t r ea tm e nt o f A c h il l es te n do n in j u ri es o r p la n ta r fa sc ii t is . I . S h ou l d e r i mm o b il i z e rs p r e v en t m o vem en t of th e s h ou l de r a n d a rm . The e lb o w s h ou l d b e a t a 9 0 - de g ree a ng le t o a ll o w f o r h e al in g wi t h ou t a f f ec ti n g c i r cu l a ti on . P.599
J . T en n is e lb ow su p p o rt s a pp l y pr e s s ur e to th e f o r e ar m t o p r o v i de pa in re l i e f an d d e c re as e i n fl am m a t io n f ro m te nn is el b o w ( i .e . , e pi c on d y li t is ) . K . W r i s t b r a ce s p r e v en t m o v em en t of t he wr i s t to a ll o w h e al in g . Th e b rac e m a y be s h ap e d t o h a v e t h e wr i s t f l e xe d s o th a t t h e t en d on s i n th e h an d re m a i n s tre t ch e d d u r in g th e p e ri o d o f i na c t i v i t y .
IX. OSTOMY APPLIANCES AND ACCESSORIES A. D e f i n i t i o ns . An os t om y i s a su r gi ca l p r oc e dur e in wh i c h a n a r ti f ic ia l op e ni n g is c r e at e d i n t he ab d om in al wa l l f o r t he pu r p os e o f e l im in a ti n g u ri n e o r fe c a l wa s t e . Th e o p en in g i s c al le d a s t o m a. O s t om i es c a n b e t e m p o ra r y t o a ll o w f o r re p ai r o r h e al i ng of t he di ge s ti v e tr a c t o r c an be pe r m a n ent . E ac h p r oc ed u r e is nam e d t o d e sc r ib e t h e a na t om ic al l o c a t io n i n v ol v e d . 1 . I n a c o l os t om y, p a r t o f t he c o lo n i s c u t an d a tt a c h e d t o t h e a bd om i na l wa l l . Th i s p r o ce du r e i s d on e m ai n ly i n pa t ie n ts wi t h c ol o n or r e c t a l ca nc e r , l o we r - bowe l o b st r uc t io n , o r d i v e r ti c u lit i s . A c o lo s t om y m a y b e t e m p o r ar y o r pe rm a ne n t , t h e d i sc ha r ge m a y b e l iq ui d o r s e m i so l id (a s wi t h a n a s c en d in g c o lo s t om y) , or i t m a y be s o li d ( a s wi t h a d es c en di n g o r s ig m oi d c o lo s t om y ) . P a t ie n ts wi t h a n a sc en d in g c o lo st om y a n d s o m e pa t ie n ts wi t h a t r an s v e rs e co l os t om y ha v e g as t ri c e nz ym e s p r e se n t i n t he di s c ha r g e. Th e s e p a ti en t s m u s t t ak e e xt r a c ar e to en su r e t ha t t he d i sc ha r ge do e s n ot c o m e i n to c o n ta c t wi t h th e s k in . 2 . I n a n i le o s to m y, t h e i l e um is a t t ac he d t o t h e ab d om i na l wa l l . Th is p ro c e d u re is p e r f or m e d i n p a ti e nt s wi th u lc e ra t i ve co l it is o r C ro h n d is e as e. 3 . A u ro s t om y i s p e rf o rm e d i n p at i en ts wi t h bl add e r c a nc e r. In t hi s p ro c ed u r e , a n i l e a l c on d u i t is c r e at e d b y a t t ac hi ng t he u re t er s t o t he i l eu m a nd t he di s ta l en d o f t h e i l eu m t o t h e a bd om ina l wa l l . B . O s t o m y a p p l i a n ce s . Th e o s to m y a p pl ia n c e c on t a in s a s k i n b a r r ie r t hat a t ta c h es t o t he s k i n a r o un d t h e s to m a. Th e s ki n b a r ri e r p ro t ec t s t he s k in an d a ll o ws f or t he c o ll ec t io n d e v ic e o r po uc h t o b e wo r n o n t he bod y. Th e s e l ec ti o n o f a n os t om y a p pl i an c e de p en ds on the t y p e o f d is c h a r ge pr o du c ed . In ad di t io n to s i z e , c ol o r , a nd
f l e xi b i li t y , ap p li an c e s m ay h a v e d et ac h ab le po uc he s a n d b e a bl e t o b e dr ai n ed b y r e l ea si n g a c li p a t th e b ot t o m o f t he ap p li a nc e. C . O s t o m y a c c e s s o ri e s 1 . Wa s he r s , p ow d e r p as t e , a n d o i nt m en t s a r e d e si g ne d t o b e u s e d wi t h a sk in b a r r ie r an d p r o v id e a d di ti o na l p r o te c ti on o f t he s k i n ar o un d a st om a . 2 . C em e n t, e la s t ic be l t s, a nd t ap e a r e u s e d to ho l d t h e a pp li a nc e i n p la c e . 3 . D e od o r iz e r s h el p c ont r o l f ec a l o do r . Ex t e r na l d e o do r i z e rs c an be pl ac e d in t o t he a p pl i an c e ; s y s t em ic d e od o r i z e rs (e . g ., bi sm ut h su b g al la t e, c h lo r o ph y l l , c h a r co al ) c a n b e i ng es t ed as in t e rn a l de od o r i z er s . 4 . M o i s tu r i z e r s a n d d is in f e c ta n t s c a n be us ed to t r ea t th e s k i n a nd p re v e n t c om p li ca t io ns . 5 . I r r i ga t i on de vi c e s a re us e d b y p at ie n ts wh o ha ve c o n t ro l o ve r th e e l im i n a ti on o f wa s t e t o f ac il i ta t e r em o va l of th e ac c um u la t ed wa s t e . Th e de v i c e s a r e u sed t o i ns ti l l wa t e r i n to th e i n te s ti n e, wh i c h p ro d uc es p e ri s ta ls i s . D . S p e ci a l c o ns i de r a t ion s f o r o s t om y p a t i e n t s. D r u g th e ra p y c a n p r es en t un i qu e p r o bl em s f o r o s t om a te s . A b s o rp ti o n o f e n te r ic - c oa t e d o r s us t ai ne d - re l ea se p r od uc ts m a y no t be po s s ib l e. A nti b io t ic s , su l fa dr u gs , l a xa t i ves , an d d iu r e ti c s ar e s om e o f t h e c om m o n p r ob l em m ed i c a t io ns in th es e p a ti e nt s .
X. RESPIRATORY EQUIPMENT A. C o n t i n u o us p os i t i ve a i rw a y p r e s s u r e ( C P A P) i s u se d i n p a ti en t s wi t h s l ee p a p n ea . Th e p r es s u r e s u pp l ie d fr om t hi s m a c h i ne k e ep s t h e ai r wa y o p e n . It i s t yp i ca l l y wo r n wh i le s l eep i ng t o a ll o w t h e p at i en t t o sl ee p wi t ho u t d is t u rb an c e. P.600
B . A h um i d i fi e r p u ts m oi s tu r e i n to th e a i r b y b r ea k in g wa t e r i nt o s m a ll par t i cl es an d b l o wi n g t h em i n to th e a i r t o be e v ap o ra t ed . H um id i f ie rs a re so m e t im es re fe r r e d t o a s c a ll ed “ c o ol m i s t v a p o ri z er s . ” 1 . V ap o r iz e r s a r e s im i l ar t o h um i di f ie r s in t ha t the y a r e u se d to de li v e r m o i s t u r e t o t h e a i r . H o we v e r , a v ap or i z e r p ro d uc es a s t e am to i nc r ea se hu m i di t y, wh er e a s a h u m i di f ie r p ro du c es a non h e at e d m i st . 2 . A n u l t r as o ni c hu m id if i e r c o n ta in s a t ra ns d uc e r , wh i c h p ro d uc es a f ine r m i st . It is c om m o n l y u s ed to p ro m ot e e xp e c to r a ti on in pa t ien t s wi t h u pp e r - re s p i ra t o ry i n f ec ti o ns . 3 . B ot h t y pe s o f h um id i fie r s a n d va p o ri ze r s n ee d t o be c l ea n ed r eg ul a r l y to p r e ven t t h e g r o wt h o f m o l d o r b ac t e ri a . C . A n eb u l iz e r i s us e d to d el i v e r m ed ic a ti on t o th e m o ut h o r th r o at . Pa t ien t s wi t h a s o r e t h ro a t m a y u s e a n eb u li z e r t o d el i ve r a to pi c a l an es t he t ic to th e t h r oa t . An u l t r a so n i c n eb u l iz e r i s u s ed to de l i ve r m e d ic at io n in t o t he lu n gs . Th e m e d ic a ti on is d i lu t ed wi t h no r m a l s al ine a nd th e n i nh a le d . A n ul t r as o ni c n eb ul i z e r i s us e d b y p a t ie n ts wi t h r e s p i ra t o r y i n f ec ti o ns , a st hm a , o r c hr o n ic ob st r uc t i v e p ul m o na r y d i se as e ( C O P D ) . D . O x yg e n i s a dm i ni s t e re d fo r a va r i et y o f c on d iti o ns . O xy g e n c an be s t o re d as a g a s o r a li q ui d o r c an be e xt r a c t e d f r om t h e a i r via a c o n ce n t r at o r . Th e am o un t o f
o xyg e n r e q ui r e d b y t he pa t i en t i s m ea s u r ed in li t er s pe r m i nu t e ( L /m in ) . A r e g i s te r e d re s pi r a t o r y t h e r a p is t c a n b e co ns u lte d fo r in f o rm at i on on th e c o r re ct p r o ce du r es , c a ut i on s , and l a ws re g a rd in g o xy g e n u se . E . A p ea k f l ow me t e r i s u s ed b y pa ti e nt s wi t h a s th m a t o d e te c t c o ns t ri c ti on o f t h e a i r wa ys b ef o r e s y m p t om s ap p ea r . Ea r l y de t ec ti on o f a n u pc om in g a t t ack a l lo ws f o r t h e r ap y d es ig n ed to s t op o r m i ni m i z e th e s e v e ri t y o f th e d is e as e. P at i en ts e xh a l e as m uc h a s p os s i b le in t o a p e ak fl o w m e te r to ob t ain t he e xp i r a to r y f lo w r a te . I f t hi s r a t e i s b el o w a p re d et e rm i ne d b as e li ne , pa ti e nt s m i g h t b e i ns t ru c te d t o c h a n ge t h e r ap y. F . H o me sp i r o me t r y i s a n on in v a s i v e p ul m o na r y f u nc t io n t es t . I t al lo ws fo r m e as u re m e n t o f ( a ) t h e fo r c ed e xp i r a to r y vo lu m e i n on e s ec on d (F E V 1 ) , an d ( b) t he f o r ce d v it a l c a p ac i t y (F VC ) i n t h e p e rs on ' s h om e . Th i s de vi c e m a y be us ed f o r p os t l u ng t r an s p la n t p a ti en t s o r p at i en ts wi t h a hi s to r y o f as th m a an d /o r c h r on ic o b st r uc t i v e p ul m o n a r y d is e as e ( C O P D ) .
XI. THERMOMETERS. Th e s e i ns t r um en t s m e as u r e bo d y te m p e r at u re and a r e m os t co m mo n l y u s e d to d e t ec t o r e v a l ua t e t h e t re a tm e nt o f i nf ec t io ns . A. A g l a s s th e r mo m e te r h as a s ea le d g l as s c o ns t r i c t i on c h am be r th a t c ont a i ns l i qu i d m e r c u r y , r ed - o r blu e - c o lo r e d f lu i d, o r G a li ns t an ( a m i xt u r e o f g a ll ium , i n di um , a n d t i n ). R es po n di n g t o te m pe r a tu r e c ha ng es , th e m e rc u r y , r e d - o r b lu e -c ol o r ed f l u id , o r G al i ns ta n e xp a n d s o r c o n tr ac t s. I t r em a in s a t th e m a xi m um te m pe r a t ur e r e g is t er e d u nt i l s h ak e n ba c k in t o t h e r es e r voi r at t h e b o t to m . G l ass f e v er t h e rm om e te r s a r e g ra d ua t e d f r om 9 6 ° F t o 1 0 6° F i n t wo - t en t hs - of - a -d e g ree i n c re m e n ts . Th es e t y p es o f th e rm om e te r s sh o ul d b e c l ea n ed an d s te r il i z ed wi t h a l co h ol a f t e r e ac h us e . Th e Am e ri c an Ac a de m y o f P e d ia t ri cs r ec om m e nd s a g ai n st t h e u se o f m e r c u r y - c on t ai n in g th e rm om e te rs b ec au s e o f t h e r is k o f m er c ury e xp o s u r e i f i t b r e ak s . H owe v e r , m o r e r es e a rc h is n e e de d t o a s s es s t he ac c u r ac y o f t h e n e we r g la s s th e rm om e te r s ( r e do r b l ue - c o lo re d fl u id or G a li ns t an ) .
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1 . Th e o ra l th e rm om e te r h as a l on g s le n de r r es erv o i r . I t is pl ac e d u nd e r th e to n gu e , a n d t h e l ip s a r e s e a le d ar o u nd t he th e rm om e te r fo r 3 -4 m i n . I n v al i d r es ul ts m a y o cc u r i f th e p a ti en t ea ts , d r in k s , o r c h e ws gu m be f o r e t he te m p e r at u r e is t a k e n ; i n co r r ec tl y p la c es t h e t he r m om et e r i n t h e m o u th ; t a lk s o r b r ea t he s r a pi d l y t h r ou g h m o ut h o r no s e wh i l e t he t e m p e r at u re is be in g ta ke n ; o r ha s o r al ab s c es s o r d e n tu r es . P.601
2 . Th e r ec t a l t he r m o m e te r h as a bl u nt , p e a r -s hap e d b ul b to p re v e n t b r eak a ge an d a i d i n r e te n ti o n. I t is in s e r t e d 1 i nc h i n to th e re c tu m a n d l ef t fo r at le as t 2 m in . A l u b ri ca n t s ho ul d b e u s e d t o ai d i ns e rt i on . Re c ta l te m pe r a tu r e is 1 ° F hi g he r t h an o ra l t e m p e r at u re . R ec t al te m p e r a tu r es ha v e be en f oun d to la g b e hi n d t he c o re t e m p e r at u re . S o i f a p a tie n t h as a r a pi d c ha n ge in co r e t e m p e ra t u re , t h e re c ta l t e m p e r at u re wi l l n o t i m m e d ia t el y r e fl e ct it .
3 . Th e st u b b y t h e r m om et e r ha s a s h or t , s t ub b y bu l b t o p r e v e nt it f ro m b r ea k in g . I t c a n b e u s e d a s a n o r al or a r ec ta l t h e rm om et e r . A l t h ou gh a s tu b b y th e rm o m et e r c an b e us ed as ei th e r o r a l o r r e c t a l, i t is r ec om m e nd ed t ha t on e r o ut e of ad m in i s t r a ti o n i s s el ec t ed an d u s ed . 4 . A n y of th e th r ee t y p es o f gl as s t he r m o m e t e rs ca n be us ed to t ak e t he ax i l l a r y t e m p e ra t u r e i f a n o r al or r e c t a l t em pe r a tu r e c ann o t b e ta ke n . A n a xi l l a r y t e m p e r at u re is ta k e n b y h o ld i ng th e th e rm om e te r s nu g l y u n de r th e a r m f or 3 - 4 m in . A xi l l a r y t e m p e ra t u re is 1° F l o we r th a n o r al te m p er a t u re . H o we v e r , th e re is c o nt r o ve rs y a bo u t t h e ac c u r ac y o f a xi l l a r y te m p e ra t u r e. U s i ng t hi s t em pe ra t u r e l o ca t io n c an be c l in ic a ll y u s e f ul as lo ng as th e s i te is r ec o rd e d a nd us ed c o ns is te n tl y .
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B . T h e b as a l t h e r mo m et e r is us ed t o m e as u r e ba s al bo d y te m pe r at u r e. B a s al t h e rm om e te r s a r e a v a il ab l e a s a g l as s o r d ig i ta l th e r m o m e t er . A d i gi t al the r m om et e r m a y lo we r t h e p o te n ti al fo r us e r e r r o r as it o ff e rs m o r e ac cu r ac y. Th e ba s a l bo d y t e m p e r at u re is us ed to pr e d ic t o v u l at i on to in c re as e o r de c re as e t h e c ha nc e o f c o nc ep t io n . B as a l b od y te m pe r a tu r e c an be ta k e n o r al l y , r ec ta l l y , o r v ag i na l l y , b u t t h e ro u te s h ou l d b e c o ns i s te n t . C . D i g i ta l t he r m om e te r s r e gi s t e r t em p e ra t ur e qu i c k l y. He a t a lt e rs th e c ur r e n t r u n ni n g t h ro u gh a r es is to r , an d t h e t em p er a tu r e is di s p l a y ed v i a a d i gi t al r e a do u t . Th e c u r re n t is s u pp l ie d by a b a tt e r y, s om e o f wh ic h a r e re c h a rg e ab l e. D igi t a l t h e rm om e te r s c a n b e us e d o ra ll y o r re ct a ll y a nd g e n er a ll y r e qu i re pl ac i ng a pl as t ic s h ea t h o v e r th e t i p o f t he t he r m o m e t e r b ef o r e us i n g . D i gi t al th e rm om e te rs ha ve b e e n in t e gr a te d i n to pa c if i e rs to as s i s t in t ak in g an i nf a nt ' s te m p e ra t u re . D . T ym p a n i c th e r m om e te r s us e i n fr a r ed te ch n olo g y t o d e te ct t he te m p e ra t u r e o f t h e t ym p an ic m em b r an e . Th e t em p er a tu r e i s d e ter m i ne d wi t hi n s ec on ds an d is l es s i n va si v e th a n o th e r th e rm om e te r s . Th e s e th e rm om e te r s u s e di sp os a bl e t ip s th a t a re i n se r t ed in t o t he ea r . The A m e r ic a n A c a d em y of P e d ia t r ic s r ec om m e n ds th a t th is t yp e o f t he r m o m e t e r b e u s ed in ol d er ba b ie s a nd c hi l dr e n b ec au s e t he p ro b e n e ed s t o ac cu r a te l y fi t i n to t he e a r . I n ap p ro p r ia t e p la c em e nt an d to o m uc h e a r wa x c a n c a us e i na c c u ra t e r e ad ing s .
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E . S k i n t h e rm o me t e rs ar e pl a c e d d i re c t l y on t he s k i n (u s u a ll y t he f or e he ad ) t o c a lc ul a te bo d y te m pe r atu r e . Th is t ype of t he rm om e te r is a li q ui d -c r y s ta l s t r ip th a t c h an g es c ol o rs ba s e d o n t e m p e ra t u re . En vi r on m en t f ac to r s s u c h as s we a t in g an d a m bi e nt te m p e r at u r e wi l l a f f ec t t he s k in te m p e r atu r e . Th is m e th od is no t as ac c u r a te a s th e o t he r s a nd s h ou ld b e re s e r v e d f o r s it u at i on s i n wh ic h ot h er m e t hod s a r e n o t p o ss ib l e.
XII. URINARY CATHETERS. Th e s e d e v ic e s a ll o w f o r th e co l l ec t i on an d re m ova l o f u r in e f ro m t he bl ad d e r . A. E x t e r n a l c at h e te rs a re us e d f o r h ea v y i n c o n ti n e nc e pr o bl em s o r c om p l e te lo ss o f u ri n e c o n t ro l . Th e y a re a t ta c h ed t o a s t at i on a ry c o ll ec t io n d e v ic e o r a le g ba g t o a l lo w f o r am b ul a ti on . Ty p e s o f e xt e r n a l c at h et e rs i nc l ud e t h e f ol l o wi n g: 1 . Th e ma l e e xt e r n al c a th e t e r is pl ac e d a ro u nd th e pe ni s . S om e h a ve a dh e si v e to a ss is t in k e ep in g th e c ath e t e r s e cu r e .
2 . Th e fe m al e e xt e r n a l c a t h et e r , wh i c h i s a c on t ou r e d d e vic e t h at fi t s s n ug l y i n t he va g i n a. P.602
B . I n t e rn a l c at h et e rs a re u s e d d u r in g s u r ge r y o r wh e n e xt e r n a l c at h et e rs a r e i n ap p r op r ia t e . I nt e r na l c a t h et e rs c a n b e u s e d a t h o m e , b u t t h e p at i en t m us t be t a u gh t p r o pe r i ns e r ti o n te c hn i qu es to p re v e n t i nfe c ti o n. Th e c a th e te r is i ns e r te d t h r o ug h t h e u re t h ra in t o t h e b l ad d er an d i s a t ta che d to a s ta t io n ar y c ol l ec ti o n d e v ic e o r le g ba g . C a th e te r s a re s i z e d b y t h e F r e nc h sc a l e : t he la r ge r th e nu m b e r , t h e l a r ge r th e d i am et e r o f the c a t he t e r. Typ e s o f c a the t e rs in c l u de th e f o ll o wi n g : 1 . Th e st r a i gh t c a th e te r i s u s e d fo r in t e r mi t t e nt c a t h et e r iz a t io n to d ra in t h e b l ad d e r. I t c o n s i s t s o f a r u b be r tu b e; u ri n e d r ai ns f r om on e e n d a nd t he oth e r en d c o nn ec t s t o t he c o ll ec t ion d e v ic e. 2 . Th e Fo l e y c a t h e t er , an i nd we l l in g c a th e te r , c an b e us e d f o r u p to 30 da ys b e f o r e c h a ng i n g. Th e en d i ns e rt e d i n to t he bl ad d e r c o n ta i ns a b al lo o n, wh i c h is in f l at e d wi t h s t e ri le wa t e r o r s a lin e to ho l d t he c a t he t e r in p la ce . Th e b al l oo n i s de f l at e d b e f o re re m o v a l . P.603
STUDY QUESTIONS D i r e c t i on s : E a c h of t he n u m b e re d i t em s o r i nc om p le t e s ta t em en ts in t his se c t i on is f o l lo we d b y an s we r s o r by c o m p le t io ns o f t he st a te m en t . Se le c t t he o ne l et t e r ed a n s we r o r c o m p l et i on tha t is be s t i n e ac h c as e. 1 . W he n a pa t i en t i s f i t te d w i t h a n a x il l a r y c r u t c h , how f a r b e l ow th e un d e r a r m s h o u ld t he t op o f t h e c ru t c h re s t ? ( A ) 0 . 5 in c h (B) 1 inch ( C ) 2 in c h es ( D ) 3 in c h es ( E ) 4 i n c h es V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . W h a t an g l e s h ou l d th e e l b ow fo r m w h en a c an e is t he co r r e c t he i g ht ? ( A ) 1 0 d eg r e e ( B ) 2 5 d eg r e e ( C ) 4 5 d e gr e e ( D ) 6 0 d e gr e e ( E ) 9 0 d eg r e e V i e w A n s we r 2 . T h e a n sw e r i s B [ se e] . 3 . A p r o du c t t ha t de l i ve r s m o is tu r e t o t h e a i r b y h e a t i n g w a t e r t o p r o du c e s t ea m is c al l e d a ( A ) n eb u li z e r . ( B ) h um id i fi e r . ( C ) ve n t il a to r .
( D ) p e ak f l o w m et e r . ( E ) va p o ri z e r . V i e w A n s we r 3 . T h e a n sw e r i s E [s e e] . 4 . An a b so r b e n t p r o d uc t de s ig n ed f o r p a t ie n ts w i t h l i g ht in c o n ti n e nc e p r o b le m s is a ( A ) b r ie f . ( B ) s hi el d . ( C ) u n de r ga r m e n t. ( D ) u n de r pa d . ( E ) c at h et e r . V i e w A n s we r 4 . T h e a n sw e r i s B [ se e] . 5 . W h en an o r a l t e mp e r a tu r e is t a k e n, t he t he r m om e t e r s h o ul d be pl a ce d in t o t h e mo u t h f o r (A) 1-2 min. (B) 3-4 min. ( C ) 5 - 6 m in . ( D ) 7 - 8 m in . (E) > 9 min. V i e w A n s we r 5 . T h e a n sw e r i s B [ se e] . 6 . T h e d i am e t e r o f u r in a r y c a t h e t e r s i s me a su r e d b y w hi c h of t h e fo l l ow in g s c al e s? ( A ) L eu r ( B ) E n gl is h ( C ) F r e nc h ( D ) g a ug e ( E ) m et r ic V i e w A n s we r 6 . T h e a n sw e r i s C [ se e] . 7 . A c e r vic a l c o l la r t ha t im m ob i l iz e s t h e ne c k i s c a ll e d a ( A ) s of t c e r v ic al c o ll a r . ( B ) h a rd c e r v ic a l c o l la r . ( C ) f o am c e r v ic al c o ll a r . ( D ) e xt r i c a ti o n c o l la r . ( E ) r i gi d c e r v ic al c o ll a r. V i e w A n s we r 7 . T h e a n sw e r i s D [ se e] . 8 . I n co n t in e n ce t ha t is ca u se d by a n o b s t r uc t i o n o f th e b l a dd e r i s c al l e d ( A ) o ve r fl o w i n c o n ti ne nc e . ( B ) u r ge in c o n ti n en c e . ( C ) s t re s s in c o n ti ne nc e . ( D ) f u nc ti o na l i nc o nt in e nc e . ( E ) t r an si e nt in c o n ti n en c e . V i e w A n s we r 8 . T h e a n sw e r i s A [ se e] . 9 . A c o los t o m y o r i l e o s t o m y c o u l d b e pe r f o r m ed f o r a l l o f t h e f ol l ow i ng co n d i ti o ns e xc e p t ( A ) l o we r bo we l o bs t ru c tio n . ( B ) m al ig n an c y o f th e c olo n o r r ec t um . ( C ) u lc e ra t i v e c ol i ti s . ( D ) d u od en a l u lc e r. ( E ) C r o hn di s e as e .
V i e w A n s we r 9 . T h e a n sw e r i s D [ se ea n d] .1 0 . P re g n an c y t e s t k i t s a re d e s ig n e d t o d e t ec t w h ic h su b s ta n ce ? ( A ) l ut e in i z i ng ho rm o ne (L H ) ( B ) p r og es t e ro n e ( C ) h um a n c h o ri o ni c g ona d o t ro pi n (h C G ) ( D ) e st r o ge n ( E ) f ol l ic le - s t im u la ti n g ho r m on e V i e w A n s we r 1 0 . T he a nsw e r i s C [ se e] . P . 60 4
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C [ s ee I . B . 2. a ]. W hen a p a ti e nt is fi t te d fo r a n a xi l l a r y c r ut c h, th e t o p o f t h e c ru t c h s h ou ld b e 2 i n ch es be l o w t he a xi l l a (u n d er a rm ) . 2 . T he an sw e r is B [ s ee I . A . 1] . W hen a p a ti e nt is pr o pe rl y f i t te d f o r a c a ne , th e el b o w s ho u ld fo r m a 2 5 ° an g le . Th is a l lo ws f o r m a xi m um we i gh t t ra ns f e r . 3 . T he an sw e r is E [ s e e X. B ] . A va p o ri z e r p ro d uc es m oi s tu r e b y h ea t in g wa t e r to p r od uc e s te am . A h um id i f ie r a ls o p r o du c e s m oi s t u r e; ho we v e r , i t wo r ks b y m ec ha nic a ll y c re a ti n g sm al l wa t er p a r ti c l e s . A n e bu li z e r is u s ed to de l i v e r l iq ui d t o th e m o ut h a n d t h ro a t . A ve n t il a to r i s u se d to as s is t in br e ath i ng . A p e ak fl o w m et e r is us ed t o d et ec t ai r wa y c o ns t ri c ti on . 4 . T he an sw e r is B [ s ee V I I . B .1 ] . S h i el ds a re pa ds t ha t a re p la c e d i n t h e u nd e r we a r a nd he ld wi t h ad he s i v e s tr i ps . Th e y a r e us ed f or pa t ie nt s wi t h l i gh t i nc o nt i ne nc e p r o bl em s. 5 . T he an sw e r is B [ s ee XI . A . 1 ] . O r a l t em pe r at u r e is t ak en b y in se r t in g t h e b ul b o f t h e t h er m o m et e r u nd e r th e to n gu e a n d s ea li n g t h e li p s a ro un d th e th e rm om e te r fo r 3- 4 m i n . 6 . T he an sw e r is C [ s ee XI I . B ] . Th e F r e nc h s c a le i s u s ed t o m ea s u r e t h e d ia m e te r o f a u r i na r y ca t he t e r. Th e L e u r s ca l e is us e d t o m e as u r e s y r i ng e t i p si ze . Th e g au g e s c a le is u s ed to m e as u r e n e e dl e d ia m e t e r. Th e m et r i c s c al e i s a ge n er a l s ys t em of m e as u re m e n t . 7 . T he an sw e r is D [ s ee V I I I . D .3 ] . A n e xt r i c at i on c o ll a r ( a ls o k n o wn a s a Ph il a de l ph ia c o l la r ) i s u s e d t o i m m ob i li z e t he n e ck . I t i s c om m o nl y u s ed i n em e r ge nc y si t ua t io ns . S of t o r fo am c e r v i c a l c o ll a rs p r o vi de m i ld s u pp o r t a nd r e m i n d t he pa t ie n t t o k ee p th e n ec k s t ra i gh t . H a rd o r ri gi d c e r vic a l c o l la rs p ro v i d e m o de r a te s u pp o r t b ut al lo w s o m e m o ve m e n t . 8 . T he an sw e r is A [ s ee V I I . A .3 ] . O ve r f l o w i n c o n ti n en c e is c au s e d b y o bs t r uc ti o n of t h e bl a dd e r . U r g e i nc ont i n en c e is c a us ed b y un c o n t ro ll e d b l ad d e r c o n t ra c ti on s . S t re s s in co n ti n en c e is c a use d b y i n c re as es in in t ra - a bd om i n al p re ss u re . Fu nc t io na l i nc o nt i ne nc e i s r e la t ed to p h ys ic a l o r ps yc ho l og ic al p ro b le m s . Tr a ns ie n t i nc on t in e nce i s c a us e d b y m e di c a t ion s , u r in a r y t r a ct in f ec t io ns o r m e n ta l i m p a ir m en ts .
9 . T he an sw e r is D [ s ee I X. A . 1 a nd 2] . L o we r - b o we l ob s tr uc t io n, m al ig n an c y o f th e c ol on o r re c t um , an d d i v e rt icu l i ti s m a y a l l r e qu i re a c ol os t om y . U l c e ra t i v e c o l it is an d C ro h n d is e as e m a y r e qu i re a n i l eo s to m y . Th e t r ea tm e nt o f a d uo de n al ul ce r wo ul d no t i nc l ud e a c o lo s t om y o r a n i l eo s to m y . 1 0 . Th e a n sw e r i s C [ s ee V . B .1 . d ]. P r e g na nc y t es t s d et ec t hC G i n th e u r i ne . Th is i s s ec r e te d a f t er t he em b r yo h as i m pl an t ed in t he ut e r us . O v u l a t io n - p re di c ti on t es ts de t ec t L H . P ro g es t er o ne , e s t ro g en , a n d f ol l ic le -s t im u la t in g h o rm on e a r e a l l i n vo l ved in c o nt r o ll in g th e m e ns t ru a l c y c l e .
29 OTC Otic, Dental, and Ophthalmic Agents J e n ni f e r D . S m i th C o n n i e L ee B a r ne s
I. OTIC OVER-THE-COUNTER (OTC) PRODUCTS A. Th e e a r c a n b e d i v i ded i nt o t h r ee di st i nc t p a rts : th e e xt e r n a l e a r , t he m i dd le ea r , a n d t h e i nn e r e a r. 1 . Th e e xt e r na l e a r i s t y p i c a ll y t h ou g ht of as th e p a r t o f th e e a r o ne c a n se e . H o we ve r , b e in g m ad e u p o f th e a u ri c l e , t h e e xt e r n a l a ud i to r y c an al , an d th e ou t e r s u r fa ce o f t he t y m p a ni c m em b r an e , t he e xt e r n al e a r e xt e n ds m uc h f a r th er . a . Th e au r i c le , a ls o re f er r e d to as th e p i nn a , f u nc t io ns t o c o l le c t s o un d an d c h an n el i t to wa r d t he m i dd l e e a r. b . Th e ex t e r na l a u d i to ry c a n a l , al s o k n o wn a s th e ea r ca n a l, is a b ou t 1 i n ch in l e ng t h , l ea di n g d i re c t l y to t he ea r d ru m . Th e ea r c a n al c o n ta i ns s m a ll gl a nd s th a t a re r e s po ns ib l e f o r s ec re t in g c e ru m e n , b e tt e r k no wn a s e a r wa x. c . Th e o u te r s u r fa c e o f th e t y m p an ic m e m b r an e is k n o wn as t he ea r d r um. Th e e a r d ru m s ep a ra t es th e ext e r n a l a ud i to r y c a n al f ro m th e m id dl e e a r . 2 . Th e mi d dl e ea r is a n a i r - fi ll e d c ha m b e r t h at p ro v i d es di r ec t a cc es s t o th e in ne r e a r an d i nd i r ec t ac c es s to t he no s e an d th r oa t b y wa y o f t h e e us t ac hi a n tu b e . Th e m i dd le ea r ho us es t h re e s m a l l b on es (m a ll eu s , i nc us , an d s ta p es ) k no wn a s th e o ss ic l es . W hen s o un d s tr i k es t h e e a rd r um , i t v ib ra t es , t ra ns m i t ti n g t he s ou n d vi b r a ti o ns to th e o s s ic l es , wh i c h i n t u rn t r an s m it th e s o un d t o th e i nn e r e ar . 3 . Th e in n e r e a r i s a de li c at e s t ru c tu r e c om po s ed o f a ud i to r y a nd v e st i bul a r c om p on e nt s . a . Th e au di t o r y c om p on en t o f t he in n er ea r ( th e c o c hl e a) is re s po ns ib l e f or h e ar i ng . Th e c oc hl e a, a s na il - s h ap e d s t ru c tu r e f il l ed wi t h fl u id , is a t ta c he d t o o n e of t h e o ss ic l es ( th e s ta p es ) i n th e m i dd le ea r . W he n t he s t ap es m o v e s, it cr e at es wa v e s wi t h i n th e c oc hl e a. D e pen d in g o n th e wa v e p ro d uc e d, ne u r al im pu ls es a re c r ea t ed a n d t r a ns m i tt e d t o t h e b ra i n f o r i n te r p re t at i on . b . Th e v es t ib u la r c om p on e n t o f t h e i nn e r e a r ( t he se m i c i r cu l ar c a n al s a nd t he ve s t ib u le ) is re s p o ns ib le f o r m ai n ta i ni ng ba l an c e a n d e q ui li b ri um . B . C o m mo n e a r di s o r der s 1 . E xc e ss i ve / im p ac t e d c e r u me n (e a r wa x) . C o n t r a r y t o c u r re n t s o c i a l b eli e fs , e a r wa x d o e s no t ne ed t o b e re m o v e d wi t h o bj ec t s s uc h a s f in g e rs , t o we l s, a n d c o t to n -t i pp e d a pp li c a t o rs b ec a us e t h es e o bj ec ts ty p i c al l y c a us e im p ac t io n o f th e e a r wa x, r a t h e r th a n i ts re m o v al . In st e ad , th e e xt e r n al ea r ha s a u n iq u e s e l f c l ea ns i ng m ec h an is m . Ea r c a n al s ki n i s c on st a nt ly s h ed a nd re m o v e d v i a l a t er a l m i g ra ti o n f r om th e t y m p an i c m e m b r a ne ( at a r a te o f 2 -3 m m p e r d a y ) to the e xt e r n a l c a na l , wh e r e c e r um en ad h e re s t o t h e s he d s k i n a n d o t he r de b ri s . Mo v e m e n t s uc h a s c h e wi n g m o v e s t h e c e r um e n o ut wa r d wh e r e it is r e m o v ed b y d r yi n g, fl ak in g , o r s im p l y fa ll i ng ou t . Th e us e o f he a ri n g a id s o r e a rp l ug s c an bl oc k t hi s o u twa r d m i g ra ti o n, d e v el op i ng ear wa x i m p ac t io n a n d l ea d in g to he a r in g l os s . a . Th e f un c t io n s o f c er um e n i nc lu d e ( 1 ) Lu b r ic at i on of th e l i nin g of t he ea r c a na l
( 2 ) Te m po r a ri l y re p el li n g wa t e r ( 3 ) R es is t an c e t o in f ec t io n o wi n g t o i ts ac id ic na tu r e (p H = 4 - 5 ) , wh i c h c re a t es a n u n f a vo ra bl e e n v i r on m e n t f o r o r g an is m s u r v i v a l ( 2 ) Tr a p pi n g d us t, d eb r is , a nd f or e ig n o b je c t s b . E p id e mi o l og y. A s i d e f r o m im p ac ti o n c au s e d by m a ni p ul a ti on , s om e p at i e nt p o p ul at i on s a r e m o r e p ro n e t o e xp e r i e nc e i m p act e d c e ru m e n , i nc lu d in g pa t i en ts wi t h a n o ve rp r od uc t io n P.606 o f ce r um en , pa ti e n ts wi th n a rr o we d ea r c a na ls , th e el de r l y, an d p a ti en t s wi t h m en t al r e t a rd a ti o n. c . S ym p t o m s o f i m p ac t ed c e r um e n i nc lu de e ar ach e , i t c h in g o f th e e a r , r e fl e x c o u gh , d i zzi n es s , v e r t ig o , t in ni tu s , a nd c o m p r om is ed h ea r i ng . d . E a rw ax - s o ft e n in g a ge n t s m a y b e us ed al on e o r f ol lo we d b y t he us e o f a n o t ic s yr i n ge (s e e I . C ) . ( 1 ) C a r ba m id e pe r o xi d e 6 . 5% in an h yd r ou s g l yc e r i n is t he on l y U . S . F o od a n d D r u g Ad m i n i s t ra t i on ( FD A) a p p r o ve d a g en t f o r c e r um e n re m o va l. W hen c a r ba m i de pe r o xi d e m ak e s c on t ac t wi t h t is s u e e nz y m e s , o xy g e n i s re le as e d , p r o du c i n g a fo am in g a c tio n . Th is f oa m in g a c t io n s o f t en s i m pa c t ed ce r um e n . ( a ) Ava i l a b l e a g en t s . M u r i ne , D eb r o x, D e n t 's E ar W a x ( b ) I ns t r u c ti o n s f o r u s e. P a ti e nt s a g ed 12 an d o l d e r s ho u ld ti l t t he he ad s i d e wa y s a n d i ns t il l 5 - 10 d ro ps in to t he ea r . Th e a pp l ic at o r t i p s ho ul d n o t b e i ns e rt ed i nt o t h e e a r c a na l . P a ti en t s s h o uld k e e p t he he a d t il t ed t o t h e s id e ( o r i ns e r t c o t t on ) f o r s e ve r al m i nu t es to i n c r ea s e c o n t ac t t im e wi t h t he c e ru m e n . Re pe a t t h e p ro c es s tw i ce da i l y f o r u p t o 4 d a ys . F o r c h il d r en < 1 2 wi t h s us p ec te d c e ru m e n i m pa c t i on , a m e d ic al p ro v i de r s h ou ld b e c o n s u lt e d. ( 2 ) O l i ve o il (s we e t oi l ) is us ed t o s o f t en ea r wa x a n d a ll e v i at e i t ch in g . ( 3 ) Mi n e r a l oi l , r e c o m m en d e d as 2 d r op s i n t he af f e ct e d e ar ( s ) o nc e p e r we e k , h as b e e n us e d t o l iq u ef y t h e c e r um en , th us ai di n g i n it s re m o v a l . ( 4 ) D oc us a te s o di um gi v e n 15 m i n b ef o r e p ro v i d er i n -o f fi c e i r ri g at io n h a s s h o wn e f f ic ac y , bu t no da t a e xi s t to s u pp o r t t he s u p er i or i t y o f d oc us a te s o di um o v e r c a r ba m i de pe r o xi d e . ( 5 ) H yd r og e n p e ro xi d e is a c o m p on e n t o f c a r b am id e pe r o xi d e a n d h as we ak a n t ib ac t e ri al p ro p er t ie s . A s an o ti c so l ut i on , h y d ro g e n p er o xi d e m a y b e d il u t ed 1: 1 wi t h wa r m wa t e r a nd in s ti l le d i n t h e e a r t o a id in c e r um en s o f te ni n g a nd re m o v al . ( 6 ) E a r c a n dl es , a ls o k no wn a s c o ni ng c a n dl es , a r e m a de of pa r a ff i n -c oat e d fa b ri c wo u n d i nt o a fo o t -l o ng c o n e . P a ti e nt s a r e i ns t ru c t e d to pl ac e t h e c o n e i n th e ea r c a na l a n d li g ht t he di s t a l e n d wi t h a m at ch . Al l ege d l y, th e c er u m e n i s li q ue f i ed an d n e g at i ve p r es s u r e d r a ws o u t t h e wa x. I n o n e s t udy o f e ar c a n dl es , m o re c a n dl e wa x wa s d e po s i t ed in t o t h e ea r s o f p a ti e nt s t h an ea r wa x wa s r e m o ve d . H o we v e r , no da t a s u pp o r t t hi s d an g e ro us pr o c es s f or e ff ic ac y . F u rth e r m o r e, co m p li c at io n s m a y in c l u de e xt e r n a l ot i ti s , t em po r a ry h e a r in g l os s , an d b u r ns . e . P at i en ts wi t h pe r f or a te d t y m p an ic m e m b r an e , e a r dr a in a ge , e a r p ai n , or a r as h i n t h e e a r s ho u ld be r ef e r red t o a he al t hc a re p ro v i de r . In t he of f ic e, p ro vi d e rs m a y us e va r i o us de v i c e s o r i r r ig a ti n g s y s te m s to re m o ve im p ac te d c e ru m e n .
2 . V e r ti g o i s a l os s o f eq u il i b ri um , i n wh ic h o n e m i gh t d es c ri b e a ro om as s p in n in g . A s de sc r ib e d i n I . A .2 . B , t h e v es t ib ul a r c om pa r tm e n t o f th e i n ne r e a r i s r es p on s i b le f o r m a in t ai ni n g b al a nc e a n d e q ui li b ri um . Th e a u to n o m ic s y s t em m a y be c om e i n vo l ve d i f t he v e r ti g o is s e v e r e, p ro d uc in g d i z z i n e s s , pa ll o r , s we a t in g , a nd n au s e a . P a t i en ts e xp r e s s in g s y m p t om s o f v e rt i go ( as id e fr o m m ot i on s ic k ne s s ) s ho u ld be r e f e r re d t o a m e di c al pr ov i d e r . 3 . T in n i tu s m a y be de s c r i b ed b y pa t ie n ts a s a ri ng i ng , bu zz i n g , h is s i ng , wh i st l in g , o r h um m i ng no is e l as t ing f r om s ec o nd s t o m i n u te s . Ti nn it u s h as b e en li nk e d t o a va r i e t y of c a us es , i n c l ud in g Mé n i è re di s e as e , h e ad i nj u ri es , o t i ti s m e d ia , s y p h i li s , t e m p o r om an di b ul a r -j o in t ( T MJ ) d y s f u nc ti o n, an d ce r t ai n m e di ca t io ns (s al ic y l a t es , n o ns t e ro id a l a nt i -i n fl am m a to r y d r ug s , am in o gl y co s id es , l o op di u re t ic s , an d c h em ot h e ra p eu ti c a g en ts ) . If ti n ni t us i s c on st a nt o r s e v e r e, a m ed ic al c on s ul t i s a d vi se d . C u r r en t l y , t h er e a r e n o F D A - a pp r o ved t re a tm e nt s f o r t i nn i tu s. 4 . E x te r n al o t i ti s , a ls o re f e r re d to as o t i ti s e xt e r n a , i s i n f la m ma t i on o f th e e x t e r na l a u d i to r y c a n a l s ec on d a r y to a b ac te r i al o r fu n ga l i n fe c t i on . a . C a us e . E xt e r n a l o t it is , f r eq u en t l y re f e r re d t o as s wi m m e r 's ea r , i s t ho ug h t to be m os t c om m o n l y th e r e s u lt o f l o ca l t r au m a t o t he e xt e r n a l c a na l ( e .g . c o t to n - ti p pe d a p pl ic a to r s , f in g er s , s h a rp o bj ec ts ) o r p r o lo n g ed e x p os u r e t o mo i s tu r e . P r o l on g ed e xp o s u r e t o m oi s tu r e ( e .g . , hu m i d e n v i ro nm e nt , un d e r wa t e r s wi m m i ng , d i vi n g ) p r o m o t es m ac e ra t io n o f th e th i n sk in li n in g t h e e ar c an a l, al lo wi n g ba c te r ia t o p e n et r a te an d g r o w. Tr a u m a t o t h e e xt e r n a l c a n al l en ds it s e l f t o s us ce p tib i li t y t o d a m a g e a nd th us ea s i e r i n f il t ra t io n o f m ic r oo r g ani s m s . Th e p re d om i n an t m ic r o or g an is m s i s ol a te d f r o m p at i en ts wi t h s wi m m e r ' s e ar a re P se u d om on a s a e r u g in o sa an d S ta p hy lo c o cc u s a u r eu s . P.607
b . S ym p t o m s . I n it ia l s y m p to m s in cl ud e i tc h in g a n d a s e ns a ti on o f p r e s su r e / f ul l ne s s i n the e a r , f ol lo we d b y p ai n , a n o ti c di s ch a r ge , an d a p oss i bl e d e c r ea s e i n h e a ri n g . Th e p ai n m a y b e c o m e qu i te i n te ns e , e s p ec ia l l y i f the o ut e r e a r i s t o uc he d o r wi t h m o v e m en t o f th e j a w, s uc h a s c he wi n g . c . T re a t me n t i s wi t h a pr e s c r i pt i o n o t ic a n ti b iot i c an d c o r t ic o s te r o i d i f b ac t e ri a l i n or i gi n a n d o ti c a nt i bi o ti c a l on e i f f u ng a l i n o ri g in , as we l l a s d is c o nt i nu at i o n o f m ec h an ic a l t r au m a an d /o r s wi m m in g (u n ti l r e so lu t i on of in f ec ti o n ). O r a l a n t ib io t ic s a r e no t n ec es s a r y u nl es s t he in f ec ti o n is un r es po n s i v e to o ti c t r ea tm e nt , t h e p a ti e nt i s i m m un oc om p r om is ed , o r a m id dl e ea r i n fe c ti on c oe xi s t s . E x t e rn a l o t i t is s ho u l d n o t be s el f - t r ea t e d. d . P r e ven t io n o f e xt e r na l o t it is is th e k e y . Me c han i c a l t r a um a t o t he ea r , b y wa y o f c o t to n -t i pp e d a pp li c a t o rs , a nd fi n ge r s s ho ul d c eas e i m m ed i at e l y . W ate r sh o ul d b e r e m o ved as g e nt l y an d ef f e c t i v e l y a s p os s i bl e a f te r s wi m m in g o r s h o we r i ng / b at h in g u s in g a to we l a r ou n d t he e d ge s o f t h e e a r o r a hai r d r y e r s et on lo w h e a t. I t m a y a l so be be n ef ic i al to ti l t th e he a d t o t he s i de t o he l p e xp e l wa t e r . If r eo cc u r r e nc e is f r e q ue n t, on e m ig h t c on s i d e r u s i ng m o ld e d e a r p lu g s , bu t c o ns id e ra t io n s h o ul d b e g i ve n t o th e r is k o f i m p ac t ed c e r um en wi t h th e us e o f s uc h d e v ic e s.
5 . Wa t e r - cl o g ge d e a r m a y b e a c o n t ri bu t in g fa cto r t o e xt e r n a l o ti t is o wi n g t o t is su e m ac e r at i on f ro m p r ol on ge d pe r io ds o f e xp o s u re to wa t e r ; ho we v e r , wa t e r -c l og g ed e a r i s a s e pa r a te di s o r der . Th e r e fo r e , l ab el i ng of p r o du c ts a p p ro v e d b y t he F D A fo r t h e tr e at m e n t o f wa t e r -c lo g g ed ea r m a y no t a l lu de t o i ts us e f o r p r e v en t ion o f e xt e r n a l ot i ti s . Th e on l y a g e nt F D A a pp r o v e d as s a fe an d e f f ec ti v e as an e a r - d r yin g a g e nt is i s o p r op y l al c o hol 9 5% in an h yd ro us gl yc e r i n 5 %, a pp r o v ed fo r us e i n p a t ie n ts 1 2 y ea r s o f a g e a n d o ld e r . A ho m e so l ut io n of 50 / 50 is op r o p yl a lco h ol an d wh i t e vi n eg a r m a y a ls o be us e d t o d r y t he ea r . Cau t i on m us t be ta ke n n o t to r e c om m e nd s e lf - t r ea tm en t f or wa t e r -c l og g ed ea r f o r pa t ie n ts wi t h s ig ns of i n fe c ti on , d i sc ha r ge o r b le e di ng f rom t he ea r , e a r s ur g e r y wi t h in th e p r e vi ou s 6 we ek s , or t ym p an o s t om y t ub e s . 6 . F u ru n c le s , a ls o k n o wn as bo i ls , a r e s m al l a b s c es s es s u r ro un d i n g t h e b a s e of a h a i r f ol l ic le in th e o u te r p o r ti o n o f t h e e xt e r n a l ea r ca n al . St a ph yl oc oc c us au r e us i s t yp i ca l l y th e o f fe n di ng o rg a ni s m . Fu r un c l es a re us u al l y s e lf - li m i t in g a n d m a y b e m a na g ed wi t h wa r m c om p r e s s es a n d a to pi c a l a nt i b io t ic . 7 . O t i t is me d ia is a b ac te r i al in f ec ti o n t ha t is m os t pr e v a le n t b e t we en t he a g es o f 3 m o nt hs an d 3 y e a rs , o wi n g to t he le ng t h , a ng le , a n d f u nc ti o n o f t h e e us tac h ia n t u be i n c h il d re n . S y m p to m s i nc l ud e e a r p ai n , f e v e r , f lui d di sc ha r ge f ro m t h e e ar , a nd p o ss ib l e d ec re a s e d h ea ri n g . A ll pa t ie n ts wi t h s usp e c t e d o ti t is m e di a m us t b e r e f e r re d t o a m e di c al pr ov i d e r fo r e v al ua t io n a n d t r e a tm en t . C . Ad m i n i s t r at i o n o f ot ic a ge n t s 1 . I ns t ru c t i on s f o r u s e of o t ic dr o ps a . W ar m t h e s o l ut i on b y h o ld i ng th e b o t tl e i n t h e h a n d f o r a f e w m om e nt s . b . Ti l t t h e h ea d s id e wa y s wi t h th e a f f ec te d e a r up wa r d . c . P ul l t he ea r l ob e u p a nd b ac k t o s tr a ig h te n t h e c a na l f o r a d ul ts an d d o wn a nd ba c k t o st r ai g ht e n i n c h i ld r en . d . U se t he ot h er ha n d t o s qu e e ze t h e b ot t le of d ro p s , c a r e fu ll y d el i v e ri n g t h e n u m b e r o f re c o m m en d ed d r o ps i n to th e e a r c an a l. C a u ti on sh o ul d b e t ak en n ot t o i n se r t t h e a pp l ic at o r i n to t h e e a r c a n al . e . K ee p t h e h ea d ti lt e d s i d e wa y s f or se v e r al m i nut e s o r p l ac e c ot t on in th e e a r t o p r e ve n t t he m e di c a t io n fro m d r a in in g o u t . I f c ot t on is us ed , it m u s t be la r ge e no u gh , s o a s n o t t o b ec om e l odg e d i n t h e e a r, an d s ho ul d no t b e l e ft in t he ea r fo r lo n ge r than 1 hr. f . R e pe a t t h e p ro c ed u re o n th e o p po s i t e e a r, if ne c es sa r y . 2 . I ns t r u c ti o ns f o r u s e o f a n o t i c s yr i n g e a . P r ep a re a wa r m s o l ut io n of pl a in wa t e r . F il l t he o ti c s y r in g e wi t h t he wa r m wa t e r s o lu t io n . b . S t ra i gh t en th e e a r c ana l us in g t h e a pp r op r i at e m e th o d, as no t ed ab o v e . Ti l t t he h e a d o ve r a s i nk o r ba s in t o c at ch t he ou t fl o w s ol u t io n . c . In se r t th e t i p o f t he o tic s y ri n ge in t o e a r, wi t h th e ti p p o in t ed s l ig h tl y u pwa r d . d . G e n tl y s q u ee z e th e bu l b o f t h e o ti c s yr i ng e t o a l lo w t h e s ol u ti o n t o e n te r t he ea r . A l l o w t h e s o l ut i on to d ra in f r om th e e a r i nt o th e s in k o r ba si n . I f p a in o r dizz i n e s s o cc u rs , re m o v e t he s y r i ng e an d c on s u l t a m e di ca l p r o vi de r . e . R ep e a t o n o pp os i te ea r , if ne ce s s a r y. P.608
II. DENTAL OTC PRODUCTS A. D e n t a l an a t om y. A n a t o m i c a l l y , t h e t ee t h a r e di v i d ed in t o t wo p a r ts : t h e c r ow n ( a b o ve t h e g in gi v a l l i ne ) a n d t h e r o ot ( be lo w t h e g i ng i v a l l in e ) . 1 . E na m el is th e c r y s ta lli n e c al ci um s a lt s ( h yd r o xya p a t it e ) t h at co v e r th e c r o wn t o p r o t ec t t he u nd e rl y i n g t oo t h s t ru c tu r e . 2 . D e nt i n i s t h e la r g es t p a r t o f th e t o ot h s t ru c tu re , lo ca t ed be n ea t h t h e en a m e l . I t p r o t ec ts th e d e nt a l p ul p . 3 . C em e n tu m i s a bo ne - li k e s tr u c t u re t ha t c o v e rs t h e ro o t a nd p ro v i d es t he a t t ac hm en t of t he to o th wi t h t h e p e ri o do n ta l l ig am e nt s . 4 . P u lp c o ns is ts of f r ee n e r v e en di n gs . B . C o m mo n de n ta l p r obl e m s a nd O TC p r o d u c ts 1 . D e nt a l c a r ie s (i . e. , ca vi t i e s ) a r e f o rm ed b y the g r o wt h a n d im p la n ta t ion o f c a r io ge n ic m ic r oo r g an is m s . a . C a us es ( 1 ) B a ct e r i a ( p ri m a r il y S t r e p to c o cc us m u ta ns an d L ac t ob a ci ll ac e ae ) p r o duc e a ci ds ( e . g ., la c ti c ac i d) t ha t d em i ne r al i z e e n am el . In it i al l y , de m i n er a li ze d e n am el a pp ea r s a s a wh i t e , c h a lk y a re a an d be c o m e s b lu is h wh i te a n d e v e nt u al l y b ro wn o r y e l l o w. ( 2 ) D i e t is an o th e r f ac t o r i n t h e d e vel o pm en t o f de n t al c a r ie s. Fo o ds wi t h a h ig h c o nc en t r at i on of r ef i ne d s u ga r (i . e ., su c r o se ) i nc re a s e th e ri sk of de n ta l ca r i es . S u c r os e is c o n v e rt e d b y b a c t e r ia l p la q ue in t o v o la t i le ac id s t ha t de s t r o y th e h yd r o xya p a t i t e. ( a ) F r uc t o se an d l a c to se a r e l ess ca r io g en ic th an su c ro se . ( b ) N o nc a r i og e n ic su g ar s u b st i t u te s a r e xyl i t o l, s o rb i to l , a nd as pa r t am e. b . O TC p r o d u c ts fo r den t a l c a r i es i nc l ud e p r od uc t s t ha t c a n a ll e v i a t e t h e p a in an d s e ns it i v i t y un t il th e p a ti en t c a n g e t t o t h e d en t is t. E xa m p l es o f i ng r ed i en ts t h a t a re b e n ef ic ia l i n th is re g a rd in c lu d e li d oc ai n e, be n zoc a i ne ( e .g . , A n be s o l , O r a je l ) , o r an o r a l a na l ge s i c ( e .g . , a s p ir i n , a c e t am in o ph en ) . 2 . P la q u e a nd ca l c ul u s a . C a us es ( 1 ) P l aq u e is a s ti c k y s ub s ta nc e fo r m e d b y t he a tt a c h m e n t o f b ac t e ri a t o th e p e ll ic l e, wh i c h is a t hi n , a c el lu l a r, gl y c op r o te i n ( a m uc op r o te i n co a ti n g t hat a dh e r es t o t he en am el wi t h in m i nu t es a ft e r c le a ni ng a t o ot h ) . ( 2 ) C a lc u l us (o r t a r ta r ) is t he s u bs ta nc e fo r m e d wh e n p l aq ue is no t re m ov e d wi t h i n 2 4 h r. Th e p l aq u e b eg in s t o c a lc if y i nt o c al c ul us wh e n c al c i um s a l t p re ci pi t a te s f r om t h e s al i v a . Ca lc ul u s c a n b e r em o ved on l y b y a p ro f es si o na l d e nt a l cl e an ing . b . O TC p r o d u c ts ( 1 ) T oo t h b r us h es . So f t , r o u nd e d, n y lo n b r is t le s ar e p re f e r re d b y d en t is ts b e c a us e h a r d b r is tl es c a n i r r it a te t h e g i ng i v al m a r gi ns an d c au se t he gu m s to r ec ed e . So m e t o o th b r us he s h a v e s pe c ia l l y de s i gn e d b r is tl es t ha t r ea c h de e p b et we e n te e t h a nd a l on g th e g um li n e t o re m o v e s ta in s a n d p ol is h t ee t h a n d m a s s a ge gu m s . E xa m p l e s i n cl ud e C ol ga t e W hit e ni ng a nd C ol g at e Ma s s a g er t o o th b r us he s . E le c tr ic t o o th b r us he s c a n b e ne f it p a ti e nt s wh o re qu i r e s om e on e t o c le a n t he i r t e eth f o r t he m
o r p at i en ts wh o ha v e o r th o d on ti c a p pl ia nc es . Too t h b ru sh es s h ou l d b e r ep l ac e d wh e n t h e y be g in to s h o w we a r o r e v e r y 3 m o n th s , wh i c h e ve r c om es f ir s t. P at i ent s s h ou ld r e p la ce t he i r t oo t hb r us h a f t e r h a v in g a n u p pe r - r es p i ra t or y i n fe c t i on . ( 2 ) I r r i ga t i ng d e vi ce s d ir e c t a h i gh - p re s s u re st r ea m o f wa t e r t h r ou gh a no zz l e t o t h e h a r d- t o -c le a n a r ea s b y g e nt l y li f ti n g t h e f r ee g i ng i va to ri n s e ou t c r e v ic es . Two t yp e s a r e a v a il a bl e : p u lsa t i n g ( i .e . , i n te r m i t te n t lo w- a n d hi gh - p r es s u r e wa t e r s t r ea m s ) a n d s t ea d y ( i . e . , c o ns t an t an d c on s i s t en t wa t e r pr es s ur e ) , n ei t he r o f wh i c h h a s sh o wn s up e ri o r i r r iga t i ng ab il i t y . ( a ) I r ri g at i ng de v i c e s s ho u ld s e r ve as a d ju nc ts in m ai n ta i ni ng o ra l h y g i ene . ( b ) E xa m p le s i nc lu d e I n te r p la k W ate r J e t, H yd r o -P i k , a nd th e W at e rp ik ora l i r r i ga t or . c . D en t a l f l os s i s a v a il ab l e wa xe d , u n wa xe d , t h ic k , t hi n , f la v o r e d, o r u nf la vo r e d . S o m e d en t al fl os s e s a r e i m p re gn a te d o r co a te d wi t h a d di t i ves s uc h a s b ak i n g s od a a n d f l uo r id e . A ls o , s e v e ra l m a nu f ac tu r e rs a re m ar k e ti n g f lo ss m a de of m at e r ia ls wi t h s u pe r io r an t is h re d di ng pr o p e rt i es (e . g. , G li d e, C ol g a te P re ci si o n ). Th e r e ar e n o d i f fe r e nc es a m o n g P.609 d e n ta l f l os s es in t er m s of p la q ue r em o val an d p r eve n t i on of gi n gi vi t is . Th er e is no e vi d e nc e o f a re s i d ua l wa x f i l m wi t h t h e u s e of wa xe d d e n ta l f l os s . ( 1 ) Th e s e le c t i on of de n ta l fl os s d ep e nd s o n t h e c h a ra c t e ri s ti cs o f th e p a ti e n t, s u ch a s to o th ro u gh n es s o r t igh t n es s o f t oo t h c on t ac ts ( e . g ., wa xe d f l o s s i s re c o m m e nd e d f o r ti g ht - f it t in g t e e th be c a u s e it ca n p as s e as il y be t we e n t he te e th wi t h ou t s h r ed di n g ). ( 2 ) Th e Am e ri c a n D en t al A s s o c i a ti on ( A D A ) re c og n i zes th e fo ll o wi n g b r and s a s s af e a n d e f fe c ti v e : Bu t le r , J oh n s o n & Jo h ns on , an d Or a l - B . d . D e n ti f r i ce s a r e p r od uc t s t ha t en ha nc e th e re m o v a l of st a in s a nd de n ta l p l aq ue b y t h e to o th b ru s h . Th es e i nc l ud e t o ot h pa st e s , an t ip la q u e a nd an t ic al c u lo us m o ut h wa s he s , c o s m e ti c wh i t e n e rs , d es e ns it i z i ng a g e n t s , di s c lo s i n g a ge n ts , an d d e n ta l g um s . ( 1 ) T oo t h pa s t es ar e b e ne f ic i al in de cr e as in g th e i n ci de n ce of de n ta l c a ri es , r e d uc in g m ou t h o d or s , an d en h an ci ng pe r s o n al ap p e ar a nc e. S om e t o ot h pa s te s m a y c o nt a in th e a n ti o xi d a n t c o e n z y m e Q1 0 ( Co Q 1 0 ; e. g . , Pe r f ec t S m i l e Q 1 0 ) . I n g r e di e n ts in c l u de th e f o l lo wi n g : ( a ) Ab r a s i ve s a r e re s p on s ib le f o r p h ys ic a ll y r em o vi n g p la q ue an d d e b ri s. E xa m p l es i n cl ud e s il ic a te s , s o d iu m b ic a r bo na t e , d ic al c i um p h os p ha t e, s o di um m e t ap h os p ha t e, c a lc iu m p y r o ph os p ha t e, c a lc iu m ca r b on a te , m ag ne s iu m c a r b on a te , a n d a lu m in um o xi d e s . Me n t a de n t c o n tai n s s o d iu m b ic a rb on a t e, wh e r e a s Pe r o xi C a r e a n d C o l ga t e b a ki n g s o d a a nd pe r o xi de wh i t e ni n g c o n ta i n s o d iu m b ic a r bo na t e a n d p er oxi d e . H i g h a b r as i ve f o rm ul a ti o ns are n ot ad v i se d fo r l o ng - t er m us e o r fo r u s e b y pa t ie n ts wi t h e xp o s e d ro o t s u r f ac es . ( b ) S u r f ac t an t s a r e f o am i ng ag e nt s t ha t a re i n c o r p o ra t ed in t o m o s t d en ti f r ic es b e ca us e th ei r de t e rg en t a c ti o n a id s i n r em o v i ng d e b ri s . Th e mo s t f re q uen t l y u s e d s u r fa c ta n ts a r e s o di u m la u r yl s u l f a t e a nd s od i um d o de c yl b e n z e ne s ul fo n a t e. S o d iu m l au r y l s u lf a te - c on t a in in g d e nt i f ri c e s h a v e b e en as so c i a te d wi t h a n i nc r e as e
i n th e o c c u r re nc e o f c a nk e r s o re s . D e nt i f ri c e s s uc h a s Re m b r a nd t Na t u ra l, S e n so d y n e, an d Bi o te n e d o no t c on t ai n s o di um l au r yl s u l fa t e. ( c ) H u me c ta n t s p r e v en t t h e p r e pa r at i on f ro m d r yin g . E xa m pl es in c l u de s or b i to l , g l yc e ri n , a nd pr o p y le n e g l y c ol . ( d ) S u sp e nd i n g a ge n t s a d d t h ic k n es s t o t he p rod u c t . E xa m p le s i nc lu de m e th y l c e l lu lo s e, t ra g ac an t h , a nd ka r a y a g um . ( e ) F la vo r i n g a g en t s i nc l u de s o r bi t ol o r sa c c h ar in . ( f ) P yr o p h o s p h a te s a r e f o u nd in ta r t a r- c on t ro l too t h pa s t e s. Th es e p r o du c t s re t a rd t a r t a r f o rm at i on ; h o we v e r , t he y f o rm an al ka li n e so l u ti on t ha t m a y ir r i ta t e th e s ki n . S o m e p at i en ts m i gh t e xp e r i en c e a r a sh ar o un d t he o ut s i d e o f t h e m o u th . Th e s e p a t ie n ts s ho u ld us e r e gul a r to o th p as te an d o n l y oc c a si o na l l y b r us h wi t h t ar t a r c o nt r o l t oo t hp as t e ( e .g . , C o l g at e Ta r ta r C on t r ol W hite n in g ). Ta r t a r -c on t ro l t o o th p as te s d o n o t p en e tr a t e b e lo w t h e g um l in e , wh e r e t a r ta r do es th e m o s t d a m a g e. ( g ) F l uo r i de is an t ic a ri og e ni c b ec a us e i t r e pl ac es t he h yd ro xy l i o n in h ydr o xy a p a t i t e wi t h t h e f l uo r id e i o n t o fo r m f l uo r ap a ti t e o n t h e ou t e r s u rf ac e o f th e e n am e l . F l u or a pa t it e h a r de ns th e e n am el an d m ak es it m or e ac i d r es is t an t . F lu o r ide a ls o h as d e m o ns t r at e d a nt i ba c t e r ia l ac ti vi t y. ( i ) F lu o ri d e is mo s t b e ne f i c ia l i f us ed f ro m b i rt h t h r ou g h a ge 12 o r 1 3 be c au se u n e ru p te d p e rm a ne n t t ee t h a r e m in e ra l i zin g d u rin g th a t t im e . W het he r o r n o t a p a t ie n t r ec e i v es fl uo r id e d e p en ds on th e c on c e n t ra t i on in hi s o r h e r l oc al d r i nk in g wa t e r ( Ta b l e 2 9 -1 ) .
Table 29-1. Daily Fluoride Supplement Requirements for Infants and Children, Based on Concentration of Fluoride in Drinking Water Fluoride Concentration (ppm) Age > 0.6
0.3-0.6
< 0.3
Fluoride Supplement Required (mg/day)
6 months to 3 years
0
3-6 years
0
6 months to 3 years
0
3-6 years
0.25
6-16 years
0.50
6 months to 3 years
0.25
3-6 years
0.50
6-16 years
1.00
P.610
( i i ) C om m o n f l uo r i d e co m p o un d s i n t oo t hp as t e i nc l ud e 0 . 24 % s od i um f lu o r id e a n d 0 . 7 6% o r 0 .8 0 % s o d iu m m o no f lu o ro p ho s p h at e (e .g . , Ai m , C r es t , Aq ua f r es h , C o l g at e ) . C r es t G um C a re c o n ta i ns a r e fo rm u la t ed ve r si o n o f s ta n no us fl uo r i de ( 0 . 4 54 % ), wh i c h m i g ht r ed u c e gi n gi v i ti s a n d b le edi n g o f t h e g um s b y an a ve r a ge o f 2 0 % a n d 3 3% . Ho we v e r , i t c a n a ls o s ta i n t he te e th b r o wn . ( i i i ) A f lu o r id e wa r ni n g la b el , wh i ch r ec om m e nd s c on t ac t in g a po is o n co nt r o l c en t e r o r se ek i ng p ro f es s i on al a s s is t an c e i f m o r e t h an a b r us hf u l o f f lu o r id e t o ot h p as te is i n ge s te d , is r eq u ir e d b y th e F D A o n f l uo r id e -c on ta i ni n g d en t if r ic es be c a use t he f e d e ra l a ge nc y l is ts fl u o ri d e a s a to xi c s u bs t an c e. ( i v) Th e e s t im a te d to xi c d o s e of f lu o ri d e is 5 -1 0 m g /k g . ( v) A c u t e f lu o ri d e t o xi c i ty c a us es na us e a, v o m i t in g , a n d d ia r r he a . Th e AD A l im i ts t h e m a xi m um am ou n t o f f l u or i de in A D A - ac c e pt e d t o o th pa s te to 26 0 m g p er c o nt a in e r . ( 2 ) A ge n ts wi t h a n t i pl a qu e po t en t ia l f o r i nc l us io n i n d e nt i f ri ce s i nc lu d e pla n t e xt r a c t s (s an g ui na r in e ) , m e ta l s al t s ( z i nc an d s tan n o us ) , p he n ol ic c om p oun d s ( t r i cl os an ) , a n d e s s en t ia l o i ls (t h ym o l a n d e uc al yp t o l ) . ( a ) T r ic l o sa n i s a n a nt im ic r o bi al ag e nt t ha t h as b e e n d em on s t r a te d c li nic a ll y t o h el p p r e ve n t g in gi v i t is , p l aq ue , c a v i t ie s , an d ta r ta r . ( i ) C o lg a te To t al c o n ta ins 0 .2 4% s o di um f lu o ri d e a n d 0 . 30 % t r ic l os an an d i s f o r m u l at e d wi t h th e po l ym e r G an t r ez , wh i ch wo r k s t o p r ol o ng t he c o nt ac t o f t r i c l os a n wi t h o ra l s t ru c tu r e s . ( i i ) Th e r ef o re , C ol g at e To t a l c o n ti n ue s t o wo r k i n b e t we e n b r us hi n gs . ( b ) C o lg a te To t al ha s b ee n ac c e p te d b y t he A D A a s e f f ic ac io us . ( 3 ) An t i c a lc u l ou s d e n ti fr i c e s i nc lu d e t he in g r ed ie n ts z i nc c h lo r id e , z in c c i t r a te , a n d 3 3 % p y r op h os ph a te t o p re v e n t c al cu lu s f o rm a t i on . ( a ) Th e A D A d o es n o t e v a l ua t e a n ti c a lc ul o us c l aim s b ec a us e i t r e ga r ds the i n hi b it i on of s u p ra g in gi v a l c a lc ul us as a no n t he ra p e ut ic us e.
( b ) Th e A D A h as di r ec t ed t ha t th e f o ll o wi n g s ta t em e nt ap p ea r on al l p ac k a g e a n d c o nt a in e r l ab e li ng f o r ac c e pt e d f lu o r id e d en t i fr ic e p r o du c t s wi t h c a lc u lu s -c o n t r ol a c ti vi t y: “ [ P ro du c t n a m e] h as be e n s ho wn t o re d uc e th e f o rm a ti on o f t a rt a r a b o v e t he g u m l in e , b u t h as n o t b een s h o wn t o h a ve a t he r ap e u ti c e f fe c t on pe r i od ont a l d i se as es . ” ( 4 ) C o sm e t ic w h i te n in g a g en t s . Th e m os t co mm o n in g r e di e n t i n t he s e p r o du ct s t h a t i s r es po n s i bl e f o r wh i t en in g th e t e et h i s 1 0 % c a r ba m i de pe r o x id e (i .e . , i n G l yO xi d e , S im pl y W hit e, o r P r o xi g e l ) an d h y d r og e n p e r o xi d e (i . e. , in C r es t W hite s t r i ps ) . ( a ) C a rb am i de pe r o xi d e is a wh i te c r ys t al th a t r e ac t s wi t h wa t e r to r el ea s e h y d r o ge n p e r o xi d e , wh ic h i n t u r n lib e r a te s f r ee o xi d es . ( b ) S om e c os m e ti c wh i ten e r s m a y c on t ai n h yd r oge n pe r o xi d e o r pe r h y d ro l u r e a i n g e l o r l i qu i d f o rm . ( c ) P r od uc t s s p ec i fi c a ll y m a rk e te d to de n ti s t s i nc lu d e Co l ga t e P l at in u m P ro f es s i o na l To o t h W hi te n in g S ys t em a n d Re m b r a nd t L i gh t en G e l . ( i ) P a ti en t s s h o ul d p e r for m to o th bl e ac hi n g o nl y wi t h a de n ti s t 's s u pe r v i s io n . ( i i ) C r es t E xt r a W hi te n ing us es a p a te n te d s of t - sil i ca te ch n ol o g y. O wi n g to t hi s t e ch n ol o g y , t he p ro d uc t c o nt a in s 5 0% m o r e s i l ic a, wh i c h g r ea t l y en ha nc e s t h e r e m o val of e xt r i ns ic s t a in s wi t ho u t i nc r ea s i n g a br a s i v en es s. ( i i i ) C ol ga t e L um in o us a ls o c on t ai n s a s il ic a wh i te n in g te c h n ol og y a nd f luo r i de . ( d ) P o ss i bl e r is k s as s oc i at e d wi t h us in g wh i t en in g p ro du c ts i nc l ud e a l te ra t i on of n o r m a l f lo r a , t is s u e d am a g e , t oo t h s en s i t i v it y, gin g i vi ti s, an d p o te n ti a ti o n o f c a rc i no ge n ic e f f ec ts of ot h e r a g en ts . ( e ) An t i s e p ti c s h a v e b ee n us ed as wh i t en e rs (e .g . , G l y - O xi d e , P r o xi g el ) . ( 5 ) D e se n si t iz i n g a ge n ts r e du ce th e p a in in s e ns i ti v e t ee t h ca us e d b y col d , h e at , a c id s, s we e ts , o r to uc h . Th e s e p r o du ct s s ho ul d be n on a br as i v e an d s ho uld n ot be u s ed on a p e rm an e nt bas is un l es s di r ec t ed b y a d e n ti st . ( a ) E xa m p le s o f 5 % p o t a s s i um n i t ra t e c om p o und s in cl u de C ol g at e Se nsi t i v e , S e n so d y n e, A qu a f re s h Se n s i t i v e, an d C re s t S e ns i t i vi t y. ( b ) D i ba s i c s o d iu m c i t r ate i n P l ur o ni c g el an d 1 0% s tr o nt i um c hl o r id e we re c l as s i f ie d a s c la ss I II pe n di ng f ur t he r e v i de nc e o f e f f ec ti ve ne ss . ( 6 ) D i sc l os i n g a ge n t s ai d in v is u al i z in g wh e r e de n t al pl aq u e h as fo r m e d . Th e s e p r o du c ts a r e f o r o c c as ion a l u s e on l y an d s ho u ld n o t b e s wa l l o we d . Th e FD A a p p ro ve d p r o du c t is a v eg e t ab le d ye , F oo d , D ru g , a n d C o sm et ic ( F D & C ) R e d N o 3 . F o l lo wi n g u s e, th e c on s um e r s ho u ld ri ns e th e m ou t h wi t h wa t e r a nd th e n e xp e c t o r at e . P.611
( 7 ) M o u t hw as h es m a y c o n t ai n a s t r i ng en t s , de m ul c en ts , de t er g en t s , fl a vo rs , g e r m i ci da l a g en ts , an d f lu o r id e . Th e y c an be us ed f o r co s m e ti c p u rp os es , r e d uc in g p l aq u e, o r s up pl em e nt i ng f lu o ri d e c on s u m p t io n . ( a ) C o sm e t ic mo u t hw ash e s fr es h en th e br e at h . Th e y a r e no n th e r ap eu t ic a n d a r e n o t e f f ec ti v e as an an t is e p t ic a g en t . Th es e m o u th wa s h es a re c l as si f ie d by t h e i r a c ti ve in g r ed ie n ts , a lc o ho l c o nt e nt , an d a pp e a ra nc e . Th e m o s t p op ul a r p ro d uc ts a re
t h os e th a t c o n ta i n m e d ic i n al ph e no l a n d m i n t. Th e h ig he r t he pe rc e n t o f al c oh ol , th e h i gh e r th e e f fe c t o f t he fla v o r wi t h i n t he m o u th . ( b ) An t i p l a qu e m o u th r in s e s. Mo u t h ri ns e s c l aim i ng an t ic al cu lo u s o r t a rt a r - c o n t ro l a c ti vi t y c o n ta i n t he s a m e a c ti v e in g re d ie n ts a s a nt i ca lc u lu s d en t if r ic es . C oo l Mi n t L i st e ri n e h as re c ei v e d t he A D A s e al o f a pp r o val . ( i ) C e t y lp y r i d in iu m c hl o rid e ( C P C ) , a m ou t h wa s h in g r ed i en t , h as be en a ppr o v e d fo r c l as s I f o r p l aq u e a nd gin g i v i ti s t r ea tm e nt . E xa m p l es of p ro d uc ts in th is c l a s s i n cl ud e C ep ac ol , Sc o pe , O r a l - B A nt i - Pl a qu e Ri ns e , a n d C re s t P r o - He a lt h R i n s e . ( i i ) C hl o r he xi d i n e is an ac t i v e i ng r e di en t in s om e m o ut h wa s he s . A n e xa m pl e is C o l g at e Pe r io G a r d . ( i i i ) S ta in i ng is a s s oc ia te d wi t h th e o v e r us e o f CP C a n d c h l o rh e xi d i ne . ( i v) F l u o r id a t ed mo u t hw a sh e s a re us e d a ft e r c le a ni n g t h e t ee t h a nd sh ou l d b e e xp e c t o r at e d. N o th in g s h o ul d b e pu t i n to th e m ou t h fo r 3 0 m in a ft e r u s i ng t he s e m o ut h wa s he s . Th e A D A h a s a pp r o v e d t he fo l lo wi n g p ro du c ts : A C T A n t i - Ca v i t y D e n t al R in s e , A C T f o r K id s , F l uo r ig a rd A nt i - C a v ity D e n t al R i ns e, an d Re ac h F l u or i de D en t al R in s e , Or a l - B Ri ns e Th e ra p y an d A n t i - Ca v i t y Tr e a tm e nt , a n d C o l g at e Ph os - F lu r . ( 8 ) D e n ta l g u ms a re p rom o te d to re d uc e p la q ue , wh i t e n te e th , po s s ib l y r ed u c e th e r i sk of t oo t h d ec a y , a n d fr e s he n b r ea t h . C h e wi n g g u m is as s o c i a te d wi t h in c r ea s e d s a li va r y f lo w, wh i c h ap pa r e n tl y p ro d uc es a b en e fi c i a l b u ff e ri n g e f fe ct ag a in s t a c i ds i n th e o r al c a v i t y . ( a ) S om e c on t ai n b ak in g s od a a s a m i ld ab r as i ve c le a ne r an d t o n e ut r al i ze ac i d. ( b ) C a lc iu m m a y b e a dde d to he l p r em i ne r al i z e th e te e th an d p r e v e nt c a v i t i es . ( c ) Th e s e gu m s a ls o c o nt a i n xy l i t o l , a s we e te n e r t h a t i s le s s li k e l y to c a us e c a vi t ie s t h a n su g a r o r s o rb i to l . Exa m p l e s a r e Tr i d en t A d va n t ag e , A r m & H am m e r D e n t al C a r e , B re a th A s u r e , D e nta l C a re , Ad v a nc e B re a th C a r e , A q ua f r es h W hit eni n g , a nd B i o t en e . B r ea t h As u re D en t a l G u m co n ta i ns a n i n gr e d i e n t c al le d P XT- 2 0 , wh i ch is a n e m ul si o n o f p ol y d im e th y ls i lo xa n e a nd po lo xa m e r 4 0 7 . I t f o rm s a th i n co a tin g on th e t o o th t ha t i s s up po s e d to r e d uc e p la qu e b u il d up . ( d ) Th e s e gu m s ar e n o t a s u bs t i tu t e f o r g oo d o r al h y g ie ne , in c l ud i ng b ru s h i ng an d f l os si n g, bu t m a y be us ef u l f o r p e op l e wh o a r e un a bl e to b ru s h af t e r l un c h . ( e ) I t is no t k n o wn if t hes e p r o du ct s h a v e a n y adv a n t a ge o v e r r e gu la r s u ga r l es s gum. 3 . G i n gi vi t i s i s i n fl am m at i o n o f t h e gi n gi va . Th e g i ng i va m a y ap p ea r l a r ge r in s i ze wi t h a bl u is h h ue c a us ed b y e ng o r ge d g in g i val c ap i l l a ri e s a nd a s l o w ve n ou s re t u rn . a . C a us e . G i ng i v i ti s i s c a u s e d b y m i c ro o r ga ni s m s t ha t e ve n tu a ll y d am age c e l lu la r a n d i n te r c e ll u la r ti s s ue s . C h r o n i c g i ng i vi t i s m a y b e l oc a li z e d o r ge ne r a lize d . Th e g u m s re a di l y bl ee d wh e n p r o be d o r b r us h ed , a n d t h e p a ti e nt sh ou l d s e e k d e n ta l a ss is t an c e. b . O TC p r o d u c ts in c l u de a ne s t h et ic s c on t ai n in g e u ge n ol or be n z o ca i n e (e . g . , O r a j e l) t o r el i e v e t h e p ain . Mo u t h wa s h es m a y f res h en th e b r e at h ; h o we ve r , i t is i m po r t an t t o c on s i d e r t he p o te n ti a l o f t h es e p ro d uc t s t o d is gu is e a n d d el a y t r e a tm en t o f pa t ho lo g ic al c on d it i on s ( e .g . , g in g i v i ti s ) b e fo r e u s e . Al s o , a c et am i no p he n ( Ty l e n o l ) c an be r ec om m e nd e d. Th e pa t ie n t sh o ul d s ee k th e ad v i c e o f a d en t is t .
4 . P e r io d o nt a l d i se a se is t he re s ul t o f c h ro n ic g in g i v i ti s l ef t u n t re a te d . a . Th e pe r io d on t al l i ga m e n t a t t ac hm en t a n d a l v eo l a r b on e s up p o rt o f t he t o o th d e t e ri o ra t e. b . R i sk f ac t o r s i nc lu de g e n de r (m en a ff ec t ed m or e t ha n wo m e n ) , a ge ( > 3 5 y e a rs o l d ), sm ok in g , l ac k o f o ra l c a r e a nd re g ul a r d en t is t v is i ts , d ia b et e s, h y pe rt e ns i on , r h e um a to id a rt h r it is , a n d l os s o f a n te r io r t ee t h. c . P er i od o nt i ti s m a y b e tr e a t ed wi t h p r es c ri p ti on p r o du c ts : ( 1 ) P e ri os t at ( do xy c y c l i ne h y c l a te , 20 - m g c a ps ule s ) ( 2 ) A t ri d o x ( d o xy c y c l i ne h y c l at e 1 0 % ) i n t he A t ri ge l D el i ve r y S y s te m . ( a ) A t ri d o x p r o v i de s l oc al a nt i ba c t e ri a l e f fe c t s . ( b ) L o w- d os e d o xy c y c l i ne i nh ib i ts c o ll ag e na s e , an e n z y m e t ha t d es t r o ys c o nn ec t i ve t i ss ue in t he gu m s , l ea d in g to t oo t h l os s . P.612
5 . Ac u t e ne c r o ti z in g u lc e r a t i ve g i n gi vi t i s ( AN U G ) ( a l s o c a ll ed t r e nc h m o u t h ) is c h a ra ct e ri z e d b y n ec r os is an d u lc e r at i on of t he gin g i v al su r f ac e wi t h un d er l y i n g i n f la m m at i on . Th is c o nd it i o n is us ua l l y s ee n i n tee n s a nd y o un g a d ul ts . a . S i gn s a n d s ym p t o m s o f A N U G in c l u de s e v e r e p a in , h a li t os is , b le e di ng, f o ul t a s te , a n d i nc r ea s e d s al iv a t i o n. b . Th e ca u se of A N U G is un k n o wn . I t i s p os tu l ate d th a t i t m ig h t b e as s oci a t ed wi t h t h e o ve r g r o wt h o f s p ir oc h e t e a nd fu si f o rm or g an is m s . c . R is k fa c t o rs in c l u de a n xi e t y , s t re s s , s m o ki ng , m al n ut r i ti on , an d p o or or a l h yg i e ne . d . T r ea t me n t c o ns is ts of l oc a l d éb r id em e nt . Al s o , p e ni c i ll i n V K ( pe ni c i l li n V i s a d e r i va ti v e of pe n ic il li n G; h o we ve r , it is m o re s t ab l e i n a n a ci di c m ed iu m a n d , t h e r ef o re , is b e t te r a bs o rb e d f r om th e g a s t r oi n te s t i n al t ra c t ; K s ta n ds fo r po t as s i um ) o r m e t r on id a z o le m a y b e u s e d i n c e rt a in ca s e s ( e. g . , wi d es p re ad le si o ns ) . e . O TC p r o d u c ts in c l ude ac e ta m i n op h en an d p ro d uc ts wi t h be n zoc a in e (n o t e u ge n ol b e ca us e i t m a y c a us e s of t t is s u e d am ag e ) . Th e pa t i en t s ho u ld be ad v i s e d t o s e e a d e n ti s t . Th e u s e of s a li c y l a t es is no t re co m m en de d if th e pa ti e n t is p re dis p os ed t o b l ee d in g . A ls o , a de q ua t e n u t ri t io n , h ig h f l ui d i nt a k e , a nd r es t a r e e s s en t ial . R in si n g t h e m ou t h wi t h wa r m no rm a l s a l in e o r 1. 5 % p er o xi d e s ol u ti on m i gh t be he lp f u l f o r t h e fi rs t fe w d a y s . 6 . T em p o ro m an d i bu l a r j o i n t s yn d r o m e is c a us ed b y an im p ro p e r wo r k i ng r e l at i on sh i p b et we e n th e c he wi n g m u sc le s a nd the T MJ . a . S i gn s a n d s ym p t o m s i nc l ud e a du ll , ac hi ng pa i n a r ou n d t he ea r , h e ada c he s , n e ck a c he s , li m i t ed op e ni n g o f t h e m ou t h, an d a c l i ck i ng o r p op pi n g n oi s e u p on o p e ni ng t he m o ut h . b . R i sk f ac t o r s i nc lu de b r u xi s m (i . e. , g r i nd in g the t ee t h ) a nd oc c l us al ( i. e. , bi t e ) a b n or m a l it i es . c . T re a t me n t c on s i s t s o f m oi s t h ea t a p pl ie d to the j a w, m u sc le r el a xa n t s, b i t e p la t es o r oc cl us a l s p l in ts , a di et o f s of t fo o ds , c o rr ec t ing t he oc c l us io n , o r s u rg er y . d . O TC p r o d u c ts th a t c an h el p re li e v e th e p ai n i nc l ud e o r al an a lg e s ic s ( e .g . , a c et am i no p he n , i bu p ro f en ) .
7 . T ee t h in g p a i n. Th e AD A h as no t acc e pt e d a n y p r o du ct fo r t ee t hi ng pa in . A f r o z e n t ee t h i ng r i ng c an p r o v id e s y m p t om a ti c re l ie f . Pe r s i st i ng pa in m ay b e t re a te d wi t h a lo c a l a n es th e ti c s u c h as b en z o ca in e (f o und i n A n be so l Ba b y an d Or a j el B a b y) . I f a t e et h in g c hi l d p r es e nt s wi t h a f e v e r , a p h y s ic ia n s ho u ld be c o nta c te d . 8 . X e r os t om i a ( i .e . , d r y m o ut h ) i s c au se d b y im pr o p e r f un c ti on i ng of t he s a li va r y g l an d s ( as in Sj ö g re n s yn d r om e a nd di a be t es m el l it u s) . Ar t i f i c ia l sa l i va is a v ai l ab le a s a n O TC p r od uc t . Th e A D A h as ap p r o v ed th e fol l o wi n g a r ti f ic ia l s al i v a pr o d uc ts : Mo i - S t i r , S al i v a r t, Xe r o - Lu b e , a nd O r al B a la nc e Ge l . C . C o m mo n o ra l le s io ns a nd O TC p r o d u c ts 1 . C a nk e r s o r es ( al s o c a l le d r ec u r r en t a ph t h ous u l ce r s o r r e cu r r e n t ap h t h o us s t o m at i t is ) a . Th e ca u se of c a nk e r s o r es i s u nk no wn . S t u die s s ug g es t t h at t he s o r es m a y b e c a us ed b y h y pe r s e ns i ti v it y t o ba c te r ia fo u nd in the m o u th o r d y s fu nc t io n of t h e i m m u ne s y s t em i n it i at e d b y m in o r t r a um a o r s t re s s . Th is is wh y p h y si ci a ns o r d e n ti s t s m a y u s e p re d ni s o n e o r a t op ic a l s t e r oi d to r e du ce al le r g ic re ac t ion o r h a v e t h e p a ti e nt r in s e wi t h a te t r ac y c li n e su s p e ns io n . P e r i de x a n d Li s te r in e a pp e a r t o h e lp de c re as e ba c t e ri a in t he m o u th . b . L es i on s c a n oc c u r on a n y no n ke r at i ni ze d m uco s al s u r fa ce in t he m o uth ( i .e . , t o n gu e , l ip s ) a nd us ua ll y a p pe a r g r a y to y e ll o w wi t h an e r yth e m a t ou s h al o o f i n f la m e d t is s u e s u r ro u ndi n g t h e u lc e r. Mo s t le s i on s p e rs is t 7- 1 4 d a y s a nd h e al wi t h o u t s c a r r in g . c . O TC p r o d uc t s c an c on t r ol t he pa i n o f ca n k e r s o r es , s ho r te n th e d u ra t io n of c u r re n t l es io n s , an d p r e ve n t n e w l e si on s . P r od uc ts in c l u de p r o te c ta n t s, lo c a l a n e s th e t ic s , a nd dé b r i di n g an d w o un d - cl e an s in g a ge n ts . ( 1 ) P r o te c t an t s i nc l ud e O r a b as e , d e nt u re ad h es ive s ( s e e I I . F. 2 ) , a nd be nz o i n t i nc t u re . D en t ur e a d he s iv e s a re no t ap p ro ve d fo r t h is us e b y t he F D A. ( 2 ) L oc a l a ne s t he t i cs , s u c h as b en z o ca in e o r but a c a i ne , a r e t h e m os t com m o n a n e s th e t ic s f o un d i n t h es e O TC p r od uc t s . ( a ) Th e F D A h as ap p ro v e d th e fo ll o wi n g i n gr e di en t s : ( i ) B e n z oc ai ne ( 5% - 2 0% ) ( i i ) B en z y l a lc oh o l ( 0 .0 5% - 0 . 1% ) ( i i i ) D yc l o ni ne ( 0. 0 5% - 0 .1 % ) ( i v) H e xy l r e s o r c in ol ( 0. 05 % - 0 .1 % ) ( v) Me n t h ol ( 0. 0 4% - 2% ) ( vi ) P h e no l (0 . 5% - 1 .5 % ) P.613
( vi i ) P h e no la t e s od iu m (0 . 5 % -1 . 5% ) ( vi i i ) S a li c y l a lc oh ol ( 1%- 6 % ) ( b ) E xa m p l es o f O TC l oc a l an es t he t ics f o r o ra l u se i nc lu de A nb e so l, B li s tex, C a m ph o - Ph e ni q ue , O r aje l , O r aj el C o ve r Me d , Zi la c ti n - B , Z il ac t in - L , B e n zo d e nt , a n d R e m b ra n dt C an k e r P ai n R e l i ef K it . ( c ) Th e us e o f p r od uc t s c o nt a in in g s u bs ta n ti a l am o un ts o f m e n th o l, ph e no l , c am p ho r , a n d e ug e no l s h o ul d b e di s c ou r ag e d o wi n g t o t h ei r ab il i t y to i rr i ta t e ti ss ue .
( d ) A sp i ri n s ho u ld no t b e r e t ai n ed i n th e m ou t h o r p l ac ed on an o ra l l es io n i n a n a t t em p t t o p r o v id e re li e f. ( e ) P r es c r i p ti o n p r o d uct s . Am l e xa n o x ( A p h t ha so l ) h a s b ee n a pp r o v e d f or t h e t r e a tm en t o f c a nk e r s o r es . ( i ) I t i s a pp li e d 4 ti m e s da i l y af t e r m e a ls a n d a t be d t im e. ( i i ) A d vis e p at i en ts t o s ta r t us in g t h e p r od uc t a s s o on as th e y no t ic e s y m p t om s a nd t o co n ti nu e u n ti l th e u lc er i s h ea l ed , a p pr o xi m a te l y 1 0 da y s . ( f ) G e lc l ai r i s i nd ic a te d fo r lo c al m a na ge m e n t a nd r el i ef o f o r al p a in as s oc i at e d wi t h a p h th o us u lc e rs . It p ro v id e s o r al pa in r el ie f b y a c t i n g as a p r ot e c t i v e a d her e n t b a r r ie r o v er t he s u r fa c e o f t he m o ut h a n d t h ro a t. ( i ) P a ti en t s h ou l d us e o ne p ac k e t a t l e as t 3 ti m e s a da y o r a s n e ed ed . ( i i ) A d vis e p at i en ts t o m ix 1 p a c ke t wi t h 3 ta b le s po o ns of wa t e r , s wi s h f o r a m i n ut e , t h e n e xp e c t or a te . D o n ot e a t o r d r i nk f o r a p p ro xi m a te l y 1 h r a f t e r t r ea tm en t . ( g ) I n ves ti g at i on a l p r o du c t s . T h al i do m i de is b ei n g s tu d ie d f o r t h e t r ea tm e nt o f A I D S a s s oc ia t ed o ra l c ank e r s o re s . ( 3 ) D é b ri d i ng a nd w o u nd - c l ea n si n g a g en t s i nc lu d e 1 0 %- 1 5% c a r ba m i de p e r o xi d e , 3 % h yd ro ge n p e r o xi d e , 1. 2 g s od iu m p e rb o r at e m o n o h y dr a te , an d s od i um b i ca r bo n at e . Th e F D A c on s id e rs th es e fo u r a ct i ve i n gr e di e nt s t o b e s a fe an d e f f ec t i v e f o r d éb r id i ng o r wo u n d - c l e an s i ng ag e nt s f o r o r a l h ea l th c a r e. 2 . C o ld s o re s / fe ve r b l ist e r s ( al s o c a ll ed h e rp e s s i m pl e x l a bi a l is ) a r e c au s ed p r i m a r il y b y t he he r pe s s i m pl e x v i r u s t yp e 1 ( H S V- 1 ) . H S V -1 is c o nt a gi ou s a n d is t h o ug h t t o b e t r a ns m i tt ed b y di r ec t c o nt ac t . An ou t b r ea k m a y b e p r o vok ed b y st r es s , m i no r i n fe c ti o n, fe v e r , o r s un l ig h t. C ol d s o re s u s ua l l y occ u r o n t h e l ip s a nd a r e r e c ur r e nt , of t en a ri s i ng in t he s a m e lo c a t io n . a . P r es e n ta t i on . A n o utb r e ak is p r ec e de d b y b u rn i ng , it ch i ng , o r nu m b n es s . R e d p a p ul es of fl u id - c o n ta in in g v es ic l es th e n a pp ea r , a n d t he s e e v e nt u al l y bur s t a n d f o r m a c r us t . Th e s e s o r es a re t y pi c al l y s el f - li m i t ed a nd he a l in 1 0- 1 4 d a y s wi t h o u t s ca r r in g . b . O TC p r o d u c ts fo r c o ld s o r es in c l u de p ro du c ts t h a t co n ta i n s o f t en in g c o m po u nd s ( e . g ., em ol l ie n t c re am s , p e t r ol a tu m , p ro t ec ta n ts ) , wh i c h k e ep th e c ol d s o re m o is t to p r e ve n t i t f r om dr y i n g a nd f is s u r in g . L oc al an es t he t ic s i n n on d r yi ng ba s e s ( e . g ., O r a b as e , wi t h b en z o c a i ne ) d ec re a se pa in . H ig hl y a s tr i ng e nt ba s e s s ho ul d b e a vo i d ed . Th e A D A c o n tr ai n di c a t es c a us ti c a g en ts ( e . g ., ph e no l , si l v e r n i t rat e ) , c am p ho r an d o t he r c o un te r i r ri t an t s, an d h y d r oc o r ti s on e f o r t h e t r ea t m e n t of c ol d s o r es . L es io ns s h o ul d b e k ep t c l ea n b y g en t l y wa s h i n g wi t h m i l d so a p. ( i ) D o co s an o l 1 0 % c r e am ( Ab r e va ) i s in d ic a te d fo r t he t re a tm en t of c o ld s o r es . I t p r e ve n ts th e c ol d s o re i nf e c ti on f ro m e n te r in g h ea l t h y c el ls . It is ap p ro v ed b y t he F D A t o s ho r t en he al i ng tim e a n d d u ra t io n o f s ym pt o m s . Pa t ie n ts s h ou ld app l y t he c r e am a t th e f i rs t s ig n o f a n o u tb r e ak a n d co n ti n ue t o a pp l y t he c r e am f i ve t im e s a d a y u nt i l t he le s i o n is hea l ed . ( i i ) V i ra c t i n g el ( 2% te t ra c ai n e) is us ed fo r th e te m po r a r y re l ie f o f p a in an d it c h i ng a ss o ci at e d wi t h c o l d s o re s . ( 1 ) I f a s e co n d a r y i n f e c t i o n de v e lo ps , ba c i t r ac in o r N eo sp o r in an t ib io t ic o i n tm en ts s h ou l d b e r ec om m e n de d . I f ne c e s s a r y , t h e p at i en t s ho u ld c o ns ul t a p h ys ic ia n fo r a s ys t em ic a n ti b io t ic p r es c r i p ti o n.
( 2 ) A l i p s u ns c r ee n s hou l d b e u se d f o r p a ti e nt s wh o s e c o ld s o r es ap pe a r t o be c a us ed b y s u n e xp o s u re . ( 3 ) Th e es s e nt i al am in o a c id L -l y s in e h as be e n us e d i n o r al do se s o f 3 00 -1 2 0 0 m g d a il y t o a c c el e r at e re c o v e r y o r s u pp r es s r ec u r re nc e o f c o ld s o r es . H o we v e r , s t ud i es h a ve p ro du c ed c o nf l ic ti ng d at a re g ar d in g L - l y s i ne a n d i ts ef f ec t o n t h e d u ra t i on , s e ve r it y, a nd re c u r r e nc e r a t e o f c ol d s o re s . c . P r es c r ip t i o n p r o du c ts ( 1 ) V a la c yc l o vi r ( V a l t r e x ) is in di c at e d f o r t he t rea t m e n t o f h e rp e s l ab ia l is. ( 2 ) Ac yc l o vi r c r e a m 5 % ( Z o vi r a x ) i s in d ic a te d f or t h e t r ea tm e n t o f c o l d so r e s i n a d ul t s a nd ad o le s c en ts > 1 2 y ea r s o f a g e. Th e r apy s h ou l d b e i ni t ia t ed at th e on se t o f si gn an d s y m pt om s a nd a pp li e d 5 ti m e s p e r d ay f o r 4 d a y s . P.614
( 3 ) P en c i cl o vi r c r ea m 1% ( D e n a vi r ) i s a n a nt i vi ra l m e di c a t io n f o r t h e t r ea t m e n t o f c o ld s o r es i n a d ul ts an d c h il d re n 1 2 yea r s o f a g e a n d o ld e r . P a ti e nt s s ho ul d ap pl y t h e c r ea m e v e r y 2 h r wh il e a wa k e f or 4 d a y s, be gi n ni n g a t t h e f i rs t s ig n o f t i ng l in g o r s we l li ng . D . C o m mo n o ra l in f ec t io n s a n d O TC p r o d uc t s 1 . C a nd i d ia s is ( al s o c a lle d t h ru s h ) i s c a us e d b y t h e fu ng us C a nd id a a l bi c a n s, wh i c h is th e m os t c om m o n op p or t un is t ic pa t ho g en as s o ci a t ed wi t h o r al inf e c ti on s . Th r u s h h as a m il k y c u rd a p p ea r an c e , an d a f fe ct ed p at i en ts s h ou l d c on t act a p h ys ic ia n . 2 . O r a l c a nc e r . Th e m o s t c om m o n o r al c a nc er is s q u am o us ce l l c a r ci n om a , wh ic h c a n a pp e ar as r ed or wh i t e le s i o ns , u lc e ra t io ns , or t um o rs . a . S i gn s a n d s ym p t o m s i nc l ud e a c o lo r c h an ge in t he t on gu e , a s o r e t h roa t t ha t d o es no t h e al , a n d p e rs is t en t or un e xp l a i ne d b lee d i n g . Pa t ie n ts wi t h a n y o f t he se s i gn s sh o ul d c on t ac t a ph y s ic i an o r a d e nt is t . b . R i sk f ac t o r s i nc lu de s m o k ed an d sm ok e le s s to b ac c o as we l l a s a l c oho l . c . T re a t me n t c on s i s t s o f e l im in a ti ng us e o f t o ba cc o a n d a lc oh o l i n a n y f o rm ( e. g . , a l co h ol ic b e v e r ag es , m ou t h ri ns es wi t h al co ho l ) . A l s o, t re a tm en t ge ne r a lly i n c l u de s w i de l oc a l e xc i si o n f o r s m a l l l es io ns an d e n bl oc e xc i si o n s f o r l ar g e r l es i on s ( i n c o nt i nu i t y wi t h r a di c a l n ec k d is se c t i on if l y m p h n od e s a r e i n v ol ve d ) . R a di at i o n, a l on e o r c o m b in e d wi t h s u r g e r y , m a y b e a p p ro p ria t e . Ch em o th e ra p y m a y b e us ed as p a ll i at i on o r as an ad j unc t to s u r ge r y a nd r ad ia t io n . d . O TC m e d ic a t io n s s hou l d n o t b e a dm in is t e re d u n t il af t e r c h ec k i n g wi t h a p h ys ic ia n . F o r e xa m p le , O TC m e d ic a ti o ns us ed fo r in f la m m a ti on c a n i nc re a se th e e f f ec ts o f m e t ho t r e xa t e . C h e m o t he r a pe u ti c a ge n ts ca n p r od uc e m a n y p os s i bl e s id e e f f ec ts t ha t re qu i r e im m ed i a te m e di c a l a t te n ti o n (e . g . , ch es t pa in , i n fl am m a t i on , u n us u al bl ee d in g ) . S om e e xa m p l es o f s i de ef f ec ts t h a t us u al l y do no t re q uir e m e di ca l a t te n ti o n i nc lu de n a us ea , v om i ti ng , lo ss of a pp e ti t e o r h a i r, an d t ro u bl e s l ee pi n g. O TC m e di c a t ion s c an b e us e fu l i n t h es e c a se s ; h o we v e r , n a us ea a nd vo m i ti n g a r e t r ea t ed b y pr e s c r ip t io n m ed ic a ti o ns su c h as o nd an se t r on o r m e to c l o p ra m i de . N on p har m ac o lo gi ca l m ea s u r es , s uc h a s a v o i di ng di s tu r bin g
e n vi r on m e n ta l o d o rs a n d v e s t ib ul a r d is t u rb an c es , m i g h t b e h el p fu l i n m in im i z i ng n a us e a a nd v om i ti n g. E . R e c om me n de d s ta n da r d p r o ph yl a x i s f o r p r eve n t i o n of e nd o ca r d i t is 1 . Am o x i ci l l in 2. 0 g o ra ll y 1 h r b ef o r e t he p ro ce du r e fo r ad ul t s , an d 5 0 m g / k g o ra l l y f o r c h il d re n , i s t he r ec om m e n de d s t an da r d p r oph y l a c t ic r eg im e n f o r a ll de n t al , o r al , u p p er - r es pi r a to r y t r ac t , a n d e s o p ha ge a l p r oc ed ur e s . 2 . F or pa t ie n ts wh o a re a l l e r gi c to p en i ci l l in , the r ec om m e n de d a l t e rn a ti ve o r a l r e g i me n s i nc lu d e t he f oll o wi n g : a . C l in d am yc i n , 6 0 0 m g f o r a d ul ts ; 20 m g /k g f o r c h il d re n b . C e ph a le x i n o r c e fa d ro x i l , 2 .0 g f o r a du l ts ; 5 0 m g /k g f o r c h i ld r en c . Az i t h r om yc i n o r cl a r it h r o m yc i n , 5 0 0 m g fo r ad u l ts ; 1 5 m g/ k g f or c h il d re n , 1 h r b e f o re th e p r oc e du r e F . O TC d e n t u r e p r o du c ts 1 . D e nt u r e c l ea n se r s a re e it h e r c he m ic a l o r a b ra s i ve in r es pe c t t o t he i r c l ea ns i ng a b il i t y . a . C h em i ca l d e nt u r e c l ea n s e r s i nc lu de al k al in e pe r o xi d e , al k a l i n e h y p oc hlo r i te , o r d i lu t e a c i ds . ( 1 ) Al k a l i ne pe r o x id e i s t h e m o st c om mo n l y u s e d c h em ic al de n tu r e c lea n s e r an d i s a va i la bl e a s t a bl e ts o r p o wd e r s . I t c au s e s o xy g e n to be r el e as ed , wh ic h c r ea t es a c l ea ns i ng ef f ec t . A lk a li ne p e ro xi d e do e s n ot da m a g e t h e s u r f ac e o f a c r ylic r es in s ; h o we ve r , i t m a y b l ea c h th e m . ( 2 ) Al k a l i ne h yp o c h l o r i te ( i .e . , b le ac h ) d is s o l v es t h e m at r i x o f pl a qu e b u t h as no e f f ec t o n c al c u l us . I t i s bo t h b ac t e ri c i d al an d f u ngi c id al . A d i sa d va n t ag e of a lk al i ne h yp o ch l or i te is th a t i t c or r o d e s m e ta l de n t u re co m p o ne n ts . It ca n a ls o b l ea c h a c r yl ic re s i n . Th e r e fo r e , i t s h ou l d n ot be us ed m or e t ha n o nc e a we e k . b . Ab r a s i ve de n tu r e c lea n s e r s a r e a va il ab l e as g e l , p as te , or po wd e r ( e .g . , s i li ca t es , s od iu m b ic a rb on a t e, di c a lc i um p h os ph a te , c a lc iu m c a rb on a te ) . P.615
( 1 ) D e nt u re s s ho u ld no t b e s o ak ed in ho t wa t e r be c au s e t he he a t co u ld dis t o rt o r wa r p t h e a p pl ia n c e s . ( 2 ) Th e A D A a c c ep t s t he f o ll o wi n g d e nt u re c l ea ns e r s a s s af e a n d e ff e c t i v e: D e n tu r e B r i t e , E f fe r d en t , a nd P ol id e n t. 2 . D e nt u r e a d he r e n ts c o n t ai n m at e r ia ls (e . g ., k a r a ya gu m , pe c ti n , m e t hy l c e ll ul os e ) t h a t s we l l , g el , a n d b ec om e v is c o us to p ro m o t e ad h es i on , wh ic h i nc r e as es t he d e n tu r e a t ta c h m e n t t o un d e rl y i n g s o f t t is s ue s. a . D i sa d va n t ag es . As t he us e o f de n tu r e a dh e r en t s i nc r ea se s , t he s o f t t is su e d e t e ri o ra t es . De n tu r e a dh e r en t s c a n a ls o p r o v i de a m e di um f or ba c te r ia l an d fu n ga l g r o wt h . D ai l y us e o f d e ntu r e ad he r e nt s i s n ot r ec o m m e nd e d. b . Th e A D A a c c ep t s t he f o l lo wi n g d e n tu r e a dh e ren t s a s s a f e a nd e ff ec t i v e: F i xo d e n t, O R A f i x, S e a - B o nd , S up er P o li - G r i p, an d E ff e rg r i p. G . P h a r ma c is t ' s r e s po ns i b i li t i es t o t h e p a ti e n t u s i n g O TC o r a l p r od u c ts 1 . R e fe r a p a ti en t to a de n t is t i f t h e o r al c om p la in t in v o l v es an ab sc es s wi t h f e ve r , s we l l i ng , m al ai s e, l ym p ha d e no pa t h y , o r pu r ul e nt e xu d a t e .
2 . R em i n d p at i en ts t ha t c o ld an d c an ke r s o r es , wi t h a p p ro p ri a te t re a tm en t, a r e u s ua ll y a s e lf - li m i t in g p ro b le m . 3 . P at i en ts s h o ul d b e i n fo r m ed ab ou t how t o us e r e c om m en d e d p r o du c ts , t he d u r a ti on o f us e , t h e e xp e c ta t io ns o f us i ng th e p ro d uc t , a nd t he p ro c e du re t o f ol l o w i f t h e p r o du c t is i n ef f ec t i v e. 4 . I f a n o np r es c ri p ti on p ro d uc t d o es no t i m p r o v e a c o n di t io n , o r i f th e c ond i t io n wo r s e n s , us e o f th e p r odu c t s ho ul d b e d is c on t in ue d an d a ph ys ic ia n o r den t is t s h ou l d b e c o n ta c te d .
III. OPHTHALMIC OTC PRODUCTS A. An a t o m y o f t h e e ye 1 . Th e sc l e ra , a ls o k no w n as t he wh i t e o f t h e e y e, f u nc ti o ns t o pr o te c t i nt ra o c u l ar c o nt e nt s a n d m a i nt ai n the s h a pe of t he e ye. 2 . Th e co r n ea is th e m ain r e f ra ct i ng s u r fa ce of t he e y e . 3 . Th e an t er i o r c h am b e r o f t he e y e h ou s e s a c o nti n uo u s su p pl y o f a q ue o us h um o r , wh i c h is p r o du c e d i n re lat i o n t o t h e in t r ao c u l a r p re s s u r e. Th e aq ue o us h um o r i s r e s po ns ib l e f o r n ou r is hi ng t he c o r ne a . 4 . Th e i r is i s t h e c o l o re d p a r t o f t h e e ye th a t r eg ul a t es th e e n tr a nc e o f l ig ht t h ro u gh t h e p u pi l . 5 . Th e pu p i l is t he c o nt ra c ti l e o pe ni n g a t t h e c e nt e r of t he ir is t ha t d i la t es a n d c o ns t ri c ts i n re s p on s e t o l i gh t . 6 . Th e le n s is f ou nd di r ec t l y be hi n d t he i ri s a nd pu p il an d i s r e s p on s i b le fo r e n a bl in g t h e e y e to ac c om m o d at e , f oc us i ng fo r ne a r an d d is t an ce v is i on . Th e l e ns c o nt i nu es to g ro w t h r o ugh o u t l if e , g r ad u al l y b e com i ng th ic k e r o v e r t im e . Th e le ns is , t h e r ef o re , s us c e p ti b le to t h e d eg e ne r a ti v e ef f ec ts o f ag in g , m os t n ot ic e ab ly e v i d e nt i n th e 5 t h d ec ad e o f li f e a s th e i na b il i t y t o fo cu s a n d re f oc us fo r n e a r a nd d is t an ce vi s i on . 7 . A pp r o xi m a te l y t wo t hi rd s o f th e v ol um e o f th e eye i s o c c up i ed b y t h e vi t r e o u s h u m o r . A s o ne ag e s , th e g e l- l ik e c ha r ac te r is t ic s o f t he v i t re ou s h um o r i s lo s t a nd s h ad o ws a re c a s t b y v a rio u s c e l ls , g i v in g th e i ll us i o n o f “f l oa t e rs . ” 8 . Th e r e ti n a is c o m p os e d of t he op t ic d is c , t he r e t in a l v e ss e ls , a nd t he m ac u la . Th e o p ti c n e r v e e n te rs th e r et i na th r ou g h t he o pti c d is c . Th e m a cu la is res p on s i b le f o r c e nt r a l v i s i o n a nd th e r e m a i ni ng pa r ts o f t he re t i na a re re s p o ns ib l e f o r p e ri p he r al a n d c ol o r v is io n . 9 . Th e op t i c n e r ve , a ls o k no wn a s t h e s ec on d c ra n ia l n e r ve ( C N I I ) , t r an s m i ts i m pu ls es f ro m t h e r e ti na t o t he br a in . P.616
B . O p h t h al m ic F o rm u lat i o n s 1 . V eh i c le s p r o v id e i nc re a s e d vis co s i t y , th e re b y e n h an c i ng co n ta c t t im e o f t he p r o du c t. V eh ic l es c om m o n l y fo u nd in op h th a lm i c p r o d u ct s i nc lu d e c a r bo xy m e t h y l c el lu l os e (C M C ) , p o v i do n e , p ol yv i nyl a lc o ho l (P V A ) , a n d h yd r o xyp r o p y l m et h y lc e llu l os e ( H P MC ) .
2 . P r es e r va t i ve s p r o v i de a nt im ic r o bi al ac ti vi t y fo r o ph t ha lm ic pr e p a r a ti on s a n d i n cl ud e b e n z al k o n iu m c hl o r id e ( BA K ) , c hl o r he xi d in e , m e th yl pa r a be n , p r opy l p a r ab e n, e t h yl en e di am in e te t r aa c et i c a c i d ( E D TA ) , a nd s o rb i c ac i d. 3 . An t i o x id a n ts p re v e n t p r o du c t d et e ri o r at i on . Com m o n a n ti o xi d a n ts fo u nd i n o p h th al m i c p r ep a r at i on s i n c l ud e e d e ti c ac i d, s o diu m b is u lf i te , s o di um m e ta b is ul f i te , s o di um th i os ul f at e , a nd th i ou r e a. 4 . We t t i ng a ge n t s r ed uc e s u r f ac e t e ns io n o f t h e le n s a nd in c l u de po l ys o r ba t e 2 0 , p o l yso r ba t e 8 0 , p ol o xa m e r 2 82 , a n d t y l o xa p o l. 5 . B u f fe r s ar e u s e d i n op h t ha lm ic p re pa r a ti o ns to m a i nt a in a p H b e t we e n 6 . 0 a nd 8 . 0 . B u f fe r s i nc lu de ac e ti c a c i d , b o ri c ac i d, h yd roc h lo r ic ac id , p h os ph o ri c a c id , p o t ass i um b ic a r bo n at e , p o t as s i um b o r at e , p o ta ss i um c i tr a te , s o di um ac et a t e , s o di um bi c a r bo n at e , s odi u m b is ph os p ha t e, so di um bo r a te , s o di um c a rb o na t e , s o di um c i t ra t e, s o di u m hy d r o xi d e , a nd s o di um pho s ph a te . 6 . T on i ci t y a d j u s t e r s e ns u r e a n is o to n ic a g en t , eq u al t o 0 .9 % - 60 . 2% s o di u m c h lo r id e . Th es e a ge n ts in c lu d e d e xt r o s e , g l y c e r in , po t as s i um c h lo r id e , p ro p y l e ne g l yc ol , a n d s o d iu m c hl o rid e . C . N o n p r es c r ip t i o n o p ht h a l mi c a g en t s 1 . Ar t i f i c i al t ea r s a r e u s e d to h yd r a t e a n d l ub r ic a t e t h e e ye b y s t i m ul a tin g te a r p r o du c ti on an d d e c r e as in g te a r e va p o ra ti o n . I ni t ia l do si ng is r ec om m e nd ed as 2 t i m e s d ai l y , up to 4 t im es da i l y , a s n ee de d . Ho we v e r , so lu t io ns m a y b e us e d h ou r l y , i f cl in ic a ll y in d ic a te d . To r e d uc e oc u la r i r r i ta t io n , p r e se r v a ti v e - f r ee a rt i fi c ia l te a rs s h ou l d b e r ec om m e n de d t o pa t ie n ts wh o wi l l n e ed t o us e t he m e di ca t io n fre q u en tl y . 2 . L ub r i ca t i n g o i nt m en ts i nc lu de wh i t e p e t ro la t um , m i ne r al oi l , a nd la no l in , wh i c h a c t t o l u br ic a te an d h y dra t e th e e ye . As a n oi nt m e n t , t h es e a ge n ts a r e a bl e to p r o vi d e i nc r e as e d c on ta c t t im e w it h t he oc u lar s u r f ac e bu t ma y r e s u lt i n b l u r r e d vi si o n . I f p os s i bl e , b l ur r e d vi si o n m a y b e m in im i ze d ( o r l es s n ot ic e a bl e ) b y d e c re as in g th e a m o u nt of o in t m e n t in s ti ll e d i nt o th e e ye o r b y a dm in is t e rin g th e o i n tm en t a t be d ti m e . I n it ia l do s i ng is r ec om m e nd ed as 2 t im es da i l y, b ut m a y b e u s ed as of t en as e v e r y fe w h o u r s , o r o nl y o c c as io n al l y , de p en di n g o n p ati e n t r e s po ns e . P r es e r v a ti v e - fr e e op h th al m i c o in t m e n ts m a y r e du ce oc ul a r i r ri ta t i on in p a t ie n ts re q ui r in g f r e qu en t do s i n g. W hen u s i ng eye d r o ps a n d o in tm e nt , dr o p s s h o u ld be i ns t i ll e d i n t o t h e e ye b e f o r e ap p l yi n g o i n tm e nt . 3 . V as o co n s t r ic t o r s ( dec o ng es t an t s) wo r k b y p ro d uc i ng a t em p o r a r y c o n s t r i c ti o n o f t h e c on j u nc t i va l bl oo d ve s se l s , t he r eb y r e du c in g e y e r ed n ess . A v ai la b le o p h th al m i c v as oc on s t ri c to r s i nc l ud e n ap h a z ol i ne , p h en yl e ph r in e , t e tr a h ydr o z o l in e , a n d o xy m e t a z o l in e . Th es e a ge n ts m a y h a ve a r e b o u n d e f fe c t (c o ng e s tio n ) i f u s ed i n e xc es s o r fo r e xt e n ded d u ra t io ns an d s ho ul d be a vo id e d i n p at i en ts wi th n a rr o wa n gl e g l au c o m a . 4 . An t i h i s ta m in e s m a y b e us ed fo r t he t re a tm ent o f o p ht h al m i c co n di t io ns a ss o ci at e d wi t h a ll e rg ic rh i ni t is , t h ou g h t he i r u se h a s b ee n c la ss i fi ed b y the F D A as l e ss th an e ff ec t i v e b ec aus e o f th e l ac k o f d a ta dem o ns t ra t in g c li n ic al ef f ec t i ven es s . K e t o ti f en , s ol d u n de r th e b r a nd na m e Za d it o r ® , i s t h e o nl y a v a il a bl e n o np re sc r i pt i on o c ul a r a n ti hi s ta m i ne an d m as t c el l s ta b il i ze r i nd ic a t e d f o r t he t em po r a r y p re ve n t io n o f it c hi ng o f t he e y e d ue t o al l er g ic c o nj un c ti vi ti s . P h e ni r am in e a n d a nt a z ol i ne a re
a l so no n pr es c ri p ti o n o pht h a lm ic a n ti h is ta m i n es , bu t a re on l y a v ai l ab le in c om b in a ti o n wi t h th e o p ht h a lm ic d ec o ng es t an t nap h a z o li ne . a . Typ i c al do s i ng o f o ph th a lm ic an t ih is t am in es is 1 - 2 dr o ps i n e a ch e y e 3 -4 t im es d a il y . b . O p h th al m i c a n ti hi s ta m i n es s h ou l d n ot be r ec om m e n de d i n p a ti e nt s wi t h g la uc om a o r p at i en ts at hi g h r is k of d e v el o pi n g n ar r o w- a n gle g la uc om a , a s p up il di lat i o n a ss o ci at e d wi t h t he us e o f t he s e ag en t s m a y c aus e th is di s o r de r . c . Si d e e f fe c t s o f th es e a g e nt s m a y i nc l ud e b u rni n g , s ti ng i ng , i tc h in g , f o re i gn bo d y s e ns at i on , d r y e y e , l i d ed e m a , a n d p up i l di l at i on . P a t ie n ts u s i n g k et o ti f en d r o ps s h ou l d al s o b e a d v is ed of t h e p oss i bl e a d v e rs e e ff e c t o f b lo o d s h o t e ye s . P.617
5 . As t r i n g en t s d e c re a se o cu l a r i n f l am ma t i on . Th e o n l y F D A- r ec om m e nd e d a s t ri n ge n t is z i n c s ul f a te , r ec om m e nd e d as 1 -2 d r o ps fo u r t im es da i l y . 6 . I r r i ga n t s o lu t i o ns wo r k to r i ns e a n d re m o ve d e b r i s a nd c on t am i n an ts f r om th e e ye , wh i l e m a i nt a in i ng oc u la r m o is tu r e . 7 . H yp e r o s m o t ic ag e n ts i nc r e as e t he t on ic it y o f th e te a r f i lm , e v e n tu al l y el i m i na t in g e xc e s s f l ui d f r om th e c o rn e a . D . E ye d i s o r d e r s 1 . D r y e ye , a l s o k n o wn a s k e ra t oc on j un c t i vi ti s s ic ca , is a c o m m on c o nd i tio n in wh i c h pa t ie n ts c om p la in o f a f o re i gn bo d y s e ns a tio n , o p ht h al m i c i tc hi n g, de c r ea se d t e a r p r od u c t io n , re dn es s , p ai n , a nd di f fi c ul t y m o vi n g t h e e ye li ds . S ym p t om s a r e t h e r e s ul t o f a de f ic ie nc y t o p r o du c e aq u eo us , m uc i n, o r l i pi d t e ar f il m c o m p on e n ts , wh i c h m a y b e a tt r i bu t ab le t o c er t ai n d is e as e s ta te s (e . g. , th y r o i d d is ea s e , P a r k i ns o n d i se as e ) , i nf ec t io n , o r m e d ic a ti on s (e . g. , a n ti h is ta m in es , o r a l c o n t ra ce p tiv e s ) . N o n p r es c r ip t io n tr e at m en t f or d r y e ye i nc lu de s t he us e o f a r ti f i ci a l t e a rs d u r i n g t h e d a y a n d o p h th a lm i c o i nt m e n t a t n i gh t . 2 . C o nj u n ct i vi t i s i s i nf l am m a t io n o f th e c on j un ct iv a wh i c h m a y be ca us e d b y b a ct e r ia l o r v i ra l i n fe c t i on , al l er g y , o r e n v ir o nm e nt a l f a ct o rs . a . Al l e r g i c c on j u nc t i vi t is s y m p t om s a ff ec t bo t h e ye s a n d i nc lu d e r e dn es s , m il d e d em a o f th e e y e li d , e xc e s s i v e te a ri n g, e xt r e m e it c hi n g, st r in g - li k e m uc o id d i sc ha r ge , an d c he m o s i s . N o np r es c ri p ti o n t r ea tm e n t re c o m m en d at i on s a v o i da n c e of t h e a l le r ge n i f fe as ib l e, c o l d c om p re ss es , v as oc on s t ri c t o rs , an d a n ti hi s tam i ne s. N o n p r es c r ip t io n o p ht h alm ic p ro d uc ts c o nt a in in g a c o m b i na t io n o f a v a so c o n st r ic t o r a n d a n a n ti hi s ta m i n e a re a v a i la bl e (e . g ., N ap hc on A , O pc on A , Vi s i ne - A ) . b . Th e c a us es of ba c t e ria l c on j un c t i vi t is de p end o n p at i en t ' s a ge . Ap p ro xi m a t e l y o n e q u ar t e r o f p a ti en t s pr e s en t in g wi t h b ac te r i al c o nj u nc ti v i t is wi l l h a v e c o n co m i ta n t o t i t is me di a . Th e re f o re it is pr u de nt f o r a ll c h il d re n p r es e nt in g wi t h a p u r ul e nt oc ul a r d is c h a r ge o n wa k i ng in th e m o rn in g an d a b ru p t o ns e t o f re d n es s t o h a ve th e i r e ar s e xa m i n ed f o r o ti t is m e di a . T r ea tm e n t fo r ba c t e ri a l c o nju n c t i vi t is i s p r e s c r ip t i on o nl y. c . V i ra l co n ju n c ti vi t i s is m o s t o ft e n a tt r i bu t ab le t o th e a d en o vi r u s a n d is h ig h l y c o n t ag i o us . Mo r e c om m o n l y k n o wn as “ p i nk e ye , ” in di v i d ua ls of t en e xp er i e nc e a n u p p er - r es pi r a to r y i nf ec t io n o r a re e xp o s ed to ano t h e r i nd i v id u al wi t h v i ral
c o nj u nc ti v i t is b e fo r e t h e o n s e t o f s y m p to m s (e . g. , p i nk e ye , th ic k o cu la r dis c h a r ge , e xt r e m e t ea r in g , f o re i gn b o d y s e ns a ti on ) . T re a tme n t is s up p o r ti ve a nd m a y i nc l ud e c o ld c om p r es s e s , a rt i fi c ia l te a rs , a n d t op ic a l v a so c on st r ic t o rs . 3 . C h em i ca l b u r n s c a n re s ul t fr om m e di c at io n s , c h lo r in a te d s wi m m i ng p oo l s , o r e xp o s u r e t o to xi c f um es o r i r ri t an ts ( e. g . , h ai r s p ra ys , ba t te r y a c i d, v i ne g ar , o ve n c l ea n er s , l y e ) . T r ea t m ent i n c lu d es im m ed i a te an d c on t i nu e d i r r i g a ti o n o f th e e ye ( s ) wi t h s al in e o r s t e ri l e wa t e r a nd em e rg en c y a t t en ti o n f r om a p h ys ic ia n o r e ye c a r e sp ec i al is t . 4 . C o r ne a l e d em a i s c h ar a c te r i zed b y ha l o s o r st a r b u r st s ar o un d l ig h ts , wh i c h a r e t h e re su l t o f a n u n de r l y in g di s o r de r ( e. g . d am age t o t h e e ye ) . O n c e di a gn o s e d b y a p h ys ic ia n , h yp e r o s m o t ic a ge n t s s u c h as Mu r o s o l u ti on o r o in tm e nt m a y b e us ed to d r aw t h e f l u id aw a y f r o m t h e c o r ne a . D os i ng s h o ul d b e gi n wi t h a 2% s o l u ti on us e d 4 t im es da il y wi t h t he add i t io n o f a 5% oi n tm en t us e d a t n ig h t ti m e if ne e ded . I f u n r es ol v e d , t h e 2 % s o l uti o n m a y b e c h an ge d to a 5 % s ol u ti o n wi t h c o n ti nue d us e o f t h e o i nt m e n t . 5 . A ho r d e ol u m, m o r e c o m m o nl y kn o wn a s a s t y, i s a n in f ec t io n o f th e g la n ds of t he e ye l id s c au s e d b y S t a p hy l o co c cu s au r e us . S ti es p re se n t a s p ai n fu l , r ed, a nd e d em a to us bu t m a y be re l ie v e d b y t h e a pp l ic at i on o f w a rm co m p re s se s fo r 1 0- 1 5 m i n 3 - 4 t im es d a il y . To p ic a l a nt i bi o ti cs m a y be r eq u i re d . 6 . A c h a la z i o n , s i m p l y a g r a n ul o ma , m a y in v o l ve t he gl a nd s o f t h e e ye lid s o r th e s u r ro u nd i ng ar e a b u t is n o t i n fe c ti o u s. W he n i n i t s e a rl y s ta ge s , t he in f lam m a t io n m a y be r el i e v ed b y w a rm c om p r es s es ap p li ed fo r 1 0- 1 5 m i n 3 - 4 t im e s da i l y. I f no t r e s ol ve d wi t hi n 1 we e k , p r o v i de r c o ns ul t a ti on is a p p ro p r ia t e, an d s u rg ic al e xc i s io n m a y be ne c es s a r y . 7 . B l ep h a r it i s i s a b i l a te r a l in f l am m at i o n o f the e ye l i d m a r g i ns , at t r ibu t a bl e t o S t a p hy lo c o c c us , s eb o r rhe i c d e rm at i ti s , o r a c om bi n a ti on o f t he t wo . B le p ha r i ti s m a y b e id en t i fi ed b y r ed , P.618 s ca l y, th ic k e n ed e y el i ds wi t h p os s i b le lo ss of th e e y e l as h es . S t ap h y l oc oc c a l b l ep h a ri t is re q ui r es a n ti bi o t ic t r e at m e n t , b ut se bor r h e ic b l ep h ar i ti s m a y res p on d t o l i d h yg ie n e wi t h wa r m c om p r es s es f or 1 5- 2 0 m i n 2 - 4 ti m e s d ai l y, fo ll o we d b y l id s c ru bs wi t h a m i l d d et e rg e n t. E . An t i o x i da n t s 1 . Th e an ti o xi d a n t v it am in s i nc l ud e v it am i n A ( r et in o l a nd β - c a r o te ne ) , vi tam i n C , a n d vit am i n E . β- C a r o t en e 50 m g e v e r y o t he r day m a y p r e ven t t h e d e v elo p m e n t o f c a ta r ac t s , es pe c i a ll y i n s m ok e rs . H o we ve r , th e u se o f a n t i ox i da n t s i n p a ti e n t s w h o s mo k e i n c re a se s th e r i sk o f l u ng ca n ce r a n d s h o ul d , th e r e fo r e , n o t be r e c o mm e nd e d . V i t am i n C h a s b ee n s tu d ie d f o r th e p re v e n ti on o f c a t a ra cts . H o we ve r , i n s u f fi c i e nt da ta i n p ub li sh e d t r ia ls li m i ts t he re c om m e nd a ti on o f t h is s u pp l em en t f o r t h is pu r po s e. 2 . L u te i n, an an t io xi d a n t p i gm en t th a t f un c t i on s to f il t e r a nd p ro t ec t t he v is u al a p p ar a tu s a n d i ts v as c u la r s u p pl y, m a y b e b en e fic i al fo r im p ro v e m e n t i n v i s io n i n p a t ie n ts wi t h d r y a ge - r ela t e d m a c u l a r d eg e ne r at io n an d p r e v e nt io n o f c a ta r a c t s .
H o we ve r , m o re da t a b y wa y o f l a r ge r an d om i zed c on t r ol l ed t ri al s a r e n ec e ss a r y t o a ss e ss s a fe t y an d e f fi c ac y o f t h is s u pp le m e n t . 3 . P at i en ts wi t h m o de r a te a nd ad v a nc e d a ge - r el at e d m ac ul a r d e ge n er a ti on ( A R MD ) h a ve s h o wn a re du c ti on in t he p ro g re ss i on of th e d i s e as e a n d i ts a s s oc i ate d v is i on l o ss wi t h a n ti o xi d a nt s p lu s z in c , as we l l a s a c om b in a ti on o f t he f ol lo wi n g s u pp l em en ts : v i ta m i n C 5 0 0 m g, v i t am in E 4 0 0 IU , β - c ar o t en e 1 5 m g, z i nc o xi d e 8 0 m g , a nd c o p pe r 2 m g . Oc u v i te P r es e r Vi s i on , a f or m u la ti o n o f t h e a bo v e an t i o xi d an t s , zi n c , a nd c o p pe r , i s a d ie t a r y s u pp l em en t c u r re n tl y u n de r pa t en t b as e d o n t h e p r o m i si ng r es ul ts o f t he N a t i on a l E y e In s ti t ut e ' s (N E I ' s ) la n dm ar k Ag e - Re la t e d E y e D i s ea se S tu d y ( A R E D S ) . S t u di es of p at ie n ts wi t h m i ld or bo r d e rl in e A R MD h a v e n o t s h o wn be n ef i t f r om an t ioxi d a n t p lu s zi nc su p pl em e n t at i on . Th e re f o re , t h is f o r m u l at io n s h ou ld be r ec o m me n de d on l y t o p a t i e n t s w h o a re no n sm o ke r s ( o wi n g t o an in c re as e d r is k o f l un g c a nc e r ) w i t h a d ia g no s i s o f mo d e ra t e o r a dva n c e d AR M D . F . C o n ta c t L e ns e s 1 . T yp e s o f c o n ta c t l e ns e s ( a ) H a r d c o nt a c t l e ns es we r e t h e f i rs t “o r ig i na l ” c o nt ac t le ns , wh ic h we r e m ad e o f p o l ym e t h y lm et h ac r y l at e ( P M MA ) . B e c au se of t he h y d r o ph o bi c n a tu r e o f PM MA , t h e p e r m e ab i li t y o f o xy g e n is l im i te d , t hu s re st r ic t in g t h e o nc e -c om m o n u s e o f h a r d c o nt ac t le ns es . ( 1 ) A sp e ct a cl e bl u r , t he i na bi l it y t o s ee we l l wi th g la ss es af t e r r em o v al o f t he c o nt ac t le ns , m a y oc c u r wi t h t h e u s e of ha r d l e ns e s . Th e sm al l d i am et e r of t h e le n s m a y al s o c o n t ri bu t e t o l os s o f t h e l en s f r om th e ey e . ( 2 ) C a re o f h ar d c o nt ac t l e ns es in cl u de s c l e an in g b e t we e n t h e f in g er t ip s , s o ak in g , a n d we t ti n g wi t h e ac h r em o v a l o f t h e l en s f r om the e ye . F u r th e rm o re , c a re m us t b e t a ke n to a v oi d s c r a tc hi ng a nd c h ip p in g t h e su r f ac e o f th e c on t ac t l e ns . b . R i g id ga s - pe r m ea b le ( R G P ) l e ns e s i nf us e o xy g e n pe r m e a bi li t y o f s o f t c on t ac t l e ns es wi t h th e f e at u r es o f t he ha r d c on t ac t l en s es . R G P le ns es a re ge ne ra l l y t h ic ke r th a n s of t l e ns es , b u t m o re o xyg e n is de li v e r e d t o t h e c or n ea b y the s e a g e nt s. ( 1 ) Th e R G P le ns es a re a v a i la b le in da il y- a nd ext e n d e d - we a r ve r s i on s , a p p ro v e d f o r up to 7 d a y s o f we a r . ( 2 ) C a re o f t he R G P le ns i nc l ud es c l ea n in g t h e l en s i n th e p al m o f t h e h and wi t h a s u r fa ce - ac t i v e c l e an i ng p r o du c t a nd an en zy m a tic p ro d uc t . Th e le ns s h oul d th e n b e s o ak ed f or a m in im um of 4 h r i n a c on d it i on in g s ol u t io n b e fo r e r e in se r t io n . c . S o ft l en s es ar e m o re c om f o rt a bl e a n d e as ie r to r em o v e th an o th e r c ont a c t l e ns es , h o we v e r , t he v is u a l i m p r o vem en t no t ed m a y no t be as s ig n if ic a nt a s t h at wh i c h is s e en wi t h R G P o r h ar d l e ns es . So f t le ns e s s h ou l d n o t be w o r n w he n a p p l yi n g t o p i c a l o p ht ha l m ic p r od u c ts , e xc e p t t h os e p r o du c t s s pe c i f ic all y f o r m u l at e d f o r s u c h us e ( e . g ., r e we t t in g s ol u ti on ). ( 1 ) E xt e n d ed - we a r s o f t c o n t ac t l en s e s a r e a pp r o ve d fo r 7 d a ys o f c o n ti n uou s we a r . H o we ve r , a r el a ti v e l y new p r o d u ct , Fo c u s Ni gh t an d D a y , i s a pp r o v e d f o r c o nt i nu o us 3 0 d a y u s e , th o ug h n o t a ll p at i en ts wi l l b e a b le to t o l er a t e t he le ns pl ac em e n t fo r 3 0 d a ys . P.619
( 2 ) D ai l y - we a r s o f t c on t ac t le ns es a re de s i gn e d to b e wo r n f o r 1 d a y , up to 3 m o nt hs , de p en di n g o n t he l en s c h o se n . B ec a us e t h e l e ns es wi l l b e d is c a rd e d wi t hi n a sh o r t p e ri od o f t im e, an e n z y m at ic s o lu t io n i s ge n e ra l l y n o t n ec es sa r y fo r t hi s t yp e o f le ns , bu t g e ne r al c l ean i ng an d di s i nf e c t i ng eac h ti m e th e y a re r em o v ed f r om th e e ye s i s a d v is a bl e . S le e pin g in th es e l e ns es i s n o t r e c o m m en d ed . 2 . S o lu t i on i ng r e d ie n t s a r e ge ne r a ll y sp ec i fi c t o t h e t y pe of co n ta ct le ns c h os en ( e . g ., so f t , h ar d , o r R P G) . Th e r e fo r e , t he pa t ie n t s h ou l d e ns ur e th e p r od uc t s e le c t e d i s i n a cc o rd a nc e wi t h t he t y p e of le ns wo r n . a . C l ea n in g so l u ti o n s ac t to r em o ve r es i du e (e .g . , de b ri s , oi ls ) f ro m t h e c o nt ac t l e ns b y n o ni o ni c o r a m ph o t e ri c su r f ac ta n ts . If not c le an e d r e gu la r l y , th e re s id u e wi l l b u il d a n d h a rd e n, c r e at in g an oc ul a r i r r it a nt , a n d p os s i b l y a n o p ht h al m i c in f ec t io n . A h o m e m a d e c l e an in g s ol ut i o n o f b ak in g s od a a n d d i s t i ll ed wa t e r m a y be us e d , b u t i s n o t t ypi c a ll y r ec o m m en de d o wi n g t o t he in c re as ed r i s k o f o c u la r in f ec t io n a n d d i f fi cu l t y i n re m o v i n g t he a g en t fr om t he le ns . b . S o ak i ng s ol u t io n s a re us e d t o p r o v id e a n a sep t ic en v i r o nm en t f o r th e l e ns on ce r e m o ved f ro m t he e y e a nd m a y a ls o a id in r em o va l of r es id u al c o nt am i nan t on t he l e ns no t re m o v e d d u r in g c l ea ni n g. S oa k i n g s ol ut io n s g en e ra l l y h a v e a hi gh e r c o nc en t r at i on of p re s e r v a t i v e th an we t t i ng ag e nts , bu t t h e l en s s ho ul d b e t h o ro u gh l y r i n se d b e fo r e i ns e rt i on . c . We t t i ng so l u t io n s a re a pp li e d d i re c t l y t o t he le n s b ef o r e i ns e rt io n i n to t h e e y e . Th e f u nc t io n o f t h e we t t in g s o lu t io n i s t o t r an s i t ion t he le ns s u r f ac e f r om h yd r o ph o bi c t o h y d r op h ili c , p r o v id e l u br ic a ti o n, an d en h an ce fi n ge r ti p a d he s io n t o a l lo w f o r e as ie r i ns e r ti o n. W ett i ng s o lu t io ns a re no t ne c e ss a r y fo r in se r t ion i f t he p a t ie n t h as s ig n if ic a nt t ea r i ng im m e di a te l y a ft e r i n s e rt i on of th e l e ns . Sa liva s ho u ld n o t b e u s e d i n p l ac e o f a we t t i n g s ol u ti on be c au s e o f t h e p ot e nt i al fo r in f ec t io n . d . M u l t i pu r p os e p ro d u ct s a re ge n e ra ll y a s o lu t io n c om p os ed o f a c le a nin g s o lu t io n , s o ak in g s ol u ti o n, an d wet t i ng s o lu t io n f o r e as e o f u se wi t h c o nt ac t le ns es . H o we v e r , a m u l ti p ur p os e p r od uc t m a y no t be as e f f ic ac io us in t he re m o v a l o f th e re s id u e o r p r o vi di n g a de q ua t e l ub r ic a ti o n as t he us e o f t h e th r e e i nd i v i du al ag e nt s . e . R ew e t ti n g s o lu t i on s m a y be us e d t o cl e an and m o is t en t he s u r fa ce of t h e c o nt ac t le ns wh i l e t he len s i s s ti ll in t he e y e. f . C o n di t i o ni n g s o lu t i on is es s e n ti a ll y a n e nh anc e d we t t i n g so l ut io n , p r ov i d i ng i m p ro ve d c om fo r t a n d w e t t ab i li t y of t he le ns . G . I n s t il l a ti o n o f e ye m e d i ca t i o n ( Fi g u re 29 . 1 ) 1 . W as h h an ds . 2 . S ha ke s u s p e ns io ns to e v e n l y d is t r ib u te in g re d ie n ts . 3 . H ol d th e l o we r e y e l id d o wn t o f o rm a p ou c h be t we e n t he l i d a nd th e eye b a ll . 4 . A l wa y s ap pl y e y e d rop s b e fo r e a p pl yi ng e y e oi n tm e n t . D is pe ns e t h e r e c om m e nd e d n um be r o f d r o ps i n to th e p o uc h f o r e y e d ro ps . Ke e p t h e e ye l id s c l os ed an d a p pl y g en t le p r e s s u re to th e i n ne r c an t h us fo r 1 - 2 m in . W ai t 5- 1 0 m i n b e f o re in s t il l in g a n ot h er e y e m e d ic at i on . 5 . O i nt m e n ts s h ou ld b e a p pl i ed to t he lo we r c on ju n c t i v a l sa c a s a 1 / 2 -i nch r ib b on . To m i ni m i z e bl u r re d v is io n , a de c re as e d am o un t o f oi n tm en t m a y be ap p lie d to t he
e ye . B lu r r ed v i s i on wi l l be l es s no t ic ed b y th e p a ti e n t i f t he oi n tm en t is a dm i ni s t e r ed a t be d ti m e , i f fe as i bl e . P.620
Figure 29-1. Guidelines for instilling eye medication. [Modified with permission from Smeltzer SC, Bare BG. Brunner & Suddarth's Textbook of Medical-Surgical Nursing, 10th ed. Philadelphia: Lippincott Williams & Wilkins, 2004.]
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STUDY QUESTIONS D i r e c t i on s fo r q ue s t io ns 1 - 3 : Th e qu es t io ns and i nc om pl e te s t a te m e n ts i n t h is s ec t io n c a n b e c o r r ec t l y a n s we r e d o r c om pl e te d b y o n e o r m o re of t he s u g g es te d a n s we r s . C h oo s e th e a ns we r , A- E . 1 . W hi c h o f th e fo l l ow in g n on p r e sc r i p ti o n p r od u c t s i s a p p ro ve d b y t h e U . S . F o o d a n d D ru g Ad m i n ist r a t i o n ( F D A) f o r t r e a tme n t o f i mp a c te d c e r um en ? I . o l i ve o i l I I . ca r b am i de p e ro x i de I I I . is o p ro p yl a l c o h ol 95 % i n a n h yd r o u s g l yc e r i n A i f I a n d I I a r e c or r ec t B i f I, I I, a nd I II a re c o r re c t C i f II o nl y i s c o rr ec t
D i f II I on l y i s c o r r ec t E i f I o n l y i s c o r re c t V i e w A n s we r 1 . T h e a n sw e r i s C [ se e] . 2 . W h ic h o f t h e f o l low i n g o t i c c o n d it i o ns ca n be t r ea te d w i t h a no n p r es c r ip t io n a ge n t ? I . ve r t i g o I I . t in n i t us I I I . e x t e rn a l o t i t is I V . w a t e r -c l og g e d e a r A i f I , I I, a nd I II a re c o r re c t B i f II I an d I V a re c o r r ec t C i f I a n d I V a r e c o r re c t D i f I a n d I I a r e c or r ec t E i f IV o nl y i s c o rr e c t V i e w A n s we r 2 . T h e a n sw e r i s E [s e ea n d] . 3 . W h ic h o f t h e f o l low i n g c o n d it i o ns is a pp r o p r iat e f o r th e us e o f is o p r op yl a l c o h o l 9 5 % i n a n h yd r o u s g l yc e r i n ? I . t r e at m en t o f i m pa c ted c e r um e n I I . t r ea t me n t of w a t e r -c lo g g e d e a rs I I I . p re ve n t i on o f e x te r na l o t it i s I V . t r ea t m en t o f e x te r na l o t it i s A i f I a n d I I a r e c or r ec t B i f II a nd I II a re c o r re c t C i f II I an d I V a re c o r r ec t D i f II o nl y i s c o rr ec t E i f II I on l y i s c o r r ec t V i e w A n s we r 3 . T h e a n sw e r i s D [ se e] . D i r e c ti o ns f o r qu e s ti o ns 4 -5 : E ac h o f t h e q u es ti o ns , s ta t em en ts , or in co m pl et e s t at em en t s i n t hi s s ec ti o n c an be c o r r ec t l y a n s we r e d o r c om pl e te d b y o n e o f th e s ug g es te d a n s we r s o r p h r as es . Ch oo s e t he b e s t a ns we r . 4 . Al l o f t he f ol l ow i ng ar e t r u e re g a r di n g c a r bam i d e p e r ox i de ex c ep t w h i c h one? ( A ) C a r ba m i d e p e ro xi d e s o f te ns ea r wa x b y t h e f oa m in g a c t i on p ro du c ed wh e n o xyg e n i s re l ea s e d . ( B ) C a r ba m i d e p e ro xi d e i s s a fe fo r ph a rm ac is t rec om m e n da t io n i n p a ti e nts ag e 6 ye a r s a n d o ld e r . ( C ) A p p ro p ri a te d os in g fo r c a r ba m i d e p e ro xi d e is 5 - 1 0 d ro p s in t he ea r 2 ti m es d a il y . ( D ) C a r b am i d e p e ro xi d e s h ou l d b e us e d f o r a m axi m u m o f 4 d a y s u nl es s o t h e r wi s e d i r ec t ed . V i e w A n s we r 4 . T h e a n sw e r i s B [ se e] . 5 . Al l o f th e f o ll ow i ng a r e t r u e r e g a r d in g ex t e r na l o t i t is e xc e p t w h i ch o ne ? ( A ) I ni t ia l tr e at m e n t f o r ext e r n a l o ti t is i s a n o r al an t i bi o ti c a nd c o r ti c o st e r oi d . ( B ) S ym p to m s o f e xt e r n al o ti t is i nc l ud e o t ic i t c h ing , p re s s u re an d f u ll n es s i n th e e a r , p a in , an d o t ic d is c h a r ge .
( C ) Me c h a n ic al t ra um a to t he ea r wi t h c o tt o n -t i pp e d a p pl ic a to rs c a n c on tr i b ut e to i n c re as ed s u s c ep t ib i li t y to e xt e r n a l o ti t is . ( D ) E xt e r n a l ot i ti s is al s o r e f e rr e d t o a s s wi m m e r 's ea r . V i e w A n s we r 5 . T h e a n sw e r i s A [ se ea n d] .P . 62 2
D i r e c t i on s fo r q ue s t io n 6 : Th e q u es ti o n i n t hi s se c ti o n ca n b e c o r re c tl y an s we r e d b y o n e o r m o re of t he s u g g es te d a ns we r s . C ho os e th e a ns we r , A- E . 6 . W hi c h o f th e fo l l ow in g i s a n a p p ro p r i a te cou n s el i n g t i p f o r ad m i nis t r a t i on o f o t i c d ro p s? I . P u ll t he ea r l o be u p an d b ac k to s t ra i gh t e n th e ea r c an a l f o r ch i ld r en . I I . P ul l t he ea r l o be dow n a n d b ac k to s t ra i g ht en t h e e a r c a na l fo r a du lt s . I I I . Fi l l t h e o t i c s yr i n g e w i t h h o t w at e r . I V . I f c o t t on is u se d to r e t a i n m ed i c at i o n i n the e a r , i t s h o ul d n o t be le f t i n t h e e a r f o r l o n ge r t ha n 1 h r. A i f I I I on l y i s c o r r ec t B i f I V o n l y i s c o r re c t C i f I a n d I I a r e c or r ec t D i f I, I I, a nd I V a r e c o r re c t E i f II I a n d I V a re c o r r ec t V i e w A n s we r 6 . T h e a n sw e r i s B [ se e] . D i r e c ti o ns f o r qu e s ti o ns 7 -1 7 : Ea c h o f t he qu es t io ns , s t at em e n ts , or in co m pl et e s t at em e nt s i n t h is s ec t io n c an b e c o r re c tl y a ns we r e d o r c om p le t ed b y on e o f th e s ug g es t ed an s we r s o r p h r as es . C h o os e th e b e st an s we r . 7 . Al l o f t he f ol l ow i ng ar e t r u e re g a r di n g o p h tha l m ic f o rm u l at i o ns ex ce p t w h ic h one? ( A ) V e hi c l es en h an c e c on t ac t ti m e of t he op h th alm ic p ro d uc t . ( B ) A n ti o xi d a n ts p r e v e nt p r o du c t d et e ri o r at i on . ( C ) W ett i ng ag e nt s r e duc e s u r fa c e te ns i on of t he l e ns . ( D ) To n i c i t y ad j us te r s a re us e d t o m ai n ta in a p H b e t we e n 6 . 0 a nd 8 .0 . V i e w A n s we r 7 . T h e a n sw e r i s D [ se e] . 8 . W h ic h o f t h e f o l low i n g i s a p p r o p r ia t e t r e a tm e nt o f d i ag n os e d c o r ne a l ed e m a? ( A ) h yp e ro s m o ti c a ge n t ( B ) va s oc on s t r ic t o r ( C ) a n ti hi s ta m i ne ( D ) a r ti f ic ia l te a rs V i e w A n s we r 8 . T h e a n sw e r i s A [ se e] . 9 . W h ic h o f t h e f o l low i n g i s a l so k n ow n a s “ p i nk e ye ” ? ( A ) a ll e rg ic c o nj u nc ti v i t is ( B ) b ac t er i al c o nj u nc ti v i ti s ( C ) vi r a l c on ju nc t i v i ti s ( D ) e n vi ro nm e nt a l c o n jun c ti v i t is V i e w A n s we r 9 . T h e a n sw e r i s C [ se e] . 1 0. Al l o f t h e f ol l ow i ng a re a n t i ox i d an t s u s ed f o r th e t r ea t m en t an d /o r p r eve n t i o n of o ph t h al m ic d i s o r de r s e x c ep t
( A ) vi t am in D . ( B ) β - ca r o te n e. ( C ) vi t am i n C . ( D ) l u te in . V i e w A n s we r 1 0 . T he a nsw e r i s A [ se e] . 1 1. W hi c h o f t he f o ll ow i n g s o l u t io n s m a y b e u s e d t o c le a n a n d m oi s t en t he s u r fa c e o f th e c o n ta ct l e ns w h i le t he le n s i s s t i ll i n t h e e ye ? ( A ) cl e an i ng s o lu t io n ( B ) we t t i n g s o l ut i on ( C ) s oa k i n g s o l ut i on ( D ) r e we t t i ng s o lu t io n V i e w A n s we r 1 1 . T he a nsw e r i s D [ se e] . 1 2. W hi c h o f t he f o ll ow i n g i s t r u e r e g a r d in g op h t ha l m ic an t i h i st a mi n es ? ( A ) P h en i ra m i n e a nd te t ra h y d r o z ol i ne a re th e o n ly t wo n o n p re s c r ip t io n o ph t h al m i c a n t ih is t am in es a v ai l ab le . ( B ) O p h th a lm ic a n ti h is tam i ne s a r e a v a il ab l e o nl y i n c om b in a ti on wi t h na p ha z o l in e . ( C ) O p h t ha lm ic an t ih is t am i ne s m a y c au se bu r ni ng , s t i ng in g , d r y e y es , o r m yd r i as is . ( D ) O p h t ha lm ic an t ih is t am i ne s m a y p r od uc e re b ou n d c on g es ti o n i f u se d in e xc e ss o r f o r e xt e n de d d u r at i on s . V i e w A n s we r 1 2 . T he a nsw e r i s C [ se e] . 1 3. W hi c h o f t he f o ll ow i n g i s t h e o n l y a s t r i n g en t us e d i n n o n p re s c r ip t i on o ph t ha l m ic a ge n ts t ha t is r e c o mm e nd e d b y t h e U . S . F o od a nd D r u g Ad m i n i s t r a ti o n (F D A) ? ( A ) e de t ic ac id ( B ) b en z a lk o ni um c h lo r ide ( C ) zi n c s u l fa t e ( D ) p o vi do ne V i e w A n s we r 1 3 . T he a nsw e r i s C [ se e] . P . 62 3
1 4 . Th e d e f in i t i on o f a s u r f a c ta n t ( a n i n g r ed i en t i n to o t hp a s te ) c a n be s t be d e s c ri b e d b y w h i c h o f th e f o ll ow i ng s ta t e me n ts ? ( A ) I t p r e v e nt s d r y i ng of t h e p r e pa r at i on . ( B ) I t re m o v e s d eb r is b y i t s d e te r ge n t a c t io n an d c a us es fo am i ng , wh ic h is us ua l l y d e si r ed b y th e p a ti e nt . ( C ) I t ph y s ic al l y re m o v es p l aq ue a nd de b ri s . ( D ) I t de t er m i n es th e t e xt u r e , d is pe r s i v e n ess , and a pp e ar a nc e o f t h e p r od u ct . ( E ) I t a d ds fl a v o r t o t h e p r e pa r a ti o n, wh i ch m a k es i t m o r e a pp e al i ng to the p at i en t . V i e w A n s we r 1 4 . T he a nsw e r i s B [ se e] . 1 5. A 1 6 -ye a r - o l d g i r l s to p s b y a p h a r ma c y o n h e r w a y h o m e f ro m s c h oo l . Sh e sa ys t o t h e p ha r ma c i st , “ I ha ve b e e n u s in g P r ox i ge l dai l y t o b l e a ch m y t e e t h in p r e pa r a t io n f o r m y s p r i n g f o r m a l. H ow e ve r , m y t e e t h a re b ec om i n g ve r y s e n si t i ve .” E ac h o f t h e f o l l ow i ng s t a t em e n ts is ad vi c e tha t t h e p ha r m ac i s t m i ght s u gg e s t e xc e p t w h i ch o n e ? ( A ) Th e r e i s a po s s ib il i t y t h a t y o u m a y da m a ge t he g in gi va l ti ss ue an d t o ot h pu l p. ( B ) O xi d i z i n g ag e nt s m ay h a v e t he po t en t ia l f o r m u ta t in g o r en h an ci ng t he c a rc i no ge n ic e f f ec ts of ot h e r a g en ts ( e. g . , t ob ac c o ) .
( C ) B l ea c h i ng te e th is bes t do ne un d e r d en t al s u pe r vi s io n . ( D ) P r o xi g e l i s a n a nt is ep t ic t ha t c on t ai ns z i nc an d s h ou l d n ot be us ed f or c os m e ti c wh i t e n i ng of th e te e th . ( E ) Th e m o s t c o m m on ing r e di e nt in p ro d uc ts re spo n si bl e fo r te e th wh i t en in g is 1 0 % c a r ba m i de pe r o xi d e , wh ic h c an ca us e s en s i t i v i t y . V i e w A n s we r 1 5 . T he a nsw e r i s D [ se e] . 1 6. Al l o f t h e f ol l ow i ng p r od u c ts m a y b e r e c om m en d e d by a p h a r m a c is t f o r t h e tr e a t m en t o f c an k e r s o re s ex c ep t ( A ) b en z o c a i ne . ( B ) Z il ac t in - B . ( C ) B a y e r as pi r in pl ac e d d i r ec tl y o n t h e o r al le si o n . ( D ) A n be s ol . ( E ) O r a je l . V i e w A n s we r 1 6 . T he a nsw e r i s C [ se e] . 1 7. T he U. S . F oo d an d D r ug Ad m i n i s t r a t io n (F D A) h a s ap p r o ve d w hi c h i n g re d i en t f o r p r o t ec t i on ag a i ns t p a i n fu l se n si t i vi t y o f t h e t e et h ca u se d b y c o l d , h e a t, ac i d s, sw ee t s, o r c o n ta c t ? ( A ) d ic al c i um ph os p ha t e ( B ) s od iu m l au r y l s u lf a te ( C ) 5 % p o ta s s iu m n it r a te ( D ) zi n c c h l o ri de ( E ) c al ci um c a rb o na t e V i e w A n s we r 1 7 . T he a nsw e r i s C [ se e] . D i r e c ti o ns f o r qu e s ti o ns 18 - 2 0 : Th e q u es t io ns an d i nc om p le te s ta t em en ts in t hi s se c ti o n c an be c o r r ec tl y a ns we r e d o r c om p le t ed b y on e o r m or e o f t h e su g ge s te d a nswe r s . C h o os e t he an s we r , A- E . 1 8 . W h i ch o f t h e f o l low in g c om p ou n ds i s/ a r e co n s i de r e d a s u s pe n di ng a ge n t ( a n i ng r e di e n t i n d e n ti fr i c e s )? I . d ic a lc i u m p ho s p ha t e I I . ka r a ya g u m I I I . m e t h yl c e l l u l o se A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 1 8 . T he a nsw e r i s D [ se e] . 1 9. C o l d-s o r e t re a t me n t m i gh t i n c l ud e w hi c h o f t he f oll ow in g i n g r ed i e nt s ? I . b en z oc a in e I I . do c os a n ol I I I . c a mp h o r A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t
V i e w A n s we r 1 9 . T he a nsw e r i s C [ se ea n d] .2 0 . P ha r m a ci s t s c an r e c o mm e nd o ve r - t he - c ou n t e r ( O TC ) d r u g t r e a tm e n t fo r w h ic h o f t h e fo l l ow i ng e a r co n d i ti o ns ? I . t r e at m en t o f a cc u mu la t e d e a rw a x I I . p re ve n t i o n o f b l o ck ed e a rs c au s ed b y a l t i t u d e ch a n ge s I I I . t re a t me n t o f w a te r - cl o g g ed ea r s A i f I o n l y i s c o r re c t B i f II I on l y i s c o r r ec t C i f I a n d I I a r e c or r ec t D i f II a nd I II a re c o r re c t E i f I, I I, an d II I ar e c o r re c t V i e w A n s we r 2 0 . T he a nsw e r i s E [s e e] . P . 62 4
ANSWERS AND EXPLANATIONS 1 . T he an sw e r is C (I I ) [s e e I . B .1 . d. ( 1 ) ]. C a r b am id e pe r o xi d e i s th e on l y F D A -a p pr o ve d ag e n t f o r c e r um e n r em o val . O l i ve o il a n d m in e ra l o i l a re us e d t o r em o ve c er um e n, b ut a r e no t F D A ap p r o v ed . Is o p ro p y l a l co h ol 9 5 % i n a nh y d r o us gl y c e ri n i s F D A ap p ro v e d fo r wa t e r -c l og ge d e a rs , bu t n o t c e r um en r em o v al . 2 . T he an sw e r is E ( I V ) [ s ee I . B. 1 .d ; I. B . 2 , 3 a n d 4 ] . P a t i en ts e xh i b it i ng s y m pt o m s of ve r ti g o, as id e fro m m o ti on s i c k ne s s , s hou l d b e r e f e r re d t o a m e di c al pr ov i d e r . Th e re is n o F D A - ap p r o ved t r ea tm e nt fo r ti nn i t us . E xt e r n a l o ti t is (s wi m m e r 's ea r ) s h ou l d b e t r ea t ed wi t h a p re sc r ip t io n o t ic an t i bi o ti c a n d c o rt ic os t e ro i d. O n l y i m pa c t e d c e r um e n a nd wa t e r -c lo g ge d e a rs m a y be t r ea t ed wi t h n o np r es c ri p ti on p rod u c t s . 3 . T he an sw e r is D (I I ) [s e e I . B .5 ] . I s op r o p y l a lc oh ol 95 % i n a n h y d ro us gl y c e ri n i s FD A a p p ro ve d o nl y f o r t r ea t m e n t o f wa t e r - c l og ge d e a rs . La be l s o n p r od uc ts o f is o pr op yl a lc oh ol 9 5% i n a n h y dr o u s g l yc e ri n s ho ul d n o t c la im t o be us ed fo r t re a tm en t o r p re v e n ti on o f e xt e r n al o ti t is ( s wi m m e r ' s e a r ) b ec au s e t h is i s a s e pa r a te di so r de r f r om wa t e r -c lo g ge d ea r s . Tr e a t m en t fo r i m p a c t e d c e r um en is c a rb am i de pe r o xi d e . 4 . T he an sw e r is B [ s ee I . B . 1. d . (1 ) ] . C a r b am id e pe r o xi d e s of te n s e a r wa x t h r o u gh it s fo a m i n g ac t io n wh e n o xy g e n i s r e l ea se d . I t i s l ab e le d f or a g es 1 2 a n d o ld e r . Th er e f o re , fo r c h il d re n < age 1 2 wi t h s us p ec t ed c e r um en im pac t io n s ho u ld be s e en b y a m e d ic al p ro v i de r . Pa t ien t s s ho ul d i n st i ll 5- 1 0 d r op s o f c ar ba m id e p e ro xi d e i nt o th e e a r 2 t im es d a il y f o r u p to 4 d a y s . 5 . T he an sw e r is A [ s ee I . B . 4. a , b an d c ]. E xt e r n a l o ti t is i s r e fe r r ed t o as s wi m m e r ' s e a r. Th o u g h p ro l on g ed e xp o s u re t o m o is tu r e i s t he t y p ic al c a u s e of e xt e r n al o ti ti s , m e c ha n ic al t ra um a , s u ch a s th e u se o f co t to n - ti pp e d a pp l ic ato r s , f in g e rs , o r s ha r p o b j e c ts in th e e a r , m a y c aus e th e e xt e r n a l ea r c a na l t o b e m o r e s u sc ep t ib l e t o d am a g e a n d m i c ro o rg a ni s m in f i lt r a ti on . P a t i en ts wi t h e xt e r n al o t it i s m a y p r es e nt wi t h ot ic i t ch in g , a s e ns at i on of pr e s s u r e o r f u l ln es s i n t he ea r , p a in , o r an ot ic di sc h ar g e. I nit i a l t r ea tm e nt is wi t h a n o t ic
a n t ib io t ic an d c o rt ic os t e ro i d , n ot an o ra l a n ti bi o tic . O r al an t ib io t ic s a r e i nd i ca t ed wh e n t h e i nf e c t io n i s u n re s po ns i v e to ot ic t re a tm e n t , t h e i nd i vid u al is i m m u no c o m p r om is e d, o r a m i d dl e e a r i nf e c t io n c oe xi s t s . 6 . T he an sw e r is B (I V ) [ s ee I . C ]. Th e e a rl o be s h ou l d b e pu l le d u p a n d b ac k t o s t rai g h te n t h e c a n al fo r ad u lt s an d d o wn a n d b ac k t o s tr a igh t e n t he c a na l i n c hi l d ren . O n l y wa r m wa t e r sh o ul d be us ed i n th e o t ic s y r i ng e , a s c ol d or h ot wa t e r m a y in duc e d i z zi n es s . I f co t t on i s u s e d i n t h e e a r t o re t ai n t h e m edi c at i on , i t m us t b e l a r ge e n o ug h t o re m o v e ea si l y a n d s h ou l d n ot be le f t i n t h e e a r fo r lo ng e r t h an 1 h r . 7 . T he an sw e r is D [ s ee I I I . B] . B u f f e rs a r e u s e d i n o p hth a lm ic p re pa r a ti o ns t o m a i n ta in a p H be t we e n 6 . 0 a n d 8 .0 . To n i c it y a dj us t e rs e n s u re t he p ro d uc t i s is o to n ic , e q ua l t o 0 . 9% - 6 0. 2 % s od i um c h lo r id e . 8 . T he an sw e r is A [ s ee I I I . D ]. O n c e d i ag no s e d b y a phy s i c i a n, co r ne a l e de m a is t re a te d wi t h h yp e r os m o t ic ag e nt s s uc h a s Mu r o s o lu t io n o r o i nt m e n t t o d r a w t h e f lu id a wa y f r o m t he co r ne a . 9 . T he an sw e r is C [ s ee I I I . D .2 ] . V i r a l co n ju nc t i v it is is m os t of t en at t r ib u ta b le to the a de n o vir us a nd i s m o re c om m o n l y k n o wn as p i nk e y e . 1 0 . Th e a n sw e r i s A [ s ee I I I. E ] . Th e a n ti o xi d a n t v i t am in s e xa m i n ed fo r th e pr e ve nt i o n a nd / o r t r ea tm e nt o f o p h th al m i c d i so r de r s i nc lu d e v i t am in A ( r e ti no l a n d β - c a r o te ne ) , v i ta m i n C , a nd vi ta m in E . L u t ei n i s a n a nt i o xi d a nt p i gm e nt th a t f u nc ti o ns to f i lt e r a n d p r ot ec t th e vis u a l a p p ar a tu s a n d i ts v as c u la r s u p pl y. Lu t ei n , is t he re f o r e, th o ug h t t o b e b e ne f ic i al fo r i m p ro ve m e n t i n v i s i o n i n p a t ie n ts wi t h d r y a ge - r ela t e d m a c u l a r d eg e ne r at io n an d p r e ve n ti on o f c a t a ra c t s . V i t am i n D is no t a n a n ti oxi d a n t v i t am in . P.625
1 1 . Th e a n sw e r i s D [ s ee I I I. F . 2] . R e we t t i n g s ol u ti on s a r e th e on l y c o nt a c t le ns s o lut i o ns th a t m a y b e u se d wh i le t he l e ns is s t il l i n t he e y e . 1 2 . Th e a n sw e r i s C [ s ee I I I. C . 4 ]. C u r r e n tl y , th e r e a re t h ree a v a il ab l e o ph t ha lm ic an t i hi st am i ne s : k e t ot i fe n , p h e ni r am in e , a nd an t a z ol i ne . P he ni r am in e an d a nt a z o l in e a r e o nl y a va il a bl e in c om b in a ti o n wi t h th e o p ht h a lm ic d ec o ng es t an t nap h a z o li ne . O ph t ha lm ic a n t ih is t am in es m a y c a us e b u rn in g , s ti n gi ng , dr y e ye s , o r m y d r ia s i s . V a s oc on s t r ic t o rs , n o t a nti h is t am in es , m a y p ro du c e r e bo un d c o ng es t io n whe n us ed in e xc e s s o r fo r e xt e n de d du r a ti o ns . 1 3 . Th e a n sw e r i s C [ s ee I I I. B ] . E d e t ic a c i d i s a n a n ti o xi d a n t a nd be n z a lk on iu m c h l o ri d e ( B A K ) i s a p r es e rv a t i v e u s ed in op h th a lm ic f o rm u l a ti on s . Z in c s ul f at e i s th e on l y F D A - re c o m m en de d a s t ri n ge n t. P o v id o ne is a v e h ic l e us e d i n o ph t ha lm i c f or m u l at i on s. 1 4 . Th e a n sw e r i s B [ s ee I I . B. 2 .d . ( 1 )] .
S o d iu m l au r y l s u lf a te is u s ed f re q ue n tl y as a s u rfa c ta n t i n m os t d en t if r ic es . It s d e t e rg en t ac ti o n a id s i n th e r em o v al of de b ri s , a nd t he f oa m i ng is us ua ll y d e s i r ed b y t h e p a ti e nt . Th e re is no e v i d e nc e t ha t s u r fa c t a nts po s s es s a n ti c a r ie s ac t iv i t y o r d e c re as e p e ri o do n ta l d is e a s e . Th e F D A c o ns id e rs su r f ac ta n ts an i n ac ti v e i n gr e di e nt i n de n ti f ri c e s . 1 5 . Th e a n sw e r i s D [ s ee I I . B. 2 .d . ( 4 )] . Te e t h - wh i t e ni ng ag e nt s u s ua ll y c on t ai n 1 0 % c a rb a m i d e p er o xi d e , wh i ch is a wh i te c r ys t al th a t r e ac ts wi t h wa t e r t o re l ea s e h y d ro ge n p e r o xi d e a nd , th e r ef o re , l i be r at e s f r e e o xi d e s . C o s m et ic age n ts c a n a l te r th e n o rm al f l o ra o r c a us e ti s s ue ir r it a t io n , g i ng i vi ti s , a nd te e th s e ns i ti v i t y . A nt is e pt ic s h a ve b e en us ed as c os m e t ic wh i t e n e rs ( e . g ., G l y - O xi d e , P r o xi g el ) al o ng wi t h c a lc iu m p ero xi d e ( e . g. , C al p ro x i n Ep i S m i le ) . E p i S m i le al s o c o n ta in s s o d iu m m on o fl u or o ph os p ha t e . 1 6 . Th e a n sw e r i s C [ s ee I I . C. 1 .c . ( 2) ] . L o ca l a n es th e ti c s c a n p ro v i d e re li e f o f c an k e r s o re p ai n . Th e m o s t c o m m on l oc al a n es t he t ic s f ou n d i n O TC p r o du ct s i nc lu d e b en z o c ai n e a nd bu t ac ai ne . So m e e xa m p l es a re A nb es ol , Zi l ac t in - B , a nd O r a je l . A s p i r in s h ou l d n ot be r et a in e d i n t h e m o ut h b e fo r e s wa l l o wi n g o r pl ac e d i n t he a re a o f t h e o r a l le si o ns be c a us e o f th e h i gh r is k f o r c h em ic a l b ur n wi t h ne c ro s i s . 1 7 . Th e a n sw e r i s C [ s ee I I . B. 2 .d . ( 5 )] . D e s en si t i z in g a g en ts s ho u ld no t be ab r as i v e o r u s ed on a c hr o ni c b as is u n le s s d i r ec t ed b y a de n ti s t. The p r od uc ts ap p r o v ed b y th e A D A i nc l ud e t h e i ng r ed i en t s 5 % p o t ass i um n i t ra t e, 1 0% s t r o n ti um c h lo r id e , a nd dib a si c s o d iu m ci t r a te 2% i n Pl u r on ic gel. 1 8 . Th e a n sw e r i s D ( I I , I I I ) [s ee I I. B . 2. d . (1 ) . D ] . S u s pe n di ng ag e nt s a r e pr o d uc ts t ha t a d d t hi ck nes s t o t h e d en t i fr ic es . E xa m p le s a r e t r a g ac an t h, k a r a y a g um , a n d m et h ylc e ll ul o s e . Di ca l c i um ph os p ha t e is c a t eg o r i z ed as a n ab r as i v e p r od uc t . 1 9 . Th e a n sw e r i s C ( I , II ) [ s e e I I . C .2 . a a nd b ]. C o l d -s o re t re a tm en t in v ol v e s k ee p in g t h e l es io n m o i s t wi t h em o ll ie n t c re am s , p e t r ol a tu m , o r p ro t ec t an ts . Lo c a l a ne s th e ti c s (e . g. , b en zo c a in e , d y c lo n in e, s al ic yl a l co h ol ) m a y be us ed . In a d di t io n , d oc os an o l 1 0% c re am ( A br e v a ) a n d t et r a c a i ne 2% g e l ( V i r ac ti n ) a r e a v a il a bl e wi t h ou t a p re sc r ip t io n f o r th e tr e at m en t o f c ol d s o r es . To p i c al c o un t e ri r r it a nt s (e . g . , c a m p h o r) an d c a us ti c s o r e s c ha r ot ic ag e n ts ( e . g ., p h e no l, m e n th o l, s i l v e r ni t r a te ) ar e n o t r e c o m m end e d b ec a us e t he y m a y fur t h e r i r r i ta t e t h e t is s u e. C o ld s o r e s a re us u al l y s e lf - li m it i n g a nd he al wi t h i n 1 0- 14 d a ys wi t h o u t s c a r r in g . 2 0 . Th e a n sw e r i s E ( I , II , I I I) [s e e I . B ]. O TC d r u g t r ea tm e nt c a n b e r ec om m e nd e d f o r a ll o f t he s e ea r c o nd i ti on s .
30 OTC Dermatological Agents L a r r y N . S w a n so n
I. PEDICULOSIS AND PEDICULICIDES A. I n t r o d u c t io n . P e di c u lo s is i s a s ki n i n fe s ta t io n p r o du ce d b y b l oo d s uc ki n g l ic e. Li c e a re s m a l l , f la t , wi ng l es s in s ec ts wi t h s tu b b y a n te n na e an d t h r e e p ai rs o f l eg s t ha t en d in s h a rp , c u r v ed c l a ws . Th r ee t yp e s o f l i c e i n f e s t h um a ns . 1 . P ed ic u lu s h u m an us c ap i t is (i . e. , th e h e ad l o us e ) 2 . P ed ic u lu s h u m an us c or p o r is (i . e. , th e b o d y l o us e ) 3 . P ht h i ru s p ub is ( i. e ., t he p ub ic , o r c r a b, lo us e ) B . L i f e c yc l e s . Th e l ic e t h a t i nf e s t hu m a ns pa ss t h r o ug h s im il a r l if e c yc les . 1 . L oc a t io n . A l l l ic e n eed h um an wa r m th t o su r v iv e . a . H ea d an d p u b ic li c e s p en d t h ei r en t ir e c yc le o n th e s ki n o f th e h um an h o st . b . B o d y l i c e l i v e i n c lo t hi n g , c o m i n g t o t h e s k in s u r f ac e o n l y t o fe e d. 2 . D e ve l op m en t a . E ac h t y p e o f l o us e d ev e l o ps f ro m e g gs ( ni t s ) t h a t i nc ub a te f or a bo u t 1 we e k . W hen t h e s m al l , gr a y - wh i t e , te a r -s h ap ed eg g s h at c h, th e n y m p hs a p p ea r . b . I n a bo u t 3 we e k s , t h e n ym p h s m a tu r e ; t he n t he f em al es st a r t t o l a y e g gs . c . E ac h t y p e o f l ou s e s u rv i v e s ab o u t 1 m on t h a s a m a tu r e a d u lt . D u ri ng t h is ti m e, th e fe m a le he ad l ou s e c a n p r od uc e 3 - 6 e g gs a d a y . 3 . E g g d ep o s it a . B o d y l i c e d e po s i t t h eir e g gs o n f i be r s o f c lo t hin g , p a r ti c u l ar l y in t he s e am s. Th es e l ic e c an s u r v i v e wi t h o ut f oo d u p t o 1 0 d a ys , a nd th e e g gs m a y r em ai n v ia b le fo r abo u t 1 m o n th . Da i l y c lo t hin g c h an g es a n d b oi li n g o r i r o ni n g i nf es t ed c l o th in g c a n e r ad ic a te bo d y l i c e . b . H e ad an d p u b ic l ic e d e p os it th e i r e gg s o n h air s t ra n ds , a bo u t 1 / 4 i nc h f r o m t he s k in . Ad u lt he ad l ic e c a n s u r vi ve o n i nan i m a t e o bj ec ts f or a bo u t 2 0 h r ; he a d li c e n it s m a y s ur v i v e u p t o 1 0 da y s o f f t he b od y . C . I n ci d e nc e . Th e in c i d en c e o f l ic e i n fe st a ti o ns in c r ea s e s e ac h yea r . 1 . Mo r e t ha n 1 0 m il l io n c a s es o f he a d li c e oc c u r e a c h ye a r i n t he U ni t ed S t a t es . 2 . Th e bu lk of th es e c as e s o c c u r b e t we e n S e pt em b e r a nd N o v em be r , wh e n s t ud e nt s a r e b ac k i n s c ho o l . 3 . I n o ut b re a k s o f h e ad li c e, 70 % o f c as es oc c u r i n c h il d re n y ou n ge r th a n 1 2 ye a rs . 4 . I nf es t at i on s t e nd to be m o r e c om m o n i n g i rl s , p r e s u m a bl y b ec a us e o f t h e ir g re a te r te n de nc y t o s ha r e g r o om i n g i te m s . 5 . U nl ik e th e o t he r t wo fo r m s of li c e , bo d y li ce a re as s o ci a t ed wi t h i m p r ope r h yg i e ne an d a r e o f te n p re s en t i n h om e le ss pe op le . Th i s in f es t at i on is ra re i n th e Un i te d S ta t es , e s pe c ia ll y wh e n p eo pl e fo ll ow p r o p e r h y gi en e ro u ti n es .
D . M ed i ca l p ro b l em s 1 . B ot h a d ul t a n d n y m ph l ic e a r e b lo o d s uc k i ng ; th e y f ee d o n h u m a ns b y p i e rc in g th e s k i n a nd in t ro d uc i ng a s m al l a m o u nt o f s a li v a ( wh i c h co n ta in s a n an t i co a gu l a n t) in t o th e fe e di n g a re a . Al l l ic e t y p e s f e ed on bl o od fo r a b o ut 30 - 45 m i n e v e r y 3- 6 h r . a . Th e at t ac hm en t of li c e t o th e b o d y c au s e s a n er yt h e m a t o us pa p u le , wh i c h m a y i t ch . b . Th e fe m a l e l ou s e p rod u c e s a s t ic k y c e me n t -l ik e se c r e ti o n t h at ho l ds th e e g gs in pl ac e o n t h e h ai r s ha f t s o s ec u re l y th a t o rd i na r y s ha m p o oi ng do es n o t re m o v e it . P.627
2 . N ei t he r he a d n o r c ra b l ic e t r a nsm i t i n fe ct i on s , b u t b o d y l ic e tr a ns m i t t yp h u s , r e l a ps i n g f e ve r, a nd t r e nc h fe ve r . 3 . Li ce an d h um a ns ha v e a t ru e pa r a si t i c r e la t i on s h i p ; li c e de p en d o n the h u m a n h os t fo r s h el t er , fo o d , a nd r ep r od uc t i v e s uc c e s s . O nc e h a tc he d , n ym p hs m us t h a v e ac c es s t o t he hu m a n h os t wi t hi n th e f i rs t 12 - to 24 - h r p e r io d , i f t h e y a r e t o s u rv i v e . E . M e t h o ds o f t r a ns m iss i o n 1 . H ea d li c e a r e m o s t c om m o n l y s p r e ad b y h e a d - t o - h ea d co n t ac t wi t h an i n f es te d p e rs o n t h ro u gh h a ts , c a ps , s c a r ves , pi ll owc a s e s , co m m un al c o m bs a n d b r us he s , o r c lo t hi n g t h a t i s h un g c lo se to g et he r ( e .g . , o n a c o at r ac k ) . 2 . P u bi c l i ce a re t r a nsm i t t e d p r im a r i l y t h r o u g h s ex u a l c on t a ct , bu t a ls o t h r o ug h s ha r ed un d e rg a rm e nt s , t o we ls , or t oi le t s e a ts . a . Th e l ic e a f f ec t t e en s an d y o un g a d ul ts m o s t of te n th r o ug h s e xu a l c on t ac t . b . Li c e f r eq ue n tl y c oe xi s t wi t h o th e r s e xu a l l y t r a ns m i t t ed di se as es . c . Sc r a tc hi ng in t he ge nit a l a r e as m a y t ra ns m i t pu b ic li ce to o th e r h ai r y r e g io ns , s uc h a s t h e e y el a s h es , e y e b r o ws , s id e bu r n s , an d m us t ac he s. F . S i gn s a n d s ym p t o m s 1 . H ea d li c e a . Mo s t pa t ie n ts ha v e fewe r t h a n 1 0 l ic e . b . Th e m os t c om m o n s ign is h ea d s c r a tc h in g . c . S ki n re d n es s a r o u nd t h e na p e ( i .e . , b a ck ) of t h e ne ck an d a b o v e t h e e a r s is us ua l l y s ee n . d . Th e li c e c a n b e i de n ti fi e d b y d i re ct e xa m in a ti on us i ng wo o d en ap p li ca to r s t ic ks o r a c o m b t o p a rt th e ha i r , t he n l o ok in g a t th e ha i r t h ro u gh a m a gn i f yin g g la s s . e . Th e l ic e a p pe a r a s t iny b r o wn i s h g r a y s po t s t ha t a re of t en di f f ic ul t t o s e e . Th e s hi n y , w h i ti s h s i l ver e g g s, wh i ch ap p ea r alm os t as g r a in s o f s ug a r, a r e m o re li k e l y t o b e s e en t ha n th e l ic e . Th e ni ts a r e i n it i al l y de p os i t ed a b o ut 1/ 4 in c h f r o m t h e s c a lp on t he ha i r s h a f t, a n d t h e y m a y be co n f use d w i t h d an d r u f f o r h ai r s pr a y d r o p l e t s . Us u al l y, ha i r g r o ws a t a ra t e o f a bo u t 1 / 2 i nc h p e r m on t h , s o the d u ra t io n o f i n fe st a ti o n c a n b e a s s es s e d b as ed o n t h is in f o rm at i on .
2 . P u bi c l i ce . Th e p r im ar y s y m p to m is s c r at c h i ng i n t h e g en i ta l a r ea . 3 . B o d y l i c e . Th e m o s t c o m m o n s ym p t om s a re bi te s a n d i tc hi n g, wh i c h a re c om m o n l y s e en as v e rt ic a l e xc o r ia t io ns on th e tr un k a r e a. G . T r e a tm e n t 1 . Th e r e a r e t h r ee s te p s i n t h e t r ea t m e n t o f h ea d a n d b o d y l i c e . a . Tr e a t t h e li c e a nd ni ts wi t h a pe di c u l ic id e a g ent . b . C o nt r ol t he s y m p to m s o f i t c h in g to p re ve n t se c o n d ar y i n fe c t i on . c . C le an t he en v i r on m e nt o f p o te n ti al li c e an d n i ts . 2 . I tc h i ng . Ph a rm ac is t s s h ou l d a d v is e p at i en ts th a t e ve n a f t e r t he c a us at i v e o r g an is m a nd ni t s h a v e b e e n k i ll e d, i tc hi ng m a y p e r si st fo r se v e r al da ys . Th i s as pe c t is v e r y im por t a n t b ec au s e pa t ie n ts m a y d ec i de to us e p e di c ul ic id es e xc e s s i v ely , t h i nk in g t h at th e y h a ve b ee n i n ef f ec ti v e wh e n t h e i t ch i ng c o nt i nu es . Ex c ess i ve u se o f p e di c u li c ide s ma y r e s u l t i n e x c es s i ve d r yi n g , w h ich c an c au s e f u r t he r i tch i n g . 3 . H om e re m e di es . B ec au s e o f t h e so c i a l s ti gm a a t t ac he d to li c e i n f es ta t io n , s om e i nd i v idu a ls m a y r es o rt t o h a rm fu l ho m e r em ed ie s . E xa m p l e s o f s uc h u nc om f o r t ab l e, in e ff ec t i ve , a nd p o te n ti a ll y d an g er o us a p p ro ac h es th a t s h o ul d n o t b e u se d i nc l ud e a . S ha vi n g t he he a d a nd p u bi c a r ea b . A pp l y i ng he a t t o t h e in f es t ed a re a wi t h a ha i r d r y e r c . S oa ki ng t he he ad in ho t wa t e r fo r s e v e r al m i nut e s d . S oa ki n g t he a re a o f inf e s ta t io n wi t h g as ol in e or k e ro se n e 4 . O ve r - t h e -c o u n te r ( OTC ) p e d i c ul i c id e p r o d uc t s ar e c o ns id e re d f i rs t - li n e t r e a tm en t s a nd i n c l ud e a . P yr e t h r i n s 0. 1 7 %- 0 . 3 3 % w i t h p i pe r o n yl b u t o x i d e 2 %- 4 %. Th i s p r od uc t i s s a fe an d e f fe c ti v e fo r t h e tr e at m e n t o f h e ad a nd p u bi c l i c e. Th e c om b in a ti o n o f i ng r ed i ent s is a n e xa m p l e o f p h a rm a c ol o g ic a l s yn e r g i s m . P.628
( 1 ) P yr e t h r i n s k i ll b y dis r u p t i ng i on - t r a ns p o r t m e c ha n is m s a t th e n e rve m e m b ra n es . Th es e n a tur a l i ns e ct ic i de s a re de r i ve d f ro m a m i xt u r e of s u bs ta n c e s o bt a in ed f r om t he fl o we r s of th e c h rys a n t h e m u m p la n t . B e c au se no t a l l e gg s m ay b e k i ll e d ( i t t ak es ab o ut 4 da ys fo r th e n e r v ou s s ys t em o f th e l o us e t o de v e l o p) wi t h a si n gl e a ppl i c a t io n o f t h is a g en t or r e m o ved wi t h a ni t c om b, i t m a y b e n e c e ss a r y t o r e a pp l y t he p y r et h ri n p r o du c t wi t h i n 7 - 10 da y s o f th e f i rs t a p pl ic a ti o n (b e ca us e th e u su al ha t c h in g t i m e o f t he eg gs is 7 - 1 0 d a y s ) . ( 2 ) P i pe r o n yl b u t o x i d e e n h an c e s t he pe d ic ul ic ide e f fe c t of p y r e th r in s b y s u p p r es s in g th e ox i da ti ve d e g r ad a t io n m e ch an i s ms o f t h e l i ce . Th e r e f o re , th e l e ng t h o f t i m e t ha t t h e p y r e th r in s c o nt ac t th e l ic e i s i n c re as ed . ( 3 ) S i de e ff e c ts f ro m e ith e r ag en t ar e un c om m on . ( a ) C o n ta c t d e r ma t i t is (s e e I V ) i s t h e m o s t f r eq ue n t l y re p or t ed s i de e ff ec t .
( b ) Al l e r g i c r e ac t i o ns . B e c au s e p y r et h r in s a re d e r i v ed f ro m a pl an t ( c h r y sa n th em um ) , th e y m a y p ro d uc e h a y fe ve r (i. e . , a ll e r gi c r hi n it is ) an d a s th m a a tt ac k s in s us c ep t i bl e i nd i v i du al s . Th u s p a t ie n ts wh o ha v e k n o wn a l le r g ie s t o r a g we e d o r c h r y s a nt h em um p l an ts s ho u ld us e t h is p r o du c t wi t h c a ut i on . ( 4 ) C om m o n t ra d e n am es f o r t hi s p r od uc t in c l ud e R I D m a xi m u m s t re n gt h S h a m p o o, A -2 0 0 m a xi m um s t r en g t h S ha m p o o . ( 5 ) D i r ec t i o ns f o r u se (s h a mp o o ) ( a ) Ap p l y t h e p r o d u ct , u n d i lu t e d, t o t he d r y h a ir u n ti l i t i s e nt i r el y we t . ( b ) A ll o w t h e p r od uc t to r e m a in o n t h e h ea d f o r 1 0 mi n . ( c ) R i ns e th o r o ug h l y wi t h wa r m wa t e r . ( d ) D r y t he a re a , p r ef e r ab l y wi t h a d is po s ab le cl ot h . ( e ) C o mb ha i r in th e p r ev i o u s l y i nf es t ed a re a w i th a f in e - to o t he d co m b to r e m o ve d ea d l ic e a n d e gg s . ( f ) D o no t e xc e e d t wo app l ic a ti on s wi t hi n 2 4 h r . I t m a y be ne c e s s a r y to r e a pp l y t he s h am po o i n 7 - 1 0 d a y s [ se e I . G . 4 .a . (1) ] . b . P e r me t h r in ( N i x) i s a p y r e t h ro i d ( i .e . , a s y n t het i c v er s i o n o f a p yr et h ri n) . I t is in di c at e d f o r t he t rea t m e n t o f h e ad l ic e o n l y. ( 1 ) M e c ha n is m o f ac t i on . P e rm e th r in ha s a s i m il a r me c ha n i sm o f a c ti on a s t he p yr e t h r i n s . ( 2 ) Ap p l i c at i o n. P e rm eth r i n c om es i n t h e f o rm of a 1% c r em e ri n se an d s h ou l d b e a pp li e d l ik e a c o n v en t io n al ha i r co n di t io n e r a f te r th e h a ir h as b e e n sh am p oo e d ( us e a s h am po o wi t h n o c on di t io n e r ), r in s e d , a nd t o we l d r i ed . Th e h ai r s h ou l d be t ho r o ug hl y s at u r at e d wi t h u n di lu t ed pe r m e t h ri n ( 2 5 - 30 m L ) , wh ic h s ho u ld r e ma i n o n th e ha i r for 1 0 m i n . t h en r i ns e d . ( 3 ) E f f ec t i ve ne s s. A s i ng l e a pp l ic at i on is g e ne r al l y e ff e ct i v e i n k il li n g l ic e. B e c au se th e a g en t i s re ta i ne d o n th e h a ir s h a ft , th e p ro du c t p r o v id es c o n t in u i ng ac t i vi t y f o r u p t o 1 4 d a ys . Th i s r e s id u al e ff ec t pe r si st s r e g a rd l es s o f n or m a l s ham p oo i ng . ( a ) E ve n wi t h t he r es id ua l ac ti v i t y, th e r e s ti ll m ay b e t he ne ed f o r r e t r ea t m e n t i n 7 -1 0 da y s . ( b ) C o mb h ai r in t he pr ev i o u s l y i nf es t ed a re a w i th a f in e - to o t he d co m b to r e m o ve d ea d l ic e a n d e gg s . ( c ) Th e r e is , at le as t th eo r e ti c al l y, t h e s p e cu la t ion t ha t be ca us e l o w- l e v e l r e s id ua l a m o u nt s o f th is a g e nt a re re t ai n ed on t he h ai r , i t m a y be po s s ib le t h a t wh e n s u b op t im al l e v e l s a r e p re s en t , s o m e li c e m a y s u r v i v e a nd gi v e r i s e t o s tr a in s t h at a re res is t an t . c . O TC p e d ic u li c i de t r ea t m e nt f ai l u r e. Tr e a tm en t f ai lu r e wi t h t he us e o f t h e p r ec e di ng ag e nt s h as be e n r e po r t ed . Sp ec u la t i on s as t o t he c a us e o f t h is t re a tm en t fa i lu r e i nc l u de f ai lu r e t o fo ll o w p r od u ct in s tr u c t io n s, n o nc om p li an c e wi t h ni t re m o v al , a n d h ea d -l ic e d ru g r es is ta nc e . S t u di es s u pp o r t t he t he o r y th a t th e r e a r e n o w “ s up e r l ic e” t h at ha v e s u r v i ve d e xp o s u r e t o p y r e t h ri ns an d pe r m e t hr i n. 5 . P r es c r i p ti o n p r o d uc ts a r e i nc lu de d h e r e t o pu t in t o p e rs pe c ti ve ho w t h e O TC a g e n t s f it in t o t h er ap y .
a . M a l at h i on ( O vi d e ) i s a n o rg an o ph os p ha t e ch ol i ne s te r as e i nh i bi t or t ha t h a s b ee n wi d el y us e d a s a la wn a n d g a rd e n in s ec t ic i d e . Re s i s t a nc e h as a l so be c o m e an is s u e wit h t hi s a ge n t. ( 1 ) M e c ha n is m o f ac t i on . S ul f u r a to m s in th e m a l a th io n b i nd wi t h s u lf u r g r o up s o n t h e h ai r , g i v ing a re s i d ua l p r ot ec t i v e e ff e c t a ga in s t r ei n fe s ta t io n. P.629
( 2 ) Ap p l i c at i o n. Ma l a t hio n is p r e pa r ed as a l ot ion i n 7 8% al c o h ol ; t h e r ef o re , c a ut i on s h ou ld b e us e d n ea r an op e n f l am e o r a h ai r dr ye r . The p r o du c t s h o ul d b e s p ri nk l e d o n d r y h ai r a n d l ef t fo r 8 -1 2 h r be f o re r in si ng. A f i n e- t o ot h ed c om b s ho u ld b e us e d t o re m o v e th e d e a d li ce a nd eg gs . ( 3 ) N o s y s te m i c a d ve r se e f f ec t s h a ve b e en r ep o rt e d wi t h t o pi c a l u s e of t hi s m e di ca t io n . ( a ) Th e al c o ho l ic v eh ic l e m a y pr o du c e st i ng in g an d po s s ib l e f la m m ab il i t y. ( b ) A l th ou g h t hi s a g en t m a y be e ff ec t i ve , i ts u n pl e as a nt od o r ( o wi n g to s u lf h yd r y l c om po u nd s ), th e r eq ui r e d t im e o f 8 - 12 h r o n t he s c al p , a nd th ose p o in t s n ot e d i n I . G . 5. a . (3 ) . ( a ) r e p re se n t t he m a in d r a wb a ck s. b . L in d a ne , o r γ - b en z e ne h e xa c hl o ri d e h as fa ll en i nt o d is f a v o r b ec au s e o f t h e p o te n ti a l f o r t o xi c i t y a n d t h e f ac t th a t i ts e f f ica c y is le s s th an t he ot h er a g e nt s a v a il a bl e ( b ot h p re s c r i pt i on an d O TC p r odu c ts ) . Re s i s ta nc e t o t h is a g e nt is wi d es p re a d. ( 1 ) I t h as ne u r o to x ic i t y p o t e n ti a l b ec au s e o f p e rc u ta n eo us ab s o r p ti o n; t h e r ef o re , it s u s e s h ou ld b e a v o i de d i n i n fa n ts , p re g n an t a n d n ur s i n g wo m e n , an d a n y on e wi t h a ne u r ol og ic a l d is o rd e r. S e v e r e c e n t ra l ne r vo u s s ys t e m ( C N S ) t o xi c i t y h a s o c c u r re d i n i n fa n ts , wi t h s ei zu r es an d d e at hs r e p o rt e d, pa r t ic ul a rl y wh e n th e l o ti o n is us ed o r wh e n t h e a ge n t i s i ng es te d . To xi c i t y h as b e en m i ni m a l wh e n t h e s ha m p oo is u s ed p ro pe r l y t o t r ea t h ea d l i ce . 6 . Ad j u n c ti ve t h e ra p y a . N i t re m o va l ( 1 ) Th e pe di c u l ic id e p r odu c ts m e nt i on e d v a r y i n th e i r a bi li t y t o k il l t h e li ce n i ts . To en s u r e s uc c e s s fu l th e r ap y , af t e r p ed ic u lic i de ap pl ic a ti o n, t he ni ts s h ou l d b e r em o v e d wi t h a f i ne - t o o th e d c om b . A s t u rd y m e ta l c o mb ( li k e t h e L ic e Me i s te r ) is re c om m e n de d b y t h e N a ti o nal P e di c u lo s i s As s oc i at i on ( N P A ) . Ma n y s c ho ol s h av e a “ n o ni t ” p o li c y— t h a t is , a c h il d ' s h ai r a n d s ca l p m u s t b e f r ee of ni ts be f o re he o r sh e i s a ll owe d t o r e tu r n t o t h e c l as s r o om . ( 2 ) A lt h ou g h v a r i ou s s u bs t an c e s h a ve b e en us ed i n an ef f o rt t o d is lo dg e th e n i ts f ro m t h e h ai r s h af ts , m os t , i f n o t a ll , h a v e b ee n un su c c es sf u l. A m i xt u r e o f 50 % v in e ga r an d 5 0% wa t e r h as be e n r ec om m en d e d, bu t i t s e f f ec t i v en es s h as be en qu e s t i on e d. A l ic e e g g r em o v e r c on t ai n in g v a ri ous e n zym e s c o m e s a s p a rt o f a k it , b u t c ha ll e ng es ha v e b ee n m ad e to i t s e f f ec t i v en es s .
b . T r ea t me n t of o t he r ho u s eh o l d m em b e rs . O nc e a li ce in f es t at i on ha s b e e n id e n ti fi e d i n o ne m e m be r of th e h o us eh o ld , a l l o t he r m em b er s s ho u ld b e e xa m in e d c a r e fu ll y . Ev e r y o n e wh o is i n fe s te d s h ou l d b e t r ea t ed at t he s am e ti m e . c . Ad j u n ct i ve m et h o ds f o r c o nt r o l l in g li c e i n fes t a t i on s ( 1 ) W as h ab l e m a te r i al it e m s s uc h as li n en s , t o we l s, ha t s, an d c lo t hi n g s h ou l d b e m a c h i ne - wa s he d in ho t wa t e r a nd d ri ed i n a h o t d r y e r to de s t r oy l i ce an d n i ts . ( 2 ) N o nw as h ab l e m a te r ia l g oo d s s ho ul d b e d r y- c l ea n ed or s e al e d i n a p l as t ic b a g f o r 2 we e k s . ( 3 ) P e rs o n al i te m s ( e .g ., c om b, b ru s h es ) s h ou l d b e s o ak ed in ho t wa t e r ( 1 3 0 °F ) fo r a t le a s t 15 m i n . ( 4 ) F u rn i t u r e a nd h ou s eh o l d i t e ms ( e. g ., ca r pe ts , c h ai r s , c o uc he s , p i ll o ws ) s h ou l d b e v a c uum e d t ho r o ug hl y . O TC s pr a y p r od u ct s t ha t c o nt a in p yr e t h ri ns a re no m o r e ef f e c t i v e t h an va c u um in g in t e rm s o f r em o v i ng th e r i sk of r ei n fe s ta ti o n . d . P ed ic u li c i d es s ho u ld n o t b e u se d a r o un d t h e e y e s . F o r e ye l a s h pu b i c l i c e i n f es t a ti o ns , pe t r o la t u m a p pl ie d f i v e ti m e s a d a y h a s b ee n u se d t o s u pp os e dl y “ as p h y xi a t e ” l i c e bu t t h is m a y on l y s l ow l i c e m o v em e nt . G en t le r e m o val wi t h b a b y s h am p o o m a y b e he lp f ul . H . H e a d l i ce m yt h s a r e n u m e r ou s . Th e f ol lo wi n g a d di t io na l fa c t s m a y r e a ss u re an d i n fo rm pa t ie n ts an d p a r en ts o f p at ie n ts . 1 . N o s ig ni f ic an t di f fe r e nc e i n i nc i de nc e o c c u rs am o n g th e v a ri o us s oc i oe co n om ic c la s s es or r a c e s . 2 . H yg ie n e a nd ha i r l en gt h a re no t c o nt r ib u ti n g f ac t o rs . 3 . H ea d l ic e d o n o t f l y o r j um p fr om pe r s o n to pe rs o n. 4 . H ea d l ic e d o n o t c a rr y o t he r di s e as es . 5 . H ea d l ic e c a nn o t b e c o n t r ac te d f r om an im a ls , a n d p e ts a r e n o t s us c ep ti b le to P ed ic u lu s h u m a n us c ap i ti s . P.630
6 . Th e he ad do es n ot hav e t o be s h a ved to ge t rid o f l ic e. 7 . W as hi ng ha i r wi t h “ b ro wn ” s o ap is n o t e f fe c ti v e . 8 . H ea d l ic e a r e u n r el a ted t o t ic ks . 9 . H ai r do es no t fa ll o ut a s a c o ns e qu en c e o f i nfe s ta t io n . 1 0 . He a d l ic e i nf es t a ti ons c a n o cc u r a t a n y ti m e o f t he y e ar .
II. ACNE AND ITS TREATMENT A. O ve r vi e w 1 . D e f in i t io n . Ac ne v u lga r i s is a d is o rd e r o f t h e p i lo s e b ac eo us un i ts , m ain l y o f t he fa c e , c h es t, a nd ba c k . Th e l es i on s us u al l y s t a rt as op e n o r c lo s e d c om e do n es a n d e v o l v e in t o i n fl am m a t o r y p a pu l es an d p u s t ul e s t ha t e i th er r e s ol ve as m ac ul es o r be c om e s ec on da r y p yo de rm a , wh ic h re s u l ts i n va r i o us s e qu el a e .
2 . I nc i de n ce a . A c n e v ul ga r is is th e mo s t co m mo n s k i n d is e as e o f a do l esc e nc e ; i t a f f ec ts ab o ut 85 % o f al l p e o pl e b e t we en t he ag es o f 12 an d 2 4 . b . I t a f fe c t s p r im a ri l y ado l es c e n ts i n j u ni o r h ig h a n d s en i or hi g h, t he n d e c re as es in ad u lt h oo d . 3 . I mp o r t an c e a . A c n e v ul ga r is is u s ua ll y s e l f -l i mi t i n g. b . H o we v e r , t he c o nd i ti on is s i gn i fi ca n t t o a d ol esc e nt s b ec a us e o f h e ig h te n ed s e l f- c o n s c io us n es s a bo u t a pp ea r a nc e. c . A g r ea t m a jo r it y o f p eo p le do n ot c o ns ul t a p hy s i ci a n f o r t r ea t m e n t o f a c ne ; th e re f o re , a ph a rm a c is t c an pl a y a si g ni f ic an t r ol e . B . O r i g i n s a nd p at h o phys i o l o g y 1 . Th e pa t h og e ne s is o f a c ne v u lg a ri s i n v ol v e s thr e e e ve n ts . a . I nc r e as e d s eb u m p r od u c t io n ( 1 ) S eb um s e c re t io n i s re g ul a te d pr im a ri l y b y and r o g e ns , wh i ch ar e a c ti ve l y s e c re t ed in bo t h s e xe s be g in ni n g a t p ube r t y . ( 2 ) O n e o f t h es e a nd r oge n s , t es to s te r on e , is c o nve r t e d t o d i h yd r o t e s t o s te r o n e ( DH T ) . ( 3 ) D H T l e v e ls i n du c e t he s e b ac eo us gl a nd s t o i nc r e as e i n s i z e an d a c ti v i ty , r e s ul ti n g i n i nc r ea s e d am o un ts o f s e b um . b . Ab n o r m a l c l um p in g o f e p it h e li a l h o r n y c e l l s w i t h i n t h e p i l o se b ac e ou s u n i t ( 1 ) N o rm al l y , k e ra t in i z e d h o r n y c el ls a re s l ou g hed f r o m th e e pi t he l ia l l in i ng o f t he pi lo s e b ac eo us du c t i n t he h ai r fo ll ic l es a n d a r e c a r ri ed to t he s k i n s u r fa ce wi t h a f lo w o f s eb u m . ( 2 ) I n t he pa t ie n t wi t h ac n e , th e k er a ti n i z at i on p ro c es s is ab n or m a l , c h a ra ct e ri z e d b y i nc r e as e d ad h er e nc e a nd p ro d uc t io n o f fo ll ic u la r ep i th el ia l c e ll s. Th i s p ro c e s s is c all e d re t e nt i o n h yp e r k e r at o s i s, an d i t re s u l ts in o b st r uc t io n o f th e o u tf l ow o f t h e p i lo se ba c eo us un i t . c . P r es e nc e o f P r o pi o n ib a c t e ri u m a cn e s ( a g r am - p os it i ve a n ae r ob e ) ( 1 ) P eo p le wi t h a c n e h a v e s k in c o lo n y co u nt s o f P . a c n es th a t a r e s i gn i fi ca n tl y h ig he r t ha n t h e c ou n ts of t ho s e wi t ho u t a c n e . ( 2 ) P . a c n es p ro d uc es s e v e r a l e n z ym es , i nc lu d ing l ip as es , th a t b re a k d own s e bu m t r ig l y c e r id e s t o s h o r t c ha i n f r ee fa t t y ac ids ( F FA s ) , wh i c h a r e i r r i ta t in g , c au s e c om e don e s , an d re s u l t i n i nf l am m a ti o n. 2 . S eq u e nc e o f ac n e l es i o n d e ve l op m en t a . Me c h an ic a l b lo c k ag e o f a p il os e ba c e o us d uc t b y c lu m p e d h o rn y c el ls r e s ul ts in a c l os e d c ome d o ( i. e ., a w hi t e he a d) . b . W hen a c l os ed c o m e do d e v el o ps , i t c an fo r m ei t h er a p a pu le o r a n o p en c o m ed o (i . e ., a b l ac k hea d ) . Th e d a r k c o lo r of th e bl ac k h e ad is a t t ri b ut ed t o a c om bi na t io n o f m e lan i n , o xi d i ze d l ip i d, an d k e r a ti n oc yt es , no t to d i r t. c . Th e l es i on m a y en l ar ge a nd fi l l wi t h pu s , wh i c h i s t h en te r m e d a pu s t u le. P.631
d . I n m o r e s e v e re c a s e s o f ac ne , pa pu l es m a y dev e l o p i n to no d ul es or c ys ts . e . Th e te r m p i mpl e n on s p e c i f ic al l y r ef e rs to wh i te h e ad s, bl ac kh e ad s , p a p ul es , a n d p us tu l es . C . C l i n ic a l f e a tu r e s 1 . L oc a t io n . A c n e v u lg ar i s l es io n s us u al l y oc c u r o n th e fa ce , n ec k , c h es t , u p pe r b a ck , a n d s h o ul de r s . A ny o r a ll t ype s o f l es i on s m a y be s e e n o n a s in g le p a ti e nt . 2 . S ym p t o m s . Th i s c on di t i on is u s u a ll y as ym p tom a ti c ; h o we ve r , s om e p at i e nt s m a y h a ve p ru r it u s o r p ai n i f la r g e , t en d er le si o ns ar e p r e s e n t. 3 . C l as s i fi c at i o n. I t is im p o rt a nt to di f f er e nt i at e n o n i n fl a mm a to r y f r o m i n f l am m a to r y a c n e to de t e rm i ne th e b es t t re a tm e n t a p p ro ac h . Th e r e h a ve b ee n m a n y ra t in g o r g ra di n g s c a le s f o r a cn e s e ve ri t y (Ta b l e 30 - 1 ). C ys t i c a c ne is p re s e n t wh e n t h e f ol l ic ul a r wa ll ru p t u re s oc c u r de e pe r i n t h e d e rm is an d n o du le s a n d c ys ts a r e s e en . Be c a us e o f the p ot e nt i al fo r s c a r r in g , c y s t ic a c n e p a ti e nt s s hou l d b e r e f e r re d t o a p h ys ic i an fo r t r ea tm e nt . Sc a r ri n g occ u rs wi t h h ype r t ro p hi c r id g es , k e lo id s , o r a t r op hi c “i c e p i c k ” p i ts . D . C o m p li c at i n g f a ct o rs . O t he r fa c to r s h a ve b ee n im pl ic a te d i n t h e e xa c e r b a ti on o f a c ne . 1 . D r u gs a nd h o rm o ne s a . Ma n y t o p ic al an d s y s te m ic m ed ic a ti o ns (e . g ., b r o m i de s , i od id es , to p ic a l c o al ta r p r o du c ts , a nd r o ge ns , p he n y t o in , p r o ge s t i ns , l it h iu m , c or t ic os t e ro id s ) c an b e c om e do g en ic an d c an m a k e ac n e wo r s e or ca n in d uc e a c n e -l ik e er u pt i ons ( i. e . , a c ne i fo r m l es io ns ) . b . Ac n e i f o rm e r up t i o ns d i ff e r fr om t ru e a c ne le si o ns in th a t a pp a r en t l y no co m e d o f o r m s , e r up t io ns a re us ua l l y ac ut e , a nd t he le s i on s u s u a ll y a r e a ll in th e s am e s t ag e o f de ve l op m e n t. 2 . S t r es s d o es n o t c au s e ac n e b ut m a y e xa c e r ba t e i t . 3 . D i e t. Th e r e is v e r y li t tl e e v id en c e t o su p po r t a r e l at i on s h i p b et we e n di et a nd a c ne . Ma n y d i ff e r en t f o od s h a v e be en bl am e d f o r a c n e , f r om c h oc ol a te s an d s we e t s t o sh el l fi s h t o n ut s a nd ot h e r f a t t y fo od s . S e ve ra l s t ud i es h a v e de m o ns t r ate d th a t c h o co l a te d oe s n o t a f f ec t a cn e . Th e m a jo r i t y o f d e r m a t ol og is t s t od a y m ak e th e f o l lo wi n g re c o m m en d a ti on s re g ar d in g d i et . a . Th e pa ti e n t s h o ul d b e e a ti n g a we l l -b al a nc ed d i e t. As wi t h m os t ot h e r d i s e as es , a n d a s a m a tt e r o f g o od h e al t h , e xc e ss fa t s a nd s i m pl e c a rb oh yd r a te s s hou l d b e a vo i d ed . b . Th e pa t ie n t wh o i ns is ts t ha t c e rt a in fo o ds c a us e e xa c e r ba t io n o f a c n e s h o ul d p r o ba b l y a v o i d t ho s e f ood s . 4 . P h ys i c a l t r a u ma o r i rr i t a t i o n c a n p r om o te th e r u p tu r e o f p l ug ge d fo ll ic l e s , wh i c h c a n p r od uc e m o re in f la m m a to r y r e ac ti o ns . Sc ru bb i ng t he fa c e , we a r in g he a d ba nd s , c r a dl in g th e c hi n wi t h t he h an d , a nd pi c k in g a t the p im pl es c a n c on t ri b ut e t o th e p r i m a r y in f la m m a ti on p roc es s . G e n t le r eg ul a r w as h i n g wi t h so ap an d wa te r c a n b e b e n ef ic ia l .
Table 30-1. Assessment of Acne Severity
Grade of Acne Qualitative Description
Quantitative Description
I
Comedonal acne
Comedones only, < 10 on face, none on trunk, no scars; noninflammatory lesions only
II
Papular acne
10-25 papules on face and trunk, mild scarring; inflammatory lesions < 5 mm in diameter
IIIa
Pustular acne
More than 25 pustules, moderate scarring; size similar to papules but with visible, purulent core
IVa
Severe/persistent pustulocystic acne
Nodules or cysts, extensive scarring, inflammatory lesions > 5 mm in diameter
—
Recalcitrant severe cystic acne
Extensive nodules/cysts
a
Some overlap with previous grade of acne.
Reprinted with permission from Berardi RR. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care, 14th ed. Washington, DC, American Pharmaceutical Association, 2004:916. P.632
5 . C o sm e ti c s . S om e c os m e ti c b as es an d c e rt a in c os m et ic in g re d ie n ts a r e c om e do g en ic ( e. g ., la n oli n s , pe t r ol e um b as es , c oc o a b ut t e r ). P r ep a ra t io ns s uc h a s c l ea ns i ng c r ea m s , s u nt an o il s , an d h e a vy f ou n dat i o n s s ho u ld be a voi d ed . 6 . M e n st r u a l c yc l e . S o m e wo m en m a y no t ic e f la r e - up s o f a c n e d u ri n g th e p r e m e ns t r ua l p a rt o f t he c y c le . Fl uc t ua t io ns in the l e v el of p ro g es te r o ne a r e th e p r o ba b le c a us e . 7 . E n vi r o nm e n ta l fa c t o rs . V e r y h um i d e n vi ro nm en t s o r h e a v y s we a ti n g l ea d to k e r at i n h y d r at io n , s we l lin g , a n d a d ec r e as e i n t he s i ze o f t he pi l os eb ac eo u s f ol l ic le o r i fi ce , wh i c h r es ul ts in d u c t ob s t ru c t i on . Th e s un , as we l l a s a r ti f ic ia l u l tr a v i o le t ( U V ) l ig h t , c a n h e lp ac ne b y d r y i ng an d p e el in g the s k in , bu t b o th al s o ca n a g g ra va t e a c n e .
E . T r e at m en t an d ca r e 1 . G e ne r a l a . Mo s t pa t ie n ts c a n b e tr e a t ed s uc c e s s f ul l y wi t h e i t he r to pi c al l y or s ys t em ic a ll y a d m i ni s te r ed m e di c a t io ns o r b ot h . Ac ne of t en im p r o v e s wh e n pa t ie n ts rea c h t he i r e a r l y 20 s . b . E ve n t h e m o s t e f fe c t i ve t r ea tm e nt p ro g r am s m a y t a k e s e ve r al we e ks to p r o du c e a n y cl i ni c a l i m p r o v em en t. Th i s a sp ec t m us t b e em p ha si ze d . c . P eo pl e a f f ec te d wi t h ac n e s h o ul d a v o i d a n y th i ng t ha t s e em s t o wo r s e n th e c o nd i ti on ( e .g . , c o s m e ti c s , c l ot h in g , c ra dl i ng th e c h in wi t h th e h an d ) . d . Th e nu m b e r a nd t y p e o f le s i o ns s ho u ld be r oug h l y de t e rm in ed t o as s es s f u r th e r t h e r ap eu t ic re s po ns es . e . S el f - t r e at m en t w i t h O TC a g e n t s i s a pp r o p ri at e on l y f or pa t ie n ts wi t h n o n i n fl a mm a to r y g r a d e I a cn e o f m il d t o m o de ra t e s e ve ri t y . 2 . C l ea n si n g re c om m end a t i on s a . B ec au s e m a n y ac ne pa t i en ts ha v e oi l y sk in , ge n t l e c le a ns i n g t wo t o th r e e t im es d a il y i s r ec om m e n de d f or r e m o v i ng e xc e s s oi l. b . A cn e l es io n s c a n no t be s c r ub b ed a wa y . C om pu l si ve s c ru b bi ng m a y a ctu a ll y wo r s e n th e a c ne b y d is ru p t in g t h e f ol l ic ul a r wa l ls an d th us s e t ti ng t he s ta g e f o r i n f la m m at i on . c . Mi l d fa c i al s o a ps , s uc h as D o ve , N e u tr o ge n a, a n d Pu r po se , s h ou ld be u s ed to c l ea ns e t h e s k i n. d . Me d i c at e d s o a ps c on ta i ni n g su l fu r , re so r ci n ol , o r s a li c y li c ac i d a r e o f l it t l e va l ue b e ca us e th e m ed ic a ti on r i n s e s a wa y r a t he r th a n p e n e t r a te s t he f ol li c l e . e . P at i en ts wi t h m i ld c om e do n al ac ne m i gh t f i nd b e ne f it f ro m c le an s er s co n t ai ni n g p u m i ce , p o l y et h y l en e , o r a l um in um o xi d e p a r ti c l es ( e. g . , B r as i v ol ) . H o we ve r , p a t ie n ts wi t h i n fl am m a t or y a c ne o r s e n si ti ve s k in s ho u ld a voi d t h es e p r odu c ts . 3 . Ap p r o a c he s t o t r e at m e n t d e pe n d o n t he s e ve r it y o f th e c o nd i ti on . Al t hou g h a c n e c a nn o t b e c ur e d, m o s t c a s es c a n b e m a n ag e d suc c e s s f ul l y wi t h to pi ca l tre a tm e nt a l on e . Ba s e d o n t h e p ath o g en es is of th e c o nd i tio n , p o te n ti a l m e t ho ds inc l ud e a . U n bl o ck i n g t he s e b ac e o us du c t s o th a t t h e c on t e nt s c an be ea s i l y e xp e l le d b . D e c re a si n g t h e am o un t o f s e b um th a t is s e c r et e d c . C ha n g in g th e c om po s i t i on of th e s e b um to m ak e i t l e ss i r r it a ti n g b y dec r e as in g t h e p o pu l at io n of P . a c ne s 4 . N o np r e sc r i p t io n t op ic a l m e d ic a ti o n s a . B e nz o yl p e r o x i d e ( 2 .5 % - 10 % ) — fo r e xa m p l e , C l e a ra s i l Ma xi m u m S t re ng t h Ac ne Tr e a t m en t C re am , P an Ox y l A q u a G el ( U . S. F oo d a n d D ru g Ad m i ni s tr a ti o n [ F D A ] c a te g o r y 3 ) — ha s t r a di ti on a ll y b ee n re c o g ni ze d a s t h e m os t e f fe ct i v e to pi ca l O TC a g e nt fo r ac ne , an d m any O TC a c n e p ro du c ts c on t a in it . H o we v e r , t h e l ate s t m o no g ra p h f r om th e F D A c ha n ge d t h e s ta t us o f be n z o y l pe r o xi d e f ro m c a te g o r y 1 ( g e ne r a ll y r ec og n i z ed as s a fe an d e f fe c ti v e ) to c at e g o r y 3 I , i nd ic a ti n g t ha t m o re d a t a a r e n ee de d to p ro v e i ts s a fe t y in r eg a r d t o lo n g - te rm ph o t oc ar c i n og en i c e f fe c t s . Ma r k e t i n g o f t hi s a g en t is pe r m i t te d p e nd i ng fi n al e va l ua t io n o f i t s t um o ri ge n ic p o t en t ia l .
( 1 ) E f f ec t s. B en z o y l pe ro xi d e h as i rr i ta n t , d r yin g, p ee l in g , c o m e d ol y t ic , an d a n t ib ac t e ri al e ff ec ts . Th e c li n ic al re s po ns e s ho ws o n l y m in im a l d if f e re nc es a m o n g t h e 2 . 5% , 5% , a n d 1 0% c o nc en t r at i on s . ( a ) A be n e fi c ia l e f f ec t s h o ul d b e no ti c ed wi t h in a b o ut 2 we e k s , bu t th e us u al le ng t h o f a t h er a pe u ti c t r ia l i s 6- 8 we e k s . ( b ) A s f o r a d ve r se e f fe ct s , be n z o yl p e r o xi d e m ay c a us e a bu r ni n g o r s ti ng i ng s e ns at i on , wh i c h gr a du a ll y d is a pp e ar s . Mo s t o f t he a d ve rs e e f fe c t s f r om thi s a g en t r e l at e to it s t h er a pe u ti c e f f ec t o f i r r i ta t in g a nd d ry i n g th e s k i n . F o r t hi s r ea s on , P.633 t h e l o we s t c on c e n t ra t io n a v a i la bl e s h ou ld be c h os e n i ni t ia ll y. A b ou t 2 . 5 % o f pa t ie n ts wi l l d e ve l op a c o n ta c t de r m a t i ti s wi t h i ts us e. ( c ) Th e v e hi c l e f o r t h e be n z o y l pe r o xi d e i s a ls o im p o rt a nt in it s o ve r al l a c t i vi t y. Th e a l co h ol g e l v e h ic le t en ds t o be m o re e ff ec t i v e t h an t he lo t io n o r c r e am f o rm u la t io ns . ( d ) B en zo y l p er o xi d e c an d is c o lo r c e r ta in t y p es o f f ab r ic o r cl ot h in g m ate r i al an d c a n a ls o b le ac h h a ir . ( 2 ) M e c ha n is m o f ac t i on . B en z o y l p er o xi d e ha s a d ua l m od e o f a c ti on , s o i t is e f f ec t i v e a ga in s t b ot h i n fl a m m at o r y an d n o ni n fl am m a t o r y ac ne . ( a ) B en z o y l pe r o xi d e de c o m po s e s t o re le as e o xy g e n , wh i c h i s l e th al t o t he P . ac n es a n a er o be . ( b ) A s a n i r ri t an t , i t i nc r ea s es th e t u r no v e r ra t e o f e p it h el ia l c el ls , re s u l ti ng i n i n c re as ed s l ou g hi n g a nd p r om o ti n g o f r es o lu t io n o f co m e do n es . ( 3 ) Ap p l i c at i o n ( a ) Th e af f ec t ed ar e a s ho u ld be wa s h ed wi t h m ild s o a p a nd wa t e r , t h en ge n t l y p a t te d d r y . ( b ) Th e p ro du c t s h o ul d be m a s s a ge d g en t l y in t o th e s ki n , a v o id i ng th e e ye s , m ou t h, l i ps , a n d i ns id e o f th e n os e . ( c ) Th e pr o du c t c a n b e ap p li e d a t n ig h t , l ef t o n for 1 5 o r 20 m i n t o t es t s en s it i v i t y , t h e n wa s h ed o ff . ( d ) I f n o e xc e s s i v e i r r i ta ti o n d e v el o ps , a p pl y o nc e d a il y f o r t he f ir s t f e w d ay s . ( e ) I f d r y i ng , re d ne s s , o r p e el in g d o es no t o cc u r in 3 d a ys , i nc r ea s e ap pl ic a t i on to t wi c e da i l y . ( f ) I f p a ti e nt s h a v e t o u s e b en z o y l pe r o xi d e du r ing t he da y, a d vis e t he m to us e a s u ns cr e en an d a v o i d u nne c es s a r y s u n e xp o s u r e. b . S a li c yl i c a c i d ( 0. 5 %-2 % ) , a n i r r it a nt k e r at o l y tic ag e nt , re s ul ts in in c re as e d t u r n o ver o f t he ep i th e li al l i ni ng (c a te g o r y 1 ) . Th r ou g h t h is e f f ec t , s a li c yli c a c id p r o ba b l y p r om o te s t h e pe n e t ra t io n o f o t he r ac ne p r o du c ts . c . S ul f u r (3 % - 8% ) , s u l fur ( 3 % - 8% ) c o mb i n ed w i th r e s o rc i n ol ( 2% ) , o r r es o r c i no l m o n oa c e ta t e ( 3 % )— f o r e xa m p l e , C l ea r as il A du l t C a r e Ac ne Tr e a tm en t C re a m , A c n om el (c a te g or y 1 ) ( 1 ) S ul f u r is a k er a to l y t ic a g en t a n d h as an ti b ac t er i a l ac t io n s . ( 2 ) S ul f u r t r ad i ti on a ll y ha s b e en r ec og n i z ed as a l es s d es i ra b le pr o du c t be c au se it m a y be ac n eg en ic wi t h c o n t in ue d us e, an d i t h a s a n of f en s i ve c o lo r an d od o r .
d . R e so r c i no l (a s a s i ngl e ag en t - c a t eg o r y 2) is a k e ra t ol yt ic ag e n t t ha t h as be e n r e c og ni z e d a s s af e a n d e f f ec t i v e ( ca t eg o r y 1 ) a ga i ns t a c n e w he n t he ag en t i s c o m bi n e d w i t h s u l fu r . F . P r e sc r i p ti o n m e di c a ti o n s , b o th t o pi c al an d s ys t e m i c , ar e i nc l ud e d h e r e f o r c om p le t en es s a nd t o p ut i n to pe r sp ec t i v e h o w O T C a g en t s f it in t o a c n e t he r a p y. 1 . T op i ca l p re s c ri p t i on a g e n ts a . T r e ti n oi n ( v i ta m i n A ac i d, t ra ns - r e ti no ic ac i d, R e t i n - A) in c re as es t he tur n o v e r r a t e o f n o na d he r in g h o r ny c e ll s i n t h e f ol li cu l a r c a n al , wh i ch r es ul ts in c om e do c l ea r in g a n d i nh ib i ts ne w c om ed o d e ve lo pm e nt . ( 1 ) E f f ec t i ve ne s s. Tr e t in o in is p ro ba b l y th e m os t e f fe c t i ve to pi c al a g en t fo r ac n e, e s pe ci a ll y ac n e c h a r ac ter i z e d b y c om ed o ne s . I t is be s t us e d f o r n o ni n f lam m a to r y a c ne . Tr e ti n oi n a ls o m a y b e u s e d i n c om bi n at i on wi t h a n ti b io t ics o r b en zoyl p e r o xi d e f o r m a na g em en t o f i n fl am m a t o r y ac ne . ( 2 ) S i de e ff e c ts . Be c a us e o f i ts i rr i ta n t p r op e r ti es , t re t in oi n c an c a us e e xc e s si ve i r r i t a t i on , e r yt h e m a , p ee l i n g, an d i nc r e as ed ri sk f o r s e ve r e s u n bu r n . The r e m a y b e an in i ti al e xa c e rb a ti on o f t h e ac n e ( p us tu l ar f l a r e ) a t 2- 4 we e k s , b u t us u a ll y b y 8 we e k s , t h e p at i en t wi l l s e e m a rk e d im p r o v em en t . B e c a us e th is ag en t m a y c au s e p h o to se ns i ti v i t y , it s h ou ld g en e ra l l y b e a p pl ie d at n i gh t . ( 3 ) Ap p l i c at i o n. Th e c r ea m fo rm u la t io n o f tr e ti n oi n , wh ic h i s l es s i r ri t at i ng t ha n th e g e l f o rm s h ou l d b e us e d i n i ti al l y fo r pa t ie n ts wi t h d r y e r s k in . Th e p a ti en t wi t h v e r y o i l y s ki n m a y do we l l i ni ti a ll y wi t h t he ge l f o rm . Th e r et i no id s s ho ul d b e ap p li e d 3 0 m i n a f te r wa s hi ng be c a us e m oi s tu r e o n t h e sk in in c r ea s e s a bs o rp t io n a n d i r r it a ti o n. To m i ni m i z e i rr i ta t io n , i nit i a ll y s u c h a p r od uc t c a n b e a p pl ie d e v e r y o t he r d a y f o r 2 we e k s , t h en da i l y . O t h e r i r r i ta t in g s ub s ta nc es , s uc h a s s t ro n g a br a s i v e c le a n er s a nd a s t ri n ge n ts , s ho ul d b e av o i d e d d ur i ng t re a tm en t wi t h t r e ti n oi n . N e we r m i cr o s i ze r e f o rm ul a ti o ns o f th is age n t ( Re t in - A Mi c r o , A vi t a) a r e l es s i r ri t at i ng . P.634
b . Ad a p a le n e ( D i f fe r in ) is a t o pi c a l r e ti n oi d -l ik e c o m po u nd th a t is do s ed on c e d ai l y. I t ca n b e a p pl ie d i n th e m o r ni ng be c a u s e of no ph o t od e gr a da t io n , a nd it h a s l es s p o t en t ia l f o r p h ot os e ns it iv i t y . ( 1 ) E f f ec t i ve ne s s. I t a ppe a r s t o c au s e le ss i r r it a tio n th a n t r et i no i n wi t h equ i v a le n t e f f ic ac y . Th e r ap e ut ic r es u l ts s h ou l d b e n ot ic e d i n 8 - 1 2 we e k s . I t c a n b e us e d as a n a l t er n a ti v e to t re t in o in i n i n di v i du a ls wi t h m il d t o m o de r a te ac ne . ( 2 ) S i de e ff e c ts . Th e s am e p r ec a ut i on s t ha t ap ply t o t r et i no in ap p l y a ls o fo r a d a pa le n e. c . Ta za r o t en e ge l a n d cr e a m ( Ta zo r ac ) i s a re t ino i d p r od r u g f o r m i l d t o m o d e ra t el y s e ve r e f ac ia l a c n e th a t is ap p li ed o nc e d ai l y in th e e v en i ng . I t ha s s i m i l ar e f fi c a c y a n d p r ec au t io n s as t re t ino i n , a nd th e d os e - r el at ed a d ve r se e f fe c ts in cl u de i tc hi n g, b u r ni n g, s t i ng in g , a nd e ry t h e m a ( r ed n es s ) . Th e ge l fo r m a pp e ar s t o b e m o r e i r r i ta t in g t h an t re t in o in . A p us t ul a r f l ar e m a y oc c u r a t a bo u t 1 0 -1 4 d a y s af t e r th is p r o du c t is be g un . d . T op i ca l an t i bi o t ic s : e r yt h r o m yc i n ( E r yd e r m ), c l in d am yc i n ( C l e oc in -T) a n d t e t r a c yc l i n e . Th e s e t op ic a l a nt i bi o ti c s a r e m os t e f f ec t i ve wh e n us ed in co m bi n at io n
wi t h b e n z o y l p e ro xi d e o r t o pi c a l re t in oi d s . C om bin a t io n p r od uc t s c o n ta i nin g be n zo yl p e r o xi d e a n d e r y t h ro m y c i n ( Be n z a m yc i n) an d be nz o yl p e r o xi d e a n d c l in d am y c in ( B e n za C li n ) a r e a ls o a v ai l ab l e. W he n t h es e a nt i bio t ic s a r e u se d a lo n e, bac t e ri al r e s is ta nc e o c c u rs ra p id l y. B e n z o y l p e ro xi d e us e in co m b i na t io n wi t h t he s e a n t ib io t ic s p r ot ec t s a ga in s t t h is re si st a nc e. ( 1 ) M e c ha n is m o f ac t i on . Th e m ec h an is m o f a c ti o n a pp a r en t l y i n v o l v es su p p re s s io n o f t he P . ac n es o r g an is m , wh i c h i n t u rn m i ni m i ze s t h e i nf l am m a t or y r e s p ons e d u e t o t h e a cn e . ( 2 ) Ap p l i c at i o n. Th e s e a n t ib io t ic s a r e a pp li e d d ir e c tl y t o a c n e s it es , th us m in im i z i ng s e r io us s i de ef f ec ts f ro m o r al a dm i n is t ra t io n . ( 3 ) S i de e ff e c ts . Th e re a r e mi n im a l s id e e f fe ct s t o th es e t o pi c a l l y a p pl ied a n t ib io t ic s . M i l d b u r n in g o r i r r i ta t i on m a y oc c u r . A l t ho u gh da il y t o pi c a l C l i n d am yc i n d o es no t pr o d uc e d e te c t a bl e l e v el s i n t h e u r in e a f te r 8 we e k s o f a d m i ni s t ra ti o n , t he r e i s a p o te n ti a l r is k o f p s eu d om e m b ra n o us co l i ti s . T e t r a c yc l i n e c an c a us e a ye l l ow st a i ni n g o f t he s k i n. e . Az e l ai c a c i d ( A z e le x) a n d s o di u m s ul f a ce t ami d e an d s u l fu r a re a dd it io n al t o p ic al ag e nt s t ha t a re l es s e f fe c ti v e th a n t he o the r t op ic a l p re s c r ip t io n a ge n ts . Th e s e a g en t s m i g ht be us e d wh e n o th e rs ar e n o t t o l er a t ed or as ad ju n c t s t o o th e r t h e r ap ie s . 2 . S ys t e m i c p r e sc r i p t ion a ge n t s a . O r a l a n t ib i o t ic s /a n t i-i n f e c ti ve s ar e th e m os t e f f ec t i ve a ga in s t i nf l am m a t o r y l e si on s b ec a us e t he y s up p r es s P . a c ne s . Th e y m a y b e u s ed wh e n t o pi c a l c om b in a ti o ns a r e n o t t ole r a t ed or ha v e f ai le d . O ra l an t ib io t ic s h a v e a n o ns e t o f a c ti o n o f 3 - 4 we e k s . Th ey a r e p re s c r ib ed f or d ai ly u s e o v e r 4- 6 m o nt hs an d th e n t a p e re d a nd ul t im a te l y dis c o n ti n ue d wi t h a c n e i m p r o v e m e n t. A nt i bi o ti cs do n ot a ff ec t e xi s t i n g l es io ns , b u t p r ev e n t f ut u re le s i o ns th r oug h th is e ff ec t . P. ac ne s re s is ta nc e t o an t ib i ot ic th e r ap y h as b e c o m e an in c re as i ng pro b le m ; e r y t h ro m yc i n r es is t an c e is t h e m os t c om m o nl y r e por t e d , a nd m i no c yc l in e res is t an c e is r ep o rt e d r a r el y . A s n o t ed p re v i ou s l y , c o nc om i ta n t a dm in is t r at i on of b e n z o yl p e ro xi d e m a y d ec r e as e t he i n ci de n c e of r es is ta nc e . ( 1 ) T et r a c yc l i n e i s t he m o s t f re q ue n t l y u s e d or a l a n ti b io t ic fo r a c ne . I t i s p r e fe r r ed b e ca us e o f i t s e f fe c t i v e ne s s , lo w t o xi c i t y, an d l ow c o s t . Th is a g en t s ho u ld b e t ak en o n an em pt y s to m a c h; foo d , a n ta c i ds , ir o n, a nd da i r y p ro d uc ts de c re as e ab s o rp t io n . Th e t e t ra c y c l in e s al s o ha v e d i re c t an t i -i n fl am m a to r y e f fe c ts i n a cn e . ( a ) I ni t i al d os e s a re 2 50 m g , 2 -4 t im es d a il y, g rad u al l y r ed uc e d t o a m a int e n an c e d o se of ab o ut 2 50 m g p er d a y . ( b ) S i de e f fe c ts . Th e m o r e c om m o n a d ve rs e e f fe c ts in c l ud e u p s e t s to m ac h , vag in a l m o ni li as is , an d p h ot os e ns i ti v i t y . ( 2 ) E r yt h r o m yc i n ( E - My c i n ) m a y b e u se d a s a n a l t er n a ti v e to te t r ac y c li ne . ( a ) I ni t i al d os e s r an g e fr o m 5 0 0 t o 2 00 0 m g p e r d a y i n d i v id e d d os es . A m a in t en a nc e d os e r a ng es f ro m 2 5 0 t o 5 00 m g p er d a y. ( b ) S i de e f fe c ts . Th e p r im a r y s i de e ff ec t a ss oc i ate d wi t h e r y t h r om y c in i s g a st r o in t es ti n al di s t r es s . ( 3 ) M i n oc yc l i n e ( Mi n o c in ) o r do x yc yc l i n e ( V i b ra m y ci n ) . E i th e r o f th es e a g e nt s c an b e ta ke n i n d os e s o f 5 0 -2 0 0 m g p e r d a y. B e c a us e o f g r ea t e r l ip id s o lu b il it y a n d
e n h an c e d p en e t ra t io n i n to s e b ac eo us f ol li c l es , the s e a ge n ts m a y be us e ful f o r r e f r ac t o r y c as es . Ei t he r c a n b e t ak e n i f b ac te r i al r e s is ta nc e i s s us pe c t e d to e r y t h r om y c in o r i f i nt o le ra b le ga s t ri c i r ri t at i on oc cu r s a f te r o ra l t e t ra c y cl ine . Th e se t wo a g e n ts c an be t ak en wi t h f o od . Si d e e ff ec t s to m i n oc y cl i ne , i nc l ud i ng d i z zi n es s o r ve r t ig o a nd he a da c h e , d is c o l o ra t io n P.635 o f sk in an d v is c e r al ti s s ue , an d d r u g- i nd uc e d l up us e r y t he m a t os us , l im it t he us e o f t h is ag e nt . D o xy c y c l i ne m a y be ph o t os en s i t i z in g a n d s ho u ld be s wa l l o we d wi t h a d e qu a te fl ui d s t o p r e v en t es op h ag e al ul c e r at i ons . ( 4 ) T r im e t ho p r i m- s u lf am e t h ox az o le ( B ac t ri m , S e p t ra ) ha s b ee n u s ed s u c c e s s fu ll y i n pa t ie n ts wi t h a c n e re s i s ta n t t o e r y t h r om y c i n o r t e t ra c y cl in e s . Mi n o c y c l in e an d d o xyc y c l i n e a r e p r ef e r red o v e r t h is d r u g c o m b i nat i o n b ec au s e of i ts s id e -e f f ec t p r o fi l e. O r a l c l i nd a m yc i n ( C l eo c i n ) i s us e d r a re ly b e c a u s e of th e ri s k of p s eu d om em b ra no us c o li ti s . b . O r a l is o t r et i n oi n ( Ac c u ta n e ) is a v i t am in A der i v a t i v e i n di c a t ed fo r se ve r e n o d u lo c ys t i c a c n e . A s in g le c o u rs e o f th e ra p y re s ul ts in a l on g - te r m s tab l e r e m iss i on in > 8 0% of pat i e nt s . ( 1 ) M e c ha n is m o f ac t i on . A l th ou g h t he e xa c t m e c ha n ism is u n kn o wn , is o t r e ti n oi n d e c re as es s e bu m p r od uc t i o n a nd k e r at i ni za t io n , an d it r ed uc es t he po pu l ati o n o f P. a c ne s. ( 2 ) D o sa g e. Tr e a tm en t is us ua l l y b e gu n wi t h a da i l y do s e of 0 .5 m g /k g an d i n c re as ed t o 1 m g /k g g i ve n in t wo di v i d ed do se s wi t h f o od f or t he us ua l du r a ti o n o f 2 0 we e k s . A m i c ro n i z ed f o r m u l at io n al lo ws f o r l owe r o n c e d ai l y do si n g wi t h no r e g a rd to f oo d i n ta k e . ( 3 ) S i de e ff e c ts in c l ud e ( a ) M u c oc u t an e ou s d r yn e s s. C he i li t is (i . e. , i n fl am m a t io n o f th e l ip s ) , d r yn e s s o f t h e n as a l m u c os a, an d fa c ia l d e rm a ti ti s m a y o cc u r wi t h is ot r e ti n oi n u s e . Th e s e e f f ec ts c a n b e t r ea t e d wi t h t op ic al lu b ri c an ts . D r yn e s s o f th e e y e s c an al so oc c u r , s o p e op l e us i ng is ot r e ti no i n s ho ul d no t we a r c on ta c t l en se s . ( b ) E l e va te d se r u m l e vel s . Is ot r e ti n oi n m a y e l e va t e s e ru m t r ig l y c e r i de s an d c h ol es t e ro l , as we l l a s l iv e r e n z ym es . ( c ) B i r t h d e fe c t s. Is o t ret i n oi n i s a p o t en t t e ra t og e n a n d s ho ul d n o t b e g iv e n t o p r e gn a nt wo m e n. A s t ri c t r i s k m an a ge m e n t p r og r am f or is o tr e ti n oi n u se r eq u i re s p h ys ic ia ns t o r eg is t e r p at i e nt s t o d oc um e nt ne g ati v e p r eg na nc y t es t s b ef or e us e . P h ys ic i an s wh o p r es c r i be t hi s a ge n t a nd ph a rm ac i es th a t d is pe ns e i t m ust b e r e g is t er e d i n a n e le c t r o ni c F D A s ys t em . ( d ) P s yc h i a t r i c e f fe c t s. Th e r e h a v e b ee n re po r ts o f de p re ss io n , s ui ci da l b e h a vio r , a n d s ui c i d e. D a ta ar e i na d e qu a te to es t ab li sh a c a u s al r el a ti on s h i p b et w e e n i s ot r e ti n oi n a dm in is t r at i on a nd de p re s s i on an d s ui c id e . Th i s i nf o rm a ti o n m u s t b e t a ke n i n th e c on t e xt t h at t e e na g er s wi t h ac n e m a y o f t en be de p re s s ed r el at e d to t h e ir a pp ea r a nc e. c . An t i a nd r o g en s a n d ho r m o n es ( 1 ) E s t ro g e ns c a n d ec r ea s e s e b um pr o du c ti on thr o u gh an an t ia n d ro ge n ic e f f ec t .
( 2 ) S om e p r og es t in ag e nt s in or a l c o n t ra c e p ti v e s ( e . g ., no r e th i nd r on e , n o rg e st r e l) h a ve an d ro g en ic ac t i v it y t h a t c an s t im ul a te s e bum s e c re ti o n r es u lt i ng in a c ne . O ne o f t he pr o ge s ti ns , n o r g es t i m at e , i s m i n im al l y and r o ge n ic , a nd wh e n it is c om b in e d wi t h e t h i n yl e s t r a d i o l as a t r ip h as ic c om b in a ti on o r al c o n t ra c e p ti v e ag e nt ( O r t h o Tr i - C yc l e n ) , i t is e ff ec t i ve i n t he t re a tm en t of m od e r a te ac ne in s om e wo m e n a nd is F D A a pp r o v e d f o r s u c h. N o r e t h i nd r o n e a ce t a te /e t h i n yl e s t r a d i o l ( E s tr os t ep ) is a l so F D A a pp r o v e d f o r ac n e. ( 3 ) S p i ro n o la c t on e ( Al da c t o ne ) i s a n o r al an t ia nd r o ge n wh i ch ac ts to de c r e a s e s e bu m p r od uc t io n a n d m a y b e u s ed on a li m i t ed b a s i s . ( 4 ) C o r t ic o s te r o i ds . Al th o u gh c o r ti co s t e r oi ds hav e b e en im pl ic a te d a s c au s in g a c ne , th e y al s o c a n b e us e d t o t r ea t s e v e r e ac n e. I n t ra l es io n al i n je c t i on s o f t r i am ci n ol on e a n d s y s t em ic c o r ti co s te r oi ds ha v e b e e n us e d f o r s e v e r e i n fla m m a to r y a c ne an d s e v e re c ys t ic ac n e, r es pe c ti v e l y . P re dn is o ne ( or i ts e q ui va le n t ) in d os es of 2 0 m g p e r d a y o r h ig h er m a y be us e d f o r a s ho r t p e r io d o f ti m e to qu ic kl y i m p ro v e a c ne fo r im po r t an t e v e n ts li k e a we d di ng . To pi ca l c o rt ic o st e ro i ds a r e n o t e f f ec t i ve.
III. SUNLIGHT, SUNSCREENS, AND SUNTAN PRODUCTS A. I n t r o d u c t io n . O v e re x p o s u r e t o s un l ig h t d am ag e s s k in . A s un t an , wh i c h h as t r a di t io n al l y be e n as s o c ia t e d wi t h he a lt h , i s ac t ua l l y a r es p on s e to in j ur y . O f t h e t h r e e t y p es of s o la r ra d ia t i on , o n l y th e U V sp ec t ru m p r o du ce s s u n bu r n a nd s u n ta n . 1 . Th e U V s p ec t r u m r a ng e s f r om 20 0 t o 4 0 0 n ano m et e rs ( nm ) . N a t ur a l an d a rt i fi ci al U V l i gh t i s f u r th e r s u b di v i d ed in t o t h r ee ba nd s . P.636
a . U V A ( 3 2 0 -4 0 0 nm ) c an c a us e th e sk i n t o t a n, a n d i t t e nd s t o b e we ak in c a us i ng t h e s ki n t o re d de n . U V A i s a b ou t 1 0 00 ti m e s l es s p o t en t th an a c om pa r ab le d os e o f U V B i n c au s i n g e r y t he m a , bu t i t is o n l y s li g ht l y bl o ck ed ou t b y t h e o zo ne l a y e r an d r e a ch es th e e a r th ' s s u rf ac e i n 1 0 - 10 0 t im es t he am o un t o f U V B . S om e h a ve p r o po s e d th a t U V A be f ur t h e r s ub di v i d ed in t o U VA I ( 34 0 - 40 0 n m ) an d U VA I I (3 2 0 3 4 0 n m ). U V A I is le s s er y t h r o ge n ic an d m el an o ge n ic th a n U V A I I o r U V B. U V A I I i s s im i la r i n e f f ec t t o U V B. ( 1 ) U s es . U V A is o ft e n us e d i n t an n in g b o ot hs and i n ps o r al en pl us U V A (P U V A ) t r e a tm en t o f ps o ri as is . ( 2 ) D i sa d va n t ag e s. U V A i s r es p on s i b le fo r m a n y p h o t os e ns i t i vi t y r e a c ti on s , p h o t oa g i ng , an d p h o tod e r m a to s es . U V A r a y s ca n al so pe n e t ra t e d e ep ly i n t o t h e d e r m is an d au gm en t th e c an c e r o us e f f ec ts of U VB r a y s . b . U V B ( 29 0 -3 2 0 nm ) cau s e s t h e u su a l s u nb u r n r e a c ti o n a n d s t im u la t es t a nn i ng . I t h as l o ng be en as s o c i at e d wi t h s un li g ht s k in dam a ge , i nc l ud in g th e v a rio u s s k in c a nc e rs . I t i s t h e m os t er yt h r o g e n i c a nd me l an og e n ic o f t he t hr e e U V r ad i a ti on b a n ds . S m a l l am o un ts o f t h is ra d ia t io n a r e r e qu i re d fo r no r m a l vi ta m i n D s yn t h e s i s i n th e s k i n . c . U V C (2 0 0- 2 90 nm ) d oe s n o t r e ac h t h e e ar t h ' s s u r fa c e be c a u se m os t o f i t i s a b so r be d b y t h e o z o ne la y e r . A r ti f ic ia l U V C so u rc es ( e .g . , g e rm ic id al an d m e rc u r y a r c l am ps ) c a n em i t t h is r a d ia t io n .
2 . Th e vi s ib l e s p ec t r u m ( 4 0 0- 7 70 nm ) p r o du c e s t h e “b r ig h tn es s ” o f t h e s u n . 3 . Th e in f r a r ed s pe c t r um ( 7 70 - 18 0 0 nm ) p ro du c e s th e “ wa r m t h ” o f t h e s u n . B . S u n bu r n an d su n t an 1 . S u nb u r n i s g en e ra l l y a s up e r f i ci a l b u r n i n vo lvi n g t h e e p id e r m is . Th is la ye r is r a p id l y r ep ai r e d wh i l e o ld c e l ls a r e b e in g s lo ug he d of f i n a p ro ce s s c a ll ed p ee l i ng . Th e n e wl y f o r m e d s k i n is t h ic k e r a n d o f fe r s p ro t ec t io n fo r th e l o we r de r m al l a y er s . a . N o r ma l s e q ue n ce af te r m i ld t o m o de r a te s un l i g h t U V r a di a t io n ( U VR ) e x p os u r e ( 1 ) E r yt he m a oc c u r s wi t hi n 20 - 30 m i n a s a re su l t o f o xi d a ti o n o f b le ac h ed m e la ni n a n d d il a ti o n o f d e rm al v en u le s . ( 2 ) Th e in it i al e r y th em a ra p id l y f ad es , a n d t r ue s un b u rn e r yt he m a be gi ns 2- 8 h r a f te r i n i ti al e xp o s u r e to th e s un . ( 3 ) D il a ti o n o f t h e a r te r iol e s r es u lt s i n i nc r ea se d v a s c ul a r p e rm ea bi l it y , loc a li ze d e d em a , a nd pa i n, wh i c h b e c o m e m a xi m a l a f te r 14 - 2 0 h r a n d l as t 2 4 -7 2 h r. b . M a n i fe s ta t i o ns ra n ge f r om m i ld ( a s l i gh t re d de n in g o f th e s ki n ) t o s e ve r e ( f o r m a t io n o f b li s te r s a nd d es qu am a ti o n) . I f t he e f f ec t i s s e v er e , t h e p at ie n t m a y e xp e r i e nc e p a in , s we l l ing , an d b l is te r i ng . F e v e r , c h il ls , a n d n au se a m a y al s o d e ve l op , a s we l l as pr os tr a t io n , wh ic h i s r e la t ed to e xc e s s i v e s yn t he si s a nd d i f fu si o n o f p r os ta g la n din s . 2 . S u nt a n i s t he r es ul t of t wo p r oc es se s : a . O x i da t i on o f m el a n in, wh i c h i s a lr e ad y p r es ent i n t he e pi de r m i s b . S t im u l at i o n o f m e la no c yt e s t o p ro du c e a dd i tio n al m e la n in , wh i c h is s u bs eq u en t l y o xi d i z e d on f u rt h e r e xp o s u re to sun l ig h t ( 1 ) W it h i nc r ea s e d m el an i n p r od uc t io n , t h e m e l an o c yte s i n t ro du c e t he pig m en t i n to k e r at i n- p r od uc in g c e ll
