Pharmacology, 2nd Edition (Lippincott’s Illustrated Reviews)

--'''''''''''-'''-''

lippincott's Illustrated Reviews: Pharmacology 2nd edition

·- ... _,., >'---'

>

Lippincott's Illustrated Reviews: Pharmacology Mary J. Mycek, Ph.D. Department 01 Pharmacology and Toxicology University of Medicine and DentiSlry of New JerseyNew Jersey Medical School Newark, New Jersey

Richard A. Harvey, Ph.D. Department of Biochemistry University of Medicine and Dentistry of New Jersey~ Robert Wood Johnson Medical School Piscataway. New Jersey

Pamela C. Champe, Ph.D. Department of Biochemistry 01 Medicine and Dentistry 01 New JerseyUniversity Robert Wood Johnson Medical SChool Piscataway, New Jersey

Clinical Consultant (Antimicrobials):

Bruce D. Fisher, M.D. Department 0 r Medical Education Muhlenberg Regional Medical Center Plainfield,

Computer graphics:

Michael Cooper Cooper Graphics 48 Van Syckel Road Hampton, New Jersey

A •

lIpPINcan WILUAl'v\S & WILKINS

A\_... KI...... ~Y

. IlahimQre • New York • Lorldon U"""", "'i"", . Hong Kong, Sj.dney • T""yo

pt,i~ia

<_

'oe_'.'

><

, >

Acquisitions Edito<: Richard Winters Sponsoring Editor. Mary Beth MlJ
lJppincott-Ra~en Pub~shers.

Copyright

This book is prolected by copyright No pari 01 ~ may be roproduced. stored in a retrieval system. or transmitted, in any form or by any means-eleclronic. mechanical. ptlotoc:cpy. reoording. or othelWise-withoUt the pnor written pemlission 01 the publisher, e~cept for brief quotalioos embodied in critical artides a<1d revieWs. Printed in the United States of Ame
9 LIbrary of Congress Cataloglng-In-Publlcallon Data Mycek, Mary Julia PharmacoIogylMary J. Mycek, Rict1ard A. Harvey. Pamela C. Champe; c~nical consultant (antimicrobials). Bruce Fisher; compute' graphics. Michael Cooper.-2nd ed. p. cm -(lippir(:ot1's Illustrated Reviews) Rev, ed. of: Pharmacology/editors, Richard A. Harvey, Pamela C. Cnampe. c1992 Includes bibliographic relen!nces and inde~. ISBN o-7fl17-2413-9 (alk. paper) 1. PhalTllacology-()ut~nes. syllabi. etc. 2. PharmacologyExaminatioos. questions. etc. I, Harvey. Richard A. II. Champe. Pamela C. III. Pharmaoology. lV. Title. V.

""~

(DNL.M: t. Pharrnacology-e~aminationquestions. 2. PharrnacoIogy-oulines. QV 18.2 M99Sp 1997] RM301.14.P47 1997 6tS'.t'076-dc20 DNlMJDlC for Library of Congress 9&9180

C" Care has been taken to confilTll the accuracy of the information presented and to describe generally accepted practices. Howe~er, the author, editors, and publisher are not responsible for errors 01 omission or for any coosequences from applk:ation of the information in this book a<1d make no warranty, e~press or implied, witl1 respect to the contents 01 the publication.

The authors, editors. and publishe, have e~er1ed every effort to ensure lt18l drug selection and dosage set forth in this text are in aooordanc(l witl1 Ctirrent recommendations and practice al the time of publication. However, in view at ongoing research, changes in government regulations. a<1d tl1e constant flow of information relating to drug lherapy and drug reactions, the reader is urged to check the package insen for each drug for any Change in indications and dosage and lor added warnin9S and precautions. This is particularly important when the recornmeoded agent is a new or inlrequently employed drug. ha~e Food and Drug Administration (FDA) Clearance lor lim~ed use in restricted research settings. It is the responsibility 01 the healitl care provider to ascertain itle FDA status of each drug or device plaooed lor use in their dinical practice.

Some drugs and medical devices presented in thiS publication

........0<_,.".- ... ....-,. Colttriblliors: Henry Brezenoff, Ph.C. Depanment 01 Pharmacolo!7i and ToKicology University 01 Medicine and Dentistry 01 New JerseyNew Je<sey Medical School Newaril. New Jersey

Rachel Giuliano, Ph.C. Department 01 Pharmacology and ToKicoiogy University of Me<;k;ne and Dentistry of New Je<sey-New Jersey Medical School Newaril, New Je<sey

Richard Howland, Ph.C. Department of Pharmacology and ToKicology University 01 Medicine and Qwtistry 01 New JerseyNew Jersey Medical School Newaok, New Jersey

Joseph McArdle, Ph.C. Depanment of Pharmacology and Toxicology University 01 Medicine and Dentistry 01 New Jersey-New Je<sey Medical School Newark, New Je<sey

Victor Radice, R. Ph. B.S. Columbia University Consutting Pharmacist Wayne, New Jersey

St/ulelll Co"triblilors: Carah Biddle College 01 Pharmacy Rutgers University New Brunswick, New Jersey

Richard F, Eschle College 01 Pharmacy Rutgers University New Brunswick, New Jersey

."'" ... _..,>'---'

>

Preface Who will find this book useful lippincott's Illustrated Reviews: Pharmacology integrates and summarizes the essenlials of medical pharmacotogy lor (1) studenls in the health-fefated professions who are preparing for ;;oonsure examinatiorllior example, the Un~ed States Medical Lioensure El<8
How to use this book OUTLINE TEXT lippincctt's Illustrated Reviews: Pharmacology uses a unique expanded outline format which allows the mpid relliew and assimilatiOfl of facls and concepts. The current knowledge in the field of medical pharmacology has been ·predigested" and the relevant information has been recast in a hierafChical organizafiOn. Important topics are shown in bold plint, whereas the names of drugs are featured in an italic typeface. This organization enables the reader to readily scan a page to locale spec;tic information Of to find a particular drug. A phonelic prOfll.l<1CiafiOn guide for dnJ9 names assures that the reader will have a conversational famifiarity with Ihe ther~utic agents described in the book. Each chapter starts with a chari thai lists and classifies lhe drugs 10 be discussed in thai chapter. This permits the reader to immediately ufl(lefflland and remember \t1e sJgoiIicant relationships among the facts and concepls. ILLUSTRATIONS Lippincott's Illustrated Reviews:Pharmacoiogy contains more than 400 original illustrations, eact1 carefully crafted to compliment and amplily the teXI- This volume fealures a new kind of diagram in which pharmacologic processes are illustrated with a btend of graphics and explanalions. This marriage of words and art allows the reader to integrate a body of knowledge without the distraction of constantly shilting from texl to illustrations. For example. 10 sort out the Intricacies of fleIJrotransmltter synthesis and release in an ordinary textbook would reqo;re repeated skipping from text to fIQures. By contrast, the lIIus/rated Review (see lor example, FlQUre 4.3, p.31) reveals the major steps and their significance at a glance.

<_'OC50'."< __ ""-"

<-- •- - -..., """"'" .. _ .... >

CROSS-REFERENCES WITHIN THIS BOOK

Lippincott's Illustrated

Review:Pharmacdogy not only perrnrts the easy assimilatioo cI pharrnacolcgic lacts and concepts blll also provides an exlensMl netweI1<. 01 mere than 400 cross-references to ctl1er relevant rnformatioo in the vollXl1e. Thus. when readers encounter a new blcck 01 inlCfffiatien. they are immediately directed by page citaticns to Il!lated material that reinlorces and e~pandS the criginaJ infcnnaticn. This elaborate matriK cI references pl"ovides a cress lertilization that increases Ieaming and retention. The student ends up with the "the big picture."

CROSS-REFERENCES TO OTHER BOOKS IN THE SEAlES A unique featu.e cI this volume is the large number of references to Uppinooft"s lIIustraled Reviews: Biochemislrr, which is the biochemistry volume in the UppincoII series. Designated as (nroUnk Il!Iereoces, they all! lecated at the end 01 each chapter. This peffilits a reader with an intereSf in learning additional inrcrmalicn related fo a particular topic to Il!adily lecate relevant material covered in the biochemistry review. InfoLink also emphasizes the interrelationships between these biomedical disciplines-a skill that is increasingly being tested by the USMLE. Step I.

QUESTIONS AND ANSWERS A total of mO'e fhan 200 practice Questions {ol the Iypes used by the Naticnal Beard cI Med>cal EKaminers and other standardized test wl'iters} are inclvded at the end cI each chaplef so that readers can check their progress in mastering the mate.ial. Answers with eKplanaticns are provided so that the reader knows beth the CClTect answer and also why the distractors in the multiple choice Questions are incorrect. Tt>ese answers and their eKplanallons all! juxtapcsed with fhe original Queslions in a special soctien at the end clthe bccI<. Thus readers can confirm lhe corre<:t answers to a group 01 study questions withcut the disorientation cI flipping Irem page 10 page.

FINDING INFORMATION An eKtensive indeK of mere than 4000 entries permifs the reader 10 instantly locate specific inlormation. Tt>e indeK includes oommonly used trade-names 01 drugs. Readers should thumb through this carefully coordinated review of therapeutically useful agents .... they may be surprised that learning pharmacology can be SO enjoyablel

·....... .."._--,. "._

• Acknowledgments We are grateful to the many friends and colleagJ6S who generously contributed their fime and effOf1 to help us make 1t1is book as accurate and as useful as possible. We would like to acknowledge the contributions 01 Drs. Zigmuod Kaminski, Edward J. Ftym, Lester A Su~atos, Uri Lopatin and Kafui DeMasio who provided many helpful comments. We WOIJld pa
<_

'oe_'.'

><

, >

., Contents UNTT I; ''''fool/dum to I'ttnrm"co/og.v Chapter 1: AbsOfJllion, Dis1ributlof1, and Elimination of Drugs Chapter 2: Pharmacokinetics and Drug Reoop!ofS 17

UNTT II: Dnlgs A/frdin8 1/,( Au/anomie Nm<Ju5 Sys'ml Chapler 3: Chapter 4: Chapter 5: Chapter 6: Chapter 7:

The Autonomic Nervous System Cholinergic Agonists 35 Cholinergic Antagonists 45 Adrenergic Agonists 55 Adreoerg<: An1agonists 71

27

UNIT 11/; Drugs A!frc/i"8 1/" Ce"tml NmJOus Sys'ettl Chapter Chapter Chapter Chapter Chapter , Chapter Chapter Chapter

6: Treatment of Parkinson's Disease 61 9: Anxiolytic and Hyprclic Drugs 89 10: CNS S~mulants 99 11: Anesthetics 107 12: Antidepressant Drugs 119 13: Neuroleptic Drugs 127 14: Opioid Analgesics and Antagonists 133 15: Drugs Used to Trea1 Epilepsy 143

UNTT IV: Drugs A/frdi"8 Il" CnnIiot
151

UNTT V: Dnlgs A!frc,in8 OtJ,rrOr8~u Systems Chapter 22: Chapter 23: Chapter 24; Chapter 25: Chapter 26: Chapter 27;

Drugs Affecting the Respimtory System 217 Diuretic Drugs 223 Gaslfointes~nal and Antiemetic Drugs 235 Hormones of the PitlJitary and Thyroid 247 Insulin and Oral Hypoglycemic DnJgs 255 Steroid Hormones 263

UNTT VI: C1'CfIlOI"(rfII",ul~ Drugs Chapter 26~Principles of Amimicrobial Therapy 27'9 Chapter 29) Folate Antagonists 289 Chapter 30; Inhibitors 01 Gell Wall Synthesis 297 Chapter 31: Protein Synlhesis Inhibitors 311 Chapter 32: Quinolones and Urinary Trael Antiseptics Chapter 33: Antimycobaclerial Drugs 331 Chapter 34: AI1~lIJngai Drugs 337 Chapter 35: Antiplotozoal Drugs 345 Chapter 36; AI1thelmintic Drugs 359 Chapter 37: Antiviral Drugs 363 Chap1er 36: Anticancer Df\l9S 373

323

1

.........,., ........ --'>

UNrr VII: 'h,n-l,ojItu"",,,1ory Drup mid lIul~ Chapler 39: Anti-inIlatrVnalory Drugs 401 Chapler40: AulamMts and A,'aooid ArUgonisIS Appenlb:.llluslraled Case Sbdjes

419

429

I'- hMlr:..qy UpdIIl~ Chapter 8: Trealmen1 al Parkin$On'$ Disease 443 Chapler 15: Drugs USed to Treat [1-'_)1 445 Chapter 20: Drugs AIl«:tio '9 8Iood 446 ~ 21: Anlitlypeiipide",it: Drugs 449 O\apef 22: Drugs Afle
Chapter 41: Immunosuppressants 470 Chac1er 42: Drugs Used 10 Trelll Obesity 414 Cha¢er 43: Drug Used 10 Treat Osll!QjlOl'Ol>is 416 Chapler 44: Miscellaneous Drugs 471

Index 479

• "'" .". 50'"

> • _

.... _ _ , >

Li ppi ncott's Illustrated Reviews:

Pharmacology 2nd edition

<.........,., ><---' >

< . . - . " _ _"",""""",' """'U . . _ . "" >

UNIT I: Introduction to Pharmacology

Absorption, Distribution, and Elimination of Drugs I. OVERVIEW

I Drug at site 01 admlTistralion I

The aim 01 drug therapy is to prevent. cure, or control various disease states. To achieve this goal, adequate drug doses must be delivered to the target tissues so that therapeutic, yet nontolC.ic levels are obtained. The clinician must recognize that the speed 01 onset 01 drug llction. the Intensity 01 the drug's effect. and tM ckJration 01 the drug action are controlled by four fundamental pathways 01 drug movement and m<xlifi. cation in the body (Figure 1.1). First, drug absoiptlon from the site 01 admlnislrlltion perm~s entry 01 the thefapeutic agent (either directly or indirectly) Into plasma (Input). second, !he drug may then reversibly leave !he bkxlcl stream and distribute into the inte<stllial and Intracellular lluids (dis\Iibution). ~, lt1e drug may be metabolized by the liver, kid-ney, or oIher tissues. Finally, the drug and its melabol~es are elimW1ated lrom the body (outpul) in urine. bile. or 1eces. Chapte<s 1 and 2 describe hoW knoWledge oIlhese processes Inhuences the clinician's decision as to the route 01 aOOlinistration, drug loading, and dosing intl!fYai.

0 Absorption

1

(InpuI)

~fJDistribution

Drug In tissues

-I-m Metabolism Melabollte(s) in tissues

/

B Elimination

II. ROUTES OF DRUG ADMINISTRATION

/

The route 01 admlniSlratiO<\ is determined primarily by the properties 01 the drug (such as water or lipid sofubility. ioniVltion. etc.) and by lt1e therapeutic: objectives (lor elCafTlple, the desirability 01 a rapid onset 01 actior1 or the need lor long-term administration or restrictlon \0 a local site). There are two major routes 01 drug administration, enteral and parenteral. (F'lIure 1.2 illustrates the subcategories 01 these routes as well as other melt10ds 01 drug administration.)

{outpull

Drug and/or metabolite(s) in urine, feces. bile Figure 1.1 Schematic ,,¥esentatiorl 01 drul/

absorption, distribution, metabolism and elimination.

. _,__. ..._c._. --_." ...- _ ' _ "

.... P. C ""'"

'''''''.'-'.'''---''

. . . . . . . . . .- . . . . . - . . - ' ........... _ . '" >

2

1. Absofption, D;stributlo<1, am Elimination of Drugs

A. Enteral 1. Oral: Giving a drug bv mouth is the most common route 01 administration. but il is also the most ~ariable. am requires the most complicated paltlway to tM tissues. Some druQ$ are absorbed lrom the stomal:h; however, the dJodenum is often the major s~e 01 entry to the syslemic circulation because 01 ~s larger ab50rptiYe surface. [Note; Most druQ$ absorbed lrom the gastrointestinal (Gl) tract en\(!< the pottal cilCUlation and encounter the liver before they are distributed In the general circulation (figure 1.3). Rrst·pass metabolism by the intestine or li~er limits the ellicacy of many druQ$ when taken orally. Fo.- example. more than 90% of n;troglycerin is cleared during a single passage through the li~er.l Ingestion of druQ$ with lood can innuance absorption. The presence of tood in the stomach delays ga6lril: emptying time so that druQ$ that are destroyed by add, for e>
2. Sublingual: Placement under the tongue allows the drug to d~­ fuse Into lhe capillary netwol1l and ltlerefore to enter the systemic: circulation directly. Administration 01 an agent bv this roule has the advantage that \he drug bypasses the intestine and li~er and is not Inactivated by metabolism. 3. Reclal; Fifty percent oIlhe drainage of the rectal region bypasses the portal circulation; thus ltle biotranslormation of druQ$ by the ti~er Is minlml~ed. Both the sublingual and the rectal routes 01 administration ha~e the additional advanlage that they Pfe~ent the destrudion of the drug by intestinal en;oo;ymes or by low pH in ltle stomach. The rectal route is also usetul if lt1e drug Induces vom'ting when given oral~ or it the pa~ent Is already ~omifing. [Note: The rectal route also is commonly used to administer

antiemetic: agents.l 6. Parenteral Parenlelal administration is used lor drugs thai are poot1y absorbed 110m the gastrointeStinal (GI) tract, and tor agents sucl1 as in&J/jn Ihal ale unstable in lt1e GI tract. Parenleral administration is also used !or treatment of unconscious patients and under circumstances that require a rapid onset of action. Parenteral administration provides the most oontrd over the actual dose 01 drug delivered to the body. The three major parenteral rCllJtes are intra~ascular (intra~enous or intra·arterial), intramUSCUlar. and subculaneous (see FIgure 1.2). Each has its advantages and drawbacks. 1. Intra~ascular: Intra~eoous (IV) Injection Is tI1e most common par-

enteral route. For drugs thaI are not absorbed mally, there is often no other choic:e. With IV administration, the drug avoids lt1e GI tract and. lherelore, first-pass metabolism by the li~er. This rCllJte permits a rapid effect and a maximal degree 01 oontrd c:Nef the drculatIng levels 01 the drug. However. unlike drugs present in the GI tract, those that are injected cannot be recalled by

._,....,., .. _---,.

• . . . . . . .- -_ _ 0"

""""",,," . . _ . PI' •

II. Routes 01 Drug Mnioi&l1allon

3

strategies such as emesis or blnding 10 activated charcoal. tntraYeI'lOUS injection 01 some drugs may inlrodoce bacteria 1:hnlt.9l mntaminalion. induce heoldfSis, c.- cause dt8" adverse reKUlS by !he kID rap:! delivery 01 h9l WI ..... lIIa1iol'ls of drug IU the plasma. and -...-.. Theiebe, the rale of ~ ITl.ISl be caretuly~. smilar WlICeiII$ apply to ftra-lll'leo. (tA) i;eded ltug$..

:t

_.......,_fhe

CIr"I ...... '

$

iid ftI

. , _..... i f , _

...... --... ----~­

•

Inu.m~r 11M): 0fugI ildol'oisIered i'llraml5Cl'a'1y eao be aqueous solutions or speciahed ~ preparaliulls often a

suspension 01 drug in a nonaqueous vehicle, such 85 elhytene gIycul or peanut oil. Absurptiun 01 drugs in aqueous solution Is last.l>Alereas that from depol preparatiuns Is sloW. Aa the vende diffuses out 01 the muscle. the drug precipitates at the site 01 lnIoctkn The drug Ihen dissolves sloWly. pro~ng a sustained dose over an I!~lended period 01 lime. Ar1 e~3fTlll& Is sustainedrelease haluperidol decsno8te (see p. t30). whoSe 6IoW diffusion from the musde prOOJces an extended neuroleptic etfecl. 3. SubcUlllrleOuS ISC): This route 01 admillislraliun, like lhal. of 1M ~1jecOOl ~ requires absorption and Is 6JJl'lf!\'A'IaI $lOWe" than the IV route. SC iiection ~ the risks assodaltld Mth .....avasar tar il~~ (NoIe: Mn.Ae amouru 01 ep;-"il1e_ 6JJl11E!tio118S Wlllbilled with a drug 10 restrict its area of action. f;:loiii!jOh.... ads as a local vasu:.ui&bidtw and decreases remcwal 01. clrtJli, such as lidocaine, lrorn !he tile of adl1illia.tlation.l Oltler _ _ pies 01 G-ugs ~ SC aollii>i&lralion io'dI.de aoitls Sld> as sia&tic Cellhal life ifrllIanIed lor Ionp-term aetMty (see p. 268). an:l atsu pm~ medlartIcal p..mp5 that can be io'llllanted 10 deliver insUin in some diabetic&.

C.OIher 1. lnh8lation: tmalallon ~ Ihe rapid delNery 01 a drug ocross the large surface area oIlhe mucous mentlranes 0I1he resplralory lrael and pulmonal)l epilhellum. producing an elfecl almosl as rapdy as by w,lravenous Injection. This route 01 admlnisualion is U5ed lor drugs IhaI life ga&eS (lor el
etIects are ~ 1_ p. 219). 2.InWnual:De ilL"" ssinisdl.· edirtra'\ll$llllyinlhel1ealment of Babelll5 Qipicl!_: saIrnon caUk».~ a pev!'
nro-

3. Inlnllheo;alllnlnlvenlriclllar: It is ~ necessary IU clJce drugs directly into Ihe cerebrospinal flt.id (CSF). such as metI'Johl!Xate in llCUIe ~ leukerria (see p. 379).

4. TopkaI: Topical Bfl9Iicatiollli used when a tocaI effect 01 \tie drug is desired. For ellB./'r1lle. dotrima;roIe (see p. 343) Is applied as a

0NsJa odmlo ...... iid ora8y .._e..-ed"'_ _.....,.bee..--,. ..... ' ..

.......

'belen

oa ....... _ ... "'-...

Fht1>858 metabofisr" tall CIa:U WiIh c.-aIy diM· lld 0'ugJ.

(IV ... illaoerilUS).

·....... _,.,.<---,. •

I. Absorption, Distribution. and Elimination 01 DnJgs

--_.

01 ..._ _

dr\lg ltl""""", .... c,*,neI

""'*"'.

cream directly to the skin in the lreatmant 01 dermatophytosis, and atropine (see p. 41) is iflSlilled directly into the eye 10 dilale tha pupil aod perm~ measurement 01 refractiva errors.

5. Transdermal: This route of administration aChieves systemic effects by application 01 drugs to the skin, usually via a transdelTl18l palctl. The rate 01 absorption can vary markeo:ly depencling upo<1 the pt1y$ica1 characterlslics 01 the skin at the sita of application. ll1is route Is moSl ollan used for the sustained delivery 01 drugs, sum as the arltiangifllll drug, nilrogyc;erin (see p. 175).

III. ABSORPTION OF DRUGS Absorplio.' is the translef oIa dl\lg trom ~s site 01 administratioo to the blood stream. The rate and efficiency 01 absorption depeod on the roule of administration. For intravenous delivef}'. absOfplion is complete. that Is, the total dose 01 drug reaches the syslemlc circulation. Drug delivery by other routes may result In only part,&1 absorption ancl thus lower bioava~abiHty. For el<3fT1p1e, lhe oral route requires that a drug dissolve in the gastrointestinal fluid and than penetrate tha epithelial cells ollhe intestinal mlJCOSa: disease states or lt1e presence oIfcod may affect lhis p.OCE!ss. A. Transport of drug from the Gl tract

figure 1.4 Sdlemalic rep<esentation of drugs crossing cell membrane 01 epithelial cell 01 gaslrointeSlinallr&CI.

Depending on their chemical properties, drugs may be abSOfbed Irom the GI tracl by eithef passive diffusion or active transport.

1. Passive diffusion: The driving force for passive aboorption 01 a drug is lt1e oonoenlration gradient across a membrane separating two body compartments. that Is, the drug moves from a region 01 high concentration to one 01 lower ooncentration. Passiva di!1usion does nol Involve a carrier. Is not sawrable. and shows a low structural specificity. The vast majority 01 dl\lgs gain access to the body by lt1is mechanism. Lipid-soluble drugs readily move across most blologlcaI membranes, wtrereas watet-soltJble drugs peneITale the cell membrane It1roogt1 aqueous ctlaNleIs (F
2. Active InInsport: This mode 01 drug entry involves specific carrier proteins that span the membrane. A k!w drugs that closely resem· bla tho structure 01 naturally occurring melabolites are actively Iransponed across cell membranes using these specific carrier proteins. Active Iranspo<1 is energy-dependent and is driven by the hydrolysis 01 adanosine tript10sphate (see figure 1.4). II is capable 01 moving drugs against a COI"Centration gradient, that is. from a region 01 low drug concentration 10 one 01 higher drug ooncentration. The process shows saturation kinetics lor lha carrier, much in the same way that an enzyme-catalyzed reaction shows a maximal velocity at high oob$lrate levels when binding 10 tha enzyme is maximal.' B. Effect 01 pH on drug absorption

Most drugs are either weak acids or Wilak bases. Acidic drugs (HA) release a H' causing a charged anion (Ai to form:~

<_f.. _••'.<

,.

< """" ......... ~ , """"'" -

_ . '" •

Ill. Absorption of Drugs

,

HA " Weak bases (eW) can also releaSll a W; however, lf1e protonated form 01 basic drugs is usually chaIged. and loss 01 a proton produces the uncharged baSIl (e).

eH'

p

e+ H'

1. Passage 01 an unckllrged drug through II membmne: A drug passes through membranes more readily il it is uncharged (Figure 1.5). Tb.Js. for a weak acid. the uncharged HA can pl!fmeate lf1rough membranes, and K cannot. For a weak base, !he uncharged form, B, penetrates through the cell membrane, but BH' does not. Therefore. the effective concentration 01 the pl!fmeable form of each drug at its absorption sIIe is determined by the relative concentrations 01 the charged and uncharged forms, The ratio between the two forms is, in fum, determined by !he pH at the site 01 absorpIion and by \I1e strength of the weak acid or base. which is represented by the pi<., (FIgure 1.6). (Note: The pI<. is a measure 01 the strength of the interaction 01 a <:OmpO\Jnd with a proton. The lower lt1e pI<. of a drug, fl1e stronger the acid. Conversely. the higher the pK •. the stronger the base.] Distribu!;e,n equilibrium is ad1ieved when the permeable form of drug achieves an equal concentration in all body water spaces. Highly lipid-soluble drugs rapidly cross membranes and often enter tissues at a rate determined by blood flow. 2. Detetmination 01 how much drug will be lound on either side 01 II membmne: The relationship 01 pK. and the ratio 01 acid·base concentrations to pH is expressed by the Henderson-Hassel· bak:t1 equation3:

pH"pKa+ log For acids: pH. pK.

[non·prOlOnated species] (protonated species]

BWeakacid

,.

II

HA""",

-m ..,

Weak base

.... ---

IAl + log [HAJ

IB' For bases: pH "pKa + log (SH'I This equation is useful in dete,mining how much drug wilt be found on either side of a membrane It1at separates two compartments that diller in pH, for example, ston'llld1 (pH 1.0 to 1.5) and blood plasma (pH 7.4). {Note: The lipid ooIUbtity 01 the r'lOl"Oonized drug diractly determines its rate 01 equilibration.] C. Physicallaclors inllueneing absorplion 1. Blood flow to the absorption iiiif'!: Blood flow to !he intestine is much greater than the flow to the stomach; thus absorption from the intestine is favored rNer that from the S10mad1. [Note: Shod<

'S
,,,f,,,,,,,,,,,,,.,.,.,.,, _"' l I l i s - '

Figure 1.5 A. Diffl.lsion of non-Ionized form 01 a weak acid fhrougl1lipid membrane: B. Diffl.lsion of non-ionized lorm 01 a weak base throo~ lipid meml:lrarle.

< ,.,.<---,.

< . - .....- - - -............ _

6

.... >

I . Absofption, Oistribullon. and Elimination 01 Orvgs

_

WI>en pH io .... tho" pIC••

Ihe ~ ,"""" >IA_ aH' p<e
... ,

•

,

--pH io lI"'.tttr "'-'

~

A·_a ..- . ..

,

...

,

•

•

"

"

Agure 1.6 The distribution 01 a drug between ~s ionized and un· ionized fOflTl depends on the ambient pH and pK" o1lha drug. For iIIustralive purposes, the dfUg has boon assigned a pK" of 6.5.

sevi!rely reduces bkxxl llow 10 cutaneous tissues. thus lTInirri;ting the abso
2. Total surface erea evailable lor absorption: Because the

Intes~no

has a surface rich in microvilli. " has a surface area about 1.000 times that of the stomach; thllS absorption 01 the drug across the intestine is more efficient.

3. Contad. time al the ab6Ofplion sorface: II a drug moves Ihrough the GI tract very quickly. as in severe diarrhea, it is not well absorbed. Converse~. anything lIlal delays the transport 01 the drug tram the stomach to the intestine delays the rate of absorption of the drug. [Nole: Parasympalhetic input increases the rate gastric emptying, whereas sympathetic Input (prompted, lor ei<.amp!e, by exercise or stress'ul emotions) prolongs gastric emptying. Also, the p.oesence of food In lhe stomach both dilutes the drug and slows gastric emptying. Therelore. a drug taken with a meal is general~ absorbed more slowly.1

0'

IV. BIQAVAILABILITY Bioavailability is the fraction 01 ad'Tlinistered drug that read1es the sys· temic crcuation. Bioava~ability is expressed as the 'raction o1lll:lfTOristered drug that gains access to the systemic circuation in a c:hemieaJty I.lnChanged form. For eKall'l'le, if 100 mg 01 a doug is adnlnlstered oroJty and 10 mg a this drug is abIlorbed unchanged. the bioava~ability is 10%. A. Determination 01 bloavailability

Bioavailabili!y is de1ennined by comparing plasma levels 01 a drug after a partiaJlar route 01 administration (for example. oral administration) with plasma drug levels achieved by IV injection. in which all 01 the agent enlers the circulation. When the drug Is given oralty. only part 01 the administered dose appears in the plasma. By plot·

<_ ••, _l.r.< ,, _ _ ,

>

< ..,... ..... - . .

,,'t"

"""'U ... _ . W >

V. Drug Distribution

ling

plasma concentrations 01 the drug versus time, one can measure 1I1e BIea under the curve (AUG). This curve reflects the extent 01 absorption oItha drug. lNote: By delin~ion this is 100% for drugs delivered intravenously.! Bioavailoo;li!y 01 a drug administered orally is the ratio of the area calculated lor oral administmtion compared wi1l1111e area calculated lor IV injection (F>glJ(e 1.7).

_.UoolllHty.

...uc_

.100

"'UC Inje<:lecl

B. Factors thai influence bioavailability 1. First-pan t>epatif;: metabolism: 'Nhen a drug is absorbed across lhe G! tracl. it ooters the portal circulation before entering the sys· temic circulation (see F'Ilure 1.3). II the drug is rapidly melaboII-ted by the liver. the amount 01 unchanged drug that gains access to the systemic circulation is decreased. Many drugs. SlJCI1 as propranolol or lidocaine. undergo significanl biotranslormation during a single passage 1I1rough the fl\ler.

2. Solubility of drug: Very hydrophilic drugs are poorly absorbed because oIlheir inability to CrOSS 1I1e lipid·rich cell membranes. Paradoxically. drugs that are extremely hY!lrophobic a,e also poorty absorbed. because they 81e totally insoluble In the aqueous body fluids and, therefore, camol gain aooess to the sorlace 01 celis. For a drug to be readily absorbed it musl be largely hY!lrophobic yel have some solubility in aqueous solutions.

3. Chemical Inslability: Some drugs. suCh as penicillin G (see p. 302). are unstable in the pH 01 !hll gaslric contents. Others. such as iflSlJlin (see p. 258). may be deslroyed In the GI tract by degradalive enzymes. 4. Nature 01 the drug formulation: Drug absorption may be altered by factors unrelated to the chemistry 01 the drug. For example. particle si~e. salt form, cryslal polymorphism. and the presence 01 excipients (such as binders and dispersing agenls) can influence the ease of dissolulion and. 1I1efe!ore. alter tI1e rate of absorption. C. Bloequlvalenca Two related drugs are bloequivalent il Ihey show comparable bioavailability and similar times to achieve peak blood concootra· lions. Two related drugs with a Sil)"l~icanI diflefence In bioavailability are said to be bioinequl\lalenl.

O. Therapeutic equivalence Two similar drng5 are therapeutically equl\lalent il they have comparable efficacy and safety. INote: Clinical ellecliveness oIIen depends both on maximum serum drug concentrations and the lime after administralion required to read! peak concentration. Therefore. two drugs that are bioequivalenl may not be therapeutically equivalent]

V. DRUG

DISTRIBUTION

Drug distribution Is the process by whietl a drug reversibly leaves the blood stream and enters the interst~ium (extracellular fluid) and/or tI1e cells of Ihe tissues. The delivery 01 a drug from the plasma to the inter·

Figure 1.7 Delermination of the bioavailabllity of a drug. (AUC = area under curve.)

•

,

,

-

_ .. ,>

• c_ ....

~-..-,

.....,..,. .. _ .....

1. Absofplion, Distribution. and Eimination of Drugs

~

Structure 01 endothelial iii ceMs In llvef

stiIiI..m pri'nariIy dtpei ld6 on blood flow, capiIary penT at OfCy, lh8 degee of bildllll of the drug to plasma aod Iis&ue proteins. and the relaliYe hyQqhlbicily d the Oug. A. Blood t\ow

The rale of blood flow to !he tis6ue capWaries varies widely as • resu~ d lhe unequal dislrb.otion of can;Iiae output 10 the Ifarious organ&. Blood flow 10 !he brain. h4r, and ~ is geater"'" that to !he $keletal muscles, whereas IldipOGe tissue has a SliI k:Mef . . of blood Ilow. B. C.plllary permNbility B "

r.tI

Structure 01

.., brain capillary

.........W'O_,.

•)

_.....ib."

•

~

..-_.-.. -

=~_::--"" ......... ---pl.,' ".. M

'

_ _ _ poe.a,,"

.....,...-.ncn_ ."~.lho_.

r.!I PermeabUity of

.-:I brain capillary

_.

Ga4>iRary penneability is detenninecl by capillary slnJcture ard by the chemical nature of the drug.

ibI • •

1. Capillary structure, Capillary structure varies widely In tB
tral nervous system (eNS) or be actiIfely transported. For ~ . Ihe large nEUral ar'I'R acid earrier lI81i$pOl11 - - . «p no the brain. l...ipiO-sokJbI drugs readily pellellale no the eNS. since they can dissotIfe in the membrane 01 the 1M dJll eels. Iorized or polar drugG generaIy lail to enIeI the CNS. Ihey are lA'\lltIle to pass Ihrol.9'1 the endoIheIiaI cells d the CNS, Y
""iaI

sn:e

2. Drug .tfllclure: The chemical nature 01 the drug strongly if1l1u· ences Itl abilily to cross 0011 membranes. Hydrophobl<: drugs. which have a uniform distributlon of electrons and r() net ctla.rge. reacttv rT'IOIfe across ITlO6I bloIogltat membranes. These ~ can dissotve In the lipid rne"banes and !helelae pi!flll8dle lh8 enIiffI cers surlace. The major ladOr Wluen::Wlg!he hydI,.,lh'oti;: drug'. dislrhtion is Ihe blood lkJw lo the area By C>::lWaSl. l'IydI upI ilic tInJgI, ~ haIfe eilhef a fllII'UliIIanTl diIlrb.DJn of EI e bOi .. Of a postive or ~ charge, 00 not readiIV penetrate OBI membranes and IT'USl: go Ihfrogh lhe slil: ;.adioo~ (see FlgUfe 1.8).

c. BIndlng 01 druga to protein.

Flguffl 1.8 Cross section ofliYer and brain capillaries.

AeIfasible bii ... og to plasma fO'oteiI'\IleCJ,IeItefS(Wgs WI a rton-ditIu$llle form .00 slows Iheir trans'er out 01 the vaS" oIar ClClfT1lB."mef1.. Billdioog III relatiYely non-sele clive 8& 10 ctJeo,lical strucllKl and takes plaoe III siles on the protein to Y
.- '.' ..,., ........

.....--,.

..........-

,-', """""

VI. Volume 01 Di&lrlbulloo

.. _. ,... 9

concentralJon ot the Iree drug decreases due to elimination by

metabo/lsm or ellCretion. the bound drug disoociates from the

pr0-

tein. This maintlllns the lree drug CClnC8lIration as a constant tractioo 01 the total drug In !he plasma. (See p. t 1 tor further dlsmss'on 01 drug binding by proteins.)

VI. VOLUME OF DISTRIBUTION The WlIume oIlislrilution (Vct) ill a hypdhelical volume of ftuid no 'Iotlictl!he drug Is ~ted. AlItlougI the voItn1e 01 clistriWtion has no physioIogiea! Of phy5lcaI buls. h Is ~ useful .0 (;(lI'I'lIafe !he distftJulion of a drug WiIh the ~ 01 the water ~ in !he body (F"'!P'8 1.9).

.... Willer oompartrnenb 1ft the body

Once 8 drug 8I'llerS!he body. from ...-.at_lOUIe 01 adlli;"iotJ3lioI~ it has the poB'ItiaIlO distribute Ir'*l any one 0I1hree "', db . .,. distinct oornpanments 01 body waler, or 10 bec:ome sequestered in liOfTl8

--_ '.

ceIlJar sU.

1. P&nmII cClnlI*b••,I: II a drug has a V«y large rmleaFv ~ or binds eldel'ISM!tf 10 plasma proteins. ~ is 100 large 10 fTIOYe lllA tIln:itql the eridolhefe' sliI juldbll of Ihe ~ an:! Ih.Is Is ellecti4y traANld wllI*Ithe plasma {va5Ol.arj ~ As a ( D llQllel"iC8,!he drug disbtlUlelIln a YObne {Itle plasma)1hal. is abaU 61l. oIlhe body we9'oI or. In a 7O-kg rdotillJal. abou: 4 L 01 body IUd. ~ 810160"-(' (see p. 314) show IIi& 1yp8 01 cislrtIut:ion. 2..

~I"'. tIuId:: II the drug has a low molecular we9ll but Is hydiophilic;. it can fTIOYe lhrOugl'Ilht er doll ..... &iii jul'lClions 01 the I .... ilaries irto!he InlenitItiaIlUd..lto..' _ , hydIqAiic drugs camoI. fTIOYe ~ !he """ '0 "ll!S 01 oelIs 10 et'fer the waIer

~ inIide !he eel. Therefore. lhe6e drugs dislribute ir*l a vol-I.mll ItIat is tht M.I'Il 01 !he plasma water IlI'ld the in1erstitiaI 1100,

-

__

-w

'Iotlictl klgethet constilute !he eldr8ceIlAaf tuid. This Is aboU 20"0I1tMi body'N8iglL or about 14 L in a 7O-kg incIiYDlaI.

3. Totlil boctv .... al.' lithe dnJg has a low rmIea"w weight an:t is hydiop'diic:, ~ can not only IT1CMI Ir10 Ihe intefSliIium 1hrDtJs1I1he sliI jln;:tiona, btA can also ll10Ye lhrOugl'Ithe eel membranes irto the inlraoeIular IUd. Thti dnJg tIleretora distributes inlo a volume 01 aboul6O% 01 body weig1I. or about 42 L in a 7G-kg ~.

pregnarcy. the Ietus may lake up drugs ard \h.lS iro'ease the V". 0!\.0gII1UCh • 1Nop«1ta1 (see p. I t 5). v.tlich are stored in fat. may atso I\ave oousuaJty higl YoII.mes 01 dslrbution.

4. Other sites: In

B. The 8pop3fenl volume 01 di'lrlbutlOf'l A drug rarely assoclate6 exclusively with aNy one 01 the water compartments of the body. Instead. the vast majority 01 drugs dislr'bute Into seve.1ll compartm8f1ts. ott9f'l av;cry binding cellular components. lor example. lipkls (8burdant In adipocytes and ce" membranes).

'-1/

--

----

@,,-.--

Figu.e 1.9 Relative sl2:e 01 various dlSlribJlion volumes within a 7G-kg Individual.

<

,.,.<- _,.

< ...... . . . - - - . . . . . . ' ........... _ . AI'

"

1. Absorption. Oistribulion. ard Eliminatioo 01 Dr'vgs proteins (abundant In plasma and within cells). or nucleic acids (abundar1t in the nudel 0' cells). Therefore. the volume into which drugs dist,.;oote is called the ;JWarent volume 0' distribution or V d_ 1. Determination of V.

'\

~,~ _o-----~--I

-

I~=:""

." I I

"'--o ,

,

1- Rotc>Id

"""

2

3

--. 4

a. Disllibulion of drug In the llbsenc:e 01 elimination: The appar· ent volume into which a drug distributes, V d, is determined by Injection 0' a standard dose of drug. which is initially contained entirely in lhe vascular system. The agent may then move from the plasma into the interst~ium and into cells, causing the pasma concentration to decrease with time. Assume lor simplicity that the drug is not eliminated /fom the body, tI1e drug tl1en ach>eves a unHorm concentration that is sustained with time (FtgUre 1.10). The concentration within tl1e vascular compartment is the total amount 01 drug aclminiSlered divOded by the volume into which ~ distributes, V.:

injection '" d
FIgUf1l1.10

Drug concentrations in serum aile< a single injec1iof'l of drug at time '" O. AsswIe that drug distributes blJl is not eliminated.

C " Plasma concentration 01 drug 0 .. Total amount 01 drug in the body FOf example. ~ 25 mg 01 a drug (0 .. 25 mg) is administered. and tl1e piasma concentration is 1.0 mg/L, then the V." 25 mg/1 .0 mg/L .. 25 L. b. Disllibution of drug when eliminatIon 1$ present: In realily. drugs are elirrinated from the body. and a plot 01 plasma concentration versus time shoWs two phases. The initial decrease in plasma concen\lation Is due to a rapid (J;stribution phase in Which ll1e drug is transfel1'ed 'rom the plasma into the inter· strtium and the intracellular water. This is followed by a sloWer elirrinalion phase during wIlich the drug leaves the plasma compartment and is lostlrom the body. lor example. by renal or biliary eli
FIgUf1l1.11 DJlJl;l ooncentratioos in serum after a single irfeclion of drug at time '" O. Assume ll1at dnJg distrbutes and is subsequently eliminated.

c. Calculalion of dntg concentrlltlon il distribution were insta.... tan_$: Assume that the elimination process began at the time of Injection and continued throughOut the distribution phase. Then the concentration 01 drug in the plasma, C. eatl be extrapolated back to zero time (lhe time 0' injection) to determine Co. which Is the concentration ot drug that would have been achieved if the distribution phase had oceurred instantly. For example, ~ 10 mg of drug is injected Into a patient and the plasma c:oncentration extrapolated to zero time concentration is Co = 1.0 lTlQIL {from graph shown in Fogure 1.12), lher1 V. = 10 "'1)'1.0 mg/L .. 10 L. d. Uneven drug distribution bet\,ee" compartmenlll: The appar· ent volume of distribution assumes thai the drug dislributes uniloonly in a single compartment_ However. most drugs dis· triblJte uneverty in several compartments and the volume 01

·....... _1."._ . . _"

• """" • " ,_ _00' .....,... _ _ .... '

VII. Binding 01 Drugs to Plasma Proleins

"

distribution doeS nol (Iesc.ibe e real, physical volume but

ralller renects !he ratio 01 (Irug ifl the ext.aplasmic spaces rei from clinical sludies) is a higher conceroalion, ~. The clinician needs 10 know hoW muctl additional dn.og sholJd be 1ldI,.lIst8led to bring lIle OIcIAaling Ie'o'lll 01 clrug 110m C. to~,

Vd • C, •

~

01 drug ~ in body

Vd • ~. llfTlOI.rII 01 drug In !he boctf needed 10 adIie."Ihe;' "ed plasma OOI ..... oba!ion

The (Ilft8lence between Ihe two .. alues is the additional closage ne I :'ed, whic:tlllQUlllli VdlCr-C,I. 2. EffeCt 01 • larva V. on the ha...... of. drug: A large Vd has an ~ inIluencIII on !he haII-ile 01 a drug, since drug eli1WIalion depends on !he ~ 01 hilled 10 the her or kidney (or ~ 0fgiItl5 'At1efe me«ilOObon oocursl pel' ..... 01 !me. Ol*<ery 01 drug to the organs 01 ~Iion
aug.,

"acIIl:a<'

VII. BINDING OF DRUGS TO PLASMA PROTEINS Drug molecUes may ~ to plasma proIeins (usualy aI:uTWll. Bou-od drugs a18 fl/'Ialr,,,," ... -..-
The blndng 01 drugs to albumin Is reversible and may show low capacity {one Orug molecule pel' ab.min moIecUel or I'lIgh capacily (3 ruT\beI 01 drug rnoIecuIes binding to a single albl.nlln 1TIOI8cIMl1. Drugs can also bind with ..arying affinitias. Albumin has the strongest affinity lor anionic drugS (weak IlCids) and hydrophobic drugs. Mo!il hydrophilic drugs and neutral (Irugs do not bind to albumin. [NoIe: Many On.rgs are hy
_.

.-c..-..,pol ", £a' 1 1 ..... "" _ _

drulI _ _ otI ..I.."

",ad" '1 _ _ _ _ _..d

<.

.0< . . . . . . . .

,.<_ ... .....-,.

"

1. Absorption. Distributioll, and Elimination 01 Drugs

B Class I drugs: Dose less than available bindIng sites

lor albumin can be divided Inlo two classes. depending on whether the dose 01 drug (tl1e amount 01 drug foood in tl1e body under condi· tioIls used clinically) is greater than or less tl1an tl1e binding capacity 01 albumin (!he nlJfl'll)er 01 millimoles 01 albumin multiplied by tl1e rn..mber 01 binding sites, Figure \.13).

1. Class I drugs: II tl1e dose 01 drug is less ihan tl1e binding capacity 01 alb.........,. theflthe doseIcapaci!y ratio is low. The binding sites are in eltCess 0/ the available drug. and the drug Ir
2. Clan II drugl5: These drugs arll given in doses Ihat grllatly el(COO(f lhe nl.Jl'l'lbef 01 albumin binding sites. The doseIcapacity ratio is high. and a .elalively high proportion 01 tl1e drug eKisls ifl the I,ee state, nol bound to albumin.

el'''ll """""'.-

... boun
-~-

of _llr\llIlo klw.

r;'I Class II drugs; Dose greater ... than available binding sites o

o

o• • • •

e

0

0

oC •o• • •

--, Mo..

_min ""","",,1M

"""""n •_llr\llI; 1M <:ofIC:8fIIrMio 01 IrN lhIg

m

rium.] C. RelaUonshlp 01 drug dlspla<:ement to Vel

Administration of a Class I and a Class Ii drug. o

o

o. •••

oe

0

!c.e•• o

3. Clinical Importance of drug displacement: This assignment of drug classificalion assumes Importance when a patient who is taking a Class I drug. such as loIbu1amide. is given a Class II drug, such as a sulfonamide anlibiotic. The toIbuiamid6is normaty 95% boln::I. and only 5% is free. This means tl1al most of the drug is sequestered on albumin and is inert in tenns 01 exerting pharo f1'\8COlClg«:: actions. II a sullonamide is OOminisle.ed. if displaces toIbIJIamide!rom albumin. laading to a rapid increase in the concentration 01 Iree tolbutamide in plasma, because almost 100% is row t'llll comparlld with the inifial 5%. INole: Thll roJburamide concentration does no! remaifl elevated since the drug moves out of Ihe plasma. info the intersliflaillvid and achieves a new equilib-

0

0

°

,_.

The impact of drug displacement lrom albumin depeods on boIti Vd and the therapaulic indIlx 0I1he drug. If tl1e Vd is large. ti1e drug dis· placed from Ihe albumin dislributes to lhe periphery and !he changa in lrae drug concenlration in the plasma is not significant. It the Vd Is small, thll r1Ilwty ~aced drug does not move into tl1e tissues as much. and the increase in free drug in the plasma is more profound. II tl1e tl1erapelAic index (see p. 22) of It1e drug is sma~. this ircrll8se in drug concenlfalion may have signnicant dnical consequences. [Note: Clinically. drug displacement from albl.lrnn is one 01 the masl significanl $O\Jrces 01 drug interactions.]

VIII. DRUG METABOLISM

<>eeUnI_.

Di........i ... ~ofClt>.. 1
Figure 1.13 Binding of Class I and Class II dfI.Igs to albumin when dnIgs are a~inistElfOO alone (A.5). or together (C).

-

Drugs arll most otten eliminaled by bioJranslomlation and/Of excre1ion into the urine Of bile. The live. is the major Site lor drug metabolism. but specifIC drugs may undergo biotransformation in othe. lissues. [Nole: Some agllnts arll in~ially adminislll'ed as inactive compounds (prodrugs) and mUSI be metabolized to their active 10005.1

<....... _,.,.<----,.

< =AU'" _ . PI"

VIII. Drug Metabolism A. Kinetics 01 metabolism:

1. Flrst-of"der kinetics, The metabolic t",nsforma~on of drugs is catalyzed by enzymes, and most 01 the reactions obey Micl1.aelis· Manteo kine1ics!

~ '" rate of drug metabolism a

V!l!lII [C]

Km + [C]

In most clinical sillJations tl1e ooncet1tration 01 the drug, [C]. Is mud1 less than the Micl1.aelis constant. Km. and the MictlaellsMenten equation redooos to V'"

",te of drug metabolism '"

Vrru [C]

""

that Is, the rate of drug metabolism is directly propo<1ional to tl1e concentration of free dtug, and first order kinetics are obsefved (Figure 1.14). This means that a constant fraction of drug Is metaboliZed pel un~ time.

2. Zero-order kinetics: With a few drugs, such as aspirin (see p. 407). ethanoi and phenytoin (see p. 146), the doses a.e VfJfY large, so the [CJ is much greater than Km. and the ~eIOCitY aquatiof1 becomes:

"The enzyme is saturated by 3 high free-drug concentratiof1, and tha rate of met3bolism rerTl3ins constant 0IIef time. This is ca~ed zero order kinelics (Of somefuJes re/erred to c1inic31ly 3S non-~near kinetics). A constant 3mount of drug is metabolized per Uf1~ tine. B. Reactions 01 drug metabolism The kidney cannot efficiently eliminate lipophilic drogs thar readily cross cell membranes 3nd 3.e reabsorbed in the distal tubules {see p. 23}. Therefore. lipid-soluble agents must tirs! be metaboliZed in the liver using two general selS of reactions, called Phase I and Phase II (Figure 1. I5). 1. Phase I: Phase I .eactions tunction to oorwef! lipophilic molecules into more polar molecules by inttoducing or unmasking a polar tunctional group, such as -0H, or -NH 2. F't1ase I metabolism may increase. decreilse. Of leilve Uf\3ke.ed the drug's pharmacologic activity.

II. Phllse I reactlons utilizing the P·450 system: The Phase I reactions most lrequently involved in drug melabolism ilre catalyzed by the cytochrome P-450 system (31so called microsomal mixed function oxidase). Drug +
-i

Dn'9mo
L I

• !,~~-::;:;.Allow_dru~

_ •. _1.,

_

-

.. IIf..

pmp<>ttl
Figure 1.14 Effect of drug dose on the rale of metabolism.

<.

.0< . . . . . . . .

,.<_ ... _,.

"

1. Absorp1ion, Distribvlioo, alld Elimination of Ofugs

_.~

....ouMIy

.

Figure 1.15 The bloIr.lnslo<mations of drugs, The oxidatioo proceeds by the drug biodlng to the oxidized form of Cytochrome P'450, and then oxygen is introduced through a reductive step coupled to NADPH:cytochrorne P-450 oxidoreductase.

hloxyme; CYP2C9I1D

w_

. ..... -Pho".tW,

,~

Isozyme; CYP2D6

Isozyme: CYP3A4J5

...... "'_ ....... -_d

-~

'" Ilpno

PNN,.luIo,

"~-

Figure 1.16

Scme .epres<alive P-450 isozymes.

b. Summary of the P-450 system: The P-45O system is important 101 the metabolism of many endogenous compounds (sleroids, lipids, etc.), alld lor the deloxicalion 01 8Xogef1OI.JS substances. Cytochrome P-450, designaled as CYP, is composed of many lamilies of heme-oonta.ining isozymes that are located in moSl cells, but mainly those in It1e live< and intestinal tract. [Nole: The term, P·450, originates from lhe s.pectr.ll peak produced at or near 450 rvn when the isozyme (in its reduced Slate) is heated with carbon monoxide.] The family name is indicated by a number followed by a capital letter !OI1I1e subfamily (e.g .. CYP3A). Another number is added 10 indicate Ihe specilic isozyme (CYP3A4). Each of the isozymes has a broad and overlapping specificity (see Figure 1.16). Some drugs can induce the synlhesls 01 many different lsozymes. thereby accelerating the clearance 01 SUbSlr.ltes of those melabolic palhWays alld decreasing 1I1eir levels. COnversely, dearaoce 01 substances can by lowered and 1I1eir levels e1evafed by inhibition of their biOlransformation. Tho Interplay of these pIGoosses is responsible lor many drug-drug interactions, c, Phase I reecllons nOI Involving Ihe P·450 syslem: These include amine oxidalion (for example, oxidation of cate' ctlolamines Of histllmine, alcohol dehydrogenation (lor exam~e, ethanol oxidation), and hydrolysis (for example, of procainamide). 2. Phue II: This phase consists of conjugation reaClions. 11 lhe metabolite from f't1ase \ metabolism is sufficiently polar, it can be excreted by lhe kidneys. However. many metabolites are too lipophilic to be retained in the kidney 1tbJ\es. A subsequenl con· jugatioo reaction Wilh an endogenous substrate, such as glucuronic acid, sulfuric add, acetic ac;d or an amino acid results in polar. usually more waler·soIubie compoullds that are most otten ther.lpel.l1ically inaClive. Glucuronidalioo is the most commoo and the most important conjugation reaclion. Noor1ates are defocient in

·..... ,....,., .... _--,.

• ""_ ....._ - . - ' "

>
VIII. Drug Metabolism this conjugaling syslem m3king them parlictAarty vulnerable to drugs such as chJonJmphet!icoI (see p. 321). [Note: 0rI.Jgs already possessing an -011. -HN2, or -C()()I-l group may enter Phase II directly. and become conjugated withoul prior Phase I metabolism.] The highly polar drug conjugates may then be excreted by the kidney. 3. Reversal 01 oriler 01 the PNIses: Not all drugs unde
is flrsl acetylated (a Phase II readon) and theo hydrolyzed 10 isonicotinic acid (a Phase I reactiooo).

Study Questions

Choose l!le ONE best answer.

Correct answer • C. 111U dlf'1 and ,ate is !he daflf'liliorl a fifsI<wder. lha l\alI.ljfe ol a crug is 6 alf'lIIIart. For fif&t<w
t.' Which one 01 me tobving stalOOlenlS is CORRECT? A. Weak bases are absorbed efhcienlly across Ihe epithelial oeIIs III the slornactl. B. Coadminist,ation 01 atropine speClds !he abso
abSOtPlion. E. If tho V. for a drug is &mal. most 01 tho drug is in !he

elCl,apla$rl"OC space.

A.

A5pi~n

!pI\, .. 3.5) is 90% in its lipid-soluble. proto-

nalOO Iom1 al pH .. 2.5. B. The basic drug promethazine (PK. .. 9.1) is more ior>Ited al pH

Co
eo',*,,!'Il ~ ~ ~

""'*"

"""""s gesll1c ~ In 1he SlOmBd> • """ base IS prInwIy .., !he ~ . ctwgIo:l IDrm, wItil does <1CI madly CIOO5 !he ~ ceUs 0I1he sllllll8Ch. Alrpgjne rs a paraoympe.....". '*em; and _ gBSlJic:~. ms delays !he fate III Cln4l absorption. A IIIrge V. ~dcr'; i that mosI III !he
"""*'

1.2 Which one III the following is mUE lor a drug ....nose e1ifTlin.'ltion lrom plasma shows firsl-
A. Tho hall·~!e oIlhe drug is pr'(lJlQf'lionel 10 the drug (XlfIQI!f11,ation in plasma. B. The amount elimif'la1OO pe, l.OliI time is constant. C. The rate 01 elimination is proportional to the pIasrna CQI'IOO
1.3 AI III the toIIowing stalemeots Sfe Ir'ue EXCEPT:

-

E

7.4 Ihan at pH .. 2.

C. Absefplion of a weakly basic drug Is likely to OCCUf tas!ef from tho inteslioo than Ifom the stomach. D. AcidiIieation III It'KIlXine the soc",lion III

0008Ief_

e ",,<,Ilk base. pI\, 8. E

E. UnctIafged moICQJles more readily CI'Q5S cell bfaf>l!S than charged mole<:ules.

Correct cllOlce. B. As lhe pH 0I11IU lIOIuIion beCOmIlll _ Ihan !he pK.. lhII ,atIo [ElI'°)llB] lna_1hJo [BH'J IIlgeaterat pH. 2 Atone pH ..... 00 1hlI acid side III pK. the [HAJ/lA') • 10. Of 90"4 III f1 bm HI\. !he 1"'
1l'llIfT1lll"""".

,....,. CfOIlS marrt>rBnes.

fl'II)IY>o

< • .0< ••• 00.1"'<_ ... .....--.."

<_._~

"

... . ,. . ._ . . .

w'

1. AbsoIption, Distribution. and Elimination of Dntgs

1.4 A patient is trcatod wilh drug A, wl1idl has a high affinity !of albumin and is adminislcrOO in amoun<s !hal do <\Ol cxceed the binding capacity 01 alblxnin. A second dl\Jg, B. is Mded to !he treatmenl regimen. Drug B atso has a t»gIl affinity I... albumin bo1 is llO'ninislorOO in IlfTlOlJ(IIs lhat arO 100 times the birv.1ing capadIy or

al>Lmh Which 01 !he follooMng tralion of drug 01

0CCUfS

1.6 Drugs showir>g ~ercrorder kinetics of elimination

A are mora common Ihal those showing lirsl orller kinelics,

e. lle<:rease in concentration C"I'QOe"tially willllI'ne. C. have e haff4i1e il'ldepeodenl 01 dose. D. show a ploI 01 r:lr\Ig concentration vel1lUS lime lhat is

alter adn"inis-

"-. E. show a oons1an1 fraction 01 1he drug eliminated per IJI"illime.

A An increase in the lissue conocntra1ic<'ls 01 drug A B. A dccmaso in !he \is.suo COI1COOlralions of drug A C. A decrease in !ho volufoo 01 dislrilMion 01 dll.9 A D. A docroase in !h0 llaff'~'e 01 drug A E. ~ 01 r'nOfe drug A signilicanlly atlCf5 the serum OJf'ICentration oll>'\bolrld drug B.

C<m!ct

llr'llMQ" •

Cl.JTee:t a.- . D. Dn.gs ..... zero.order ~ les ol elimination iIlow a IInelll relatlonshlp Detween drug ooncentralOon and ~me. In mosl dinicaI sllualionB the concee MichaeliS_en consIanI (,y. A decr_ rr. ch'Il concerJlrallon is __ ...... lime. The llaIl-lile d hi drug io'lcree_ Vl\1h do!Ie. A ccnstanl a-nount fJ drug is "*'-00 par ..... limo.

A Dnlg A is ....gety bculd to

at>t.mn """ only • Wi8lllraetioo illroo. MDIlI d lhlg A is SOQl.lOSIC«ld on I'IIJu'I"M1
exeno,g ~ acIi<:fIs. ff lhlg B is adn'*lislenfd. KdispI&cQs drug Air...,., a!llurnn. lIladIng IQ
lfln'n8 01

llon d r,ClEl d"'{l A In plasma. booa..o;e almost lOO'1lo is now frea. Drug A "'0\'0& WI d lIle plasma Uo !he O1lersIitlal water
1.7 A drug. given as a 100 mg single dose. 'esul1s In a peak plasma concentration 01 20 ll9'mI. The apparent volume 01 distribution is (assume a rapid distribution ard rlflgI;gible e1i"*'a1ion p,;or 10 measuring the peak plasma level)'

A. 0.5 L

e,

I L

C.2L O.5L 1,5 The addition 01 gh,>CUfonic acid to a drug

E.IOL

A. deamlses its watcr solubility. B. l.lSUlllly leads 10 inactivation ollhe '*ug. C. is lin Cl
O. occurs at the same rnW in adllKs and the newtlom. E. invo/lros cytochromu P-450.

a.

CorrecI 8l'"I9W8f • The &ddiIion 01 gIuroronic ocld p<events recognllfon 01 lno drug by lIs ~ .... Glucuronic acid is charged. and me

_e<

drug conjugate II. messed solubility I'tJose II rellCliolr. NeooeIes are dotlclanl In tho conf
C
or_ or.-_ ...... on_.-y.

'sea p.52lnM

' ••_.(2rId.cl.)lcIe ........im

'SM p.1lrr.lI'c 'V,_.(2ndfld.j'cn ...... ..xJ.-dGr_,.

_or

.""",

....,."._--"

Pharmacokinetics and Drug Receptors l. OVERVIEW Pharmacokinetics is defined lIS the quanlitative, lime-dependent dIanges of bolh the plasma drug cooll::e,,\ralion and !he total amount of drug .. the body, toIlo\o.YIg the drug's adllIiolislration by various routes (Itle two most COO'I'lI'AOn of these IOUIeS being ·~irrlusion and Ofal bed-dose. fil<ed-time interval regimBns-fof , cOf'l8 IabIet every lout hours"). The interactions of the p descTibed .. Chapfet 1 c;IeIl!ITI"Iin8 the pha"lIiUlkiioetic proliIe ell a dnJO. 'The significance 01 identifYing the pharTnalxllUnef of II dlVg lie$ noI only .. der.lioijj 1he ta::lors IIlaI influencI its levels and pel ·SIIli iOfI .. f'Ie body. bA also .. Iaioli"g the 'Ilenlpeulio:; use of drugs ltoat tllMI • I'91lOl1:ic poIenci1l. [NoIe: The IaIowing (i.....ssim asst.meS 1hlI1 the admillis1efed drug
II. KINETICS OF INTRAVENOUS INFUSION W~h

COI1tinuous i"t,"weflOUs infusion. the rate 0' drug entry Into the body Is COf'lStant. I" the majol'ily at cases. the e1~tion at a dn.og is first-ordef, that is. a constllf1t fnlc:tion 01 the agent is cleared per lriI time. ThlflfOfe. the rale at drug e_it lrom lhe body Incfeases proporlionalefy as Ihe plasma ooncenltation inoooses and al every poIr1 in time Is propoo tiu lalla Itle plaSl'llll con::enlf3tioIl of 1he Oug.

A.. StellCty-e;tate drug leYetIl In blood FcAowiig the ililialio.. of en ioba.ellollS Qusion, the p&;sma c0ncentration of drug rises tnil the rate 01 drug eIirr*'lated lrom the body precisely balancea the illpUl rate. 1lIuI • 5leady·a1ate is ldIieo:ed .. wtW;:ti the plasma CCliC&obalion of drug femaina c0nstant. (Note: The rale ell drug ~Iion from the body • (Cl,)(C). ~ is total body dellhIOiOfI (see p 24). and C is the jllasma CCliC&l!:Iatioo of drug.] Two questions C8Il be asked Iboul ac:hieving the Sleady-Slate. Fr.lI, whalls the relali;lnship belW88Il the rate 01 drug infusion and the plasma CCI iC& ,tration of drug act1leved at the

Agure2.1

a..

AI s1eBdy slate, input (l3Ie ell infuaioo) equals 0l/lplJI (rale 01 eIi'Tlio1ation),

--_ -.

....... _ _ A. c._ , - _ a _......... 0...." ~

t7

_,>

• .....o.aoJ . . . . _ ...

18

• .-. ....._ _•

. w>

2. Pharmllcolcinetics and Dfug Aeceptors

_A_.. .

« SIOady slale? Secord. wtlal Ienglh d reacI1the steady-Slate drug conotIi 'l'alo,1

plateau. ~

" __ ---~

k>~

-....-"",," ... -coo_" e-. ..... s

\

5'

r

~

tme is required

10

8. InfIuencoI 01 the nlte 01' drug Infualon "" the ateady-slate A' 1)' state pIasmB UA ..... t1aJion ol dNg oa:urs wt1en the raleol tnog eIit,iI... lkw, is ~ ID the rate ol ~ (f'q..e2.1). as desoibed l:rf the equation:

" ••

c.. fVl<.V•• R,JCL, ~e

C. • f'le steady litale ~ralion d

dn.og

Ro. the Wusion rale (for e>lamp!e. mgmOOl) 110 a

fitsl-ofdef rate constant for dWg elimWlation

nom the lOla! body

V." voILmfI ol disfriWfion

Ct.. lOlal body doolance (see p. 24)

'........

~ Tate on the lilale UA """,,~,ation d tnog io'l plasma. (Ao * rate

El1ecI d

~,.

d~dtnog.)

Since 110, Ct., and v. are oonstanl lor most drugs showing lineal kine6c:s, C. Is directly ploportional 10 Ao. !hal is. the sleady-Slate pIa9na UAlCfIOtlatio.. is directly jIIopatio"allO the Wusion 1318. For ~. if Ihe infusion rale is ..... tJled, Ihe p' ,... UAIC&IlI.'.

mately aChieved at the Sleady Slate Is doubled (Figule 2.2). Fu"t1eorllOI&, the stea dy stale UAce t1a1ioo' is inversely poopooliOlel 10" dSiraice ollhe C4 Thus. any lacIDr that deaease5 , I ....... liUdlas liver 01 kDley rf e, i lOW tie rt ....' stale CDIC& ol an i1Iused eng (assuning v. ,ell_IS CD &SIa~).

m,.

fl.,

C. nm. required to rueh the steady atate tlN\l eoncentr8tlon

The CD lCfIOlltalion or drug rises hom Z8lO at !he Slat of !he io'llusion 10 its lItimale Sleady-state level, C. (F9I'e 2.3). The froc:tion8llllte of approedllO a steady stale is actoieved by a fin;l~ process. 1. Expo""nllal approach to ate8dy alale: The lale conslant tor attairrnerrt ol steady stale is the lale COI>Slant foI total body eliminalion of the drug, 110. Thus, 50% of the tina! steady-state concenlratlon of drug is obsefved altor time elapsed since the Inlusion. I, Is eqoal to t"2. where 1"2 (or tl8W·l~o) is the lime fllquired 10< the dfug concenlrotion to change by SCI'%.. Wailing al10lher half.jile allows the drug concentlalion to approach 75% of C. (see FIgu'e 2.3). The dnJg COI'Centration is 9O'J. 01 the final steady-stale concentllltion in 3.3 times 1m. For convenience, ltIeiefOle. one can assume IIlaI • drug .... read1 sleIIdy ~te in abolA 4 hd·ives.. 2. EfIect of !tie .-Ie or drug WuaIon: The sole del~ ol Ihe rote thai a MIg ~ S1el1d'f ~18 is lhe 1m 01 Ie.. n this rate • inIuM>ced only by ltle l8aDrs Ihal aIlect Ihe hIIl-ile. The rate of approadllO steady stale Is noll a/lected by the f8te ol drug infusion. Although irlCfeasiOll the rile of infusion 01 a drug ira_the rale al ¥d1idl any glven CDce,balion of drug in the plasma is achieved. ~ does not innuence the lime ,equiffld to <eilCtl!he ultlmate steady-slate COllce"tration. This is because lhe steady·state concentration 04 drug rises di<-ectIy wil!llhe infusion rate (see Flg.JfO 2.2).

..... , ....,."

... _ _ "

.c..... _ _..-...-.., _ ..

III. Kirletics ol Fi>:ed--Dose. Fi~ed- Tine-llllf!fV31

S' .. d_..... - - -

$

, .

19

r=~

c..l:j------::::~

"

~~'b.lofI ....... ..-1 In ....

Re9mens

'.

2 ll",)

U,""

.iC;:;: &ue--- , ,

,,

~'

,:

_·w'

Hl.wy_of Ihe d..c1jl . . . .

........,In U'...

Figure 2.3

Rate ol altannent ol ~staleoonoentration ol dn.lg In plasma.. 3. R_ of !hog deo;llne when thfl Infusion Is Mopped: When the imlsion is stopped,!he p/lISmIl ca1C&lbaDon ol a drug dldrlilS (washes DUl)1o zero with the same One lXlUrSe obsefYed in ~.'!I!he$INdy $lllte (see Fq..-e 2.3). •. l.GedIng dose: A delay In IIdIie.iog the desifed plastnllleveJs of drug may be clinicaly ooacceplable. Therelore. a ~ dose· d drug can be ~ed as 8 slngle dose 10 1Id1l_ !he desired plasma level rapidly. 10110""00 by all 'Ilfusion 10 ma,ll,al" the steady slale (mainleMl'\CEI dose). 111 general. lhe loading dose can be calculated as:

III. KINETICS OF FIXED-DOSE, FIXEo.TIME.JNTERVAL REGIMENS Adl"iliblIation of a drug by lilted doses rather Ihar1 by oontinuooA i1fu. til::rl is ott-! mere ca ••aeol. Hl;wwa'. bed doses, given at filo:EIO:tIn'Ie intelY8Is, .E!5tM In ~dall "'",
-

A. 5lrge In\r1lvenOUs Injection

For 51 'ft'lic:irr', assune Ihe inja::Ied drug r3PllY lisIribules Inlo B single COfTlI)artment. Since the fllle of eliminalion is \ISl.l8Iy firsl order In regard 10 drug OO!'lOO!1lration. the ciroJla!lng level 01 drug decreases exponentially wfth lime (Figufe 2.•). [Note: The I,ll' doell not depend 011 'he dose of drug admirIisfered.1

<......0.00.1.'.<_ .............. ,. 2. Pha<maookjr.elics and Drug Aooeptors

I

1110

"'~-

I

" \

h·~'("-

J"

I..

I'III"~

_. ---

KolHfN (t,,,) 01 dfug

.... Ii.. of .:l......., _

Figure 2.4 Effect 01 dose of sir.gle imraveoous injection of drug on plasma levels.

B. Multiple Intravenous Injections When a drug ls given repealed1y al regular inlervals. the plasma concer111'ation increases until a sleady slale ls reached (Figure 2.5). Because most drugs are given al imervals shorter than 5 haN-lives and are eliminated exponentially w~h time, some drug from the first dose remains in the body al the time lhatlhe second dose is adminislered, and some from the second dose al lhe time that the third dose is given and so lorth. Theretore, the drug accumulales un~l, within lt1e dosing interval. the rale of drug loss (driven by elavated plasma CO
out:

C. Orally admInIstered drugs

I

j

I - I1

o

I

I

..,.

2

I

I~:

3

Most drugs lhat are ad'ninislered on an outpatient basis are Iaken orally on a fixed-dose fiXed-lime interval regimen. for exallllie. a specifIC dose. takl!f1 one, two or lhree times daily. In contrast to intravenous injection. Ofally aoninlste.-ed drugs may be absorbed slowly. and the plasma corw::enlration r:A the drvg is inlluenced by both the rale r:A absOfption and the rate of drug eIifrWlation (FIQure 2.6).

IV. DOSE-RESPONSE aUANmATION FIgure 2.5 Predicted plasma concentralions 01 a dnJ9 given by infusio<1 (A). twCe daily '"/OC1iO<1 (8). or ooce daily ~ladion (C). Model assumes rap;r;l mixing in a single body ccmpartmeot and a t 1/2 01 12 hours.

A. Drug receptors A drug feceptor is a specialized targe! macromolecule. prese<11 on the cell SlIrlace Of intracellularly, that binds a drug and mediates ~s pharmacologic actions. Drugs may interact with enzymes (for example. inhibition ol dihydrofolate ,eduetase by trimelhoprim, p. 294),

·.'O< .....J., ........

... ....-..-.-.....' . _..... ""

~,.

nucleic adds (Iof example. blockade of trarl$Cripllon by daclino171)'dn. p. 384) Of ~ne 'ecep!Of$ (for example, aJlerlltion of rTIB,bane penTleabiIity by ac:etylc:hcIrIe). Ir'l eactI case. !he Ion'nalion allhe mq.recepto' COfIl)lex leads 10 al:lOo9l ,espulSe. ancI !he magnIIul;le of the f1!SPOI'Sll is popootia laIlO If1e rurbeI of drug-

-=

reoet"O (Xlil . . . .

""""","

-__....._..

~Ill

P,

"

fbclll doN

d _ _ ....

rIND""'" ""

I_

~_"'"'

-.." , I_ ,

Iioo .... ~ t

DIug .. Receptor ..... ~cnliPex ..... EI'Iect TI\is ecnc:ept is closely rel~lled 10 ItIe lorn\lliion 01 eompIexes between enzyme and SlJbslrale' or antigen Ind antibody; Ihese

inIer........ haYe many tXAl_IUI Ieidures.

~

lie rTIOI5I no&e-

WOI!tlY being ~. Ho"'e\'ef.the 'ecepIOI not ~ t\a$the iJbiI. ily 10 1«:ogiWD!! a Igand (ong), bLJ: ea'lltl5O~ 01' IIanstU;e" billClio "" InIO a f1!SPOI'Sll by c:::ausrog a contormalionIl ct\llnge 01' a biodoe"ioII eIIod. [Note: For rTIOI5I c*ug&. !he na..... of ... IargeI rnoleo.Ae Is ~ The ......... of a lew dIug:s are nol melialed by spedfie receplOr$. bLJ: depend

(lIl

IlOIlSPdlc chefrjcaI or phy$I.

callnlllfllCtions. For example, aneSlhelic gases (see p. 112) are It100tqlt 10 litellhe 5lruc1ure of !he merrbrilI>e.j B, GrIded cion response eulVfil At1 agonisl Is

deIined as an agenl that can b/r(I 10 a rec:eplor and elidl a response. The magUlude of the drug elled depends (lIl ~s ooncenlration al the receptor sile, lMlich In lurn IS determined by !he dose of dl'ulladminislemd and by lacton; c::hBfactlll1slie of the drug. wc:h as rale 01 absorption, distribution, and metabolism. The effed of a M.og 1$ mool easily analyzed by p10nlng the magrilude of !he respollse versus the log of the drug dose. lhus obtairing II graded ~ eurve (FlQUl"e 2.7). 1. EffleKy: Ellieacy is the maximal

"-., . . . -""= SIngle flue! dooM

drug. It epor O(MI~xeslli"i"edand

-,._In. eonc:.,

... pIMmo

.1,_,

oJ

~o~_"'drvg

Figure 2.6 Predieted plasma concentrations of II I7vg gyen by repeated oral

admio istrallons.

re5I)OIl&e PlodlK:ed by II

depends (lIl!he I"UTlblii o.-ciiiJg:'Br

!he elfiderlCY with ¥ItlictI1he lIICliY!Iled recep!0I plodl Q1$ a eel... Iaf aetiOI'l (see Fogu.e Effieacy Is analogous 10 maximal 'IiIkJeiIy 101 1111 enzyme eata/yled ~. (Note: A 0Ji,~ may tww;IlO Ihe ,eoepIDl and nol eIdl I teSj)U 1Se. It is Ihus said 10 "-le«l~, an:! may aa as 1II111l0l3!lP_1

2.n.

---_. DNg",Ie ......

8.buI _ _

2. Pllt8nc:y: Paenc:y, aIse .... "MOCl etIecliYII ex- OUIc:&.ation, is a ~ of hoW nu:tl drug is IeQIMed 10 eIaI I W>'en teSj)U _ . The loWer the dose required lor a given re5POf'lSe. !he ITl(lfe poIIenl!he drug. Pole cy is rTIOI5I oIIen ~essed as ... dose d drug Ih8t ~ 5O'Il. d!he maJlirnaI respulSe. EOso (see RguIe 2.7). A drug ...., a kJW ~ Is more potenl tIIII1 a drug will a "
SlofM 01 the doH-relponH w ......: The slope of the midpOI1ioI, d lhe dose-resporlSe alIVe Vilf1e$ lrom drug 10 (lrug. A steep slope 1n
c/lange In response. ,

Figure 2.7 Typical 00Iie tesponse CUMlIoI drugs shovMQ diltefer.::es in potency 1I'1d eIIIcaey. 1:0.. ;crug dose !hal

shows 50'% at maxtmal response.

·.........,., .... _-,.

• - - .....

22

-----,....,.... .. ...,... .... >

2. Pharmacokinetics and DIl.J9 RoceptOlS

C. Aeverslble antagonists 1. Compelltlve: These agents interact with receptors at the same site as the agonist and, thus. ~te for bincIing of the agorist (Figure 2.8). A competitive antagonist shilts the dose-response curve to the riglt. causing the drug to behave as if it wllfe tess polent. This beha-"or is analogous to a competilive inhibitor lor an enzyme-cata~ed reaction? 2. Noncompetitive: These agenlS either prevent the binding of the agonist or prevenl the agonist from activating the receptor. A nOllc:ompetitive anlagonist decreases the maximal response and is analogous to a noncompelitive inhibitor lor an enzyme-cat-

alyzed ,eacllon.~

... -'. 1

w.

~

3. Partial agonist: Partial agonists bIoc:k the agonist binding s~e but cause less response than a full agonist. A p8l1ial agonist ma~ have an affinity for the receptor !hat is increased. decreased. or equivalent to that of an agonist.

Inp ,""
V. THERAPEUTIC INDEX The therapeutic index 01 a drug Is the ratio of the dose thaI produces toxiclt~ to the dose that produces a clinically desired or effective respoose in a population of individuals.

Figure 2.8 Etlects of drug antagonists.

Thl!fapeulic index

~

toxic doseIeffective dose

The therapeutic index is thus a measure of the drug's safety. since a large value inclicates lhat there is a wide mal'gin between doses that are etlective and doses thaI are toxic.

A. DetermInation 01 thenpeutlc Index

The therapeutic index is determined by meaSlJling the frequency of desired response and toxic respoose at valiotJs doses of drug. For exafT1lle. F"lQure 2.9 shows the response to warlan'n (see p. 199). an Cfal anticoagulant with a narrow therapeutic index. and penidllin (see p. 291), an antimicrOOial drug w~h a large therapeutic index. 1. Warfarin (axemple of a dl'\l!l with a amall the
's... P. 2li for

----------

------.....

""'*'" role",•..,.. to _ _

in .... - .

.

·_ .....J., ........ __ ,. VI. Drvg Ellminalion

"""-

.., . """"","

_.

a low the
drugs i"l wI'Odl doGe !hose drugE ~ v.t\ic:tI ~ is ~ 10 Iesull i"l a u-apeuIica:rosequenoe 1_ p. 7).

Agent$ with

is critically

~, are

2. P.nlcllli"l (eomp6e 01_ drug wlth _ large 1twr8WlWt1c: IndU): fa' d""Ol with 8 large lherapeulic Index. 5Udl 8$ petliciIIirI (see Figufe 2.98). II is safe and 10 give doses in excess (dlen abl;U ten-k*l excess) oIlhat ~ Is " •• 'iiII)' ~ to lM:He... ill deWed response. ~ !his case. !he bloavai'abi'ily rWJl 0I11icaltt ale toe lheflll"e ilk: eIlecl$.

001,.,....,

ooes

VI. DRUG EUMINATlQN

... Warfarin: Small

iii therapeutic index

-

n.: ....

~ 01 a drug from ihe body may ootU Ioia a IU'Itler of rotAeI, !he m05l ~11I ~ IIvougl !he kkhly ~ lhe urine. 0Iher lO,lles ~ .... bile. 1nlesIine, U1g. Of milk in nur$ing IIlOIhets. A peOOnt in renal lailufe may unclefgo exIrlKXlrpOfeal dialysis. which ".,. remove small rnoIeo.Aes such as ~

A. ReMI ellmlMtIon of. drug 1. Glotr'Ierular IlItnltlon, Drugs enter !he kidney lI1rough renal arteries. which divide to form a glomerular capillary plexus. Free drug (not bOund 10 albumin) flows lhroogh lhe capillary sIlls Into 6oWman's space as part 01 the glomerular Illlrale (Flgurll 2.10). The glomerular jlUralioo rale (GFR • 125 mVmln) Is normally aboul 20% 01 the renal plasma. (RPF • 600 mlImln). ~

now

soIubillry and pH do not Influence the passsge 01 drugs Into !he glor,,,,,uiar llhrale. 2. Proximal tubular nr;retlon: Drug lhal was root transterred ....0 ihe glomerular IiltIale leaves !he gIorneruli through et1erent arl8Ues• ....tIiltl divide 10 form a capillary plexus suflOlrding hi ""JA.ie lumen i"l Ihe proximal 1llboAe. Secretion primariy occurs in the prOllimal tubules by two .-gy.requirfng actiVe lranspor1 sys_ leIr4. ON 101 anions (101 e....."~. deprlllOllated Iorms of weak lIClds) and ON 101 calions (protonatlllf klrms: of weak bases). Each 01 Ihese transport systems 5hows 8 low spe .. ~y and can bllllSPCJl1 many ~ Ihus. co'iP"!'iIiOi, bel\,eEll' drugs lor fle carriers can ootU Mthin each Ira ....... t 5ystem (lor eJI:8l'I1)le.

Plob&llllid, P. 411).INoIe: f>rerrIall.q ~ and neonil1eS haYe i1lWi,~ de'<:l 'P"d tt.tdar $flCrefOI'y mechanism and . . . may retU'l ceT1ain ~I _

~ : As a li'\.Ig _ $ IOWan! the dstal alrMlIuIed lJbUIe. its coll;::e"tralion increases and e~' eer's !hat of the perivasoJar space. The ~. if ur'ICharged, may diffuse QUI 01 tile nephric lumen back Inlo the systemic:: clrculalior'L ~ting the pH 01 the urine 10 increase the krillllf lerm 01 the drug in lhII lumen may be used to mIr1imizl the amounl 01 b6dl diIIusion and hence increase the clearance of an Uldesirable drug. For exalTllle. a patieI1t presenling will1 II pIIerIolNlrCital OYertlose can be given bicarbonale, which lllkaIlnl~es lhe urine and keeps the drug ionized, Ihereby decreasing its reabsorplloo.

3. OWtel tubular

r-'I Penicillin: Large . . . therapeutic index

"

<•.0<'.'''''''<

''

"

2. Pharmacokinetics and Drug Reoeptors ~ tile drug is a weak base, acidirlca\ion 0I1he urine with NH,O leads to proIonation ot the drug and
_drug_. o

-_.-

4. Role of drug melabollsm: Most drugs are lipid soluble and dilfuse out 01 the kidneYs tubtJlar lumen whe<1 the drug coocentration in the @rale becomes greater than that in the perivascular space. In order to minimize this reabsorption. drugs are modified by the body to be mom polar using l....:) types 01 reactions: Phase I reactions (see p. 13) that Involve either the addition of hydroxyl groups or the removal 01 blocking groups fll)rn hydroxyl. carboxyl or amlno groups, or Phase II reactions (see p. 14) that use conjugation wittl su~ate. glycine, or glucuronic acid to inaease drug polarity. The conjugates a,e IoniZed, and the charged molecules cannoI bacl<.-dilluse out 01 the kklney lumen (FIgure 2.1 I).

B. Ol,lllntltslive aspects of renal drug elimination Plasma clearance Is expressed as the volume 01 plasma from which all drug appears 10 be removed in a given time. for example. as ml/m;n. Clearance equals the amounl ot renal plasma flow mu~iplied by the extraction ratio. and since these are normally Invariant over time. clearance is constant

1. ExlrllCllon rallo: This ratio is the decline 01 drug concentralion in the plasma from the arterial to the venous side 01 the kidney. The drugs enter the kidneys at concentration C, and exil the kidneys at concentration ~. The eKlraclion ratio = ~, 2. Excre110n rale: Excrellon rate s (clearance) (plasma concentration) mglmin ml/mif1 ",",",

The elimlnation 01 a mug usually follows first order kinetics. and

figure 2.10 Drug elimination by the kidney.

the concentration of drug In plasma drops exponentially with time. Thls may be lISed to detl!ffTllne the half-life allha drug (the time during which the concentration of the drug decreases from C to'l,C),

t,.:I = In O.5IIl.- 0.693 V.,tCL

C. Total body clearance The total body (syslemlc) dearance (C~) is the SlIm 01 the dear· ances flom the various drug metabolizing and drug'eliminating organs. The kidney is often the major organ 01 excretion; howevllf. the liver also contributes to drug loss Ihrough melabollsm and/or excretion Into the bile. A palient in renal failure may sometimes benefit from a drug !hat is excreted by this pathway into 1l1e Intestine anclfeces. rather than through the kidney. Some drugs may also be reabsorbed through !he enterohepatlc circulation, lhfJs prolonging their halI-lije. Total dearance can be calculated by using the follow· ing equation: C~

'" Ct..-.., + Ct........ + Clp. : ,.. _I + Ct.-.,

..........,.,.<---,. VI. Drug Eliminalion II is not possibla 10 measu'e and sum 1tlese Individual ckla,ances. However. total clearance can 00 derived from !he steady state equalion(seep.18):

1

D. Volume 01 dlstrlbutlon and the hall-llfe 01 a drug

The haN-lila of a drug Is Inve,sely relaled 10 its cklarance and directly proportional 10 ils volume of dlSlribution.

I,,,,., 0.693 V"rct....:.. This equalion shows IMt as the volume of distribution incleases, the halHle of a drug becomes longe,. The larger !he volume of dlslJibution, the mo,e d,ug Is oulside the plasma compartment and is unavailable for excre~on by lhe kidney or metabolism by !he live,.

-

E. Clinical situations resutllng In Increased drug half-life has an abnormality lhal allers the hall-lile of a drug, adjuslmenl irl dosage is required. It is importam 10 00 able to P'edict irl ..midl pali&nts a drug is lil<eIy 10 have a langei haN·lile. The haltlife of a drug is Inc,eased by:

Wher1 a

pa~eot

_I_-

"""....._Iom

t. diminished renal plasma llow, for axample, 111 cardiogeolc shock, hearl 'ailure, or hemorrhage.

J

2. addition of a second d,ug Ihal displaces the Ii,Sl Irom albumin and, hence, Increases the volume 01 disvibulion of !he drug.

Ion_ or poOl8f

ct;'"

3. decreased exll8c1ion ,alia, for example, as seen in renal disease. 4. decreased metabolism. lor example. wheo another drug inhibits Its biolfanslormalion. or hepalic irlsufficiency as with cirrhosis.

Figure 2.11 Effect of drug melabolism on ,eabSOlPlJon In lhe distallubule.

Study Questions Choose !he ONE best ansv.e'. 2:1 A drug with a lIaII~de 0112 hours is administered bV continuous Inlravenous infusion. How long w~1 If lake !Of !he drug 10 madl 9O'r. 01 its final stll8lt)'-Slale """'11 A. 18 hours.

B. 24 hours. C. 30 hours. D. 40 hours.

E. 90 hours.

.. I'

.......... eo-.at"'j

eor-_.o,ONIAI . '.. ~

a,30Ul_40

[ ......!!-~~~~--J

,.,

.. _--,.

• <.... - - - - - , . . . . , . . . . , .. _

2.2 Which 01 _ Iollowi"g resu"" in • clOtIbIing 01 1) Sla'eco '...1iCIn of.~?

A. Dout*Ig

tt.

of...-.. ir*.IIiotI . . . but clclo.t*og hloall-

a ","

... _

c. 0I::U:Jlng h ceo "alia,

D. TriI*"IllhllJaleol ............ E. ~ h rare 01 inIu$Ion.

'O,.,. The:

Comld _ _

:u WI'dI 01 Ilelolluwi

'*-Y drIIc:.r*- !hi dear· : is inIused . , . rare d . "'9'min and praUl8iIlllelld't-6llI11 ooocenuilion ol 6 rrq'L in ,he plasma?

'y.a'e co_,n

10"

. . . . . . . . . w_._, d._

A. 67 """'"'". B. 132 mVmin. c. 3lXI mVmin. D. 6l!7 .... min.

E. 1.200 rrMrrin.

:Hc*I"'_

...... : . .

......

W1CllI mi. 01. ~

Ilan 01. dr\Ig II;
ila

. . . . dr\Ig """ _

"'-

ingdDM.

... of m.soon ...., doI.tlIing ... ".".. of h inIused ~.

_'O

.'*

CorIea o. a is . . _ _ 01 ,.,..... _1>f'dt II drug is ren'IOIIIId'" • g;...

ltugco_......

_fin . . _ " " ' .......).

2.3 v.tOctI of Iha IcIIo:Jrow>g WoIao,eolt8 • correct?

mi.""'"

prcdI.Ices"'"""

A. " 10 mg 01 ~ A response Il$ 100 mg of d"'ll B. drug A is more e/licadcus IhIIn drug B. B. The greater lhe .Illeacy.!he gffl.l&r Iho poIenc:y 01.

-

C. In H'.:Iio'll. drug, polency is U6UOll'y more imporIarC tIM eIfiaK:y. D.AOOI'P~ U-.... iUgoloa~... Ec.. E. Y.n.ion'" ,"""". . 10. drug...-aog M.a,... hi...a- is ..... 1iRly 10 OCCU" ~. dn.tg *-'ll. IaogIo ~.~ i ' - . C
'O D.

~

In N P'

~

ca

PQIllnCy l*I VIIIY _. . ."""

,_ _

~

is Dfl8rl

2.5 The IIT"IIimicrobiI drug. lelracyclinfo. is Iound 10 boo !he.IjlOItlen 250 mg 01 drug ... presenl In ... body. Tha '''' at tetraeydina • 8 hCIl,n. Whal is .... camet rallollnlulicn? A. 7 m;ttw. B. 12 mgoh. C.22 mgoh.

CO QI • cu...... , QI dr\Ig II;

10 _ . glrIwI ,_ _

N.~_

_'O.

lIw .....tiun . . IrlIuIion nq'min. Thua. del.llnCI (mllmln) •••cretlofl 'a'. jmglm:)lpIa.... ooncenl••11On (rnglml) '" (. ~00lln'IfilInil'O 6l!7 'O

..............

... ,

bel: , .. ' P 5 _In . . p.Il_.-lIca 01. dr\Ig is _ lniPOl". ~ ..-c_ _ DclI; ~ . . nof '*J' II

0.31 m;{tw. E. ot5 m;{tw.

ElIcIcV n

• C. The c:r:w...cl . . d ;,...., • I(" '" 01lllo'l.,.'O o.-.s ,-'O O.086Iw'"': . . . . e. .. ~ , . 01 IDslI d h -..;:yctin& is all '" per IT QI ~ 8I'\"'lOI,01I d <:W\IlI ill prersenlin . . bol.t,I. (VJt, .... IOleIII'flOtrIl 01 0'Uu in bol.t,I.) When 2!ll mg 0I18lnlI¥*-'" pr-.I It-. body, . . _ 01 0'Uu 1016 III 250 mg • all "Mlour • 2l5O • O.ollll Ccn8d _

-"'VJt,. _ _

8I'ld ... .........., ~'",,"1lIf.'"

!he amount 01 drug r-..d 10 M:I1Il1w •. For

-.-... in Cbalo!o A. no i'b" .....'" proYkled IIbOIIIhe ~ ol drug A. SO III onlI """ .y ill .... dr\Ig A l! more Pl*fllllwl drug a VarIMlIily

ta'"' • 21.5 notr.

... ....... ,. i(:lncl·C~I~~~'~'=::=---; .... ~~.~,,~.~.:'=?=:a'~'~'~"'=~"'::l:~:;:':-~=~l ol"~""""Q1_":t •. d """""'-''''''''__ ; N d _ os. ... !I4-6lIln. ...._ <1""'< • • • _ r

~._,

:

r (2nI;I-.d.\ b a

........,. •
___

~

·

..-J

........ _'.' ....... _,. ,

_-_. -- .. _....

..- .....

,

UNIT II: Drugs Affecting the Autonomic Nervous Svstem

The Autonomic Nervous System I. OVERVIEW The autonomic nervous system, along wilh lhe endoeline system. C(lOl'dinates !he regulation and inlegrat~ 0I1xldy luncfion!;. The en:!ooine system sends signals 10 large! tissues by varying the levels 01 blood-borne ...... "lOi... ln oontrast, !he ner'\IOt.I5 system exef'IS Its inIluenoe by the rapid 1r3rl$miUion 01 eIeclrical IIl'lpuIses over ileNe libers !hat lee ,!'! aGe 01 a neo.rornediatof s' I .... Drug!i IhaI prtI(U::;e lheir primary f'ler.Ipeulic etrea by ,•• ,i1ctiolQ or alIe,iI", the Iurdions oIlhe aulonomk: nervous sysI8m _ C8Ied auolOi,lit drug:s and are dsl::u5!;ed nile IoIowi"1g lou" ~ These ......... ,lit agenl$ act .... by 5lin'Ua,. porliorls of the autOl ....,lit nerYOUlii r;ysaem or by blod
roo

II. INTRODUCTION TO THE NERVOUS SYSTEM

INervous System) Periphernl Nervous System

Central Nervous System

...- .. -.l

[~':::l

.~-

... ,"",k

The nervous l.,stem Is dMded i110 lWO analOl' ic:aI divisions. !he <:enIraI f"Il!t\IOUS Ii) , n (CN$). woNdl is (lOI'iPOIflll cI!he brain and spinal cord, lWld !he peliphelal nervous syslem. ....tlittl indude& rll!UrOf"O$lfX'3IAd VUlsio:le the brain and spnaI cord, !hal is, any ner'W!S !hal enIer or leave lhe CNS (Figure 3.1). The pe'\)Ilf!lal rIllf'VOUI system can be Iuf1her dMded into the efferent cIYision, whose neo.rorlI carry sigliis away from !he brain and spinal cord 10 lhe pel ipheralli&sues, and the allerenl ctvlsU1. 'It'l'lo&e neurons brio'og information from the ~ 10 the CNS.

"'"

S" •

SO"

'."

,

,

"

Figure 3.1 Organization oIlhe netYouS system.

---_ .....-....,J.__..

'-_1_",

c"'...... c_

..........,., .. -... --,.

.<....

--~,_

28

.. _

..... >

3. AU!Ol iOl1lk: NeMIUS System A. FUnc:1lonai divisions within the nervous system

The etIefenl poftion 01 Ihe peripheral nervous s)'Stem can be IuI1hef dMded Into two major !I.n:tional ~ Ihe somatic and auIOIl(lITjc $ysIemS (see ~e 3.1). The 5D1T1a1lC etlerents 8fe irM:l/Wlcl ~ YOb'ItaIIty conbolled fu lCIioIl$ 5Ud1 as IXIl'lIIadia'l ollie skeIe&aI musdes In lu:u,lUIiu L The aublOfTlic system fUllCl10ilS ~ 10 reg.Ale Ihe everyday needs ar'd rfICIIAoe'elts of the body wiIhCd Itle COIl5dcI.Jf; palticipation of !he rrh1. II: is ~ 00 primarity of 'oiIalraI1Tll*lr (effererC) 0IU0flIi !hat FoneMile smoolh rrIlSde a

• S

• U

• •

-

Flgur, 3.1 El\efenl neurons 01 the autor'oOtl'Ic I"IllMlUI> system

Ihe viscera. awciilc m.JSde, YllSClAature and tie B. "",,lomv' of the autollClhk

~

exocme gtands.

system

~ The iill.-:Jo lOfTIic Illlf'o'ClIA ~ carries nerve imp net' from the CNS to lhe etleclOr or~ by way oC two types 01 ellerent neurons (FIgu" 3.2). The 'irSI roe..... oelI is caIed • ~ neuron and il$ cell body is Ilxaled wilIW1 the CNS. Pregal9iOllic neurons emerge trom lhe brain sto:TI Of r;prIlIII COld and make a s)fl3Ptic co. ltlCliol'lln ganglia (an aggregation 01 netVe cell bodies located In the pel ipIli1lal nefVOolS sys!em). These ganglia Iu1c:tion as relay $Ullion& betweef1 Ihe preganglionk: neufCfl and a second nerve cell, !he ~I!l""!ililonlc neuron. The lanet' neuron has a cell body ~Iing in It1e gaogRon. II is generally nonmyelinated and lermlrnl1es on effector OtQ3!lS such as smooth muscle$ 01 the viscera. cardiae muscle.

1. EfterenI

and the exocrine glands (FIgure 3.2).

2. Afferent neurons, The affefl!llt neur0n5 (ftllers) at !he autonomic nervous system iue imporIanl In Ihe reflex regutallon oI1hls system, lor eKllmple. by sensing pl'eSStIre In !he ClIrOlld sinus and 8OI1ic arch and signaling !he CNS to lntluence the etIe<en1 branctl oIlhe system 10 respond (see below).

3. Sympolothelk ~ The etlerenl 8IAOllOlTllc netYOUS syslel'n is divided lmo !he sympalhetic and Ihe parasympelhelic nelYOUS syAemli (see Figure 3.1). The Pleoao9lOiic na.-ons d!he S)m'palhMic sys1em come !rom Ihonlc:ic llrld lumbar .egions d !he sp'I8I COtd and synapse in two ccrr;S-Ike c:hain5 d glWlgia 1tlaI ru'l in parallel on each side d !he spkIa!lXWd. Allons d fie postoangIionk: neuron exlefld !rom _ _ gangIilI 10 I'Ie glands and Ylsoera. (Now. The adrenal "*,,4:a,like" qor'IlliIlheUc giWlgia., reee/Yes preganglionic libe.s from the sympathelic system. Ladcing lWlnS.!he3Ch!nill in lespollM 10 5IWTUaIion by neuolransmitler inIuenc:es r::Mler organs by 5eCleling Ihe I'umone epineph.lne, also known as adlenaline (and lesser amr:ua d ncrepi oepIl. oe) into !he I*lod.J

"*"..

4. P...aympMhetlc .....ons: The parasympalhelic Pleganglionic Iiber$ allse Iran !he <:rarial and sacral areas d !he spinal COtd and 5ynap$lI in glWlgia near or on !he etIeaor organs. In bolh Ihe ~ and pilrasympalhetic system5. posIglIngIil:ri lirers eldeod "om the ganglia 10 effector organs.

._ .....,., .... _-,.

..-.. ""_""'-'"

_ _ . . _ . PI"

"

u. Introduction to the NefVOfJS System

LACRIMAL GLANDS

EYE

SALIVARY GLANDS

TRACHEA AND BRONCHiOlES HEAorr

GASTROINTESTINAL D K . - In "",""II moIiIity ..... ,,,..,.,

contr_ CII""'*"'.....

1...,_.......,1e fr.,til"y .... ""'"

GENITALIA-FEMALE

URETERS AND BLADDER

_ _ CII uteru.

ReI. . . . -..su, eonlraclion CIIlrlgo::onoo ..... spllincte< CcnIIOC1""0I ;to<

BLOOD VESSELS

I_muodo)

GENITALIA-MALE BLOOD VESSELS (....... _ " ....ot>o

'II ..,

Figure 3.3 AClion of Sympathetic

(bokllyj>Ol)

and parasympathetic (lighItypej ne
C. Functlons 01 the sympathetic system Though continually active to some OOgo"ee (for e~ample, in maintai~ ing the tone 01 vascutar beds). the sympathetic division has the property of adjusting in response to stressfut situations. sum as trauma, fear. hypoglycemia. cold, or e~efl:ise. 1. EflUCl:S of Slimutation 01 the sympathstlc division: The elli!ct 01 sy~thehc output is to increase heart rate and blood pressure. to mobilize energy stores oIlhe body, and to increase blood IIow to skeletal muscles and heart white diVerting 1Iow from the Skin and internal organs. Sympathetic stimulation also results in dila· tion of the ~Is and the bronchioles (FIgU'e 3.3). 2. Fight or flight respon..: The changes e~pertenced by the body during emergencies have been referred to as the "flgt11 or flight" ,espol1se (Figure 3.4). These reactions are triggered both by direct sympathetic aetivatiof1 ollhe el/ector organs and by stimuLation 01 the adrenal medulla to release epinephrine and lesser

.....

_)

..... ,......, ....... _,.

.c_ .....

=

_~_,_

30

.. _

.....

3. Aulonomic:: Nervous System

.....

-F\ghl Of nighl:"

amotlllls 01 noreploephrlne. These I'IoI'mones enter !he blood stream and llI'omote responses In efleaor organs Nt contain &drenergk: r«:eptorl; (see FIllure 6.6, p. 60). The sympathetic nefVQU5 fOY$IeITl tends to Iunaion as a l.nit and ot1en discharges 8$ a complete system, fOl' e~,
0. Functions of the pa.asympathetk: tyStem; The ~ Orision ~ eaentiall:Jcdy tutdiuos, such as digestive proce5Se$ and elimination 01 wastes. and is ~ed tor IiHI (see FilPB 3.3). II usuaIy aetIii 10 'W'Fe Of balance ' " aetiorl$ 01 Ihe ~thelic
.,.. "RetIland digest" .tlmull

I ... ._---:

,,' ... 1 " -

E. Role of the eNS In autonomic cont.ol 01 vllc:Bfa Allhougt1lhe au!oflonljc nelVOlJs system is a motor system, ~ doeS require sensory Input from peripheral Slruc1lJrBS 10 provide In/orma· lion on the state 01 allairs in the body. This rOO(!.badlls provlded by $lreams 01 allerem Impulses. arising In lhe viscera and other aulOnomically Innervated SI!\lClures. thaI travel 10 Inlegrating cence,s in the CN5-the hypothalamus. medulla obIongala, and spinal cord. These O8I'Ilefs respc:lfld 10 the stio'rtlIlI by seocllng out efferent fl!\IeJ: ~ via the .... 1Oo001l1ie nervous system (F9Jre 3.5).

1. Rail•• a'CII: Most 01 the allerenl Imputs&s are lrafl$laled into reIIe. respol sw wIIhoUI i:1YoMng consdou5ness. For e>cample. a lall In blood pressure causes preu.....-5Bf!Silive neurons (bIUoreoeplOrS In the heart, Ye08 cava. lIOl"lic arch. and caroticf sn.oses)lO send fewer fl'pJ$eS to ~ t'fRBIS in the bran This pru:1jAS a reI\ex respome d ircreased ~Ihelie oupuI to the heart and 1I3SClAatln, -.l dec:l'eased ~ fletic ~ to the heat!, 'IIIIflif;:h rB$fA$ In • ~ rise in blood preside and 1aC:hycar
F.lnnerwtlon by the autonomic

nervoua syslem

1. Dual In,.,."atlon: Mosl organs In !he body'AI innefvaled by bolto 6vi5ions d the auloooilie nervous system. Thus. the heart has VlIQiII par8Syr'Il)athetic innervation lhal sIow1; tale at contraaion, and 5ympalhelic imefvation thaI speeds contraetior1. Despite this dual innefva~on, one system usually llI'edomirlates In conlJoIIing !he activity 01 a given organ. For example, in !he hearl. the V8g.JS Is the prll(\(lfT'jnanl conltolling faetOf lor ralB.

• 00<

'0...,., > . . . . . . ..,..•• ,

• "'''''' •

>

" " " ' -.. , H><:NIl .. _ . "" •

"

III. Chemical Sigl'llliing BelwOOl'1 Cell6

2. o..gllnl recelvlng ooly lymPIIlhetk In"'
a

AFFERENT INFORMATION

•

OKIpln _ _

• n' ,_ _J_oIt.ro.In _ _

G. Somatic nervoUI Iyttem The etler8f1t somatic nelVOUS system diIlers from the aulonomic system in that a single rnyeIinaled oTW:*;lr neuron. originating in the CNS. Ilavels directly 10 skelelal muade wilhout the mediation 01 ganglia. As llOled earlier. the 5Cm8lic nervous system Is o.nIer v0luntary control. whereal .... aulOilOi,1ic is an ~ system.

IlL CHEMICAL SIGNAUNG BETWEEN CEllS ~ in the 1IU1OI1Oi,1ic I"III"VOUS system is an eJllln1lle of tie more geoe
Most cells in lhe body MOe18 cher,liutls Ihat a:t 1oc:8Iy. f\aI is.1hey act a\ celI$ in tlIIir i!1.,oedilIJe 811""'011,.'" TheIle ct.... lical sigl11 are rapi(Iy' desbo,'ed or I'8I'I'IOVed: they do net BIllet" fie blood

and llItI net distrb..ted 1t1fol9lOU

and pn:l5tagIancIin (see p. 419) _

body. ~ (see p. 420) eX81l.pe$ 01 local rrecIat
8.1101" .........

"*'

Speda'iZed eto::kDi! '" oells secrete hor"ulll'$ hi blood stream. ¥h!re tley Iravel IIvOf4lOul fie body Bllerting etIe<:1S a \ brolKIy di$lribuled latgel c.I. In lhe body. (Hormones are desoibed in

ChapIers 25-27.)

I'll!\IrOIl

ill a dstiid anatomc

e-.-..,

.'

u,*,

I '

.....

..,-.._

--- ......... ...., ,,,.\>1

C. NeI.W'olnn.mlttell Each

BREFlEX RESPONSE

~

and no strudU'lll oonIirUly

exisls beh.een II"IOSl netA'OlW. CommlriCaliOn bet ee , _ ceI9and between nerve celli and effector orgallli oc:o Irs Ihrough the r1)leaSB 01 specific chenier! signaII. caIed nrtlI'Dtranlimiers. from the roerve te""*"als. Thl$ release depellCls on pnxl"$6es thai are triggered by ea·· uplake and reglAMed by phosphor'ylatio 01 synaptic prcleins. The neurctrtlnimitIers rapkIy dilful;e across the synaptic cleft or gap (~) bet"ee" IlBI\'B etlllillQ6 and oor'OI6 wiIh specific receplor$ on the postsynaptic (tatgeI) cell (6BB pp. 37 and 57).

1. Membrllne receplor.: All neurotrllOl;mitters and most hormones and local medialors are 100 hydrophilic 10 penetrate the lipid bilayer 04 U1qJet-eel1 plasma membranes; inslead, their signal is med'ated by binding to specitIc receptors on !he cell surface 04 larget organs. INoIe: A receptor is defined as a reoognition sile lor a substance. II shows a binding specificity and is ooupled 10 processes that evenlually evoke a re6pOllS!!. Most receptors are prolelns. They need nol be located In lhe membrane.]

Ape 3.5

8IlI0Ieceptor refle~ an: responds, 10 a decrea$B In

....

.........,...._--'>

3. Aulol'lomic Nervous ~slem

32

----

SOMATIC

AUTONOMIC Syft'lpllihelk

_",!dIO'''.

,!~

•

NlcoUnIc:

•..,..,101

NleoIlnlc

.aceptor

-£1'-

', ..

"

....h _

~

~ ,or I

;

Effector organs

"lei. . . .

,

• f.2?:\

,-

"-

•

~ =-- .......... ' Striated muscle

Agure 3.6

Sunvn8IY 01 the neuroltansmlners released and the types of recep1on; touod withl" the autooomic and somatic nel\lOU5 systems. [Nole: This schematic diagram does nol show lhlll the p3rasyrlllalhetic gangtia are dose to or OO"Ilhe Mace of the effedor org8I'Ie al'ld lhat the poslgilngliork fibers are USU8lIy shorter lhan the preganglionic fibers.]

2. Types of ......otnnsmltteq: AJlhough OYer SO cheolieal s9'IllI moIecotes in the net\'QI.lS system h8Ye terUliYefy been idetdied, 6 sigoaI . (and the doseIy relaled epiloepIlrine). ~ dupai..... se«*rin. hisI.arrnI. 8I'd l""arnirw:JtIutyri II' OJ llfll mast (lOl1"UIly' invdved in the adioo. 01 ~ usetIA drugs. e.dl 01 Ilese dll!IlQ signab; bindlIlO II specific family 01 recepIOnI. O'oohltgic and ao-enetgk: neuotrafIsmiI1ers are lhe primary chernic:lll signals in lhe &lAOnomic nervous system. oM1ereas II wide variety 01 08urotn1...• mltIers fundion in !he eNS.

..... ,....,., ....

-

-..-. ,

.

• ..,.. • _ _

...... .. , """"" ... _ . PI' • ~

IV. Seoond Messenger Systems inlntraoellular Response

a. Acetylcholine: The autonomic nerve fibers can be cIassffied ifllO two groups based on the cI1errJcal nature oIlhe neurolransmitler released. 11 lransmission is mediated by aoetylchoIine. the neuroo is termed chollnergk:. AcelYJcholine mediales the trans· mission 01 nerve i'npulses across aulonanic ~ia in bo1t1 the sympathetic and pa1aSyfl1p8lhetic nervous systems (FtgJre 3.6). ~ is the neurolransrrltter al the adrenal medulla. Tronsmission 1ran the auI<JOOrrOc postganglionic l1E!tVeS 10 the effector organs in lhe parasympalhetic syslem also irwolves lhe release of acelylcholine. In the somatic IleIWUS syslem, IransmIssia1 at the neuromuscular junction (Illat is, between nerve fibe<s and voluntary musdes) is aJoo d1dinergc.

b. NOrl1Plnephrlne and eplnephrll'fl: II norepinephrine or epl· nephrine is the transmltler. the fiber is called adrenergic (adrenaline being another name for epinephrine). In ll1e sympathelic system. norepinephrine mediales the lransmission nerve impulses lrom aulonomlc postganglionic nerves 10 et!eclOf organs. Norepinephrine and adrenergic recepl0rs are discussed in Chapters 6 and 7. A s..-nmary 01 the neuromedi· atOfS released and the type 01 receptors within the peripheral nelVOus system Is shown in Figure 3.6. [Nole: A lew sympathetic fibers. such as those involved In sweating, are ctIoIinergic; for simplicity. they 8f(l not shOWfl 011 Figure 3.6·1

r.-

iii

Receptors coupled to Ior'I chafll\els

""""I'l....

• CllOIl".. gIt _

• GA6A _epION

-~~. <J,

_

or

.p-dioo""

The binding 01 chemical signals to receptors activates enzymatic pr0cesses within the cell membrane that ultlmalely result in a cellular response, such as lhe phosphorylalion of intracellular proteins or changes in the conductivity llf ion channels. A neurotransmitter can be thought llf as a signal. and a receptor as a signal (letecto< and transducer. "Sealnd Jl18SSlll'l9llr" molecules. produced in response to neu.rotransmitter binding 10 a receptor, translate the e~lraceliular signal inlO a response that may be further propagated or ampl~ied within !he cell. Each componenl serves as a lin<. in tt1e oommurkalion between extracellular events and chemical changes within lIle cell. A. Actions of membrllM receptors Neurotransmitter receptors are J'rl&r1lbr8t1e proteins lIlat provide a binding site thaI recognizes and responds to neurotransmitter molecules. Some receptors, such as !he postsynaptic receplors 01 nerve or muscle. are direclly linked to membrane ion channels; lhus, binding oIlhe neurotrarlsminer occurs rapklly (within fractions 01 a millisecond) and dire<::tly aHects ion permeability (Figure 3.7A). The effect of neurotransminers on these chemically gated ion channels is discussed on p. 82.

.

~

--ATP

IV. SECOND MESSENGER SYSTEMS IN INTRA· CELLULAR RESPONSE

....

• "'"Ado..""

cAMP

<J,

<J,

Receptors coupled to dlaeytglyc:erol8fld lnoahol trlphosphate

•• ""Aclroo"" ,lOr. QIollneoglt.......,..,..., ,~,

"'" S.u.

blpl.......-

......co··

_~j11ld",

_,"" ,,1".

<J,

1HTRACEL.l.JJLAA ER'~CTS

Figure 3.7 Three mechanisms ""'araby binding 01 a netJroiransminer leads to a cellular effect.

.c_.....__,_.. _· . . ·

.... '.' ..,., ............... , .

3. AulOi'lO
B. Regulation involving second mu..nglH molecules Some receptors are not cIredly coupled to Ion gale$. Ralhet, . . le<:f!I*lo ~ its 'EIOJgililia, of a bol.nd netnltransminer by iriIiatiog • series of INdioiIS, wtlidl uIIimIneIy A!$Ul$ ... a sve<:* inInIcellul.r response. "Second messenger'" rnoIec\Jles-tIO named .......... Ihey ~ bet. Ban !he originaIlT ge (Ihe flIIUlOb81l$illliaer or hoi II 101 e) and !he lAlimaMI etlect on 1hB' • ae pen 01 !he ",......se 01 events Ihal translales neurotransrritter biildillg inlo. ,.,..W respoilse. The Iwo mosl widely lecogolized MCO'ld m 19B15 are !he adellp1yl eydase 5\'$IBn'l ard !he caIcUTIIphospha~ system (Rgure 3.18 and C).

Study Questions Ctooose It-. ONE bBsl . . -

3.1. M 01 '''108owlng lllllIltol• • (lI;IIamI'lIhI auIOrlDmil: --.s splem ... In» EXCEPT tar -.;n one?

._-

A. The ....... ,ic _ I ¥ ' * " is B. The

CQ''- erWwfy

",,''lJMlIlMic chIIian ill ~ WI ''''''''''''' 10

~

siIuMicnI.

C. The ""'S}'n'4Ia~diviMln origInalB5 &_ cal bodiIIs ..... <*'*III _ . , . . . , . .

oingIe. ~ system. C. The pIII~ <Msion is involved io IIOOOfI'>0'I0dsliDn at . - ......... ..-...... 0I1ood. WId ~

-.

D. Tho ,_~"" .......~ . . libsfsd "l*iiS,,,iP&~OIIlic:~ 1IiDn .... 1ong, f;:OI11*eclllO -.:os. 01 ... S'/1I1jl11ll1Stic

~E. The .asr'...... b . _ _ sysl8M .............. _

O. The CCIfl\fd '" I*'ocl ~ II ,..ny • ~ il: 1ICIivily. with essenlillly no pIImripetion 01 the

ec...ea_.c. The pail',

The pllras~1IBtic ~ sysl... is not requiIed lor lila.

"s"'"i".,

Ga.,..... anl dad.9N. \IIIcJ6le

... a .. 6C11vatad SI(>6,at.ly. T~. p:>s11Ja"lJIlonk: Iit)effl at 11>0 ~ltIBIic aySIem lite &horI coml"l,ecllo llle symllal~.t1c division. TIl(l

'*""""

Corr$a ct"*:e. E. The ~ . . . . is us "" liIII. V/lilC8rIII _ (eIlererW) nBI.IlIlnS ~ 9\'100II""- 01 ....... on. aw-. _ . and Ihll ~ P'ds. The......." - - . at ~.......,.,. 1It'I*n ... iIT......Iii. in "9--" ""

eo

,,,,~....-.g~,,,

~

....

.. ... --amorv--"-_'" wei -..e aIdI wei ...... Ill CNS 10 d>_ . IIMI ane.aOI b.ar>c/'l. ollhtl ..,....... to .......01 eo 1aar.1'l'PO" ~-.

_..-

I'*c.---._~_

"'COId_p

-11'1; I bV ...,..... _oI' _1cnL

12. Whdl_

~ i .....

'~

at ... """"",,,Ill _ _ w ....... IllIhll

~_IY'*".CORREcn

A. The ~fIBIicsystem . . . nooopilflploi .. as

• 0B\IftlI1aI'lSm. B. The flIIIBsympa1helic: s)'Slem oltlln disd'wges as •

,. . . . . , - . .

mPttsios _liaIllodOly 1""c.""15, suctI . . - . ....,...... at tood., Il'Id '"""""'" " . _1)'ChoIio ... not_ ... ~

patlI$). 14JldlhBtic system.

E.

.... ,d

_

0.-

~

II lnISt 00'llJllI 0I1I>e &yr'........

3.3. 'MIicI> _ 01 ............. Illischeledeoislic '" paruyrnpelhelic slimLMIion? A. Do;o

51 ..

~

,

B.• fi1ibiri
1l'OliIiIy.

U",L

C. COI......., a t . . - muadoo in It-. iris at ... ..,.. (~

D. COI.......'d itA...... 01 '"-Ytuddef. E•• c

I

uio _ _.

e:e:-:l_.C.

I

........ _,., .... _-,. Cholinergic Agonists I, OVERVIEW Drugs affecting Ihe autonomic nervous system are divided into two sub9fOUp$ accordlng to the type 01 neuron involved in their mechanism 01 action. The choline
CHOUNERGIC AGONISTS ~'
-

.em",

.~,-

"~

II. THE CHOLINERGIC NEURON The preganglionic fibers terminating In the adrenal medulla, the autonomic ganglia (bo\tl parasyrrpalhetic and sympathelic), and Ihe post· ganglionic fibers 01 the parasympathetic division use acetylcholine as a neurOlransmilter (FlQure 4.2). Cholinergic neurons innefVale voluntary mlJSCles oItha somatic system and are also found in tha CNS.

INOIRECT .cmoG

-

I-I ~ £dr1:JpI>Onium

~~

A. Neurotransmlssion at cholinergic neurons Neurotransmlssion in choline
1. Synlhellis of acetylcholine; Choline is transpol'led from \he eldra· cellular lIuid into the cytoplasm 01 the cholinergic neuron by a carrier system tl1at cotransports sodium and can be inhibited by the drug hemjcholjnlum. Choline acelyltranslerase (CAT) cat· alyzes the reaction 01 choline with acetyl CoA 10 form acetylcholine in lhe cytosol.

f-

",,~

L Pyr-.r.ipm/M

L

INDIRECT

'CTING

(In .....lbIej

"~1>01""""""

REACTIVATION

OF ACETYL·

CHOUNE ESTERASE

2. Storage 01 acetylcholine In vesicles: The acetylcholine is packaged into vesicles by an active transpon process coupled to !he ellluK 01 protons. The malure veside not only contains acetyl· choline bUt also adenosme triphosphate and proteoglycan. The fundion 01 \he laller subslances in the nerve terminal is unknown_

Flgu•• 4.1 Summary 01 cholinergic agonlsls.

. _J.__.. _ . . "-_'_" ;.. pO.,,,,,,,, _ _ _ _ lOa'

'". _ _

_C.O--

35

. . . . . , . . . .l e i ) , _ " , _ , )

36

4.

OloIinefllic Agonists

3. ReP".. of -'Yk:hoIirlII: When 8fI aetlon potenIiaP propagaled by the acUon oIl1Ol1age-sensilive sodu'n channels arriVes at a I'lef"<e ~. voltage-sensitive caJci.om channels in the p«Isynap~ membnlne open. causing IIf'1 increase in the COl iCer ilnltioo'l of ilbacelUar ca:un.. EIeYated calcium ...... promote h Iusion of .synaptic vesldes wilh I~ cell membrane and relell$Cl of acelylcholine inlO the synapse. This release is blocked by bc**un klD\. 9y COl iIlast, bladt """doJo spider \91Of'II eao ...... 81 01 ..........., aoetyk:hclinB sb"ed in S)'"oIplic , . 1M to spill if*! . . synaptic gap.

4. 8lndlng 1O..cepIOr: AcetyIcOOIinB"*,o ad tn:rn hi ~ vesides cliltusBs across IhB syoepIic spIlOB and bn!s to eilher post. S)'I1lIIltic Al'OBJ)Iors on IhB tar-gBt oeI or 10 presynapIjc recepIorS in the membrane 01 the neuron that released the aCEItylchollne.

----

AUTONOMIC

AoICylc:I'IOIIIIII

-• &

_h_ . t..$

Ell'

P ••

Noi ;

.(,.

• ~

•

$.

~ ,

-

"')1" i

-l

•

r .a

-

.WOWjMOO

I • • •11I

.().

,

SOMATIC

I

Eftector organs

.(,.

•

~ ,,: ;

Sbialed rnu.eIe

. . . ,......,.._--,>

.e....

..' _ .. _ . w >

_~

II. The CholInergic Neuron

",,:.---.[:::r .~, - ~~.~I~~~ ;;;::; iI SYNTHESIS OF

y

ACETYLCHOLINE

•

T~ClI_

•

_1>1'1 ••""......

_,tel".

.0..._

r:1II IL:I

I

/.'

RECYCLING OF CHOLINE ~~-

/'!

fJ

1';1 UPTAKE INTO

U

~ • ./

c.·~c... f

STORAGE VESICLES

-

.. •-,u":.c::r ,-·' """'"..,

.£ll" "

<j- \

/-.~~~~~ r:I

').

r::I

DEGRADATION OF I:!jI ACETYLCHOLINE

.

~.,.....,.,.

""'~ 1>1'
. " , _ '" Ihe IY'"'I'I*<

""

FIgu.. 4..3 SylIllIf:sls n

~

'---' -~~L"':'~~~"='''':;:;;:;:::''';4.:r:'~==':"'_.J

..... ;:>-. / /1'";. /' ;;;::::::::~n~,i:B~IN~D~I~N~G~T~O)l iiJII RECEPTOR

c!j

release of ~ 1rO'n" c;tdi .... gic newcn.

Bidr'lg kl tie 'etJI4lIO leads kill I......... 'espDI_...-on the 0III5UdIas the ntiabcn 01. roet'Ve ~., II JQ"rrlgioiic Iibef or ac:liII3Iion of spedic enzymes ., eftector eels lIS med3Ie
RELEASE OF

~ NEUROTRANSMITIER • _ _ 1>1'

Oegr~ of

acetyk:holl.-: The $lgnIII at !he posljunctional etledor siIe is r8pdv terrilaIed. -ms 0C0JI'Ii ., !he synaplie deft where IICeIylchcIinesrase deaYes IICBl)4ctoofine 10 ~ and

acetate (see Flgufll4.3). 6. Reqtcllng 01 choline: Choline may be recapluflld by II scdun>~ high affinity l.ptake sys'em that trllO$fXll1S the moIewle beck InlO the neuron. where it Is ecetyleted and alored until released by a StbseQUenIeetion polenllal.

._-_

1 I ' 1>1' tIinI:Ir"I/

•

fo. "'01

.<.... _ - , _ .. _

, •

"

......

4. Cholinergic Agonisls

III. CHOUNERGIC RECEPTORS (CHOLINOCEPTORS) Two lamilies at d'lolinoceplOfs, designated muscarinic and nieol:inic recepIors. can be ~ from each O!he' on !he basis 01 their difJefenI 8Ifinities tor agents IhaI rnirrWc the 8Clion 01 IIC8tyIchoIine (chellOlOII.'14l11ie sgetIts).

A. MUSCMnlc rKeptorI:

These reeepIOIs. in

·'flio., 10 birdolll~.

also ftlWQlizi'!

~ . a"1 8kaIoid V\aI is presenl in oeItain poisalDUS ~ 1'OOrTS. By ccntrast. the musc8rinic recep«IfS onty a weak aIIinily tor rifxltine (F9S8 U). Using birldillg $f\.Idies an;! sp+ Ii

.now

.

.''''':'~.

o

I ~

•

..

I

,,* •

'10

s.

tt

I

•

inhibiIors. several pibdavP$ of rnusearirlic: reoeplor!i have been ~ ~ l I S M , .Mz. ~ M., an:! ~ 1. LOCMlo... of ""lISC8rinIc recIIfIIors; These receptors have been b.nd on ganglia cI !he periphefal neMlUli syslem and on !he 8tM:nOrnic eI1eaor orgMS. suctl as hean. !lITlOOth muscle. brain and exocrine glMds (see F9A •. 2). SpeQfil;:atf, 8Ihc:lu!t' as IiYe

stJbIypes hllve been Iound on neurons. Mf reeeptOf's a'e also

foI.nd on gaslric parietal cets. M:z reoeplors on CllIdiac eels an:I smocltl musde, and M:! ,eoepton: on exocrine g1ends an:I smooth muscle. lNole: Drugs with muscarinic actions prelerertiaHy stimulate muscarinic receptors on these tissues. but 8t high COllC.,,,tra· tlon may show some activity at nicotinic feceptors (see Figure 4,4),]

2. Mectlllnlsmi of _tylchollne s19".1 transduction; A number of diflerenl moIecuIaf medtanisms trMsm~ the signal g&n&raled by I!108ly1c:holine occupation 01 the receplor. For example. when the M f or ~ f&OOplors are adivatad. the reotPIOf' undergoes a confonneliOf'tal change and inleracts wiltl • G protein, ...t.ic:h in IUnl activates phospholipase C. This leads to the hydrolysis 01 phoshalidylinosilol·(4.S)·bisphosphate (PIP.) to yield diacylglycerol (OAG) end inosilol (1.4,S)-tri$pho5phete (IP31, which

cause an rcrease in itt.......... Ca". This C8IicrI can then ner-

-.U Type$ 01 d"" ......... "'· leoeplOoS.

act to stimulate or inhbl enzymes. Of C*lSS hyperpolarizati .....etioI, or oor*aclicn,' In COIot1_ IIdivalion cI the .... $ltltype on Itle C8ldee rn.JSde ~ a G prot~ IIaI irHlits adei "'Yl cyclase and increases K' <:onelop ITlt.ISCllfDc _gcrists and ant.agcrists that _IS direeted against speciIic reoeptOf' IUbtypea. For elC8fl'1lle. ~, a Iricydic anIichoIinergie druG. sellleWel>' ilhibits M, muIClIrinic receptors. sucn lIS in !he gastric mucosa. At ther.tpeulic doses. pirenzepine does not eeuse many 01 lIIe side elfeets seen with U1e non-sublype·specilic drugs. Therefore, pkfJt'lZOl}fn8lT\BY be useIuI in the treatment ol gastric end dU0denal uloeni (see p. 239). [Nota: At the present lime are no clinieaUy important agents thai interad with the Mo and ~ reoep.

u-e

-I

·_ ... _,."._--"

........

_... -'...,...........,-_.....

'

IV, Direc1-Ac!ing Cholinergic Agonists

39

4. Nicotinic receplor.: These receptors, In addilion 10 binding aoeIyk:hoIlne, also ~ ~oe bill show only a weak aftiniIy lor muscarine (see FIgUre •.•). Nicotine initially stin\lJlales and !tlen blocks the receptor. Nlc:oIirk receptors are 1oca1ed in the CNS. adrenal mecUla. autonomic ganglia, and the neulOlTlUSaJJar junclion (see F9Jre 4.2). 0nJgs with rOoolDc action stirntAate the nlcolinic ,eceptors Ioc8led on these iissues. The niooIinic IeoepIOiS ofllUlOflOtllic ganglia difIeI' from lhose of I1Il neuon'USWar juocIion. Fa ~ . Qilnglionic rooepIOr$ are selectively b40cked by heltilmethonium• ..me,eh neuromuscular junction 'eoepIDiS are spedfio8lIy blodIed by II.b:lanIrin! (see P. 50).

IV, DIRECT-ACTING CHOLINERGIC AGONISTS Cholinergic: Ilgonisls mimic !he elfecl$ of acelyk:holine by binding ~ 10 d"'ltItlliIJI'OrS. 1llese agents "" $yIllloetic 8SIefS of ctdle. suctI as CIl~ and b8fhBnftchoI. or naturaly ~ akaIoids. suc::h as piJocarp;r.e (Figure 4.51. AI of the di,ec1-llC!ing dloIinergic drugs haYe Ionglw Iblliio. of lldion..,., llC8I)Icholine. $l;me of I1Il more Ihernpeutically U5etul (lrug$ ~ and beftlanIldIoll prt'fetenliiIJy bind 10 ITllI8Cllrinic and . . $OIToE'ti",es ,eIe'ed 10 as Illl.JSClItir*: agents. [Note: ~ .ec~s "" h \ad primarily, ~ not exdl'Si'~. I l l " f'I(IUOIllfeelOf ~ of !he ~theIic nervous sysIem..J However, as, group, I1Il drea-aclW'og ll\Plists sh;)w Iinle specific:ily in fIeir ....... wtictllirils theW dUcall.ISetI.*>BSS.

,eoepIoo,

A. Ace!yk:hoIl,... ~ III se teel KOE leenl is. qullrItlmilfy amolUlii.m oompoood ItIaI C8rnot panelr8le membr8nn. AI!tIou!tl II is fMt neI.WOtrllnStrOIIe' of perasympethelic llfId ddi"e,gic nefY(!S. it is Ihefa· peulicaIy 01 no ~ . . . . . . 01 Q ""~iI:y 01 adilni and lis rapid inadivalion by ~ Acelyk:tllllii ... has boIh

ITUSCllfDc and .1iCClCii lie llCtMIy, Its ~. inclJde: 1. DeaeeM In hHrI .... and ~d18C output: The acliolS 01 ace~ ctldi.... on the heat! rni1lic !he efledS 01 vagal stimulation. For ~.llCelyk;hdir1e,if"ieCled inInlvenousIy. proroces II brief dec,ease in ca,dlac rile and stroke volume as a resull of a ~ in !he nile of firing lit the slIlO1llrial (SA) node. [Note: 11 should be remembered thai nonnaI vagaJ acIiviIy regulates the heart by the release of aceIyIctloline al!he SA node.] 2. Dect"Il'. In blood preuu.., InjecIlon of acetylcholine causes vasodilalion llnd the lowering of blood presstJre. Although no iMefVlltiotl of the vasculature by the parasympalhellc svstem elIists. there are d10Iinergic receptors on lhe blood vessels thaI respond by causing vasodilation. The vasodilation is due to an acetylcholine-in<\u(:ed rise In inttacellular Ca"-
o •

• ... Di,

,

"~-C-O-01~Oi,-N-%

- -., c._."

C

...

-' III

'

.,...

Di,

'''''''''-'.'''---'' 4. O1oIinergic Agonlsts tered cholir.ergic agents, the vascular receptors have no known fIJnction, since aootylchoIine is never roleased ioIo the blood in any sigMicant quantilies. Atropine (see p. 45) blocks these muscarinic receptors and preveots acel)ok::holine from proclJcing vasodilation.

3.. other action..: In the gastroir1testinallracl. acetyk:ho~ne increases salivary secretion, and stimulates ifltestinal secretions and motility. 8fond1iolar secretions are also stimUlated. In the genitourinary !rae!, the tone of the detrusor unnae muscle is Increased. In the eye, ac:ety\d1Oline is involved in stimulating ciliary muscle contracboo for near vision and in the constrictioo 04 the pupillae sphincter muscle, causing miosis (mar'Ked oonstriction althe pupil),

B. Bethanechol Belhanechollbe THAN e kole]Is strUCturally related to acetylcholine: the aC(!t8te is replaced by carbamate and the choline is methylated (see Figure 4.5). Hence, it is not hydrolyzed by acetylcholinesterase, although it is inactivated through hydrolysis by OIher esterases. It has little or no niootinic actions bUt does have strong muscarinic activity. Its major actions are 00 the smooth muSClJtature of the bladder and gastrointestinal tract. It has a duration of action of aboull hoor.

1. Actlon.: Bethanechol directly slimulates muscarinic receptors, causing increased intestinal molility and tone, and it also stimuLates the detnlSOr muscles of the bladder while the trigone and sphincler are relaxed, causing exptJlsion 01 urine. 2. Therapeutic applications: In urologic Ireatment, bethanecholls uSlld to stimulate the alonic bladder, partictJlarfy in postpartum or postoperalive nonobstructive urinary retention. 3, AdverB
C. Carbachol (Carbamylcholine)

carbachol [KAA ba kole] has both muscarinic as weN as nicotinic actions. Like bethBnechoI, carbachol Is an ester of carbamic acid and a poor substrate tor llC8lylcholinesterase (see Figure 4.5). It ;s biotranslormed by oIher esterases but at a much slower rale_ A single administration can last as long as one hoor. 1. Action,: carbachol has profound eUecls on both the cardiovascular system and the gast,ootestinal system because of its ganglion-stimulating activity and may lirSI stimulate and then

depress these syslems. It can cause release of epinephrine from the adrenal medu"a by its nicolinic actlon. Locally Instilled into the eye, ~ mimics the effects of acetylcholine, causing miosis. FIgure 4.6 Some advetse elfecls observed with cholinergic drugs,

2. TherapeuUc usea: Because of its hi\t1 poI.6f1Cy and relatively long duration of action, carbacholis rarely uSlld therapeutically, excepl irlthe eye as a miolic agent to cause contraction of the pupil end a decrease in intraocular pressure.

·_ '0' ..I., ..... _-.0.,

• c.,...

>

~

__..,

.....

V. AntichoIinesterases (Reversible) 3.

A~

"

ettecU: At doses ll!lOd optl~aJIy, 1tlefe are little

to no aide eflocts.

D. Pilocarpine

The alkaloid piIocafpifIe [pye loa KAA ~I is 11 \8f1iaty llITWlO and Is 51ab1e 10 hydrolysis by acelylcholinesterase (see FIgUre 4.5). Cotf1lanld with aceIylctloIine and its ilIIlrMWes, ills lar less pttenL ~ 0lIhbIs ITLISCaItril;: ~ and is pmIBrily used WI optr

"""lOIogy, 1. ~: Appjed Klpk:BIy 10" ~ ~ pmdIl(l!l$ a rapd rnosis and .... lbar::tiu' oIlhe dIiary rructe. The ¥1,I'l(ler. goes a spasm 01 kOJi,.,lOda\ion. and IIision is filled a1 SOITIII particular dislarat. making it impossitl'e 10 Ioc:us (F9JAl 4.7). [Nole 1tIO ~ efIeas 01 atn:pine, a rTW..8CaIlnIc bIodIer, on lhe ¥ ( _ p.. 45).) P'iIocarpine is ore 01 . . I1lD5I poMInI SlimuIalors 01 &9CIellOlls sud1 as sweal. 108IS. and saIIIIa. bUl it is no! usec:llor \his purpose.

druo

2. ~.- r. gIlI~: ~ Is the 01 ctooIoo r. !he emergency lowering 01 i'llraocular pressure 01 bolh narrowangle (also called dosed·angle) and wld&-angle (also called open-angle) glaucoma. PiIocatpioe Is elClrernal'y etIeclive r. open. ing the trabecular meshwol1l around SchlelTWT1's cansl, causing an Immediate drop In intraocular pressure as a result ot the increased drainage 01 aqueous humor. This aetlorl lasts up to 1 day and can be repeated. Cholinesterase Inhibitors, sucll as IscIIurophaIO and ed1o/tIieptIalo, ha~e longer dUrations 01 action. [Note: Cafbonic anhydrase Inhibitors, such as 8C6lazclamlde (see p.. 226), epinephrine (see p. 61), and Ihe ~ adIOllOigic bIockor, limoIoJ (see p. 76), are effective In treating glaucoma chronlcdy but are no! used lor !he emergency Io\lI8ritlg 01 intraoo.JIar pressure,l

3.. AdYtrM tff«:U: PiIocaqJrre tall enter lhe br1Wl and cause CNS listurbar"ce5. h stmlIat8s ~ ~ and aalivatIcn

V_ ANTlCHOUNE$TERASES (REVERSIBLE) Acetyk:tlolineSleraN Is an enzyme that apecIfIcdy cleaves acetyldloIl .. 10 lIOOWe and dloiollL Ills located bDlh pre-and posI-synap!icaIy r. IhII _ ~. where if: Is II'llllb bot.nd. lrtlibilors d ~ idiec:tly pnMdII a d gic IEIion by v ing Ihe 1il0lime 01 aoetyk:tlohI pmdI'CAd • iOOgeo IWlif'f 81 . . ct gic . - endings. TNs resulls In Ihe aco.orrU8llon d aost~ .. In thO synaptic space (FtgUre 4.8). These drugs can !hUs provoke a I8SpOnM at all cholilloooplors In Ihe body, rdudirlg boIh ".."sc:arnc and r..... 1Ic rilCllplOiS d lhe aukJI .... ,ic nerIOUS system as well as the neo.o~jl.n;:lion

and the brain.

- ...

<""'.'''''''<---''

<..-. . - - ' .....,.". .. _ ....

>

4. Cholinergic Agonists

A. Physostigmine Physosligmine [Ii zoe STIG moon] is an alkaloid (a nitrogenous compound found in plants) and a tertiary amine. It is a substrate for acotyk:holinesterase, and forms a relalively stable enzyme-substrate intermediate lhal rev8fslbly inactivates acetylcholineSlerase. The reslllt is potentiation 01 d10Iinerglc activity throughout !he body.

1. Actions: Physostigmine has a wide range 01 actions becaUse it stimulates not only muscarinic and nico!i<1lc sites 01 the autonom· ic nervous system but also the nicoli,,;,: receplOfS 01 the neurOomuscular junction. Its duralion 01 action is aboul 2-4 hours. Physostigmine can enter and stimulate the CNS.

2. Therllpeutlf;: uses: The drug inc,eases intestinal and bladder molility. wtj(;h serve as M theraplWtic action in atony 01 either organ. Placed topically in the eye, it produces miosis and spasm of accommodation and a lowering of intraocular pressure. 11 Is used to lreat glaucoma. but pilocarpine is more effective. PhysostlgrrWle is also used in lhelreatment 01 0VDI'd0sas 01 drugs with antichollnergK: actions such as atropine {see p. 45). pheoothiazinfls (see p. 127). and tricyclic lII1tldepressar1ts (see p. 119). INCRl:ASt:D INTRACELLUlAR

"''''''"'

FIgure 4.8 Mechanisms 01 action 01 indirect (reversllle) cholinergic agonlsts.

3. Adverse effects: The effects 01 physostigmine on the CNS may lead to convulsions when high doses are used. Bradycardia may also occur. Inhibition of acetylcholineslerase at !I1e skeletal neuromuscular junction causes the accumulation of acetylcholine and ultimately results in paralysis of skeletal muscle. However. these effects are rarely S88f1 with lherapeulic doses.

B. Neostigmine Neostigmine [nee oh STIG mean] is a synthetic compound that reversibly Inhibits acelylcholineslerase as does physostigmine. Unlike physosrigmine, neosfjgmlne is more polar and lherelore does not enter!l1e CNS. lis eflect on skelelal muSCle is greater than that of physostigmine. and it can stimulate contractility belore it paralyzes. NoostlgrrWHiJ has a moderate duration 01 action. usually 2-4 hours. It is used to stimulate the bladder and Gt tract, and is also used as an antidote !of IIJboQJrarine and other competitive neUfOorTIlJllQJlar blocking agents (see p. SO). Neostigmine has found use in symptomatic !<eatment of myasthenia gravis, lII1 autoimm.me dis· ease caused by antJbodijes to the nicotinic receptor that bind to the acetylcholine mooptors of neuromuscular junctions. This causes lheir degradation, and lhus makes lewer receptors available lor Intefaction witl1 the neurotransmiller. Adverse effects of neostigmine Include the actions 01 generalized dlOlinergiC Stimulation. sum as salivation, Ilushing, decreased blood pressure, nausea, abdominal pain. diarrhea, and bronchospasm.

C. PyrldO$llgmine: Pyridostlgmine [peer id doe STIG moon] is another cholinesterase inhibitor that is used in lt1e chronic management of myasthenia gravis. Its duration of action (3-6 hours) is longer than that 01 neostigmine (2-4 hours).

. - ,., . .,., . . . . . _ - - - , >

VI. Antichollneslcfases (lffevcf'Sib4e)

O. EdrophoNlJm The 8ClionI of edtophonivm red foe FOE nee urn] afe similaf 10 !hoM of ~ except lhal it is rrue rapidty absorbed and hal a ShOl'T cbalion of adUI (10-20 minuteI). EdI...".... 1iLm Is a quanemary amine and is used in lhe diagnosis 01 myasltlenia gfavis. Inlravenous Injection 01 et:JrophonJum leads to a ,apid n:.ease in ITIJSde Sb.. .grn. Care rTI.JSt be taken N'loe elQl&S drug may pr(M)k,e a dlOioll(hgiecrisis. ~1s lhe antidote.

PHOSPHORYLATION OF ENZYME

• ' - .Ir_~'_" •

", 'I"

(PAM) c . I

_

4. .lOi

VI. ANTICHOUNESTERASES (IRREVERSIBLE) fUI"Cer d Il'fflhIic ugaqllOllPllallB lXlff1l'CUltI& hlNe th8 ~ 10 l*1d 0Ch It ill)' Kl ~ The . . . . . . klng Ias*ag ila e in aoeIrtetoc:A. 81 aI silos ..neru ills niB I S~ Marly d 'hes8 ch.ogs ilf& extsemely Io~ic wad ....ere dgo.;elcped by the rrililary as nerve agents. AehWld 0l:lflllCUlds such as padlllion life GI, ijJkiyed . . Qer,tM • las

A

.........-

~

A. Isoflurophate

l, MfIoCh.nlsm 01 K1ion: tscflurophsle [eye 110O FLURE on late] (dii&opropylftUOfopllosphale, OFP) 1$ an orgllf1Olll105phate thaI covalenUy binds 10 a SElrine·QH al lhe active slle 01 acelyl· dlOIlneslef8S8 (Figufe 4.9). Once this OOCUfI, the enzyme is pEIf-

manenlly Inactivated, and feSloralion of acel)llct1olinestefase activity requIres lhe synlhesls 01 new en~yme molecules, Followlng covalent modilicallon 01 acetylcholineSlerase, Ihe phosphorylaled enzyme slowly .eleases one 01 lis isopfopyl groups (Flgufe 4.9). The loss of an all.yI group• ...mich Is called aging, makes it impossible lOf chemical feaetivators, Sudl as pI8/idOI(ime (see below). 10 break lhe bMd oor- the remanIng drug and the enzyme. Newer nerve agent$, available 10 the mililary, age In ffWIuIesU" seculd& 0fP agee In 6-8 hWrs.

_lylcf'lOll...........

{1nK_1

f'-- '.0

"'1

C.HptJ

o •

''",oN>< / .0

2. Actions: Actions include gene.allzed chOlinefglc: 5tJmulation. paralysis d fl'IOIOf function (causing breathing (ilfoc:ul:ies), and ~ ~ pnxllo::es . . . . . - " . . . and Ihus has k:u'lll t:h8rapeI.IIi(; use. Abopi1e in N\11..... age can _ many d the fl'USCaIiI lie and canual eIIecu d i:sorbl:lphale. 3,

o,

C.H~H,

An ophlhalmic; oillb lie•• d Ihe drug is used lopicaly in Ihe eye lor the diU ... IfeaDn8nt cl open-angIe gIaulXlffIlI. The elleds fflllY last lor up to one week alter a single adnWrstration. (Note: Ect/OltIit:lpIIBl6(ek 08 n"l1 oh IlIIe] is a

~ ~

~ drug lila! oova.kVltIy bonds is Ih8 same as ~1e.1

t o ~ .Its

usa

4. Reactlntlon of acetylc:hollnell-= P,/IlII;i;lMine (PAM) Is a syntheIic pyridi1iom COi'IJXlUld thai can rea<:tivale Wlibiled 8IC8IyletlOlineslerasB. The presence of a charged group allows ~ to approact1 an anionic site on !he enzyme where ~ essentialy cisplaces the organophosphale and fagene.atell the eruymB. If rjNfIl'I before aging of the alJ(ylated enzyme OOCUI'8. ~ can reverse Illo eHects of ~rophaleeooepl for !hose in the eNS. With the newef nerve 1Igef1\s, which produce aging of the anzyma complel wilhln seconds, pralidoJ
Aging

/

CClI

...."t~.::;".FIg..... 4.g

CovaIenl modificalion of aoelylcholinesl8fll58 by

isonuropOal8: also stooMl is the reactivation 01 !he enzyme with pralidoJ
,..........,.,.<---,. 4. Chollnefgic Agonisls c:orr.II_ .. A.

PIl:ia""." «ot

f!lII .."",. • II ... II II

4.1. Which ot !he 1olIo'Mng is NOT an expacled symplom ot pOsoning wI1h isoIIurophale?

A.. Paralysis Of sI<eIetIll muscle B. Increased bronchial &flCrnlions

C. Miosis D. Tac:hycan.lia E. Convulsions

eon.ct_ ..

ItCI/hl . . . . " .. net

at 171

uMli~

__ dooIot for ...

0"""'" .., --... INc

N". IlIndII ...." 10 f""

rw-. N:oopll. II ..

. .. .. n

eM .~.....-.ord

4.4 Neostigmine:

A.. is conlraino:lcaled in glaucoma, B, has a shorte, dUmIion 01 aetlon !han edlophol.ium. C. clecreases the acetyfd>olioa coooenlratlon althe nwromuscuIa, junction.

o.a. . . ~ ...

cwdlIte 'lI4*5 . . . ~M=1~ ... U."'SI~?~ '1 Sill'. __ .ACpl"'III3lII33I*) _ ata ..... ,d Ijld".

. ,............. ,

•

I

_.5 ."'1.....,..... .... ,.,........

-

D. may result In bowel hypennolilily. salivation, and SWIIa1ing. E, eX8Cf'llbates \I.Jl:>OCU'arine POisoning.

4.3. PiIocatpIne: Pc is used to Iow!H intmoculer pre6Sf.II9 in l,iaucoma.. B. is delIved by aoely\<::holinesllll'llSfl. C. seIeC:liYflly binds to ni001hic rece¢ors, O. 0"l!Ill/ts _ions such as sweat. Iea~ and saliva. E. carnot ante, Ihe bflOO.

...,..WI.' efero ..... 1

9 • fll'IcltllL) b ....

.,,_~. . .

.... .. 1lIW1 •• '

,

C1trM:oddI • • "",1

.Cfr!dtllL)b•••. . . . . ......'

·_'0.....' .• _- ......... '>

.eo...........

_

.., _ .. _

.... >

Cholinergic Antagonists I. OVERVIEW The ~ antagonists (also calecl choIio.... gic IllocUrs Of anti............gic drugs) bind 10 ddlloeeplOfS but do not lOgger !he usual ,eoeptor-mEdalecl eflBds. The most useful ollhese ageou selectively bIoc:k tile muscarinic synapses 01 the parasympathetic neI'WS. The enects 01 ~ InnBrvalion are lhus inIooupled. and the aclkYls 01 syrnpalhetic SlJ'r'Ualion are IetI Uhoppuswl. II second group 01 drugs. the ganglioric: bIod<ets. shoW a plelelence Iof the ,1ii>Jtit ole receptors 01 the S)Tll)iIthetic and parasympalhellc ganglia II third ramty 01 OOfTllOlJnds. ltle neurorTlUSClAar bIodtiog agents. irller1ere with transmission 01 effe<enl IflllUlses to skeletal muscles. F9're 5.1 summaridlS the dloIlnergic antagonists discussed In INs chapter.

.'bi1M "W

CHOUNERGIC ANTAGONISTS

-

lhese agentS, lor eKample. atropine and SCClpOlanWle. bIodI ~ reoeptool (Figure 5.2) causing inhibillon 01 aI ITWJSC8rnc IU'lClions. ~ additioI'I. Ihese drugs block the lew llI(ceptlOIl8I IYmpalhetic neurons lhat are dlOlill8lgic:. such as lhOSe rnervatalg aweat glands. In mntrast 10 the ctIolinergIc agonisls. Mlich have iIriled l.Ill8!une6s IherapeuticaJy. ltoe ctdo I8lgic bIcckers are bllllllficial in a vaMry 01 diroicaI silvau.. Becllll&e lhey do not block ,icdiiM: reeeptOfl, ltoe 8fIlirrU;carini drugS have little Of no action al skeletal neutQ'llUICl.II il-cliolls Of "kAD,ic ganglia.

--

OAHGI..JOMC

...0"'....

III<

'l)'fMl/I. ,

os

•

n..."...-.

-

".1,

AtJi.pi'lllIA lJOh pee"lL a beIadoma 8 .... haS a hil;l attnly tor muscarlnk: receptors. where it bindl competillvely. preYerliiog aceryIcholine from bioocing to that siIe (Flguq 5.31. A/1'Cpi'16 is bolh • oentral and peripheral fTJ.ISC3rWc bIod<er. ltI ~ lM:tiu .. last about 4 hotn 8lIIC8pl .....-.en pIaoed topeaIy In the eye, where !he acliorl may Iasl: lor days.

.,""""""'"

--"0_----• ----

...0<. . . .

•

1. ActionI. •• Ere: AtropkIe blocks all dlOlillMglc aclMty on the eye. resulting In mydriasis (dilatlon of the pupil: see FIgu.e 4.6). l'lrespon$iveness to lighl and cycloplegia (Inability to focus 10. near "'Ilion). In patients with glaucoma. intraocular pressure may rise dangerously.

.-

........ ',m

-

II. ANTIMUSCARINIC AGENTS

..."",

'HnMU"""NC

'"

oo'*-

",,,,,,,,,.

,

Figure 5.1 Summary 01 chollne
' - ' _ _.....

a, _ _

"_"'_c. _ _ _1_" ..

",-'J. _ _

~A._

45

.

<0.0< .....,.,.<- .... ,-,.

<


_ " , , _ , - . . . . . ... _

....

>

5. Cholinafgic Antagonists

Autonomic Sympalhetlc In~lIlion oIlIdrenlll medulla

Somatic

Sympathellc

PlIrasymplllh IIlIc

"'~lcn ..11ne

_.

~J.;;;;iii~~~!~1.:':=~8;::~:;~~~~1 Nk:cllnlc

Sites of action of ganglionic blockers

V

I~""

Site of action of neuromuscular blockers

Ach'nal medulla

---

EplMpIwtne re'Iq~·'.'" In. blOOd

In'"

-!J,

.L

•

~

Effector organs

Striated muscle

Site of action of antimuscarinic drugs

Agure 5.2 Sites of actions of cholinergic antagonists. b. Gastrointestinal (GI): Atropine can be used as an antispasmodic to reduce aetMty of the GI tract. Atrepine and sc0polamine (wt1ich is disaJssed in the next SllClion) are probably the most pol8f1t drugs available that produce this effect. Although gastrk: motility is reduced, hydrochloric acid production Is no! significantly aftacled. Thus. the drug is no! etlective in promoIing healing or peptic ulcer. [Note: PiTetv:epine (see p. 239). an M,-m.Jscarink: antaQOf1ist. does reduce gastric acid secretion at doses that do not antaQOf1ize oIh8r systems.]

Figure 5.3 ~titioo

of atropine and scopolamine with aoetyIcholine lor the muscarini<: receplOf.

_.

c.lJrinIIry sySlem: Atropine is also 8I'\'lllO)OO to reduce hypermotiliIy states of the urinary bladder. It is still oocasioMl1y used in 9n\Jresis (involuntary voiding of urine) among chlldr8f1 but CIadrenergic agonists may be more effecti~e with fewer side

·_ .........., .... _-,.

•


: , _. . ,

K><:1>U" _ .

w.

II. Antimoscarinic Age<1ts d. Cardiovascular: Atropine produ<:es divergent effects on the cardioVascular system, depending on the dose (FIgure 5.4). AI loW doses the predominant effect is a decreased cardiac rate (bradycardia). Originally lhoughtto be dUe to central activation of vagal elferent outflow, newer data indicate that the effect results from blockade of l!1e M, ,eceptors on the inhibkory prejunctional neurons, thus permitting inc,eased acetylcholine release. W~h higher doses of atropine, the cardiac receptors on the SA node are blocked, and the cardiac rate iocr&ases modestly (tachycardia). This generally requires at least t mg of atropine, whid1 is a higher dose than ordinarily given, Arterial blood Pfessure is unalfected but at toxic levels, atropine will dilate l!1e cutaneous vasculature.

e. secretions: Atropine blocks the salivary glands to produce a drying effect on the oral mucous membranes (Kerostomla). The salivary glands are exquisitely sensitive to arroplne. Sweat and laaimaJ glands are also aIlected. InhibiliOl1 01 secretions by l!1e former can cause elevated body temperature.

2. TherapetJllc uses:

a. Ophthalmic: In the aye, topical atropine eKerts boIh mydriatic and cycloplegic effects and permits the measurement of refractive errors withOut inter1e'ence by the accom",odative capacity at the eye. [NoIe: Phenylephrine (see p, 66). or similar a·adrenergic df1JQs, are pre!lln-ed lor pupillary dilation if cyc1oplegia is not reqUIred. Also, individuals 40 years of age and older have decreased ability to acoornrnodate, and drugs are nDl necessary for an accurate refr
b. Antispasmodic agent: Atropk!e is used as an antispasmodic agent to reli!)( the gastrointesllnal tract and bladder. c. As antldota lor cholinergic agonists: Atropine is used lor the treatment 01 Cl'o'8r'Ooses of organophosphate (oontalned in certail insecticiOOs) and some types of mustHoom poisoning (oortain mushrooms oontain dlollnergic substances). Its ability to enter the centlal nelWUs system (CNS) is of particular importance. Arropine bIod<s the effects of 8lCCaSS aceIyk:hoIine that results from Jililition 01 acetylcholinesterase by drugs such as physostigmine(see p, 42).

d. Antisec....tory agent: The drug is sometimes used as an antisecretory ag8<1t to block secretions in the l.IJlP8f and loNer ,espiratory tracts prior to surgery.

3, PharmacolUnellcs: AlfopilB Is readily absorbed, partially metaboli~ed t7t the liver. and IS eliminated pOroarily in the urine. It has a half-~Ie of a.bolIt 4 hours 4. Adversa effects: Depending on the dose, atropine may cause dry mouth, blurred Vision, "sandY eyes', tachycardia, and constipation, EUocts on the CNS include restlessness, confusion, halluci-

2.Qrng o.~mg

Figure 5,4 Dose-dependent effects of alropine.

• "'" ••• _,., > ..........-

, >

• . - . • _ . _ - , """"" .. _

.... >

5. Cholinergic Antagonists nations. and delirium, which may progress to depressioo, collapse 01 the tifCtJlatOfY and resp;ratory systems and death. In older indi\o"iduats. the use of atropine to indvce mydriasis and cycloplegia is COfISidered too risky since ~ may exacerbate an attack 01 glau· coma in someone with a lalent cood~ion.

B. Scopolamine Scopolamine [skoe POl. a mean). anolhllr belladonna alkaloid. pr0duces peripheral effects similar to those of a/roplne. However, scopoIa1rWI6 has greater action on the eNS and a longer duration 01 action In comparison to those of atropine. It has some special actions indicated below.

1. Actions: S«>poIamlne is one of the most effective anti·motion sid
For MuMO

-

'" . . .

Mollon Sickness

Figura 5.5 Scopolamine is an effectlYti llI1!lmoIion sickness agent.

2. Ther8peut1c uses: Though similar to a~ ~s therapeutic use is limited to prevention of motion sickness (for which soopo/arnifle is panicularfy effective) and blocking of short-term memory. [Note: As with al! such drugs used tor this eond~ion, It Is much mora ellective prophylacticatly than lor treating motion sickness after ~ occurs.. The anYl!Isic action of scopolamine is sometimes made use 01 in anesthlltic procedures.] 3. Phannac:oldnelles and adverse efleets: These aspects are similar to those 01 atropine. C.lpralropium

Inhaled iJ]ra/rOPum [i pra TROE pee urn]. a q.;aternary deriliatiYEl 01 al1(lpi-le (see Figure 22.5. p. 220). is useful in treating asthma and Chronic obstructive pulmonary disease in patients unable to rake adrenergic agonisls. Iprat~ is also used In the management 01 chroric obstJ\lctM) ptJImonary disease (see p. 222). Important chatacrerislios oIlhe rruscarinic llI1lagonisls are somnariZed in FigJre 5.6.

Ill. GANGLIONIC BLOCKERS Ganglionlc blockers specifically ad on the nicOtinic receptors. probably by bIodfOdiCIable. making ~ ir11>OSSible to achieve selective actions. Therefore. ganglioni(; blockade is rarely used therapeutically today. However. they often serve as tools in experimental pharmacology.

<_.Q._,.,.<-.. . -...,.

<

e-o . . . ~.

.",.. , K><:1>U." _ . PI' >

III. Ganglionic Blockers

-

"'*""""'"• ................

I

Therapeutic uses

0"'9

-.--.:>--.

In flIltllhal
_.Iie

To _ , <11....-. Of GI _ lowwlRlMy tr.e< To I<eaf _nOPflOIPIIDO pof-*'lI

Muscarinic blockers

To_.~_.

p"'" 10"""ve
In~_mo
~---­ Iit-..

Topoocvenf.-on

Ganglionic blockers

. t] ,

Adverse effects commooly observed with cholinergic antagonists Figure 5.6 Summary of cholinergic antagonists.

A. Nicotine

°

A eo
B. Ttimethaphan Trimerhaphan [!rye METH a Ia:1J Is a short-acting. ~titiw nicotinic ganglionic blocker that l1'llst be given by intra\o'&nOUS infuslon. Today, the drug Is used for Ihfl emergency lowefing of blood pressure. !of example, in t¥pertensiol"l caused by pulmonary edema Of diSSOCllng aortic aneurysm when other 3gElf1ls cannot be Used.

<-'.'''''''<---''

<.-.. - - ' -..... .. _. '"

>

5. O1oIinergk: Antagonists

C. Mecamylamine Mecamylamine [mek a MILL 8 rneoo] produoas a compelitive nicotinic block 01 the ganglia. The duration 01 action is aboot 10 hOurs alter a single adminisllalion. The uptake 01 the drug ~ia oral abs0rption is good in oontrast to lrimelhaphan.

IV. NEUROMUSCULAR BLOCKING DRUGS This S(lCtion plllS(lf1!s drugs that block cholinergic transmission between motor nerve endings and lI1e nlcotlnic leceptorS on the n8UfOmusaJlar end..plate 01 skeletal muscle (see Figure 5.2). These neuromuscular blodw's ara structural analogs 01 acetylcholine and act either as 8J1tagenists (nondepolarlzlng type) or agonists (depolarizing type) at the roceptOfS on the end·plate or the neuromuscular junction. Neuro· muscular bIodIers are clinically useful during surgety to produoa c0mplete muscle relaxation, without having to employ higher anesthetic doses to achieve c:orlll'Irable muscular relaxation. A second group 01 musc::1e relaxants, the central muscle relaxants, are used to control spastic muscle tone. These drugs Include diazepam (whictl binds at GABA receptors, see p. 9O), dantrolene (whidl aets direclly on rnusc::1es by intOOering will1 the release 01 calcilJm from the sarcoplasmic retial· lum), and badofef1 (which probablY acts at GABA receptors In the central nervous system).

A. Nondepol",rb:lng (competlti~e)b1Ol:kers

The first drug lhat was kMJnd cacabIe of bkx:king tile skeletal neon> musc::ular junction was curare, which the native hunters of the Amazon in South America used to paralyze game. The drug rl.Jt» curarine [too boa kyoo AR ean] was ultimately purified and Introduced irlto clirOcal praetk:e in the early 19408. The n8UfOmUSCIJlar blocking agents have siglificanl/y Increased the safely 01 anesthesia, since less anesthelk: is required to produce muscle rela.xation.

1. Mechanism 01 action

a. Allow doses: Nondepolarizlng neuromuscular blocking drugs combine with the nicollnlc receptor and prevent the bindftlg of acetylctloline (Figure 5.7). These drugs lI1us prevent depoIar· lzatlon 01 the muscle cell membrane and inhibit muscular c0ntraction. Because these agents compete with acetylcholine at the recepIOr, they are called compe~live blacken;. Thelr actiort can be overcome by Increasing the conoantrallon of acetyl· ctloline ., the synaptk: gap, lor example, by admini8lraliorl of chOlinesterase inhibitors SUCl1 as neosligminfl (see p. 42) or edrophonium (see p. 43). Aneslt1esiologsts oIten empk7,t this strategy to shorten the duration of the neuromuscular blockade. Figure 5.7

Medlanlsm of action 01 competitive neuromuscular bIoclIing drugs.

b. AI high doses: NondepoIarizlng blockers block the ion chan· nels oIlhe end..pIate. This leads to further weakening 01 neuromuscular transmission and reduces the ability of acetylcholinesterase inhibilors to reverse the actions 01 nondepolarizing muscle relaxants.

<....."" ..,.,.< .. _-,.

<

<.............

.., >=AU'" _ .

~_

PI"

"

IV. NeUrOffiUSClJlar Blod
2. Actions: Not all muscles are equally sensitive to blockade by compe~1ive blockers. Small, rapidly contracting muscles 01 the lace and eye are most susceptible and are paralyzed forst, followed by the fingers. Thercarter the limbs. neck, and bUnk muscles are paratyzcd. then tho intercostal muscles are affected. and lastly, \l1e diapmgm muscles aro paratyzcd.

3. Tl1erapeutIc uses: These blod<:ers am usod therapeutically as a~ van! drugs ill ooostresia dumg surgery 10 relax skeIclal muscle. 4. Pharmacokinetics: All neuromuscular blocking agents are

injectod intravenously since their uptake via oral absorption is minimal. They penetrate membmncs very poorly and do nOl enter cells or cross the bIood-brain barrier. Many 01 the drugs are not melabollzed: their actions are terminated by redistribution. For example, tubocurarine. pancuronium. mivacurium. mo/ocurioo • and doxacvrium are excreted in the uline Unchanged. Atricurium is dogrndod spontaneously in \l1e plasma and by ester hydrolysis.The aminosteroid drugs (vecuronium and rocuronium aro deacetylated in the liwr, and their cloarnnce may be prolongod in patients with hepatic disease. These drugs are also excreted unchanged in tho bile. The onset and duration or aclion or !he neuromuscular b1od
'-'genta do not

_ill' ef1lef

cell.

5. Adverse elleclll: The effects 01 the neuromuscular blocking drugs are shown in F"lQure 5.8.

_r

.J

.....

6. Drug Intl'f"llctlons

a. Cholinesterase Inhibitors: Drugs such as neostigmine, physostigmine, and edrophonium (sec p. 42) can OYllrt:OlOO tho action 01 noodepolarizing neuromtlSCUlar lllockf1f's, but with increased dosage. cholinesterase inhibitors can cause a depolarizing block as a rf1SU1i 01 elevated acetylcholine COflCCnIra· !klns at the end-plate membrane, b. Halogenated hydrocarbon anesthellc" Drugs such as halo/hano (sec p. 113) act to enhance ncuromuSClJtar block· ado by Cllening a stabilizing actioo at the neuromuscular june-

"'".

c. Amlnoglycoslde anllbioth::S: Drugs like gentamicin Or lObramycin (see p. 315) inhibil acetylcholine release from cholinergic nerws by competing with calcium ioos. They synergize wilh rUbocurarlne and other competitive blockers, enhancing the blocl
Neuromuscular Blockmg Drugs

<•

.0<.0. . . . .

'.<_ ... _,.

< . . - • - - . . . . , . . . . """"'" .. _

....

5. Cholinergic Antagonists

Therapeutic Disadvantages of Neuromusculaf Blocking Agents

Onset and DUfation of Action of Neufomusculaf Blocking Agents

1hempeutlc Advantages of Neufomusculaf Blocking Agents

,

~-. T1me to mulmol _

'

(min.)

TIme 10 reoo-' (min.)

I

Benzyllsoqulnollnlum compounda '-,\

-_

I •

Tul>c>ourarlneme:y _ hI.Iom"'" ","'__ lid

......

"

~

••

_.

1>10<:_"

is _roes_.

'01"

~\~~

,.

bIoc_.

~e_1Ion1c

n... g """ _100 _

--

AII-..m.mt>o......... 0 1 _ _Io'to thaf 01 ..._ ...... buf NCOVeon 0UI'lI1clol pt<>Oe
A_um meclllo_ II useful _ '" 01 <:rlU<:aIly II paIllen\o.

I

A I r _ opontorIeOUO/'/ :t-"'~_ndis-

--

..

~ ~-:o-_

dote.-.:l not be _ _ in poIienI. - . ,..,.. 101.......

Amlnostero Id compounds

I~

,.

Rop III onoet 01 _

--~

-- -L'

rna""" _uselullOf_ kltubotlon '" petlent• ....." gMtrIc <:oI ..... 'tI. SlIOot
~

""..,Ii'Iurn""" lor oI>ort....,.,"""""" ou,gleaI ou~

--~

FlgureS.S Onsel and duration 01 action 01 neuromuscular blocking drugs (remer coIurm); summary 01 therapeutic consi6erations. [Note: 'New drug' indicates drug approved aller 1992.J

• .....0'_'.') ... _ _ ,)

..-., .......

,....."..,

"""""' ...

_.

"")

IV. Neuromuscular Blocking Orugs

"

B. Depolartzlng agenll 1. Mectlanl5m 01 action: The depoIariling neuromuscular blocking drug. sur:dnyIchoIino ISllk !WI ~I KOE Ieen]. allaches to !he nico~ receptor and acts ~ke aceIyIcholine 10 depolarize Ihe jln:tion (F"1QUIll 5.9). Unlike aool)1Cholino. .....ncn is instantly destr<¥ld by ~ . Ihe dllpoIarizing agorll persists al IWjh ancenlralions In Itlo synBptic doll. rcmailWog allaChod 10 It1e rocep. lor lof a relatively long li'no. and pr<Mdlng a consliInI stirTUation 01 the ,eceplOr. The depcWizing agont first causes !he q>e<",'ll 01 lhe socIilwn ctIannel asscda\olI wiIh Ihe ncxo lie f\lOeJItOrS. ...mictl resultS In dllpoIafizaOOn ollhe roocpIOf (Phase I). TIis loads 10 a Ir.lnsiDnt twitd iii 'll 01 Ihe musdo (lasc:OIlalions). The mntn.oed

bRiI'll ollhe ~ lIgllf'Il,Oildus lhe rDalplor irrapaNe ol II'lInSfTrilg lunhor ~ With time, lhe cmIinuous depoIariZalion gives WRoJ to ~ ropoIilfiZ.alion as the sotil.m channel dOSeS or is 1.·Ioocl. This causes a , . 'iVICe 10 dcpcIlarizalion (Phase II) lWId a IIacdd parat,1is. 20 Actlona: The soquanoa ol pItriItr-lis may be stighIIy dir.erent, but as is lhe ~ I:*x:Io:ers.lhe ,eopilaby!TUdes iInI pa
&eef\"'"

PHASE I

•

.,

Ii

~~*'

\i0iL::..JJ~

lfW

---" . ' =-~

b

_.

-=

Because 01 its f3Pd onset and short lUaIion ol action, ~ is UIOIuI ......... I3pid eldollact II! InIlba-lion is ruq..oirod flJring 'hi Rludion ol ane'" Efa la f3Pd iICtOl is esse r:1 if . . . . . , 01 gastrie a:rolonts is to be iMlided lUing Intubation). n is atso employed clumg elecIroconwl:sM shock

3. ~

.00......

t. Phwm.acokInMlc:s: SuccinyfcboIine is injected Intravenously. ns brief ibBlion 01 aclion (~I mnnos) resultS !rom Iapid IlPdysls by plasma ctIoIInestcrase. nis lherebe usually s;wn by antnIoUs~

S.

~

e«.ets:

e. Hypffihemlla: WhGn halo!tlano (soo P. 113) is used as an anesthetic, adrnilllslJ'a1ion 01 ~ has occasionaIy caused malignant hyperthormia (with muSC\llar rigidity and hypofpyrexia) In gonotically Sllsooplitllo people (FfQure 5.8). This is troalod by rapicIy cooling the palicnt and by adrTWlistralion ol danlrootono. YitIidl bkx:ks roleaso of ea" 'rom the sarcoplasmic reticulum 01 muscle cells. tllus reducing Ileat production and r..ladng muscle tone.

b. Apn..: A genotically relatod dolicloncy 01 plasma cholinesterase or presenco 01 an atypical form or tile enzyme can lead to apnea duo 10 pamlysla ot It1e diaphragm.

..,. •••

PHASE II

<..0<'''''''''''<-'''-'' Ouestions 5.110 5.6 For aach dew-iptior1 (bllIow) Sl;l1l;lC! the most awrOllriam d"'ll (A 10 I).

5.1

DIlpolari~
5.2 ReVl;lJSl;lS lhe e!lacls 01 nondepolarizing bloc~ers. such as tubocurarillll 53 MaV cause!he'~ 01 tvslllroirlol

5.4 Acts al pl.!fipheral and cent,a) muscarinic choline
-~

5.5 Used as adjunc1ive therapy in t,eating asthma 5.6 Dograd
o.

,. """""'"

ScopolatrOno.

F. At,acurium G. Altopine H

Ipralropium

""""'~

5.\

A:.~

5.2 5.3

B: NeoeIlgi,"ue

5.4

0: Stopc&nIIoe

5.5 5.6

H: Ipaltopk.m I: Alriwrtum

C:T~

Choo&e the ONE besl answer.

.-

5.7. Which ONE 04 the IoIowing drugs mosl closely resembles atropina In its p/latma(:ok)gic 1IClions"l

B. Trime\hapIIan C. PIlysosligniM O. Ace\'jlc:hoIine

E. CarbBchoI The cotl8Cl _ _ .. A. So' , ..... oel\ill6-"'tcls Similar 10 It..- 04 BIropIne. T~ II e Ol"ogllorlic I:*:loI<er allecting nlc:otWc ~~ IIlropi'"e aIlects prJnlI1lv lIlUKalinlc ~,. PITYSO.1illu.oe. an &&1,. i I&ue chIg. It hi antidote to' an e_ss of alroplne. AIfOPI". I:*:JcQ "" eIfectIl al ~ aro::l dred·lId..... agcrista, ouch "" cart>ech:lI. 5.8. Which ONE al too lolIowtng drugs does NOT proO..oce miol;is (marl<ed constrX:tion ot the pupil)?

."""""'"

5. Cholinergic Antagonists

B. lsotlurophal
cllOioeogic8QDnltl), ~(",,~. Ing clo:a~ 1IgOtIIaI), pIoc:IaIplre la 1lI18C1«:1Ing choUnargic l\gon!Sl), _ neoatlgrnlne (an lnthcI-acIio:'I c:hOIl'*lllc ll(ICRsl) llJI mimic "" ellIIcI alpBl_'li.,alIlltk:"*'UaIlon a>d produce

......

.

5.9. Which ONE ollhe following drugs woold btl use'uI In the IonltIeIYn Ireatmenl of myllSlhenia ",avis?

"'-'""

0.,s. Alropine

c. Neostigllli..e

lomtIlc...-... d ""esIheloie ~ by Wib;ling ~ .-.::I Iher«ly incteasO'>g MDyIcI'IOIIne. In conIrlulI. edlCVO Un, "" InllIred dlOi I8lglc agrrisl, III usef\.lln "" dIagoOliiii

d ""'-.... gr8IIis, bulb _ d.:llon III too short lor etlocllve lOng-term trealment Alropl. . end S<:OpOIl\mlne bIod< me IIICIIon of ~oe on'" d'di6glc 'ecepIOoa d the ~]trdloo.0 ' ••II
the foIov.Ong lrootments is indicated? A. Ptv,tsostigmine

B. Norepinephrine C Trimethaphllfl O. AImpine E. Edropllonium

The lXIIf1IllI _

.. D, ThIl

pIIlIerIlt lIId1t:j1ttlll

o.igna d ChOlInergic atim.....tion. SInoa he Is e _ , i .. " • '" It e II<elV o:lIagnoUI.

"'*""*'"

llu>_~~~_d

aIftI9ll\ll ..e

InllIcated 10 ""tagonb:e Iho mlJ5· Plr.~o"ll11m;ne end edrophonitlm al1l ctloIlnestetase InllJJHort ,nd WOUld e.tllCeft>ala the prolllern. NofepriEl\>l"~oe _ nol be e f t _ in ~ng tho cholw..rglc slim.........,. Tr\melI'IaptIan being a ganglIOnic

_

-vt''*'',..

IIlocket -.lid eIso 000fMI1

..... cotdliG ..

·....... _,., .... _-,.

• ""'"" • ........

~

.,.. ,....,... . . _ . PI' •

Adrenergic Agonists ADRENERGIC AGONISTS

I. OVERVIEW The adrenergic drugs allect receptors that arc stimulated by norepinophrino or epinephrine. some adrenergic drugs 3Cl directly on the adrenergic receptor (adrenoccptor) by acti\l8liog ~ and are said to be sympathomimetic. Others. wt1ich will be doa~ wilh in Chapter 7. block the action 01 the neurotransmillers althe receptors, while still other drugs affect adrenergic lunction by inlerrupting !tm release 01 norepinephrine from adrenergic neurons. Tnis chapler describes agents that either directly or indiroctly stimulate the adfcnoccptor (F'!Iuro 6. \).

OIRECT-AcnNG

-_. _. .......,..., ,-"'-~

-"-'

!sDp""" .......

II. THE ADRENERGIC NEURON Adrenergic neurons release norepirwphrine as the neurotrnnsmittor. These neurons are found in the contral nervous system (eNS), and also in the sympathetic ne.....ous system where they serve as links between ganglia and the effeclor organs. The adrenergic neurons and receplors located either presynaptically on tho neuron or post-synaptically on the elfe<:tor organ are tho sites of action 01 the adrenergic drugs (F'!Iuro 6.2).

N onp/nep/Iri...•

_",101'1"'..

...-

INDIRECT·ACTlNG

A. Neurolrllnl;mlsslon al adrenergic neurons NeurOlransmission in adrenergic neurons closely resembles lhat already described lor tile cholinergic neurons {po 37}. except that norepinuphrine is the neurotransmitter instead 01 acetylcholine. Neurotransmission lakes place at numerous boodlike ~ments caUed varioosilics; the process irwO/ves IiYo steps: the synthesis. storage. release, lIl1d receptor binding 01 the norepinephrine, IoIlowod by rerTIO'J8l 01 the neurotransmitter from the synaptic gap (Figure 6.3). 1. Synthesis of norepinephrine: Tyrosine is transported by a Nil'· linked carrier into the axoplasm 01 the adrenergic neuron, where ~ is hydloxylated to dihydroxyphenylalanlne (DOPA) by tyrosine hydroxylase'. This is the rate·limiting step in the formation 01 IlOffJPinopnrine. DOPA is decarboxylated 10 form dopamine.

'SoleI'. 70 tor - . . . ,_....,.,."'_ bO<JI<Jl .. 1his serIN.

'---

DIRECT and INDIRECT ACTING (mlxed llCIlOn) EpNclI.....

Figure 6.1 Sunvnary 01 adrenergic agonists. Agents marked witll an asterisk (') are eatecholamines.

< ,.,.<---,.

< . . - • - -......... """"'" .............

6. Admncrgic Agonisls

Dopamine is transported into synaptic vesicles by an amine transporter system thai is also involved in lhe re-vptake 01 preformed noropincpl1rine. This car· rier system is blocked by roserpine (see p. 78). Dopamine is hydrOKyiated to form norepinephrine by the oozyme, dopamine lI·hydroxyiase. Synaptic vesicles contain dopamine or nore· pinephrine plus aclcnosine triphOSPhate and the Il-hydroxylase. Not all 01 tho norcpinephrioo is packaged in vesicles: some exists in a cytoplasmic pool Ihat can be displaced. In the adrenal medulla. norepinephrine is methylated to yinld epinephrine; both are stored in ctll'OrTIalfin cells. On slirnulabon, the adrenal medulla releases about 85% epinephrine and 15% norepinephrine.

2. StOO'lge 01 norepinephrine In vesicles: NleOdnlc:

Adrenal medulla

3. Release 01 noreplnepnrlne: An action potential arriving atlhe nerve junction triggers an jnftux 01 calciLm ions from the I!l(trace!lular fluid into the cytoplasm of the neuron. The Increase In cal-

cium causes vesicles inside Ihe neuron to luse with the cell membl3M and eKpel their corllents into the synapse. This mll!ase is blocked by drugs SUCh as guanclhidine (see p.. 78).

Effector organs FIgure 6.2 Sites 01 actions of adronergic agonisls.

4. Binding by receptor: Norepinephrine released lrom the synaptic vesicles diffuses across tho synaptic space and binds to either postsynaptic rm:eptors on the effector organ or to presynaptic receptors on the nerve ending (see Figure 6.3). The recognition 01 norepinephrine by lt1e roombl3ne receptors lriggers a cascade 01 events within Itle cetl. resulting in Ihe formation 01 intracellular sccood messengers that act as links (II3nsducers) in Itle commu· nication between the neur01ransmiltOf and the action generated w~hin the elloctor cell. Adrenergic receplors use boltlthe cyclic adenosine monophosphate (cAMP) second mossenger system and the phosphoinosltide cycle. described on p. 33, to transmit the signal into an effect.

5. Removal 01 norepinephrine: Norepinephrine may (1) diHuse out 01 the synaptic space and enler the general circulation. (2) be metaboli~ed to O·methylated derivatives by post·synaptic cell membrane·associated catcchol Q-melhyltransfcrase (COMT) io the Syoaplic space. or (3) be recaptured by an uptake syslcm thaI pulls the norepinephrine back inlo tile neuron. The uptake by the neuronal membrane inVOlves a sodium-potassium activated ATPase that can be inhibited by lricydic antidepressants such as imiprnmine (soc p.. 119). or by oocaino(soc Figure 6.3). 6. Potenllat fates 01 recaplured norepinephrine: Once oorepi· nephrine reenters the cylOplasm 01 the adroocrgic neuron ~ may be taken up into adrenergic vesicles via tile amine I13nsporter system and be soqucstcmd for rell!ase by anotl1cf action potential or persist in a protected pool. A1tolnativcly, norDpincpllrine can be oxidized by monoamine ollidase (MAO) present in neuronal mitochondria. The inactive products of norepinephrine metabolism are e)(C(Cled in the urine as vanillytmandelic acid (VMA). mctancphrine and normetancphrine.

<

,., ><---'

<.,... .....

>

, >=AU" _ .

PI' >

II. The Adroncrgif; NClJron

57

iI

SYNTHESIS OF NOREPINEPHRINE

• Hydn>l<)'lafloo of Iyfoslne I. tho "'..... imiting IIeI>

- ¢=;-:-~~-:.~""'liE~;"iJ

Ilf

,,':':;. :j::1"",,!£.~

T

ICI UPTAKE INTO E";:I STORAGE VESICLES •

DopoImine enl... _ ond If; """ ,0<1 '0

_. --""'"""'"'Pt,......

•

•

NcI<epInephrI

II profe<:lod

TI'INj>CIf1 "'''' \IeIlcIo ,,.,,,_ by ..... pIo .. 10

r;'1I RELEASE OF ~

NEUROTRANSMITTER

• lnllu. cau.... _ c'"l__ _

--ce
• _blcc_br

r:II

REMOVAL OF NOREPINEPHRINE

l!.I

• R.I•• oed.-.plnepto-ine II ,''''''' "'ken _ """"'" •

IJptoktIIi

'"":,:'.':1""

COCIlIne and

BINDING TO RECEPTOR

m

METABOLISM

•

Norepi nepI"rine 10 meltlj'\lted b\~' .nd 0.1dized y mone>-

Imino o.klaoo

FIgure 6.3 SYfllhcsis 1md release 01 rlOl"flpinephrino'rom lho adrenergic neuron.

e. Adrenergic receptors (adrenoceplors) In the sympalhelic nervous system. several Classes 0' adronoceplors can be dislinguished pharmaCologically. Two families 01 receplors, dosignated "0." and "It. wore initially ioontilied on the

<..0<'0.-_""<_"'_" 6. Adrooergic Agonists basis 01 lheir responses 10 lhe adrenergic agonisls. cpinephrino. norepinephrine, and isoproterenol. The use of spe<;ifio blocking drugs and Ihe clo<1iog 01 9Onos havo revealed lhe molecular idcnblies 01 a number 01 sublypos. These proteins belong to a mUltigcne family. Meralions in the primary slructure of 1t1e rCC(!p!OfS influence 1t1eir affinity lor various agents. 1. a, and Cf:l receptors: The a admnoooptors show a weak response fa tho synlhcfic agonisl, Isoproterenol, but am responsive to 1t1e naturally occurring catecholamines, epinephrine, and nor· epinephrine (Figure 6.4). For a receptors the rank ordel of potcncyis: opinepllme::> isoprolcronol

The a adrcooccptors are SlJbdiviOcd Into lwo groups, a, and «2, based 00 tl1cir altlnities lor a agonists and blocking drugs. For example, lt1e a, ro<:eptors havo a higher affinity for ph()(Jjllcphrins (sec p. 66) than 00 lhe «2 roccptors. Conversely, the drug donidine (see p. 67) selectively binds fo «2 receplors, and has less ellect on a, recepfors. 8.

-...

..."..

...

~y~I-_0:0:_:~_.Iii::, '!j ...........

.:r.: ~~-----.:::., y

Figure 6.4 Types 01 adrenergic receplOrs.

a, receptors: These receptors arc prosent on the postsynaplic membrane of the effector organs and mediate many of the classic cflccts, origillllily desigllllted as a-adrenergic, involving constriction 01 smooth muscle. Activation of 0., roccptors initiates a series 01 'eactions through a G·protoin activation 01 phospholipase C, rewlling in the go<1oralion 01 IPJ from phospha1idylinos~Ol, causing tho release 01 Ca" Irom lhe endoplasmic reticulum into 1t1e cylosof (Figure 6.5).

b. Cf:l receptors: These receplors, ~lcd primarily on presynap-tic nerve endings and 00 Olhcr colIs, such as lhe ~ cc~ 01 lhe pancreas, canUel adrenergic ncuromcdiator and inSlJlin oulpul, respectively. When a sympathetic adrCf1ergic nerve is stimulated, the released norepinephrine traverses the synaptic C1cfl and intcracls wi1t1 lhe 0., receplOr. A portion 01 the released norepinephrine 'circles bad<" and reacts with the a" receptor on the nooronal membraoo (soo FIQum 6.5). The sllmulation 01 the 0:2 receptor causes leedback Inhibition of the ongoing relcasc at TKJI"DPinopt1rinc from the stimulated adrenergic neuron. This inhibilOry action decreases lurthcr output from lhe adrwergic neuron and serves as a local modulating mechanism lor reducing sympathelic neuromed,ator OOIPUI when there is high sympathetic activity. In conlrast to 0:, ro<:eptors, tho cffocls of binding at oz receplOfS are mediated by inhibition of adenytyl cyclase and a lall in the levels of intracellular cAMP. 2, ~ rec:epIor15: ~ roccptors eKhibil a set 01 responses differool from those of lhe (I receplors. These are Characterized by a strong response to isoproterenol, with iess sensilivily to epinephrine and norepinopt1r1ne (see Figure 6.4). For ~ receptors, lhe rank order 01 potency is:

isoprofrxenol:> epinephrine:> norepinephrine 'Seep.70Ior

Io _ _ ., _ _

'-'''-'''''''---'' m. Characteristics of Adrenergic Agonists The II adrenoooptOfS can be subdiVided into two major groups, II, and lh. based on their affinities for adrenergic agonists and antagonists aRhough SC\Ieral otheno have been identified by gene Cloning. Ii, Receptors have approximately equal affinities for cpinephrioo and norepinephrine, whoreas 1\:0 rocepfors have a higher
3. DIstribution 01 receptors: Admnorgicalty innervated organs and tissoos tend 10 have a predominance ot one type of receptor. For oKample, tissues such as tile vasculature to skeletal muscle hallll bolh 0., and Ik ((lC(llJtors. but the Ik receptors predominate. OII18r tissues may have one type of rocoptCM" eKclusive!y, with practically no signific3nt numbers ot otl1or types ot adrenergic receptors. For eKample, the hoart contains predominantly II, receptors. 4. Charncterlstic responses mediated by adn!nooeptors: It is useful to organize \he physiologic responses to adrenergic stimulation according to receptor !ype, since many drugs preferentially stimulate or block one type of receptor. Figure 6.6 summarizes the most prominent effects mediated by the ad,enoceptors. As a generalization, stirT'OJlalioo 01 0., rllOOptOfS characteristically produces vasoconStriction (particularly in skin and abdominal viscera) and an increase in tOlal periphcral resistanco and blood pressure_ Conversely. stimulation of II, receptors characteristically caus.es cardiac stimulation, while Ik produces vasodilation (in skeletal vascular beds), and bronchiolar relaXation.

S. oesens1tlzatlon 01 receptors: Prolonged eKposure to the cato' cholamines reduces the responsivity of these receptors, a phenomenon known as desensitization. Throe mechanisms have been SU9QOstlld to IlKplain this phenomooon: (1) sequestration 01 the receptors so that they are unavajjable lor interaction with tho ligand: (2) down-regula1lon, that is, a disappearance of the receptor either by 6estruction or decreased synthesis; and (3) inability to couple to G-p,otein because the receptor has boon phosphorylated on the cytoplasmic side by either protein kinase A or II adrenergic receptor kinase (IlARK).

Ill. CHARACTERISTICS OF ADRENERGIC AGONISTS Figure 6.5 Most of tho adrenergic drugs are derivatives of II-phenytethylamine (Figum 6.7). Substitutions on the benzene ring or on the ethylamine side chains produce a groat variety of compounds with varying abil~ics to differentiate betWll(!n 0. and II receptors and to penetrate the CNS. Tv
Seoond messengers mediate the offocts of II receptors. CAG " diacylglcerol: IP J = inositol triphosphate.

..... '0...'.'.·- ... _ , · 60

I

ADRENOCEPTORS

a,

-.... '--. ....

....

'pulp/.i11

, =="~-,I ._='.. . 1= l Uttl .af

--

,

I

P.

~,m • • .... .....

too"

P. v....

f

'ttl , . ''''I

!!',

-

,_. _...... 110 ....d'

J

?II

I". . . . . _

_ _ .-,

'-'"

•

i

OIl,'"

~

......... ","'1eO 01 h_

'" g... ;

•

-~-

Figure 6.6

Major cHocIs mediated by u- and I\-OOrenoceptors.

~ ..t._ItlatIXl ,Ihe3,~1JDl4) (sud'las. llpiJE¥hi'1(!, ,lOItpi lll. .i5lopoolarenot and t1¥*'j.~ anl caIDd caltd'OI..",i-.. (Nokl: 1,2~ is call1d'd, F9nl6.7.1 These llClIl1lOUflds st&e !he tAluoWog plq;e1ios;

1, High potenc:y: Drugs that are catechol OOrivatiYes (wilh-()H groups in !he 3 and 4 posOOi IS on Ihe benzene mg) show the lirj SlI polon;:y in activating Q or ~ rOCdplUls.

2. Rapid lnectlvatlon: No! altf1 81e the ~ rnetalxlned by COMT postsynapIicaltV and by MAO irTtrllrleun;Jn, but !hey am also mclatxllizad in Olhcr tissues. For CltllI\'llle. COMT is in !he g.JI waN and MAO is in !he llIIIll' and gtJl wal, Thus calecholamnos I1IlYc onty 8 briet period of acliorlllo1'lon given parcnlCr'illty. and aro inollocliYc whon aOOrinistofll(l Ollllly bocause ol inoclivatiofl.

0' • HODCH-CH:.

). Poor penetrltion Into !he eNS: ealoctlolamines are polar and mcrolore do not readily penetrate into the eNs. NoYer1lIeless, most of 1hose drugs have sane cIncaI ettects (anxiety, tremor. heatl8Chcs) Nt are atlribulatlle 10 action on the CNS.

ha'-

0' •

O~

~ ~'!l hl eated'd ~ groups haYe Jonger lives, sWlce they are no! in3clivaled by COMT. Tl\e$e incll.l6e phen)1ept".. iile, qJleLhre, and ~ . PtIeny1ep11rine. 8I'l analog of ~ . has onty 8 $ingle OH al position 3 on !he berwIoe ring, """-""eas ~oedI;"e Iadls I'Iydn:lK)4s on !he mg 1M has a methyl substitution ill the a-carbotl, These are poOl' substratos lor MAO and Itus show a plOlQl'lgod dlRlOl of action. sn::e MAO Is an ~ route of llc!Qxifica1ion. Increased lipid ~ of many 01 lhc non-cateeholaminos pormils groalcr access 10 It10 CNS, Tho:so compounds may act indiroc1t)' bV causing !he rcloaso of stored catoeholamioos.

_

....................-..., .. .....

•....... _1., ....... _ ' .

.."",.,

IV. Direct-Acting Adrenergic Agr:lrisl$

"

C. Subslitulion on ItfIlne niboge" The natlKe and IA* of !he SlbsDIuenl on the amine nitrogen is ..Ilpor..... n 00tentri'Ig fle 11 sele CliviIy 01 If1e adre..... gic aga_ For ~. ~ \ilIilh a -C~ ~ on the IIfTW1e

, ''''

nitrogen is more potent at 11 leoeptoB Ihiln lXlrepl"'.ltI. ....-..:tI has iltI U"ISUbsliluted amine. Similally. iscproIetefId VI'i#l an isopropvt Slbsfjluem -CH(C~ on !he amine nitrogen (see FIlIure 6.7), is a strong II agonisl with ~le a activity (see Fll/Ure 6.4).

"

~.

O. Mechanlsm 01 a<:llon of adrenergiC: .gonlsls

I. Direc:t.actI"SlIlgonIsII: These d'lJgs ad diredly on a or II receptors. pr<xlucilg ellects smlcanlIles 01 dired-ading agmists nc:kde epirlE¥Jhriillt. toepilit!JJ...... iscpOi&era, and pIle!l)lt¥h....

Z_ Indirec:t-.cllng .gonisls: These agents. which include amphetamine and tyramine, are taken up into !he presynaplic netl"0fI and a1use the release 01 ~ from the c:yIoplasmic pools or vesicles 01 the aclrenergic neuron (see FlQUre 6.8). As wilh neuronal stifrlllation. the norepinephrine then Ifa' Wr5eS the synapse and binds to !he .... or II rnoeplors.

"

'" f \~\

3. Mixed·acllon 1iD'lllts: some agonists, such as ephedrine and melafilnWtd. have !he c:apacily bolh to directly SlilTl,tlate adrenoceplors and to release norepinfIphrine"om !he adrenergic: neuron (see F9Jfe 6.8).

,

0" ~

IV. OIRECT-ACTING AORENERGIC AGONISTS onc:t-ac:ling aga oiIls bin:! to adrenetgic: rec:epIOtS WIflout i'llflradif'lg Mfl the ~Iic neuron. The ae:wvated receplor ntiatelll)'illll!Sis 01 SE'allld ~ and ~ inlraceIular .pls. As • llJ'Ol4I these agents are widely used dir'lically. AIItnIty for 11I.Dopten

..........

Inc-. .. group an ami,.. r«rogeri

A. Epinephrine

rep

Epinephrine ee NEF rin] is ooe 01 live calecholamines-8pl"nepMne. not'ePinepltrine. tXtpamj
6.7). Epii

latter ~ are

is S)r&

.

ed

5Yf1IheIic: CXlrflllltlndS

from

(see F9Jre adleua! rnecua 01 tlOl'epilllP".llt. .-.0 !he

~"!he

rei ell, 8Icng wiIh small qu,uilies tbx:f stream. Epa ............ i'Iteracts wiI'I blllh a and II f• ., • • 5. AI. low doses. 11 etlIds ('..as ,M4Ool) on the wsn.... syslem pedD"''' nate.......,e,eas at hiltl doses. a etIed$ ('oeso::u LitJidu) 81(1 Sb()ogest.

and

"0

"0

1

""""' .,

DE'.·

"

~01 several ~ adrel ... gic agonisl$.

..........,

_'>

"

6. Adrenergic AgonistS

---

t. Ac1lofw: II, Cwdiovnculir. The ITIiljor aclions of epilliJA'o.1fI arll on !he ,",JUju ,Ur system. EpillEf'h/il6' .... "'lglheIos the cotllaclililf

INDIRECT-ACTING

d';or¥h"'."'''-

roe •

-

of IhII ny;lCIIl'di.Jm (pDIsitHe idlopk;: ~ aaionl and its rIlle of COlli""'" (posiINe ~ ~ ac:tion~ ClwtIac <:UplA .ltIebe ira !s W"", lhese etIecls comes ~o !lISed acygIIl demandS on 1hII ~ Epilrepo.e constricts a"",ioIes in !he skin, ITlUlXlI:lIJ membranes, and viscera (0. etlecls) and diJaIeS \ ESsets PIll W) !he liver and sketetllIlT"UIJde ~ eIte<:ts). AenaI blood Ilow is decreased- The ' pled 'Mlh a Slil;.t1t deaease in diastolic pressu-e (FI{lUI'II 6.9) lhal can fesUl in a refIeJc slowing of the heart.

MIXEDACTION

'---I~:::.a-

....

b. R"pI..tory: Epinefi1me causes powertul brondlodilation bV acting dlre<:tly on broncnial smooth mJscle (~ action). This ad!Qn relieves all I
H~milo: Epiuept••• has e sigi,;;ieao. ~ eItI!d because of iraeased gIyccgeI d)'Sis in liver ~ etlact). ina'easec:t ,elease of gIuc8gcn lilt eftea), an:! a dea"eased release of inst.*I (~ettea:). etfects are ITlIICia1ed via the cydil;: AMP fTIflC:hoVIism.

n-

d. lipolysis: Epineph1ne initiales IipcIysis IhreJUgl its agcni51 aaivity on !he II recepIorS 01 adipose tissue, ..tIicto ~ sWroIation, lldlvate adenytyl cydaslllO inerease cydic AMP kMlls. Cyclic AMP s'imtJlales a homl(ll'le-sensi'ive lipase. which Ilydrcly.zes triacylglya!fCIs to 'ree fally acids and gyoerd.~

-~f1 -~

T....'W'

Y;

lk\ \ .....1,

-0

J

'II

I

fpmeph,,,,e

2. BIOI.llnslonnlllions: Epinephrine. like lhe other cate<:hoIamines. is metabolized by two enzymatic pathways: COMT. which has sadenoSflmethionine as a COfaClOf. and MAO (see Figure 6.3). The 'inal melabolites blIld in the urine are metanephfine and vanillyimandelic acid. INote; Urine also contains nOflneta,iIIphI.... e product of OOIQ:liIJePh'.metabolism.l

'--

L Bre"c:no ~Mm: EpilJePh'1fI1s Ihe prWnary aug used ~ !he emergency lreab'I8l' of arry co olio" of lhe 'espWalOif \JlIICI 'IWl'lere the presence of bfonc:hocooslriction has reSl.tlecl ~ ojnOl'oished respilalOif t!Xdlllnge. Thus, in Ireawnenr: of lICUUt asthma and ~ shock. epinephrine is !tie drvg of choioe; 'IriI:IW'I a lew minules alter sutx:utaneous 8li'rinistration, greal'y improved respiralory ekchange is obServed. AdITWlisITation may be repeated after a lew hours. llo",eye•. selective ~ agonists, such as tarOOtBIim!. are p,esently laYorecl in the ctuonic treatment of asthma because of a longer ckJratlon of action and minimal cardiac stimulatory etlecl.

'see P. 70b _

.............. .., _ _ .. INIi ........

·

,.,

.<.- .........

-....,.

~

..,-- .. _. "" •

"

IV. OirecH~Cling Adrenergic AgonislS

b. Glaucoma: In 0flI11halmology, a 2'llo epinephrine solution may be use
Anaphylactic ahodc Epillephilla is the drug of cfloIce lor the treatment of Type I hVpeI'S6f\S~illity reaaions In response 10

""'d. In annlhellc.: Local anesthetic solutions usudy contain 1:100,000 parIS epinephrine (p. 118). The ef1ecI ollhe drug is 10 ~1Iy inctease the
••

~

,neuibr.illMlS 10 oonlnll

~ : Epfl6phtir. has a rapid on&e'I tIIA briel dl.r.tIitWI at action. In ..,.... ~ duations epilept"ir. is gillen intfa.-.ousPy lor !he most rapid onset at aetion: ~ may also be given stAlculaneously, by ~ llbe. by Inh*foi~ (If 'r' 10 the eye. Qr.lI adIniuistnllion is noflet."1ive. since epilE!Jll'ri'le and lhe O1l1er Cfneeholamines a.e lnac1ivated by intestinal etIZyTTIeS. e;:wy metabotileS 8ffI 8KCrfl'IOO In !he ......

_,lit

S. AdVetSe eftects:

e. eNS dlSlutbancn: E ~ can PflDJCe adverse CNS eItads'tlal n:t.de ~ 1elW. terlSiu .. he .... he. af"d treI'rn'. b. Hentoon'hagr. The

~

...,

"It

H

n-v lnWoe cerebral hei.o.hage as a

,

restAI at II IT'Iiltked eleYalIon at blood ptesS! .... Co

can:liac wrtIythmln: Eplqil.W can

mas. ~iflhepat>enl

is.eceMilg dphlis(see p. 157).

d. Pu1moNlYtderna: EpI......... canlnWoe

~edema.

~"" . ..-11'

6.ln~

a. Hyperthyraldism: Epil6pht• .e may tIaIIlI erhanced cardaws· aAar 8c1icII'IS In patients wi1h hypefthyroidism. II ep;l6pht.... is req.Jired In sod'llll'l 1ndiYicluaI, !he do&? mu&l be redllOPd. The mechanism appears to iflId',op n:teased prodllClia'l at adrenergic recepIOf$ on the 'o'8SClAahK? of !he hyperthyroid inlIvid-

ualledlg 10 a

"

_....... 1_" .

trWr cani3c anhyth-

~

response.

b. Cocaine: In the pr'Psence at cocaine. epinephrine produces exaggerated cardiowscular aetIof1s. This Is due to the ability of coca/tle 10 prevent fe·uptake 01 calacholamlnes imo the adrenergic n.uron: Thus, I,ke flO/epinephrine, epinephrine remains st lhe r&C?pTor site lor Iooger periods 01 Time (see Figure 6.3).

,

FlgUnl 6.9 C a ~ elle<:ts

of Intra~ infusion at low doSeS at epirlephl .....

< ..... 0 . . .

'.'.< ...... _,.

< . - . • - - - - - . """"'"' ............. >

6. Adrene
B. Norepinephrine Sll'lOO norepinephrine [nor ep ee NEF lin] is the neuromedlator 01 adrenergic nerves. 11 should theoretically stimulate all types 01 adrenergic receptors. In practice, when the drug is given in thera· peI.llic doses to humans. the (I·adrenergic receptor is most affected. 1. Cardiovll5<;uIar Aclions a. Vasoconstriction: Norepinephrine causes a rise in peripheral resistance due to Intense vasoconstriction of moSl vascular beds. Irduding the kidney (an CI,-receptor ertect). Both Syslo1ic and diastolic blood pressures increase (Figure 6.10).

......


I)

,----"t-\:,,

)1 •

'I

c. Elleet of atropine pretreatment: II atropine (which bIod<s the transmlsslo<1 01 vagal effects. see p. 45) is given before nrx· epinephrine. then norepinephrine stimulation 01 the heart is evident as tachycardia.

,~

l~

,~

~

"'"

Ii

Cl

2. Therapeutic uses: Norepinephrine is used to treat shock because it increases vascular resistance and. therelo,,~, in<:reases blood pressure: however, dopamine (see p. 65) is beller, because It does no! reduce blood Row to the kidfley as does norepinephrine. Other actions 01 norepinephrine are not considered dinically significant. II is never used tor asthma. [Note: When norepinephrine is used as a drug, it Is somelimes called levarterenol [lee\! ale

l;,

/ ',1

~

b. Baroreceptor reflex: In isolated cardiac tissue norepiTIepIltin stimulates cardiac cor1tractility: however, in vivo. little if any cardiac stimulalion is noted. This is due to the increased blood pressure that induces a reflex rise in vagal activity by stlmulat· ing the baroreceptors. This bradycardia is sufl'cie!1t to counter· act the local actions of norepinephrine on the heart althoogh the reflex OClrll)ef\Sation does no! alfect the posllive inolropic etlects of the drug (Rgure 6.10).

TEA a nole].]

C. lsoproterenot

•

"

nM(.........)

II -

J

_.1'$""_.,-

~

---g

"'. '>lIe PI'"

_"""""""~ .... CGnIIIrid. . .

In<_~""_

Flgure6.10 Cardiovascular etlects 01 intravenous inlusion of nofl!pinephrine.

Isoproterenol [eye soe proe TEA a nole] is a direct·acting synlhetic catedlolamine thaI predominantly stimulates both fI, all(! tI2 adlenergic receplO1S. Its non·selectiv~y is one 01 ~s drawbad<s. Its action on u roceptors is insignificant. lis chemical structure is given in Figure 6.7. 1. Actions

a. Cardiovascular: lsoproterenolproduces intense stimulation 01 the heart to Increase Its rate and force 01 cor1traction. causing IflCreaSed cardiac 0lIIpUI (Figure 6.11). It is as active as epinephrine in this action and is therelore lISehA in the treat· merit of a1riovenlJ"icular block or cardiac arrest. Isoproterenol also dilates the arterioles 01 Skeletal muscle (fl.). resulting In a decreased peripherol resistance. Because of its cardiac stimulatory action. it may increase systolic blood pressure slightly. but il greatly reduces mean arterial and diastolic blood pressure (FigtJre 6. 11).

........ _1.' ........ _ , .

• """" .........."""""""'.., """""", .. _ . "" >

65

IV, Direct·Acting Adrenergic Agooists b. Pulmonary: A prob.wld and rapid brondlodilalion is procluced by the drug (!\t action. Figure 6.12). Isoproterenol is as active as epinephrintii and rapidly 8le';iates an aaJte attack 01 aslt1ma. when laken by Inhalation (which is lhe recommended route). This acOOn lasts aboul ooe hoUr and may be ,epeated by "Neq !&rll doses.

-_.. ,,--

' - .....o:A_ V r I 'I • 1M *-lIlY

c. Othet" efiDds: Other aetions on p reoep!OrS. sudl as increases i'I blood sugar and i'lcreased lipolysis can be dernOllstrated. but are I'lOI di licBIly sigllif.ca..... 2. Therapeutic: .....: ~ is flOW rarety used as a bronchodilalor ., asttvna. It can be employed 10 lilimulale the l1earl in emergency situaticns.

1. ~. .tics: IstJPlOfollf8llolcan be absOIbed systemically by' the st.tiit'9I8I fllI,IC(l58 blA is fl'IOt& rriabIy absatled when given parenIefaIy 01' as ., inhaled le<usoI. It is a nwginal subs1raIe 101' COMT and is stable to MAO ~

4. AiIt¥efM ef!ecIS: I ~ illl'Wlfse effects lhoIie at epiltjJ.i....

are srniIa. 10

~

... ,

!~ •• 'OOf H~

,m

I

n

13)

I'm

O. Dopamine L\q'laTIine [DOE pa meen~ !he jnmediate meIabdie prear.;or at ,.... epitephl.NI'. 0ClC:\n naltnly irI the CNS irI Ihe basal gaogIia

...ne.e II ""dialS as I

ner..-otransmilter as ~ as irI fle ueilal meO.AIa. ~ can lahW'e (l- and fkIdoelle.gie ,~ Fa ~ , at ~ do6eS II can cause ¥iISOlXIOSlI'dc bV ac::ti ali: 'll a Ia:~ .. \Iota at Iorooef doses, II s&-rUales p" cauk reoepbs. In .~ ..... ~ D, and 0, ~ ,-flj*.s.listrlcllrDm Ihe (land fHIOe.leI'gic ,..,. flj ..... ClClCU irIlhe ~ " 858 lletic an:! renal Wi!iaAllr beds, where bio oil'll at ~ prodl oces '65 • ".a· '10:'1. 0, ,eo epIO" are aIIo b.rd on ~ adi....... gjc neuo'lS, whenllheir llCIMllioO irlllll1etes ......, rollpillP'iiNl' ,e

.. """""

...

-,

I-

ii

,

~

"

:==tl-In . ."". . . ,

.. ~Iar. DopamtIe ~ a stim.Jla1ory eItecI on !he ill lecepkn at !he ~ h8'o'ing boIh inolropic and dVonolropic etlecls (Figure 6.12). At \Ii!l'Y Ngl doses. ~acIivalesa

I

_

-_.

"Of _ ..""_

.-udIr..... • t __

_-..r~...

re
arterioles by a<:fivatjng dopaminefgie feoep!OrS, thus roeasing blood flow 10 the kidneys and other uiscera (see F'9Ure 6.12). These recePlOl'S are not aNacted by u· or P-bloc:kirlg dnigS. The<eloIe. dcJ)8rn1'le is clinically useitJl in the lreatmenl 01 shodI. in which SVlificanl increases ., &yrT1)8theIic aaivity might compromise refllli tunction. INOIe: Similar dopamine reooplors are Icu1d In lt1e autonomic ganglia arld In !he eNS.]

2. Therapeutic .....

.. Shod<: [)q:J8nioB is the CWg d choice b s/1Odl and is gven by contnJorJs lnIusia'l. " raises the bao::I pressure by stimJlaling

•

2

1

AgUAl6.11

cal'dioYascular etIecls at 1r'Ilra"lltlOU6

Infusion at iscpI'«erenol.

.

............., ....... _, . Isoproterenol

ard"

In .-..~ I erhances pl!ftSon kllhe dl ... . - . as deso'tled sto.<e.. kI i Cl er ... tioo::lllow to hl ~ ~ h ~ i rail! an:! carSY SOlIl.-n dUesis. In INs Jegard. ~ is Iar superior 10 ...............; ... v.t1ich (i""islles hi blood Sl4lllIY 10 !he Idl;hey am may C!IU5e kidney studoM't.

!he ' - t lJ', kili'ley

aeticn~

'JOt'''''. ....

3. Adverse efllt(:ll: An overdoSe of dopamine prodl.lCes the same ,,!teas as sympathetic stimulation. Dopamine is rapidly melabo-

It!ed 10 ~11ic acid. &rod Its adVerse ettects (Muooa, hypertensiorl. a~) a.e lheretore shorHMe
E. Dobutamine I.~,

Dob..'."'1doe

B'tOO18 moonl_ a 5lY'''ll!tic, di'ed-ad. il'Ig calt!d.... i.~ Ihat is. ~-ff!ICePIDr agcnst. II is lIIa'8b1e as a ,a:&,ic mixIufe. One d hi sE,euisulners has a lDnJlalofy a:a;.,. Jry. It naeases CllItliac rme and 0LCpUl widllew 'rsow efIeds.

,I~ ---

1llI - -

--

Dopaminergic

Dopamine

Agu.. 6.12 Clnc::aIy ~ adU'II at isoprofet8odancl ~

2. Thtlrapeutlc 1iSeS: DvWtamne is used to increase cardiac oolpUl in congestive heart fa~ure (p. 161). The drug iOCt'eases cardiac ootput wilh lillie change In the heart rate and does !'ICI sigl'lificantty elevat.. oxygen demands 01 the myoca'dium-a major

ad\Ianlage 0I/fI1 Oltler ~1hoo1.,l(!tic drugs. 3. AdYefse eftects: ~ should be used wit! caution In I!ltriaI fibriIaticn, since !he drug increases iItnlMlntnc\Aar ~

0Iher adYerse efleas are the same as 1hoSe tor epiuepl·.nne. ToIeillllCe may deYeIop on piololl{lOO use. F. Phenylephrine

Phenylephrine [len ill EF rinl is a direct-aclirlg, synthetic adre!'lefgic drug !hat binds primarily 10 (.t receptors and lavoo'$ u, receplors ever ~ rec;:epbs. It is Il()I a cate<:hol del'iva1Ml and lhefetore not a Sl.tIstrate tor COMT. Pt1er7yIephme is. II3SOOOllStric1or IhaI raises bolh syslOIic: and diaslOk: blood pressures. It has no ettecI on !he '-ft ilseII bul incU:es rellex ~ when gver. paren~ II is ot1en used klpicaIoJ on fle nasa muocus """,oad and in ophIh~ ~ lor mydriasis. Phenylephrine acts as a nasal decoilgeSliU'll (p. 221). and produces prolonged vasoconstricIio. The drug is used 10 raise blood pressure and 10 Iermirlale episodes 01 supraventricular tachycardia (rapid hear1 acIion arisir.g boltIlrom lhe alrioveJ'llricular jUJ'lclioJ'l aod alria). Large doses caJ'l cause hypertellSive headacl1e and cardiac irregular~ies.

G. Methoxilmine AAe!h:War.IiJ",[melh OX a _ l i s a ditea-aeting synlhetic ..........gic: drug thaI binds primarily 10 Q receplorS. with u, receplOrS IaYored (Mlf cr.t reoep4ors. AldlUCarrWle raises l*lod pres$ld br stirrUating u, r8Ollpb's in Ihe ane.iuIes, causing vasooonstriclIo This causes an R:rease in IaaI periphef31 resistarlce. Because cl its etIeas on !he vagus. mef#IoIG&mne is used dir1ica1ly to relieYe attad<s 01 parcocysmal 5IJpI'ilV8I'ltrlar tachycardia. 111$ also used

<....... _..,.<---"',.

< """" ........... . - -.. , H><:AI\O . . _ . '" •

"

V. Indirect-Acting Adrenergic Agonists to o,tercome hypotension during surgery involving halothane anesthetics. In contrast to moSt other adrenergic drugs. methoXamine does not tefld to Iriggef cardiac arrhythmias in tI1e l\eart that is sensijized by mese general anesthetics AdVerse etIects irdude hyper· tensive headadle and vomiting. H. Clonldine

CIonk/infl [KLOE ni dean) is an U2 agonist that is used in essential hypertension to lower blood pressure because ot its action in lt1e eNS (see p. 189). It can be used to minimize lt1e symptoms that IlCCOfT1pany withdrawal from opiates or benlodiazepines. Cionidine acts centrally 10 produce inhibition of ~thetic vasomotor OBf1ters. RecenUy, an endogenous substance. agmantioe. which appears to be the natural ligand at donidine binding sites, has been ident~ied.

0N.01 of blood>odllllllOn llUrMlon of boonet-.Ion

I

l. Metaprote,enol

Melaprolerenol[met a proe TER a noIe). although chemically similar not a catecholamine and is resistant to metllyla-

10 hioproterenol, is

bon by COMT. It can be administered orally or by inhalation. The drug acts primarily at Il" re<:eptors, producing linle effect on the heart Metaprolerenol produces dilation of the bronchioles and ~ s airway function. The drug is useful as a bronchodilator in lt1e treatment 01 aslt1ma and to reverse bronchospasm (FIQure 6_13).

J. Terbulaline

•

TetfJulaline Iter BYOO te leen) is a I\::i: agonist wilt1 fTIO(e selective properties lt1an metaproterenol and a longer duralion 01 action. TeroutaUne can be administered eilt1er orally or subcutaneously. It is used as a bronchodilator and to reduce uterine contractions in premature Labor. K. Albuterol

• •

,

..

Albuterol [al BVOO ter ole] is a selective I\::i: agonist wilt1 properties similar to those of re,butaline. The drug is widely used as an inhalant to relieve bronchospasm.

V. INDIRECT-ACTING ADRENERGIC AGONI$T$ Indirect-acting adrenerg;c agonists cause norepinephrine release Irom presynaptic terminals (see Figure 6.8). They potenliate lt1e effects of norepinephrine produced endogenously. blJt Ihese agents do not directty strect postsynaptic receptors. A. Amphetamine

Amphetamine's [am FET a maen) mar\(ed central sbmJlalOfy action is often mistal<.en by drug abusers as ilS only action. However, lhe drug can increase blood pressure signilicanl!y by «·agonist action on It1e vasculature as well as II- stimulatory effects on the heart. lIS

Figure 6.13 Onset and duration 01 brondlodiLalion effeds d inhaled adrenergic agonists.

<'.0<'0''''''''''''''_''

• .-. • _

"

... ~ , """"'"' ............ >

6. Adrenergic Agonists

peripheral aClions are mediated primarily through the cellular release ol stored catecholamines; thus, amphetamine is an indirectacting adrenergic drug. The aclions and uses of amphetamines are diswssed IJI'Ider stimolants 01 the eNS (see p. 103).The eNS stimu· lant etlects 01 amphetamine and its derivatives have led 1o their use

in the therapy of depression. hyperactivity in children, narcolepsy, and appetite control. lIs use in pregnancy should be avoided because 01 adverse ellects 00 the deVelopment 01 the felus.

• •

B. Tyramine

AAAHYT.U'AS

Tyrnminfl {teye ra meen] is I'd a dinically usefU drug, but ~ is found i1 fermented foods, soctl as ripe cheese and Chian~ lWIe (see MAO inhibitOl'S, p. '('3). It is a normal ~-product of tyrosine metabolism. Normally. it is o~idized by MAO, but it the patient is laking MAO rhibiIors, it can precipitate serious vasopressor episodes. UolarTW1e acts 00 aclrenocepIorS. HEA"ACHE

VI. MIXED-ACTION ADRENERGIC AGONISTS Mixed·acHen drugs induce the release or norepinephrine Irom pre· synaptic terminals and activate adrenergic recepto<s on the postsynaptic membrane (see Figure 6.8). • 'PERAelMn

A. Ephedrine

NAUS'A

TAEMOAS

Figure 6.14

Some adverse etlects obse
Ephedrine /e FED rin]. a plant !llkaloid. is rt(ffl mMe synthetically. The drug is a mixed-action adrenergic agent. It not enly releases stored norepinephrine trom nerve endings (Figure 6.8) but also direetty stimulates both (J and II receptors. Thus, a wide variety of adrenergic actions ensue that are similar to those of epinephrine. a~hotJgh less potent. Ephedrine is r\Ot II catechol and is a poor soo. strate lor COMT and MAO; thus. the drug has a long duration of action. Ephedrine has mcallent absorption orally and penetrates into the central nl!f\lOUS system. It is eliminated unchanged in the urine. Ephedrine raises systolic and diastolic blood pressures by vasoconstriction and cardiac stimulation. Epfledrine produces branchodilation. but it is less potent lt1an epinephrine or i5QP
........ _,., .... _-"',. VI. Mixed-Aetkln Adrene
" DN9

Therapeutic uses

AeceplOf specificity

......,

--

~,.ll>

"' ........

WlIocal_1O

_ o i o I i C I i ~ _

CATECHOLAMINES •

Ra,>lcl_ Of """""

•

BrW""""""'",_

•

_ _. _ orally

•

Do noI pooroebotB_

-

Nrnpl""pM ..

....

......

Quja'."

.~-

Compwed 10 _I>olaml.-; • •

..

L<>nger duration Of _ All.,." "" _1nI.._ ~

r

...... ----

Dopoo,.... gi<

p,

p, 0,

~

_

T_oI_

....

T.....-- 01 "'" ,gesti...

=;:.:"~•.•g••••''''' ........... de<:otg

-----

•

T' •• '.... 01 _ _

",

~

",

,

"""

""~'"''

_

~,.ll>

~

t:l
NON·CATECHOL· AMINES

"'.'" p,

•

o.~

o,~

Figure 6.15 Summary of the adrenergic agonists.

B. Metaraminol Melammlnci [met a RAM i noIe] is a mixed-action adrenergic drug with actions similar to norepinephrine. This agenl has bew USed in lhe lreatmenl of shock (when an infusion of norepinephrine or dopamine is not poss1ble) and 10 lreal acute hypotensioo. II is given parenterally as a single injection. It enhances cardiac aCllvity and produces mild vasoconstriction. The importanl characteristics 01 the adrenergic agoniSI$ are summarized in Fogures 6.14 and 6.15.

T

~

__

T_."..«olboud...-"

• •~, ro•••

J.,

.<_.__..._,IWCAII,l ..............

,•

ro

6. Adre<'lergic AgonislS A. 'raeases cardiac 0UIllUI

B. 0ilaIes . - VISaJIat.Jr. 6.1

c. 0iIaI0s bronchi

is increasel! alief lie ~__ '11 dougs?

o;e......... '" ,

at """'*ft one at lie

o. 10""

res blood '"""'" E. Incn!ases proeIo ........ 01 ......

A. .................

( ~ ch:Ice. c.!>, , . . . ", . . . ".01 . . U"lI-

8. Ep"OIlIvi.. C. IIo:Ip

'*".. d

0._

6...... at !he 1oIowii'll IIatiIl'I'IefU

E.Terb::.

q:hineareW??EXCEFT' A. • is., a agonisI .... CMlIeI

__ , ... ; . .'"',...,.0

CClfNd _ _ • A. Ib......... pDdI.II;leI

........... F

$.

100

.-.cs 01

B.

a, no ..... balIl .,sdc _ _ I' _ 00 £p""",a. e-diM: out;I'. w,"*Uo _Uw ... (a

_ l . -.1 _ _ . . . -
............... ~o

"'~~

. . J$IlIlInd

.0 .

-

o. II CMISe$~'-'-

_.-lStridiof.. agon
~

it'*>he-,e.

C
n'" .IC

"'_'.'1)0

~ ~

E. II is o1tetl kuld in _.1I>e-oclure- nosPl deoooY*

~specific

_gonl.: thlt ~ ClUlp.t jlGIlpl'>... ,,! ....... nligI'Il in .YltOlIe: bIOOCl pren.url! end • • Ignlllc;..,t dIcr _ in 4 ... bIood~. AbIIerol end klIIMeIron 8ftI" • • • .... .,. Milo NOipb'lI. ?.clIlroterlMlol II I

_

c.1t is used 1O~ bl... d~'"

:

. . P'lI lID

1I1s.~ ~

)

1

11.5 A 58·yen.~kl temale hPl unclefVO output. and cooIusIon) consistent with oep4lc sIIod<. To """"'llI! he< CAre, whet ~rnic; S<.qlOrI WOIAd be

.....'

A. Fluid actninIslr.1IOrl

B.

~

Ink.tsion

C. Antbotic ~tion o. FUd:s ..-.d ::>q.mIne

cc.r.ct_.D.... i'...... .,ic

................=.•

....

<:aRline: """"" 10 10'......... ""'YlIII" ~_

..........._.. .,,'• • aQicA ..

CNS _

.:

_0. I

[ lite-d-.o.E.~-",,~,;!'o. r.slltle .... j~

11.3

-.,

~

~

_

eauseo" but _

's. 11-261.,81

onlI Ollhe ........ 9

... ,l2hl ....j"" ...... _

..... ~ DOPA """" $)'I
__ p.2Q"" '..'_.{2rdnclllor ............. dl...

"o.........-.

........

mel?"

~

,,-.I ........ patient

SirIDe _

.~de8l'd_.-'w_~it.d>

.<0& · . _ . . . . . _~ba>allklm ltulcl U-npy. An inotropic ngen:. SUd> as

CIotM'iI.... wooAd ..., 10 . . ~oell.vd""'­

output end . .lion at 1M '-&I vaK1llatu... [M3e: AI 1OgII'*-. I. • IF•• ...., W'"*U

........... _....

• , a' 1'd~. . . ~.IW''''"'yr.,....

. . . . . . . . . .,IiI _ _• is

ciao

'

b
rs. 11-2111 .. .,_ W. b~(2rd""I"".""'_ _ dlP• "'''~

. . .,. . . .,.._--,> Adrenergic Antagonists I. OVERVIEW

ADRENERGtC BLOCKERS

The adrenergic anIagollists (also called~)bmlo &erBlo:eplOiS but do no! l.igge. Itle usual .eceplor-mediated Intracenul8J et!ects. These drugs I!lCl by either reversibly Of ir.evertiibly anaching 10 the ,eoepklr, thuS Pf(Ml(ltiog its adivalion by endogenous catectoolanW'oes. Uke lhe agonlsls, the adfeneryic antagoniStS are classified IIOOOfling 10 their relative atflnity fOI a Of ~ receptOfs in lhe peripheral nefYOUS SYstim. INote: Antagonists lhat blocl< dopamine reoep!QfS are mosllmportIInt in lt1e cen1ml fleMl\.JS syslem and will be considered in Ihat section (see P. 127.) The receptor-blocking drugs discussed in It1ls chapter are Slrrlmari~ed In Figure 7.1.

I-

...-

_. ,-

_,011_

"'-'j'WtIl.........

'---

II. a-ADRENERGIC BLOCKING AGENTS

n-8LOCKERS

P-8LOCKERS

.-......... .

"',h ,.4

Drugs lhat bIod< <:r. adreuoceptors profourKIy af\e<:l: blood p.-essure. Sinoe normal sympalhetic (l()(Itf(ll of !he IIllSO.Aatl.o'e oo::oJf$ ., large par1 Ihrough agonist idio ... on <:r.-adnlner{lic reoeplOrS. t*xkade of lhese redllces !he ~ tone of Ihe t*lod YeSSeIs. ,lIStAIing in decreased peripheral vascular reslstan<:e. This induc:es a reflex ~ restb'og hom the b 'Ired blood Pilli nL INQIe: II feceptOfS, Including fl. adJenooeptOfS on the hearl, a•• nol aNected by ul;jocl<arle) and ~l'\;MllimitedetncaII

, t .co' ..

'P_

,"""'*""

...." .. "....

,..., "

-

pt""_,oenza,.....

"---

,

'

DRUGS " " """" H ~

.._.

UPTAKE OR RD EASE

[tEn OC 00 BEN 13 _~ a ~ relaJed III the ,libClgell muslards. is '","' sets tive. IilIcir'lg ocwalanlly 10 both a,-posI~ and ~ receptors (F9J'fI 7.2). The t*'d< is irreversible and norlCO"ipE!ti~O'l!; the only mechaniSm Ihe body has to OWfcome the block ;s 10 synthesi~e new 8drenoceplOf5. which requires a day or more. Therolore. the actions of ~ last about 24 hou's after a single administration. AlIef the drug is iI ~, a 0eIav 01 a lew hou's O(ll;US belore a blod
'"

~

At .. ,..,.

FogUle 1,1

Summary of block.n9 agents and drugs aflectr.g neuro-

transmitler ~e or release.

. . _'-._..

............ _ _ .. ' - _ ._ _

c.._

a __ ~A

.. _

71'

<''''''.''''.''<-'''-''

"

7. Adfene
1. Actions:

Q

II.

Cardiovascular effects: By b1od
b. Epinephrine reversal: All CI-adrenergic blockers rewrse the a-agonist actions epinephrine. For example. the vasoc;on.stridive action epinep/lrine is lntem.opled. but vasodila~on of other vascular beds caused by stimulation or l}-receptors is not bIod<ed. Thererore, the systemic blood pressu.e decreases in response to epinephrine given in the presef1ce of phenoxy. berlurmJna (F'9ure 7.3). [Note: The actions 01 norepinephrine are not reversed but diminished. since norepinephrine lacks signiricant Il-agonisl action on the vasculature_] PhenoxybenUfmine has no eftect 0f'1 the actions 01 Iscprolerenol. which is a pure [l agonist (F'9L/re 7.3).

or

E"",,1Of cefl

...... "bn"...

Figure 7.2 Covalent inactivation or 1;(1 adrenoceptor by phenoxybenUlmine

~

_.of pu;

~lcblof:"""

_ .. ..., -

"" me

~0p'0f_.

_ h 1••

"

8~gon ....

"' - --_.

-

-~.

::.~"\/ "'v" j\"., ~

4>1....1. ~

•

./'...

~

"'-

.I'....

...-

"""''','''igle bloc...... _mev....,..

•

ooonotrlctl.... 8
Figure 7.3 Summary of effects of adrenergic blod<ers on the cha'VlS in blood pressure induced by ISOptOterenol. er;;ir'lephrine. and norepinephrine.

•

or

2. ThenlpouIIc uses: Ptlenoxyberlzamine is used in the treatment 01 pheo<:hromocytoma, a catecholamine-secreting tumor of celiS derived from the adrenal medulla. Prior to surgical removal ol the tumor, patients are Ifeated with phefloxybenzamine to preclude hypertensive crisis that can resu~ rrom manipulation or the ~ssue. This drug also linds use in the dnonic management of these fumors. particularty when lt1e catecholamine-secreting cells ale diffuse and therefore inoperable. Phenoxybenzamine or phenIoIamine are sometimes eftecliw in trea~ng Rayr'\lltxl's diooase. Autonomic hyperreflexia which predisposes paraplegics to strokeS can be managed with phenoxybentBmine.

3. Adverse ellects: PtIenoxybenzafl1jne can cause postural hypo. tension, nasal stuffiness, ar1d nausea and loOmiting. It can inhibit ejaculation. The drug also mllY induce tachycardia. mediated by the baroreceptor reflex and is contraindicated in patients wnh decreased OOfOflary pe!1usion.

B. Phentolamine In oontrast to pIlenoxybenzamine. phentolamine [len TOLE a mean] produces a oompetnive block 01 Cli and Cl2 receptors. The drug's action lasts for approximately 4 hours aller a single administration. Like phenoxybenzamine. it produces postural hypotension and causes epinephrine ,eversal. Phentolamine had been used in the diagnosis or pI1eochromocytoma and in other dinical situations associated with excess release 01 catecholamines. Phentolamineinduced relll!J< cardiac stimula1ion and lad1yC11fdia are mediated by the baroreceptor reflex and by blocking the fX2 receptors or the car· diac sympathetic nerves. The drug can also trigger arrt1yttvnias and anginal pain and is contraindicated In patients with decreased OOfOflary perfuSion.

.""' .....1.' •• _ .............. ,· III.Il-AdIllf'lefgic BIoc:king AgeflIs

PtlUOSi'r [PRAY zoe &in), IerazDsAof Iter AY zoe &in) and Gbuzosirr AY zoe sinl ate seledioE (Xlhp:ci~\18 bIoCkel'$ orlhll (:t, receplor, In contrast 10 ptl~amine and phentolamine, lhese
I
or .........., 1.

~

efteels: Prams:in an:! II!raZOSi1 deae3se peripheral vasaaar resistal'lal aqj Io'Wer arterial blood presswe by CIiI.IWIg Ihe relaxation or boIh anerial and....-..;:u; SIT.....' ITll/fiICle. Thew~""~an:l~.e:ause

nWwnaI chlWlges" cardiac~. renal blood now. and gblleuIar NIralion Itlle. 2. ThenIpeullc uses: IncividuaIs wiIh elevaled blood pressure v.tlo h8I'e been Ire8Ied ¥>iIh ptaZOSin or IerazDsAof do net beool, 181OleranllO its aclion (see P. 189). H~. the lifSl dose of these dn.gs PfOdtoces an exagger.lted hypolensiYe oespoilSfl thai can res.un il'l syncope (fainting). This action. termed a "tirst-dose" ettecl. may be mif1imized by adjusting the 1m dose to one lhin;l or one fourth ollhe normal dose. and by giving the drUg al bed time. The u, antagonists have been used as an alternative 10 rorgery in plIti&nts with s~ptomalic benign prostatic hypertrophy. Blodade 01 tile 0 receplors decreases tone in the smooth muscle 01 the bladder neck and prostale and improves urine How. (Note: FinaSlerlde. which inhibits dillydrotestoslerone synthesis. has been apprOYed for treatment ol benign prostatic hypertrophy. but its eltects are 001 evident klr several week.s.) 3. AchIerH e«ecla: Pramsin and terazositllTllly cause ciuiness, a lack 01 energy, nasal congestion, lleadaeh8. drowsiness, and 0rlh0SIaI1c hypotension (although 10 a Ie8ser degree than that ol:l&erwd wilh ~ a n d ~ .An adciIive ~ eHed OCCU'S prBZOSIn is given wilh either a diuretic or a p..bIocker. flereby necenilating a reduction in its dose. Due 10 a lel'ldellcy 10 retain SlXIi.m and IlUId, ~ is ~ used alMg wilt! a diuretic:. Male _ _ kn:iion is not as Moecet)' atIeded by _ _
...men

III. Ji-ADRENERGIC BLOCKING AGENTS All lhe dinically available Il-blockers are c:ompetili\'e amagonisls_ NoiseIBc*'1ll1\-blOCllef's ad at lxllh ~ n 112 ,eoeplOiS. 'IOtlereas car· (lioseIBc;ti.. Il-anlagonisls primarily block. p, recepIofs. These drugs also
<......

0 ...

'.'.<_ ... _,. 7. Adrenerg;c Antagonists

rrryocardaI inlarcIion, and glaucoma, as weH as se<W'g in the prophylaxis 01 migraine hea
Propranolollproe PRAN oh lole] is the prototype ~·adrenergic antagonist and blocks bolI1 ~, and ll:! receptors, Sustained release preparaOOns torOf'>OO:arday dosing are available. 1. Actions

... CardlOV8Kular: PropranoIoJ diminisheS cardiac output, having both negative inotropic and cllronotropic el1ecls (Fogure 7.6). It diredly depresses siOOrauricular and atrioventricular activity. The resulting bradycardia usually limits thl! dose 01 the dnJg. Cardiac OIJIpuI, WOtk. and oxygen consumption are dea'eased by blockade 01 ~1 receptors: these effects are useful in /he trealmef1t 01 angina (see p. 176). The Ilc-blod<ers are el1ective in attenuating supraventricular cardiac arrhythmias but are genemJly not effective against venlfbilar arrhyll1mias (except those Induced by exercise).

e

. , M

b. Peripheral vasoconstriction: Blockade ol ~ recepto<s prevents ll:!-mediated vasodilation (see Figure 7.6). The reduction in cardiac output leads to dec/eased blood pressure. This hypotension triggers a reflex peripheral vasoconstriction. whicll is relfected irl reduced blood l10w to the periphery. On balance. there is a gradual reducliOt1 01 both systolic and dias· tolic blood pressures in hyperlensive patients. No paslural hypotension occurs. since tha ClI·adrenergic receptors that control vascular resistance are unaffected.

e' ,. 10.'" ....

"

'

,

),4 nro

c. Bronchoconstrlctlon: Blocking l~ receptors in the lungs 01 susceptible patients causes contraction ot the bronchiolar smooth muscle (see FIgUre 7.6). This can precip~ate a respira' tory crisis in patients with dlfonic obstructive pulmonary disease or asthma. fl-6Iockers are thus contraindiaed in patients with asthma

"'''''of

1'1_. "

-

FIgure 7.5 Elimination ~

blockers,

14,24 hr.

ha~-ljyes

tor some

d. Increased Na' retentlon: Reduced blood pressure causes a decrease in renal perfusion, resu~ing in an increasa in Na" retention afld plasma l'Olume (see ~'9ure 7.6). In soma cases this compensatory response tends to elevate the blood pressure. For these patients, fl-blOckers are otten combined with a diuretic to prevent Na' retention. e. Olstufbances In glucose metabOlism: ~ blockade leads to decreased glyoogenoIysis and decreased glucagon secretion. "Therelore. H an insulirHlependent diabetic Is to be given pr0pran01oi. very carefUl monitoring o! blood gtocose is essef1lial, sinoe pronoulCed hypoglycemia may 0CCUf alter insulin injection.jl--Bkxke<s also atlenuate the normal pl'fisiologic response to~.

·""" .....,., ..

_--,.

• .........._ _..-...-'"

K"""U" _ . PI' •

Ill. ~Adreoergic BIod
75

.... 'r' --,

.... '," "

"

. "

~,

'-

" ', -,',""'-' -'" "

"

'.' .~

1lI ~-

II. Hypertension: Proptanolollowers blood pressure in hypertension by deaeasing cardiac oulplJt (see p. t76).

b. Glaucoma: Propranolol and other !I-blockers, particularly limolol (see p. 76). are el1ec:tive in diminishing intf<\OCllAar pressure in glaucoma. This OCctJrs by decreasing the seaetoo or aqueous Illlmor by the ciliary body. Many patients witI1 grauooma have been maintained with these drugs lor years. 1l1f:!y neither aflect the ability of the f!!f& to /oQ.Js lor near vision. nor cl1ange pupil size. as 00 the ct'oolinefgic: drugs. However. in an acute altac:k 01 glauooma, pilocarpine (see p. 41) is still the drug ot choice.The ~blockefs are only used to treat this disease dUQrically.

fi1IR_.~t "v~c1lon

c. Migraine: Propranolol is also elte<:tiViI in reducing migraine episodes (see p. 427). The value Of 'he ll-blockers Is In the treatment of c:tlronic: migtaine in which the drug deaeases li1e Incidence and severity of the altac:ks. The medlanism may depend on the bIocI
Figure 7.6

Actions 01 propranoJoi and other ~1 blockers.

...,,, .....,., .. _--,. 7. Adrenergic Aotagonists

"

myocardial irlfafdion reduces iorarcl SQe aod hastens re<::ov. ery. The mechanism lor these efleds may be blocking or the aclions o! circulatiog calechoiamil1eS. which would ioerease lhe oxygen demand in an atready ischemic heart muscte. PropronckJI also reduoes the IflCidence o! sudder1 arrl1y1t1mic death afte< myocardial irllarctiof1 (see P. 171).

3. Adve.se ef1ects: Propranolol has a serious aod potenHally lei hal side effect when adminlSlered to an asthmatic (Figure 7.7). An immediate contracHon or the bronchiolar smoolh muscle prever1Is air from enteriog the luogs. Dealhs by asphyxiation have been reported ror asthmatics who were inadvertently administered the drug. Thererore, propranolol mustllllYer be used in trealing aoy individual wilh obsll\iCUve pulmonary disease.

8. BronChoconstrlcllon:

b. A"hythmlas' Treatment wilh the jl.-blocl<ers musl never

be

stopped quickly because of 1I1e risk ot precipitatlog cardiac arrhythmias. which may be &e\lere. The 1l-b1ockers must be tapered off gradually lor 1 week. Long-telTTltrealmenl wi1I1 a jl.antagon;stleads to up-regula1ion of the jl.-receptor. On suspension of lhernpy, the increased reoeptors can WOfSefl angina or hypertension.

c. Sexual Impalnnent: Since !;l!J
Flgure7.7 Adverse eHecls commonly observed in individuals treated wi1I1 propranolol.

d. Dlslurbances In metabolism: UBlockade leads to decreased glycogenolysis and decreased glucagon secretion. Fasting hypogtyoemia may occur. [NoIe: GardioseIecIive Il-blockers are preferred In treating ~I'lt aslhmaliCS. (see beloW).] e. Drug lnlernctlons: Drugs thatlnlerfere wilh the metabolism of propranolol. sud! as cimetidine (see p. 236). furosemide (see p. 227). and chiorpt"omazine (see p. 127). may potentiate ~s amihypenensive el1ects. Conversely. those that stimulate its metabolism. sud1 as bIIrb~urates (see p. 94). phenytoin (see p. 140) and rifampin (see p. 333), can m~igate ~s erlects.

B. T1molol and nadolol: nonsetecllve ll-antagonlSIS

TtmOJoI [TIM 0 IDle] and nadolol [NAH doh loIe] also block. II, and 112 adrenoceplors and are more potent lhan propranaioi. NadoIoI has a V9l)' long duration 01 action (see Figure 7.5). TIfflO/o/ reduces the prodUClion 01 aqueous humor m the eye and is used lopicaily in the trealmenl or chronic open-angle glaucoma. and occasionally /or systemic treatment 01 hyper1enslon.

..... '....1.' )... _ _ ,. n

•

C. Aatbulolol, alenOk>l. meloprolo( and esmolol: selective 111 8fltagonlllts

Agonists

l a _ ... __ ••••~.1 Orug$ Itlal plekM,ulialy t*lCk the IJ, tflOE!'l)tOlS Mw been developed: kl eliminate Ihe UI"IWW'lled blOnd "":::,,..strldor ellect Ok) of /Nopranok>l seen among asthmatic patients. Cardioseleclive p..t:b:Ufs, Sl.ICh as acebufDloIla se BYlX> toe klIe}, 81eno1011a TEN 011 1oM!). and mefDploId lme TOE proe klIeI. ~ ~ 'eceplOos at doses 50 10 100 tmes less !han Ih3se <eq.lired 10 tb:t Ilot reoeplOf$. n-s cardoouleetMty is thus mosl pronoooced allow doses and is Icl5l al higl drug doses. {Nl!'e: IV:et:xJtoIoI has some intrinSIC agonist actMty.! 1. Actlorls: These chlgs lower blocxl pressure in hyper1e1'1sion and increase e>ceroise lolernnoB in angina (see FIgUre 7.6). Esmo/GI IEZ moe lole] has II very 6hoft lifetime (see FIgure 7.5) due to metabolism or an esle, linkage. It is ooly given \ntravenously if reQt.Jlred durtng surgery or (jjagooslic procedures (fof e~arnple, cystoscopy). In oontrast kl proprclnokJl, the ca,diospeciJic bIocke<s haWl relatively little eflecl on pulmonary 1IJnction, peripheral resistance, and cartJohydrate metabolism. NeYerthe4ess. 8SlhmaDcs treated with these agenls tnl.I$I be <:aIeluly !IO"Iitored 10 make ~ f\ld re5l*alOry acliYlry is I'I(ll co",""ullised.

t.

~_~,*,",*"._

~

~ISI

8Cllvlly 1. Aetlons:

a. cardiovascular. Aeeoololol and pindoIoIlPIN doe loIe! 8.e not pure bIod<ers: Instead they have the ability 10 weakly slWnulale bolt1 P. and D2 receptors (FlQure 7.8) and are said to haw intrinSic ~ltIomimetie adMty (ISA). These partial agonists stimulate tile p·receplof 10 which they are bound, yet ltley Inh.ibit stimulalion by the more potent endogenous cate· ~ and norepinep/'IIiM. The tesull of ltl8se 01>,.,.";'9 adioilS iii a much di,lilisl.cl ef-.cl on cardac rate and canIlK:oulpuI. ~ to ~Mhoui1SA.

c:tIcllanWles.

--

b. Dea

d II'leUIDoIie

e«ec:ts:

BIod<e<$ Mth ISA

".""ile fie

disluItD"oces 01 IiP:l and cart:loI¥hIe lTlIl'aboliIim soon Mth

2. Thetapeutic U5e In hypertMwlon: p..bIoct<ers wiIh ISA are eIIecIi-..e in hype<1ensive patients wiItl lTllXlerate ~ s:irlce a lurltler decrease in heart rate is less pronounced wilh these drugs. Carbohydrate melabolism is less al1ecled vmh aeeoolvlol and ~ than it Is wilh propraookJI, making them wluable in

the traalmerll 01 diabeticS.

•

Cl:U.UlAR EFFECTS

Antagonists (lOre_ _,

__,

. . . . . CpIo ..... , .

Thenpeulic U$e In ~ : The eardo:n'BclMl ~ . . useful in ~.... ISi.e piItiei lis with ~ ~ tU'lelion. Since these drugs ~ less efted on pelijJltItal >e$O ..... PJ, receptors, ooldness of ell1remitie$, a conwnon s.ide eflea 01 p..1*ld<er~ .• 1ess I~ CaidicselEc....e ~are useIuI in dabetic hjIpellellSi..e palia ItS 'fttlo _ <ecel.i 'Il i'lsuIin Of oral ~ ageru.

O. Plodoloi and a<:ebulolol: Ilfltagonlsts with partial

I

---

Partial agonists

llor '"""""1'10> , - -

<.........,.,.<- ... _,.

<.-oK _ _ • .....,..... ......... W>

"

7. Adrenergic Antagonists E.labetalol: lin Ctand I}blocker _Pt"",_OIc>\ """"P"O"of,lImo1ot, ea.dlac ~_.-

_.

.nd _ _ ""'"".

OIll

G.~

TIrnoIoI. and _

8 bloc......

-..ce _ ..... Ian 0 1 _

-----

Migraine

1. Actions: U!belaJol [lay BET a loIe] is a reversible I}blocker with COI1COrrent lXl·blod\ing actions thai produce peripheral vasodila· tion, thereby reducing blood pressure. Labetalolthus contrasts with the other [l-bloc:kers that produce peripheral vasoconstriction. and it IS therelore uselul in treating hypertensive patients lor whom iocraased peripheral vaSClllar resistance Is undesirable. Labetalol does not alter serum lipid Of blood gllJ(;(lSll 11Mll$. 2. Therapeutic u.... In hypeoteuslon: Labe/alol is uSlllul/or treating the etderly Or black hypertensive patient in whom increased perip/leral vaSClllar resistance is undesirable. iNoIe: In general biack t1)opertensive patients are not oontrolled with I}blod<' ers.] Labelalo/ may be employed as an aliernative to hydralaDne in the treatment or preg.-.ancy·indUced hypellension (PIH).

we"

3. Adverse aIIecls: Orthostatic hypolensior1 and dizziness are associated with Ctl blockade. Fogure 7.9 summarizes some 01 the indications !or 1J--bIockers.

IV. DRUGS AFFECTING NEUROTRANSMmER RELEASE OR UPTAKE

Thyrotoxicosis

As was noted on p. 68. some agonists. such as amphetamine and I)'mmine. do not ael directtv on tile adrenoceplOl. Instead. they exert tIleir efteds indirecfly on the adrenerg;c neuron by causing lt1e release 01 neurollBnsmil1er lrom stOlBge vesicles. Similarly. some agents act on the adrenergic netJfOf1. to e~her interlere in neutOlransmil1er release or alter the uptake 01 the netJrotransmil1er into the adrenergk: nerve.

Pt ~ ""'<:oil"'
CW
po!tInIloI'Df

A. ReserpIne

.nhl'l~_.

• Anhytl"mllI plophyIlll
andre
• Supraventrlcull.. llIchygnlias ~,-'andacd>ul_

_

AV c:ondIlc1ion _i'y.

0_

• Angina pectorR Pro,nnolOl, nadOI<>I; and Il-I>'<>c""" NIIuoe cmlloc raIe ..... Iore..

Figure 7.9 Some clinical applications 01 il<'OO<~.

Reserpine Ire SEA peen], a plant alkaloid. blocks the Mg"/adenosine triphosphate (ATPj-dependent transport ot biogenic amines, norepinephrine. dopamine and serofOrlin. Irom the cyIoplasm into storage W!SicIes in the adrenergic nerves or all body ~ssues (see p. 57). This causes an ultimale depletion of norepinephrine levels in the adrenergic neuron. since monoamine oxidase can degrade the norepinephrine in the cyIop1asm. Sympatllelic tunction. In general, is impaired because of decreased release 01 norepinephrine. Hypertensive patients taking the drug show a gradual de<:line in blood pressure with a cooromitarlt slowing of the cardiac rate. The drug has a slow onset of action and a long dumtion of action. When one stops taking the drug. the actions persist/or marry days.

B. Guanethidine Guanerhidine [gwahn ETH i deen] inhibits the response 01 the adrenergic nerve to stimulation or to indirectlY'actlng sympathomimetic amines. Guanethidine acts by blocking the release 01 stored fJ()repinepflrine. This resulis in a gradual tClffllring or blood pressure in hypertensives. and a de<:reaSll In cardiac mte. [Note:

...........,., ........ ..-'> IV. Drugs Allectlog NeorQIransmitle< Release ()( Uptake lJlefe is also an accentuation 01 parasympelhetie tooe 01 the gastroWltestinal trael] GJane/hidirle also
respo ...

COClIrirllJ [koe KANE] is ~ lln'IUlg Ioeal aneslhetic:& .., having Ihe IIbiliIy 10 tMdllhe Na'-K'-adivaled ATPase (req.ired lor ceIlAar l4JIlIke 01 norepinephrine)1ICI06S the oeIlTlEll'O_ ollhe achner· {lie neuron. Consequently, norepinephrine accumulales In the synaptic: space. resulling in enhancement 01 sympathetic activity and potentiation 01 the adi
~

•••

Blockers

......

Adverse eltects oonvnonIy observed with P blockers

.......

_ -~. . -~~~.~.~. .~.~t=':-:·::· ut

e:.. .

"'•...

B~AOYCA~(>IA

Figure 7.10 Summary 01 [l- adrenergic anlagonists.

_

-

••• •

llWM. . . .•

11Jpeo

,

..' .' ~

.

.."....~

1'.....

~ ~ ....

...........,.1

.<....

> ....... _ _ , >

M _ _~ . _ .. _

'" •

S~olIc preuure ill ,*=rellCed wtWch 01 IolIcl
'--

.lter'''- Ilijec.io" 01

c._ ADoxaZlWn

D.? pi .. E. NooepO ...... io ..

B. Labelalol

o.n

eor..d_ .. pt. . . . . . . . . . . . CIlI ioWDio. _ .... .... _ • ., .. to:: IOf •• _ n . . . . . . lnlbd.. " 1••••• ... poe •. _ •, • &1IOad; "*-" , &1IOad,. "14M_~NgiI~""" ~

c, ""**'.,.. -Dr'" ,.,

.-..EpI_...... .".sk-' • • tDo:I .. .? _~

.n~

,.....-.:t

..., , • • ib

-,, .-

72 WhicI'I .... CIl", IcA:>wIolg fi'\.IgI •

.-u In IreMing

8.IoopcOlUa",

C.PtIa_,•• o.P1upad>l

e - _ _ o.i\;p , '

..__ =... ,~

.-.

'

I

h

, 5

CIl I • tIliDcfI.- • I ca_hD' ,at

_ _ PI"\lI" ..... lIdlJ=...... ;

.........=.

7

..

i

.. ; .-.IIl to .;'• • IIbJd_~.' D til , ... T!'lIL ........ I

....

-.:II Q~ . . _tI5

__

a""'_ .. II6lIocl

1._ pcIlIIr'II ,

I ••

"",,'" aer .... ~ .. P ...........

••

7.3 A 6O-yN,-dd asthmllic man 0CInl8I .. lot. chedt·14I and 000' IpIaL os lllal he II haq -.... dtfIouIly .. "$tlIrto Ing 10 ..male". PItysIcaI examinBlion indIeD1ealMllhi man has • blood pressure 01 1601100 mm Hg and a sIilttdYer1Iarged proaale. Whidl CIt !he ~0lI fTl«I. cations wouIt:l bI usehA io1lrea1itlg boIh of IheSe oondI-

....,

C. Ept«lih,

•

>

7. Adrenergk:: AntagonisTS

Choose tile ONE best _ _. 7.1

....

• kit .,.,.

....

D. p,opalOlol

e. .........0IU ..... " " _ _ .. A

...... *"-

.. . _=..., l:ICaiade

C

'1

£

'1

.....--. 1

"

and . . .

IItlIlIIf

..... _

tlr.-.,_"" ... '''101'' • 11ILr '

. . . I• • I'

_

'

-~

....................... I •• _ _ -. 1 ...., ........ ........ ' , _ ' 8IIlI1i

---....

;1,

~

. . . t;;I_..

_-*II

..... ,....,., ........ _,>

UNIT III:

Drugs Affecting the Central Ner\'()Us Svstem

Treatment of Parkinson's Disease I. OVERVIEW OF CNS

Mo6t dfUOS lhal at1eCIlhe centrall1eI'\OOS system (CNS) act I1y' artemg some SleP In Itle neuroI/'llIlSmi process.. DnJgB atl9cting the CNS may act pre$yrIllpIicaI by influencing the production. stomge, or temlinab'! of 8C\ion of neu'OIIlli 1SI,1itte,S. QIher agenIs may aetiva1lll or bkx:k po51Synaplic reoaplCn. Ths ~ P'oriOOs an ~ ol lhe CNS wi1h a!lX:Ul on fIOfiJIIlIIlU"OInInsmltlhM are ~ In lhe aJioios olllle dInieaJy ~ CNS dnGS- These 00l"""iJb are uselu In understancIng 'hi eliology ol and lhe ~ SlraIegies lor Part
ANTJPARKINSON'S DRUGS

Ao,.

r ..

.. ""100 ......

c..::

,

~('S'J

U

.

r'

.......

A.'i

II. NEUROTRANSMISSION IN THE CNS

,"

In tnllI'l'f ways. IIle basic IullCtiOllio og of nel.nlIlI In Ihe CNS ill tmiar kl Ih8l ol !he atAolonie nervous system desaibed In Chapter 3. For

8lU\f11lle. Ir1lllSlTlissio.. ol irIIormaIion In Ihe CNS and In

Ihe peliphely boCtl irM:lMl Ihe release 01 neurotransmitler$ thaI dilfuse across !he synaptic space kl t*1d kl opecif. . ,eoeptoos on Ihe pl)5l$ynlIptic neta"OO. In boOl syslemS. Ihe 'ecoglilion 01 U. newotransmiuer by !he membrane Iecepb' 01 .... poslSynaptic IlelXOO Iriggers Inlr80ellbr ctIanges (see p. 33). StMlfal major differences exist belween OOUI"OllS in !he ~ all\OflOlTllc ne
!,

......,

''*: ..'

Sunmaty ol agenlS

U5e(\ in lhe lreatmentofParNi ..... ,·sdis o"B. 'Described In PtIamwtooIDgy updBla, p. 443.

. . -... _ _,,

_ _ _ _ or

,-

..,

..

._c_ 0;:._

, ..... _

81

<

,.,.<- _,> 8. Treatme
Receptor empty (no agonlsts)

III. SYNAPTIC POTENTIALS

t

In the CNS, receptors at most synapses are coupled to io
A. Excitatory pathWays

Receptor binding of excitatory neurotransmiUer

--ity. EnIry or

_

001<_10 ...

depc>IM.....

T'

Figure 8.2 Binding ol excitatory neurotransmitter. aoetvk:ho~ne, causes depolarization of neuron.

Neurotransmllters can be classified as excitatory Of inhibitory, depending on the narute ol fl1e action fl1ey elicit. Stimulation 01 excitatory neurons causes a movement of ions that resu~s In a depolarintion ot the postsynaptic memb.ane, These excitatory postsynaptic potentials (EPSP) are generated by the following: (I) $timulatioo of an excitatory neuron causes lt1e release of neurotransmitter molll(;ules, such as norepinephrine or acetylcholine, wtlich bind to reo::eptors on the postsynaptic 0011 membrane. This causes a transient increase in the permeability 01 sodium (Na') ions_ (2) The Influx 01 Na' causes a weak oopolarilBtion or excitatO
'.

<_ .....,., ........ _'> IV. Owrv\ew 01 Parkinson's Disease

B3

synapde polential (IPSP) that mcMlS the ~ potential twr.foI tram its Ilril"lg threshold. This diminishes the generation 01 action polantials. (See FIgUJ'8 B..3lor an ~ 01 an Inhibilory pa!tlwlly.) C. COmbined etlects oIlhe EPSP

~

IPSP

nu..

Moril neurons in the eNS lilI 'Of; bolt! EPSP and IPSP q.uL &eYefIII ditlerenl lypes 01 fMU"Otransmitte mllY ad on !he SlIITI8 neuron. 1M eaeh binds to its own specifie reeepIOf. The 0YefllII resulanlllCtion is due 10 !he su I 01 !he ~ 8di
Receptor empty (no agonists)

..

,",13tioI

Erroptr. I Ia _ _~ Iado.d. ~.-

..nose

!IOfI

01 eenain neIIl'OOIlI pathways.

IV. OVERVJEW OF PARKINSON'S DISEASE Plukins
Receptor binding of inhibitory neurotransmitter

A. Ellology The cause 01 Par\
St~rigra:

The 9ManIia

plIfl oIlhe ~ system, is lhe souoe 01 dopao,oieQie ~ t\llllefll*We in !he striatum (F1gt.nl8.4). E8dl dopao'oi"'Qie rwuon makes ItJooj. sand!> 01 S)NIpIic lXlrlts:ts ~ the striIllLwn and Itoetebe moouIste. . . s;ti¥ily CIt II large numbel' CIt eel$. These dt4O&,oi I!'igic profecliollS In;lm !he Slbs\antia nigra fire 1l;Jroi;:aJty, I'llIher !han in response 10 specific rTiF04ar movemenlS or sensory inpul. Thus. the dop8rninergic syslem appeanI 10 serve as e torIic. susUWWlg Intluence on motor ac1ivity, ralher than parlicipatil"lg in specific

_

-'-

_ l h o d .... 1cIo

..... _"'-.

•••

~

...

2. Striatum: Nonnally. the strialum is conl1eCled to the substantia nigra by neurons that seaetIl the inhibitory lransmittef GABA al their tefmlni in lhe subslan611 nigra. In tum. cells 01 the stJbstantia

--.......

~"

0" 0" 0"

'.11 . . . ..-., £'*Y of at " -

_ Nurll ';' _ tw._ ....

<."" •••

_1.,

,<

,

>

so

8. Trealment of Parkinson'S Disease

s~

.. oIlnhlb11lDn (-J


-

o-m:t-<+

-

nigra send fle\Jrons bad< to lhe strialum, secreting the inhibitory lransmitter dopamine at their termini. This mutual inttibi!ofy pathway normally maintains a degree of inhibition of the two separate areas. Nerve fibers from the cerebral cortex and thalamus secrete acetylcholine in the neoslriatum, causing e~cilalory eflects that initiate and regulate gross Inlentional movements 01 the bextt. In Parkinson's disease, deslruction of cells In the substantia nigra resutls 101 the degeneration of neurons respoosible lor secretiog dopamine In the neoSlrlatum. Thus the normal modulating inhibitory innuence 01 dopamine on the rte05lriatum is significantly diminished, resulting In the parkinsonian degeneration of the c0ntrol of muscle movement (see Figure 8.4).

3. secondary parkinsonism: Parkinsooian symploms infrequenUy toIlow viml enoept1a1itls or multiple small vascular lesions. Drugs SI.JCh as the pheoott1i~nes and haloperidol (see p. 127), whose major pharmaoologic action is blockade of dopamine recepto<'s in lhe brain, may atso produce parkinsonian symploms. These drugs should not be used in parkinsonian patients.

..... Figure 8.4 location of dopaminergic neurons deficient In Parkinson's disease.

DA=dopamine; GABA.. 'famino-butyric acid: A~Acel'y1dloline.

B, Strategy of \re"tment In addition to an abunclance 01 inhibitory dopaminergic neurons, the neostriatum Is also rich In excitatory choIinergk: fle\JfOOS !hat oppose the action 01 dopamine (see Figure 8.4). Many 01 the symptoms of parkinsonism reflect an imbalance between Ihe excilalory choIinergc neurons and the greatly diminished nJmber 01 inhibilory dopaminer' gic neurons. Therapy (s aimed at restoring dopamine in the basal ganglia and antagonlzing the excitatory eIfect of cholinergic neurons, ltlus reestablishing the correct dopaminet'acetyld1oIine balance.

V. DRUGS USED IN PARKINSON'S DISEASE Currently available drugs oller temporary relief from the symptoms of the disorder, but do not arresl or reverse the neuronal degenerallon caused by the disease.

A, Levodopa (l-dopa) and carbidopll LevcxJopa is a melabolic precursor of dopamine. II restores dopamine levels in the extrapyrami(laJ centers ($lbStBntla nigra) lhal alroPtri in paridnsonism. In palients with early disease, the number 01 residual dopamlnergic neurons in the substantia nigra (typically aboul 20% of normal) Is adequate for conversiOf1 01 levodopa to dopamine. Thus, In new patieflts lhe lherapeutlc response to lev· odopa is consistent and the patieflt rarely complains !hal !he drug effects "weer off." Unlortunalely, with lime the number 01 neurons decreases and there are lev.er cells capable 01 laking up e~oge­ nously edmInistered ~ and conwrting It to dopamine lor svbsequent slorage and release. Consequenlly molor control fluctuation develops. Relief provided by levodopa Is ooly symp' lomatic and lasts only while the drug Is presenlln the body.

• ....... _1.' ••

,.

•
....-w-,o ,,-, """"'" _ _. PI' •

v. Drugs Used in Parlc.inson's Disease

85

1, MeChanism of acIion

a, Levodope; Since parkinsonism results from insufficienl dopamine in specifIC regions oIlhe brain, attemplS have been made 10 replenish \t1e dopamine deficiency. Dopamine itse" does not cross the blood-brain barrier. but its immediate precursor /eVOdCJp8 [lee voe DOE paJ Is reacllly lransported inlo the eNS and Is converted to dopamine in the brain (Figure a.5). large doses or /eKIdopa are required because muc:t'l or the drug Is decarbo~y'ated to dopamine in the periphery (Fogure 8.5), resulting In periphef8l side efleets (nausea, vomit· ing, cardiac ant1ythmias, tJvpotension).

b. Carb!dopa: The efleets 0I1ewdopa on the eNS can be greatly enhanced by coadministering carbidopa [kar bi DOE paJ, a DOPA decartloxyIa.se inhibitor that does not cross the bloodbrain barrier. CartJidopa diminishes the metabolism 01 levodopa in tM GI tract and peripheral tissues; \t1us, it increases the availability of Ievodopa to the eNS. The addition or carbidopllloWers \t1e dose of levodopa needed by 4- to S-Iok! and, consequently, decreases the sevefity of the side effects 01 peripherally Iormed dopamine.

2. Aetloos; Levodopa dB(;reases the rigidity. tremors, and olher symptoms or parkinsonism.

-',- I I

A. Fate of administered levodopa

I Administered levodopa

~.

-, I I

r.

®

I

..............

"lu·m~

~

\

--

Ur '

B. Fate of administered levodopa plus carbidopa

-

...... , . . - - - - - -• .,.-"A'dmlnl....8d IeYOdopll

fe-=-ef

DB

~

' ..

It'

_--..rl

h

..IpI."-

)':j

'

,

Figure 8.5 SYl1lt1esis of tlopwnine (n the abseooe and preoonce of carbidDpB, an inhibilor 01 dopamine decartloxylase In the peripheral tissues.

<

,.,.<- _,. 6. Treatment of Pafkinsoo's Disease

66

Diminished eftec:t due 10 Inc:reased peripheral metabolism

LJ Levodopa

Hypertensive crisis _ 10 inf;:roosed cateetlolamlnes

Figure 8.(; Some drug Interactions observed with~.

3. Therapeutic: uses: Levodopa in c:ombination with caltJidopa is a potent and efficacious df\l!l regimen currently available 10 treat Parkinson's disease. In approximately two thirds of patients witl1 ParkinSOfl's (\jsease, Jevodopa/caltJidopa treatmeot substantially reduces the severity 01 the disease for lt1e firsllew years of treatment. Patients lt1en typically experience a decline in response during the tI1ird 10 filth year of therapy. 4, Absorption and metabolism: The df\l!l is abSOfbed rapidly from the small intestine (when empty of food). Levodopa has an extremely short haH-life (1 to 2 hours), whicl1 causes !luctuallons in plasma concentmllon. This may produce fluctuations In motor responsa ("on-off" p/lenOmeflOll). which may causa the patient to suddenly lose normal mobility Md elCpe.feocO tremors, cramps, and immobility. Ingestion 01 meals, particularly il high in protein c:ontent, interferes with the lrMSport of tevodopa into the CNS. large. neutmI amino acids (for example. leucine and isoleucine) C
5. Adverse efIects

s. Peripherllli effects: Anorexia, nausea, and vomiting oco:::ur because of stimulation of the emetic center. Tachycardia and ventricular extrasystoles resu~ from dopaminergic action on the heart Hypotension may also develop. Adrenefgic action on the iris causes mydriasis, and in some IndiViduals, blood dyscrasias and a positive reactioo to the Coombs' lest are seen. Saliva and urine are a brownish color because of tho melanin pigment produced lrom catecholamine oxidation. b, eNS etIects: Visual and audilOfy hallucinations and abnormal involuntary fIIOVlImenls (dyskinesia) may occur. These CNS effects are the c:pposite 01 park1nsorian ~ and reflect the overactivity of dopamine at receptors In the basal gBf1glla. ~ can also cause rrood changes, depression, and aro:leIy.

lEVOOOPA

6. Interactions: The vitamin pyridoxine (Be) Increases the peripheral breakdown o! levodopa and diminishes its effectiveness {Figure 8.6}. Concomitant adminislration 011eKJdopa and monoamine oxi· dase (MAO) inhib~ors, such as phenelzine (see p. 124), can pr0duce a hypertensive crisis caused by enhanced catecholamine production; therefore, cau~on is required when they are used simUltaneously. In many psychotic pa~e<1ts, IeYodopa exacerbates symptoms, possibly through the buitdup 01 central amines. In patients wilh glaucoma, Ihe drug can cause an Increase in inlraOCl.llar pressure. Cardiac patients mould be carefully monitored because 01 the possible development 01 cardiac arrflythmlas. Antipsychotic drugs are contraindicated in pari
....... ..,., .... _-,. ,

• . . - ....

,_., """'U . . _ . PI' •

"

V. Drugs Usel:l In Perklnsons's Disease B. Bromocriptlne Bromocriptine (brol'! mol'! KRIP leen]. an efgotamine (an alkaloid with vasooonslrictor action) defivalive. Is a dopamine receptor ago.nist. The drug produces lillie response in patients who do not react to tevodopa, but it is often used with /fNOdopa in patients responding to drug therapy. The dose is Increasel:l gradudy during a period of 2 to 3 months. Side effects severely ~mlt the utilily 01 the dopamine agonlsts (Figure 8.7). The actions of brr:Jmo(;riptine are similar to those 01 Ievodopa, e~cept that hallucinations. confusion. delirium. nausea. and orthostatic hypotension are more common, wt1ereas dyskinesia is less prominent In psychiatric illness, bromocriptine causes the mental condition to worsen. SeriOUS cardiac problems may develop. particularly in patients w~h a history 01 myocardial Inlan;1ion. In palioots with pelipl1efalvaswlar disease. a worsening 01 the vasospasm occurs, and in patiOOls with peptic ulcer. there is a worsening 01 the ulcer.

C. ArTIIlnlacline II was accidentally discovered that the antiviral drug. amanradine (a MAN ta deen). effective in the trealmenl 01 influen~a (see p. 363). has antiparkinsonism action. It appears to enhance the synthesis, release. or re-uptake of dopamine from the surviving neurons. (Note: II dopamine release is already at a maximum, amantadine has no effect.] The drug may cause leSllessness. agitation, conlusion. and hallllCinations, and at high doses ~ may induce 8C\Jte toxic psychosis. Orthostatic hypolension, urinary retention, periphemJ edema, and dry mouth also may occur. Amanladine ;s less efficacious than IeKldopB and tolerance develops more .eadily. but il has fewer side effects. The drug has l[ttle effect on tremof but is more effective than lhe anlicholinergics against rigidity and bradykinesia.

t

D.Deprenyl Deprenyl (DE pren ill). also called seJegiline (se LE go Ieen] selectively inhibits monoamine Ol(idase B (whicll melaboli~es dopamine), but does not inhibit monoamine oxidase A (which metabolizes norepinephrine and serctOl1in). By thus decreasing the metabolism of dopamine. deprenyf has been found to increase dopamine levels in the brain (Figure 8.8). Theretore, ~ oohances the actiOl1s 0' levodDpa, and when these drugs are administered togelher. depren)II substantially redl.oc:es the required dose of Ievodvpa. Unlike nonselective MAO inhb~ors. deprenyf al recommended doses has lillie potential for causing hypertensive crises. Hcwever. il deprenyf Is administefed at high doses. the selectivity 01 the drug is lost and the patiootls al risk !of severe hypertension. Recent data suggest !hal eariy use 01 rJeprenyi may actually prolong the period before severe symploms set In by as muet1 as 50%, possibly by reducing the lor. mation oI'ree radicafs.

E. Anlimuscarinic agents

The antlrnuscarlnic agents are muet1 less e"icacious than Ievcdopa and play OI1ly an adjuvant role in antiparkinsonism therapy. The

Figure 8.7 Some adve<se eflecls 01 bromocriptine.

~ --.

-~ ~-

lMAO a <..&L. ~V1

--

Figure 8.8 ActiOl1 01 deprenyl in dopamine metabolism.

<."" .....,.,.<---,.

"

6. Treatmoot 01 Parkinson's Disease actions 01 benztropine, tJiheXyphenidyl, and biperlden are similar, althot;gh Individual patients may respond more tavorably to Ofle drug. All these d'ugs can Induce mood changes and produce IWros· tomia (dryness ot the mouth) and visual problems, as do ail muscarinic blockers. They interfere with gastrolntestinal peristalsis and canoot be used in patients with glaucoma, prosIatic hypertrophy, or pyloric stenosis, Blockage ot cho1in.e.gic transmission produces ettects similar to augmentation 01 dopaminergK: transmission (again, because 01 the creation 01 an imbalance in the dopamine/acetylcholine ratio). Advefse effects are simiiel 10 those caused by high doses or alropine (see p. 45), to, example. pupillary dilation, contu· sion, hallucination, urinary retention, and dry mouth.

See pp. 443-444 lor B descripllon 01 the newly approved drugs, pramip&oI. ropiniroliJ and lolcapone.

StUdy Questions Choose !heONE best answer.

6.1 Which !lOll 01 the following statemenlS is correct? A, CNorpromazine is Indicated in trflating the nauOOa oIle>odopa tmatment. B. \fotamin Bolncnlasoo the ""eo::tiveness 0I1e1o'()(lopa. C. Admirlslfation 01 dopamine is an """,,tive treatment 01 Parkinson's
Correct ...... er • D. c.rt>la Inhibits the p81\AlMlI ~ d~. permit. ling lower clo&a\lB. ~ I:*.>d:s!he do::Jw,llooe 'BOej:b ilia In 1IMI InIn and Iharelen - . 1IMI beneliciaI al'IeclS 0I1eYOdopa. Vbrrin Do eo lhe peo rp teo aI dac:artIolo:rIallon oIlevodopa. Dopamine does nol 11$(1/1 crou 1IMI _ _ b8nief. ".... iBIlIoiB InhIJJiI:8 ltoe 01 ~ and . .cD Iif, and "'eV proWo!I' ~ C\1IllIL

'181"""

""""*"*"

6.2 Which one 01 the following st.tements is lNCOR· RECT'! A. Parkinsonian patients a'e characterizfKl by an i.-.creased ratio 01 dopamInefQiclchol!ne
----

D. Dyskinesia is tile mo&I Important side (IHect 01 Ie~·

E. Tmatment with dep,enyl can delay lhe on$(li 01 partOOsonIan symptQms.

a (Ielkjeoocy ot dapao.oiIowgIc nfU'(InA,...w.;u (I deo In crdo ... glc aetlcns. a..-l . . . d doparT*le can IfwlID bfItlavoo1Bl lIIonlen;. ~ and 1iafVa. roeoAr/II ..nr.o acltls tI\ef(I a lranIpcrI ~ hit II """""" III enler lfw brain; Ihus high pmIBIn dletI """'r lNod III . . ....ted IiMM ot dn::o.IetIr>g ......., ...... ~ In • deo In IeYotlDp;i uptake. ~ t. ......1)' _ wWllonger-tetm t!IefaA' and If; desa >elm I and Ill.e"lt,.... The or........." or

8.3 Aa or tile loIlowing statements am COfmcl EXCEPT: A. Atl'l'lpine blocks the cholinergic pal!lway In the

lriatum

tIllOG-

_n.

B. Deprenyl Inhibits monoamin(l oxidase Band i"o E"ses t:lopamlrle Ie~s In 1IMI C, B,omocnpllne
D. Amantadine Inhibits !he metabolism of Ievodopa. E. AntimuSCllnnil': agoot:s am generally less efficacious than leoodopa in the ifeatrnani of Parlcinson's dis· .~

• O. The

Comlct _ ~

ot

ell8d *'*"*" "'_arelrUB. noI

the 11

~

oIl1C1k1n In

"".""lUdlll • ...-daar. • ~ 11

oIlewdopa. The cflef

<_ ••. _1."< __ - , '

< <:1>U _ _ • PI' •

Anxiolytic and Hypnotic Drugs I. OVERVIEW is an unpleasant stale 01 lension, appret1ension, or uneas;ness--a !ear thaI seems 10 arise lrom an l.l1Imowr1 source. [)isomers imoMng anxiety are the masl common meotaI dislUrbances. The symptoms or severe anxiety 8Ie simitar to those of leal (such as, tachycar· dia, swealing, lrembling, palpilations) and invOlve sympalhetic activation. Episodes 01 mild anJ
ANXtOl vne AND HYPt«lT1C DRUGS

f-

_ .. N_ ,-...... ....... rffq ,'~-~

-.-

"0',..,,,,,

'""-

II. BENZODIAZEPINES

'

used anxioIytic drugs. They haw largely replaced barbiturales and meprobamate in the lreatment or anxi· ety, since the benzodiazeplnes are more effecIi"'B and safer (FIQure 9.2). Approximalely 20 benzodiazepine derivatives are currently available.

BenzOOa.zepines 8Ie the most widely

A. Mode 01 action

Binding or .,...amioobutync acid (GABA) 10 ilS receptor on the cell melTbrane lriggers an opening of a chloride channel. V
...........

L-

OlllER ANXlOlY11C

-""'"'-

ORUG.

Figure 9.1 SLmITlBfY 01 anxiolylic and h tic drugs. continues on ned page.)

(~re

"' .......- . . _...

..."

'a. _ _·

c.a--

......-_._.. ' ........0"'"

·

- _,.

, ..

.c...

_ _, _ . . _

90

9. Anxiolytic and Hypnotic Drugs ~epines and

ANlOOlY11C AND (continued)

f-

f-

d'Iamel~

...............

B. Aetiofls

---

""'..."..,

The ~'epole$ hiM! no antipsychoclc .ctivity. nor any analge$ic Ill;tiQn and do not aIlIIIct !he 8UIOI onie I'WINOUS sysiem. AI 01 1he berLzocIalepine I!Jlhibil !he JoIIowing ..tiD"s to • greater or

...... """"

....m'R.,'" I

•

.

GABA mutuallY Incre85e tile affinity of their

bin:ling lites wilhou1 actuaIy changiog !tltl IOlaI nunar of sites.1 The d1nic8J el1ects of the various benzodiaHpine& correlaJe well with each drug's binding a/finity lor \he GA6A receptor-dlloride ion

HYPNOTIC DRUGS

1. Aec!JI"'lon 01 enxiety; Allowdo5es,lhe benzocIazepines BAl anllioIytie. They are fIatq1. 10 recluc8 lIrUIiety bV sel ~W!tlj i~"'li l{l I'IllUfOn8I cimJits in the limbic syslem 0I1he brain.

t .

. ,.., 'tt., , . n' , 0'"

'Iltl/

L

......

M

2. 5edlltI... end hypnotic ec:tior&: AI 01 .... ~ used 10 IreaIl\f'II\iety haw some ~ jlOopei1iM. />.A higIef doses, cer· UWl bef1l"dall, oill!S prolUle twnosis (artifici+, jlO(lrlI!08d sleep).

HOteARBmJRATE SEDATIVES

............

3. Antloorwulunt; &M!raI 0I1he ~ hIMl iVlIic:orM&san aclivIy Md are used IOtreal epilepsy and ~ SlliZ\xe diSOldl!lS.

~,-

4. Mu.cl. rel.unt: The benzodiazepines relax lhe spasllcity 01 skekllal n1\Jsckl. probably by Increasing presyr1apllc Inhibltion In the sp(nal cord.

Figure 9.1 (conllnued) Soolmary 01 enxiolytk: and

C. Therep,nrtlc uses

-drug.

The in
...

_10lXI_.-_

-.....

"'lyIlicIIl-;

CfIIlwp"" """' .

~

"'<'-

,

'.

I'

•

Fig..... 9,2 Ratio 0I1et1a1 dose 10 et1ectiYe dose tor

fIlOIJItW1l!O (an opiold, Chapter 14),

=:;;l~:l~.

hypnotic df\105. ~nobarbitaJ

and diazepam.

live anxlolytic, anticclnvulsanl. and sedall"", properties. Howewr. the durallon of aClion verles widely among Ihls g'oup, and phafTl\lllCOlmelic considefations are otten Important In choice 01 drug. 1. ArWety di~: The ~ are useu in treating \he anxlely !hal accompanies some lorml 01 depression and ~ . These drUgs should not be used 10 aleYiale the I'lOfmIl &tress d lNef)day lite. bl.C should be reserved klr c0ntinued -..ere lWCieIy. and tlen shoukl be used b shut periods d lime because 01 a
cnv

..-u

2. MuscUlar disorden: l?iIIzcpam Is usetuI in the treatmenl d skaleIaI moscle spasms sud111S OCC\II' in musde straln, and in treating spasticity trom degenerative disorders. &U;h lIS Il'Ilttlple sclerosis and cerebfaI palsy.

••,,< .....1.'

> ...... _ , >

.........- - : .....,.., """""," .. _

.... >

" .... _'empty w(noegon....)

""",,~a

. ~

"".0 -~

=L.. ~-" .... .

- ... " '. ___ <:1. ._ -.

~~:.:~~._~~. J mR.~

bindlug GASA

~

..

. .

..

a

• • a

r.:I Receptor 800 t:I btncAng GABA 8nd benzodlazepine

.-

.......",GAU _ _ ....""". . Ion _

f

FlllUf1l !U SChematic diagam ~ benzodiaZepi1e-GA8A-<:hIoride ion d1amel oornpIex. GABA-.,..~ acid. ~

(\doe NA ze pam] is usettJ in the d1ronic l'l 'ilel 'S~, whereas di&nlpsm is tho drug of dDce in l~ goand mal epieptil;: seizures and Slalus epiepCicu$ (see P. 149). ~ [klor d n e POX ideL cbazer;late [Idol /lZ. e pateL ~ and ClICllzepam fI* A ze pamj are uselU in theacule Ireatment of alOohcl wilhdlaNll.

3. 5elNfes: trearment

4. SIMp

~

ell_del., Not III 01 the ~ are ~ 8$ tw-

nolic agents, allt1ol.Igl III have sedali\Ie Of c:aIming eflects. The hoe most OOl'.'1U ~ pft!saibed berl>Odall" _ for sleep disa~ are lOn9"acmg ~ (llunI /lZ. e paml. me" Iledaleacting temlU'epam Item A2 e paml and shon-aeting rriaroIam [tr;e AY _Iam~ ._ Fluf1Izepam: This Iong-acling betlzotialepine signilicanUy reduces bolh ~ time and the runber of awaken~. and .-.creases the dilation 01 sleep. FMazepam has a lOn9"aetinlI efled (FlQUfe 9.4) and causes little rebolnd ins0mnia. WI!h C(lOIinued use. the drug has been $hovm 10 maimain ~s e!1octNClleS!l !of 14l 10 4 weeks. FIu~ lind ~s active motabolrtcs ha\l(l a haW-life ~ IIppoxlmatcly 65 hours. which may rcsut in daylime sedatioflllnd ac:curoulation ~ the drug.

I

..........,., ....... _'>

. . . . . . . . . .- - - , ....,..,. .. _

"

..... >

9. Anxioly1ic and Hypnotic Orugs b. Temazepllm: This ~ is usclul in patients who experience lrequcnl wakerW1g. I-lowewr, the peak &«la1lYo efIecl occurs two 10 Itvee hours aftel' ilf1 oral dose. and thereIore II may be

gNen severaJ ho:us beIore be
Of BENZODA2EPlNES

..... ,

,~"

c. lliazolam: This benzoo:ia<:epin has a .8IalMlly shan lU'ation oIlICIion and is Iheretore used 10 in(U;e sleep in palieo ~s with rtlCUlTIg irilOf'..... Whereas ~ . useIullor in&omrill caused by fie inabiIiry 10 s&ay asleep. ft1alDIaoII is eI1eaiYe in lJeating ifIdivO.als who have ditlictJlIy in going 10 sleep. To6efitnce 1.~1Iy deIo 'cps wilhin a few days, and with· drawal 01 Ihe li'I.og often f8lds in rebound InWfI ilia. le :f, og palienl 10 <Semand another' Pf~ion. The.eIore. this ck'ug Is besl used intermitl~ 03..... lhIn daily. In IF'oer.II. I'rtPdics shlU:l be gNen lor
me

= ........... . . "",

1. A.bIorptlon Mel d1s1ribullon: The benzodiazcpines are lipophilic and are rapicIy and ~taIy ab&ortlod lIttor oral lIdrrinistratioo and are ctstrbJled th.oug.out the body.

2. Duratlon 01 actions: The haH·llvos 01 tha benzOdiazepines are Wf)' Imporlant crncaJly. since the duration ot action may deter· mine tho therapoutic usefulness. Tho bonzodlazcplnes can be roughly divided ink! shon·, if1,ermeclia,o- and long·acting grOWS (see FIgure 9.4). Tho longer acting agcflts Iofm active me,aboIiles ..-ith long I\aH-li:Yes. .0 20 Hours

" r.., " -..

'''' @ •

3 8

,

•

•

Hou,~

Figure 9.4 COfT1)aMon oIttle clI!ations 01 aaion 0I1he benzodazepines.

3. hie: Most benzodiazepines. including chlordiazepoxide and ~ lire metaboized by lhe hcpalic micJoliomaI me!3boiZ. ing system (see P. 14) 10 ~ lhal are also active. For these benzoclazepines, the ilpparent haIl-"e 01 f1e I7ug .epra_ _ lhe OCi.tlii lGd lIC1ioIlS d the parenl drug and its meI3boIil.es. The benzodiazepines are excreted in urine as gIuct.ol"Ollides or OUdIzed metaboIib:ls.

Eo OepeoidellOe

Pstch>" ...... and

phvsicaI depeodence

on

benzodiazepWles

can

d8\ • 'I , ~ Ngh doses d the ctug are gMln ewer a plt*:llo,ged period. Abn.ip: c:hc:orW'uaIion d f1e benzociazepines f1ISf.AIs in wib:hwal SYfT'llOmS, Including oonfusion, arWely. agilalion. resllessness, insormia. 8f'd I....s...u Because 01 the Iorog tIall·1i¥es d SC<'l'lI d f1e berlzOliazepir-. \OI~a..a1 ~fI,*"I" may not OOCU" unliI a rumbar d ~ alter
F. Adverse elfect. 1. DroIOIslnn. and contusion: These otfect8 are lhe lwo rrost c0mmon 15100 eflects 01 the bE!r1zodiazcpin(l$. Alaxia OCO:;Uf$ a, high

·..,..0...'.' ••

,.

..........

~ thaI reqlife line molOr coordina.lion, such as driving an automobile. Cognil;" impairment (occmased Iong·term rocaI and acquisition 01 new ~) can occur with use 01 ~epines. T~ Ifle benz
:

... . ~

,_ _."". ...

93

doses and predudes

anxiety. along with am2.

TIw ....... _

.. _

s·' and ocOusicn

Use befllQ
~

a. alcohol, are Iaken concurrC<1l1y.

........ ,-.

-_.... '--

4"_ _ . . . .

~_

-~•

III. OTHER ANXIOLYTIC AND HYPNOTIC AGENTS

""0

A.

Zolpldem Although the hypnolic zoPidem IZOl.. pih dam) Is nof a benzodiazepD!, II. ac:ls on a a.t:J&el: 01 I1e benzaiazcpIne rflCCPIOl' 1ai'hIy. ZOIjlidem has no antialnvulsanl Of rrusde relaXIng properties. It shows no wiII1aaWal eflocts. edlib/I$ minimal rebound onsorrria and little Of no toletanee occurs wilh prolu 19t!d use. Z; is rapidly absomed 'rom !he gastrointestinal tracl, and has a rapid

"-IMI

onset d action and short eliminalion han-lite (aboul 3 hO'Hs).

Adverse elleets 01 zolpidem include nightmares. agitation. headache. gllSlfoinleslinal ups.el. dz2iness, and daytime dr0wsiness. Although ~ poler,1iaIy has advantages over tile benlO
'rom

as-

c._~

~ \hYe DAOX I ~een] is an antihistamine wittl anliemetic activity. n has a low tllfldonl::y for habituation; thus ~ I, useful for patients with anxiety, who have a history 0' drug abuse. II Is also oIten used for sedation prior to dental procedures or surgery.

·20

... ..

0

20

_-

010

so

SO

_ , _ _ l'1ol

r:...-,:,,--

TIw .-,. ~_....... t-.-_qo •

--:0£......... __ •

0lio.'14

..........,., .. -... --,. 9. Aruciolytic and Hypoolic Drugs

IV. BENZODIAZEPINE ANTAGONIST

-

t

ft

••Om_. .~-_.

~r.::':':·::"":·~·~·:·=·l I:............. -

u

:=::r__

7

._..... .... _15 . . ·

,

,

j

,

o

FbnIJzeniI [llcc MAl eh nilij is a GABA rceeplor antagonisl lhal can rapilIy fC\Ief'Se the ettecIs d ~ The (tug ill II' Ie I:lIJ r.I at,......,
V. BARBITURATES

1

........ ~~~ Flgu,. 9.6 Comparison ct common adveose efIects d buspiralll and ~oIam. Aesull' are el
The barbiIuI3Ies _e b.'""ty the mainslay d Iroalmelll U&Bd 10 lledate the patienl or lO nM:.e and mainlllin sleep. Today, they ha\Ie been Iargety .0jlAa000 I:lIJ the benzodiilz~. marly because bartlillr.llOS Induce toklriInce, dnqrmetabol0ng enzymes. physical dependence. and YOfY liCI/CI'e :MIhdrawaI ~ fercmosl is theio abiliry 10 cause ooma In ICDCie dories. Ceo'tWl baobitlr.llcs, sud'! as the very shcrt-aeting /tW)pental, arB ,til U&Bd 10 Indu::e anesthesia (see p. 115).

Bar1Jiluratcs are lhought to intorlere with SOdium and potassium transport aCfOSS cell membranes. This 1000ds to Inhibition 01 the mesencephalk: reticu~r activating system. PoIysynaplic transmission I,lnhibited in OIl areas olltle eNs. Bar1J~urales also poll'fltiale GABA action on chloriOe entry Into the fl(lt.rofl, aIlhougtl they do noI bind al the bcnZocliazepine roceptcr.

B. Adlon,

atWI" '!II 10

Ihcir dlwaticrl oll!ldOl (F~e dl PEN IaI). wtWch aces wih-l seQ: ondIi and has a c1r.Ilion 01 adion 01 aboU 30 "'*Ucs, is used In I1e ~ inlU:Iion 01 anesth '. 8y' oontrasl, phenol:;adiIaI [fee nne BAR bI taIL v.t'idl has a cbalion of adion grealer IhiIn a ~ is ...setl.t in fie ~ ol seizufes (see P. 148}. ~(per11De BAA bi tall. •• lwtlilaIl_ Itoe BAA bi \alj and allOt&bitdI[am Ph BAA bi \alj are short..at*1g barllituo3Ic5, whictl are d1ei r O'B as SJedit. 1M! and tt,opncIic (b..t nol: anliiIruiety) agents.

8afbi\I.lratcs are dass&d 9.7). fer eKarnpIe.

1titv&1IaJ~

I. CleInulon f1I CHS: AI. low do5es. Ihe bartlilI.r.lles pooduoe sedalion (calrning etIeCI. reduc:rog e
*

2. Aftplnttooy depresslotl: BarbilUrates SOPPfOS$ the hypoxic and dlemoroccplor response 10 ~. and a-crdosago is Io/loWed I:lIJ respiratory dcpo"essiOfl and dealh.

• ,.0<

'Q' _,.,

> ....... ' - , >

95

v. Barbituratcs

3. Enzyme Induction: Barbiturates Induce P-450 microsomal enzymes in the liVflf (see p- t4). Therefore, dlronic barbiturate administration diminishes the action 01 many drugs that are dcpcndent on P-45O motabolism to rcdoce theiJ COflCel1tration.

C. Thenlpeullc: us. .

01 a barbiturate 1& strongly inltuenced by the desired dufalion 01 action. The I,lIra·lhort..acting b0rbiturates. such as thioper'l8I; are used intravenously to inclJClI anesthesia.

I. An8llhesls: Sek!c1ion

DURATION OF ACTlON OF BARBITURATES

2. AnllcorWUlunt: Pht!nDb8ttIitalls used in long-term management 01 \OfIilxlOniC selzures,. status cpilcp6cus, and edar'r4>sia, f'tlen(>b8ttIitaI has been regardod as the o:nog ot d10ice tor lreatrnenl 01 young ~cn with rllClnenl klbrile seinKCS- llo"wer. pheno-

bBtbiIaI can deprea oognitlwl pert:wman;e in d ildoCll, and Ihe drug shedd be used ca~. PNl/lobarbiCaJ has spec::n: amiC01Y\AsanI acWily thai is dislWlguIstled from the nonspeciic CNS

..........

3. Andely: BarbiUales hIMo been used as mid sedaliYes 10 teIilNe ~ I1l!f'o'QUS IONion. and w ... Most I\ao.e been leplaced

,.ia.

bylle~

....

'

n __ Barbdurales are 8bslOIbed orally and clstrbAed M:lely ltVoo.J;IhOut fle body. M ba~tes reclislJitule in !he body from the brain 10 !toe splanctrie Weal. IQ ~ nusde. and ma.y 10 + Ii· _ tissue. nws ITlCM!fflCfll is irf1Xwtant in ClIl.5ing !he short dlnlion 01 action oI'hiq;t6l1'lII and &imlar shor1«:ting derivawes (see P. lIS}. Barbitlntes lUe metaboliz«l in the 1iYet. and inaaMl mecaboliIes are exaeted in the ...... E. AdYene et1eeUi

I. CNS: Barbi1urates ~ oO"si IllS&, ifl1laired ooncertration, and menial and phy$iCal ~ 2. Drug hallgo...r: Hypnotie c;Io5es at barbilunlles pnxt..oce a Ieelng 01 tiredne$S welt after the patiCrll awakes. This drug haflQlM!f loads to irJlIairod ability 10 h.nction normally lor many hours after waking. 00casi0naIy, nausea and diZZiness occu".

3. Precaullom: As noled prev\ou$ty. barbiturates inl:luce !he P-45O system and tI1c<etore may dccmase the ctlecl 01 MJgs that are metabolized by those hepatic: enZymes. Barbiturates increase porphyrin synthesis, and .re contraindicated in patients with acute lntCflrit10nt porphyria.

4. Addiction: Abrupt withdrawal 'rom barbiturates may cause tremors. 8ll~icty. Wllaknoss, restlessness, nausea and ..c:rniting. selzurcs, delirium. and cardiac arrcsl. Withdrawal Is much more severe than that associated with opiates and can rCSlJiI in death.

Agure9.7 Bartliturates aassitied according to !heir duration 01 actions.

·.........,., .... _-,. "

9. Anxiolytic and Hypnotic Drugs

•

--

5. PoI$Of1lng: Barbilurate poisooing has been a leading cause 01 death among dn.9 OVCfdoscs lor many decades. severe depression of respiration is coupled with oonIral cardiovaSClllar depression. and msu~s in a shock-like OOf)ljfion with shallcm, InlmQl.lerJt breathing. Treatment includes artnicial respiration and purging the stomach of its contents if the drug has been recently taken. Hemodialysis may be necessary il large quantilies have been taken. Alkalinizatioo ot lhe urine often aids in the elimination 01 phenobaJtJilaJ (SCfl p- 24).

VI. NONBARBITURATE SEDATIVES A. Chloral hydrate

Chloral hydmt6 [KlOA al HYE dratc) is a trichlorinated derivative ot acetaklehydo that is corrverted trichlO
'0

B. Antihistamines Nonprescription antihistamines wrth sedating properties, such as diphenhydraminsand doxylamine ($00 p. 422), are ellective in treat· ing mild types 01 insomnia. HoweIIer. these drugs are usually inef· lective lor all oot lIl9 milder form 01 situational insomnia. Further. they have numerous undesirable sldc eflects that make them less uselul than the benZ«lia>:epincs. These S6dativc aJ1tihistamines are marketed in numerous over·the-counter producIs C. Elhanol

Ethanol (ethyl alCOhol) has antianxiety and sedative effects, but its toxic potential outweighs its benelits. Ethanol [ETH an oIJ is a CNS depressant, producing sedation and ultimately hypnosis Wilh increasing dosage. Ethanol has a shallow dose-respo<1se curve: therelore, sedation oceurs OYer a wide dosage range. AloohoI syncr· gizes wilh many other Sedative agents and can produce scvore CNS depression with antihistamines or barbiturates. Figure 9.8 Metabolism 01 ethanol.

1. DISulfiram: Ethanol is metabolized primarily in the liver, first to acelaldcl1ydo by alcohol dehydrogenase. and Ihcn to acetate by aldchyckl dehydrogenase. Disumram [dye SUl Ii ram] blocks the Oxidation 01 acetaldehyde 10 acetic acid by inhibiting aldehyde dehydrogenase (Fogure 9.8). This resulls in 1M accumulation 01 acetaldehyde in the blood. causing flushing. lachycarda, hype<. ventilation. and nausea. Disulfiram has tound some use in the patient seriously desiring 10 slop a!cohol ingcstion. A C()Il(jtioned avoidance response is induced so that the patient abstains !rom alcohol to prevent 'he unpleasant elfects 01 disulfiram-Induced 8CClaklehydc accumulation. Figure 9.9 summarizes the therapeutic disadvantages and advantages 01 some 01 the anxiotytic and hyp001ic drugs.

"""'0<_""''' _ _ ''

.........

.. , .....,... . . _ . PI' •

VI. Nonbarbiturale Sedatives

Therapeutic Advantages of AnxlotyUc and Hypnotic Agents

Therapeutic Disadvantages of Anxlotytic and Hypnotic Agents

0--_

0""'''

I

'ow.

........ ~'1Oo1 ctuooI luoetlo"',,y 1M mofOr

.

•

Tho 1lenm
c1epe"c1e"ce end .......

dr_..... zuree ~.

0

1

WIfhdrew.. of drulIlltten '"""" In reboun
-~

........

_

........

W ...

_ •Ex_

"~ . ,, .

._""wllhdr__ . minimal , - . . ,

lneomnl...

./

•

L/lIIe 0< no _ _ _ 000..... wIIIo pOOoyec:luM.

•

UseM u......"Il\l'Inof1OnIt1""" clwonlc .,xiefy

~0 1 It)' 1M hoaIU;ly.

Barnltu

.....

-"""---

•

•

-

Oon nal " " ' _ the CHS fIep'eOolon of Low pOfeflI\eIlo<_

-, _ ':::-:;;::;:::::~_':O":-=-::~::.::K:::h::'.J1 Figure 9.9 Therapeutic
•

.~,

'.f ..J.,

............... , •

.c....

, _ .. _

96

..... •

9. Arudolytic arod Hypnotic Orugs

e:t'IooM ... ONE OOst _war.

(

9. I WIlicI'lone dille toIowlng SUI!""" tis it CORRECT? A. 8enzotlia>;epines
2 ... 4

poi"",'"

O. ,. blNodiRepnea t.w ..... ~ oIleda. E. ~. 'ke olher CNS dep...... nl$. .-Mv~~

••

in

Cor,-.;I ene_ • O. IIlrhougih ae ~o­ ~ can atUH ucs-tIon. !he ClfllOS . . . . , 1lan.... • • two in ~ 11.1

_ .....'..-b .. _

oI*'"P ........

~.,

~oIGA1lA

1D ............ _ l t o

....." .....

o I ~ Tho ~ngI ~lloll-V_. . ......,

l*<-

~ ..

1fl
...... ..

.. aid . .

MA04'tib..... ~_....,. ......... l'lotn of MIt, ......... 8M,......... pinos do noll P"~ gene
*'., _

io .... " ..... O. Phef'oobartlMl inCluces ,.Ipiratoty depreuion• ..tlidlit ~ b y " ~oIelhancL E.. euspw",,", hel adM''''' """,",, 10 the benzcdt-

--

ee.....e. _ . 0.

~....,....-.:c

ar., polei . . . . ...,... _ .. unebIe lID .......

~"'-­

pelf> h-"dd.

0nfJp/'e~~"*-". . . .

.... 01 the h....lIc cytoch.ome P'oI5O drug lI"IIlIebolizing .J$l..... Phenot>arbitaI is conI .. ,,***, ill ' " . _ , . , 01 _ porpl1yriL e, f Iedle . . , ~ ...., moa:kH' plopsnile '" ... boonzo
"'''iIol&'

""..... _ _ CII"I1 ........

~

9.2 "" cf ... IoIIowing fOSpcnCllO troalmOOt with bllnzodi· lIlopinet EXCEPT:

A. TOllln....

e. SchiroIlluenia. C. Epiloplic seizw•. O. nonria. E.~.

Tho DlIRKf _ . B. ...

9.3 Mli<:tI one 01 ...........og. a sI'llln-.g ~polOlic? A. "to."cb.bilIl e. De per" C. CtiIo;w6a>ep"iole

0._

~-

..

_ _

genzadie ...._

I "."." ..... ,. , ill _ 1iAJA'll 7

f

~

.... _

tt1'" e/I::d'Iol""'" 1Udl. a..... o:Ia4f

_

..

~

....

'1Il~_

1Il

p l - ' " They _

tiIeI .......

"'IUil.

......

,~._,.,

....

_-,.

·.,...·_~

..

,~

.._·w·

eNS Stimulants

I. OVERVIEW This chaplCf lklscmes 1W
CNS STIMULANTS

-

~

~~

II. PSYCHOMOTOR STIMULANTS

Mer"yI~

-~ n -.. ,>Ino

A. Methybanthlnes Mettlyli<3I1t1lines include theophylline [tIloo OFF I lin]1ol.oxl in tea, lheobromine [thee 0 BRO min]lound in cocoa, and caffeine [kat EEN]. Caffeine, tile most wK:lely consumed stirTllAanf in the world, is Iound in highest concentratk.1 in 001100 but is also pmsent in tea, ooIa drinks, chocolate candy, and cocoa.

1. Mechanism of action: lhe melhylxanthines may ad by several mechanisms. including translocation 01 extracellular calcium, increase in cyclic adenosine rT"lCIOCIphosphte (cAMP) and cyclic guanosine monophosphate (cGMp) caused by inhibition 01 phos. phodiesterase. and blockade 01 adenosine reccp\ors.

2. Actions:

II. Central ~s system: The caffeine contained In one to 1W
...-

PSYCHOMOTOR $TlMULANTS

TMophylli,.

L

PSYCHOTOMIMETIC ~UG' tyHrgic_~(l.SO)

~(PCPJ

Figure 10.1 Summary 01 CNS stimulants.

<''''''0'''''''<_'''""",-,,,

'00

10. eNS Stimulants b. ClIrdlDVllscula, system: A higt1 dose of caffeine has positiw

inotropic lind chronotropic elfoc,s on 'he heart. [Nots: Increased con,raetility can be harm/ol to patients with angina pectoris. AoceIerated heart rnle can trigger premature ventricular CQntractiorls in others.]

C. Diuretic Bellon; Caffeine has a mild diuretic action that increases urinary output 01 sodium, d1loride, and potassium.

d. Gastric mucosa: Since all methylxanthlnes stimulate sec.&tion of hydrochloric acid (Hel) from the gastric mucosa. indio viduals with peptic uloors should avoid beverages containing

- I -..

malhylxanlhincs.

3. Therapeutic uses: Caffaine and its derivatives relax the smooth muscles of the bronchioles. PrevioUsly tl1e main-stay of asthma therapy, ffleophylline has been largely replaced w~h ll-agonisls and corticosteroids (see p. 220).

NARCOTICS

-

----~-----.., Figure 10.2

Relative potential tor dependence tor commonly abused sllbstanoos.

4. Ptlarmacoklnellcs: The mcthylxarnhines are well absortled OI'ally. CafffJine dis1fibutes throughout the bOOy. including .he brain. The
5. Adverse ef1e<;ts: Moderate doses 01 caffeine cause insomnia. an»eTy. and agnation. A h9'1 dosage is required 10 show toxicity. which is manifested by emesis and convUlsions. TIle lethal dose is about 10 glor caffeine (about 100 cups 01 cellee), which in
1. Mechanism of actlon; In low doses, nicotine causes ganglionic stimulation by depolarization. At high doses, nicotine causes ganglionic blockade (see P. 49). Nicctine receptors exist in the CNS where similar actions occur. (SOO nicotinic receptors, p. 39.)

Figure 10.3 Actions of nicotine 00 tha cetllral 08IV0US

sys'em.

2. Actions: a. eNS; Nicotine is highly soluble in lipid and readily crosses the blood-brain balrier. Cigarette smoking or administration at low doses 01 nicotine produces some degree 01 euphoria. and

• ".".0.....' •• _ .... ...-,·

.""""'

..........

~'.....,.,...,.

....-.,...

II. PsychOmOtOr Stimo..dants

'"

arousal, as wei as relaXation" and improYes attention. learning. prOOlern llClIWog. and reaction time. High doses 01 niQ::UJe re$UlI in ceolral respiralOfy p8fB1ysili and S8\Ieflil "'fPOIension

•

caused bV mecUary paralysis (F"lgO.lfEl 10.3). b. """'''' ..... dfeds: The peripheJal elIects 01 rli::loli'16 llIe complelL SlimuIation 01 sr,mtM11l!Ik ganglia lIS well as 11'18 8OU>al ~ blood pressure and r - t rBIe.. Thus use 01 IOl» I >C> is ptlI1icUar1y I\;1ITllIU in twe<1ensMt pelients. Mant pelients wiIh periphelal ......... AI di I e:o;petielce an 8ll3OOrbIltion at symptoms with smoking. FOf example. nicotinelncIuo&d O'llSOOOllStridion can r:Ieo'ease COlQ'IlII'Y bkIod loW. adYerseIy atleellng the patient with angina. Sb'nulaDon 01 peruyrt'lplllNllic ganglia also inc!uI&eS motor acIMIy 01 !he boWel. AI. h9lel" doses. blood Pf'8SSld talIs and IIdMIy ee 5 in boIh !he gastn","testihal tract and bladder lT1llliCUature as a red ola r~16 iLQ.ooed bIod< of ~lheIicganglia.

n:reases

3.

PNI~Ics: NiooIi16 is tjghIy~ dble. TtlJs, absooplion readily OCCUrS Ilia the ooal mucosa, lUngs. gastrointestinal mocosa. and skin. Nicoline ausses lI\e placentalll'l8fl'tl<ar1e and Is li8Cftlled in the milk ollactaling womefI. Mosl cigarettes contain 6 to mg ot nicotine; the acute lethal dose is 60 mg. Over 90% of n;colifltJ inhaled in smoke Is absorbed. Cleerance 01 n/cOlifltJ involveS me18bolism in the lung and the liver. and urinary excre· lion. Tolerance 10 the tOKic eltects 01 nicotl(l(J develops rapidly, otten within days alter begirning lJS398.

e

•

..

11

:r

'!1'W'SOa"'"l PATCI1

,;'P_~~

·100

•

10

10

4. AdVerM effects: The CNS ellects 01 nicotine inClude Irritability and lrer'l'lOfS. Nicotine may also cause intestinal CfllITIpl1o.. diarmea. and il'lcreased heart rale and blood pressure. In addition. cigarene smoking increases the ral8 at metabolism of a nt.mber at O'ugs. INoIe: It is not: known wtMch 01 the 0YllJ" 3,000 c0mponents 01 cigarette smoke are responsible lor this phenomenon. aIlhough !he befIzoWrenes have been iLr.picated.]

So w-.1dI_el .~rwdlOIr.: As wlln the other c*ugs in tnis dass, ni:::o-fine is an 8dlIcIiYe Sl.bslancB: ~ depeideJce on ,1i::loIi'.., de\;e! , . rapilIy and is _ e . W.odiawal is et"erllaerized bv imtabifty. ~ty. restleSSl18$$, ditlicully in concentrating, head8Ches. and inSCltl'll'U. Appetite is atlected and gastroinlescnal pein olten oa:us. INote: Smoking cessation ~ \I'lat combre pt\8Irr.'.9C and behaWltaIllenIA' are !he mo&I St'f'CeS lui in heI~ i(j inchilluals lO slOP smoking. The transdem'laI patd'I and chelliLi(j gum artairJing ,1i::loIi'1lt heMI been snown to retloce ~ symplOmS and to help liITlOIo:ers SlOp smoking. For example, the l*:lod COllCelllBlion 01 f'lIiootineobtained!rom Chewing gum is typically aboul one·hall 01 !he peak level obserVed with smoking (F"'9Uf8 10.4).) S

C. Cocaine

Cocaine [koe KANEI is an ineKpensive. widely available, and highly addictive drug that is currently abo.lsed daily bV over 3 million people In the Un~ed States.

POTENTIAL 101 ADDrCTrON

/

IIlIIiOlI

."." ........., ........

_,.

)0,

10. CNS Stimulants

NEURON

1. Mechanism 01 acllon: The primary mechanism ot ac1'on underlying cocalne's central and peripheral effects is blockade Of nor· epinephrine. serotonin. and dopamine re-upta~e into the presynaptic lemlinals from wtlich these transmtners are released (FIgUre to.5). This block potentiates and prolongs the CNS and peripheral actions 01 these ClItechoiamines. In particular. the pr0longation ot dopamonergic effecls in the brain's pleasure system (limbic system). prodIces the intense euphoria that cocaine in~ tially causes. Chronic intake ot cocaine depletes dopamine. This depletion trPggers the vicious cycle ot craving lor cocaine that temporarily relieves severe depression. 2. Actions:

lNalEASEO RESPONSE

Agure 10.5 Mechanism 01 action ot cocaine.

I. cenlral fMH'VOUS system: The behavioral ettecls 01 cocaine resuk kom jXM'l!rtuI Slimulation 01 the COf1l1~ and brainSlem. CocakJe OCl.Jtely increases mental awareness and proWces a feeling 01 well-being and euphoria that is similar to lhat caused by amphetamine. Li~e amphetamine. cocaine can produce hallucinations. delUsions, and paranoia. C0C8/ne Increases motor activity. and al high doses causes tremors and corlVlIsions, lolIowed by respiratory and vasomotor depression. b. Sympathetic nervr:>lJS systems: Peripherally, cocaine potentiates the action ot norepinephrine and prodJces the "fight or fligt1t" S)TlClrome characteristic of adrenergic stimulation. This is associated with tachyCllrdia. hypertension, pupillary d;la· tion. and peripheral vasoconstriction.

3. Therapeuttc uses: Cocaine has a local anesthetic action that represents the only current rationale tor the therapeutic use of cocaine; cocaine is applied topically as a local anesthetic clJring eye, ear. oose, and throat surgery. While the local anesthetic action of cocairle is due to a block 01 voltage-activated sodium channels. an interaction with potassium channels may cootnbute to cocaines ability to cause cardiac arrtlythmias- [Note: Cocaine is the only local anesthetic that causes V8SOCOI1S1ric1iorl. This ettect is responsible Dr the necrosis and perforation of the nasal seplUm seen in association with chronic inhalation of cocaine powder.] 4. Pharmacoklnetlcs: Cocaine is self-administered by Chewing. Intranasal snorting. smo~ing. and intravenous (IV) injection. Pea~ effect OCClIfS alt5 to 20 minutes alter inlranasallntake of cocaine powder, and the high disappears in 1 fO 1.5 hours. Rapid but

short-lived effects are achieved lollowing IV injection 01 cocaine, or by smoking the free base lorm ot the drug ("Crack"). Because the onset 01 action is most rapid, !tie potemiallor overdosage and dependence is greatest with IV injection and crado; smo~ing.

5. Adverse effects: a.

An~lely: The to~ic response to acute cocaine ingestion ClIn precipitate an en~iety reaction mat includes hypertension. lactrycaroia, swealing. and paraJlOia.

<_.0......'.. _..........-,. II. Psychomotor Stimulams

'"

b. Depresslon: Uke all slimulant drugs. cor.;;:tine stimulation of the CNS is folloWed by a period of mental depressioo. Addicts withdrawing Irom cocaine exhibit physical and emotional depression as well as agitation. These symptoms can be treated with benzodazepines (see p. 89) Of phenolhiazines (see p. t27). C.

Heart dlsea....: Cocaine can induce seizures as well as tatal cardiac arrhytlYnias (F"IQUl1l to.6). Imravenous diazepam (see p. 89) and propranolol (see p. 74) may be required to comJl)l cccain&lnduced seizures and cardiac arrhythmias, respec· tively. The incidence ot myocardial infarction in cocaine users is Un/elated to dose, to duration of use. or to route 01 adminis· tration. There is no marker 10 idemify those irH:Iividuals who may IlaYe liIe-threatenting cardiac effects alter taking cocaine.

D. Amphetamine Amphetamine shows neurologic and clinical effe<:ts that are quite similar to thOse of cocaine. 1. Mechanism 01 action: As whh cor.;;:tine. the elfeets 01 arrphetarrma Qf1 the CNS and peripheral nervous system are indirect: tllat is, ltley depend upon an elevatiQf1 01 the level 01 catecholamine transmitters In synaptic spaces. Amphetamine. howevef, aalieves this effect by releasing intracellular stores catechotamines (Figure 10.7). Since amp'leramlnealso blocks monoamifle oxidase (MAO). high levels 01 catecholamines are readily released into synap6c spaces. Despite dil1erent mechanisms 01 action. the behavioral effects 01 ampheIamine a.e similar to those cocaine.

or

or

2. Actions: a. Central nervous system: The major cause 01 the behavioral elrects 01 amphetamine> is probably due to release 01 d0pamine rather than release 01 norepinephrine. Amphetamine stimulates the entire cerebrospinal axis. cortex. brain stem. and medulla. This leads 10 iJ'lCreased alerlness, de<:reased latigue. depressed appetha. and insomnia. In high doses, c0nvulsions can ensue. These CNS stimulant allects 01 amphetamine and its derivalives nave led to their use in tI1e therapy 01 depression. hyperactivity in children, narcolepsy. and appetite control.

b. Sympllthe11c nervous system: In addhion to hs marked action on the CNS. amphetamine acts on the adrenergic system. indirectly stimulating the receptors through norepinephrine release (see p. 68). 3. Therapeutlc uses: Factoo; \tiel ijmit the therapeutic usefulness 01 amphetamine include psychological and ~sioklgical dependerce similar to those with ~~ and the deveIopmer1t of tolerance to the euphoric and anorectic e!lects with chronic use. [Note: Less t0lerance to the l<»lic CNS ellects (klr 8J
.,.1

Figure 10.6 Major effects 01 cocaine use.

.".".0....... '.< .. __ ,. 10. CNS Stimulants

'" B No amphetamine

a. Attention de/lcft syndrome, SOme young children are hyperkinetic and lack the ability 10 be in\IoIVed in any one activity lor longer 1han a few minutes. Amphetamine, and more recently the amphetamine derivative methylphenidafe [meth ill FEN j date]. alleviate many 01 the behaviorat problems associated with this syndrome, and reduce the hyperkinesia that lhe chi· lIren demonstrate. Their attention is thus prolonged. allowing them to function better in a school atmosphere.

b. Narcolepsy; Methyt>het!idareis used to treat narcolepsy. a cisorder marked by an uncontrollable desire 10< sleep. 4. Pharmacokinetics; Amphetamines are completely absofbed from the gastrointestinal Ifact, metaboliz:ed by the liver, and excreted in the urine. Amphetamine abusers often administer the drugs by

intravenous injeclion and by smoking. The euphoria caused by amphetamine laStS 4 10 6 hours, or 4 10 6 limes longer !tlan the effects 01 cocaine. The ampt1etamines produce addiction--
5. Adverse effects; RESPONSE

m

With amphetamine

~

8.

Cen'ral ellects' Undesirable side eHects ot amphefamine usage inclUde insomnia. irritability, weakness. diulness. tremor, and try"perac1ive reflel«ls (Figllre 10.6). Amphetamine can also cause confusion, delirium, panic states, and suicidal lendencies. especially In mentally III patienls. Chronic amphetamine use produces a state of "amphetamine psychosis' that resembles an acute schirophrerOc attadl. While amphetamine is associated with psychic and physical dependence. tolerance to its effects may occur within a few weeks. Overdoses of amphetamine are treated with chlorpromazine (see p. 127). which relieves the CNS symptoms as well as the hypenensiOrl because of its a'bIocking etfects.

b. Cardiovascular elfecls, In addition to its CNS eflects. amphetamine causes patpilalions. caraac alTtrflhmias. hypertension, anginal pain, and circulatory collapse. Headache, chills. and excessiYe sweating may also occur. Because 01 its cardiovascular effocIs. aTT¥*-etamine s/IolId no! be given 10 patients with cardiovaswlar disease or those receiving tMO inhibitors. c. Gastrointestlnal system effect.: Amphetamine acts on the gastrointestinal system, causing anore~ja, nausea, vom~ing, abdominal cramps. and diarr'hea.

Agure 10.7 Mechanism 01 action of amphetamine.

III. HALLUC[NOGENS

::::...:.:===.::..._----A few drugs have 8S their primary action the abilrty to induce altered perceptual states reminiscent or dreams. Many 01 these altered Slates are accompanied by brighl. colorful changes in the environment and by

<_ '0''''.'

><

, >

III. HaRvOOogens

""

a p1aSlici1y 01 constantly changing shapes and color, The individual ~ !he inIIuence 0I1hesII dn.gs is ~ 01 normal decisioo, makWIg. since !he drug ;,~lli1eIes with raliona11houghl. These 00I'!'lp0Ulds are knoMl as tIaIucinogerlS or psychdomi, oetic drugs. .. Lysergic: acid dletllyt8rMSe (LSD)

MlAliPa silas In f'lI CNS are a'Ieaecl ~ LSD. The ch.g shJws liI!fOo IOnin (5-HT) iqOliillt ~ ill pesyn;tplIie lilOiij*)iS ~ f'lI "oitbarl billing to ~ 5-HT, and 54iT~ 18(",A.5. AcIio.9lion at f'lI sympalhetic: nervous system occurs. wtIictl causes pupillary cliJation, io w! UOOd... "f!, pioeoecb~ and ia e~ blxt;' BI"""a. ua Talten ~ lew dooos of LSD can nwee hBlbJoUlicl ......... tJrt. bnt eolofs. and mood alteralion occurs. Toletanoe and phy$iCal dependence h8Ye oeo..ned, tr.Jl lru8 depeudeiiue is rare. AcMlfse eftectll include hyperreflexia. nausea, and mu$CUlar WfIIkne$s. Soo.elines h9l dalles pn:xb:e Iol g I 5f '9 pr;yc:hrJtic de 'lII"S In lIllSceplIitAe iRM:;UlIs. HaIopaW(see P. 127} and ohr .........i S can t*:d< t>e hak:lnalory aaion of LSDand qUckty abor11he 5yl dOl I.

The rnUl alkaloid cootained in marijuana Is dronabinoI [droe NAB i noll, also called At·'etrahydrocanna~ [tetra hi dro can NAB I noll (THe). DronabinoIprOO.Jc:es euphoria IhllIls bliowed by clrowsiness and relaxation. depending on 1he social situalion. THe j~ifs shortterm memory 8nlety afref ~ bUI maximeI eIleds Illl<e aboU: 20 milules. By 3 hour$, !he eflects JargeIy dlsappea,. Ar:lVerse ellects include an Increased hearl fIIle, deaeased blood ... e5S' we, and a .edder_lQ 01 the ~ 1'4 h9l doses, a taac P5)'Chosis de.eloJlS. Toler...... and mild phy$iC:iII depeildellU8 oco.r ...... conIin.>ed freql&l use oIN aug. THe is SOI'I'l8!imes giYen lor lhe se.oere emesis c.used by some cancer thlilltAl"",,** agents (see P. 243).

C. Phencyclidine (PCP) ~ lien SYE kli dean] ("anoel cUI") i.,.,;ts . . ~ke 01 dopamine, S.HT. and ~ . It Il1&o has IlIllictlOliiier9C aclivily, bul suprisil'li'l produces "fpe1$3lil.ra1ion. Phlinc:)d:fne. an anaJog oll0lamine (see p. 117), causes Ois,odative anestnesia (lIlSenSiIMly to ..,. wWltA lo$s 01 consciousness) and analgesia. In l\js stale, ~ produces I'IUITIl:lness oj e ~ slaggered gail, sluffed speech. and musculaf rigidilV. Sometimes rIOslile and bilarre behavior oa::urs. In increased dosege, anesthesia, stupor. Of coma ,esull, bul Slrangely. Ihe eves may remain open. Increased setlsitivity to external slimuU exists. andlhe CNS actioos may persisllor a week. Tolerance often develops w~h continued use.

Figure 10.8 Adverse effects ol ampllelamines,

. " " , . . . . ., . , . ' - - - ' >

10. eNS Stimulants

'"

lOll Whid1 one 01 the Iollow'Jlg drugs is INCORRECTLY paired wiItl its to>:ic effec1s?

10.1 Which of lhe following is NOT cila,acleris1ic ot oo<:aine OYerdo6agoe?

A. Ampnelaminll: Paranoict psy<1lOSis B. Nicotine (low dose): Decrease
""""'-

A. Dilation of the pupil. B. EuphOria, C. Tac;hycarda. O. Peripheral vasodilalm. E, Halocnalions [ CoIf8d c:tdoe. D.

C. Coca.,...: Anxiell' and depression D. LSD: Hallucinations E. Ga!ltiine: Insormia and egitation

c:.a:.r. - - 1*11:'_111

1

to.2 Which allhe tollowlng statemenlS aboul amphel· amine is (NCORRECT?

A, Overdosage of amphetamine ClIn be managed with dIlorp'OITIlIdne. B. Amphetamine is uSlld as an adjuncl wilh MAO inhibilors in 1he treatment of depression. C. An1l/>etamine has a IOroger oi.!,ation 01 action than D.

""""'.

~Iamine

depresses !he l\tIngIIf """Ie, In 1he

hypolhalamus. E. Ampne\llmine &<:IS on n- and

1H'll<_'gic p<esy·

naplictemtnals.

[ 10.5 A very agitated you-og male was brought to the eme<· gency room by the police. Psychiatric e>
A. Phenobarbital S. Lora>:epam

C. Cocaine D, Hydroxyzine

E. Fluo.etine eor.tI CI'IlIO:lI. B. Al"pl'z' ,.... Ilhldd nol be U8eClln pderIIS receMng MAO lo.llJIuIl, .-.,.,.. , ,,10 .. _ ~ ........ NAO.

Colrel:l.-. B. The.otlcIyk; PlOl*_ d

~ .......... 1he

'IIwn .... dnJgII d d'lDice In ~ the andely a>cl4 '., ofax:elne "'011808, Lorazepem . . , 11M J'IWInclIc PlQJl101ltoe. Phtod>a~ .... ~ pl\4* .... bul It's ~ plOl*teI .... Inl.nor 10 lhoM d the benzOdiazeP . Cocaroe .... -*' COtd8f8Cl the 01 HItIdo••,.. tul .. . - MUd nol be P"'Jl:* . apy.~ ilIl ,"'ik:,ltelllK:llw as .. I'rfpnCIIc WId ,.'--' 10 dBaI

.-.:l . .

~

beNodI8ZeI'1 .ee. such . . lo.aupam. make

CNS lY"4"O'''.

b'/.'' ' , ,.,.

_ - of Il1 DCloc:lOng

...... n. fIllIlhorizI c..wd

. . . 4 10 II htU'z, (It II 10 8 ..... 1clrI(IIIf..." ... IIftIcts of cocan..

10.3 Which of Ihe lollowlng slatements concerning retratrydtooarv'lab (THe) is CORRECT?

A' 118............

.... . - y .... "

THe da<:reases heart 'ale. B. THC il1creasee muscle st,ength. A.

. . e/IedF en 1U1FleIy.

C. THe decreases appetile. O. TliC causes hypoloos"". E. THe has antiemetic actioo.

--

CorTIICI _ _ • E. THe It . .,..". ' - ' 10 ......... _ ....... --.:Iby_ctwno-

[

]

plobla1l.

rt_no~

• ..''''0'''''''<_'''_''

Anesthetics

I, OVERVIEW Geooral anesthesia is essentilll 10 surgical practice because It rendefs patients anlllgesic. amnesic. and ul'lCOnlcious while causing muscle lellmition IlfId R.qlI1!SSion ol undesirable leIlexe$. No single drug is capable olllChievWlg 1hese etleI:U tapkIy and SllIetV. Rlllher, &eYeraI
II. PATIENT FACTORS IN SELECTION OF ANESTHESIA

AQJUNCTSTO

ANESTliETlCS

f--

'

e."

.--

...,so f RftAXAHTS ~

I

. "'I"""'"

GENERAL ANESTHETlCS

'-i=~_~.'!!'~"=::JI

-.. -- ,t _. ,. ,

coklOic state.

F!gurt11.1

A. Status of Of"9IIn systems

u- and

_ "'., I......-• .."'_ ... ........• ,

During the pleopenuiYe phase, the 81 es1I .• '.oW sek:cls drugs It1aI pI(Mde • sale lll'ld eI1it:ieIt 81 I itoelic fegillll!ll based on the nature ol the surgical plocecUe as wei as ttoa palient"$ ~ s'ngic and pha.fma-

1.

~I

SurnmaIy ol anestnetics.

w...enoe

kkh!y: 5n;e the ~ and IcO"oey I"(( odf Ihe Iong-lerm di5lribulion and clearance ol a"es1lietic llg8I'!Is, but also

(F"ogu.e continues on next page.)

---"* '.-.. -..._ _.. _ ___'_'

_c. _

I

C......

107

. . . . . .0 . . .' . ' • •

,.

""

11. Anes!helic& ~

_

as !he IargBI 0I'gIn lor kIcic eh:lds, hl ~

,•

'iJ'

statw of _ _ organs ITW,JS( ba ....1Sii:teied. 01 partiaJar ..... l(&n, 'E' se of Iuoride. br(»lIide. WId Ohlr ,,,e,lbo'ic pol)(1Jl;ts of hlJIl). gEnIU8d 1'¥'o0000tuili (3'l af*:l . - organs. e .... _ ~ lhese

.............

GENERAl

meta!· t

1IOCUI1lAale ...... rIlJl

' 1 81

relic ad"i"isMlic...

' ay$bIm: The cao::likll. of .... resPral(»y sysIeITi rn.ISI lSideI'ed if "".,'alio" ao ! h!Iic& are irdcaled. For elG!ll'llplit. llSIhmlI. 01' Yenlilalicn 01' p8ftusion abnormailies ..... ,•• IS conliOI of an inhaIalicn anesthetic.

2. pE'

ba

,•

---" .~

W

p.;:

,

"

.-Aokwplil".

Dop._

}--

LOCAL AHESntET1CS

• •, , , • ," , • OM

•, •

F9'~ 11.1

(c:ontinU8dJ 5lnwnary of aneslheIics.

n'lO$t

anestlle'ics is sometimes desirable, ischemic injury ot tissues could IoIIow reduced perfusioo preSStJre. Should a hypotensive episode during II surgical procedure necessita'e treatmen" a V?SOllctMl substance mus' be selected alter considering the p0ssibility thaI the sneslhetic present may ~ the hear' to the ~ eIfecIs 01 syrnp£l'l'lOrt'Wl'lelic Ilg81ls.

1-1-

Pi; ,

•

3. c.rdlO'llEKU,ar .,stem: While the hypotensive elfecl ot

,EIem:

4. Nltrvou•• The existence 01 neuologic disorders (lor tllCiIm. pie, epilepsy, myaslhenia gravis) inRuences!he selec!ioi, 01 an 8ltes1l'ietic. 100, 'I'>'OtAd a patienlllistory p ggesWe 01 • geneti, : tyo:dele",i"ed sensilivity to h?logeoBted ~ maIigIlllIlllfper1helnia (see P. 113).

so.

B. Conc:oonlIanI UM of drugs

1.

8Cljunct.,a.: QUle oller\ Sl.Wgical plllienls ,ee IMl CI'IfI or more 01 the Iollowing preaneslhe,ic medications: benzodiazepiolllS (lor~. c:ialepam. see P. 89) to relieve ar1ICieIy and 1acilita1e h' barbiIurllles (lor exarT'flIe, penfobattJifaI, see P. 94) br sedation; antlIislarTWIes lor ple.olltio" 01 aIergic reaclions

~

&I,.

(lor

ex~, ~,

see II-

422) 01' to ,&Wee gastric

ecicliIy (dmefidir>e, see p. 236); antiemetics (lor exarfllle, droperidol, see p. 242); opiOids (lor example, fentanyl, see p, 139) lor aroalQesia; and/or IIIltkholirlergics {lor example, soopo/amine, see p. 48) to preYefll bradycardia and sectlllion 01 fluids in,o the <8sptr ralory Ir'BCI (Figure 11.2). These agents tacilitale smooth lncluction 01 anesthesia, and wOOn oontirluously adminis'ered. they also lower hl dose 01 aneslhetic required 10 maintain he desirecllevel 01' ~ (Slage III) alleslt Sip. However, such OCHld'nilistratiDn can also enhance uncIesWabIe anesthelic eflects (lor exarnPe, hypo.oerdlllicn) and may proO.IoI negaM effects not ob5erYed 1IIItIen . . samE drugs are gMln alone. 2. Concornltanl UN '" additional .-..-.1heIic dfugt: Surgefy paIiel lIS may be (h(»ieaI)' e'¢'C led to lIgef1Is lor he treatment of !tie U'Iderlying cf w, as wei as 10 drugs of abuse lhat aII8f.". response 10 aneslheIics. For example. ak:ol ..... haYe eleWled IeYelII of hepeIic "iaO$Olnlll ~ in¥oM!d in he metabolism of barl;jwrates. and drug abUser1; may be 0YeI'ly IOIeranl 01 1he aneslhelic, since augs 01 abuse and anesthetics can act on the same biochefricaI palhway(s).

...... '0'

"'co. <

,.

• """"' .....

,....,..,. .. _ . "".

III. lncll.lcOOn, MainteoarlCEl and R8CCMIry from Anestt'oe$a

III. INDUCTION, MAINTENANCE AND RECOVERY FROM ANESTHESIA

109

Some functions of

adjuncts to anesthesia

Ai 55'hesia can be c;Wided inIo Itwee stages: induction, manena-ooe. f8CllMlI'Y. Ril'c!ion is def".oe
A.lnduetlon During induction it is essenllal 10 avoid lhe dangerous exc~alOlY phase (Slage II delirium) cna~ !he slow onsel QI action 01 some anesthetics (see beIoW). Thus. general aneslllesia is nonnatly inlb;:ed wilt! an inlflMlnOUS anestt.elic ~ke Ihiopenla/: .... iCOi lSCiousfl&$$ teSUlts within 25 $8l;(Iil(ls aller illjection. Althal lime, adl5lional inll.alalion or inllllvenouS drugs comprising Che selected are r.etie may' be!JYen 10 prOOJce lhe desired depIh QI sugicaI (Stage MI) Illl£rt ·a. [Nelle: This otten ird!wlec; Q[)-adliiflistlalion QI an r.travenous skeletal muscle retaxanI 10 ladlOtate ....lbalion and relalulll0n. Currently used muscle relaxanls include YeCUrOrlit.m, 81racurium. and sua::inylcholine (see p. 52).1

B. MalntefWnce of lInesllw5lil

~_

,or.

.1

I

' .....1 " ... _1. _I

C,

Reeovery Fostopelalivety, the 1lIll!Slt5f 'agiSl wiIhdraws the llIteSU"oetic millI\Q and "r:nlilots!he i"meciale retln'I at me patient to consciou&ness. FOI mos. anesthelic agents. recovery is the f8Yf1(H of

maim; thaI is, redistribution from the site of action rattler than The 1lI ,..,.,' ·'ljiR mnIinues 10 "r:nilor the palienllO be sure thallhere are no delByed IOIcIe feat'tions, tor exa"pe. Iiltusion hypoIG8 lor nitrous QIlide, 8ft(j h8pBtOIOllicily ...,;., halogenated t¥lloc:Mloi....

metn-" UlderIies ,eoc oery.

D. Depth 01

.nes~

The depth 01 anestheSia can be liW:led into a series 01 IoUI sequenCial stages: each is characterized by IllC«!ased CNS depression thaI Is c:aused by accumulation Qllhe anesthetic: drug in the bmir1. With

t

~'"., -----~ '

.........

FIgure 11.2

Cu,~llIIltsat balanced

MU'IIenanoe is the lime dumg whid'llhe patienl Is surglc8Iy 8I'Ie5lhetizecl. Alter administering 1he selected aneslhIllic: milflUf8. the ane5lhesiologiSl monilors !he patienl's vital signs and response to various Slimu~ 1t"«lughoul the surgical prooedufll in order to caratully balaoce the amount 0' drug inhaled andfor In'used with the deptl1 01 anesthesia. Anesthes1a is usually mair1talned by the adminIstration 01 gases or ..ootlle aneslheties, sirlCEl these agents oller good lrinut&-Io--minule eonlrol OYer the depth at anes\t'.esi8.

...

" - _ V ' I'

<""'.0.......'.<

,. II. Anesthetics

'"

eifler, wtlich produces a slow onset of anesthesia. all me stages are discernible (Figure 11.3). However. with tlaJolhane and many other commooly used anesthetics. me Slases 'He diffiCuh to clearly cl1araCleri~e because of the rapidity of oosel of anesthesia.

,

1. Stage I-analgesla: Loss of pain sensa.1kln l'fl$lJ1ts from interlerence wim sensory transmission in Ihe spinothalamic Ifact. The patient is conscious and COI"MlfSalional. A reduced awareness of pain occurs as Stage II is approacned.

lOSSOfPU. S£hSATlOh

2. Stage I~xcltement: The patient experiences de/jrium and violent combative beI\atIior. There is a rise and irregularity in blood pres-sure. The I1lspiratory rate may be increased. To a-
.'

.......

3. Stage III--sllf51k:>ll anesthesia: Regular respiration and relaxation ollhe skeletal muscles occur in mis Slage. Eye reflexes decfease progressively. until the eye movements cease and the pupil is fixed. &Jrgery may proceed during this stage.

." "t.....

~~ ~ = , .z......

4. Slage IV--rnf!odulfary p3raly.,b,: Severe depression of me res.pira-

tOf)' center and vasomotor center occur during mis stage. oeam can rapidly ensue.

IV. INHALATION ANESTHETICS UEDuU..... ~y IV PARAl"SoS AN

Agul'flll.3 Stages 01 anesmesia.

ATH

Inhaled gases are the mainstay of anesthesia and are primarily used for me maintenance 01 anesmesia alte, administlation of an inlravenous agent. Inhalation anesthetics have a benefit that is noI available with inlravenous agents, since the depth of anesthesia can be rapidly altered by changing me concentration of the Inhaled anesthetic. Because mos! of these agents are rapidly eliminated from the bodY. they do not cause postopemtlve respiratory depression. A. Common fealures of Inhaled lInesthestlcs

Modem Inhalation anesthetics are nooel
The potency 01 Inhaled anesthe1ics is defined quantitatively as the minimum alveolar concentration (MAC), which is the concentration of anesthetic gas needed 10 eliminate movement among 50% of patients challenged by a standardized skin inCision. The MAC Is

........0 . . .

'.'.< .. _ _ ,·

IV. Inhalation Aneslt1Enics usually expressed as lhe percent 01

111

gas in

a mixtufl .equired 10

acheYe ItIe etIecl NUlTleticllly, MAC is smallor poM!f'IC aneslhelics, $UCh as hakJttlane, and IafVe tor less poIef1l agents, $UCh as nitrous cwictt. Theielofe. 1he ~ of MAC is an inOOX of poI(n;:y d !he .ob1I... tic. The MAC Y8IuelIare useU in C(lITIplIIing pt8rmacCJk:l.,;io etIel;:ts of dr"""'1 iIfleSltdcs (F'9M8 11.4). The _ ~ an ~ ItIe lower !he u ..... ,traaion of III P....... ne ;..1 all

-

.-..---

C. Uptake and DistribUtIon ollnNllatlon Anesthetles 1

The partial pr8SSUl1l d an aneslhelic gas at P1e origin of !he <espifBlOry palllway is Ihe driving Ioroe thai rTlOYeS the anesthetic into the aM!olar space and thence into !he blood. W'I'j(:h delh/efs the drug 10 the brain and VIlrious olher body COfTIj)ilrtments. Since QIlses rTIOVe 'rom one compartment to anolt1ef witt1in the body according to partil'll pressure gradients, a steady Slale is llChieved when !he par~lll preS&ure In each 01 these eomparlrTlents is equivalent 10 that in the Inspired midura. The time course lor 8tlaining ltiis Sll1ady slale is de!ermined by Ihe IoIooMng lhree lac1ors:

-

, -..,

Flgur.11.4 MinifTl8l 8tveolar concentrnlioos (MAC)!Of 8neslllolie gaseS.

1. Alveolar wasIHn: This I8nTI retefS 10 the fepIacemenI of !he rormal loog gases wilh the inspi.ed anesthetic fT\Ixlure. The lime .equioed tor Ihis pliO( I S is diretlly plopoo1iollal 10 7le fuflctia laI . $alai eapaciIy d !he loog. and ~ proportional 10 !he vetIIiIaklry rate; iI: is iido4iedei. of the phy$icaI PO ....... ' d fie gas. Once fie partial Po 51 'AI bUilds wiItWllhe II..ng. 1lI--"'1ic ~ ITOTIIhe loog ~ 2. Solubility In bloOd: The firsI oomplIrtment lhat the IlIlllSIhetic gas etlCOUllefS is the blood. SolubiIily in blood is delemllned by iI phy$ical property d Ihe WleSIheIic moIewle calec! the bloodIgas pattition coeffiQem, which is the ralio 01 the IOlaI amoonl 01 gas in the blood relative 10 the gas equilibrium ptlase (Figu.e 11.5). Drugs with low versus high liOlubilily in blood ditfer in their speed 01 induelion 0' aneslhesia. For eX8mple, when 8n aneslhetic gas l'Iilh low blood soIubilily. sud! as n/trws oxide, diftuses 'rom the 8tveo1i inlD !he circulaliofl. ItlUo 01 lhe anesthetic dissolvos in !he blood. Therelore, the equilibrium belWl!etl Ile inhaled anesthetic and arte.illl blood oc::cu.s rapidy, 8nd rel8Wely 8ddilion81 moIeaJles 01 aneslhelic ar. requirod to raise wteri81 Iension (thaI I$. s1elldy-state is etie gas with I'igh blood soIubiIiry. suc:tt as haIt;ltIIane. ~ _ Ulmp1e1ely in Ihe blood. end gJealer amounls d the eneslhelic and IDnger pel iods 01 time 8fII rellt*ed to flIise 8f1eriRI tef llIiOi L TNs fesUIs in increased limes d irdtrim and fllUM!'lY. end sloM!r ctJanges in hi de4JIh of anesll • in to dlanoges in P1e

'ew

OOflCa.lralion d lhe imaIed~.

...... --j -,

..-

" ,E,,""'_

-,.

'l!SfJUf-

3. Tluue uplake: The 8fteOal CWCUalion dstritUes the _ _ ~ ...lic 10 various lissues. and Ihe pressure goadie<. ~ tree enesthetir: gas Ir10 ~SSl ii!S The time ~llCIlor a particular tissJe 10 lldlieIIe a stelIdy-sla1e with !he partial pressure 01 IIf'l anesthelic gas in the inspired mixture is irtYersety proportional 10 !he bIODd Ilow to lhat tissue (laster !low .ost.Jfts in a more rapdy acI1iEM3d sleady-SlB.le).

lind directly proportional to Ihe capacity to store aneslhelic (larger

F".gUtfl 11.5 _ ... partition ooofficierlls

tor lhe inhalalioollllllStheIics.

...........,., .. _--,. '" ~

restAts ... a longef lime k) ItChew 5i

1y stale).

~•

... un. is diredly pIqIOrlDW 10 hi tissl.e's YDkme, In:llhe lis-

SUIlItiDod rit*y wef1iL:itn of !he SleSlhetic fTlOIen'e QlItle besls of ItIese OOIlS1deoaliorlS, lou" ITlIIjof OOI,.....,8l1$ delel.,liIl(1 Itle lime lXlU"Se of a.esI'Elie l4)t!lke:

,.

Induction ',0

•• Brain, heM.lfwf, kidney. endoal,le glands;: These hlg1Iy pel"f\.lsed !issues rapi{Iy a Slea(ty-stale wiltllhe plIrQ! pres~ of Ihe aneslhe6c ... blood.

anar.

b. Skele'-' 1TlI.OSCln' These a'e poOfIy perlused during 1IfIeSltlfl.. siB. TNs and !he lad lhal!hey have a large YOlI.mB. proIalll the Tima required 10 achilNe Sleady-srate.

e..

F-'; This Tissue is also pooI1y peJ1used. However. polerll general anestheTics are very lipid 'Otoole. TherelOfe, rat has a large capacity TO store anestheTk:. This oombinalion 01 slow delivery to a high capacity comparlment prolongs the time

reqWed k) llCNeYe steady slate.

o

d. Bone, Wgaments, and CBf1llaoge: These are poorly pel1used and have a rela/ively low capacity 10 slo.a anesthetic. Thefelore.lhese !isS'e$ ~ Oldy a slilt'l ~ on IhB Iirne eotne 01 aneslhetic cIislrb..eon ... Ihe bod)t

•

4. Rel\.om 01' gil. deplekd bIoocIlD the lung: As !he YBnlllJS dro.JBlion relu'n6 blood dep6e1ed of aneslhetie lo !he k.r1g. more gas fl'lO'\Ie$ hi t*xld ITorn Ihe Ulg acx:of(if III k) hi pertial presSUfe difference'. OYer time. !he pa.lial pre55UfB ... !he atYeolar spaee: do$ely eppn;rUna1eS the plIr1ial pressure in Ihe irlsplred rnilll.lre: h i is.. the
.-wo

,.

' ,0

• •

Figufe 11.6 01lwIges ... Ihe atYooIar blood OOIlOtii

.,a\ion of IhIIl inheIaIion

aoeslhelics with trne.

5. Uptake cu"'" for inhaled ane"het!es: FIgure 1 1.6 iIIuSllalBS IIle uplake curves rOf lour inhalation aneslhe~cs. "Tho 'Otubilily in blood. as well as tissues. is In lhe rollowing Of<:\e.; hatcthane > enfwrane> i9Of/urane> nitrous oxide. Because 01 ns lOw SOlubilIty. the par~al pressure or nitrous axide In /he inspired mixture and !he body f!lOSI rapdy acmeves a SlBlIdY-slale. 6.. w.shout: When !he adminislrolion 01 an inhalation aneslhelic Is
ar..s

once allainmenl of S1eady-$ll1lB ..... an inspI"ed anes~ deter· mine the lime course of deallltlCe 01 the CWg Irom the body. Tllu5. nltn:us oICide exits It1e body tasIer thiIn halothane. C. Mec:hctnIsm 01 Actlon Inhalation aneslhetics are nonselective in Iheir action. Thai is.. in addition 10 the.. dlnicaIy Impor1anl eflecl on the cenlral nefVOUS system (eNS). !hey also aIIer !he Iooction oj various peripheral eel typos. The taclthat dlemicaly unrelated rnoIecI.lIes proWca a stale of general anesthesia arlPls &gaInsl a specific anesthetic .eceptor. Further, whereas anesthetics aile. the funclion 01 receptors ror neurotrlmsmllters (for example, y-aminobulyric acid, glutamate),

-_'0'''''''<,, _ _ ,, IV. Inhalalion Anesthetics !hey do SO nonseIecllvety. ThUs, lhe lad !hal CNS regions. like !he relicular adMIting syslem and corte<,...... ml ~ $iles d aneslhetic adion is appermly Uf"'A"eIaIed toile poes! Q o/a spec:ific oeoeplOo ... a par1ic:ulllf region, tu: raIhef 10 !he role d ltle CNS ... CXIf'IIrolFog lhe wef8ll swe 0/ consciousness and response to .....",-

0. Specifk: irlhal8lion _thetles

Each 0/ !he halogenated gases, has charaaerisl:ics benetidaI for selecled dinical applications. No one anesthelic is supe.ior 10 enoIher under III cira.mslanees. [Note: In a Yl!IY &n'I8I population of patients. all d the halogenated I?fdror;arbon aneslhelics haYe the polenlial 10 induce malignant hypel1hermia While lhe eliology 01 Ihls cond~ion is unknoWn, h llppeS'S 10 be inhefiIed. Thus. asking wI1elt\ef a family membe•• espooded adversely 10 gaseous anesthesia could provide the warning ne6ded 10 avoid a ra.e eoc:ounler wilh this pathology. Should a pellenl el(hibillhe hyperlhe.mia Ilnd mosde rigidity d1arncteristic (]f mIllignanl~.dllntro.fene is!to'en 8$1he aneslhelic ff'ixlu.e is wlIhdrawn.j 1. tWothane: 1lIis agenl is the prototype 10 which . - . . agents in Ihls series (]f iIIll!SlheIic$ life UlIT1pIIred. WhIe ha*Jtlall! [haIloe thane) is a potent anesthetic, ~ is a relal~ weak _1ge$iC. Thus. h/JkJIh8ne is U$l.lIIlIy co-adoroi . stered witl nihouf cQ:ie. opt. olds, or local Ilf tel" l.JIe olher tNllogeo e '. . . . hydlaawbolls. hIIIdJ_ll! is ","""""r iii Uic and wiI cause atl"":c serlSilAe tIradreardia. In adcilion, ~ has !he l,lI"Idesirabie property (]f causing CiI.diac ll.rhythmlas. These are esped.alfy serious if twercaprliir. ('lI'OCJeased arlerlal ~ dioQde lensia") dlloo 'ops due to .elb::ed atveoIDr ~Iion. or if lhe plasma COllOllO Ilf8lion 01 altedloliltrines messes. The IaI1er fad is 01 particuIa. siglificance since IlaIotIvJne produces hypolension. Shor.Ad h I:lel;xlme necessary to OO\.lflle. excessive hypotension during Mlolhane llOeSlhesia. ~ Is reoommended lhet a dired-llding VIlliOCOflStriclor (lor eIlample, phenylephrine, see p. 66) be glven. Halothane Is 01
agent OIl dloice ... dlben.1 2. Enftu..-: This gas Is less potent Ihan ~. tu: ~ produces rapid InliJcIion and ~ About 2'\l, (]f I'oe agent is rneIabolil:.... to fluoride ion, ~ is excreted by the kitrley. Therelore. enf/urlrI':c [EN noo moe] is oonlraindk:ated in patierlts with kidney tallu.e. Enflumne aneslhesia exhibil$ lhe fol~ dllferences from haJoIhane: !eWer arrhythmias. less sensill.tellon (]f the heart to calecholamines. sod gresler fXllenlialiOf') of muscle relaxanls

'"

• ......0._'.' ••

,. 11. Anesthetics

'"

due 10 a fTlOfe potent ·cumre·like" effecl. A disadvantage 01 ent/u· mile is that it causes eNS ellcitatioo at twice the MAC and at loWer dosf:!s it hyperventilation redUces the pCC".

3. lsotlur_: This is a newer halogenated anesthetic that has loW biolransfonnatioo aoo low Ofgan toxicity. Unlike the other halogenated anesthetic gases, isoIlurafIfJ ley soe FLURE ane] does not indoce cardiac arrhythmias aoo does not sensitize the heart to the actklf1 of calecholamines. ISDfIurane is a "'lry slabie moIeaJle thatlXldergoes little metabolism. as a result 01 wI1ich, less fllJOfide is produced. lsoflurane is not currently believed to be tlssoe toxic.

4. Melho.y1turane: This agent is the most polent Inhalation anes· thetic bec
En"ut1Jne

Halothane

~ -

.--B..

~ .... ~-

L L Decreuod .... ~i....,

..

I

-

Inhlbi10d

HoopefIc 1O.1dfy

.••

~-

I ~ .... I ~ R...,.....,..., ........ ij ~ BIood_......

lso"urane

-I I

I -- .-

Ooa Mft .. ..••.!hen r-.covero

~~h

Figure 11.7 Chameteristics of some inhalatiOll anesthetics.

,~.

Nitrous oxide

< ••"

'0. MI.,

>< . . . . . _ , >

,os

V. Inlravwoos Aneslhetics

SlJre (siruses) wilhin closed body COl11partmBr1tS. Furthermore, ilS speed 01 movement alloWs nitrous oxide to retard OKY9erl uptake during rewvery, Ihus causing d
V, INTRAVENOUS ANESTHETICS Inlravenous anesthet;cs are oIten used lor the rapd induction of anestllesia, which is then maintained wilh an appropriate inhalation agent They rapidly induce anesthesia, and must therefore be injected slow1y. Rewvery from imravenous anesthestics is due to redistribution from sites in the CNS. A. Barbiturates

Thiopental (see p. 94) is a potent anesthetic and a weak analgesic. It is the most widely used intravenously administered general anes· lt1e1ic. It is an ultra-short·acting barbiturate and has a high ~pid soIubiily. When agents such as thiopenlal, IhiamylaJ [thye AM i lalJ, and mefho/lexital [melh oh HEX i lalJ are administered inlfaveflOusly, they quickly enter the CNS and depress function. often in less lhan , minute. However, ditfusion out 01 the brain can occur very rapidly as well. because 01 redistribution of the drug to other body tissues, including skeletal muscle and ultimately adipose tissue (Figure , 1.8). This laller site serves as a rese""Oir of drug from wtlich Ihe agenl slowly leaks out and is metabolized and excreted. The shor1 duralion of aneslhetic action Is due 10 the decrease 01 its concentra· tion io lhe brain 10 a level below thaI necessary 10 produce anesthesia. Thesa drugs may remain in 1he body for relatively long periods 01 lime aller their administration, since only about 15% 01 the dose 01 barbllurale enlering the cirCUlalion is metabolized by the liver per hour. Thus, metabolism 01 Ihlopental is much srower lhan tissue red<stribulion. TIle barbilumles are flOt siQr1ijicantly analgesic and require some type 01 supplementary analgesic administration during anesthesia, otherwise Objec1ionable changes in blood pressure and autonomic function may enSOll. Thiopental has minor efleets on the

,L~~~

, "

tOO

1001I

Figure 11.8 Redistribution oIlhicpel1la from brain to mlJSde and adipose tissue.

<

.~,

'0...,.,

> < ............. , >

11. Anesthetics

'"

_I_

Therapeutic Advantages

Therapeutic Disadvantages •

lncompNle

•

No "",,",,Ie-.-lion

•

MuIU 1>00 used "~h _

Inhalatlon nesthetics

•

_ l o r eL>rgleOll

-._--....... ·--_ ·""""""'" ..._ "..111

•

• •

IlelllIc _

:>

renal

Nifroue cxl<M

__

PI.""'"

•

L.IltIemueclo_

•

RIIpkl ""....,,,."',,...

_ I agont In p6CliaI....

~,-

•

8
10< " , , _ wtth

• """'fItlm1.

Pocrana~

•

:~~§~_.~~~~.~-~~~~:;;:~

Lowers blood _ _ myocaldlum Ie

•

.--

Intravenous nesthetlcs

•

....

•

Good IllUKIo _lion

•

.....

•

Aepid f«OYWY

SUlbllily 01 car
·"", . . _01 •

./

I/OOd

~

v..-r><>If1III. "",-,,,,,,lei _ . .....

_

I" fIIllneph.......

01_

•

RapId...-

•

Good_guIa

•

Goo
•

• •

Potent _ _

anaIl1nl.o

--

Aepid ""...

Lowers

Inlrec,,,,,1a!

Figure 11.9 Therapeutic disadvantages and advanlages ol some anesthetic agents. cardi<Mlscular syslem, but it may contribute 10 severe hypolension in hypoYoIemic or sl'lock palienls. All barWurates can cause apnea,

coughing, chesl wall spasm, laryngospasm, and bronchospasm; !hIs is a oonoern lor asthmalic patients. Barbiturales are con1raindicated in palieflls wi!h acute intermirtent or vaJiegale porphyria. B. Benzodiazepines

Allhough diazepam (see p. 89) Is the prototype benzodiazepine. lorazepam and mldazolam are mare poten1. All three facililale amnesia wtlile causing sedation. Etomidate [e TOE mi dale) is a hypnOlic subSlance lacking analgesic properties lhal can cause unoontrolled skeletal muscle activity. C.Opioids

Because ot their analgesic property. opioids are frequently used together wilh other aneslhetlcs: lor example, lhe combinalion of

"••" '0...,., ........ __ , •

."""" ... "

_~,

'""""" ..

_.....

'"

VI. Local Anesthetics morphine (see p. 135) and nllroos oxide prcNide good anesthesia klr cardiac surgery. I-lOWIM!f, opiokls are nor good amnesics and they can al cause hypotension, respiralory depression, and muscle rigidity 85 well 85 poslaoes1hetic nausea and vomiting. Fentanyl {see P. 139) is more Irequently used 1tlan ~ne. Opioid etEcts can be antagor&zed by nalmone (see p. 141). D. Neuroleplanesthula

The mmblnalion of droperidcII and IenfanyI is a filled ratio lJ"epaf
o c

E. Ketamine

0 1CH,l.

4'.

"

Ph........

[KET a _~ a shorl·8CIing nonbaIbittnte an t-etic. irO..IOes a d'i 1500ated slallll in whictI tlIl peliet1 tIJIPIl8fS awake but ~

is ultx.usaoul and does not teel j:8in.. This "'ssO'ia'Ml ar.. sthesla provides kdalio". ! 9il, and il,.,dliliIy. KeCaonre stirTlJl;Mes Ihe centriIllJYi.lpIlltztic outlIow, ...tlich in &1m, causes stmtJalion of Ihe hearl and increased blood ple$$Ure and cardiac outpul. II also increases plasma catecholaminll ieIIeb and inaeases l*Iod 1Iaw. K£l&Iailre is twetln used when QroJ;aIOly depression is undesirable.. On Ihe other hin:l. these efleds mitigElle aganst the use 01 kela'ni?e in hyper1enSiIIe or strolo:e pelients. The drug is 1ipqJ0Ic and enlerS the bram circt.Ution very quiddy, to.n n~ the barbiturales. ~ can redislriIule 10 ott.- organs and tissues. n is metab0lized in the liYer. bull smal 8rTlOl.lI1S can be oa"eled uro::hanged. Kela<Tine is ~ n'IlIiI1y in ~en and )'DUIlg aaits lor shorl ~ but ~ Is noI ""'dely used, .......... _ • increases cerebml l*Iod IIaw and irO..oces po6I(lpet8We hallul:inalions r"iglolr"ares1.

Ill'.

.....

-~ ,

~ »

-

,-~

F. Propolol

-..... -

p".pald (po PCf 01] is an tv seda~ used in Ihe irdJc.. tion or maintenance 01 anesthesia, Onsel is smaoltl and ocalrs within about 40 se<::onds 01 administralion. Supplemenalion with IlllrC(l(ics lor anaIgesiB is required, WtiIe (JIopoIoIlacilitales depresr;;c., in the CNS, high plasma IeIIels can cause exQlalion. Pmpolol deaeases l*Iod pre$$Ure without depressing the myocardium, 11

A. Sll'\ICIUraIlonnIJ8 of procart#J. B. Pt1armacokif1eI properties 01

also reduces inlmcmrial pressure,

tocalllneslt1etics.

Some therapeutic adVantages lind disadv80tages 01 the anesthetic agenls afll sum:nartzlld in Figure 11.9.

VI. LOCAL ANESTHETICS These drugs are applied locally and block nerve conduction 01 sensory impulses from the periphery 10 ltle eNS. LOClII aneslhelics abolish sensation (and in higher concentralions, motor aClivity) in a lim~ed area 01

figure 11.10

<''''''.''''.''<- ... .....-'' II. Anesthetics

'"

lhe body Il'ittlooJl producing unconsciousoess. They inhibil sodium channels the net'Ve The small, unmyelinaled nerve litlers, lhal CQnduCl impulses for pain, lemperature, and aul0n0mic activity, are 1T'()S1 seosilive 10 actions 01 tocat aneslhe1lc:s. Alt of the Iocat anes1tlelics consist 01 a hydfophilic amino groop litlked throult' a connecting goup of variable length 10 a lipopt1ilic aromatic residue (Flgo.lre 11.10). 60th poteocy and toxicity oI1he local anesthetics increase as the oonnecting Ql"oup beoomes Ionge,. Adverse ellects ,esult from systemic absorption tOJ(ic amounts 01 the locally applied anesthetic. Seizures are the IT'()St significant of lhese systemic elleets. By adding the vasoconslrictor epinephrlne to the local anesthetic. lhe rnle of absorption Is decreased (see p. 63). This bolh minimizes syslemlc toxicity and increases the durntiol1 of aetiOfl.

or

membfane.

or

Study Questions Ouestions 11

1 - 11 7

GI\'efllhe follo¥>io(I dn.>Qs;

eo...cI_ .. F (TNopeoillll).

A. Mettlo>
(

D. Halolhar>9 E. Nitrous odlle F, ThIopenIaI G.lnnova.e H. l(.l8ITMr'Ie

Comld_ .. G(wouo.e).

11.6 Used solely In obstetric pmctico. ComlcI_ .. A~).

I. Etomidale K.lsoIIurana

Meldllhe mosJ appropriate aneslhe!lc or adjunct lrom the lis! aIxwe V
Qtggr.!llll. ONE bolst answe.-

11.1 Ads at ttl. neu,omuscula, jOOClion tn cause If\U!lCkI .xdtatioo.

11.6 Which
( ComICI _ _ .. 8 (~).

8. HalclIhane

C. Me1t>cJ>
11.2 Contains lissue tone bromide.

D. BenzOOiazepinos

E. Nitrous oxide

ConecI_.O

.. E. ...,.. IlOIIdt

-..v

no m_1e reI.xing p_nl

Etlter,

(;cro.a: _

11.3 PQ1enr anWgesle; weak anesthetic:.

j cc....et_ .. E~ . . .).

In~ial

-

and beftIodlueJ*oe ~ 1'IIIeUIlon: _ _ pooduces

_~

good _

"lOdeo" ...... ..-...cIon.

• ..." '0...,., ........ _ "

Antidepressant Drugs I. OVERVIEW MaP

depfessskln and bipolar lholdef are pervasiYe mood aIlemg illnesses allecling ene
ANTIDEPRESSANTS

I-

--Am/.$>f)"'. Amau, ' .

~Imfp<_w..

I'Iljoll/'"

p,"" ..., ....

r.... /p<_

I-

"""0_...

Rl._= ,

""f' &:L • Fa=.......

s.....

n_

....

f--

,

'

,

•

MOHOUIINE OQ)ASE

......OOS

'u.

«dess

s1ighlly dillerenl pharmawkinetlcs.] All the tricyclic antidepressants (TCAs) have similar IhempetJllc efficacy. and the choice 01 drug depends on 10lerance 01 side effects and duration 01 action. Pallenls who clo nol respood 10 one TCA may benelit from a (l;fferent drug In this group.

.....cmn; SEROT~ REUPTAKE

"'MOOS

II. mlCYCUCIPOLYCYCUC ANTIDEPRESSANTS The tricyclic and polyr:ydif; anti6epfessants b6od< norepinephrine. and serolonin up&ab inIo the neuron. P1.... ogecl ~ pmbably leads 10 *
TRlCYCUCIPOlYCYCUC ANTlDV'RESSANTS

• .....

n ....*"po.......

'-

,....".ANA

""""" ""'" ro ~-

Figure 12.1 Summary 01 onlidepressanls.

I

<

.~,

'0...,.,

> .............. , >

12. Antidepl"essant Of\IQS

120 A. Mode of action

1. Inl>ibillon 01 neurotransmiller uptake: TCAs inhibit the neuronal

Normal monoamine transmission

I RESPONSE

reuptake of norepinepl>rine, and serotonin into presynaptic terminalS (FigtJre t2.2). By bIoc:lo:lng the major roote of neurotransmitter removal. the TCAS Ielld to increased concen· trations 01 monoamines in the synaptic delt. resllmng in antidepressant effects. Tl>is theory I>as been discounted by some because 01 several observations. For example. the patency 01 the TCA in blodis suggests that decreased uptake oIl1e\Jrotransmitter is only an initial event that may not be related to tl>e anlidepressant eHects. It has been suggested that monoamine recaplOr densi· ties in the boain may change l)IIef a 2 to 4 week period will> dnJg use and may be important in the onset of actillity. ntlMl

2. Bkld
B. Actions

Effect of tricyclic antidepressants

@ ·I-.......... .nr-. ..~"

TCAs elevate mood. improIoe mental alertness, increase physical activity, and reduce moIbid preoccupation in 50 to 70% of individuats With major depression, The onsel 01 the rl'lOCIO-elevalion is slow. requiring 2 weeks or looger (RgtJre t2.4). These drugs do not prO' duce CNS stimulation or mood elevation in normal Individuals. Tolerance to the anticholinergic properties of the TCAs develops within a short time. Some to/emn<:e to the autooomic effects of TCAs develops. Phys;cal and psychologi(:al dependence have been reported. The dnJgs can be used lor prolonged treatment of depression without loss 01 effecIiver1ess, C. Therapeutic

uses

The trfcydic antidepressants are effedive in treating severe major depression. panic (ison:!ers also respond 10 TCAs. Imipl· aminBhas been used to control bed-wetting in children (older than 6 years) by causing oontl3ction 01 the inlemal spNncler the bladder. At present it is used cautiously. because 01 the inducemef1t CIIfdiac antry1hmias and alher serious car
some

or

or

O. Pharmacoklnelics

Rgure 12.2 Mechanisms of acIion of tricyclic and potycyclic antidep<essant dnJ9s.

1. AbsOeir lipophilic nature. are widely (istributed and readily penetrate into lhe CNS. This lipid solubility also causes these dnJgs to have long I>alf·lives. for example, 4 to 17 hours for imipromlne. AS a result of their vari· able first pass metabolism in the liver. TCAs have low and inconsistent bioavailabilily. Therefore the patient's response is

• "'" '0...,., ........ ...- , •

• ""'"' ....

, .....,..". .. _ .....

I" TricydiclPolycydic Antidepressants

-I. ===., . T~.

-

,

•

•

,

,

•

-••... • - -

...... "..,

P

UPTAQNW ......

an

•

121

•

Reialive le<.'ePl''' specificity at some lIIoliclepi

-

•

-

•

...

.... .......•

N!C8'IOA .......... ES I'

'

•

•

•

•

'M! MJg5.

used to 8djusl do&tge. The irilial treatmenl period is typicaIty 4 10 8 week$. The dosage can be gradually reduced LW'lleu relapse oocurs. :2. hie: These drugs are metabolized by the hepatic microsomal system (see p. 14) and conjugated wllt'l glucuronic acid. Uhimalely. the TeAs are excreled as inlIcliw rnetaboliles via the kkloey.

E. Adverse etlecla 1. Anllmuacarlnlc etlects: Blockade 01 acetylcholine receptors Iellds 10 b1ufred vision, lCeroslomia (dry moult'l). urinary reteo-

tiOn. constipation, and aggavation at glaucoma and epilepsy. 2. Cen\loYescullr. Increased cate<:holarnine aetMty rewlls In car· diBc OYBI'SlirTUation. ¥otOd'l can be We-lhrealenil'lg ~ lin l;M!fdo6e at one at the drUgs Is taken The slwIing at a~ conQ.IcIion among depfessed eldef1y patients Is at plIr1icu1<1r con~,

3. Orthos'-lic hypotension: TCAs b60ck a-adfenergic 'ec:epIOr.>. causing ()t1h(l&taIic I'Jpolension an:! refter: tae:t¥:aldia. In dQ. cal pnKJice l!lis Is the mtISi SlIrious p
5.

~ The Iric)dc ~essants sto.Ad be used with caution In ~~ palienls, sincB they may lnnlISk manic behH...;or. The llicydic anlidepressafllS have a nalfOW It1eIapeutic indell; for ex..,,""'. 5 10 6 Wnes !he maxmal ddy dose 01 1I,*"amiile can be 1eIt1aI. Depressed palie
"'_'~,""""'n

of

an'..,..,,'e....n'

._ 'K_I., >,

, >

'"

12. Anlidepre!>Safl1 Drugs POlenllele nflBClS 01 blognnlc ami,," drugs by ,,",v,,"Ung thnl, relTlO\lal from synaptic CIett

<7-

--. DINct-«tlng edoe....1c ~

Tricyclic antidepressants ~

ad.... f'>JIc

'N~

~

BlOCk fIllflctfl 01 indirect_aetlng syfTipnlhomimetic drugs by preventing the drugslrom reaching the.. Intrae:elf""r sites 0l1lCl1on

Figure 12.5 Drugs interacling wittllricydic anlidepressants.

III. SELECTIVE SEROTONIN·REUPTAKE INHIBITORS The selective serOlooin-reuplake inhibilors (SSRI) ;,lIa a new group 01 chemically unique anlidepressant drugs lhal specifically inhibil sero· looin reuplaka (sea Figu'e 12.3). This coolrasls wilh lhe Iricyclic antidepressants lhal nonseleclively inhibit the uplake 01 norepinephline. and serotonin, and block muscarinic. H,·histaminic and «,-adrooe
--

Figure 12.6 Fluaxetine ;nhibilion 01 P·450 drug metabolism.

Fluo~etine

1. Aclions: F/tIoJre/ine [FIoo OX e teen} is lhe pr010type 01 antidepressant drugs thaI selectively Inhibil serotonin rauplaka. Fluoxc/ine is as effective in the treatment 01 rnajot' depression as tricyclic anlidepressants. The drug is free ot mOSI oIl1le lroub1ing sida affects 01 tricyclic antidepressanls, including anti· cholinergic effects, orthoslalic hypotension, and weighl gain. Fluoxetino is pnlfarred over tricydic antidepressants by nonspecialists who wr~e most of lhe preSCfiptions lor antidepres· sant drugs. As a rasult fluoxcline is now lhe most widely prescribed antidepressant in the Un~ed Slates. 2. Therapeullc uses: The primary indication for fllloxe/ine is depression, where il Is as effective as the tricyclic an~depfes­ sanls. Fluoxetjne is effective in lrealing bulimia nefV(lsa and obsessive-iXlmpUlsive disorder. The drug has been used 10< a variety 01 other indications, including anorexia nerwsa, paniC disorder, pain assodated with diabetic nooropalhy, and lor premef\slrual syndrome. 3. Pharmacok;neflcs: FIuoxe/ine is available thempeulically as a mixture ot the R and the more active S enanliomefs. Both com-

<_ '0''''''

> ....... _ , >

IV. Monollrrine Oxidasllinhibitors pounds are demelt¥aled 10 the active metaboIi1e, norlIuoxeline. ~Me and norlIuoxe&le are sloWly deaJed lrom the body. with e 110 10 day half-life !of lheparent~, and 310 30 days !of the active melabolil:e. Fl' ' .... is 1d1i;1i;sJe<ed orally, with a oonstanl 00$e. a Sleady-$lale plasma COllCf!lllIation of he MIg is ad'ieYud atler seYeIBI weeks of lr~ FloeIIine is 8 pllttn Wtior of a hepelic q.kld"Itoo,. P-450 is0enzyme felIPOnStie !of !he elWninelion of Iricydic anlidepressanl drugs., ~ drugs, and !IOOlll .-.tiarrtlyf"mc and ~en­ ergic 8rIllllIgCrist !tugs (F9Jre 12.6). (Nelle: About J
4. AdYerM e11ec1.: COii,lOIofy obsen«I iId'4rM eI1ecls of IIuaol>h alllllUlTVl1llrized in Figtxe 12.1.1..t1ss of Iibda, delayed ejaculalion and anorgasmia are probably uno:;let-reporled side eI1ecls ohen noted by dini::iBns buI: alii not proo,.... lIIy lealured In the list ol standard side effocls. lIS ol IIuoxBfjne do

o.e'"

not cause cardiac: alrhythmias bul can cause seizures. For 8IC8Il1ple. in a repo
IV. MONOAMINE OXIDASE INHIBITORS

MoiOOill'""

··.'nsll (MAO) is a "Mliochotoial enzyme kuld In I'lIIUfaI and of1ef pm _. such as the glA and w.. In the neuron, MAO hn;lions as 8 "safety vaMl" 10 00
isocatt:lo>tarid [eye soe kar BOX a zid]. and tmnylcypr'omlne [Iran In

roe

moonl: r-.:J one drug 1$ a prOiotype. Use of MAO inNbitors 1$ now Wmiloo because of the oompIicated dietary restrictions required of patienfs taking MAO inhiMors. SIP

Flgure 12.1 COl,.' .....lly oberved adverse ellect ot /IuoJfeline.

some

• .... , . . . ." , . . . . . . . . - - , >

'"

12. Antideprossanl Drugs

A. Mode Dl action

Normal monoamine transmission

,,

~.

~-

Most MAO Inhibllors. such as isce8rtJo.azkJ, form stable c0mplexes willi !he enzyme. causiog Irr_rsible inactivation. This "sohs in inc,eased stores of norepinephrine. serotoo'n and cq:.:Ii"e within lhe neuron, and sUbseq"ent ditIusion 01 eKCeSlS neuroltansmiller into !he synaptic S4)llCe (Figure 12.8).These (kugs IrWWbiI not criy MAO in brain. but Oltidlls. thai ~ o:rldIllM: deanWlation of ~ end potet'GaIy lOlcic substances. such as tyramine, which Is Iound in cerlaln 1OOds. The MAO W1ibiIoni Itlereb"e show a hIg1 iicldei iCIi 01 c:mg.drug and dn.I!t Iood inteIcdiu15 (see"Adw!rse eIleds"). B. Aetlons

o

01 ...........,. s..,1L •• 1.........°: .•• ~

--'C

Effect of MAO Inhibitors

.....0 ,~ilbllLOl _ p - ._ t _.tlonof

. _ . . . .
AIhough MAO is lui)' iltoililed after _era! days at lIealmenl.1he -*'epressanl action 01 fie MAO intlIIiIcn.. IiI<e lhal 01 fie TCAs (see Po 119), is delayed seYenll weeks. Phenelzine and IrlJt¥'W'tw,iiie haYe a mild afTllheIamine-liI<e sUrrUanI et1ed. C. Ther.pe<.rtle uses MAO Intibiloos are indicaled tor depres5ed palients who are uvesponsIve or alergic to lricydic antidepressanls or who experience Wong anxiety. Patients wittllow psychomotor Ildivity may benem t,om the stimulant properties 01 MAO inhibitora. These drugs are also usatul in the treatment 01 phobic states. A special subcate-

gory 01 depression. called atypical depression. may respond to MAOls. Atypical depresssion Is characte,lled by labile mood. ,ejec1ioo sensitivity and appetile disorders.

0. Phanneeoklnetlcs

ILd_InIo .., :1' _ _

\

o o o

'A • -v,...... I .

-I ,........,. S.OIL ••

""'-?' ••

=::::::==

'==

FIgure 12.8 Mechanism of action 01 MAO iflhibilofs.

These <Wgs are well absorbed on oral iO,liilistralion. but antidepres.sant etlecls require 2 10 4 weeks oItrMlmerl. Enzyme regen. fIfillion. when ifTeYefSibly inacliYated. va,ies bul usually occurs _e..11 weeks ahe< termination of the drug. Thus,. ~ swiWliilg anlidepressant agenls, a minimum 01 2 weeq delay musl be allOwed atIer let"i1lll1itA, 01 MACl-Wlililor V'oefapw. MAO ~ are n ....ElWIiled and eoCicled rapdIy il .....

ume.

E. Advef$e effects

severe and oIlen Ulip".laHe side etfeds limit 1he"';'1

;-eacI

. - 01 MAO i'"'lbilors. For ....... 1. . . lyrarlli-. w::l&iiled il certain Iood:5, st.dl as aged rt es. ctoidIen 1iYet. beet, and ted \Wnes, is normaly lnaclivaled by MAO il the gut. lnclMO.lals 'eceiWlg a MAO iNlilol are U'\ilble to degade tyrarTIine obtaired \rom It>e diet. Tyramine caelSes It>e release oIlafllll amou:'It5 of stored caled'loIamines \rom fIl!fVf! lernWlaIs, ,esulting il he!lORChe. tact¥:atdia, nausee. hypertension. ca'diec a,rhythmies. and stroke. Patients must lherelofe be educated 10 eo,()jd ~ IoOOs. Phcr1tolilmine (see p. n) or pmzosin(see P. 13) are heIp(U

in the me08gement of tyramine-Induced hypertension. [Note: Trelllmeni with MAO inhibllcm mey be dengerous in severely depressed patients with suicidal tendencies. Pu,poselul consumption ot tyramioe-
._.0...'.' .....__ ,.

· . , . . . . · _..· 0 . . ' .......... _ _ ·01'·

"5

v. Lithium Salts side effee1s of treatment wiltl MAO inhibitOfs include drcmsiness, orthostatic hypolensioo. blurred vision, dryness of the mouth, dysuria, and constipation. MAO inhibitors and SSRls shoUld not be co-administered due 10 the risk 01 life.ltlrealening "S€fOloninsyndrome". Bolh drugs require washout periods of 6 weeks before administering the other

v.

UTHIUM SALTS

Uthium salts lire used prophylactically in treating manic-depressive patients and in ltle treatment of manic episodes. They are also effec· tive in l.ealing 60 to 8O"Ib ol palOenis exhib~ing mania and hypomania. Allhough many cellular processes are altered by treatment with IiIhium salts. the mode or action is UOkf1OWf1. [NOle: It is currently proposed that lithium acts by allering lhe cellular coocenlration ot the second messenger, inosilollriphosphate (tPi). see p. 33).] Uthium is givllfl orally, and the ion is excreted by the kidney. Ulhium sans are very tOllie. Their satety factor and therapetJtic index are extremely Iow-comparable to those of digilaUs (see p.t61). Adverse effects include ataxia, tremors, confusioo, and oonvulsiorls. Ulhium causes no noticeable elleel on normal individuals. II is not a sedative, euphoriant or depressant. Figure 129 wmmarizes the therapllUlic disad-vantages and advantages of the antidepressant drugs.

Therapeutic Disadvantages of Antidepressant Agents

.MM,,

, •• •••

.-_.••

Serotonin reuptake inhibitors

-- ... . r/woQrn",..

f

•

.

::;::"'.--: --,

~I"'-_" Tt_

v."""."",,

--

MAO Inhibitors

•.

- -:

I&oc-..uid • •

: ~_____

•

.-~ T'~",.·

Figure 12.9 TherIlpe!Jlic disadvantages and adVanlllges ol some drugs used to treat depression.

jlow

pol.....

I

~-"gic ,

.,,.

..... '0...'... ·- ... _ , · 12. Antidepressant Drvgs

ConacI dw*IIo • A.

Choose !he ONE besllltlSWllf. 12.1

a_1. .-_. wtm. _

...

of kiluwifg;. ...

8jlpi'~" ~

I.e lor illlp..,.,.,

A. ,,_•• oiI

c. B

_

100Ui..

12.2 MAO inhibiIon

n.

IlllIii:I)dc ....

001 _

_

of..,.

..._ and C1n:'tod ol . . . 01. 7?<;; : • .ulllh .. __ , • • _ lOIItod ol iL• .£:: ..... n. IIl:':; • •• ; Mle: • • _ .......... 01,. pi ;e . . . . . I( . . _ o l . . . , .. 2 _ Of DIgIf. " - " . . .

- ....... ""'*'~.

ellihgnd"'."

D._

0:nIi:t_.c..

P"

t

'_."fj '-

12.4 Which 01 _ common 10 11M lricydie .. iIlidoPfc .. _IMO i4oibilois?

• _ .. .-! _

w1..................

01 . .

a,. COI'lII1lindicaWd wid1 aJ at 111$ fol-

lowing EXCEPT:

A. indiI'lICI ~ ................. ~ .

B. uqcLc WIIidup"_rrIto.

.- f=- '..--..

A. Ther can produce Mdali
~~ .

c. They SIlow arrong h'oleriloCtiorl wiIh cert8n 1ooCIs. O. The\I can produce posIUfal hypolenllon.

E. They elec'.... ~""illlbllity 01 lonln In 11M synlIplic deh

~riN:

and Nn>

( CorNCt_.O.

C. bMr and dweM.

O. $ISpWI.

12.5 'Mlil::tl of ... " II ""'" .iIlidoPf_r'Il agentI uhtIiIi

e - _ . D. 11IIO ......_ _ .....

....,.... r'io.lik.CNS ............?

. . bI . . . ............ _11

a ...... c. Tmnw

. . . . dllllO

. I

o

tte

.

:

"

..... _QlIoi; 2 ... - - . . .. : ..

-

: u. -.Ii ..

... d

.,..,

_01

",,-do•. "'lfIqdl:

11IIO If • ,

,

01.."....

Pf1 .. h "" .:to w...cllllwlfl. T,........ lllI Ioocl$. IMlII .. ~ '" ... P

atIlI:=

'*"-I

"·"id ..01 =?:OIl '...- -_ -*", _ ........ lMO

104" AlNf_lO..

DC

,

If.

W

10 ......' ....

A.. .,ip.,lilb

.

O. T.azodone E. IAIi.o'fl . . . ( Comd _ _ C.

12.6 A ""'Y upset mcthef bringII if'l he.- 10 yell' Old ...., 10 aol< holIp in dc:lllinsl wilh Ill, beG-wetting. W!lictI oIlhe toIIawinO CIovgI rrOQh1 .I\eViSI. IN. pRltllem?

A. Flucx
* •• $lIOW . . . . . Ille<.

A. M oflhol uqcLc ...._•..,,_, $jl$UIic $tlicaocy.

B. ~ ;. •• ~ C. Tile lricydic .l'IIidepf ........ of,

C.T~

O. TO'8ZOdIDr1a • 8 n.1IIt)dc

TN ....., _ ' ..",.,.. $I!«:t. m lecIively InIiltliI if*l ........

'.r • en;. 'licall«:t.

D. n..drug& i .. E. n-drugs_bliido.io·

.a~.

_and..,

11iolb_'-"-"

",cor • • •

~

EIIdI;If-. _

_ _, . . ; I •• _

. ._

01 _ •

.1Iidop:_

w. . . ...-..

''>10'%

ll*,l .

FIoooae~.

ancl ... fill

...,.""bIIilldIt~ TI.~• • ' "

WoO lmIIlIOr., wIo:II» o:ilIIo . . . . .

....".0...'.' ....... _ , .

• ...... • ..........· 0 . . ' - . . . . . ..

_·01'·

Neuroleptic Drugs I. OVERVIEW Neuroleptic drugs (also called anlischizophrenic dougs. antipsychotic drugs. or maiO<" tranqu~izers) are used primarily to treat schiZophrenia but are also eHective irl other psycholic slates. SlJdl as manic states and delirium. The traditional neuroleptic drugs are competitive irhbilOrs at a variety of receptors, but their antipsj
NEUROLEPTIC DRUGS

I-

"-~

~ ~

I-

II. SCHIZOPHRENIA

PI1ENOTlIIAZlNES

BENZlSOXAZOLES Ri_kb,.

Schizophrenia Is a particular type ot psychosis. that is. a mental disorder caused by some ;merfJfll dysfunction of the brain. II is charaCleriZed by delusions. hallUCinations (otten in the form of voices). and thinking or speech disturban<:es. This mental disorder Is a common affliction, oo::urriflg among aborJI 1% of the population, Of al about the same Incidence as diabetes mellitus. The illness often Initially a"eels ~e during adolescerlCe and Is a chronic and disabling disorder. Schizophrenia has a strong genetic component and probably reflects some tundamenlal biochemical abnormality. possibly an OYfJractivity of the mesollmbic dopaminergic OfJIJrons.

OIBENZOOlAZEPINES

-

BUTYROPHENOHES

NEUROLEPTIC DRUGS

I

H........ _

L

m.

0--

f-

TttIOXANTttEN'ES n»orI>i_

The neuroleplic drugs can be dvided into frve major dassificatioos based

on the strucItfl! a the drug (Fogure 13.1). This classification is of modest importance, because within each chemical group. differoot side chains have protound eIfects on the poleocies ot the drugs. The management 01

Figure 13.1 Summary of nemolep!ic agents_

--.---- _..-..I. __.._ .... _c.O"'" .... P.,,"""" ......... _ £ _ _

121

..... '0...'... ·- ... _ , · 13. Neuroleplic OrllgS

I

.v

0;

psydlolic clison;llM can ~ be achieo'8d by lamiliarily wilh lie efleCls d <:roe ()f IWt' ~ ... eadl class.

••

••

1. 0!:lt*1." 'lKlpb~:toi"g Idhlly in br*I: AI d hi 1lllUl..... drugs l*dc in hi brain and in lhe peI''''' ,. (F9.a'e 13.2). d o:k4J<*ni .. I· ...·05 have bewI idIIr*lied: 0, and l:\ r ~ ac:tivaIe 8der1~ qdase, ¥otlereas D2. Da and 0.. .ec:tlI)tt'iS ~ "de"t¥ qdase.. The neuroleplic ~ biroit' Ihese r~s 10 YBfying degrees; ~. Ihe dinieaI efficacy CIt !he Ir.KliIionaI Il9Uft'leptic ~ COOTelales ~ wiIh IleW relIlliYe llbiIiIy 10 l*x:k ~ receplt'rs in !he mesoWnbic SysIefTI t'I !he br8ln. The actions 01 !he neunJleplic drugs are antagonized by BgeOls !hal raise dopamine coocentrl:llion, lor ~, l-dl;pll (see p. 84) and Ilfrllhetamines (see p. 100).


2. serolOnln rllCltptor-blocking activity In bfaln: The newer "a1)oPl. cal" agents appear lO exert PIlrt t'I their unique aclion lhrOlVl ~ t'I $8fOlorWl (5) receptt'f$. Thus. ckWJpine IKlOE za peen] has high allinily lor 0, and 0... ~ and fMld,energic: 'eceplol s, bul it is also a dopamine Orfeoel:*lr iIf'ltagCrist. Another ~ agent, risperidone [rit PEER j dohn], blocks S, I~S It' a ",Baler exts'II l!'Ian it does ~ ,eeepors. 8t'ltl 01 'Ilese drugs extoibil a low ilicld&ia 01 eI<1rapy'CM.1idaI side eItecu.

mJsc:arnc

B. Actions The 8I'ItipsydloIic adit'ns CJf

oeurolElpeic orugs renect bkxhde al

dopamine and/or sefOlonin ,eceptors. Ho¥Iever, rnany of lhew agents also blodc cholinergic, adie"81gic, and histamine lecoeptOIS, causing a \Ill.rIety of side effecls (Figure 13.3).

NEUROLEPTIC DRUGS

.... . ". _or '

-

-

~ .. '1IJ."gk 00

..

p.

".

F ....

--

Figure 13.3 NlIl.JroIeptic dlUQS bIocl< al dopamInergic and serotonergic receptors as well as at adrenergic, dlolioergic.

Brld hislarTil'e-binding faceptt'fS. GA8A '" )"aminobvtyJic add.

• •.0< . . . . . ,., . . . . . . . _ , .

'"

Ill. Ne<Jrolep1ic Drugs 1. Antipsychotic II(:tlons: The ne<Jroleptic drugs reduce the hallu:;:j· nations and agilatloo associated with schizophrenia by blocking dopamine ,ecepiOfS in the mesoIimbic system of tt1e brain. These drugs also have a calming eHect and radu<:e spontaneous physical movement. In COO1trast to the central netVOUs system (eNS) depressents. such as barbiturates, the neuroleptics do not depress intellectual function of the patient. and motO!" incoordination is minimal. The antipsychotic elleets usually take several weeks to occur. suggesting that the fherapeutic elleds are related to secondary changes in the cortioostriatal pathways.

_to ... ~--

2. EJllrapyramidaieffecb: Parkinsonian symptoms, akalhisia (motor resllessness), and tardive dyskinesia (inappropriate postures of the neck, trunk. and limbs) occur w~h chronic treatment. Blmjng of dopamine receptors in Ihe nigrostriatal pathway probably causes these unwanted parkinsonian symptoms. CIoziJpine and riS{XJtidone !!lChibit a low incidence of Ihese symptoms. 3. Antiemetic effect: W~h the exception of 'hloridazine [thye ot1 RID a zean], most 01100 neuroleptic drugs have antiemetic effects that are mediated by blocking D2 dopaminergic receptors of the chemoroceplOf trigger zone of the medulla (see p. 241 lor a discusssion of emesis). Figure 13.4 summarizes the antiemetic uses of ne<Jroleptic agents. along with the therapeutic applications 01 other drugs that combal nausea..

F........_ _ 10 ••.

--, -''''go

~

~

"""'"

SIckness

"-~

".""....

4. Antimu&Catinlc effecl.: All of the neurolepli<:s, particUlarly thi~ ridazine and chJo<promazine. cause anticholinerg;c eUecIS, including blurred vision, dry mooth, sedation, COO1fusion, and inhibition 01 gaSlrointestinal and urinary smooth muscle. leading to constipation and urinary retention. 5. Olher effects: BlOCkade 0' «-adrenergic receptors causes ortho> static hypotension and Iighlheadedness. The neurofeplics also aker temperature-regulating mechanisms and can p
~( _ II- :lotI)

r

@ @X:: C§)

,~-

_

,-

10 ... Chemothernpy

c. Therapeutic uses ThialhyfpetDbne

1. Treatment of &Chizophrenill: The neuroleptlcs are the only efficacioUs treatment lor schizophrenia. Not all patients respond, and <:orTlllete normalization 01 behavior is seldom achieved. The traditional neuroleptics are most etfective in treating positive symptoms of schizophrenia (delusions, hallUCinations and thought disorders). The newer agents with oorOfonin bIoc\(jng activity are etfeetM! in many patients resistant 10 the traditiooal agents, especia"y in treating negative symptoms 0' schizophrenia (withdrawal, blunted emotions, reduced ability to relate to people). 2. Prevention ot severe nausea and vomiting: The neurofeptics, (most corrmonly prochlorpera;One), are uooful in the treatment of drug-induced nausea (see p. 24t). Nausea arising from emotion

".""....

For .......

d"'I0 .. ,

~ Radiation

Figure 13.4 Therapeutic application of antiemetic agents.

...........,., .. -... --,. ""

13. Neuroleptic Drugs

should be 'r9illed with sedatives and antihislamines. I3Iher than with Ihese powerful drugs. SccpoIamine (see P. 48) is the drug of choIc:e lor lJealrnllnl of motion sickness. 3. OIlier u_: The neuodeptic dnJgs may be used as ~ 10 manage agitated and disrupWB behlWlor. Newoleplics iIf8 used in WI.tliilillion witl natallic anaIgeIics lor 1reatrr&1l 01 mOllie pain ......, _ _ ~ ~ i sused Ioweel r.actaNe tM(;..

DwCJlE!fict:l(d"oe PEA i dolel_ a C::OlliPCllfll_ 01 newok:ptalllShlsia (see P. 117). ~ [proe ME1l-i a zeen] is nol a good ~ drug. bUt the IIgl'1l is used in "ering prurikJs becaJse 01 its ~",oper1iBilsee P. 422). a.IpIJ.

D. Absorpt\orl and metabolism

I

The neu,._io i &how IIlUiilble iiOb&orplio.. ahet Ofill~. These agenl$ relllily pass inlo lhe bran. have a Iatge IoIllUne 01
0'

Adverse eltaets the neurolep,lc drugs oc::cur In prec'ically all patienls and are signifIcant In abool BO'lr. (F'ogure 13.5). Although antip$yd'Iolic drugs have an anay of adVerse el!ecls. !heIr Ihefllpeulie io"deIc is high.

1. P.rtdnsonlan efteets: The ilo'lllilOry eI1ecIs 01 dopaminergic neurons are normaly balanced t¥ tle acilalory . .Iia 15 of cho'i"''''· gic neurons. Blocking dopamine receplors aners this balance. causing a 'eIatiYe ~ of diOlii ... gic inlluenoe and ~ in ~ n'Il*Jr ,,!teas.

f11lure 13.5 Ao:t\Ief'se etlects WI ,•• oily cb5eNed in 1ndMdu
drugs.

.. Eflea 01 enticmlinergi<: drugs: 11 dlolillSlgic activity is also ' •• ~eQ, a . - . more nearly normal ba', ICe is <eslOred. and ~ eflects are nWWrized. TlWs can be 8dlieo'ed by adl,liilislrailon 01 an liiltictlOlio ... gic drug. ad'l 85 ben.ztltJPi'lli. The lherapeubc tradeoff is fewer ..trapyramidal etfects in achange lor the side ef1acIs of pa'll$YfT1P8thetie blodergic 8CtMty. such as ~ . stOo¥ lew exIrltf¥amida/ dis/urbances, since the diOliioergic actMty is S!lorogly dampened. This OOI'WJasls witl hakJperW and ~. I'o'tG1 have loW 8IltichoIirlerg;c activity and produce llIl'rapyramidal eflee::ts because 0' the prelerenlial bIodting of dopaminefgic 'Iansmission withou1lhe blocking 01 <:hoIinergic IlCfMty.

._ '0'''''' ........ _ , . til. Neuroleptic Drugs

b. CIouIPne end rlsperidone: These drugs haYe • low polenliill lor causing eKtr~,a,idaI sympIOIT\$ and lower rislt 04 IiItdMl dyskinesilI. These MIgs appear 10 be superior 10 tlBIopeoidol and dDpromazine ~ lreD1g !he 5)'" ipbTIs 04 ~ especially lhe negative sympfoms. Ri$peridone shl:KAcl be included among lhe llrst-~ne enlipsycholic drugs. whereas ckUapine should be reS4lrved lor S4lIIerely schizophrenic palleolS who are refractory 10 lraditional lher'lIp')'. C~apine can produce bone marrow suppression and cardiovascular side ettecrs. The risk 01 severe agranuloc:ylosis nec::ess~ales Ireque
'"

I.

...-

00 • DlbpiOO

,.

'.

---. _0,_ 0,., I. 00

•• _ _ 1ypiaIl

-

111-.,. f ...

--...... 00 •

I'MIopooIdol •

~

3. Other etler;ts: 0r0M;iness occurs due to CNS depression, usually dtri1g the tirsl 2 weeks of trealmenL Conlusion is 5(lITllIlimes encountered. The neuoleplics oI1en produce dry mouth. ..mary reIeRion. c:endIp8lion, and loss of iMXOir.,o<' .. 'L They IlIod< u· adrenergic recep&ors. resulting ~ lowered blood pre&Sl.We and Oftho$tatiC h)'poIension. The neuroleptics depress !he hypoItIafa-nus. C8US1fIg lWll8OiOill-.. gal r\l;WTtIee, inIerblity, and ~

......

4. Cautions and conll'lllndlC81ions: ActJIe agilalion ac:cDI'I'lpllIl withdrawal from BIcohoI Of oIher dr1J95 may be aggravaled by !he neuroleptics. Stabi~~alion wilt1 a simple sedative. such as a benzo. diaxepine (see p. 89). is lhe p<eklrred lrealmefl1. C/lJOrprom.uine is conlraJndicaled in palients wiIt1 5f!iztJre disordefs. since this drug can Iowef selnJre tlYeshoid. The r18I.«lIeptics can also llQllIllvlIle epilepsy. The ~ incidenoe of agranl.b:ylosis with cIol"apire may Iin'Ill its use 10 palients resistanllo alheI drugs.

F. Maintenance treatment Petie: lIS v.hl " ' - had two Of more liChlzopho llllic epi$OOe:II s/'IoIAd receive maintall8nce therapv lot al leasl live years. 8nd some experts preIer ir<'elirlile Ihet
HI. I H

IdoIl25mll

1. . . 1doI(5CnllI

HI.,

_l'~

II

-l2IlOMIll

•

..........", ........ --,. ",

13. Neuroleptic Dn.gs

."",r_-.._ _-

Therapeutic notes

Drog

H', ._

D1bp," 00

•

UIIII adO

--

Of

ik: KlIWy. " " _

... ..,. f.-_.r.·,·WefIecft;_.p ." '·,..,d..-a.

' ..

_d _ _

....~

' ..

-

_...-,-~

fij;

_.

S«rl tln... -.:l

._......

car"''' N'· etIecIs ...... "o,,:y

-

oammoootr - . Mth

__ with agent. In Ihe Io
8glIn" In the Uppet

pew tloi' of 1KJle

Figure 13.8 5un'w'nary ot fl8\.IroI8ptiC agents,

Study Cuestlons 13.2 ..... af !he rollowrig IQllementli abouIlhII ewapymm;. dill effedl al neullll!plicl life IXIfled EXCEPT:

Choose the ONE best enswer. 13.1 The neurtJlell* dnlgs:

et1eclive wgarost Ill! po5iliYe and negaM 1Y"'I'*Ji". d ldoiZopl.e,,;...

«+>Ill".

A. They. . - - . l by '*de. d ''''''''I*W5. IIrtI less ilIeI't '0 .. pnx10ced by dozapirIe

A, ... equdy

8. They

ClIU1C1 blu"ed ..isian. uno-y retention and afIe< . . . d rrdCllI'ri: .......... C. biNI w· . ~ '0 Dr6:4:e'iloeogic rlC1lJ9lOla.

C. Tt>ey cao be COl/oI.rl'd 10 lOme degree by

B.

Cllf'j

Iharoby~.

..-....-nc~

D.-.e~eIlecIs""IO~.

E. ' - a ...., 0"IIet d a'llipsydlalic: Klicn

,,

......

0. II I. E.

iclaI doe:; 0CIl _

Neo.o'*'*'" may _

. . .

,

7

7

,

.:..

~.,

,,~

_ ....

~,

s

s

"

s.'


-.
a.

e...:t

~

. . .

p ......

are ~ In patienIs-.g neu"*'t* ~ EXCEPT:

13.3 AI d . . 1
dy5ILnaiIn

8. R:n!a5ed tbId~. C. a/IIered el6Jtlio ... 1uodion. D. c:o'lSIipodicn E. or1ho6latic hypolenIian.

eoan.t...... . ......._, _.....

I,S

~Wldo.

'fl I

: ..

<_'00 ..'."'''''''_''

• <_ ~ "".....__.'0'"

_

..._ .....

Opioid Analgesics and Antagonists I. OVERVIEW

Opioids.,e natlnl or

synthetic compounds lhat produce "lOOfjtli:lC ~I<e eIlect6. The 181m opiatas is.8S8Mld b' drugs, such as /llQph'e an:! txJdcinc, obtained from the juice 01 the opUn powf. All drugs in this category &<:t by binding to specilic opio'd recepiOfS In the central nervous system teNS) to pfodUCe elfe(:ts thai mimic the action 01 endogerous peptide ne....-Olransminers. the opi(lpeptins (lor example. lhe endorphins. and the enkephalins). Although the oplolds have a broad range 01 etlOCls. 1Ileir primary use Is to relieve Intense pain and lhe llnxiely that accompanies il. whether it be !rom surge.y Of as a result 01 injury or a disease. such as cancer. However, their widespread availability has led 10 abuse of those opioicls wlth euphoric properties. AntagClf1islS tI1at can rewrse the actions of opioids are also very imporlant clinically in cases at overdose. (See FlglJre 14. t lor a summary 01 the opioid agcrisIs an:! antagonists.)

OPIOID ANALGESICS AND ANTAGONISTS

-

"''''''''

AGONI$TS

-~"

I '........

_

1.

5o"'_lIiI'

II. OPIOIO RECEPTORS Opioids inleraCl stefeOSpElCjlic ..... PfOl"'l reoepIOr$ on the membIBnes oj cerl3ltl eels in hl CNS. on r'lCfVe IenTWlaIs in thB peripl"",-, an:! on CIlI5 01 lhe gasVointestinal Irad. The major ettec:& oj tie opt. oicIs are medialed by 4 la, r sol ~ dil';"aled by lhe Greek Ienefs, J.l. ~. G end 6. eactl 01 wtlictl extIIlils a dilJeia" ......,A:ity tlr the ONg(S) it bnjs (Fogure 14.2). In gBfB"aI, binding pOIeIlC"" COll'elates

wiIh analgesia. The analo9

ic: propel"tie$ 01 the ~ are ~ medialeCl by !he J.l feoeplOr$: ho,,_. 1he " ,eC8fIIOr$ in the dorsal homallioc;aobibule. TheenkeP1ahinteradmore ' :foetywillthe 1I 'e<:epc-s inlle periphery. OCher reoeplors /of Ile .':J"+ts such as the o 1'808flIOr, ~ been shown 10 be less spec:dic; lot exampIa, the 0 'e<:8j:l4'" also bonds nonopioid agents. such as !he ~ ~ C)dirifle (see P. 1(5). The G fOOepIor may be .esponsible b the tI8Iucinations and (Iysphoria sometimes ali50Claled with opiolds. [Nole: NakJiItr:Jtle Ina! OX own) cloes not afltagonU:e binding at this rec:epkll as II does at the Olheno.l All opioid recepklrs are CDtJI)Ied 10 lnhbi10ry G proteins. and inhibit adenylyI cyclase. They may also be associaled wl1tl ion Channels 10 increase K' efflux (hyperpolari~a'ion) Of reduce eainftux. thus i~ing neuronal firing and transrnille< release.

c-

._"" , ......MODE"""

'

f-

•

IIIXUI AGONIST-

"""."""'" ........ ,..

f-

:

I

,--

~.

-

ANTAGONISTS

FIgure 14.1 Sonvnary of opioid analgesics and antagornsts.

._.__ _.__.. _.....,-_c, . '-," -_

",-_0_"

0""""

133

·....".,......, .. -... --,.

14. Op;old Analgesics and Antagonists

MaWy agon!f;lOCtIoro • II 'eceploi .. buI _ _

Agoral action

.-hi"",,,,

.-

•

.,~wllh

llCtIof .. on 0Iher ~

p8f1laI ~ KtIoro.

e .....""" •

II'

eC'lie

e

... ·CO.

FIgure 14.2 Adicns 01 agonists and antagonises ill opioid 'ecepbs.

A. Distribution of recepton

I-iltI densities 01 opc;d JeOeplOf$ life presenl in tiYll gene
8faln_,~ ClI:**l recE9"" rneliMe 19StMalioi~ ClOUII\ roausea ..., ,ohilig. maiI'IIefI;YlC:e of bkla:l Pffl$5U'8, p"pj!ary diameter, and oantn:lI of Sklf,liidl seoetiolll$..

2. Meclisl lhalllfT'fUs: ThIs area mediates deep pain thaI is poorly knli>ed and 8l'llll*'o I8Iy influenced.

3. SI*'III COfd: RooepIors in !he SI.tlsIanIia gela.tnJisa 8tlI irMlIIIed wilh !he receipt aod intega1ion of jiiCOliijiiQ seoso
<- .....,.,

>'''--' >

< ...- ........

lIl. Strong Agooists

,~.

, KI"OUJI .. _ . PI' >

'"

5. Umbic system: The grealest concenlration ot opiale rElCeplors in lhe limbic system Is located in the amygclala. These receptors probably do nol e~erl analgesic aclion, but lhey may inlluence emolional behavior. 6. Periphery: Opioids also bind 10 peripheral senSOfY nerve fibers and lheir terminals, As in lhe CNS, they inhibit Ca+<-oepenOOnt release 01 excitalOry, prointtammalory substances (lor ex.ample, substance P) /rom these nerve endings. It has been suggested lt1atlt1is may contribule to lt1e antiinllammalory effects 01 opioids.

7. Immune eells: Opioid·binding sites have also been tound on imIT'lJne cells. The role 01 these receptors in nociceplion (response or sensitivity 10 paintul stiIT'lJli) has not been detem'lined.

III. STRONG AGONISTS Morphino [MOO teen] is lt1e major analgesic drug contained in crude opi...." and is lhe prototype agonist Codcjf16 [KOE deen) is present in lower concenlralions and is inherently less potent. These drugs show a high affinity tor II receplOrs. varying affio1i1ies lor Ii and ~. receptors, and low affinity tor 0 receptors. A. Morphine

1. Mechanlsm 01 acllon: Opioids exert lheir major effects by interact· ing with opIoid receptors in the eNS and the gastrointeslinaltract. Opioids cause hyperpolarization 01 ner\o'll cells. inhib~ion 01 nerve firing, and presynaptic inhibition of lransminer release. Morphine acts al I< receptors in lamina I and II 01 the subslanlia gelalinosa of the spinal cord. and decreases lhe release of subslance p. whicll modulates pain perception in lhe spinal corel. Morphine also appears 10 Inhibitlhe release 01 many excilatory transmitters lrom nerve terminals carrying nociceplive (painful) stimuli.

2. Actions: B.

Analgeala: Morphine causes analgesia (relief of pam wilhout lhe loss of COOs600snllSS). Opioids ,elill\l(l pain both by raising the pain threshold at the spinal cord level. and more importanlly. by altering the brain's perception 01 pain. Patienls treated w~h morphine Bre still aware of the presence 01 pain. bUl the sensation is not unpleasant. The ma~imum analgesic ellicacy and the polenlial for addiction tor represenla~V11 agonists is shoWn In FlQure t4.3.

b. Euphoria: Morphine produces a powerlul sense of COt1tenl-

maol and well-being, Euphoria may be caused by slimulation of the ventrallegrnentum. c. Respirftlion: Morphina causes respiratory depression by re
Figure 14.3 A comparison 01 the maximum etficacy and addiCliorJabuse liability of commonly used narcotic analgesics.

·"'" ••• _1.'

"'6

>,

, >

• •_

K "'_ _" ' - " ' "

-..... .. _

...

>

14. Opioid Analgesics and Antagonists

is acwntuated as the dose increases until. uRimately, respiration ceases. Respiratory depression is the most common cause 01 death in acute opioid overdose. d. Depression ot cO"'llh "'tre~: Morphine and ccxJeine have antitussive properlies. In general, cough suppression does not correlate closely wiltl analgesic and lespiratory depressant propl!fties 01 opioid drugs. The receptors involved in the antitussive action appear to be differenl than those involved in analgesia. e. Miosis: The pinpolnt pupil. characteristic of morphine use. results lrom stimulation of II and", receptors. Morphine excites the Edlnger-Westphal nucleus 01 the oculomotor nerve. which causes enhanced parasympathetic stimulation to the eye. There is li"le tolerance to the effect, and all addicts demonstrate pin-point pupils. This is important diagnostically. because most OlI1er causes 01 coma and respiratory depression produce dilation 01 the pupil. t. Emesis: Morphine directly s!imulates the chemoreceptor trigger zone in the area poslrema thaI causes ~iting. However. the emesis does not produce unpleasant sensations. g. Gastrointestinal lrac!: Morphina relieves diarrtlea and dysentery. 11 decreases motility of smooth muscle and increases tone. It Increases pressure in the biliary tract. Morphine also inc,eases the tone 01 the anal sphir.cter. Overall, morphine produces constipation. w~h little tolerance developing. h. Cardiovascular: Morphine has no major effects on the blood preSSlJre or heart rate elCcepI al large doses. when hypolension and bradycardia may occur. Because 01 respiratory depression and carbon dio~ide retention. cerebral vessels dilate and increase the cerebrospinal lluid (CSF) pressure. The,elore. morplline is usually contraindicated in individuals with severe brain irljury. I. Histamine releue: Morphine releases histamine from mast cells. causing urticaria. sweating, and vasodilation. Because ~ C8Il cause bronchocor1striclion. astl1matics should not receive the drug. j. Hormonal scllona: Morphine

inhib~s release 01 gonadotropinreleasing hormone and COfticotropin·releasing hormone and decreases the concentration of luteinizing hormone. folliclestimulating hormone, adrenocortiCOlropic hormone, and Jl-. endorphin. TeSlosterone and cortisol levels decrease. Morphine increases prolactin and growth hormone release by diminishing dopaminergic inhibition. It increases antidiuretic hormone (ACH) and thus leads to urinary retention.

. _ ' . . . . 1.1 . . . . . _ _ ' .

'"

III. Slroog Agonists

3. Thclrapeollc uses: •. Analgell" Desplte illienstve research. lew other drugs have beet'! deYelcped that are as elfective In lhe treatment 01 pairl. Opicids Induce sleep. 8J"I
sedaM effed ill the p<8S8I'ICe cl penl b. Truunent 01 di....h••: Morphine dec,eases the ~ muscle aod inCffllIS8S tone.

1TlOl~1ty

of

c. Relief 01 cough: MoJptlirltJ liUJ)Jlfe$58$ lhe allJ!jl reflex; how_ . codeiIltJer Qener''''ofIlDrphan(see p. 222) are mcrewidetv used. COdelne has geater ~ llCbl tl8tI i1bphile. 4.~:

L AdmW.Il .lion: Ab&t:o plio I cl lib"""" from !he 9 I oil : # naI IIact is slow aod erretic. ..., the !tug is ~ not gM:!n oraIy. CoOOne. ~ contrast, is wei absorbed ...toen given ~ ITQIf'l. SiolliUd h pass metabcisrn d. merphil(! cex::urs in

the live,; lheretore. intra"" ISCl ~.r. subcutaneous, Of intrawncus if....... pnxU;:e hi most ref He iesptlI Opiales hIMI ~ CO"'Olly laken b Io"oecIcaI Pl"P" ~ WIiJlalion cl the 5lnllke from tuT'W1g aude cpUn, Mlif:tl prtMdes a rapid onset d. dr\.O;l.aicn.

tiss_.

b. Oiatribulion: Morph,1tJ rapidly enlBrs aI body inclt.dif1g lhe Ietvses of pI8gI'IIIrll women. ..., $hDlAd ncl be used b ...... ila dumg Iaber. . . . . . bern cl .. ltljo I!t":t moiles shew

physic:lW 08perode..oe on opi7'es aod elChibit wi! oawal ~ Ioms if • p";1S .. ncl admiI iSll!f8CI. Only • small peroentage cl i111(liptlirJe crosses hi ~ barner. sirlOll i1lOfphlltJ is lhe least Iipoplilic cllhe CO"'Ol This alfIIrasts wilh !he fTlOfe Ial·soil_ opioidlJ, such as lentanyl and heroin. ~ readit'I pe..ebllle illao the brain ..., rapicIy pnxU;:e an inloose "rush" cl 9\4)hOrill.

·,-ids

c. F.te: Morphine is melllbolized in the liver 10 glucuronides. Mo
&mil"

5. Adverl•• Hec:t" Severe respirlltory depression oocurs. OIher effects include \IOf'Ilitlng. dyspt1Ofia. and aIIergy·enhanced hypoIensMl etIects (F~e t4.4). The etevalion cl .,'rllCl'llflial pressure. particularly in helld Injury. CIIn be serious. Morphine enhances ooreb
Agure 14.4 J'.dverSB elfeets mmmonly ooserved in individuals treated wiltl cploids.

...........,.,.<---,.

<.-. - - - - ' ............ _

".

.... >

14. Opioid Analgesics and Antagonists respiraloly exchange ill efTllhysema or cor pulmonale paliertts. If employed in such ind;viduals. respiration must be caretully watc/led. Patients with adr6!1al insutticiency or myxedema may experieoce wclended and increased effects f'l)fO the opioids.

6. Tolemnce and physiCal dependence: Repeated use produces tol-erance to the respiratory depressant, analgesic, eup/loric. and sedative eflects ol morphine. HowlM!r, tolerance usually does nol develop to the pupil-ronstricling and constipating effects 01 the drug. Physical and psycholo{Pc dependence readily occur wilh morphine and with some 01 the other agenisfs to be described (see F;gure 14.3). Withdrawal produces a series of aulooomic, motor and psychological responses that incapacitate the individual and causes serious, almost unbearable symptoms. However. iI is very rare ttlat the effects are so proloond as 10 cause death. AbK>lute contr...

Indication to meperldfntf

and relative conl",-

Indication to 0Ih«

""rcolic _lge8.ica becauoe of high Incidence of hypetpyJeKk: co.....

_.

"'-

I"",eased eNS pal1lcular!y respl"'lory

",,,...-

7. Drug lnIera~: The depressant actioos 01 rnorpIIineare emanced by j:t1emft1iazines (see P. 127). ~ 0>:idaSe I'tlibbs (see p.123), and lricyclic antidepressants (see p. t 19 and FlgUre 14.5). low doses of amphetamine (see p. 103) strangely ema.nce analgesia. Hydroxyzine (see p. 422) also enhances analgesia.

B. Meperidine Meperidine [me PER i dean] is a synlhetic opioid wilh a st,ucture unrelated 10 morphine. It is used 1m acute pain.

""

1. Mechanism olltCllon: Meperidine binds to opioid receptors, par· ticularly I< receptors.

Narcotic analgesics

Inc:tf!lIsed lledation; varlablll eltecta on ....p1'a!Ory depression

Figure 14.5 Drugs i~teracting w~h narcotic analgesICS.

2. Aclions: Meperidine causes a depression at respi,atioo similar 10 that 01 morphine. but there is no signllicani cardiovascular action when the drug is given mally. On intravenous (IV) adminiSlration. meperidine produces a decrease in peripheral resistance and an increase in peripheral blood flow. and may cause an increase in cardiac rate. As with morphine. meperidine dilafes cerebral vessels. increases cerebrospinal Uuid pressure, and contracfs smooth muscle (the Iatler to a ~sser extent than does mQlPhine). In fhe gastrointestinal t'acl. meperidine impedes motility. and chronic use results in COflstipation. Meperidine does not cause pinpoint pupils. but rather causes the pupils to dilate because of an alfCJll~like activily. 3. Tllerapeollc uses: Meperidine provides analgesia for any type of severe pain. Unlike morphine, meperidine is no! dinically useful in the treatmenl 01 diarrhea or cough. Meperidine produces less of an increase ill urinary retention than does morphine. 4. Ph.annacoklnellcs: Unfik8 morphine. mepcndine is well absorbed from the gastroinfesfinallracl and is useful when lIf1 orally-administered. polent analgesic is needed. HOWlM!r, meperidine is most often administered in1ramuscularly. The dO\Jg has a duration of action 01 2 to 4 hours. which is shorter than that 01 morphine (see Figure t4.6). Meperidine is N-demethylated in the liver and is eJ
<- .....,.,

> ...... _ , >

< ....- .........

: "'V"'"

............ _ . "" >

til. St,ong Agonists

""

terent route of metabolism. meperidine is pl'ekmed fo, analgesia during labOr.1 5. Adverse effecte: large doses of meperidine cause t,emors, mus· cle !witches, and rarely. lXlI"MJlsions. The drug differs hom opioids in thaI in large doses ~ dilales the pupil and causes hyperactive refle:o:es. Severe hypotension can oocur when lhe drug is administered postoperatively. When used with major n6lJfOleptics, dep.es· sion is greally enhanced. Administration to patients taking monoamine OlCidase inhibitors (see p. t23) can pl'ovoke severe reactions such as convulsions and hyperlhermia. Meperidine can cause dependence, and can substitute for morphine or heroin in use by addicts. CrOSS-lolerance with the other opioids llCCUrs .

C. Melhadone

•

TIme Ie peak ellect a 20 min DI"'.1ion of acllon a • hCU.

........

Methadone [METH a don) is a synthetic, orafty effective opioid thaI is approximalely equal in potency 10 morphine. bul induces less etJphoria and has a longer duration ot action.

1. Mechanism ot 8cllon: MelfuJdct1e has its greatest action on Il receptors. 2. Actions: The analgesic activity of mothlldonc is eqUivalent 10 that ot morphine. MelfuJdone exhibits strong analgesic action wilen administered orally. in coo1rasllo morphine. which is ooly parlialty absorbed from the gastrointestinal tract The miotic and respiralory depl'essanl actions of methadone have average halt-lives of 24 hours. Like morphine, methadone increases biliary pl'essure, and is also conSlipatiog.

3. Therapeutic uses: Mertl8dono is used in the controlled withdrawal 01 addicts from heroin and morphine. Oralty Ildminislered, melJla· dOfle is substiluted tor the injecled opioid. The patient is then slowly weaned trom methadone. Methackme causes a milder withdrawal syndrome, which also develops mofe slowly than thaI seen during withdrawal lrom morphine 4. Pharmacokinetics: Readily absorbed following oral ilOOlinistration. methadooo has a longer duration of action than does morphine. II

accumUlates in tissues. where il remains bound to prolein from wh'd1 it is slcwiIy released. The drug is bioIransformed in !he liver and extreled in the urine, mainly as inactive metabol~es. 5. Adverse eHeets: Methadone can pl'oduce dependence like that of morphine. The withdrawal syndrome is much milder bul is mOle pl'olracted (days to weeks) than with opiales. o. Fentanyl Fenlanyl [FEN la nTl). which is d1emically related to meperidine. has 80 times the analgesic potency 01 morphine. aOO is used in anesthesia. It has a rapid onset and sharI duration of action (IS to 30 minutes). When combined with dropuril:1o/ (see p.ll7) ~ pl'oouc:es a neurolepl anesthesia. Sufenran~ [soc FEN ta nil), a related drug, is even more poter1t lhan fenfan}4.

Figure 14.6 Time 10 peak effect aOO duration of action 01 several opioi(ls administered intravenously.

<._

,.,.<---,.

<

'"

0

•

....,.... . . _

.....

14. Opioid Analg&sics and Antagooists E. Heroin Heroin [HAIR a inJ does nol occur naturally but is produced by acetylatiool 01 morphine. which leads to a three·1okl increase in its potency. Its greater lipid solubility allows ~ 10 cross the bIood-brain barrier mora rapidly than morphine. causing a more exaggerated euphofla when the drug is taken by injeclion. Heroin is converled to morphine in the body. but lasts about half as long. II has no accepted medical use in ll1e United Slafes.

IV. MODERATE AGONISTS A. Propoxyphene

Propoxyphene [proe POX i leen] is a derivative of fOOlhadone. The dextro isomer is used as an analgesic 10 ,el;eve mild to moderate pain. The lavo isomer is nol analgesic wt has antitussive action. Propoxyphene is a weaker analgesic than codeine, requiring approxlmately twice the dose 10 achiew an equianalgesic effoct as codeine. Propoxypheno is olten used in combination with aspirin (see p. 403) or acelaminophen (see p. 4t2) lor a greater ana~sia than ll1al obtained with e~her drug alone. It is wen absorbed orally. with peak plasma IeYels ocaJrring In 1 hour, and ~ is metabolized in the liver. Propoxyphcne can pmdoce nausea. anorexia, and oonst~ pation. In toxic doses. il can cause respiratory depression, convulsions, hallucinations and contusion. When toxic doses are taken. a wry seliol;s problem CID1 arise in some individuals. with resunant cardiotoxicity and pulmonary ed€rna. (Note: When used wilh aIoohoI and sedatives, a severe eNS depression is pro
B. Codeine Codeine [KOE deen] is a much less pOlent analgesic than morphine, but it has a higher oral efficacy. Codeine shows good antitussive activity at doses that do not cause analgesia. The drug has a lower abuse potenlial than morphine and rarely produces dependence. Codeine produces less euphoria than morphine. Codeine is often used in combination with aspirin or acela" minophen. [Note: In most nonprescription cough pleparations, codeine has been replaced by newer dflJgs. suct1 as dexlromelhcJrphEm (see p. 222). a synthetic cough depressanllhal has no anal· gesic action and a low polent;al lor abuse.] F'9ure 14.7 shows some at the actions of codeine.

v. Figure 14.7 Some actions of oodeine.

MIXED AGONIST-ANTAGONISTS

Drugs tllilt stimulate one rvceplor but block another are termed mixed agoniS!oi.nlagonists. The etfecls of these drugs depend on prE!lo'Qls exposure to opioids. In individualS who IliIIo(! not recently received opioids.

.""'.0...'.' ........ ..-,·

•

"""" w

. . , ....,."". . . _ .

w •

'"

VI. AnlagoniSIS

milled agcrisl~ sOON agonist actMty and are used to teieYe p;Wl. .., he piMienI oMlh ()fliOid depeo deo ICe. IhlI ag:nsI.anlagOnIsl may shoW pTnariIy blodIing et1eds, lhal is. produce wiIhchwal sympIomS. Most d the in m !1OOP cause ~SJll aia. ralhl!J hW"ol!\.9lO-

augs

augs

na. fIMItia!lld bv lldio.0Iion d

(I

JeCef*lIS.

(pen TAZ oh seenj acts as an agonisl 0I'l .. ,~s and is a ......,.. anlagOIlisI 1lI J.I and li 5. It also bFds 10 (I recepIOfl•• which rnay account lor its dysphoric prop."lies. FWfl(azocirle promotes analgeSlil by aetMlIng reoeplors in the spinII cord. and Is used 10 reIieYe modelille p8II'I." may be adl,.lisIenMll!llher ~or pareneraly. Awxaman8p!OdllCeS Il!ss eI,IJlhoria than does morphine_ In higher dosn, the drug causes respiratory Oepression and decfeases the activity d 1he gastroinlestinal lnlet. Higt closes increase blood pt"essur8 and can cause hallucinations, ni\t1lmares. lac:t¥::aldia. and diuiness. In angina. petlfazodne inaeases the mean ilOfbC pressure and pulmonary arterial pl'essur8 and IOOs increases the worl<. d !he heaft. The drug decreases renal flIasma flow. Despite its antagorisl action. pentazocine does rd antagonize the respiralory depression 01 morphine. bul ~ can pl'ecipilate a wilhdrawal syndrome in a morphine abuser. Penrazocine should no! be used wilh agoniSIS such as morphine. since lhe anlagooi1lt aclion of penUlZOCine may block the analgesic eneclS of morphine. Tolerance and dependence develop on repealed llW. ~

""""'*'"

B. BUpl'f!l'lOl'phine AlthougJ bcJfuenrxphine [byou preh NOR teen] is classified as a partial agonist acting at !he J.I rec:eplor. ~ behaVes like morpIWle in naiYe patients. HoweYet, it can also anlilgonize rnotphirt8. SupIef/OIPhine is admll1lslered pan!f'lle.-aly and ha$ a long duration 01 action because d its tighI bildillg to Ihe .ecepIOI.ll is tneIaboized by lhe IiYer and excreled in the bile and wine. Adver$e enects include respiratory depressioo. clecrease (or. ra.eIy. increase) in blood Pf8SSU1l, nBUS8iI and lizziness..

VI. ANTAGONISTS The opioid antagonists bind with hiltl affinity 10 opioid rempon; bul tail 10 iJClivale !he receptol'-mediated response. AdrnlMtration 01 opioir;t anlagonists p,oduces no profound enec1s in normal individuals. ~,in patients addicted to o".)I(Is, antagonIsIs rapdy rewrse 1he efleet 01 agorWsts, such as hen:lin, and precipi\ille !he S)Ii.ijAOmS 01 0piate wilhe.a""'. A. NalOJCone NaJoxorle [nat OX own] is used to reverse the coma and respiralory

depression 01 opioid ove'dose. 11 rapidly displaces all receptor·

•

Figure 14.8 Compelilion 04 nalOl«XI8 with opioid agonisls.

• •

..........,.".- ... .....,.....,. ''''

14. Opioid Analgesics and Antagooists

botJnd opi(lid molecules and therelofe is able to reverse the eflect 01 a heroin ~rdose (F'1jUre 14.8), Within 30 seoonds 01 intravenous injection 01 nalOxOne, the respiratOfy depression and coma characteristic 01 high doses of heroin ate reversed. causing the patient 10 be revived and alert. Naloxone has a halt·rote 01 60 to 100 minutes. Naloxone is a competitive antagonist al~. I< and S. receptors, with a 1Q-1old higher altinity for ~ receptors than for 1<. This may explain why naloxone readily rewrses respiratory depression with ooly minimal 'eversal ollll\illgesia that results lrom agooist stimulation of I< recept(l(S in the spinal con:1. Naloxone produces no pharmacologic effects in normal individuals. but ~ precip~ates withdr,.lW<11 symptoms in morphine or herokl abusers. B. Naltrexone

/IIa/frexona lnal TREX own] has aclions similar to those ol na/olWfle. This drug has a longer duration ol action than naloxone, aOO a single oral dose of naltrexone blocks the effecl ollnjec1ed heroin for up to 48 hours. Nalfrexone is used in opiate-depenclence maintenance programs and may also be beneficial in t,eating ct"onic alcoholism.

Study Questions Choose the ONE beSl answer.

_.

14.1 All 01 the IoIIowing !;ta1~ts

concemng methadorHl

are correct EXCEPT: A. II has less potent analgesic aClivity than thaI of

B. It hils a longer duration of action than lhat 01 mor· phine.

CcfNcI c!'dcII • D. Perlazol:hI (a mI>i:ed agorisI~ shoUd noll be used .... "llO' I su::h afI """Ihroe. t.c:e. ... It C8'l _ I!leir IlClIons.. (Penlazodnol _ as an "llO'*l en ~ ~ buI is IIIl1111lgOn1s181 ~ end ~ ,ecepbs.l

t4.3 Which ot the IoIIowing Stll_1S about ororp/1ine is INCORRECT?

C. It is effective by oral ..m..,istralion.

A. It Is used therapeuticaly 10 Sf'I\Ier'e IIe8d injury,

D. It causes a mildef withdrawal syndrOme thlln mor.

B. Its withdrawal

phine. E. It has

~s

g,ealest ac:lion on ~ rflCflP10rs

--

14.2 WIIich of the follooMng Slatemen1S about pentaloc;ne

is INCORRECT? A. It is • mixed agonis<·antagooisl.

B. II may be administered maa;. or pareoterally. C. 11 produces less euphoria than lOO<'phine. O. II is 01100 a;lfnl,>
..

pan caU!iOO by

s~mploms can ~e

relieved

~y

methadone,

Comld: dIOice • A. ~ sh<Ms . . _ ge.1e aell"" similar to lhal 01 morphin •. -.cloooe is ~'Ollor 15 10 20 ..... _ _ " ...plllllll_ tor 4106 hr. Amajol ~ OILVlg ""oabw in the <:oobtIIed williin and .,oophOoe IlhJsGra ill thai ~.,., be

E. HIgh OOS
~e

or

perltalo<:ine increase blood pres.

C. II CIIlJSeS constipation. D, Kis most effective by PtI.ent&ral administration. E. It 'apidI\I ent6f$ all bOOi \issues. Including lhe lelUS ot a pregnant WOfTIfIn.

CormeI choiOIt • A. MorpI\iroe _ _ li iCl Mad ~"'llbK~li.... Iuid _ - . . odary 10 ...... 01 <:erebrlII vucul8ture. ~ .. can feIIllve ...ottOe 411 ay"4*>o"5 0!*JldIl sl-..cnl8S seoillllolly. lila ,"*,111 : "" 81 . . . . . . . . . . abs<:wjMol, Iftm!he gASIl'* I nllll1facl1s IftllI.

-

._.0...'.' ........_,· Drugs Used to Treat Epilepsy I. OVERVIEW OF EPILEPSY Epilepsy i$ wideSPieacl among hl general pop ...ion ......, 0Wf two mIIU'l artected indMduals in the United Slates. Epiepsy 1$ nol a single entily; • is a IamiIy d
The neuronal disd\alge in epilepsy re5IJls kom IN! Iimg of a smaI pq:U;il1ion of neuons in some specilic area 01 !he brain. relerred 10 _!he primary Joc:us. AnaIOrl'ically, ItWi local area may &IlI)eaI" perIec:IIy normal. There is usuaIy no IdentifiabII cause lor epilepsy. lIIIhol.9lltW1 tccaI .eas Ihat are tu ICtioll8ltf IIbflOl'ITlal may be biggered inIo aaMIy by changes in any d a variety 01 enWonmenlaI tiIdors.. inI::l.ding _1aIion in tbld g;sses.. pH. B'B hQlyles. Of gt>cose lJ\ '1 1..1'

1. Primary epllep1l,: When no specilic llnalomic cause !of the ~ . sudl as traumi!I Of .e,' m.1s eoicletl fle SJlidlu,els c:aIed il;iopahc or prWnafy epilepsy. These se0.ves may be procb:led by an Wh!riIed abnormalily in . . OBf'Ilral neroous sys&em (CNS). Patients are treated ctloulicaly with ar,tiepileptic ~. oIten lor life. 2.

ANTIEPILEPTIC

DRUGS

-0;.

;

[It

l'

C t,

-"

••

.,

....,

.... I' •

,.. r., r......", VlJj , Ui f

Secondarr e,)ileps,: A

numbet cI reYf!f5iblll disturbances, sud1 head injury. hypoglycemia, menlngeal inledioo. 01 rapid withdrawal of alcohol lrom an alcoholic, can precipitate seizures. Antiepilepric drugs are given unt~ !he primary cause 01 the seizures can be corrected. Seizures secondary to stroke or trauma may cause irreuersible eNS oomage.

as

tUmofli.

F"lgure 15.1 Summary 01 agents used in Ihe treatment 01 epilepsy. 'Descr'bed in F't\armaoc>low update. p. 445

. __.. _ _c._ --_ __~

'-_0_'

A.,......

••

143

,.,.< •• _-,.

<

<'-OM....-............' ............ _

'"

.....

15. Drugs Used to Treal Epilepsy

B. Classification 01 epilepsy

EPILEPSY

I-

1. Partial: The symploms of each seizure 1ypIl depend on the sile of neuronal discharge and on the extenllo whid1 the eloctrical activ·

PARTIAL

~y spreads 10 other neuroos In the brain. Partial seizures may progress. becoming generalized lOf1i<x1onic seizures.

(Focal)

8. Simple partial: These seizures are caused by a group 01 hypemetive neurons e~hibiting abnormal eteclrical actMty and are conlined to a single 00Js in the brain; the electrical disorder does nor spread. The patient does nor lose consdousness

-" 'm"

~

GENERAUZED Tonle-clonk: (grand ~ A-":.(~~

Myoclonic

Febrile ........... In

Seizures have been c1assilied into (wo broad groups, parlial (or local). and geoerallzed. ChoioB 01 drug treatment is based on the classification of the epilepsy being treated (Figure 15.2).

cl>ik!~

Slatua epUe\lllcuo

Figure 15.2Classification of epilepsy.

and olten elfhjbi!s abnormal activity of a single limb or muscle group lhat is controlled by the legion of the brain experiencing the disturbance. The patient may also show sensory distOftions. Simple partiat seizures may OC(:\Jf at any age. b. Complex pIIrtial' These seilures eKl1ibil complex sensory hallucinatioos. menial distortion. and loss 01 consciousness. Molof dysfuncOOn may involve cheWing movements. diarrhea. urinatioo. Most (80%) of fndividuals with compla partial epilepsy eJfl)erience \heir iriIial seizures before 20 years 01 age.

2. Genem!1zed: These seizures begin 1ocaIty. but they mpicty S()'ead, IlfO(U:ing abnonnaI t!l€dJil;aI cisdlarge tl'fou!tlO'.ll both hemispheres 01 the brain. GeoeraIi2ed seiz\.Jres lTI3Y be CCJrM.JIsiW or noocorwsi'I'll: the patient usually t
< .........,., . . . . . . . _ , .

It. Antiepileptic Drugs

'"

e. Status eplleptieus: Sel2:ures are I3pidty rE!ClJrrent.

c. Mechanism 01 action 01 antlepllepllc drugs Drugs that are elfective in sel2:ure reduction C
II. ANTIEPILEPTIC DRUGS Inmal drug treatment 10 suppress or reduce the incidence of seizures is based on the specifiC type 01 sel2:ure (SE1fl Fogure 15.3). Thus. tonicclonic (grand mal) seizures are treated ditferently than absence seizures (petit mal). Several drugs may be equally elfective, and the tOllicity 01 the agent is often a major conskleratioo in drug setedion. Monotherapy Is Instituted with a single agent until seiwres are controlled or toxic signs occur. When therapy with a single drug Is ineffective, e second drug may be added to the therapeutic regimen. Anliepileptic 1l1erapy tor tDr1ic-clonlc seizures should never be terminated abruptly. otherwise seizures may resull.

Types of Epilepsy

Anticonvulsant Agents

PARTIAL (Focal)

Key:

IlIlIilIilI - -

I

Doug .......

I "'-a...

I ... , .. GENERAUZEO

= -.-

I.....,-I~I~)

~I

-

"'j",*".. ,

Hi'M Figure 15.3 TherapetJtic indications for anliconvulsaflt agents.

..........,., .. _--,.

• <...

"6

M _

...._

...,

""""'"' . . _

....

>

15. (}fogs Used to Tre
Phenytoin {FEN i toy in] (Iormerly called diphenylhyrJantoin) is elleeTiveln suppressing tonic-dorOc and partial seiWres. and is a drug ot choioe lot initial therapy. parliclJlarly in t,eating adults.

1. Meehanism of action: Phenytoin stabilizes neuronal membranes to depolarization l1y deaeasing the flux of sodium ions in neurons in the resting slate or during depolarization. It also reduces The influx of calcium ions during depolarizatiof1 and suppresses repeti~ve firing 01 neurons.

2. Actions: Phenytoin is root a generalized CNS depfessant like The barb~urates, but il does produce some degree 01 drowsiness and lethargy without progression to hypnosis. Phenytoin reduces the propagation of abnormal impulses in the brain.

3. Therapeullc uses: Phenytoin is highly elfecTive lor all partial seizures (simple and complex), lor lonic-clonlc seizures, and In the treatment 01 status epilepticus caused by recurrent tonicclonic seizures (Figure 15.3). Phenytoin is not ellecHve lor absence seizures, whidl often may worsen il such a patient is treated with this drug.

4. AbsO
_

'-'Ie

~o,y\Ou""

'y_II"CfNIeI beC
....-

~ ""'. . . IlIrll" ~

0

t

•

_

....... "'
i,• ~'! " '" ~

"

I

are high. Chronic administration 01 phenyloin is always oral; in status epllepticus, it should be given intravenously. The drug is largely bound to plasma albumm. Less than 5% 01 a given dose is excreted unchanged in the urine. Ptrenyroin is metabolized by the hepatic hydroxylation system (see p. 14). At I(lW doses the drug has a hall-life of 24 hOl.JrS, but as the dosage increases, the hydrol(ylation system becomes saturated. Thus, relatively small increases In each dose can produce large increases in the plasma concentration, reSUlting In drug-induced toxicity (Figure 15.4). Furthermore, large genetic variations in the rate 01 the drug's metabolism occur.

••• • •

- -

Figure 15.4 NOnlinear ettea of phenytoin dosage on plasma contef1tration of drug.

5. Adverse e1lec1s: Depression of the CNS occurs particularly;" the cerebellum and veslibutar system, causing nystagmus and ataxia. Gastrointestinal problems (nausea, vomiting) are common. Gingival hyperplasia may cause the gums [0 grow over teelh, particularly in children. This hyperplasia sloWty 'egresses aller rermination of drug therapy. Coarsening of facialleatures occurs in dlildren. Megaloblastic anemia occurs because the drug interleres w~h vitamin 6 2 metabolism. Behavioral changes, such as ' conIusioo, hallucination, and drowsiness are commoo. Inhibition of antidiuretic hormone release occurs as well as hyperglycemia and glycosuria caused l1y inhib~ion of insulin secretion. Phenytoin is also an antiarrhythmic drug. Treatment with phBnytoin should not be stopped abruptly.

6, Teratogenic e1focts: Phenyloin causes teratogenic effects in 011spring 01 mothe<s gven rhe drug during pregnancy. "Fetal hydantoin syndrome" includes cleft lip. cleft palate, congenital heart

< .....

'0. MI., ......... ...."...,. , •

'" disease, as well as sloWed growth and mental deticiencv. A1mosl hall 01 untrealed epileptic women hllVll an increased :;ei;rure Irequency cluri"'il pregnancy. These seizures can lead to anoxic episodes, which yield a higher incidence 01 congenital birth deIe<:ts. Antiepileplic drugs are given at the lowest possible dose to control seinJ<es.

7. Drug IntenN:tlon':

a. Inhibltlol'l of phenvtOkl metabollun: Inhibition 01 mioosomaI meIabolisol' 01 pt!enyll:WIln the IiYer is caused by cNoralp..... 001, dia.maroI. C1rnefidire, suIonan'ides. and isoniazid. When used dlronically. these ~ Increase the ooncenlra6on 01 ~ In pIa$n'I8 by preo.lli "" og b metaIxJIism A deCIease In the plasma concentralion 01 phfHJyfoin is caused by calVa11II1l8pir1e, VUI.." 01 other drug, by ~...: ~ a:li'Ilnduces 1he P-450 5ySIem (see Po 14) ~ leads 10 an roB¥e In the metabolism 01 other.1liepiIepbcs. ._01""9" IarU. ooal ~fiI(~1MIs, ~..",idi...,~, CYC"t5P-ile.

me··w"' .... ~ an:l1tft~9o'

B. Carb8mazep1ne

--

........ , r

-O·

,cflli*''''''

d ......

Q ,--

~.,.

1. Ac:tionI: ~~ba MAl apeerll rewees the PfOPit' gation 01 abnofmal ~ s in the braln by bloclung sodiI.ml dWV'o8ls. the<eby •• oitIilii'll the generation of repe~ action po«lo c' ... Ifl!he epilepfIC 100.& 2. Thenopeutic u_: ~ is ~ ~ tor .. PiIrtiaI seizures (simple and cornpIexl and I' ollen the drug 01 first choice. In addilioil the lin,lg is highly eNectiYB for IOf'Iic..c:Il:r seizwes and os used 10 tTeallrigerrWlal neualgia II has ocmsion-ally been used In ~ pallents 10 ameliorate the syniJllOl'l!I.. C = m _ " ,. . .

3. AMorptIon lind melabclttsm: ~ is absMled slowly

following ooal aanlnistralion. II enters lhe boain rap;dIy because of b t"ifJllipid $OU:liIily. ~ Inl1loes the dn.lg meraoo. IiZing enzymes In the 1iYer, and its hall.Jife lhefetore decreases with choOllie adminIstllllion. The enhanced hepatic P--450 syslem

aetMty also Increases the metabolism 01 other ill oIiepileplic drug$.

S. Drug Intel'llCllons: The hepatic metabolism o! calbamazepine is inhibited by sO\leral drugs (Figura 15.6). Toxic symploms may arise ij lhe dose is not adjusled.

o

--..... -

'.'''01 .,.,11"" ... Clo, _ _ ".,

4. Advena alleet.: Chfonic; administration 01 cartJamazepine can cause Slupor, coma, and respiratory clepression. along with dfllW5ine$$. _tigo. a1ilJria. and bluffed vision. The dfug is irrilat· iog to the Slomac:h. and nausea and vom~ing may oocu". APastic anemia. agranulocylosis, and thrombocylopenia ha\I8 ocwn1ld in some patients. ThIs drug has the polenlial lor inducing serious livef lOi:icity. Therelore. af¥lOB being lre.Bled with cart:larnaZepjoo should haVll Ireql.lBflt liver IUf'lCtion tests.

-t- ............

$

£.)l'1oOo'''''''

Figure 15.6 Drugs affecting the melabolism of CBrl)amBZep;n6.

<00<'''-''''<---''

< -

'"

• - - - _ . , _. ., ............ _

..... >

15. Drugs Used to Treat Epilepsy C. Phenobarbital 1. Actions: PfJenobarlJjlal (see p. 94) has aIltiepilepti<: activity, ~m~­ illg the spread 01 sei.rure disdlarges in the brain and elevating the seizure threshold. Its mechanism 01 a<:tion is unknown but may invotve potel1tiatiOll 01 the InhibitOlY effects 01 y-aminobutyrie acid (GABA)-mediated neurons. Doses required lor antiepilepti<: action ara lower than those that cause pronounced CNS depression.

2. Therapeutic uses: Phenobarbital prOlildes a 50% lavorable rasporlSll rate for simple parlial seizures. but it is not very elfective lor complex partial SllWJras. The drug has been regarded as the first choice in trealing recurrent seizures in children, including febrile seizures. However, phenobarbilal can depress cognitive perlormance in children treated lor febrile seizures. and the drug should be used cautiously. Phenobarbital is alSQ used to treal rOOJrreot tonic-donic seizures. especially in patients who do not respond to diazepam ~us phenytoin. Phenobarbital is also used as a mild sedatMito relieve aIl~iety, nervous tension and insomnia, al!h<:lug1 benzodiaZepines (see p. 89) are superior.

3. Absorption and metabolism: Phenobarbital is well absorbed oralty. The drug treaty penetrates the brain. ApprOlCimately 75% of the drug Is Inactivated by the hepatic microsomal system: the remaining drug is e~creted unchanged by the kidney. Phenobatbitalis a potent inducer 01 the P-450 system. and when gM!ll chronicalfy, it enhances the metabolism of other agents. 4. Adverse effects: Sedation, ataxia, nySIa!1J1uS. vertigo, and acute psychotic reactions may occur with Chronic use. Nausea and vomiting are seen as well as a mortlillitorm rash in sensitive indIviduals. Agitation and OOI1tusion occur at high doses. Rebound seizures can occur on discontinuance 01 pIIenobafbital.

D. Primldone Primidorle [PAl mi done] is structuralty related to pheflobartJiUlI. and reserrtlles p/Jf!OObarbilal in its antioorNulsant activity. Primidorle is all a~emal8 ctloica in partial seizures and tonic-donic seizures. Much c:A prirnidonfts efficacy comes tram its melabohtes phenobalbit8l and phenylelt1ylmak>namide (see Figure 15.7). which have Iooger haHlives than the pa'ent drug. Phenobarbital is effective against tonic-

............ Figure 15.7 Me1abolism 01 primidone.

clor1ic and simple paltial seizures. and phenylelhylmalonamide is effectMi against comple~ partial seizures. Primidone is Often used with carbamazepine and phenytJin, allowing smaller doses 01 ltlese agents to be used. It is inetlective in absence seizures (Fil;J.l18 t5.3). Primdone is we~ absorbed orally. ~ eidlibits poD< protein bindng. ltOs drug has the same adverse elfects as those seen with phenobarlJital.

E. Valprole acid Va/pm(; acid [val PROE icl reduces the pfOpagation of abnormal electrical discharge In the brain. 11 may enhance GABA acHon at inhibitory synapses. Vatpro;c add is the mosT effective agent avail-

<_'0< MI., >< . . . . . _ , >

II. Antiepileplic Drugs

10'

able lor treatment 01 myoclonic seizures. The drug diminishes absence seiZures but is a seoond c:t1olce because 01 ~s hepatotoxic potl!f1tial. Vollpror"c acid also redu<:es the incicleoce and sewrity at torno-clonic seiZllres (see Figure 15.3). The drug is effective orally and is rapidly absortled. About 90% is bound to plasma proteins. Only 3% Is e~creted unchanged; the rest is converted to active metabolites by the tivef. valproic acid is metaboliZed by the P-4SO system, OOt it does not induce P-4SO enzyme synthesis. The glucuronylated metabolftes are e~creted in the urine. va/pro;e acid can cause nausea and lIOI'Tliting: seda»on. ata~ia. and tremor are c0mmon (Figure \5.B). Hepatic toxicity may cause a rise in hepatic enzymes In plasma. which shook! be monitored frequently. In some individuals. II rllsh and IIlopecill may occur. Bleeding times may increase because ot both thrombocytopenia and an inhibition ot platelet agg.egalion. Valp.oic acid inhibits pl!enobarlJUa/ metabolism, thereby increasing circtJlaling leVels of that barbituf3te.

F.

ethosu~lmlde ffi.\lORS

Ethosuximide [eth oil SUX imide] reduces poQPa9
G. Benzodlazeplnes Several ot the benzodiazepines show antiepileptic activity. CIOnazepam and clorazepara are used for chronic treatment. whereas diazepam is the drug of choice in the acute trealment of status epilepticus (see p. gIl. Clonazepam suppresses seizure spread from the epileptogenic flX:us, and is effective in IIbsence and myoclonic seizures (see Figure 15.3), but tolerance develops. Ctorazepate is effective in partial seizures when used in conjunction with other drugs. 01 all the antiepilePlics. the benzodiazepines are the satest and most flee lrom severe side effecls. All benzodiazepines have sedative properties; thus. drowsiness. somnolence. and latigue can occur wi1h ~ dosage as well as ataKia. dizziness and behavior changes. Respiratory depression and cardiac depoesslon may occur when given Imra\l8flOUsly in acute situations. H. Gabapenlln and lamotrigine For the lirst lime In many years, new classes at arltiepileplic drugs are becoming available. Gabapenlin [gah bah PEN tin! is an analogue of GABA. but its mechanism is nor known. LBmotriginlJ [Ia MO tri geen] inhibits glutamate and aspartate release, blocks sodium channels. and prevents repetitive firing. Both drugs are appl"Olled tor the treatment 01 simple or oomplex partial seizures and generaliZed

Figure 15.8 Some adverse effects of va/proia acid

."'" .....l.r ><,, _ _ ,

>

150

15. o.ugs Use
tOflic.donic seizures. Gabaper1tin does nOl bind 10 plasma proteins and is exaeted unchanged through the kid-1eys. minimizing the likelihood of drug inleraClions. Lamorrigine is metabolized in lhe liver. Its t,f.! is decreased by enzyme-inducing drugs (car/:J8mazep;fl8. p/16flylOin) and is wease
Study Questions

15.3 AI the IoIowing drugs a,.. usel... in lreatinQ oompIex

Choose the ONE best answer.

1"'"..1seizlX"" EXCEPT:

1s. 1 Fo< whidl one olll>e Iollowing 00Jgs is I!lfIlhefapeutic in8lbit11l: C. DiazePam:

D. PllenylOin: E. Gafb""",zepoo: CorNd

A. ElhoSUlCimide

B. Phooobarbilel C. Gafbarnaz&pine

Absence seizures F~ seizu'eIi In chilOfen

Dr Phenytoin E. Gllbapentifl

SlaluS epileplicus

Absence SEliZurllS Tonio·<:Ionic seizures

'*"*'" • D. PhenyloIn Is -w. In

~ IO"ic-doo.., and puIUl ...-a-. InlIrl .... b_'•• or~~'III~ ~ <ecuID'1II1OtIio-<:IDrk ...--. " Is .... -'lac_10< IIllw"o:e seIZInS.

15.2 Which or lhe following SIlIlemer>ts COfIC(Iming pheny. loin is INCORRECT? A. Causes less sedation lhan pheoobart>tal.

B. GaJses gin{jvaj hyperplasia. C. May ~ retal hydantoin syndfOme

_.

ng p<egnancy.

n given dJr·

D. Is excre1ed und\angee urine. E. The plasma halt·life increase5 115 the close Is

Correct choice • D. ~ Ih8n !l"Ilo or ~ is . . .. . , .. d.ogad ~ 11'11 MIs ~ llzed by the hepetic hydroxylation ayiJletn. &idI./nItio
.n.r.

r

(

~_.A.~Is...-lin"" ) ~.

"' ....oce ealzI.-es..

15.4 Which 01 the following drugItolCici1y plIirs is INCOI'I· RECT? A. Valproic aci
NlIuseo. and \IOnIi1ing

B.E1ho5~:

S~_

C. Cart>emlllepir>e: D. Prinidone: E. Phenobarbil8l:

Bone marrow S'-Wfi5ion

ConecI_.

O.

HepalOlt»
5ed8tion PI~loIdoo.

_

.... ca.-

._.0...'.' ......._,.

Treatment of Congestive Heart Failure

DRUGS USED TO mEAT CONGESTIVE HEART FAILURE -

VASODILATORS

-.,

I. OVERVIEW OF CONGESTIVE HEART FAILURE

&w"'pril

~I

}

,leE Inh~

""-

Congestive heart failure (CHF) is a oondition in which the heart is unable to pUmp sofflcient blood to meet the needs 01 the body. CHF cal'I be caused by an irT'1Jai'e<J ability 01 the cardillC ITllsde to coolracl Of by an increased worldoad irrposed on the heart. CHF is ~ied by abnormal inc.eases in blood volume and interstitial fluid; the heart. veins, and capillaries afe therelore generally dilated with blood. Heooe the term ·congestive" heart failure. since the SY'T'9toms include pUl· monary congestion with left heart lailure, and peripheral edema wilh right heart failule. Undertying causes ot CHF include arteriosderollc heart disease. hypertensive hear' disease. valvular heart disease• dilated cardiomyopathy, and congenital heart disease. Lett systolic dys. function secondary to CQfooary altory diseaS6 is the most common cause 01 hearl 'ailure_ The number of newly diagnosed patients with CHF is increasing because more individuals now sorvi~ aClJte myocar· dial infarction.

-"',

.,-_. _. -~~

-,

So<JIIJfII nHtoptvalde

-

DIURETICS

I

HydrocNor<>l_kM

''''''''''''' AGENTS

The therapeutic goal tor CHF is to increase cardiac output. Three classes ol dfugs haVe been shoNn to be clinically eltoctive in reducing s}o'Tlllloms

DlglrOMln }

and prolonging life: 1) vasodilators that reduce the load on the myocardium: 2) diuretic agents that decrease ex!,acellular lluid volume: and 3) inotropic agents that increase the slrength of cootraclion of cardiac rruscle (F'll1Xe 16.1). [NOIe: lhese agents relieve the ~oms 01 cardiac insulficieocy but do roOl rIl\o'eISE! the underlying pathologic condition.) Knowledge of the physiology of cardiac muscle contraction Is clearly essenIlaI 10 an understanding of the COITpeflSaI«y responses eo.dIed by the failing heart. as wei as the actions 01 drugs used to Ireal CHF.

~"'"-

-~

A""j",,,,,,

ll--,l~

..-

~

/.Iliff""""

Figure 16.1 Summary 0' drugs used to treat coogesliw heart 'ailure.

,-"",", _ _-f'

..... _ _

........ _ _ ...

c.........

~

' _ _' _ f '

:

",PA;>""""

151

<''''''0'''''''<_'''_'' 16. Treatmen1

PHASE 0: FAST upsmOKE

• TN InMiaI rapid .".... cl

II_to:

~lDn

ljlnlcll....lon 01 N I + - - ..

..

2) 1 ( · _ 1 '1\lldlY _ ...... do.. c:auolng' IrInoIont

""n"", 11; bIo<:_ bjI ...... ontl\'lhmk: - , " , ouc:h . . qulnldi"".

• Sod......

COnges1iVe Heart Failure

PHASE 1: PARTIAL REPOLARlZATION

• NoI· chontlellOl*l ("'''I~NnneIlI') .....Iing In 1,. .1 _ c L

• lh>sfraoe """" .. NoI· cNIn ......yl<>lctl_.

(II

-

~Qlr"''1L

~

.... ....

No·

,. ,,.

.

....

.

~

;-

••

PHASE 2: PLATEAU

1

0

I

•

0 3

.~

O. T1mol_l

" .."obo8l"

on_

• eo++-ch_ ~"'"". • 1(.

-d>Irl.-....--.gto """"' fft.UIIl<'Ig In

"",-_r"",,-ion. • Thlt .... ",..,,, oIlhe ......... 10 11'111 pOInl If. not lIIIn cl No· ...... 1011 of 1("". TIlII fm!llllr'l<:
PHASE 4: FORWARD CURRENT

,. ,.

.

• Ine.rHII"" ~1On ......... !rom ....... _ ... In_m

~-

arla:::= ~~~

F1gure 16.2 Action po1€fl~al

(II

a Puridnje HOOr

r>nt_

• The lpontoneouo depoII_ boInv-lhe - 10 II.. 1 <Jf.t>o

._.0...'.' ........_,. II. Physiology 01 Muscle Contraction

II. PHYSIOLOGY OF MUSCLE CONTRACTION The myocafdium. like smooth and skeletal muscle, .esponcls to stimula00n by depolarization 01 !he membrane: tl1is is followed by shortening ot the contraclile proteins and ends w~h relaxation and return to the rest· ing state (Figure 16.2). However, unlike skeletal muscle. which shows graded contractions depending on the number 01 muscle cells stimu· laled, the ca.diac muscle cells are interconnected in groups that respond to stimuli as a unil, contracting logether whenevef a singe cell is stimulated. A. Action potenlial Cafdiac muscle tells 8l'e electrically excitable. Howe\Ief, unlike the cells 01 other muscles and nerves, Ihe cells of cardiac muscle show a spontaneous, intrinsic rhythm generated by spe<:ialized "patemaker" cells located in the sinoatrial (SA), and Iltrioventric\J\ar (AY) nodes. The t8l'dia<: telis also have an unusually long Ildloo potential, which can be divided into five phases (0 to 4). FlgI.lre 16.2 illustrates !he rnajof ions contributing to depolarization and polarization 01 cafdiac cells, These ions pass through dlannels in the sarcolemmal membrane and thUs treate a current. The mannels open and dose at difle.ent times during !he action polentiat; some mspond plim.'lrity 10 manges in ion COflCef1tration, whereas others afe either adenosine triptlosphate (ATP)- Of voItage-sensitive. B, Cardiae contraction The contractile machinery of the myocafdial cell Is essentially the

same as in striated musc:le. The Io«:e 01 contraction of the cardiac muscle is directly related to the toocentration 01 f.ee (unbound) cytosolic calcium. Therefore agents that incl'ease these cakium leV· els (or inaease the sensitillity of the contractile maminefy to calcium) result in an increase in the tOfte 01 to!1t.aclion (Inotropic effecl). [NoIe: The inotropic agents lnaease the contractility 04 the hearl by diroclly or indirectly altBfing !he mechanisms thal control the ooncentraOOn at intracellular calcium.]

1. Sources oflroo Int.8oellul8r calcIum: calcium comes from two sou.ces. The !irst is trom outside the c:::eIl, wtlefe q:lBf11ng of voItage-sensitive caIdum mannels causes an immediate rise in tree cytosolic calcium. The second source Is the release 01 calcium trom !he sarcoptasrric retitlJlum and mifochondria, whictllurthef in(:roases the cytosolic level of cak:iIim (Figure 16.3).

2. RefflOl/at 011'00 cytOSQllc c81c1um: If tree cytosollc calcium levels were to remain high, the tardia<:: muscle would be in a (:(lOStanl state of contraction, ra!hef than showing a penodic contraction. Methanisms 01 removal InclUde two alternatives.

a. SodiurrH:lIlClum exchange: caJcium is removed by a sodiumtalcium exchange reaction that reversibly acha.nges calcium Ions for sodium ions across Itle cell membrane (Figure t6.3).

'"

..... ,....,.... - ... _'> 16. Treatment of C(I'lQf!SIive Hea,t Failure

~a~~::~_~=;~_-:.....-: U"'~.C8'"+""+ __", Na+/CaExchange

Vottage-sensitive sklw Ca- channel

I

Na+n( ATPase

.

~----

o

_.._..

-

_ c a " :0''::'.

.......

po

•

I

F1gure 16.3

"" ~m,leI"""'dtmg !he OOf1lraclion 01 cardiac 1rI.I8de. This Inlefadion beffieeu I"oe

~l

of calcium and SOdium

ions Is signiIicant. since changes In IntracelhJlar sodium can at1ect cellula! ~ of calciom. b. Uptake of calcium by the l18n:oplasmlc retiCUlum arid mltoctlondrl.: Calcium is also recaptured by the sarcoplasmic re'bJIl.lm and !he mitoctlondria. More than 99% of the lntracet· Iular cak:ilIrn Is Iocaled In these organelles. and even a fTllXle$\ shift bet\' eIll. flese slores and lree calcil.m can lead 10 large chlrol;Jes in 1hll concentfaliOft of free c:ytosolic calcium.

c. COfllflensatory pnysiologic:al re$pOn.-ln CHF The ~ ' - t tM:lkes hee major CCi,.,eo ?!cry rrec:hanisml1O enhance C8ldac ~ (F9Jf8 16.4). I.

kG_." .ympathetic.ctIYlty: BarortlOllplCf$ sense a dec> :.S8 in bloacI po SIn. and !rigger acMIiOft of ~adrllllelgic 'eceplOrS in the heart. This f1!SUItS In an i 1tI Me in hear, ralB and a grealer Ion::e of conIr1lCtion of the heatt musde (F"9're 16.4). In addiIion. vasocotlst,ietion (a,·mediated) enhances venous return and inc,eases cardiac preload. These compensatory responses Increase !he wOO<. oIlhe heart and. therefore. can contribule to !he turther decline In cardiac f...-.ction.

..... ,....,., ....

_-,.

III. Vasodilators

155

Z. fluid retention: A tal in cardiac 0lJlpJI decreases blood tow 10 lhe kidney, prompting lhe release of renin, with • resulting D:rease in .... synf1esis 01 ~ II 'e olle (see p. 181). This results in increased peiiphelal.: s'S'lWlCe anclr~ tion of SOdium and wat8l'. Blood YQIume increases. and more blood is returned to the heart. II .... heart is lnlblG to ~ Ihls extra \dune, \I8I'lOU$ pressure Wloilases and lJi!lipheral edema and pumonary edema occur (FlllUre 16,4). These eompensatory responses increase the WCIfI< 01 fie heart and. therelore, can c0ntribute to the Il,lrther decline in carlfjac function,

and".

3. Myocardial hvperlrophv: The heel,t Increases In size. and the c:hambers dilale. tnilialy, strilll:tWlg of the heart nISde leads 10 a slronger alf'IlfaCtion of the hearI. HoNilYer. ,"",",rive elongation of the tillers l-.rlls In weaker COtItI3dions. This type 01 failure is termed SVSloIic: taik.nl and is a result of a ver'lfide""" to plnll ellt:dody. Less (U.il1lC1!tV. paIients wit\ a-F may haYe oj • d)'SUe:tiOll • Ierm appied the venlrides' IIbiif)' 10 'eAi!x ltd aocept blood is ~ by A'UcbIlI d1anges. su:tlM trophy. The lhid<ening 01 the venlricuW wall and SUbsequenf del;fease in YeI1Iric:rJIar \dune ooerea5ilS hi ability 01 hear1 rl'lISde 10 relaX. In Ihls case. the venlride does na: iii ~ and the nadeQual:y 01 cardac output is termed diasIolic hearllailult.

..non

twer-

O. Decompensaled hellrllailure It the mechanisms ~sl(ld aboYe aclequatel)l reslore caldiac output, then the heart tailure is said to be (U'ipililS3ted. HoweYer,lhoseoompensalicns inl:fea$e the work 01 hi heafI and c:onlfbJle 10 lur1lef dedi ... in can;liac perIormanoe, It the adaptive mectIanlsms IaiI to maRain caodiac ~ the he0Jl1aiUlt iii \lefnoed detxA ...... 561: j

Eo Thel'apeYtic: stnlteg;es, in CHF Chronic heaI1 IailI.n is fVpically managed by redr!dion in ptl'fSical acMy, low cieIary ~ 01 scdlm (Ies.s flan 1500 mg scdlm per day), and lrretmenl 'o'rilh vasodilato's. dUelic$ and ilOlropic agenlS. Ofugs thaI may precipitale Of exacertlale CHF-lonsleroicial antiInflammatory drugs (NSAIDs), akXlhoI, B-blod<ers. c:alcUn c:hilnneIblod<ers and some antia,rhythmlc drugs-should be avoided if possble. Patients wiltl CHF ~ oj dyspnea on exertion. orlhopnea.. p
III. VASODILATORS In CHF, hi i'$I<'lied iXAlIidie tn:tion of fie hear! is exaoarba1B:l by COil"'" '" i ... asilS in bolh preload ancl aherloid. Prdoed i5 fie Idt.me 01 blood lhat ills the ventride cbing 'fasrAe, EIeYated prelood .... ooa16rg 01 the heM. ¥Itidl iO'?'S$il51le wor!doed. Af1ertoad is .. presslft"" rl'I.lsl be ave......,oe lor fie heart 10 Pl.n'fl blood inIO the aneriaI system. EIeVaIed after1O;Kl .,.''Ses the hila" 10 work harOOr to ~ blood Into !he W1eriaI system. VasodilaJors ere usetuI In reduti'1g excessive preload and allerlollcl, DiIalion 01 venous blood ,.....sels leads to a decrease in cardiac preload bv increasing venous capadIanoe; arterial dilators reOOoe systemic arteriolar resistaoce and decrease altonoae\,

(r_l,--~,

- -....--'"""'

"

I I Edema

Agur1l16.4 CardioYllSCular consequences of heat! lallure.

.......0._..'.. _... _,·

'"

16. Treatment 01 CongesliYB Hearl Flbe

_...

-,

Agure 16.5 Effeds 01 ACE lmitlilon;. A. Angiotensin converting enzyme (ACE) lnhlblton ACE • ihibilors are lhe agents 01 choice in CHF and lie superior 10 olher vasodilatoJl~.These drugs block lhe enzyme that cleavS$ angiolensin I 10 lorm !he potent vasoconslrlc:lor. angiotensin II (....e 16.5). These agenlS also dilfMlish the rale DC bradyIlrin ~ [Nelle: VModiaIion 00l:ln as a I'esuI 0I1tIe COlltJiled elJects 01 lower ~&$OCOtlSlric:tion cauood by diminishec:l Ievet5 DC angOoIens>n 11 and lhe polenl vasodilatinll et!eel DC increased bradylD presenl: ~"*' ~ on er:erlioi,¥d do no! show signs or s~ d vduTIe 0I'e!10ad. ACE rtobbs are useIul in deer . iO CHF in ~ paIienls wWI sis :1;,., bactio" Ies$ Iha'I 35% (left W!lltril:Uar dys/l.ncIOl). Patients ....t1o ' - had a reoenI myocardial imaIcIiOn also bener~ !rom Iong·term ACE inhibilor the.apy. Patients with lhe IoWesI ejection !racllon show the greatS$t benefit. Early use of ACE

...no

..... '0. . . '.' . . . . . . . _ , .

. ........._--,:... ...-

V. InoIJopic Drugs

inhibitors is ,,*ated In treallng patients wiltI all slages orlet1 ~ Iriallar taiUe, with l!Wld ¥tthouI $)'I 'ipb', l!Wld fle
',0

to decrease ~ ner.oJ$ actiYity.

IV. DIURETICS Diuretics 'elieYe pWnonaIy Wi '9"5I;on and ~ 8detrIa. These

agents al8 useftj in recb:i'lg fle SV"ipb'15 or vobne CM!IbId, inducJ.i'lg OIlhopllea and paroxysmal nocunaI dyspnea.. ~ decrease pIasmll wluI'ne l!Wld sub6eqJenlI'y decI_ venous return to fle heM (pIeIood). This decreases the CIfdiac WOIkIoad l!Wld mcygen Qemand. Diu,etics atso clecfease alte,load by reducing plasma vokme, thus deO'easing blocx:I pressure. ThIazide diuretics (see Po 229) ale ,eLalively mild di.....etics and Io5e efficacy if patient creatinine clearance is less than 50 rnI/mln. loop diu'lItlcs (see Po 227) a,e used In patients with renal insutftcie....cy. [Note: OwfdoSIlS or loop diuretics C4f1 lead to pro-

found hypovoIcmia.1

v. INOmOPIC DRUGS Fosili\Ie Inolropc agents enhance cardiac muocle WilIractiIity, l!Wld Ihus IncIease cardiac ~ AIlhougtl these c;Irugs ad: by diflenlnl Inl!Idl&.-sn.. In eech case !he Inolropic adion Is the II!SUIl 01 .., Increased cy'Op'" ,lie eaIcilm 00l1G& ..aJion ht IIrilances Ihe (l(lI'I(r&CliIi of taI-

---A.. DigiQIl.

The C4Ictiae ~ are often called d9Iab 01 dlgiIais rJvoosides because moot or the drugs come from fle 6gitalis (bgll;M!) pla1t. They a,e II group or chetTicaIIy similar ccmpounds that ClII'I Increase the contractility 01 the heart moscle and afe therefOle widely used In beating heart !allure. Uke the an~a,fllylhmlc O-U{JS descllbed in Chapter 17, the cardiac glycosides Influence the

_

.. .....

'N

H t al . . . .

l.

I

.'

... -

... :.... ~

! • <>

Dilation of venoos blood Ye$seI$ leads to a dec,ease In caro;ac pl'81oad by Increasing ve<1OUS eapacilanoe; arterial dilatOlS 'educe systcmlc arteriolar resistance and decrease aflertoad. N~ratos (see Po 175) are commonty employed venous dilatOlS lor patients with COf19IlStiYe heart failure. 11 the palient is Intolerant 01 ACE irlhibitOls, the COI\"IbInalion or hydralazine and isosorbide dinitrare Is most c0mmonty used. ArtlIodpiIJel!Wld If1IodPns (see p. 188) tIa~ less nega. tiYe InolI'OlliC effeeI than oIhef caldum c:tliImel ~ arc! seEm

~

,:

"

o,e~.2

TlmellolCNl,'-)

Figure 16.6 EfIecf olenllllJprit on mortality or patients with C
•• '0...J" ~,

".

............... , >

16. Tfealmefll 01 COngestive Hearl Failure

~-

-1 ..

~- ----~-

D ec....•, ..' • ~.

HoI' ~ ...

AguNI6.7 Mochanlsm 01 action 01 cardiac gIycosides,

or di9ta1l$.

sodium aod calcium Ion Hows in the ca,diac muscle, thereby increasing C(ll1traetioo ollhe atrial and ventricular myocardium (pas. ~IWllooIrI;IpIo:: aClioo). The digitalis glyC06il;los 6hoW ooly a small dit/cfl;lflC;Cl bolwOOn a therapeu'ically e!llletlw
1. Moo. of aclloo:

-. r

o

•. Aegu\llllon 01 cytosalic ~lCium o;once cell via tie SOlil.m-calcil. 8IldIange rnectIa-nism (Fq.n 16.7). The elevated inl...........• CIIiciun levels 'BlilAIIn., roaease in lhe syslclc loroe 01 callraaiolL b.. InI;rNHd c:ontractillly 01 ..... canll.e ....,.g,,; Admnslralion 01 digi'*' fir •Tilles the kllCI 01 cardiac mntradIity causing the can:tiac ~ 10 more doseIy r ,tAll ItIaI of Ihe normal heart (F9-e 16.8). 1vl increased tTl)'OC8f{iaI conleads '0 il decrease io end dial>lo1lc YOklme. lhus Increasiog !he efficiency 01 C(ll1Il&C!ioo (increased ejeclioo IractUll. The reWIing improved drcuIalion leads 10 reduced

n:reases

.,aetioo

~1he1ic activity,

wI*tlltleo reduo8$ ~ 'esisIance.

Together, Ihese etIects cause a rlll)Jclioo In heart rate. Vagal lone is als.o enhanced so the hearl ra'e decreases aod myocardial 0Ie normal heart, the posiIiYe i lObopic etleo::t 01 digitalis Is OOUfl\CfilCled by COfT\pef'IsatOfY
'_10,,,,,,,,,,,,,,_,,

".

v, lnotrop;e Dfogs

o

.--....,-.. _-....... -

II

NORMAL HEART

-...._.

• _ _ _ _ _ _ _ i.

.11

-

,

,

. .*"...", . . - " , _ .

.",

-

lID 10...

................ - t r 21

r

..... -,.-.

t

t u

Symptoms of ~ inacSequate ""'JU, lor example, I

~

I [3 to Ii))_

_ _ """PlL

• .. _ _ .....= ..

~""'II.·.

V

-

~

~ Yeo ••

~

.Doo._d~'·b

,10 ........... odF"poinl

.elo ____

=___

•.... '_._IiIlI,

........ -0IIIIpuI

. . .Id...", ... _ " , ....

DlGlTAUS TIlEATIIEHT

__

CHf ..... dIIvIt=ll.

Unit ... dCOt!'

•

-.....- .__ "-"""

.

- - -

. . .'" II

$.";' .. ",

/L fJ

DECOMPENSATED HEART f ....LURE

. . .M....

'1fli;;,"' " ltaCfillly 1_k>0lf'.

FAli.~E

.-.."

~ ....... ,Qk>[3IIn .. otlot1k>

(Ok>

• $rmJ*Im&
COMPENSATED HEART

0

-.

. - . .. aSI; _'-_put. .",.10........ _ .. _ . _ "......... _ a aym;l""'" 01 ~Ion,IOf

Flilure 16.8 Veo>lrictAar Itn:lion CU!"o'eS in he noomaI heart. in CCI'lgeSliYe heart laib'e (CH=). and In CHF treated ~ digilalis. 2. Ther.pMltlc uses: Difpdr!lhetapy is inlkated in pPeru wiIh severe left ventr~r SyslolN;: dysfunction after Inillallon of diuretic and vasodillllion therapy. DigoItin Is no! indi<:ated In palia-Tls with diastolic or righI-sided hear! Iailure. Dobu1atnf'1e. lWlOIher inolropic agenI, can be given ~ In he hoisptIal. bul 31 present no good oral inotropic agenl$ ~ ~ tha'1 digI:»Iin.. Palients with mild 10 mocIerale heM failure wi. otlen respond 10 treatmenl ~ ACE llihibitors and diurelk:s and do not require digoI<'in 3. Pft8rmacoklnetlcs: All digifalis g1ycosicles possess lhe same pharmacologic actions, bulfhey vary In polency and pharmacokinetics

......pIe.ctv-.

1., ............... , >

•• ~, r....

''0

16. Treatment of Congestive Hearl Failure

= E:~T:""-::;';:':~'~T _ . ....

-.. ,

Agwe 16-9

f

•

S

(F"9Jre 16.9). These ~ are 8bsoItled after ooaI OOoI.!istrali(:n. Note lhat dPfOOl bn:ls Slrongly to prOlens ~ Ihe extraves<:ulaI space. ~ in a Iatge ~ 01 distrtluIion. DipoU'l has !he acIYanlage 01 a rela~ shorl hall.... ~ allows belle<" 1re8I. menII 01 IQlde reoda .... ~ al50 has a more filpid onset 01 action. makWlg iI useu in elilelgelll:;:Y sitialicns.. DigoIOn 1$ eWrinated Iargety unctIanged in !he ume. DigifOrin is exl.et~·Jely ,Ie' tooljzro by tie heI' bebe exa'eIion in h! Ieces, an:! hepalic: s. Side efIeeIs caI'I often be managed by discontinuing cardiac glycoside therapy. determining serum potasshJm leVels. and ~ Indicated, by giving potassium supplements. In general. decreased serum levels of potassium prodlsp
indude:

A ~ 01 h prcfIe<1ies of djpcifl an:l cfgio.Ian.

.. C«dlK etlKb: The majof efled is PlOO'e!isi'od)1 more_ ~ InIMng from deO !Meet or l:*x:J<ed a~ Iaf nodal mrWdioo. paracy&mlII ~ ~ 10 Ile CD"f\III!t'Sio 01 aIriaI Ilunef 10 alrial fbillation, pnmattn ~ depl:llariUlbon ~ ~, and 1inllIy, 10 .......:lele hear1l*xtL A decrease in illllac"ur pctani", is Ile prma,y predisposing factor in _ _ e/tects. b. GastrolntKUnal eflect.: Anorexia. nausea., and vaniling 8Ie COl •• , a ~y IlOCOU'llered ad'o'l:lr'$e efleds. f;:.

eNS effects: TI1ese include headache, latigue, contusion, bluued vision. alteration 01 color pef'C(!ption, and haloes on

dar!<. objllCls. S. Faeton pred/IpoIlng to digitsn.toa:lclty:

Enhanced potential

for cardiotoxlcity

oe. '_af _PO' !

_

._.Ii.. ,.

•

T1'IluIde'"

5

FlgtK1l16.10

Dn.9S inlefacling >Mth diQoxin and othef digitalis ~ .

.. ElKbol)ltlc disturbances: Hypokalemia can predpilalll serious

anhyflrl'ia. Red!1Mjon 01 seo.wn po!a$siom IewI:s Is ~ Ireq..oenIty oI:l6e<\Iild in patients .eceMng tiWuide OJ loop dIurel· ics. and ean uSlJaMy be prevented by use 01 a poIassium !ipIrirlg diu'etic OJ suW1e",e.iUtion ¥riCh pooassiolfTl cNooide. HypeJealceJllia and ~ also predispose 10 cIgiIlIIis IoQ;:iIy. b. Dr\IgI: Ouioidlil6 can C3Ul;(I dO;.*, ~ boal by displIlc:ing dgitajs from plasma. proIein ~idi~ siles. and by oempElting with digitalis lot renal exe.etion. VerapamU also displaceli digiIaJis from plasma proIein ~ ldi lQ sillls and can incfease diIgaU1leYels by 50 to 75%: !his may require a roouclion in the close 01 digarin. Potassium-
GOste.oIds, and a valiely 01 Other drugs can alsO inc.eese digitalis toxicity (FIgure t6.10). Hypolhyroidism, hypoxia, lenal

........ -.., ........ _,.

•

• ,_0

~

00"

..,.,..,. . . _

.....

16' laue, and myocarditis UJfs 1OKicity.

alfI

also po-edj1;posirlg Iaetols 10 digi-

B. ~AdI"llIIlIlc .gonIstli

lJ-Adlerleigic litimulation ~ cardiac pe!tofmWlce b'llX'SiIive r.otropI(: ettec:ls and vasodilation. Dot1utIJmit'IfI (see P. 66) is the most commonly used inotropic agel'll other than digllalis. ~ leads 10 an iI 0 eas'll ., !rib + cAMP, MCtl teSUIs in f1e lICli\ ,. of ~ IQnase. Sloloo caldl.m dlannel& are ore ~ site of phosphorylation by pnxein kr.ase. wten pitl6fA 10~ Ihe entry of eak:ilm ion ina:) h myoecwdaI c:elIs incoeases. thus enhIndng eontractiorl (F"'9'Ure 16.11). ~ must be gMn by i1tla~nous infusion. aod Is ~ used" Ihe trealmenl 01 aeue . - t tiliUe in a t.:l6pitaI setting.

"!Iar

I,

C. PhosphodleS\IlIfue inhibitors

Arnri10tJe [AM ri nonej and miIrinc:Jne [MIL ri none) are phospt1cldr eslef8Se inhibitors !hal increase the inlnteellUlat cooc:enlJalion or cAMP (F9Jf8 16.11). This results 111 an roease" irItrac::eIIAar calck.n1, and It1efetore cardiac conll3Clili!y, as discussed abcMt tor the lHtdrenelgic agon/sts. [Nota: Aecef>t clinical trtals haw shown !hat ~ did I'lO! reduce the Incidence of sudden death Of proIono;l survival In patients with CHF (see P. 172). MiJrinone showed Increased lllOflality and no beneficial etleets.]

IlIncIrIg

O f_

..

_

Voltage Ier'Isltive alCftllt ea++ channel

,

'

$

~

ad • •

gW:.-....

,:s ·If'IICT' ..... ,

~-

-.__ (II

Ill·.....

••

,

&,

2 -..... ,~'*­ _In .,'.....,

.....

Figure 16.11 S~es daction oIl}adllmergic agonisls on hear1 musde.

0·'--

r,

,

_• •"'"

..........,., ..... _-,.

.<..... _ - - , _ ... _ .....

",

16. Treatment 01 Congestive Hearl Failote 16.• wtWch one 01 ... 1oIo>o1t'll ,wlmen.. CIlfK:e...ioiQ CIlf'll -.. _ 18i1ur. is c:anecl?

16.1 wtWch aI .... 1clIDioitlg _ dite<:Iy deIaIles .... ,,aI ..... aI,lij ,?

O,~,tOl<'"

"&J...

A.

A.tmit:iIs~AW-.

8. sen." _

B. DeaIII.~

qUnidN. C. lOOj) dllJletiQ ... used In Pl"ienU; with .--1

c.~o

·s

·.~CIlf_._C

io

le'JelalATP.

aI cAMP. E. DecnI!taseI.eINse aI calcium from ... SlIfCOPIasmic reticukrn.

.. ...., _

~

d . . (IfCIdI,lcIicn

at cNIP ..... ,,&J.""" 01 8C:Ik:ft 01",. odI. . . jjc."..' &\lito

........

~~

·""It.

. . $R .. _

b"

- . . ... <;allbn.

162 wtIch one aI ...

at digol
hean detOClS ar. the most COITIIOOI'l ca»se 01 oonges~"" I>eart ,"illHa.

E. Congenilal

(

ComlCt _

..

c.

16.5 Whio;Il one 01 .... incl>oad

""""""''II aggraw... a

aoTtIyn,..?

.'11_._

A. Dea II ~ ....... QIll:iom. 8 Dea p~~ C. Dou8.8~_sodl.m. O. Deaelll~ -.n P" m. €. Oauw:oe<.l_..............,.

1oIIowIt"" drugs..ould be !he II'lC6l

"Wf'OIJfiale siro;lle dNg

~

101 mid c:ongesM

heart fail...?

A. A vasodilaIof such as hydralazine. e. A can:liac gIyCotide such as digQxin. C. A II-adr_rgic llgIlrist such as raapintpl'rine.

O. A ditnlir: such .. hydIcxJobullOl6D:lt. E_ An ACE i41ibib. such as ~ ..

16.3 AM 0I1he ~ aN usefU in "1I811--.t 01 dig>IiIoIis ~ EXCEPT: A. 8nb-digClldn FAG tl8ll"""'"'S. e. dielaty I)OIaIl$io,n supplements ,'" PI'~8nts oo;ng t.eated 00i iCOII;\aI1!ft' wit!l tWurlllics. C~.

D.1lhooi)'luh E.~. ~~"E.~...... iO

.... co_t... , t ¥ ~ _ $

• .....

pl. "lui.... used tar - . I a d.....
.

*'" ......

~

oclWm

AgenIc ~ dk> dminiIIIlhc loxicily 011,

~

1nIo ... <;atdal:

a the '-1 _ ...." Iu

at ctigjtcIis.

low .. ru1I

01

.....-

cad8l:: 011I. - - . .. : ~r.iII*' CUn I!lI:NI 'llL

_ "*'

digi\8li$-

CorrecI _ .. 0, I..- senrn pdl Ih8l d80ta_: .......... aI SoOdio,.., from thII CIC"' diac oe4l. lINIOIng 10 an omal'1C8d 1OliIcItr. I.cw leYeIc 01 dfCuI:1lng coIcium "im"":11 the digi-

ICIIlrn

CCmld_ .. E.ICE. beCD>~ _ ~ in peIiwIs p..~._ Otl 10, _ ooto do noll '--signlOI' ."t'*"'.01-.....-.

by

~. D. [);go..n 1I eIitnIt1oo.led primarily' in Ihe bill.

o. ~lI"'dto::Wvl

Correct_ .. A. n. <*Ileo:: ~ I*"l III ..-.:l1llDd< h " " ' " 01 .... ~ AlP.... n.. caodlac glyooskles inllltJ;lllle -..on 01 . . . . . tram 011, -..g III an It.. • in -"urn 1eYels eel. ThII ~oIATP .. "" ...,d.igedin

il mo•• widel, " ..... \han digol
. . . . . II ' - ......... tIIII-ae.

loon ...

·....... _.., .. _-_... ,.

• . _ ..........

:

, """"U _ _ . PI' >

Antiarrhythmic Drugs ANTIARRHYTHMIC DRUGS

,..... ,

I. OVERVIEW

I-

In contrast to skeletal muscle. whidl contracts only When ~ <ecei\les a stimulus, the heart contains spaciaijzed cells that exhibit automaticity. that is. they can intrinsically generate rhythmic action potentials in It1e absence 01 external stimuij. These "pacemaker" cells differ'rom other myocardial cells In showing a slow. spontaneous depolarization during diastole (Phase 4) caused by an inward positive current carried by sodium and calcium currents (see p. 152). This depolarization is tastest in the sinoatrial (SA) node (the nofmal initiation site of the action potefltial) and decreases throughout the normal condlJClion pathway Ihrough the atrioventricular (AV) node to the bUndle 01 His and the Purkinje system. Oys1unction 01 impulse generation Of ronducIion at any of a number of sites in the heart can cause an abnofmality in cardiac rtlylhm. Figure 17.1 summarizes the drugs used to treat cafdiac arrhythmias.

(Na' CMnnel bIc>cl<en) ~_(IA)

FI>ocUII<'- (Ie) UdDc_(IB)

MaHe_fIBJ ~(IA)

Po""'''''IOI'' PC}

a..._(IAJ

T~IIB)

I-

II. INmODUCll0N TO THE ARRHYTHMIAS

IThe arrhythmias are conceptUally simple-
-

_.

CLASS II

(p.AdI"lOI~or

--.-"""'~

CLASS II (K' Cl\lInnei bIocl<en)

CLASS IV (c." CMnnel bIol:......,

,.~~

-

.-

Other .nIl.
Agure17.1 Summary of anliarrtlythmk: drugs.

. . . . __,,_ _c._ ----"." "._~

~_._."

10lIO.

163'

·

, ,-

".

_'>

_... _, ...

h,...,.. ..._

....... -....-"'--

Tl*=,"= •••

t

~

........ _ _ n.._..... _;

_

•

• ....,(101)150 _ _

_l_~'

t

W

_

•

• _ _ 1Ib

........ .....

•

0-, -:::,m:.:- 0-,,£

•

//

1

.. _ _ ~

......._ __ ' _.d 01 _ DC_ •_ • _

• • CII~ • •

d .... _ 1 1

CO

_1n

D-lI ......... _ ....m"." _...,.

f-

.-

'-~=--

---

Ceo.e: ...

~......,...

AV _ _

.~

--,-

....

_,

UN¥I

~

~

..,.. •••"" ...... _==,

_.= ...," _&i' ..

_

_~

__

In,-.u _ _

" .CInIlK .......... •

~

".

m

001_;;.._

D ••'"

figure 11..2 Thefapetl1ic indications lor liOfTIll commonly eflC:OlWltered arrhy'!hmla.s.

$~

dor

·....... _,., .. _--,.

• ._ .....

:

, """'U _ _ . PI' >

'"

I" Introduction to the ArThytt1mlas A. Causes of arrtlythmlas

Most arrhylhmias arise either !rom aberrations n ifTl>ulse genera· lio<1 (abnormal automalidty) ~!rom a deIec1ln impulse condudion. 1. Abrlormal automaticity: The SA node showS the fastest rate of Phase 4 depolarization and therefore. exhibits a highe. rate of disdlarge than that or::cumng in other pacemaker cells elChibiting automaticity. The SA node thJs normally sets the paoEI of cor;. traction 10< the rl¥lC8rdium, and latoot pacemakers are depolarized by rnpulses ooming lrom the SA node. However. ij cardiac siles other lhan the SA node shoW enhanced automaticity. they may generate competing stimuli. and armylhmias may arise. Aboormal automaticity may also OCCtJr ij the myocardlat cells are damaged. for example, by hypoxia or potassium imbalance. These cells may remain partially depolarized dumg diastole and therefore can reach \tle liring threshold earlier than normal cells. Abnormal automatic discharges may thUs be indI.Joed. A Normal

2. Effect of drugs on automallcity: Most 01 the antiarrhythmic agents suppress automaticity (1) by decreasing the slope 01 Phase 4 (diastolic) depolarization andlor (2) by raising the threshold 01 discharge to a less negative vottage. Such drugs cause the lrequency of discharge to decrease. an effect that is more pronounced In rells with ectopic pacemaker activity than in normal cells.

3. Abnormalllies In Imputse conductIon: Impulses lrom higher pacemake< O8f1lers are normally conducted down pathways that bifurcate to actiw.te the oot;re ventricular surlace (Figure 17.3). A pheoomenoo called reentry can occur ij a unidirectional block caused by myocardial injury Of a prolonged relractory period resulls in an abnormal COfldUctioo pathWay. Reer1lfy is the most common cause 01 arrtlylhrrias and can OCCtJr at any level of \tle cardiac conduction system. For example, oonslder a single Purkinje fiber with two conduction pathways to wntricular mus' de. M impulse normally travels down bo\tl ijmbs of the conduc-~on pam. Hcmever. ij rnyocardlal injury results in a unidirectional block. the impulse may ooly be conducted down pathway ~1 (see FigJre 17.3). II the block in pathway 112 is in the IofWard direction ooly. the ImpUlse may travel In a retrograde fashion through pathway 112 and reenter the point of bifurcation. This short·circuit pathway results in reexcitallon ot the ventricular muscle. causing premature contraction or sustained wntficular arrhythmia.

4. Effect. of drugS on conduction abnormal1tie.: Antiarrllythmic agenls prevent reef1try by slowing conc:tuctlor1 and/or Increa~ng the relractory period required to ~rt a unidirectional block into a bidirectioflal block.

B Un'd're<:lI0n8,1 BlOCk

FIgure 17.3 Sct1ematic representation of reentry.

..........", .. -... _,.

• <....

M",_--",-' _

'66

W •

.. _ .

17. Antiarrhy1l1mic Drugs

B. Antllln'hythmic drugs ".."".... """"""1

£"".lnlM

1'1"",.I",M

As noIod llboYe. the anliant1y1hmic ~ can rncdfy impulse gan. eralion and oonduction. More lhan a dozen su:tI ~ thaI a.e potentialy usefU in lreatng arrhyll'lmia$ are c:urrenlloJ avaiable. HoweYer. oMt alimitec:t ruTber of ltlese agents ate dnr:aly benefidaI in the treatmenl of se'e :ted arrhyltlmiltl.. For exatnP'e. the acute te.mination 01 ventricular tachycardia by lidocaine or ~ taehyr:arda by adti ....... or ~are elGImPes in ...nen IWIIiarThyttmie lt1erBA' te$UII:S in decreased morbidicy. ~ <Xlr'IIrasI. many of the ~ ~ ar& now knDwn to ~ lethal ~ aetior.. ht is, to ClII.ISe lltJf¥Ihrni;lls

1f"""",I""

-'. f:~;~ ?• -

- _ . _ - . '

~.

'_

!

m

,

,

. . .

I

drug.'

r ..._

1. P1_rt'r'lhmk etlecb of .m."h~k In !he Cardi3c Antlyt'oria Suppo e ion Trial {CAST} trea\l'Tlel'C with ~ lIr'Id JIecaio li:f&, two class IC antiarrtlylhmic agents, 5'.' t AIy preoeliled wntril:uIar • • 'I ole beals in patients who had myoc:ar. cJaJ Intarction. Hov<ever. oontinJed ~ with either drug was 'SIIOCiated with 8 two-IO three-totd mease in dealh we 10 car· diBc anb,1hmias. Similar resuts _ reported lor moricil:ir>e. Increased death was probably due to drug-induced !alai antlytlmlas irWred by rec:u1Tllnl myocardial ischemla. resu~s of CAST challc'
2. The u...."pe<:t&d conclU1lIon: The

III. CLASS I ANTJARRHYTHMIC DRUGS The anfiarrl'Jyf'wr'Oe ctugs can be dassl'1llCI aa:crdiiig 10 \heir precbnin8l'II ellBds on hi aaion PJlei IIiaI. AIItlougI .,. classkalion is CXlOYenienl, ~ • noI enOrety cIear-e:ut, bec:8use many of !he ctugs haw

___-

Mechanism of Action

• • •

FIgure 17.5 AcIlons 01 antiarrhythmic drugs,

...... ...

Comme"t

51...... _ ) . . . . - -

.... _

....... _ _ 0 , ; : . •

_. d

,.

---

_Ion

<'d . . . . ., . , . ,

, >

< ._ • _

....

:

, """"U _ _ . PI' >

'"

III. Class 1AntiarThythmic Drugs actions relating 10 more than one class or they may have actiw metabolites wilh a difle,ent class of action. Ctilss I antlautlylhmic drugs act by blocking l'OIlage-sensai\le sodium channels by tI1e same mect1anism as local anesthetics (see p. 117). The decreased ... te 01 enlfy 01 sodium slows tI1e ralll 01 rise 01 Phase 0 ot tI1e action potential. [Nole: AI lt1erapeutic doses, lhese drugs hlMl little eflecl on the resting, fully polar~ed memtmme.j Class I anliantlythmic drugs lt1er&fofe generally cause a decrease In excitability and conduction veloe-

.,.

Group IA drU\IfI_ ph-. 0 ~1zatiDn, prCIDng _ _- concluClIOtI. pDf_ill

A.U~ndence

Class I drugs bind more rapidly 10 open or inactivated sodium channels than to channels that are tUlly repolarized folloWing recoIIBry from the previol.ls depolarilalion <.yde. Therefore. these drugs shoW a greater degree 01 blockade in tissues that are fre· quently depolarizing (tor example, during lactJycardla when lt1e sodium roannels open otten). This property is called use-dependance (or stale-dependance) and enables lhese drugs to block cells that are discharging at an abnormally high frequency without interfering with the normallow-frequency beating ot lt1e heart. The Class I drugs have been subdivided into three groups according to their eflecl on the duration of the action potenlial. Class lA agents slow the rate of rise ot the action potential. thus slowing conduc· lion, and prolong the action potential and increase the ventricular elfecti\le refractory period. They hlMl an Intermediate speed 01 association with activatedlinacli\laled sodium channels. and an inlermedlate rate 01 dissociation from resting channels. Class 16 drugs ha"lllittle ellect on the ralll of depolarization, but rather they decrease the duration ot the aetiotI potential by shortening repeIarization. They rapidly Interact w~h sodium channels. Class IC agents markedly depress the rate 01 rise of the membrane aetion potential, and therefore they cause marked conduction slowing but ha...e little effect on the duration of the membrane action potential or lhe wntricular elledlve relrnctory period. They bind slowly to sodium channels. [see Figure 11.5 lor a summary of the aetions of the antiantlythmic drugs.]

,. ~.

K'

,

K'

B. Quinidine QuinkJjne [KWIN I deen] is lhe prototype Class IA drug. At high doses, ~ can actually precipitate arrtrythmias, which can lead to falal ventricUlar fibrilation. Because ot quinidine's to>
_~bIock - . Of 1nIoctI_

1. Mechanlam DI action: Quinidine b
~

sodium channelS and prevents sodium inMux, thus slowing the rapid upstroke dUring Phase 0 (Figure 17.6). It also decreases the slope ot Phase <1 spontaneous depolarization.

2. Af:liona: Quinidine inhibits ectopic arrhythmias and ventricular arrttythmias caused by increased normal automaticily. Ouir>idine also pre\fents reentry arrllythmias by producing bidireclional block lt1rough decreasing membrane responsilleness and pro-

--_ m--......_

_ ... I"te",_. """ 01 _ _ with

IDdlumc_..

Agure 17,6 Schematic diagram of the effects ot Group IA agents.

.."",.,... _,.,.,----,.

_---....

"'~

'-~-;:..' ..'---J

17. Antiarrtlythmic Drugs longing the effective .elraclory period. The drug has litue effed 00 normal automalicity. [Note: Quinidine can induce a tachycar-

dia in normal individuals because of its atroplno-like (anlid1olin· erg;c) ellect.]

3. l1ler.peutlc use.: Quinidine is used in the treatmool of a wide variety 01 arrhytt1mias, ioouding atrial, AV jlJllClional, and ventricular tllChyarrtrythmias. Quinidine Is used to malntaif1 sinus It1ylhm after direct CUfTent cardioversiorl of atrial ftutter or fibrilialion and to prevent frequent ventricular tachy<:ardia. 4. Ph.rmacoktnetics: Quinidine sulfare is mpidly and almost com· pietely absorbed after oml administmtion.

_ ......

AV'ri _ _• 0;'

'"

figure 11.7 Drugs affecting the metabolism 01 quinidine.

5. Advsrss sffll'CtlJ: A pot8(ltial adverse effed of quinidine (or any antiarrhythmic drug) Is e~acerbation 01 the ar.hythmia. Quinidine may cause SA and AV block or asystole. At toxic lev· els, the drug may induce ventricular tachycardia. Cardioto~ic ellects are e~acerbated by hyperkalemia. Quinidine can increase the steady state concentration 01 digalrin by displacement of digoxin from tissue binding sites. Nausea, YOfTliting, and diantlea are commonly observed. Large doses may inooce tI1e symptoms 01 cinchonism. lor exampie. blurred vision. tinnitus. headache. disorientation. and psychosis. The drug has a mild a-adrenergic blodIing action as well as an arrup'no-like effect Drugs Interacting wil!1 quinidine are shown in Figure 11.1

C. Procttlnamide 1. Actions: This Class LA drug. a derlvarive of rhe local anesthetic procailB (see Po \ 17), shoWs actions OO1ilar to those 01 quir«Jine.

2. Pharmacokinetics ProcainamkJB [pro kane A mida) is absort:led 100lowing oral administration. [Nore: The intravenous route is rarely used because hypotension occurs If the drug is 100 rapidly Infllsed.] ProcainamkJB has a relatively shor1 hall..Jife ot 2-3 hours. A portion 01 the drug Is acetylated in the liver to Nacelylprocainamide (NAPA), which has lillie effect on the maximum polarization 01 Purldnje fibers bUr prolongs the durafioo ot the actioo potenHal. Thus. NAPA has proper1ies 01 a Class 1I\ drug. NAPA Is eliminated via the kidney, and dosages 01 prrr cainamkJe may need to be adjusted in patients w~h renal lall"~.

3. Adverse etlects: With chronic use. procainamide causes a high Incidence of side e!leets, Including a r8Y8rsibje lupus erythemarosus-like syndroma that develops in 25 to 30% 01 patients. To~ic corlC8ntrations of proc8inamidB may cause asyslole or Induction of ventricular anttythmias. Central nervious system (eNS) side effects include depression, hallucination and psychOSis. With this drug. gastrointestinal intolerance is less frequent 111M with quinidine.

< .......

_1.,

><

, >

< .go . . . . .

: __=''', """"U _

........

w

>

III. Class I Antiarrhythmic Drugs

'"

D. Dlsopyramlde

1. Action.: This Class IA drug shows actions slmilar to those of quinidne. Disopyramide [dye SO PEER a mide) prodllCeS a nega. live inotropic effecI1tIa1 is grealer lt1an the weak effect exerted by quinidne and procainamide. and un~ke the Ialter drugs, disopyramide causes peripheral vasoconstriction. The drug may pr0-

Gfoup Ie drug• ......-

..-

phMe3~ion

_

duce a dinicaUy i~rta.nt decrease in myocafdial cool!aetilrty irl patients with preexisting impairment 01 left ventricular function. Dist:Jwramide is used lor lreatment of vef1lricular arrt1ythmias as an attemative 10 procainam/de or quinidine.

deer...... "'"

durMlon Of_KIiDrl

2. Pharmacokinetics Approximately one half 01 the orally ingested drug is excreted lMlChanged by the kidneys. About 30% of the drug is converted by the liver to the less active mono-N-dealky· Iatel!

melabol~e.

3. Adverse effect.: Disopyramide shows effects 01 anlictlolinergic activity, lor example, dry mouth, urinary retention, blurred llisioo, and coostlpation.

e. L\doc.iIlne Lidocaine [LYE doe kane) is II Class 18 drug. The 18 IIgents rapidly associate and dissociate from sodium channels. Thus the actions of Class 18 agents are manifested when the cardiac ceU is depo-

~.

larized or firing rapidly. Class 18 drugs are particularly useful in treating ventricular arrhythmias. Lidocaine Is the drug 01 choice for emergency treatment of cardiac arrhyttmlas.

1. Action.: Lidocaine, a local anesthelic. shortens phase 3 repoIari~atlO<1 and de<:reases the duratiOfl of the action potential (Figure 17.8). Un~ke quinidine. whid1 suppresses arrtytlhmias caused by increased normal automaticity, lidocaine suppresses arrhyltlmias caused by abnormlll autOffillllcity. Lidocaine. like quinidine. abolishes ventricular reentry.

2. Therapeullc uses: Lidocaine Is useful in treating ventricular arrhyll1mlas arlslng du.ing myocardial isd1emla, such as thaI experiel'lOed dUring a myocardjal irlfan::tioo. The drug does not markedly slow conduction and thus has little effect on atrial Of AV iur.ction arrftyttmias.

3. Pf\a.mscQkI""'tlcs: Lidocaine is given lntravenoo$ly because of extensive first-pass transformation by the liver. whidt precludes oral administration. The drug Is dealkylated and eliminated almost entirely by the ll~er. consequently dosage adjuslment may be necessary in pallenls with liver dysfunction. 4.

Lidocaine has a fairly wide !(»(ic.to-therapeulk: ratio; it shows little Impairment of left ventricular flJl'lClion, and has nO negall~e Inotropic effect The eNS effects Include drowsiness, slurred speedt. paresthesia, agitation, coofusion, and convulsions; cardiac antlylhmias may also ocwr.

_Of_eel --"""-

Udoc.... _ _,..,

oodium ~ . 1'l>eN dlUflS _ .. rapid

. _ Of ••

_Ion wlfh

.O
Ad~_ efled.:

FIgure 17.8 Sdtematlc diagram oItha effects 01 Group 18 agents.

<

,., •• -

_,.

'"

17. AI1liantly1t1mic Drugs F. Mexlletlne and localnlde

"These are Class IB drugs with actions similar to lt10se 01 lidocaine. These agents can be administered orally. MvxjJeUne [mex tL e teen] is used lor d1ronic trealmenl 01 ventricUla1 anilythmias associated with previous myocardiallnlarctioo. Tocainide [toe KAY ride] is used for treatmertl 01 ventricvlar tachyarrtlythmias. TocWrltI& has puhlonary to>cidly. which may lead to pulmonary fibrosis.

G. FlBcalnldB F/e(;sjni(;Je [na KAY nide] is a Class IC drug. These drugs sl(M'ly dissociate from resting sodium channels and show prominent effects. E!\ten al normal heart rates. These drugs a,e approved only for relraelory vent(ocular arrhylhmias. However. rec:ertl data have cast se.ious doubls on lt1e safety 01 tl1e Class lC df\Jgs.

1. Actions: RecainidB suppresses Phase 0 upstroke in PUrkinle and rJ¥lClIrdial fibers (FIQure 17.9). This causes marked sloWing ot ror.ductiorl in aU cardiac tissue, with a minor effeCl on the duration 01 Ihe achon potential and refractoriness. Automaticity is reduoe
,. ~.

1("

,.

1(.

,. I,.

2. Ther_peul1c un.: Recainide is usefulirl treatiflg reiraClory venlricular antly1t1millS. It Is partiOJlarly useful in wppressing premature ventricular conlraction. Fleceinide has a negative inotropic efloct and can aggravale congestive heart lailure.

3. Ph..maeoklnelies: Flecainide Is absorbed orally, undergoes minimal biotransformation. and has a half·life of 16 to 20 hours. 4. AdverM etleet.: FIecainide ClIIl cause dizziness, blurred vision, headache. and nausea. l.il<e other Class IC drugs, flecai.·,de ClIIl

aggravate preexisting al1't1ythrnias or induce li!e·ttlreatllfling \It!f)triaJiar tachycardia lhal is resistant to trealmet1t (see p. 166). H. Propafenone

---drug._-_

Of lna<:'llva_

This Class IC drug shows actions similar to those of flecainide. Propilfenone [proe POF en onel. like flecainide. slows conduction in aU cardiac bssues lI1ld is considered a broad spectrum antiarrhythmic agent.

Bodlumc_.. _

"'01 .._ _ lOdium cMroIoll..

-.M~

IV. CLASS II ANTIARRHYTHMIC DRUGS The Oass II agenls indude ttle !}-adrenergic antagonists (see p. 73). These drugs diminish Phase 4 depolarization. tI1lJS depressing autD-

Figure 17.9 SChematic diagram or the effects 01 Group Ie lI(jfJflts.

mallclty, prolonging AV conduction, and decreasing hear! rale and contractility. Class II agenls are useful in Ireating tachyarrhylhmias cauood by Inc:reased sympathetic activity. They are also used lor atrial flullllf and fibrillation, and for AV nodal reenlJant \lIctJveardia.

<."" .....,.,.<----,.

<

<_ ...... :__',

w •

""""U _ _ .

V Class III Antiarrhythmic DfUgS

A. Prop.-8110101 ProprafIDIDi reduces the incidence ot sudden arrhythmic death after myocardial infarction (the most common cause 01 death in this Qfoup 01 patients). The mortality rate in the lirst year alter a heart attock is signilicaotly rcdJccd by propranolol. partly because 01 its ability to prevent ventricular arrhythmias. (PropranoloJ is described in detail on p. 74)

B, Meloprolol and pinclolol Propranolol is \t1e f}adrenergic antagonist most widely used in the treatment 01 cardiac antlylhmias. Howcvc<, IIl"spccilic drugs. such as meloproloJ (see p. 77) reduce the risk 01 bronchospasm, and drugs with partial agonist activity. such as pindoloJ (see p. 77), may decrease the Irequency of cardiac lailure.

Gfoup II ""'9- prolong

plwIse3.-.po_.....

wIIhoul _ _, pNse

o.

C. Esmolol Esmolol lESS moe 101) is a vcry shon-aCling II b1od
0..,,,

V. CLASS III ANTIARRHYTHMIC DRUGS Class III agents block potassium charlncts and thus diminish lhe outward potassium current during rcpoiarization of cardiac o;ells. These agents prolong the duration of the action potential without altering Phase 0 01 depolarization or the resting mcrrb
A. Sollliol

SoIatc1lSOE ta 101]. although a class III antiarrt1ythmic aQCf1t. also has potent f}bIoc:kcf activity. It is well established that II-blockers rclluce mortality associated wilh acuto myocardial infarction. I. Ao;llons, SOlalol blocks a rapid outward potassium o;urrent. known as lhe detayed rcc:tifier. This bloc:k.ade prolongs both repolarization and the duration 01 the action potential, thus lengthening the elfoctive relractory jl(!ricXl.

2. Tllerapeullc uses: Il-Blodmrs are used for long-torm therapy to decrease the rate of suddcf1 death following an acute myocardial infarction. II·Blockers havo modest ability to suppress ectopic beats and reduce myocardial oKygon demand. They have slrong anti fibrillary effcc:ts. particularly in the ischemic fT¥'C8rdium. SolaJol was moro cffoctivo in preventing arrhylhmia rC(;urrence and In decroasing mortality than imipramine, mexilerine, proca;namide, propatenonfl and quinidine in patients witll SlJSlllined ventricular tachycardia (F'9ure 17.11).

~,.1

--

K' K'

t

~.

n

Figure 17.10 Schematic dag,am of the effects 01 Groop III agents.

$'

<""""-'."'---" 17. Antiantrylhmic Drugs 3. Advene effects: This drug also had the lowest rate 01 acute Of long-term adllerse effects. As with IIlI df09S that p
a. Bretylium 1. Action': Brel}1ium has a nurrbcf of diroc1 and Indiroc1 eledrophysiological actions, the most prominent 01 which am pr0longation of tho rcfractOf)' period and raising of the intensity 04 the electrical current necessary to indllCe ventricular fibrillalioo in tho His-Pur1dnje system.

Figure 17.11 Comparison of SOlaIo/ with six ether G'ugs with respect to deaths due to cartiac arrhythmias.

2. ThefllPOOllc uses: Brefylium is reserved lor likl-thrcatcning ventricular arrf-rtlhmias, especially recurrent VCfltricular fibrillation or

-""'.

3. Ptutrmacoklnellcs: Brelylium is poorty absortled from tho gastroir1lestinallract and thereloro is usually administered parenterally. The drug is excreted In:hangIld in the urine, and dosage may haw to be adjusted in patients with kidney dyslunctions. 4. Adverse effects; Bretyfum can cause SCYllro postural hypotension.

C. Amlodarone 1. Actions: Amiodarone [a MEE ot1 da rooe) contains ilXfne and is related structurally to thyroxine. It has complex effects showing Class I, II. III and IV aetioos. Its OOminant effect is p~tioo of the action potential duration and the refractory period. Amiodarone has antianginlll as well as antiarrf-rtlhmic activity.

2. Therapeutic uses: Amiodarone is effective in the treatment of SCVIlrEl rcf
4. Adverse elleclS: Amiodarone shows a variety 01 toxic

effects, Alter long'Ierm usc, more than one haW 04 the patients receiving the drug show side e1focls sufficiently SCl/Cre to prompt its discontiruation. Some 01 the more common eHccts include intersti· lial pulfT'lO(lllry fibrosis, gastrointestinal tract intolernnce, tremor, ataxia, dizziness. hyper- or hypotlTjrokfsm, liver 100000000, photoscosifivity, neuropathy, musde wcaknl)ss, and blue skin W;coI. oralion caused by iodine aocumulalioo in the skin. As noted eal1illf (see p_ 166) recent c1inic.altrials have shown that amlorJarone did not reduce incidence of sudden death or proloog sulVival in patient witll coogocstive heart failure (CHF).

'''''' "0 ...., ....... __ ' >

'"

VI. Class IV Antiantlythmic Drugs

VI. CLASS IV ANTlARRHYTliMIC DRUGS The Class IV dn.ogs are calcium channel blol;:IIers. Thoy decrease the ~ Cl.mIf1l carried by cak:ium, resuIWlg In • dol;rcase In !he rale d Phase .. sponaneous depolarizalion and $lowod IXlfDJdion In tissues depefl(l(l.1 an c:alcil.nl cunerll$, sudlll$the AV node (FlgUfe 11.12). Although \'OIlage-sen:sitiYe calciool ehar'neis (l(X:Ul' In many diItef.n ..so 'CS. Ihe rnllfcr elted: d caIcil.mdIIImeI l:IIodIers i$ on ''350 "" ~ n'lI.tSde and the heart

~ftI ......

_pt.-4 _ _ dr, ' I : 1 ___ ' I In

...... ', _............

A. Yerap&mllancl diltluem

_ _ _ AV_

~ l\(!f AP 8 ~ shows grcalcr 8dion an !he he8I1 Ihlln on '?SO!la, smooch muscle. wOOfelIs de .,.... a c:alcU'n tfIBn. nel·bIocker used 10 I,eat hypertension (see p. 187) exerlS a SIfDOgcr etIoc1 an YiISClIIar smooth muscle than on the hearl. DilrianJm [di1 TYE a zuni is inlermedialo In its aaiorlS.

1. Ad~: Calcium on~rs cells by YDIlage-~etlBnncls and by 'oc:cpIof-operated ct.amelli that aro o:lrItrolled by tho bi odi og aI agonlsls, such as cateeholamincs. 10 fT\Cf'Ilbfane 1'COl!flI0fS. Calcium chBnncl blocl<efs. such as ~ and ct/liazem. are morc elloctivo against the YOItBgo-scnsitiYc channels, causing a dccrcaso In the slow inwafd current thatt,iggcrs cardiac canlraction ($(!(I p. 152). Verapamil and diltiaum blnd Oflly 10 open, depolarized channels. thus prOV(lnling repolariZation unlil the drug dissociates from the channcl. These drugs aro lherefore uso-
'*

3. PNnn8c:oklnetics, ~ and iMiazem are Ilb50rbed afIet oral adIl.lil>1laOOlL ~ is CIdonsMlIy mcI3boIzed by be livcr: thus, care shoUd be taken in uni"istI.lion d tI'is drug 10 petionts ~ hcpillic dys1ln:tion.

4. ~dve... eHecll: 1Ienfpamt/8nd c1ilrillzem hllVo negative inoIrOpic properties and therefore may be torllr.indiealed in paliCf11s with procl
-_.....

_'v.,_JiJ. . .:_ i

_

...

. _

~_.

,1

Agure 11.12 Schematic clagrarn 01 the effects 01 Group IV agents.

< ,.,.<---,. '"

17. AntiafTtridlmic Ofugs

VII. OTHER ANTIARRHYTHMIC DRUGS A.Oi9 0 )(ln

Digoxin (see p. 158) shortens the re!laclo'ith IidocainfJ 01 phenytoin.]

B. Adenosine Adenosine is a naturally occurring 11tJdooside, but at high doses tho drug de<:roases COnduction velocity. prolongs the rolractory period. and decroases automaticity in the AV node. IntraYilnous adeno!;inf) is 1hc '*ug 01 choice lor abolishing acuto SUpmvet1tricular tad1ycardia. It has low toxicity, but causes flushing, chest pain and hypotensioo. Adencslne has an Cl(tromely short duratiOl1 ot action (about 15 seconds).

Study Questions

a-.oooo t"eONE best answer.

11.3 Which one ot ttlll following statements Is INCOR· RECT?

11. t All 01 the 100Iow;ng mochanisms 01 action coa&cHy

matdt a drug EXCEPT: A. ().Jni
reftaClOry period.

Na' cha.....

C. Verapamit Blocks Ce" char'w'l8IS O. Propranolol: Blocks ~ edfOOllOllPlors E. Procaillarnide: Blocl<s K' cI\aIVIeIs

~er>swet .. E. Proe8InarrOde blocks Ne'

0uInidi1ll,l pr-oIongs repola.riUltion aod the effective

B. Mexiletine shortens repolllrization and decreases the elfecti.... 'dl"ac\OrY period. C. Propranolollncr&aSeS Phase 4 depoIartzation. O. Verapamil shortens the duration 01 the aCllon

B.8re1ylj<.m: ElI
(

A.

potenlial .

E. Amiodarone prolongs repdariUl~on. )

17.2 Wh;Ch one 01 ttlll following statements is INCOR· RECT?

..,

(=C.~"

11.4 Which one 01 ttlll lollowing sta1ements about antiar· rtryIhmic 00gs ~ CORRECT?

A.lidocailll,l must be giv«l parooteraJy. B. Lidocaine Is used mainly lor atrial ar
A. They may llC1 by cawerting unidirectional block to a

C. Procaillarnide is associal9<:l with a reversil:lle 1l4lUS

B. They olten cause an increase in cardiac OI.IIpuI. C. As a group !hey ha~ mild side effects.

".,......,., O. Qu;nidine is act/V1I orally. E. AI antiarrtlylhmic drugs can suppress cafdiac <XlOtractiorls.

C<Jmlct _ _ .. Ii U
mellon

by Iha lIve., which precludes o.al ~ AI 01 "" anli-.ytvnic ctuge can

exM

a f"08\l9IIVe InalfOlliC (lIlect.

bldirectionallllock.

O. They all allecl. Na' etlannets in lhe cell menilralll,l. E. They are equally uselu! In atrial and ventricular arrtlylhmias,

Comlcl

~

• A. A bIdIr _

block ClIn

decrftM .000000000mias caU8a
Include .""vthmialr ttlal cen lee
ca" dw>naIa.",p .."..0

..........

..........,., .<----,.

<._~

.... ,.. . . .,--_."".

Antianginal Drugs

I. OVERVIEW Angina poctofis is a chanK:lcri$tic chest pain caused I7t COfQOII!y blood IIow thaI is r.suttIcient to mool !he orygen demands of !he myocan:lit.m. The irrCaIar'Ql between ocygen ~ry and ~tion mlly fCSUlI lrom tl S4)asm of !he "a&cls ...... JSed by athefOsderoIic lesions. Angna is tNraclerized I7t a suddon. SIM!f1I pressing stb6tcmtll plIin . . r ,. IY 10 !he Ieh arm. llYoo

dr5Se5 01
(also Clllkld Ptinzimetal's anginal caused by spontaneous coronary

spasm, eilhef at

ANTlANGINAl DRUGS

worII Of al rest, f1iIlhcr IhIIn by increases ~ myoc:ardaI Is ~ I7t organic ritrall)S or eab\.WrI chan-

oxygc<1 requifemet lIS,

nel blockc<s. but ~bIockers are oontrllindicaled. (See F"ogJ'o 18.1 for a sunvnary 01 thoso antiar"9nal agoots.l

f---

ORGAMC "m......

-

....... t''''_....

II. ORGANIC NITRATES Orgaric rVlratl)S (and rilriI:cs) aro 5in1JIe ni1fic and nitrous acid oSIers 01 tllcdlols. They diItef ~ lhcir VCIIadily; lor ~ isosotCidIf dinifmkl is solid til room lempefalu<e. nJlrogIycerin is onty maderalely IIOIatile. wt\erolI$ an¥ tWalB i:I; extrcmcty YOlatie.. These 0DflllCIUI1d& <:ause a rapid .oduction ~ myocardial CIK)'gPl demand 'oed I7t rapd fclieI of ~ They an:! efiIIctMl in IUIbla and UI ratio Mgina. as wei as PrinzmetaI's Of variant angina pocbis.

f---

....-

1l8LOCKERS

"'

"*

c.-CHANoIn

'--

". ,

NiUalC$, ~ and caIclum channell.*:ld<ers arc ~ eflecliVe b ,cIieI of anginal ~ Howew!<, /of proillpll1lliol 01 ?r1 ongoing anack 0/ angina Pfodpilaled by eltllrciso or emotional sllcss. sutlIingual (Of spray lorm) ntroglycerin Is the !tug 01 choice..

I

OF

"""""'" 0

1\ ' .

w. ,

.,.

F1gu.. 18.1 St.wrvnIry 01 anlianginal augs.

<""' ••• _••, •• _ - - - , .

'"

18. Afllianginal Drugs 1. Mechanisms of action: The organic nitfates, such as nitroglycerin [nyc troe GLI sor in], are thooghllO relax vascular smoolh rn..oscle by their inlrac<:!lluLar conversion 10 nitr~e ions and 11100 10 nitric oxide (NO). which In lurn aclivates guallylate cyclase and Increases the cells' cyclic GMP. E~ted cGMP ultimately leads to dcphosphorylatiorl of the myosilllfght chaiIl, resuKing in vascu· Lar smoolt1 rT'OJscle relaxation (FlQllre 18.2). 2. Effects OIl cardIovascular system: At Ihorapeulic doses, nitrog/y«Jrin has two major ollccts. First, ~ causes dilation 01 the large \leins. resulting in pooling ot blood in the veins. This diminishes

preload (venous return 10 the heart). and reduces the work of the heart. Seoorxl. nitrog/y«Jri11 dilates 1t10 COfonary vaseutallJre. providing increased blood supply to the hoart rn..osclo. Nilroglycerin causes a decrease in myocardial oxygen consumption because of decreased cafdiac work. 3. Pharmacokinetics: The time to onset of action varies from 0I'llI mirlUte for nitroglycerin to more than one hour for isosmbide monon/tmla (Ffgurc 18.3). Sign~icant first·pass melabolism of nitrogtyoerin occurs in the liver. Therefore. it is oommon to give the drug either sublingually or via a transdc,mal patch. 4. AdITene effects: The ft106I common adVerse eftcet of nitrogIyoerin. as well as the othe< nitrates. is headache. Thirty to sixty perren! of palients r«eiving intermittent nitrate therapy with long-acting agents develop heada<:hes. High doses 01 organic n~rates can also cause post1Jral hypotoosion.lacial fiushing, and tachycardia.

Vascular smooth muscle relaxation Figure 18.2 Effects 01 nitrates and smoofh muso::le.

n~riles

5. Tolelance: Tolerance 10 the actiorls ol n~ratcs develops rapidly. It can be ovcrcomo by provision 01 a daily "nitl8te·fme interval" to restore scnsillvity to the drug. This intorvat is typically 6 to 8 hours. usually at night becalJSll there is decreased demand on the heart al that time. Nitr0g/yc8rinpatches are worn lor 12 hours and removed for 12 hours. However, Prinzimetal's or variant angina worsens earty in the morning, perhaps 00e to drcadian catcd10lamlne surges. These patients' n~ratc--lroo interval shoold be tale afternoon.

on

B. lsosorbide dinitrale IsosorDIde (fm/trale [eye see SOR bidlI]ls an orally active n~rate (Figure t8.3). The drug is not readily metabolized by the liver or smoolh musde and has a IoWllr potency than nitroglycerin in relaxing vascular smoolt1 muscle.

III.

~ADRENERGIC

BLOCKERS

The j}adreocrgic blocking agents suppress the activation ollhc heart by blocking II, rccepfors (sec p. 73). They also reduce 1tIo work of the heart by decreasing cardiac ootpul and causing a s~ght decrease in blood pressure. Propranolol (see p. 74) is the prototype 01 this class ol compounds, bu1 other fl-blockers. such as metoprolol and alenokJl ara

• ....... _,., . . . . . . . . _

... , >

• co- • _ _ : ......." """""" _ ........ ,.. >

on

IV. Calcium Channel·BIockers equaDy elleclive. However. ag<:mlS with ~rinslc syTll)lIlhomimclic activ· ity (for example:!. pfnddo/and sceourolol) aro less ertect/Ve and should

be 8YOidcd. The Il-bIoc:kers rec)uoo the Ircqucncy and SCYI!rity 04 angina anacks. These llgf)flts are particula'ly uscIiJ in the lrea1mont 04 patil!nls with fT1)'llCMiaI .-naretion. The ~ can be USBd with ni1r.ltes 10 Increase twIrcise oulll1ion and lolerance. They are, howeYef. c0ntraindicated in patients with diabBIBS, periptl9r8l vascuIat diseasoB. or chronic obstrvetive pulmonary clisease.

Key;

IV. CALCIUM CHANNEL BLOCKERS The Qlil;ilm chamell*:ld<ers ~ the cnlrllnc:o 01 eek::iun inIo c:aRiac and smooch nu;dB cBlls 01 f'oB 00f00llfY and syst8i ,lit arterial beds. AI calcium channel blocks,s ara tha'efore va$Odilators thai cause a dea e in 6ITIOOIh rnu:sdB IOnfI and \OlIsolfar resistance. (See P. 187 lor a oflha meet• •" of8dion 01 INs got4l 01 dIugs.) At dri::al dose$, these lIgElrllS affec:t: primarily hi Iesistanee 01 vaso ...., a,iOIlfl nu;dB and 1t1B ~ [Nl;Jte: ~many affects hl fT¥lCiIIdil.n\. ~ .1IiIfe4:ti.. -.s a g<eater eflod on Sf, .......... rrus-dB in 1t1B pe9191a1YBSO' ........... DIIrianlmis inlefTnBliaIe in itslldions..]

dBsa"""

_:, ""......

A. Nifedipine; Nif6dl'pine [nye FED I peen) lunctlons mainly as an a,teriotar This drug haS " ...., . et1ed on eattiac alI'ldu;;tion or

F"tgUl'e 1L3

heal1 rate. ,~ ••'" Is aOl.ilskllod ~ and has a shor1~-Me (aboU 4 houIs) ~ rnAPo ~ The vasedalion eflod 01 nI.fedP'le is uscliJ in the tmatment of variant engina caused by ~taneous COIonalY spasm. Nifedipine can cause flushing. t ..... he. hypofcnsion. and pilI~ ooema as side ettods 01 its vasodilation activity. The drug may cause rellex tachycardia iI perij:tIBraI PS ;datior'l is marlled Iesulling in a sUl5IantiaI decmase in blood peSSl"8.

cI action tor two organic nitrale

'75 dilator.

B. VMlplImil

\Ierapiwnit [ver lIP a IriI) slows can:liac ClOfl(b:lion diroclfy and rhus OBcreases hearl rate and oxygen demand. VBrapamil causes grealer negalive inotroplc: ellocls Ih8n does nifedPine. bul it is a weaker vasodilator. VBntpam/l if; CQrllraindicaled in patlents with pi B isling depressed can:iac Il.nction or AV c.ondudion abnormalities. II also causes constipation. ~ $I'QA(I be used with c:a...... tior'l in digitai2ed pationls. since it inl;:rea$cS digoodlleo'els (see P. 160).

C. Diltlazem DiItiaz8m l
nne to peak etled ~ cU1lIion

-'"

..........,.... -... _,. 18. Antianginal Drugs

'" DRUGS COMMONLY USED

CONCOMITANT DISEASE

IN mEATlNG ANGI'tA

.... ",,,,'INFARc'TiON w "'"""""'" H

ASTMMA. COPD

I

Ilona. Ilo",""'.te]

HVPERTENSIOti

H

I

DIABETES

"""""" ""..."

11M

DlSE1'SE

ha.

KEY;

Coo._•.

_~

Ic.. -.- I _~

Figure 18.4 Troatmenl 04 angina in pl'I1icrrts wiltl corcomitarll disc8scs. COPO. chronic obsUUdiYe ~ disease.

Study Questions Choo$c lho ONE besl answer.

."'_011 00l1Clll'"''ll

18.1 .... DI hll
~

A. ncauses ..... - - . Of ."'. "liar cQ,F. 6.. !'owgoes IigniIicaII firsl-pass "'8"9boli:!m'" hi

....

C..may_ .... ilkao...... ~ D. • """'.... "Y dIa "" I AV CClI'ft1cticnCotraDI chDIaI • D. '" _ III ot. ......-v.. 4oI.lgI."". --,. ' •.., ~

..""' ..... gic tIIOCb<'&. ,... ogIyoorln does MIl blOCk impulse condUClIon in the 1lHr1.

... "", ..;,, _ _ ,. I

I'~.~m

1·. . ......,.,...-.. I.~ Th& lJUgll ad ~ Ot 'alOdor· mally to II\ICIlcl holpatk: in&dWation. 1ocnI&_

W'.'OilY' GF.·

[

_.

'-'1 rate h'tm!he _ ... in .... -..... ' . lilI iOO 8IId drllp in I*XXI ~ .. r.:u.d by

182 Whidl

al8d""'"

D1!he ",*",iolg adverse eIIeds II

assoo;j.

c._ .-

CII1'Y01rIn?

~-

6. TlwtottJO'll ~ D_selUlll~

brG I. . . . . . 311m lIO'II. DI

WIirG IN

n... _ d>cl:u .... io ' "'<4\JCOO;,' mill' _ ~ Itjp
I

'_ Lj

·....... _,., .. _--,.

• •_

•••

.~_~ •• ,

-.... _

Antihypertensive Drugs

........ PI' >

1 ANTIHYPERTENSIVE DRUGS

I-

,--DIURETICS

""",,,,,.,-

I. OVERVIEW HypcrlensiOf1 is defined as a sustained diastolic blood pressure groater than 90 rrvn Hg accompanied by an elevated systolic blood pressure (,.140 mm Hg). Hypertension results I,om increased peripheral vasct.Jlar smooth muscle tone. which leads to inc0<1 people). Although many of these individuals have no symploms, cllronic hypertcnsioo-eilhor systolic or diastolio----ean lead to congcsti\lll hean failure. myocardial infarction. renal damage. and cercbrovas<::ular accidents. The incidonce of rno
II. ETIOLOGY OF HYPERTENSION

-.-. ----- ... '...... Tn...'oht'....

-

II BLOCKERS

~

n_

ACE INHIBITORS

Although hypc,tensiOf1 may occur secoodary to other disease processes. more than 90% of paticms have essential hypertension. a disorder of unknown origin affecfing the blood pressure-regulating roochanism. A family history of hypertension incroascs the likelihood that an individual win develop hypertensive disease. Essential hyperten· slon occurs four times more frequently among blacks than among whites. and ~ occurs more oIten among middle-aged males than among middle-aged females. Environmental factors such as a stressful lifestyle, high dietary intake of sodium. obesity. and smoking all further predispose an individual to the occurrence 01 hypertension. Figure 19.1 SfJf1YI13lizes the drugs used to treat hypertension. [NOIe: Nonsteroidal anti-inflammatory drugs (NSAID) (see p. 403) interfere with the hypolensiVII action of many antihypertensives.]

capropril

'-' Moex.;,rll

""-'

L

ANGIOTENSIN II ANTAGONIST

I

~

Figure 19.1 Surrmary of antihypertensive drugs. (Figure continues on IlCxt page.)

---

......-.-....-.,,-, .... c.e-.,oo. .. _ ..... e."""'........ J. _ _ A.

~_._

'"

.

< ,.,.<----,. 100

19. AntihypertensiVe DnJgs

ANTIHYPERTENSIVE 1DRUGS __

III. MECHANISMS FOR CONTROLUNG BLOOD PRESSURE Arterial blood pressure is regulaled

-

a narrow range 10 provide adequate perfusion of the tissues \\lTIhout causing damage 10 the vascular system. particularly 1hfl arterial inWna. Arterial blood pmssura is difBCtly proportional to the product of the cardiac output and !he periphefal vascular resistance (FtgUr9 19.2). In both normal and hypertensiYD indiviWals. cardiac outpul and peripheral rcsislance are controlled mainly by two CM!rlapping conlrol rnochanisms: the bamrellexes medialed by 1hll sympalhr;tic nervous system, and the renn-angiotensin-aldosterone sys!em (Fi9ure 19.3). Most antihypertensive drugs lower blood pressure by red.ocing cardiac ou1put ardfor deacasing periptJerat resistance.

c." CHANNeL BLOCKERS

'",-

"'-

fflt:~

Nit«J/pinfl

~

m_,w.

"'-' -

""'''' -..........


A. Baroreceplolll and lhe sympathetic nervous syslam

I

e~

r..........

~

,-

,"",-

-~, , ~ Sodium Figure 19.1 SummaI}' of antihypertensive drugs.

BaroreMcxcs involving 1t1e sympathetic nervous system are responsible lor the rapid momenHo-momenl regulation ot blood pressure. A fait in blood pressure causes pressure-sensitive neurons (baroreceptors in the aorfic all:h and carotid sinuses) to send lewer imputses to cardiovascular C(!nlers in the spinat cord. This prompts a reflex response of increased sympathefic and decreased para· sympathetic ouIput to fhe heart and vaSCtJlafum, resulting in vasoconstriction and incroased cardiac output. "These changes restJ~ in a compensatory riS(! in blood pressure (Figure 19.3. and FIgure 3.5. seep. 31). B. RenirHInglotensin-atdoslerone system

The kUley provides lor the long-term control ot blood pfllSSUre by altering 1hc blood lIOIume. Baroreooptors in the kidney respond to reduced arteriat pressure (and 10 sympalhetic stimulation of ~­ adrenoceptorsj by releasing the enzymo renin (see Figure t9.3). This peptidase CO!MlfIs angiotensinogen fo angiolensin I. which is in turn OJrMlrtod to angiotonsin II in the presence of angiotensin c0nverting oozyrTl(l (ACE. see P. 100). Angiotensin It is the body's most

[~I

ITI ,*1 1 lANCE

Arteriolar val....... Conlractl'it~

Figure 19..2 Major lactors influencing blood pressure.

< ....

'0._1.'

><

, >

<

<_ ..... :__.,

l
....... PI' >

'"

IV. Treatment Strategies

Response mediated by lhe .ympllthellc

nervcu••y.1em

Decrease In blood pressure

I

A.ngk>Ienoln II

_- ......

Response med'-t8d by lhe renin-angIOlen-'n-aldo6Iefone.ysIem

Figure 19.3 Response 01 the autonomic nervous system and the renin·angiolensin-aidolitIlfOrle system to a decrease in blood pressure.

polent drculating \IllSOCOI'lStrictor. causing an ncrease in blood pres· sure. Furthermore, angiotensin II stimulates aldosterone secretion, teading to increased renal sod'Lm reabsorption and an increase in blood vollJrTl!l, which contribute to a further increase in blood pressure).

IV. TREATMENT STRATEGIES Mild hypertension can often be controlled with a single drug. More severe hypertension may require treatment with several drugs that are selected to minimize adverse effects of the combined regimen. Treatment is initiated with any 01 lour drugs depending on the individual patillnt: a diu.etic, a (\-blocker, an ACE inhibitor. or a caJcilm channel bIod<ef. It blood pressure is inadeQJ)lItely controlllld, a second drug is added. A J\-blOc:ker is usually added if the initial drug was a diuretic. or a dl ....etic is added if the first drug was a l\-b1ocket. A vasodilator can be added as a third step fof those patients who stililail to respond.

• • .0< . . . . .

",

'.'.<

'> 19. Antil1jlpertensive Drugs

DRUGS COMMONLY USED IN TREATING HYPERTENSION

CONCOMITANT DISEASE

I

ANGINA PECTORIS

ACEIn_.

I

• Ch""nel b4<>cknro

DIABETES

Ch~"n.1

!>jocke,.

(lNSUlIJ'H>EPENDENT)

HVPERUPIOEMIA

:.•••.••••A'VOid•••••• --':

COHClESTNE HEART FAILURE

.-

-1c PREVIOUS MYOCARDIAL INFARCTlON

-1

CHRONIC RENAL DISEASE

ACE ••h,Me,,"

Diu","",

-1P ASTHMA, CHRONIC,EI PULMONARY DISEASE

KEV:

~!':'..;

!~_

j

ACE mM'lero

'--,~.=u=~=.--,I

I

:

I

ACE

I

ACE Inl\illilcd )

Inhibi~

)

--

Figure 19.4 Trealmenl 01 hyper1ension if1 patief1ts w~h oonoomitanl diseases. A. Individualized care

Certain subsets 01 the I1yper1ensive population respond better 10 one dass of drug than anottlef. For llJyper18f1sive patient popula\iof1.

.......0._'.')._ ... _')

'"

V. Diurelics

e. Patient compliance in anllhvpeften&lve therapy Lad< at patief1t c:ompIianc:e is lhe mosl CIOrmlOIl reason 101 faJul8 at antihrPOrteosMlthefllPt'. The twer1ensiYe palient is usuatv asvmPlomatic and is diagnose
V. DIURETICS ~

anrVor

tl-1:lIod!ers are curenllv 'flCOIIOllIfllled as the 1irsI.me

drug IherapJ klr ~ ll7 I' :'0 '5"' diuretic Ihefilpy is sate and etlediYe in prB'oBiolihg Slroke. tI1)'OCafdial inIardion, a ...,esliw heart Iaiure and kltill mortality. Reeerol d81a suggest IhaI diuretics llf1l Sl4l&riO!' 10 ~ in okXIr ~

AJ 0f3l diuretic Ougs _ etIeaiYe in the !fMlI1....... 01 ~ bulthe ltiazides IwIYB t:Jtnj Ihe mosl widespread use. 1. AetIons: ThiiI.zKle diuretics, soctlas h)Oor;hbrolfiazjde Ih'Je ctoe Idor oh THYE a zide). IcoIter l*lod pressure. iniriaIy bV IlCf lI5ing sodilrn andweter eJ
2. TI1erapeUdc uaes: Thiazide cliuAlIics decrease l*IDd pressure in boCh the supine end $landing positions; posl\lral /1)'poIen:sion is ra,ely observed. except in ekleffy, volume-depleted patients. These agents counteract the sodium and wate, retention observed with 0Iher 8gllf1ts used in the trealr"nllOl 01 twertension (1oI9K8f11I)Ill, Ilydra/anirle). Thiazidlls are the,elore useflj in <::ombination therapr with 8 variety 01 other anIih)'pertensive agents including fH>IOCkeNil and ACE inhibitOrS. Thiazide diuretics are particularly useful in the trootment ol black or IIIdlIrIy patients, and in those wilh chronic renal disease. Thiazide diuretics are not elleclive in patients with inadequale kidnev function (c,ei!tinine clearance less lhan 50 mis/min). LooP diurelics mar be require
",-",+1 " ..

~~

.-

o

5

10

15

'rr"......::r:::::

F"rgure19.5 FI8Ql&ICY III oa:urrenoe III

OOIlCO loiLanl disease among the h)'pllrtllnSiYB petieroI P'lJ'.etion.

Thiazide diuretics

Pwrlpl.'"

-dd ...

Oacreasc In blood pres!lurl1 FIgure 19.6 Actions 01 thial:idll diuretics.

<.........,.,.<---,.

< """'" • - - ' """"'"' .. _

".

.....

19. AntitrypertensiYll Drugs 3. Pharmacokll1t!tks: Thiazide diuretics can be administered orally. The~ induoe considerable disturbances In electrolyte balance. For example. blood I~s of K+ and Mg" are reduced, and Ca" is retained by the body (see p. 229).

4. Adverse effects: Thiazide diuretics induce h~pokalemia and hyperur;r;emia in 70% of patieflts, and hypefglycemia in 10% of patients. Serum potassium levels shoUld be mon~ored closely In patients who are predisposed to cardiac al'l11y1tlmias (particularly Individuals w~h lett ventricular hypertrophy. ischemic heart disease, or chronic congestive heart failure) and whO ara concurranlly being treated with both thiazide diuretics and digitalis glycosldes (see p. 160). Diu.etics should be al'Oid&d in the treatment of hypertensive diabetics or patients w~h hyperlipidemia.

B. Loop dlu.etlcs

The loop diuretics act promplly, even in patients who have poor renal function or who have not responded to thiazides or other diuretics. The loop diuretics causa decreased ,enal vascular resista/1CE1 and increased renal blood flow. [Note: Loop diuretics Increase the content of urine (see p. 227), whereas thiazide diuretics decrease the concentration of the lJrina.]

ca-

ea"

VI. P-ADRENOCEPTOR BLOCKING AGENTS J\-BIocI<e.-s and/or diuretics are ctmently recommended as first-line aug therapy for hypertension. These drugs are efficacious but have some conlJ3indications.

p-Adrenoceptor blockers

•

.....:::.......-9 ._.J! I

D~"I Figure 19.7 Actions of I\·ad.enoceptor ~oo
Oecreasa in blood pressure

< ........

_1.'

><

, >

'"

VI. jl-At!renoceptor Blocking Agents

A. Actions

The J}-blockers reduce blood pressure pri'11af1y by docreasirlg car· diac output (FIQure 19.7). They may also dec<ease sympathetic out· flow from the CNS and i1hibil the release 01 renin from the kidn8)'s, thus dlK:reasing the !ormation 01 angiotensin II and sec.etion of aldosterone. The prototype /HlIod.er is propronoIoI. which acts at both II, and Bz receptors. N _ agents. such as stendal and melrr pmlo/, are selective for tl, receptors. These agents are commonly used in disease states such as asthma. in which propanoJoJ is c0ntraindicate
1 LlL"--'

B. TherapeulJc Usefi

1. Subset", of the hypertensive pc:>pulatlon: The J}-blockers are more 9ffective for treating hypertension in white than in b1ad< patients, and in young patients compared to the elOOrly. [Note: Conditions that discourage the use 01 (HlIockers (for example. severe chronic obstfl.lClive lung disease, chronic congestive hean lailure, severe symptomatic occlusive peripheral vascular disease) are more commonly found in the elderly and in diabetics.]

2. Hypertensive patterlls with conc:amltan1 diseases: The J}-b1od<ers are useful in treating conditions that may coexist with hypertension, such as supraventricular tachyatlhythmia, previous myocardial infarction. angina pectoris, glaucoma (applied topi· cally). and migraitlll headache. C. Pharmacokinetics

The lI·blockers are orolly active. Propranolol undefgoes elllensive first-pass metabolism. The jl-lllod;ers may take S9V(lraJ weeks to dlMllop their full effects. D. Adverse effects 1. Common elleets: The jl-blockers may cause CNS side effects such as fatigue, lethargy. insomnia, and hallucinations: these drugs can also cause hypoI6f1sion. The J}-bIockers may dec<ease libido and cause impotence: drog---induood sexual dyslunction can severely reduce pallent compliance (Figure 19.8).

2. Allefstlons In serum lipid patterns: The f\-bIDckefs may disturb lipid metabolism, decreasing higlHlensity lipoproleins (HOl) and increasing plasma t.iaqlglycerol.

3. Drug wlthdtllWal: Abrupt withdrawal may cause rebound hypertension, probably as a result of up-regulation of II-receptors. Patients should be tapered 011 of J}-bIocker Itlerspy in order to avoid precipitation of arrhythmias.The lI·blockers should be avoided in treating patien1S with asthma, congestive heart lailum, and peripheral vascular disease.

Ff9ure 19.8 Some advafse ellects 01 II blockers.

..........,.... _----,.

".

• <_ ....---........' _

.. _ .....

I : -..._ .. -._... I I •0 Dm~1

I--=...

."'hl ....... ---iii'e •.";::::::, $

i

ACE Inhlbltors

-- - t ..' p

,

-,,",

.... ""

Agure19.9 ElleclS or ACE inhibilof's.

VII. ACE INHIBITORS The angiotensin·converting e~me (ACE) Inhibitors are 'lICOf'I'ImElf ideO when the preferred fIrst·1ine agents (ditlfetics Of 1\-I;lIodlefs) are ... 41..•• a,ed Of inefledil'8. Despite lheir vride-spfead use,. Is fIOI dear .. antihyper1eflSiye Ihefapv with ACE inttiors inc:feases the risk ol othe< major ciseases

The N:;E iolilbiklos kM$l:*lOd p < _ by ,lDJcing pelijAMIfIII VIISaAar resistanc8 wilhoul ref\eldy ioe lying Cllf(iac 0l/lplA, rate. Of ......ill...... ~ These 00Jgs t:b::k \toe 8I1gio...sili COf'M!rting llI1ZyITl8 that cleaves angiotensin I to Iofm the polenl v8SOCOf'l$lriclOf, lIf90teflsin It (F"IgUf9 19.9). These inhibilOfs also ~ the l'8Ie or b.adykinin Inactivation. Vasodilalion OCCUfS as a ruull 01 the combined eli&cCs or lowe. vasoconstriction caused by diminif>hed levels 01 angiOlensin II and the potenl vasoditating el1eel ot incfllllsecl bradykinin. By reduCing ei'CtJ!aling angiotensin II levels, ACE Inhibitors also decrease the secrellon ot aldoslerone. resu"ing In decreased sodium and water retention. 8. Therapeu1le UHa Lite ~blodo;e.s. ACE WliI:llon; are fl'oO$l. etleaiYe in hypeftenSive patients whO lIfelWhite and )'OI.Wlg.liowlMlr, when lISOO in ... ,tliollllion with. ditlfelic, the ells solACe ioihitlQs is.,..., in white and black hype.tensiYe palienls. Unlike ~bIockefS. ACE il~s are etIecliw in Ihe management 01 PilOOli1s wilh choilic conges'M1 NartIaiUe (see p. 156). ACe ioiotJibs life now a ~ da.d in !he care 01 a palietll loIIoWiflg a myocafdial infarction. TheIapv is &IatI8d 24 hcufs all&' Ihll em olthe ~

I·...

•

C. AdYerse eftectI, Figufe 19.10

Some 00fm"l0f1 adverse elleds or the ACE inhibitof's.

Coii.''''' side eIt9cls include dry oough. f3SheS. ilMI., 3lteIed tasle,

h)'polen$!on (In hypovolemic slalils), and hype.kalemia (Figure 19.10). Potassium '-Is rrust be monitored, and potassium supple-

..........,., .. _--,.

"-~""

"-',--_."".

'"

ments Of spifonoIadone (see II- 232) 8fe contraindiCated. Angi0edema is a ra<e but polentially ....It<
VIII. ANGIOTENSIN II ANTAGONISTS The rIlIIlOp8p!lde losMan (lOW sat tan]. a highly sel8diYe aogioIensin If receptor bIocke•. has .ecently boon apptcMld lor antihypertensive

therapy. Its pharmacologic ellects 8fe similar to ACE Inhibitors in thaI ~ prod\Joos vasodilatTon and blocks aldostef008 secretion. Its ad\t(lrse eUeels prOfile Is improved lMlr lhe ACE inhil~or5, a/Ihol1gh ills lelO-

tco:.ic.

IX. CALCIUM CHANNEL BLOCKERS CalcIum chamel blod<ers are reoonmended when hi pela,ed

Iif$l•

...,. 8Ig8fll$ are Wi 'bai"dicaled Of • oeIlilldiYa. DesPle !heir IIJide $plead use. it is rot dear what eflects IIf'ItitlypeftensiYe 1hef3P)' with lhese augs hes on ITliljor disease In hypeft8flSi.. palietlts, one -1iYe study 5"£ sts 1haI usa aI shOf1«:ting caIciun chamllll:*xtas, espe-

,8tI,..

cially in high doses, is assoriated wiltl an ncreased risk aI myor;::atciaI inlardion. • Wi,liomed in lTIOfe rigorous .a"do,,~ lrials.ltlese find.ings wi! .ei"bcelh8 impOf1anoe 01 tiu'etics and ~~rs as 1irsI-linEI agents

r,II Dilation of W coronary vessels

,e \

.~".

DN

"

.ness conIr8indicated.

A. ca..... 01 calcium ct\8lnnel blocker.

h.

Va;

m

-

AV Conduction

The calcium channel blockers are divided into lh.ee Chemical classes, eadl with dille.8n! phafTTl3COkil1etic propenies and clinical indications (FIgUres 19.11 and 19. 12). 1. Dlphenya.II'ylamlnes: VorapamiI rver AP a mil] is Ihe only mem-bel of Itois class tI\ill is cunen!ly ~ in Ihe United Slates. ~ is Ihe Ieasl seI9CIiYe 01 any c:aIdl.m d'\lIf"neI blocI<er. and hisS signiIic8nt efleQ:s on both cardiac and vuc:ular 5mOOlhmuscle oeIIs. • is used 10 t.eat angina. supraVllfllrictABt tad1y. ~ and "oigIaine Medadle. 2. 8efv.othl.-.",. -.: DIi*i&zem Illi lYE a zem] is It>e ody rTI8fT'tl8f" 01 Itois dilss Ihal is CUffera!y approwd in Ihe '-"*'d S&ales. like I'l!f'apami/. ~ atIects both cardiac and vascular SITIOOIt>-fTII,lscle cells: howeve•. it has a less pronounced negative inotropic effed on Ih8 hNrt 1hlIn does ~ DiIirl.la'n has a

laYOfable side-ellec;l: profile. 3. Dlhydropyrldlnes: TtWs rapicIy ~ das$ 01 calcUn chamel bIod<ers includes the ~fSl-generalion nifedipine [nye FED I peen].

0e
I!I adver5e Frequeocy ot effects

lI'll._ :..;. ·:·:'=··:~~:~I .., ,... OIl;" • • •

no

Agu.. 19.11 Actions 01 calcium chameI bIocl<er.i.

..... ,....,.... - ... _'> '88

THERAPEUTIC INDlCATlONS

"''''''''''''''''

SUPRAVENlJlICULAR TACHYARRHYTliMIA

SAFE IN MIlD-TO-

APPROVED CALCIUM CHANNEL BLOCKERS

Dkd_MMI##4Ia11D§f§&

-=

--

--

MOOERATE CHf

KEY:

--....

I

Rgure 19.12 Some \hefapeulic awbtionf; c:l caIcUn chameI bIoctters. Cl-F. oongesliYe '-'1labe.

and five new agents lor treali1g cardioYascuIar disease: 8ITIIot:Jifr ine [3ITl LOE di peen]. ~ IIeII OH di peen]. ~ leyoo RAD I per1]. nicardpine Inye KAR de peer1] and niscIdipine [Ili SOl de peen]. Those seoond-geneI8lion calcium etl8nne1 bIodIefs dil· ler in phermilODkinelics, approoied uses. and drug interllCtions. AI It'oe ~ !'lave a much greater atftlity lor vascula< CIII· dum chamels Ihar1 lor calcium ctIaMels in lhe hearl. 'They 8f' lherBlcnI patticullIfty atlral:tiYe In Ir8aIing hypertension. Sane c:l ! h e . - agents, $LICtI as and ~ haYe the lldYarUge II..-: they shoW Iilde ~lElfat1iol. wiIh 0Iher ClIfclt:nrso'" Ougs. suc:h as 6goU1 (see p. t6O) Of Mo6IiriII_ P. 199)lhal are ofWo ustod COl iOOililai illy dI c:IIIciI.rn d'Iamel t:b::l<8f drugs.

"'*'<APi"

B. Actions

The illbac....' COIlOOIlbalioi. c:l c:8t:ium plays an mportanl role In ITICIintaining the lone 01 SfTICIOlt>.mJsd and In Ihe COl itl a:Jioi I c:l !he myocardium. Calcium enters ~ eels ltlrou\tl spacial YOIlagesensilMI eaIcium channels. This lrigger$ release 01 caJciI.m from \he salooplasmlc retlc:ulum and mitod'londria. wt1ictl lurthe< incf88$8$ the cytosolic level 01 calcium. Calcium dlannel antagonists bIo<:k

..... , •• _l.O

,<

, >

<
, __ • __.,

.... >

'''' the ~ mcwem8f1t of <::ak:UTl by billdiilY 10 L -type calcium <:hannels in the Narllnl in SfT'lOOltHTusde of the lXIrOIIiWy 1nI per1Jheral vasaJialUfe. This causes vasculaf lIfTlOOIh muscle 10 feIax, dialing mainly 8I1eo kAe$. C.~

..._

CaIcit.m chaMeI I:llol;:br$ haYB an intrinsic natrilJre!il;: eIfea: 1hef'" be, they do not usually reQUire the ad6tion of a diuretic. These &gllflIS are use'ul inlhe treatment of hyperlensive pa1ients who also have asthma. diabetes. angina. and/Of pefiphefRI vascular diseaSll. D. Pl'\lIrmllcoklnetlc:s Most 01 these agents haYB short twllI·1iYes (l,~_ 310 8 twus) IoIowirlg an 0faI dose. Treatment is required It\(ee times a dey 10 maintain good c:cmol of twertension. Sustained ft!1BaSlI preparabons permlle$S "equent ~

E. Adl<erse etfec1s

1"'"

AIthougtl inlreque.... skle ellects indude <:onstipation in 01 patients. dizziness, n e ~ and • feeling 01 taliglle ........ed by a deaease in blood pressufe (FIYUfe 19.13). Verilpamjl shoUkl be aYOlded in treating patients with c:ongestive h6art fa~l!rll doe to its negatiVe ino\1opIC ellec:ts.

X. a-ADRENERGIC BLOCKING AGENTS Pnuosin, 0lCaZ0SiI'I and lenuosin (see p. 73) produce • ~ bIoc:k 01 a, adrel'lOCepKlls. They d8<:te8se ~ VSSQlIar fesi$tanee 1nI loWer arterial blood ~. by C&usWlg the felnalion of bof'1 arterial and *lOUS SfTJXJIh rrusde. These O'ugs cause orlIy rrnmlIl dllIllgllS in C8IdiIc: output. renal blood bot, and liIbatia, f8J8. Thel......' Iong-Ierm lad1y(:ardia 1nI joe ssw renin release do not oa:uf_ Postural hypolension may OC:Wf in some indMduols. Prit-

iJD'.'"

zosirJ is used 10 lI'etll mid 10 nWJdsr.lle hypefteroliUl and is prescribed in \XIrIiIinalion with propran01oi Of a diuretic b additive etlects. Re'lex lachycardia and 'irst dose sync:ope are almost univefsal adverse elfects. Concomitanl use of a ~ockef may be nocessaoy 10 blum the shorl·lerm o!!oct 01 ro~e. tachycardia. Flgur. 19.13

XJ. CENTRALLY-ACTING ADRENERGIC DRUGS

This aragonisl 6",;"isloos c:enlfal adf8nergic outflow. Cblidine

[KLOE rri dllenl (see p. 61) is used primarily lor Ihe If1Iatrl&lI 01 mid 10 fTl(l(ief"8!e hype
Some oommon adYetse eIIects 01 the ealeiI.n1 chamel blod<ers..

..........'., ........ _'. "'0

19, Antihypertensive Drugs

absorbed well alte, oral administration and 1$ 8!lC.eted by Itle kidney. 6ecause it causes sodit.m BOd wale, ,etention...... ulfIls usually administe.ed in combination with e (liu.etic. AI;Mlrse effects life gene.aly mild, but Itle drug can produce se
B._

TNs u.a s.. -~ is CCfMlrted to rnett1yRlf~oentraIy ID aa-gic Otdow Imm . . CNS, "'nfqg to re
iii,.", h

ished. Because tbld ~ to !he kiltley is noI 1iI,.1ished by its use, a-ma~ [math il DOE paJ is ~ YllIuaUe in trealing hypeftensiYe patients with renal insufficiency. The most common Qde etlects of a-me/hyttlpe are sed91ion and dfowsines&.

XII. VASODILATORS The di.ect-ecting smooth muscle ,eLaxants, such as hydraJazine and minoxidil, have trad~ionaIly not boon used as primary drugs to tleal hypertension. Vasodilato,s ael by producing relaxation 01 vascular smooth muscle. whict1 decreases resistance and tllerefore declllas&S blood pressure. These agents produce 'eflex stimulation of tile heart, ,esu~r.g In tile competing symptoms 01 Increased myocardial contractility, healt rate, and OKygen consumption, These actions may prompt angina pectoris. myocardial infarction. or car
'*_

A. ttydnIlazlne

TNsdrug direct VlISOdiation. acting primarIy on 8ilel'ies and lIr1erioles. This .est*!; in a decreased ~ resislanoe. wtj(;h in tI,.m PfOI'T'IlS • f1llIell elfMIlion in hurt rata end ClIlCiac outpl.C. ~ (hre ORAl.- a _ I is used to tr_ modemeIy severe ,."peoteolSio~ II is amos1 always ..arliistervd in ...... ,tillltitA,.wtl a fH:t'odo:er sud! as prorxanoIoI (to be. QI thti .etID 13d'1yeardia) ..-d. diuretic (to decrease srxIU'n ,~). Togelher. the ltYee drugs dec e ClIlCiac 0I.tp.t. pI8sm8I voll.me. and peop lilfilI vasaAar resi$tance. Adverse effects 01 hydralazine thelapy include heaclac:he, nausea. sweating. a'rtlythmi., and precipilation 01 ~ A Iupus-Jike sy.ou"e can 0CQ.lr ~ t-.;. dosage. tu it is reversible on cisr:altn.Jatio of !he drug. B. Minoxldll

1Ns drug causes dilation of ,esiSlance vessels (arterioles) but not of capacitance vessels (venules). MinoIfidiI [rri NOX i dill] is administered orally lor lreatrnerrt 01 _ a 10 malignant hypertension thBt is

·

,.. -

_,>

• c....

~ ,

1CI'CNUl _ _ , ... >

'"

XIII. Hypertensive EmefgfIflCY relractcwy to 01tlll. drugs. Aefle~ tachycardia mBy be _ e and may require the concomitant use 01 a diuretic and a iJ.-b1ocker. Mn:»dcJiI causes serioUs sodium and water felenlion. Ie ± '9 to vdume oo.oertoed. edama. and mngeslMl heart laJb'e. [Note: MinoIdfM treatment also causes hyper~idusis (the grow1t'I 01 ~ hair). 1ljs drug Is now used IopieaIIy to treat mala patIem b8b I

,~op

•. $

XIII. HYPERTENSIVE EMERGENCY ~*ISi .. liIfTliWgeriCY is a rare. blA Ida-ttnlaRW'lg silUalion iI'l VIItdl 1he (IaStOlic: blood pressure is 0lI9r 150 mm Hg (with systoic l*lod pi ... greater flan 210 nm Hg)'" an oIhlIl .. ise halIIIt'tj' person. Of 130 nm Hg in an indMdtIaI with pre&' isIing WiIiPiC8tioll$, such as eo ~lIlkoflaltly. C$'llbfal t8'nontlage. Iefl ~ 1lliUe. Of tic lo18i 10M. Thelher8peUic goal is 10 repety .ewe. blood plMSUfa A. Sodium nitroprusside

Nitropt1JS5iOO [nye troe PRJSS oe] is lldminislered Intravenously, aod causes prorl'fJl wsodilillion, with rellellladl)lcardia. It is C8PII1:*I 01 reducing blooxl pressure iI'l an patients, regardless oIfhe caUSll 01 hypertension. The drug has little etIect outsicle the IAIIswlar system, acllng equally on arlerlal and venous smooth muscle. INote: Because nitroprussido also acts on the veins. II can reduce cardiac preload.] Nitroprusside is mEltabolized rapidly (t,,o: 01 minutes) aOO lequlres continuous Infusion to maintain its hypotensive action. SOCfum nlrropnlSSlde (ll<8f1S lew aclveffle etlecls except lor those 01 hypotensiOn caused I:7f lIII9rdose. Nitroprusside melabolism results In cyilrlk:le ion proOOcIion, altt"oogl cyanide toxIdIy is rare and can be etlec:lk!eIy treated with ilI1 iI'ltusion 01 sodiI.m ttVosultale to procklo8 ltiiocyaf1ale, wtW:tI is less \oIlic: and Is eliminaled by the kict1eys (F"lQ\Ire 19.14). INote: Nitroprosside is poisonous il given orally because 01 its l¥loly'Sis to Cf
8. DLazoxIde DfazoIdOB [dye az OX ide] is a direct-acling arteriolar yasntli!ator. It has vtlSCl.l1a. effects like !hose 01 hydrlNZine. For patients with cororery ~ 6amIlide is 8O'l'ini$lef«l ~ with a iJ.-bklcker, which diminishes reUp act,vation 01 the hearl. ~ Is useluI in 1he treatment oIl?,'perUlnsMI .... gerlCieS, ~ tlfIClOfltlaIDp, and 's E~c Ml hypotertsion Is thti most serious toDcity.

ectal,.

C. . . . . . I efIdfIId (see P. 78) is boIh an a- and ~ 1hnI has been sueoas:sIuIy used in twerfenSM:I _98' ICies. l..8bctaId cloe6 ncl cause the .ef\EIllact'rfC8ldilllhal may be as." ilIted WIth ~ L/JbCl.1IOI

c:ames 1he IXlilbail(i(;atiorlS 01 a 'OlSel

tiwl ~ (seep. 78).

1"'9'-" 19.14 De&oJealior. at cyanide WIth l'IosUIlate and rhocIltr Me

..... ,....J., •• _ ... _ ... ,>

'"

19. Antitwertensive DNOS 19.... 'M'oio:tI _

0I

W<elyto_ 19. I wtocn 01 ... 1tA>wir'll

"*Y~-hydi""

__

"'''''?

suiIed 101' poi-

~

B. ,.01........ D.tt,do ......

_

~

,eswog

C"-'

(

Iltl$_.

Con-et D. M'ong tAd<.-uents. diI.relIIc lWId ca;u" d'lIrneIl*:d.ers are ...."., etledMl lhan ACE ,nhlbtlOfI Of ~.IIlod
111.2 ... 01 .......... '11

PiOV."i·

O. C8pl1lp1il E. Hyli'a/lI.lQ

_-'lM-

c._

(

a iI\l'. . . . deo_ n

~

A. c:tvcnc i6•• OIti

01 dUetoc:I.

B.~.

) 0I'Ie

01 the lollowfflg drugs ids al C&f1lral

P''''~1IlIt'IiC ~ r«:eJ*lol?

A. MirloQliI

B. V.",,1iI C.Cbd...

0.'E.1t,;dtoJ...... oiIti>;IOt

eo.- _ . c. ~ I'I6..cM ~ '-;"'*-by ~ ~. . .9C 0Il0EIP" IDfS. MInodcll ii, di....:l--*'ll VIiSOdilotIOf". V. . . . . . . . -

•

dum Ion _ If'iII> 5fTlOOIh t*ldls .... enryme ... (lOll

iby"_""", EM&IpnI

, 110

..-.giolensln II. H)'droc:hIofOlillazide eels by

de<>

P,opt"8f'J01ol bIod<, )

g¥ ....., .

19.6 WIj(;h _ 01 ........... '11 dIvgi; shot*l nor r;,. ~ to. P'''ll' . . . h,per-' •• , woman?

A. .t,Ood....... oiu:de a PiOP_"*"

c._ D. I..i5inopiI E.V.........

D. ACE lti,blt:h. E.dolidil ....

19.3 Which

-

C. Ni!edipine

-'*' .......

~

=-::.::-" J -=-- -

A. PrazO&in B. P,opranolol

doonee 01 eIevaled caleCholllm1ne6 e.e beSl 1fM1e
--

Con8d_.D.I~

1Iojj?oAIo......... -

19.5 From ... IisI ot ~
_to

""*'

~?

c._

D. B.dl ...... a'ld eIdefl\I ~. E. PalierU will ~ r.... 1l..aicn

~"""IIypeo,,**ikp!

~._

A. PrOP_"*"

hypa._ ....,..

A. PPeo ...... gOlA B. P" . _ c. Vow.g ~

.... -

•• _

~II'I

1t*7wing

1'""Ilboo:l-.....

-.,.,.

tiort 01 .tgklMolfllti II. -..tidl II ... IIilllIor r'lOI' oml \lfOI"lh lIf'Id do\ I, 116 il 01 !IIlaIIl<Jdrley '""

·

,.,

.. _---,.

• -_.....

:

, __ -

_ . PI"

Drugs Affecting Blood DRUGS AfFEC'1Y«l

BLOOD

I. OVERVIEW

f-

ThiS chapte< desCflbes drugs uselul in trooting three Important dysfunclions ot blood: It1rombOSis. blooding. and anemia. Th,ombOSifl-the lor· mation 0' an unwanted clot within the blood YBSSels or hearl-is Ihe most 001'.'0' abnorrnllIity at hemostasis. Bleeding disorders lnIIoIving labe 01 hemoslasis ere less oorrmon than tIYomboembolie disMSes end n:lude hernophiIirl Md vitan*l K deIicieney. Anemias caused by rutItional def........ciBs can be treated with eithef dietary or pharmaceutiaII suppIelUlll,lalion. FleceIoty. ~ has been Iculd \0 be benefieial in the lfeatm8lt of sidde cell anemia. See F"9Jr.. 20.1 lo< a SUTIT\lloI)' at Ougs atIedii '0 bIooO.

PhysIcal trauna \0 the

''i/SOolat 5)'Sl8'1l.

such as a pmaure or aA.

C/o""'' ' ' ... r_'

f- ............... 1 ~~

nw~YTlCI

,_ s....... ~' .... 7'

ates a mmpleJc se.ies 01 interactions bet\, .... " platelets, endolheIial

f-

(II'A)

I

""'-..~ RlfFOWG

_"""",ole "'r..... ..... "... _.,.

..,/cI

.",il:_

A. formallon of a clot

V~_K

CIol bmalion requires p1etel8l activation and 899'egaOOn, loIIoMxf by bmation 01 It1rombn This senom protease C8lalytGs the pro.. duclion ollibrin whictl. when 0' 1ilk8d, ~ the dol t. RdiI of ptalelets· PIalel8ls respond to \lII.SCU8r lr8um8 by "actiYalion" proc as, ¥>fictI irMIIYe lhree steps: 8(1' '00 to lhe site 01 ;n;..y, release of intnIceItAar grarules. and aggregation of lhe p1I1lE ats (figure 20.2). NormaIy. plalelels ~ in lhe blood in an r.actMl torm. blA In response to variD<.G stm.AIlhey beOOl'lll 8dMlled. AdMlted platelets l.IOOgo "lOOlIcarions that okIw>ate In '11OIpI d)jjic dl!WlgeS lind in the ~ '> I 01 pmteirB and cell ~ For ~ aller acIllllwl!I \0 R'Ip"'68d ooIagen in Ihe subendolt1..lia' layers 01 inlure
---

~idomoIoo

EpI_g-

~

0lIl1s, and !he coagulation cascade. This results in the lormelion 01 a platelet-fibrin plug. The I;feation of an unwanted thrombus invoMls many ot !he same steps, e.cept that !he triggering stirrloArs is a pathologic: alndilion in Ihe wscular system rather than pt1ysicel lrauma.

I

AlJCi.o_' A.,,;rin

f-

11_ NORMAL RESPONSE TO VASCULAR TRAUMA

~n~

. ...-TORS

f-

---C)a

fl, ... ;

f-

I

""'-..~

•....., (8.'" ,

ti..

.1

TREAnEHI'Ol' SIClU..ECEU. A""'M&

~

•• ..-TORS

I

L~_

flgUl'l 20.1 Suom'Iary ot drugs used in treating dysfuncbons of blood. 'Oescrtbed in Pharmacology update, pp.446-448

--

~--". , -_._" ... ~O"""" .......1 _ _ ...

... 0 -

193

...........,., ....... ...--,.

......

",""

"'..........'

"94

- .. _.....

20. Drugs Affecting Blood

D collagen Damage to vessel exposes of subendothelium

2. Roa. of fibrin: local stimulation 01 the CO"9' llallon c:ascade b'l1actors re'eesed from !he i~ed tissue end p1etelels ,esul$ in the Iom\eticn 01 thrombin (Faaor II). In tum, ltVoo'l'tWl. 8 serine pr0tease, catalyzes the 0Xlfl\IefSi0n 01 fibmogerllO Ibin. wI'idl is illXllpaated inIo!he pIl.t'!J. &aeque,,1 0' linking oIlhe fibrin strands SIllbiIiZes the dol and forms a hernolIlalic plUg. 3. Tt.Ol,obuII _ _ embolus: A dol \tIal . . . . es 10. vess:el Will is c:lIIed. lhou,tJus, whereas an -.meG 'W dot IhiIIlloats wit1in the b600d is termed an embolus. Thus.• detldled Ihl"anbus beooilles .... err'IboUi. 80ch Ihou"bi and emboli 01''1 dangeruJs. .......... IVO they mil)' ocdI de l*Iu:l 'I 5 5 5 and depriI.oe 1isSI!(l$ 01 0Ilygen and nutlienls. ArWi&l thfombosis most oIten inIIoIIIes meditm-l;izel;I'c ds '(lOldeied lhiUilbog."ic by A.rtIc8Iesions oIerldolt1elWll oeIIs ..... "Sed by iIItlenlIdenlslln WliIIIiiSl WInOUS hUilbosis is triggered by blood stasis or ~ IIICfiIralion 01 Ihe CClI\PoIliJIion CIISCll
f)

Platelet adhesion and release of granules

nortl'IlIl defense tN:vnostaIie mechlnisrns.

8. Abrinolysls

Dl.rif'Ig plallllet plug formation, !he libMotyllc palhway is locally adiV&tecl. Plasminogen is enzymalically p,ocessed to plasmin (fibrInolysin) by plasminogen actiwuors p4'oser'll in the tissue. Plasmin inlerte,es in clot propagation and dissolves lhe librin network as wounds heal. AI pr8S9f1t. a number of librlnolylic enzymes are 8\1il.ilable for treatment of myocardial infarctions or pulmonary emboli (see p. 201).

D

•

III. PLATELET ACTIVATION

Platelet aggregation and formation of fibrin plug P1......

'ibII'

The outer mernl:lf3ne of pliltelets oonl8in$ a va,ie4y 01 receptors that furlc:j;on lIS sensors Olpab!e ol lospoudillg 10 physloIogic $ign&1s preser"t in Itle pIa$mll (FIgUre 20.3). These dlemic8tI !itimuIi are das#fed as platelOlt-llClMlmg if !hey pomOle plateletllg(p'803lion end the Slbsequent release of granules Slored in ltlOl platelet. ConYerseIy, olher chemical 5Ogl'lllls classified as platelet-inhibillng. if they intibit

.,e

platelet attivlltion and the release 01 platelet glanules. Whether p1etdOllS remain in e ,,'iss (lOll state U" bOlc:ot'lOl activaled is oed by N balance 01 aetio.oalDg and iotitJilio 'Y ctl8i,.... signals.

deb.,.

A. CtMmIc:aI signals that oppose platelel KliVIlIiott

•

l.

prostac:ydln levels: In a norrTlltI. undameged ~ , pial lits dn:uIate lrMy. silce lha bd 101 01 d1el,lical S91llIs rdcates thlt the vascular system is noI damaged. For el
spec.

figure 20.2 Formallon 01 8 hemostatic plug.

...... ,....,., )'---')

• <_ ••••.•._-~~....., - - .. _ .... >

'"

1

--._--"" .. .....

II'Iy,InIalCI.'olOa ......

--~-

• "'01111....., _

".,IIbo•• ,

10 .........

I'

'-'

.

.,-.",,~

" ,,<:co_a..

pM

;

~

rFlgu" 20.3 Chemical mediators In~U(lf1c1ng p1atelel &CIivation and aggregation (r9la&.tfl size 01 platelets and endothelllli cells lire not 10 seale).

2. Deer_ed plas"", levels 01 Ihrombln and thf'OmboJranM: The platelet membrane also 00f\l8irls .ecep!OtS lhIl1 can bind ttvombin. ttwornboI
I. ChBmIc:lll signals that promotB pllltetBt lI9!l'eyatloo 1. OK,. .SIId prostacyclln I,vets: Damaged endoIhelial <:ells syn. theslze less prostacydin, ,esulllng If'l a Ioc:alized reduc:tlOf1 In

...........", .. -... --,.

• <........---........' _

'"

.. _

.....

20. Drugs AlfflCling Blood

nwee ....,

"-'_ ~

XII

I

.

...

...,

'""'0.... ,..."t>to
2. bposed collagen: Wrthin S8CQfds 01 wsr;:ular injury, platelets . . . . 10 and 1IrtJaIy COlIer the 8'
'i...:

.I (;)

~

m ,........ (;)

ptOSlllq'Clin levels. The t>R:iWIg 01 proslaCyClin l(l plalelel fflC8P" lOtS is Oacteased; Ihus Iowu levels of inlraoollUl8r cAMP pemil pIa1elel8Ql1ega.lion.

SI'f"'I=o' 0' ,.....,

II

a P'OIh..... "'" {III

3.

~1Cf

1I"I...

eel sy..t1

!

of It.G'

: 5IirrUation of platelets

'otio.. ()OIIa.j8f " and ADP rest*s In 8dMIlion d

b'J

pIals's' ".,.,.,..,

braw phospl <>IiI B5, ...t1ictl1ller8te liactidOl '" acid In:lm membrine phospholipid, Arachidonic Icld Is fIrst converted to prostaglendin H, by cydooxygenase, an enzyme Itlat is irr", YerSibly inactivated by aspirin (see p. 4(3), Proslllglilndin ~ is metllboli~ed to thf()mbO~.ne A2• Which is released into the plasma. n.om~ ~ produced by the CW'egaling platelets rurther promoles the dumping process It1II is essential to lhe rapid Iormlllion or 1I hem:lsl8tic plug (see Fogure 20,3).

IV. BLOOD COAGULATlON

-..

oI ....... " '''. .. oM " , _

,

'

The ooeguIalion process thaI generates thrombin consists of two interrelated peltlway$---tll8 extrinsic and the Inlrlnsic systems. The extmsic syslertl, wl'lich is probably the more if'IlxIrtanl in ..-va, is rwtiated by the actMllion 01 dolting Factor VII by a tissue Iactor, thfomboplastin---e phosphoIpid end proIeil rrlxture. The intmsic S)'$Iertl is IfiIIIIered by the ilCII'o81icw, 01 dOll• .., Fedor XII, IoIowiI'lg lis conlad: in vitro with ~ or NgtIy ch8tged sufaces. BoIh systems IrMIl'Y8 a cascade of enzyrTlillic reactions that sequentially IriInslorm various pIIsms tilctofs (proen: zymes) 10 It.- aaMl ( ~ J torms. """tsly ~ ItriG,tiil (F'\IU"e 20.4), ltI'omtlin plays a key role in <XIIll'JIation, since iI is 'espol~ lor gellle.atioi1 of fit:nl, a gI'Joopo ....... lhat lorms . . meshliN matriIc d It-.1*Iod dot. TI'G"b" illso lICli>e* .....lilllll Facb" xnl (".. '55 ry lor S'shii>ing and CfQSSIirti'lg the Mlm moaea ' J S ... an Insoluble dol) as wei as aetiYlting 0Iher blood ~ IacIors and ill\lWegalioIL Illhoo ,otio, is no! b",ed. Of its ILo1clion is iI,'P801ed. lor~. with llI'i&l .... ,ollii' 1M, 00S9"'t1ctl is h'i::iit8d.

'*' '

-

V. PLATELET AGGREGATION INHIBITORS PIa1eIel e.ggregation Wlibitors decrease the Iormation Of !he lIdion d cto8i,ieel signals ltlal JM! lEt aggragslitn These agents haw proyen belllll\cial in !he pr1Mlfllion antllrlllllm8nt 01 oo::lUsiYa cardiowsWar diseeses, the mainlElrlllnCe of vaso.Aar grafts and arterial patef'lC)', llI'ld as ~ to Ihromboly1ic therapy in r'I¥lCll'
poG"'.

F\gUR20:4 Formation of robrin dot and Its uIIim1lle dissolution.

............, ....... _,.

A._

VI. AnIico8gulants

'"

AspnoIIAS pit' ill blocks Itvoml:laIlilne ""- syrlll psis from 8t8Chiclor1it ari::I il pIa\8klls bV i'rEMlf'Sti8 acelyIaIion and II tulia I 01 ~ nBS8, • kev enzyme il poOll"'gl"llCIl I and hOI ibo:I:ai 18 ""- syrlll . 1 (See P. «I51cr. tko '>1 0I1he IlClions oIlI$pftl O'l plalelels.IThe il'libibyelted is Iilpid, ~ oc:cumg il portiII ~Iicn. The ~ Sl4lP' • " 01 'ro,tloio.twle ~ and .... fe5IAli'lg Sf.4lPl EI '. I of pia 7 7 aggoegalioll last b .... iIe of Ihe I' " Wocil I 7 ')' 110 10 days. A!piTIis <::UIT&1lty IIff'4l1OrIed il .... pl...... -tit Wll*nenl of .... . • C8iebal isc:t'.-I. 10 rUJc:e tie iliCideuoa 01 teCUTeft fT¥XA1ldial il_diu, and 10 dao I IIlO1ra1i1, in~ naaio....... i1s. ~. silgle 1oedil'O dOOOoI 200 10 300 my 01 'lid bV a dnily dD&e of 15 10 100 my is ll1Wi ," l8lldecl BeE'" l!jllime is po tU yd, CllU$ing GO1!picaIiLiIS lhat ird.ode an ilo8llSOd illCideo iOII d till 1101,7 oagic stroIoa IS ....... IS gas....... u'nlll ~B :111"', ........ 'fat t-Ogt'erdoses d Iha chJg.

,.'p

aspirrI'.

e. TlcIofl'dlN TidcJlidIlO

~

ClO pih doon] also lids IS

gef1 and

buI

bV •

an

inhibiIor d pIalelel

ltllIfllt1lll d aspiIil. The ~ r.tIbitS the AOP pathway ~ il'lthe bh;lil1g 01 platelets to fIlrino. ~

~ oIher

10 IIICh othef. TICIcpi:1iIO has boon shcloMllO d8a8ilSoll Il1e

il1cidence of lt1rombolic s1roka. Attar oral ingestion it Is exlensilo(lly bound 10 plasma proteins and undergoes hepatic melabolism. The drug cafi cause prolonged blooding: irs most serious Ildvarse eIfed is neutropenla. Therefore. l is .aserved !or patle>1ts who cannol tolerate

-.

C. Olpyridamolli Dj:l)o,idsmolllidye poor 10 a mole). " GO'Ofl8fY '<5 5~. is ~ 10 prophyIlIdially trealllf9na pedOris. II is usuaIy gillen il GOllbiie\io'I \MIh ~ ~ ina 7 as illbllOlllUar Ieuels of qdic AMP bV ilihibiliil!jl eydie r.......... lltlOlifl...... lem J. TNs il'Ilbits hOlilx«ai18 ""'" synttl8sis and may flCI8' tiale the etlaa d pra;tacrdin (~11O lW"Iagl>lize platelet s1idrir III and lheielae cleo EBI? platelel actleslon 10 hOiioogallic striIces (see RgJre 20(2). The meager daltl available sugges7 that dipyridamole mal
Vl AN11COAGUlANTS Two!)PeS oflnigs are ~ il p8,UD'O blood ~ tqllril and Ile W3rnFI K antagcrists. Thl* rroed ..... ,1S of action liIlaf, as do lhei' dri;:8l uzes. A. Heparin

Heparin [HEP a ,in] is an InJectalMl. rapldlf-llding &ntiooagulant 1l1at Is of tan used acutely to Intarle.e with the formation of th.ombL

<,,,,, ••, ..I.,.

,

,

>

< _

•••••••

'00

. ., KI'<.Mll ............ >

20. Drll9S AlfOCling Blood

13 No Heparin SlOw

•

~

,

_ _ .1

II With heparin

Figure 20.5 Heparin binds to antithrombin III anr:1 enhances ~s proteolytic activity.

HopaJin normally occurs as a macromolecule comple~ed w~h histamine in maSI telts where its physiologic role is unknown. II is eKlracted lor commercial USB from porcine intestine or boJine lung. Heparin is a miKlure 01 s1raighl-ct1ain anionic g1yoosaminoglycans wilh a mean molecular weight of 15.000. It is slrongly acidic because ol the presence 01 sulfate and carboxylic acid groups". The reali~ation that low molecular W8'lght forms of heparin also can act as anticoagulants led to lt1e isolation ol enoxaprin [e NOX a prin]. the first low molecular weight hcp8n"n«6000) availa~e in the USA. 1. Mechanism 01 acllon: Hoparin acts indirectly by binding to anlithrombin III to cause a rapid anticoagutanl effect. Ma~;mal anticoagulation occurs within minutes alter intraYerlOUs heparin injection (unlike vitamin K antagonist anticoagulants. such as warlarin, whose ma~imum activity requires 8 10 t2 hours). Antithrombin Ill. sometimes referred to as heparin cofactor. is an Ctijlobulin that inhii)1S serine proteases. including ooveral ol the dolting factors. lor example. U1rombin (Factor II. Figure 20.5). In the absence of heparin. antithrombin III inleracts wilt1 U1rombin very slCM'ly. The bnling of heparin to am~hrombOn III produoes a conformalional change allowing the antilt1rombin 10 rapidly com· bine wilt1 and inhibit thrombin e~ooptlhat already bound to fibrin. [Note: While U1e hfJpBrin-antitllrombin III complex readily inactivates lhrorrtlin. the c:ompIe~ of low molecular weig,t heparin with antithrombin is more specific against Factor >
Heparin limits lhe expansion of thrombi by preventing fibrin formation. Heparin is the major anlithrombotic drug lor the treatment 01 deep vein thrombosis and pUlmonary embolism. It decreases the incidence of recurrent !hromboemboIlc episodes. Clinically. heparin is used prophylactically to prevent postoperative venous thrombosis In patients un(fergoing elective surgery. and in those in lt1e acute pIlase of myocardlal infarction. Coronary artery relhfornbosis aller thrombolytic trealment is reduced with heparin. It is also used in eKIracorporeal devices (lor example. dialysis mad1ines) 10 prevent thrombosis, It is the anticoagulant of choice lor treating pregnant women w~h prosthetic heart valves or venous thromboembolism. because ~ does not cross the placenta. Heparin has the advantage of speedy onset of action, wtlich is rapidly terminated on suspension of lt1erapy. ErlQXaprin has boon approved fOr p.'lMlfltion of deep win thrombosis following hip replacement.

2. Therapeullc uses:

3. Ph.-macokinetics a. AbSOrplion' Heparin must be given parenterally either in a deep sutx:ulanaous site or intmvenously. because the drug does not feadily cross membranes. Enoxaprin is only given subcutaneously. [Note: Intramuscular administralion of either hep.arin is conlraindlcated because o! hematoma formation.] Heparin is often administefed intravenously in a bolus to act1ieve iJ'mlOOlate anticoagulation followed by lower doses or

..........,., ........ --,> VI. AnIicOBgulilnlS contil1UOUS infusion. The taller is then malntainEld lor 7 10 10 days. tilrating the dos4l of hepam so ltlIlI the IlCtiIoeted partial 1t... ,oI>,b lli.. 1ime (PTl) is 1.5 10 2.5 Ii'nes the t'IOf1TI8I CU1lfOl

It1e blood, IIepariIl brds 10 many proleins lhaI ~ in its ac:1Ntly and can cause rasismnce kllhe drug. AIlhctql

b.. F••: In

genertlIy .eslricIed 10 the eirr::ulation. heparin is Illken up by the .&liaADeIidotl elial system and U!l"'ooes cIopotymerizalion 10 naa;... prrdocts Heparin ltlaebe has a Iong8r hal· lile II'l patients with hepBbC drrho$i$. De$uIftltion OCOJfS in moncn.odear phagocytes. The inacINe meItlbolites as wei as some of N pllfenl heparin . . 8llCt8ted -.0 hI~. lher&Io.e .enel insuffICiency also prolongs the half.lile. [Note: HI/IpaIfn does noI aoss hi pilIowUl bIrrier.1 The t'4 of hap.em inc:reasoes oMt1 dose; lhaI of f1e low mol............. weiltI t-oep. ems is about dor.tlIe lhaI of hi larger SP"O'" 4. Adv_ effects: Despite earty hopes of ' - side eI1ecls with llfIOI
•. Bleeding compllcallons: The <:hiet oomplieation 04 heparin 1hefIIpy is hemont1age. Careful moortOfiog of blooding time is requlred to minimiz.. this problem. ExcessMI bleeding may be fT\fll.... ged by suspending th.. drug Of he.. ting witt1 profamlni:J sulfa/o. Infused slowly. the latter corrtIioes ioniceJly w~h heparin 10 Iorm a Slable. InacliYII complex. b. HypefHn'ltivi!y .eKtions: QUIs, !eYer, u.tlcaria. Of anaptlylaetic $hod< are possible. siooe the htJparin preparations are obtained Irom animal soorces and may therefor.. be antigenic.

c. ThrombOcylop."ia: A decnlase In the number 01 ciralIaling platetels may OCOJ. after about 8 days of t ~ In some PlIlients, ~ platelet aggregation is !ole '00 by hi lormalion of ~!elet .. ,til <de- DisoontirulII'l of It1e Orug then OOOOIll"S necessary. Shedd ~ tIYom~ ~. therapy with a
-

cL COntf1olnd~: Heparin is contraIndic:8ted lor pali....IS IOtlO

a.e hw8l_ositiAlIo it or have b'BI£1O lIisonlers.lor tlk»hl:l6Cs, and Jot patients who have had turgery of the brain, eye. Of spinal oord.

B.W.rl..... The co.marin anlicoagulanlS. which include wal18rin [WAR tar in) and dicum8ro1 [dye KOO rna role] (Iormerty bishydro.ocycoumarin) owe Iheir action 10 theW ability to antagonll." the colactor !UllctioflS 01 Yitl!tTWl K. Initially used as a rocIentidde, warl8rln is rtI:1N widely emplOyed clinicalty as an oral antieollgulai"lt. COnftlcling opinions ..xist CCIOCerning the usefulness ot these agents in dlnieal s~ualions sllCh as myocardial Infa.ction and hlp arthroplasly. The potootial

--10 _ _ . , -

........-:

~

-d

'

'"

<....... _,.,.<- ... _,. '00

P,

_01

t"~&.r

20. Drugs AI19C1ing Blood

mortlldIty argues tOf a way to identify lI10se patients WhO are truly at risk fOf thrombosis. Even careful monitoring to keep prothrombin time at 1.5 to 2.5 times longer than normal values does not prevent blooding compHcations in about 20% of the patients. 1. Mechanism 01 action: Several of the protein factors (IncllJding Factors U, VII. IX. and X: see Figure 20.4) that are invotved In the ooagu~tion reactions depend on vitamin /( as a colactor in their complete synthesis by the liver. These factors undergo vitamin /(dependent posttranslational mod~icati(lf1, whereby a number of their glutamic acid residues are carbo~ylated to form y-carbmcy· glutamic acid residues" (figure 20.6). In this reaction, lI1e l-'itamm K-dependent cart>oxyla.se fi~es to form the new COOH group on glutamic acid, and ledoced vitamin K oo-factor is converted to vitamin K epoxide. Viramin K is ragBr100lted from the epoxide by vitamin K epoxide reductase. It is this 6f1zymt! lI1at is inhiMed by warfarin. The y-earbOxyglutamyl residues bind calcium ion and are essential for interaction with cell membranes. Warfarin or dlcumaroltreatment results in the production of inactive dolling factors, since lI1ey lack the y-cartx»
co..

.......

_. -

2. Pharmacokinelics of warfarin is rapidly and completely absorbed alte, OfBl administratioo. Though food may delay absorption. it does not affect lI1e extent of absorption 01 the drug. Warfarin Is 99% bound to plasma albumin, which prevents its diffusion Into lI1e cerebrospinal fluid, urine, and breast mille However, drugs having a greBler affinity for the binding sile. such as sullooamldes, can displace the amicoag· ulan! and lead to a transiBm elevated activity (see p. 12). The drug readily crosses lI1e placental barrier,

a. Absotption: The sodium

Figure 20.6 Mechanism of action of warfarin.

SB~

b. Fale: The products of warfarin metabolism a,e inactive and, alter conjugation to gluwronic aOO, are excreted in the urine and stool. 3. Adverse effects II. Bleeding dJsonlers: The principal IJI1towald react;on is hemor· rhage. Therefore, il is important to frequently monitor and adjust the antiooagu~nt effect. Minor bleeding may be treated by withdrawal oIlhB drug and ao-ninistralion of oral vitamin K,: severe blBeding requires greater doses 01 the vitamin given Kltraveoously. WhoIB blood, IfOzen plasma, or plasma cooceo· trate-s 01 the blood factors may also be employed to arrest hemorrhaging. b. Dntg ;nterllCllons: A number 01 drug interactions that potentiate or attenuate the anlicoagulanl effects ot warfarin have been identified. A summary of thB most important 01 these interactions is shoWn in F.gure 20.7.

..... ,......, .. -... ..-,.

.c.- ...·•

, .........,.....:NUl _ _ . . . . .

VII. Thrombolylic Drugs C. DI...N Sblles, These can also innllllOCEl !he IY;poprothrombirllwnlc stale cI Ihe palienl and intluen::8 the 'esponlle 10 !he aoti<:l:la(luIalS. For example. a vitamin K deficlency. hepatic disease thai Impairs synlhesis of lhe cloning laclOfS. and ~ states that iroease catalxlli5m 01 IhlI vitamirl K-
-o

",• .,'1

""

"'.

......... '01 .........1

-.eou" ,

d. COntraind>c8lio1'1s: The aug should never be used ., pregnarqt b8c:allSe it is IeraLy"uic and cwo cause alxJr1lDfL

VII. THROMBOLYTlC DRUGS

Potentiation 01 anheoagulahon

Acute ItJillilol:x:6l1bolic disease n selertsd patillnls may be lrea1ed by the adIni "Inllion 01 aget1tS ltlal ?divale the COrl'<'8fSiOn 01 plllSf'.1t>g?I'1 10 pla$tIWl. I pnHease thal ~ fibrin and ltui 659 tIeS dotB (FIgIUfB 20.8). The first sud1 agents 10 be approyed, ~ and urollinase. cause 8 systemic fibrinulylic Slate Illal can lead 10 t'eadil.,. ploblems. AltepUJse. also IuloWfl as lissue-I)pe pI!I:smI1ogefl acIivlJlof" (IPA), ac\$ more locally lli'1 the Ih'lli ,ibollc fbrin 10 prOlb:e fib,inoIysis, and is a polentially ~ant agent i'I treaMg t,uomboembolic disease. (SBe FIgure 20.9 lor a comparison of the commonly used Ihrumbolylic agents.) OinicaJ experience has shown abUiJI eqoaJ efficacy between streptokinase and ,Ait Unfortunalely. thrombolytic lherap,r Is unsuocesslulln aboot 20% of Infarcted arteries and about 15% of

seme

those opened, loclooo. A. Common characteristics of thrombolytic agents 1. ActIons, The lhOlTtlUlytjc agents share some c:ummun leatures. All act ellh8I 6<eclIy Of" i ldil eclIy to 0Dnl01lfI plasIlli lUgeI' to pIasrrWI, ¥r'hk:tl n Ium deil'/(l$ liJm. !hue lysing blliUbi (see F9Jft! 20.8). In eadl case, dol d" ss • ilion and reperfu$ion ucan wilt! a higher lrequency ..men ItoefapJ is iniIiated earty aftet dol Ionnatiun, since dol_ become more resistant to Iy$iS as they age. lJr*;lIluI'Ial8IV. ncreased local hOllti, may oc::o.. as the dot (issoIYe$, ler Ii ljj 10 emanced platelet aggr"ljjl'tMy lWId hlli'ib06is. Slrategies 10 plewnl !his indude adminlsIralion at antiplatelet dn.ijjs. ad! as ~ or ",1liII.llillbo4ic:l, ad! as hepalirL

2. AdrnWW.cion: For rr,ocanial nlatetIun, illlJawrotIary deIiYery of Ihe 0'ugI is ItoB mosll ,. Itle ~ terms of .chie.i", recanalizalien. 1101 _ , cardiac caIhelerizalion may IlOl be prJ He ~ the 2 10 6 hour "It\erapeulic window; beyond which l5ignilicanl rr,ocanial &a/IIage IlllOllllleSIes& 1IIely. ll'...sllYcWr'ibolylic agenlS are lJI5UlIIly adtr"nslered illJa.ell(lusly. since !his 'OUIe is rapid. illlllq)llll5i'Je. and doeS nul ~ ItoB risks of cathetllrizatiu. 3. 1'Iler8p8Utlc uses: Origirrat)o used tor ItoB lreatmeol 01 dllep-Yein IhromboSil5 and serious purnonary embolism, \t1rOIl'IboIy1I drugs arll now being used with increasing frequency to treat acute myocardial Inlarction and peripheral afterial thrombosis ilnd emboli, and lor unc:lolling catheters and shunta.

Warfarin

......... '" AttenuatIon of anheoagulalion Figure 20.7 Orvgs attOCling Ihe antiooagl!lant ellec:l of warfarin.

<.""'....'0"<

"

< . - . • _ _ -",,"0' - . . . . . . . _

202

.....

20. Drugs Affecting Blood

4. Adverse effects: The thrombolytic agents (\0 not distinguiSh between the fibrin ot an unwanted thrombus and the fibrin of a

A''''p''....

IT,u"" pum",og." ""t,.1l1o<')

--

beneficial hemostatic plug. ThuS. hemorrhage is a major side effect. For example. a previouSly unsusped:ed lesion. such as a peplic ulcer. may hemormage following injection at a thrombolylic agent (FlQure 20.10). They are contraindicated In paUents will1 a healing wound, pregnancv. history at cerebrovascular actident. or metastatic cancer. Continued presence 01 thrombogenic stimuli may caUSEI reth.ombosis aher lysis at the initial c10l

B. Aneplase (tPAI

,~"

.~

Alfeplase [Al te place] previously known as tisslJe.type plasmitJo. activator (IAIl). is a serine protease originally derived 'rom cu~ tured human melanoma cells. It is now obtained as a product 01 recombinant DNA technology.

ge<1

Figure 20.8 Activalion at plasminogen by fiblinotylic agents.

A. AHTIGEMCITY

=~::::::: ~

1. Mechanism of tlCllon: AlleplBse has a low alfinity for 'roo plasminogen, but ~ rapidly activates plasminogen bound 10 fibrin In a thrombus or a hemostatic p1ug_ ThUs. afteplase is said to be "fibrin selective" and at low doses, has the advantage o! lysing only fi~ nn. without unwanted degradation 01 other proteins. nofably fi~ rinogen. This contrasts with urokinase and sJrep/Okilase, which act on tree plasminogen and induce a thrombolytic slate. [Note' At dose levels at alfap/ase currently in use clinically. circulafing plasminogen may be activated. resu~ing in hemorrhage.] 2. Therapeutic uses: Currently aJleplase is awroved for the treatment at myocardial infarction. massive pulmonary embolism. and acute ischemic sfrol<e. Alreplase seems to be superior 10 straproklnase and urol
8. FIBRIN SPECIFICITY

3. PharmtlCokineucs: The agenf has a very short t l2 (about 5 minutes) and therefore is administered as a lQO.mg 'dose with 10 mg injected intravenously as a bolus and the rest over 90 minutes. 4. Advet58 eflects: Bleeding complicafions. including gastrointesti· nal and cereb
C-HAlF-UFE

.......

-

c. Streproklnase

SlrepfolrlnBse [strep foe KYE naoo] is an extraceQuiar protein pun. 'ied from culture brolhs 0' Group C [}--hemolytic streptococd.

~

o

-

10

20

Figure 20.9 A comparison 01 commonly used

thrombolytic agerns_

1. MeChanism 01 .clion: Streptokinase has no enzymic activity: instead it forms an active 1:1 complex w~h plasminogen, which !hen converts uncomplexed plasminogen to the active enzyme plasmin (FlQure 20.11). In addition to the hydrotysis of fibrin plugs. the c:ompIf:!x also calalyteS the degradation 01 fibrinogen as wen as cloning Factors v and VII.

........ _'.' •• - __ '> VII. Thron'tloIyIic Drugs 2. ~ uses: ~ islJlPfDWl(llcf lISe ~ lIOJIe PIJrl'IOIlary embolishl. deep venous !ti()fIlbuis. acute rnyocan1iaI intan:tion, iIfleriaI lIma i ibusis. and ocdl'l:led .. I stults..

3. PhltmlCoklnetlcs: SrreptokinaS#! therapy Is InsliMed willlin 4 hours 01 a myocafdiaJ inlarctioo and is InllJsed lot 1 hout. Its tlf,1 is le51 than a hatt-nour. ThtombopIastin lime is rnotVtored arld majn. Iaroed all'M) 10 fiYe tnIes oontn:ll value. On ~ 01 treat· m«t, ~ heparin or oral antio»egI!larfS ITIlI'f be adminislered.

........ -..

..

!iii

Untreated patient

( I J:X X l ' . IX J J

c-'nlx)L ...

lW'd oeutraile its rbiodytic ~ erties. 1lle<etore. suIf.cieJ It quartities of SlrepIo/(inase must be administer«! 10 0WIWt1eIm the anlibOdies and pn;JYicle a lherapel.ltlc concentratlQf1 or plasmin. Fever, allergic reac· tions, and therapeutic failure may be associated with the preoonoo of antiSlreptooocc:al antil:ll::des In the palierll. The incidence 01 alls.gic reactions is llJlI)I'OllimaI3'll.. COfIti'le

'Attn

~

n"lc

lIP

.. Bleeding disonlef.: Activalion 01 cill1.llaling plasminogen leads 10 e!eYllted IeYels 01 plasmin. 'Mlic:h may precipll.lle bleeding by dissolving hemostatic plugs (Fogure 20.12). In the rare instance 01 lite-threatening hemorrhage, aminocaproic acid(see p. 204) may be admirlistered. b. i+ypenoensitMty; Streptokinase is a Joreigrl prolekl and is antigenic. RasheS, lllYer, and rarely. anaphylaxis occur. Since most indi\IiliIIls hlIYa hlKI a sbep!ll ••• II' i oleaioi I tomelime ~ Iheir IiYes, on::tAaling 1M 1Ib.-.;ps against sb EJ*OWio 5J are likelY 10 be pr8lielll in ITIOIl paliefIt$. These aUiliQ(fu can

1_

Patient treated with plasminogen actIvator

-

.x I..-:r

1 1:. L 1

x.,-:r0", lOco

t

lit

~,."

.~'"

Ani:srrepIase (atne STREP lase] (~Ied ptasrJl.......' sttep-

tolUnsse activator ccmpIex: APSAC) was synthesized in vitro 10

,

SlI ;' 'I

.

,

Plow•• C

I

E. Uroklnue Urokinase [yoor ot1 KINE ase] Is an enzyme capable or directly degtadlllg bolh Iibnn an(l foblillogetl (see Figure 20.12). IJrcJIrjnr,;e was originally isoIaIed hom tunatl urn" IxA ~ is now obtained hom aA.nMl of IunirI tetall8nill eels. (;0/01 5B is fllOfe ~ than stI Ef*lI
' .J

-- -

CJ

O. Anistreplase

improve the kJnetice of the strepiolfinBse·plasminogen complex. Acv\lIIion IXldIs the lysine III the actiVe site 01 plasminogen so that the compleK is inactive unfil it binds to fibrin, a property that is retained. On binding, the anisoyl grol4l is r8f'l'lO\l9d and fibrinolysis plOO8Elll$; Ihus the mmplex is sem', Is ctil'll lor lysis aI the cIOl site. The plasma. haIf-1ile of ~ is long (about 90 mi"uIes) oompared 10 $lf~, "is ~ed illbauenously 1rorrI2 10 5 ~ ule•• Reperlusion 01 the 'issue comparls ravorably with ~ like 0ltW" Ihruilitlof)tic agents. bIB 1i41 is a ~ caJiDn, as ~ as _ ~ IIfld hypolensjon.

•

-

o,

< ,.,.<---,.

< ..,... • - - - -• ....,.... .. _

.....

20. Drugs Affecting Blood

VIII. DRUGS USED TO TREAT BLEEDING BIeedlng problems may have their origin In naturally OCClJrring palt1ologic conditions such as hemophilia. Of' as a resutt of fibrinolylic states that may arise after gastrointesfinal sullieI)' or prostateclOITIy. The use 01 anticoagulants may also give rise to hemoIrt1aging. Certain natural p«>leins and l'ilamin K as well as synthetic antagonists are effec1ive in c0ntrolling fhis bleeding. FoI example. hemophilia is a cOllsequeoce of a deficiency in plasma coagulafion factors. most frequently Factors VIII and IX. ConcentralBd preparalioos of lhese faclors are available from htJman donors. However, lhey hold the risk at fransferring viral inlec-

....

A. Amioocaproic acid and t,anexemic acid Fibrinolytic stales can be controlled by lhe administration of aminocaproic acid [a mee roe ka PAQE ic] or lranexamic acid (tran ex AM ic]. Both 8g61lts are synthetic and inhibil plasminogen activation. A potential side effect is intravasaJlar thrombosis.

1.1 Figure 20.12 Slropiokinase and urokinase ~rade both fibrin and fibnnogen.

1.1

B. Protamine sulfate

Protamine svtfare {PAOE la meen] antagonizes lhe anficoagulant etIocts 01 heparin. This protein is derived from fish sperm or lestes and is ~ in Btgin1ne content. which Blq)Iains ~s basicity. Tl1ll p0sitively charged protein interacIs with the negatively charged heparifllo bm a ~ compIBx witholJt anticoagulant activity. Prolamine ~ fata itself CllJ1 interfefe in coagulation when ~ is given in the absence of 11epam. sinclIthe basic prole;" interacts V>'iIh pIaleleis and Iibmogen. Adverse elfects include hypersensitivity. as well as dyspnea. tIusnng, bradycarda, and hypotension when rapidly injectlld. C. Vitamin K

Thai vitamin K1 (pllylonadione) administration can stem bleeding problems due to lhe oral anficoagulants is nol surprising. since those substances act by intelfllring in the action of the vilamin (see FIQurB 20.6). The respol1se to l'iramin K is slow, requiring about 24 hours; thus if immediate hemostaSis is required. fresh frozen plasma should be infused. [Nofe: Vitamin K supplementafion is required tor patients receiving the ceptlalosporins, celamandole, ce~rarone. and moxaJaetam (see p. 3(6).]

IX. AGENTS USED TO TREAT ANEMIA Anemia is defined as a beloW·normal plasma. hemoglobin concentration resulling from a decreased number of cirwlaling red bklod oelts Of' an abnormally low tolal hemoglobin content per unit of blood volume. Anemia can be caused by chronic bklod loss. bone marrow abnormal~ ties, increased hemolysis, Inlections, malignancy, endocrine deficiencies, and a number of oll'>€r disease states. These cond~iOf'1s can be corrected by lransfusion 01 wtlole blood. A large number of dRJ9S cause toxic elfects on blood cells. hemoglobin production. or erylhropoielic

............, ........ _,. 205

IX. Agents Use
whic:h in Iurn may cause anemia. In addition, ~ritional anemias iIIe caused ~ dieIaIy deficiencles olsubstanees (lor example, Won, folic ~ llilamn B,,(C)al(lOObslsmitl)) necessary lor normal &fyIhropoiesis.

«garIS.

A. tron

Iron is SlOfed in intestinal ITIlXXIS3I ceUs as kl«itin (an ironIprotein complex) IKltil needed by the body. Iron ooficlency results Irom acule or ctwonlc I:*IoClIoA.. !rom r.tuIIident intake <1Img periof:E 01 •• Ieraled ~ in dIiIdren. or in neaWy mensuuaIing or prag-nan! women. Therelore ~ es&entiall'y resuns from a negatiYB iron balance d<e 10 dePe\iorl of iron 5loI9I and ~e intake, aJlrnoating in hypoct~o",ic rricfoq1ic anemia. ~ .,.;u, ~ ~1\!I1s required to correct the deficiency. ~ disturbances caused by local Irritation are lhe most common ~ enec:tsNII''Se
.

B. Folic acid

.,

The primaty use 01 .I:lIic .cid Is in lTeating def.cief lCJ' states thai arise from irw'eqIlBte ....... 01 the YitanW1. FaIlIlt! denielll;:y ITIlIy' be ca ....... by (I) inc::feUecI demand (lor ua-npIe. pregnancy and ladaliorl). (2) poor abIorption ca'ffe
C. Cyanocoto.~n (vitamin B,1l Deficier Des 01 \IitarlWI B., I3l.BllUIIIrom either low dieCiMy le\IeIs or. more (XlI1., .... y, from poor 8bIIorpliorl 01 the vitamin lUI 10 fle fai1ure 01 gastric: parielal eels 10 proO.Ic:e i1',illSic Iador (as in perricious anemia) or to B IoU 01 IICtivity of !he rec:eptor needed lor inIestinai upIak8 of me wamin. 5 Nonspecific malabsorption syndromes or gastric: resec:6on can allIo cause 1Ii/lltJli1 Btl defic:ienc:y. The vllam ITIIly be ad"si;lisIered orally (lor dietary defdeudes). 01' intramuse:ularly 01' deep subcutaneously (lor pernicious anemia). [Note: Folic tICid IIdmlnistfBtion alone feveBes lhe hemalologic abnormaIiIy end 1hu8 masks the B,ldelic:lenc:y, wtoic:h CiII1 \heI"l pnr ceed to sevefe neurologic (lysrunclion and disease. Therefore, megalobI8slic: IIIlllrria shoukl not be uealed INith 1oIic: acid alone, b:J1 rather wlIt1 a (XlI,lbiIl8lion 01 Io/a/ll end IIiIamin B.2-lTherapy nlllSl be continued lor the remainder 01 the lite 01 a palienl sufklring from pernidous anemia. There are no known ~rse ef/ec::Is 01 this vitamin.

'see p. 206 lOt ""'*"" ",--=-10 olll/lf _

..... _ .

,.

DIETARY OEACIENC'I'

•

.... ,

~po,,-,"'

.~

FOlATE OEAC1ENCY

J~t I

D.:=;:.. I O?= I ."'>-

,

t~J

Megaloblastic anemia

Figure 20.13 Causes and c:onsequenc:es 01 folic acid depletion.

_

......... _,., .. _--,.

..-.. ----. -..... .. .....

206

20. Drugs Affecling Blood D. E'ylhropoietin

Erythropoietin [ery throw PO IllItin] is a gIy<:oprotein. normally made by the kidney, that regulates red ceM proliferation and differentiation in bone marrow. Human ef)'lhropoielin, produced by recombinant DNA technology, is effec1ive in the treatmenl of anemia caused by and-staga renal disease. anemia associated with HIV·infe(:ted patients, and anemia in some cancer patients. ~emerttalio<1 with iron may be required to BSStJffl an adeq<.Jate response. The protein is usually administered intravenously in reoaI dialysis patients, but in others the subcutaneous route is preferred. Side effe<:ts such as iron deficiency and an elevatkln in blood preSSlJ.e occur. [Note: The laner may be due to increases in peripheral vaSClJlar resistance and/or blood viscosity.]

X. AGENTS USED TO TREAT SICKLE CELL DISEASE Re<:ent Clinical trials !lave shown that hydroxyurea can relieve the painful clinical COOfSe of sldde celi disease (Mamia). Hydroxyurea is currently used to treat etllonic ll'lyelogenous leukemia and poIycyII1emia vefa In sid<1e cell disease. tile drug apparenlly increases letal hemoglobin (HbF) levels. thus diluting the abnormal hemoglobin S (HbS). This process lakes several rnontns. PoIymefizat;on 01 HIlS is delayed in the treated patients SO that painful crises are nol caused by sid<Jed cells blocking capillaries Md causing tiswe ano~ia.8 The optimal dose of frtdroxyurea. and ils safely over the long run remain to be detenrined.

See p. 448 lor a deSCfiptio/1 01 the newly approved drug /epirlXk1.

Study Questions Con9ct ct"CloI. "- Rjlao"ll"' inOOees Iha hep-

20.1. The an6coagulant ad"rvily of ",arlaoo can be pclten'" ated by an altha IoIlowIng EXCEPT;

A. RiIampin. B.Asp ..... C. Phenyll>lllawne_

alle mad lunc1lon _ _ 'hili ..-elabOli•• wao1arin. Plat.... fnhIbilO... 5UCh liS aoplrln. inclaasa tha anlk:oagulOO1 atla<:1 of ",&I1.nn. PhOOylbuIazona can '",_lty increas. tha IaYeI 0I1rea wwtan'l by dIoplodng ~ Ifom It1e pIaoma ......... bitdrJg siIe. a.IIQlidi"e io:'IhlbiIs -.nn,,- ..", and c:BII8Il5 poler1IlDIion 01 I.... a n ~ . Disulftram Inhlblls w&l1arln

.........,.,.,...

O. Ciroelidina. E. Disuffiram.

----

"See p.l4t1n1llo

'."1"7(2nd_IIQn~ "Seo P. 33fl1n 81

'" lt10 "'""""'"' 01 t1olperln.

'See p. 32e1n1Mo".' ...... (2n
--<

"' . . ~oIcMF.

"sea

,*,_,

(2nd od)b .............

p, :lI\1n8f""',,-, {2rolfJCI.l b .--.-..,

",_CEIII_

<........ _,., ><---'

<

>

<_ ....-

-..,

>UC>U _ _ • PI' >

Antihyperlipidemic Drugs

I. OVERVIEW Comnary arte
ANTIHYPERLIPIDEMIC DRUGS

'_M CJctiIJrar.

eo•• lip<>l

-FluwIslllli"

1.0....

111""

0'

II. HYPERLIPIDEMIAS The hyperllpidemias are a complex group 01 diseases IIlat can be des· ignated eilher prima.y or secondary. depending on lheir causes. Primary hyperlipidemlBs can resull 'rom a single inherited gene defect, Of more commonly. are caused by a combination 01 genetic and envi· ronmental factOfS. Secondary hyperlipidemias are the resull 01 a morlI generalized melabolic dioolde•. Suet'1 as diabeles mellitus. excessive alcohol intake, hypottryroidism. Of primary biliary cirrhosis. Therapeutic strategies tor lrealing secondary hyperlipidemia caused by one 01 these disorders include dietary intervenlion plus a regimen 01 drugs used to treat the primary cause 01 the hyperlipidemia. Figure 21.2 illustrales the nonnal metabolism 01 serum lipoproteins. and the Characteristics 0' the major genetic hyperlipiOemias.

Figu.e 21.1 Summary 01 antih)JlB!lipidemic drugs. 'Described In Pharmacology updale. p. 449.

"-"--_._

--

.. _ _ ... _ _c."*,,,,_ _ _ _ _ _ P'IOiIOOO. -.~

207

...........,., .. _--,.

.

...,... ---..-,

............

206

_.....

21. AIltih}1lerlipidemic Orugs

c:i===>

",,""-'OM>

==::'1

IV

Figure 21.2 Metabolism of plasma lipoproteins and related gllf1elic diseases. CM"Chylomic
' .........,-....-....,...0\'>

<..- .....

..... , .. _,., " - - - ' >

U. Hyperlipiclemias

Type I (FAMIUAL HVPERCHVLOMICRONEMIAl

.=.::..-:::1,:::::d.. ,

ellol_""a1'~

Ioo'........ '... _IcII<J>olrlg_-.ryr.,-..-..nlng ln

ll'-,._1I>d

_0' Iipno "" " , , _ ... Of .-mal ............ oteIn CI (...~

ln~hNrI_"', .,,,lMod with." lo ... eTNOtmont: Lowr.tdiel. Noflnlgmenpy II eIl_ ... Typo '''''... I.... 'oiL

• TyJIe 110 _

Type IIA [FAMIUAL HVPERCHOLESTEROLEMIA] • E_LDLwhtl_V1.Dl._
,

.e..-dbr_.....-.oI_UlL~.

.1.....

'''Ic-._,._lJIr

.T............., dooklll.. 01 _ _er_n.

.Ied.

_101

law In "'" del ~ ~:""_pO.Io_

Low

CIocIeoll"*J'll""
Type liB [FAMIUAL COMBINED (MIXED) HVPERUPIDEMIA] e SIma. to II'" exorpl VlDl..e ..... 1nco_1-..Itlng In _Mod __ 1tIacylgIycetoI .. _

• ee..ed""___

... ""," .,01.

01 V1.Dl."" "'" 11_.

• -..IyCUOi"",,'.

• T..." ... ,1. Diet8O)' ,..._ ,IcIIoo,oIdocl _ _ 01_ oau_ r.. _ _.

Drug "'"'"_ _ fa " ...

ex""l'l~

Type III [FAMIUAL DVSBETAUPOPROTEINEMIAJ • ~ CUO_iO ....... aIlDL ... lo""

• c..e .. _

d - ' I n O.....

_1rIeqlg/ycenll_

c!lOIeolen>f levels.

~ er..-.llrullbollo 01111..
• x..itl ...._ _

aoccele<_

.Tr-......: Welgt'o.-~~ .:r" .......n_doOfibel.(.. lIfIIIWI

• =_lIonol0l101 I ) . e r _ .. me.a '"In}.

,

oI _ _

D r u g ~ _

Type IV [FAMIUAL HVPERTR1GLVCERIDEMlAl

-._LDt.-_.._ ......... "i\_"IIIn_fa_a"""d_ol.oI, _

• VUlt._ . . 1...... _

grHlIy

zIco 'w clralIetlng tnacylgI.,.,..,.

~ . - 01 VUlI..IrIacyIgIy<:e . , . . .. a.--rcuo'.,..' _... I1'-lew .._ _ _ _ _ ..._ " " ' _ - . _ P_ _ thltdl_ . . " - ' l J I r _ . - ' _ ~ e.....'-.",....... In 1heIf\hlrd b" or _ . e r . . _oIlo;.

...... _'".-....

I&_.......

.n_b'.'1. Welp'rt.-(II. .... boh'jdo .... "O>IlIIIed 111I. law _

'~1&0I~~llIeI.-yrHlr\ctIoo'oICUO'b_

............,..

....',ito...., (",,_*~Ollo_ (er_~

'-"B81, dru; ",","_Indudltll.- ondIer

Type V [FAMIUAL MIXED HVPERTRIGLVCERIDEMIA) lWI_In _ _...... • sen.on VUlt.~ .........Iacl. L.DL I. _ er ct!CI

.T_

-llJ&IlY

• c... .. _

trIacyIg.,=oI_.. ....._ prodo><1Ion er doa oMec'

,

,

.,""oIvLDt._~ .

.-,

........

• 0ccurS_ cuo"'""ilrln _who •• _ _ -.....

U-_

We!lIh''-(lf......"..--,.1I. ImpoRonI. Diot _ _ _ c n . _ r . _ _oo_ COItocIlyU".... _ no - . 11......"..--,., flnIg 1nclL>ile& . - . . . - _ _ .... iillboUliI. 01 lcw..,..lin (00 _~

Figure 21.2 (continued).

<........ _,.,.<---,. 2t. Antihyperlipidemic Drugs

'"

III. DRUGS THAT LOWER SERUM LIPOPROTEIN CONCENTRATION Antihypef1ipidemjc (!rugs target the p~em of elevated serum lipids (in both primary and secondary hype.lipidemias) with complementary strategies; some oIlhese agents decrease production 01 the IipopIOtein carriers of cholesterol and triacylglycerol. whereas others increase lipoprotein degradation. Still others directly increase cholesterol removal from the body. These drugs may ba used singly or in combination. but are always accompanied by the requirement that dietary lipid intake be tlgnilicantly lOW. especially cholesterol and saturated tats. and the caloric content 01 the diet must be closely monitored. FMI'( IlCIdl

A. Niacin (nicotinic acid)

l

TrWqr11lt,..•• ,u1

Nicotinic acid has a broad lipid-lowering ability, but its clinical use is Iim~ed due to its unpleasant side etlects. Derivatives 01 this drug that are not available in the United States appeal to have fewer adverse ellects.

,, ,,

,, ,

~,

v

,, ,, ,, ,-

,~

,,

~,

v

.~

Figure 21.3 Niacin inhibits lipolysis in adipose tissue. resuRlng in decreased hepatic VlDL and LOL synthesis.

~

, I•

• '00

u

~

2. Thllrapeulic uses; Niacin lowers plasma levels 01 both d'loIesteroi and tJiacylglyceroi. Therefore, ills particularly useful In the treat· men! 01 Type lib and IV hyperfipoproteinemia, In \'itlich both VLOL and LDl. are elevated. Niacin is also used to traat other severe hyperchoiesterolemias. 01ler1 in combination with other antihyper· lipidemic Bgants (see p. 215). In addition, it is the most potent antihyperlipidemic agBllt lor raising plasma HOllevels.

,-

•l~ ,

_.

, ,

1. Mechanism 01 Aetion: At gram doseS. niaCin {NYE a sir1I, a watersoluble vitamin'. strongly Inhibits Hpolysis in adipose tissue-the primary producer 01 circulating free tatty acids. The livef normally utilizes these circulating fatty acids as a major precursor lor tria· cyIgIycerol synthesis. Tnus. niacin causes a decrease in liver tria· cylglyceroJ synthesis. which is required for very low density lipoprotein (VLDL) productklr1 (Figure 21.3).2 Low density Iipoproteif1 (LOL. the cholesterol-rich lipoprotein) is derived from VLDL in file plasma. Therelore a reductioo in the VLDL concentration also results in a decreased plasma LDL concentration. Thus. both plasma trillCylgtyceroi (In VLDL) and chOlesterol (in VLDL and LDL) are lowered (F"lgure 21.4). Furthermore. niacin treatment increases HDL"'Cholesteroll8\lels (HDL Is the "good" cholesterol carrier). Moreover, by boosting secretion of tissue plasminogan aetivator and lowering plasma fibrinogen, niacin can reverse some of the endothelial cell dysfunctiOl1 contributing to ttvombosis associated with hyperd1olesterolemia and atherosclerosis_

•

Figure 21.4 Plasma levels of cholesterol In hypel1ipidemic patients during trealmllf1t with niacin.

• •

3. Ph8rmacokinetiC$; Niacin Is administered orally. Ills converted in the body to nicotinamide, whictl is Incorporated into the cofactor nicotinamide adenine dinucleotide (NAD'), Niacin, its nicotinamide derivative and other metabolites are excreted In the urine. [Nola: Nicotinamide alone does not deaease plasma lipid levels_l 4. Adverse eltects: The most common side effects of niaCin therapy are an intense cutaneous fluSh (accompanied by an uncomiort· U·Soop.2.alor

t<> _ _ " _ _

...........J., •• _ .... _ .. ,.

• c

_ _~.__"' _ _ .. _

>

Ill. Drugs That Lower sen.'·Il lipoprolein Coocer1llalion

'"

atlIo ~ 01 wamlCh) and prlri:l,I$. Mnristralion 01 aspim prior 10 Iakirag I1iac:j't cleaeascs tho Ikosh. ...tIich is prostagIanlli~ aRld. SaTIO patients aI:Io experiel ce nausea and abdu Iii oaI pain. Nic:dii lie acid ftlibils tubular secretion ol uric acid and ltui predspo&es 10 hyperl.R:emia and go.L ~ gttO)&fl Ioioollce and hepaWr:Pici'y have ~ been repol Dl.

These agents are 00rivaIN0s d Iibrie acid and boltl hINe tho _ mecharlism ol action. HowcwIr. gernij:IroliI (gem FYE bro
-

1. Mechanism of action: Both dfl,lgs cause a docroase In pla5ffi8 tri-

acylglycerol levels by Slimulatlng lipoprotein lipase activily. the.eby hvdrolyzing triacylglyeerols in chylomicrons and VlDl, and thus hastenillg thc Icmoval 01 these parlicles t.om the pl.asma (Flgt.ltc 21.5). In mnlrasl, HOlleYels risc moderately. Animal studies show !hat the fibr.ltes can cause a IoWemg 01 plasma c:ho6estcml by il~llI choIcslerol synthesis in the hoer (med'lanism unknown) and by increasiog biliary excretion 01 cholesterol inlo lhe leees. The tibrates also appear 10 lowe. plasma Mll io 1OgB" levels.

-

2. 1ll...peutk: uses: The librates are used in the lreatment 01 "rperbVl'OOlmIMs.. ClIU5ing a siylorcant doaea$e in plasma triac,1glyeerol levels. {Noto: They are r'IOt indialtcd kif Type I hypE;'1ipidemia in..-tlch d¥orllic;rul IeYeIs are eIeYalod bul VlDl Icvels are nonnal.) Clofibf7!lle and gemfibroz;' arc particularly use'ul in heating Type III hyperlipidemia (dysbetalipoprOlcinemia). in which intermediate density lipoproleins (lOll particles acclXTlulate. Paliellts with Ilypcrtriglyccridcmia (Type IV (eleVlltod VlDl) or Typo V (elevated VlDl plus chylomicron) disease) who do not respond to diet or other drugs may also bonelit lrom lrcarment with these agools. 3. P'h8mIacoklnetic:a: Both drugs are CCfI,petcly ~ aller an oral dose. CIo/ibtBI8 is dceslerilied 10 the acliYe doIibric acid. whic:h bWlds to albumin and distributes widely In body IiSllues. l..ll\ewise. gemIibroziI distributes extensively. bound 10 all:Jl.nW\. ~ drugs Ui idelgu extol iSlO'fl biotransIormalion and art! excreted In the l.Ule as their ~ CXlfiugates.

4. AdYelH effects

adverse ef1ccls art! mild gas. troinleslinal diSlufb8nOes. These lessen as !he therapy pro-

.. GI efIect&: Tho mo!il Wi.IIO" g~

b.

.-

Uthlllsls: Because lhe50 drugs increase biliary choleslCfol excretion, \hero is a prodisposition to the Iormation 01 gan-

~

,.,

Fig'" 21.5 AcliYalion ollipop
< .......

_1.,

><

,.

21. Antihypet1ipic1emic Drugs c. Malignancy: Treatmenl wilh cJo/ibralfJ has resuMed in a signifi· cant numbe. of malignancy-related deaths.

d. Muscle: Myositis (inliammalion of a lIoh..o1tary muscle) can occur with both drugs. thus musc:Ie wcakllcss Of tcndemess should be evaluated. Though rare, patients with renal insufliciency are at risk.. M~ and rtlabc\eftlyolVsis have beef1 reported in a lew palillnls tal
'M

e. Drug Interactions: Both tibrates compete with the cvumarin anticoagulants tor birdng sites 00 plasma proleif\s. thus transiently pelcnliating anticoagulanl activity. Prothrombin levels should therclere be monitored wtlCO a patient is taking boIt1 these drugs, Similarty, these drugs may transiently elcVale the Ievcls 01 stJIeny1 urcas. f. ConlJ3lndlcallons: ThC sately el these agents in p.egnant or lactaring women Ilas not been establisl1ed They should not be used in paticnts wilh severe hepatic and renal dysrunction or in patients with prC-(lx;sting gall bladder disease.

_-

C. Bile acid binding resins: choleslytamlne and colestlpol

_ 0111I. bI. Kldo _ -". 11IM ~ ooocroted Inlo_

..,_ ....

B. Hypet1ipklemk: patient ~ wilh bile acid binding ",sins

e:-trr--.,..~ 1<1<>II.,..,__ ~.

with tI\oo Ill• ....,• ...., ..no, pr'WefTl1"'llllltlr "'lbootpllon

frOQ\

the 1_ _•

Figu1ll21.6 Mechanism of bile acid binding resins.

1. Mechanism of acllon: Cho!estyramifl6 [koe less TYE ra meen) and coIestipoi [1Ioc LES tih poIc) arc arlort exchange resins that bind ncgalivcly chargod bile acids and bile saMs in the small intestine (Figure 21.6). The rcsinlbile acid complex is eXCfCtod in lhe roces. thus preveoting the biIc acids rrom returning to !he liver by the enterol1epatic circulation. Lowering the bile acid conoontralion causes hopatocytes 10 increase cOfwersiofl 01 cholesterol 10 bile acids. resulting in a replenished SlJpply of Ihese compounds, \\lf1ich are essential oompooents 01 the bile. Consequently, the intracellular cholesterol concontralioo1 decreases. \\lf1ich aClivaies an increased hepatic uplake 01 d1oiesterokoo1taio1ing LOL particles. leading to a fall in plasma LOL INote: This increased uptake is mediated by an lJPfOQulatioo ot ceU·sut1acc LOl receptors.] In some patients. a modest rise in plasma HDL levels Is also observed. The linal outcome 01 this sequence 01 events is a decTeased 1OIa1 plasma choIcsterQl concontration. 2. Therapeutic U6eS: Tho bile acid binding resins are the drugs 01 dlOice (olten in combination with diel or niacin) in treating Typo lIa and lib hypcrlipidemias. lNote: In those raro individuals who are homo~ygous lor Type lIa, that is. ler whom runctional LDL receptors are totally Ia<:king, these drugs have lillie etlGCl on plasma LDL levels.) ChoieSlyramif/8 can also relieve pruritus caused by accumulalion ot bile acids in pallents with biliary obstruction.

3. Pharmacokinetics: Cho/estyramine and coIestipoi are taken orally. Because they are insoluble in water and are vory large (molecular weights are greater than 10&). they arB neither absorbed nor metabolically aflered by the intestine. Instead. they aro totally excreted in the feces.

........ _'., ........ _,> III.

...... _ - , _ .. _

.... >

I:lf1.9S ThaI lOWCf Scrvm ljpoprotc;n Conoontra!ion

'"

4. AdvotfM etIect5

.. Gl effects: The most oonvnon side of1octs am gaSlfWltestA'lal distl.dJBnces. sud1 il5 <Xlf'lSlipatOl. nausea. and IIaIuIcnoe. b. .......eel 8tl.co ptlDilS; Abi:ujAio, oIb tlt-&ok.tiB Wiwrins, A, 0. E. lWId K can be i.lJldied if t"V1 dDses 01 the rosi'18f8 pescrL FoIc acid lnl asu.wbic aoo absorjAio IITlllV also be rCld'ooed

c. Dnlg inCetlCtior ..:

~

lnl I· ... op i inlcftcre with

the i ....... absorption 0I1TlIIfI'f ~ lor ~ ~ ~ ~ c:JgoUl. lOarlati'l; P:~4S' :li~ /Iv. sa.". aspmn. and thiazide diurelies. Therctore. dnJOs shou6d be tat.on .. Ioast 1 to 2 hotn betore. or 4 to 6 hours atter. the tlile acid bi oil III re9ns.

6);--= 0--l.Dl.

_E

><-cr.. .....

ProbucollPROE byoo koIe] was introduced in the 1970s, bul bc<:euse ~ redl.lccd HDlleYels to a greater extent !han !hose 01 lOu. it lell into disfavor. Newer information indicating that lis antioll:idant properties may be irnflortant in l*:dclng atherosclerosis has reStJllod in renewed interest. 1. MKhnltm of acllon: A number 01 mcd\llnisms haYC been pro.. posod 10 explain how probucollowcrs serum ct1oIeslerol. but ~s mechanism 01 action remains uncertain. Ac<:ently it has boen tound that prob(IooI inhibits tho oxidation 01 cholesterol. resutting in the ingestion 01 the oxidized cholesterol-laden lOls by macrophagell (Figure 21.7). loaded with cholesterol. these macrephagcs become loam cells that Ilcthc,o to the vascular endoIholium and are tile basis tor plaQoo tormaIion. Thus preYCOtion 01 tile cholesterol oxidation rOOdlon njght slow thII doYeloI> mcr"4 01 a!holosclcoosis.

2. Thenopeutic ...-: PrctNt:x1I is uschJI in IrOatrlg l'rPe IIA ard liB twod ....-sk1... ,lia. although less 1IO than the bile acid bin,tng ~ Bocause a low HOl level is al least as groat a risk lor alhclosdeil)lsis as an eleYakld lOL IcYcI. Ihe usefLAness 01 ItiIS drug is limited to ~ s in whic:tl other antihyper1ipidcmic agents_ irelloctiwe.INote: ProbUcoldoes flO( atled plasma hi-

--,

3. PnermIColcIrMtl PrtlQ..QlI' is very Iipc:lptlko and il$ absorption is hlgtjy YBriable. AOnir"islraIion with Iood irlopoowes absorption and reduoes YllriabiIily. ProbucoI is carried in the lot. partides and ao::umulatcs in adipose tissues where it may persist lor 1'1llI rltrs. Exc::retion is Ilia tile bile the Ioces.

no

4. AdYefH .fteds: Mild gastrointestinal disturtlanee Is a lXIil.'IllI' ac:tvorse efkld IhaI generally wzn '0001; with continued treatment. A more seriolJs plotllcm is its tellooncy 10 plolong the aT interval. Thus probucol is contraindicated in those PlItionls Who have an abnormally long aT interval. Cllle should also be taken wilt1 patienls receiving drugs that prolong this Interval. such as

---

II • • " , . - _

or .......,

c."

_ por.

.~"orpIwquL

F"ISIure21.7 Aokt of ptrJINt::tJI in prevcr6"og oxic::Ialion of Iipoprolcins.

<

,.,.<- --,. 21. Antihyper1ipidcmic Drugs

digil<.llis, quinidine. 601<.1/01. astemizole and tertenadinfJ. Because of its long sojourn in the body. a woman s/lould diSCOf1tiruc !he drug at lcast 6 moolt1s belore attempting pregflarq'. F. HMG-eoA reductase Inhibil0f"5: lova5talln, pnvastalln, simvastalln end fluvastalln

o o

01. OH C

C CI', 01.

?

c, Co'"

IIMG-CoA 2 NADPti+ 211 +

I I Figure 21.8 Inhibitio<1 ot HMG·(;oA redllclase.

,

Tl1is novel group 01 antihypcr1ipidemic agef11s inhibits the first comm~ted enzymatic step of sterol synthesis. As structural analogs ot the natural substrate. 3·hydrOlly·3·methylglutaric acid (HMG), alt members of this group compete to block hydro~ymethylglutalyl· Coenzyme A reOOdase (HMG-CoA reductase)." E~ccpl lor flwas· IBM. lhc olher HMG reductase inhibitors am dlerrkal moditi<:ations 01 oompounds occurring naturally in fungi.

1. Mechanism 01 ac:llon a. Inhibition 01 HMG-CoA reductase: lovaS/alin [100 vah STAT in] simvasl8lin [sim vah STAT in], pravastatin [prah vah STAT in] and fluvastalin [flew vah STAT in] are analogs ot 3--hy'llroxy-3melhylglutarato, the precursor ot dloIestcrol. lovssUllin and simvaSialin are loctones that are hydrolyzed to !he active drug. Pnwastatin and f1uvastatin are active as such. Because of lheir strong atlinity /of the enzyme, all compete eHcctively te inhibit HMG-CoA roductasc, the rate-limiting step in cholesterol synthesis. By inhibiting de nove cholesterel synthesis, they deplete the intracelfular suppty 01 cholesterol (Figure 21.6). b. ~rea&e tn LDL reoeptOfll: Depletion 01 intracellular ctlolcs· torol causcs the cclIto increase the oomber of specific cel'·sur· tace LDL I'(lCCptors that can bind and internalize circulating LOLs. Th,ls lhe end IOSlJM is a reduction in plasma dlolesterol both by lewered cholesterol synthesis and by increased catabolism of LDL. [Note: Because these agents undergo a mar1\ed first-pass eKlraclion by lhe liver, lhclr dominant effocl is on that organ.] The HMG-CoA reductase inhib~ors. like choIestyramine. can increase plasma HDL levels in some patients, resulting in an additional lowering 01 risk lor coronary artery disease. Small decreases in triacylglycerol can also occur.

2. T"herapeulk: uses: These drvgs am ettcctive In lowering plasma choleSlerollevels in all types 01 hypertipidemias (FigurE! 21.9). However, patients who are homozygous lor lamilial t1ype'dJoIesterolcmia Iadl LDL receptors and therelore benclit much less lrom treatment v.ith these drugs. [Nolo: These drugs are olteo given in combination with other antihyperlipidemic drugs, see later.llt should be noted that in spito 0I1t1e pcotecDon al1ordod by c/lolcstcrol lowering, about one lourth 01 the patients treated v.ilh lhese drugs still presented with coronary events. Tl1Us, additional strotegies SlICh as diet. exercise. or add~ional agents may be warranted.

Flgure2T.9 Effcd ot prsvastaM therapy on deaths from all cardiovascular =~.

'see p, 2161", _

"lie....."... k> _ _

In"'"

~

..... I ••

u'.' ........ _ ... , >

• <_ •

"""", -:.u .. ...,...... >

III. Drugs ThaI Lower Serllm Lipoproleins COOOCrltration 3.

215

PhllrmacoldnetJc. Pf/lVaSralin and IllNasUlIin are almost oornplclcty absoIbed alter

oral adminislralion: o
,. U".r, Bioc:hemieal abnounalil1es in li\/1i!r lunclion have occurred wilh ltle HMG-CoA IOOdase il4liJilUiS. Thereklre II is plule. 6r)'ltnWI1)ci'l. {;$iJtb'Dd. or niQL PWmlI aualine IQnase leoets 5hCIIJd be delelmi led regWIly. Co

Drug 1n'-
IS. Co"bllinl'k.IJont;: These dnJOS are c:onIraildcated in pregIlilIICY ancIl'lnIio1g mothers. They lihoIAd not be IJ$Jlld in chilom 01 1OllrHlg8Ia.

COOOTU ~oo<:." ~ '" .... G>o' "" T

Agu.. 21.10 Sc::n1e ~ eftIecU and precatAioosiIss HUG-CoA ...... w;tase i4ibibs.

....-n

I

!• 0

G.

Combln,uon Drug Ther.py

•u 1• ••

Q-

! •

•

II is somelimes nooossary to employ two antihypel1lpil:lemia drugs in Older 10 ad'icYe a slgnilieanI docIease in plasma lipid IcYels. For Illlample. in Type II hyper1ipidcmias. patienls are ~ Iroatod with a ~lion ol riac:in plus a bile acid binding agonl, such as cho'9sIyr"anin6.jNole: Remerrbe< that cho/eslyrsmine callses an lnerease In LDL receptors lhal clears lhe plasma 01 clrclilating LDL. whereas niscin decreases synthesis ol VLOL and Ihorelore also Iho synlhesis

figure 21.11 Response 0110181 plasma ctooIes1erol

olLDL] The combination 01 an HMG-GoA roduclase inhibitor wilt1 a bilo acid birO'ng agon' has also been shown 10 be liselUI in IowCring LDL choleslerol (Figure 21.11).

hVPCrd1oleslerolemia 10
1.<1. . ._

~O,

• 110,.

Co" 1\ '

in patients with hclorozygous lamilial

<

,.,.<- --,. 21. Al1tl'ryper1ip;oom;e Drugs

'" Choo!;e 1M ONE besl answer.

21.1 Which on" oItha 1oIowi"ll is 1ha most mrrrnon $idfI effect 01 antihyp&rljpidemic: drug lherapy? A. Eleval9d blood prllssure B. Gflstm;n"'s1ina1 Bsturbfln<::
hflpdc~

1 ~

ClUESTIONS21.4·21.7 DIRECTIONS: The group 01 queslions below ccnsisls 01 live drugs (A-E) followed by a lisl 01 numbered slate·

Correct "llSWfIr • B. OastrointeBtinal dislur· I>aI'..- J\"flqullr1Il\
[ ~_~~:==':..=

Ihenpy.

menu. For each numbered slatemenl. sele-cllhe ONE drug "om Ihe Hsl (A-E) 1hat Is mo&I closely associaled with~. Ea<:h drug may be selected once. mom than once. or not al all.

Ma1Cl1 each drug wilh 1ha Slalemenllhal best describes lis mode 01 action:

21.2 Which OOe 01 rhe following hype~ is char...,. le~led by elevaled plasma levels 01 chylorn;crons and has no drug lherapy available 10 lower lhe plaSma ~mtein levels?

A. Niacin

B. Clofibrate C. ChoIestyralTW1e D. Probuool E. Lovaslatin

A. Type I B. Type II C. Type til

21.4 Binds bW ac:ids ill lhe ",,,,stine, lhus preventillO lheir mtum to !he liver via !he enlerohepatic circulation.

D. Type IV E. Type V

Comld

.e: CI. fl51}1.' • •'

21.5 Csuses a decfease m plasma Iriecylglycerollevels by increasing 1hlI aetMty 01 Iipopro1ff1 lipase.

21.3 Which one 0I1he lolowiog drugs llocmases de novo choleslerol synthesis by Inhibiring rhe enzyme 3· hydroxy-3-melhylglul"ry1 CoA reductase? A. Clotibmte B. Niaci
21.6 Causes a decrease m liver triacylgly<:erOl synlheais by IimtliIlO available """ /any ac:ids FlOOded as buildIr\{I bIoo:ks tor lhis pathway.

I

E. Gemtib!I ~ an:l . . .

Is... p.323In_._y(2nded.jlDr" ....._ c;f_ •• - .

'sea

con;::t..- .. 8: 0tAbala.

p. 200 In "': " . I

c;f lh8 ryo"

[ c;f d

0'

,(2nd _l I"..
MIl.

Cor<ect...- .. A:.NDl.

21.7 Inhibits 3-hydroxy·3-melhylgh,l\8ry1 GoA reduc1ase. !he rale-1imiling slaP in choIesl....ol synthesis. __ •

: l.ovM\IaI.

,

....... _.., ........ _,.

.._.-

,_.,_

. UNIT V:

Drugs Affecting Other Organ Systems

Drugs Affecting the Respiratory System DRUGS AFFECTING THE RESPIRATORY SYSTEM

-

jl.-A_e
syst~

OO'sd»" _

rnochaoisms.lor~. by

-

AsltWTlIi is a d ....n.. di5E8se Itel: atlacIs -4 10 5% of lhe U.s. pq:Uaimd by 0,,","",,,," of aaAe biUiUiOGUlStlitJia, ClIUSing .... bl6SS of btealh. cough. chest tightness, wheezing and rapid .espifalions. These ae:ute S)'I'I'1lCOn'IS may resoWe sporl\aIlOOUSIy. or more often. ~ therapy Sl.d'l as a fl:. ;()!oisl (see p. 218), A seoorw;J dcIayed or Iale-ptlase response may occur 4 10 12 hours Iator, and may requi.e Iroalmcnl wilh steroids. Asthma. unlike chroni<: broflChitis, cystic fibrosis Of bfonchlcctasis, is usuafty nol a progressive disoose---C does noIlneVilab1y lead to cripplit Ig chror'Oc obslructive U1g disease. Aalhor, lhe dinical course 01 asthma is characterized by exllCCfbllliof'ls and/emissions. Dcalfls due to asttlma arc Inhcqucnt, but mortlidity results in slgniIic:ant hospitalizalioo and oulpalionl costs. Tho goal of !heraP'1" is 10 rc~cve symptoms and to Pf"(l\'Cf1t rfX\lrrcnce 01 aSlhmlltlc attacks. ~ possible.

.......... ro T'AEATIll". 'IS

co-Ado .....-.- .. ,

~

II. DRUGS USED TO mEAT ASTHMA tiorI. or ~ 10 n6:ln patier'U. The di!'er,p is cterader·

._""".

71'......., _..

s;oo

cllods. Clinically usclul roIaxlng blOIdial smooth mu&do, or modulaling the inllammaloty fesponso. Drugs usod 10 IrOat asttma. ~ cI1n:lric obstr\Jccil,oe ~'Y di~ ,se. and cougtr-oOI'.'lOilty 0flC0Uf'llefed rcspiralOfy disoldeo"S lire sum-marizod in F'fllUrlI 22.\.

---, -, . -. ..........

Dwg:s ren bo delivered to lhe lungs by inhalalioo, oml, Of parenteral roules. Inhalalioo is olten preferred because lho drug Is deliwrod (lirOCftV to lIle target tiSSl e !he airways--and is clfoctivc in doses thaI do 1"10I cause sigllifica,'lI

T~T"STHMA

.....

I. OVERVIEW

dru;s ad by various

DRUGS USED TO

00

-

j'

)/1

ORUGS USED TO TREAT

~'I. MOfrl.MY

"·SU _Adl...,-,, •

.... .,,, Coot

-

'

,

IJ

.......... ro -,~

-

I

IlPlo,_P'*,

Agure 22.1 Soomasy of 00Jgs alfocti"lllhe respiralory syslom. lDesc
<........ _,.,.<----,.

< ..,... • - - _ . , -..... .. _

.....

22. Drugs Affecting lt1e Respiratory System

'18

A. Role of Inllammallon In asthma

Some clinic.... c...._ tI1~ - . . ...- . oItI>ouVh efleclive '" mild ~ bII _ _ IOf _

..........._

_ld

..!olIo

...IlI_r1.....

01 plOlOO>go
,,-...

glucoc
T_ _

befonIlr_hn...1

---' .pOr- --._..- - ... ---

LeM-.abl..._ _ _ k:lf..

-~Mc~ _..."" _

.......Iocl~.!'

"

I' ?

21>; ... _

_ _ k:lf ..

$1

-..

ill_lie_

.pl"~..

Figure 22.2 Summary o11featmcnts lor asttma 01 varying severity.

Airflow obstruction in asthma Is due to broochoconstrlcfion reSllning Irom contraction 01 bronchial smooth muscle, inftaJTmatiOf1 01 tho bronchial wall. and Increased mucous socretion. Asthmatic attach may be related to recent exPOSllffi to allergens, inhaled Irritants leading to bronchial t1ypCractlvity and inllammatlOf1 01 lt1e airway mucosa. The symptoms 01 asthma may be ellectively trealed by scycral drugs, bJt none 01 the agents provide a cure for this obslrudive lung disease. A. Adrenergic 1I90nlsls Inhaled adrenergic:: agooisls with Il:l aetivify are the drugs 01 choice for mild asthma. tf1at is, in patients showing Oflly occasional, intermittent symptoms (Figure 22.2). (lz-Agonlsts arc potent bron· chodilators that relax airway smooth muscle directly .

1. Short acUng drugS: Mosl clinically uselul JHlgonisls have a r~ (15 to 30 minutes) 0fl00l 01 action and prcMdc rcflll1 tor 4 to 6 hours. Thoy are used tor symptomatic treatmenl 01 bron· chospasm and as "rescue agents' to oombIlt acute brord1oconstric\iorl. [NoIe: Epinephrine (sec p. 61) Is the drug ot choice tor treatmenl 01 acvte anaphylaxis.] Ih-Agonisfs ha"'C no anti·Inflam. matory elfccts and they should m:M:!r be used as lhe sole lhera· pcl.Jtic agoots tor patients with cf1ronic asthma. Tho fl.rseIoctive agents. such as pirlJutsrol. terbutaJine, and albvteroi (sec p. 67), oller the advantage 01 providing maximally attairlable bronchodilation wilt1lilUo 01 tf1e urxlcsired effect 01 a or (1, stimulation. (Sec p. 60 for the roccptor-spcc:ific actions ot adrenergic agonisls.) The (12-agonists are not catrrcholaminos and thus arO not destroyed by catechol 0-mcthyltransforase (COMn. Toxic sido effects. such as tachycardia, hyperglycemia. hypokalemia and hypomaglcscmia, are minimized when the dfugs are delivered by inhalatiOf1 rather than by systemic routes. Though tolcran<X! to the 6·agonists' efleets 0f1 non-a1rway tissues OCCUfS, ~ is uncom· mon with normal dosages. 2. Long acting drugs: $almBteroi xinllroare [sal MEE tor 01] is a Chemical analog of alburerol, but diffors by having a long lipophilic side chain that increases the affinity 01 the drug lor the ~adrenooeptor. $almeterol has a Ior1g duration ot action. pro-viding broochodllation lor at teast 12 hours. $almolorol has a slow Of1set 01 action and shoUld not be used In acuto asthmatic attadls; ~ should only be prescribed tor lIdminlslratior1 at rcgolaJ intervals and not to rellc"'C symptoms. Ukc the others In this drug class, II Is not a subs~tuIe tor antHnllammatory therapy. B. Corllcosleroids Inhaled g1l1COlXlfticoids arc the drugs 01 first choico in patients with moderate to severo asthma who require inhalation ot Il:l-adrcncrgic agonlsts moro than once daily (sec Figure 22.2). Sovere aSlhma may also require systemic glucocortlcoids. USllaily lor short tenn. Inhalod glucooortiooids olten redUce (or eliminate) tho need for oral glueocortiooids in patients with severe asthma. To be

·.... ,....,., ........ _,.

• co- • _ .

: ......... , I
......

II. Drugs Used To Treat Asthma

clloctiYc in eontrol~ng inflammation, gIlJcoODr1k:oId must be taken oonlinlJOtl!.ly. (See p. 272 lot a summary of the mcd1anism of edian d oortio06lel'liIs, lVId T~ PIiAollplld (se.etaI " ...h1 ~.IilIaIioi, 01 sbuids redl ..... lh&hypoo,. . . . lSi.&ess of hair-,. 5'~ rI'USde to a varidy 01 tooud"o::Uiltldol' stmt.6. SI.dl as lIIcolleus. inia
,.-

•. Inhaleel d'~" The devetopmcnt 01 inhalod steroids has mall<.cdy I'edlcerllhe need lor syslomic: OOIli(J)slhoid treat· men. t-laweWr, a lew pmcitUIions are roq..iIod lor 51·' es '... ilVWllation therapy. A Iatge fradiorl (typically 80 10 90%) 01 inhalod gIUCOOOftilXlids is depo5itod in the IIlOlIIh and pharo ynx. or is swallowed (Figule 22.3). These Ilh.lCOCOrticos· teroids arB absorbed from the gut and entor the systemic ci'aJlation through the liYCI. Ho
--... ,~

b. Sy'Iemlc ,Iuolds: Palients with $Cycro exace,bation 01 asttrna (status asttmatic:lls) may I'C(JJire intra'o(lfl(lUS IIli'TW'tls!ration 01 methylpfedrJisolOt or oral pI ..dn;S<:M'l6 (see p. 275). Once the palienl: has impn:MId. the dose of drug is (jI1I(l.Iafy re
c. SplICer.: A spacer is a la,go \/O'umo chamber Ihal is altaehed to the mete,ed·dose inhaler and is used 10 doerDMeIho dep>sitiol, 01 ~ in the tTIOIAtl (F'v-we 22..4). The ~ serves to I1ICklce the \docity 01 the ilijeded aerosol bcIore il. en\eI$ the mouth. and alows large ~ partides 10 be deposited in the deYioe. The smaller. low\/IiIIlx:ifV ~ partides are leSS MIeIy 10 be tIepoIiil.ed ... 1tIe !TIOUth and more likely to read! the Iarget airway lissuo_ Spacers irT(nMl delivery 01 inhaloll fI'_ •••• \iooids and are a<Msc
3. IutIIerH etfrlcla: Oral or parenteral gluaxxl!ticoids I\aIIo a variety 01 polontialy seriouS side cfb;l:s (900 p. 277). 1-IowlMlr. W1aled gIulxlcorticoids. particUarty if UllOO with a spaoor. have lew systemle crtcets. Oropharyngeal CIlndidlasl....-scmetimes CIllled thrush--may be a problem in pationts who Intlalc gIul:::ocortioo.

-&w .......

Figure 22.3

PhannaCllllOOolics of imIllod g1l,JlX1OO1\icoi
< ,.,.<--_ ,. 22.

Drugs Atleeting the Respimtory System

partiOJIa~y

ill1l1'O,.J'lOSuppt"essed patients. Spacers minimize the problom 01 adrenal St..WfessiOO by reducing the afI"lOI,rl\ 01 glucocorticoid deposited in It1c oropharyrlx.

,

C. CromQ/yn and nedocromll C ~ [KAOE moo tin] and nedtxromililleh DOC ro mjl] arc ottectivc prophylactic anti-inflammatory agents, but are not useful in managing an acute asthmalie attack because !hoy are not direct brOflChodilators. These agents can block the precipitation ot immediate and delayed asthmatic reactions. For use in asthma. cromolyn is administered by inhalation of a microline powder. or as an allrOSQlized solution. Because il ;s poorly absorbed. only minor advc<se eUccts are associated wilt1 it Pretreatment with c;romolyn blocl<s allergen-induced and exercise-induced bron· choconstriclion. CfCIfllO(yn Is also uselul in reducing the symptoms 01 allergic rhinitis (see p. 222). A 4- to 6-week trial is roquired 10 detenn;ne efficacy. Gi\len ~s salety, an ;n~ial trial of crOfTlOlYn is otten recommended. partlcularly in children and prcg1ant women. TOlI:ic reactions are mild; !hoy Include a biller taste and Irritation 01 the pharynx and la!)'l1x.

.

D. Cholinergic ant&gonlsls _

""""'" io onoId'8d in..".. parti(:Io. _ """" __ ~ _ l C

vo-

Figure 22,4

Effect 01 spacer on the deliVery 01 an inhaled aerosol.

Anticholinergic agents are gefl€rally less effeeti\le \han !l-adren· ergic agonists. They block lhe \l8.gaJly mediated conlractlon ot airway smooth muscle and mllCUS secretion. Inhaled iprotropium Ii pra TAOE pee uml, a quaternary (leri\l8.tive ot atropine (Figure 22.5), is useful in patients unable to tolerate adrenergic agonists. Ipralropium is slow in onset, and is nearly free 01 side-effects.

E. Theophylline

Thoophy/Iine [the OFF ; lin] is a bronchodilator that roIiOl/Cs airllow obslruCloo in dlronic asthma. and docrcascs the symptoms 01 tile dlronic disease. Previously the main-Slay of asthma lhcrapy. thro-phyIline has been largely replaced with ll-agonists and corticosteroids. Th90phyIIine Is ~I absorbed by the gastrointeslinal tract, and SlM:!ra1 sustajned-fclcase preparations are available. Tho drug has a narrow therapeutic window. and an CMJf'dose 01 tho aug may cause seizures or potef1tially 1a1al1l1r!l)1thmias. Furtl1cr. theophylline interacts adVcfsl)ly with many drugs. pp. 450-451 lor description ot newly appIO\(!d drugs. zilwlofl, mfirlukast, and monrelukast

see

a

III. DRUGS USED TO TREAT ALLERGIC RHINITIS

Figure 22.5 IptatropiWl. a qliatemary amine derivative 01 atropine.

Ahinrtis is an inflammation 01 the ml,lCOUS membranes ot the nose. and is characterized by sncc~ing, nasal i!d1ing. watery rhinorTt1ea and congestion. An attaell may be precipitated by inhalation 01 allergen (such as dust. pollen. or animal dander), which interacts with mast oolls coated wiIt1 IgE, generated in response to a provious exposure to tile allergen (Figure 22.6). The mast oofls release mediators, such as histamine, leukotrienes, and chemotactic lactors. wt1ich promoto brondliolar spasm and mucosal thickening trom edema and cellular inliltration. Combinations 01 oral antihistamines with dCCOO9CSlants are the first-line therapy lot allergic rhinitis. However, the systemic

·.... ,....,., .. _--,.

• --" -

IIl.l:ln.Ios Used 10 Treat ChroNc Qbslructive

A. AntIhistamines (H. receptol blacken)

are

ageru In !he treaImenl: of ~ an:! walety ,tliolOilhea assoeiet«l with alergic rhinitis.. H,-H:sIamine 'ec:epIOi blod<.ers. such as ctp/let_"itdanioe, ~,

_ . PI"

~ r y Disease

elleas sometimes associated wi1h these oral preparallons (sectalion, NQmnla, and rarely caJdiac a
ArIlihisIarl'*l

: _""", _ _ -

IhB ITIOIt lrequenIly used

Ioratadine, Il!rlenadne and _emizoIe (see P.

422). are useful in treat'Wlg!he ~ 01 allergic rtritis caused by histamine release. COrnbinIlIions of an\llistan*\es with
'"

-_ _t :_

iI MAST CEll

-

SENsmzATlON

"po t 1'01 . ' 1._ _

_ ._.

_01

tion 01 action.

B. o.·Adrenergic agonrsts o.-Adrene'gic agonists ("nasal decongestants') SUCtl as ~ ­ ephrinfl. constrict dilated arleriOles in the nasal mucosa and fedla Uway resiSlMCe. l.or'O"~ ~I~ I mel AZ oil Ieen] is also available. When 8dITWlistered as an aero&Ol. tlese drugs have a rapid onset ol action W"d show lew ~ eItects. Oral administration fBsu'tli in longer duration 01 action but Irlcreased systemc el1ects. Combinations of theM agents wi1tl IIf'JItIisIafnn _1n:Iquetay used. tIey IholAd be used no longer than _fill dIyS because rebound nasal ~ otIen oa:urs upon lI8l;l;lntiruan ollhese drugS. Thelefon!. (1adrenergic agents ha..e no place in lhe long-term treatment 01 llI\erglc fhinitis.

~.:JU , '''';'''-{'"o

Ho,,_r.

C. Cortlco$ten:lids

Corticosteroids. such as beckxnelhasone, fIutice5one. fIunisoIide and IriIlmcirJclol1e (see p. 275). are etlective when IldminislBfed as nasal sprays. [NOla: System;': absorption Is minimal and sida ellects 01 imranasal corticosteroid ueatment are Ioea~zed-nasal Irritation. nosebleed, sore throat and. rarely candidlasis.] Topical steroids may be more etfect;ve than systemic antihistamlnes in relievWlO the nasal syn'4lIoms 01 bolh allergic and nonallergic rhft\is.. The etIecIs ollclng-lerm usage are ldnown. 8Ithoult' ..., are considered 10 be geneflllly sale. Periodic assessment of lhe petietf is adYised.. TrtI8IJnBfW of ctvoric rtnIis mav not resuI in ~ ...-.IiI 1 10 2 weeks af1et stariillQ ~

CI MAST CEl.l [";:I DEGRANULATION 5'$

~

.... _

19II! ...:" .... n._

.-_ I

D.Cromottn

o"'lOI)nmav

1nIl'ana1l81 be useful. par1il::Uart'/..men ad""listered betore WlItad with 8l'I aIlergetl.

IV. DRUGS USED TO TREAT CHRONIC OBSTRUCTIVE PULMONARY DISEASE Ct1ron1e obstructive p1Jmonary disease (COPO) affects apprOllimalely 30 million people in the U.S., and Is the fifth most comulOl' cause 01

t. "'"

.. - . . . -

. - In tlr-.g '

'

' .. _

' '_

•• _-.Ins:: ale ... a: ....... _

• ' --po _pollenltl

:

:.,'"

...

f}gure22.6 Hypefsensitivit reaetior'ls rneciated by IgE molecules can cause rt*lilis.

. . ._

'''''''.'-'.'''---''

•• ,._ _••_

222

. ., KI'<.Mll _ _ .... >

22. DrugS Aftecllng lhe Respirato
V. DRUGS USED TO mEAT COUGH Codeine, hyc:kocodone. and hydromorp/lone decrease the sensiti,my of CNS cough centers to peripheral stimuli, and dec<ease muoosal secrellon. These actions OOCtJr al doses lower than required !or analgesia (see p. 135 lor a more complete discussion of lhe opiates). Dextrometnorpllan [dec lroe melt1 OR fan], a synthetie derivative of morphine. suppresses the response of the cough center. It has 1\0 analgesic or addictive potemial. and is less constiparing than codeine.

Study Questions

0uesli0ns22.11022.4:

22,2 The drug most likely to provide sustained resolution 01

A 12·year-<>ld gi~ wiIh II cM
"'

For each oIlhtt stalements below d100se lhtt priate drug the loIowing islo

'rom

mosl

appro-

A, Inhaled uomoIyn B Inhaled bedomelhasone

the palienl's synllIOmS.

22.2 Corr8cl _ _ • C...... atdII_.._ at. . ctIeoI 1V cootec.,! ..... lII:IIlI meIilrlI . - bacb'''"''..-.e ..... IlllI ~ _ .nough stefOkllO lully corrbaI _ y

1=0,.,

~'lIoo'"'.liotI.

22.3 A drug COflImindicated in this patient. 22. 3. [

Comict ..--r. F. Prop<MIOIoIIs a ~ ] and ~ iQ)a_ the ~a11 ... brOn-

~

. d"""".bk:tloo'

.

C. 0mI or IV meltrylprednisolone D. Inhaled lprn.tmpium E, Inhaled albuterol

22.4 A drug ,ktIIy to be ineMecbv
'*'

F. Intravenous propranolol G. Diphenhydramine

22. ... eo-a __ • A. c.omottn bt ..-:t prophylacllcally 10 'ltduce .... InllM'wnato
H. Inhaled salmeterol

."..."..

I. Oxymelll.Wline

22. I TOO most IIppropr\11te drug to rnpldly revet'SO bfono:hct.

"""""""'-

·.... '.. _'.' .. _... _,.

• .........

:_0»0,

.....

Diuretic Drugs I. OVERVIEW Ofugs inducing a 5UIte 01 inc,eased urine lIow are called diuretics. These agents are Ion IJ8tlSPM ritioo's!hal dea? the reeb&olptioo, 01 Na' • ciftele,,' siIes in . . ,lept.OI'L 1.$ a ll!SUl. Na' aov:l OCher ions suctl as a- enIer . . urine in lireatef emcu'Il$ !han normal ~ >Mt1 water, which Is carried passively to meintain osmotic equilibrium. Diu.etlcs thus increase the YOllme 01 the urine and otten de¥' ifs pH as wei as \he ionic c:or"posilio" ofltle I.rine aov:l blood. The ellieacy 01 the cilferenl classes 01 diurelics varie$ COI'I$lderabIy, with the Increase in secretion 0' Na' varying 'rom less than 2% lor the weak, potassiootsparing diurelics, to over 2Q% lor the polen. loop diurelics. Their major dinical uses are 10 managing disonters Invol\llng abnormol fluid retention (edema) or in lreatlng hypenenslon in which thell diufellc ection causes a deaelIsecl blood YOlLme, Ieacling to a leduction in blood pre$sure. 10 tNs~, the ciuretic (!rugs (FIg.>re 23.1) ere tiso'Sssd in the Ofdef 0I1heir siIe 01 action along Ihe nephoOl , (Flgwe 232).

CHURETIC DRUGS

....,.,...,. CARBONe

f-

.--«.,-

....1ll10fl$

COO. DIURETICS

I--

T..__

=~

I-

II. NORMAL REGULATION OF FLUID AND ELECTROLYTES BY THE KIDNEYS

,

,b

a ..... CMoo •

Appooai"""tety 16-2O'Jl. 01 the blood plasmll ellterillllhe kidney$ is Iitered from Ihe gIomet ulal ....pilaries lnIo Bowman's .... psule. The fi1.trate, allhougl'l flOfmaly 'ree 01 proleins and blood cells, ooes oonlain mosl low !TlOlflcu'af weight plasma components in aPl)l'oximately the same COI'lCf!f1trations as are tound In the plasma. These Includa glu· cose, sodium bicarbonate, amino adds, and other organic liOIutes, plus elearolytes, sucl1 as Na', K', and C'-. The kidney fegulales the ionic OOlnposition and Io
fr

•

- .... --""""'" --

, , . , . . _. . 1 , 11

Mol

I-

,

POTASSIUM-SPARING ~""rncs

T'.'......

L

A. Prm::imal convoluted tubule In lhe extenMly OOf'IYoIuted p«Une1 IubuIe located in !he cortex 01 .he kicttey. almosl all 01 the gluCose. bicarbonate. amino acids, and other melabolites are reabsortJed. ApproJlimately two lhirds of the Na' is also reabsorbed In the proximal tubule; chlollde and

. r

DlURE'1CS

FlgIKe 23.1

&wnmary of diuretic drugs.

. __..

_ _ _ _. . . . . -.~

'-_._"

e._ . . .

L_ _

...... 0""'"

""'''

..... ,°..... , •• _ ... _,>

'" AC£'AZOUoM
......... t.. -, ;

• ~. _

......

'

_

.....".,..

.-_ ---• --.,1II._IIIloo,d_. ='1<>:"';':":''''

.oUICO,-

I_~~~

t!

--.

....

---PO'P'"

""""",,,-,,=wE,

_amvE.

. .... .......

._--.--... ..... _.TRlAMT£RENE

.~ "

'

....,_lhIolckNoo'~

-

.... oll(' _

..

• _ _

.,.-

oce
......

"""/K'a- _

... nr ... III, "... ..."_ _ .aI

No', g._ _ "' .........

Figo.Jte 23.2 Major locations 01 Ion and water Cl
loIIow passively to maintain eleetrlc&l and osmolar equality. It

~re nol for the extensive reabsorption 01 solutes and wale, In the prOIllmal 1tJbtJ1e, the mammalian org.anlsm would rapKlly become dehydrated and lose its normal OSITlOI9rity.

It

1. Add Mer'lory .yst...., The pl'oxlmallubule is the slle 01 the organic acid and base secrelOfY 'yslems (Figure 23.3). The organic 8Cil;I seaetory system sectetes a variety 01 organic acills (Sl.dl as urie acid, some anti'W I. diurelics)1rom the b1oodstream ~ !he poolla l1lule'. Unen.. Mosl: dUelic drugs are deiYefed 10 the II.tdat IIuid via IN5 system. The organic acid seaecory system is salurable. and dlUetic drugs in the bloodslreln ....,iP£le lor liOlI,sfer .... 8I'Idogenous Olgalli(; acids, IUCh Il$ ..-Ie 8dd. TNs aplaiilS the ~ seen wiIh cenaWI 01 Ihe dUe1k: ~ Sl.dl as fIJI' I midll or dUiAlliluidlJ.

B. Descending loop of Henle The remaining filtrate, which Is isoI:onic. nexl enters the descending limb oIlhf1 loop ot Henle and paSS8$ Into Ihe medulla of the kidney.

........ _Jo, ........ .....-,.

..._.-

III. Kidney FU'lCtlon kl Disease

:---,_ .. _.....

225

The osmolarity increases along the ~ portion of the loop 04 Henle because 01 the OCU1tetCUrrenl fIl(l(hanlsm. This results in a lI..ItUar fkj(l wiIto a lhree.fold lncrellSe in S8II Q)j .... dilllion. C. AKendIng loop 01 Henle

The celI& 01 !he IISC8l dio 9 hbtAar epilheIUn are ur*lue in being impermeable 10 water. ActiYe reabsorption 01 He'. K' and is rnecial«l by a Na'/K'12(T ......a ......... ter. Mg" and Ca" ~ fle ~ . . . . . . IUd vie fle pwaceII*'. patn"a'!'. 1hB ..... dllllloop is IhUs a ltIutrog region 04 the roql.cn ........ w,i8!efy:25--3l)% 01 the !l.tUi8t socII.m cNoride retI.nls ID !toe illBiAilliallluld. thus t",,* 'II to 1TWW1..... IIle fUd's IWgh osmolarity.. Sinoe !tie loop of Henle is a me;or site lor sal: reabsofptiof~ cIrugs 1IItectii'll II*; site, such as loop ditntics, lIf1I itIe mosl efIc ... i() IS 01 aI the diIntic dasses

a-

0. OIsbl

~

l\Ibule

The eels 01' ttle (lismJ convoluted Iubule are also impenneable to water. Atx:oA 10% 01 the littered sodoo1 ctlIOOl;le is reabsofbed vie a Na'/CI- transporter, which is sensitive 10 Ihla
"

, ,7, .,~

h"

A. COngetlive r - t fallon

The deCreased ability 01 the tailing hearllO SUSUlin adBqIme ear' dlac OUlput causes (he kidney to respond as II there were a decrease In I*)cd ..:;Jlume. The kidney. as pan 01' Itle normal oom-Pfl(ISatory 1IlI8d'Iarism. recans more sail and waler as a means 01 rals/rlg blood YOIume and increasing Itle amounl 01 blood thai is returned ID the hean. However. the diseased hearl cannoI increase ~s ootpuI, and the Increased Wlsculaf Yolume results In edema (see p. 151 lor causes and \realmenl 01 congestive hearl rail....e).

-.-..... ---

----

-----~~~--

,.

~.

til. KIDNEY FUNCTION IN DISEASE In many dinens the amounI 01' SO(Ium dlIor1tie ItIlIb80rbed by !tie kJd. ney b is abolOl"19I)' twg\. Ttis IeaOs to the .eteo Ilioi , 01' water. an increase In t*lOd ~. and ~ 01' the ~ IIuid com-piilb, ...... reaJIing In edema 0I1I'le tisso_ Sl!\eral Q)j,.,lOIty enc:oo..>lered aM ISCS of ectema i"IdI.de:

.

o

•

E. Collecllng lubule and duet The principal and Inlercalaled cells altha cOllecting tuOOle are responsible lor Na'- K' e~change and lor H' secretion and K' reabsorplion. respectively. St;mulatjon 01 aldosterone re<:eplOrs In the principal cells resuUs In Na' reabSOlplion and K' Secrelion. Antidiuletic hormone (ADH, vasopressin) receptors promole the reabsorption 04 water from the ooIectilg ~ and dIds (FI{ME! 23.3). This actic:W'l is medialed by cAMP.

,

~.

~.

."

I

• ~::.-( ..... Ii.....

FIQU"23.3 Sites 01 \TatISpOr1 01 solutes an:! walef along the nep!VQIl.

. . . . . . .00 . ." '

•• _

.<.... . . . . - _ . , _ .. _

... . . . - - , ·

.....

226

23. Diuretic Drugs

B. HtopaUc . .dte. Ascites, the aa:umuIation 01 IUd in the abtloonl"al taYlly, is a c0m-

mon oomplicalion of dnt10sis 01 the liYef.

now

1. Inct-.d ponat blood preuw.: Blood In the portal system it otten obstructed in cifThosis, resuIIing In an increased penal blood pressue. Fmt-, " ... II' 0l5l1WAic po ... of the blood is decreased as a . - - of i, lplllIed ¥1II e1'1 01 plasma ~ ~ fle '" tted 1Mlr'. Increased ponal blood pressure and low 0iSfTl0' Iarily of lhe blood cause IlI.*i to ""C'IP" hom !he porlal vasa... $y5lIlm and ooIeelln the abdoo, ...

._-

~.+-I.~.

2.

.j.. No·

seoo....,

hfpwaldosliBtofllsm: Auld ,etEdiol. is BIso pro,"""" eleYated IeYels 01 drcul8tlng aIdoslB'one. This secondary ~eronismreso.Ats hom the tleerBased abilily of the liYet to lnac:Dr.lte the sreroid lu"Ule and leads 10 Increased Na' and water Ill8b6otptiol .. Increased V8$CUlir volIme, and exacetbaIion d IUd aca.nulation (see Figufe 23.3). ~

C, Nephrotic .yndrome

Ag..... 23.4 Role 01 ClUb«« anhydrase in sodium

When damaged by disease, the glomerUlar membranes allow plasma proIeins to enter the glomerular uIlrafiRrate. The loss 01 pro. lain 'rom the plasma reduces Ihe collc:lidal osmotic pressure resUting in edema. The ll;m plasma YoIlXTlB stimulales alCloslerone secfBlion through the renin-angiotensin-aldoslerone system (sea p. 180). This leads to retsnllon 01 Na· and I\ukl, Iu1hef aggrtlllllting the edema.

"""..

retention by epithelial cells 01 renal

D.

Premenstrua. edema Ec:lam8 BsmllfOO with menslrualion is Ihe resuII 01 imbalances in hoo"Ul8S sud'1 as estrogen excess, wt'ich laciIilates the loss 01 rtuid inlo the BldraceUular space. Oiuretics can reduce the edema.

IV, CARBONIC ANHYDRASE INHIBITORS AoeIuolamidrt [a set a ZOLE a ....1is a stAlon8mide wiIhota • iIbiLterial IICllvity. Its main IIdion is to Inhlbil !he enzyme carbonic an'It-

~.

draH in the proJdma' tubular eplthe'ial cells. However. carbonic ~ ilotitas are more otten used tot their oItle< phaflie ,.,;aaiol.. rathef' ...., tot '11'8 dUetic efIecl, .......... IS81hese BgBfU are In.ICh lesseff- Alb" !han the lhiezides or 1oopditJretiQ.

1. Mec:tIBnism 01' KIlen: ~ ir.'Iibits carbcnic ~S8, located IntraoeIUarty and on the apical membrana 01 the proximal l\b.JIaf epithelUn (Figu'e 23.4). [Note: Caftloolk; IIt'l1ydrase au·

elytes 11'08 reaction 01 Co.: and ~ leading 10 H" and ~­ (blcatborlete)J. The deaeased ebility to 8llchenge Na' lor H' ., the p.esence acetazolamide re$ulll It, a mild diuresis. Additionally, ~- is retained ., lhe luman with marked eleYation In u.lnary pH. The losS of HCO,- causes a hyperchloremic

0'

............' ........ --'>

.<.............~ , - - _... >

v. Loop or High-Ceiling Diurelics melabolic !ICk:Iosis and deaeased diufetic elticacy IolIowirlg several OOVS d therapy. Changes WI the composllion 01 urinary eIec-

In;lIy1ee Irduc8d I7f ~are

~~

FIgure 23.5.

2.~_:

L nUlmenl or gmucorna: The most COiI.,IO" use d ~ /Imldeo II 10 A:ldUoe the eieYaIed lrItracIct*I. pressue of openangle g19ucoma ~ ~ !he prOOnim of aqo.... os tuner. probatfy I7f blodrillg carbor'ic IlfIl'1'IdraSe ~ Ihe c:lIiary body of Ihe eye. • is useful ~ ' " ct.OI lie treatmenf d gill' I()()ITllI " ' " shot*! nrx be used la an 80.118 alladl; piIoCIIJ1)IJe (see P. 41) is p1eterled la an ac:uIe IIDiIdt because of n lldion.

.,.,lIKliale

b. E~: Acet.ul:llarnid8 is SOiflelimlS used ~ !he Irea/tneI'lI d epi\epGy--Ooltl generalized and pertiaL It Ndl108S Ihe _ -

ity end magnitude 01 the selzur~. Dlten aceflIzoIamide is used chOl ically .. c:onjtn::lion wilh ll' I1iepllepIic medicalion III enhance !he action d these ocher drugs.

e. Mountllln *'
leet. Acetazolamidll' given rOgI1tly lof S days before !he asoenl prevenls the weakness, bfeathlessness, dizziness, nausea. and csfebral and pulmonary edema characterlSllc of the syndrome.

3. Phafmac:oklnetlu: AoelazolamkJ9 is given Milly once a day. 4. AdvetH eUeeb: Metabolic addosis (mild), pola5Sium deplellon, renal $lone lonnallon. drowsiness. and peresltlesia may oocur.

V. LOOP OR HIGH-CEILING OIURETlCS Bume'lInk1e Ibyoo MET a nidal, furosemide llur OH lie rnide), bseollde ITOFl 51 mydel and ehIa)rlc tJdd leth a KAlN ik)_ to cllnlicllhal haYe Iter map lJIdion on the asoerodilog liffj) d hi locJp of Henle (F~ 23.2). Gcmparfld lO .. other dasses d dUetlca, these drugs hiM! the llijioea ellic8cy ~ n'UliIizWlg Na' WId O""lI'orn Ihe body. EIhacr)flic: lJl::idt'Bs a steeper" e iESfAA be Cln'lI (see P. 21) Itlan lui' GlOde•• shoWs greelel"'" etIec:ts Itlan Ihose _ wiIh !he at- loop dUeticI and 15 nrx as ~ used. is much moAI polenI Itlan MOSS Iide. and its use is

i.

-

&me""

A. Bumetanlde, furosemlde.lorSemide, ethIIerynlc: ackl 1. Mechenl,,,, 01 ..etlon: loop diurelics inhlbit the Na'/1('JCr ootransport d the Il..i'l'WlaI membrane r. !he asr::er odil og Iirrtl 01 the loop ot Henle. Therefore reabsorption ot Ne·. K', and Ct- is decreased (FtgUrlI 23.6). The loop diuelic:s 8fe the most effica· c>ous d !he diuretic drUgs. because the ucendIng limb accounts \of !he reabsorption d 25-30% 01 fi~ered NaCl and down61raam sites 8fe nol able to compensate !of this Increased Na' load.

yo ................

F"tgu.e 23.6 RelaIiYe d1anges ~ the ~ d uflne Inl:tIoed by loop diuretics..

<......

0 ...

'.'.<

,.

< ..,... •

_~

•• ICI'
..... >

23. Diuretic Drugs 2, ACUons: The loop diurelics act p.omptly. even among palients who have poor renallunc1ion or who hEM! not responded 10 thlazkles or other diuretics- Changes in the oofT1)OSition ot lhe unoo Induced by loop diuretics ar1l stlo.Yn in Figur1l 23.6. [NoIe: Loop diuretics increase !he ca" contenl 01 urine, while thiazide diuretIcs (see p. 229) docr1lase the Ca" concenhatkm 01 lhe urine.) The loop diuretics cause decreased renal vascular resistaflCe and Increased renal blood t\oW.

-W "~"'O

3, Thempeutlc uses: The loop diuretics are the drugs 0( choice !of reducing the acute pulmonary edema 01 congestive heart lallure. Because of their rapid onsel 01 action, the drugs are usefut In emergency siltJalloos, such as acule pulmona
ea"

4. Pharmacokinetics: Loop dlurelics are acIministl!f1!d 0flI11y or parerne rally. Their duration of action is relatively brief, 1 104 hours. 5. AdYetse effects:

a. otoIoxk:lty: Hearing can be af1eaed adver~ by !he loop diosel· ics, part;cUar1y v.tIen used io1 conj.Jnctiof1 with the amir1cgyco-

1 HypQT(NSnN

side antibiotics (see p. 314), Permanent damage may r1lsull with continued treatment Vestibular lunction is less likely to be disturbed, but it too may be aflected by combined lreatment. b. Hyperuricemia: Furosemide and elhllcrynic acidcompele with uric acid for the renal and bllia
d Potassium depletion: The heavy load 01 Na' presented to the coIecting tubule results in increased exchange of tubular Na'\or K', with the posstlilily of ndudng hypokalerria. The loss of K' from cells in 8J(change for H' leads to hypokalemic alkalosis. PotaSSiLm depletion can be avened by use of potassium-spar· Ing diuretics or dleta
Fi9lJre 23.7

Surrmary 01 adverse eflllCts commonly observed with loop diuretics.

VI. THIAZIDES AND RELATED AGENTS The tfliaZioos (Ire !he most widely used oIlhe diuretic drugs. They (Ire sulfonamide derivatives and (Ire rel(lted in structure to lhe carbonic anhydfllse inl1ibitors. The thiazides have slgnificamly greater diurelic activity than aCiltazolamlde, and they ect on the kidney by dilferent mechanisms. All lhiazldes aIIect the distal tubule, and aU have equal maXimum diuretic eflect, diflering only In polency, expressed on a pel miftigmm baSiS.

.......,....,........ _,>

. . ._ . _ -

""~,_

.. _

.... >

VI. ThiIuIdes and Related Agents

A. Chlorottolazlde

ChIorofh/a1:ide [\dOl oh lHYE a l:ideJ, the prototype IhlazIde dUetic,

,.oodet.,

dUelic that was aclive anItf and was. "l'8l;lle ollllteetinil the _ a edama 01 ciI,hosis and ccngeslMI heart tailIQ wifl a n*WTun 01 sida eflaets. Its pq)ei1ias .... fepleSeillalive 01 Ihe thiazide group, alIhuugh ~ (IefflatNes sud'l as ~ dbotlliazide« d~1ItIIf8 fW1/N used /TlUfll (0".0 Ify. W8S the first

1. IrHchanIam 01 acdun: The ItilI2De c;Iari\oelNes tlet ~ in !he r:IsIal tIbJe III decrease the reab6orpbon 01 NIl' byUibliuI. 01 a Na'fa- colranspol1er un !he luminal membrane {see F'9"re 23.21. They haII8 a Ies5er eI1ed in 1he PiOai",a11tDJe. As a 'llSlA. these drugs lho (DICe itIaliui, 01 lila' lIfld in the !l.b.r lar 1Iuid. The acid-base balance Is flU( usually atlecled. [Note: 8«aI1Sft the $iIe ol acliUn of the thluicIe derivatiYes is on !he Il.minal marrtlrane, Ihese G'Ugs must be excreted Infu lho tuIUar lumen 10 be elteetive. Therelura. with decreased renal tunctiun. ltliazida liu"1!Iics lOse efficacy.1

cr-

ncrease

z.~.:

.. IncreaHd Iltcreliun 01 Nfl' flnd cr: ChIoroIhi8zid6 causes diuresis wiltllncreased Na' and cr eJtCfeliun. which can result In the eJtCretkln of a very hyperosmolar urine. This latter et1ect Is unique among the other diuretic dOS6ElS, whlch are unlikely to produce a hyperosmolar u,lna. The diuretic aellon is not altec1ed by the ackI-base status Ulthe body. nor does chIofo. Ihlalld6 use dlange the acid-bBse statuS ot the blood. The relalive changes in the ionic composition ot the urine during It1ertIpy wiltllhiaVcle diurelics Is given In Flgt.we 23.8.

b.

u.. 01 K': Because thiarides lnaease the Na' In !he filtrate arriving at the dlslal tubule, more K' Is also eJtdl8ngecl for Na'. Thus. proklnged use ollhese drugs results in concinual loA 01 K' Irum the 00dy. Theretore. if is .iiperatiWlIo measure serum K' once per fTOlIh (more frequendy. the begi"ning 01 ~llO assue that tl)'pc+:a1 lila ooe. not de\'Olop 0Iten, K' ta'l be Sl.,""iBliled b'I diellllcrle, P.d'1 as b'I increasing the inlake 01 dInJs IrUts, bManas. and pn.nes. In sume cases, K' sail ,,_,.. iBl cation may be 1'18' n If}l ss

c. o.creflHd u,lnary ClIlcium UUllIon: Thlazide diuretics oecreaselhe ea- toVenI: ollrt'le by PiOiliOcillllhi reabficfpliun 01 ce". ll'lis0DnlJ'aSs ..... the Ioup du'ellcs (see p. 2271. whidl.1Cf! BSB the Ca" ooncenuarion 01 the urine.. It. AljllCld pellpheoal Y3SaJ1flr ....._ Q. An initial ,adl!Clion In bloud pre$$fJfe resuII:s from a decrease In blood YUIl.me and lherelOl'e a decrease in carcIac outpuI (see P. 180). WI1h c0ntinued therapy, volume rllOOYElry UOCtJ~. However, there are COflIInueCI h\'PD(enslYe eflecls, resulting from reduced peript>eral vascular resistance caused by relalt8flon of arteriolar smooth muscle. TNs usually OCCU~ prior to the diurelic eltec1.

~.

.",,,

.....,., .. _--,. 2:3. Diuretic Drugs 3. Therllp8tlllc uses;

e. Hyperlension: Clinically. lhe thiazides have long been the mainstay 01 antihype'tensiYe medicallon, since they are inexpensive. convenient 10 administer, and well tolerated. They are effective in reducing systolic and diastolic blood pressure for e:
d. Hypercalcluria: The thlazides can be useful in rreating idiopathic hypercalduria because they inh'bit urinary ca- excrelien. This is particularly benericlal lor patients with calcium oxalate stones in the Uflnary tract. CAAtNAC AA"~'T"UIAS

e. Dlabeles insipidus: Thiazides have rhe unique ability to pr0duce a hypelosmolar urine. Thiazides cart substiMe lor the antidiuretic hormone in the Ireatment of nephrogenic diabetes insipidus. The urine volume 01 such i"ldividuals may drop from 11 Uday to llbotJI:3 Uday when treated with the drug. 4. Pharmacokinelica: The drugs are effective OOIl1y. Most thlazides take 1 103 weeks 10 produce e slable reduction in blood pressure.

~'PE"CAlCEIOA

Figure 23.9 Summary 01 adverse ellects commonly observed with thiazide dluretlcs.

and they exhibit a prolonged biological hall·lile (40 hours). Allthlazides are secreled by the organic acid secretory system of the kiQo1ey (see p. 224).

5. Adverse effects: a. Polllsslum depletion: Hypokalemia is the most freqU8f1t problem enoounlered wilh the thiazide diuretics and can predispose patients On digllalls (see p. 160) to ventricular arrt1ylhmias (Figure 2:3.9). Activation of the renin-angiotensin· aldoslerone system by the decrease in intravascular volume contribtJles signnicantty to urinary K' losses. The K' deficiency can be overcome by spironolactone. which Interleres with aldosterone acIion. Of by administering lriamlerene, which 8CIS to retain K' (see p. 223). Low sodium diets blunt the palassium depletioo caus.ed by thia~~ diuretics.

.......0._'.' ••

,.

VI. Thiazides and Related Agents

b,

231

H~perurio;emla: Thiazides increase serum u.ic acid by decreasing the amount 01 acid excreted by the organic acid secretory system. BeIng insoluble, the uric acid deposits in the joints. and a full·bIown anack of gool may resuR in individuals predisposed to QOl.1l~ attacks. It is important, there'ore, to perfofm pefiodic blood lests tor uric acid levels.

c. Volume depletion: This can cause orthostatic hypoIensioo or light-headedness. d,

H~percalcemlll: The thiazides inhibit the secretion ot Ca", sometimes leading to elevated levels Ca" in the blood.

0'

e. Hypergtycemla: Patients with diabetes mellitus, who ale taking thiazides tor hypertension, ma~ become hyperglycemic and have difficulty in maintaining appropriate blood sugar levels. I. Hypersensitivity: Booe marrow suppression, dermatitis, necrotizing vaSC\Jmis, and interstitial nephritis are very r1lre.

B. Hydrochlorothlarltle Hydrochloror1liazide is a thiazide derivative that has proven to be more popular \t1an the parent drug. This Is because it has far less ability to inhibit carbonic allllydrase as compared to chlOrothiazide. It is also more potent, so that \t1e required dose is considembly less than that ch/orofhiazide. On the OIher hand, the efficacy is exactly the same as that the parent drug

0'

0'

C, Chlorthalidone Chlortha/ldOflB [klor THAI. i done] is a thiazide derivative that behaves like hydrochlorothiazide. It has a very long duration actiOf1 and therefole is oIten used to t,eat hypertension. (t is given once per day tor this indication.

0'

D. Tlliarltle analogs 1, Metolazone: Melol
<_.0' ..'.' ....... _ , .

'32

23. Diuretic Drugs

VII. POTASSIUM-SPARING DIURETICS These agents actin the roIleC\i11g tubule to inhibtt Na' reabsorption, K' socretiol1, and H" secretion (FIQure 23.10). Potassium-sparing diuretics are used primarily v.t>en aldosterone is present in e>ccess. The major use of potassium~ring agents is in the treatment 01 hyperlension, most ollen in combination with a thia~ide. It is extremely importanl that patients treated with any potassium-sparing diuretic be closely monitored lor potassium ~s. Exogenous potassium sopplemel1talion is usoally discontinued when potassium-sparing diuretic therapy is instituted.

A. Spironolactone 1. Mechanism of action: Spironolactone [5IlY0 row no LAK tone) is a synthetic aldosterone antagonist that competes with aldosterone lor intracellular cytoplasmic reoeptor sites. The spironolactonereceptor complex is inactive, that is. tt prevents translocatioo 01 the receptor complex into the nucleus 01 the target cell, and ttxJs does not bind to DNA. This results in a failure to produce proIeir'ls that are normally synthesi~ed in response to aldosterone. These mediator proteins normally stl1'lJlate the Na'-K' exchange sites ot the collecting tlb.de. Thus, a lack 01 mediator proteins prevents Na' reabsorption and therefore K' and H" secretiol1.

--

2. Actions: In most edematous Slates. blood levels 01 a'dosterone are high, which is instrumental in retaining Na' (see p. 225). When spirorloIadOlle is given to a patient with eleVated circulating levels 01 aldosterone, the drug antagoniles the activity 01 the hofmone. resulting in ratentioo of K' and excretion 01 Na' (Figure 23.10). Where there are no signfficant circulaling levels of aldosterone, such as in Addison's disease (primary adrenal insufficiency). no diuretic etlect 01 the drug occurs.

3. Therapeotic uses:

Figure 23.10 Relative changes In the composition or urine Induced by potassium-sparing diuretics.

a. Diuretic: Although ${Jirono/aCloOe has a low efficacy in mobili~­ ing Na' from the body in comparison with the other dn.Jgs, il has the useful property 01 causing the retention of K' (Figure 23.10). Because 01 this taller action. spironolactone is olten gi\lel1 in conjunction with a thia~ide or loop diuretic to prevent K' excretion that WOlJld othefWise oc:cur with lhese drugs. b, Secondary hyperaldosteronism, Spironotactone is lhe only potassium-sparing diuretic that is rouIJ)ely used alone to induce net negative sa~ balance. It is particularty efleclive in dinical situations !lSSlX.laled with secondary hyperaldosteronism.

4. Phannacalrinetics; Spironolactone is completely absol1Jed orally and is strongly boUnd [0 proteins. II Is rapidly coovarted to an active metabolite, canrenone [KilN ra nonel. The action 01 spironol8ctone is largely due to the effect of canrenone, which has mineralocorticoid-blocking activity. Spironolactone induces hepatic cytochrome P-450.

<."" .....,",.<---,.

<

._.oN " __ --.ou'

.

PI' >

VIII. Osmotic Diuretics

5. Adverse effects: Because spironol8done chemicalty resembles some 01 the sex steroids. ~ does have minimal hormonal activity and may induce gynecomastia in males and menstrual irregularIties in females. Because 01 this, the drug should not be gMffi in high do!les on a chronic basis. It Is most elfectM*y employed in mild edematous states where ~ is given for a leW days at a time. At low doses. spironolaclone can be used chronically with lew side effects, Hyper1lalemia. nausea. lethargy. and mental coorusian can

occtJ,.

B. TI'Iamte<'ene and amiloride

Triamterene It rye AM ter een] and amiloride [a MIL oh ride! block Na' transport channels resulting In 8 decre8sa in Na°-l(' e~dlange; they have K°-sparing diuretic actions simHar to that of spirono/BClone. However, the abillty of these drugs to blocll the KO-Na' exdlange site in the collecting tubule does not depend on the presence 01 aldosterone. Thus, they have diuretic activfty eYen in individuals w~h Addison's disease. They, like spjrono/8CIonC, are not very efficacious diuretics. Both triamlcrene and amiloride are frequently used in combination with other diuretics. usually for their potassium--sparing propefties. For example, much like spironclaC' lona. they prevent KO loss that occurs with thiazides and furosemide. The side effects 01 trjamlerone are leg cramps and the possibility of increased blood urea n~rogen (BUN) as well as uric acid and KO 'etention.

VIII. OSMOTIC DIURETICS A number 01 si~e. hydrophilic. chemical substances that are filtered through the glomerulus. such as mannifoJ [MAN i tole) and urea [yu AEE ah], result in some degree of diuresis. This is due to thair ability to carry water wfth them into the tubUlar nuH:!. If the subslance that is hi· tared subseqoefltty unde'llOOS little or no reabsorptiOn. then the filtefed wbstance will cause an increase in urinary output. Only a smallamoum 01 additional saft may also be ellcreted, Becausa osmotic diuretics are used to effect increased water e~cretion rather than Na' excretion, they are not useful in treating conditions in which NOlO retention OCCIJIS. They are used to maintain uril1e !low IoIlowing acute tOleic ingestion 01 substances capable of praooong awte reoallailu,e. Osmotic diuretics a,e a mainstay of treatment lor patients with IOC'ease
J

AolI..........\de

loop_'ief; ThIazido _lief;

...._... _

K' ••«0110<>

r

-• -

Figure 23.11 Summary of relatiVe changes in urinary composition induced by diuretic drugs.

<_.0...'.' ..........-,. 23. Diuretic Drugs

23.1-23.4 From the list of lliuretOc drugs below CIlOOS8 ttle agent that Is mosl appropfi.ale j", !he numbered con-

23.9·23.12 MaICh ttle drll9 lrom the list below to its mosl

"PPlqlriala adverse eltect.

"""'"

A. EthIlaynic acid

A. Acetazolam>de B. Amiloride C. OlIomthiWdo D. Furosemide E. Spirooolaclone

F. Triamler-ene

B. Chla1halidooa C. Acc1alOlll.mide

D. Furosemide E. Spironolactone 23.9 OIoIoxicily

23.1 Acute puImoI'\ary e
(

CDfred

.. D(F~I.

23.10 Hyperuricemia 23.2 Acute hypercak;Gmill.

I

Cornlcl......- .. D ~J.

I

C
Cormd_ .. B(~). 23.11 Gynecomastia (_topmenl 01 onlafged bmatS) in ~.,

Coned _ _ .. E (SpIronolactone). .. C (~l.

23.4 GlallCDfTlll.

Cormc1 ".-. .. C (AoeWoIan"ide). ( CDfred_ .. A (h>etazUlo,idel. 23.13 ChlorolhiazX!e can prOOx:e which one 01 tha follow· ing actions? 23.5·23.8 Match !he o:hJg trom the list t>eIow 10 its appropriatelargol in lhe nephron. A. Amiloride

B. Acetazolam>de C. Chlo<1l\alidona D. E1ha<;rynic acid E. Spircoolact"""

I

Comld: _ _ .. 0 {E1l1acryrOl: addj.

23.6 Ca
23.1 AJdo!;terone receplOfS

( Co-IEId_ .. E~I. 23.8 NII.'/Cf" <x>1r;w;ponar

A. Hyperkalemia

B. Hyperuricamill C. JnclUase in blood pressure D. HypogIy(;emiIl. in diltootOc patOe.-.l:S E. Hypercalcemia Correct answar .. B. Thiazid& _ _ 1tle e>Uelion 01 uric aiel by 8'l9 ecic! Sf.ICfl.IlOIY S)"$tem. Hypokalemia is lhe most frequently encountered lI.
:=-"';::::7Ide

may 1rdJail ~

23.14 III an Addisoniat1 paloenl. an 01 !he lollowing agents would have diuretic actions EXCEPT which one? A. Amiloride B. Chlorofhiazida C. Triamtereoe D. Spirooolactona

,,-

_.

Correct ctIolce .. O. SpiJl;lflOlB<:lone COffllIlIlBS

-'llIclo8lIeoona. and tt-...s 1tle df\JlI YoO.Jd ' no slfed In ItJa _

01 anOOganous 1lOr·

......... _,., .. _--,.

Gastrointestinal and Antiemetic Drugs I. OVERVIEW This chapter describes drugs used to Ireat three wmmon medical condi· lions IflIIOIving the gastroirllesbnal tract: peptic ulcers. control ot chem0therapy-induced emesis. and diarrhea and constipation. Many drugs descr'bed in other chapters also find application in the Irealmeflt of gastrointestinal disorders. For example, the rTlOfphine derivative rJphenaKy/are (see p. 244). v.tlich decreases peristaltic activity of the QUI. is usehJ in the treatment of severe diantlea. and lI1e corticosteroid dexamethasone (see p. 275) has excellent antiemetic properties. OIher dnJgs. (for example, !V.eceplof anlagonists and proton pump inhibitors ~ to heal peptic uw::ers. and the seIecI~ inhibitors 01 the serotonin recaptOl'5. sudl as ondansclrm or granise,ron. v.tlich prevent vom~ing) are used almost exdusi\lllly 10 traal gastroin1estinal tracl disorders.

DRUGS USED TO TREAT PEPTIC ULCER DISEASE

-

Bi.... u t h ~

-~'$-

-

II. DRUGS USEO TO TREAT PEPTIC ULCER OISEASE Although the pafhogenesis 0/ peptic ulcer disease is not 'ully under· stood, three major factors are recognized: inleclion with gram-negative Helicoba.l
-_. _. ,-,--

I

ANTlMlCROBtAL AGENTS

H._ HISTAMINE RECEPTOR BLOCKERS

"-

-

PROSTAGLANDINS

I

-~

-

INHlBIT04'tS OF PROTON PUMP ~

0'

Oplimaltherepy patients with peptic ulcer disease (both duodlll'lal and gastric ulcers) who are iflfeCIed with tI. IlY!sl!i requires antimicrobial trealme<11. To document inleclion with I::L 0'100. eocloscopK: biopsy 0' the gastric mucosa or various noninvasive methods ara available. including serologic tasts and braath tests for urea. Frgura 24.2 shows a biopsy sample with I:!. 012Ii doseIy associated with the gastric l1lUCOGll. Eradication of I::L I:Ml!li results in rapid healing

Rgure 24.1 Summary of dfIJgs used 10 treal peptic ulcer disease. (Frgure continues on next page.)

_ _ _ _ ,' .., l. _ _ _ _ .. _ ....._c.aw-

_ _, _ _,,,'.o.D"""'-

"r-,.~

235'

<_ '0''''''

> ...... _ , >

24. GastrointesCinal Drugs

DRUGS USED TO TREATPEPnc ULC~~!~SE

-

-

AHTlNUSCARlNIC

--_M

'Gem<

I

B. RegUlation 01 gastric acid secretion

ANTACIDS

0'

A/
""'*"_

M.gneolum SodI..... blc• . -....

-

MUCOSAl. PROTECTIVE

'Gem<

of active peptic ulcers and low recurrence rates (less than 15% compared to 60 to 100% per year 'or patients with initial ulcers healed b)' tradltional antisecrelOry therapy). Success'u1 eradication of .li. Ib'\Qd. (80 to 90%1 is possible wilh various combinations of llI1Umcrobial drugs. For example. a current regimen ot choice based on efficacy (about 90% eradication rate) and cost, is a two-week CQllrse oflriple lherapy wilh bismuth, mcfronidazole and telracycline. Often an antlsecretory dll.lg is added (see p. 239). Second-line regi· mens include combinations of two antimicrobial agents (mcfrofflda· zole. amoi
I

Col_ttl_ Suc"""'r~

Figure 24.1 (continuted) St..mmary of drugs used to treat peptic Ulcer disease.

Gashic acid secretion b)' parietal cells the gastric mucosa Is con· trolled by acetylcholine. histamine, prostaglandins E~ and 12• and gastrin (Figure 24.3). The receptor·mediated binding of acetyl· choline, histamine. or gastrin results in the activ3tion of a H'!1<'· ATPase proton PlJmp thilt secretes hydrod1lorioc acid (Hel) mto the lumen 01 the stomach. In contrast, receptor binding of prosta· glandins E~ and I~ diminishes g3stric acid pro
0'

C. Hrreceplor antagonisls

Mhough antagonists of the histamine Hrrec:ep\Of (~antagonists) block the actions 0' histamine at all H2 receptors (see p. 421), their chiel dinical use is as inhibilOrs 0' gastric acid secretion. By c0mpetitively blocking the binding 01 histamine 10 H~ receptors. these agents reduce intracellular concentrations 01 cyclic AM? and thereby. secretion 01 gastric acid. The four drugs used in \he United States. cimetKline [sye MET i deent, ranitKline Ira NYE ta deen]. famolidne(fa MOE ti dean] and niZatidlnelnye ZAT I deen]. potently inhibit (>90%) basal, food·stimulated. and nocturnal secretion of gastric acid after a single dose. Cimelidine is the plOlOtype hist· amine HTrec:eptor antagonist. 1. Actions; The histamine ....receptor antagonists---amctidine.

faJli.

tidine. famoridine, and nizaridin&--3ct on Hrreceptors in the stomach. biood vessels, and other sites. They are competitive antagooists of histamine and are tully reversible. These agents completely inhibit gaslJic acid secretion induced b)' histamine, or gastrin. However, !hey only partially inhibit gastric acid secretion induced by acetylcholine or bethaned1d . 2. The",peutlc uses: FIgure 24.2 Helicobacter pylori in association with gastric mucosa.

a. Peptic ulcers: All tour agents are equally etfective in promoting healing of duodaf1aland gastric ulcers. However, recurrence is common after treatment with H,. antagonists Is stopped (60 to

<.

.0< •••

_,.,.<_ .... ...--,.

II. Drugs Used To Treat Peptic Ulcer Disease

Plrenzeplne bIocb ct>ollnotrglc receptot.

'"

ClmerkfJne bIocl<s H. ~IStl.mlne _plot.

•

HIstamine

&/ircpro$toi stimulat.. prollaglandin rac.plo<.

Prostaglandin l:I _

E

Gastrin

[VJ

r

G,

G,

---.

I

,--_ _,-----, I Protein Id.-I (actlva*l)

prOlon pump.

• PARIETAL CELL

*

LUMEN OF STOMACH

Figure 24.3 El1l!C1s 01 aoetyk;holine. histamine. prostaglandin 12. and E2. and gastrin on gastric acid seaelion by the parietal oells 01 stomach; G. and G, are membrane proteins that mediale the stimulatory or lnt1'b~ory el1ect of receptor coupling to adenylyl cyclase.

100% per year). This can be effectively preuenled by eradica· tior1 oIl::l..mw. and H2 antagonists COf1tinue to be widely used in peptic ulcer therapy in combination with antimiCrObial drugs.

b. Zollinger·Ellison syndrome: Zollingel-Ellisoo syndrome is a rare condition in which a gastrin· producing tumor causes hypersecretion of Hel. With H:! antagonists. the hype<seaetion or gastric acid can be kept at sale levels in patients with ZoIknger-8lison syndrome. c. Acule stress ulcers: These drugs are useful in managing acute stress ulcers associated with major physical trauma Ir'1 high·risk patients in intensive care units.

d. Gastroesophageal reflux disease (heartburn): Low doses 01 H, antagonists. recently released lor OIIer-the'counter sale. appear to be effective for preventiOl1 and treatment or heartbtJm (gastroesophageal renux). Because they act by slopping acid secretion, they may not relieve symptoms for at least 45 minutes. Antacids more efficiently neutralize secreted acid already in the slomach.

<_ '0''''''

".

> ...... . . . - ' >

24. Gastrointestinal Drugs

3. Pl\ilrmacoklnetlcs: 8. Clmelidine: CimclkJine and the other l-!z-antagonislS are given

orally, dislribute widely throughout the body (including in breast milk and across the placenta) and ere excreted mainly in the urine. Cimetidine normally has a short serum hail-life. which is increased in renal failure. Approximately 30% 01 a dose of dmelicine is slowly inactivated by the tiver's microsomal mixed lunclion oxygenase syslem (see p. 14); lhe other 7ll'l'o Is excreted Unchanged in the urine.

Clmel,d,ne

b. RlIflltldine: Compared to dmeticfne. ranifidine is longer acting and Is live to len limes more potent. Rani,idine has minimal side effects, and does not produce the antiaoorogenic or proIaclifl'stimulating ef'ects 01 cimetkme. Unlike cimelidine, ~ does nol inhibil lhe mixed lunclion oxygenase system in the liver, and thus does no! affect the concentrations of Olller drugs.

c. Famolkllne: Famolidine is similar to ranitidine in ~s pharmacologic llCIioo. but ~ is 20 10 160 times more potent than dmeli· d'ne and 3 to 20 times more potent than ranilirine. d. Nlzatidine: Nizalickle is similar to raniIidine in its pharmacologic action and potency, In COI'ltraslto cimelidine. mnilKJine, and farnofit:WIe (I'otiich are me!abolized by the liver), rizatidne is eliminated principally by the kimey. Since litlle lirs1-pass merabolisrn occurs with riza1idi1c, its bioavailabilily is nearly 100%.

...........,C/_ _

4. Adll(!fS(! effects: The adverse eNects 01 cimelidine are usually minor and are associated mainly with the major pharmacologic activity 01 the drug, namay reduced gaslric acid production. SiOO eltacts occur only in a small number 01 palients and generally do not require discontinuation 01 the drug. The most common side effects are heada<:he, dizziness, diarrhea, and muscular pain. Other cenllal nervoos system (CNS) effects (confusion. haUucina.· lions) occur primarily in elderly patients or after prolor1ged admini's\ration. Cime~ can also have efldocrine elfeds, since it acts as a nonsteroidal antiandrogen. These effects rx:kJde gynecomastia. galaclorrhea (contil'llJOllS release/discharge 01 milk), and reduced sperm count. CimetjcJ;)e inhibits cytochrome P-450 and can slow metabolism (and thus potentiate the aetoo) 01 SEM!ral drugs (tor example, Wi.lrlarin, aazepam, pI1erly!OO1, QlIEIii;fue,~, theophylline, O'l1ip'Bmine), sometimes f6Sl.l~ing in serious adverse clinical etleds.

D, Prost;tglandins MoloboUtel Prostaglandins E2 and 12. produced by the gastric mucosa, inhibit secretion 01 HCI and stimutate secretjQn 01 mucus and bicarbonate (cytoprotective etfect). A deliciency 01 prostaglandins is thought to be involved in the pathogenesis 01 peptfc ulcers. MisCJ!rosloi [miz 0 PROS 101), a stable analog 01 prostaglandin E" is CUrTefltly lI1e only agent approved 'or prevenllon of gastric Ulcers induced by nonsteroidal anti·intlammalory ageflts (N$AIDs) (see p. 405). It is less effective lhan H 2 anlagonlsts lor acute treatlT\ef'1t 01 peptic ulcers.

<'''''0''''.''<

''

<..- •

.., """""" - _.

U. Drugs Used To T,eat Peptic lJIceJ Disease AmlOl'gh misq;roslOl has cytoprOiective actions, it is clinically efloctive only at higher doses that diminish gastric acid secfelion. Routine proptJylacbc use 01 misoprosfol may not be Justified except in patients taking NSAIDs who are at high ,isk 01 NSAIO-;nduced ulcers, suct1 as the ek:Ierty 0< patients with uloor complications. Uke other prostaglandins. misq;roslol produces uterine OOrltraCUOns and is contraindicated during pregnDJ)(.)'. Dose-related diarrhea and nausea are tho most common adverse el!ects. E. Inhlbltot1l ollhe H'/K'·ATPase prolon pump

Omeprazo/e 10m ME pary zoI] is the ~rst 01 a new class of drugs that binds to tile H'/K'-ATPase enl;yffiEl system (proton pump) of the parietal cell, suppressing secretion 01 hydrogen ions into the gastric lumen. The membrane4xlond proton pump is the tir.al step In the secretion 01 gastric IlCicI (see Fl!JUre 24.3). A second proton pump inhibitor, lansoprazole!lan SOP ra zoIl, is also available.

1. Actions: At standard doses, bolh omepl8ZOi6 and Iansoprazol6 inhibit basal and stimulated gastric acid secretion more than 90%. Acid suppression begins within 1 to 2 hr alter the first dose 01 Ian-sq;razole, and slightly ear1ie< with omepr.W)le. 2. Thenlpeutlc Ule.: Omeprazole and lansopmzole are used !of shoft-tefm treatment of erosive esophagitis and active duodenal ulcer, and tor Long-term treatment at pathologic hypersecretory COnditions (lor e~ample. Zollinger-Ellison syndrome). Only omeprazole is approved lor relractory gastroesophageal 'e"u~ dlsease and maintenance therapy at erosive esophagitis. Clinical sludies to date have shown /ansoprazole. like omeprazole, is more ellective mthe short term than the H, entagonist, ranilidine. Omcprazole is successfully used with lII1timiaubial regimens to ecadicatel:i 0':!llIi-

3. Phamlacokinetictl: Qneprazo/e and ~ are eoteric-alated to protect them Irom premature activation by gastric acid. After absOrPtion in the duOOen..m, they are transported 10 the acid parietal cell canaliculus, where they are convefIed to active species. Metabolites 04 these agents are acreIed in urine and feces. 4. Adverse effects: 0mepraz0Ie alld lansoprazole are generally

wett

tolerated. but concerns aboullorlg-term safety have boon raised. In animal studies, both drugs increase the incidence of gastric carcinoid tumors, possibly related to the etfects of prolonged hypochlort'rydrla and secondary trypergaSlrinemia. Incre
PI' •

. . . . . .0' .... ' . . . . . . . . _ , .

".

24. Gastrointestinal Drugs

reInIctory to S1andard lheropies. In QlfI\raSl 10 the classic anlicholin8fgics, the relatively specific muscarinic M,-receptor antagonist ~ is unde< ..-...estigillion lor its ~ useMness as an 8i1fsecretofy agenl (see p. 38). PJrenzt!pine basal and slimlAated gastric acid at doses heW1g ef1ecl on satvary glands. !he heart and eye.

SIlCletiol,

aw8SseS 8,,",llll

G. Antacids

An&adds Bfe WIllIk bases ItIat r8ild will'I gastric acid 110 term Willer and 8 sail. 1heretlV dimiilishiilg gasuic ac:il;IIy. SinoB pepsin is iliacIiwI at pH>4.0. arwadds also rewee pepIic lICtiYity. They may hIM! Olher ICtIons as wei. such as reduction all::L 0tlltl <:cIclNlation and Slin'UBliorI aI ~ SYilll . 1. Chemhilry of ftKids: Antacid pmducts vary wideI)' in their ctleinical CO''-dim, acid-neUIJ8~ ily. $Odium CDlIenl, palatabiity and price. The acir:kleoJtr8llz;ng abiliIy of an antaDd depenos on its capacil~ 10 neutralile gastric HCI and on wl1eIher the stomach is lull or ernply (load delays stOlTIlIch emptying, allowing more time lor lhe antacid to read). Commonly used antacids are sallS 01 aluminum and magnesium, such as alvmmum hydrOJ
r,"'....

ductive. Systemic absorplion 01 sodium bicsrtJonale [NaHC~1 can produce transient metabolic alkalo6is: this antacid is not recommended lor long-term use. 2. l'Mrapeutlc uses: A1uminum- and magnesiunH:ontaining ani' acids can promole healing ol duodenal UIc:er's; eooideuce kx ellicacy In tJeatmenl ol acute gastric IAcer is less cunpelI~

3. AoMne eflKts:. Ao\.miI"urI h)odn:Wde may be CO'lSlipeting; magnesMrI h)da!lide may prodl.Ioe cianMa. PrepelBIions that mmbine f1ese agents aid in ~ bowel tunclion. In .. 'Mil ., 110 lhe poterwial b ~ lIIIkalQsis N8HCCX1 liberates COz. eausk'lg batt• .., and 1IatlAenoe. Absa I.joll aI calions /rom IlI1tacids (Mg". N"', ea-l is usually I'lOI a plotNm in palier:c$ with normal renall\nclion, ~ !he $Odium contWll 01 llI'UOds can be an in'lportar'( colSidelalion in palieills wilh hofper\enslon or cU'j live Nart laiUe.

4. Dn>g inter.ct~, II is usualI)' &dYisable 10 avoid CU'lCUITent ad'ninistralion olallacids a1d Olher ctugr;.. By eIIerlng gastric and urinary pH or delaying gastric etflltYing, antecil:ts can aIIect rates al6ssolution and absooplion. biorMlilability, and renal ewtWlation 01 many drugs. By binditlg to drugs (lor example. ret/aC)'dine), AJ'" compoynds can lorm insoluble compleKes that are not

absorbed. On the other hand, antaeids can incfease the mle 01 absorption 01 some ~, lor example. ~,

< ........ _,.,. < -

, >

<..- .....

.. , >U<:AU" _ . PI' >

Ill. Of\lgS lIsed TO Control C~-Irduced Emusis

241

H. Mucosal Protective Agents TIlese oompounds. known as cytoprolective. have several adions that enhance mucosal protectiOn mechanisms, thereby preventing rTIlKXl&lll Injury, reducing Inflammation, and healing existing uloers1. SUl;:rBlfale: This complex 01 aluminum hydroxide and sulfated sucrose. binds 10 poskively charged groops 111 proteins, glycoproleins, ale, ot both normal and necrolic mucosa. By forming romplax gals with mucus, sucrs/fale Isoo KRAL late] creales a physical balrier!hal ir\1)airs diffusion 01 HCI and prwenls degradation 01 mucus by pepsin. 11 also stlmulales prostaglandin release and mucus and bicarbonate output, and Inhibits peptic digestion. By Ihese and marry other mechanisms, sucraffafe eHectively haals duodenal ulcers and Is used In long-term malnle· nanoo !tIerapy 10 pr_nt their recurrenoo. Because k requires an acidic pH lor adivallon. sucrslfate should not be administered with H;, antagonists or antacids. Lilde 01 the drug Is absorbed sys· tarrkally. Ills very well tolerated. 2. Colloidal bismuth: Preparations 01 this ~ eHecti\lety heal peptic ulcers. In addition to their antimicrobial actions (see p. 236), !hey inhibil!tle adMty 01 pepsin, increase mucus secretion and interad with proteir1s in ne<7otic mucosal tissue to ooal and pfOIect the ulcer crater.

-

III. DRUGS USED TO CONTROL CHEMOTHERAPY· INDUCED EMESIS A/Il'1ot.gl nausea and YOI'TliIing may occur in a variety 01 conditions (Iof 8I\arT1)Ie motion sid
""-'"

-- --"'"-

EMET1C POlENTIAI.

Two brain stem snes ha1I9 key roles in the '-
Agora 24.4 ~rison of

emetic potential 01

anlicance. drugs.

<_ '0'''''' "2

> ...... . . . - ' >

24. GasllointestiMl Drugs ing. The vom~ing center also respoods to afferent Input from the YeSlibular system, the periphery (pharynx and gaSlrointestinall1act). and higher bminstem and cortical structures. The YeStibolar system runctions mainly in moHon sickness.

B. Emelle actions of chemotherapeutic agenls

DRUGS UseD TO TREAT CHEMOTHERAPY~NDUCED

NAUSEA AND VOMITING

-

-

-

----

PHENOTHIAZINES

SUBSTlTUTED BENZAMIDES

I

........

BUTYROPHENONES

C. Antiemetic drugs Considering the cx:mptexity 01 the mechanisms involYed in emesis, ~ is nol surprising that antiemetics ,epresent a variety of dasses (Figure 24.5) and offer a range 01 er1icaaes (Figures 24.6 and 13.4). Anticholinergic drugs, especially the rnoscarirk receptor antagonist scopolamine (see p. 48), afld ",-receptor antagooisls, such es dimenhydrinate), mBCJizlne and eycIlzme (see p. 422), are very uselui in moIion sic:*ness, bUt are ineffective aglllnsl substances that act directly on the cl1emoreeeptor trigger zone. The major cate· gories 01 OOlgS used 1o control chemolherapy·induced nausea and vomiting include:

Dlup.. 1Q;JI

~-

-

-

BENZOOlA2£PlNES

~-

-

Chemotherapeutic agents (or their metabolites) can directly activate the medullary dlemoreceptor trigger zone or vomiting center; several neuroreceptors. including dopamine type 2 (DA:!. see p. 128) and serotonin type 3 (5-HTJl. play cribl roles. Otten, the ooIor or smell of chemotherapeutic drugs (and BYeO stimuli associated with chemotherapy, sud1 as coos In the treatmBr1t room or the physician or nurse who administers the therapy) can activate higher brain centers and trigger emesis. Chemotherapeutic drugs can also act peripherally by causing 0011 damage in the gastrointestinal tract and releasing serotonin from !he enterachromallin cells or the smell intestinal mucosa. The released serotonin activates 5-HT3 receptors on vagal and splanchnic afferent fibers. \'It1K:h then carry SerlSOIY s;gnals to the medJHa, leading to the emetic response.

CORTICOSTEROIDS

at drugs shown to be effective antiemelic agents, phenothiazines, such as prochlorperazlne (proe kIor PEA a zeBn], ac1 by blocking dopamine receptors (see p, 129). They are effective egalnst low or moderately emelogenk: chemotherapeutic egenls (lor example, IIuorotJracil and doxoru· bicin, see Figure 24.5). Al\hQugh increasing the dose improves an~emelic activity, side allects, including hypotension and restlessness, are dose·limiting. Other adverse readions inelude extrapyfBl11idal symptoms and sedation.

I, Phenothlazlnes: The tirst group

~.-

-1~_

f-

'---

-

CANNABINOIDS

15-KT3 SEROTONIN ; RECEPTOR BLOCKERS

I I

~-

--~ Figure 24.5 Summary 01 drugs used to treal dlemotherapy-ioduced nausea and vomiting.

2. Substituted benmmldes: One at several substituted beozamides with antiemetic activity, melocJopramk1e [met oil kloe PM mide] Is highly ellective at high doses against the hi\tIIY emetogenic eJsplalin), prBYenting emesis in 30 to 40% at palienls and reducing emesis in the majority. Antidopaminergic side effects, Including sedation, diarmea lind extrapyramidal symptoms, I1mit its highdose use. These adYerse rllllClions are most common in younger patienls. 3, Butyrophenones: Haloperidol, droperidoI and domperidone act by blocking dopamine receptors. The butyrophenonas are moderately eHectiYe antiemetics, but high-dose haloperidol was Iowd to

"""0._'.'.'_"'_"

'" 4.

ThB antiemetic potency of ~ and apa.wtvn (see P. 89) Is IoN. Theil beI~1claI eHect:s ITIIIY be due to their sedatiYe. MxioIylic and armeslc pnlpllItiM. These same ptq)efties make ~ useliJ ., lreatng ~toryIIQ , . ig.

~lMeplnes:

5. C001ic:osterolda: DeKameltlotsOne and ~ U5ed alone afe eUIldi'Ve agalnsl mildlv to moderately emelogenic chemolherapy. Thf!;r .. 1liemeIic mechlrism Is not kf'oI,n, bullTIIIY InYOlVe blockade 01 prostagllndlnS. T'he$e drugs can cause r'lSOI'IYIiI and ~ ., paIienls Mlh diabetes mellitus.

_.."'111·, .•• 8oIrze6-

6.

derivative$, ~ ~ (drOll NAB i no/] and natJib.. are etl9c:tiYe agan;t IOOderateIy ~ genic: c:hemOlherapy. However. they are seldom lirst-llne antiemetic:s bfaluse 01 Ihelr seriau!i $ide ettec:l$, ~ dy$+ phoria. halluc:inllion!i, $8daIion, vertigo, and cborienlation. In $pile of Iheir psychoUoplc: propec1ies (see p. 105). the .. iliemetic: ac:tion 01 c:annabinoids may n.ot invol.... the brain; synthetic: c:8NI&billOids I'\aImg no ps)d'lotropic: tldiYil)'. fle'o1!flheIe$s are '" Itieo 1ielic:.

.•

Cennat*l~; MI~

FIgure 24.6 ~ 01 poIencyoltype ol

aRier ..elic ~

7. 5--HT3 .erOlOlllo, rec:eplor bloc:l<en: The spec:il'ic: anlagcnIsts of the s-HTI rec:eplor. ondInMllOI'l [on o-.N $8h Iron) and gr.mise/fOrl [grtIn lZ e Iron). s I rtiw!foj t*xt< 5-HT1 rec:eplOIs in !he periJI.... V (Visc:enll aflerenI~) and in Ihe btlI*1 (<:heIlOeoeptor trigger zone). These dfugs c:an be admi islered 8$ a sW1gIe dose prior 10 c:l1eiIiOlhe.1py r.illa.... lllUSfV or oraIy) and are etlic:ac:iou$ against all grades 01 emetogenic: thefapy. One trial reported boIh ~ ~ emesis in.50 to 60% of, qlb'h treated peIienls. ~ is IIppl'(Mld also lor prelOElllioll 01 poslCJpef8!iye nausea Ifd'or "",,,iii,,,. Headadle Is a 0001110. side fIfled. These drugs are ~ .. CombinlIllon ~: A"liemelic: ~ IlI1I otten Ull,tilled to inc:tease antiemelie ae:tMty or cIec:,ease to
IV. ANTIOIARRHEALS lrereased moIilily 01 1M gastrointestinallrllCl and de<:reased absorption of lluid are major lactoo; In diarrhea. Anli
~.} P• •,ido

...

opr.w v , 'Ill

.~

" } . .,ido

!;----;;;

AgunJ 24.7 Effectiveness of entiemetic: aeti>Ay ol some drug combinatiOO$ agaIfI6t emetic episodes in firsl 24 hours atler c:isplatitl d1emolher~.

<_ '0''''''

> ...... . . . - ' >

'"

24. Gastroinlestinal Drugs A. Anllmotlllty agents

DRUGS USED TO TREAT DIARRHEA AND CONSTIPATION

-

-'--

AN'TlDlARRHEALS

I

,-~

_...-.,""''''

1MtI'7k:ol'--

~fIy-IlfUpuIgl"

-~

~

<-

LAXATIVES

------~~~

-~-...." ~-

h __

"'-fum _/lIN

Two drugs widely used 10 conlrol diarrhea are diphenoxylate [di PHEN ox a lale and Ioperamide [Ioe PEA a mide]. BottI are analogues of meperidine (see p. 138) and have opiokHik.e actions on lhe gut, activating presynaplic op;oid raceplors in the enlerlc nero -ws system to Inhibit acelylcholine release and decrease peristalsis. Side ellects lrlclude drowsiness. abdominal cramps 8rld dizziness. Sirlce these drugs can cause lo~ic megacolorl. lhey should not be used in young children or palienls with severe colitis.

B. AdsOfbenls Adsorbent agents such as /<solin. pectin, mefhyk;e1Mose and actio vated a/Ulp(JJgite, magnesium aluninLm silicate. are widely used to control (iarThea, although their eHicacy has not been docomented by controlled clinical trials. Presumably these agents act by ads0rbing intestinal to~ins or microorganisms. or by coaling or prolecting the inlestinal mucosa. They are mud! less eHecliYll than anlimolility agenls and C8/1 intetfere with absofptiorl 01 other drugs.

C. Agems that modify nuld and electrolyte transport Experimental and clinical observatiorls Indicate that non-sleroidal Brllt-inllammatory agents (NSAlOs, see p. 403) such as aspirin and Indomelhacin are ettective In controlling diarrhea. This antidiarrheal actioo is probably due to inhibition 01 prostaglandin synthesis. Bis/Tltllh subsalicylale (PEPTQ-61SMOl). used ror traveler's diarThea. decreases Huid secretiorlln the bowel: its actiorl may be due 10 Its salicylale component.

V_ LAXATIVES laxatives are commonly used to accelerale the movemenl of rood through the gastroinlestinal !nlcI. These drugs C8/1 be classnied on the basis of their mechanism of action as irritants or stimulants 01 the gut, butking agents. and stool solteners.

M-'<mI n)'dn:lx/doo

~"""fIIYcoI

-~ ._~

FIgure 24.8 Summary 01 drugs used 10 lreal diarmea and constipation.

A.lmtanls and stimulants

Caslor oil is broken down In the small intestine 10 ricinole~ a.dd, which Is very irritating 10 the gut and promptly increases peristalsis. cascara, senna, and aloe contain emodin which stimulates colonic activity. Onset of activity is delayed 6 to 8 hr because emodin is excreled into the colon after these agents are absorbed. Emodin may pass Into breast milk. Pheno/pflthaJein and bisacodyI are also polent stirnJlanls 01 the colon. Adverse effects include abdominal cramps and the potential tor atonic colon with prolonged lise. B. Bulking agents The bulk laxatives include hydrophilic colloids (rrom indigestible parts of fruits and vegelables). They Iorm gels in the large intestine. causing water retention and intestinal D'stension, thereby increasing

......... _1.,

>,

, >

V.Laxa~ves

peristaltic aclivitv. Similar actions are produced by agar. methy1ce1lulose. psyllium soods. and bran. Saline cathartics SIid1 as magnasiU'l1 sulfa/e and magnesium hydroxide are r.onabsoI"bable satts that hold water in lhe Intesline by osmosis. and distend the bowel, increasil1g inlestinal activity and producing defecation in abOut one hour. lsosmolic electrolyte solutions containing poIye,1Iyftme glycOl afe used as colonie lavage solutions to prepare the gut lor radiologic Of endoscopic procedures. Lac/Ulose is a semisynthetic disaccharide (fructose and galactose) that also acls as an osmotic laxative.

C. Stool Softeners Surface-active agents thaI become emuls~ied with the stcol produce softer feces and ease passage. These Include docusa'e sodium. mineral oil and glycerin SlJPpOsi/ories.

Study Questions

24.1 Which 01 1he '0110 wing is the most Important approodl in heallng peptic uIoers? A. Coa~ng the ulcer aa1er B. Eradicating in!9cl;oo with Ij,IlJIQr:i c. Inhlb'~ng secrellon 01 gaslric acid at lt1e protolt

'""" ,..,

o. EiIocking

rllCep10f

acr",ation 01 g,aSbic ae;" set:fe.

24.2 Given In combination regimens 10 enhance antiemetic: potI"lnCy

24.3 HigNy eNectlve againsl cispialirl-ln
(

ComId.- ..... (Gr•••u..'1

E. NeutralWng set:felll(l gastric acid CorT8C1 -.wei" _ 8. Ef*WeIi
II'llo

eo mIlllN.llIl""'-_ PII8rM hMI8d blJ ........ -

;

"'y IIIlq).

I.

D. M9dillne

E. Lorazepam F. MelOdopramide

''', .,bl

24.5 ApprOWd lor managing postOpOrawe nausea ancVor vorMing

.-..

0ue5lirm24.2=247 For each numbered d&<:>Ip!ioo, below. selecl the most appropriate drug trom \he IolIowing list:

A. Graniselmn 8. Ondansetron C. Qexamelhasone

CClmId _ _ F(t1

(

ComId _ _ 8(Oodlo"'~

24.6 Use'ul in managing nausoa and vomNing due 10 motion sickness

CClmId

0 (Medblloe)

24.7 Low antiemetic polency

)

,...

. . . . . . .0 . . . . . '

........ _ , .

24. GlISlroinlestinai Drugs

'N'fMN: 21,8::2.4.!3

--

Fa< Nth rurbefed descriplion below, select . . tnOfit ~ll(W\I;I.. clrug

24.15 DimInishH

/rom lie toIl:lM'Ig IisC

r rtal8

.... 6i5muIh B.Pl.~

.. C.l')x>=_ -.:lllium

~strk:

acifl produc1ion by lnhit>iting

D.U¥*amidI E, 14iIgI IT' "" . . .

F. Acw

I

rap "lli"e 2'-11 Brds 110 .....::ou k:Ifmo'lg 1lhl'iic8l bIotriet 110 HCla'd

-.

I

(I~CO~~'!~!:!.!'~IF~.~']_~·",;,~~t ~,~.~,~'~'~IC==I

Q 't"io"E 21 18-2422 IV fYdl .... ,Qq(I dMOipIlon '-klw. ulId IIw most "'llPiopriale dOug from ... loIooolI'lllisC

24,10 ClinlorOshes IIuid _lion in IIw _

I

co-:c _

.. A (8IIndl."

';7

I

.... Sodum 1lbrtJonlI'" B. CifT..,.;,s.

)

c. ~ lXllI'IpClf.O'l D.~

24.11 Irri!al. Ihe gut and causes inCf'e_ perklalsl,

,.""""""" F.

24.12 Relains ",al", and produces intestinal dlstenslon

[

e:e.-_.E~

__l

Proc:hlo
24.18 GyIl9COfTIa5l1e

(

eon.c:t_.B(Q'liIllkh)

21.19 Melabalic ...........

0Ilt0Ic:l_ .. 0 (I.

.'*"oJ

"I

Q 1 =21 'H1,11 IV Ndl .... ,...'" dMo\llioo' _ • .....,. ... _ ~""",io. dIug "':1m'" kAlwio'lllisC

A._.._._ B.tr,1"OAOl

c.-_.E

C...........0' Eo

0._

2422 TOlI:ic "lelI'" ....

E. H···-<:orllIoNlg rucicl& F. 1... ~'"iclIt..>lc* 24.14 Aj:Jpooed lof .....

.-

'IlIOi, d

~

guri;

<......

,.,.<

0< . .

,.

<


........,..., - . . . . _ _ •

PI' >

Hormones of the Pituitary and Thyroid HYPOTHALAMIC AND ANTERIOR PITUITARY HORMONES

I. OVERVIEW The neuroendocrine system, which is oontrolled by the

p~uitary

and

hypothalamus. coor'diMtes body tunctions by transmitting messages betwOOll IndiVidual cells and ~ssues. The nervous system communicates locally by electrical impulses and neurotransmitters directed It1rough neurons to other neurons or 10 specific target organs, wen as muscle or glandS. NefW in'lpI.jses generally act within miliseconds. In cDr1trast, the endocrine system releases hormones Inlo the blood stream, which carries these chemical messengers to target cells throughout lhe body. Hormones have a much broader renge of response times than do nerve impulses, requiring from seconds to days or 10000ger to cause a response that may last tor weeks o. months. The two regulatory systems are closely interrelated. For example, in several inslances, the lelease 01 hormones is slimulated or inhibited by the nervous system. and some hormones can stimulate or inhibit nerve impulses. Chapters 25-27 in this text focus on drugs that ailed the synthesis and'or secretion of specific hormones. In this chapter, the c:eotral role 01 the hypoIhaJamic and p;tuilary hor· mones in regulating body functions is briefty presented. In addllion, drugs affecting thyroid hormone synthesis and/or secretion are dis· QJssed (Figure 25.1}.

Cor1Icotrop/n (ACTH)

=:'~P>Q

""'.i<JCo

0,.".," _ ."(OH1/lf), " " - _...,,_

--"',-. -

~'1~"f".;:.=~

S<><7Y_..... OCb_

Soma,.""""" (GHrHJ, _ _ _

HORMONES OF THE POSTERIOR PITUITARY

DRUGS AFFECTING THE THYROID

II. HYPOTHALAMIC AND ANTERIOR PITUITARY HORMONES The hormones secreted by the hypolhaJamus and the pituitary are all peplides or low molecular weight proteins that act by binding to spacnic receptor sites on their larget tissues. The hormones 01 the anterior pitu~ary are regulated by neuropeptides, called either releasing or inhibiting factors or hormones. which are produced in cell bodies in the hypothalamus and reach the cells or the pituitary by the ~slal portal system (Figure 25.2). The interaction 01 the releasing hormones with their receptors results in synthesis and release 01 the hormones by the pituitasy into the circtJlation. Ead1 hypolhaJamk: regulatory hormone controls the release 01 II specific hormone from

Figure 25.1

Some 01 the hormones and drugs affecting the hypolhaJamus. p;llJitary and thyroid•

..--.-_1'1.,

... __ ",- _ _ ..

_ _'_"

A. _ c. _ _

'''.'0''''''"-

247

·_10.....'.... __ ,.

• tt"" ...........- " " " " " " , _

".

.. _ , ....

25. HorrnonllS Q1lhe p~uitary and Th)'roid

HYPOTltAlAMUS

_P""

~

0.-

~

""

""

,--

~

~

~

-! "-

~

~

! ! ! !A ~

-

s"" _

-,j, ,-!

......... ...

"

r ...

'

~

.

" Th"""". ...-. ;

I

!

,

"'""

"-

PI ;

!

...

T

e,- ! ...

Figwe 25.2 ~ ~ OO""'le5 ancIlClioilS d anceoor piIuiIaIy 00,....... GAHa QfOWlh 00""'8'1'+0 . '" hom'llile; l'Ri-ltIyrdropin-rel hc:i"'... .e; CRH: c:or1ioobq>i ... osing hoo"lOilfl; ~H (l.HRH)=gonild: re'e r'ng horTTlOioe (luIeio iziily hoi" ... liH 'e sing hormone): f>IH,. prolactin-. tlI;lilii '" h(lrlllOi.. (dopilmil'le): lind PAH" ~ hoo"lOie; AC'Tli:a .,... lOCUlitxAJ..... hoImollil; TSH- ~ hoolilOilfl; fStl,. ~ hooillOi..; LH-1ullIinizing hOOlilOrlil I

1he anterior piluilar)l. The ~ IllllI8sOng holillOrleS 8I1l pOmarty used lor diagnostic purposes (lhal Is, 10 detenTlW>ll pituitary Insutfldeocy). [Nole: The hypothalalTlt1!i also synlhesizes !he hormones vasopressin and oxytoc:Wl. which IlI1l lranspor1ed 10 1he posterIOr pilui\aly l\ot1efe ~ ere slOr'ed until released.) Although a rurtler or pituitary hormone preparalions are currenlly used the~1y lor spec/fic: honnonaI delidencies (f!l(amples 01 which 1olIow), most ol lhese agents h3'-'Illimited therapeutic appIlc8.tions. Hormones oIlhe anterior and posterior pituitary are eclminlstered either intramusctAarty (1M), subcutaneously (SC) or intranasally but no! orally, because their

...... '0.....' ....... ...--'· 11. HypoIhaIamic end Anteriof p~uitary Hormones

'"

pepIidie nature mal<es !hem susceptible to deslfUCllon olytic: enzymes of the dgestiYe lr'aCl A. Adrenoc:ortlcotropk: hormone (ACTH

Of

tTt

the pr0te-

corticotropin)

ACni Is a proWd of tie posl:trin1Iatio pro' Euing of tle largeopnanor ~ pro.opial ' 00C0i\il~ Is Ultgel organ Is fie UenBI ttlf1BIl ....tlete OOl1icXJIopio. [lora ~ IoD8 moe pi'l] bnds to speciIW: reoeptoB on the eel 8diY8la G proleirH:cupIed fO''' Un slirrUates Ihe rale $yi.etic; pelhway (chJlest 01

",IiIii

Ihe S'J'i1ll Esis

~

The °a;"p1ed reeepIOrS 'e5 to ,lClE85a cNIP.....t'littI in

-

_,, .......

step in Ihe DtlllOC(ll1io '15'eroid prl9MlIdDooe). ~ wilh

anct rei: Bse of the adleroocortioo5lerokls, and lie

~.

adrenar androgens (Fogure 25.3). The 'Y8~.bility of synthetic ldoerll)(lCll1io;o:oerolds v.tt\ spedfic pope-'. (see P. 275) his ....... iIed tle use d cortiaJtrqlin 10 serving as a dialPlOde tool lor diI1er.

entiaIing bet1

B!lI'l pmwy adrenal nsutiden&y

'

0~

(Adlison's nise....e,

associBted wilh aci'enal atrophy) and l.OlCOi idary 8drenIl ~ c:ierq (ea"·' tTt inadequate secrelion d ACTH tTt the pituitary), 1l'oerapeutic o::orticttropin preparations lire ~ lrom fie ani&: rioI' pituitaries of domestic animals, or synthetic tunan ACni. The Ianer, COS)n~ 11<0 sin TROE p;n], Is p..efefred lor diagnosis d BOrenaI lnsuffociency. TOlidties life simlla, to those of g1uax:orticolds, Antibodies can form to ACTH deriYed lrom anIm8l sooteeS. [Note: The anterior pituitary is stimulated to synthesi~e co,ticot,opln by corocOlropin-releasing hormone (CAH), produced by the hypclhaIamJs (see FlQUr8 25.3). CAH Is used dll\l1'OSticaly to di!\eferltieIe between Cushing's Sylldn;me and eclOpic ~ ctJ<:WIg cells.]

I

n

,

1-:1••

S, Grow\tI hormone (somatotropin)

Sotmirotrop!n [see rna. toe TAOE pin) Is a lerge polypeptide, lele85ed tTt the anterior piluitary in lespoiiSoB 10 growth hormonereleasing t!ollilOloe (GHAH) pmd"aM' tTt the ~ It is p,odllced synltlelicaty tTt 18OOi1ibli ..... DNA techdogy. GfOIw1h. hormone (GH) Irom animal sources Is lnelfective in humans. SOfl'liUtAltPi'!lnIluences a IfIliOO Yllri«y of tiOcJel ..... fnlC es, a p:ample, thmugh stirrI.4ation of prol4lWl synlhetic processes. eel ""oiIeratioil and bone gmw'I1 are protnCIled. 1r1Ol 3sed Iormalion d ~ from proli'Ie alsO bol:Isas cartiIaoe $)i. : . Therebe, somatoIropin is used in the IreIItr!Blt of ~ ­ mone (GH) defic:ieflC)' in c::Itien. (NoIe: II Is ~ 10 esW:Jish ..tlelher the cIe/ici in GH is -.dy o.oe 10 ~ since normaIlt¥roid status is essential 10 5'.' 'tA SOf\"Il!llUlopio. h!rapv,) A It1erBp8UticllI &qIjvaIenl drUg, soma/rem [see rna TAEMl. ~tra terminal meJh;orryI group not Iound in soma/Olr"Opt'I. fhoultl the haI-tiws d IheS'!I drugs ere short, al:lOlrt 25 miooIes, thBy induce the release If~ the h'8f of somalomBdin, Ihe 1nsu1in·1ikB IIfOWIh factor-I (IGF-I) 1tlel is responsillIe lor subsequent growth l1ormonlHiI<e adions. SomalOtmpin and SO'Il8ttem should not be used In individuals wilh dDsBd epiphyses or with an enlarging inltllCf8r'liai mass. INole: Inlusion 01 GHAH, known as serrTlOn1linlSilf moe REH Iyn], can be used to assess the status of

conIains an

GH delldency.)

C 7

I

....-

"'

. .,

"

Flgo.n 25.3 SeaeliDn and adlons of adreflo. c:orticoIroplc horfTlOlifl (ACTH). CRH. oortic:olropin-rBieasing

""""""".

..... 10. . .'.' . . . . . . . . . . . - , .

2SO

25. Hofma'leS 01 the Pkuitary and Thyroid

0riginaI~ isdated

hom !till twolhatarrvs, somalOslalin is a smal pol)1lePtide lhat is also Iound in neurons IhfOl.lgh;lut the body. as wei as in !he inlesme and pancreas. SamaIOslaIi't thetelOle prediclably has a I'UTtler 01 actions.. Odreoti:M lawl< TREE dllide] is a sYI'lheIic octapeplide analog ol soma/
honnone-t"eteaalng

On"'

lnhlbnors t..<;: ,..

--G

... ,

hoi',....... (LHRH)

GnRH. « dAo .... +i\Aide obtained hom !he ~ controls the release 01 • • '8 sWrlAaIing hormone (FSH) and Iuteftzing hormone (Ui) !rom the pituitary. GnRH is ~ 10 sOOUaIe gonadal hoolilOllB proolidion in~. A runber 01 syn!tlelie analogs, such as le!.pDlldll (100 PROE tide], goserelil [gall SEA e tin], naJare#in(Neh FAA elin] and tHstretin [HIS TAE lin]. ad as inhibitors 01 GnRH (Figure 25.4). These are eItectiYe In suppressiflg production oIlhe gooadaI hormones, and lhus are et!ec. live In the treatmenl or prostatic cancer (see p. 395). endomelriosis, and precocious puberty. Eo GoNdolroplnl: human menopauul gOOlldotropln (hMG). FSH (urololltropln), hUlNln chorionic gor'IBdoptropln (hCG)

figure 25.4

Secretion ot toIlide slimulating tlOl'''OIIl1!FSH) and kJtenizing

""""""LH).

The gonadotropins Nod use in the rraalrT1el'l1 olinle
may "'" "ev gynecomastia. Ill. HORMONES OF THE POSTERIOR PITUITARY ~ 001 iIlesl 10 the hOl"lOIlEIS 01 the anIerior kJbe of the pituitary, those 01 the posterior kJbe, ~asoplesskl and ~ ere not regulared by ,!l ring tlOl II .... IM. Instead, they are 5yI ill' ujzed in the hypolhalaOll,l$, transpot18d 10 the posterior pituilary and released in response 10 specific physiologic signals, such as h;gh plasma osmolarity or parturition. respecliWIy. Both are nonapeplide$ wiltl a cifcular Slructure due 10 a lisuMide bridge (F9JrB 25.5). Aeduclion of lhe disuMide inaclival85 !he hofmones. They are susoeptible to proteolytic cleavage and thus are given p8l'8f1lef81ly. 80tIl haw wry shot1 hall·liYes.

...... r....

..........

,.1 .........._ , •

IV. Thyroid Hormones

--_.. _..... , .............

'"

A.Oll)1o<:ln

Oxytocin lox ee TOE sin], originally exl.acled from animal poslerior pituitaries. is new ehemicalty syn\tlesl:l:8d. Its ody USB is in obsIe1rics. where ~ is employed 10 stimulate uterine WI Ibidioll 10 ioduoe or reintorce lllbor or to p10m0te breast milk ejeclioll. l~: The serI$itMly d \tie lJterUS ID owylOCin increases with !he dlfation d pregI8l'ICY wtlen it is under estrogenic dominance.1 To inch,ll;l! labo!'. lhe d.ug Is adminislered inIll111enously. However. when l.ISed 10 induce "milk 1e(-
mon

n

IeIaI pesenI8Iion. letallistress and ~ birIhs..) e.~in

\.1I:si;p m (\Illy _ PRESS in)(~ 1,0...101", ADHl. is stru::ttnlIy related 10 0II)'I0Ctl (f9.ore 25.5). The syn. \I'lesized nonBPi ..... has replar:8l thel ..... aded fIoom rinaI p0s.terior pib.iIarie5. UISlope_ hIlS bt*llll'llidiuetlc and vasop .. eftecIs. In Ihe ki:;lney it binds 10 .... V,..-pb' 10 i ... 'sa water permeabilily and resorption in the coIIec:ting tub hs Thus the mlliDr use 01. :p his 10 treat diabetes ~ ... It also In1s use in ...... bleB~pg we 10 esophageal varices or ......... dM!r1ialIll.. 0Iher efIeds 01 ~ rsp! 818 mediated by the V, ~. louncI in ._ow 511100Ih rnusde, IIi>'Br and oI1I!f l'ss1"'S 115 rni{;'II be expet1lld fie mlliDr to*iIy is Wider i,hi:alj"n and tryponalJefT'ilL II! biOi d'iOCiOf'" iclial 8I'\d tremor also can ()(ll;U'. Caulion must be lI$8d in treating patiems with WlOll3
<:te,- ..,.

"'.'0

.-..:re.

~ -'" . ,

-

.-

asa

.... -

C. Deunoprenin

Bece"se 01 fie pres&Or popectiu 01 'asC>pi! ssM, ........ ,lpOlnl has been modified 10 desmoptO$sJtt (dez moe PRESS in] (1~ ~ YllSOp'llSSin). This IlfIlIIog is now prele
IV. THYROID HORMONES The Ihyrold ~ lacilitales normal ~ and mallJration by maintaining the level 01 melllbolOsm in the tissues the! is oplimal lor their rormalluf1ction, The two major thyrold hormDIlBS are T, (trliocloIhyronine. \he mosl llCIillll Iorm). and T. (lhyroxlne). Allhougtllhe thyroid ~nd is not essenlillllor life. Inadequate secretion 01 thyroid hormone (hypolhyroldism) re&lIlts in bradycerdia. poor resistance 10 cold. Ilf1d mental and physical l;lowil"lO (in d1i1Oren this can cause mental ratardation and dwarfism). If, however, an excess 01 thyroid hormonel; is

""'@"-;,::-::.... ;::"

-

Co', II ...

Figure 25.5 Actions d oKy1ocin Ilf1d 'fIlSOPI1lS5in.

• "". '0' .. ,., > < .....

< , ....

I >

~""""""""

252

- - .. _

.... >

25. Horrnorl8$ oIlhe Pituitary and 1'try'toId

THTiOOcaL

CXll' CWl

n.r"J

eo,

./""-

f)-iodide

3

6'• '6'

* '0'

4 Cond..... Ullon

•

H-(; 10100

?'> • coo·

T

• T.

H-(;-N1o'

?'> • coo'

* '.,'':''_ To

IodInation

~~==:

T

FIgure 25.6 Biosynthesis 01 thyroid hom'lones.

secreted (hyperthyroidism). tachyca,dia and cardiac arrhythmias. txxIy waSling, nervousness, trelTlOl. and 8Ilc:ess heal production can occur. In mammets, the Ihyroid gland also sec>etes the hom'lona caJc:I.. tonin. a se
The 1hyIoid gland is made ...., 01 nUIipIe t6Jes thai OOllSist 01 a single IIlyer 01 api!helial eels stIITOIning a k.men filed wif'I oollaid (~Ilin). the storage loon 01 thfroid hormCll8. A ciag.am 01 the S1eflS in ttJvrcld hoiilu18 synIhesis and SOOielicli is shewn in f"9J'1I 25.61. AegoMtion 01 SVI.11 T'a: Thyroid ~ is OOl.,cIed by a IJqlic hoo"l()l18, ~ tormcrl8 (TSH.llly.ctropill). a ~ protein synthesized by the antarior pilLitary (see F9Jre 25.2). T$H ganerellon is goYllmed by the hypothalamic thyrotA;lpin-

..... ,....,., ........ IV. Tl1yroid Hormones

-- . ,

• co.. "

OM'

III'I:UJI . . . ._

.....

. ljj tu"U" (TRH), TSH llCIion is nlElllial.d ~ dWtP and leads 10 litirntJl;Uon ~ IocIdII ~.e. OKididU'Io iodi'e ~ ~ 8 pelook'sse is k)/kIo''lld by icdnlItion 01 tyrosines on Ihrf09oblllin. C#IdensaIion ~ lWO~7'oU1e ,...,,_ ~ rise to T. or Ta d bouf'Id to the prolen The hormOl'les are leleltSed loIowirlg proteo:Jtyk deaYage 01 the It1>;r'ogIoWin. I '

en

2. Regul&llon 01 RCrellon: Secretion of TSH by lt1e all\8fio.r pituitary is SlimUialed by the hypothalamic TAH. Feedbadl inhibition 01 both TAH and TSH sec«ltion OlX:Urs with hil1lleVels 01 cirtulating Ihyroid ho,moll8 or iodide. Mosl 01 the I\oolllOi" era end To) is bound lo ~ glcb "in in !he plasma. 3.. PharmKolUnetlcs: Both T. and T a are absorbed alter oral iiidI,.oisllaliOi~ T. is c:ot'IO'erfed 10 Ta by one oIlwo·r r d deiodinases, dep:idiiljj on the \issue, Ta OOl,lbiI_ oMIh a reoeI*W 10 slim~1e ujbseqllenl protein synlh&sis raec:essary lor normal metabolism. The hornlOile$ are metlII:lobed thl'CJUltl!he microsomal P-450 system. Drugs Sld1 as phenyIoin, riIampIn, phenobarbital. etc. that induce the P-450 en!ymes accelerate metabolism 01 \tie thyroid hormones.

'.'.

8. Treatment of hypolhyrotdiam Hypothyroidism is trealed with ~ (T d. The drug is given once daily because of its long halt-+ite. Steady Slate is ~ et 6-8 weeks. Tooicity is direcIy related 10 ~ leYeIs and manifests itseIl as neNOUSneSS, heat1 palpitations and 1al::l1rca1dia. inloIefanoe 10 heal and ~ ~ loa

C. Treatment of hyperthyroldism (lhyrotoxlanls) Excessive amounts 01 thyroid horlTlOf1es in the cir<:ulation ale associated with a ""mbef of disease states, including Graves' disease, Iollic adeiUIla, and goiIer, among olhers. The goal ollherlIA' is 10 decrease syl'llhesis arD'c. releue 01 adlitiol'lal hot.lIc.le. TlMs ClW'I be ~ by remoYing pIW1 or .. of the Ihyroid gland. by IMibiOOg synthesis or the horrt1Olle5, or by blodting r" se 01 tht hottllOileS trom lhII!I fcA::Ie..

1. 1'1010000.11 01 J*1 c. lilt 01 the tf¥'okl: TlMs can be aet:ul.pstoed either surgic8lPy or by destnoction of !he ~nd by bela particles emitted by radioactive Iodine (131 1), wI'kh is seIe<:tiveIy taken up by the lhyroid loIIiclAar cells.

2, lnhlbilion of thyroid honnone Iynlhelll: The lhioamides, propyfthiountci [proe pill thye oh 'f'OOR. sill (PTIJ) and mefl». mazoIe lmeth 1M a mlel. are 00l1OOi ttrated in the \ttftOld 'M1ere !hey irV'ibil boltl!he DIOOatlw poe SItS <8Cp.lired lor \odJleIion of tyYO$ylli'Ol.lP5 end !he ooupling oIludlA"osiIes 10 lorm fa and T.(see Fo-e 25.6). PTUcan abo blcdr!he oorMlfSion 01 T. 10 T$o [Nola: Ttese drugs haue no eIled on \he It¥~''' already slorec:l in the gland; lherelore observ8tion of any ciricaI etled of Ihese drugs may be delayed tWltil ~ stores are depleted.] The ltbmkles are wei absorbed from the gas-

....-,,.,..,.... -

: eM·

--

• "". '0' ..,., .....

, ..

'5<

25. Hormones of the Pituitary and Thyroid

lrOiI'lleSln.l trad. but !hey he\Oll short ha!l·IiYes. Sewral doses d P1U _ required per day• ..me.eas tl single dose d ~ m.uofe suffices due to !he duration d iU antiIhyroid efIecL The etleds d Ihesa drugs are slow in onset .-.d ltus !hey eN I'd etlective in the treatment of Ihyroid storm. AeItlliYely nile 8dYefse etlrIds indude ~ rash. and e
p.75). 4. Btodr" d />onnoooe re'Ine, A phermeo' ogic: dose of ioclid9 inNbits the iodiNltion d 1yrOSioes. thus decreasing the supply 01 slOI'ed thyroglobulin. Iodide also Inhibils Ihyroid hormone releese by mec;hanlsms not yet under1;tood. Today. iodide Is rarely used as sole therapy. However. ;1 is employe(\ to treat potentially fatal thyrolrnelc crisis (lhyrold storm). or prior to surgery. sincll ~ decreases the V8scular~y 01 the thyroid g1end. iodide Is no! usefuiloJ Iong-teml therapy, because the thyroid ceases to respOl'ld 10 the drug alter II lew weeks. Iodide is adnWlislered Ofally. Adverse etleds are relatively mioor and indude sore mouth and throet. rashes, ulcerations d muoous .,.. ,ollI_"", and a metaIi:: taste in the mouth.

Study Questions

~1hII

ONE

besI._.

Oor-=l _ _ .. 0. ,.•....,., ..... t*>cb ... ....

2$.1 50,0'4*JmS cI hype
EXCEPT: A. 1lOCI'oycMIia. 8. nervoosness. C. poor rCl,Slllrl(:e to cold.

2$.3

e. 'remer.

-.IlIll_ nal

-' ,.-~

ca'l

bel lrOOlItll by all bui _

.... ol " .

"-T~

~ .. C. kI'd [. .e.:.. . . . . oIIIn , ia . . _ _

MlIII.., " ' -.....

2:5.2 Which 01 IhII .........g _ ~ ~~

-

A. _ '*d<s ....

~

J

"'~ _

~

....

et\eo;t 01

noo"iOI. PI"""''''''on?

oIlhyto11"""rfl,

. '9 horn

e.. • WMbls I4Uke 01 iodide b¥ Ihyn>id c:ek. C. kll'8 ellS .... rek!Me0l ~ ro"lOI"""" 'IlyrogkDlIin.

n coupling 0I1y1'll41ines ~ ..... toglobI*' 10 b:m Ihyrcod IlOIl' ....L

....

ol ... ~ ,.. " ..

~ _ .

D. Ilolt\I waSling.

D. " IllDc:ka

s

lIifIeo::II II-. ..-.. 0I1oc1d1, P" '>"c IIQI of ..................... 01,.. "u_ _ .. lI'f1roId ~ The Ihyn>id noo....._ WlIbIIIhII ........., '" ~ 1100"0" Irorn . .

._"·M_"·.,

E. " IllDc:ka .... feIeNe ol ~ .."., the Ihyroid

B. SurgiaIl ~ "''N1I'p'fDid gIancI

c_

£., ...., -

(-c.on..t __ A.T't

.... 'u.... Ia.1lydd )

. _ ro...'.1"

.... ..-....,.

,

.....

-..---..,--_.....

Insulin and Oral Hypoglycemic Drugs HYPOGlYCEMK: DRUGS

-

I. OVERVIEW The para8aS is beth . , el doca i ... glarJ:l IhaI pmdIl!WS .... pepide hoomolle$ .hsLlIn, gl!ocagnn 8I'd IOITWlIoSlalWI. and an - . a i... Pld IhllI pmdI'l;f'S dgesIiYe enzymes. The pq:iCide t.... ,llOile$ _ seaeICd ~ oils klc:aled In the islets of or 8-cBlls prod:Jce NAn, fAr or A-<:eIs pnxll.Il;le tJ'1CSQOfI, and aO" or D-celI& prolU:e somelostam}. These r"""lClleS pIBy an illlportant role In regPaling .... meIaboic: activities of the body, and In dl*og so. help mIirtBin the homeastasis 01 blood Dl'lCO'ie ' Hyperin$ulinlIm (die, lor eumpIe. 10 an Insulinoma) can cause - . . . hypogIyoemia. More QOl' 1ITlOl1ly, a llIlative or absolule ladI of Insu*n (such as in diabetes melhIUS) can calJSe serious hyperglycemia. AclmlnislretiOfl 01 ~/ifl preparetlons or hypoglycemic agenls (Figure 26.1) can prevent morbldily and rer:!1,IQ8 morlalily associated wilh dlabeles.

..... , -_. , . __ . , ..• .-_................ ,

, ,,_

Laigi!f'''IS.

,

,

,

~

-

---,

---_, ,,

0fU,l. HYPOGl. YC£MlC

OAUGS

....

Cllbpo

II. DIABETES MElUTUS

a.. "

DIabetes is 1"101 a 9ngle me.sa tnsEad, il is a helGicgeo_ ~ of syndromes al characleri:r:ed by an elevation of blood glucose calIS«! bv ....1iIIe or lIlbosoUe de&:iet""Y fA ~ MequenIIy .... .......Ie, e':ase of insulin is awrallllled by an .........,. fA gfllC89O""Die'; !leJ 8flIicts aboU: 10 IT'iIicn ~ or about S,," d .... pDPlT Lation of the UriIed $ta'e$, and is 1he e91lt> Ie lji '\l cause 01 de8ItIln lhis country. Diabetics can be cfv'ded m t'M) grot4lS bBsed on lheir requiemelts tor insulin: .....r
ca;,

_, ...

....'

GI)oDwldoo

...." ,

,q

,.

8

r_'

t

Type I) and n o o - ~diabeles ",eftl"s (NlOOM or Type 11',2 AbouI: one 10 tVWl million patients haYe 1DClU; lhe remaining 80 10 llO'Jlo fA diabetic patients have NlOON. FlglO 26.2 SUfTIfTWlIims the characlerislics fA Types I .nd II diabetes.

.........

I

e _' ,

'I

,

__...--

......,. _ _ .. ~_._

c.a...o-.

.......... _

2SS

.<-" ....-......,,: .., _ .. _.,....

"""'00 ...., .... _ _ , • ." .

26. losulifland Cf81 Hypoglycemic Drugs

,,,..,,.

-~.,.


depelldei ,I

....... ...... ....- .-. --.... -... cr• ....,,,,

-.-- -..... ._. _. _.... ...... ..' _.. -" --..._,._'". _._.ol --"-....~

~

"-

.~.

p,

,

Q

"Z~

50:1:

We

'!ilII_.

,

. . . .cy-

,

I=.,"""" .............. •,

0:-,_

~

Rgura 26,2 Comparison ollnsu!in-dependenl diabeles and non-il'1sullrKlependerlt diabetes.

1 •, •

hl:lugl tte 8dioi1S 01 auIllirnrlule .. dooo·! I dIoeded again:sl: the 1H;:eI. A$ a rest.« 01 !he desln.dion of jk:eIs, the pancreas tails kl respond to ingestion of glucose. and the TyPe I diabetic shows das5it: S"fI'lpb'lIS 01 ~ def...... ...., (polydipsia. polyphagia an:! polyuria). T)'Pfl I diabetics require ellOQ81lOl1S /nsufI'I 10 a.oid ~ and Iile-Ihrmering ke1oec'dolil. 1.

e - 01 T~ I diabetes: A Iusl 01 .i'JscAi'I seoelioil normaIr occurs alief ingestion of a meal in rasponse 10 tlansienl inaeases ifllhe Ie\IeIs 01 <:ifaIlaling glucose an:! amino acids. In !he postabsoqlIiYe period, low, bIlsllIleve/$ 01 ciraAaIWlg i'Isl*l ara maintained Itlrough lk:el secrelion. 1-10"_1. the Type I diabetic has virtually no functional lk;ells. and can neither respond kl variations ifl circUaling luels f'IOf maintain even a bual secretion IewI 01 i'lsl.tin (F'lJU"l 26.3). The de.elopollenl: and PfOIT8SSion 01 neuropalhy. nephoopalhy and reliroopathr are dilec:ly (elaled 10 the ettent 01 glycemic control (most ollen measured as blood lewis at hemoglobln A,d.~

2. Treatment 01 TYpe I diabetet<: A Type I diabetic mUSl ,ely on exogenous (injected) Insulin In order 10 conlrol hyperglycemia, mainlain aoceplable levels at glyoosylaled hBmoglotiin (HbA1<)' and aVOid ketoacidosis. [Nole: The rate 01 tormatlon at HbA,ciS pl'oportion8l 10 the average blood gluoose ooncerltmlion over Ihe pl'lMous 5eYI!ral ITlOfllhs; lhus. HlA,c pl'OII\des a rneasule of hoW wei lrealment has normalized blood gluoose in diabeIit:s.1 The goal in i'Oniristering insulin kl Type I diabetics is to rnaintIlin blood glucose COIlCIIlnIraiions as dose 10 normal as po'ss·..... an:! kllMlid wide swings IrI blood glucose levels that ITIllY contribute to long-le<m cu'lPieatiofl;5., The use of portable blood gl''OOse analyzers tacililates close sell-moniloring and

,-

••

,Ji• •

~ c:iabetes most ccmmonIy alnicls juveniles, but 100M C8Il also oa:ur among IIlUIs (FIgUre 25.2). The disease is d'IarKterized by an abscluIe cIefit:iel w::r of tl8c.*I ceused by mas!We IH;:elIes'ns or necrosis. Loss of ~ h.n:lion ITIllY be due 11) InYasion by Wuses. lhB action of ct:e",ical mins. or usuaIy,

. ..•

•I , _.. _.-

B. T'ype" diabetes (O'll»1nsulin-dap«odottlt dilIbetes mellitus,

NIDON)

';

• I •

•

_- .•

"

FIgure 26.3 Release of inslAirI that occurs ifl :esponse 10 conslanl infusion of QIulXI$e in nonnal Sl.tljeds and in diabelic palients.

Most diabelics are in Itlis calegory. GeneIic Illdors lBIher than virvses or auloinvnune antibodies .,. apparentty causal. The metabolic allerations obsefved are mIder 1han those oj!! 'bed lor 100M (lor example, NrDOM petients t)'JllceIy are fWll keIotic}, but lhe Ior9'lerm dinit:aI oo..sequerus cen be just as devastating (lor exampte. vasaQI comptications and subsequent Iflleclion can lead kl amputation ol!he Iowef Ilmbs). ,. c.vM ol Type II dillbetK: In NJOOM, Ihe pln:f8as relains some lk;eIllurdt::ln, resulting in variable Insdin ~s !hat are hsufIi· clenl 10 mainlain glucose homeostasis (sae Figure 26.3).

.... '0...I.' > . . . . . . - . . . ' >

,.,

III , Insulin

PaIiens with TWe liliabetes are dten obese.. Type II dBbetes is freqIBllIy ~ by Iafgel 0fVilIl ~ resisIanoe !hal limits <esponsiveness 10 both endogenous and exogenous ...." In scme cues. ilsLllin' .!"lee is 0.. ID e dlIel i . . I'UTlb8t or mulalions of .i'lsuIi'l ,.... .."s. 1-IDwwer, ." 11$ yet U1ldeio llId defed in f"e IMlnls lhBt oowr aflet ilsLllin binds ID its 'e' ..... is b r !>'lId ID llCCDUI1llor resist.., ..... in lIlOSI pelielll:s.

2. Treatment of Tn- • diabetes: The QOBI in treating TWe II 6abetBS is 10 meinIain blood gucose (XlllCf!l ,trations within IlOfJ110I limits and 10 prevenllha de\leIopnel t of long-term /JOI'l'oPliCations of the disease. weight reducIion, exen:rse and dietary modifica. lion dec<eBse ~1kI resistance and 00IItld Iha ~ of Type II diabBtes in some patierlls. How8Yef, mosl are (i8pelldel. on phaflTlil' 'ologic: intervention with oral hypogIyeemil;: agents (Agln 26..4). In&ofn 1hefapf ~ be reqWed ID achleYe salisIadDry senm "'. .oose IeW!Is. INote: See F9J
MI. INSUUN Insulin [IN sill Iinl is a sma' protein consisting 01 two J)(l/)'J'ePtide thains that ara connected by disulfide bonl;Is. II is synthesized 11$ a precursor protein (pro-hsWn) that unclergoes proleolytic cleavage 10 form insWin and peplida C, both of whil;h are seaeted by the I\-Oells 01 the pancreas.- [Note: Normal individuals secrete less pro-Insu/ill than insulin, whe<eas NIDOM patients S8CfBte hil1' levels oflha pro. hormone. 5nle ra<:!iomo'lUi"OOSS'l"(S do no! distinguish bet\!JlNlI'I the two Insulin ~ NrDOM patierlls may haYe loWer IM!ls 0I1tle DYe homIDne than !he assay kxicates. Thus measuremetll r:J di'tUa1ir1g C ~ pn;Mdes. beIler r.deX 01"'" 1eveIs.)

.t"Isr.8l seaeliOll is regIAated no! ody by t*lod ~.ooose IeYeIs 001 also byOlher hoo"Ol8S an:! aJJIO
$80.,

8. Sou,,;e$ of inSYlin /nt;(Jkl is isolated lrom ~ is ~

beef and pone

pellClOO$.

Hc._.

hc.man

the iPnaI hotmone lor" II1efap\/. Htman AufrI is pmb;ed by. special sl
one amino acid. 'see p. 262 let ~ .."'...... ID _ _ in tiI_

.~.=a~~'~.~~-

No " _ _ •

0100

0100_

.48<".

..-. .

• no' '0' ..,., ............... , •

".

....--~,

............

-, ....

26, Ins",in and Onll

~

Drugs

C. 'nsulln administration Because Qulin is a pfOIein. it is degraded In \he gastrointesmal tr8cI if ~ llf8IIY. II is IhefeIont g&ll8lall~ administered by Sltlcutaneous .ljeclion. (J'«lle: In a ~ emergency, regular ...... is itfeded intraYl!flOUStV.] hsuIn is inKtivalecl by the recU:-

r.g enzyme• .h:sufn.\se. bnl rnainfy In !he lioIer ..., ~ lnst*'

preparations V3JY pm.arily In Iheir lImeS of onset of lldMIy and duration of 1diYify. TN!; is m..e in large part to . . size and ~

siliM of the .hsuIi1 aysials in . . prep&I8ticrlI.. (NoIB: The less sduble an In:wIin preparation is. the Iongef it acl$.] Dose. site of it ...... ~ blood SUflPf'I. and ~ ae:tMty can 8fled !he dlntiorl of edion of Ihe \IIIrioU$ prepatlIlion$. I-t.marn i'lsl.*f is IIb50rtlecl moftI quidIIy In)m its • of it;ectiol , IIwl are Ihl! beef 0<' pork huliilUill!$. Tlv.ts, the cbaliDn of acIion of htman i1suIrI is srone.. llf'ld doses rrosl. be adjusled .......di W

"",..,.,.1IIl.nI

D. Adverse ructions to "sulin

The &yn'4)Ioms 01 hypogtvoemi8 are !he s,,,.~

,._

by ,,", ""."'''''

ITlO$l serious

and

Q)ITI-

mon adverse reactions 10 an OYlIfdose 01 inwIin (FlQUre 26.5). long-tBml diabetics often do ncI. produce adeQUllto amounts of lhe ~lofy l1oIlrtQIll!S (glucagon. epinephrine, corti9Ol, and growth hormone) that OlOmIaIly provide an el1ec::tive deIense against hyp<:lgycetnia Other adverse reecOOns Irdude lipodystroP"'>' and aJlergic .ellclioo5. [ Note: l\-Blod<e.s (p. 74) cause hypoglycemia. Because lhey Inhibit the adrene.gic physiologic symptoms 01 ~ia 8li:C8pllor sweating, lhese drugs can mask the ooset 01 insulin ooma.]

IV. INSULIN PREPARATIONS

Most 01 lhe It1SUIIhs derived from beel and portl have been latgety replaced by !he human klrm synhsized lItilizing recomtw\lll'lt DNA lech~

A. Rlopid action In...... prepantions

/

PlY •

"....

":J ~. ,.of':~,:7; ., .

"'u·12.

::i.:;'~:.::!.

...

AdY~

effects obsefved with inst4'n:

J'«lle: Iipodystroptly is a local alrophy' 0<' tryperIrophy 01 subcutaneous 'atly Iissoe at the sito 01 if1jections.

fleo.*r

inst.*J is a shuI1---ading WHe ~ ~ ~ II gillen Sl.tlctJtaneous (0<' nt~ in eiilel\ji!ilties) n loWers t*:lod sugar within ~ (f"'9-Q 26.6). It is the orIy i'lsuiitt preparation suitaDIe klr intravenous fldministratiDn. The buflered Iorm Is used in external INu6t> pump$. Both human retlDI,ti..", lWld arWnai SOUIa! .hsuIi1 are .. 'Ne Irt this klrm. A . - Iype of iI'Isulin. which cnntains • modificalion in !he amino acid seqlHlOCe of nalurally oocuring Irtsullrt, has .ecenlly been &pproYed. TN!; inslAin ads Iaslet than regular Insulin. is

"Fl·....

B. Intel mediate llclion insulin pl'e'pamlons

1. SIlmilente l'-Ulin suspension: TN!; i1scAi11s an amuo pllUilS precipitate of insWn with zinc ion in acetale bufIa. thaI is noI su~· able lor intravenous administmtion. 115 00581 01 actions and peak elled are rapid. but somewhat slower lhan for r8fPa' itlsv/in.

< _

r......,

>< ...... _ _ , >

...........- - , """"'" .. _

.... >

259

IV, InsUlin Preparations

REGUlAR "'SUUN

",",,"""UN _ _ _ _,......

• OnIy _ _ ItI _ _•

.~d1O%l¥.I

• ~,;,..c:~':"':·:;C:-·

• _..-., _

•50<._,_....._ __._-. . . . . . ..,_d_

• IJMlIIlyml_ ...... _ . .. ,"Mill_

.v:,. ="""'-

, ,, ,•• ~

~

240

: 160

· •

•

,,

,

-••

NPH" '

,

'-.. _--_.-"

_.

o

12

"

24

, ,~

•, •

315

• ••

•

~

•

//

s.:.:,,-

,~

,

•

.'-c~~~~~

o

~

~

-,: ,

"""" 01 ........

V

~', ... "'-.!:-/ '''f"

'...__.....

lJ/fra1f1n/e nul"

,

"

Figul'll 26.6 Extent and duration of action 01 various types 01 insulin (in a lasting diabetic). NPH~ neutral protamine Hagedorn.

2.. lsophana insulin suspension: This InsuUn. sometimes called neutral protamine Hage
3. Lente Insulin: This insvlin is a mixture of 30% semilente Insulin (prompt acting) and 70% uNralente insulin (prolonged acting). This combinafion provides a relafively rapid absorption. w~h a sustained action making Iente insulin the most widety used of the Iente series 01 insuIins. It is gwn only slJ>cutaneousty.

4. Insulin combiMtions: Combinafions 01 human insvlif/s such as 70% isophane ... 30% regular. or 50% 01 each oIlhese are also IMlilable.

C. Prolonged action Insulin preparations UNralente insulin is a suspension line iflS/Jlin (porcine or human) crystals in acetate buffer that is COf1llOS8d 01 large partdes which are slow to dissolve. producing a slow onset 01 action and a longlasting hypogycemic elfect

D. Standard treatment vs.lntensive treatment: Standard treatment ot patienls wilh diabetes mellilus involves injection 01 insulin twice daily resulting in mean blood gluoose lev· els in Itle range of 225 10 275 rng/dL, with HbA1C 01 8 10 9% of total hemoglobin. In contrast. intensiva treatment seeks to normal-

<

hO' '0...,.,

,'"

> .............. , >

• ".... • ....--.......,.,. . , out:IUUl . . _ . W >

26. Insulin and Oral Hypoglycemic Drugs

Fogure 26.7 Effect 01 standard and intensive care on the Iong--term complications 01 diabetes.

ize blood glucose through more Irequent injections 01 insulin (three or more times daily in response 10 mooitoriflg blood glucose tevels). Mean blood glucose levels 01 150 mgfdL can be acNeved, with an HbA,c 01 approximately 7% 01 total hemoglobin. [Note: Normal mean blood glucose is approximately 110 mgldL. and HbA,c is 6% or less.] Tl1us, lolal normalization 01 blood glucose levels is no! achieved even in intensively treated diabetic patients. Nonetheless. patients on intensive therapy show a 60% reduction in the long-term complications 01 diabetes-retinopathy. nephropathy, and neuropathy-compared to palierlts receiving standard care (Figure 26.7). However, the frequency 01 hypoglycemic episodes. coma. and seizures due 10 excessive /nstJlln is particularty tjgh with intensive treatment regmens. See p. 452 lor a descriplion 01 the newty approved drug. lispro

"""" V. ORAL HYPOGLYCEMIC AGENTS

Sullonylureas

n

,-,

:=

-u _. u...., ----...... ...., CloiII><...

~

:=:.~

_onyluo_

~

...-

0

0

Sullonylureas Figure 26.8 Drugs intefBC/ing with su~onyI­ urea drugs.

01"

These agents are usetul in the lreatment 01 patients who have non-insulin-dependent diabetes (NIDDM) but canoot be managed by diel alone. Tl1e patient most likely to respond well to oral hyp0glycemic agents is one who develops diabetes aller age 40 and has had diabetes less tl1an 5 yean;. Patients w~h long-standing disease may require a combination 01 a hypoglycemic drug and Insulin to control their hyperglycemia. Oral hypoglycemic agents should not be gven to patients with Type I
A. Sollonylureas Tl1e mechanisms ot action 01 the sullonylureas include: (I) stimJ· Iation 01 insvlifl release trom the jXells 01 the pana-eas. (2) reduction 01 serum glucagon levels. and (3) increased binding 01 insulin 10 target tissues and receplOfs. Tl1e primary drugs used today are tolbutamide [lole BYOO ta mlde], and the SB<:ond generation derivalives. g/ybtJride IGLYE byoor ide] and glipizide [GLIP i zide]. Given orally. they bind to serum proteins. are metabolized I:ri the liver. and are excreted by the liver Of kidney. These drugs are con· lraindicaled in patients with hepatic Of renal insuffICiency, because delayed exaelion of the drug, rewlting in ~s accumulation, may cause I?ypoglycemia. Renal impairment is a particular problem in the case or those agents that are metabolized to active compounds. The sutfonylureas travefSB the placenta and can deplete insulin Irom the lelal pancreas; theretore the NIDDM pregnant women should be kooted w~h Insulin. [Note: Acetohexam!d6 [a seat ot1 HEX a midaj, and ro/a1:amide {tole AZ. a mille] are rarely used today. Chlorpropamide [klor PROE pa mide) shoutd be avoided in the elderly. Its eflects are very long lasting and it has the highest incidence of side effects in this drug group, causing hyponatremia, hypoglycemia. and if laken with alcohol, a disulliram reaction (see p. 96) and hypotension.] Figure 26.9 summa-

. " " ' . . . . .,.' . . . . . . . . _ L >

V. QraI Hypoglycemic Agents rizes some properties or the Ilyp!:9ycemIc drugs and Figure 26.10 i"ustrales some 01 the common adverse efIecIs 01 these agents.

B. Blguanklas Metformin [MET lor min] is now evailable lrl thtl Un~ed States. A blguanide. il dillers rrom the sulfonylureas in not stlmulating insUlin secmlion. Thtl risk at hypoglycemia Is less than with suIIonyturaa agents. Metformin may be used alone Of lrl combination with the sulfonytureas. Metrormin acts primarily by dEH:reasing hepelic glucose output. largely by inhibiting gluconeogenesis. A very important property is ~s ability to reduce hyperlipidemia (LDl and VlDl cholesterol concenlrations fali and HOl cholesterol rises). The patient otten loses we~. MetfomWl is consldered by some e;ocperts as the drug or choioa In newly diaglOsed Type Ii diabetics. Metfrxmin is well absorbed o
C. n-Glucosidase Inhibltor Recentiy. acarbose lay KAR bo6e]1Ias been approved es an omlly active drug lor the trealment of patlents with NIOOM and as e po& sible adjunct to insulin lor those with 100M. Acatbose int1ibits nglucosidese in the intestinal brush border and thus decreases the absorption 01 stafct1 and disaccharides. Consequently the postpl"andial rise or blood glucose is blunted. Unlike lhe other oral hypoglycemic agents. acaroose does not stimulate insulin release from the pancreas nor does it increase Insulin action in peripheral tissues. Thus acarl:>ose does no1 ceuse hypoglycemia. The drug can be used as mono1herapy in those patients being conlrolled by diet or In combination wilh oral hypogiycemic agents, or with insulin. It Is poorly absorbed and its major side effects are lIatu· lance. d'arrIlea. and abdominal cramping. See pp. 452-453 for a description of the newly approved hypoglycemlc dl'\J9S. gJinepIride. ropagiilidB and trogitazone.

,G,LUC06E, \GLUCOSE/

","=J "YPOGLYCE~IA

Figure 26.10 Su'nmary 01 the adverse elfects observed with oral hypoglycemic: agents.

~1rIr"", eflOC'lln IObout 3O'!i.
r

7'

Pi

"

-.........Figure 26.9 Summary of the properties 01 oral Il~emlc agents.

<_ .....,., .... _ - - , .

• """'" M _ _.... MP'.. , """"",, . . _ . W >

26. Insulin and Oral Kypoglycamic Drugs

Choose the ONE best oos_.

26.3 All QI the lolIcMing are correa EXCEPT; A. One 01 the most common &ide e1lects '" oral hypogtyoemic agents is gaslrointesti1al disturbance. B. The most serious oonseqLJll<\08 <J insulin ~ is hWOgIyc:ernia. C. Weight reduction is ollen of Iherapeutic help In obese Type II diabeIics. O. $ullonylureas ere oonl'llIndicatad In patients "","h heflIltic insuttiOency. E. Insulin and glucagon have similar allaets on metabolism.

26.1 Which one 01 the /oIIo-,o,;ng statements is correa?

A. SuKonytureas deCrease the seaelion <J lru;uIin. B. T<Jbwlmide is el!f:>cliv9 in Type I diabetic&. C. SuIlooylureas increase Ixllh the release 01 insulin and the in6Ulin-soosilMty QI target tissue. D. Glipzide increases glucagOn se<:retion. E. Cliorpropamide blocks insulin receptors.

Corred ...--. c.

~ i"l<:reo$e 00Ih In.....in ralease and target liM"" sensllivlty. S~IIc-nylllr.u cannOI act 10 lnc.._ ,ns~lin -.Vlb, in Type I '...·'b:o ...."._ ' - IfI(ivid~ala hava no 11'«111 I~ncllon. O.al hypog')'COImlc .~nla ollen c.~... a d&Crean In

glolCagoo .........

26.2 Which one oIlha \cIlloWIng statements is correa? A. Insulin can be admlnistemd orally.

B. Insulin is 8/Ways reqUfOO thempy in Type II <:babet·

26.4 A lemale patient with non';"lUlin-dependenl diabetes has ~ mairltainad on an oral sulfonylll,ea h'yPOgIyc:&mic agent She becomes pregnant. The doclor swik:hes he< to insul+n. Thio iI nooeSSllry lor al 01 the 1oIlo.,.,;"g reasons EXCEPT:

""

c. Protamioe is added 10 inaulin 10 decrease the ,ate oIeboorption olll>e lIonnone. D. SuIlonyk.Jreas am usetul in !he treatment 01 keload-

A. SIllIon)4ur8aS can traverse the p1aoenla and act on the 0slaI oeDs 01 the panc,eas 01 lho latus 10 deplete !ham orlnr;ul;n. B, SullonylurellS mey prOVQke pregnancy-Induced

OO&is. E. Inalllin eels by binding 10 receplors in the nIldeus 01 target tiSSile.

C. Insulin does not pass thJ<>Ugh tho pIaCoola. O. The,. is • gralllar demand lor insulin ;n pregnancy

hyperlension.

than can be provided by sulfonykJreas. ~ ~ wI1h lin ~ oa,ipI&lc lI\8Il WI ~

CormcI_ -C. .......... 10 101m

aboorbed. Inaulln II not adml<1lsooJ'1Hl orally baceuae M II _oyed by prola_ III It>a GI lrlICI. DlIII1tolnIpy llRIfOf SIMooylLnM "'" oIIan ~ ~ 8ddIIonaI "-'in In It>a 1he"P)' 01 Type II dIebeIio:;$. ",* .. idoGIs 1& !he moat . . ltre8Illnlng CCA"I88qUOlr1C '" Twa I cIIlbelicl and

er.... ...

req..Wes ~ IreImwft ...., ~ nor lUIlonylureaa. lnaulln IICII by binding to opecillc

racepto.. in tha cell memb,ane. not In the ~

's.

p.2lllI .. el I ,{a>cled.)"" ...... _ orl>olmoolaloegoJlltionol I ....'.

"SM

p.3'!".

'."I.. y(2nll ...po..........

or han>ogjotJO, A'e-

n. ~ .... • _6 tn P''ll''''CY. not 01"1I)' II

1hll ~ ....-.g _ - . a drug td 10 WI tie tonu.. In !HI c.M•• IIIn'9llf\IlnI _ tie ialet t * or h fetal pWc:reBI not brt llIlecBl by !he ~ ~!he lnIIonIls born hyp:>g!yaln'C.. ~ r-- no elIec1 on blood ~. The 'ect _ lneulin _ not pau ~ Ih8 pae.ma ........... W;I ~

f'IOlI'I'I8IIt, YMlIhe

~ d b I8lIls, ,.., aM _ on alllo::l\' .. II r M"d II'uI an ~ II> !III :t da",aoKl 00 lnk*I. ~

If_

'sa. p.2IilS .. e1 ' . ' 01 Typt._Typt "s.

p.

21'D" II

ollJb¥"

I y{a>clood.jloruh",.""

, . , _ , l2nd ".j tor ...........,

I ol~

._ .....

,.'~

......

_'~

Steroid Hormones STEROID HORMONES

I. OVERVIEW

...........

-,---....."""" --, ._-............

I

CtI..........."" • ..

_ ~ _ f n > t

SHlroid hormones include the sex hormones (androgens, progestins and estroglllls), and the hormones 01 the adrenal cortex. Sex hormones produced by the gonads and adrenals are nllCessary lor (X)r1(eption. embryonic maluration, and development 01 primary and seoondary sexual characteristics at puberty. The gonadal hormones are used therapeutically In replacement therapy and, In the case of estrogen, lor cootracepOOW) major classes of steroid hormones; the adrenooorticosteroids (g1uc:ocorticoids and mineralooortic:oids) and the adrenal androgens. Their synthesis is stimulated by corticotropin (previously caMed adrenocorticotropic hormone, ACTH, see p. 247). HormoMs 01 the adrenal cortex Ilre used in replacemer1t therapy, in the treatment and management of inflammatory severe allerdiseases such as rheumatoid arthritis, in the treatment gic reactIons, and in the treatment 0' some cancers (see p. 393). Inhibitors 01 adrenal cortical steroids are used to treat hormonal dystunctions in which these oompol.nlls are producecl in excess. Figure 27.1 lists the steroid honnones relerred 10 in this chapter.

~.-

~-

f--

I-

0'

II. ESmOGENS Estradiol less tra DYE oleJ is the most polen! estrogen produced by women; the other major estrogens, eslrone [ESS troneJ and estriol [essTRI olej, have about one tenth the polency of estradiol. These naturally occurring sleroids are subjecl to a large lirsl-pass hepatIc metabolism and when admislered oratly show low b'oavailabllity. PREMARIN-a preparation of conjugated eStrogens (contains suRa-te esters 01 estrone and equilin) obtained trom pregnant mare's urine--is a widely used oral preparation. Synthehc estrogens, for example, ethin)'I estradiol [ETH eye nil ass Ira OYE oleJ, undergo less first-pass metabolism and thus are elfeetive whet1 administered orally at lower doses. Synthetic nonsteroidal compounds with estrogenic activity, lor llJ
"""""'"

IIQDlI ATORS

ANllESlAOOEMI

I

Quo,.."....

I-

.........

I

!'I)odn>"l'P' _teo", ..

.......

~.r

-~ I""'-.nN L

- -....... ...........

I

I

~

F~._

1\11,,..0loi..

FlguAi 27.1 Summary steroid hormones. (figure cootinlleS on nexl page.) 'Described in Pharmacology update, pp. 454-455.

or

'-'.''''''''''--''

' ' ' - M ........._ - . . ... ,

""""", . . _

.....

>

27. Stei'OO Hormones

A. Mechanism 01 action

STEROID HORMONES

I-

-

AHTlANDROGENS

----..---,-

I

C)........ "' .. ..,.,.~ ~~

I-

CORTICOSTEROIDS

I

-.b,..IfI
~

1oM1I'r)1p ....._

~-

f 'i _ _ ..

'---

INl-MBITORS Of ADRE.NOCOlmCOID BlOSYHT1iE$I$

---

~ide

'--

Ali,.,.........

Figure 27.1 (continued) Summary of steroid hormones.

fSlrogens

Stei'OO hormones dilluse across the ceM membtane and bind with high afrinit~ to specific nuclear receptor proteins (sao p. 393}. Affinity lor tile receptor varies with the particular estrogen. [Note: The estrogen recepfor is a member of a superfamily of '8«!ptors lhal includo those for lhyroid hormones and vitamin D. as weH as ligands nol yet identilied. The attachment of two estrogen.linked receptors 10 the genome is rllQuired for a response.] The activated steroi
B. Therapeutic uses 01 estrogens The most frequent uses of estrogens are for conlraception (soo p. 268). fOf postmenopausal hormone lt1erapy and for osteoporosis. Estrogens are also used extensively for replacement therapy in pa~ents deficient in lh;s hormone. Such a deficiency can be due to lad< of development of the ovaries, menopause. or caslra~on. 1. Poslmenopausal hormone thefap~: In the past. eslrogen thefllPY was reserved for postmenopausal women experiencing "hot fIasI1es". atrophic vaginitis and urelt1ral changes. and women wish-ing to reduce the riSk of osteoporosis. Toda~, evide! iCe is accumulating thai all (except for !hose wilt1 specific oontraif'ldications. such as a history of estrogen-dependent cancer) ma~ 8l
2. Primary hypogonadism: Estrogen therapy mimidling the nalural cyclk: pallern, and usually in combinalion with progestins is instilute(! 10 stimulate development 01 sacondary sax chamcteristics in young women (II to 13 years of age) wilt1 hypogonadism. 'see p. 278 lor 1 _ ,"fe'eo""", 10 oil...- _

in hs S<'ri<>o.

. . . . . . . . . .1. . . .

,.

........

__............'_ . _.....

II. Estrogens

'"

SLEEP

•

OSTEOPOROSIS

• CARDtOVASCULAR

•

&&oavon' a: ... 01 hip - . . . - DIoW7_(1,DOO1O '(II ~'i' _ _

,.soo,..-,,_

_ _ _ 01_1

•

T. _ _

._-oow-_.. . .

_2",'_01". : _ . _ IIpoe_

VASOMOTOR

UROGENITAL TRACT •

Eotroven bWb, .."t...--

.......

_~.c~""hypotl''' ,ok:~'"

, 1

~-..

...",-

01 "hoI_'

"db i

...... ". Bel."

M'""Cia!ed"'" poslIliGloDPa''Sa' esaogell '8j- &'iGlll.

c._ 1,

--,

AM. uo II

oocun1ng estrogens: Thelie agents and IhW eslerified Cl:rfugaled deriYatiYes are readily absorbed ~ !he gasIroinIestinaIIIBCt, skin, and muoous meniboa"es. Estrogen is also quic:tdy absortled wherI iSlered r.tramuscuIarty. M'ni istered

."

~

._

Of

• Lcw'9 _

lIO,.

_

$

1

--,.

."IOl.

- . ' ........ 110

orally, esIfBdid is IlIpid1y melllbolized (and partially lnIlctivlIted) by the microsomalllf1~es 04 the livef.

2. The aynlhetle estrogen _Iogt.: These cornpounda. for ilXilmple, eIhirtyI eslladlol and mesfranOl [MES lIlI noIeD. aAi wei abSorbed eft. oral ad"ioistralion, and lhrough the slIin Of muoous memtKBoes.. Mestrcni is quidlIy Ollkized 10 6tII/nyI esIfBdid, wt'id1 is meIiIboized more ~ than the naturally oca.wmg estrogens by the lNer and ~1'81 tissues. Being fat solt.tH, Ihey are Stored in adipose Iissue hom wtid'l !hey are $lowly released. Therefore, the synlhelic estrogen analogs have • pro6ongOO action and Itig.- potency as COI'lll8red 4D natl.r.ll eibogElll$.

3. Metabolism: Estrog_ are \18n$pOf1ed in the tllood bound to aerom altunin and sex hoffl'lOO8-binding globulin. They ate ~ in hlliYer 10 deriYatiYes aw are Slib5equenlly giltCU'Of'idaled Of sul\a:ed. These ~ producU are exc«rled in the ..me. [Note: In rdviduaIs wittlliYer damage. serum estrogen leIIels may ncrease due 10 reduced metabolism, causing Iemiritalion in males Of signs 04 esIrogen excess in Iemales.J

.......11•• 11110-.

QaInl! 1m cartIot • II

.T_-,...... _ _

-

• "1'

.......

1.'.-........

_01 _ _ _._ • _tIf

_ 0 1 ....... 0.

$

_

._ ..... .... _-,. ,.,

27. Steroid Hormones

D. Adverse effects Nausea and \
E. Antiflslrogens Antiestrogens, which rnodity or oppose the action or estrogens. include the nonsteroidal antiestrogenic compounds clomiphene [KLOE m; feen] and its structurally related analog, famoxifBn Ita MaX i ten]. Both inhibit the action 01 estrogens by intetlering with their access to receptor s~es. They act as competitive antagonists Of, ;n a k;m estrogen milietJ, as weak agonists of the natural estrogens. lheso nonsteroidal antiestrogenic compounds are equally etfecti\lll whon given by mouth or by injoction.

By interlering with the negative foedbadl of estro· gens on tho hypothalamus and pituitary, clomiphene increases the secreoon 01 gonadotropin-releasing hormone (Gn-RH) and gonadotropins. leading to a stimulation ot ovulation. The drug has bean used successfully to treat infertility associated with anovula· tory cycles, but it is not effoctive in women whose ovulatory dyslunction is due to pituitary Of ovarian Iailure, Adverse etfects are dose-related and includo ovarian enlargement. vasomotor ftushes, and visual disturtlanr:es.

I, Ciomipheno:

2. Tamo.ifen: This drug competes for binding to the estrogen receptor and is currently used in lt1e palliative treatment or advanced breast cancer in postmenopausal women (see p. 394). [Note: Normal breast growth is stimulated by estrogens. It is Iherelore not surprising that some breast tumors regnlSS following treatment with antiestrogens.] Tamr»:lfen's most frequent adverse effects are hot lIasl1es, nausea and vomiting. Monstrual irregulari· ties and vaginal blee
See pp. 454455 lor

a descrip!ion of

the rIe'.\oty approved selec1Ml estr0-

gen modulator drug, ra/ool
III. PROGESTINS Progesterono, the na\lJraI po-ogestin, is prOO.Jced in

F1gure27.4 Some adverse etfects associated with es!roge<1lt1erapy,

response to luteinU;rog

I'ormone (lH) by boIh females [secreted by the corpus Ml!IJ'T1. primarily dJring the seoon:l half of the menstrual cycle (F.g..re 27.5), and by the placenta] and by males (saaeled by the testes). It is also S}Tllhe$ized by the adrenal oortex in boIh sexes. In females, progesterono promotes the d€MlIopmont 01 a socreIory erdOmelrilrn that can accommodate implantaliool 01 a neoMy forming embryo. The higllevels 01 progesterone released during the second half 01 \tie menstrual cycle (the luteal phase) irhbt the pn:xluctiol 01 gonadoIn:lpin, and themlore. further' ovulation. If COflCeplion takes place, progesterone continues to be secreted, maintaining the et ICloII oetrium in a lavorllble stato lor the continuatiorl 01 the preg1ilncy and reducing uterine contractions. II cooception does not take place, the release 01 progesterone from the corpus luteum ceasllS abruptly. This decline stimulates \he onset 01 menstruation, {See F9Jre 27.5 lor 11 SIJrfj. mary 01 the hormones po-oduced during the menstrual cycle.)

._ .....,., ....... _,. III. Oral and Implantable C«1traeeptlves

267

A. Therapeulk: use, of progestlllS

The ma/Or clinical use 01 ploge6tilae is n alntraceplion, n which they are generally used with estrogen" either In combination or in a sequential rnannet'. ~ by itself is not used wideIv therapeWc:aIy because 01 its rtlf)id rndaboli&m, te$I.IIing nils bN bioavaiIIIbiity. SynlheIit; progeslins used .. conttaeejAOu Bfe more Slat*llo r..st-pass mell1bo/ism, aIowing for lower doses wtBl admi"is1e1ed oraJIy. These agents include me')Pt096S1etn'l8 sc:etate [hye DROX Be proe JESS ter oneL ,iOfethildioflll Ira efllN droneL and 'lOIgesaM Ira JESS tnlij. [NoliI': Na.ffhi"dtJlltI and 'lOfJJfi'5bcN are someIirnes caled the nortesloSlerone progestins because 01 !heir $II\JdI.lI'al sWritariIy 10 the ill 0 oget ~ They also IX , soma arodI'ogrric ~ J Olher dir*:aI uses oIl11e progestills are .. !he <XlICrOI 01 dysIunctional uterine til" ~i"g. the IrOillment 01 d)S"fflIlOi,taea. suppression of postpartum ladalion, and the management 01 • doI' .... OM. Thev ate 8Iso used 10 \Jeat III odol'lMliai can::inomas.

-;f\ 1

\

.1 -~

\ ..

.l-_........:::...

•

B._ Pn:>pe$/m:Irte! is rap;cty ablotbed ,ftet its ad",iooistralion by' any route. It hIlS a stlOft haloWB .. ll'Ie pasn.. since it is * u t c0mpletely metaboliZed .. one passage Ihrough the liY«. The gluCUfI:Jl'IidIlled meubolite (pregnallcdol glucuronide) iii exaeted b,' the ~ Syi ,ltletic: ~ are !eM rapicIy rnetaboIiz«I.

C. AdverM etteca

The ma;or IIdverse Bf!iBctI a""'t'VIted ...... the use 01 plDgestills ate IdIma and dlp'1$Iion. The .ooget~ pogesms can roease the flItiool LOt.. to HOL d'lclesterol. cause ..... , ~ and PtI-mcnary Cll,otxJbi,~ as well as BaI8, l'liratism ..., ~ gain. D. AntIpugestin 'I"' pisb... (1lIIIo d 'Jeled FI) 486) iii a ptJgfllitin anIllgDnist MIl partial agcrist 8ClMtt [No!« ~ titepisbJe .. also a polenI ~

cnv

t:OIlitxJid (see P. 271).] Ad"illisltaliDn 01 ... 10 lemaIes eart;' .. ~ results .. mo&l alMS (85%) .. abOlliot'f:A the Ietus l1Jeto the ~eflc. with progesterone and IflI dedii.... human chorieric; gonadotropiol (hCG). The major acMne eIteas are sign;(lC8nI uterine bleeding and the possibt!ity 01 an lnoomplete abortion. ~ , admi"islflllion 01 ~ E, intravaginal)'. or ~ pIOStt;J (miss oil PROH stol] orBIy, elter a fiirge oral dose 01 mitepristone. eItodiYeIy IcmW\aUlS gesIlIlion. ~ can also be used as a OOI .. ac8IltiW. giverI 0I'IC8 a month dJmg the oridIulool phase 01 the cyde ¥otlen progISI8fOnI is r'IO<maIy Ngtl (F'llU'" 27.5).

IV, ORAL AND IMPLANTABLE CONTRACEPTIVES Drugs have been idenlif'8d thai decrease fert~iIy by a tuTtler ot differall I'llflCharisms. tor ClIQlmple, preven~ ovulation. impairinlJ gametogenesis or gamete maturation, or inlerfering with gestation. Currently. interference with ovulalion Is the most oomrnon pharmacologic: interventoo fotpre.tenliog pr8Vlilncy (Figure 27.6).

•

1 ~al,

,. to ......_

•

<_,.,,,,,,,<_'''_,,

''''

Z7. Steroid Hormones A. Major' classes of oral conlracepllves

"

"

Figure 27.6 Comparison 01 contraceptive use among U.S. women ages \51044 years.

1. Combination pills: Products containing a combination of estrogen and a progestin are the most common !)'p(l 01 oral contraceptives. The estrogen component suppresses ovulalion while the progestin prEOotents implantation in the endometrium and makes the cervical mucus impenetrable to sperm. Combinalion pills contain II constant low dose 01 estroge<> give<> over 21 days plus II concurre<>t lOW but increasing dose 01 progestin given over 3 sucoesslve 7-day ptlriods (called the "lript1asic regimen'. The pitts are taken lor 21 days followed by a 7-day withdrawal period to induce mensas. [Note: Estrogens thaI are commonly present in the c0mbination pills aIEl ell1inyl esrradiol and mesrranol.] These prepara· tions are higtlty effeclive W1 acllieving oontraception (Figure 27.7).

2. Progestin pills: Products containing a progestin only. usually ncxethindrooe or norgeslte/ (called a ·mini·pilr). are taken daily on a continuous schedule. Progastin--<)nly pills delive. a low. ron· tinuous dosage of drug. These preparations are less eHective than the combination pill (FIgure 27.7) and may produce irregu~r menstrual cycles more frequently ttlan the combination product. The progastin--onty pill has limited patient acceptance because of an~iaty over the increased possibility of pregnancy and the frequent occurrence 01 menslruallrregu~rities.

3. P.ogestln Implants: SUbdermal capsules containing levo·

---

Re\cltlve lallure rate

om 0.13 IeNlhII" 0.2

'-lii~~E~ --

_ _ (IlIO)

O1Iphr1ogm

U

U

~

Sp'~.:: ,..'u.... -~::~"~.~ , W

Flgu,e27.7 Comparison of failure fate for various methods of oontraceplion. Longer bars indicate a higher failure rate. lt1at Is.

more pregnancies.

fIOtpesrrel ollar Ioog-terrn oonlfaception. Six capsules. each the size of a match stick, are placed subcutaneously in the upper arm. The progeslin is sIowty released from the capsules providing oontracaptive protection for aJlPfOlrimately 5 .,.,ars. The implant is cheaper than oral contraceptives. nearly as reliable as steriliza· tion. and fotally reversible if the imp~nts are surgically removed. Once fhe progeslin-containing capsules are implanted. this method 01 contraception does not rely on patient compIfance. This may. in part. 8lq)lain the low failure rate lor the method 01 oontra· Ception. For oxample. Figure 27.8 shows lha.t this use of tevonorgesrrellNOAf'lANT) implants by adolescent mothers results in significantly lower mtes of new pregnancies when lXlITlpllred 10 women using oral contraceptives. Principal side effects of the implants are irregular menstrual bleeding and headadles.

4. Poslcoilal contraception: A fourth type 01 contraceptive strategy uses high-dose estrogen (for example. ertlinyl estradioIor c1ielhyf. stilbestrol) administered within 72 hours of co~us and continued twice daily for 5 days (the 'moming-after" p~l). Anernaliv<9ly. two doses of elhinyl estradiol plus norgeslrel are given wilhin 72 hours of coitus. followed by another two doses \2 hours later. A single dose of mileprislone has also been used.

B. MechanIsm 01 action The me<:hanism 01 action of these oontracaplives is no! ~ely und9fStood. It is bkely that the combination of eslrogen and progesIin adminisle<ed 0"'Ilf <JWro.imately a 3-week period inhibits wulation.

• ......0' ..'.' . . . . . . . _ , .

V.Androgens

[Nc:lle; The estrogen provides a ~ 'oocIlad< on the felease 01 LH and FSH by the pituitary gland. thus prwanting OYUIation. The progestin stimulates nomlal bleElIing at the IIfICI 01 !he menstrual cyde.] ThiOOIning 01 cefVical mucus prtlYEln\S aa:ess by 1he spemI. C. AdIIerse effects Most adverse etfecIs are

belieYed 10 be due 10 the estrogen CllltT1Xl'"

nent. but c:ardioYasoAar ettects refted 1he adion 01 boCtl esboger,

C_"""'PIIon _ IwgoIr bec

","_d.. 1n

"'_0 ........... c:lt_uo. .... ,.

.•..

an:l progestin. The inc:idelCAi 0I1ide etI8ctli with OtiII ...... 'bliG¥lI8S is relaliYely low and is delermined by the speciIjc ClDflllOUllIs an:l ......nbir181ions UMd.

"

....l!t;

.. ,

"

0nIl

S

; '

1...... advene ertecls: The major side etfecls are breast IuIIness, depression. cizziness. edemB, headed1e, na''SC8, and Wllliitiog.

z. CaIdiCwaIetJkN, The mo5I MriouI side

eH8cl 01 ail! oontracep.lives is cardiovascular disease, including thoomboembolism, lhrorTlbophlebitis. hypertenaion, and increased incidences 01 myocardial infardion and cerebral and coronary thromboSis.. These adVerse effeclS ara mosf ...... 1.,iOI'I among women who smoke and who are _ 3S years 01 age, alltloultl fhey may aftBd _ _ , 01 any age..

3.. CWdoOOll*HElt). 0r1If eortia' '44 _ ~ ~ shown 10 ducleasa fhe ir lCidui CAl 01 .ldoo Il8II iN llfId 0lI1l1'Iiln CllOC«. Their IIbIity 10 irlllJce ClIher ~ is CXIfllnMInial The pmdl!Cfion of ber'i!J"o lLmllrS 01 . . 1M.- ~ may ~ llfId hel,lOlTI\iIgII is rat&. 4. Ne~k::

Deereased dietary Clll'tlohydrata absorption by the

InI8StWle ;. 80011"""65 with an

'5~ wilh

ail! c:ontrae:epliYe ab1g

n:reased irlCiduia of abnormaf

~ ~ 1OIeranoe leslS

(sirillr fa lhe dlai 'ON seen in ~. ~plda: The ~ piI causes a change in 1he serwn lipoprotein profil4l: estrogen causes an increase in HOl and a decrease in 1Ol_ desnble ~ progestins haw the 'W'N'8 etfecl.. (Note; The poltnll""ogestiIl, nDlgestle(

5. SefUm

causes the grelIlesl ira as'll in the LDUHDl ratio. ThelefDle, esbogerr·do",iilanl pl'epllfllliOnB are best tor in6YiduaIs with elevaled serum ch:lo5t8lOf.1 Chulest:alic jalnic:e, d1oI9cysliIis and et'IuIangtiI afa also encountflnlll. 6. Contnlndketl(lns: Oral ......... aceJl4i_ are c:ontrairdc:aled in the prasE ooe 01 oerllboo;asmMr and thrDlllboo",bok lIsoose. estrogEl! rdepGi idenl neopIasma.1iY« clsease. and migmina he9dache.

V. ANDROGENS The androgens ara a group 0' SIetOids thai have anabolic an
•

a

•

Q

tr •

P' • •

F'S!u1927.a SoJpafo,ly ul Illloal.... pes6e1 in pnwenling prBgliIfIC)' in adol eI mdhels.

c..

• ,.. r

,.,

,

>

27. Stefoid Hormones secretion by Leydig cells is cor1trolled by hormooal signals Irom the hypothalamus (Gn-RH), by way of the pituitary gland secretion or FSH and LH (wtlich was originally known as interslrtial cell·s!irnJlating hofmOlle, (leSH) in males). [Note: LH stimUlates steroidogenesis in the Leydig cells. whereas FSH is necessary lor the in~iation 01 spermatoge"esis.] Testosterone or its met3bo/ite 5-a-dihydrotastostetOflf! (DHT. see later) inhibits Pfoductiorl of these specirlC trophic hormooes and thus regUlates lestosWIOOO produetlon (Figure 27.9). Synthetic modifi· cations 01 the androge" structure are designed to (1) modify solUbility and susceptibility to enZYlTliltic breal<.dOWl'1 (thus p'olor1ging the half-lile of the hormone), and (2) separate aMbo/ic and androgenic ellects.

A. Mechanism of action like the estrogens and progeslins. androgens bind to a specilic nuclear receptor in a t3rge1 cell. Although testosrerone i\seW is the active ligand in muscle and ~Vflf, in other tissues ~ must be metaboli2ed to derivatives such as DHT. For eKample, alter dilfllSing into the cells or the prostate. seminal vesicles, epididymis and skin, wstosterone is converted by 5-o.-redUCIase to DHT. which binds to the receptor. In the blain testosterone is biotranSlormed to estradiol. The hormone/receptor complex binds 10 DNA and stimulales the synthesis 01 specific RNAs and proteins. 2 {Note: Testostorone analogs that cannot be converted 10 DHT have less eIIect on the reprodudve system tha" they do OIl the skeletal mUSClJlature.] B. Therapel.ltlc uses 1. Androgenic effect..: Androgenic steroids are used in males with

inadequate androgen secretion. [Note: Hypogonadism can be due to Leydig ceH dysfunctoo or, secondarily, to failure 01 the hypolhalamic-pituit3ry un~ In each instance. androgen is indicated.]

o

2. Anabolic effects: Anabolic steroids can be used to treat senile osteoporosis and severe blJms, to speed recovery Irom surgery or from chronic debilitating diseases, and to counteract the cat3boliC eIIects 01 externally administered adrenal cortical hof· ~~.

3. Growth: Androgens are used in conjunction with other hormones to promote skeletal growth in prepubertal boys with pituitary dwarfism.

4. Endometriosis: Danazol [OA na zole]. a mild androgen. is used in Ihe treatment o! endometriosis (ectopic growth or the endometfium).

5. Unapproved use: Androgenic steroids are used to increase lean body mass, muscle strength and aggressiveness in athletes and body builders (see "Adverse E1lecls1. FIgure 27.9 Regulation 01 secretion 01 tastosterooe.

'seep. 27810< _

~IO

_ _ ... Itd _ _

v._

.."'" ....,., ........

....-

..

,,,

C. PharmacokInetlcs

1.

nacwa-

l1lis agsnl is illrifectioe 0I8Iy bee8U$111 01 lion by lirsl·pa$li metabolism. As with the other sex steroids, teslOSleR:wle is rapi:Iy absorbed by the IMIr and OCher tissues, an:l is me«abo'ized 10 relalMlly or WI, ..... Ill~ ~ CUf'plUn(l:s thai atl eICreled primarily in the urine buI liso in the Ieces. T~end its C-17.eslet'$ (tor _I""'. ISS' 8 PJII9~ OftIIte or - - . t e j _ red ~ [Note: The ii(ldi!ion 01" estC.~ lipid 1T1lIles!he ho"lOIle m:nlipilHoU1Mt. lheteby lna-eesing its cUation 01 acllon.) TMOSt&'Dfle and its eslierS deI'lOIi6t1atB ill 1:1 ~ ratio oIl1tduget*= II) aneboli:: T"'otI~:

110'.' .

....,.

. 'Will del 1.:oIf.es. Agents aJd'l1ll5 .Il.ol)mlElStQ'Or. [Iloo e:M MESS lie lOne) and danamI also ~ ill Icnger hili. . in Ihe body fieri does !he ~ oca.rN'lg adogeiL ~ Is el1ective when given orally. and it ha. a 1:2 androgenic 10 lItlllbolic ralio. 6ee8"se I is ncl read1y ~ to OHT, i is less actr.e 1h8tl /ElSfCIsterorle in !he reprocloQiW syslem aOO does ncl R1.loe puberty. It has a Iongef hBJI.ife lhen does res... I&PJI ....

2. TllIi

D. A d _

I«eel.

1. In lemal..: And,ogans can cause masculinization wilh acne, ~ of facial halr, deepening 01 !he voloe, male panem bak;Jness. and excessive iTUsele deYelopmool. Me!1s\n.I81 irragularlties may also OOC:Ut. Testoslerone shoIJld not be used by pregnant women. because of the possible ~riliultion 01 the IemaIe letus.

2. In mel..: Excess androgens can cause priapism, impolenee. decreased spermalogel ~sis, and gvneoomastia.

3. In c:tolkh,,: Andn:lgerts can cause growth disturbanoes resulting from P~lure dosing 01 the epiphyseel plales and III:lnormaI se>cueI lMluraIion..

ANDROGENS

.. aener.l ef1KU: AsdogetiS in::reBse senm LOl end ~ liIl'fUITl HOI.. ~.-.eretore fley ic IhIl LOl..ttiOl.I8lio and polentidy increase the risk for premature ooronery heart disease. AsdogGi is can aI!Io cau:se IUd 'elt. Itioi I lI!!a:lt ljj to edema. 5. In MhleIQ: use 01 anabolic steroids, (lor ~. Il8tdulol/la (nan ORO lone) or sIantizoIoIlsta NO zo 101). by athletes ean eause premIllln c....illll 01 tie ePiltIfsis 01 the long benes. whietl in18m1pls da>o~lcpmenL The h9l dose. raken by these rounll ath6eles may resul in hepatic abnormalities. i'lere&sed aggression ("rold rage"). and psychotic episodes, IS well as the OIher ~rse effects desuibed aboYe.

CONUI,o,'NlllCATED IN PR£GN,o,~CY

<,,,,,.,,,,.,,<_'''_,> 27. Steroid Hormones

272

E. AntJarldrogens Antiandrogens .:::ounter maJe hormooal action by interfering wilt1 lt1e synthesis or andfogens or by bIodting their re.:::cplors. For elQlfl1ple. at high doses. the an~fungal kerooonaJ:lOkJ (see p. 340) Inhibits several allt1e cytod1rome P-450 enzymes involved In steroid synthesis. F!f18steride[fln I'S ler eyed]. lt1e steroid-like ctug recenlJy apProved lor the freatment or benign prestatl.::: hype/trophy (BPH). inhibits 5-0,. leductase; the resulting decrease In formation of DHT by the ptoslate leads to a reduction in prostate slte. Anliandrogens, SlJd1 as cyprolerone acetate [sih PROf tar one] and fflJlSmide [FLOO ta miOO] (see p. 395). act as competitive Inhibitors 01 androgens. They inhibit lt1e action 01 the androgens at the target cell. cyptolefOOlI 8CelSte has boon used to treat hirsutism in lemale$; wherease Itulamide Is used in the treatment 01 prostatic carcinoma In males.

VI. ADRENAL CORTICOSTEROIDS

o

ll1e adrenal cortex Is dMded into three zones that synthesu:e v,lrious sle/oids!rom cholesterol and secrete them (Rgure 27.10). The outer zona glomerulosa produces mineralocorticolds (tor example. alOO5· terorJe). whK::h are responsible!or regulating salt and water metabolism. PrOduction of aldosterone Is regulsted primarily by the reninangiotensin system (see p. 180). The middle zona tascirolata synlt1esizes glucocorHcoids (!Of example. cortisol [KOA ti sol]). which are ooncerned with normal metabolism and resistance to stress. The Inner zona reticularls secretes adrenal androgens. such as dehydroepiandrosterone. Secretion by the two inner zones. and to some extent. lt1e OUler zone, is controlled by pitu~ary rorticolropin. which is released in response to the hypothalamic corticotropin·releasing hormone (CAH, see p.247). GJucocorlicoids serve as feed:lacil inh,bitors of corticotropin and corticotropin·releasing factor (CAF) secretion (Figure 27.lO). A. Mechanism 01 ae1ion

Figure 27.10 Regulation or corticosteroid

secretion.

The adrenocorticoids bind 10 spedfic intracellular cytoplasmic ICCeplOrS In target tissues. The receptor·hormone .:::omplex then translocales into the nucloos where It acts as a trenscription tactor to tum genes on or 011. depending on the tissue. This mechanism requires ~me to produce an effect. The,e ere Clher glucoconic:04d effects. sudl as their requirement for catecholamine-mediated dilafion 01 vescular and bronchial mus.:::ulature or lipolysis. whose effects are immediate. The bases lor It1cse actions are unknoWn. B. A"lions some normal actions and some selected mechanisms 01 adrenocor' ticolds are described in this section. Underslanding these ac~Ol1s aids the reader in better comprehending the ,eSlllts ot adrenal Insufli<:iency and the uses 01 adrcnocorticoids as therapeutic agents in a variety 01 disorders.

·..." ......, .. -... --,.

• . . . . . ......--

VI. Adrenal Corticosleroids

1. Glucocortlcolds a. Promole normal Intermedlllry metllbollsm: Glucocorticoids 1a\lOl" gluooneogenesis bV boIh Increasing amino acid uplake by the liver and kidney and elevating activities of gluconeogenic enlylTl8s. They stimulale protein catabolism (except in the liva) and lipolysis. thefeI:¥ p~ing the bJildng blocks and energy needed for glucose synthesis. (Note; Gluco· corticoid insuft\ciency may rasult in hypoglycemia, for exarT"4lle, du"ing stressful periods or fasting.]

b. Incr_ reslstance 10 stress: By mising plasma gluoose lev· els. glUCQC()fliooids provide lhe body vmh the energy It requires 10 corrJb.at stress caused, for example, by trauma, fright, infection. bleeding, or debilitating disease. Glucocorticoids can cause a modest rise in blood pressure, apparently bV enhancIng the vasocoostrictor actioo of adtenergic stimuli 00 small vessels. [Nole: Individuals with adrenal insufficiency may respond 10 severe stress by becoming hypotensive.] c. Alter blood cell level. In plasma: Glucocorticoids cause a decrease in eosillllphiis. basophils. nlOI"oOCYtes. and lymphocytes by redisUbJting them to ~hoid tissue from the circulalion. In conlrast, they increase the blood levels of hemoglobin, erythrocytes. platelets and polymorphonuclear leukocytes. ]Note: The decrease in circulating lymphocytes and macrophages compromises the body's ability 10 fight inlections. Hoo.vewr, this property is importaI1t in the treatment oIletJkemla (see p. 393).] d. Antl.lnflammatory action: The most imporlant therapeutic property of the gluOOCOl1icoids is their ability to dramatically reduce the inflammatory response and to st,.ppress Irrmunity. The e~act mechanism is comple~ and incompletely under· stood. Hcmever, It is known thal the lowering and inhibition 01 peripheral lymphocytes and macrophages playa role. Also involved is lt1e indirect inhibition of phospholipase A:l (due to the steroid mediated elevation of lipocortin). v.t1ich blocks the release of arachidonic acid, the precursor of the prosta· glandins and 18I.Ikotrienes, from membrane-bound ph0spholipid (see P. 403). e. Affect other componen!$ of the endocrine system: FeedbaclI iflhibition of corticolropin productioo by elevale(l glucocorticoids causes inhibition of further glucocorticoid synlt1esis as well as thyroid stimulaling hormone produclion, whereas growth hormone proc1Jction is increased. f. Effects on other systems: These are mostly associated with the adverse effects of the hormones. High doses of gluoocorticoids stimulate gastric acid and pepsin production and may exacerbale ulcers. Effects on !he central n6fVDUS system It1at influence menial status have been identified. Quonic~­ ticoid Itlerapy can cause severe bone loss. Myopathy leads patients 10 ~in of weakrless.

", K><:>IIJI .. _

.....

<"".'''''''<-'''-'> 27. Steroid Hormones

2. MlneralocOl1k:olds Mineralocortiooids help contrQl1he body's water volume and c0ncentration of electrolytes. especially Sodium and potassium. Aldo5terooe acts on kidney tubule cells, causing a reabsorption of so
C. Therape1.ltlc uses ollhe adrenal corticosteroidS SeveraJ semisynthetic derivatives of the gll)COC()I1icoi(l have beep developed that vary if) jhe;r anti-inllBJ1Yl1atopin a<mlnistration). HydfOCOfl>Sone [¥ droe KOR tl sonol, IM1icfl is identical to 1he natural oorfisol, is given to oorrect !he deli~ Failure to do so results in death. The dosage 01 hydrr:x;on;.. sane Is Iividod so that two lt1irds oIlho normal daily dose is given in the rnomirlg and one third In the altemoon, [Note: The goal 01 ttis regimen Is to apprOl
<..... ,......'.<

L>

VI. Adrenal Corticosteroids

Short-llCllng glueocortlcolds

Inlermedlal&-acllng glucocorllcolds

p_!0.3 _"_r!i5 4

--..-~5 T_~5 Long-Kling glucocorllcolds

• Deul,_ _ ..

"neu.-Io"

p"..

"

Mlneralocortlcolds

·"iI••••••••••••• •

FlgureXT.l1 Pharmacologic properties 01 some commonly used nalulal and synthetic corticosteroids: activities are all relative to hydrocortisone ..1. Time relefS to duration 01 action. synthesis 01 one or more IIdreoal steroid hormones. Treatment or this condition requires actninistration 01 sufficient corticosteroids to normalize the patient's hormone levels. Choice 01 replacemenl hormone depends on the site or !he lesion. 5. Relief of inflammatory symptoms; Glucocorticoids dramatically reduce the manilestatioos 01 illllammalions (lor exarT(lIe, rheumaloid and ostooarlhritic Inflammations, illflarrmalory conditions 01 the skin). Including the redness, swelling, hea~ and tenderness that are commonly present at the mflamrnalory site. The eflOCl 01 gIocooorticoids on the inllarml8lOf)' prooess Is the resu~ 01 their effects on the distribUtion, c:oncentralion. and function 01 leuk(>.

_12ll

<'''''.''''.''<-'''-''

",

27. Steroid Hormones cytes. These eHects include an increase in the tonCef1tmtion 01 neutropt1ils; a decrease in the concootration of lymphocytes (T and B cells), basophils, eosinophils and monocytes; and an inhibition 01 the abilrty of leukocyles and macropt1ages 10 respond to m~ogens and antigef1s. GIvoooorlicoids also influence the inflammatory response by their abili!}' to reduce the amount 01 his· lamine released from basophils and to Inhibit the activity of kinins. [Note: The abilily of glucocorticoids 10 inhibit Ihe immune response Is also a result of the other aetions described abovl:!.]

,-",""""",,Wfl1c

"r"....

IV.'"

6. Treatment 01 altefgle1i: Glucocortiooids are useful in the treatmel1l of the symptoms of drug, serum, and lransfusion allergic reactions, bronchial asthma, and allergic minilis. These drugs are 001, however, curatioe. [Note: BccIcmothasone dipropioIJate [be kloe METH a sone], triamdn0i0n6 [Iri am SIN 0 lone] and otl1ers are applied lop4cally 10 the respiratory Iract through inhalalion lrom a melered dose dispenser (see p. 219). This minimlzes systemic et1eas and allows the palient 10 significantly reduce Of eliminale the use 01 oral steroids.] D. Pt'rarmacokinetlCll

1. Absorption and metabolism: Naturally occurring &drenal oortioosteroids and their derivatives are readily absorbed from the gas· trointes~na1 lract. Selected con rpounds can also be administered intravenously, intramuscularly, topically, Of as an aerosol (Figure 27.12). Grealer than 90% of the absorbed gJucocorticoKis are bound to plasma proteins: most 10 corticosteroid-binding globulin. and the remainder to albumin. Corticosteroids are metabolized by !he liver rTicrosomal oxidizing enzymes. The metabolites are c0njugated to glucuronic acid or sulfate. and the products are e~creted by the kidney. [Note: The hall-life of adrenal steroids may increase dramatically in lndividuafs with hepatic ctysIunctlon.]

2. Dosage: In determining the dosage of adrenocortical steroids. many lactors need 10 be laken into consideration. including glucocorticoid oersus mineralocorticoid ectivity, duration 01 action, type 01 preparation, and lhe time of day thel a steroid is adrninisterecl. For exa~. w!1ef1 large doses 01 the hormone are required over an extended period of time (mora then 2 weeks), suppression 01 the hypotheJamic-p~ullary·adrenal (HPA) axis occurs. To prevent this adverse effect, a regimen of allema!e-day administration 01 the adtenocortlcal steroid may be useful. ThIs schedule allows !he HPA axis to re<:ovarlfunction on the days the hormone is not figure 27.12 Routes 01 administration and elimination of c:orticosleriods.

_.

E. Adverse affects The common side effects 01 long-term C(lrticosteroid therapy are summarized in F'ogure 27.13. [Note: Increased appetite is not nacessanly an ~rse effect. since II is one 01 the reasons lor the use 01 prodnisone in cancer chemotherapy.] The dassic CusNng·like syndrome-redistribution 01 body fat, puffy laoo. increased body hair growth. acne. insomnia and increased appente-are observed when e~cess conicosteroids are present. Increased Irequency of

..........,." ..... --..,.

......

--~-,

catarects also occurs wilh long-term cOrlicosterold Iherapy. Wlthdls"" from !hi drugs CSl be a serious protJeo ,~ beceu9a illhe patient has expetiellced hypoChalal'nic-pituitary adlella) suppes..... llbr\4:lt removal d lie (Xflit;r,'d5 oldt CS' an 8CUUlld'I!lllll imutliciency S\J1 OQl,lfj h i can be Ieth!ll. Tlis Iaet, "'" lpIed wiIh IhI! possibility d ~al dependence on !he eng ...cI h lacI I1a1 wid dswel rnistIt cause an ~ d !he clse8911. means thet!he indi\IiO.laIllChecUe lor widdawallTWly be based on Irial and encr. The patienllTl.lst be carefully mOllitQled.

""""",,

..

_.

"" 2T7

..,."".

~'G'·

,.

COLC .....

F. Inhlbltors oilldrenocorllcokl biollyntltesls Several substances have proven to be useful as inhibitors of the synthesis of adrenal ste.oids: metyrapone lme TEEA a pone]. ao,.lOgItJtcll'l.mid& Ie mea nee g1u TETH Imide]. IreIOC01azO/e [kee IOe I(()N a role!, and spirrJnoIacIont Mifepistone co,.... tes wiItl

gil. I CQtiouids lor the .eoepIOr.

1. ~. U5ed lor !he treatmenl d Cust*Ig's ~dtw'" and ClWI be used lor tests d adle". f\.rIeticft. INofe: C\elIa....- fl6S(liJlll supp.ession is now used mor, commonly 10' diagnosis.) Mefyrapone inlerteles wilt> corIicostemid synthesis bot tlIodQng Ihe fWl8I step (11~1ion1 in gil- n.OfIic:rJid syild .... IeaOing 10 ao increase in l l ~ as well as adtenel arw;Wgens and lite potenl rm.eraloc:oflicold. ll-ryc:ortic:osterone. The &dYefs8 etlec:ts encountered witlt melyrnpotle include san and water releollon, hirsutism, transient dizziness. and gastrointestinal diSlurbences.

I

2. Am~Ivt.etlt1lnlct. acts by WlibiIing Ihe COl'1\o'eI'-sio of choteSWiol to pregnenolone. As a resoll. tile synlhesis of al hormoneJty active steroids is reduced. A1rinof1Mc/hiltlide ltas been used d&'4'" .....,., in Ihe Inla....". d bmasl. cancer 10 reo..oce Of eIifn.lli d"ogel, ...cI pmdo non.. In fJese if: is used in ~ wiIIt ~ Ai'.-rg6 ta•• ,aida may abo be useful in . . lrMlmenI d maligi&lCies d!he adle.iillI eorIeJl: 10 reduce Ihe &eCleUon d SWiuids.

nne

8$Il"""'"

cases

3. ~ (an antif\rlgaI agent. tee Po 3401 strtw'lJ'l imibils all gonadal and adrenal Sle
4. Mlleprlst_ is a potent glI.lcocortiool antagonist as well as an ar,lipIogestit, (see p. 267). lilorms a ""'''pelt with Ihe gIuoooorIiccid receptor, but tlte IlIpid dissociation of tIte drug lrom Ihe receptor leads 10 a Iat.fty translocation into lite n del is lis poten. tiel use in Ihe wealrl1eriof QJstWlg's &yIdooone is being e...... ed. So ~ ""'"c:Jetes lor !he lIille.1IIooortiooid 'llOePb and flus illtils liIOdum reabsaplioi, in h kidney (see Po 232).11 can also antagonize aldosterone and testosterone syntltesis. II is elIecfM:! against Ityperaldostefo The drug is abo useful in lite Inlawnent of Nrsutism in women. r.wotlabtY we 10 inI8fleoe.iOO a11he a.d....,...' teceplOi d Ihe ItairJolide.

Agu.. 27.13

Some OOl'.'1Oi1y ob6et'ved effec:Is of long-term corticosteroid llterapy.

<,,,,,.,,,,.,,<_'''_,,

",

27. Steroid Hormones

A. leslores bone loss ~ osteoporosis. B. mAy inl:lUce "hot tlashes". C. may cause atrophic vaginIIis, O. is rro::>sI effective II Insli1u1ed at the tirst signs

Choose the ONE best answer.

27.t All 01 the foIKlwing statemenlS aboul g11.1COCO<1ic<:1i lire c:o«ect EXCEPT: A, They may produce

P"ll'ic uk:e<s.

oj

-~

B. They ale useful in the treatment 01 rehactory

E. 'equires higher doses 01 es"ogen than a'e required with oral cootraceplive therapy.

M_.

_.

C. They are contraindica1ed In glallC0m8. Coml<:t III19l¥ef' • D. Eslrogens decrease but do not restore rhe aijll·reteted Ion oj bone. VIlSiOOllllOr S\',,,plOons 01 ll"1llI'lOP"use, sudt as hot tlashes. ere decreased with estrogen replaoom(rtt .....lIP'i. ~ ol~, suc/'l as a!rQpl>lc wginllis. am daaeesed wlltt estrege
D. They am used in lhe treatment DI Addison's dis-

E. They e.e
00.

27.2 Whictl one oj the folklwing statements is true? A- Die1hylslbeslrol eohances lertili1y by blocI
27.5 P,ogestins A. are not produced In males. S. increase HOI. IU1d decrease LOL C. attenuate the Increased rW< DI endometrial callCllf associated with eSlrogen-only oral cootracep~""

inlibilory elled oj el;trogen 00 the p~uitary. B. Tamo.iIen is an eslrogen antagonist. C. Del
-

--

O. Estrogeos am mainly e><ereted ullChanged in the

D. sucnllS progesterone am widely used in olal traceplives. E. COImlOOIy Ino:luce weigl~ loss.

urine,

E. T""",.iIen is used 10 treat inIet1itity. Oofrecl answer .. B. ~ III II synthetic eelrogen that acts directly 00 ta'981 tis·

The 00trIIQ .......... C. P
sues. ESlrooens "9 se<:<81ed as wHated 0< gUculOOidaled melabolllea. TamwtiI..... Is used in the trealTUll 01 adI.olnced

con-

br_ """""'.

a:lr1.1 ed.p:cg SI <>lIIislafgely~ by hepatic fi~1lIlSS ~ W9qIl gein Is ......
27.3 AU of the following lire adverse ellacts associated with the use '" oral oontra<:efl~V'IIagents EXCEPT: A. Edema.

27.6 Whictl one oj Ihe 10000"';ng is a synthetic estrogen used .., oral <:OrItrace¢ves?

B. Breast _mess. C. NaUS'!a. D. locrease
A. Mestranol S. NorgeSlrel. C.~.

]

O. Es1rlldiol. E, NO
'see p.2t3in_1ry (2.-.:led.llora6sn ...... CII pIestne Iijx>p.........

rretaboISn _

/IflmIrWsIoold orally.

'sea Po 383 In _""~1tI t (2.-.:l ed.) lor a C111tle

a.... Ipiuo.CIIoo.*ery<>1icgenao.

6sn""'"

< "'"

. . , """"'" .. _ . It' >

, __ •

, . . . . . . , >< ...... _ _ L >

UNIT VI:

Chemotherapeutic Drugs

Principles of Antimicrobial Therapy

_"'_ ---+ -_.. -

... ......... --poo. . ,*,. ---"'.,• , ."•. EmP
~

I. OVERVIEW

nogoIi.oo ..... _ _•

Antimicrobial drugs are effective in the treatment of infections because of their selective tOl
.........

A"","_

- """""-

_-.

II. SELECTION OF ANTIMICROBIAL AGENTS

~

selection 01 the most appropriate antimicrobial agoot requires knowI· edge 01 (A) lt1e organism's identity and its sensitivity to a particular agent. (6) the site 01 the irlfectlon, (e) the safety of the agerll. (0) palient factors and (E) the cost of therapy. However. some critically ill patierlts require empiric therapy. that is. immediate administration of drug(s) coverirlg irlfectlons by both gram-positive and gram'negative microorganisms (Figure 28.1).

_.-

A. Empiric therapy prior 10 organism ldenllflcatlon

Ideally. the antimicrobial agent used to treat an intection is selected after the organism has been idant:ified and its aug sensilMty established. However. in the crilicaJly II patient. such II delay cook! prove Iatal and imme
~-­

I''''.... gr.... -.•_go.";

Figure 28.1 ll1erapeutic strategy in tleating patients \\lith IIrl infliction of Url!mown origin.

~_,_'"

''''A.,_

.

~

.

c

.---.--_.... ...--

. . . . . J. _ _ ...

279.

. . . . . .0 . . .' . '

•• _

... _ , .

200

28. Principles of Antimicrobial Therapy

infection),

Of a patient with severe headache. e rigid neck, and sensitivity to bright ligt1ts (symptoms charaeter;slic 01 meningitis) require immediate treatment Therapy is joliated aftef specimens !Of laboratory analysis hll\le been obtained but before !he results altha culture are available.

:z. seleCting a drug: The choice of dnJg in the absence of sens~Mty data is influenced by site of Infection and patient history, lor example, whether the infection was hospital- 01 community-acquired. whether the palient is Immunocompromlsed, as well as the patient's travel record and age. Empiric therapy with a combinalion 01 antibiotics or a single drug covering Infections by both gram-positlve and gram-negauYlI microolganisms may be staned initially. Flgllre 28,1 summarizes a typicallherapeuhc strategy lor a patient witt1 a suspected bacterial inlection 01 unknown origin.

B. IdenUflcatlon and sensltivltv 01 the organism Characterization 01 the organism is central to the selection 01 the

proper drug. A rapid assessment 01 the nature cA the organism carl sometimes be made on the basiS 01 difte,enVai stains. soch as the Gram SlaIn, b.rt it Is gencmlly necessary to culture the inlectiYe 0rganism in order to arrive at a conclusiVe dia!Jl'lll5is and to determJle the sensitivity 01 the bacteria to antimicrobial agents. Thus, It Is essential to obIain a sample alllure 0/ the organism prior to initialing treatment ~ possible. Newer methods thaI use moIeCtJlar biological tedYliques 10 identify rnicf'lXll'98l1isrn are making a pulX: health irnpacl in identification r:J the souroe 01 an outbreak 01 inledious diseases. C. Laboralory methods olldenllllc"tIon

~ft-"

·~t

"-~' ~.Y'I'1o anU....._ _ nt

figure 28.2 Disk diffusion method tor delellTlining the sensitivity 01 bacteria to anli· micfobial agents.

The most com:nonly used method 10 test susceptibility to antibiotics has been disk diffusion. in which disks containing antibiotics ara placed on cukure dishes inoculated with the microorganism to be lested, and !he organism's growth (resistance to !he drug), or lack 01 growth (sensilivlty to tha drug) is then monitored (Figure 28.2). Although this method Is still employed in some clinical laboratories, il is being replaced by minialurized automata:ample, fermentation 0/ gluoose). Other _lis may hold various ooncentra~ons 0/ clinically useful antibiotics. Results are obtained and printed aUlomatically, identifying the organism and the minimal inhibitory coo ICelltm~on altha antibiotics to wt"dl it is susooptible. 0, The ellect 01 the site ollnlec;tlon on therapy

Adequale I_Is 01 an an~biotic must reach the site 0/ inlectioo in order lor the invading microorganism to be effectively eradicated. Natural balTiers such as those described below may cause inadequate penetra~on of Itle drug into oertain tissues sudl as the brain, pros late, and bone, although inllammation can influence Ihe rasponse 10 drug therapy irlthese tissues.

< ""'

r...... 1'<

..... _

I >

< "".......- - - , """""" ... _

.....

281

II. Selection 01 An~microbial Agents

1. BlQod-braln barrier: Treatment 01 central nervoos system infections, sod1 as meningitis, depends 0f1 the ability 01 a drug to penetrate ilto the ~ fluid (CSF). The bIood-brai1 barrier (see p. 8) ordir.arily exdudes many antibiolics. However. Inf\armlalion lacililates penetration and a/Iows sufticienl ~ of many (but not aJ~ antibiotics 10 enter the CSF. [Note: For ClNll 01 rneflirVtiS. ~ is

D_Nn

important that a bactericidal rather than a bacteriostatic elfecl is achieved in the CSF. Yet, this is not without its problems, since rapid bacteriolysis in the infeded CSF wiIIlibemte high coocentralions 01 bQl;teriaJ cell walls and lipopolysaccharide that can exacerbate the Inflammation. This has led to the use of adjunctive (simultaneous administration of) corticosteroids. which diminish the inflammatory process and neurologic sequelae.)

2. Proslate: Bacterial prostatitis Is diffIcult to cure, probably beca1Jse 01 the failure of many antibiotics to cross the prostatic epithelium. and, therefore, not entering the prostatic fluid and tissue. Furthermore. the pH 01 prostatic fluid is relatively acidic (pH 6.4) compared to the plasma (pH 7.4). Trimelhoprim, a basic antimicrobic with a pi(.. of 7.3 is effective in bacterial prostatitis. About 50% non-ionized in the plasma, and witt1 good lipid sohbility, the drug diffuses Into the prostate and COfICef1trates due to Ion trap. ping in the relatiVely more acidic prostatic fluid (Figure 28.3). In contrast, acidic antibiotics tend to be predominantly ionj~ed at plasma pH in the ptasma and do not cross into the prostatic fluid. For eKampie. oonsider peniciHin G, whidl is poorly lipid solUble and has a pK. 01 2.7. The calculated ratio 01 charged to uncharged drug in the plasma is abool 100,000. SO it is not Sl,l"prising that ~ is ineffective in the treatment of prostatitis even in suscepti~e organisms (see Ion trapping, p.24).

E. Status of the pall&nl In

selecting an antibiotic, atIenlion mJst be paid to the COIldiliol , rcA the

patient For~. the status 01 the patienrs irrmune system. kidneys. and liver must be considefed. In ....::men, Pffl9nancy or breastfeeding an ntant also affect the selection rcA the antrnicmbiaJ agent. 1. Immune system: E1imil'l8lion of Infecting organIsms from the body depends on an intact immune system. Antibacterial drugs decrease the miclOOial population (bacteri<Xlal), or inhibit fur1ller bacterial growth (bacteriostatic, p. 283), but the host deIerlse systern must ultimately eliminate the invading organisms. Alc0hoIism. diabetes, 1nIecIion with the hlXTlan inYrlunodeflcieocy virus (HIV). malnulrttion. or advanced age can affect a patienfs inYnunocompatency, as can therapy with imn'luflOSl.tl'Pn!ssive dfugs. Higher than usual doses of bactericidal agents or longer treatment are required to elirnil'l8te the ;nfeCtJVe organisms in these indiViduals.

2. Ran.l dysfunction: Poor kidney flXlClion (10% or less of normal) causes accumulation 01 antibiolics that are ordinarily e1imif\ated by this route. This may lead to serious adverse effects untess controlled by adjusting the dose or the dosage schedule of the antibiotic. Ahhough senm creatinine \eVets are sometimes used as an index 01 renallunction for adjustment of drug regimens, direct mon~oring 01 serum levels of some antibiolics is preferred

-

.......

Trim-ll t

.......

K"Jp"""""

figure 28.3 A Diffusion of noo-ionized foon of a penicillin through prostatic membrane: B. Diffusion of noo-ionired form 01 IrimetfqJrim through prostatic

m.m'"',,.

<-'.'''''''<-'''-'> .,,,

26. Principles of Antimicfobial Therapy to identify maximum and minimum values. Rising minimum values alert the ptrysician to polenlial tOlCicity. [Nole: The number of func-

tioning nepllrons decreases with age. TIllIS elderly patients are particularly lI\Jilerable to 8CClrnulation of drugs eliminated by the kidneys. Antibiotics that undergo extensive metabolism or are excreted via the biliary routa afe faloOred in such patients.)

,...,... _

_COOl'", .....

m_.

T~IU AWnln/c:la.oole

contraindicated in treeling palients with liver disease. 4. Poor Perfusion: Decreased circulatio!1lo an anatomic area, as In the lower limbs of the diabetic, reduces the amount of lll1tibiotic

I $6

oubuliql.,.,

3. Hepatic dysluncllon: Antibiotics that are concenlraled or eliminated by the liver (for example, erythromycin, tetracycline) are

lhal reaChes lhe extremities and makes Inleclioos nol0ri0usly ditticu" to treat.

$11

Ammtk:/Ilin. $11

5. Pregnanc:y: AU antibioHcs cross the pl&c:enta. Adverse effects to

~" Figure 28.4

Cost of some drugs'or treatment of peptic ulcers caused by He!icobaCler

lhe !etus are rara, except for toolh dysplasia and Inhibition of bone growth encountered wilh the lelracydines, However, some lll1thelmintics (lre embryotoKic and leratogenic (p. 359). Aminoglycosides should be a~ed in p<egnancy because a! their 010toxic etrecl in the felus.

",;,; 6, lactation: Drugs administered to a lac1ating mother may enler the nursing Inf8l1t via the breast milk. Even though the concenlra!ion of an antibiotic in breast milk is usually low, the 100ai dose to the infant may be e<JOUgt1 to cause problems.

,-

7. Age: Renal or hepl.ltic elimination processes are often poorly developed in newborns, malting neonates particularly VUlnerable to the toxic elleets of chlorampfJenicxJI (see p. 320) and sulfenamides (see p. 289). Young children should not be treated with letracydines (see p. 311) wt1ich alleet bone growth. or t1uoroquinolooes (see p. 323), which Interlere with cartilage growth. F. Safety of the agent _1ostaI1c _ ,

=~~)

""'.0 "

8a<:l .._ _,

_jOUCh ••

"'L_._~C··_-'-"'~""~Cl,­

....

n~

Addition

Many of the 8I1tibiotics, such as the penicillins, are among the least toxic of all drugs because they interfere w~h a site unique 10 Ihe growth of microorganisms. Other 8f1limicrobial agents (for eXIl/TIflIe, chkxatnphenirol) 81e less specific and life reserved /of life·threaten· Ing infections because of Ihe drug's potential for serious toxicily. [Note: Safety is related not only to the inherent nature of the drug but also 10 patient factors that can predispose to toxicity (see Section E).]

G. Cost of thenlpy

Figure 28.5 Effects of bactericidal and bacteriostatic drugs on the growth 01 bacteria in..Wr.o.

Ollen, several drugs may show similar eflK:acy in treating an infection, but vary widely in cost. Figure 28.4 illustrates the cost of some antibacterial agents showing similar efficacy in eradicating the gramnegative baciQus ~ m1cfi from the gastric mucosa. None of these agents shows a clear therapeutic superiorily and thus a combination of metronida-:o/e with bismuth wbsalicylalft plus one othef antibiotic is usually employed. Selecting cJarilhromycin would have a considerable cost impact.

._ .. . '

--_.. _.. _....

...........

'.,~.""'_""'~

,

~

283

III. BACTERIOSTATIC VERSUS BACTERICIDAL DRUGS AllIioloioobial drugs IIAI dBsSiIied as eilher blde" static or becleril::JdaL Baderio5lalic c:kugs llITeSl the growth and replication of bIIderia at IN!fUn _ _

... --..

.ene. L'

~.,

............

.. _

pll........ '''' ~ ",:~".~.::_~",:::HK!

UI

y",

lion wtliIe Ihe body's i'nnule $y$lem llbBcks, il",,,. _. and elmnBIeB !he patlltJgl!i I$,. If .... O'ug Is fIImCIIo'ed before !he il'IYnl.ne s)'StIem has ~ !he orgaR&ms. enough ...-.e ~ mII'f I'flfnUl to begirlll secorId cyde d ildectiolL For exMlflle, FlgU"e 28.5 el'Iows II Iabonllory expe!Ynent ~ wtjch the growth d bllcterill is am!Sted by !he IIdl;fIion of a bBcterioslatic eoent. Hole thaI viable remain. ~ In the poesellce of Ihe bltcterioslatic drug. By oonlrtlsI, acIcIi\O:ln d a bectericidaJ llQl!l1! kills bBcteria and the tollll number of viable organ1&fI'lS decreases. Though practiCal, this classification may be too simplistic because it Is possible lor ao antibiotic to be bacterlostBtic 'or one Ofganlsm and ddallor anoltle •. (lor ~~, dllotampllenicclls slatic l\QIlillst grBnl negalive rods and cldaI against PneumocoooI).

orvanams

r.II.......-

a:.&I apednIm • •,

rv.

CHEMOTHERAPEUTIC SPECTRA

bider.

The chemotherepeutic spectrum of a particular drug refers 10 the speOea d OIoa"i$fIIs aI!eded t,llhal Oug. In . . book. that are COI'.'U~ ~ as • .,. t"u; agents IIAI Pi '",ad in pie dw1I in wt'Iictl elId'l segment lepI e5! Its II gel .... aI dIIss of .,oioCOl~ isrrs.1or ~ ~ coed (F''liJUfi! 28.6A).1n eKtl5eCticn of lhe 8t oovemg a partiaJar antibIolic, Ihe microblllI de e5 \hal are getleIdy treeted ~ that agenllIAI 11!J1igl1ed (Figu"e 28.68). INCIte: IIeClion of the pie d1IlI1 II libeled "Other' and rep'esenta lII'r'/ of &eYer.aI micloorgmWI is specificaIy ~ in cWIe1enl dl8pIer$.J U

one

A. NalTOW spectrum Cllemolhenspeutic agents IlCIlng only on a singla or a ~m~ed group

of t10i0OOlganisms lUll said 10 NMla narrow spec:tn.rn. Fer eKBlTllle. GonIazidis adive only egairlsI Mycob&cteria (FIgure 28.6B).

8. Extended speclNm

Exlencled spedn.m is Ihe term "A"i"'11o .,th41o:11hII1 are elleco IlYa against ~ 010..... ,16 and aI50 agairlsl a ......... no..wnbeI' of ~ becteria.. Fer f!lCaI1llIe. ., , is alnlIldered to have an 8li:tended spectrum because it acta against ~ and _ _ gam.nega\ille baderift. C. 810M! spKlNm

On.lga su;h 8$ ImIC)diIle and ~ IIfIed a wiclII1IIIriefy of microbial speciell and are .elerTed 10 8$ braid speclnm .LtibioIics (FIgura 28.6C). ~tion cJ broBd spec:lnm anIibiotic& can aasIicaIly alter the nature of the 1O'rne? bacterial flora wid can Pi.......l>Ile e IK4lE!rinfectioo of an organism, SlIdl 8$ candida whose lIfO\"M is nOffnl\lly kepi: in c:hed< by the presence of oIher mIctoorganismll.

,c.

t'

,'*''''

,,.

• . . . . .0 . . .' . , • • _

...

_'>

• C'" • .....-_ _... ....,..". _ _ . '" > 26. PI'lnciples of Anlimlcl"obiall'tlefaw

V. COMBINATIONS OF ANTIMICROBIAL DRUGS It is Ihefapeulicaly adYisabIe 10 !real wiIh the single agenllhal Is mosl specific 101' !he inlecting otgiII"ism. This strategy recU:es Ihe possibility of~. <:Iecrea5e$ the e;'leIgeilDll of resistMt Otgarisms ( _ section III), and minitrizes Ioxicily.. ~, silualioN in ....tlidl CO'lIbi~ of drugs In! et'I'IpIoyed do elCi5l. 101' ~, Ihe Ireatment: of ~ beolefib !I'Om dnJg mmbinaIions (p. 331).

It. AMntagu 01 drug

fJ .......

__....-,,,,*,

_.'

n.. _

... ' 7'1_,,; "'«)1

elR • •

'!

H 9 . _ ...... _ 8 ... _, 'I I _ _" IN.

com~lion.

Cenain c:ontlinaIicns of . . . . . . .,$1 Jdlas ~ end . , . o,h,."..;.:tee shcw syregiso,~ I1aIIa, :he 000'**",11011 Is ITlOI'Il ~ Ihlln eiItIer oIlhe augs used ~ AecwIH such !¥... gi:sll' &TlllI'lg • • ,lIcootlial ageru is 1Bfe.1he11lhou1d c:rif be U$ed in spedel riIuaIionI S\.MTnIlIrized in FigLnl28.7)

A fUl'Ibet CIt andliotics act only ....tlen organisms life ~ Ttus, OOOlOOOllitBnl a:Ii I. istJalial of a seoond agenl tI\Ill resulls in bBderioSUISilI may Retlete wiIh the adion olltle firSI dn.Ig IhBl is bllcteriddal.

0'---__

VI. DRUG RESISTANCE

"'.,.. ..............,......,.. --. .......... _.b,,,,,"'1M

Bacteria are said to be .esistant It their growth Is nolhalted by ltle mwd· mal level 01 an Mtibiolic !hal is tolerated by lhe host Some organisms

wr-_ ............ ,, _ _

.....

"~I

a_...... _

are InhElrenlly resistant 10 an antibiotic. For example, gram'negative

0fVB0isms lUe resistant to ~ However, microbial species r'IOr. mall)' responsive to a particular druo may develop resistant strains. Many organisms have adapled. through sporuaneotls mutalion or acq.oi,ed resistance and seledioo, and de'oeloped lTlOI'e virulenl Slnoins rlWl)I of \'d1ich are resiSllwlI 10 rrUtipI8 lWIIibIoPica The emergmce of fleae re ;[slant SIlains hllli been ascribed 10 Ihe impruclEwu and inappropriale U5Il of in ooodtiollls flat trighl .eIOIYII wilhouP: treatmens 01' 'IlNdl are not l!lI"I'll!fIlllo .Itibiolic ~ Ior~. Ihe comroon c:oId. Health prolessionals are obligll.led to ""€I anlibiolic agern d1 ~ restraint.

.,litJiutics

_

...

l-

t' ,,, ...... ' 9'1'0< pi ...... R• • ;N) ... UI....

....

'

"

Flgun 28.7 Scme c:trbI siIualions in ~ amt:inalioI'lI ollll'llliiaobial drugs lUll irldicB91l(\..

PI . Wee de. I 9S clJe 10 the 8bMy 01 DNA 10: 1) IIfldelgo spanIar'leouS fftJlation. 01' 2) fOOlI5I In:nl ore organism 10 .l(l$hel. r. Ihe fir!il Instanc:e. ctvomosanaI alteration may 00ClIf ~ inserb. delelioo 01' ab5liMion 01 one 01' lTlOI'e I'M !(1eotic:Ies within the genome'. 1. Sporo.-. fTUallonr of DNA: Tl1EJ ~ m..rtalion may persist. be almlCIed, 01' blllethallO the oeI.. Howeuer. if the cellU"~. is may replicate and lransmit propMies 10 daughler eels. thus PfOl1Ong resistarM strains that may proIitenlte under certain

'SolI ~. 268 "" lnfcllnI< _ _ '" _

- . It> 1flI.1O<\oII.

..........

,

...... 'Or . ., . , . . . . . . . _ , .

VI. D
selecti...e

presstlfU

AA

ex&flllIe is the emergence

-_.,--_.....

285

01 riIampin-

Mvn1Y'CY'bD .."....,..... '
2. DNA b.lStet or dNg rniat8nc:« Of partialIar dri:llIIl UA ......T1 is resistance acq..Wed IlJe to DNA transfer from CIl'le aganism to 8llOlhel. A . I It8 popeofu are 1'5'71)' . . iWdeClln en...li... mosomaI R lao::to<s (pIumid$). These may enlet eels by pro, e sses 5UCl't 8$ batlSCb::tiorl ~1edI. baIlSlomIIlIion or, rr'IQI5t inlJortanlIy. bIIclerilll ~

Drug rasistance may be mediated by a variety 01 med\arlisms. sudl Of an a/le!1ltion In a target site. Iowe<ed penelnlbility 01 the (lrug due to
as IacII of

1. ModIIIcation of target til. .: AIIefBlion 01 the target slle Ihmugh muteIlon can cooter ~ as oocors with lie ~ ~ log proteins in melhicilH......esistefll So. aurtol, or 1tIe ef\Z)Ime (lihyclrololate reclllCtIM. ~ is tess sensitNe 10 irVlibition in orv-'isms r~ s' '8"" 10 U.1llfht:p1i1L

......'.

.. '.' ..... .-.... . - .,.. -

Tabla 28.1 IIECKAHISIIS OF RE&>I$TAHCE TO AN1BI011CS

on.p. . •t

•

•

Idlli;

£."•,

CMli:

ca,... "'r

.

~..,~

••

l Pwit s '''f

'1

;. .

.I

• IClt, "

t

r'

,, , • i~"

•

I{r~' 11

"

,

~

biz. . . . .

,, •

...

:::!!;

$

•

~-\\ • ................ .. ......... ,-1=,,:. .............. _ ......... ,.• ..... -. --...-. ........._--IqaIy_. ---_"' .... •

,. , • •, , • lilt

~n

,

•

'~Ihc*V=l

, t 'j •

,

M

,

~,

.,'.·i•

p;noct•• r

, 1~"1qaIy , , .'" ,'., It ' ...'., , , ~. , ,, '_"'Ihc'old " -",,' • p;nodla._ ......... • , '0,;...-_ _bcepl' t

.~

,.•

,

1.

"00'

,

_Oh

~

1"

t

-.-

,~

"'p ...,'

_"'__,"cc._

'" ...0' -

,

• . . . . .0 . . . . . ' • • _

~

.e-o.

... _ , ·

...

.....

28. Principles 01 AI'ltimicrobial Therapy

o

2. OKre.sed Kcumula!ioo: Decreased penelr8bi~ty 01 an i1get11 can protect organisms againsIlIlat lIfItitliotic bec8use ~ is unable 10 gIlil'l ecces s 10 the site of action due 10 Ihe fjfeSeflCe 0/ either a Iipopolysaec;:hide layer (grar'I'l-fIllgIiYe bllcteria) or 01 an etIIux syslem IIlat ~ oul the ctug (l&IrB&)di;es. potnaqui'Iej.

.In

PlI ......,"' ......

--_, . . "._, ,.,..... ... - ._. _U ,

. . . . . - . II'iIolory ~

-. ....

"--_

3. ElU'ymlc: Inactiv8l.ion: The ability 10 destroy or inactivale the anlimlc:robial agent also can tonier resistance on rniaoofgani$ms. For example. IH8C1amases destn:Jy many peniciIins and oephaIosporWls and an acelyltranslel"ase CWl CQI'lY8f1 dIkJnIrrt. phfIRcd 10 an rectiYe
20

EI

" --. ..., _,._ .'1 doA _

- . ... , . _

--

"'-lon"'~,

c-'ot-"'1110

"

wIl~

C
Im..,l

Cer1ain ancat situations (F9.Ire 28.8) requWe .... use 01 antibiotics lor lhll p'8'111~ion raIlW" It\an the IreIlIment 0/ 'Ndions. Since the indisaiminale use 0/ llfIIimicmbiaI agents can result In bacterial resistanoe lWld supefinleetUl. propt¥actic use is reslJic:ted 10 ctricllI situations in wtidl benefits outweigh the potenlial risk$. The OOJll,tion 01 prcphy\axis is dictated by !he DJration o/tha risk 01 inIection.

1

g--. . In

VII. PROPHYLACTIC ANTIBIOTICS

,..

~.

VIII. COMPUCATIONS OF ANTIBIOTIC THERAPY

p.tloont..

••

t _............ c.IIin

-..-,.-....c_ • _ """9I'Y• ....,

..- -

'II

••• _ _

~

~

",. ..,gI.-.

$eleeljve toxj(;II~ to lhe Invading organism does not Insure the I'1ost ageirlSl BCM!rSB etIecls, sInl:e !he ~ may pmduoB an allergic response or be toxic In I'o8YS ooreIated to !he ~·s anti",liuobiaJ activity.

_......

I-lypersenPMry reactions 10 anti" liuobial drugs or Iheir metabolic produet$ lre
-_..t,

........ _

rw"""In"_""..

-

-...

1 . ". . . .

Higtl serun levels 0/ c.ertaiI'l._jt+tIio S may cause toIOdry ~ aIlea· ing oe"" poe ses" tha host direetty. For exMlliB. .,oiIl1Jg1)<::osil;les can C&.lSe ............... ~ ~ in\efter'*llI MIh meoTtll.oe tunction .. tha hair oeIIs o/tha orgwl 0/ CarlL C. Supef1nfeetlon.

Drug hnpy. J&1icuIarty wiIh broad spedrum 8r'IIirnicrobia or c0mbinations 0/ agenIS, can lead to aher:alions of !he normal microbial

AlI Ute28.8

Some ~ M1J31ions ....tlere proptryIactie antiliolics are indicated.

tIorll o/tha!,.Wef respiratory. inIestinaI and geni40uriflllfY lr1IdS, per. mItting tha 0IIeI'gf0WIh 01 opporIlristic 0fVlrisms. especially fungi or resislant b&cteria. These inlediol ~ are often ditllcuM to treal.

..... to' ..

1., ........ _ , .

(

<0<» . . . . ._ - . -••• _

. . . . ._

,.,

.... )

IX. C1a$$ificalion 01 Antimicrobial Agents

IX. CLASSIFICATION OF ANTIMICROBIAL AGENTS AJltillliotbiai dru;s can be dassified in a t'I.llTtler 01 v.eya, lor~. according 10 their chemical stnJClUte (~Iactam •• arnlnogIyc:osids). mechanism 01 action (eel waf syoAtesis W\IliIor$). Of acliYiIy agPlsl pBf'M;::ular type5 01 organisms (bederia, Iungl. viruses). The IoIowi'lg d\acJlers wiI be 0J0llI'ized by 1he mechanismI of lICtion 01 the aug (FigIn 28.9) Of IMXOidii '1110 Ihe tKJe 01 ~ aI1ected bot fle !tug.

Inhibitor. 01 Inhibitor. 01 cell wrll .yntherJr (Chrpte,3O

Inhibitors 01 metrbollrm (Chrpte,29)

I!-'

1\,.,

nucleic rcld

proleln .ynthe.l.

function or .yothe.lr (Ch.ptet 32)

.-

(Ch.pte,31)

,..;

........ . ,

'w

r'

ViM .. ";",,,

SuflILl . , P ph

Inhibitors 01

-'

ca_'I)Qi. CNDo.'ijW.

I P , _

fllljo

I ....

I

.....

f""IlI unl28•9 0assiIicaIi0n 01 some 8iSilllioobial ~ by their sites 01 action.

Study QuesUons ea-:t _ _ not Po

_e..

• E. Co"'b"•••• 01. _ 7

7

..... 1 _'_01111 2Il.1 .... 01 ... 1cAJooiI'll dinceI

may....-... '*' • titv-

~1ionI

c:otrC:Iiiwlion 01 . . . . . . (.....

EXCEPT'

~

cc..._.", ••

_ _ Ii· ~,

.....

t

r

_ Iioi. C~$ . ril,. _II' , ..

i......."I"".r.

crdIr~. .

.............. '" IJli/Ied Po iIec1ioo •.

C. tteoI..... o l ~ O. "Ntment 01 c
~

1 _ _ .oI...-dPo'

8._oleo...oc........ ~.

iI-.

0 • b'

...-..-....ltd

1 .. -_

01 01

. . . at

...

''''''.8I'IllQW>(Wi.... icIr' 8 1'1

$

,...•. Ooug

• d" I • ="' (lot Iloo....., 8I' I ll ""-"*' iii.. i.' 01 .... . . . , _ . . '

$

i

,

ptA ~

IIll' ~ OIl' ..,111 liIlliolb -'<1'1'110' • • 01 ........ ,~

'$

_

.,,.. ,.' ..,., .. _... _t. 28.2 wtIoch _

'" IIIe Idlowing pa1ienlo i5 IeMI ~ely ., ..-qwe • •'.... otJiooIIlM_' ••• lailo<MllO!he ~ ..... <XA idilioo (!

A. PI8enl .. deogoirlQ ,*",*,ct.''''''spy. 8. ~ ...... kiO'-.y diI •••• C. EIclerIy pDenl.. O. PwiInl ...... hVJM;eo .... L E. PMenl ...." ..... diI••• Correa _ _ • O. EIIQIed llIood

...... "*' M_

~

B. Adl.hi

IY9'I 01 Inllmieroblal " . .I....nl ''''9loyld. ~ Il Itnml.nI lUncIlon. Inc! _ pU_ oequire addilb.. .. 1IlIcllc61O .." " ~ ......... '''............ IIn:lIOn nwy _ 10 ~ '" IOJdc IIMlliI ~ AenIllllld ho.lJaIk: kn:IIofI ... ohlin diu 'WflOfll "1lclIo'ly. ~

~

_

1i'Cl"' 01

"

• C. lNI PZ"-'" II aerklI.*y • bldll. ; . _ tyol ... nodOi.tlt _101 _ >ed-..

"""*'

ilion.. Ta..,..,.• • _

,.iI&d?

II !he

A. P'e ' 01 " • • ogiIi5l1ff'O'lQ ~ in c:k.oore.ct wilh i........, FIi ... 8. wiltI • " . .rt pros,""... hiving • IOOIfl

P.,..... .......

.....

C.~i! " • •

-CCmlcl_. ....

""i,."..,

.",.Npproe..

O. ~ wto ~.inI '" Ireql*ll .I!I$pIfalOfY ..

E. P'KtJrgicll Ir... t.....'" in g.SIfOIntestinai ~

o. n

j' lIIOij _ _

rnayt:- '"

Wal otIgin; blhe<. 001 I • WlOI '" etwarok:_. det m.y nol war"'" pn:opllylKllc UQ 01 ....1· bioIlca. _.YlllII COflIIlCIioo.e and IMDus _It projlIly\IC'lIc 01

"=

* - '" .......... Fi1lluwll.,. _ _, IN ..... caviIy .., ..-;IIy ...... !hi clIO'

01 . , ...., wbb on. jlfI)II -.Fog. aer\oI..nd Often "lilli'll_ion. InIe>;Iiof! Iollowlng

.._..I

......

-' ,......... '/ ....." iillilc*o' .. ad! • ..,Iao.a i.;.

glIItJoi'l

'01'~"""'"

.... ....-geory _

_ .. _,.1Id.

1 .. _

.........

_.~,

01

plopll/l-e ....

II <:IinclImycin end

E. AllminiIt". IZireonem.

\XIIIl d
28.3 In YiItOc:t> _ 01 . . IcIuMnQ dinicsl Pf'lJII'Il" -X '" _tiDIicI NOT

t!tr8CV-

D. Adnkois'__ c:IirldImycin

y IMd 10 IIIe ~ 01

IewtM '"

brl*1 spedr\.nl.dliolic like

C. I\dminister • CIln'lCiNI'" suc:I'l

'" .lIiI,"'ObiII Iaidf;

.''''\11'..,

A. send I CIinicel semple., 1hI1Nlo1"', "" ~ CIIion end iiO,.i:Ae> .... ~ .....

"""*',..,. t:- .~ 10 " . ' 1:1\' ............

..... Iuncllon

28.4 Aro.year old _ _ wto hid ... ldeV'"". cn.,lOfle<. IIPY "" IymptonI Ihe wee. ~ • brotq'II 10 !he room. SIle has. "'- 0I101opeolic. Gram libine oIn ume .-.d!ipl.ll.lTlae ~ WI"D1 Q'l9 otltllr ........ 1lI IOCIicns II moolI ....,.., be bIIWliciio1 ., _........,

..

~

i.

'en ... .....,

1

-

••

..

..-...."'.-..., _ _ .-.i . dI,JI to en. h AM M' ' we 1 frIquInI _ '" ilflC:lb. In __ pIIiwnIIa. ThIo 1M,

...... -...r It """*-" _ _ ""*'"

.'.'CWI_tIIi N,0I.4 •• _ boIh go... ~: 111.1 Ifad gram «

III

10:(1)

'1IijiIi'" G;U:ia'.:'=_II. (2)bI' .. "P1_CP • "-good...... driI"""" b¥'. • __ a-. _ _ di_.".., '*" .''''"'lIrC
.j

IA_ iTD - - .

CW " ". ._

III

·

"')

<*0:

. _ ,. . . .,.' . . . . . . . _ L >

. _ ..... - ~ ' ............ _

.... >

Folate Antagonists I. OVERVIEW Folic acid coenzymes are required lor the synthesis 01 purines arid pyrimidines (procursofs of RNA and DNA) and other compounds required lor cellular gowlh and replicaliof1. In the absence 01 folic acid, cells CBfIf10I ~ Of divide. The sulfa drugs are iIlhibilOfs 01 folic acid synthesis. They originated from the dye prootosil. whidl was shcMr1 if1 the early l~s to be effectiVe agaiost hemolytic streptococcal inlectior1s because the body COflYE!f1ed ~ to suJfanilamide [sulfa NIL a mille]. Marly coogeoers ot the latlar compourld were syfllhesl~ed arld found to be eIlec1i\le in Ihe treatmel1t ot infectiolls diseases. Today, particularly Ir1 da'.ielopillg COUr1tries, the sullas are still ~ because oIlheir low OO5t and efflC8CY in certain bacterial infections such as those 01 the urirwy tract, and trachoma. However, to the emergence of resislar1t bacterial strains. (Ie>oelopl'tef1t of palieflt allergies. and the l.ldYer1t of the penicillins, the sulfes were less IrequenUy prescribed lor a time, until their synergistic affect wiltL /rimethopItn was recogni~ed. With the .... trodUClion in the mld-1970s 01 the synergistic combination of sulfame/tK»lazoIe {sui III meth OX a roIa] with trimethoprim [try METl-l otl prim] (generic name. co-trimoxazolB [co try MOX a role]). there has been a renewed Imerest In the sulfonBmides. Cc-trmc»IBzoIe is etfaeti\l'e in trea~g conditions such as f'netJrnocmi.s C
we

FOLATE

ANTAGONISTS

1-

-_ ...... -...... .............. . .ft_ ....... _-~

~~

~~-

~"""

I-

II. SULFONAMIDES Ail sul10namldes in clinical use are synthetic str\lCtural analogs of p-amirtObeozoic acid (PABA). They differ Irom each other oot 0I11y In their chemical arid physical properties tut also in their phamlacokioelics.

••=I....~

I'Ol.ATe ......"

• • •, .... 01'

rr...",u""fH/m

L

.a.IClII 01' 1"OI.ATt:

~

A. Mechanism 01 action

Being 1mpennea!:Ae to folic acid. many bacteria rrust rely 011 their abi1ity to synlhesi;re Iolate from PABA, pteridine. and !1tJtamale. In COI1IIast, humlll1 beif1gs cannot synthesl~e Iolic acid and must oblain preformed lolale as a vitamin .... their diet 80callSB 01 their struelunll simiarity to PABA, the sulfor'larlj(les COIllleta wilt1 this subGtrate lor the enzyme dihydropteroale syolhelase. thus preveI1Iing the synlhe·

Figure 29.1 SurrWlllllY 01 folate IlI1lagonists.

' - ' _ _ Au

........."- _ _ .. _ ,-

a_A'

"._~_

.... _c.<>w-. .. ,""ue
2~

. . . . . .0 . . . . . '

.... _ _ ,·

29. FoIatB Anlagonisls

290

",.....

sis of bacterial Iolic acid and Iormalion of il5 one-earbon c::arrylng aJfactorL' This depriyes It1B cell of esseotial "nebs tor p.R1e. pyii'...... and amino acid synhIsis (figlnI 29.2. liM IIIso F"9lf8 295). , _(pABA)

'

6. Antib&ctefl.l ~trvrn PIEolllk....

-=I ._-

0<"·""- H/l

_

The suUas. inclUding C(HrimOXll~ole (sul'amefhOXll~oIe plus frimefhoprim. see P. 293). BIB boclerioslalic. TllesB clr\JgS BIll active against selected enterobacteria. chlamydiB, pnoy!TlOC'tSlls. and nocardiB. Typical dinical applications afe shown In Figufe 29.3. In additoo. sul/adiazine [suI fa DYE a zeen] in combination with tile dihyU'%late redlJ(:tase inhbitOf pyrimelhamine [py ri METH a meef11 is the orlty etlectM!Ilotm 01 chemothetapy lor tCllloplasmosis (p. 353).

01o

1SUN""I0_ __ -..... _01 C.

Resls"'n~

any organisms !hat syfllhesize lhoif own IoIale llfe ~ 10 h! SllIona'nides. Baaerial res>slan::e 10 h! liUbs C8I'I .,;so ffom !*IS' nil! II'llnSklrs Of r.-iCb,. n1IAllIionL The resistance is ""'.......... irreYerstie and may be clle 10 tJnf 01 Ihe IolIoMng Iv1le possjbijties lNole: 0'g0Rsms resistant 10 one membet' 01 .... drug Illmily BIB resistarI: 10 1IlI. b.It!hey may be SllSCBPlil:lle 10 aH~J

"..,-_ca........-_bf.if> In_.''$.' · _

.......IIo ...

~

T'_'

.... 1eII

CNom""".",_ cr.

\1'

c_

''''''_

""'" ""-""'"

---

' ••

•

TRACHOMA

'

a ..

. ._

r

URINARY TRACT INFECTIONS .l"novIcuslyUi'b ••1

~_.

, - - - ' 10 " ' " _ .

well •• _"'~.

.0Wii COf1luncIlWl_ CfO.IfinlI _ _""'bll_ .7.-....... _._..,""._ "'.U = _t4Ido,

• CoUUl1,"" >genI. ~\lKbllmiI

In

_

'*...

ditl;Uld~

• £Klll:1Ic!!!Llillll ...... _ 1 _ _ co... '" cyatIIJ&,

InIlommti1lon,

~

• 50e FIgI.n 2t.71<>o

'tiro.....

flgul1J29.3 TypicallhfJr'apeI.lijc 8flpliadions 01 Sl.l/IorIan'Ode.

U_,.,'"'I

_un_Ul .... ·

un. urinary tract infec1icn

...... r...... 1.'

..... _

II. SuIlonaJrOcles

I.

_

....... ----' """"'" .. .....

1. Altered enzyme: Baclerial dihydropteroale synlhelase can undergo mutalion or be transterred via a plasmid 10 resutl in a decreased affinity tor lhe sulfas. The drugs the<etore become less ellective compelilors of PABA. 2. Decreased uptake: Permeability to sullas may be reduced in some resislar1t strains.

3. Increased PABA synthesis: Enhanced production 01 the naltJml SUbslrate, PABA, by the microorganism throogh selection or mutation can overcome !he inhibition 01 the dihydropterOllle syr>thetase by the sulfas.

D. Pharmscoklnetlcs 1. Administration: Mosl sulfa drugs are well absorbed atter oral

adrrinistration. Svlfasal<Wne (WI fa SAL a zeenl. when administered orally or as a supposilory. is reserved for treatment 01 chronic ;nftammatory bowel disease (for example, Croon's dis· ease or ulceraliw colitis), because ~ is noI absorbed. Similarty, suocInyIsu"all1lazo/e lsuks in ill sui fa nil a zoleJ is used for the lreatmerlt of salmonella and shigella canie<s. InlnlvenoUs sutfonamides are generally reserved for patiell1s who are unable to lake oral preparations. Because of the risk of sensilizaliol1. sullas are nol usually applied topically. In burn ooils, creams of mafen/de aretate (p-amltlomeltJy/bf:llllensv/fonamlde) or sl1v&" suJfadlazintJ have been ellective In reducing bum sepsis. However. superinfeclions with resistant bacteria or fu1gi may OOCU".

Sul/ollom/des

2. Distribution: Sulfa drugs are distribuled throughol.lt b<xJy water and penetrate well inlo cerebrospinal fluid. even in the absence 01 inflammation. They can also pass the placental barrier and into breasl milk. Sulta drugs are boUnd 10 serum atlumin in !he circulation; the extent 01 binding depends on the particular agent

3. Metabolism: The sullas are acelylated at N4, primarily in lhe liver. The pnxluct is devoid 01 antimicrobial activity, btJI it retains Ihe toxic poIential to precip;tate at neutral or acidic pH, causing crystalluria islooo formalion1 and therefore poIential damage 10 the kidney (Figure 29.4). Sulfasalazine is ellective in the trealment 01 infIanvnalory boWel disease because local inlestinal flora spIillhe drug into wlfapyridine and 5-amlnos
There/ore. depressed kidney function causes accumulation of boIh lhe paroot compounds and their melabolites. E. AdVef$e effects

1. Crystalluffa: Neph.otoxicity develops as a resun 01 crystalluria. Adequate hydration and alkalinization of urine prevent the problem by reducing Ihe concenlration 01 drug and promoting its ion-

Figuftl 29A Inactivation 01 sultonamiOOs.

""

·

,.,-

_,. 29. Folale Antagonists

292

izalion. Nllwef ilgOOls, such as sulli$aJuUOle IslA fi SOX a zde) and suIfamBIhcJ1uux 8I1l fTIOf1I ........... al urinary pH !han are the older $lIIlooBmide$ (fDl' exBfl'llle. SU'fsdiprlne) and are less liiItJle 10 c:ause crystaIuria.

2. Hype1Moslllvlty: Hypersensitivity reactions. such a$ fll$he$, .""",,1&,18, and Stewns-Jctlnson S'J!DUioe, _18lIty OOOi"IOi~ The 1Bllef 0l;:CU"$ more freIJ.JenI!Y 'frifl the longer ading agents. INoIe: MatIy Ougs are derived from the IlAlas and cross BIer· geoicit) has been nlP(lrled klr the dk.reIic:s, ........ """'mfde. tN..... Iu, itil, tunewIide............. (see Po 226) and I'le MAIonylunle ~ drugs (see Po 260).1

M~rl'tonamln"

3. Hel'~ d1stui .......' lle"~ ..lEIi. is erw;:culIlered in plllients vrilh glucose ~le ~ defic;iellcr (p. 351). GIllRlloc:ytqlen and hOi.ibocJ1Opei1i8 can also 00Cl.I"• .. KemlcIeNs: This <1isoIdet may 00CUf in nemxms because stMas 6sp!a<;e ~ from bio I(1io '9 sites on i8f\m aIlUmi'l. The bilirubin iii then tree 10 pass into the oenllal /'lllI"VOU& system. 5. Drug poIentl8tlon: Tra'\Sief1: poIeI1:iation ol the ITiPO\llyoemil: ef1ed ol ~ (see p. 2EO) or the 8IlticoeguIant etlect of IIo3Ifatin or ol ~ (see P. 199) f9sUls from their (lisplitoemeoI from bir.diog sites on serum al'oomin. Filla rTlfHhoIrexale (see p. 376) levels may also rise through displac:emenl s. Contralndl<:allons, Sulfas should be avolded In newborns and inrants less than 2 months old as well as pl"eQ"I8l'II women B11enn, due 10 !he danger of kernicterus. Bec8use Sl.lWonamides ooooe"se oMch 1ormaldehy(le. they should rIC( be gio.en to patients '81 ;"•• '9 ~ (sell Po 327) tor LrinBry IIa:1 ;, -=tio os.

-

,

:=: . . . 0 .... --I-t-_..".-_•• ,. ~'" o

i ,... --

.." _ .,ii 1

Agu... 29.5

Inhibition oIletrahydrofolate synthesis by soIlonamk1es and IrlmeIhoprlm.

'Solo! P. 296101 _ , ........... If> _

booi<s

In,,_

-

,

•

5

..... '0. . .,., . . . . . . . _

L>

'~

.."__'.'_"_.W·

Ill. TRIMETHOPRIM Tli'n6ttq>liH [trye METH oh priml. a potenl rl\I)ilor of bBcterial dihydrdoI8te ~ . edlibilS an antibaderiBl spectrum sWniNlr 10 the SlMonarr'Iides. Ho"BO'llr. /l1I7leIhoptWn is mosl often ~ wiIh

$I!

INl~

The acINe IDm1 01 kllate is !he ~ lhal is billed ~ redo"*'" bv ~te """d'llie. TNlIBflZ)mlIlic res:lion (FigI.I'e 29.5) is i1.ltited bv bjo,.......... t~ 'e ""1110. declease in 1he Iolllle coenzymes b PlftIe. pyii,idii .. n llIl'Wlo acid synIheSiI. e.:teo ilIl redo·· se has a rn.dl $1l0lijjl!li 1Iffinity ..... IJinefho. prim !han does lhe mammalian enzyme, whlch lIOOOUnls lor the lhlg'. li8IedMt ~ [Note: ~ 01 0Ihef Iolllte redo dase inIibiIors ft;:tude ~/t1tlmi1(l.YltIich is Ulifld II¥ilh SIAlonlWnides in peIUilic Uectlorlli (see p. 353). and nl6ltlCtte.oalte. v.tIidl is Ulifld in cenoer d 181' OCChelapy (see P. 378).] 8.

Arttl~tert.1 apectr\lm

6P8C\rUTl of /tjo'oo(Ill:Jl'tl'i is sWnilal" to lh9t d sdfameIloIaUOIe (see p. 290); hcweo.ef, tItoofilOPlrn is 20 to 50 times more potent lhan Ihe 6lMmamide. 1/ill6lll;p'W!l miry" be used alone in acute urinary tract Inll,lctlons and in ttle heatment of baclerlal prostatilis (1hl:Jl.ql ~ life preWlml<1). The lInlibElcteriel

C. Rest-tance Resistance In gnlfn·negative becteriI is due to the prase lC8 of an .altered d~te """lClase thai. has a lower atllrlty f()' the drug.

"'.

D. PI'II~Ic.

ctlarxleristics of bft,1tIItJoprjon are sWniNlr to $UlBmefJo: a""'*. tJ..I ~ WilMltIlJliOIlI are achilMld in fie eelItivefy addic prostatic end vaginel . . . . Iinoe iI t- a weak base. Ttjo,NI!hq:Irin, Ui ideigoes ~

The

~

Tttnelhcpr*n can produce the eneeu 01 Iolllte deficiellCy. that Is. rnegaWMstie anemUl. 1etA
f

1l1li

!

i~ • I o!-'" ;"~;.~::::::===,':-o 0

IV. CO-TRIMOXAZOLE Trlmelhoprim is most often compounded wlttl lhe aulfa drug, wJfa· melholtuolB. The reding WillbiolllOOn, caIed CO-Ir#m(»rIUDle. shoWs groote< antirrOcrobial activity than equivalenl quantities of eiltler drug Ulifld alone (FIgure 29.6). The c:.ornbioation was MIecled because d the similarity in lhe pt\al1'l\llCOlUnetics oIttle two drugs.

'sa. p. 2llll b

......

""""""'*'

Ie _ _

n lhiIO ........

...,.-

......

figure 29.6

Synergism bet_,,~OO.4, /tWneIhoptfm

Ilfld svII~on the rHbitlon d Ilrowlh 01 ElIfhArit!!i!! ~

............".- ... _,. 29. Folate AnUlgoni.1lI

GEHrT...... It4FECTiONS

PflEUMOCYSTlS CARINIl PtfElJNOHlA IPCP) .~~~_._ ........ _, PI .... •

...

I _ i .....

_-i~__ _ .... i"

n

.Oot"

_~_

.c....._.. .,.'" 00""'_"; ........., ._

'=ac:o,~_

'.t_,.«..__ ..

_"'"

I

....... l n l l d h _ - . l - .

... ·n

'~

p-""",-

""""""'" ~

RESPIRATORY INFECTIONS

• ..... tMemoP!llli. ....

PROSTATE AND URINARY TRACT ItlFECTiONS

~"",.wffwctl !!!~

_Sl,o;

'pn@'OI'I

ClASTflOlNTESTlN...... INFECTlOttS

• eo,wt• • .,. .....1

".-"~_"_,"'II

._fO>:typIlold"',,c:o '.

FIgure 29.7 Typeallhc
A. Meehanl"'" 01 8ClIon

Tho &yI ... gis1ic: 8illi"it;,,:bilIl activity cI co-~ resutr:s Iran its • ~ 1ibiIioi, cI lYoO Slllplf1tilll SIepI in Ihll $yo atesis 01 ~ Idic -.cl: ~ •• Iitlils ItIe i ....... paation 01 PABA ~ tolic ltCid. and fri'nefflOpIlin, P'~ .edudion of dihydroIoIale 10 tetrahydn:Jlolate (see Ftgla"e 29.5). Co-lrimalrazole ekhibits more poIenI .lIiiliclttial actMly IhiIn ~ or fI.lI..lI.......im alone (seed F'Igur8 29.6).

· _ ,. . . . . . , > . . . . . . _ , >

• ..,.. .....' - - , """"'" .. _

IV. Co-Trimoxazole

295

B. Antibacterial spectrum

The combination 01 trlmethoprlm·sulfamethoxazole has a broader spectrum of action than the svlfas (FIgure 29.7).

C. Reslstance Resislance to lhe trlmethcprim-sulfameth{)xflZ{)/e combination is less frequently encountered than resistance to either of the drugs alone because it requires simu~aneous resistance to boI!l drugs. D. PharmllCokinetics

1. AdmInIstration and metaboltsm: Trimfllhoprim is more lipid-solubIe than wlfamethoxazoie and has a grealef volume 01 distribUtion. Administration 01 1 part 01 trlmethoprim to 5 parts 0I1he sulfa (!rug produces a IlItio of the drugs in the plasma 01 20 parts 01 sulfamethoxszole 10 1 part trfmettloprim. This 1lI00 is optimal for the anlibiotiC eHect Co-lrimoxazoJe is genelllily administered orally. An exception involves iniravenous administration 10 patienls with severe pneumonia caused by pneymocystjs kW:inii, or to patients who cannot take the drug by mouth. 2. hie: 60Ih agents dislrlbule throoghoullhe body. Trlmethoprim conoentllltes in !he relaliYely acidic milieu 01 prostatic and vaginal nuids and aCOOUl1ls lor the use 01 the trimfllhoprlm-SIJIIamelhoxazoIe combination in inlections at these wes. Both pal'l!nl drugs and their rnelaboljjes are e~creted in the urine.

E. Adverse effeel! I. Delmlltologlc: Reactions involving the skin are very oorrvnon and may be sevet"B in the elderly.

2. Gastrointestinal: Nausea, alilis are no! unusual.

.... >

\(lITl~ing

as well as glossilis, and stom-

3. Hematologk:: Megalotllastic anemia, letJkopenia, and thrombocylopenia may ocx:ur, all 01 these effects may be reversed by lhe conwrrent administration of folinic ackJ (see p. 379), wf1ich pr0tects the patient and does not enter the rrjcroorganism. Hemol)'tic anemia may occur in patients with glucose-&phosphate deliciency dUe to the SIJIIame/hoXazol6 (see p. 351).

4. HIV patlenls: These immunocompromised patients with PoeumQC\/s!is pneumonia Irequently show drug·induced lever, IlIshes, diarr1lea and/or pancytopenia. 5. Drug Interacllons: Prolonged prothrombin limes in patients receiving warfarin have been reported. Plasma hall-life of pheny. loin (see p. 147) may be increased due to an inhibition of ils metabolism. Methotrexate (see p. 378) IeYels may rise due to disp1acemenllrom altlumN1 binding s~es by the sulfamethcJxazole.

<'''''.''''.'><-'''-''

«

. . . . _ _. - . . . . . - _ . " ' ,

29. Folate

are ..... efIec'iwe IIglIlrISl QI
Choose the ONE best answe••

IlI"Id

29.1 Sullonamides a", useful in the treatment 01 wt>ich

one 01 the llJllo',o,;ng? A. Inlluerlza.

II...."""". T)l(! &
_ _ IIf'd 10 IOnTl crySUIIS in lhe kiOney '" bUlddoI. ~ r lIriMry CiUIPUI iii low.

B. Gonont>ea. C. Most streplococcalln!ections.

O. Urinary tract in!C<:lions. E. Moningococcal in!ecliofls.

Conwd a.-. .. D. _lhe

~

29.4 $ul!onamidcs Increase the risk 01 neonalal ke.· nicterus because !hey

~

or1he

ealed O"IeaioolS at lhe

III

A. dil'l'lin$h the pJmln, Df10I _

B. increase the tu"",""". 01 red blood c"'s. C, inIlibit tho metabolism 01 bilinJbin. D. lXI'lipCl!llO< I:*\bn bin<:*'o;l sites on plasmlI aI;unin. E. depress the bone marrow.

_ t
~

1raCl

29.2 TnmelhO\lflm:

A. is less pot...,llhan suWamelho>olc.

'ee! _ .,.1!Iltu'r'i<>boit:t> can penelr
Co'nlcI....- • D. ~ OJ

B. inhibits the enzyme diIl\'dK>P1Croate S';T11l>elaoo. C. lowers the ratio 01 tC1rahydo-old8W to loIaW in the

orgarism D. ~ hasnolbeenobseesis. ~ _ . C. Trlmethoplim is 20 to SO times rAOnI potent than suIllimelt1o""zt"-. h inhiblls 1M lIflZyme dinydrokllll,. feductase.

hJS

Antagonists

p"ha"'oo bot> ~ and Pl"'ffl
Questions 29,5 - 29.1: For each phrase, select the ONE dnJg (A·E) tnat is moSI cloSllly associaled with it. Each drug (A-E) may be selected Of>Ce. mOl''' than once, 0< not at aI.

A. SY~asalarine B. S<>'IaeetamiOe

5)'f>"

C. Trimethopim--sulfamelho.aroIe

thuls. T.imethopflm 'Silstancli has bllen _ in _ CWoISIld by ~

th. p..,..nce 01 II plasmid "'at COdeS !Of lin IIltlirod Iihydrololate .!lduclase with a 1Ow1l' -*Y do\.g.

10<'"

<:a_......,

O. MaleniOe lICetate E. S<>'Iiso.azole 29 5

is used 10 p
~

Corroct IIns ..." • • D. Creams containing ""Ieride used ., bum .... its

..nem

29.3 All 01 the lollowing slatements concerning wllen-

are ..eel ~ 10 pIOIeCt agoineI inteetlon with e ve
amldcs ai'll con-eel EXCEPT:

!tilly

A. ThO)' "'
~~.

B. Allergic rcactOons IIrc heQUeflllltlvoe<Se _IS.

seve", ",nal insu!!i-

C. Treatment 01 palients with cieflCy m8~ lead 10 crystalluria.

2Q 6 Ills usee troatment of ulCCrali.-e colitis

Gareet.-•• A.. ~ is--..db ~ l 01

D. They dininisllaetivily 01 wal1arin. E. They compete with p-aminobGn~oic ae;" !Of the enzyme dihyd
polen

ol "'"

IInticOagulanl 1I1l.a
-uta

rrom 1htIlf diSJllac-,....,I!rom bin
29.1 It is ellcetiw in the lJeatment at pneumonia causec by Pnetmocyslis CilIilliI, Con-ecl _ _ • C. Co-to>:.II- ill <:u
'see p.2S() in Ilio<.l.'illliry (2nd ed.) to< II _ d ~ atl<JllC Il<:id ar
"s.

uI<:e
not alloortled Irom IhIIlP IlI"Id _~.

p, 325 in Bio<._l
-...

'see

p. 115 in --.lIIlry I2rId eel.) "" a ........Ion or It'e"..,. d I'>omoIyIIc _ """"""'" in " " _ ""'" gIuco&e 6-ph:>sphate ~ doIiciencY.

..... '0''''01 > . . . . . . . _

L>

< __ • , . .

0' K><.UJl" _

.... >

Inhibitors of Cell Wall Synthesis I. OVERVIEW Some antimicrobial drugs selectively inteffere with the synthesis 01 the bacterial cell wall. Unique to bacteria, this structure is not Ioond in mammalian cells. It is a polymer of glyclln units joined to eact1 ott1er by peptide cross-links, hence, the deslglation 01 peptidoglycan cell wall. To be maximally effective, these agents reqUire actively proliferating microorganisms; they have little or no elloct on bacteria lt1at are not growiog. The most impof1llnt members 01 the groop are the j}-laetam antibiolics, named after the J}-Iactam ring, which is essential to their activity (Figure 30.1).

II. PENICILLINS The peI1iciliins (petl i SILL in] are II1e most widely etf~ antibiolics and are among the least toxic drvgs known; the major adverse reaction to penicillins is hypersensitivity. The members 01 this family differ Irom one another in the A substituent anached to the 6-aminopeolcillanic acid residue. The nature 01 this side ctlaln ertects their antimicrobial spectrum, stability to stomach acid, and susceptibility to bacteriel degradative enzymes (J}-Iactamases). Figure 30.1 shows the main stl1.Jc1llla! lealUres 01 the penicillins. F9Jre 30.2 shows the classifiCation 01 agents affecting oeII wall synthesis.

A. Mechanism of action

The penicillins interfere with the last step o. bacterial cell wall synthesis (transpeptidation or cross-lil1kage), It1IJs exposing the osmotically less stable membrane. Cell tysls can then OCClJr. and these drugs are there'ore bactericidal. The sucoess 01 a penicimn antibiotic in causing cell death Is related to its size, charge. and hydrophobicity (see p. 300). Per1icillins are, 01 course, only ~ against rapidy Vowing organisms tllat synthesize a peptidogycan cell wall. COnsequently, lhey are inactive against organisms deoJoid 01 this structure, such as mycobac1eria, PrOl<noa. iurlgi. and viruses.

SIlO' al clo' . _ b y _ ~_OfbyllCld

Figure 30.1 Structural Ieal1Jres 01 J}-Iactam anlibiobcs.

,,-,'__" __c.-. '-'--';;._-

. . - _ . _.. '

"""'-

297'

·.... ,....,., .. -... _,.

• . - • - - -.., """""" -

_

.... >

30. Inhibitors 01 Cell Wall Synthesis

INHIBITORS OF CELL WALL SYNTHESIS

ll-lACTAMASE INHIBITORS

,--

C/otl'UlMl{,; Kid

~-LACTAM

OlliER ANTlBlOnCS

NTIB,oncs

_.

v_yrin

PENICILUNS

I I CEPHAlOSPQRINS

_nG _l/jnV

CAABAPENEMS

MONOBACTAMS

~_atJn'

~~

I.I
OIIKlllln Cionc/lllln DIcIo_ _

----A",.",lcI/j/n

~II;"

~.

,-"

, .. G£HEJIIlTlON

I

2n6GeNERATION

---~cellIdro~/I ~~jn

-""

~

~-~.-

~-

I

:lr
~-

Celi}t/me

I

... Of:NERATJON

I

~-

Cer_.._

~-

~~ ~ ~m_

~-~ ~

_

m

Figure 30.2 SUmnary 01 antimicrobial agents al1ecting cell wall synthesis '[Note: Cilastatin is not an antibioti<: but a popticlase Inhibitor that protects imipenemlrom degradation_l 1. PenIcillin bindIng proleins: Penicillins inllClivate proteins present on the baClerial cell memlll'ane_ These penicimn binding proteins (PaPs) are baClerisl eI1zyrnes involved in the synthesis of the cell wall, and in the maintenance of the morphologic fealures 01 the bacterium. Exposure to \t1ese antibiotics can therefore not only prevent cell wall synthesis 001 also lead to morphologic changes or lysis 01 susceptible baCleria. The number 01 PaPs vary with the type 01 organism. Alterations ill some of \t1ese target moleaJles conte, resistance Dr1 the organism. [Note: Mcmicillin-resistant Staphylococcus aureus, MASA, apparently arose ~ause of such an alteration.] 2. lnhibltloo of tranapeptldase: Some PBPs catalyz.e lormatioo of the cross-linkages between peptidoglyt::an chai"s. Penicillins inhibit this transpeptidase-catalyz.ed reaction, thus hin
..... , . . . . . . ' . . . . . . . . _ L >

< - - . . . ._ - - " , """"",, .. _

.....

II. PeniQlIins

299

3. Autolyslns: Many baderia. particularly lhe grarn-positiye COlri, produ:e degradalMl enzymes (auloIysins)lhal participale in lhe r'lOfmal remodeling of the bacterial cell wall. In the presence of ~Jjn, lhe degradalive action of lhe autolysins proceeds in lhe absence 01 cell wall s}"'thesis. "The exact autolytic mechanism is L.rimown but may be due 10 a disinhibition of the autolysins. Thus, the antibacterial ellect of penkillin is the resuII of both inhibi/ial of cell wall synthesis and destruction of existing cell wall by autoly$ins.

B. Antlbactetlal spectrum "The anfibacterial spectrum of the va,ioUs penicillins is deterrnned. in part, by Il1eir ability to cross Ihe bacterial pepfiOOglycan cell wall and 10 reach the penicillin·binding proteins that are located in the periplasmic space. In general, gram-positive microorganisms haw cell walls that are easily IraYefSed by penicillins and fherefofe (In !he absence 01 resistance) are sosceptible 10 these dn.ogs. GrarTHle9ll' tive microorganisms have an Olller lipopolysaccharide membrane surrounding lt1e cell walilhat Presef1ls a baniar to the water-soluble penicillins. [Note: for lt1is reason, penicillins have lillie use in the treetment 01 Intracellular pathogens.] Gram-negative bacteria have

PNEUMOOOCCALPNEUMON~ .~~

•• ""'10<...... 01 1:*<:1_

_

USTERIOSIS •

F........ eNS dIII.wt>o"""" ... ""'"" .....

''In''_~

• _lion _ 0':''''" In an

I n _ MltIng I n - . . . . .

• "om_,*--

--~,

Figure 30.3 Typ;ealtherape\llic applications 01 penicillin G.

•

Ua!ftIll.ean .,... co.- - - .

.......,.... conJunctMtlo _

.boi lIDo..

<"""'.''''.''<-'''-'> 300

30. Inhibitors 01 Cell wall Synthesis proIeins inserted in the lipopolysaccharide Iaye. that act as wate.filled channels (also called potins) and permil transmembrane e<11Iy. Factors that determine !heir suscepllbility 10 1tlese IIl1tibiotics include !he~. charge and hydrophobicity 01 !he particular [Hactam.

1. Nalural penicillins

Stable to acid permiuing Of'al administration Natural penicillins • ,._.~ PMlcllllnGo PfHIlclllln V

Antlstaphylococc:al

These penicillins. whict1 Include those listed as antistapl¥ococ· cal. are oblained from fermentations 01 lhe mold Penic[lIium chrysogenum. Olher penicillins are called semi·synthetic because !he diflereot R groups ara attached ctIemicalty fo 1hB 6aminopeoicillanic acid nucleus obtained lrom lermenlatioo broths of the mold.

a. Penicillin G

(~/lin) is !he cornerstone of therapy for infections caused by a number 01 gram-positive and gram-neg· ative cocci, gram·positive bacilli, and spirochetes (Figure 30.3). Penicillin G is susceptible to inaclivation by [Haclamases (penicillinase§, Figure 30.4).

b. Penicillin V has a spectrum similar to penicillin G, but it is not used !or trea!mel1t of bacteremia because 01 its higher minimum letllal concentration (MLC. !he minimum amount 01 the drug needed 10 eliminate the infection). Penicillin V is more acid-slable lt1an penicill/ll G. It is often ~ in lt1e treal· ment of oral infections where it is e"eclive against some anaerobic organisms. 2. Antlslaphylococcal penlcllllna: Methicillin (math i SILL in]. nafelllin [naf SILL in], oxacill/ll [0lC a SILL in], cloxacillin [idOl( a SILL

Antlpseudomonal

Adoclll/n C........ /c/ll/n ~/ocm/n

PlpMllcl/l/n Tlclireill/n

Rgure30.4 Stability 01 the penlcIliins to add or the action d penicillinase '[Note: Pen/dll/ll G is largely inactive
in]. and dicIoxac;ill/llldye kIOlC a SILL in] are penicillinase-fasislant penicillins. Their use is restriCled to the trl"ltmenl 01 inlectioos caused by penicillinase-producing staphylococci. Because 01 its loxicily. methicillin is rarely used. Melhicil/in-resislant strains 01 Staphylococcus ayreus (MRSA). curref1tly a serious source 01 nosocomial (hospital·acquired) infections. are usually susceptible 10 ~. and rBlely to ciprofloxscin or rita"fJln.

3. Extended spectrum penicillins: Ampicillin [am pi SIL in] and smoxidliin [a rnox i SIL in] Ilave an anlibacterial spectrum similar 10 lhat 01 penicillin G. but are more effective against gram-negalive bllcilii. They are lt1emfore referred 10 as eltended spectrum penicillins (Figure 30.5). Ampk;lliin is the drug 01 choice for the gram-positive bacillus. Ustena~. These agents are also widely used in the treatment of respiratory inlec~Qf1s. and amoxldllin is employed prophylacticalty by dentisls lor patioots will1 abnormal hear' valves who are to undergo eltoosive oral surgery. Resistance to these antibiotics is now a major clinical problem because 01 inactivatioo by plasmid·mediated penicilli· nase. [Note: EscIleDcbIa lOPII and Haemophilus inf[uenzae are Irequen~y resistant] Formulation with a !Hactarnase inhibitor, such as cliMJlanic ackI or sutbactam. protects amoxkiHin or 8/TfJiCiIIin, n!spectively. from ~tic hydrolysis. and extends !heir antimi· crobial spectr\lm. (See p. 307 kr a discussion 0I1tlese inhibitors.)

.... '0...

,.I~'

......._,

~

n. Plmicillins

301

4. Anllp••udomolllli penicilli",: CBrbenicillin [kar ben I Sill in], tial/til/In [lye kar SILL in]. and piperadllin [pip or a Sill In] are called antlpseudomonal penicillins because 01 their activity against PsooA mol 1M -t9!ll!llB. PfptmJdItl is the most potent These ill rtIlIotlcs ale ef!el;tiye against many gram-negatiVe bacilll but not against K!eb:sj'9la, beeaU$8 01 its oonstitulive penicillinase (FIgUre 30.56). FonTUation oIlic.ttellrl or pipetadIIirJ >Mth clawlan/e add or lazobactsm, respectively (see p. 307) extends the i11llirllj"""Xllal $p8CbUTl 0I11le&e anlibiolics 10 Indude penicillinasepl"oO..ICing «gaI""IS. Me~b . , [mm: Ioe SIll in) ardllZlodlin [82 Ioe SILlInI (sc:wnetimes 10 as ~ penicjIi1;s) allil a/s(J etIediYe aganst P-Il!mmat; iMllJ ogionM and a lar"ge number of gram-negallve organisms. They are susoeplible to p..Iactamase bfeakdown. ( _ F\gln 3t:l.4).

'''eel

5. Pwllc:lIlne .M ...-....y~: The atdJaderial eIfeds 01 aI the jl-Iaoam .1lU . . . . . ..,..... gistie wWl .... • I.~ The abMy 01 pili ~ " (a'ld 0It8" agents thai inhibit c:ell ..... synthesis) 10 alIor peo II I lbifty 01 the baderial c:ell c:an IacilitaIe ertry 01." ..... that ~ not CI'dI'Iariy gain ace 1110 tatget sites, thus ,esulting in ~ .,lir,liaobial actiYity. AIthoogh the ~ is ~ djliieall~ IIle&e drug types stlOlJd_ be pIac:ed in Ihe _ infusiOn IUd, ........- on poloued oc:n-tact, the positively ctlarged ~ Iorm an Inactive ( 0 .............. Ihe negatiY8Iy <:hafgMl peo.......

NIil:un1 ,-Ill t__ 10 fwI peorldliilS occurs in organilinB that eihIr Lad< a ~ eel waI (lor i!kiWTlpIe, Ml"'" "asma) 01 that haw eel wall ... are illlpeom I He 10 the drugs. AcquINd . . . . _ 10 the peo rIdlii IS by pi ,rid \rlItI$ter has beoorne a sigl ifical ~ dricaI probleln, ainoB an aganiIm may t9Sistar'Il 10 $(!I, (Kat .1Iibiolia due 10 ac:qr f • • • i 01 a pi Irid that eolOOdtos I . t o/IDII lor ~ agenta. Ml_iIJ'i' ar~, oIl1Udl . , 0fgiIlism .... lead 10 Increased disstminlttion 01 the reststatlOa genes.. By obtaining a ,E . t Il'108 plasmid. bllclerill ITIIy ~ one 01 both oIlhe Ic*:Jwlng pl"operties. IhW llICMWlg illO withstand IHaCWn

B. Anlhlikoctilll ~ at QMliw. l~"

Md,,, , .,"'4

beooo,.

.,ltioties.

1. ~ KtMty: This Iamily ol enlY'\'l88 t¥:!fOlyles the cyctic .,..,. bond 01 the jHBc:tam ring. 'At1ieh ~ in loss 01 bfIcte(,g.

dal adMty (see F9Me30.1). ~ ..e ~ ~ or, lIlOfe c:cmrnonIy. are acquI.ed by the trant;f.. 01 plasmlds. Some 0I1he P lee...." 8f1litlloties are poor Sl.tlslr8les Iof ~ mases and resist. deav3ge; 1huS they retairl their aetMty against ~ organisms. [Note: Cer1ain OfQllillSi'1$ may have ct.n:mosom..IlSsociated j3-1al;Wnases lhal are Indu(::ilIe by

I3-laCtam alliliotic:s (Iof exlWlllle. cefaKifinl·] 2. Decreased pennesb/tlty 10 dfU5I: Deor6llsed penetration 01 the an~bioIie ttvough the oulor cell membrane prEMlf1lS the drug !rom fead1lng the target periOlW~ng proteins (PaPlI).

Agure 30.5 Typlcat 1llerapeutic ~Mk>t .. 01 ar,¥**'l (AI and rl& 8I1tipS8"d(~ mona! penicillins (8).

<.... '.''''.'><-'''-'

>

30. InhibilofS of Cell Wall Synthesis 3, Alt8f8d penicillin binding proteins: ModHied PBPs haYll a lower affinity for lJ..lar:m'n antibiolics, requiring c~nicalty unattainable c0ncentrations 01 \he drug 10 et!ecl binding and inhibition ot baclerial growtIl. This mechanism may explain meltlicillin-resistanl staphyloc<)(:(;i, although H does not aJrplain Hs resistarn;e to non-Iadam antibiotics like etyIhromycin to which they are also ratractory.

D. Pharmll<:oklnetk:, 1, Admln1strMlon: The route of administration is determined by \he stability of the aug to gaS11ic acid and by the severity of \he lnfeclioo, 8. Route.. 01 IIdmlnlslrallon: Methicillin, ticarej/lin, carbenicl'lh"n, mezloc;illjn, pjperacimn. az/ocillln, and the combinations of ampicillin with sulb8ctam, licarcillin with clavuianic acid, and piperacillin with lazobaclam must be administered intrawnousty (IV) or intl
Oonnol ratoo Into "'" eNS u .. ....n/nvM .. IJ1I1anw
""'

'--.r,,,,.

Pen/c,lIm

DepoIIOOTIS: Procaine penicihl G and benzaltlrle pcrW;i6in G are ad'nirnstered Intramusc:ularly and StifW as depoIlorms. They are slowly absortled into !he circutation OYer a long time period,

2. Absorption: Most of the penicillins a,e incompletely absOfbed after oral administration and reach the intestine in sufficient amounts 10 allect the composHion of \he intestinaillora. However. amoxicillin is almost completely absorbed. Consequently, H is not appropriate \her(lpf for \he treatment 01 shigclla- or salmonelladerived entelifis, since thelapeulically eflective levels do not reach the organisms in \he tI1testir\81 crypts. AbsOfption 01 penicillin G and all the penic~lir\8se-rcsistantpenicillins is deo-eased by Iood in \he stomach sirlCe gastric emptying time is redoood and the drugs are deslroved in the acidic enviroomenl. Therefore, they must be administered 30·60 minutes be/ofe meals or 2-3 hours postprandially. Other penicillins are less aI1ected by food. 3, Dlslribution: Distributioo 01 the free drug throughout the body is good. All the penicillins CfOSS the placental barrier, buf none have been shoWn to be teratogenic. However, penetratiOf1 into certain sites such as bone Of cerebrospir\81 fluid is insufficient lor thmapy, unless these siles are inflamed (Figure 30.6). During the acute phase (!irs! day), the inflamed meninges are fTl()fe permeable to penicillins, resulting in an increased ratio in the MlOUf1t of drug In the cenllal ner.QlJS system compared to the amount in the selum. As \he inlection abates. inllanvnation subsides, and permeabilily barriers are reestablished. 4. Melllb01l!1m: Metabolism 01 these drugs by the host is usually insign~icarrt. bIJt some metabolism 01 penidllin G has been showl1 to occur in patients wfth impaired renal lurlClion.

..... '0...,., ........ __ , > II. Penicillins S. EJ:~tIon: The primaIy route 01 BIlCfBtion is lhrough IhB orgarjc

acld (llb.Aa') secrBlOtY system oIlhe kidney (see Po 224). as welt as by gIomet'lAar filtralion. PatiBo1ls wiItl ~'ed ,enaI Ioodion must haYe de age ,egiI,iEII is adjusted. lhUs 1he I.... 01 psolicilii, G earl Increaselrom a normal 01 '/1 ·1 hoI.M'1O 10 hrX.Ir.i; in irdWiJaIs with renal lailwe. PJobelledd WIb1s 1M seoeUon 01 pe;cilIQ. NafdIfn if; primalily eliminated II'lfoIqIIhe b/li8fy fQl.I\&. 1Nole: This is also the prelenrrlial nllAB lor lhe aqi.IreIi:i:> ~ cilinsin cases oIlenallaiUe.)

Pe"iellillB a,e .1.... 'lII1he salest drugs. 8I'ld l*;lQd IeYels lTOllilOled. aIIhoult1 alM!Ise ,1liIClUIS do occur.

a,e

.lXU,_,_......._ ,,,.on ...

1*'
...... 1

.-.., __..

not

n-s is Ile mo&I ~ ~ efIed d lhe peelc:ili ... The rnafOI aliligeoic d 18 d peetieAi, ~Si"" My Is Its m«atri'e. pee ...... add. voticIl,GIlClS wiIh p~ is an;j _ _ as B haplen 10 cause WI mon.ne le&:toiL ~ 5%

1.~

"il.,

01 patienI$ ha'o'8 liO!'I18 kind cI ,6lldioo~ "''lIJii '" from fIVICI *'9'P 4a' rash 10 .lgioedema (m8I1Ied sweI~"'lII cI Iipa, lOngI.l8. pee IDlbitaI area)

lW'ld~ Cn:ss

alacgicl9aaionlOOlXXU among IhB jHactam a ItbioIics. AItt10ultl rashes Cl¥l dlM3Iop wiItl althe perj. dllil"ll. mllQJlopapula, rashes are most comlTlOll with Bmpicitlll"l_ Among patients wilh I11OflOfJ..IdOO \\tIo are treated wilh ampicJ/IirI, the .dderlCB oIlT'1ilClJopapular rash approaches 100%.

2. Diarm.a: This allect. which Is caused by a disruption ollila r'lOf. mal balance of inleslinal rnictoorg.arjsms. Ii a /XImlT1OII problem. It occurs to a g.ealer extB1ll with those agents thaI a,e incompletely absoIbed and I\av8 . , extended arllibaclBrial spectrUm.

3. r+eph.III.: All penicillins, but partieula'ly methicillin, have lhe pole"lliallO eause aan inIerstilial nept.itis. 4. NlMroIoalclly: The peuicilli"s are ~ 10 IMU'OnIl tissue and can pn;Mlb 5BizLnls r ;lIjected ;111".«1,> or it very I'ql tbxl kMlbare leadl8d. E, ..... patienls ..........." " II risk. S. F't8lIIlet ~ Tl'I$ side etIBc:t. whic:to irMWes decreased aggIvIination. is obseMld wiIh the 81'.. 11 ~ peelicilliils (c:M:ll!It...., IWId IicaJaiIinI WId. 10 _ .... ~ GIl is gel.-ai. a a;J<1C8i1"l when treating polilnts pecliSl.:sed 10 hemorrhage or 1t"cse roooi.io'lll8l1lieoagl .....

,..ai::iIi.

6. Cation loxlc:lfy: Penieinins a,e gene'a11y adminlsl•• ed as the 80dUTl or potB$siIm sal. TOOcillBs ~ be calSBd by the large quariitleIlI 01 liOCitm Of poIassitm flat llOOOf'I1)8I'ly the pellolh Sodum eX( I SI may .esuII ... hypokalemia. This can be iMlided by UIlIlng the IT'OSt poIBn1 .. fib;otic:, wI'Oct1 penniIs lowe< doses 01 drug and acaJIT1llII¥ng cation5.

I

!,L~_~~_~ o Houra, 2 _ 2

,,-

•

Figure 30.6 EmaI"lOOd peroeIIatlon 01 penicillin into the ce,ebllli spinailluid (CSF) dLwing infI8fI1<'l\8lio<1.

<.... '.'''''''<-'''-'

>

30. Inhib~ors of Cell Wall Synthesis

Ill. CEPHALOSPORINS The cepIlaIosporins are p..laCIam 8111iliOOc:s that are c::toOOy relaled bolt1 Stl'UO~ (Fi{pe 30.7) and fin:;:tionaIy to the peni::ilins. Mo5l cephalospori'ls are J:fcdl!OOd ~ l)J the c:herli:al artao:"h'lEll~ side dktns 10 7~ add. CephaIo:sporins Mel ~ h:M:lthe sarna mode 01 acliorl as the pel lic1Ins Mel are affected t1; the same ,e&stal iOO mechWithey tEnd kl be more resistaf1llt'a1the pel ....... 10 ~

a

semkynlhetlc cephaloaporlns _ prep2red by lII1actll~l\t chemical groups at R, and R,.

.nsms.

A. Antibacterial spectrum ~ haw been classified as first, seoond a thrd goneration, Sgely oo1he basis 01 baclerial ~ patterns Md resistance 10 I} Iadamases (f9.Jre 30.8). [Nole: Tht¥ are ineIIecIiVe againsI ~ resistant Staphy1ococC\Js aureus (MRSA), Listeria monocytogenes. Cbi!ridwJ ~ arcIlhe enleroco:x:i.]

genemlion (Fogure 30.8) oct as ~ G S\bsIiIuIes thai are resislwII to Ihe ~ cal penicillinase. They also haVe activity a{lainsl PIlllm!i mlrabilis, Eschericbia CQIi. and K!ebsje!la poElL!DO!ljae (the acronym PEcK has

1. FinIt gerenlllon: CephaIosp:lrins designated first

7. Ami llOCePh alOspo<1Inic a<;id

Site 01 ~1e.Vllge by baclerial p..l1lCtam8SeS .... b acid.

Figure 30.7 S!IUClurai JOOfUles 01 cephalosporins.

-_.

2. second geollr8tion: The second generation oephalospodns display greater actiVity against three addiliooal gram·negative organisms. Haoovvt,-Ius jnfluenzae. some Enterobacter aerogeoes and some tls'f:::da species (HENPEcK).l'>t1ereas aclivify agaffi ~ organisms is weakQf. [Note: The c ~ are effective against B;;gooj1es IJi!lH; cebrlil is the most potert.]

3. Tl*d g&I i8iati
coed,the third generaliof1 ~ haw tri\ar(:(ld aetMty agam garn-oegatr.oe bedl, irtJdrg ltDse mentirJ1ed ooow plus most 0Iher enIaric orgar09ns Md Serralia !D!!lIffl"fflS CeftTia.n:ne (set tree AKS 0Ml) a cebIaXiTlelsel oh TAKS sem] h:M:l becor'18 agenlSoId1Oice i'1 the treatmerrt 01 meolir,gtis. Cefrazk:kne (set TAl id eem) has adivity agairB Pw I'1Jnrnas aensirffil

4. Fourth o.i8illtioi~ Cdepffle[SEF eh peem) is the mosI ciric:aIly ooeful !ol.rtl generation ~ Md ITUSt be oU,lirlislEHOO PaI'(lI1IQ!lIIy. CrJMjj;ile has a oMde anIilacIerial specrn.m lJejrg aclM! vs. Strepococd Md ~ (orly It10se lhat ale fTEfhiciIin S\..lSOOpIllIe). It is iWo etlecIiVe agaI'lst aen::tlic Gran Ilf:9llive org
rtvmas aeruc;1X§jl

8. Resistance Moc:harVsms 01 bac:terial resistance 10 lhe cap..alosporins are essef1tial1y the sane as It>ose descri:led fa Ihc peniollins (see p. 3(1).

C. Pharmacokinetics 1. Achlrolsbatio", AlIhc oephaIosporins (~ fa those ~ in RgJre 30.8) mosl be oUlinlisleoed intraYenOUSly because 01 \heir poor 00II ibIo 1fu1.

< ..... , . . . . . . , • • -

... _ , >

III. Cephalosporins

.. ow' - . " -~.

-.~_.

__

._~

~~hualongoo­

t.II-II.lIIan - .-.lean 808'1tS. l>a " .......... _ _ batriar __ lor ~8dbOll
~l'l"'-.r-.lb

poIioRswho ... ~ .

Oral oOl.il&tialion!'Moo doiIl'. waI abaor\locl. _ ~ 1lia<\amII_ p«l<\lCFog .. ",,"""'"

Good ..... a.... ,IrfoCSF.

Rgure30.8 Characteristic 01 some clinically useful oophalosporins. NOle: Drugs that can be adminlstefed orally are shown In U.SU. More uselul drugs shown in bold.

<.... ,.,,,,,,><_'''_,

>

30. Inhibltors 01 Cell Wall Synthesis 2. O;slribulion: All 01 these antibiotics distribute very ~I into body lIuids. However, adequate lI1erapeutic I~s in the cerebrospinal fluid (CSF), regardless of inllarrmatiorl, are achieved only wilhlhe third gene'ation cept1alosporins (lor 8)(ample, ceflriaxone Of cekr taxime are ettecIive In the treatment 01 neonatal and childhood meningitis caused by ~ (nllueozael. Celazolin (se FA U> lin)linds appIicalion in OfthopediC SUfgery because of its aaiv· ity against penicillinase,pfOducing S!.<whylocOC!'us i!Jllim$, its half.lile and lis ability to penetrate bone.

""nl cepllalosporln.


go""""'" oogeml

_.InCSF --~

3. Fate: BioIranslo<ma~on of cephaIosporins by the host is not clini· cally importanl. Elimination occurs through tubular sec,etlon and/or glomerulaf fillfation; thus doses must be adjuSled in the case of S8\lere r6l1al lailule to guard against accumulation and lo~icily. Cefoperazone (set oil PER a<: own) and ccftriaxone life e~creted lhrough lhe bile into the feces and are frequenlly employed in patients with ranal insufficiency.

'--1"

'"

O. Adverse effecte The cephalospoflns produce 8 number of adverse aIIocts, some of which are unique to particular members of the group.

Cephalosporins

1. Allergic manifestations: The cephalospoflf\$ should be avoided or used with caution if1 Individua.ls allefgic 10 penicillins (aboul 5 to 15% show I:ross·sensitivily). In (Xlfltrasl, the incidence 01 allergic real;!ions 10 cephalosporins is 1·2% in patients withoul a history of aIleryv to penicillins.

2. A disulflram-l1ke affecl: When cefamandoJe [sa FAM an dol] or cefoperazono is ingested with alcohol or ak:ohot-containing medicaliOflS. a disulfiram·like eilecl is S9IIf1 (see p. 96), because lhese cephalosporins blod< the seoood Slap in aIcohot oxidation, which fesulls in the aocumulation of ocelaldehyde'. 3. BlDfIding: Bleeding can ocaH will1 cefamandol6 or cefoperazone, because of anti-vitamin K effllcts; adminislraliof1 of lI1e vitamin COrfOCIS lhe prOOem.

IV. OTHER !l-LACTAM ANTIBIOTICS A,

Car~pen ..ms

carbapenerns are synthetic IHaetam antibiotics that dittsf from !he panidllins in thaI the sulfur atom of the thiazo/idine ring (Figufe 30.9) has been exlernalized and feplaced by a carbon alom. Im,penem Ii mi PEN em] is the only drug of lhis 9roup anrenUy available. 1. Antibactllflal spectrum: ImipenerrldI8starin is the broadesl spectrum p..t.actam antibiotic prepara~on OJfmolly available. Im;penem resists hydrolysis by mosl lHactamases. The drug plays a role if1 ~ric therapy since il is active againSl penicillinase-produCing gram·posltive and gram·negalive organisms. anaerobes, and

's.... p, 310 lot' _

"'''''........

10_

OOOU In ..............

. . . . . .O. . .,.' . . . . . . . _ L >

...,....

---.. - .. _..... '

""7

n mIl' laB ~,

althoUgh at- pseudomonas strains Resistanl stsaN 01 py."'''Jlll!W! illlfI'liOCM haw been ,eported 10 arise cbing 1tleraI¥1

PM'

are reslstart. [Note:

2. I'twmacoklnetlca.: ~ ill adllli"ilihhed intr!W8l'lOUSly and penetrates wei irlkl body IissUes a'ld lIuids including cereb.... ss*l8I fluid when the meninges are irlllamed. II Is 8lOCfeted by gIornef\.IIlW and w1deigoes dell'.age by a ~ due tound irl the bfush tIon* 01 the JIfOIlftIal t1..tll.Ae 10 lorm an inactiVa metabolite IMI I. potentially nephrOlOxic. ~ !he .'¢le7l with ..... $fI>fioI, e ~ W.Ilib. protects the par'" drug trom deltiorge and Ihus pre......... the b"iMlol. 01 a IaIIX: me&abolile. TNlIi lIIowto ..... drug to be adiY8 irllhe Ifearment of urinary !fad Iollecllcw-. [Note: The do5e must be ......... irl palient$ with r8fllll1nUlcient.y.1

1iIIl""'"

r.,.

.tNoC!.,

3. Ad\oeIM 11l ....... l&itcilasta~ can <:8IJW nll''lI88. Wlffliliiig, and dlanhea. Eosinophilia and neutroplInIa 818 less com,1Of\. Hilt' IeYel$ oIlhis agent PfO'I'Oke seizufes.

mav

B. MonobacUlml The monobaetams, 01 'ntIidl azlrl!OfI8f1l [az TREE oh naml is the only OOffVfIlIfdally available axafTllle, ... e unique because lIle ~ lam ring II nol fused 10 anethllf ring (FIgure 30.9). Monobaclams also disrupl cell wall synlhesis. The drug's nerrow anllmlcrobial spectrum p,ecludes ilS use alone In empiric lherapy (p. 279). AzllUOOlllTlls reslstanllo the aetiOll of ~. 1. AnlibK1er1al epeetrum: The antibacterial eetMty 01 azlt80flafflls primarily direcled agains1 the enterobacteria. Azlreonam ill usef\A because 01 lis ectiorl 8!Jl*lSl aerobic gr8f'I'H'l8g8ti ,oos. It lacks aaMty agairlsI gram-posilMl orgaoIsms and anaerobe&:. 2.

Il-lllc\.lm rlnll

OJ

CH.-CH- C I

o'

renallaiUe.

"eeI.:

v.

jl-LACTAMASE INHIBITORS

Hydroly5is DIther ~ mg, either by enzymatic de.. age Ioill a ~ tamase 0' by acid. destroys anlimic,oblal aCllvlly. ~·laClamase ImibitolS. sud! as claVU/Bnic BOd lela vue LA "'cl<]. Su/tlBClBm [sol BACI( tlwnJ and tazcb/IctBm Ita zotl BAa< tam]. OOIllain a ~ ring, bo.A lhey do no! have significanI antibaclerial actMly. Instead. they bind to and lracdve!e IHadernases, thereby protecting ltle antibiolics thai are nDIma1ly subs!rates lor these 8IIZ)IfTle$. The IHaeternase inNbiIoIs are Ioimulaled wflh lhe

penicil~n

derivatives to prated the latlBl from enzy.

1

-c::> "" 101

I

C-"

-CHP.-N-C=-N

""'"

1·- .....·") ..""""I "'" ~

AzlreaJBnlls a:li,lioiisIBfed \'Ia IV Of 1M roules. II Is ftCI'et8d irl the urine and can 8OCUI'I'lUlale irl pelierlls with

~

3....crw..... Aztreonam Is relaliVely nomOldc. but it may CIOA8 ~ skin r.ssh, and ac- lcz~. Ilbnofmel IiYer Il.nl> lion IIstl. Azr,eonem has a low irnrr'IunogenIc potential and shoWs Iitlle ~with .~jl··rrs irdlC8d by Oltler I'-laotal'nI. Thus lUInIonam may oflef a sale eltBflliltiWl Ioi lfeating ......... aM! gic 10 pel"" is enaror ~ ••.

101

o I

101

H

H

, ,

R-C-N-C-C·01,

o'

C_-SO.H

"'d'_.....

(e"",

wn)

figure 30.11 Stn.JCtUralI~es

""""'-

01 ifnPeirem

, .... '.''''.''<-'''-'

>

. ,-......-_.. .

«_._~

30. Inhibitors 0'

~

>

Wall Synthesis

ITIll~C inaclivlllioo. FIgura 30.10 shows the IIflacl 01 c/avulanic acid IlfICI amoxic;lIin on the growth 01 IHaetamase-pnxtucing Escherichia l
..'

VI. OTHER AGENTS AFFECTING THE CELL WALL A. VancomycIn

va/lCOfr1)Q'n [Var1 koo MYE sin] Is II tricyclic glycopeptide that has booome Il1Cfllaslngly important because 01 ~s eIlecllwl'1OSS againsl multiple drug resistant organisms such as melhic;l/itHesislanl staphylococ:ci. The medical community Is preserrtly concerned about reports 01 emergence 01 va/llXlt"lljlCin .esistanoa In these Slralns as weU as tile Ol1terooocd.

.....

..·L----,:;:c---"'--

1. Mode 01 aclion: vancomycin inhibils synthesis of bacterial cell wall phospholipids as well as peptidoglycan poIymerizatioo al a site aarlfer than that Inhlbifed by the I}laetam IlllIlbiotics. 2. Aotlbaclerfal speclrum: In order 10 curtllil tile Increase il1 van-

figure 30.10 The growth 01 ESC
comycin-resls'ant baCleria (for example. the EnlercocQCCus laedum IlfICI Eoterm
0'

--Does not pe _ does enter CSF K

.........

Vancomycin

bul

3. Resistance: Qc:curring rllrely. valll:omycin reSiSlanl:e is due to plasmid-mediated changes in penneabmty to 'he drug IlI1d is aloo due to deCfeased binding of vanromydn 10 receplor molecules.

4. PharmacokinetiCS: Slow intravenous inlusion is employed lor treatrnerll of systemc In'ections or for prophylaxis. Because vancomycin is not absorbed alter orill administration. this route is only employed for the traatrnerll olllrllibiotic-Induced colitis due 10 ~ djtllclle. Inl1llmmation allows penel/atlon Into the mer1lnges. Metabolism is minimal; 90-100 % is eKallle(! by glomerular fittralioo. [Nole: Dosage must be adjusted in refl8t 'ailure Sifl(;e the drug will a<:wmulate. Normal half-Ine Is 6-10 hours compared to ovef 200 hours in end-stage lenal disease.]

5. Advellle effects: Side elfe(;ts are a serious prcblem with vanoomydn and Indude lever. mills. and/or phlebitis at the irlfUsiort site. Shodr has occumtd as a result 01 rapid administration.

.........,., ........ _,.

,..-.

---_.. -- _..... ,

'"

~ ("rod man synQvne1 and 5hodI .esUllbllO histamine release caused ~ rapid IoW5lorl. Dose-nlIatod MwIng Io6s has 0Ql;tlIT9Cl in patieo lis wiIh ,enallaii.... who aocuraAale Ihe (lrug.

8, 8.cltrKin &dI...., [bass i TRAY 1In1" lI"*luIe a' ~ I M IhlII irHlits bBderilII 0IIII Will ~ It II ac:cMl agaWla II wide VlIliety a' "81' r-posie'o'e 0I'glrisms. Its use ill IllStIJdad 10 IllIlicaI 8Pl'" al\()l, becllIlM of iIs polerJlillllol '1lIPl".'*»
Study Questions

311.1 Whleh _ oIll1e lolIowlng dfUgl II both penk:~li, nue-rosItilanl aro:I etrecltw b'JI ORIII ~? "- MelI*Ao .. 8. ea.t>oiitilio. C. Pel it." V. O. ""......... plII"""""-::.c:id.. PIpei &iii.

..,

""'*"'"

"-V~

8.,.,

e.

30.2 Which one allhe tollowlng

30.3 A 70 yea< old RIoohok male wiIh pool" denial hygiene 'I 10 hllV9 his ",mllnlng leoth ext~ 10< IUbI.. QIJll

,

C, T ,eiI.. D.cu-.i, .....

Inlibio~cs

is INCOR·

RECl\.Y maltheCl with an lflI)I'llllrille diIIItaIlndItlo·

"-

Peolt~11n

G: Pneumonle eaUle
-_.

30.4 .... col !he

"*""''11 I'

'Iments -.out pe
ClOfIectEXCEFT:

"- It II eocaeIed

8. Mil" ,

--

$

Mlm'" body Pii.oaolty . . . hepe-

ed~.III

... I I t i y - " ' - t - -..

of ill degllddao. b l ' - Idd. C. I 11_ 1"1"". . -.. ~ ~ gloW'll I . 1I ........ ll"'. .' .. p'-.

n'"

D.llcanKtS)1.g· r

,

• .....

'io~' .....

e. l.ew/I5 in ... bkxld can be intreNed t¥ edI'iII$iWa. KIn 01 '" Clbeo oecid.

• "0< '0. M'.' ........ _

,•

•

C. . . . _ _

~

''0

. .,

.....

30 Inhibitors of Cell Wall Synthesis Correa ctJoiOe • A. T'hlo prIn\NjI _ flI _ lion (II pel 'c',1 •G II WI ltIe _~. er.I - - . . IIlral"'" 01 J)elnltUltlon 01

C _ _ A. 1.bl1OJOi~ drug cldloloe.

30.7 An eigt·monlh pregnunllllGlItiII

"*'

...._.i>...,,·......

..

C8JJl'i8lD'CIoo_os_ mo. en

again5I stapl'ly't:o: c:81

~lIKlioo ..........

gar....... QIllI

..

_

1I'Iird

c. eeoo-en • lnalike!l' tel

an !PC ,.-:lion in a peliert 11'81 .. hype, tel pet' . , . G V. D.The ~ of ~ pet~. ,ldrnihile<ed ~ i I ~. . . . . .....-flIpet!idIin G .ohio ell ~ E. ~_ CAijAOIII
...,.pel.....

tel

Il-Iaa'

10. . . _

-.y....,., "' . . . . . . _

- . lrdudn;

A. ceIadrod ~ flEl'll!IlIlkH, ee9l11bipo-,j

B.CoIovno_~

C. P1io

V

!bdget61111Ol ~ l

D Celb

E.T~

eon.c:t _ _ A. .... ~1rIII1o""". due '" E. llllIl. ..., can ....., be ....-ol

_

lied pafllnllI.In _10, ...

.... aMlo,

IBn'I'lllnd 1hII ~ ... iNanI

_

'"

"',oideo

n-.

"'_,,"",,_.~-'11

OfIPopoiolio -...:.. - ' " boa er-€ :ti •• 0<1IIJ agaNI penlcWlin... pr01l
cer.o-.' ........ 1 _

- . II> boa

V

II

ncl

boa

10'.' II '"" 1*

WOIN

Pal' X.

et..... IOQIina e. do T."rdN"

i_

I ,_100 CSF.M

eII.a.

ltoe~,

. . . .10.1011

I

""MOl.

x , v, -. poaa.

~

...

gar . . .-.;;c: _".10 PI' WI. G. celoldtltl - . IltI uoed ... !hIM palienIs. 110 •••••• _ . . - be <&ad, enoa __ II tIbo:alI 510 t5'Jo_ _f

risIls IOn Ielus?

~.

Cor.-:'l d'>oloa _ E. Un!II<. .........

..-.e

he< sho'IIIs proceIn. buI no blood e gIuco&e. A Cl.ilIllItI is 18I<en. wtach of 1he toIowirto is uneIuI lor Irealing hsl.O'inary IrlI<:I inlllf;lion 0f1IlIy wiIhouI _

Ue' '" pen!'" paniot . . . . ojl·

bII;lod _

30.5 WI'lic:1'I on. 01 11'1. lollow;n, 1I.'..... nIS aboul Iokillilos flI c:eI .... synNlMi in INCOAAECT? A. n. __ 1i8lloJ CI pe, I A, in1hll ~ IUd in . . . . wI'Ien 10..10 I ,ed tel PBfieoltl_ ""'... .AI ""'.lgiM!ten ~ is when gi-.Io fIIlffNll ' . >I:iL

a F"or1I gar..""

s~ ~

at lowe. IIbdominat pain lind • 48-hou, hislQ<~ (II ¥UIia. StJa dOes fIClI _ any _ : lin anetysoa (II

'.Iei.hlGI'* """'....

poobeIiedd ..... _ ....... III

ThlI_.d+6t_IIl'iA"up-'

ll\f.

30.8 " pel;em ""lh degeneralive joInl i. 10 insenion 01 • hlp PfO'Il'*iI. In _ 10 _ _ .....,•• efo .. _ II) pou-opaollNe Iootlldioo~ !he ~ wiI Pfelr'6ll ... pMienI ....... an aflIibI. otic:. TlIin ~ has. sillflihcan' problem WOIh "erlicilii, , - IMIl SliIll!)1ocoocu ~ Wha:h 01 1hII ......,;"g a,libooli<:II shc:Ud IhIIU1Q11lflIJllec:l?

"'-va

A."" ........

B. ~'ipa.,' -unin C. GlnN,itioo\4llli...... J

_ tram. holiday ... '.1 • flI hM days; (II ctvsone 1Il doIicharQII. You Ila;r-.lI'Iis 10 be • _ or ~ WhIctJ Ol !hi kAiwing is IIlPP«4>iNlle bNb'''.?

30.6" 25-)'OIf-dd

lhII Far Easlllnd lind. puMerII

flo.. CeIlrial<_ ...

B.Pei ...... GIM C. Genlafricin ....

D. f'ipe
'Sla p. min iIIoc:J... ,~""Y (2rY:I ad.) "". ".... ...... cl.......,. ....1lbOliom.

D. ValCOTlJOo' CCO. . . .

eon.c:t.-_ D. llla"",,, • _ _ • .fle.;:l;ye .o.,n.' m.lhlellHn·...I".nl

!ilf!rlInArIr:J. ~ II . . _,.,on.

.........,., .. -... _,.

......

_-' _..... ...........

Protein Synthesis Inhibitors I. OVERVIEW A oomber of antibiotics el(ert their antimicrobial effects by targeting the bacterial riIx>some. wI1ich has components that dijfer structurally from those of the mammaliarl cytoplasmic ribosome. The bacterial ribosome is smaller (705) than the mammalian ribosome (80S) and is composed 01 50S and 30S subUf1its as compared to 60S and 405 subunits'. The mammalian m~ochondrial ribosome, however, fT10flI doseIy resembles the bacterial ribosome. Thus, aJIhough drugs that interact with the bacterial site usually spare the host cells. high levels 01 drugs like dlkYampheniccl or the tetracyclines may cause toxic elfocts as a rewlt of interaction with the m~oc:hondrial ribosomes. Frgure 31.1 lists lhe drugs (flscussed In this chapler

PROTEJN SYNTHESIS INHIBrTORS

-,---,.. --,-,..

""""""'""'

I

.....NOGLYCOSlOES

I

,-

~_.

II. TETRACYCLINES Tetracyclines [tel ra SYE kJeen) are a group 01 closely related com· polXlds thaI. as the name implies. consist 014 fused rings with a system 01 conjugated dooble bards. Their small differences in dinical efflCaCy reflect a variation in their individual pharmacokinetics due to wblStitu-

MACROUDES

lions on these rings.

-,.. ,-,..

A. Mode 01 action

£IylI>o""" .....

Entry 01 these agents into susceptible organisms is mediated by transport proteins unique 10 the bactllfial inner cytoplasmic membrane. Binding ot the d'ug 10 the :lOS wbunij of the bacteria! ribosome is believed to block access ot the amino acyl·tRNA 10 the mRNA-fibosome comrex at the acceplOr site. thus inhibiting bacterial protein synthesis.

B. Anllbaclerlal speetrum As broad spectrum antibiotics, the tetracydines are also ellective against organisms other than bacteria. Tel1acyclines are generally baCllJfiostatic and are the drugs of choice tor intections shown in Figure 31.2.

..J

CHLORAIrIPHENICa

I

-l

WND""""

I

Figure 31.1 Su'nmary 01 protein synthesis iMibitOfS.

Usee p. 322!o< InI
",-,J. _ _ ..

_ - . _ _ ..

to

=,_~ c.~

.. ..... """'-

311·

. . . . . ' . . . .101 • • _

• <.........- - -.., ....,..". -

... _ , .

_

.....

31. Protein Symhesis Inhibitors

312

-

'"'"

Go... (oj

...""""'",.... ,"",",n,.. ,' .... ,,,"ce<..

LYME DISEASE A q)IfochttallnM;1Ion

•

. . - by !!!!!!:!!!I1l!l.

g'

"toM.

• ...... r:-':'':~~.."lt .... _ ...... J o:lngcllo"l_ • •• 1r " ('I, ....,.,; ...

-----"'.'

-._Pl_·.... _.. . . f._~,

Agu.. 31.2 Typieallhenipeulle~.· alions of le~.

V>>despead ref513flCe 10 tetrae)dineS irTib Iheir clinical use. The mosl WI, .IOIty IlnIXUltered ~ occurring R laaof WIllets an InabiIily 01 !he organism 10 aa:urnulate the rhus prcl(IlJcing

cn.o.

'esistance. Ttis is aocolllp'stoed ~ a Mg" -depillld,iid active eflk.ol 0I1he drug metialed ~ f>e resiscanoe ptOlein TilIA. 0Iher mechanism5 liUCh as I" siJMl fT'NdifCalion 01 !he tetrlPeyl;lWle binding site hiMi also been reported. Ani organism 'esislBtt 10 one tetraeydine is resistanI to all. The majority 01 penici'l~ staphylooocd are (I(JN also ioseosiIive to ~

<........,.1'<_",,,,,,,,,,,,,

'"

II. Tetracyclines

1. Ab&Of"ptlon: All tetracyclines are adequately but incompletely absorbed alter oral il"lgllStion. However. taking lhese drugs conconcom~llf11ly ...,;It! dairy foods in the diet decreases absorption because 01 the tlmlation 01 l'lOl'IiIbsOt'be chelates 01 !he Ietracyclines with ~ ions. This is less 01 a pu;blem with ~ dine ldoll I SYE kIeen). NonabsorbaIM chelates lire also Iooned .,.;,.. olher diYalent and IriYalslt cations (br 8lUImp!e. 1ho5e Iound in magnesil.m and aluminum IIr'Itadds. a-.d in iron preparations). (Note: This PO! I e Its a potMm if Itle pe.1ient seIl-lreats Itle epgastric upsets caused by tetracycline ingestion w~h anlacids (F'vsa 31 .3 ).j 2. OlstrlbU1kln: The tetraeyclines cOllceutrate in the !Ner. kidney. spleen. and stdn and bind 10 rissues tlIldetgoit.., calcificaticw, (b .,...'. teelh and bones). Of 10 1...-notS Ihal ' - e high caIcit.m content (lor sample. gasIric carciroa'na). fW1eUalion inIO most body IIuids is sdeqllIl". AIItloogh all tetracyclines enlef" the cere-

I

r ij •

•

0"

•

if

-~-~~ --.•••• - ••

•

_ _ &olo,..... _ . "'_.jd~.

brospinal nuid. IeYeIs are insuniciet'd tor therapeutic efficacy. ella!fll1Df .,llilOC)CJi_lrni noe SYE kleenJ, ~enler& Itle twain in Itle aDMno8 01 nI\amm8tiOr1. and also fRl8IIIS in aears and 5iIIiYa. ThDugtl usetIJ in 81• • alH.., ... me""C!OOX' al carrier slate. mi'Ioc)dne is not eItec:tiIoR IDf cennl 0llI\QIS systEvn (CNS) iIIectiou$. AI tetrac)dineI 006S the placental bilrrier and QOI'lC8"IIrate in IeIaI ~ and deiotilial 3. F81e: Allhe tetraqdines c:onoenlrlde in Itle 1MIr. where Ihey are. in part, l'I'letabo'ized an:! ClOrfugaled to b'm r i ..... ~ The p&tenI drug anclIor its metab08_ are secqtOO inao he bIe; ITlO6I teIlal:.ydinM we I'6lIbeotbed in f1& inlllSline and enter the ..... by gIoil.LMi" liIlalioi~ ~ is 111'1 sin::e its metaboIile is ""elet...._,. mcaeted .... lhe blIe no Itle Ieces. TlUI, IriIut Olher ~ lbI)qdir'Ie e:atl be enIJ*¥ed in trealWlg i,lectioi. in -'Y COllpOF'led patielolS.

"",.,_iul

PO'"' ' __ ___ '

;:r/ h_¥ ...,,-............ -

D t)l')dI.glUI> II

E. Advene eftecU 1. GMble Iboot,Ifut t; Epigastric cistress COl.' ..... tv .esulls Imm in). taliotl (lithe gaslric fTlU:XlU (F"ogunl 31.•) and is oI1an respollSille IDf nco rCOil,pianoe in pelients lr8llted wiIh these drugs. The discomlDft can be COIltr....1ed if the drug is taken wilh toods othef f\an dUy products. 2. EtfeCb on cakIlIed .'-.. _, Depo6ition in the bone and primary denmion occurs during caleificatiOf'l In growing children; this causes dist::oIof1Iflon and ~sia (lithe teeth and a Iempotary $I~

(lI1lfOI"lh.

3. FSUlI hepttolOxlcIty: This side etfect has been lw1o.¥n to 0CQ.If in pregwlI women ....tlo received high doses of tetracyclines. especialy il they are experienclng pyelonephritis.

... cw

1 1

~, it

-.". ....-

__

-'"

'''''''.''''.'>'---'' 3t. Prolein Synthesis Inhibitors 4. PhototOl
S. Vestlbular problema: These side effects (for 8llample. dizziness. nausea, I,()miting) occur wrth m~ine, which concentrates in the endolymph 01 the ear and affects IUnclion.

'l

6. Pseuclotumor cerebrl: Benign intraaanial hypertension character· Qed by headache and blurred vision may oo:;ur in adutts. Tho\.Jgh discontinuation 01 the drug reverses 1I1e COf'Idition, it is rot dear whether permanent sequelae may oo:;ur.

7. Superlnlectlon.: Overgrowths of Candjda (tor example in the vagina) or 01 resistant stapt1ylococci (in the Intestine) may occur. 8. Contl1llndlcaUon.: Renally·impaired patients should nol be treated with any 01 the tetracyclines exccpI doxycycline. Aca;mUlation 01 tetracyclines may aggravate pr-e-existing azotemia by Interlerlng with protein synthesis, thUs promoting amino acid degradation The tetracyclines should not be entployed in pregnant or breast-k;e<J· Ing women. Of In children under 8 years 0/ age.

III. AMINOGlYCOSIOES Aminoglycoside antibiotics had beeI1 the mainstays oItreaiment 01 serious inledions due to aerobic gram-negative bacilli. However, since their use was I;mi!ed by serious \OlliciIles, they have been replaced to some erl8llt by saler antibiotics sud1 as Ihe third generalion cephalosporlns (see p. 3.14), the lluoroquinolones (see p, 323), and imjpenerTtcilastalin (see p. 3(6). Aminogtyoosides that are derived Irom Strectonwres have "myein" suUixes. w!1ereas those lrom Mi<:romonOSQQ!l! end In "micin." The terms "amlnoglycoside" and "amlnocyclilOr stem from their structure - two amino stJgaIS joined In gtycosidic tinkage 10 a central hexose (am;nocydltol) nueleus. A. Mode 018l:tlon Agure 31.4

Some adverse eIlects of te1racydine.

AU members 01 this !amity are believed to Inhibit baC1erial protein synthesis by the mechanism determined for s/Jeptomycin [strap toe MYE sin]. Susceptible organisms have an o>:ygen-dependenl systam that lransports the antibiotic across the cell membrane. The an~blotic then binds to the separnted 30S ribosomal subunit, inter· tering with assembly of 1I1e functional ribosomal apparatus, or causing the 30S subunit 01111e oomplete ribosome to misread 1t1e genetic code. PoIysomes become depleted because the aminoglycosides interrupt lhe process 01 polysome disaggregation and assembly_ [Note: The aminoglycosides synerglze with jl·laclam antibiotics because o1lhe ~ners' action on cell wall synlhesls. which enhances diffusion o/tha eminoglycosides Into the baC1erium (see p. 3(1).J

.."" .....,., .. _--,.

..............

.,

III. AmioogIycosides

_,_ .. _.....

INFECllON5 DUE TO

PSf:UOOI.lONAS AERtJGINOSA .~

..

!@W~ . . . . _-.,.~"'AT IiiACM_~_~dro.=' :

'-

TULAREMIA •

56",*,,''''''''' _ _ In 1fN1lr>g_

--IIn9-

, . . lymp!'l
dI_.

• T _ .. com""""Y lICqIII.od d'"'V In,,,,ted _ _•

•

Figure 31.5

-"-

~

byb

_

by

toun*- ........... ng

....b_~"""lloo,

",.,. fCUle,G"by

be"'_

TypQlI~&j.... alionsof~~~andami/l3dn.

Alao,oiIlOgtyoosides are badericidal. They lU ... ""-~ od1""'l61 aerobic organisms, since anaer0be5 lack the oxygen-requimg ............. 1 $ySI8fTl. sr~is used 10 treal ~ p!Bgle. luIartn'ia. lWld WI (lCIfTIbW1alicn wit! pa.... ~ • idocaIdilis ca'Se1 by ... ~ gIOI4llbef*Xn.i. Some ~ ...........tio..s 01 tour calf,..."" used &j,oiIKJgty<:osides. amikac:rl (lWTll KAY sift]. ~ 0I(jen Ia MYE sinL ~(toebra MYEtinj8l'ld $ ~ are 5hown WI Flgllf'l! 31.5.

C. Resll-'Resl6Ia1oe can be callSed by 1) doa Xed lIltake 01 drug whetllhl ~ Iranspol'1

31'1 aIIered

system lor aminogl',o:llsid is abse"t:

'&ee\AOt where the 30S ribo8omal Stb.lIlil bifodi '9 site has

a IoWafed affifIiIy

Iof ~ : ~led syothesis

or enzymes (fof llIlarrpe,

~.

I1lIClflo(idyIIrarISIerases. and pho6phoIftlIISIe,ases) lhal moQfy and ioadivate llfl'lifIo\t;c:

'"

,_.. _

..-.----..

. . . . .0 . . .' . ' . · _ . . . _ , ·

'"

.... '

31. Proleifl Synthesis InhibI\orS

enl)'ITlfI has lis own specilic:ity as to tubIt.ebe. ~ is not an irJvarebIe rUe.

aI'IIitlioli::a E8dl TWle of lilrale .. ..rtiotic;

NeIi6.1iai11l'lll TIL

~

sinl and wniMl:i't_1ess "'*'erable to these

enzymes It\8I'l are lie llf1er .. 'i"" • 0I1toir; group.

0._ 1. AclmlonIstnotlon: The highly potat, po/ycalionic stlUClwe 01 the ~ pce'lli U adeqI!Me IIb6orplior, after oraliO,..... trilliotl. n-08lebe. ill l\".oJr'lIides (~ tl(I(ltI'1)O'Il~ 011 MYE sinD must be giYcn pIlJBfII8IaIy 10 ac:hieYe adeqle~e 5eI\Itn IcYeIs.[Note: The severe nept.iAOxicily nsoda1ed with ~ pred"(1e$ petenlcral lldlT'lllistflltion, and ~s a.mII'lI use Is Wmiled 10 10plcaJ applicallon or oral treatment In hepatic coma 10 reduce 1M irlles1lnaJ bacterial pofIIAatioo.]

2. Ol,trlbo.llk)n: All ollhe aminoglycosldes have similar pharmaooklnetic properlies. Levels achieved in mo6t tissues are low, and penetration irlto most body fluids is variable. CoooonIrations In

AmmoglYCOSld~s

os<et:wospInal fluid are inadequate _ when the tro&llii '9ilI are inflamed. Except for neomycin, the aminoglycosides may be administeted irllraIhecaIy. High concentrations aocU'TIUIale In the

mer

renal oortBll and In the endolymph and periymph 01 the eat. votoich Il'IIy acou't lor lheir 1'IBphiOb
:L

S

3. F-'" Melabo'ism 01 the 3I'.oJyaleides does not oocur In the host. AI are rapidly BIla-eted into the ume. prl!domil\anlty by glolneo'l.llaf liltralion. AlXu'I'Uation occurs in patients with ,~ taillft. and ~ dose modilicstion (F"oglWe 31.6).

E. Adverse ettect. It is importarItlo mon~or peak and trough plasma leYCls (see Po 2Q) get1/llmicin. 1Cbrn1!1)til. netil~, and amikadn to a\Oid concen· trations that cause dos&-related tl))(icities (Figu,e 31.7). [Note: Peak levels are derlned as those oblalned '~ 10 I hour after infusion. Trough levels afe obtained Immediately belate Ihe ne.t oose.1 Patietlt IactoIs. such as old age, prlllllous BIlllOS' IfB to ~ sides, gender, and liver disease, lend to predispose pallents to adVerse reactions. The elderly are particularly susceptible 10 'lBPhooblidty and oloIo>IiciIy.

at

Agure31.6

--

sen.n co ... GaIXln5 01

/Otll~

IulkmiilQ "',liilisobaliol, ollhe same

do6e 01 0Ug to nomIlll and aaAei.it; patieRs.

1. otdoitIelty, Ok*WciIy l' n· .., and comlear) Is cinldly related to higfl peak p&asma Iew!fs and duration of lfeatmert. Dealne&s Il'IIy be ne-e.si:JIe and has been knoWn to atlect ietuse&., rMro. Pa\ietlts sirrUtaneousIy 'B( I·'i"g .. die 0klt0ICic .nog llOltl as the loop dUetics liM. flide, bumetanide, efhacr)nic add ( _ Po 227) 01" cispbtlin (see p. 396), are particutary al risk. Vertigo and loss 01 b8Iar1ce may also oocur because tht!se afIect the IIllSIb.Aar awaraIus..

avos

..........'., .. _... _'. IV. Macmlides

2. NeptnlIoxldty: RelEW1liorl 04 the ~ boIthe I)ftPnal lublAaf cells disrupts cat:ilm-mediated t
.r.:

3.. Newornuscular l* tljs side etIect most often resuts aftB"
IV. MACROUDES The maerolides are a g
"'a

A. Mode 01 action

The macTOIides biI'"ld ""-trsibly to a site on the 50S .uburIit 04 the bacterial ribosome. thus irlhibiting the translocation steps of protein synlhesis. Gemlfally T:XlI'ISicIered 10 be bacteriostatic, they may be tidal at hi{toer doses.. The binding site is either idenlicallQ or in dos8 pro#nilylOlhatlof ~ ~ ,a n d ~

B. Amlbecteri.1 &J)ectrurn Is etfective agaiflst the $8I'l"I(l orgarisrns as ~ ciIin G; lI""ebs, it II used in paIiens a' 19ic lOlhe pelicAos. In aU.; .~ it is the drug 01 cholce lor the trBDnenl 01' the "oI11Ctions shown in F"gure 31.8.

T. ErythromycIn

2.

~ has • spectn.m 01 anlibaderiaI ac:1iYity similar 10 !hat 01 ~ bUI illllso effa:::livg against HlWd.5 ill!! IftClIIB. lis actM1y against intracelluiat plthogenI such as Q"aaM1ia "" •• de lIf'Id UrNIQI1!5'M is higher Ihan lhal 04

err-

ItlfOll)ti'l (F"
Figl.IR 31.7

Some 80Iefse effeds of IWninoglyc·Udes

............., .. _... _,.

'00............._ _'

· .. •

'"

31. Prolein Synlhe8l8lnNbitots

UREAPI ·SMa

CKAMYOlAllNFE.CTlONS

.~

.e:-.ct"

~~ 0

......... _a1 _ _ ........ _bftdl .....

MYCOPlASMAL PNEUMONIA tw:__

.c.ole
t_-zlto.myt~~_

b I I _ .... _ l I " .............

lEGlOHNAIRES' DISEASE (LEGiOtIEI I (515)

...

. ~ ;;:~~aI

..

Figulll 31.8

TypicallhefapeIAic applicalions 04

~

3.

--

~ II'ool.9" less ac::Mt agIWlSl: sbepkXQI d an:l staphrll:Jl:l:xxj !han ~ is IaJ rrw:lfC adNe again5l: respiralDfy

inlections due to Haemoohilus influenzae and Mota~ eatantIaIiI. Ela;ept tor is msl. it is now lhe pteloned IhetaA' lol' urethritis e.. 'Md b'f CtJIanMiIlracbornalis. lIS activity against Mytrtw1llrilm il'iiI.!m in!rllNlllu!No callplell has no! proyen to be dinically important. except in AIDS patients wilh disseminated inIecIiof1s. C. Rulslanet

ErythtomycllI Ant",. om yc,,, C"",,t/lromyclll

Resislance 10 ~ is becoming a serio\.I$ elinieal problem. For ~ rrlO5t strains of sl8phytococ:ci ... ho6pitaI isola..... are resislan: to . . drug. $eYefal mee:haniSm!i haYO beef1 ~ed: (11 the inability 01 tho Ofganism 10 lake up Ihe anlibiotic; (21 a decreased etmily of the 50S tb:IolIomal $l.lb.rit lot !he .'I~ _lIiC resulting Irool lhe melhylalion of llr'I ~ of !he 23S blIcteriaI ribosoo'rlel ANA.; and (3) ptounce of a plasmid-associated eryItIromycirl esterase. BoIh dariltlromycjn and lulthromycin $hOw

o:rosS I . lance with ~

·."', .....,."

..... ..-,.

· _ · ...._ _ ..· .............. _ · w '

'"

IV. Macro/ides D. Pharmaf;:ok!netlu

1. Admlnllllrallon: The erythromycin base is destroyed by gaslric acid; thus either eoteric coated lablets or esterified forms are administered. AH are adequately absorbed on oral administration. Clarithromycin and azithromycin are stable to stomad1 acid and are readily abso
Comparing !f)'l#Iromydll •..wIth cIarltht'onrydn

.._"'~'"

..

~

'"--''''''.....

~~''''.~_M

2. DIstribution; EtylhfO(l'1)'Ci'l distributes well 10 all body nuids except the cerebrospjnal lIuid (CSF). It is one 01 the few antibiotics that difruses into prostatic tluid and has the unique characteristic of accumulating in macrophages. It concentrates in the live!. Inflammatioo allows fof greater tissue peoetration. Similarly. clar· iltlromycin and azirhromycln are widely dislriOOted in tissues, Serum levels of aziltlromycin are low; the drug is conce'1lrated in neutrophils, macrophages. and tibroblasts,

3. Metabolism; Erythromycin is exlensively metabolized and is known 10 inhibit the ol
j

"",

'd'

f

lli! aN

"iIC'

'.I1ob .!I.B,," ,,1,1

• .• wtth 8Zlthromycln 4. exf;:f'(lllon: Erythromycin and azittlromydn are primarily concen-

trated and excreted in aro active Iorm in the bile. Partial reabsorl'" tion occurs through the enterohepatlc c1rculatioll. In colltrasl. clarirhromycin and ~s metabol~es are eliminated by the kiQoley as well as the liver and ~ Is recommended that dosage be adjusted in patients with compromised reoaltunction. E. Adverse effedll 1. Eplg8lltric dllitreslf; This side ef1ect is common and can lead to poor patieot c:ompIian<:e lor eryrhromycin. The new macrolides seem to be beller tolerated by the patient; gastroilltestinal problems are their most common slde etlecls.

2. Cholestatk: jaundlc:e; This side effect OCO.lfS. especially with the estolate torm 01 erythromycin. presumably as the result of a twersensilivily reaclioo to the estolate fofm (Ihe lauryl sail ot the propionyl esler of erythromycin). II has also been reported for other fofms 01 the drug. 3. ototoxicity: Transieot deafness has beeo associated with eryIhromycin. especially at high dosages.

4. COntralndlcatlona: Patier>ts with hepatic dysfunc!ion shedd not be treated with 6/)'Ihromycin, since the drug accumulates in the liver.

. -

"",., ill' "''1 •., 0

",,,,,"';"":':.11

"!FdiIlS' 1

au

eN '

Figure 31.9 Antimicrobial activ~y 01 two new macrolides compared with thaI

of erythromycin.

·

,.,

.. - _,.

320

31. Prolein Synlhesis Inhibitors $.

•

. t

,r,

C&_........ C) $ 10. r--"-...

-r. . . . M

"w••",hi..

......."......

"eater

s._ _ .. ~oa

5'---£1,....

By!hromycin and dBri~ irlhibil the hepatic metaboism of /IIeq1IlyIirMI. warfarin, /erleII8dine. ~. car· ~ and cydospotine wt1ictI can Ie&d 10 IOlOc aca.rrua. tIons 01 Ihese drugs. An intel'llCtiDn with d/goxiIl may oo.:ur in _ patients. In Ihis case, the ao IIibiofic eIiminales a $JI8Cies 01 lntesUnllI !lora IhaI ~ lNictivat... 6goUJ, Itlus I ! *'11 10 reabsorpliorl 01 c:tigoG'llrom Itle II"IIen:lhepel cJn:Ua:tiorI. In~:

v.

CHLORAMPHENtcOL

cr...'......

)"*"

liod (kIor am FEN i kale) iii ~ and grart'I'fIega\iYe

-

acIve

~

a".;(le rarve 01

Oi\j3I""'" bl.t .......... 01 its kllcidry. ils use iii ,e6tIided 10 liIe-healefling .......... in whdlllere are no

......

1Se

1$

A. Mode oIl1Clion

The
~ 1eYeIs.

producing borIe maiTOW t~

e. Anllmlcrobl.lllpecirum

_.

Chloramphenicol, a broad spectrum antlblolic. Is active not only agalnSI bacteria but also against other microorganisms, such as rickellsiae. Chloramphenicol has excellent activily against an· aerobes. The drug is e;thllf bacteriCidal or (more commonly) bacterioslatic, depelldio Ii) on the orgatllsm. C. Resistance R"klmnce iIIlXIIllelled ~ 1hlI pres moe 0Illl"l R 1acIor. wt1ictI oodes lor .... acetylcoenzyrne A biilSleoase th3I inacIMlIes d*"lM~. ocI. Anolher mechanism lor resistarce iii essoda!'!ld ~ an inability d the 81llibio1ic 10 penelriIle 1hlI organi8m. This change in permeability n-.y be 1hlI basis 01 mollidlvg Ie '.s'lll"lCe. D. Ph8t1NlCOklnetlcs

ObampteWwlmay be adl'.!isle<ed eilher illtnr.oenousIy or oraIjl. It is

oompIeIo;y Ilboorbed via the oral

I\8tI.Q and

i'OlMi because d its lipopIlik

is widely dislr'b.MId Ihn:luo;;IOUIIhe ~ •• eadily mlers

Ihe normal CSF. The
dues. Excretion ollhe drug deperlds on lis ~ in the We< CIl'C/< .mpllen ,C'OI

to a glucuronide lhat is then secreled ~ the ronatlubtAe. Only 10'4 01 the parenllXII'ipOUOd is exaellld ~ glomeuAar fiIIra·

abotJ(

""'.

E. Adverse etlecls The dirOcal use 01 d1kxamphenicd is

Iirn~ed

because ol the serious

."""'" .

• .....0._'.' ....... _ , . VI. Cllndamydrl

--_.. .. _..... , """"'"

ad\lefSe etIects ee.....-lgted wtth Its IIdminiSlration. In addition to gastrointestinal upsets, overg
--_.. "

1. Anem"': Hemolytic IU'IOO'Ii8 ocx:uniI In patients with loW IeYaIs 01 ~uooae 6-ptIo6phate ~ (flOO P. 351). Qlher types 01 IU'IOO'Ii8 occurrlng as a !Ide etled 01 ~ i1c:Iude reV8fSlble anemia. I'«llch Is apparerllly doae-related and occurs concomitanlly wtth lhef8l7f, and aplaSllc anElITU, wtich Is idiosyn-a8tic and ~ !alai. [Nola: Aplastic anemia is ill(lepellde"t 01 dDae and may oceur after ~ has eel' 111 2.

3.

.00

o...y l*ry syndrome: Tl'is ar:Mna etled

oa:u~ in neonates if \toe do6age . , . , 01 ~1s rot ploperty aq.ostell Neonates hBYa a loW c.,.-My 10 glucoronidate !he llfIlj)jotic and Ihsy hBYa ~del
."iIdIol..: a ....,p.u isllllia 10 WU I5iOfT'8 01 \toe la.-piIIic n

met"'·

1d euctI 'ide, flus eleYdng , . .........IIIico. and ~ h!ir etIacIs.

rrilflld Iln;:licn "",.,

!I

drugs as.-1arin, ~

\Ius C8n t:t:Jck the

Iph-,an cNctp

VI. CUNDAMYCIN l'*'
1-10._.

.-",.

'"

If . . .

I I

"

......0._..,..

'· 31. Protein Synthesis Inhibitors Conlc:l _ _ • II. A.t ""'"

al lie kot>w'll .,

31.1 WtOctl _

"" _ NOT W-...;I

ns",

"Ii

lle

10

.... 1If ...._

]

'11'. llllIlib

It. They a.. poorly IIIlaoot>ed fmm ll'l$IfQinl8Slinal

,

._
........

......... o:lica........... Ill ......

Co
~

• C. M . . ."'\he ....... , .. , 010' • "" ..-. ur-" .........., and

pogrIr ~ 1Ic>m . . g

'" &1'' ' ' '_ricldal. ..... _ _

tapIdIy

in,""" _

T1IIy rtloIon'IIIl iii; .... 30S - . . . ollhl _'~'II riIJo. ll>t 01"11<: C
e. litll\l ol ....... , ....

*""" 10

'"
I.c~ thl o'Yll',,·dlplndent .~.tlm lllal I• •upon.lbl. ler "a"sportlng lhl anliblotlU ar~ the cytaplalr'Nc _ _• tM
Con_ ........... It. W~read rMlt\lln<» '0 1Itraqdr>e _ , If.- dII*:aI . - 01 ,... drug. 0ep0ribI 01 blllac:ydIne in ""*'lI)Io'll ...... 01 .... leila ..., lI'owinO cHdnln c... OCCUI. ThIt

lty ift

paleo1i;ll 1m ~

-.... t

31.3 v.tich _

al'~

Il;\ldI:-

mol..... o.Jty food, in

_"orb"

...

uaet

B. They ""... bIcI&ricidIIl propertilll. C. ThlY c.rl ac.... v. adrKlUall "rUm ... VilIS alto'" oral ~flIlicn. O. n.y tond 10'" 3DS ribotomIlI ~ E. ThIoy _ flCII ~ ~ ~.

3,2 v.tIocII
ltI4ll1aS

I _10

..

31.. All ol ... IolIcMlng prope
Corno::I
--

I ....

i' .. 0CIClft_ .... pIIIIierII....-....o .."a,el'.

- . . pt;': • _ .

B. LYlMtf C. Rod
~

'

-.roo _

-..."

It. Its ... _

concem.-....s.

tIr dilution and if'IIt;_ ..... " " ' ..... odolal ribo-. Ill . . . - _,, _ "' .... ......., . , . . _ _ .._ ..'

dl" ,," "..._~ t

_~. ' ...... _01 ... """ •

II

'"

""""*',.. , ....

18fIeI_.

31.5. ,. paliInI boling _ lor ",,"1:.1 an "PI*' Htt raceNes" anlibootic: _ ~

wr. _

wiIh I . . ~ ptOtIIe....

""1' ••• C8nlillc

.... lil<ely.dldc?

oIl1ll1lo7o:»4oQ alllleo.61t1-...1JBq'-

_INCORRECT? ,.. M;cumul,lion 01 tlt.acycfinfl, by 'UKlptibll organls"" i, mldilild by tlan,pen p,ote,n,

~

IocatId in 11'1I bectenal membra..... B. T.... r&q'ClinIr, even 111 higIl COl u"I,alloot, do nol 1111_ ITIIImmII~an CflIllTIIIIaboIilm.

C. Teuacydine' bn:Ilo 1h8::CS o.ubo5ornI WId bloc:lI prolein $)'1IhIslt. D. F'fIoIOlDllX:tly _ IInC
"ThI COfJ'ICI _ _ it C. Erylht<:rnycin lind _

..."...... Wd ... " <w" cllIIIIredna '1"i'4l- '" car> do pcitl&).

~and~_

E. 00xyr;:ycllnrI1t lie odf ••

_,dO......... may Iher

be

. - i n - - ' ; puienls..., _

's. p.3ll! ....

01_01,-

1........ (2W'IlId)"" ...........

,_

'Sea "'_ OI~~

I....bIlZ''''.I'''' ....._ .-..._

..........,., ........ _,.

Quinolones and Urinary Tract Antiseptics I. OVERVIEW Introduction 01 the first f1uorinaled quirlolone. norf/oJ(acin [nor FlOX a sin). has been rapidly followed by new members 01 this class. These ager1ts are totally synlhetic and are closely related structurally to an oor1ier quinolone. nalidixic acid [na! I DIX ik]. The principal member Of this goup Is ciprofIOJatCitl [sip ro FlOX a sin], v.tIich has the widest clinical application. Other antibiotics in this QfOUP available In the United States are primarily employed to treat urinary Infections (FlQUre 32.1). 11 seems likely lhal the sQe 01 this class 01 antibiotics will increase due to its wide anlibacterial spectrum. favornble pl1armacokinelic propel1ies and relalive lack of adYerse reactions. Unlorlunately. their overuse has already led 10 !he emergence of resistanl strains resulting in limitalions 10 lheir clirlical usefulness.

QUINOLONES AND URINARY TRACT ANTISEPTICS

f--

FLUOROOlIHOl.ONES

II. FLUOROQUINOLONES

I

~

,-

The older drug, nalidixic acid, is a nonfluorinaled qulnolone, and is not eHeclive against systerric infections. Its use in !he treatment 01 urinary tract Infections (uns) is lim~ed due to !he rapid errergence of resistant strains. JI win be considered In a separale section below. Unless care is laken to employ these druga In appropriate Infrective stales. il is possible thaI their value will be lost

-au_ ._-~~

r......_ _'

f-

A. Mechanism of action The rluoroqulnolones enter the cell by passive diffusion Ihrough water·tilled prolein channels (porins) in the outer membrane. Intracellularly. lhey ~ Wlibit the replication of baderial DNA by Interfering with the action of DNA gyraae (topoisomerase II) during bacterial growth and reproduction. [Nole: Topolsomerases are enzymes thaI change the confi!JJratiOn or topology 01 DNA by a nicking, pass--lhrougJ and re-sealing mechanism withoul changing its primary structure (f9.Ke 32,2).]' Binding of the quinolone to both lhe enzyme and the DNA 10 form a lernary complex inhibits the rejoining

"-

URINARY TRACT

""""Pr<S

I

_N

FIgure 32.1 Summary 01 drugs described in this chapter. 'Descrbed in Pharmacology update, p. 456

_ _ _ _'ft.

'". _ _

...... _ _ ..._

_c...........

~

~_._

•

PAD......

323·

<"0"0'''''''<_'''_'' 32'

32. Quinolones and Urinary Tract Antiseptics step and can cause cell death by IndUcing cleavage or the DNA. Since DNA gyms£! Is a distinct target lor antimicrobiallherapy. cross· resistance with other more commonly used antimicrobial drugs is rare butlncreasillg In the case ot multi-drug resistant organisms.

B. Antlmk:robllillped:rum All 01 the rluoroquinolones are bactericidal. In general. they are effective against grllmonegaliYe organisms such as the enterobacteria, pseudomonas organisms, Haerooohilus jollueuzae. Mornxl)lla calanbalis. Looiooella. Chlamydia and mycobacteria except !of M. iolrnoollulare complex. They are eflective In the treatment 01 QOOOrfhea but not syphilis. Though active against some ~posi­ tive organisms. they shOUld be ll\'(IKled In the treatment or pneumoccal or enIerococcal infections. Their 9CIiviIy against anaerobes Is poor. II used prophylactically belora transurethral surgery. they loWer the incidence or postsurgical UTIs.

aw.m

1. Clprol'IOIl8dn: This is the most polerlt ot the fl~nolOneS and has an antbacterIaJ spectrum slrnilar kl that of norlIoxacin (figure 32.3). CiprofIo"adn finds use in the treatment or pseudomor\lls iolections llSSOCiaIed IMIh cystic fibrosis. The serum IEM!is l\d'ie.Ied are effectiYe agai'\sI marry ~ iI1JecIions with \he exception of serious inrections caused by mertlidllitHesistant S18D11y1ococcllS ll&IUlWi (MASA), the enterococci and pneumococ:ci. ~ Is parl1cularly userul In treaUng in/ectlons caused by many EIlIerobacIerIlc and other ~1iYe bacil~. CiproI/OllaI:in is an a1temaliYe to f1"IOlll lOI
j

§

2. NorIIoJt8Cln: This agent is effectiva against both gram·negative

j

(including Pse!!dornonas aerugjoosal and l1am-positive organisms in treating complicated and ur.complicated UTis and prostatitis, but not In systemic infections.

§--Fron..... _

ol_

.. " ••• led

FIgure 32.2 Act;on of type II DNA topoisomerase,

3. 0fI0JUIC1n: Uke ncrtk»i8Cin, ofIoxacin (011 FLOX a sin] Is primarily used in lhe treatment of prostatitis due to E. .l
See p. 456 tor a description 01 newly 8PPfO\I1'ld drug. IrovaIloxBcitl. C. Resistance When the lIuoroquinolones were first Introduced. there was optimism that resistance would not develop. AlIhough 00 plasmid..fOedt. ated resistance has bean reported, resistance or MRSA, pseudomonas. coagulase-negative staphyk;lcoccl and enterococci has unlortunately emerged due to chromosomal m.Jtalions. Crossresistance eldsts among the qUioolones. The mecharisms responsible lor this resistance include:

<

'.,.<_

.....-\>

""

II, FlUOroquinolones

eC_.ndtwoclWl I . . . .

_II

_1O_oI _ _rt>o_

Hi..,...... " ..

figure 32.3 TypicalltM:!mpeutic appIic:alions 01 ciprollox.8cin.

1. Altered target: Modifications in the bacterial DNA gyrase. especially in amino acids al the N-te/mlnus or the A subunit. have been aSSOCiated with a decfeased affinity lor the ftuorOQUinoione. The B subur1it 01 lhe gyrase is rarely rnJlaled. 2. Decreased lClCumulallon: Reduced Inlracelh,lIar ooncent/ation 01 the drugs in the bacterial cell is tinked 10 two mechanisma. One lnYoIves a decreased rllnlber 01 poriI1 proteins in the outer membrane 01 the resistant cell, thereby impairing access 01 tile dnJgS to !he in1faCellular gyrase. The oIhef medlar1ism is associated wittl an energy-dependenl ef1\ulc system In tile cytoplasmlc IllefTlbl ana.

•

D. PharmacokineUcs

1. AbsorptIon: Only 35-70% or oral norfloxacin Is absorbed. However. 70-90% 01 the other rluoroqulnolones are absorbed after oral adminlslration. BioaVallability Is grealest lor oflOJ/8Cin and /om6flOll8Cin Intravenous preparations 01 ciprof/OXaCin and ofloxacin are available. Ingestion 01 the lIuoroqulnoiones with sucrallale, antacids conlainlng aluminum or magnesium, or dieIa1y supplements containing iroo or zinc can Inlerlere with the absorption of these 8I1tibaclerial agoolS.

Fluoroqumolones

'''''''0''''''''_'''_'' 32. OJinoloI1es and Urinary Traet Antiseptics

2. Distribution: Binding to plasma prolelns ranges Ifom 10 10 40%. [NoIe: Plasma levels 01 free norf/oJaJ(;in are insufficient lor trealment of syslcmic infectIOl1S.] All lhe f1uoroquinolot1es distribute well Into aU tissues and body fluids. Levels are high in bone, urine, kidney and prostatic tissue (but no! prostatic fluid). and conCen1raHans in 100 lung exCOO(/ those in serum. Penetration into cere· brospinal fluid is low except for o/iolracin where concenlrations can be as high as 90% ot those in lhe serum. The lIuoro· quinolones also accumulate in macrophages and poIymorpho· nuclear leukocytes. lhus being effective against intracellular organisms such as Lootooella.

3. Metabolism: EJccepl b" ofIoxat;in and ~ . these agents are partially metlbolimd to C()I"Il)OIX1ds with less antimicrobial activify. 4. Excretion: The parent drugs and their metabolites are ex(;reted into the urine where high levels can ()(;(;ur This is lhe major CJ
E. Adverse reactions TOxicities similar to lhose for nalidixic acid (p. 327) have been reported for the tllXlroquinQloncs (Figure 32.4). Besides diarrhea. the following ad\IC,se reactions may be encounlerc
1. CNS problems: The masl prominent side effecls are nausea, headache, and dizziness or lightheadedr1ess. Thus. patienlS with CNS disorders, soch as epilepsy. should be ,reated caul;QUSJy wilh lhese drugs.

2. Nephrotexk:lly: Crystalluria has been repor1cd in patients receiv· ing excessive doses (3-4 limes normal).

3. Phelelexlclty: Palienls are advisc
"EP~~OTOXocm'

..::...\;11.. .c\::.. .'

Agum 32.4 Some adverse reaetiol1s 10 ftuorlXlu;nolones.

'.

4. Coolralndleallons: Fluoroquinolones should be avoided in preg. nancy, in nursing mothets and in children under 18 years 01 age, since articular cartilage erosion (arthropathy) experimental animals.

occurs

in lmmalure

5. Drug Interactions: The eUecl ot antacids and cations on the absorplion 01 these ager11s was consi:acin can increase lhe serum levels 01 theophylline by Inhibiting i1s metabolism. They also may raise levels 01 warfarin, caffeine and cycJosporine. Cimelidine interieres w~h the

•

· - . . . . .,., > . . . . . . . - - - , >

_ _ M ....

,

"""""" .. _

....

>

IV. Urinary TraCl Antiseptics elimination 0' lhe 'lllOfOquil1ol00es. EnOJl'acin wt1en adminislefed concurrenlly wilh anti-inflammatory fenoprolen has been reponed to cause sei~ures.

_N --w_

,.."

COf ...... ~i.llon

CycJc¥C-lo ..

III. QUINOLONES Na/i(jx;c add is a t\Of1f1l1Or\r\aled quinolone wilh !he same mechanism 01 action as thaI 0I1he fluoroquinolones. 11 is effective egainst most 01 !he gram-negative bacteria that commonly cause UTls but gram-posilive orgaJ1isms are resistant. Its ctinical Usefulness is limited by the rapid emcrgencll 01 resistant S1rains. Well-absof'bed. most (>90%) of the drug Is protein bound and levels oIlroo drug are therefore inadequate lor lreatmenl 01 systemic infed;ons. HydtoxyIalion leads 10 the mora potenl bactericidal compound, 7-tr)'drOl
'.-0-

.. "'''''", 0fI0.-:In

ellecls ara nausea, vomiting and abdominal pain. PholOS11nsitivity, urticaria and lever can occur. eNS problems ranging 'rom headache and malaise to visual disturbances are rare. Therapy lasting longer !han 2 waeks can advf:!rseIy alleet livef fUnction.

IV. URINARY mACT ANTISEPTICS Urinary tract Infections (UTI, most comrT\Of1ly uncomplicated acute cystitis and pyleonephritisj in \VOfl'oOO 01 ctlild bearing age. and in the elderly, are one of the most common problems seen by primary care physicians. Escberictlia J
un may

A. Melhenamlne

1. Mechal1hllJl 01 actkm: 111 order 10 act, methenamine [rneth EN a meer1] must decompose at lll'1 acidic pH ot 5.5 or less In the unne, thus producing Iormak\ehy(le, which Is loxic to most beetefia (Figure 32.5). The reaction is slow, requiring 3 hours 10 reach 90% ~ioI'l. Methenamine should not be used in patients with il1dwelling catheters. Bacterial reSiStance to formaldehyde does I10t develop. [Nole: MellJenarrnne is trequel1t1y formulated with a weak acid such as mandelic acid, which lowers the pH of the urine thus aiding decomposition of the drug.] Figure 32.5 Formalion of lormaldef1yde trom methenamine at acid pH.

'''''''''''''''''-'''-'' 32. Cluinolooes and Urinary Tract Anliseptics

2. Antibacterial spectrum: Methenamine is prima.ily used tor chronic suppressive therapy. Urea-splitting baclefla lhal alkalinize the urine, such as proteus. are usually resistanl to the action (J rne/l1enamine. Methenamine is used to lreat UTI. but Is not effective in upper UTI. 3. Ph.........coklnetlca: Merhenamine Is orally admlnistered. In adlfi. tion to formakletryde. ammonium ion Is produced in the bladder. Because the live. rapidly metabolizes ammonia to form urea, me/l1anamine Is contraindicated in patienls with hepatic Insufll· cilfficy, In which elevated levels 01 circulating ammonium ions would be toxic to the eNS Merhenamine is distributed throughout the body fluids. but no de<:omposition 0I1he drug occurs at pH 7.4; thUS, systemic toxicity does r'101 occur. The drug Is eliminaled in the urine. Sullonsm'des

4. Adverse effecIs: The side effects include gastroinlestinal distress. Al higher doses, albuminuria, hematurill and rashes may develop. Merhenamlne mandalare Is contraindicaled in treating patients with rCrlal insutfideocy, because mandelic acid may precipitate. Sullooamicles read witt1 formaldehyde and muSI not be used con· comilantly witt1 methenamine.

C. Nitrofurenlo;n Nifrolurnnto
an

active agent thaI inhibits various enzymes and damages DNA. Activity is greater in acidic urine. 2. Anllmlcroblal SpeClrum: The drug Is bacteriostatic. It Is useful

against Escherichia Q:lli, but ott1er common urinary IraCI gram· negative bactelia may be resistant Gram-positive coed are sus·

ceptible. 3. Aeslstance: Resistance Is constilutive. It is associated with an Inability to reduce the n~rogen goup in the presence 01 oxygen. Resistance does not dcveIop during therapy. 4. Pharmacokinetics: Absorption Is complete after oral administra· tion. The drug is rapidly excreled by glomerular fmratlon. The

presence 01 tile drug turns the urine brown, a surprise for unsuspoctlng patients.

5. Adverse eftects: s. Galltrolnleatlnal dillturbllnces: lhasa side etfocts Include ne.... sea, YOrlliting, and diarThea. The macrocrystalline form is bet· ler tolerated. Ingestion wilh food or milk ameliorates these symptoms. b. Acute pneumonitIs: This is a serious complication. Other pul·

• ..., '0, ..,., .......

,•

•

.,.,.. M _ _ - . -. . ,

""""'" .. _

.....

IV. UMIiry Tract Antlaapliai

ACUTE PYELONEPHAmS

•

__ • "I•_no"!' _ _ _ _ fIwa'.oog/')"'IIM

"'~a,;!

"oF

'-

',_

pod . . . . ' . -

•

roonary fltlecta. such

a.

if'ItetStiti8l pulmonary libtosiis. can

oceur n plltients being d;CWLlly In!llIed.. c. ...... rologlc8l probIe....: Neulologiell side elfects sud'I as he "ladle. ~ and polyrlIuOpalties wi1h del I ,eli oar IioI'I (90"'l'lih6Iedlg 10 lootdIop) mey de\ I~ cL '1eo11Olylle _ _: The drug Ia ~lld gItK(I! B

~ pelienIs ~ 6 phoIphatl deI1ydrogeIlase 00fieiency. neonates.

and pregnant women,

Agenlll Wi II.IOI'Y UI8ll ~ U11Wi liPIlealed un IIIl'fl !lI.IT\'TIlIIIZ n P'OIJI'fI32.6),

. . . . . ,., ...._-,> 32.

32.1 IIlI 01 lhe IDllowing statemenlS about methenamine are tr\.Ie EXCEPT: A. It is used ;" ctll"Cltl4<: supp.-essive therapy 01 urinary

Clf.Jinolones and Urinary Tract Ar1llseptlcs

32.3 A 26·year-old )'e best choice In lmating him? A. CiproIIo>
II&Cl infll<:tions. II has its major anlibactentralndb1ed In rena) insutfociency. D. /I may all1$II gastric disluoba<1cel;. E. 11$ anlimicJObiel activily is contined 10 ItIe umary

a

E. l.omello>tacin

,~

Cor..a._ _ D. ()I\()ll.cln he. the but lII:tMI)' cf .. Ihro ~""""_lIlIIW* bolh IJO"O'. _ end ~ . _... NillkbIc 8Cld II

CClntod c:IdI:e. B. MeIl1eI..'." _ b ....... ......., .,..,. • -**' pH---I'liI: II ... - . tr.l Ihll ~ II oI1etl ~ wlIl'l I _ IClll lIUCh as 1181_ add 32.4 32.2.

I~

whicll one dtM IolIowing Inl9Clions 8fl1 tl>e Iluo-

rcquinoIones Ineffective?

~rofIo>:acirl

and le1l8Cydine have aN ollila follow·

ing p
6. Pneunx>nia due 10 Strep!prorOl5ll!l!l!Jl'1lQfj C. EKace,llation of chronic b.onchitls due to MOfillCella ca1autlaJ!§.

A. AesiSlam otgIlnisms lla.e an increased ab;lity 10 ~ out the drugs. B. Absorption cen be decreased by concurrent administration with aluminum or rna~ c0ntaining antacids. C. Botll can cal1$ll severe phoI01OI
D. Urinary I.actlnfection due 10 E. Q;l!j. E. UTIs due to P... ithnmas perugioo<;i.

E. 60th are depoSiled in devfIloping bones and leeth.

A. UTIs due to a !l--Iaclamase-produclng strain of

KIebsiIllIa..

Col'oecl _

•

e. n-.

~

D. 60tll accumulate wlIll dIl<:rtla$ed renal fundion.

do

nor " - sUIclmt acntrv . . . S. IIl'MlllO: liM '" be eIfcIivI. SInce 1tII¥ we not ~

11...... the lIuoroquinolonN ••e eff1ICtIvfI In IrMIIrq UTIe cauoed by ~ "'\Jif"'''~_IIIOIo.

1or_,.Cclth&_._.-.

I

Co"ee. choice. E. Ollly tltrlcycllne II del> • 110l bene and 1lJJI1s lX>I'I> • • 1Io j Iol cN'lg e>:pllrim8IItII anlmIls. which 101 wrly K Ie cont
011..- ...

,.,to~lobolh~

• .....o. . . . . ' . . . . . . . _ L >

•


,

.... >

IM:AIIJI . . _

Antimycobacterial Drugs

,I. OVERVIEW The modern era ot tubefculosis lt1erapy began with the introduction of streptomycin. isornazid. and p-i.HTIinosalicylic acid and today multidn.>g lt1erapylllCludes drvgs liSled ir1 Figure 33.1. The number 01 cases of tUberculosis waned and Ihere was hope 01 complete eradication. Indeed. predittions were made lt1at tuberculosis would be almost nonllllislent in the Uniled Slates by the year 2002. However, In the past decade, tuberculosis cases have signifil:anlty increased, dlielly among AIDS patients and the homeless (FlQUre 33.2). Today tuberculosis is still the leading cause of death by Inlectious disease throughout lt1e ~.

ANTlMYCOBACTEmAL AGENTS

II. CHEMOTHERAPY OF TUBERCULOSIS MYcobaetf!rjum tuberculosis, O!1e of a number of mycobacteria, can Jaad 10 serious intllClions 01 the lungs, the genitourinary trae!. skeleton, and meninges. The myoobaeteria are class~ied 0!1 the basis oIlt1e1r staining propertles. [Note: Though difficult to slllin oocause 01 the presBOOB 01 an outBl coal of mycolic acid, once stained they hold the stain BYIlO in the preseoce of destaining agBf1ts such as acid. Thus they life referred to as "atid,'asl".) Treating tUberculosis as well as other mycobaclerial infections presents therapeutic problems. The organism gows slowly. and thus the disease may have to be treated lor I..P to 2 years. especially it it is caused by a resistant organism.

I-

Amlr7 • 'i
-,

......-

'-

A. Strategies for addressing drug IeSlstanee

DRUGS USEDTOTFIEAT

Because strains ot the organism resistant 10 a particular agent emerge g therapy is employe
or prevent !heir emergeoce. lsooiazid, rifampitl, elhamlJutol, streptomycin, and pyrnziflamide are the principal or so-called "first line" drugs because 01 their efficacy and aceeptable degree 01 toxicity. HoweYer today, because 01 poor patienf compliance and 0Iher factors. the number 01 multidlllg-resistant organisms has risen. Some bacteria have been ideoliIie
--""" .- ,,---

DRUGS USED TO mEAT

LEPAC)S,

Figure 33.1 Summary of drugs used 10 treat mycobaclerial infections.

--_ ........ J _ _ "-

.....

....-_~_...

'".-c._.

..P"-D_

331

< ,.,.<---,. 33. AntimyoobaClerial Drugs

m-lnlLt JI,.I. .. _ _ ~ 1 0

40

In AIDS'" ...,11I11>0_

~

in duration and in agerns employed, they always include a mininun 01 two drugs, prelerab/Y bott1 cidal (see p. 283). Togethef!hey should prevent the emergence ot resistant strains The regimen is c:ootinued well beyond tile disappearance 01 clinical disease so as 10 eradicate any persistent organisms. For example, the SI"lOrt ooursa ctIemottler· llP'Iloc tubl!rClJlosis includes iscniazid, rifampin and pyrazinamide for 2 months. and isoniazid and rjfampin lor the next
B. lsonlaxid

.

..

'.

".

•

"'m-~,m;-~,_=-~-~,_=

Figure 33.2 Incldence of new cases of tuberculosis.

Isooiazid [eye soo NYE a zid]. the hydl'i\OOe 0/ isoniootinic acid, is a syntheIic analog 0/ popicb:ine. It is the most potent 0/ the anti-1JJJeroJ1al" dnJgs. b.JI is nlMlI" liven as a singe agent 001 the trealmef1t 0/ acIiw tuben::ulosis. Its irl1r'o
.

1. Mechanism of actIon: Isoniazid, otten relerred to as INH, is believed to target the enzyme responsible tor assembly ot mycolic acids i"to the Ollter layer of the mycobacteria. a structure unique to these organisms. M)'COIic acids account to< the add-fastness ot the mycobaaeria; this property Is lost alter IIXpOSUre to isoniazid.

2. Antlbaclel1a1 spe<:trum: For bacilli in the stationary phase, the drug is bacteriostatic, bullor rapidly dividing organisms. II is bactericidal, It is effective against intracellular bacteria. Isoniazid is specific for llaatment ot M. tuberaJlosls. slthoUgh MlICObaclerium kansasii may be sosceptible at higher dfug 1ev€oIs. wt1en It Is used alone. resistant organisms rapidly emergll.

3. Reslslance is associated wilh lhe constitutive Inability 01 the organism to accumulale !he drug. There is also suggeslivG evi· dence that the targe! oo:tYfTlll may be altered so as ootID bind the isoniazid, or that excessive amounts 01 the enzyme may be pro1n"p1d~

_ld ...... _

r..rl-IH. t~

1h.,

Figure 33.3 Bimodal dislribution of isofliazid halt· lives caused by rapid and slow acetylation 01 drug.

duced so that the drug is overwhelmed. No cross-resistance exisls between isonial:id and other anli'llA>ercu~ drugs. 4. Phannacoklnellcs: The drug is readily absorbed orally. Absorpfion is impaired ~ taken with Iood. particularly carbohydrates, or wifh alurninurn-<:onlaining anlacids. Isoniazid diffuses into all body fluids, cells, and caseous male rial (necrolic tissue resembling cheese); levels in the cerebrospinal Iluid (CSF) are about the same as tl'losa In the senm. Infected tissue lends to retain the drug tongar. The drug readily penetrates host cells and is elIective against bacilli growing I"tracellularly. Isoniazid undergoes NacelylaHon and hydrolysis. resulling in inacfive products. Acetylation is genetically regulated; the last aootylator trait is autosomally dominant. A bimodal distribution 01 lasl and slow acetylatofs exists (Figure 33.3). Chronic liver disease will decrease metabolism. and doses must be reduced. Excretion is through glomerular fitlralion, predomioantly as metabolites. Slow acetylators excrete more 01 the parent compound. Severely depressed .anaI lunction results in accumulation ot the drug, p1i. madly in slow acetylalors. The drug is also excreted into the saliva. sputum. and rnilk.

'

. . . . .0 . . . ' . ' . , _ . . . _ , .

• .._M ...._

............. ' ............. _

.....

U. Chemotllerapy oIlUbertlJosis

333

5. Adverse effects: The ioc:idence 01 alM:irse eHeets is Iairty loW. Except /of hypersensitivity, they are related to tha dosage arld duratiorl 01 adminiS1fatiorl.

a. PeflpheraI neuritis: Peripheral neuritis (manifest as paresthesia) is the most commoo advefse effect, which appears to be due to a relative pyridc»:ine deficiency. This has been allJibuled to a competition 01 jscni8zj(j with pyriooKal phosphatv lor the

.,,,,,,,,.-

enzyme apotryptophanase. Most of the!oll:ic reactions are corrected by pyrido~ine (vitamin B 8 ) supplementation. [Nota: Isoniazid can achiave levels ill breast milk that are high enough to cause a pyricloI(illO 6eficiency ill tile inlalll unless the motIler is supp~ted with tile -msmin.) b. Hepatllis and Idiosyncratic hepaloto~lcity: Potentially Iatal hepatitis is the most S9Yfl(e side effact associated wiltl isoniazid. It has baell suggested that it is caused by a tOKic metabolite 01 mOlloacetylhydrazine tormed during the metabolism of isoniazid. lis incidence increases among patients wi1h increasing age, among patients who also take rifampln, or among those who imbibe alco/'(lI
--

Figure 33.4 /SOfIiUjd potentiates adverse effects 01 phenytofn.

c. Drug interaction.: IsooIa.zidcan potentiate the adverse effects 01 phenytoin (for e~ample, nystagmus. ataxia. soo p. 146) because the isoniazid inhibits metabolism 01 phenytoin (Figure 33.4). Slow acetylalOrs are particularty at risk. d. 0I11ef adverse effects: Mental aboormal~ies. convulsions in patients prone to seizures. and optic neuritis have been

observed. HypersensilMty reactions include rashes and

~.

c. Rilampin RifampinlRIF am pin), derived !rom the soil mold Strectornyces has a broader antimicrobial activity than iscnilUid and has tourld appli· cation irl Ihe treatment 01 other bac!efial irlteetiorls. Because resistant strains rapidly emerge during therapy. ~ Is never given as a single agent irlthe treatment 01 active tub&rculosis.

1. Mechanism of action: Rifar1¥Jjn blocks transcription by inIemcIing with the li-subunit 01 bacterial DNA-dependent RNA polymerase', Itlus inhibiting RNA synltlesls by suppressing Itle initiation step. The drug is specific tor prokaryotes. 2. Anlimlcrobial spectrum: Rifampin is baCtericldallor boltl intracel· lular and e~tracellular mycobacteria, Including M.. IlJberculosls, atypical mycobacteria, and Mycobacterium ~, It Is effective against many gam (+) and gram (.) organisms and is lTequenUy used prophylactically lor household members ell:POOOd to menin· gitis caused by meningococci or Haemopbjllls jn!lu8nzae. Ri/ampin is Itle most active antileprosy drug at present, but to delay emergence 01 resistant strains It is usually given in combi· nation with olher drugs. RifablJtin. an analog ot rifampin. has some activity against MYCQhar!erium in:iwll jntracelluiare com· pIex. but is less active against tuberwlosis. 'Sole P. 336101' _

""",....,..10 _ _ in It>Ol -w.o.

... e '--

~

•

/'

•

.r "

=~MS\

h_

!sanoazrd

I

I., ><

<_ro, ..

, >

3. Resistflflee: Resistance may be caused by a mange in the affinity of the DNA-dependent RNA polymerase for the dfUg, or by decmased permeability.

• ~ !<:)i

---•• ..#'JI ----

4. I'harmaeoI
./

0'

_boI~

,~

an. thin! 01 t

In the l>I1ne

,

\

/' \

,)

Distribution rifampin occurs to all body lIuids and organs. Adequate kM!ls are attained In the CSF even in tho absence 01 inflammation. The drug is faken up by the liver 3Ild undergoes enlcrohepatic cydfig. RIfarnpfr! itselt can indoce tho hepatic rniJre
RilampUl

5. Adverse alleels: Adverse ellects afe a mInor problem with ritampin. but can inetude nausea and vom~ing, lash, and lever. The drug should be used judiciously in patients with hepatic fail· ure because Of the iaundice that oocurs in patients with chronic liver disease, alcoholics, or in the elderly.

6. Drug Interactions' Because ri/ampin can induce the cytochrome P-450 enzymes (see p. t4), ~ can decrease the haff·lives of other drugs that are coodministered and metabolized by this system (Figure 33.5) This may lead to higher dosage requirements these agents.

'or

C. Pyrszinllmide

Rlrampin

Pyrazinamide [poor a ZIN a mtdeJ is a synthetic oralty etleclive bOOtericidal anti·fubercular agent used along with isoniazid and li/ampin. It Is bactericidal to actively dividing organisms. Pyrazinamide must be enzyma1icalty hydrolyzed to pyrazlnoic add whict1 is the active Iofm Of tho drug, SOme resistant strains fad< the pyrazinamidase. However, the mechanism Of rts actioo is unknown. It is active against !Ubefcle bacilli in the acid environment Of lysosomes as well as in macrophages. Pyn:uinamide disllibules tIlrougflOul the body penetrating the CSF: it also undergoes extensive metabolism. About '-5% of patients taking isoniazid, rifampirJ. and pyrazinamide may experience IMir dysfunction. Urale retention can also ocx:ur and may precipitate a gouty attack (FIgure 33.6).

D. Ethambutol

Figure 33.5 Rifampin Induoos P·450. whict1 can decrease halHi!e 01 coadministercd drugs !hat are metabolized by this system.

Elhaml}utol [e THAM byoo tole] is bacteriostatic and specific Iof most strains 01 M. Iubefl::ulosis and M. kansasjl. Resistance is not a serious problem it lhe drug is employed with other antituberculous agents, £thamoolol caI1 be used in combination with pyrazinamide, isoniazid, and I;tampin to treal tuberculosis. Absorbed on oral administration, elhamoolol is well distributed throughout the body, Penetration into the central nervous system (eNS) is therapeuticalty adaqJate in tuberculous meningitis. 80th parent drug and metabolites are excreted by glomerular filtratioo and tubular secretion. The most Important adverse elfect Is optic neuritis, whict1 results in

<_

,.,.<_ ... _

'0' ..

L>

._M

. . . .'.. . . . . . _.....

III. Chemotherapy 01 Leprosy

3J5

diminishad visual acuity and loss 01 ability to discriminate be\V.~en rad and green. Visual acuity should be periodically examined. DiStXl!1~nuation 01 the drug resutts in reversal 01 the toxic symptoms. In additiotl. urate excretion Is decreased by the drug. thus gout may

be ~cerbated (Rgure 33.6). E. Alternate $Kond-.lne drugs

A number ot drugs-aminosalicylic acid [a mee noe sal i SIL ik]. ethionamide [e lttye on AM ide]. cydoseri'Ie [sye kIoe SER 00<1]are considered second-line drugs because they are no more effec-

I' /e «... ",."",,~

tive than the rirst·line agents and their toxPcities are ollen more serious. Streptomycin. the rirs! an~biotic effective In the treatment ot tmerculosis. has been discussed wIh the ami~sides (see p. 314). I1s action is directed against extracellular organisms,

Flgul'1! 33.6

1. Aminosalicylic acid: Because it is pollfly tolerated, aminosalicylic acid [a moo noe sal i SIL ik] is inrraquenUy used today. It is a baC-

attacks.

"~Pyrazinamide and e/t1aITItwIoI may cause urate reletltion and gouty

teriostatic agent that acts as a competitive inhibitor tor paminobenZoic acid (PABA) in lolale biosynthesis'!.

2. Elhlonamlde: This structural analog 01 isorliiWdis ~ieYed not to act by the same mechanism. It is etIeclive after oral administration. and is widely distributed thr'OU(tiout !he bOdy, inclUding the CSF. Metabolism is extensive. Ethionamide [e thye on AM ide] can Inhibit acetylation of iscnlazJd (Rgure 33.7). The urine is the main route 01 excretion. Ad'vefSe eflects t!lat limit its use include gastric irritation. hepatotoxicity. peripheral neuropathies, and optic neuritis. 3. Cycloserine: This orally effective tuberctJlosta1ic agoot appears to antagonize the Sleps in bacterial cell wall synthesis involving Dalanine. It distributes well throughout body lIuH::is. including the CSF. GycJo$erine [sya Idoe SER een] is metabolized. and bOth pa.ent and metabOlite a.e excreled in urine. Accumulation occurs with renal insufliciency. Adverse elleets Involve CNS disturbances; epileptic seizura activity may be exacerbated. Peripheral neuropathies are also a problem.

111. CHEMOTHERAPY OF LEPROSY Leprosy (Hansen's disease) is caused by M. ImlEMl. Bacilli from skin IesKlns Of nasal discharges of ir1teeted patients enter sosceptible individuals via the skin CO' respiratory tract. The Work! Health Organization recommends the triple drug .eglmen. dapsone. clolazimine. and rifampin (see p. 333) 10. 6 to 24 months.

A. Dapsone Dapsone [DAP sane] is structurally related to the sullonamides. It is bacteriostatic lor M. k1m:i>ll. but resistant strains are encoonte
'see p. 336 Icf - . 1fI~ III <JItIo, _In ttJiI_.

,--

0«'''''''''~­

Figure 33.7

Aminosalicylic acid and ethionamide can inhibillhe acetylation 01 isoniazid

<00<'0'''''''<

'' 33. An~myoobacterial Drugs

PABA antagooist to inhibil folate biosynthesis. The drug is well absorbed lrom !he gastrointestinal tract and is distribUted It1rough0UI!he body. The parent drug enlers the enterollepatic circulat'on and undergoes heptic acetylation. Both parerll drug and metabolites are eliminated It1rough the urine. Adv9rse reactions include hemolysis, especially in palioots w~h gluoose-6-phosphate dehydrogenase deficiency3, methemoglobinemia. peripheral neuropathy, and the possibility ot developing erythema nodosum leprosum. [Note: The latter Is treated with cortioosteroids (see p. 272) or thalidomide.! B. Clofuimine CkJtazjmine [kloe FA zi mee<1] Is a phenazine dye lt1at binds to DNA and Inhibits templale function. tts redo. properties may lead 10 the gene'ation 01 eytotOlOC o~ radicals that are also toJdc to the bacteria. Clofazimine is bactericidal to M. !Wr
does not enter lt1e CNS. Patients may develop a red-broWn di~­ oration of the skio. Eosinophilic enter~is has been reported as an untoward effect. The drug also has some anti·iotlammatory activity. lt1us erythema nodOSufn lepfosum does not develop.

Study Questions 33.2 All 01 the rollowing stalf!lllllmS aboul isoniazid a,e

Chooso the ONE best answer. 33, I AD 01 the lolowing SlaI9m&n1S about ritampin are cor· feet

A.

EXCEPT:

~ Is !fflque<1tly used prophylactically to.- I1OoJSehold members exposed to me"ingltls caused by meningococci Of 1:Jae:~ jo!!ulIo7arl

<:Otf9C' EXCEPT: A. It produces age-depeoOenl hepaloto>
mycobacleria. D. Ii may indllCtl the sl'fI"(ltoms 01 cyanocobalamin (Yilamin B..l deli<....-.cy.

B. It <:(lIorS body secnltiofIs orang&-red. C. II dls,upts bacterial lipid me!abol;sm lIS Its major mecharism ot a::tion. O. AItIJoul,tl rare. ~ can ClItm1l SOlfious hepa\OloXloily, E. When used alone. If\e'e is a high risk CJ/ ..... emerQ9I'IC9 ot resislBnl st,ains 01 mycobacteria.

Con.a d"c>ice '" C. Rlfoo',",'

me.

IhII

lind . . . irIlIlIlI fW
-

~

poleoliates the a<MI..... ellects ot p/IeI1ytOO'I '"'IlIe patient ,eceives both ..-liClItions concUfTently.

CorrecI ctIIIloe. D. I8OI1lazid . - . . ~

(........., BU.

~

""*'" "... cau" a _-

clancy 01 'hie vhmln.•sonlalid (elKll.y ; * _. . . inI:> InIected

'i ~

lI-....bunil 01 bacteri.. ONA-clIIpendItn1 RNA ~

E.

celI5"" _

If,

otllldM . - becIII grooooIng in\n!IoeIkUfly. ~~lhefi""" i1j"i'oI~

eece,"

"s.

1'1.

P. 325 1.'_.{2ndld-llor ..........., .. 1Ile ...... _ ' . _ ....... IIdcII'I_ I

-."e

<""'0'''''''<_'''_''

Antifungal Drugs I. OVERVIEW Inl9cbol.ls diseases caused by tungi are called myc:oses and are often chronic In nature. Many convnon rJ¥X)lic inteclions are wperficial and only involve the skin. but fungi may also penetrate the skin. causing subcutaneous inlectioos. "The funQal inlections that are most difficuk to treat are the systemic mycoses. which are often life.lhreatening. Unlike bacteria, tungi are eukaryolic. They have r9d cell walls ~ing chitin as

wet

lIS potysacchaJides and

a cell mOfl"brane composed

01 ergosterol.

Thus. tungal inIectiorls are generally resistaflt to antibiotics used in the trBatmenl 01 baCterial inteetions. ConYersely, bacteria are resistant to the anlitungal agents. The incidence or tuogal intections has escalated as the number 01 lmrr..mosuppressed individuals (e.g. cancer, transplant patients) as well as those debilitated by AlDS. has risen. These patients often suffer Irom s
ANllFUNGAI. DRUGS

II. DRUGS FOR SUBCUTANEOUS AND SYSTEMIC MYCOTIC INFECTIONS The drugs used in the treatment 01 sulK:utaneous and system;t rJ¥X)sos are amp/IOferldtlB, lIucytosine. and the new group 01 azoles. kelocontu:"oIe, fluronazole and itmc:onazole.

A. Amphoteflcln B

-

AfrJJholericin B [am foe TEA; sin) is a naltJraJly occurring polyene ma<:rolide antbiotil:, j)fO(Iuted by Streotonwces oodos! 'S. In spite 01 its toxic potential, amphotericin B is the drug 01 dlOiaI used in the treatment 01 the systemic mycoses. It is sometimes used in oombination with fluqtI05ine so that lower (less toXic) IfMlls 01 ampholeridn are possible.

Figure 34.1 Sunvnary 01 antitungal drugs.

..____ __.. ...., '"._E_ c....,... -.~

, , - _ 1 _.. '

,",.U",,",-

337.

<'''''0'''''''<

''

< .._

• . . . . -.... Mf><.. , lM:AU _

..,..... PI' >

34. Antifungal Drugs

1. Mode at action: Several polyene molecules bind to ergosterol pre!llIOI in cell membranes of sensitive lungal cells to form pores Of channels that IrMllve hydrophobic bonds between tlle lipophilic segment of the polyene antibiotic and the sterol (F'9Ure 34.2). This disrupts membrane function. allowing electrolytes (particularly potassitxn) and small molecules to leak from the ce~, resulting in celi death. Since the polyene antibiotics bind preferentially to ergosterol rather" than cholesterol, lhe sterolklund In mammalian membranes. a rela~ve (but not absolute) speci1icity is conferred.

,.

Figure 34.2 Model of pore formed by amphoIericin in lipid bilayer membrane.

2. Antifungal spedrurn: Amphotericin B Is either fungicidal or fungistatic, depending on the organism and the (:(If'lOOntration of the drug. It Is ellective against a wide range of fungi, such as Candjda a1bicans. ~lOOtasma l
3. Resistance: Fungal resistance, though InfmquenL Is associated wifh decreased ergosterol content of the fungal membrane. 4. Phannac:okinetics: Amphotericin 8 is administered by intravenous Inlusion. The intraltlecal route is sometimes chosen lot" the treat· ment of meningitis caused by lungi that are sensitive to ampIJotericin 8. Amphotericin 8 Is extensively bound to plasma proteins, and Is distributed throughout the body bacomlng highly tissuebound. tnftammation la\lOfs penel/ation InlO variouS bOdy fluids, but Iinle is found in the cerellfospinat fluid, vitreous humor, or amniotic fluid. However, emphoW'ic/n B cloes cross the plllCenta. Low IIMlIs or the drug, mosdy metaboliles, appear in the urine ewer a long period 01 time; some is also eliminated via the bile. Adjuslment of dose is nof rBQI.Ilred in patients with compromised renal or hepatic function. Liposorna! preparations of arrphoIcricin B are available and have shoWn therapeutic etticacy.

Minimal ..... .etI ..1on

Into .... eNS

FJ:.

;>

--0::_::01.

PtII1Cl_\ -~

e ll_Ion " ~11_ D11Ot\ j'

5. Adverse etlecta: ArrphoIeridn 8 has a low therapeutic index. A lOIal daily dose should not exceed 1.5 mQlkg. Small test doses are usually administered to assess the degree of a patienfs nega. tiV(l response, for example, anaphylaxis or colwulsions. Other toxic mamestalions indude the folloWing:

a. F.....er and chills: These appear with intraveoous administration but usually subsicle with repeated administration 01 the drug. Premedlcallon with a steroid or an antipyretic helps prevent this problem. Meperidine (see p. 138) can abort lever and chills fhal have already started.

.

#!I!!J-.~

-"\ •

Amphollmcm 8

b. Renal impairment: Despite the loW I9veIs of the drug Bllcreted in the urine, palients may exhibit impaired renal lunction (decrease in glomerular filtration rate and tubUlar function). Creatinine clearance drops and potassium is lost The nephroto>::ldty may be potentiated by sodium depletion. Nom1aI renal lunctioo usually retums on suspension of the drug, but resid· ual damage is likely at high doses. Azolemia is exacerbated by oItler nephrotoxic drugs SUCh as aminoglyrosides (see 314),

._.0.....,> ...... _ ' . II. Drugs lor S\.tlcutanoous and Systemic Myrotic Inrections cydosporine, Of pentamidine (see p. 353), hydration can decrease its _lity.

aItt1oul1l

339 adequate

c, Hypotension: A sllodl-like ran in blood pressure aceompanied by hypokalemia may occur, requiring potassium supplementation. Care must be eIlertised in patients taldng digitaUs.

,., i)'

" FII.q.-_..

o

d. Anemia: Normochromic, normocytic anemia caused by a reversible suppressiOfi of erythrocyte production may occur. This may be exacerbated In patienls with hUman immunodefi· ciency virus (HIV) who are taking~, e. NeUrological effects: Intrathecal administration can cause a ~riety oIl'\eOrologic problems. I. Thrombophlebitis: Adding heparin to the Intusion can alleviate this problem. B. Flucytoslne F/ucyrooi/le [000 SYE 100 seen] (5-FC) Is a synthetic pyrimidine antimetabome used ooly In combination with amphotericin tor the treatment 01 systemic mycoses and meningitis caused by CMl!r£9f2 '5 OlIO!ormans and Candida. 1. Mode 01' actlon: The drug ooters rungel cells via a cytosine-specitic permease. an enzyme notlound In mammaliar1 cells. 5-FC is lhen COfMlr1ed by a series 01' sleps to 5-000r0de0Xyulidylic acid (5-FdUMP): !his Iatse r.ucIootidEI inhibits Ihymidylale syrlthetase, thus depriving the organism ot tt¥ni~ic acid, an essential DNA compooent (F9JIll34.3). The unnalllral pyrimidine Is also metabolized 10 the nucleotide (5-FUTP) and lnoorporated into rungel RNA. to disrupt nucleic acid and protein synthesis. The combination or fItJcyIosine and Bmphotericin B is synergistic. [Note: The Bmphotericin B altects cell permeability. allowing more 01 the fIvcytosine to penetrate the cell.]

j ~-

j o

dUMP"""'f--
Figure 34.3 Mooe of action 01 flucylosine.

Z. Antilungal spectrum: Flucytosine is fungistatic and et1ec1ive In treating d'll'Of1'lOl)lastomycol;is and in combination lor candidiasis, and cryptococ:cosis. 3. Rlllllslance: Aesistance can develop during therapy and is the reason that fIucyIooine Is not Used as a single antirTJyQOlic drug except lor d'll'Of1'lOl)lastomycosis. The rate at emergence 01 resistant fungal cells Is lower with the combination ot amphotericin B and f/(J(;yIOSine than It Is with "ucyfOSine alone. Decreased kweis ot any ot the enzymes In the oonversion 01 5-FC to 5-FU and beyond, Of Increased synthesis of cytosine. can cooler resistance. 4. Pharmacokinetics: F!Ucytosine is well absorbed by the oral route. distributes throughout the body water, and penetrates well into cefebrospinalltuid (CSF). 5-Fluomuracil is detectable In patients and probably Is due \l) meIaboIism ot 5-FC by Inteshl bacteria. Excretion ot both the parent drug and its metabolites is by g1omerular filbatiofl. and the dose must be a'*->Sled ill patients with c0mpromised renal fi.o::tioo.

FLUCYTOSINE

AMPHOTERICIN B

..........,., ....

_-,.

340

34. Antilungal Drugs

5. Adverse effer::ls; Some oIlhese adllerse effects may be related to 5-FU tormed by irlteslirlal organisms lrom 5--FC.

a. Hematologic toxlcily: FlJcytositJe causes rewrsible

~

nia. thrombocytopenia, and occasional bone marrow dapres-

sion. CaUlion must be E!>lOOsed in patients undefgoil '9 ra(ialion Of dlemolherapy

wiltl drugs that depress bOne

marrow.

b. Hepalie dyslunctlon: RfMlI"Stie tlepatC dysflsction wiltl ekMItion 01 serum transamlnases and alkaline phO$phatase may occur.

c:. Gllstrolntestinal dlsturbllnces: Nausea. wmiting. and diannea are common. and severe enterocolitis may occur.

C. Ketoconazole

Keloconazo#e (Koo 100 KeN a zola). a SUbStituted imidazole, is one ot a lamity of azoles uselul in treating systemic mycoses. In add~ion to its antilungal activity, ketoc:onazole also Inhibits gonadal and adrenal steroid synlhesis In humans by blocking C17-20 lyase, ltp.. hydroxylase. and choleSlerol side·chain cleavage; thus, it suppresses testosterone and cortisol synlhesis. 1. Mode of ac:tion: Ke/OOO'lazOle inte
activity. 2. Antifungal spectrum: KeloconaZo/e is either lungistatic or lungicidal, depending on the dose. Although active against the same Iungi as amphotericin 8, It is most usetut in lhe treatment 01 histoplasmosis. KetCJOOtl8U)/e is also effective against nonmeningeal coccidiomycosis and blastomycosis. Candjda, and various cler· matophylic infections. including lOOse resistallt to grisoolulvin ate also susceptible.

3. Resistance: No ,esistance has been observed.

Rgure34.4

Mo
4. Pharmacokinetics: KeloconazoJe is only administered orally. It dissolves in the acidic gastric oontents and Is absort:led thl"OO\11 the gastric mucosa. Food, antacids, clme/kllne, and rlfampln impair abSQ(p~on. Coca'CoIa being acldi<: has been shown to improve absorptiofl 01 /ce/0<:0r18Z0Ie. The drug is hi{tlIy bound to plasma proteins. Although penetration into tissues is limited. it is effective In the treatment 01 histoplasmosis In lung, bone, skin. and soft ~ssves. It does not ente< the CSF. Extensive metaboljsm occurs 111 the liver, IndlJction of the cytochrome P.450 system enzymes (see p. 14) irl the liver shortens lhe halt·li!e of ketocooazoIe. but the drug can also inhibit certain cy1o<:hromes P--450 to potentiate the effacts 01 soma drugs (see P. 341). excretion Is primarily It1rough the bile. Levels 01 parent drug in the urine are too low to be effective against urinal)' tract mycotic inIectioI1s.

. . . . . .o. . . . . ' . . . . . . . _ L .

• .... M _ _- . . . - ' - . . . . . .. _

.....

II. Drugs lor Subcutaneous and Systemic Mycotic Infections

341

5. Advern etteets: These effects are primalily gastrointestinal. In addition to allergies. OlI1er IOXicities include the IoIIowing el1ects:

KETOCONAZOLE

•. G..strointestllWll dlstresa is a common side effect.

b. Endocrine effects, These resuR from the bloddng 01 androgen and adrenal steroid synthesis by ketOClJflaZ(J/e. Among the effects are gyr1ecomastia, decreased libido. impotenee, and menstrual irregularities.

~

contraindIcated

/

c. li&patlc dysfunction, A1ttloogh the incidence is low, hepatic dysfunction, with elevation 01 serum transaminase levels. is a serious toxic manifestation. Ketooonazole may aoxumulate in palients with hepatic dysfunction. Plasma concentrations 01 the drug should be monitored in these individuals.

...... J

AMPHOTERICIN B

d. Contralndlcatlons: Ketoconazole and amphotericin B should

not be used together. e. Drug lnt",actJons: By irI1ibiting cytochrome P-450, ketoccnazoJe can potentiate the to~icities 01 cydosporine, phenytoin. and the H,-hislamine antagonists. terfen8dine and astemizole. It can also increase the leVels 01 sucrolfate, folbu/amide and warfarin. Rifampin, an inducer 01 the cytochrome P·450 SfSlem, can shorten the dum.!ior1 of ketOC()r1azo1e and lhe othe< axoIes (see F'lIUre 33.5, p. 334). Drugs that decrease gastric acidity such as H"receptol blockers and antacids also can decrease absorp6or1 01 ketOtXlflaZOle.

-~I"

O. Flucol\lllolG

Fluconazole (floo KON a zole] is clinically important because of its lack of the endocrine side effects 01 ketoconazoJfl. and its excellent penetrability Into the CSF. Auronazole is employed proptry1actica.lly, with some sllccess, lor reducing fungal infections in recipients of bone marrow transplants. 1. Mod. of ..etlan: It inhibits the synthesis of fungal membrane ef'gOSll:Irol in the same manner as l<eIoconlUOle. 2. Antifungal spectrum: It is the drug of choice lor CrvptOOOCQJli neoformans, tor candidemia, and for coccidioidomycosis. AUCXXIazoIe has also been shown to be useful in the treatmenl 01 blaslOmyCOSis. candidiasis. and hisloplasrnosis. These inledioos are characteriZed by a high rate of relapse, and flUCCJflaZOIe has proved el1ective in chroric ambtJlak:lfy treatrnenl

3. Resistance, Treatment faJlures have been reported in some HIV· infected patieots. 4. Pharmacokinetics: Fluconazole is administered orally or intravenously. Its absorption is elleellent and, unlike 1<eI00000azo/e. is not dependent on gastric acidity. Binding to plasma proteins is minimal. Its importance lies in its ability to penelrate the CSF of

-

","'",,,,-

-

<-'.'''''''<---''

.",

34, Anlifungal Drugs normal and inflamed meninges. Unlike keroconazole. fIuccIlazole is poorty metaboli~ed_ The drug is eXCfeted via the kidney, and doses must be ,educed In patients witt1 ~romised renal tunc'

...

5. AdvetH etIec1,,: Its edVeroo slleets are less at a problem than with kefoconazole. FAJcona~ole has no endocrinologic elleets because ~ does noI inhibit the cytod1rome P-4SO responsi~e for the synthesis of and,ogens. However. it can inhibit the Cytocl1,omBS P-450 that metabolize the other drugs listed on p. 341 under kef~. Besides nausea lll1d ""mlting. rashes are a prOOlem. Hepatitis is rare. Recent ,eports Indicate that flu· conazole is a potent teratogen and suggest that other of the azoIes may also be tllratogenic.

----- -.... _... _. - - --- --Ro
~

.

' m (hluoOl CSF ___

"

~

Oo'ol,W

,. --

~

""....

"

'-

Ilraro<Jazoie I~ fa KON a zde)ls a recent adalion to the azde family

...- ...•• .

• -- ,. -

E. h'lK:onazole

~

~

~-

~

~

~

Figure 34.5 Surrmary o! azole fungistatic drugs.

•

at antifungal agents.

Like fluconazole it Is a synthetic lriazde, and

~

also lacks the endocrinologic side effects ot kefOCOl!8UlIe. Its mode of action is the sarna as that ot the other azoles. Ifraoonazole is now the drug of choice for \toe treatment 01 blastomycosis. Unlike ke/cr conszo/e, it Is effecllve in AIDS·associated histoplasmosis. However, ClJlrent studies show that it may also be e!feclive In the treatment of aspergillosis. candidemia. coccidioidomycosis. and cryptococcosis. Thus ~ has a broad antifungal spectrum. 1. Pharmacokinetics: /lraconazole is well·absorbed orally and food

increases its bioavailabitity, It ls extensively boond to plasma prcr teins and dishibules welllhroughout most tissues. including bone. sputum and adipose tissues. However. therapeutic concentrations are not altained in the CSF. Like kelCJCOrl8zo!e it Is 9JffensMlly metabolized in the IMlr hut does not inhibit androgen synthesis. UttIe ot the pa,ent d'ug appears in the urine and thus doses do not have to be reduced In ,enal failure.

2. Ad\f'llt'Se effects: Adverse effects include nausea and vomifing. rash (especially in immunooompromised pafients), hypokalemia. hypertension. edema. and headache. Drug interactions listed above are also possible with ilmcxmazole. Figu'e 34.5 summarizes the azoie antifungal agents.

Ill. DRUGS FOR SUPERFICIAL MYCOTIC INFECTIONS Fungi that cause supefficiill skin infections are called dermalophytes. Common dermatomyooses. such as tinea infections. are ellen referred to as fingworrn, wtlich is a misncmer. sirooo fungi raltler than worms cause the disease. A. Gffseoflllvin 1. Mode of action, Griseofulvin [gri see oh FUL viol enters suscepti· bIe tungal cells by an energy-dependent process. It is believed to

. ..., .....,., .......

-- . ,

•

.,.,.. M ....._ _. . ,

""""'" .. _

.....

3<,

Ill. Drugs lor Superficial Mycotic II'lfoctions

interact with the microlubtJlas wilhln the fungus to disrupt the mitOOl;: epir.lle and inhibit m~osis (FIgura 34.6). II ac:c;:I,lIl'Uate!l in the inlected, nowty synthesized. ketatin..contiWWIg tissues. mak· ing them unsuitable lor the growIh of !he h..ngi. lllerapJ rrust be continued ootiIl'lOfJT\8I tissue rapIaoas infected tissue. This usually rBqUires weeks to months of ~

2.. Antifungal &peetrum: The drug is principaIy lu:'lgistatic. II is ertectiYe ody ageNt the ~Trm.tMpn Ltjppsprvyr'a In:l Epjde!mootNlOO It is uMd in the treatmenl 01 6fMIf'8 trea i IleUioi lSi . . . do not responcllO othDr 8f'lIifI.rGal agents.

_i~X·· 1 0t

- I

m,. 10 ... Iadl 01 tt. eneqw-depert-

at

4. Ph,tm.eokln,tlc:r: Ultra·llne e.ystalline praparatioR$ are ebsotbed adequately fTOm ... ~ ItaCI. Absorption is

~ lli:liliOi 1of

3. R"""I"QI: Resis'!....::e " dent uptake syslem.

jlfuldId if ilg8SlOd willi. tigh lei diet. PhenobartitBIClWl interiere wiltI tt. abIotpliotl of ~ The drug Is ilflllBd:i. Klp~ Gri5alIuMn distriUes cNDlly 10 iikted ke
".,bo!isrn

i ' "'..

FlgIIrII 34.6

Gt.

mitosis by ~

..., to

5. Advera. ,ffeet.: TOIlic:ity i.

nol. genetlIlly a clinical problem gic 18IIdiot. and. rrurrter 01 adYllrse efIBds (e.g., Ilfw".l.., nausea) h8Ye been t8pCII'Ied. GrlsooU'\IWI may cause hepak*+i ily and" ......... dt:a18d in palietU with 80Ae inlet· triItenI porphyria. The drug ~ tie i olt:«it:8li '9 eflBcIs of ClIt:dd. Gri:seofuI'riniJ I8nlIOglIoIie in ~ ali• •

aIIhotJstl '

... t . .

B. Ny.tatin

,"tiblo1ie;

Nystatin [nye STAT in) is. poto,81" its struelln, chemistry, mode of .dian, and reslstanoe resemble those 01 BITf'hoteri(:in 8. 1I.s use i. restricted to t0pie81 trealment of candida intecIions because of itT rystemic tDllicity. The drug is negligtiy ab:sotbed from the gastrointestinal IraCI, and it is reMf' uMd patenleraly. II is Idrni:'list8r8d tIS an oral agent ("swish and swaIow') lor the treatment 01 oral (:8I'ldidiasis El«:retion in the Ieces is nearty ~taM. AcMlrse etlac:ls 8I1l I1lt8 bDctl"w r:J its Iadl of abso
C. Mlcon.zole,nd ott-toplc.1 agent. MiconazoIe (my KON a zoIe], ~ [Idoe TRIM a zoIel, and &CO'llllOIe [e KON a zoIe]are topically active drugs and are only raraly a6mlnistered parenterally because of their saverl! toxicity. Their mechanism of action, antilungaJ spectrum, dislrib..Jtion. and type of metabolism are the same as ketoaomuokl.

FlgIIrII 34.7

Ind"ction 01 hepaIic cylOCtoUI"

P-45Q a::Dvity by griseo/kNirl.

<00<'0'''''''<

'' 34. Antifungal Drugs

Choose r..... ONE be$1 answer.

D. 11 enhances CNS depfessant cffocts 01 clhane>l.

A_

Questions 34.1 • 34.3: For each OI.fJ'lbo:!"ed phraso, select !he

ONE doug \A·Elllal is mosr dIDseIy associa1ed wilh.. Each d-vgmaybe_ed once, more lIIan onoc, or nor aral.

E. Its uS!! in 1he
CumId _

Eo

..

~...,......,

!he intdId, ~ s,,""'"""'d

"*.... lor . .

..... """'*'" -..must be CUfIIn.oId urd hll.rlgl. lIlIII_

B. Griseo!uMn C. PeniciBin G

~

Ii.....

~

in

-CCli~ ~ 01 ~

Inlede-d lliWfl. This usually

I&lJ*- iDf'9-Wm 1hanIpy.

D. AmpIIo1cricirl-B E. Kelocooazole

34.7 A Z5-year-old mall! AIDS palll!nt lIaS a Ie..... 01 102'F

34.1 Binds to ergosterol prcsen1 in ccl mombmnes III sensitive luogaI cells. thereby (lsrupling membr_ lI.oldion.

34.Z Bklcks IMosle,ol demeillylatioo 10 c.goslerol. IIIUS disnJpIing ~ membrane inl"llrily.

I n.corred __ ~ E. ~l. 34.3 Is ml!tabolized to a prodUCl lIlal inhiMs IhymidyIal0 syntllc1aM and !hus pr..... en1s fungal DNA synthesis,

.nd COOIplains ot &eve,.. he8daches during ll1e pest week. Slairling d lIis eo'eb'usplnal fluid wiIh India ink '""eels CrvPltl!'1X'fflS neolorITlans. The parient is admitted to II1e flospil&l an:I is treated wilh:

A. Inrf8Vet1OO5 ampIlOleriOO B plus nl.'C)'1oM>e. B. 0.a1 ketoeon81Ole. C. Inuslheeal amptIofelicin B. D. Oral tluc:onazoIo. E. Inlfav
The tlon 01

.. C. ~

eflec1lye

W8J 10

B ..

b~l~

~..

ado,

~

.. mcr;l

t_ CfyplOCOOCIl Jl'lllringitIs.

"""'lcir,

~ ~ ..a.G .... olIl .... B ""'Y t. .... .... hlKl
34.4 WIlicllooe 01 tile tollow;ng drugs is 001 used lor till!

Ifealml)nt at systemic fungal iolcetions? A. ~tI!ficin B. B. FlucyIosinI!.

and lICIl t~

C. KI!10c00azQle. D. Griseolulvin. E. AJJCC<'\!\lOio.

!' I:hIJ _

1rlenIpy. Ond k1IlDconazule I$lIlal "'"""lI .......... 01 b ~ 10 _ irIICI CSF. AIIhulqI1II>""'~ote Is very ef1et;k Ctvp"I"ln l'4Il!orrnaN end doelI emer the CSf'. I:hIJ oral __ Is 0Itt UNd lor cMifliC IlWO 'W11t>enit>1'

".'.glIlL

The ~ 0I8fT1lho-

e and ~ It. pool" one tince

~

*'-'* Iun\)Il ".,

and .... ~ ... _

..... , . IICliorl 01 . '

k.o"dun

otAeo\oIll

••

c:t ~ ffIyC:Ollc: lroIe"t1ulIl.

34.5 All dille foRowlng stlfcmerrts cunedly describe keto-

34.6 A 30-year-old male lias Ila:l a hean lransptall1 and is being maintained on the immunosupp.essant, cyclospurino. I"I! developS • ~ inlecIion and Is Ifeated wilh kelOCOMZOle. wtr.t is !his poor tfll!rapy?

conazQle EXCEPT'

A. Keloconazole is not cffectrve against CarMa,

A. ~ ioIlibils IIl1! CUfl\II!fSion d lar1osIerollC> etgostCfol. B.lt may produce gaslruin1l!S1inal upsets.

B. KeIocunaz<*l .eacts wiltl cydospurine to inactivale~. C. Ketoconazule has. polCntiallof can:1ioloxicily.

C. t1 can cause gynecomastia in males. D. t1 peno1ratcs into t..... c:e.ellruspinal ftuid. E. ~ shook! 001 be comllincd wilh amphotericin B,

O. Kel0C0MZoIe inhibits cylochrDml! P-450 enzymes IIIal inactivalo cycloSpurine. E. KC\OCOl'lal:QIe causes gynecomastia and decreased libido in II1e male.

(

=~"O.~doeIl~_

l

34.6 All ot llle t()lluwlog SlatCR'l(mts cunc:e11lirlg griseohllllin

awcor,ecl EXCEPT: A. ~ is unIy eftectiw .-.gainsl dermatophylic: intections. B. ne>
.nst

The correcl _ _ .. D. Keloconezclc IS elIecIlIIe CMJ!de bul M does lICIl fG&CI with cycIoo;porlrle nor .. ' ...,•• ".~ I<elo<:unuDIs InIllbIIi ... hepaIIc cylOchrume P-45Q ~ 1t\8l~. r,'8kl cyduso>olille. Thus .. !his ~ tile p.Uiltru wotlkl be In d1tnger 01 Increueol.9'I ~ cIl:.c:a.o ~ II'Ill decreIuoId 1Ibidu,_ I'lOUI'd nor t.. 01 Pf\'n8ry CUfIU9lT\.

< _

'0...,.,

>< . . . . . _ _ t >

Antiprotozoal Drugs ANTlPAOTOZOAL IJAUGS

I. OVERVIEW protozoal infections ara comrr.oo among people in underdeYeloped tr0pical and subtropical countries wh&ro sanitary ooncliOOns. I¥.lienic practices, and control of the vectors of trensmission are inadequate. However. with increased world travel. protozoal diseases such as malaria, l¥nebiasis, leishmaniasis, lrypllnOSOIT'Ii, tridlomoniasis, and gianliasis BnI no longer confined to specific geogaphic locales. Because they are eukaryotes, !he lricelluar prolozoal cells ha'we metabolic pr0cesses closer to those of !he hJrnan hosl tI1ar1 to proka~tic baderial pathogens. Protozoal diseases are thus less easily treated tI1at1 bacterial infections. and many of the antiprotozoaJ dllJgs cause serious toxic affects ir11he host, particul8.rty 0f1 cells showing hi{tl metabolic ac1ivityneuronal, renal tubular, intestinal and boI'\e marrow stem cells. Most ~zoaI agents have not pru.ted safe for pregnant patients. Drugs used to treat protozoan inlections are summarizad in Figura 35.1.

-

--_. -..... ............. ....... -= --,. .....-

-

.............'"

-

'w

01"'7

D ooh)-'-" ,~-

-

OP _ _

CI_ q....

Pt., ..,.....

_ ~ M

II. CHEMOTHERAPY OF AMEBIASIS

-

Amebiasis (also called amebic
A. Life cycte of E. hlstolVtjn E. his!rlMira exists in ~ Iotms: cysts thet can survive outsidB the body, end labile but invasive ~~es that do not persist outside the body. Cysts, irJ9!lStecl thl'OU\11 feoes-eDf1taminated food or water, pass io1to the i1testine whera lrophozoiIes are liberated. The lrophozoiles fTIlJlllply, ood either IflIfade and ulcerate the mucosa of \tle large ir1tesline. or simply food on intestinal bacteria. [Note: One stral· em' for treating luminal amebiasis is to add antibiotics. such as telra-

mlBW"YOP TJmfANCl8OlI'_

, ..",~-

'-

............,'" , ............,'" .........-

.,..,.-

O""IlI'W

~

Agure35.1 Summary of ootiprolozoaJ ~

..--.. _ _ ". ......... , . - . _ ..

_ _ 0-"''''

a. _ _ c..".,....

....... 0"""""

345

<"0"0'_""<

<.._ • _ _........,.., """""" - _ .

"

",

PI' >

35. AnliprotozaJ Drugs

o

Pe.-.etratiDfl Intestl....1 well

Muttlpllc8ttDfl of trophozoltes within colon well

•

tAIKcd omeblc,de

CyoI_

w.o.u.

(lurnlnel8nd

•fI."",,_. 0++-

systemiC 8Cl1Vllyi

Lum.nal ameb'cldes • 0."'..,,,,,,, '"",,"" • ....omomycm

• ''''''
• Figure 35,2 Life cyde 01

CYSIS diseerde
Entamoeba histoMica shoYIing sites 0' action at ameIlicidic chJgs. C)d'ne, 10 the treatmenl regimen rnsulting in e reduction in intestinal flom., the amebae's major food source_l Large ntJfT\l:le<"s of tropho-zoites within the colon wall can lead 10 systemic invasion. The l/'OpIllnOites within lhe inlestiroe are slowty carried loward the reclum wh&m they relurn to the cyst form and are excreted in leces A summary oIlhe ioo cyde of this organism is prBse<1ted in F'9Ure 35.2.

B. Clssslficetlon of antlprolozal drugs Therapeutic agents are classified as mixed, luminal, or systemic amebicides accordif1g to the site where It1e drug is effective (see Fi!ll.Jrn 35.2). For example, mixed amebicides are ellective against both the luminal and systemic forms of the disease, though luminal concenlm!ions are too loW lot single drug t,eatment. luminal amebicides IlCI 00 the parasite in the lumen 01 the bowel, whereas systemic agents are etlective against amebae in the inlesliroe wall and

the rlVer_

<.. ,....,.,.<---,.

",

II. ChemoIherapy of ArnllbiaN C. Mixed ameblclde: meb OI,ldazc*

Amebiasis is gell8f3lly IreBtBd witI a oombinaIicn III 1T....... lid.uoIe (me troe Nve da zoIe] pIu$ • Iurl'W'Ill ameblcJdaI ~' suc:tl lIS ctb
r:me

1. Mode of Ktion: MeI1onlOalole is s 'ecliil'8tj not ody tor amebae but also tor ....... 'ollie oryanisms rlf'lducing bacteria), IWId lor IlflOlCic or twoU: eels. Some anaerobic proIozoBn pant.... rn::lUding amebae) p"'lees latJtldOOn.like, IoW-redoI< polenlial, electron tran$pOri proleins lhat participate In melabolic electron rerToOY8l reactions. The nitro group of melrcndazole is able 10 serve as en ele:tlOrl ac:cepIOl, 1l;lrn'jng recb::ed eylotoIlic compounds that bind 10 proleins and DNA 10 reSlJl in cell dBalh. 2. Anllmk:roblllllpllC1f\fm: MetronkJamla is the agenl 01 ohoice lor treating inIections caused by E.. hjs'Pbrtira in wtoch it kills the f. bisloMjca trophozoitel, Gjardia Ianillja. and TrjchoonguBS mi: DlIM in boCh males and famaIes. Metrorllidalole Ill", firds extensiYe use in the IJ8lIImen1 III i ,Iections CN'5fId by ann obic oooc:i and anaerobK: gram-nega.~ baOIi (lor example, bacteroides species). Anaerotlic grarrl1JOSitive badlll, such as G'Pslridja. wNttI cause p5P·... ·,... 'o.oous oolitis. are also . . 1Iili.... The drug is e11aclive in 1hls Ir8atmllnl: III br.lin at+ rism C8'Fe<' by flese OIgalliso 'I$.

3. RealItance: R . 'ance is not a lherapeulic .... dlIem. allhough stf1lins of Irichomonads ,eslstant 10 meltOt'IidtuDIe haYe been

--

4. Ph.Irmacokinetlc. •• Admlnlstnltlon IIfld dlatflbullon: Metronidamlfl is aJmpIetBly and rapidy lIbsorbed al1er oral administration ancllor the treat· mGf11 01 amebiasis. Is USUlllIy ed.....-.steree' with a lUminal arnebicide, such as dilox8nidf1lurOllfe. tt diSlribulllS welllhA:lU{ttlout body tiSSUlls and fluids. Therapeutic levels can be found in vaginal and seminal lIuids, sativa, breast milk and cerebrospinal fluid (CSF).

n.eo..,.

b. Fate: Metabolism dGperds on hepatic oxidaJion of lha 01a"?la sidB-chBin by mlmd Iunclion 'ted by glucurooidation (see P. 14). lhetelore, conoornitanc lr1latment with inlt..ocers 01 ..... enzymatic 1ySIetn. $IJCI\ ... phenobsItriIaI

'Wide_,'.

(see p. 94), enhances the rale 01 metabolilm. CorM!rseIy, tlow that r t t i ..... sys&n, suctl as ai,lll6cfI., (&Be P. 236), prolong the pIasfTIlI half-liM (tl"). The drug .ca.wnutate5 in palients wiIh _ I l l hepetic
-..... T

,

bo,*.

·... ......, ........ _,. "

(yea$t inl8clion of the mouth) and rarely. l'\lItJtOtOIO:icologic probIemlJ.. such 8$ cininess, VIlfIigo. and e or pBresttoesias ifllhe perip'oer8l nervous system. {Note: The IBtIer are rees "IS lor

,....,b

5

ciseonrinuing the drug.111 taken w;u., ak:ohol, a Ii'stdf"lflUJ>-lil<e eIt8c:t 00Cl.Q (see P. 96). D. luminal amebk5dw: Dilounlde 1~1e DiloJranide ruroale (dye lOX a rjOOl Is U50hA in the trealmefll of Its Ol'tv ildice~: ,it in h treabT"8I of ~ anM' $i. Af\ef 0f8II ad""inilllatiol'l. <:tbca1idB f!ftIst6 is ~ in lhe ildeSliioal ",,'COS' .-.dlhe ciloxar'lide is lIbl:U: 9l:l"'- ebeoo'bad. I \aI _ , lhe ooabsoItle:l ctl..ig is Ihe adMI lW'Ilebidde. AcIwIrse efteds are mild. ~ IncUle !atIAenc:e. (kyness of lhe moulh, prurilus. and urticaria. The .nog it conlraio dealBd in pregrIlril women and cl1idIeol t.nder 2 years 0I8gII. ~ piI$$8I'S of cysts.

o..Io.."""'Iuroate

E. lumlnel emeblclde: P_omydn f'8l ... ,iOtn)d'I [pet on moe MYE 6in~ lII1 ~ i1i_il. 4ic. is Ol'tv e~ 8g8flsl1he intestinal (UninaI) forms 01 Eo bi
F. Syalemlc ameblclde: Chloroquine

CNotoquine {KlOR on i<wWlJ is used in ~ ~ met":,,,ida· zoltJ and diloxt/nH:1e fU1Oa18 to treat and prevenl amebic live. ""'c'9llS'9ll It tJIiminales trophomi&es in IiYer ."v"U9', buI it is IlOl useI\A in treeting turrinal amebiasie.. ~. aJso ~ i"I .... IrealITletII 01 malaria. and is mDIe fuIv (e I '\bed i"I the malaria ~(_p.349).

G. Spt.mk ameblcldes; E_tIne and dah~.... tlne Em«ine [EM e IOOnllVld ~ Ide ..". dro EM e IOOnI aIIemele agents lor the tre I 01 amebiesils. ~ rt"ti: proby' ttJd
..,.,.,....

9

9

'See p. 3S8 ... -.... .el""...... IO_-'Oin ..... _ .

..... ,.. 00'.'" ,•• _ _

,

t.

.........---..'

III. ChemoIhetapv of Malaria

....,..".

_ ,.

.. .....

III. CHEMOTHERAPY OF MALARIA Malaria Is an lICIIIe illeo ,0." tJifeue ............ t:¥ tow species of Ihe prolOzOal gerus plastnoclUn. The parasiIe Is IIll1'isuittec:l to tunans hcug1 . . bi&B of female 8llOP~ ,'el mosQIitn, lIItictl1hfio.e5 .. turm. tv'.I .... - . Aa.'IT<"tilm lahien.m is . . mosl: diIllgllllfDUlil species, c:a.JSing an ae:ue, rapidy IlkniNJting dil sse cha..-inld bot persi$1&nC high tewet. Ofthostalil;: t¥Polension and rnas.si'oIe erythrocytosis (tv,oIeti tnd ,eddish contii.ion of Ihe limbs). pte5!1lfW1j!m f!lltirlanm illection can lead to eapIary obsIruction and dealh If Ireamenl is noI nIiMed prompIly. P'e5fl!'!!1!m!dlllll ca,...es a milder Iorm of !he tJifease. B m"Yiee is common 10 fTIllI\' Iropical regions but fIaSrg1jy'n Q'4kl is r8tely encountered. Rellistan<:e acquired by lhe rroosquilO 10 inseeIicicIes. and by the perasile to drUgs, has Iud to ~ thenlplltJtic challenges, perticularty in !he 1I'0otment of f. IalCiDarum.

A. Ute cycle ollhe mel8rle po"'lle When 8rl inteded fl'lOSQlWl biIea, il qads P'wl't""& m ~ into lhe blood stream. The sporoZDiIes fTligla~ 1Mlu{tl1he blood 10 the IiYar where 1hay lotm cysI_ strualnls wntaini l(j IhousIlnds 01 merozoites. [Note: Diagnosis d8paf (Is on laboratory id& Ililit:alion of Ihe parasites .. rOO blood oellI of ~r'8I blood _ _ (FigInl 35.3).1 Upon I el _,..n merozoiIe irMDls I'8Cl blood oells, usWlg hemoglobin as a n.rtrienI:. EvetIIUllIIy the infect.... call ruptufes. , ' Bsing heme and merowilas IhaJ: can enEf olher ery'flruq1lls. The efIecli,elloss of a li'ug 1r88l1'1la1t is releJBd to !he partic:Uet spec:ie$ of i ....liny P'BSmodU'n and Iha stage of il:5 life eyda. A IU'I'If'!IiUy of Iha Iita cyele of Ihe paIaSitB and !he sites of Ihet apeutic inlervwItions are ptllSBrIl8d in Figu'a 35.4.

B, TI"ue adlizontlckle: Prlmequlne Primaqvine IPflIM a kwinlls an 8·ominoqlJinol(ne that oraticates e~oerythrl;ll;ytic forms 0' f. talCiDarum and B ~ and the secondary exoerythrocytic forms of rllC\Jn1ng malarias (B ~ and e.llalB). In addition, the 5eJW8l (gametoeytic) form, of all lour pIasmo(b are deslro;ad in the blood or are prewnled 'rom maluring Ialer .. Ihe mosquilo. Beel!' IS" of its tadI of aetMty aglWlst tho eryIhfOCylic sdlironIs. prm.quine is often used in CClflun:;IiOn II>'i
primary

lICfua1Iicide.. I, Mode 01 edion: This is no!
mill BflC:f:IIOefed as " • jo .,.

2, AntI..... obiel ~ : In spilB of sln.d.Iflll

timiIarily to Ihe 4·

.,illOCfJir.... i8S ( f e r ~ , ~ , "8 Bl'foillOq.li .... _

~ (1issua).sla\lBS an:! nollhe erytvocyIic $laga of malaria. It i& Ihe only eganflhal can -.l to I'a
are etlactiYe only againsIlhe

e

e

Flgu.. 35.3 Red blood oaIs 0ClfltUling P'8f"'pf'lID ~

•

1.' ••

,.

350

35. AnliprolOzaI Otugs

Fem.... mosqullO pk:k:a up U-metoc:,_ from lnfl'ded Indl.4 1'''1

go •

..---....,

a_

.... !"""' .....

--~

f\)\

'&

~ 1.;.,.:.......~

.

Ruplure of f1Ml blood CIIls rele_ merozoite. whlc:h tMl lnled

ather red blood OllIs.

Flgu.e 35.4 Lile cycle 0I1he malarial parasite showing Ihe sites 01 adlon 01 antimalarial drugs. ellminaled. 6llclluse primaquine Is also gamelocidlll lor all tour p1asmoclill species. transmission oIlhll disease can be lrllerrtJPled.

well ebsortled on oral ~ li'ation ..-.cl is not concentratlld in Iissoes. II is ropdy OlddIized 10 meny~. ltle major one being hi am .liilo1lted drug. II has not been esla'Hllld whictI <:ompOt.nd po sas 1hll schizo IIicidllI acIiYity. M tphc (fes eppeIll" In urine.

3. Pharmacoklnetlcs: ~ is

4. A""erN effects: Primaquine has II low irddllooll 01 lldrooIrse eftIcts except b dnJg-induced l'e11Dlylic .Ullia in palillots with geneticaly low IllYeIs of g"':nce 6-phospha1ll dehydrogenase (Fogure 35.5).' Other toxic manife5talions obserVed afillf Iargll doses 01 ltlll
mav

• •..,. ro. . .", ..... _

....- , •

35. C. Blood IChlzontlclde: ChIoroquiM Chron::lqurIe [KlOR oh kMlJ is a s~ I~ oetic ~ that has been !he mainstay 01 antimalarial ~ until !he recent appe;uance 01 drug re:sistcn stnWls 01 """iNnm

e.

,. Uo* 01 klk>n: SewraI ~ heYe been icIentified by 'oONctl d*»oqui'Ie Io:.lIs fle organism .rw. aocurruatrog ., ltoe UiglWi&ll

•• D• ...-g. mediated by accumul.t.d h.....: Chloroquine ent.rs the red blood cells atld Interferes with a unique enzyme Nt is esse eSal to the SLnMlI 0I1he paraslles" fle red t*xId OBIs.. The parasites ligest the ho5I CIlI's henJo. glat*l to get essential arrWlo acidI; 8nd lion. HoweYer, tis poe s also re'e"SB$1arge ~ 01 ~tIIe hlIme thai is toKic to the parasites.. To proted itseM. lhe parasite ~ polymerizes the heme to hemozoln (a pigmenl) \hat is sequestered in the parasite's Jood vacuole. Chloroquine Inhibits the polymerase and thus soluble heme kins the organism by inhibiting proteinases in the loo
•

'p

err

b. Alkalinization 011000 VllCUole: ChloroquIne Is taken 141 into the parasUe's food vacuole by an actJye transport system. Inside \he acl
e. DKr.ued DNA synthnb: The drug un also deCrease DNA IY' Id . in the parasite by dsrupling IIle Iertiary &truelure dille r'IJdeic acid. 2. Rnlstancr. Resistance 01 plasmodia to lMilable
_ _ 01 Central and SouIh America.

~

.e.

bIhiPevD 0CIflt<Wl membllllie

BS~ed P-gt,<eopdm (see p,. 377) 1ha18IdNdes lhe drug from IIle organiIr'rt.

3.. AJotiI.ikiatliat ~ Chron::lqurIe is the drug 01 choice in itIe Ire.' Ie. 01 erytwocytic ttq:>an.m meI8ria, 8li:OIlpl in re l'slant straiN. 0JI0I0llu0'Ie is less etIedive agein&t vI\eJc malaria- It is ~ specific b fie "S8'Q!&Ilorm d.e.mlIls and.e. !e!riooum It is also ellocti4 ., f>e treatment of eKlr8inleslWlBl amebiasis (see p. 346). The an!i·inllammatory action 01 chloroquine eKPl__ its UiX'8sionel use in rheumatoid arthrtli$ and discoid

.....

-

4. Pharmacokinetics

.. Admlnlstrll110n and dlsltlbutlon: CNoroquine is rapidly and c:omplelely absorbe
~ kI_GIH I<> GS$(l; 11 ,_ 10 ......1mIo I<> ..",..Izo I<>xlc_do

as...

_d_ _.. Flgllre 35.5

hetrdytic aneriIia. GSH. reooood g1uti11tione; GSSG. OlCidized g1utilfU'le; NADPH• ....,......,., nioolinlwnidB 8derirlB dW1udeolide

..........,.,., ...... _,> 352

35. Antiprotozal Drugs days 0I1hefapy suffice to cure the (huse. The c;rog COloce .. trates in ery1hrocy1es, liYer, spleen, ~, ling, IWld melaninc:ontainrog tissues as wei as 1eoIIocytes. TOOs h has a vet)' large IIOlurne 01 listribulion. II persislS in 8f)'lhrocytes (see rrode 01 aclion atxMl). The drug ~ penelraleS lnlo the ceoIr1lI n8MlUS system IWld IIlIVerMS Ihe paoenlll. b.. F...: ~ is deaIkyIaled by lhe hepatic mboed bIdion 0.... n (see p.. 14), to liCIme metatdc pIOlD:ts retain anltl1\llIari8I ~ BoIh parent drug cn;l metabaIi_ iIAI B""'::lEkld prlldDrmilnlly in Ihe L01e. EJia...., r-. • enhiR::ed as...-Y1e

iii adoitIed.

5. Adv8rM eIlItcls: Side etIeds are rrinirrIlll .. low doses used in the d.'·.oppression 01 malaria. AI higher do6Bs, many more ll:Jtjc etllIcIS OOCU', such as g ','*otesIilllll up&eI. ptUrilus. ~ $ "lao hils (Figure 35.6), and visual disturoances (an ophthalmological ~ ~ be roulineIy peibllled). tlisaobation 01 the nail beds and mucous membfanes may be seen on ch.onic ~licn Ql/oroquine shotAd be used cautiously in patierts wit~ hepatic dyslunclion Of severe gastrointe6tinal ploblems. Of in palients w11~ neurologic or blood dlSOt~. Chloroquine can ceU&e eIectrocardiogf changes, 6lnce h has a quirlidjne-like elleel (see p. 167). It may also exacerbate oermeli!is prOl1Jced by gold (see P. 414) Of phefl)I//JIAazone (see p. 411) lherapy. (Nole: Palients wllh psoriesi$ Of porphyria &hoold nol be trealed wilh chJoroqvine because an &CI.Ile altack may be pr'O'ro(Iked,] Agur.35.6 Some acM:lr$e etIects COl'., .... ily Il6todaled with d'kxoquinB.

D. Blood achbonticlde; Ouinine

Ouint'le (KWYE nine] is now reserved lor melarial strains resistanl to 0Ihef II(/Bflts. The drug can afIed: DNA synlheela. 1. Phf,'IlIKt*lnetics: When a chkN'oqu.irle-.eslstant organism is 8I"ICCU'lt8fed therapy usuaIy co l$isls at a 00II'tIinati0n at qunne, pyrimelhltmine, and a stJIIonanWde. AI life aorinislefed oraIy. tHole: fANSlOAR, a combination 01 pyr1mcI,r.-nvne and sulfa· dJUne Is usea.] Taketl ~ quhine is weA
_,.og.

.-.ems

reIUl lD a Coombs' test b ~ 0CClHS. Alrong the drug ill8ladiDol6 are 1) recardalion 01 ab&ooplior, when qufwhe is taken....., ~ ~ 2) poklnlialion at nEUl'OII"USCUIar bIoddllll agents, IWId 3) ele.atiol, of digad1 (see p.. 158) kMlIs ~ taken ~ Mth t;Unine. Ouirirle is telDtc:II6e.

E. Blood schlzontlcide: Mefloquine: M6~ [MEF

10 kweenJ appears ptQmising as an effective single

agenl Iof suppressing and curing mullidrug'fesistanl

torms

01

f ..

<

.~,

10. . . . . , > .............. 1 >

353 !a!cioarym. Us e.ac1 mechanism of action remains to be determined, bUt ~ apparently can damage the parasite's membrane like quinJ'ne dOeS. Resistant strains have been Identified. Me~ is absolbed well at1er oral administration and COiICel,trates In the liver and llong. t1 has a long ha/l-lifa (17 days) becalJSe 01 concentration in various tissues and because of its COI'11inuous circula1lof1 IhrolJ!11 the en1erohepatic and enterogas1ric systems. The drug undergoes e.tensive metabolism. Its major excretory fOute Is the feces. Adverse reactions at high doses range !rom nausea, YOmiting, and dizziness to disoriental1on, hallucinations, and depression. Electroca~abnormalities and cardiac arrest are possible if mefloqulne is taken concurrently w11l1 quinine, or quinidine or ~

-"

TRYPANOSOMIASIS

I ~

F. Blood schizonticide and aporontoclde: Pyrimethamine The antifolate agent, pyrimethamine, Is lrequently employed as a ijood schizonticide to effect a radical cure. It also acts as a strong Sj)Oronticide In the mosqu~o's gut y,tlen the mosquito iflge$1S ~ with the blood of the human host. Pyrimethamine inhibits plasmodial dihydrololate reductasi' at much lower concentrations than those that inhibit the mammalian enzyme. The Inhibilion deprives the protozoan 01 tetrahydrololate, a cofactor required in the de novo blosyn\hef;is of purines and pyl'lmklines, and Interconversiof1s 01 cenaln amino acids. Pyrimethamine alooe is effective against taldparum. In combirlalion wlfh a sultonamide, ~ is also used againsf IIliIlill: il.llI. and I""gp!asma goolii. If megaloblastic anemia occurs, it may be reversed with /euc:oIIorin (see P. 379)

e

e

,-//f

soe

prole] is a derivative 01 mefSalyi O>Oide, a

1. Mode of action: The drug reacts wi'" sulfhydryl groups of vanous substances Including enzymes in bolh the orgal1lsm alld has!. Parasitic enzymes may be more sensitive !han are those of the host. There is evidence that mammali.m ceUs may be less perine· able to the drug and thus prolected from ilS 10l(i(; ellects. 2. Antlmlcroblal spectrum: MeIarsoproIIs limited to the treatment of trypanosomal infections, usually In the late slage with eNS Involvement, and Is lethal for these parasites. ,""" .. ""'.'" _ _

in,._

nIl

L ___ ,II . ,

AFRICAN

-[_. -. 'll -_. -I ~I

11blel

ll8l

....

e-

_

0

!

•

: , CI

Trv~Mrtf

rlOOdIfi,....

~

A. Melarsoprol

trivalent arseoical.

Chagas';'1

,..... :t..., TfYpaI'ffl'Nl

Trypanosomiasis refers to /WO chronic and eventually fatal diseases caused by species 01 Tryoaoo§Qma: African sleeping sld<.ness and American sleeping sid\ness (Rgufe 35.7). In African steeping sickness, the causative organisms, nyoanosoma brucej Qambjense and TrvRM95O"'" 1ln.K&i rbodjeose, initially live and grow In the blood. The paraslle invadeS ll1e CNS, causing an inflammation of the brain and spinal cord that produces the chatllcleristlc lethargy and E!Vef1tually c0ntinuous sleep. Chagas' disease (American steeping sid
Melarsoproljme LAA

carrsedby

Tf)'~cruzl

"~

IV. CHEMOTHERAPY OF TRYPANOSOMIASIS

's. p. 358 !of _

.

AMERICAN

.... ......... = ~

,,

min and pentMnkllM used only In the eerty of d l - . . MHoI,..",. 01 when Ihefe Is eNS ~

Figure 35.7 Summary 01 trypanosomiasis.

..... , •• " " " ' - " ' - ' >

35. Antlprotoul Drugs

4. l>tWmKokinellc.:

.. AdmWlllltrallon 8f>d dlarlbutlon: Melat'$OplOlls uwaIly ~ 80TIinislered ifllr.M!nou:sty IIYwgto a fine needle. even II1olJl1l ~ is lltlliofbed from the ~ tract. Because i( is ~ irritaq, care stoJd be WIetl 110I10 irMftlle swfOl.nding tis_ . AclE'oQlI!lIe lJypiJIu:idaI Wi ....... IIIiu .. appear ifl1he C8f&bluspinal tid, wt«:h Wi'l1nlS1S wi.-. ~ (see Po 355). wIlictI dOes 110I enIer!he Cle'eboospinailluld. Me0'sopool is therelore the agem 01' choice in the treatment 01' L ~ " ' 1 's 1M. \Irt\id'I taPI:Jy lnvadn the CNS. as wei as lor m8i1il yoe~ ca'lsed t:Iy lP°pl 0""' .'M.

t_

•

b. F. .: The horit readly ",a,es 1he drug 10 the relatilletJ non-mie penlavaJenl lIIsenic oornpourlCl. The drug has a very short h:aIl.(1Ie and is ~ 8lCaeIed inIo the urine. 5. AdY.... eflKls

.. central _ Iystem todcltllll: These side et1ects Ilf8 1he most &eriouli. Enc:ephaIopalhy may appear soon at1er 1he first CC1lJrse 01' treatmef1l but U!luaJly wbside&. II may. t1owlMlr, be

"'

•.

b. Hypersenlltlvlty teaCfIonI: Such ,eaelion. may also occur. Fever may follow injection. C. GallroInle$tlNlI dls.... l'l:Nmee: SeYera -.omaing and abdominal pain can be II'il1Imized If the p8lienl ill in the t:Isling stale durIng drug Iidnliltl$trlllion and lor several hours lhereafter.

d. Contrslndlcatlons: MeIarscproIIlI c:omrsirodlaue
B. Pentamidine .se~te ~ {pen

TAM i deen] is ........... Il"*l1OIll illfeeticwlS"

lIS Ihol;e "",vd t:Iy PIe k!!""'tiF taD.. INcM: f. !Olllili i5 f'IOI/ c:onsicIered 10 be a ftwVlS, buI i( is no!51'Cl ",.jl"'l0 a-oliIu'lgal

•

wei

OlJllI.J Beca_ 0I1he R:mased

illCidellOt 01' prlllU1'll:ria caosed t:Iy thls organism in imrnutlOCOi'lpfOi,'led patients S\.dl as those inIeded Wllh ta.m.l irm'u w:ow:leficiellCy Ww (HV). ~ has &SSl.n'iId an ~ pIaee in de'lOII....,... ~ is UfIlI fA the drugs lor the prevention and t,.almenl 01 the hemaIologk: . . fA L lI!J,Qlj \01'''' M.

1.

ModoI fA -=tlon: L tll:l..!I;§i wr:celltra1e5 !he drug by an energy. dependerll. high·alfinily uptake system. Although its mode 01 IlClion has not been lleI>-Ied. ew:senee exists f,aj the drug binds to the parasite's DNA, Ilfld interte,es in lhe synthesis 01 RNA. DNA, plJi:JstJtUlipid and proter. fA the parasite.

."",

... """'-"'-"

. . .-

......_ _... , -

.. _

..... >

355

IV. Trypar1OIiOffiia

2. Antlmicroblal spectrum, Penla
e.

IncIvb.iaIs who arll aile giG 10 SlMonarnidlII. It 15 WI ~ lhog 10 S'il"1l" ........wI!I1n h! trealn&1l of IeisIYn8niasis. 3. Re·..._ , pC" 1ih1Ce is aull1ialed ..... WI InBbIliIy of h! Wy......., . 10 COi ltAli!llale h! O'ug.

•• f'tWmIoeoIdlllttica .. ~dllt,,'lion and d"1IitfIbul1on; Fresh ~ 11111 8O,.listeflId W:1'8lI'l.lSClJar Of lIS WI aelorlOl. [Note: ThlI inIr.lYenous roule Is...ooed of severll edYerse readiollS such as II &harp tal in blood pressu.e and laChyeardia,] The <'"Ug is concentrated and stored in the live. and kidney lor a long period 01 time. Because ~ does not enlfIf hi CSF. It Is ineftfIc.tive against the m e n ~stage of ~

"""'1SP

b. Fete: The drug Is not metabolized and Is excreted very slowty Inlo thO urlnll. lis t'.\I15 about 5 days. S. Adversa ."KIII: Se.ious .enal ctysfuncllon may occur, which feverses on discontinuation 01 the drug. Other ~ ,eactions are hypoter1$loo, dizziness, rash WId lOlllclty to !Kells 01 pan· 0 ....

C. Nih.lrtlmox NifIxfjn'o( [nye FOOR 11 fTl(lI(] has b.Jnd U6El only In the Ireatmenl of llCIA.e I.1OIlolD ~11ec1ioi IS (Chagas' disease) alhlugtl tteIIlmenI 01 the ctvonIc stage 01 such II alia IS has led 10 Vtlrlable reMh (NoIe; NlurIfncw II SUJlPi 5S,"~ na: D.r.IIiVe.1 BeIng a nilroaromalic aimpound, niIurtimoK U1odergoes reduction and eYOOlualy gellef1illles ~CIiK*."" 0Irf0tn f?lCIaJIs such as Sl4)eltltide radcals and hydr0gen pauckle. In boll . . amas'lrM and b'yPOn'IaSligol 01 L awl. These liaW.eadMI AdicaIs are IaKic 10 theOiglO_'~ whid'llad<s aca'8"~ hn eels are poteded from such SIbsl¥Ioas br the pese ICe 01 enzymes such. aca'as e , ~ perooidase. and r;upen:Pida
Ma,"'

pili""'"

cruo

'S-P. 3SB1or _ , ........ '" _ _ i'lIf1iI~

... .... t. - f. ,.

.

"'"

<-'.'''''''<-'''-'' 35. Antipmtozal Drugs D. Suramin

Sutamin [SOO ra minI is used primarily in the early treatment and especially In the prophyla~is of African trypanosomiasis. It Is very reactive and ilYiibits many enzymes. among them, those involved in energy metabolism (e.g., glYl:erol phosphate dehydrogenase) wtlidl appears to be the mechar1lsm most closely oorrelated w~h trypanocidal activity. Suramin is also the drug 01 choice in treatment of patients with the adult forms 01 the lilarlal parasite, Onc!locerca yoIyulus. The drllll must be in]ected intra...enously. It binds to plasma proteins and remains In the plasma lor a long time, accumulating In the liver and in the proximal tubular cells olthe kidney. The severity olthe adverse reactions demands that the patient be carefully followed. especially if debil~ated. Although inlreqlll!f1l. these reactions include nausea and vom~lng (Yotlidl causes further debilitatior'l ol the patient), shock and loss 01 consciousness. acute urticaria, and neurologic problems that include paresthesia. photophobia, palpebral edema, and hyperesthesia 01 the hands and Ieet. Albuminuria terw;ls to be common, but wt1en cylindruria (the presence of .enal casts In the urine) and hematuria occur, treatmer1t should cease.

V. CHEMOTHERAPY OF LEISHMANIASIS Figure 35.8 Mucocutaneous Ieislunaniasis.

There are three types 01 IeishrT\al1iasls: the cutaneous. I1l\.ICCICIIIans (figure 35.6), WId vIsoeral. [Note: In the visceral type (liver and spleen). the parasite IS In the bloodstream and can cause very serious problems.) leishmaniasis is transmitted from animal to humans (and between humans) by the bite 01 infected sandlIies. The treatments of k*lhmania· sis and trwanosomiasis (see P. 337), are difficu~. because the eIIective drugs are Iim~ed t7,0lheir toidcilies and failure rates. Pentavalent antmonials, such as sOOum sti/:IOgIl.lCCt18te. are the COrlV€OtionaI lheraI7:f used ir1 the treatment 01 leishmaniasis. with pentamidine (see p. 354) and anyJhoterldn B (see p. 357) as bed;·up agents. A11opurinoI (see P. 417) has also been reported to be elfectiw. The drug Is oorlllerled to a toKic metabot~e by the amastigote torm. The ~ is made by demonstraUng the organism in biopsy material and skin iesions. A. lile cycle 01 the causlltive organism, leishmania

The sandtly transfers the flagellated Pfomastlgote form ol the pr0tozoa. which Is rapidly phagocytized by macrophages. In the macrophage, the promastlgotes rapidly change to non"agellated amastigotes and multiply. killing the cell. The newly released amastlgotes are again phagocytized. atld the cycle continues. B. Sodium stibogluconate

SIIIKJgluconale

Slibogluconate [slib 0 GlOO koe natel is not elledlve in vltro; therefore ~ has been proposed that .edUetlon to the trivaler1t antimony compound Is essential for actMty. The exact f'\"oElCOarlism 01 aetlon has not been de\e""";ned. Evidence lor inhibition ol glycolysis In the parasite at the phosphofructokinase reaction' has been found.

·SMp. 35Ilklr _ r e t _ l O _ _ in IIQ_.

<......

0 ...

'.'.< .... _,.

...-M ....·

VII. Chemotherapy of Giardiasis

Because ~ is not absorbed on oral ~";'Ostr3Iion, sodium stibogluCOMte must be administered parenterally. 11 Is distributed In 1t1e e>rtravascuiar compartment. Melabolism is minimal and the drug is E!>lcreted into the urine. AdYefsa effects include pain at the injection site. gastrointesUnal upsets, and cardiac arrhythmias. Renal and hepatic tuncIion should be periodically mon~Ol'ed.

VI. CHEMOTHERAPY OF TOXOPLASMOSIS One of the most common inledions in man is caused by the protowan, ToxooIasma IlOOli/, which is transmitted 10 humans wher1 they consume raw or inadequately cooked, Inleded meal. Infected pregnant women can transmit the organism to the fetus. Cats are the only animals thai shed oocyslS that can lr11ed other animals as well as marl. The treatment of dloloe for this conditioor1 Is the antifolate drog, pyrimelflaminfl [peer I METH a meeol (see p. 353). A oombinalion 01 sutfadezinlJ (see p. 269) and pyrimethamine is also efficacious_ Leucovorin is often adminlstefed to protect against Iolate deficiency. Other inhibitors of folate biosynthesis. such as trimethoprlm (see p. 293) and sulfametfloxazote (see p. 289) are without therapeutic efficacy In toxoplasmosis. INote: At the firsl appearaooe of a rash. pyrimetllam~ should be discontinued since ~rsensltivity to 1t1is drug can be seve<e.1

VII. CHEMOTHERAPY OF GIARDIASIS Giardia !amblia is the most cornmonIy tiagnosed intestinal parasite in the United States. II has only two Ilfe--cycle stages: the binucleate trop!1o:roite with 4 Ilagellae, and the drug-resistant 4·nucleale cyst. tngestlon, usually from conlamir1ated drinking water, leads to Inlectlon. The trophozoites exist in 1t1e small intestlne and (ivide by binary fisslon. Clccaslonally, cysts are formed that pass 001 in the stool. Though some inIecllons are asyrl1)lomatic, severe diarrhea can occur Which can be very serious in immune-suppressed patients. The trealment Is usually either ~inacrine Ol' metronidazole (see p. 347). A. Quinacrlne

Quinacrine is an acridine derlvallve lhalls primarily used in the treatment of giardiasis, but is also etfecti\l'e against tapeworm and malaria, and topically, against leishmaniasis. II bindS to men-bane ptlosphoIipids. blocking phospholipase ~ activity. OJinacrine also binds 10 the acetylcholine reoeptor. Given orally, quinacrine concentrales In the liver. Because II crosses the placenta, II should be avoided In pregnant women. Adverse etIects range !rom the more common diUlness, headaches, and vomiting to more serious PSYchosis. urticaria, extoIiative dermatitis and plgmentallon oI1t1e skin. OJinacrine and primaquine shook! not be given together because of incteased toxicity.

' ............ _·W· '5'

............, ........ _,. 35. AnliprOlOZa1 Drugs

358 0!.>ePcn& 35.1 .35.3: FOI' each ~ed.,.,.... ICIocI ... ONE drug (o4·E) _ is rmst do$eIy II$5ClCilIled .... It. Ea::tl drug (A·E) may be' , c1H OI'laI, mare 1fIan....:e. OI'noI . . . .

35.5 AI of tie IQIIowing 'Illl1Ofl'lefll1 aboul mutrooidazole IInllfue

EXCEPT:

A. "' i, admlnktctred InTravanously because it i, poorly ab50rbeCI _ CIf1lI ~

.......

A. SodUnttitw9......B. Diluxaidll " - ' "

B. " is eIledive ~ a w;de vanety of l1naI!ftlllic

c.P\J..............

C.II produces a . . . . ." ....... ""

D.E-. E. I 'lelo Of Iiduole

D. ClosagB _

:IIS.lo4 ..

-......-

1hII....

f

,

be -..oed ifl ...... lIS .... 1IeplIic

E. Thetapeuac ..... can be b.-.d on ... ceeblal

_'oic.'.... Io1&

spFoal ....

[I~c:~.~.~.;:':.:D:..~"~..:.:':::::===1

:llS2u-l ...... _ o l l o " . '

Conecl c:f'cIb .. A. :- 7 CriG'""" .... ~ _ [

'lDiiis.

=,001', II, .tI~~"",_---:

!

356 AI d !he kt>Mng ,,-.-15 abcU" I 1CIp1
I c:ew-_.. Al*ldi.rn~ _ _~

trypallOSCm-'

C. AOoQuaIll Irypanocldal flOI'IC(Ifltralions appeal in Iho oorobral S(lfn&IIluid. 35.4

0.11 can cause seas 8 very ShCf'l MII'Iito In 11111 body,

ot lho kldQwlng slatements about dllofQquino ar1,l

1" EXCEPT,

(=:..~::~':~ )

A. II bk>Cloa P"l!(lZOlll DNA and RNA synlhoM.

B. InleClod cott, can concenltal0 the dlug

Ie

a

IIflallH eXlQnt llan can UfW'Ilec;lod cdIs. C. II II lhe dnJg '" Ch
E. Only

"'I*"A II •

35.7 WhId> one oF the ~isa><ma?

' _ _ 'C2RI_lb ......

I'

0I'._10I~_00lb"

._-

"sMp. 250 ..

01"

ha _ , C2'r'<1_llor._....... .. _01._"..,••1 n

"sMp.90in.

I

.......

'(2nclafl.lb' ...... _

-"'ll ".lemanls aboul pri-

A. " is e/lediIoe "lIlli'* eryf'oocyIl: lofm5 d maIariII. B. " Is i ..1ltM;:Moe ill w--.g reIIpoIing vlvax trl8laria. C. Hio,;l (Io>ic) dol.- rnay ~ CIOfY-> ..... D_ GIucoH~" dIihyclrOgII_ do!kieo'" ~ ... ItI""lDfl"'dylic"""" E. • is ad",. I ell ~ bl' It......",. 1OUIiI.

a,e

;< "10 _eqokoe.

'SMp.3&I ... "

"'the drug

"saaP.lISln.

"'_,C2'r'
oI~S?I<'il_claI\d ..... _ _

"sae

P. 114 oI _ _

I.' ' C2R1_jbs_ oor,ova'l . . ., ••

___ . "",;,·...

''''''0''''''''_'''_''

Anthelmintic Drugs I. OVERVIew Three major groups Of helminths (or worms), the nemalodes, trematodes aod cestode&, ir11eet humans. As in aP antibiotic regimens, the anthelminthic drugs (Figure 36.1) are aimed at metabolic fargefs that are Jlfesentln the parasite but are either absent from or have differOOI charac1erislics than those of the host Figure 36.2 inustrafes the high Incidence helminthic Infections.

_ . -

CHEM01ltERAPY OF

H...-ntIC INFECTlOHS

0'

-

-=-

~.,,-,

"',,,,.

11_ DRUGS FOR THE TREATMENT OF NEMATODES

Pr-"A"~"

~-

Nematodes are elongated I'OlJndworms fhat possess a complete digestive system, including both a mouth and an anus (Figure 36.3). They cause Intections Dllhe intesfine as weH as the blood aod tissues. Agure 36.4 summartzes the infecfions caused by nemafodes, and the common therapies used for fhese inlectioos.

-

~_

~=-

Pr-.zI
-

A. Mebenda>:oIe

'"""""""" r.uTe-fl

_'co _ Mebendazole [me BEN da role] a synthelic benzimidazole compound, Is effectlve against a wide speclrum 01 nemalodes. 11 Is a drug of choice in the treatment of inlections by wtlipworm Urichuris trk:bjura), pinwo.m (En1~~ yermicularjsl, hookworm (Necator amerlcanus and Ancvlostoma dUQdenale), and roundworm fAsrarles1s lumbrjgjOO<. FIgure 36.5). Mebendazole acts by bindIng to and Ir1terlering with the synthesis of the parasite's microtubules and also by 6ecreasing glucose uptake, Affected parasites ale e"pelled with lhe fe<:es. Mebendazole is nearly insoluble in aqueous solution, and little Qf an oral dose (whim Is mewed) Is absorbed by the body unless taken with a hi!1l tat meal. Theretore, this drug Is relalll'Bly 'ree Qf tOKic eHeds, although patients may complain of alXlominaI pain Bod dian1lea. However, it Is oonlraindicale
. .

Figure 36.1

SlJfI'dnllfy of anthelrrinthic agents.

B. Pyfantet plImoale

Pyranlel pamoal8 \Pi RAN tel] along with mebendazoIe is eltective In the Ireafment 0' Inledlons caused by roundWorms, pinworms (see Figure 36.4), and hookworms. Py,antel psmoale is poorly absorbed orally and exerts its effeds in the intestinal trae:l. It ads as a dePOlariZing neuromuscular bIod
..

_ _ ,,

~

_~

"-_'_"'

'i. _ _ c.o-",PM,"'"

359

. . . . . . _ _....-po'"

'''''''.''''''''---''

,-

360

,......

"--

""""U _ _ . PI' •

36. Anlhelminthic Drugs

("..,.,.,... <JI """'" P«IlUaIion)

0102030

aetiva1ion 01 the parasile's nicotinic receptors. The paralyzed worm is then eKpelled lrom the host's lr1tesHnai lract. Adverse etfBoets are mild, and include nausea, vomiling, and diarrhea. C. Thlabenduote

'""""""

,~

"

,--.'"

"

(100 mIiionI)

Figure 36.2 Relative IncldencB 01 helminth Infections worktwide.

Thiab«ldaZtJIB [lhye a BEN da rolel, anolher synthetic benzimida· :role. is ettactivB against strongyloidiasis due to S1rongyloides ~ cora[js (thread.....orm), cutaneous larva mlgrans (or creeping eruption) and early stages oItrid1inosls (caused by TrIchInella W:: .m!.is). It, too, aff8Cls microtubJlar aggregation. Though nearly Insoluble In .....ater. lhe drug Is readily absorbed on oral adminiSlration. The drug IS hydrexylated in the liver and excreted in Ihe urine. The adverse effects mosl often encountered are dizziness. anorexia, nausea, and laTliting. There have been reporlS of ceotral nervous syslem (eNS) symptomatology. Among the cases of erythema multilQrme and Stevens-Johnson syndrome reportedly caused by thi· aben<J
lvermecfitl [eye var MEK llnjls !he drug of choice for the treatmanl ordlocerciasis (river blindness) caused by Oochooorca volvulus and has been shown to be etlective against scabies. ~ targets the parasite's l"aminobu1yric acid (GABA) receptors. Chloride influx is enhanced and hyperpolarization occurs, resulting in paraly· sis 01 the worm. The drug is given orally. II does not cross the bloodbrain barrier and has no pharmacologic etfects. However, it Is contraindicated In patlems with meningitis. since their blood-brain barrier Is more permeable. and eNS etfecls might be eJ
or

III. DRUGS FOR THE TREATMENT OF TREMATODES The trematodes (flUkes) are leaf-shaped flalWQrms thaI are generally characterized by the tissues Itley infect. For example, \hey may be calegoriZ&d as liver, lung, intestinal, or blood flukes. A. Pru.iqu8ntel

Figur.36.3

PinwoIms leavif1g !he anus ol a fiveyaar-old child who presented with crying, res1lessness and aIxlorninal pain.

Tremalode infections iIle generally treal&d with praziquantel [pray zI KWON tel]. This drug is an agenl o! choice tor the trealment 01 all lol1l1$ 01 schlstosomlas~ and tor cestode intections like cyslicereosis. Permeability of the cell membrane to calcium is increased, causing contracture and paralysis of the parasile. Praziquantel is fapidly absorbed after oral administration and distribules Into lhe cervbrospinal fluid. High levels occur in fhe bile. The drug ~ extensively metabolized oxidatively, resulting in a short half-lite. The melabomes are inilClive and are excrel&d through lhe urine and bile.

·_ .....'.,> ......

_L>

Ill, Drugs lor the Treatme<1t 01 Tramatodes

'"

ONCHOCERCIASIS (RIVER BLINDNESS)

e e--rv. __: O,,1t H e Cammon In .._ of MpIcO, SouIt> _ _ ~

1fqIIc8l A......

_

e

CII8o.""a:'.:l. ."" _ _ """"'*,oft...

~.Idn

MA>aJfanecuo

TRICHURIASIS (WHIPWORM DISEASE)

_ n g In bllnd-.

_.

eTlwapy: _ _

e c....- __, Trlc!>utillridlluno. e=,..:~~~:.,

ENTEROBIASIS (PINWORM DISEASE)

e ea-.... ~

Ep!e(OtJluI-...k:uIao1..

...... ,-

e_ e

c:omnwnor, helminthic Inl_In tlw

HOOKWORM DISEASE

1'
e e--tI¥a _ _, Ancy\oOf...... (Old Wo
In .. ooI.o<~ragIon.

_to_ __... __

p-..worIdr

,_"').

e .......... Worm IOIlOdMoa k> , _ llk:ef1lka.",

1_1lIaod .... 11I..

e

ASCARIASIS (ROUNDWORM DISEASE) e~"""'_.""oboF

•

,'' '

T'Mb"..." "'.

e '"'-f>Y: PynnI"~O<-""'"

5ac:ondoriyk>pI
_.,11

~

~"""-lntlwU"""'S-;

.

STRONGYLOIDIASIS (THREADWORM DISEASE)

l

_g<_ln .... _ ......n"".. ,.,lnduclIng ..._

~.-

to_

,-*,O

_ _; """dwQ ........ _

.nd IIftcI .... Iunga.

e

.

....,. In ...." ........' _

I' ..

Of>I>rO-.oIy _1II1n:l " ' _ .........

e

. . . . - caualng ,. _ _

,ng ....

e

e

e e--rv.--.oa' _

bal .. otl!,

""" ""'"_""""""'''''If''''

of ,'''''''''-:

1IIlo... I,

e --~ "'_IIiII""' e

n.-p,:

-

1lI1_IIuI
Ilb
_

ng~

DlIeltI~

.._

.....

..._,••"", .......ad _ _

e'"'-f>Y:~

FILARIASIS

_

~

Inr..clnol _ _; • r-..Iy IMnIgn In .......... 1 _ ; . , . . , pI'CIgI'.10 IIlhil
Tl>e<1py:PrranfM~"'_

e Wcrmo

~agoont:~,~

TRICHINOSIS

e e

e:a.--~: T_~

._,

u..:'J e..-

by ~ '" tnaullldantly ......... padlflty pori<.

e '"'-PI': m_(onIyln-'Y _ _

Agure 36.4 Charactenslics and thetapy for commonty encountered nematode Infactions.

<-'.'''''''<---'' 362

36. Anthelminthic D,ugs

common

adverse effects Include drowsiness, dizziness, malaise, and anore~ia, as well as gastrointestinal upsets. The drug is nol recommended lor Pfegnant women or nursing molhefli.. Drug interactions due to increased metabolism have been lepolled with doxamcthaSlJfllJ, phenytoin, and C.1rtJamazepine. Cimelidine, known to inhibit cytochrome P-450 isozymes, causes increased pr.uiqvantel levels. Praziquanlel is rontfllir.dicated for the kestmant of ocular cysticercosis since destflJCtion of the organism in the eye may damaga tha organ.

IV. DRUGS FOR THE TREATMENT OF CESTODES

_-..._ ..-. Figure 36,5 Nmbricojdes

~

worm in

lUmen 01 small bOwel 01 S2-ye81old woman from Africa.

The cestodas, or "t,oo tapewoffTIs; typically have a flat, segmented body and attach to lhe host's intestine. (jke the trematodes, the rapewonns lad< a mouth and a dfge1>tiYe tract throughout their life cycle. A. Nk;l05llmlde

Nidosamide [nl KLDE sa mide] is the drug 01 choice lor mosI ces· tode (tapeworm) infections. Its action has beef1 ascribed to inhibition of Ihe parasite's mitod1oodrial anaaroblc phosphofytatlon 01 ADP which prodl.lCeS usabla energy in the form of ATP. The drug is lethal for the cestode's scolex and segments or cestodes but not lor the ova. A laxallve is administered prior to oral administration of nidosamidc. This is done to purge the bowel 01 all dead segnenlS In order 10 preclude digestion and liberation oIlhe ova, which may lead to CY1>ticercosis. Alcohol should be avoided wilhin 1 day of nidosamidc.

Study Questions Ouesrioos 35. I • 35.4: For each rumbered phrase, select !he ONE drug (A·E) tIl8t is mosl <:Io£llly associated wiIh~. E8dl drug (A-E) may be selflC11ld once, mora than OflOfI, or not at all.

35.4 Drug 01 choica inlections.

I

tor the

treatment ot most tapeworm

com;a _ _ • c (IIld
A. M-.-.dazole

B. PraziQUantei c. Nidosamide D. Py<8rlIel pamoata E. "lliaberdazole 35.t A drug which alledS micm1ublJlar function in roundpinworm, and h:>okworm. ( Con9ct .. A(r,_· Ia z<ej

"""m.

35.2 Ads as a depoIanzlog oour~r bIockiog ag&nl. 0 (p';ranIeI patnOllle)

Conecl_.

353 A drug 01 choice tor the treatffll;fll 01 d forms 01 schis10000000sis. Cornlct _ _ • B (praziqI.WlIIlf

I

35.5 All 01 !he IoIowing stalementS aboU roabentla..wIe life correct EXCEPT;

A. It is coolfaiodica1ed in pregnant women. B. II 0; lhe o:hIg 04 ctv.>icu in the ueatmenl 01 whipwo<m infections. ~ 0; elfedive by orel admlnislr1lllon. D. II is active apainsl ceslOdes. E. II inlerleres with gluooso uptake by the parasite.

C.

CorNcl_ .. D. ~ Is eIlec:tlYe 19InoI:.- • ... In III' dooa I 'II gUxIMo ......, IIu -...Ir4l h ~ 11> _ _ t h8I bien " - ' II> tle ~

,e

'*'

MICl'"'*'lJef*: In~"""'"

• "'" '0...I., ....... __ , >

-_

..."" ....---.--' .. .....

Antiviral Drugs AHTMIW. DfIUGS I. OVERVIEW

-

Viruses are 00l1ga1ll Intracekrlar parasites. They IactI both _ eel waI and _ cell membnlnll and do noI carry 0lA mel8bole ptOOllSse' Viral •eproductlon uses mllCtl 01 lhe host's metabolic n'lIII:Nnery, and lew drugs are seledr.e enough to prevent Wal replk:alion wilro.rc Injury 10 II1ll host. For 8UIlllle, Wuses 8re noI aflacted by antirnlcroblal egents. Nevertheless, some drugs sutIicientIy discriminate beffieen cellular and viral reactions to be eltoc1ive and ~ relatively nontoxic. Uni:)r1LJf18tety, only a lew virus groups, Including those thlll cause tI1a v1mllnlections discussed In tI1is chapter, responOlO It1ese drugs (FIgure 37.1),

-

-_., ... ..... •

FOIl HEN'OlA.NDCYTo-

""""""'" Ac,._. -~

,C/III
......

,--w;:::::=:=:. Fcc" 1M

II. mEATMENT OF VIRAL RESPIRATORY INFECTIONS VlrlII respinltory ll'ad Irdedions lot ~ b....btl&lIs exisl indude those 01 inIIuenza IypeS A ..., B. and respil8lOty ~ Wus (RSV). [NoIe: Irnrnuriz8lion against lnftuenza A is IIle plel""ed epproech. Howeoiet, anIMraI agetU are employed 'Itt1en patienls are aIergIc to Ihe \IllCO'le or ..men IIle ouIbrMk is we 10 811 ~ variIInl dille virus ncl CDfe<ed by ......... es.. tUbieab 01C0.X among tJr"I\'8Ccineted RIYiduaIs 1lI risk who _ in dosed settings. lor ~ in _ rusinog home.l

.. .... _

fOfl M ~TtlRY

-.- """,

-

~

,...~

Ab",," •• 16•• '

Of"""

,

Ao. . . . . . .•

... ,....,

, I . . . . .•

OF.

£10 . . . .,

....... ""'......

,

t ..... '

In many YiraI ~ the ctDcaI ~oms appear late in the cxuse of Ihe 58 III _ lime \'>'hen I'r'lI::I61 of the YinJs plMlides hlMl 'Olj • •...., [Note: This oonlrasts wilh bedeic. (lsea5!1 In ¥It"ich Ihe dn:al 'Y"lpIOl'lS are usuaIy wi ....d.... with b8cIeriIII plCOMlIioq /4J !his late. 'YUlpiOh Illlic: stage ollhe virBI i ,Iedioi ~ ao,.lisba!io, 01 drugs .... blrdt "'rill repIio:alio, hlMllmled ellectioollioess. ~. some riviral agents are usehJ 8S ~1Hojr, agents. For emm~ _fal1ile I_ MAN 111 deen] and lis col'lgelle., rtnantadine [m MAN 111 deerl] hlMl been shown 10 be equtIIy eItectMIln preo.ec lI:i l{l Influenza A h'lfecllons. [Nole: AmantBd'ne Is also elfectivll in the trea1menl 01 sorne cases 01 ~'s diseese (see p. 87).J

_.,1' ' S"" ._1'

*

1. Mode 01 .etlon: The pmcise antiviral rnecnanlsm of amantadine

.sa ..... IoN')

, . , : .• ..-:;1 t,

-

FOfI

..... (An)

HEP_m.,u:'.""

_~"'1lOl)MA

".1000",

FIgure '.fT.1 SufTtll8l'Y of antMml drugs. lDesabed In Pharmacology update, p. 457.

I

<""".'''''''<---'' 37. Antiviral Drug>

AMANTADINE TREATMENT ll
_-.ck_1n

pIliaoIt. MIll uneornpI_ ........1Iy oe<:u'
=-

J

1. Mode of roetlon: The precise antiviral med1anism 01 aman/Bdns and ,iman/adina remains 10 be established. Recenl evidence painls to II b1ocl; protein. M2. whict1 functions as an ion channel. This channel is required lor the lusion of the viral membrane with lhe cell membrane that ulti· mately Iorms lhe endosome (crealed when the virus is internal· ized by endocylosis). [Note: The acid environment 01 the endosome is required for viral uncoating.] These drugs ITlIlY 11150 inlerfera with the release 01 new virions.

2.. Resistance, Inltuenz.a A reslslance to amantadine and rlmanta· dne is not a dinical problem lIS yet. although some viral isolates have shown a high incidence 01 resistance. Resislance has beer1 shown to be due to a change in one amino acid 0I1he M2 mllui>; prot:eln. Cross·resistance occurs between lhe two drugs.

Figure 37.2 Improvemern in symploms 01 Individuals with nahelly occurring Innuenza inrection lreated with amanladine.

3. Antiviral spectrum: Amanlad"ne's lind rimanradin8's therapeulic antiviral spec1rum is lim~ed to inlluenza A virus. Their eff&cIiveness is directly related 10 !heir administration relative 10 inlection, for e>
4. Pharmllcokinelicl: 80th drugs are well absorbed orally.

R_ _ .e

.'--~.

Amanladina distributes throughOul lho body and readily penetrates into tho cantrlll nervous system (CNS). whe.ells rimanra· dine does no! cross lhe bIood-braln barrier 10 tho same elden!. Amanladino is not el(\ensively merabolized. It Is excreted into lhe urine and may acculn.llate 10 1OJ
bolin_.

5. Adverso effects: Amantadine:s side eflects are mainly assoclaled with Ihe CNS. Minor neurologic symploms include insomnia, dizziness. lind ata~ill. More serious side eflects hllve been reported (for example. hallucinations. seizures). The drug should be employed cautiously irl patients with psychiatric problems, cerebral alherosclerosis. renal impallment, or epilepsy. Rimanradine CllUsas !ewer CNS reactions sO"iCe ~ does flO'- elflciElnlly cross the bIood-brain barrier. Amantadine and rimanradine should be used with caution in pregnanlllnd nursing mothers, becIIuse they have been foUnd to be embryoto>
AmanrarJme R,manlarJme Ribavirin [rye ba VYE rin] is a synthetic guanosine IInIlI09. II is elfective against a broad spectrum of RNA and DNA viruses.

• •.0< . . . . ., . , .

.<_. __.. .-..-' _ .. _.

<_ ... _ , .

w·

III. Treatment of Herpesvirus Injections

""

1. Mode 01 action: The mode of aclioo has been studied only lor !he inlluenza .... uses. Rib3v1rln is first lXlrMlrted 10 !he 5'-phosphate derivalives, the mljor product being the compwnd ribavtrinlriphosptlale (ATP), whict1 has boon postulated to ellen its antivi· IlII action by inhibiting viral mRNA synthesis. [Note: Rt1inoviruses and enteroviruses. Whictl contain p<etoerned mRNA and do not need to synlheslz1l mANA ~ the host cell to initiale !he infection, are ~ resistant tothe adion 01 nbIJvnot] 2. Antlvlrlll spec:tnlm: R ~ is used In treating inlanls an:! ~ chilchtl infected with severe RSV i ,leaioi IS. [Nole: It is not InI:ieated!of use ~ adlAls.] Fao.oIatM respoI 59S oIllCUle hepaliIis A Yirus and ~ A and B irlBctiotlS " - also been ~ . RblMirin may Itllb::e the mor18IiIy and viremiB oIlassa laYer.

3.

m..i;i;l is etIediYe Ofally lIn:l 0nM!n0usIy. lis Cl.mlr'Il use is 85 In leIosolln ~ .espiJaIOoy WaI ~ lions, such. the IJe1IlmefIl 01 RSV 'rledU~ Shdes of drug dis· tri:JuIjon ~ pftnates showed ieteotion in II tisso_ excep: bran The <*Vg lIn:l its mellt('lljres are e1ir" ' d in !he t.ftle_ ~:

Rlbavmn

4. AdvetM ettec:ls: Side eI1eets reponed lor oral Of parene.al use of tit8vim ' - n:i 'ded dl:: 51 ~ odele hal . t anemiB in Lassa feller \fic:tims. Ele\;ate
III, mEATMENT OF HERPESVIRUS INFECTIONS

I

CONTRAINDrCATED IN PREGNANCY

Herpesvinlses Ire IIssoe;,"«I ~ a bro8d spedrWn of diseases. e.g., cokI SOles. vifaI ~ II'lll getlital i rIedtoIlS. the IetIeI being a h8nln:l 10 !he newborn ckIMg p8ItUIilion. The dIugs IhII are ~ againslttoese viruses uert Ihei. IttioIIS dtrilg !he aeuI8 Plase of viral idations and Ire wiItouI efteel in the IaIenl phase. Except lor bscarnet, aI Ire ~ Of !lY'.''''18lnaJogs Itl8t i"lti viral DNA synthesis. A. Aeydovlr

AG)'dovir lay SYE kJoe _I

(~

has beeune one of

the most pleseribed antlvirel (\lugs because of its ellectiveoess

aPlst helpes.i.uses. 1. Mode of Ktlon: 1'\e)'eIoW. a guat1O$lne IiW\8klg !hal I&d<s a true sugar moiety. Is monoptlosptlofyted in tM 0011 by the herpes virus-enooded enzyme. lhymldirte ki'lase. The.etoIe vinJlrinleeted eens are most susceptible. The monophosphate 8I1aJog is eonV8Ited to the cji. and t~te forms by the host eels (F'ogJre 31.3). Acyelovl. triphosphate eompetes with deoxyguanosine lI1Jhosphate (dGTP) as a substrate for WaI DNA po/ym&Iase. and is ~self Inoorporated into the viral DNA causing plemature DNA· chain termlrlation (see Fl{lUre 31.3). Irreversible binding of the acyclo~ir·eontalnlng template primer to viral DNA polymerase in&elivatas the enzyme. It is less effective egainsllho) host enlyffiO_

AcrclOW

"""'0''''''''''''''_'' 37. Antiviral Drugs

2. Resistenee: Altered 01 defiCient thymidine kinase and DNA polys merases have been foIJnd in some resistant vilal strains. [NoIe: Cytomegalovirus (CMV) is resistanl because il lacks a specific vimlttrymidine kinase.]

'4

S

3. AntIviral spectrum: Acydovir has a greater specificity than vidaras bine againSlherpesviruses. Herpes simplex viruss' (HSVs'), HSVs2, varicella-zoster virus, and some Epstein-Ban virus-medialed infections are sensilive to acyclovir, but CMV is .esistant Aqo::/oW is the treatment of choice in herpes simplex encephali s tis. and is more efficacious than vidarabinc in increasing lIle rate 01 survival (Figure 37.4). The most common use 01 acyclovir is in therapy 01 genital herpes inlections. [NOIe: In all cases. acyckNir inhibils only actively replicating viruses and has no elfe<:t on latent viruses_l It Is also given prophylactically to seroposilive patients belare bOne manow and aller heart transplants to protect such individuals during posttral1splant immunosuppressive treatments.

I

.,

4. Pharmacokinetics: Administration can be by an intravenous. oral, 0.- topical route. The efficacy of topical applications is doubrtul. The drug dislribules weilltlroughoul the body, lnctUding ltle cerebrospinal fluid. Acyclovir is partiaJly metabolite
'

5. Adverse efIe<::b: Side ellects depend 0fI the route of administration. For example, local irritalion may occur from topical appIicalion: headache, dlarmea. nausea, and vomitir1g may resUl1 alte.oral administration; lfansient ,enal dysfunction may occur at high ooses or in a dehydrated patient receiving Ille drug int,avenously.

B. Ganclclovlr (DHPG) The lack of ellect 01 available nucleOside analogs on cytomegalovirus (CMV) InflM:~On led to Ille synltlesis 01 the acydovir analog. gancic/ovir [gan SYE kloe verI (9-{(f.3-dihydroxy-2~ propoxy)melhylJguanine, DHPG). It Is currently available for treatment 01 cytomegalic retinitis in immunocompromised pa~ents.

""'''poI1It\ol, 01 o.cydo-GMP 'ram acydo-G'O' 1,"0 Itle

1. Mode of ""lion: Uke acyclovir, gancicl/)'Vir is activated throogh OQrwersio.-1 to the nucleoside triphosphate by viral and cellular entymes. the actual palhway depending on the vlrus_ Cytomegalovirus is deficient in thymidine kinase. and ltlerelore forms !he triphosphate by anoll1er rOllle. The nucleotide compeIitively inhibits viral DNA polymerase and can be incorporated into ltle DNA to decrease It1e rate of chain elongation.

growing_ _ ." ""..Ion DNA c.._

......e acye!o-GMP lac.... • 3' Iryd~ gn><4>.

2. Reslsblnc:e: Resistant CMV strains have been detected, but ltle meo;:hanism of resistance is not yet known .

Figure 37.3 Incorporation into viral DNA, causll1g chain termination.

3. AnUVi ..... spectrum: Its activity in vitro is lt1e same as that of acyclovir, but ganciclovir is approved only for" treatmenl of cytome s gallc retinitis.

.."" .....,., ........ ....-..,.

,


_

.........,...,

_ _ .. _

.....

III. Trllall'rlel1t 01 He,pesvirus Inlections

4.

367

~lnetlcs: Gancidovir is a~ered intl1lYenOl.lSlY and disbibullld ItwougIlo.lt the 1XXtf. induding !he oet~ fluid. Exaetion inlO the ume OOCUl1; lhrotql glomerular IilIration and tUbular secretion. like acyclovir, gancJclov/r accumulates in patients wilh ,enallailure.

s. ~ erfiecla: AlM!rse effects indude SlIYeI'e.'"

• depoildEd

neut.openla. [NoIe: Combined treatrMnl with zidcwudine can lesrJf in adliliIo'It oeutrq:llll'lia.) ~is caI .... as wei

"""'"1ic

as ~ a-Id teralOgellic in ~ Wlimal$. C, Famcldwir

y

......,

FlImrxkJNif Ilam SYE kloe verI. anolher acyclic analog 01 2'~ , is a prodrug thai Is fTle'IaboiZ8CI to lhe acWe Pf* odoW (pen SYE kIoe wor). The antIWaI spectrum is sin*lr to lhal 01 gallaict",rtll,l( ~ is presently apprOI'I!d my tor treatmef4 01 aaIIlI herpes zoster. The drug is eftectMl oraIy. M.oerse eI*ts indude headaches and nausea. Studies In exp8fimental animals have st1O'M'l an increased incideroce in n181Tl1'l1ary adenocarcinomas and

NIl·O'. :00 ....• T

,.............

testlcula. tokiciry. D. Fc.Carnft un~ke most of the antiviral agents, foscsmol [FOS car nayl is no! a purine or pyrimidine analog; it is pt1osphonolormate. a pyrophos· pt1ate derivative. Despite its broad antiviral activity In vitro, it is approved only as a treatment for cytOfTleQBlic retin~ls in immuoocompromised HIV·intecled patients, espe<:lall~ ~ the infection is resislanl to ganddovir. Foscamet works by rllYer5lbly Wlibiting viral ONA and RNA polymerase$, thereby lermina'ing chain elongation. Mulatlon 01 Ihe polymerase structu.e is responsible tor resistant viruses. [Note: C'OIiS-fesislanoa bsc8meI and (}8IICicIovk 01 «)doMir is U1lCOl'moIL) Foscamct is poorfy 8bllOIbed ~ and must be inJllCU!oolthe 1XXtf, G.eater than 10'1'. enter'S the bone mal,ill hom which it sloWly leaYes. The parent drug is etinw\atecl by gIomeIuler liIbatior, a1d Iub.ilar 5&l etior, inlo I1e I.ri'le. Adrooerse eIl8ds indude 'M:\:h (ll(Joieity. anemia, nausea, al'ld leve•• Due 10 chelation with divalent ClItion" hypocalcemia, and hypomagnesemia are also seen.. In additlorl. ~ hypophosphalemi, seiZla'es, and arrtlyIhhaw! been reported.

bet"'.e"

mas

""

..

,eo

Ac:ydoolo

, •

V'dol

•.,•

~i.

20

E. VlI»rablne (......, VicIllIabi'l8Ivye DARE

a beenl (~ad8lli.. /Ifi1.A,. adf>..

nine Bf3bIrIosIde) is one 01 !he most effective 01 1tle nucleoside iWl8Iogs end is also the least IoIcic. HoweYef, ~ has beef! ~ dO"icaIy by «)dlMr. I'ofIict1 is more ef..... b 1$ ancl safe.. Although vidarablne is active againsl herpes simPlll< virus type t (HSV-t). HSV·2. and variceIa·mster virus (VZV). its use Is limited to lreatmenl 01 Immunooompromised patients with herpes simplex keratitis or encept1aflIs. or vz:.J infections. Vldambinll. an adenosine analog, is converted In the cell 10 its 5'-lf1>hosphate analog (Ara·ATP), 'M1ich is postulated '0 inhibil viral DNA synthesis. Some reslslnnll1efpes vifl,J$

0 0

3

• • " " " "'olltl.

Flgur.37.4 Comperison 01 wrvivalln patients with ~herpes ~xenceph­ alitis treated with "'dilfllbine or

..-

• .,._ • . . . . -.........,.. , l
• • .0<'0. . .' . " ' ' ' _ _ ' '

w

>

37. Antiviral Drugs

368

mutants haVe been 6eleded

-

_ell,

"

ltlat haVe altered DNA polymerase. To be etlective systemlcally, poorty solUble vidarabfoo must be aQ-ninis· tered iolraveoously in large volumes rmr a ptolotiged lime, usually 12 hours. Vidambine penetmtes into the brain and tl'o..Js Is ellecllve In !he treatment of herpes simplex encephalitis. Vidarabine ointment is effectiva in !he treatment or herpetic and vaa:irIiaJ keratitis and in hef· pes simplex keratoconjunctivitis. Vidarabino and its metabol~es are found in the urine. AcMlrse effecls during s!lof1·te<m use are r(lI serious. CNS disturbences and fluid overload. however, eat1 be a prOblem in patients wilt1 impaired hepatic or renal 'unction.

F, Trlliurldine Trif/uric1in(J [try fLQO ri dean) has replaced Ihe eariier drug, idaxurick>e [eye doll 'ltor I dean], in the topical Ireatmool 01 keratoeorljlrdiviti due to herpes sifTlllex viruses. Uke idoJaJridir>c, tllis p>,'rimklr.e analog is inrxlfporaled into the viral DNA to disrl4lt its f\n:tion.

See p. 457 loI' a description of newly apprcwed drugs, pendclovir and cidofovir. V'darabme

IV_ TREATMENT FOR AIDS Presently six drugs ere epproved to light human immunodeficiency virus (HIV] intection. FMl are either pyrimidine or purifle nucleoside analogs, and must be COOV'erted to their nucleotide torms to exert their antMral etfect. [Note: The 3' position ollheir deoxyribOse moiety eilhe, Iad<s a hydroxyl group or is bIodo:ed by an azide subSlituerl1 (Figure 37.5) II1us prevenmg dlain elongation.] The sixth drug is an HIV protease inhbitor. AIIhou\tl not curalive, these agents Interfere In 1I1e mutllpocetoo of the virus and sloN progression of me disease to possibly prolong survival. A, Zidovudine j3'-A,tId0-3'-Deoxythymldine, AZT) One of the most eHeclive drugs currently approved lot treatment of HIV Inteclion and AIDS is Ihe pyrimidine analog, S'·azido·3'dooxylhymidino (AZ7). AZT hes the generic name of zidovudine [zye DOE vyoo deenJ. AZTis presently employed in patients shown to ha~ documented HIV Infedion. Improvement in immunologic status (increese in absolute number of helper·induced T cells) hes been reported. Most e
1. Mode of ItClion: AZT must be converled to the corresponding nucleoside triphosphate by mammalian thymidine kinase in ortle< lot ~ 10 e~ert Its antiviral a.clivily. AZT·trlphosphate is then incorporated into ,he growing dlain or viral (but not mammalian nuclear) DNA by reverse lranscriplese'. Because AZT lacks a hydro.>
..... , . . . . . . , . . . . . . . _

L.

....,. .......................' _ .. _

.....

IV. Treatmerrllof Acquifedlmmonodefic:iency DiseaSe

369

lallon of deoxythymidylic acid (dTMP) 10 Itle corresponding diphosphate (dTDP) is inhibited by the azido-thymldine

- ".

IOOllOpliOSPhBte (AZT-MP).

.me.

2. lWt.Itt8nCe: Effecti>,eness deaeases I"ith Some ,esislant Isoiales haYe m.rtaled reYefSe ~ . wtMctl has a loWer aI&'Mty lor the AZT-a ....'1osp.'We.

3. AnInoinl sptCtn.m: Presculty the cny ~ .... treatmenl of plIlients if Iteded Wiltl HIV.

U$8

f!'

P

III

lor AZT is ...

.c.~:

The dn.fg is wel8b!iortled 8tler onII G,...... IfIIIion. It t8IIen MIt1I1ood. peak IeYeIs may be lower but kItlII aug llb50fbed is not afleded. F'WlelraIion aaoss .... bklod-brain barrier Is ell( e' e ., Inl fle drug has • helI-6le of 1 hour. Most oflhe AZT Is gIucl.Ircri:fat bot the IM!r and Iherl exolted "'lh8 ume..

n,

=

s. ~ etfKts: In spite of its seeniftg spedfic:iIy, AZTIs IoIcic 10 bOne 1TI81TOW. For example. SEYI!f8 aoemIa and \euklpEria DCO.lf ... patients receiving high doses. Headed18s life also common. Seizures haVe been reported in patients with advanced AIDS. AZrs toM:ity Is potentiated if gIl.tct.M'OfIidlion Is decreased l7f c:oadmlnistralion of drugs like probenecid, acetaminophen. I
...'I"

B. DIclanoslne (ddl)

-

The second drug appllMld to \real HIY-1 i"fecliQr, was ddBnos.ne [d)e DAH no seen] (~ ddfj, wtictlls also rrissing Ihe 3' hydralyl. It Is not ,llmilwnerw;led for lnililll trea\l'l'lel't of H1Y liseese, but ,altlef Is used tor AZT-resisUlnt HlV ........ 15. 1. MKNnlsm OI.ctlon: Upon entry inIo !he tal eel. 6cIanosi1e is blotransformed Into ddATP ltlrough II series of reactions ltlat ~ phosptocryIatio of !he ddI. anW1aIion 10 ddAMP and ..... !her phosphorr1ation The resr.Alirlg
2. Anls_: Vnl isolates from plIlients oMlo hiMI UlideflP" pr0longed IhefIlJlY Wiltl ddI c:ontain "",e,se 1111I l!ICfiplase w1fl amino add SUbSlitutions. Cross-resistance wittI the other nudeoside agents has not been repMed.

3. Arrtlvinil spectrum: Its adMty Is .... ,fired 10 retroviruses, specifically lilY·' .

.c. PhannKOldnetics: Due to its acid lability,

c1Iidanosintlls GiliilisIered as eitMf ~ . buttered tablets Of In II butlered solution. Abso,pTlon is good if laken in Ihe lasllog SlaTe: food causes decreased 1lbsorpIion. The drug penetrates into !he CSF bulla a lesser exterll Ihan AZT. AboUT 55% of !he parent drug 8PPllBfS in the urine.

I

'S

ito> ito>

""d~ " .. = I_

-

~~

',",

Ftgure37.5 NudoosIde anatogues used in HIY

","""y.

<_'0...'."'''''''_''

""

37. Antiviral Drugs 5. Adverse eHeets: Pancreatilis. which may be fatal. is a major toxi· city of ddllfelltmenl. and requires JllOI1itoring 01 serum amylase, The dose-ljm~ing toxicity of didanosine is peripl1eral neuropathy.

{Nola: The buffering of stomach conlants may interfere In the absorplion at other drugs It1at require an acidic milieu lor absorption. such as keIOCl:ltl
C. Z8lcitablne (ddCj

h )

An analog of deo>IycyIidine. zaldlabine [za1 SIT a been] (dideoxy(y/idine. d:fC) is used either in coojunC1lon with AZT or as rnonolhe,' apy in patients who cannot tolerate AIr. Uke other drugs in group. it is CO!1\Ierted 10 the llCtive triphosphate (ddCTP), which

,h'.,

miMles chain elongation wt1en incorporated into viral DNA and also inhibits viral reverse transcriplase. Point mutations in the reverse trllt1scriptase lead '0 resistance. Zalcitabine is very well absorbed orally, but food or MAALOX Ie reduces absorption. The drug is distribuled throughoUt the body but penetration Inlo the CSF is lower !han that obtained wilh AZT. Some of the drug is metabolized to the inactive dideo>lyuridine (ddUl· The urine is the main foote of excretion 01 ddC. although fecal e1iminelioo 01 ddC, along with ~s metabolile ddU, occurs. Rash and stomalitis are common bUt resolve on continued treatment Peripheral neuropalhy is tile major toxicity and Is probably a consequence oIlhe inhibition of the mammalian m~o­ chondrial DNA polymerase y. Pancreatitis resulting in death has occurred, especially ~ ddCis given with pentamidin8 (see p. 354). D. Stavudlne (d4T)

Stavudinc [STAY vue deen) is an analog 01 th~idine in wt1~h a double bond joins the 2' and 3' carbon of the wgar (see Figure 37.5. Uke the oIt1ers in this group staVUdine must be coover1ed by the Imracellutar klnases !O the triphosphate (d4TTP) whktl inhibits the rEMlrse·transcriptase to cause DNA d1ain lermlnation. In adelltion it inhibits cellular enzymes such as lhe II and y DNA polymerases thus reducing m~ochondrial DNA synthesis. I' is loa early to assess lhe Clinical advantage or resistance to staVlJdinc. The drug is almost completely absorbed on oral ingestion and is nOl sHeeted by rood. Sta..wine penetrates the blood brain banier. About hall the parent drug can be acalUnled for in lhe urine. Aeflal impairment interferes wilh clearance. The maier and most common dinieal 'oxie~y is pedpM
·

_,.

,.,

..-.K

' _ .. _

.....

V. IntGftGron patianls. raquiring stopPilge 01 the drug. AdmlnlSlration with trYneItloprimIsilfT1eltloxazol increases the area l.I:'Ider the a.orve

(AUe) 01 1amM:.dine.

---

•••••• _ ...'" I.,.

, , :r----. ::-....

.

'..,..' ~i

F. HlV Prot_", InhIbilors D'MI~'1f!I'I1 01 lOOdly Oland rf!Sistlltl(ll!l 10 the _n;e.~ lase i1'ibib'sled 10 the IargeWlg 01 the HV protease.. asperlaIe ~ is essenliallOr the IinIJl H!p 01 WIll piOlilaaliol .. It is e....oded in the HV gellome, and ttus is absent in IAIitIll8ct8d
n.

FiYe HIV proIease inM,;IOfS haVe been aP\lfClWd- SBQooa..r [sail KWIN a veer]. ritonavir [rih TONE a veer], indinavir (in DIN a veer]. nolfinavlr [1'181 FIN a veer} and ampronavir[am PREN a veer]. These drugs are described In detail on p. 461. Ills cr1lical that Ihese drugs be giYen In dosages t»gh enough to completely Sl(lpreS$ ,,;ral repli· ClItion, Olhefwise resistanl. ,,;rus can emerge. They afa lraquenlly gven in oomblnation with ~ and /arMt..dioo. Some emss· resi$tllflCe occurs with the protease irtlibilors. cessation 01 trellt· me
'"

:

&, ~~;~~-.'" W'b:fff- _ONA

l,. _ONA

'lY~J.

-

If ~ ~ _RHA PGfJp< ~";:"._e I $

'i

~7/ V'. ...., I'Jl _ _ ..... ...-:;.'.

•

~

~

Figure 37.6 Role 01 H1V protaa.se in

replication.

wal

See p. 458-463 lor a descriptioll 01 newly approved prolease

llltlibitots and r'lOf'H'Ldeosill1lY8rSlllranlicJiplaselrlibilors.

V. INTERFERON .~, lin

*' FEER onl is a brityol naIl.nIIIy

~ Rio ......

r:1'r

cq)foteil. thllI inler1ere...mh fle abiIiIy 01 Wuies 10 . . . . ceIs. AtiIough ilkri.'ron i .itJits lhe !JOWlh 01 ~ vinJses in vitro. lis aetMry in '0+.0 IIgEIIl$I Wuses has baM "'is 'It 'POi Il:i og. AI preser'f lhe inIer1erons are synthesized by rec:o",billanl ONA ted.""*'w. A1leaslltvee types 01 ~ e>cisl, a.1l and y(FlglR 37.7). One of the IS tH1IeIiet ....... (to 2b has been llppfCM!d lOr trearmenI of hepatitis 9 and C. as wei as BgiIin$l: ca-ooers 5UCh as haioy eel kU<erria and KajxlsI"'s sara:ma (see p. 398). It$ anMaI rne<:h8ri5m is ilCOi'petety underslood bUt appean; 10 ~!he nduction 01 00sl eel enzymes (e.g., a polein kinase. 7.5'oigoaOanyIata syr'Ithue, in:I a phospnocIesterase) Ih8l inhibit viral RNA uanslati::ln, and ultirTllllely lead to the degradation 01 ,,;ral mANA and tANA. InlorlofOtl is g ....en intravenously and crosses into the CSF. AdYerse altects incluOe !eYer. lethargy. bone marrow 00pressi0n. cartioIIiISC\Jlar prOOI&ms sucl1 as CO<1Qeslive hean tailurs. and acute hypefsens~ivity reactiOns. Hepatic tailure and pulmonary !ntiKrates are rare.

.......- ........" ,, ._, ~

. . . . . . .·1

1:=,"'..''11 , • ~

--- . ---. t'

" ellllo",

, ,•

'1eoIo' .eR ~-

Flgure37.1 Some approved indications lor iIllerfCfOfJ$.

~

........ _'.' ........ _'. 37. Anliviral Drugs

37.1 All 01 !he lo101oing lUll_IS abou' llCydavif ara

_,ed EXCEPT:

It. If is !he If.lr'nef1l 01 choice lor If>lIuenza i11teG1i01.. B. If is iQ)ollCl'altd ~ the vftII DNA C8UIIng pl. lfIIII..a DNA

ttIIlln 1""'*'t11ion.

C. If i. lhe 11. .'''''''1 01 etlOlee in herPee Umpie_

eo lCfIIIheMiI.. o. If

r~ !he euallion 01 '-'anI associeled \MIh g.nilaI hIlrpIIII i~ .. E. 11 inhibits only flCtftre!y replialting ........ r>ol

--

Q!

lilt lollowlng .1II1ernff11. Ibwl lklowdlo.

(AZT) are Cfltfect EXCEPT:

A. II nUS! be oonve<1t
"""1lSII

......

"'" c.•.is CU1en9ly . - ! If> _ _.Ilerpttvirw .-.d resp;,atury O.

AI,. 1. Ie . . '*4l
inII~a

A

if .........

B. I _ _ CNS~.I'igIldaMa. C. II reclucn !he dufMion .-.d _r.ily of II}._ _'-': •

.,..,....'.01 .... ~1t.

0.11 _ _ .,81) ntt t [?ell. E. II iT ~ .. ln Ihe " . ,• • <11

".......... ,

e;;",..,. d"'*- .. 0.

.All.'.

10 bone .... rcw _

ca. . .

of

~""*"

..

C.IZfIr ...... .-d~ . . I • • •
-_.....

_ n ._ _ ?&

CId:al d . .

... ClJrM,.,.

~

PtIl:

() - '.37.5~'S1.7: Fa ~ .... :twrad~. MIed lilt ONE
Ie C

. . ",:;;pI" III
••

~

.

..."·.It "' .. _01'" .. ... : '_-llr
It is IOI
_1f

.yncy1ia1 vi.... Inlec!ior • • • ,qjl ...

,..,eN' .... I!IlIIdL E. It penelrfI8S . . eNS.

.,.oIadio._

372 ..... of !he Il:iaMinQ ....,• • ~ 0ClmId EXCEPT: It. II is erItIf;Iive in Ihe ~ 01

.

..

-':+'$ H.OI

"."...... A irS • '"

"'* of . . k:JIowW.g tnIiWaI egents e.hbls

h~_1 t

37.4 All

AOOS.

ee-.. ctlcIIte ..

37.3 WNo:fl

[

·•• ~IorShe~"""?

~e.~oIadio•. C.AqdorW. o. ZidcMdnlt.

e. RitwWWl.

ryMIfCI in She otSl b\l' lilt hef1l • I 'IE.. II ~ tnzyme. 1IlyMldlne kInaM. Thus. ......,,_

It.

All"""',,,

B. ZidIMdine (AZT}

c. ....... O.V

.

E.~

37.5 lis UIl9d 5dott in . . ,_,.1 d

~ A ....... &

37:6 II is an adenosine anrIog 1hltt it acWe fIglIiMl" membe•• ol the herpe.vi."" group tllfl inlect.

I '=_..

_.

01'01'

~,=====JI

I.,...

37.7 It is used in Ihe Iffl8Irl18flI 01 ~ inlecIicns in .....,................, .• d patleo ItI

'.,.'_

,

_'.

Anticancer Drugs ANTICANCER DRuGS

_. • --

AN1lMETAllOLJTES

---

1

,

I. OVERVIEW

~4PF

II is estimated that 25% of the population of the United States will lace a cancer diagnosis during their lifetime. with 1 million new cancer patienlS diagnosed each year. Less than a CjtJiIJ1er of these patients will be cured solely by surgery and/or Iocalladiation. Most ollhl! remainder will receijve systemic chemotherapy al some time dUriog their illness. (see FigtJre 38.1 lor a summary of anticancer agents.) In a small fraction (apprOlCimately 10%) 01 cancer patients representing selected neoplasms, the chemotherapy will result in a cure or a prokJoged remission. However, in most cases. the drug therapy will produce only a regression 01 the disease. and compli· cations and/or .elapse may eventually lead to death. Thus. the overall 5year survival lor cancer patients is abotJt 40%, ranking cancer second only to eat"l1iovaswlar disease as a cause 01 mortality.

'H1If'pu, ....

f-

--

.~~

'II

~

,

~~

P_li,'" II "

r--

AlKYlAnNG AGENTS

e",,_

c,,,,

f-

,",_, _ _ _

,Ao>

MlCR01UBULE INHIBITORSI

-'-,-_tl",

_/Toot}

STEROID HDfUoIONES ANO THEIR ANTAGDNlSTS

.......-

A. Traillmenl strategies

,-

I

O~M

Goal ollrealmenl: The ultimate goal oj chemotherapy is a

Wfe. that is, Ioflg-term. disease-tree survival. Cure requires the eradication of every neoplastic cell. II a cure is not allilinable, then the goal becomes palliation (that is. a1llMation 01 symptoms and avoidance of Hie-threatening toxicity). which allows the individual to maintain a "normar existence. In either case. the neoplastic ce~ burden is initially reduced (debulking) either by surgery andfor radiation, followed

I

.......-..... ...,. CI'<'<¥>~'4

Cancer chemotherapy strives to cause a lethal eytotOlCk: lesion that can arrest a tumor's progression. The attack is generally directed against metabolic s~es essential 10 0011 replication. lor example. the availability of purine arxl pyrimidine precursors lor DNA or RNA synthesis (F"og.Jre 38.2). Ideally these drugs should Interfere only with oonular prooesses unique to the malignant cells. However. currel1lty available anticancer drugs 00 not specifically recog1lze neoplastic cells, but rather aIIecl all proliferating cellsboth normal and abnonnal. Therefore, almost all ant~umor agents have a steep dose-response wtve lor both toxic and therapeutic effects; thus ~ is mportant to tailor the drug doses to the ptlysical state 01 the patient

1.

I

DM:'~ ... ,'tclo,

_fA

II. PRINCIPLES OF CANCER CHEMOTllERAPY

>II.

"4

.....

c-"-,,c.~,p

..'"

••",IM"",

Figure 38.1 Summary of cancer cherrv>therapy agents. See Pharmacology update. p. 463, for Illklitional drugs.

......-.--_....-.......,.J.-._,,

...__ ..-..._"'

c.e-.oo ,,"""'-

373·

<

,., '<---'

<
>

:

. , """"U _ _ . PI' >

'"

38. Anticancer Drugs

Purine

_ .... _.

Md

~

""""""'"' .". .....01,...,......

pyrimidine synttwasls

by chemolherapy, immunotherapy, ment modalities (FlglJrEl 38.3).

or a combination 01 these treat-

2. Indication. tor treatmenl: Chemotherapy is indicated wtlen ~ plasms are disseminated and not amenable to surgery. Chemolherapy is also used as a supplement to surgery and radiation treatment to attack micrometastases. INOle: Tumors most susceptible to current chemotherapy are undiflerentiated and have hig1 growth fractior1s.]

3. lIJmor susceptibility Ind the growth eyde: The \raclion 01 tumor

"""em.'"". RIbonucleotide.

cells that &e in the replicative cycle ("growth rraclion1lntluences their susceptibility to most cancer chemotherapeutic agents. Rapidly dividing cells are generally more sensitive to anlica.ncer drugs, whereas nonproliferating cells (those in the Gc phase) usually survive the toxic e\feCts 01 these agents.

and tumor cells go through a growth cycle (Figure 38.4). Howevef, ncmnal and neoplastic tissue may diller In the number 01 oolls Itlat &e In \he various stages 01 the cycle, Chemotherapeulic agents tl1at are etteclive only in replicating cells. that is those ooP' ·"at are cycling, are said to be cell-cyde specilic (see FlQure, '), whereas other agents are ceU-cycIe nonspecilic. The nonspealic drugs such as the alkylating agents, allhough generally more toxic in cycling cells, are also uselul against tumors wiltl a low percentage ol replicating oolls..

I. cell-cycle specificIty of drugs: Botl1 normal cells

_1fTW.,.•

--

CYTA1U'rI1ItJe

Tso". ,

DNA_

Deolily-

b. lIJmor growth rate: The growth rate or most tumors in vivo is

DNA

.. ",._01 ..........

--_ . ----DACJWClMYCW

8. Treatment regimens and scheduling

00'''''''''''''' DA""""""'"

_ ,*.. ,..

"'lIItA

IlHA_

.

initially rapid, but decreases as the tumor size increases because or the unavailability of nutrients and oxygen due to inadequate vascularization (see Figure 38.3)_ Reducing the tumor burden through surgery or radiation promotes the recruitment 01 the remaining oolls into active proliferation and increases their susceptibility to chemotherapeutic agents.

J

Proteins

Figure 38.2 E~les at chemotherapeutic agents affacting the availabitily at RNA and DNA prec~.

1. Log 11111: aestructioo 01 cancer cells by chemotherapeulic aQef1\s lollows lirst-
Howeve'.

<..., .....'.,.<

'.

• ..,.. "_-.......' .....,.... .. _ . w •

II. Principles ol Cancer Therapy

'"

SIGNIFICANCE OF 19 TUMOR MASS •

dc_.

10" CcIhI,,1ho .""'...... lu..burden tN: .. phJSlcally

PALLIATIVE CHEMOTHERAPY •

lnIU•••_ _ onlr.n_, with oympt."". _"""" bef •• e" 1,...lmenlL

•

Survlwal .. UIeIKIed. blll pat!eoll _luoIly!lies 0I1ho ....._ .

• n - 1 billion "..,.. _ , • 'umo< ...

,gt>lo" abaut 1 11'''''11'_.

ot llboIIt!he.1zoe 01 • _

•

_.tthl

.

uaIIy Q....

~~(

10"

".

CHnll:al .ympt."".

. . - ...·4

----nU.-

.......... i

. 44 0 •

.. -......-

•----''7,.Tr

,,'

CURATIVE CHEMOTHERAPY (dlaemlr'lllUld cancef1O, ......... Ie<Jl
• Cornbl_ clrug lheM><:e

•

CURATIVE CHEMOTHERAPY (ocNd 1...-., """h .. _ ..... ""<:1""""') •

T...- b...- liolnltlaHy re
•

T,caln'le<"( 01 OC:<:U" ..11:...........1.0_ .. <:<>nUn<*! ....... eMn_ .Ign. 01 cancer h""" diHpp!1Orfld.

•

or clrug ,...- .

hc:h d"'ll" . _ . to

_

E;oo:h clrug I. _ otDO
Figure 38.3 Elleets ol various treatments on the cancer ceU burden in a hypothelical cancer pat;em. 2.

Ph~rma<:oIoglc

sanctuaries: Leukemic or olher tumor ceHs find sanctuary in lissues. tor example, the central nervous system (CNS). into which certain chemotherapeutic agems cannel enter because of transport constraints. Therefore, a pat;ent may requ;re irradiation of the craniospinal axis Of inlrathecal aOOlinistralion of drugs to eliminate the IelJkemic cells at that sileo Similarly, drugs may be unable to penetrate certain areas of solkl tumors.

........ dlllc<enl"..,.......

01 ""'Ion '" !llt!o<enl tell eye," opedllcity.

to ..."" • dIIlere<>l

• ..... ro. _,., ,,

,

>

376

38. Anticancer Drugs

m

Cell-cycle specific drugs

The cml Cycle

Synlhftle of

cell"'""

r:om_r. req"ecl '01 mM"","

1011'011<: pNM

,,-

-~,

R..llngelale -'.,.,," rKIIclIllkling

,...~:;"~ ~

r4'1

•

~~'~ _""DNa ........

!EII_'... tIIgIl ~

Syn_ofen.y.....

:::1:-,.-

-V V .---- ----.-ArIU1.... 'bol_

Il~,~=,pefItlcle !E~

""

C8I1-cycle nonspecific drugs

• .g..

~_.

IE~ "" _h klw

~--

~ • .g.• ee high 9'"_ fr.._

Figure 38.4 Effects 01 chemolherapeutie agents OIl the growth cyde 01 mammalian cells. 3. T1ealmant protocols: O::IfTlbinatlon chemotherapy is more eUee-

tive than single-drug trealmenl in mosl cancers for

'ch

ctlemolherapJ is effective.

a. Comblnatlons 01 drugs: Cytotoxic agents willi quahlalively dif· ler€f1ltoxidties and w~ diffell!l1t molecular sites and mecha· nisms of aclion llIe usually combined 81 lull doses. This resuks in higher response rates due to both additive Of potentiated cytotoxic effects and non-overlappillg host toxicities. In con· nast, agents wilh similar dose·limiting loxicities, such as myelosuppression, can be combined safely only by reducing the doses of ead1. b. Advantages of drug combtnatiom: The advantages of such

combinations llIe; 1} II1ey provide maximal cell kill within the range 01 tolerated to,dcity: 2) they are effective against a broader range of cell lines in the heterogeneous tumor population; and 3) they may slow or prevent the dewlopment of resistant celllif1es.

c. Trealmanl protocols: Many cancer treatment protocols have been developed; each ona Is applicable 10 a parlicullll neoplastic state. They are usually idenlilied by an acronym. For example, a common regimen called POMP. lor tM treatment of acute lymphocytic leukemia (ALL) consists 01 Prednisone (see p. 393). Oncow'n (vincristine, p. 390). Melholroxato (saa p. 378) and Purine/hoi (mcrcaptopurinfJ, p. 381). Therapy is scheduled intermittently to allow recovery of normal tissue,

.""' .....,., ..

-... _,.

II. Principles 01 Canoer Therapy such as lI1e patient's immune system, lI1at has been afk!ded by the cWgS, thereby reducing the risk ot serious infection. C. Problems associated with chemotherapy Canoor drugs are toxins that presefll a lethal threat to the ce~. II is therefore nol surprising that cells /lave evolved elaborate defense mechanisms 10 protect themselves from d1emical toxins, including chemotherapeutic agents. 1. Resistance: some neoplastic cells, for example, melanoma, are inherently resistant to most 8I1ticancer dfl.lgs. Other tumor types may be selected /of 01 acquire resistance to the cytotoxic effects 01 the medication, particularly after prolonged administration of low drug doses. The deVelopment ot drug resistance is minimized by short-term, intensive, intermittent therapy witl1 combinations 01 dlUgs. Drug combinations are also effective against a broader range of lesistant cell lines in the tumor population. A variely 01 mechanisms are responsible for drug resistanoo; each is considered separately under the partjcular drug. 2. Multklrug Resistance: Stepwise selection 01811 arnplitied gene that codes lor a transmembrane protein (P~ein for "permeabil· itY' glycoprotein, Figure 38.5) is responsible for multidrug resistance (MDR). The resi51ance is due to ATP-dependenl plJnl)ing 01 !he drug out ot the cell, associated witl1lhe presence 01 P-gIy<:oprotein. Cross·resist8Jlce among structurally unrelated agents occurs. For example, cells resistant to the cytotoxic efleets 01 the vinca alkaloids (see p. 390) are also resistant to daclinomycin (see p. 384) and the anthracydine antibiotics (see p.385) as well as to coid>idr1e (see p. 416), and vice versa. These drugs are aU naturaly OCClJrring substances, have a hydrophobic aromatic ring, and carry a positive dlalge at neutral pH.JNote: P-glycoprotein is normally ellpressed at low levels in most cell types, but higher levels are found in kidney, liver, pancreas. sma!1 intestine, colon, and adrenal gland. It has been suggested that its presence may accoont for lhe intrinsic resistance to chemotherapy obseNed in adenocarcinomas in these tissues.) Certain drugs (for example, verapamil, p. 187) can intIibit the pump and thus intenere wUh lI1e efflux oIlhe anticancer agent. However, these augs are undesirable because o! adverse p/larmaoological actions 01 their own. Pharmacologically inert pump bIod<.ers are being sought.

IIInc:mr/ne,

_iM

~MJI>iciI>. ~

''''P'''ide _ _

3. Toxicity: Therapy aimed at killing rapidly proliferating cells also affects normal cells undergoing rapid prolileration-lof example, buccal roocosa. bone marrow, gastrointestinal (Gl) mucosa, and hair cells-contribumg to the lolOc manilestatiorls 01 chemotherapy. a. Common adverse effects: Most chemolt1erapeutic agents have a nB/row fherapeutic index. Severe vomiting, stomatitis, and alopecia ocaJr to a lesser or greatBf eJ<\ent during therapy wUh all 8I1~neopIastic agents. Vomiting can sometimes be controlled by administration ot 8I1fjemetic drugs (see p. 241). SOme toxici~es such as myelosuppression, which predisposes fo infection, are common 10 many chemotherapet;tic agents (Figure 38.6),

Figure 38.S The six membrane-spanning loops oIlt1e P-glycoprotein form a central channel lor the ATP-dependen! pumping of drugs trom the eel.

<_'0...'."<

"

< .-. •

378

., """"'U _ _ . PI' >

38. Anticancer Drugs

whereas othe, adverse reactions are confined to specific agents, lor exaflllle, cardiotoxicity with doxOflJbicin (see p. 385) and pulmooa.y fibroois with bleomycin (see P. 386).

b. Duration of adverse effects: The duration of the side effects varies widely. For example, alopecia is transient, but the cardiac, pulmonary. arK! bladder toxidties ara irrevefslble.

c. Mlnlmldng advers.e alleets: Some toxic reactions may be ameliorated by interventions, such as perlusing the tumor locally (lor example, a sarooma ollhe arm), rernovil1g some 01

,

the patient's ma"ow prior to intensive treatment then .eimplaming it, or promoting iolteosive diuresis 10 prevent bladder

toxicities. The megaloblastic W1emia that occurs

w~h

mc/hlr

IroKafe (see below) can be ellectively oounleraeted by admin-

---

istering lalinia add (/evcovorin. 5·/ormyltcrrahydrofolic ar;KJ. p. 379). With the availability or human gfllnJlocyte colony stimulating 'actor (filgraslim), the nelllroP€'nia associaled with trealment 01 cancer by many drugs C!II1 be partially '€!Versed. 3. Trealment-Induced Iu~; Since most antineoplastic agerrts are mUlagens. neoplasms (fo, example. aCllte nonlymphocybc leukemia) may a,ise 10 or more years atle, the original call00r was cured. Treatmem·indllOOd neoplasms are especially a pr0blem aile, therapy with a1kylaMg agents (see p. 387).

III. ANTIMETABOLITES

---- ..... .......

Arltimetaboliles a,e struau,a11y related to no,mal cellular components.

They generaJly Inlerfere with the availability of normal purine or pyrimidine nucleotide precursors by inhibl~ng their synthesis Of by competing with them in DNA or ANA synthesis. Thel, maximal cytotoxic effeas P"", S-phase (and lhe'elore celk;ycle) spetille.

A. Melhotrexate

~

myeiosu"", uian

Figure 38.6 COrnpariSOll 01 mye!osuppressiYa polefltia! 01 at1ticanc:er drugs.

Metholrexate [meth oh TREX ate] (MTX) is structu,ally relaled to toile acid and acts as IlJ'1 arrtagonist of that vitamin by inhibiting dillydrofolate redllctase'. the enzyme lhal conve,ls tolic acid 10 its active, coenzyme form, lelrahydrofolk: acid (FH.); it theretore acts as an antagonist 01 thaI v~amin. Folate plays a central role in a vari· ely of metabolic ,eactiofls involving the transfer of one-cartlon units. (Figu,e 38.7f. 1. Site 01 aclloo a. Inhibition 01 dlhydrololate reductase: Aller absorption 01 toIic acid from dietary sources Of 'rom lha.t produced by intestinal flora, the v~amin undergoes reduction to the telraltydrotolale form (FH4) by tha irltracelllliar NADPH-dependent diltydrofolala reductase. Metfl(]lroxafo ente's the cell by an actiw transport process, Which normally mediates the entry of N5·methyl FH4. At high MTX concentrations. the drug can diffuse irlto the

,

........ _..,.,---,.

'"

III. Antimetabolites cell. MTX has an unusually strong Ilffin~y for dihydrofolate reductase, and effectively inhib~s the enzyme. lis inhibition can only be reversed by a thousand-told excess of the natural substrale, dihydrofolate (FH;e. see Figure 38.7) or by administration of /eucxM:Nin, """ich bypasses the blocked enzyme and replenishes the IoIate pool. [Note: LeUCOKllin, or fo/inicacid, is the N5_tormylgroup-carrying form 01 FH".j b. Consequern::es 01 decreased FH4: Inhibition 01 dihydrololate reductase deprives the 0011 of the varioos folate coenzymes and leads to decreased biosynthesis of thymidylic acid, methionine and serine, and the purines (adenine and guanine), and thus eventually to depressed DNA, RNA and prolein syJ1thesis and to cell death (see Fogure 38.7).

c. Polyglulamated MT)(: Like tetlahydrofolate itself, MTX becomes potyglutamaled within the 0011, a process thaI favors intracellular retentiOl1 ot !he compound due to its larger size and increased negatiV(l d1arge (see below).

2, Resistance: Nonprolilerllting oolls are resistant 10 mefhOtrexate. Resistance in neoplastic cells can be due to amplifICation (production 01 aOd~ional copies) of the gene that codes for dihydrofolale reduCtase resulling if1 increased levels of this enzyme, The enzyme affinity lor MTX may also be dimif1ished. Resistance can also occur from a reduced infkJx of MTX, apparently caused by a d1ange in the carrier-mediated transport respof1slb1e tor pumping mclhOfrexate into the cell.

-- . ,.~

~

•

.0"-- Uo llw;;Oex.m •

0'". /

~'~FH~~:~:eFH.~

)

""".-

dUMP

N"toI'· I.IeU"k,-.ft\,

I I ~mlcIytlc_

Leucovorln rescue A
3. Thel"ilpeutic applications: Methotrexafe, often in combination with other drugs, is effective againsl acute lymphocytic leUkemia, choriocarcinoma, Burkitt's lymphoma in d1ildref1, breast cancer, and head and neck carcinomas. High'dose MTX is curative lor osteogenic sarooma and choriocarcinoma; treatment is IoIlowed by administraliOl1 of /cUCDVOrin ("c:itrovorum faetor") to rescue the bone marrow (see Figure 38.7, and the discussion of adverse effects. p. 380). In addilion,low-
(IetIOOVO
whld> Is conftfle<eby...._

1he In_cd ieduetMe

Figure 38.7 Mec/1anism of aclion of mclhDlroxate and the effect 01 edministration oIleuoovorin rFH~ '" dlhydrofolate; FH. '" tetrahydrololate].

..... ,......, ........ _,. 38. Ar11icafloer Drugs potygIulamales. These are preferen~ally retained inside me cells and are usually more elllde"l colactots ltIlln are lhe rro'lOgIutamates. Mettlt;)lrella/(J is also ~ 10 poIy-gkr tamale 0BtiVBIives. This property is ~anl, because me poIyglulamllles. whidl also inhibit dihydrololale reductase. ,emain wittlil'l lhe cell eYer1 in me ebserlce of exlrac:ellula.r drug. TNs is iI'I mntrllSI 10 MTX per sa. wt'il;h rapil:Iy Iea'oes the cell as !he exlracellula, drug IeYeIs 181. High doses 01 mclhofJexala undergo ~liorl al tI1e 7 position. TNs del ;"8!Ml is less waler r i He• ...., may lead to crystalluria.. Thereoe, it is imporlant to keep the ...me aIWrle and !he pelienl wei hydrated 10 BYOid renal kBcieiry. Excrelioo 01 !he p.renI drug"'" he 7-()H mellltloMe 0C0JfS via hI...me.

5. Adverse ettects:

.. Commo"'Y obs«ved 'OIlIc:ities: Mo5I I,equenr. lOlr::idties are sromatiIis. ~ ~ rash. urticaria. a1opecia. nausea, 1IOmiring, and diarmea. Some 01 Ihese can be

pr8Y8l'lted Of rellefSed by 80TWliscemg 1et.aMri'l (see Fig.Jre 38.7), wtidl is 1aken up mont re8Clily by f10fmIl oe/ls than by tumor cells. Doses of Ieul:oIorin ITW,IS1 be kepr minimal 10 lMlid inlerfe,ence with the antilumor lICtion oflhe mc/hclrf!x8tc.

b. Renal dllmege: A/thougII UllX>i"'lOr'I duriog COI'lVeflIionalIherepy. renal damage is a oompIication of hIgh.do6II mertl(JlfCxale.

c. Hepatic !unction: Hepalk: lurlCllon should be monitored. Long-

MclhotroliDle

term use may lead 10 fibrosis. d. Pulmonary lOlilcity: Children beWlg rTIairllail'led on mclhotrell' ale may develop cough. dyspnea. lever, and cyanosis. Inlift1'818S are seen on x-ray. Tta loxicity is reversible on Stl$' pension 01 the drug.

a. Neur1IIoglc laIlictties: These are essoti"ted with intralhecaI ~ and rdude p ..... M rr.."iilgeal initalion, still fl(lCk, ht-eda<:he. and lever. SIlizunIs. encephalopathy, Of paraplegia occur fiIfflIy. ~ enect5, such as IearYWlg cisat__ hIM! been seen ... doiklleu wtlo lee " 't!d he drug by !tis route. l COntnoIndlcatklns: Because mc~8J(l is lefttIogerjc and . , abo< Iiliit:ien if: shouk:I be IMIided iI'I pregrwrocy. [Note: II is used oMth .,.........osrd(see P. 419) 10 n:tuoe 8borliorI.1

a

6 Men:aptopurtne

The drug ~ I m e rkap toe P't(X)R 8«11 (6-Mp) is the lhiol anaklg 0I~. II and 1hioguIInine(6-TG) were1he first p.Irine anaJogs to prtMl beneficial fCf treating neoplastic cisease. AzlilhOJ",Iile, an imfTu'losuppressant. exel1$ its elleets eller corrver· sion 10 6-MP.

••"" '0...,., ..... _ _ , • III, A/llimelabolitos

381

1. Site 01 action; a. Formallon 01 nUCleOtide: To exet't ilS antiletJkemic elled, 6mercaptopurine must penelrate targel cells and be alI'IYefled to the corresponding nucleotide, 6-mercaptopurine ribose phosphate (6-MPRP better known as 6-thioinoslnic add, or tI'OQ-IMP, Agore 38.8). The IldlitDl 01 the rt>ose phosptlale is calalyzed by the saMige pattrway enzyme, hypoxanl:toif>e.gua. nine phOSphOribosyl translerase (HGPRT).~

b. Inhlblt/Qn

purine .ynlhnle: Although the nature 01 lhe step is no! knoWn. the LrniIIuraI nucleotide, Ihio-IMP. like AMp, can Ie BtI>8d< 10 Wti the firs! sSep ol de I"I(M) l1'me ring bla5yn1hel;is as ...... as lormation ol MF and Kar'IIhirt)'IiC aDd (XMP) In;m ino5inic acid (IMP)! oj

ellaCt cytolOllic

,.. =.. . ..-._ . _.....

~ --....

c.. ltiCOfpoilltlofl Jn10 IM.delc tdd,: 0ys1uncIi0naI RNA and DNA ,esul lfO'Il incolptlialioil d ~e analogs generaled Irom U. tn'Iallnl Ri(leoWles Ttil;HMP is ~ted 10

~

GMP. ...t'ktI alter jlhosphor)'lation 10 Ii- and IriphosphiIIeS, can be inoorpofaled into RNA. The deaKyfitXn ..... Ie analogs ItlaJ. 8AI aI!O b,'liId lint i1COipoolled ~ DNA. • ialed oMIh (1) an nability 10 bio-transform 6-MP to the COffespondinll nucIeoIide because of deetea5ed IeYeIs d HGPRT (tor 8It3IT1Ille, in lescto-Nojt\a'l S)n' drome In wtlfCh patients lack !his enzyme); (2) an increased dephosphorylati; or (3) increased rnetaboism of the drug to tI"Ool.ric aod.

2. AeslsleriC'" Resis'ttnOII is M

3.

~ ~ 6-MPis

niWiC8

4.

d

,eo, '5 I'l"

used pil-ij tyinlhemanein aetAe lyil9-t' f IelAIemia (All).

Ph~coklnetlc•

.. Adn*Wstratlon and melmollsm: AbsotpIion by Ihe oral route is emltie. The drug is ..tdeIy distfiluled thfoughoI.A the body -=epI b" the cerebtospinallluid.. 6-MPlIdtHgoes metabolism in !he liver to lhe ~ (~ derillalive Of to Itliouric acid. The latter reaction is cataJyzed by lta"lhine OlticIase. Beca~ II/IoptJrinOI (see Po 417), a >.alit .... ~ W1Ilitof, is I,equently a<miIli$tered 10 callC8f patients receiving d1lImOIherapy 10 tTtPeruricemia, it is impoItaot to dectease !he dose 01 6-MP in II1ese inaIs to lMlid accumulation 0I1he drug and eKaC8lbation 01 \oIOOIies..

ThID C'II'

,eooce

b. Eltcretlon: The pa,ent drug and its melabohtes are eJlcreted by !he kidney.

Figure 38.8 S. Adver1Ie ef!1ICtI: Sil:le eltects include nausea, \oOffiiting. and diasmea. Bone marrow depreuion is the ctieI toKic:iIy. Hepatotoxicity has also been ,eported.

AcIionsol6~.

....

...... r., ....,. , _ " , _ ,

>

382

38. Anticancer Drugs

--

,~, bo.'

~'f::J

/HNoptJllni'l6 [~ otl GWAH neenl (6- TG). anothef purine analog, Is primarily used in the I,eatment of acule nonlymphocylie 1aulr.etNa ... COITtination ~ d1It11'lC1f'tb1dn (see p. 385) and <:ylaIabi'l8 (see p. 383). L..ile tHtfP. 6-TG "'-'St Iirst be ~ed to !he ru .... '0 Iorm• ...tW::tl1hen il'ibits !he biosynlhe5is 01 Ihe purine ring and !he ~tion of GMP 10 GOP. 6- TG can also be lllcoopooated "10 ANA and DNA. ~ occurs betu.een 6-MP and 6- TG. Lkllike 6-MP. ~ does not poIEW'11iale 6- TG aclion hera _ Yef)' little ollhe MIg is mecabolilGd klltQ.ric acid. 01. ",ise, ···vips llle Itlesame as tho5etor 6-MP.

0. s-n-ourecll 5-F/uofocJnJcjIlrue oh VOOR a sill 15-RJ)•• P'1,i1,oidii16 analog. has • SlabIe IIuorine atom ... place of a ~rogen 810m at position 5 01 the uracil ling. The nuonne intelferes with the conversion 01 deoKyuridyIic acid 10 Itlyrnid)1ic acid. ll'US deprMng !he cell ol one 01 the ! sse ItiaI precursors lor DNA synthesis. 1. Site oIection: S-FU per sa is deYoid 01 antineoplastic: aetMIy and must be converted to the correspor1ding deol':Yllucleotide (5-

fdUMP, Figure 38.9). which compele' with deoxyUlidine mOl'lOphosphale (dUMP) lor thymklylate synthetase. 5-FdUMP lICIs as a pseudosubstrat. and is entrapped wilh the &<1zyn>e and ils N',N,o-melhylane tetrahydr0401ic acid coer'llyn1e in a ternary complex ,hal cannot proceed 10 p,oducts. DNA synthesis decreases due 10 lack of thymidine. leading 10 imbalanced cell glOwlh and cell death. [Note: LeUCOVOrin Is given with 5·FU because the redJced k>!ale coenzyme Is requifecl in the lhymidylate synlhelllse reaction. Lack 01 SlJfficienl coenzyme (educes the etIecliveness of the amiA',imidioltl.1 S-FU Is also incoIpoIaled no RNA and kJW IeoIels haYe been detected in DNA.

','->c:r.

2. R. . Resis.ant eels Ble enmunteled thaI have lost !he abijity to convert 5-FU into its adlve Ioim Of have altered Of 10 iCl ad ItTfmid'Ilale synthelase Of haII8 an ifICIfllSed rate 01 50FU 0IfabrAism. ?

3. Thenopeutlc appIic:a~ FbJrourlJd is ~ prWn;riy in the treatmenl 01 sio¥o1y ~ so5d ll.mOfS (lor ~ colOfectal, blBllsl, O\Iarian. pancreatic. and gastric Cllfcinomas). ~!heIap¥ Wth le\a'lIisoole. a Y8terinary ........ agent, 10'''''0•• the surviYaI 01 palietots Mlh aU.. cancer. 5-FU is also elleetive tor the llealrnen1 of superficial basal cell c:a,,::illOi'•

,.&

..nen !JWi"d 1Opically.

4. I'hannllc:oklne.: Beca'lSe 01 its severe Iolcicily to the G"rad, 5FU is gillen Io1J3WnOUSly Of, in the case 01 sm canc:ef. tqlicaIIy. Tl1e drug penetra'es well into al tissUes ~ fle eNS. 5-FU is melaboized in the wer. Ia.-geIy to COr. ~ Is apired. The dose rnJsl be adjusted in the case oIlmpaired hepatic fu.-.cOOn.

. . . . 10• ..,.1 > .............. I >

< ..............._

. . , " " " - .. _

.... >

III. Antimetabolites

o

~:-Jr' I

O)...N

"

5-FI<J<>m....,~

(s.FlJ)

Figure 38.9 Mechanism of 5·f1uorooracifs cytotoxic aclion. 5-Fluorouracilis converted to 5-FdUMP, wtich competes witll deo"YIJlidrne mooophosphale (dUMP)'or the erllylTlB tIlymidytate synthetase. 5. Toxlclll...: In addition to nausea. vomiting, diarrhea. and alopecia. severe ulceration the OIal and GI mucosa. bone marfOW depression (with bolus injection), and anorexia are frequently encountered. A denTlopaltry (e.ythematous desquamation of the palms and soles) called the "hand·tOOl syndrome" is seen after

0'

extended infusions.

e. Cylarabine Cytarnbine jsye TARE a been] (tyIOsil'le arabinoside, ara-G) is an analog of 2'-deoxycytidine in whid1 the natural ribose residue is feplaced by o.arabinose. It acts as a pyrimidine antagonist

1. Site of action: Uke the other purine and pyrimidine antagonists, ara-C must be sequentially phosphofylated to t!le corresponding nudeotide. cytosine arabinoside triphosphate (ara-eTP). in order to be cytotOllic. It Is $-phase (hence celI-<:ycle) specific. M-C is also inoorporaled into DNA and can terminate dlain elongation. II can also inhibit the reduction 01 COP to dCDP.

2. Resistance: Resistance to sm·G may resull Irom a delect in the transpOlt process. a change In phospholYlating enzymes. Of an increased pool 01 tile natural OCTP nuc.leotide. Increased deamination to uracil arabinoside. ara-U. a pharmacologically inactive me~ite. can also cause resistance. 3. TheraPfiltlc IndicatIons: The malor clinical use is in acute nonlymphocytic (myelogenous) leukemia in combination with 6-T6 (see p. 382) and daunorubicin (500 P. 385). 4. Pharmacoklnetlca: Ara·C is not effective when given orally because of its deamination to the noncytOtOllK: uracil arabinoside (ara·U) by cytidine deamina.se in tile intestinal mucosa. Given IV, iI distributes throughout the body. but does not penBlfate the GNS in suHident amoonts to be ertective against meningea.l leukemia. However, iI may be injected intralhecally. Arn-G undergoes exten·

Fluorouracil

<_'0...'."<

" 38. Anticancer Drugs siva oxidative l!eamlnation in the body 10 ara·u. Both Bra-C and ara·U are excreted by the kidney.

5. A " " - "HflCls: Nausea. vomiting. diarrhea, and severe myelosuppression (primarily granulocytopenia) are the major tcocdlies. Hepatic dystunction is also occasionally encounlered. At high doses or intralhecal Injeclion. Bra·C may cause seizures or altered mental states.

w

,~.

Cylarablne

F. F1udarabine FllJdarabine [flu DARE a beenl is the 5' phosphate of 2·fllJOfO-adefline arabinoside, an unnatural purine nuclectide. Allhough the exact cytoxic lesion is uncertain. the lripllospha.le is i~led rrto both DNA and RNA 10 decrease their synthesis and Mer their 1uncIion. Fludarabine is useful in the trealment ot chronic lymphocytic leukemia. II may replace chlorambucil. the present drug of choice. AudaJabine is also elfecli\.<e against hairy-oolileukemia. It is administered inlravenously rather than orally because intestinal bac1eria spl~ ofIlhe sogar to ~ the very toxic metabolite. nuoroadenine. Urinary ellcrelion accounts lor partial elimination. In addition to nausea. vomif· ing and dant1ea. myelosuppression is the dose-limiting toxicity. FeYef. edema. and seYefe neurologic: tOJ
See P. 463 for a description of newty ~ drug. capedtabine.

IV. ANTIBIOTICS These drugs owe \tle;r cytotoxic action to their internelions wittl DNA, leading to disruption 01 DNA function. They are cell·cycle specific. A. Dactinomycin

Daclinomycin ldak ti noe MYE sin). known to biod ...",ists as actin0-

mycin D. was ttl" first antibiotic to lind therapeutic application in tUITlOf chemoIheraP'/. 1. Site of actIon: The drug intercalates into the small groove oIlhe double helix between guanine-cytosine base pairs o! DNA. bming a stabkl ""cIinomyo"n-DNA complex. The complex inter\e(es primarily wittl DNA-depeoclent RNA polymerase, although al high doses. dactinomycin also hinders DNA synthesis. The drug may also cause strand breaks. Evidence exists that daClinomycin stabilizes the DNA·topoisomerase II compleX (see p. 397). 2. Reslstance: ResistMoo Is due to an iflcreased efflux ot the antibiotic lrom the cell Wi PijIyc<:lprolein (see p. 377). DNA repair may also play a role. 3. l1>erepeollc applIcations: DaClinomycin is used in combination wilh surgery and vincristine (see p. 390) lor the t,ealmenl 01 Wilm's lumor. Wittl methotrexate (see p. 378) if is effective in lhe lreatment 01 gestational choriocarcinoma. some soll·tissue sarcomas also respond.

<..........,.,.<- .... _,.

<..,...

M ~• •,_ _ ., ~ _ _ .....

IV. Antibiotics

4. PharmacoklneUcs: The drug. il
5. AdvefSe efIeocIs: The majol dose-limiting to~iciIy is booe marrow depression, and the drug is immmosuppressive. Other adve<"se reactions include nausea. vomiting. diarmea, stomatitis. and alopecia. Extravasation during injection produces serious problems. Dactinomycin sensitizes to l8diation; inflammation at sites of prior radiation therapy may occur.

B.

Do~oroblcln

"

and daunorublcln

DoxorubK:in [da>:: oh ROO bi sin) and daunorubicin [!law noe ROO bi sin) are classitied as anthracycline antibiotics. Doxorobidn, ollen relerred to by its trade name adriamyc;n. is lIle hydroxylated analog of daunorubicin. ldarubidn. the 4.-Qemethoxy analog of daunor~ bicin is also available,

DaclinomYCIrI

1. Site of acUon: The anthracydines have three major activities that may vary wilh the type of cell; all are maximat in the 5 and Gz

phases: a. Inlen:alalfon in tIM DNA: The drugs insert nonspeci!ically between adjacent base pairs and bind to the sugar-phosphate bacldlone 01 DNA causing a loca1uncoiling, thus bIoding DNA and RNA synthesis. Intercalation can ioIel1ere with the topolsome.ase II-catalyzed breakage·reunion reaction of DNA strands to cause llflreparable breaks. b. Binding to cell membranes: 1l1is action afters the tunction 01 transporl processes coopled 10 phosphalidy1inositol activation.

c. Generatlon of oxygen radicalS through lipid peroxidatlon: Cytochrome P-450 reductase (present in cell nuctear membranes) catalyzes reduction ot the anlhrac:;yc:;!ines to semiquinone free l8dicals. These in tum reduce molecular 0,., producing superoxide ions and hydrogen peroxide that medi· ate single strand scission 01 DNA (Figure 38.tO). Tissues with ample superoxide dismutasa (SOD) or glll!athiOl1e pelOICidase activity a,e protected. s Tumors and the heart are generally low in SOD. In addition, cardiac tissue lacks catalase and lhus cannot dispose ot hydrogen peroxide. This may eJIPlaln the cardio!Ol
2. Resistance: Resistance has been ascribed 10 increased efflux via the ampIdied transport P-glyccprotein (see p. 377). Cells rich in glutathione peroxidase ale also resistal1l. Decreased cytochrome P-450 rewctase, topolsomarase II and DNA ,epair may also play a role.

• ..../

.""

FIgure 38.10 OOxon.i:Hcin interacts with molecular oxygen producing superoxide ions and hydrogen peroxide which callSll single strand breaks in DNA.

.........,., ).- ... --,. J86

38. Anticancer Drugs 3. n-apeutIc ~Icallon.: AppIk:ations b' these two agents ditIef

despoile lt1ei, slructulill simila,ity and their apparently similar rnec:hanisms 01 acUon. ~ is are 0I1he mosl i'ipOIliiI. and >W;leIy used ;lll.icalll:e 0\.95. II is used b' treatmenl 01 $lIfcomas WId a variety 01 carcnlmaS. in::lucIing bfOOSI and IunO. a5 well as acute Iymphocylic leukemia and lymphomas. ~ is used in the Ireatmenl 01 acute ~ and ~~

4. Pharmscoklnetics •• AmofptlorI .00 dIllltfbutlon: Bolh drugs must be ad'nillisleled inll'llYlll"(lUS/y since !hey ara inadiYated in the gastrOOt8$tinal traeI. Extravasation is a serious problem that can tead 10 tissue

necrosis. These drugs bUld to plasma PfO\einS as wen as 10 tissues whefe they afe widely distributed. They do r'lOI perletrate In.o the central nervous system. DoxorublCOIl Dllunorublcm

b. Fat,: Both dfugs U1dergo e~te
5. Ad...... ,fleets: Ineversible. c;Io$lt-dependenl cardiolOllicity. apparenlly a teSUl 01 the geneo'lIb 01 Iree radicals. is the mosl serious ~ reaction. mriarinn 01 the \hofax increases !he ri5k 01 <:aJ6ol(lOM ity. There has been some $l'l"O'SS wiItl the ifcn chelalor. deJtrtlZ'Ofle. in prolecting ~ the C8'dioloxidty 01 dolfOfublcm. As wilh dac,inomycin. both doXOfubicin and daooonobicin also cause a traosienl bone marrow supp<essiorl. stomiIlitis, and GIIIId dislurtlllnc:es. Alopecia is usually severe. C. BleomyCin

Bleomycin (blea oh MVE sinl is a mil(\ure 01 dil!eroot copper chelat· ing glycopeplides that, like the anthracycline antibiotics. cause scis· sion of DNA bV an oxidative prooes$. 1.511' 01 action: A DNA-bIeomycin-Fe(II) comple~ appears to undergo 0Kida1ion 10 b/eorJ1)'cin-Fe(lU): the ~berated electrons react with 0lI)'gen to term superOlIide or hydroxide rarle<>1s wNctl in tt.m at1adl the ~ l . bonds of the DNA, restAting in sIrand breakage and chromoSon'IIl abemltions (F1glnI 38.11). Redox ,ecyding regellelates the Fe(II) Jorm.. ~ is oeIIcycle $p8Cific, and C8f 'Set oeI:s 10 ao:::um.MIe in 'I'oe ~ phase.

2."

1

Ianca:Ttese" ...... li:su(.s)t.wfllllbeen .... io' I 1,..-aq,

apai' .... 1iIl S)Yen'S hlM! ill.... ed 'ilCllllilsed IeYeIs 01 ~ ~ (or ~). gluta\hiofle-S-Irao 5': ase. and pcl '4y increasedetU.oI thurln.9- DNA ....... also ~~ 3. ThetJlpeu'lc appllc.ltlons: BIeom)Ci'l is primarily emplofed" the treatment of lesliaJlar tLmOfS in cc;mbiI ~tion with vinblastine (see p. 390) 01 eroposide (see p. 397). Response rates are clc'Sa to

............., .. _--,. v. Alkylaling

~

_

..... ...-....----" """""'" - .....

Agen~

100% i1 risplalin {see P 395} i5 added to II1e regimoo. BIfJomycin is also effective, although not curative, foI squamous cell carcinoma5 and lymphomas. 4. Pharmacokinetics: Bleomycin is administered by a number 01 mutes, including SUbcU!a1'\eOU5, inlramu5Clllar, intraven
5. Adverse effects: Pulmonary toxicity is !he most 5l!fiOus adverse effect, progressing from rales, cough, and inhllrate to polentially lalal fibrosis. Mucocutaneous reactions and alopecia are com· mono Hypertrophic skin changes and hyperpigmentation 01 the hand!> are prevalent. There is a high incidence 01 te..ar and dlilis and a low Incidence 01 se.ious anaphylactoid reactiorl5. B/eomyoil is unusual in !hat myelo&.opp.ession is rare.

DN"~_·

D. Plicamycin Plicamycin [p1ick a MYE sinl (mi/hramycin) aloo exerts its cylOloxic· ity through reslriction 01 DNA-directed ANA synthesis. Resi5tance is due to P-glycop.-olein efflux. P/icamycin has a r'*l;e with bone tumors. Toxicities include hemorrhage as well as effects on the bone marrow, liver, and kidneys.

./

~-­ Figu.e 38.11 Bleomycin causes break5 in DNA by an oxidalive process

V. ALKYLATING AGENTS A1kylating agents exen lheir cytotoxic effect5 by oovalefllly bif1ding to nucleoptlilic groups OIl variOU5 cell constiluoot5. Alkylation 01 DNA is probably the crucial cylotOJ
MechJoreIham.-.e [me kIor ETH a mean] wa5 developed as a ve5icanl (nlllQ98fl rT\U5tard) during World War I. I~ ability to C8u:oe Iymphocytoperia led to its use in IyrrVIatic cancers. 6ecau5e II ca.n bind and react at two 5ep8rate 5ites, rt 15 called a blunctional agent." 1. MechanIsm of actfon: Med!Iorelhamine i5 trarl5ported into the 001 by a c:tloIine Up!llke process. The drug Io5es a dlloride ion and forms a reactive intermediale !hat alkylale5 lhe Nt nitrogen 01 a

•

387

..... fo' ..1., > . . . . . . - , .

reso.oe

guanine in Ole 01' 004tl strands d a DNA rrdeo lie (F9Jre 38.12). TtiIi alkylation IeiIds 10 ~ between ~ .....0 ~ in the DNA chains, andiOf depurination thai IaciliIaleti DNA 5I/lIfId /)l e ill 'l'.}e AkyIaIion ClIfl also caJS8 i' liscc:df 'll f'l'Uao lions. AlltW:lUgh al(y\llion can 0C0Jf in boIh cycling and fes&lg cells ("ebe oeIqde rKAlSf*ilio), PO' fali'll cells are_ senslMllo the drug. "'"1-' 1ty ..... in G, and S ~ 51

Resis'anr:e has been llSCIibed 10 deal!ased permeability d ... drug. roeased COfliI.9alion wilh It** Sf.dl as glutalhiotle. and Po ssHy increased DNA <epa;'.

2. RetbtwlcR:

3. 1llefap'MIc ItflplICllUonS: MecIYoIelhamine is used primafily in the treatmenl 01 Hodgkin's disease as part ol the MOPP regimef1 (MechlOfethamloe, Oncovin. PfedniSOOll, Procarbazine). and Is also useful in the trealmef1l 01 some solid tulTlOfS. 4. JIt'Illrm.ooldnetlc:s: Mechlarelhamine is very unstable. and solulions must be made up lust prior 10 administration. ~1hamin6is also a powerflJl ~t (bIis1llfif'og agent). and is administered only IV. beaM_ it can cause seYefe Iissue damage if ecbansation oa::ura Bel;at_ ol its reaclMty. hllldy

:.tnt dfug is excreIed.

s. r ..

... _

::o:t: . ",.

.-

C=.I,_

et1ecU: Its adIo'erse etIects inc:lude severe _ and medaI-'). (NoIe: These effeds ean be ~ ished by pelreatment ~ ~ (see P. 243J 01' ~ thiazine (SM P. 242).1 SeYoere bone marrow depression limils ~ use. LaterC vifaI il'*':lioflll (lor exat\'llle. I PReS Zt:lliIll[) may appear beca_ d immunoliuppfession. Extravasation is a serious problem. " it oox:urs. Ihe area shoUld be inliltnlled ...mtl isoIo..ic iIIOdit.m Ihio5tMiIe 10 inadNate . . drug.

_,iiIi.., (........, Actgef . .

e. Cydopho5Phamlde and I10slamlde These drugs i1re very closely related mustard agents lhat share most ollt1e same Ioldc:ities. ThlIy are !rique in !hal (1) they can be taken 0filIly, and (2) lhey are cytoIaIic only oller generation ollheir alkylal' Ing spade$, lolIawWlg!heir Ilydn::IIyIation by cyloc:hrome P"'50.

1. M-.;h.nlsm oj .c:tion: Cydophosphamide (sye kloe FOSS iii midells the most commonly used atkylatlng agenl. 8
• "'" 'Q' ..,., ..... - - - , • V, A1kylaling Agents

3. Ther8peutlc Ippllcilionl: TheM agenls hlMl II bf"oad clinical speclrum, being used either singly Of as p1111 01 a regimen in treatment of a wide variely 01 neoplastic f:iseases, lor example. Burkill'S lymphoma and breast cancet. Non-neoplastic disease entities. $UCIl as nept1101ic syndrome and ~bIe meumaloid arthrili:s, are also eHectiYeIy treated with cydophosptlamid. •. Phlrmicoklnillce: Unlike mosl of lhe alkylaling agenls, cycIoptIot;pIlarrW;1e and ill:ls1t:lrrW;1e are PfeletentiaJly ~Iered by the oral route. Minimal amounts thl palant drug ara excreted inlO the teces (alter biliary uansport), or into Ihe urine by glomerula, fi.ralion.

0'

5. ActverM efI«:Is: The moll 11'01'';'«11 f(D(ic:ities of bolh drugs (atter alopecia, nausea, vomiting, and diarmea) a,e bone marrow depression. especially leukocytosis, and hamoffhIIgic cystitis. Mlicto can Ml 10 fibrosis 01 the bladder. The Iallef Iacicily has been altril)ulad 10 acroleW1 in the urine on lhe case of C)dophosp"amicle and 10_1e melabolites 01 ilos'lImkJe. INole: Adequale hylkalion lIS well as inIr.M!nous irojectioh of MESNA (SCIdiIn 2~~, Mlicto flidvaIes lhe toac compounds, minimizes this problem. Ol:her 1000icities include etIects on the gemr oeIIs ~ In ametlOUhN, testicUlar auo. ItlY. and 5&4rily. A fairly hil1l i itidei .... of nelI'ubUy has been reporled In patlerU on ~ ~ p..~ cb 10 lhe metabdile, ctoloroacetaldehyde. Secohcsary malignancies may appear ye;n atI8f Iherapy.

CamllJ$/iIIe [kar MUS leen) and Iomustine [Ioe MUSteen] are ckJsely fellliad ~eas. [Note: Shptozofoc:i1 [strop Ioe ZOE Ice sin) is .dle ~ . , . is specif"- " Ialic co Iha JH:eIIs of !he islets of ~ Its use is In the IreatmenI of Insl*Jo. mas. II is ~ .. and can cause 1lI"815ilJte renal dar'nage-) 1. Mer;Nnlsm of action: The l"lilrosooreas - ' c:yI(*D: etteas by an aIk)taIion lhat QO links SIrIInds 01 DNA CO ftlbI its replicao lion and. fMWllua~, RNA and prolein synthesis. AIltoough Chey alkylate DNA In 'esUlg eels, C)Ulloxicily is elCPfessed criy on cell division; Ihe,ekxe nondMding cells can escape death if DNA

,epair occurs. 2. RlIlstance: Althougtl!he II1J8 nature 01 resrslanoa 10 nitrosoureas is L.nknaroYn. it ptQbalJfy re5IAts DNA repair and reacIion 01 !he druJ!l with I11ioIs.

'rom

3. TherapeuIJc appllcallons: Because oIlhair ability to penetrate inlo Ihe eNS. !he nilrosoureas are primarily employed In the treatmenl 01 bfl'lin tumors. They lind limited use in !he Ifealmenl 01 oIt\eI

~" 4. Pharmacokinetics: In spite at the similarities irI Itlejr sInJct1Jres, Cllrmuslin6 Is admioislarad Inlrllven
389

_,-

C)ocIlOpt

... ¢ ...'ridIo

-

_ P ' ;h"'.

--" ' b'"

::...,="~ '.

,

~

.J

l.

,.

f

,,,,,' '''' ...,.,><- ...

~,.

<

~

< ••••• " - _••,.. , """""'" -

300

_

.....

38.

Anticancef Drugs

giYef1 orally. Because 01 their Hpophilicity. they distribute to many tissues, but their most striking property is their ability to readily penetrate into !he eNS. The drugs undergo extensive metabolism. Lomusline is metabolized to active products. The kidney is the majof excretory route'Of the nitrosoureas. 5. Adverse effec18: These inClude delayed hematopoietic depression, which may be due to metabolic products. At>. aplastic marflJ'N may develop on prolonged use. Renaltoxici!y and pulmonary fibrosis related 10 <1Jration oIl1leropy is also eooouniered.

./Jp

--

-,., lIMo uri..

CarmustineILomusllne

VI. MICROTUBULE INHIBITORS The milolic spndile is pan of a larger intracellular skeleton (cytoskeleIon) that is essential lor the internal movements occurring in the cylOplasm or all etJkaryotic cells. The mitotic spindle CQnsisls of chromatin. and a system of microlubules composed of the prolein tubulin. The mitotic spindJe is essential lor the equal panitioning of DNA into the two daughter cells formed when a ookaryolic cell divides. Several plantderived substances used as anticancer drugs disrupl this process by affecting lt1e equilibrium between lt1e polymerized and depolymerized lorms ot the microtubules. thereby causing cytotoxicity. A. Vincristine and vinblastine

Vincristine [vin KRIS teen) and vinblastine [vin BLAST een) are structurally·related compounds derived from the periwinkle plant, ~~. They are there!ofe relerred to as lt1e vinca alkaloids. A structurally related new (and less toxic) agent, vinorelbine [vye NO rei been) shows promise in the treatment of advanced non-small cell lung cancer.

1. Mechanism 01 action: VincriSline and vinblastine are bolt1 cydespeciHc and phase·spe<:itic, because they block mitosis in metaphase. Their binding to lt1e microtubular protein, tUbUlin, is GTP-dependent and blocks the ability 01 tubulin to polymerize to form microtubule$. Instead, paracrystallir.e aggregates consisting of tubulin dimen;; and the alkaloid drug are fomle
• . . . . . - . . - _. . , IO'I:AIIJI . . _

• • .0< . . . . .' . , • • _ _ . . . . . . . . . . .

'"

VI. Microtuoole Inhibitors

a Normal mitosis

mMitosis blocked by

..........

"r-

., - "t

),

I"

Spindle

.....

vinca alkaloids

.,.;;

-, (iJ) .......... Tubulln molecules stackeclto form

spindle

<

o

/

Tubulln molecules la/I 10 polymertze In p.....nce 01 vlllCll allulloidS

Figure 38.14 Mechanism ot action of the microtuoole inhibitors. other rapidly proliferating neoplasms. [Nole: Vincristine ( \fade name is OHOOVlN) is the "0' in the MOPP regimen (see p. 388) /of Hodgkin's disease and a m.mber of other prolocols.j V/flbIastine is administered with bleomycin (see p. 386) aOO cisplalin (see p. 395) tor lhe treatment of metastatic testiclJlar carcinoma. It is also used in the trealmenl of systemic Hodgkin·s and non-Hodgkin·s tyrn~omas.

4. Ph8fl11llCOklnetlcs: Intravenous Iniection of vincrisb·OO or vinblasline leads to rapid cytotoxIC eHeets and cell destrUClion. This in turn can cause hyperuricemia duB 10 the oxidation ot purines to uric acid. The hyperuricemia is amelioraled by administration of the xanthine OlC.idase inhibitor. aliopurino/(see p. 417), The agElflts are concenifated and metabolized in the liver and are excreted into bile and feces. Doses must be moditied in palients with impaired hepatic lunction or biliary obstruction. 5. Adverse e"ecls: II. Shllred toxlcll1n: Vincristine and viflbIastine have certain 10xi· cities in common. These include phlebitis or cellulitis. it Ihe drugs extravasate cl\Jring iniection. as well as nausea, vomrting. diarrhea. aOO alopecia. b. Unique loxlcrtles: The adverse ettects 01 vincrislioo and vinblastine are no! identical. Vinblastine is a more potent myelosuppressant. whereas peripheral ne..,.opathy (paresthesias. loss of reflexes, footdrop. and alaxia) is associated with vincristine. Gastrointestinal problems are also more trequently encountered with vincrisline. B. Pllclllaxel Bener!
I

(,.... ,"'_..,,<- ... --,.

• eo- ...._ _ " .. ,

392

H>'CAIUl _ _ .... >

38. AI1ticancer OrI.Igs 1. SIIf! of acllon: Paclitaxel binds rllV8l"Sibly to lubulin, bu1 unlike the vil'lCiI alkaloids. ~ pfOmOles polymerization at1d s\abilizalion of the polymer mtOOr Ihan disassembly (Ftgura 38.15). Thus it shifts the depolymerization-polymerization 10 lavor the Iol'mation or microtubules. The overly stable microlubtJles Iofmed in !he presence 01 pacJilaxeI are dystunctional, thereby causing the dealh ollila cell. 2. Resl..",r>ce; Like the vir.ca alkaloids, resistance has boon assoc;j.. ilIad with the presence 01 amplified P-glyooprotein. Of a mutation in tUbulin structure.

3. Therapeullc Indlcallons: Pacl/laxel has shown good activity against advanced ovarian cancer and metastatic breast cancer. Early Irlals indicate favo.abIe results in small-cell lung cancer, squamous-cell carcinoma oIlt1e head and ned<, and several other cancers. Combination therapy with Olher anticancer drugs Is being evaluated.

e Normal mitosis

........

-GJ) / SDlndIe"'._ .he<_phlI..

.'lowInv 00'1110 d"'lde.

o Mitosis blocked by paclltaxel

........

4.

Pharm8COklnetlc~: Padiraxel is infused over 3·4 hOl.Irs. Hepatic metabolism and biliary e~cretioo lltlI responsible tor e~minalion of pacJitilxel. Thus dose modification is not required in patients with ret'1al impairment. but doses should be reduced in patients with hepatic dysfunetiol'l.

5. Adver5ll

effl!<:t~

a. Hypersensitivity: Because 01 serious hypersens~ivity reactions (dyspnea. urticaria. and hypotension). the parientlO be treated w~h Pilc1itaxel is QJrrently premedicated with dexamethasooe (see p. 275), 8r1d diphenhydramine (see p. 422), as well as with an H;, blocker (see p. 236). b. Neutropenia: The dose-limiting tOlCicity of pactitaxel is neutropenia. Treatment with granulocyla coIooy·stimulating 1aclor (filgraslim) prevents the problems associated with this condi·

tio<1. c. Other to~lcltles: Peripheral neuropathy and a transient asymptomalic bradycardia are sometimes observed. Alopecia occurs, but vomiting and diarrhea are uncommon.

VII. STEROID HORMONES AND THEIR ANTAGONISTS

Flgure 38.15 Padilaxe/ stabilizes microtubules, rendering them

IlOOfunctiorlai.

Tumors that are slero;d hormone'sensitive may be either (1) hormoneresponsive, where the tumor regresses ~lowing treatmet'1t with a specifiC hormone: (2) hormone-dependent, where removal of a hormonal stimulus causes tumor regression: or (3) both. Hormor1e treatment of responsive tumors is usually only palliative, e~cept in the case or the cytoto~ic ailed of glucocorticoids (for example. prednisone) on lymphomas. AemOll3l of hormonal stimuli from hormone-oependent tumors can be ao::omplished by surgery. tor e~ample, in the case of orchiec· tomy for patients with advanced prostate cancer, or by drugs. for e~am­ pie in the case 01 breast cancer. treatment with the antiestrogen

•

. . . . .0 . . . . . ,

. . . . . _ _ ...

-_.. _. -, ....

.,......

,>

VII. Steroid Hormones and Their Amll!iJOf'lisls

tamo.o1isrl is u&ed 10 prEl\lef'lt estrogen stWrUalion 01 bnI8S1 cancer eels. For a steroid hofmooe 10 haw an influence on a cell. lila, cell mus' haw cy10$0liC receplOfs lhal ara specific lor ttla' hormone (Fogu.e 38.16A).

A.-"'"

,

n

Mechanism 01 steroid

IIiI hormone acllon

--

cI?

Pl«h'soIllIPftED r-. sone] is a polenl ." ...... atlIi-inIlarrma IXd.. ~ II'oiIh less Iiliealowtlitd:lllC:tMly...., oor1isol (see p. 272). The use oIlIWs oonlPQi.nllr.1he Iraaln'Ienl oIl)ilillllu, _ _ 'fohen. was observed 1haI patients......, Cushing's syIidlane (. sytOo",. associaled wit! hypersecrelioI' 01 WlIisd) hIM! ¥n~ IIf'ld decreased tympiOid mass. These ...... from 001"Iioi: S oid 8dicn a1 Iyi Iormation IIf'ld cislrtJJlion. flat is, mcM!mef1I: 0I1hese eels from Ill! ciraJUlion 10 l)illlphoid 1issue. t

,"'1OC}'Ie

s

I

,. MectIanlam 01 IIdIon: Prednisone itseIl is ir\acliIIe and rrust IirSl be radUc8d 10 ~ bV 11~ dahydrogenase7• The sterokl binds 10 a receptor lhal lri0ge<S IhIIl produc1ion 01 specific pro1eins (see F9JI'El 38.16A). The specific mechanism for its ~ic action after Intllf8etion wi1h DNA remai'ls 10 be eluCidated.

2. ",,,Ialane,, ResislaJ'\Ce is associated with an absence 01 '00 receplOf' protein or • mutation that lowers receptor affinity for \he hormone. However. some resislanl cells appear to have luncIionai receplors, but some subsaqu&rlt step(s) is atJecled, 3. Thefapeutlc IlppUcallom: Predt1isotlS is primarily employed to Ird.lC8 rami$Sion in palief11S with aetAe lymphocytic 1euIIemia. and in the treatmenl 01 both Hodgkin', and non-Hodgkin's Iyrrclhomas.

4.

9~

see

a

p. 272 for rtisn,sUon 01 Ill! phaImaco01 plednisoll6and Its 1Oolic.etions.

~:

lOgic

--- ---

C -P 'r:'I

Actions of 8nti-

. . . estrogen dNgs

TlWnOXiMn Ita MOX i ten] is an estrogen anlagOrist. strueluraly <eIaled 10 Ill! S)'idhelic estJoge<~ ~ an;j is adiYe in .... Ireunenl 01 ~ ogell ~-pcn... bleasl CB'IOIlr. Tamaa"ilen ha5 ...... 6Sboge< lie IICiWlly.. 1. MKhInIIm 0I1IC1lon: TanJCliiil&l brId6 10 the esiloge<. recepklr but the ~ is I'lll' produclive. lhat is, the WI,iple>;: tails 10 nluce estrogen-respon genes an;j ANA synlhesis does I'lll' ensue (FlQUra 38.166). The rasulis a depletion 01 eslrogen receplofs, and Ihe ~ etlects 01 the natual hormone and OCher gowtlloclors are Sf.ll'lPAIssed. [NoIe: Estrogen oompetes wilh 1amOJ(ifeff. lheretore, the drug Is not ettective in pftHTleIlOp8US9 'Mlmllfl.1 TafTlOJlifens aaion is not related 10 any specific phase 01 Ill! eel cycle.

2. A..lalane.; Resistance is associated either wittl a decreased al&lity for Ihe receptor, a deCreased nt.mber 01 receplon;, or \he pnlsente 01 a dyslunclional receptor. 'Sofl ~. 4C(I for _

",,"," __ II> _ _ . , , . . . . _

,

&

dI'

[I

dI'

.---

-- = ,,",",",._-" ,

FIgUf' 38.16

Action 01 sleroid hormones and

anlieSlrogen agents.

(,.... roz_'."<_"'_"

• . . - .........

~ ,

39'

H>'CAIUl _ _ . . . . .

36. Anticancer Drugs 3. Thenlpeutlc applications: ItS dinical use is confil'llld to the treat· ment of estrogeo-depefldent breast cancers.

4. PharmacoklnellC5: Tamoxifen is et1ective OIl 0IIIl admirlislf
,"""

5. Advet'Se effects: Side effects are similar to lhose 01 natural estrogen, that is. hOt flashes, nausea, vomiting, skin rash, vaginal bieediog aod dlscharge (due to some slight estrogenic activity of the drug aod some of ilS metabolites). Hypercal<:emia requiriog cessatiOfl of the drug may also occur. TBIIlOXiIen can also lead 10 ir\creased pain if the lumor has melastasized to bone. Tal1'l(l;l(ifen has !he p;lteotiailO cause endomelrial caocer.

6. Potenllal beneflts: Tamoxifen is being ev.tluated for possible P as ethinyl estradiol or diethylstilbestrol. are used in lhe treatment 01 prostati(: caocer. Estrogens inhibit the growth of prostatic tissue by blocking the production of luteinizing t\ofmone aod thus decreasing the synthesis of androgens in the testis. Thus. tumors dependent OIl aodrogens are allected. Estrogen treatment can cause serious oomplicalions, SUCh as thromboemboH, myocardial infarction, strokes. and hypercalcemia. In women. loss of libido may accompany menstroal Changes. Men laking estrogens may experience gynecomastia and impoteoce. D. LeuproUde lind goseralln

Tamoxlfen

The synthetic oonapeptides. leuproHde [100 PAQE lide] and goserelin [gah SEA e lin} are analogs of gonadotropin'releasing hormone (GnRH, LHRH). As LHAH agonists, they OCCUP'J' \lle LHAH receptor in the pituitary. which leads to ifs desef1si~zation and consequently inhibition of release of fSH aod LH. Thus. III1drogen and estrDgOO synthesis are reduced (figure 38.17). Aespor1se to leuprolide in prostatic cancer is equivalent to that of orchiectomy (surgical removal of one or both festes), with 40% regressiofl of tumor and raliet of bor1e pain. LetJPfOIide is etlective either lIS a daily (SC) or depot (1M) injection against metastatic carcinoma 01 the prostale. Gosere/in acefate is implanted intramuscularty. [Note: Depot torms are administered monthly.] Levels of androgen may initially rise, but !hen fall to castratiOll IlIvels. The adverse effects of these drugs, including impotence, hot "ashes aod tumor flare. are minimal com· pared to those experienced with estrogen treatmem. E. Flutamlde FIuUHnidelFLEW tah mide] is a synlhetic nonsteroidal amiandrogen used in the treatmf!f1t 01 prostate cancer. It is metabolized to an active hydroxy derivative that binds to the androgen receptor.

<..0<'.'''''''<_'''_' >

< ......

. . , IO'I:AIIJI . . _

.....

VIIi. Other Chemotherapeutic Agents

Flu/amide blocks the inhibitory eflects of testosterone on gonadotropin secrelion causing an increase .n serum LH and teslosterOl'\8 levels. Fluramide is always administared in combination w~h leuprciide or gosereiirl. 11 is aa-niniS1ered orally and deared through tne kidney. Side eflecls indude gynecomastia and gaslrOinleSlinaf distress.

F. Amlnoglutethlmlde Aminogiurerhimide lah me 1'\0 glue TETH I mide] is useful in second liI1e therapy lor lhe lreatment or metastatic breast cancer. It inhibils lhe adrenal SyniheSiS of pregnenolone lrom Cholesterol. and the eXIra-adrenal aromalase reaClion responsible for the synthesis 01 estrogen from androstooediooe. Aminoglutelhimid6 is administered ondly, and is metabolized by the hepatic cytochrome P·450 system 10 ir.acrive prodUcts. Because or ilS ability to induce this system, ~s own metabolism is accelerated. and inlernctions 1I1al increase Ihe melabolism of dexamethasone (see p. 275), rhlWphylline (see p. 220) and digoxin (see p. 158) can occur. AminoglUferhimide causes transienl eNS depression and a maculopapular rash.

""

VIII. OTHER CHEMOTHERAPEUTIC AGENTS A. Cispialln and CllrbOpllltJn

_.

Clsplafn ISIS pia lin] is a men1ler 01 the platinum coordination c0mplex class 01 anlicancer drugs. Because 01 dspiarin's severe b
-

1. Mechanism of action: Their mecMni!;m 01 action is sim~ar to that 01 the allIyIatlng agoots. In the hig1 chlOride miliw 01 tne plasma. cispiarin persists as the neutral spocies. which enters the oeU and binds to the N7 01 guanine or DNA, forming inler- and inlm·strand crosslinks. The resulting cytotoxic lesion inhibits both DNA and RNA synlhesis. Both drugs can afso bind 10 proteins and 01l1er COfnl)OI.lncls conlainr,g SH groups. Cytotoxicity can occur at any slage or Ihe cell cycle. 001 the cell is most ~ulnerable to the aClions of these drugs in G, and S. 2. Resisiance: Sensitivity to these agenls is decreased if cells have elevaled gluta1l11one levels Of Increased DNA repair, or if metalk>lhionein (a protein rich in SH groups) is inOJced. 3. Therapeutic appllcallons: CIspIalin has fou1d wicIe application in the Irealmenl 01 solid tumors such as metastalic 1e5licular carcinoma in combination wilh vint:/aslirle (see p. 390) and bleomycin (see p. 386). ovarian carcinoma in ~r.ation wi1l1 cydophosphamlde (see p. 388). or alone fQr bladder carcinoma. Catbo· pia/in is employed when patients cannot be lligorwsly hydrated as is required lor cisplafin Irealment, or if they sut!ef from kidney ayslunction Of are prone to neum- or ototoxicily.

Es~s

Figure 36.17 Effecls 01 some anticancer dnJgs on 1I1e endocrine syslem. A. In tnerapy 01 proslatic cancer. B. In therapy 01 postmenopausal breast ~,.

(,00<

,.,.<_ ... _,.

r", ...

396

38. Antcancer Drugs 4. Pharmacokinetics: Cisplaffn ar.d carboplalin are administered IV in saline solution: they can also be given intraperiloneally forovarian cancer. Over 90% of cisplalin is bound to sel\Jm proteins. Highest concentrations are foI;fId in liver. kidney, intestinal, testicular and ovarian cells. but little penetrates into lhe cerabraJ spinal fluid (CSF). The renal route is the main avenue for e~crelion.

5. Adverse etlects: severe. persistent vom~ing occurs 1 hoIJr alter administration of cisplalin and may continue lor as k>ng as 5 days. Premedication with antiemetic agents is usually helpful (see p. 241 for a discussion of antiametic drugs). The major limHing to~icity is dos~Helated nephrotOJeicity, lnloOOing the distal COI1VOIUled tubule and collecling duets. This can be ameliorated by aggressive hydration and diuresis. Hypomagnesemia and hypocalcemia usually occur conctJrrenlly; ~ is imlXH1antto correct caldum levels before correcting magnesium levels. 0Itler toxicities include otOlOJeicity. with high frequency hearing loss and tiMiIllS; mild bone marrow suppression; some neurotoxicity cllalOClerized by pareslhesia and 10&5 of propnocepliOf1: and hypersensitivity readions. rangirlg fmm skin rashes to anaphylaxis. Patients rece;v. ing aminoglycosides (see p. 314) concomitantly are at a greater risk for nephrotoxicity at1d ototoxicity. Untike cisplatin, carbopiatin causes only mild nausea and vomiting and is not nephro- I'IeIJro- or ototo~ic.lts dose·l;miting toKici!y is myelosuppression.

e. Etoposide (VP-16)

CJsplslon

Etoposide [e loe POE sideJ and its analog. leniposide [TEN ih poe sidel are semisynthetic derivatives of the ~at1t alkaloid, podophylkr lO~in. They blod< cells in the late S-G2 phase of the cell cycle. Their major target is topoisomerase 11 6. Bindirlg of the drugs to the enzyme-DNA comple~ results in the persisterlce of the transierlt deavable form of the comple~ and thllS remler.; ~ StJsceptibie to Irrevernble doubIe~trand breaks (Figure 38.t8). Resistance to topoiso-merase inhibitors is conlerred by either the presence 01 lhe multi-drug resistant P-glycoprotein, or mutation 01 the enzyme. Eloposide finds its major dil1ical use in the lreatment 01 oat cell carcinoma 01 the lung and relractory testicular carcinoma. It is currently being tested in other therapeutic prOIOcois. Etoposide may be administered either IV or orally. II is highly boofId to plasma proteins and dislributes Ihroughout the body, but it erller.; the CSF poorly. Metabolites are converted to glllCUrorlide and sulfate conjugates and are excreted in !he urine. Do5e-limiting myelosuppression (pri_ marily leukopenia) is !he major toxicity for both drugs, Other 1000ici· ties are alopecia, anaphylactic reactions, nausea, and vomiling. Hypotension may occur ~ the drug is irljected raptcty.

C. ProcarbaZine Procarbazine [pfoo KAR ba zeet1J inhibils DNA and ANA sythesis, Procarbazine is used in the treatment of Hodgkin's disease as pari 01 Ihe "MOPP" regimen (see p. 388). and also otller cancers. Procarbazine rapidly equilibrates between the ~asma and the CSF alter oral or parenleral admirllstraHon. Metabolites and the parent

...... '0. . .,.1 •• _

... _ _ I >

•

.,... K

..,

............. _

.....

'"

VIII. Other Chemotherapeutic Agents drug are excreted through the kidney. Bone marrow depression is lhu major loxicity. Nausea yom~ing. and diant1ea are common. The drug is alSO neuroloxic. causing symptoms ranging lrom droWsiness to hallucinalions 10 pa<esthesias. Because il inhibits monoamine oxidase, palienls oooold be warned againsl ingesting fOOds thaI c0ntain Iyramlne (for example, aged cheeses. beer. and wine). Ingestion of alcohol leads to a disulfiram-type reactior1, sea p. 96). ProcarI;Mine is both mutagenic and teratoget1ic. Nonlymphocylic leukemia has developed in patients t<eated with the drug.

O. l-Aapa.aglnase

l-Asparaginase [a SPAR a gi nase] catalyzes the deamlnation 01 asparagine 10 aspartic acid and ammonia. The lorm 01 the enzyme used chemothl!faPlllJlicafly is derived from badena. 1. Mechanism 01 action: some neoplastic cells .equire an e~temal source 01 asparagine. because 01 their ~mited capadty to make SlJI· Iicienl L·asparagine to support QKNIlh IV'Id function. L-Aspamginase

hyO"oIyzes blood asparagne and thus depri'v'es the IumDI cells 01 this rutrienl required br proIein synthesis (FlQUre 38.19). 2. Resistance: Resistance is due to increased capacity 01 tumor cells to synthesize asparagiM. 3. Tl1el8peullc application: l-Asparaginase is used to treal child· hood acute Iympttocytic leukemia in combination with vincristine (sea p. 390) and prednisone{sea p. 393). 4. Phllrmacoklnellcs: The enzyme must be administered eilh&r IV or 1M because it IS deslroyed by gastric enzymes. Disposition remains undefined. S. Adverse elfeelS: Toxicities include a raflge 01 hypersensitivity reactions (since ~ Is a foreign protein). a decrease in clotting faotors. and IMlr abnormal~ies, as well as pancreatitis, seizures. and coma due to ammonia toxicity. E. Interferons

1. Clas.slflcallon: Human inlerlerons have been dassilied into three type"S, «, ~. and"/. on the basis of their antigeflicily. The« intef1erons are pnmanty leul
Eloposlcle leaots 10 (Iocmlll stnInd lQIIks In DNA

Ft<>r-IM

I

~--A ~-v

Figure 38.18 Mechanism of action of aloposide.

(,.... ,,,,_..,.<- ... --,. 38. Anticancer Drugs exert their eflects. Boond interterons are not internalized nor degraded. The « and ~ intefferons compete for binding and presumably bind allt1e same receplor or in close proximity; "y interlerons bind at ditfefent receptors.

.. ........ -

"-.... t= ••'.

,

G1utamlne GlutlI.... t.

11' A_'" jI.

_'~sy-

_.Ol._rag'"

I'fI>fTr>el cell. haw high .~_

....tH

to ....... sulllc'-"t _ . . . 10, "'Ohln synthosl...... cell gn>WIh

3. Therapeutic Indica lions: «2(A)/nterleroo is presently approved lor the management ot hairy cell leukemia. More than 90% 01 patients treated w~h« interferon have shown resolution ot cytopenia. reduction in tim incidence ol serious inlection. and reduction in the need t:.tr transfusions. DIller interlerons are being fested in lt1e freafmen! of various tumors, including squamous cell carcinoma. melanoma. and mutliple myeloma, among others. 4. PtUllmacol
The anticancer agents are summarized in FIgUre 38.20 See pp. 464-466 lor a descnption 01 newly approved drugs. topotecan, trashJZumab and rilWlfflab.

Study Questions ChooGo!he ONE best artSw....-.

38.1 Which one oIlhe loIIowing agents shows cyIotol
or

~.

Figure 38.19 Mechanism ol action 01 L -asparagnase.

to hIM a

~

eIl8elln eyeing cells. C1!;pIIdin and II.. .o
-

• ..... '0'"'''''_'''''''''''''

. . ._

• •0 _ _. . '

IO'<.AIIJI . . _

.....

>

VIII. OtherChemotherapeulic Agents

Therapeutic uses

-..--...,.. ----v_ --"""'"' -'-

Dose-limiting adverse effects

Drug

I

"""~~

:

r'~

..................

CClr'ntJina'ic::fi lhOrapy ., IIOllII'I\etlt a

6'~

.....1 ·....

""'"'"'"

NiIl_

...... .......

v~_

,~

".,.,..

.....1<0...

ComtlO'oalion ,hOtaPi In tmolt'no:!tll a ~'sdisllasa

f-

-

~

8Ms: .....

.

.................................. .................................

..-.:IGI~

'"""""'"

~""'- a llcatmenl

~

__

6t~S;

~~cyuc leukemia

_._.-..

--

-...

Wilma'

tumor (cl1lldoMl

e.AS;
Therapeutic uses

1lMS: tIW1Il;IIO
llMs: ,..,...,, _ _ _

------.-~

BMS: t>em<>rrI\lYC..-

ComI>lnaIic<1

~:~

tmalmenla teStiwIa, J\JIrIaS

............. ....................

~

FU:l-.lYyptooeo ..... , ............. _

..... ~ I d _

""""'" .-.I ~ .... aI _ -

.-.I >e<'I'NIng

MBtgic--

~

Me'IJIC - . ; _

BMS: oIe9:'-'

Adverse etftH:ls and Pt'tH:llutlons commonly observed with anticancer dl1,Jgs Figure 36.20 Summary 01 cancer d1emotherapy agents BMS", bone marrow SUPPfllsslOO.

....................

...... ,"' ...,.,.<- ... _,.

< ..- • _ _

~

,

H>'<:AIUl _ _ .... >

38. Anticancer Drugs

"Xl 36.2 Which one 01 the IdIowIng drugs is melabolized to a cyrotoxic producI?

,_.

38.5 Cells rMlstant to methotre_ale may A. havo higher than normal lovets ot dihy
A. \fJlCristine.

8. Oacli'>om~. C. 5-AuorouraciI. D.lom.Istine.

8. have higher levels 04lormyllct,ahydrotolalo. C. metabolizo the drug to r-.octiva proO.>c!s. D. have a dectcased molabo/iC need tor folale. E. show an Increased uplake of metllotrexate.

E. PacliIlll<el.

ThlI c:
01...

• I ';

'O

C.

The COfnICI _ r • A. RIosislBnI calla lTIlly

~._

~

IlI'ld II'Al be ccr-*l lO ... co'........ dI"'d8clo:)o" ...... ThlI_

~

"....

_.1 _

j

01

levels ~""""'a'" InI'libIlII Olhydoololale rtdtoctMe

W'd.

egBnISe-1lhlllr~~ ~ .

...-101<-. ........... _

I·.....

of !he reduced letrahydfotolalfl clariV.lIvea.

t

....

38.6 AI 01 thl! foIowIng statements are true EXCEPT:

_ogeo, rec8I*>r 1lI'ld""'. an .ot&goitlst.

00BIn.tlDn ~ .....'

en- underVo "......." bv ..

~

dt*l-.,

A. DoI
C. CydopI>ospllami. D. Mechlorotharnine. E. ClspIalin.

?

- . W IW. 1'10I a W:loI ~.' .... lhe rne'rlldo; ' - ' to< _ . Ngh ill .. r8j:dy _ ,. dea pst irlllAll< rrey be _ _

36.3 All ot Iho following agents cause their cytotoxic cttOdS by ..,tor'Ilm!nce In DNA transctil>tion EXCEPT:

ill DNI'l WId . . . 1rMr-

ler.. In tr.roscriptlon. CYClOphoaphamlde, ~_~"*' croea_

A. Pabcnts with ~'s disease being treated with p
wIIh CNA --.do ro tmtlII ill bdol\

"""".-

O. Treatment with aJ
.,......

E. TalnO.llen complexes with DNA to inhibit RNA

A. VInblasline. 8. Cyclq>hosphamiOO.

ThlIeorta:I dIOice .. E. T.......... ' ....... II (XlIl>o

_oven

C. Cylarabino. O. Mec.:hloretharrne.

E. l-Asparaginase.

pIn ..... 1h8 """"PIO<.~ Inhibit. InOll(Nlmlne oxidase, an anzyme

..,quRd to ft'PtrtollH!yf8mlne Iounclln tar· ... I . ICf.lfQI!IIl, IPtICtt IllI _ IlfIll some "*-. X-lmdation Is ellectlYe In e-kdng C8IIl wIIIcIl hIlw _ ~ In

"""*'*'

-

drugs are IllIAlIQItnIc IIIId ""roInc>gMlIc:, PIlnlc:u'-r!y IhIl ""'y\3ting

IhIl eNS. Man)' ..... _

"_e...... irllJ'l!"enling "'" 6vIsion.

_

"Sell p.34$ i18k>o::htwnr.1
'See p. 247;" BIocNomr.lry 12rIl<J< .. ,lil:>iIioo, al purine Syr1_.

'See p. 3SO irl BIoc_ry (2nd ed.) ...
0Xl'l)fN1 inIe
'see P. 224 i1 Bkx:hftnlolry (2rxl ed.) lOr """ 01 11 {II\yIltoXyOleroid ~in_~

","",..iM oIll!t1~meteI>olism.

<see p. 1 '4 on BIoc,*"lolry (2nd eel.) for """ 01 r1!1lCli>-e I&,e p. 365", BlDc:hftnlOlry (2nd ecl.) lex rolIl 01 topoloorneraoIl"' DN"'~

,.""

.....'.,.'

'.

,

_

...... --_.,....,.".". .. ..... UNIT VII:

•

Anti-inflammatory Drugs and Autacoids

Anti-inflammatory Drugs I. OVERVIEW

ANTHNFLAMMATORY

DRUGS

......

tnllammalion is a normal proIediwI response 10 Iissoe iflury ........ed by physical trauma. noxious chemicals. or mic.oblolOglc agenls. InIl8trwrIalion is !he bod(s efb110 I'Ial;tivale Of c;Ieslrt¥ hIeding orvanisms, _ ft&ants, and set .... stage tor Iissoe ffJPlW, WIWI heaIrlg Is complete. the inflammatory process lISUally subsides.. IIo"eO'llf, ~Iion Is som (,_ iI'lapproprial:ety Iriggeled by an Irron'",s agant. suctI as polen. Of by an ~ resp:n$e, as In asdil", Of mec.matoicI arttrils. In suctI cases. 1he defense reactlollS themseM!s may C8U5e prOQl: SNe tssue injury, and antHntlammalory or i'nnu1o~ ed i"I Ihls chapIer are sunmarized in FIgUAl 39.1. [Note; The use 01 cortico5Ieroids In Ihe Ifeatmenl: 01 inIIlwnma1ion is diso ... sed on P. 276.)

II. PROSTAGLANDINS Many 01 IhB f'IOnSleroidal anll-irlllamrnalory ~ (NSA'Ds) act by llollibitil'll hi synlhBsis of pros18gIandns. Thus, an ur'IdIrstaolIrI of NSAlDs requires a tDllpfeheusion 0I1he adion$ and bios,i1doesis 01 prostaglar>dins---i.onsatu.aled latty ad
-----__._ ,-0._ -. . ........ -WI ,

.... "". . Ru*",." , ......, ,, ,

h

I(elUpoloon

""

'

-~ 50!! ' r

,..,

COll-2INlEfTOAS

C'

NOIl'~1C ANAlGE9CS

~

•

:

....., , ,

I

.

,- ,.. _..,.<- ... _, .

"

39. AntHflflammatory Drugs

A. Role of prostaglandins as Iotal mediatOf$

ANTI.-lNFLAMMATORY DRUGS (contlnued)

I-

c_ --

DRUGS FOR ARTHRmsl

~N~

Me_",,'"

~-~

C-

I

DRUGS FOR GOUT

Prostaglandins and related compoonds are produced In minute quantities by vinually all tissues. They generally act locally on the tissues in 1Itlid1 they are s}"1thesiled. and are rapidly metabolized to Inactive products at their slles of action. Therefore. the prostaglandins do not circulate in the blood in significant concentrations. Thromooxanes. leukotrienes. al'\d the hydroperOl
B. Synthesis of prostaglandins Arachidonic acid. a 2O-carbon fatty acid. Is the primary prerorsor of the prostaglandins and retated compounds (see Figure 39.3). Arachidonic acid is presenl as a component 01 the phospho~pids of 0011 membranes, primarily phosphatidyl Inositol and other comple>< lipids.' Free aracNdonic acid is released from tissue phosphoIip;ds by the action 01 phospholipase ~ and other acyl hydrolases, via a process controlled by hofmones and other stimuli (see Figure 39.3). There are \V,(l major pathways in the synthesis of the eicosanoids from arachidonic acid (sea Figure 39.3).

""""'~ p"",..~

Figure 39.1 (continued) Summary 01 nonsteroidal anti·inflammatory drugs.

1. Cyclool
a..tter -'ler tt-..lnlIlel PG, ....". . .

_u...- on

",.0••.0,H. ..reno ... the C'f<'Iol>ent,,,'Ie tinII. The m<MI

_ ..",,", CDnfiVur..- ere:

'1'

0

<& . 0: .

that is, tho prostaglandins. tlYomboxanes. and prostacycins. are synthesized Via the cyclool
.~

2. llpoJ
on arachidonic add to form 5-HPETE. l2·HPETE and l5-HPETE. wtIictl are unstable perDl
~n~E,)

~~=

-

~Ind

~

••

-.blo _

n_\\

__ In !he _

Ilu""'...... It-.. 2·_el. _ ~

Figufe39.2 Structural features of prostaglandins.

.....1

C. Actions of prostaglandins Many of the actions of prostaglandins are mediated by their binding 10 a wide variety o! distinct membrane receptors that operate via G proteins. wt1lch subsequently activate or inhibit adenytyt cyclase or

stimulate phospholipase C. This causes an enhanced tormation of diacylglycerol and inositol·l,4,S·trisphosphate (tPa). PGF"", the Ieukotrienes, and throml)o)(ane A2 (TXAz) mediate cel1ain actions by activating phosphati(lylinositol metabolism and causing an inaease of inlracelluler [Note: Some prostaglandin receptor arnagonists have beef1 developed but they have no dinical use.]

ea".

D. Functions In the body Prostaglandins and their melabol~es prodJced endogenously in tis· sues act as local signals that fine-toroethe response 01 a spedfic cell type. Their functions vary widely dependng on the tissue. For Bl
• • ~, . . . . .,., , . . . . . . . . . . . . . . I

•
>

p".' _

.. _

.... '

Ill. Nonsleroiool Anli-nllarrrnalOfy Drugs p1alCle\$lor awegalU'l (!he ~rst Slep kl doIll;m"ellon). HoweYer, kl OIher tissues, ellMlled IeYeIs 01 ~ 0Df'Mly a (ifI&renI signal; lor ell8fI'lPle. kl ~ S/'I'lOOIh 1TIJSCle. 1hi:s tDliPOd\d nb:es c0ntraction. PrOiSl3g'landins are one 01 lhlI chemical mediatOl'S \hal are ,ela eel i'! ah.\iC and irlI\arl'I'r\alOl'y p' o::a ssw (sea P. 221).

Ill. NONSTEROIDAL A~NFLAMMATORY DRUGS The nonsteroidal antHn!lammalory drugs (NSAlDs) a.e a group of dlem
* ...; ':

CQ,.

~

C¥

NSAlo.-~,

A. AapJrin end olhel" salicylates

ASpirin lAS pir In] is a weal<. organic acid lt1al Is unique among tile NSAIDs in Irreversibly aoolyla~ng (and lhUS lnaaivaling) cycloa
Figure 3~.3 Synthesis 01 prostaglandins and Ieukolrienes.

....._

01

<- ,....... ,.<- ... _,.

",..

<

eo- •

_"""MP<'" """""'" __. "" > 39. Anh-inf13mmatory Drugs

a. Anti-Inflammatory actions: Because aspirin inhibits cyclooxy·

_.".... ---

......."'--1.0

["'="'"1 [~[ co",

~

....,..,

SaHcylIc; ... 1<1

Figure 39.4 Metabolism 01 aspirin and acetylation 01 cydoo~ygeNlSe by aspirin.

genase activity, ~ diminishes the formation of prostaglandins and thUs modulates those aspects of Inftammalion in whidl proStaglandins act as mediators (see Figure 39.3). Aspirin inhibits inUamrnalion in arthritis. 001 il neither arrests lhe progress of the disease nor does it IndUce remission. (Nole: Acetaminophen, atthough a useful analgesic and antipyretic, has weal< lUlu·lnflammatory activity and Is therelofe 001 useful In the lrealmen! of Inllammation such as that seen with fheumatoid arthritis (see Figure 39.5). Acetaminophen is therefore discussed separately (see p. 412).)

b. Analge.if;: action; Prostaglandin Ez (PGE2) is 1l1ought to sensl· tize the nerve endings '0 !he aellon 01 bradykinin, histamine, and other chemical mediators released locally by the inflammalOfy process. Thus, by decreasing PGE2 synthesis, aspirin and OIher NSAIDs repress the sensallon of pain. The salicyIiItes iIllI used mainly lor the management of pain 01 low 10 moderate inleflsity arising from integumental structures ralller lIlan that arising Irom the viscera. NSAIDs are superior to opiolds In the management ot pain in which inflammation Is irrvoIved; combinations 01 opioids aod NSAIDs are ettective In treating pain In mll~gnancy. c. Anlipyretlc acllon: Fever occurs when the set-point of the anterior hypothalamic thermoregulatory cenler is elevated. This can be caused by PGE 2 synthesis, stimulated when an endogenous fever-producing agent (pyrogen) Such as a cytokine is released 'rom white cells thaI ale aClivaled by infection. hyper5ens~ivity. malignancy, or Inflammation. The SiI~cyIales lower body temperature in patients with fever by impeding PGE2 synthesis and release. Aspirin le5ets the "thermostat" toward normal and rapidly lowers lIle body temperature of 'ebrile patlenls by increasing heal dlsslpalion as a rasuR 01 peripheral vasodilation and swea1lng. Aspirin has no effect on normal body temperature. d. Rnpiratory actions: At therapeutic doses, aspirin Increases alYoolar wmtilatiOn. [NoIe: Sat;cylates uncouple oxidative prosphoryIation, wt1lctl leads to elevated CO:! and inmlased reiSptration.] Higher doses work direetly on the respiratory center in the medulla, resulting in hyperventilation and respiratory alkalosis 1hat is lIWIIlly adequately compensated for by the kictley. AI toxic levels, cenlral respjratory paralysis occurs and respiratory acidosis ensues due to conllnued pro
e. Gastrointestinal effects: NO/mally, plOStaeyclin (PGI 2) inhibits gastric acid secretion. whereas PG~ and PGF2u stimulate synll1esls 01 proteetive mucus In both Ihe stomach and small intestine. tn the presence 01 aspirin, these prostanoids are nol formed, resuking in increased gastric acid secretion and diminIshed mUCtJs protection. This may cause epigastric distress, ulceration. an
•

. . . . . .0 . . .' . '

.......

_'>

"

....

III. Nonslefoidlll Antl·lnflammatory Drugs

--_.. . _..... ,....".,.".

<0,

much as 3 to 8 ml 01 bIoocI may be lost n the reoes per day. [Nole: Bu1rered and enteric·coaled p.eparations are only ma~lnally helpful In dealing with this problem. The PGE, ~ Illlis<:f)l~. i$ used., !he Ireawnent of gasflic damagelnO.lced by NSAtDs (see P. 238).] f. EIlec1

on platelet.:

TX~

enhances plalttlet Iggregation,

...tIe< eas PGb dea yes it. low doses (60 10 80 mg daily) of aspirin can irreversibly inhibit ltlromboxane production in plIlelelS without mar1<edly &fleetiug T'XA, plodllCtion in the el o:UI4lia1 eels of Ihe bIoocI vessel lNoIe: ThB ace4yIalion of ~ Is ~,eoE''''''. Because 1*' Iet$ lID; rudei, !hey C8IYICIC syt III oesile . - enzyme, and .... Iadl; of Ihoomboll· _ persisIs lor the iteti",e of 1he plaleIet (3 10 7 days). Tlis contraSIS with the endothelial cells.. whid'I haYI nudei and ...etore can procb:e..- ~ . IM a resuIl of !he decrease in ~ ~ aggegation (the fitsl. Yep In Ihrombus Iormation) i$ reduced. pI~ an IlIl'k:oaglIlant efled

_.,

-

,

wilh a p!olo..ged b1e&~"il .-no. [Nole: ThB lIClions of aspirin aSln antithromboIic drug
Ii- Af;\Ion. on the kidney: Cyctoolcygenase i1l1l1bi1ols Pie'E'~ the synlhesls 01 PGE.!, and PGlrlrostaglandlns that are responsi· ble lor maintaining renal blood !loW. particularly In the presence 01 cll'Q.l\atlog vasooonstridors (figure 39.6). Decreased synthesis 01 prostaglandins can resuM In retention 01 sodium and water and may cause edema and hyperkalemia In some patients. Interstitial nephrilis can also occur with all 01 the NSAID$ e~cepl aspirin.

Figunt 39.5 Actions 01 NSAlOs and aOOlanWl<:phen.

Response of renal bk>od flood Ofsease states k!ading

to Increased vasoconstrictors

-

.,.--

-

.....• , •• • • • 1-/ ~' '0 • ,

, ,

---

Q

Figunt 39.6 Renal effect of QSPitin inhibitiOl"l of prostaglantlin synthesis,

-'~

I •'" "
(:"'--"';~)

••at ""'1'. . . . . . .10_•• _1 ........

~I~ to. . . . . ,

I......... '

_.-_.__.

, _ r"" ...

,.,.<_ ... _,.

'00

39. Anli·inllammatory Drugs

3. Thefapeutic uses a. AntipyretIcs and analgesic.: Sodium salicylate, choIifl8 salicy· tale (in lha liquid formulalion), choline magnesium salicylate, and aspirin ara used as antipyretics and analgesics in lhe trealment of gout, rheumatic lever, and rheumatoid arlhritis. {Note: Salicylalas are the drugs of choice in the treatment of rheumaloid arthri~s.l Commonly treated oonditions requiring analgesia incIlKle headache, arthralgia. and myalgia. b. btemsl spplicatlon.: Salicylic acid is used topically 10 freat corns, callUses, and epidelmophytosis (an alUption caused by fungi). Melhyl salicylate roil of win\elgreenl is used exlernally as a cutaneous counterirrit<mt in liniments.

c. Cl!rdioYalCular applications: Salicylates are used to inhibit platelet aggregalion (see above). Low doses of aspirin are used propnylaetically to decrease tne incidence of transient Ischemic atlack and unstable <mgina In men as as lhat of COfOIlary artary thrombosis. (See p. 197 for a further discus· sion of this phenomenon). Aspirin also raalitates ctosure 01 a pat8f1t ductus arteriosus (PG~ is responsible lor keeping the ductus arle'losus open).

we"

d, Colon cancer: There is evidence that chronic use of aspirin red.Jc:es the incidence of coloredal cancer.

4. Pharmllcokineltc:s

a. AdmInistration and distribution: Salicylates, especially methyl

o

Fi9ure 39.1 Dose-dependent elle<:ts ot salicylate.

salicyf8le, are absorbed Il1rough Intact skin, Alter oral aclmllllstration, lha unioniled salicylates are passively absorbed lrom the stomach and the small infcs~ne (dissolution 01 the Iablets Is favored at the highar pH of lhe gut). Rectal absorplion of the sarlCylates is Slow and unreliable, but ~ is a useful rOUle for administration 10 vomiting children. Sallcylales (excepl for diflUfliS8~ cross both the blood-bfain balrier and lhe plaOl!f1ta.

b. OoIage: The sali(.)'lates exhibit analgesic activity at low doses; only at higher doses do these drugs show anti·lnllammalOfY activity (Figure 39.7). For example, two 300 mg aspirin tablets adminislered 4 times a day produce analgesia, whereas 12 to 20 tablets per day p~ce bot!l analgesic and anti·inflamma· tory actilrity. Low dosages of aspirin (160 mg every othcr day) haw been shown 10 redJce the incidence of leclJfreni myocar· dial inlarctioo and to reduce mortality in postm)'OC8ldial infarction P81iel1lS. Further. aspirin in a dose of 160 to 325 mg'day appears to be belleficial in lhe prevention of a first myocardal InillfCliol1, at least in men over the age of 50 years. Thus, prophylactic aspirin therapy is advocated in patients wiItl clinical manifcslations of coronary disease if no specific contralndica· tions are present. c. Fate: At normal low dosages (600 mglday), asp",n IS hydrolyzed to salicylatc and acellc acid by asterases presoot in tissues and blood (see FIgure 39.4). Salicylate is converled

. . . . . .0 . . .' . '

........

_'>

, .... 0

0.' _

.. _

.....

."

III. Nonsteroidal Anti-lnlTammalO4 ~. lhe hepalie metabolic paltM8y sal<.nled. and zero..order kinetics IIl8 observed. with the drug having a haW. . of 15 hctr.; Of _ (FlliJUfe 39.81. Saturation of the hepatic enzymes r8qI.IQs lreatment lor ~llflII days co 1 - ' t . Being an 0f9iPC acid, sakytale Is 58Cl eled i1Io hi tAle and Cilfl affect uric acid aaeti:
beoof,_

5.. AdYene effect. &.

gg g

Gl: The most '~~""'.D"' GI ettects of lhe saIicyIales 8f8

bic cblress. nausea. and ~ . Mia06QOPiC Gl blee
(beooI,_

b. 8100d: Th. irreYllfSibie acetylation of platelet cycIooxygenase reduces the level of platelet TXA2. resulllng In inhibition or platelel aggregation and 8 prolooged bleeding time. For IIlIS ,cason aspirin should not be taken tor at least I week prior 10 surgery. When salicylates are administered. anlicoagulan1S may h8YlIlo be given in reduced dosage.

c. R.spl•• llon: In tOl
d. .....

t.

01

~lSBted

prvcnl!Ii·l..argadosesols l' .'

respiraIory

~acidit­

..tr.oe ~ The entl'll't OlOilioall. used lor It"e pmdi odion

OIl ATP is dksVtted as heat. ............ is lhe h)'per1heIn. rafSCd by WIlCfl taI<8n i'l Die q.,84i . f

•.

,'MPS

15% 01 paDenIs takirIg aspirin experiel'lee hypersensitivity reac1ions. Symptoms of uue allergy irdlde ~ b .. dlOCUlStJi<:tio<~ or ........elJlOlic «lema. F8IBI anapt,.lac1ic shodr.l$ rare.

H~~

I. Reye" .yndn;Nne: Aspirin given dlnIg viral ililec:tiool$ has been associ8led with an increased InddeilOll 01 Reye's S)'Ildrome, an oIttr'l liual, IuIminaIWlg hepalitis wiIto 08febral edema. This is especial)' enc:ountered in children. who theretore shwld be given ~ instead of ~ when sucIl medicalion 1$ required.

g. Drug Inlel1lC;tlon.: CoocomiTam administration 01 sallcylales with ma"y ctasses 01 drugs may produca undesirable sitle

ollCClS (F'I(/U,e 39.9).

1",3noUf5

Figure 39.8 EIlCCl of dose on lila hall·lile 01 aspirin.

,,,,,.,......,.,.<---,. "'"

39. Anti-inflammatory Drugs

Sallcylates

-8ln~n

Dec...ued unite excretion (contr8indicated In plllier!ts with gout)

~ ~~

Incre8_ piss..... concentr8l!on leadin9 to prolonged hlIlt-llvetl, thel'apeuUc etIect.. 8nd loxlcUy Figure 39.9 Drugs interacting with sal~lates.

6. Toxicity; salicylate intoxication may be mild or SB"8re. The mild rorm is called salicylism and is characterized by nausea, Yllmitlrlg, marked ~tilation, headache. mental oonfusion. dizziness. and tinnitus (ringing or roaring in the ears). When large doses 01 salicylate are administered, severe salicylate Intoxicallon may result (see F"Igure 39.7). The symptoms listed above are followed by restlessness. delirium. hallucinations. convulsions. coma. respiratory and metabolic acidosis. and deatll trom respiratory fail· ure. Children are particularly prone to salicylate intoxication. Ingestion 0' as little as 109 of aspirin (or 5 9 of melhyt sa/icyfa/e. the lalter being used as a oounterirritant in linimentS) can cause death in children. Treatment of salicylism shoold include measure· pH to determine ment of serum salicylate c:onoontrations and the best form ollherapy. In mild cases. symptomatic lreatment is usually suHident. Increasing the urinary pH enhances the elimina· tion of salicylate. In serious cases, mandatory mellSUres Include the intraver10lls administration of fluid. dialysis (hemodialysis or peritoneal dialysis), and the frequenl assessment and corrOClion of acid-base and electrolyte balances. [Note: Diflunisal does not cause salicylism.)

0'

Ibuprofen {eye byoo proe fen) was the hrst in this dass of agents to become available in lhe United States. II nas been joined by IUIfHOXBfl [nah PROX enl, fenoprofen [fen oh prce fen), kafoprofen [key toe proe mn), flurbiprolen [liur bye proo mn). and oxaprozin lox ah PAOE linl. All of tI1ese drugs possess anti-inflammatory. anal· gesic and antipyretic activity and have gained wide acceptance in the chronic treatment of rheumatoid and osteoanhritis because their gastrointestinal etrects are generally less intense than Inat ot aspirin. lhasa drugs are reversible inhibitors of the cyclooxyge· nases and thUs. like aspirin. inhibit the synthesis 01 prostaglandins bul not that of leukotrlenes. All are weft absorbed on oral admil1istra-

•

. . . . . .0 . . .' . '

• <..... - - - " , _

.... _ _ ,.

.. _

.....

Ill. Nonsteroidal An~·lnftammaIOfy DrOOS tlon and are almosl totally bound to serum albumin. [Note: Oxaprozin has the IOngeSl ha~'~ and Is adrmstered once ooity_l They undergo hepatic metabolism and are excreled by the k.O!ey. The most common ~ elleet is oast'oil
1... oclofnelt>Kin; llIls NSAIO is more potenllhlln aspirin as an 8fIli. Wlammiltory agent, bill ~ is inIerior 10 itIe salicylares al doses !derated by rheumatoid arthritic patients. In eef13in Instances, hOw8¥e' (lor example. with acute gouty Ilfthritis. llr'IkyIosing spondyIili$, and ost.eoarhilis 01 the hip), "Idomethacin is more eltective in ,elielo*lg inIIIIrnrTIation itIan Is ssp;m or any 01' the 0Ihef

NSAIDs.

L T1IentpJtltic uoee.: Despile lis pol8llC'J' as iII'l a'IH,,~1ai,.'lalOlJ' ...... ~ : s bdciIy Imts its use 10 the namert 01 the tx. .itioilS described -.:-. "lCb,~ is also benefi· cialin the control OIl pain as"""""wt wilh \MliIis and p'S"~­ ative ophlhatmic procedures, and as an antipyretic lor Hodgkin's ellsease, wl'le1l In. !eve. Is .elr8ClOfy 10 other agenlS. Ul<e ssp;ritJ, illGb,le'I'haoI'l can delay labor by supPfes5lno uterine oonuaetions. II is aI$O eflecliVe In treating p8ler1I cloctus Ilf1l!riosos. b. ~ ; IrJd:me(hac::in Is rapi(Iy and almost: c0mpletely absorbed In:lm the GI U3d afIer oral acllliilislla-

""*

tiofl. II is metabolized by the Mver. Unchanged drug and metlIbolIles are 6.Jlcreted io1 bile and lrtle.

c:. AdYene en.cta: AdwIrse effeccs "'" ilCb,ef'olIl:lin ocos ., l4) b 50'% OIl palienl5 treated; approUnaIely 2O"Jl, lind !he ad\Ierse effeccs 10 be i",*,,_ (f9d 39.1 0) IIOd (b:alli LIII use d t>e drug. Mosl8dll8tse eIleds 1lAI" I ,elated. Gl O)f,~1ts oonsisl 01 nausea. 'IOi'illil(j, ........... lIarrhea. and alxb,lilial pan Uloeraliol, dille upper Gt lraCl can OCOS, !iOO'eIi'leS ..... perto. ration arod l\efTlOf'fNgll. The most _ e and frequent CNS etlecl is frontal her :ladle, ¥otkh o:x:urs In 2S 10 50% d pa1ierts ...tIo ct...dcalty use .lCb1~ Olt'er tr~ CNS eIIecIs are daiI e5S, Yl!f19l. ligtII-neadlldl and manlaI confusion. AoIIe p;n;:reatilis has been knoWn kI 0lXU'. Hepatic eI1ects are flIfe. tr..rl some lalaI cases ct t'i8pa1itis and jaIrdoB I1a\Ie been reported. Hemalopoietic reactions repor1ed with i'Id:trnettIIIc Include neut,0peni8. th~ and (flIf~) aplasticanemla. HypersensiliWy reactions i"lcUle flIShas. urtiearia. itctWlg. !lCIJle altad<s ct IlSlhma, and 100% cross-mactMty ....,jth ssp;rn ConQJffent 80111nlSlration of Indomelhacin may decrease !he iII'llilypertensMI e11oc1s d fu/ClS6rl1lide, tha tI1ilQil:le (liuf(!lics, IlbkxtJng drugs and ACE irNJ/tora 5

Figure 39.10 Some advef!8 effects of indomelh8cin.

."".,........ ,

.. -... _,. 39. Anti-inflammatory Drugs

2. Sullndac: Tills Inactive pro·drug Is closely related to indomelhadn. Metabolism by hepatic microsomal enzymes pr0duces the acWe form (a SUlfide) 01 lhe drug, which has a long duration of action. Although the drug is less potent than indomethacin, ~ is useful In the treatment of rheumatoid arthritis, ankylosing spondyUlIs, osteoarlhrlHs, and acute goul, The adverse reactions are similar to bot ~ severe thart thOSe 01 the Oltler NSAtDs, ~uding indomelhacin. 3. Elodolac: Tnis drug has effects similar to those of the other NSAIDs. Gastrointestinal problems may be less common. Hcmever, otl1er adverse effecls such as fluid retenlion and abnot'· mal kid1ey and liwr function have been repo
Presently, ooly piroxicam [peer OX I kam) is available In the United States. Other members of lhis groop are being lested and may become available. lis mechanism 01 action has not been established, bot pirw:icam is used to treat rtleumaloid arthr~is, ankylos· ing spondylilis. and osteoarthritis. Its mean hail-life 01 50 hours permits administration once a day. Gl disturbances are et\COl,Jntered in approximately 20% of patients. The drug and its metabomes are IIJCcreted in the Urlne. Piroxicam C3l1 interfere with lhe ret1al excretion of IilhilJ11l. E. Fenamates Mefenamic acid [mall FEN a mick] and nwcJoffJnamale [meh KLO fen a mate] have no advantages over the other NSAIOs as antj· inflammatory agents. Their side effecls, such as diarrhea, can be severe and associated with inflammation of lhe bowel. Cases 01 hemolytic anemia have beef1 reponed.

F. PhenylbllUtlone

Phenylbutazone [fen III BYOO ta zone] haS powerful ant~lnflamma· tory offecIs but weak analgesic and antipyretic activi~es, If is not a firstlir.e drug. 1. Therapeutic uses: PtlenyIbuIau0n6 is p!"escribed chielly In short· term therapy 01 acute gout and in aeule rtleumatoid arthritis when other NSAIO agoots have failed. The usefulness 01 phenylbutazone is limited by Its loxicity. Aspin'n and newer N$AIDs are Sup&nor to phenyt~In most applications.

2. Pharmacokinetics: Phenylbutazone is rapidly and completely absorbed after oral or 'ectal administrallon. OxyphenbJtazono Is art active metabolite and contributes to the actiVity 01 the parent drug. Uke most 01 the other N$AIDs. phenylburarone is e_tensively boUnd to plasma proteins. This property causes displace-

..........,., .. _--,. menl. 01

wartam, ooaI

~

• ""'" • _ _ , """'
." and

r.g sites 0fI pIasrna ~. ~

$IJIlOnarI'i(Ie !rom bFd~ . . .lions .. \he

free l,adO' 01 \tlese drugs. 3. Actv_ .neel.: ~ Is poorly klleraled by many paIienl5; ~ effects ocaw .. nearly one hllII of Iho6e Ifeate
Go Other agents 1. Diclolenec: A cycloo~ygenase Inhibitor. dicJoIenac [dye KLO Ie naklls approved lor Iong-letm use in the lreatmeolt 01 rheumatoid arthritis. ostOO8J1hritis and ankylosing spooclil~is. Ills more potent than indomethacin or flaPrc»r6rl. An ophthalrric preparation Is also available. DicIoIenac ac:etJITI(jlales in synovial fluid. The urine is \he primary roule 01 f!l(aelion lor the drug and its melabolites. Its kOOcities Rfe simiar 10 those 01 the other NSAlDs, lor eJlarrPe, gaslloilil Slioall""otAems areGOl"'u,. and \he drug can also gve

rise 10 eIevaled hep8Iic enz)'Tl81ew'e1$. 2. KelorolK: TNs drug acts Ii<e lhe CIt.- NSAlDs.In ...1jI'" to lhe oralllJlM, klHllldiK: {key TOE row IBkI can be ad".liYered i'ltraml'S"Mrly in \he IrealJTlefll 01 po&tOpefalM!! pain, and k)pial~ lor allergic conjl.WlClMlis. K8klr00c I.'Odergoes hepali: melabolism; !he drug and its melabolites ar. eliminated via !he lrine.. It causes !he same side eIfeets as the other NSAlDs.

_............

3. Talmelin end I\llbumelone: Tohootln ["TOLL me lin] and na.bvmetone Ina BYOO me lone] are as polenl as aspirin in lreating aW~ or iuven~e rf1eumatoid arthritis Of osleoarthritis. but may have

(See FlQUfe 39.12 lor a !lUTIffillrYoIlhe therapeuIic ~ ~ 01 rnerrbers dille NSAlD tamty.)

~

See pp. 466-467 b a desa,*", 01 nEMfy ~ COK-2 WIbIor• •

I

(-t>

IV. NON-NARCOTlC ANALGESICS Noo-narcolic analgesics, unlike \he NSAIDs, have little Of no anti·inflammalory activity. They have a. thetapeutic advantage over nan:otic analgesics in tha.llt'ley do nol cause physical dependence or tolerance.

.,..,.,........,

.. _... _,. 39. Anti-inllammatory Drugs

'412

Therapeutic adv. .teges of selecb!d NSAIDs

Therapeutic disadvantages of seklcted NSAIDs

....... '.[. , -~--

1::..-1'..· ·. · · · ·. ·.· · <"........" .....

-_--.... -.

,...... .~........,..-oNr ~-

CNS_

....", ,

l>aicw

,

1""''''''''''''

."""

--............. .•='" '" .... _ --_.,..-

........ £ a . -

Pytatoln.:

. . . . . . . . . . . . .J=.,..,=, I ......·.,.·.·.·'. '. ·1 I l _ GI irrilIlion .... ~

~ldcl!BC etJc IlClds:

,.....

Fa.,

~ ~=~-.g

) , ,

_

~

111:

Figure 39.12 Summary 01 noosteroidal anti-inllalnmalory agents (N$AID$). A. Acetaminophen and phenacetin Acela"oi~(e seat a MIN oh ten] and phenacefin [Ie NASS e lin] act by inhibiting prostaglandin synthesis in lhe eNS. This ecp6ains theW arwip(reljc and ar'olIlg . properties. They have less efteCl on C)'doooYgenase ., ~ 'issues. wtlidl aocDUnts for their weak anti-inflammalory aclivity. AcetamInophen and phenItcetin do not atlect plalelet U'lClion or;,o 8se blood cloning time, and they lack many 01 the $ide-ef1ects of aspirin. INote: Phenacerln can no longer be prescribed in the United States because 01 ils potential lor renal 1000icily. However, it is present irl

some proprietary preparations.!

1, n-&peutlc: uses: AcOOmklopOOn is a suitable substitute for the analgesic and anlipyretic etlects 01 aspirin irl those paIienIs wtth gastric lXln'¢lints and in those for wtoTI prolongBlion 01 ble ;lji'll lime woukI be a disadvantage or who do no! require the antiinIIatrmalory lIdion 01 aspIrtl. lNote: 8ecal15e of its Iowet lmlidly. ~ has repIal:ed ptrenaoe6n in virluaItt 811 hea """, products J ~ is Ihe ana'gesic-antippelic of choioe for dillcll... ,....., WaI i ......... or d'IidIen poll (recallhat aspiYI increases the risk 01 Aeye'$ $yndrome, see p. 407). Aceta" • .....,... does not an&agcrize flB unc::os...lc agenl plooenedd ancIlhefet;lre may be used in patients wilt! gout ~ hlI drug.

.... '0...,., •• _ .... _ , .

.~

_----,- -

..

-

- . w·

2. PhaffTliOCOklnelb: Acetaminophen is rapi(Iy absof'bed In:lm the Gttracl. A signil'icanl first..pass metIlbolism OCClJfS in !he luminal cells of the lrlles~ne and in the hepatocyte$. Prlenacetin is largely conve
f'9,Ke 39.13). the urine.

AcciClw'."""'IWI a-d its mlMlIboIiles are eJlUeIed in

~

-,j. CIH

r........

...."..,

3. Advefse et1ec1S: With normal lherapelJlic doses. 8C(lIanWlop'Jen is Wtuafy nee of any signili""i1t adverse eIIects. Skin rash and minor BIB gic radiulS oor:u intlllq.lefllty. n-e may be minor a/leralions in IeUkoc:V'e CCJUr1.. bUl1hese are gene

~-

"""'" ~Q---~

o ~"':'c:*'

ado,'

V. DISEASE-MODIFYING ANTl-RHEUMATIC AGENTS In contrasl 10 !he N$AlO drugs desaibed eafIier. remiltive fefTlission~ artIYiTis li'ugs are stow-ar::Wlg. They do not .a by Wlibitrog

cydoarygenases and may haYe no Iillle""',; or ~ a;:UviTy. These li'ugs are t)Sed pWna~ Icr rtleurnalic dI3Ofders. especially in cases whl!f8 the inflammation disease does not lespond 10 !

cycloo~ygenase

inhlbllorS NSAIDs. They disease·modltying anllcourse 01 the disease and may can induce re" .• ~ preooaltioig Iurther destruction ot Ihe jc*lts and irMlMld tissue. They have a long onset ot adion, sometimes taking 3 10 4 fl"lOfllhs. Their onset 01 action maybe !,4l1O S8YI!faI months. ~ agetU (DMARDs) slow Ihu

.... Gold Nils

GolcI ~ .... Ihe ottw dn.Igs ., This ~ c.n:Jl rtIPBir existing dartBge.. Rather. Ihey can oriy plewa. IOOher ~ The cufe01l1y avaiabte gokl pt"epalllion5 ale gold socIcm fhiomaIala, aur0thioglucose. and 8ur8flOfin II is belieYed thaI gotcI salls are laken up by macropOages and liUppfess phagocytosis and lysosomal enzyme ~ Tljs meet... _" retards Ihe poOQI .• , ot bone an:l1ll'1ic:Uar destr\.diOn. e:-e- meet__ ,IS have also been propo&ed..

1. Thanlpeutlc 1lSft' The ma;or lISe ot gokl salts is ., lhe trealmenl of rheumaloid arthritis thaI does not respond 10 salicylales Of

Agure39.13 ~2botism of

ac:elalT.q:tlEn

"""W"""'_"''''-''

'"

39. Anli-lnnammalOfy Drugs Olhet nonsteroidal anli-lnllammalory therapy. They are the rnosl etfective agents tor the
wilhouI serious Ia
B. Chloroquine lind hydroq-chloroqulne

The pharrll8OOlogy 01 these drugs. which are also used in the treat· ment ol maillria, is presenled on p. 351. The medl8rW$m of their anlHnl\aJrmatory activity is ~in. Besides inhibiting nuc:IeC acid syrd)es.is, they are known 10 stabilize IysosornIIl rnemI;lrane$ and lr8p tree radicals In lrealing lnlIanvnalOfy cisorders. they are r--.ed lor rheI.maIOO arttnis !hal has been l.I'lIespor.w..e 10 !he NSAIOs or else Ihey are used in conjl.nClion with Ill'1 NSAID, whicto dows til kJwer dose ol dIJoroquine or hydfoqdlJofoquine 10 be adrrinisIered. These
C. 0

Penk~1lImine

D-Pet. 'I niPrelPen i SIll 1I _1.

-'Og of !he arTWlo acid cysteine. SlOwS the plDglsss ol bone de$truclion and rheumalOid arthrilis. lis rnactwVsm 01 action is ~. but rheomaklid tador levels IaII with administralion. PIOlonged lrealment with penicillamine has serious side eI1eas .
belore use 01 corlicosteroids h8S been lI11empled. INota: PenIdI1amine Is used as a chela.ling agent in the treatment 01 poisoring by heavy metals. It Is also 01 ber'IeI~ in Creating cystinuria.]

..... '....'., .. _............ ,. VI. Df\lgs

E~

'"

in lhe Trealmeo1t of Gout

D. MethotrelUl!e Melhotreufe [melh oh TREX ate] i$ used 10, the treatment 01 patients with severe fheumatoid arIMIis vmo haYe ncl ,esponded adequalely 10 NSArDs and at leas! one other slow-acling agent Response 10 rneltIolrexBfe oa:uni sooner lh8n Is usual lor other sic r ti", agenlS-
tlyJl

.." .

::+0-"',

-

-te _

u •

'd

'd

~-

au-

See p. 467 lor a deso""lioi, ofl'll!My appI'OYell drugs used in treating rheumatoid disease

VI. DRUGS EMPLOYED IN THE TREATMENT OF GOUT Gout Is a metabolic disorder chamctetinld by high lBll8ls olurlc aticl in the blood. This hypeMil)emia reSlJRs in the depOs~ion 01 crystals 01 sOOium Oilile In tissues, especiaUy the kidney and joints. Hypeniticemia does nol lllwayS lead to gout, bot gout is aIw8ys preceded by hyper' u'icemla. In humens, sodium urale is the endproduct or pu,ine melabolism. ~ The 0ep0siIi0n 01 urate Cf}'SIals initial" 811 inllanYnalOry process moMng the inlillralion 01 granulocytes thel phagocytize the utlIte crystals. Tllis process genero!" UiCYliJIlfl metabolites. wI*:h damage dssue, resulting in1he re6ease of !ySOSOfTlllI enzymes lhat eYOI<e an inIlan'wnaIOfY fl!SPUilSe. In addi60.., lactate prod' 'dian in lhe synovial Ms,*, increases. The resulting IocIll decrease in pH losters fui1hef deposition of uraIe crystals.. (500 F9I'e 39.14 Iof a ~ of this ploe s ) The cause of Ilypen.ft:emia is tlI"l 0\ ec po\"" IC'ljon of \Iic relaliYe kl 'tie patierV'$ 8biIiIy 10 eJlO"N it Mo5I 1lenIpe'" straIegies tor gtll..t irM;M IO\flIef'ing lhe uric acid IiIMIl baow if1e ~ poW. . . . ple'lnOng the "epos!O;)n 01 urale crystals. ~ Cllf1 be aocompWled by (1) inIec1eliolg ¥Iilh uric add SY"" . with ~ (2) ilo E'Sing uric acid excrelion wiItl probentJQd Of ~ . (3) il~iIliIii"" Iel*ocyte entry ioVO the 'flecled joio"II wifl ",ddlidue. Of (4) ad"M1istJ1llion of NSAlDs.

--" .. .,(._.HI ,.

_ < A ..."

.....

-*'

A. Treellng KuIe gout AaJIe gouty anacl<s C31 resut tmm a noo1ber 01 OOUdtioolS, if1dud..ing llIlCeSSiIIe 8Icohol ~. II die! rich in pumes. or kidney d1seaSll. Acule llllacks lire trealRd wi!h colchicine 10 decrease ~ of grarUocytes into the alfeClod lilfea, and ¥lith NSAlDs to decrease pain and inIIammalion. [Note: Aspft'1 is conb'aindialted, because It competes with uric acid lor the organic acid secretion mechanism in the prOlllmaltubole or !he kidney.]

_

::'!";\':.'~~

... ",..,.."..,-J

---,.~ ..;,:",:;;'=---Flgure39.14

Role 01 uric acid in the inlIammation d """.

'"'''''''' ..... ,

'"

.. _...

_"

39. AIlti-inf1ammalOry Drugs B. Treating chronic gout

can be ca"sed by (1) II genelic deIect, lor eK8f!1)Ie. one r8Sl.Alil'lg in atI increase in Itle l8le 01 pwine 5)'1111 nil (2) renal defio ienty, (3) l.esd1-Nytrlwl s.,ilcflo"'.... or (4) e' sT. syntl sjs 01 Uric'" tlScocia1ed ...... cancer ~ Treatmenl $lJ1lIlIgies lor chronic gaul indude lhe use 01 uricosuric drugs lhal increase1he excretion 01 uric acid, Ihereby reO.Jcing its c:a1Oili1b. lion in plasma. and the use 01 aNopurlnol, which is II seklctiYe irttior ollhe lern'*lal S$et)S in the biosynlhesis 01 Uric .:ill Qworie gotl

C. Colchicl..... CoIchII;;IN lKOl c:t1i seen]. a plant alkaloid. Is reservecllor!he treatmen! ot acut.. golrty at1ad<.s when they occur. It Is no! a urloosuric

nor In 8M1gesic agent, although it relieves pain in acut.. ItltlClcs 01 goul. Cck;hicine does not prevent the progression 01 goul 10 acute gouty arthritis. bot ~ does have I suppressive, prophylactic eHeet thaI reduces lhe frequency 01 acute Iltadls and reliews pain. 1. Med\enIsrn of action: Co/chic:ir-e birlds 10 IllbIJin, a ~ prolein. CIlU&ing its depoIymerization. This lions. soctl tIS lie mobiily 01 ~ thUs decreasing their

miglalion no the afledecl ....... Fur1tletlllOie. cddtid"el*ld<s eel tIvis10n by binding 10 m.oc;c;: spidl 5 Cc&I"'1e alsO rHbils !he synlhesIsend r I : SI ollhe ~ (see filp'e 39.14). 2.

~ uses: The 8flti..inIarTma1Ory ac:tivily 01 ~"'18 5 speciIc lor gout. usuaIy alleYialing lhe pain 01 aa.ae gotl within 12 hoIn. n Is only lWei)' etlecliYe in 0IhlIr kinds 01 ar1hriIiL

3. Pharmacokinetlcs: CaUtioile Is 8O:Iliilis1ered Oldy, Iollowed by rapid abeorplion Irom Ihe Gl Iract. It Is also available oorllbilled oMth prob6rledd(soo bek:lwl. CoIctIidIlels rocyded in the bile and Is exaeted unctlanged in Ihe feces or orne.

4. AdII8tM flfeet.: Cok;l1iclne treatmenl may cause nausea. vomi1. ing, abdominal pain, and diarrhea (Figure 39.15). Chrooic lOOJio. Isll'alion may lead 10 mYQP8.~. agrlll'UocytOOs, apIasIjc anemla, and llopecia. The drug should not be used in pregoancv. end shoulcl be used wilh caution In patients with hePatic. renal or car-


F"tgl.n 39.15

SOme adve<se etIects 01

~licille.

AIopc.ri1oI [. oh PURE ; noIel is I PtP'I8 analog. It .to'Oes !he Pf"!"'1I"tion 01 Uric acid by c:alopetitivety li.ibiliilg the Iasl two SlI!lp5 in uric acid biosynlhesis. ..tic:tl 8rtl catalyled by xanltWl8 (l'" e (see F9l'e 39.14).1Nole: Uric ac:ld is less water-soluble IhIn its precursors. When xanlhine C»liclase is inhibited. !he circulating por;ne derivatives (xanttWle and hypoxanltWle) are more soluble and lt1eretooe are less likely 10 predpilalej.

'S-II.• '8 lot - . . . ... --':"10 _

bolol
<."" .....,.,.<- ... _,. VI. Orugs Employed In The Treatment 01 Gout 1. Therapeutic uses: Allopurinol is elleclivf:l in the treatment of primary hyperuricemia 01 gaul and hyperuricemia secondary to other cond~ions. such as that associated wiIt1 certain rnalignanc>es (those in \\ltlich large amounts of purines ara produced) or in

renaJ disease. 2. Pharmacokinetics: AIIO(Jt1rinoi is COfTllletely absorbed after oral administration. The prima1y metabol~e is aHollanthine (Ol" pressant, azillhioprine, requiling a redvction in dosage of these drugs. E. Uricosuric agents: probe
Probenecid [proe BEN e sidl, a general inhibitor ot Ihe tubular secretion 01 organic acids, and sulfinpyra:rone [SUi lin PEER a mne], a derivative of phenylbulIHOlle (see p. 411). are the two most commonly used uricosuric agents. At I!lerapeutic doses, they blod< proximaltl.tlvlar resorption of uric acid. [NOIe: At low dosage. these ageolS block proJlimaltuboiar secretion 01 uric acid.) These drugs have tew adverse eIIeclS although gastric diSlJess may Iorce rnsoontinuance of svlfinpyrazol1e, Probenecid blocks the tubular secretion ol penicillin and is sometimes used 10 increase levels oltha antibiotic. II also inhibits ellcrslion of naprollen. I<efopfofen. and indomethacin.

,""'-,"" .....,.<- ... _,.

'"

39 An~-inflammaIOfYDrugs

Choose lhe ONE besl answer.

ComK:I choice. O. ~ """ nol IIf'IIagllRze \he urIcllaurIc -oerI p_1IICId and lherelOO'e ....1' be UMd In patlenta .... goul,

39.1 In whk:h one 01 Ihe lollowlng condilions would

Acelamll>Ophen has lillie anlHMlammatll<j'

asp;.... be conullindicahld?

etlecI, bull\aS anaIgasic end .'lipl,elic IlC'Mm equ8l1O _ of upIm. II • "'" ........... an"pyrellc of choice lor child,en wllh vl,al

A. Myalgia

B.Feve'

Infec'lon.: e.porin c.n II'\(,NSe Ihe risk fo< Reye'. syndrtme In dlIldren. - . , . " " ".., 1& • luileble subelilule fo' the analge.lc .tId anlipyrMic et!ects of a5l'i"" In thoa pa_ IMth gas!fIc ~

C. P8plic uIoe'

D. Rheumaloid IU1tIriris E. Unslable angina

w.' • C. Am""g Ih. ,*514.10.,

Corr..:t .... ~ .. .....:JIll!

_ lor caIIirG gMD!I: intaIllln.l\aJ*IIll& " .. ~ _ .. u.ed 10 'educe mu.cl. pain. II al.o ha. .. . . . " , . IIl:lillnr; can be .-110_ ........ eac... d . . .lti-lo " """"'" _ ~ • .-lIO_peln lC .... 10Iloo..' ......" 1"(: Ill< -.,la, i'1 _.

39.4 Which 01 fhe following statements conce,nlng gold

IIl>'"•

...~sls

m.nl of "'eumelllld arthrills. Low ooaea '"

"'1'''.110 d&a

iact>amlf;: ar1ad<&

"!tie .. I(I(leo iC8

d Ino

CORRECT?

A. They may provldc Immeo:*ate ,clle! '" arthtilic pah B. They acI by InhOiting proslaglandin synt!>esis, C. They f""lue
. •

Corroct _ _ • C. Got! _

39.2 Ovttrdoses of salicylale. lead III all 01 the tcllllwing

"'"'Y not prtMde

0nprCYell1ent .... ""'" _1lI _

01

EXCEPT:

~

f<. Nauaea and vomiting.

adm-.ckln. They are Il>oughl III _ ... phlIgoCyIllaiI ar
B. Tonn~us (ringing or ,oaring in !he ears). C. Marl<1Id hypervenlilali(ln. D. Increased melabolic ,ale. E. Inc'"",,,,, In blood pH.

eon..:. _ .

[_ _ _ ao:::!dllIIa

~ Gc*l_1II'II UMdIn ~ ar1tl,i1ia that
f
E. 1'zI ......roo- d salic)'IollIll

J_

39.5 Which of !he following;'; INCORRECTLY paIre
39.3 f
ca........ "ontal headache. Long haH·lifil ""'mils daily or

A, Indllmelhacin:

SoA<>dac:

C. Nap'0""":

EXCEPT: A, II Is a asPirin.

weak., anll·lntlammalory agent lhan

...,

B. II 'edt.ces f""'" '" vi'8/ infections In c!1ildren. C, If is an aspirin subslilUle In pallent. wilh ptlpIic o II exacelbales Il"lJl E. II causoa hepatolO.ic efIects 81 high dll$e$.

'see p, 1r.'1n l1li ' _ olIN
0, PhenytJutazone: E. Aspirin:

Correct _

~

\twl

twIlla dalty do6ing Bette' l(lIemled lhan aspirin in 80Me patients Less lOXic It'Ian aspirin Can ceuse GI symptoms

• D, Pl>enyt>uW:one I, """e

~

and _

ba ..-:l ""'" __

'"" lOIdc agenIS have proyen .. illI'Jeai.....

(2nd 811) "" ....... _ .. - .

P. 3G01n l1li 1_ _ • (2nd ed.) "" ..... , Ie • oIpoaIna ...............

'see

p.308 ... .., 1.'_. (2n
Laao:l' N',tIao. ~

•• ~, 10• ..,., . . . . . . . . . . . . . . . , >

• <0_ M _ _ - . - . . . ' .....,.... . . _

.....

Autacoids and Autacoid Antagonists I. OVERVIEW Prostaglandins, histamil'\ll, and serotonin belong to a group or com· pounds called autacoids. These heterogenous substances have wi
AUTACOIDS PROSTAGlANDINS

-' ._n _ .....

I

" '-""-

-

H, ANTlHISTAMlNES

I

~_.

Fe~_'

II. PROSTAGLANDINS Prostaglandins are unsaturated fatty a£id derivatives that act on !he tissues In"""'ich ll1ey are synthesized and are rapidly metabolized to inaclive products at the site 01 action. The biosynthesis and actions 01 the prostaglandins ale presented on p. 402 and Figure 39.3.

-

H:t AtmHlSTAMINES

I

C;merldi""

~-

_r_

A. Therape\rtic uses of prostaglandins Systemic administration 01 prostaglandins evokes a bewildering alray 01 et1ects, a fact that lim~s the therapeutic usefulness oIll1ese agerll$.

-

DRUGS USED TO TllEAT MIGRAINE HEADACHE ~

Dif>~do

1. Abortion: Several of the naturally occurring prostaglandins, such as dinoprosl [DYE noe prost]. dinoproslone [dye noe PROST one], and cartJoprosl [KAA boa prost], find use as abortitacients (thaI is. agents causing abortions. Figure 40.2). Mi$Opfoslol in combination with me/tJolrexala is particularly e!lective in tBfrrOrlating pregancy in !he first trimester.

.... ,...._

' 'Me"'r--l/idO Figure 40.1 Summary 01 drugs affecting the aUlacoids. 'Described in Pharmacology update. p. 470.

........-----..... _c.O,_£-. ........J.-._.............. ' - - _ 0 _ " ' , .. PAC......

419.

'''''.r''' ..... '.<_ ...

_,.

•

~

•••• ' 0'"_ _" " ' ' ' ' """"",,,'" _

''''

.....

40. AutacoKls 2. Peptlc ulcers: MisoproSlol [MIZ 0 prost 01] is a synlhetic prostaglandin E, analOg used to inl1ibillhe secretion 01 hydrodlloriC acid in the stomach II produces inhibition 01 gastric acid and pepsin secretion and enhances mucosal resistance to injury. Misoprostol is particularty useful in patients with gastric ulcer who are chronically taking nonsteroidal anti-inllammatory agents (see p. 238 lor a more compIele discussion 01 !his drug).

Dinoprost. dinoprostone. carboprost, misoprostol •

AcI dIrec1Iy on m_ y_ to """-c:onlraC_ lobor.

•

_ InlnIwyIrIaII-..eKIo_ ....... loby I n _ tr_ h 12lII _ ItJrouvh tho """""" Of

3. Erectile dysfunction: Alprostadil injected iIllO the corpus cavernosum of the penis provides elfective treatment 01 some forms 01 male impotence. The drug incraasas arterial inflow through vasodilation and decreases venous outfloW by causing relaxation 01 tha corporal smoolh muscle that ocdudes draining venulllS. Possible side elfeclS includa pain at tha sita 01 injeclion and, rarely. prolonged erection.

~-_.

•

_ .,.1._. . . _111...-..

MiOCf"Wtoilnoomblnl_ _ In .......1rwtIng I'f"IIM'IC'Y In tho

Ill. ANTIHISTAMINES Hislami1e is a dlernical messenger thaI mediales a wide range 01 celuiar responsllS. including allergic and inllammatory reactions. gaslric add secretion, and possibly neurotranSlrission in parts of the brain. Histamine has no dinical applications, but agents lhal interfere 'o\liIh the acDon of his· tarrine (antnstarrines) haVe important lherapeutic applications. A.locatlon. synthesis, anc! release 01 histamine 1. locallon: Histamine occurs in practically all tissues. but it is unevenly distributed, wilh h9\llf\'IOI)I"l!s Iound ill lung. skin, and the gastrointestinal tract (siles wI1era the "inside" 01 the body meets the "outsiclej. II is Iound in high concentration in mast cells or basoptlils. Histamine also occors as a component of venoms and in seaetions lrom insect Slings.

Mlsoprostol •

._ _ aI HCI.nd _,n _ rnuCOUl

...10_.

F'9ure 40.2

Therapootlc applications 01 prostaglandin derivatives.

2. Syn!heals: Histamine is an amine formed by lhe decarboxylation 01 the amino acid histidine (Figure 40.3). This prOCl!SS occurs primarily in the mast cells. basophils, and in fha lungs. skin, and gastrointestinal mucosa---Ihe same tissues in wtOch histamine is stored. In mast cells. histamine is S\ofed in ganullls as an inactive comple~ composed of histamine and the poIysulfated anion, heparin, along with an arnonoc protein. II histamine is not stored. ~ is rapidly inaaivated by amine OlCldase enzymes. 3. Release of histamine: The release 01 histamine may be the pri. mary response to some stimuli. but most often. histamine ;s just one of seYerai ch&micaI mediators released. Stimuli causing the release or histamine Irom tissues include tha destruction 01 cells as a result of cold. bacterial to~ins, bile slirlg venoms. Of trauma. Allergies and anaphytalCis can also lOgger release 01 histamine. B. Mechanism 01 action 01 histamine Histamine released in response to the stimuli just described e~erlS ~s elfeets by binding to two types 01 receplors, designated H, and

...........,.' ..

,.

_

.""... .....-_.. - . ..... ,

Ii.!. lQcaled on the surtaees 01 cells. SOme 01 hislaminofl wide range 01 pharr'l'laOO'oglc etlect$ are medaled by bolh H, and Ii.! rBCeJ*lrs, whereas oltoers are mediated by cny one da$I (Figure 40.4). For example, the H, f'1lOlIJI*lfs are .lIpo,tan! in prlXIuc:rog ~ ITI,I$<:Ie tultlactiu, end inooeasil'lg capiIary pe" abMy. ~ pro. ITIO'eS • .Ijla...... by causing 'AlP" It,,, .. oOOCllllllil.rn to ,!' as. rWIric odele: tns d"Jeo,y tigniiII diffuses to Ile 'AlSON' so,iOOII'I roo&de whare it stimulales cGMP production. causing vasodilation. I rsta , Ii.! "'lJ'OIs meclate gaslric acid seoetion. The tv.o hisIarnine ' s BlI:E!f1Ihair efleds by dir""... second " over pathways; lot eJl3fTIple. binding of an agonist 10 lhe H, reeePlDf stimulates the intraoellUlar actiYity 01 lhe po!yphosphalidylinositol pathway. whereas stmJIalion 01 Ii.! recepIOr$ emanoas the prod.» lion 01 cAMP by aderly1y1 cyclase (see P. 33).

N~N

1--

DO,

". •, "'OH I' ., ..

co,

--J

,

, ""'

H.N CH.

There is a similarity between the symptoms resutlil'lO from Intra~nous (IV) i Ijoctior, 01 hisIamine and those assodaled with anaphy-

lactic !hod< and allefglc feactions. These Include f;Of1lraclion 01 smooth fI'W.ISde. stmAation 01 seoeCiol'ls.lilation and Wv::reased per. m '.~yof thecapilaries, and ~ 0 1 sensory nerve erdolgS.

H,_Receptors

'~of

Hie" ,....

FlgUf.4O.3 Biosyrlthesis 01 hislaoToio'le.

H,-and HrReceptofs

_

CARDIOVASCULAR SYSTEM

EXOCflINE EXCRETlOH ..

b
0

N~N

C. Role 01 histamine in allergy and anaphyla.is

~

'"

__

a-s~_I"_po

~i*4A"'._.

lood............. - . . ..

• ..,.

ee.-~ct"""_I'

'..,.11J '-*"1_'

(td' 0 ~io"""""i1111

f

""'!lI'

_H,_Ho,-..:ool,

BRONCHIAL SMOOTH MUSCLE ConoIri<:lion of b .. _ ..In~of_.do<>.... ~

""'-

SKIN

INT£STINAL SMOOTH MUSClE

0ilICiat>_;'1(J <e1 """._. cl ... ",,-, ... _ i n . - - c l

(:Q'IM .. , - . . . i'I

In",_",_in"'_

~

--...-..

~~-SENSORY NERVE ENDINGS c... _

__ If1o""-'

....... r;:..-·_bll . - _' " ,_",__

5 ....

\ Stomctc:h

...,_. 510, 0

figure 40.4 Action$ 01 hislamine.

'ofgootrict""'tdbic:

< c.- •

• ..,. r",,,'.t •• _ ... - . . . , .

.. , _

.. _

.....

40. AutaI;:oids

'"

--

.

...., ,._:

First geneqlion

of .. lec:tId -'tiM••min••

8

" ••••

a

.

c:.- ..........,••

:". fj",-

,

[It.

$

•• _ .

••• ••• •• • • •• • •

•..... .-...5. •• •• .:•

p\ ktIi..., ,.

•

'If

Qpd...

Second ger.etatlon

, . . . . . . . . . . . . . ' . . . . .M . . . . . ;

AguN40.5 Sl.mmary d lhefapeulic adIIllI'Ilages arl:l ~art*iIgeS 01 the HI-hislan*le reoepl(lr bIol::king agenI&. I. Rol.I or medl.tors: $ylT,poiilS IlSIOC'iaIed with aIefgy and _ . phyIiI(:lic .ood< resuI from fie reI! 35e d 0Irtlin medalOrS from Iheof saorage siles. Sodl 1'l1Eda!(Q include tistamine, serollltlin Iel.*;llriene$ and 'he eusifqJil ctwnolac:tic lador of ~ In some eases. Ihese <::aU5e a IcaIlimd allefgic reac:1ion, p1Xl.oc> ing. lor example. aaions on 1tle ~ or respir.l1Ofy lrad. l.JI"der QI!'oer Ol;lllditiOllS, these mediators may cause a IlA-bklWn anaphyIactie (esponse. It Is Ihol.lght lhal Ihe diflerence beh.eel"l these two situaliOf'lS resuUs Irom differences il"l the siles from wtIictl mediators ere released arl:l their rates 01 release. For example, ~ Ihe release of hisfamil18 Is slow enoogtllO permij its if18CtMl\iorl belofe ij cnlefS lIle bIoodSlream, a local allergic reaction results.

. .

, ... '0. . . . . 1 • , ............. I >

~

III. Aotihistamines

----_.. .. _..... , """"""

Histamine H1 - receptor blockers

-

-

-

«-Ado ..... gI<:

~­ 'eots>IOi

-

HlIla1"Onoo H,

."""",'"

Figure 40.6 H ,-antihistamines blocl< al histamine receptors as well as at adrooe
D. Histamine H, receptor blockl!l'1l The term "antihistamine," withOllI a modilying adjective. refers 10 the classic H, receptor blockers. These compounds do nol infllllll1Ce the Iormalioo or release of histamine, but rather they compelitM!ly block the receptor·mediated response of a target tissoo. [Note: This oonTrasts with the actioo 0' cromoJyn (see p. 220). whid1 inhibits the release 01 histamine 'rom mast cells and is useful in !he treatment 01 asthma.] The H, receptor blockers can be divided into 'irsf- and seeond genemtion drtJgs.(Figure 40.5). The ,irst genemlion drugs are still widely used because IheV are eflectiYe and in~pensiYe. Howevei, lhe second generalioo agents, because they do nol penetrate the bIood·brain banier, show less eNS loKicily than fhe older those that drugs. INote: The histamine receplOrs are dislincl bind serolonin. acetylcholine. and the catecholamines,]

'rom

1. Acllonl: H, antihistamines antagonize all actions 0' histamine e~cept tor those mediafed solely by H" receptors, The action 01 all 01 the H, receptor blockers is qualilatively similar. I--IoweJer. most oIlt1ese blockers have additional eftecls unrelated to their blOCking of H, receptors; these effects probably reflect binding 01 the H, antagonists to d1ofinergic. adrenergic, or serolOr1in receptors (Figure 40.6). SOme H, blOCkers. SlId1 as diphenhydramine. have good local anesltletic activity. 2. TherapeuTic UBes a. Allergic Conditions: H, Blod<ers are use'ul in lreating allergies caused by anligens acling 00 IgE-anlibody sensifized masl

, _ r", ...

,.,,<_ ... __ ,.

<..-.

'"

....

>I>'C>IUl _ _ .... >

40. Autaooids cells. for example. antihistamines are the drugs 01 etoice in conlrolling the symptoms 01 allergic rhinitis and urlicaria because histamine is the principal mediator. However, the H, receptor blockers are inefledive in treating brondlial asthma (see p. 217), because histamine is only one of several med"latOIS. [NOIe: Epinephrine (see p. 6t) has adions on smooth muscle that are opposite to those 01 histamine and ~ ads at dillerenl reteptors. Therelore, epinephrine is Ihe drug 01 moice In treating systemic anaphylaxis and other c:onditions that Involve massive release 01 histamine.]

•..

-t.-o£.... ~ .... '

Z-~

~ z.•• .-' .'

b. MoliDn alckne.. and nausea: Along with the antimuS<:8rinit agent scopolamine (see P. 48). certain H, receptor bIod<ers. soch as diphcnt1yr1ramnc [dYe len HYE dra meanl, ~. dr/nale [dYe men HYE dri natel, cydizrw [SYE kli zeeol, and moc/izine [MEK Ii zeen] (see Figure 40.5). are the most eltective agents for the prever1lion 01 the sY""4>!OmS 01 motion sid<. ness. The antihistamines prevent or diminish vomiting and nausea mediated by both the dlemoret:l:!p!Qr and VIlstibUlar palhways. The al1lieme\i(; adion 01 these substances seems to be inc;lependent of their anlihistaminic and other actions. (Other antiemetic agents are wmmarized in FIQure 24.6. p. 243.). c. Somnllaclenb: SOme of the antihistamines, sud! as diphenhydramine. have strong sedative properties and afe used in the treatmel1l of insomnia.

3.

TRUIORS

figure 40.7 some adverse effecl observed with first generation H,-histamine bkx:kers.

Pharrnacoklnet~: H, receptor blockers are well absorbed after oral administration, with mal
4. AdvelSe effects: H, receptor bIod<ers have a low specificity. that is, Ihey il1lerac:l not only with histamine receptors bUt also with mUS<:8rinit tholinergit rec:eptors, a-adrenergit receptors, and serotonin receptors {see Figure 40.6). The extent of Interaction with these receptors and, as a reSUlt, the nature ot the side elleC!s, val}' with the stru<:ture of the drug. Some side ef1eCls may be undesirable, and others may have therapeutic value. Furlt1l!fmore, the inddern:e and severity 01 adverse reattions varies between individual subjects. a. Sedatlon: The most trequently observed adverse reaction is sedation (FlQIJre 40.7). Other central actions include tinnitus, fatigue, diZZiness, lassitude, incooroination, blurred vision, and tremors. Sedalion is less oorrmon with the second generation drugs that do not readily enter the eNS. b. Dry mouth: Oral antihistamines also exert weak antic:holinergk: effects, leading nol only to a drying of the nasal passage bUt also to a tendency to dry the oral tavity. Blurred vision tan also occur with some drugs,

•

.~,

ro...

'.1 ............... , >

IV. Drl.lQs Used to Treat Migraine Headache

"5

c. Drug interactions: IntefaClion of H, receptor blockefs with Dlher drugs can cause serious consequences, such as the polentialion 01 the effects 01 all other CNS depres$anls. induding aJco. hoi. Persons laking MAO inhibitors (see '" 123) should not take antihistamines. since the MAO inhibitors caI1 exacerbate the anticholioergic etlects 01 the antihistamines. Ery1tlfomydn and darilhromycin interlere in the metabollsm 01 lorfcnadine and aSlomlzoio and mav cause serious cardiac arrhylhmias. d. Ovtordoses: Although the margin 0' sa'ety 01 H, receplor biockers is relatMaly high and chronic lOllicity is rare. acute jXlioooing Is relatively common, especially in young children. The most common and dangerous effects of aClJle poisooiog are those on the CNS. including halludtlations. 8lldtement. ataxia, and COfflulsions. If untreated. the patient may eXpel"ience a deepening coma and collapse 01 the cardiorespiratory system.

See p. 470 for a description of foxolonadine. E. Histamine H2 receptor blocllers Histamine H 2 receplor bIod<ers have little if any affinity lor H, receptors. Although antagonists of the histamine liz receplor (liz antagonists) block the actions 01 histamine at all liz receptors, their chiel dinical use is as inhibitors of gastric acid seaetion In the treatment 01 u\cefs. (see p. 236). By compelitively bIod
IV. DRUGS USED TO TREAT MIGRAINE HEADACHE It has been estimated that 18 million women and 6 million men in the States Stiffer 'rom severa migraine headaches. Migraine can uso-

lkited

Migraine

,-

-- ,-Family hlot<>ry

" - 1' .........

Cluster

_ _-....-,-

~

_'IIat1 ........

Tension type

........

_

"",, ............ thon ........

or .........,.,.,. Ilyll

-..In _ _ _

.~

UruaIIy .....-

c_.,...~

PuINIing, d._'lI

&<:
DuI~poniolenl.~

Two 10 n houra pet op/I
15 '090 mInulao p e t _

3D""""" 10 7
_.""'.- .....

<-

~lloc;OI
VI_I ........ oenlitmty 10 lighf ..,., -"nd. pOoIo _

"""'""ling

Agure40.8 Characteristics

0'

-::t...

1.OniIIIw1l.,.. bilateral r..~ 1'Iua/Iing,""" ~

plOIio.18CrimIIIcn, fiUllilIary

migraine. cluster lind tension-type headaches.

_

lnIoiorance 10 Iigh• ..,.,

noiH.ooo..ltiI

...... ,"' ....., .. -... _,.

'"

ally be distinguished clinically Irom lhe two other common types 01 headaches---the duster headache and tension-lype headache---{)y lis characteristics (Figure 40.8). For ex;:llTlple, migraines present as a pulsa~le, throbbing pain: doster headaches as e~cruciaUng, sharp, steady pain; whereas tenslofl.lype heacIadles show dull pain .with a persistent 1ighIening fee~ng il'1 the head. Migraine heaOOChes typically ailed patients for a major pan 01 their lives. and result in consiclerable health cosls.

A. Types 01 migraine There are two main types 01 migraine headal::hes. The firsl, migraine wilhout aura (pre\liously called l::onlmon migraine), is a severe, unilateral, pulsating headache that typically lasts from 2 10 hours. These headaches are often aggravated by pnysical adi",ity and are accompanied by nausea, vomiting, ptlO1Ophobia (hypersens~ivity to light), and phonophobia (hypersensilivity to sound). Approximately 85% Of patients wilt1 migraina do nol have aura. In Ihe second type, migraine wilh aura (preViously called classic migraine), the headache is preceded by neurologic symPloms called aura. which can be visual, sensory, and/or cause speech or molor dislurbances. Most oommonly Ihese prodromal symplOms are visual. occurring 20 to 40 minutes before headal::he pain begins. In the 15% or migraine pat>ents whose headache is preceded by an aura, fhe aura ilself allows diagnosis. The heada<;he itself in migraine with 0< without aura is Similar. For both types 01 migraines, women are three limes more likely 10 experience either type 01 migraine than are men.

n

B, BlolO9l1;: basis 01 migraine headaches

The ~rsl manifestation 01 migraine with aura Is a spreading depresssion 01 neuronal activity accomparlecl by reduced blood lIow in the most posterior part 01 the cerebtal hemisphere. This hypopertusion gradI.Jally spreads lorward over the surface 01 the cortex 10 other c0ntiguous areas 01 the brain. The vasclIlar alteration is acoompa.nied ty functional changes, lor example, the hypopelfused regior1s show an al:n;mnal response to changes in arterial JlCOL. The hypopertusion persists throughool the aura and well into the headadle phase, alter which hyperpertusion OCOJr&. Palienls wilt1 migraine withoul aura (10 not show hypoperfusion. Ii:lwever, lt1e pain 01 boIh types 01 migraine may be we 10 extraaanial and i1tracoanial arterial dilalior1leading 10 release 0( neuroactive rnole<:lAes such as subslance P.

C, Symptomalll;: lrealment 01 al;:ule migraine A migaine can usually be aborted nthefaw is iniDated at the onsel 01 syrnp!orns---@ither during the aura or at the first hint 01 migaine pain without aura. The most useful drugs for averting lII1 aa.rte atlack are suma~an, ergotamine. and nonsteroidallll1tiintlammatory drugs. 1. Sumahiptan: Suma/riplan [sew mah TRIP tan] rapidly and elfe<:lively aborts or markedly reduces the severity 01 migraine headaches In about SO % 01 paljllflls. SunJ8/riplan is a serotonin agoniSl, acting at 5-HT w rel:8ptors, a subgroup of serotonin

.............'........_L. .27

IV. Drvg Used 10 Treal Migraine receplOr$ tound on small, peripheral nerves thaI innervate the Intracranial vasculature. Their aclivation probably stlppresses release of sensory neuropeplides, sudl as "Jb6tance P: The nausea lhal occurs wiIh ~ and the IIl\SOCOflSlJictiofl caused by etpofamine (see next sections) are mudl less pro-I'I(llJfI(lll(l Mth suma~ ~ III giYen ItAlctAaoeousIy Of oraIy. The onset of !he pal1!f1lefal drug III about 20 minutes cunpared kI I kI 2 holrs lor ~ ~ 0faIy. The aug has a 5hort cUalion 01 aaion. wlIt1 an elirT*'lalicWl hall-lile 01 two I'Icu's. Heada<:he 00l1111Oiily' rean wilhin ~ kl48 hotn afIef a lingle dole 01 ~ in mosI patiems a ......... id dole is ef\Il!dWe in aboi1io og !he hoorto/tIe. Bec:ause 01 iIs high lXl5t. .$lmftl1:lbn sI'lOlAd be reserved IOf palierU lot Moom Olhef augs hlWe been iletledMl, Of were nol-.l-lOleraI!Id,

Agents used In prophylaxIs

-

-

~BLOCKERS • I'ltduelng ProfI'_ - " " " in ...IIfr-..ncY _

•

SUMAmlPTAN ~~_""'~_ot.....uelly'-""

''''' .. ~ of mlgr_ " " _ ht _ 1 0 ...... 01 ~1I._oIooill . . . .I...

• £1"._..

11 ....,,,......,

~-y-_ ....1' .

.....

"KT. n, _.. ANALGESICS

-------

• AI'IIIinhonmifo< *"90.-

....~.~-

_11<,..... '11 ........

....",.,. ..

METHYSERGIDE ~

lfClIng OIl

ERGOTAMINE

. - t l y of Illig.............

.

•

Agents used to treat an ecute atlack

~

•

'

-Ain-.g

ot'4 .....

Start 01 attack Asymptomatic phase

5ewtoepoln _ . . . . .,. . . . U ,,,. ........

...... _ ..... ---_.-

Prodromal phase .~-

• ·roo'

.__

.... iclio~_

Figure 40.9 Drugs uselvl m lt1e treatment aOO prophylaxis 01 mll/falne headaches.

.P.. . -

Headache phase

' _ .. --_....... _ ..lIlo'll

."-',

P" , _ _

""""'" - " .

, .... ,"' ...,••• <- ... _ , .

40. Autacoids

a meen) has in the past been the drug of choice for treatment of moderate-lo-seve<e migraine.

2. Ergotamine: Ergotamine [er GOT

Ergo/amine and dlh)/droergolamine (see below) ha~e similar

actions to sumatriptan. but they have less selectivity for the 5-HT receptors. Ergo/amine can be given Ofally, sublingually, rectally or nasally, and is effective in about 50% of patients. The gastrointestinal absorplion 01 the ergot alkaloids is variable, but it can be increased by csffe{oo (that is. coIIee increases elfectiveoess 01 ergot elkalok:ls). The drug is most elfadive when administered dur;ng the early phase of an allacl<. The most common side ef1ects are dianhea, nausea, and \IOIl1iling.

3. Dihydroergotamine: Dlhydtocrgotamine [dye hye droe er GOT a meen), a derivative 01 ergo/amine, is administered intravenously and has an efficacy similar to that 01 suma/riplan. but nausea is a common allYerse ef1ect.

4. An8Igesk:s: Analgesics or nonsteroidal antHnflammatOfy drugs ere of tan effective in mild"o-moderate migraine. Aspirin, acctaminophfln, naproJlon, propoxypheno, acetaminophen with bu/albi/al, and caffeine are all effective in treating a migraine allad<. D. Prophylaxis

'0

TI"erap/ prevent migraine Is indicated ~ the attacks occur two times or more a month. and it the headaches are severe or c0mplicated by serious neurologic signs. Propmnolol (see p. 74) is the drug 01 choice, but othef p-bIod<ers. particularly nadolol (see p. 76). have been shown to be etfective. Methyscrgide [meth I SEA jide). another ergot alkaloid. is etteClive tor prevention 01 recufTent, refraclory, severe migraine (Figure 40.9).

Study Questions

....:-:1.11_............. ......n e ".pc.M •

Choose the ONE besl 8OSW8r.

_........

40. t Ergol alkaloids:

t .. PC Iqt • • "

~lOn.h

A. caose vssodilation. B. exert their actions by binding to specific ergO!.

--~

C. are llSehA in treating 8C\Jle migraIoe headactle. O. 8<e l.fS8h.oI to maintain lJleMe muscle tone oo,;ng

..,.,.,.

X • . lIetlld

Ie 01 en II . . . . . . ",",'

traa1mel'llolllC of thet~ EXCEPT: A. ur1lcarla. B. seasonal rhiritis. C. drug reactiofIs.

c..et_.C.8D 'a_.GIlI" .. '.'.117 t.....,. .._ $ 'at

O. b
I

. . 1IId...... _ " . . -...rt. ,A • • t

' • • 11'1'

1JI In..•• ,,", II'ld .Ii •

's

n.

*JIc.

I til 4 ....,

S'"

+ ..

40.2 Histaml...... H, receptor blockers are usetul 10 the

E. have aetioos similar to those 01 ritropruSSlde.

.... _1llII1 '1

,lIi'l1

II

l'

(

ea...tdlDb.D.f+,=~!",J; t·

'-'''''''''>'''--')

<

eo- •

" .. ,

H>'Co\>IJI _ _ •

w

>

I_ OVERVIEW These extended case studies complement the basic information presented in Chapters t to 40. They reinforce basic principles of pharmacology, such as the role 01 patientlaetors in empiric antimicrobial therapy. Most 01 the cases provide dinical informa~on obtained from a single patient: some (;BOOS deSClibe a oompos~e 01 typical fee· \1.Jres derived from SlMlral patients. These cases illustrate simple pharmacologic principles, as ronsideration or kidney function in drug dos!ng--ooncepts useful in answerir.g examination questions, and in the dinics

sum

CASE 1 A 53-year-old man was admined into a hospital with fever, a cough that produced purulent sputum, and wortness of breath that had been present lor several

"''' Two years eartier he had developed Kaposi's sarcoma and was human immunodeficiency virus (HIV) positive. In the interim. therapy with anti-HIV drugs had been disc:onlinued because of his inabmty to tol· erate them. However. the Kaposi's sarcoma was treated with anticancer drugs, includir.g doxorubicin. He was being maintained with oolrimoxazole. fluconazoe. and rifaoolin (a r~amycill antibiotic similar to rifampin) and receMng weekly treatments with fiJgramstin {granubcyle slimulaMg fac/ol} and e/}'lhropoielin. At the time or admission lor the CO\.Illh his hmper-indJced T-e:ell (CD4) rount was 131llL A roest X-ray revealed a cavitary lesion of the rigtlt upper lobe. Cultures oblained from brom::hoscopic biopsy and broncho-alveolar lavage specimens yielded methicillin·resistant St8phyl0CQC(;lJS aureus (MRSA) with no evidence of lungat Of acid-last organIsms. Treatment with the normal therapeutic dose of vancomycin. 1 gram intravenously (IV) every 12 hOUlS, was begun. Because he insisted on receiving his treatment at home, he was disd1arged with a peripherally-inserted central venous catheter in place. Though his revers abated initially, he again experienced Ireqoont dlitts, fever, cough producing white-toyellow sputum. and progressively disabling weakness 48 hours after the YllfIOXlmYCkl had been started. Several days later he was admitted to the hospital, wtlere it was noted that he was alert. fully oriented,

and extremely weak. His temperature was l03.6"F, his plJlse 130 beats per minute (BPM), his blood pressure (BP) 80160 mm Hg, and his respirations labored at a rate of 28 per minute. He was eldremely cadlelic at 6'4" in height and weighing 135 pounds (61 kg). There were purple lumorous plaques rover~ ing parts of his body. His chest revealed dullness and coarse crackles throughout the right upper and rridlung fields, suggesting pneumonia. A chest X-ray oonfirmed the diagnosis (Figure A.l), ll
maI _

.how •• ~ .,.. h_linllllbilily la

whlct> X""y"



TNo

I~

puo

_1Mn

___

In _Iu"ll _C11

i._ 1 ....

IN. lndlc

.,.,._pra-.caof;,,_..

_

Figure A,l Chest X-ray of patient

...".......---_. ..,--

",..,.~

_ _.. _

_ _. _ "

_c.......... '

,......

429

, ..... ,oz",."<_,,,_,

>

""

Appendilc: IlIuslrated Case Sludies

The palient was profoundly leukopenic with a wMe blood cellcoont 01 7001IlL~28% polymorphonuclear leukocy1es (PMN'sj, 53% band Iorms, 3"4 metarnyeIocytes, 11 % lymphocytes, 5% monocytes. [Normally, the total while blood cell CO\.Jnl should be belween about 4000 and 10,000 per mL.] The serum crealinine was 3.6 I1'l9'dL (indicaling significant rerlal dysfunction, normal crealinine ordinarily should not exceed about 1 mg/dL). A random plasma vancomydn level was 48.8 jJglmL. (Thernpeutic range /0( "'peak" levells 18 to 30 jJglmL.) Ouestlon A.1: Was vancomycitllhe appropriate drug to' treating this patient? A...o....ar; Yes. V!ll"JC(lo'1lyc.... IS I~a drug 01 choice (in laCl.!he etfective aug Cl.W,,,nUy a"1l'oble) lor 1M UeBlInenl 01 melluc,'lln·...islsnt SlaDhy~.~ lILI:ll:I.Ill {MRSA} inlec1lOOS. II is bIIC1ericidal and lhus ~ lor Uealmenl 01 a lEU
c::nv

The vancomycin regimen was oospended. and blood. SPI'lum, and urine Cultures were obtained. A gram Slain of the patient's sputum revealed many poIymofpnonuclea. leukocy1es and many grom-nega.tive rods (Figure A,2). Urine \TiIm stain showed no organisms. The patienl was treated with tV tluids, and, based on the gram stain and olher data. ccftBzidime (one gam IV every 12 hours) was begun. In addition, the granulocylo ce/ony-stimulating fac10r was increased to daily doses, in an etlort to improve his Quanlitative leukocyte defenses. The patient's lemperalure came down and his renal rUOC1ion improved to nearly normallel.els O\IBI" lhe next 5 days. allowing resumption 01 .egula.l y s<:hedJled I'lIflOOl'I1}'C doses. Cullures of sputLm and ~ yielded Pseudomonas iiWlWilmiI.

Ouestl"", A.2 ; The best e>;planaliorl for Ills eldremely hlg~ plasma level <:i vancorTl)'drl is:

A. The very low C04-posilive lymphocyte counl B. The excessi\lely high dose 01 vancomycin tOJ this patienfs weight

C. The impaired rena' lunctioo O. The leukopooia

E. Inhibition 01 vanccwnydn metabolism by /IuoonaroIo 1he co.. ,,<1 answe<

IS C (ilT\gei,ee kid· ""yo, with renal c1ell1llnce Ij.... a~y fl'llaleel 10 thai 01 creell'1ine. HO'fIOO. even 101 palien1s wi~' modosl . . ~,"",nl "'''><»mycln legimEN n'lU61 be _ . me patienl, p.esumably because of sep1i<; d>ock, e begM to .etall ~ signiIicanlty. A (vel")' low C04. posiriYe Iymphccyte CQU1t} ia ~ to oancom""", kk1etb. B (e~ <10"" lor wel!tr') Is nol ~le besl answer because, will! a ,llCQITImef>(leI 0161 ~g <;aIlo:j too' ab<>Ul 900 mg per Oose. only .lighly lcsa ~ ..... 1he dose IhaI he was r~. D (le"""""nis} does noI ot itself result In d""'l/iling the hopetio microsomal en~ ~ .....""""""'" ia nQ1 one 01 !he tile
•

Figure A.2 Gram Slain of patienfs spulum.

........ _'.

,- ."' ..'.'

< """" •

.....,

Question 1..3: Wss Iha ooloction 01 coltudims. mli
~ ID _ . r.lecllC.... WIlh O'~ .odf;. KPf'C""ly U"'!\lllQU The paller,... l;pl*lM0'''' __ iii in.-:celld..., a.och III rleclJCln. Co/WIdi'm'" 'ird gerws""'~_ cove•• many ",_negative OIgllfl~ includtog

e.
".,..0""'115 ....,OOCM ... -.0........--

Ouestlon A.4: Why _s Ihe Pllieni fIOl Irealed COIlCUf· ."""' ...... n ~ . suctlas ~ _ lhe~.hghse
t"".

~ d . I ~ . fOOJ~"'JT"OgI1IIIs-..~

uselh eehv_ • db _ U'cIrc:n.

q

"

lhe

«- _.

Dl1he 1DIloooil'O ""...., . " , _

a.-Ion A.5: Wl'dI _ .... Ia r:eIIazidimd/


A. El\edi>Ie on 8. Eloelron clej:eodlon'" ~ t C. IrIer1era .. ~ It t,n;aion ID _ D.

...-. c... $

d

neutropenia. Which led his physicians to suspect Pseudomonas on the lirst day. Had he nOl been 1realed with the righl drug from the very beginning, the outoome \Io()\jd noI have been good.

CASE 2 A 27-year-old woman with a history of asthma 8(;l;i.

denIIy inhaled a smaJ r'llA from a candy bar she was earing. The poesence of this Joreign body in fie air· way IriggeredllO explosiYe series of ocughs. I>kllch UIimalety elqleIlecI !he food ~ bom her Iu'lgs. After seveoal mRJtes the aiJway was fuIy cleared, bul she experienced progressiYe I9lb teSS in hef chest. Hel breathing became dillicull and soon she was gasping b breath. She rlllTKMld a c:aI"ISter trom herpurse and inhaled several pulls of meclcaliotl. Her ~ resolYed CM!r !he red 20 mirUes. .,....t! tI01 ....6: wtWc:h 0JlII 01 . . 1c*Mw'll _ ;"'lId ~ icatiDns wa.sel poo.ed reliellrom 1he _ _ bOi d'I<x:oi~ SIOdon descriled 100 . . worren?

C. fbJul ..........' It'l

lilticDy-

iidI," II ,

Id~

0._ CaJecr _

aou_·

("'010_. o»peodl on INlIlod: depend en . .

CcIIu_. _aIDJI.

Ia ft'CJiKlO'I po_'• • oIly ...-.....l ~ ~. . n-... ..... ~ INIcID6oIdc' li,.,M:UcI_lIlbl"o'( ddue 1Il"~_ ........ (ellecMencnl scrl5IabM) is roc:arll;l. Csf""*"'o .. ..,... 1*"'*"3Iy C ~ . 1'1 - . . . It 1l.I'ldicn III _ III • • '"'ll MnleI!ect)os ..... ,ecI. Ib5PC4Jf!Jl•• pea>"" III ~1Wld cr' I....... 0 ( - . - e«>to'lClly .t "Igh ilium I.....'.) .. """ cDlrect E ceI'.udt>o iI WI_ .... "ed 1\1 0/ ....1IMJIQ.8tr (N) ~

",

E. He<*x:JUIli'

lte cmecr _

"""')

w •

a """-

-.c:lIyll hogtIl8JUm IeWIlI.

E.~ ..

... .....,.,..,. ... _ .

o-n

This case iNustrales the impOftance ot considering palien!-relaled QormaOOn In seleetil ~ empiric an6microbiallheoapr. Impaired renallunction caused hm to relaln vatll':QI11Yl:' 10 wry high levels. requiril'lg StJb. srantial modification oj Ihe oosage (thill is, wailing while the drug was very sIo¥o1y IXCflted). The renal failure alsoo Inlluenced on lhe dosage of ceftazidime that was initially given. An adull wilh normal renal function requires 2 grams 01 cellazldime avery 8 haulS. The other lmportam pal16l'1Heiated In!ormalion lhat guided the antibiotic choice was his prolouJld

IS D. J

~

• ere DI _III d lit

tt."~k:f_,(jj.dtr(l'l>

dllXU"-" _ _ . . . - d aclJOJ'l lS"pod

efteas "" _

=•••

d - . ....... lis 10 10 ......._ ) _ a rr II t>oon

~

l~

... ,w,..,U; IIso

_ ClI'OIef DI "'" U!lI!ClI'l _ _ ~ II, Ii QocmoIrn snd ~ •• uMd pooptlylscflcly. but Ife not eileen.... if' acul. ultl.... C 8ec1fO: -"esolt iI III ~ SId 100 "-_1Il - . . ........... _ /;IOl;bf _ • ~eQa:~ IIJWay .",.,,,01110/. buI III _ "'" ."'"' ..": .... o-ug IS . . . . . .eo"ed d'oCACllly, boA. is "'" ettec_ 1'1" 1Oeune<'t d ... _ _ 01-'

ICIICI'l snd ..

.,"*,

soar-.....

-

Sin'4l1e spiromelric testing wiIh a

bronctlodilalOr challenge can identily patients with revel'l.ible airway obstruction, sud1 as asthma (Fogure A.3). The pali1nt fills his or her Iurlgs max.-nalty aJld then expels the air as rapidly as possible. First a baseline reading Is taken for this Iorced expiratory \(lfI.Ir'OI in the lirst second (FEV,). Nell;!, an aerosol bronchodilator, such as albulerol. is adminiSlered aJld lhe leSI Is repeated aller 15 minules. Airw~ obstruction Is tXK1side!ed 1(I be rl!Yl!rsible wh6l'1 the FEVI improves by more than

(,.. . ,.. _,.,.<- ... _,. ""

AppendiK: Illustrated Case Studies

,

Remarkable physi<;al findings were oonfined to the abdomen, which contained an obviously enlarged uterus. The spleen tip could b€ fe~ 3 em below the left oostal margin at the end of deep inspiration (definitely enlarged).

~-", FEVl

•

f'=

,

j,

1/

!,.4

, ,, ,

/

Her hemoglobin level was 10.9 g/dL (moderately anemic), White blood 0011 count was 52OG'JIL (normal). and her platelet oount was l03,OOl),IJIL (the lower timit of normal for platelet count is 140,OOOIJIL). Examination of a peripheral blood smear revealed clear evidence of malaria due to Plasmodiym ~ (Figure A.4).

-

345678

FlgureA.3 Effect of bronchodilators (1l2 agonislS) pulmonary air flow.

on

15% following bronchod~ator use. Figure A.3 shows results with an aslt1matic patient in which the FEV, increased by 50% following administration of albulerol.

CASE 3 A 21-year-otd woman was seen in consultation because of intermittent fever of 6 days' dUration.

She had been in good health and, at the time 01 onset 01 the currenl COfI"4llaint, she was in the twelfth week 01 her first pregnancy. Seven days prior to admission she developed a lever as high as tOl·F, with chills. These symptoms occurred on alternate days, beginning about noon and IaSling 10< several hours. On the days that she didn't have a fever she felt re~tively we'. The day after the onset 01 fever and chills she began 10 leel pain in her left side. Two days later she developed dysuria, but had no urinary urgency or frequency. Because of persistence of the symptoms, she was admitted to the hospital the day b€tore the coosullal1t's visit, for presumed sepsis 01 urinary tract origin. At that time it was determined that she had gone back to visit her family in India. Her illness began 6 months aha she had returned to the United States. Upon admission_ her tellllllrature was 97"F, her pulse 60 BPM, and her BP was 100/65 mm Hg.

F1gureA.4 Peripheral blood smear.

Question A.7: In II"neraI, what are the drugs 01 choice Ie< the 'rea'men' 01 malaria due 10 I'lasmodjum ~?

Ansv.'et. Fe< a -'adoc8l C\JIe·. peI_ II/e \lealed ...,IM a 14-d.ay course 01 primBqUine. It uSUllN~ follows 1\ cou.-se 01 cNoroq<Jit>e 01 0Ihe.- blood schizon!Odde, Ftffl1quine is aC1ive &genst h ti"""'yItYocytic lanns 01 E.1'il/Ilo;. 11;$ lII${) strongly gane!OC;OO; agb1$1 all l<:u pI3sm>
-

o .....t1on A.S: What a,e lhe uwalloxieties associated with

AIlswe.-: AI the us....1 dose!;

• is

lI"""'alflll'<>ll tOleo-

IIled thc:ugh paljenl$ ""'Y c;ornpain of g.aslloinleSliml pooblems, SlJC~ as abdorJ,;na1 cramps. flElusea. and epigII$lllc pa"" as weN as of ll9ll
""'-' The patient was lfeated wdh chloroquine phosphate

..... '.....'., ................... ,. (I gram by mouth. folkwed by 500 mg 6 hours later and 500 mg once on each 0I1he SlbseQUenl2 days). She was advised 10 lake CllIotoquinB phosphate 500 mg Oltllti orote ~ for approximaleIy Ihe next six

""""""

-,

00 I t"'n A.9: WiI

Ii""""'"

JhA;fN_ ef!«I • ~

This paIiBnI also iIIt.lslraIe:s Ihe ~ of a Ira\IeI ~

iI'l

~

mediciloe. Her "irltermiltetll" lewrs r~ on aIemaJe a 1M$lOry ItI8I S11Q9l!StS malaria iI'l 81'1 ir1lliYDJal who has be«I in an area in wtWdl meIaria is knoWn kl exist Her lIar* pain was not we 10 • """*'Y trad il ......... ~ blA was at'1t,'''y re6ated 10 !he splel'lic enlargemenI Ihal is so charaderistic of ~

oavs.

came wilh strilcing

~ No.

n. drug • • t:*lollllClllZOiIioOe 8td

.as •• ,.................

Ikrf.-.

cur.- ..... pn.

Questlon A.10, The 1l!!oilSOIllhill"r.adical tNQUN_ I1CI "'dto ~., kr Ihis paMna Ie;

A. VIII" .... ,.,~ ClInnol be e,adicated.. only supPOllled B. Chlc1n:lquWIIl alOne is """q! ,,'" b ... l;U'll d \Itvu

C.

heallhy), 6 IOOIIItIs afler her malaria was diagnosed. At that lime she was given anolh8r 00Ul'Se 01 cNclfo. QUine. IoIIowed by 14 days 01 primaquine, and she temained asyfT1lIOmatic. Malarial forms "';appea<ed Irom smears 01 her periphefaI blood.

.......

,.,;,I~.OOIll1aiildic.lted

In pregnancy. was too low 10 allow

D. ThII palient'. hewoglobi, llMlI usad~

E. WoIh ooIy 7 dilys 01 , _ . the malaria lished enough Ie 19<JJIfe radical ClJre.

was not estab-

1M COffee? answe< is C (p'H'nllQ 1l'ugrW1C)') I'rirrJaqUne iii IOldc 10 h I _ n sI>c:uld not be r,j-Jf!n 10 Il'egnant worroen. A (........ lTIIlllriiI Glnl t". eradicalen by ~ but is.l'kan~ by ~ 8 ladeCJ.8CY (II (II""""",-in "--"'lI f.liiiiIIJ tor the just stat..:!. D (Ihe ulen? 011.... ..................) is inco'I'e<:? because. !I'vtiI d 10.9 g/l1 is net ....... In potog-

'''loOn'

."'Cf'lI

to.,....,..,...,

nIr'lCy• .-,oj .10 llIIeopecllld in.".... ............

thIt '-llIIo'IO'QUI'll ...... ~ _ _ d red blood celli is pan 01 ... ;:JIlI>Qd -.: _ I f ,

1IOtI

CASE 4 A 'MllTWI, age 36. entered Ihe cliric: (lOI'lllIaining of taUgue. nude weakness and difficulIy in breathing.

,_led

A ph)'sicaI exam pneumonia. A sputLm sample was taken and she was placed on olal clarirhromycjn. Two days later. lhe labora,olY linding Indica,ed that the organism was Klebsiella ooeuQ)Q: lJillfI and she was switct1ed to amilracin and celoxitin. While the respiratory Infecllon began to resolve the patient COI1~nued to oomplain 01 latigue and muscle weakness. Ptosis (drooping of 'he upper eyelid). diplopia (percepllon 01 two Images of a single objecI-"OOUbIe visiorl1 and difficuIly in chewing and swallowing developed. A plovisionaJ diagnosis 01 myaslheria gavis was matle.

,-

Oual6on A.11: tnaa_ _ i ........ d 10tkh one 01 ... k:6:>wWIg agons QOUId r:.. used 10 CO'IIitm .... cIagncJsi:s. B. Acef>IcI'lofu. C. E"ltqJu""",,

~'*""'IS_CU1I-.~ lhecdf

0._

lCml (II _

E. PIIJcapii..

'eq..a"9"

....... tt:aI does net IIllID'ICl d ""'A' is _ _ • ~ b ' ( - - " .... 01 tlIDCId aCl>l ... II"diw:t..III.~.... f . - . ~

,-

srao .... iI ... ~ J R t s e i n _

This pelien1 iIustraIes the ~ 01 pregnancy in guiding the choice 01 an any drug! AdYerse etlects 01 drugs are 001 only eJrierted on the patiEnt. bIJl also Ihe fetus, IItt1lctl cannoI awid exposure '0 drugs ItI&t ale taken by the mother, and wI'Och cross the placenta. With this patieot. mdical curB had to be delayed until the delivery 01 her baby (who was born perleclly

Corect _

~c.

AdiIO_oI

gas

.,.. be COli' i e.""'*'4Ju.....

T....:. rrQdlnl.-...g" giIwIlY , . o ro $IP:ul: sidI etlIcIi atJllt* 30 MCOlOI. lin Id:litiallll 8 "'II is 11'''. In" m;a>1t"&w: paIient shown on p. C34. is lin - . . ~

m,.

'*.

....." 11 lie ...-..nge, d . . . . . . . . . . illIlllW'og 11"'"· ~ wiltI edqlllO>un(F"ou A.S).

..... ......,.,.<_ ... _

-_

.""_. ----,---" - ......

I.

Appencix: Iluslrated case Studies

FtgUr. A.5 em., d ... ~""' ...~~1Ii.m in a patienl shoMlg symploms of myaslheflill gavis.

1TIIldo;a~ may hilve c:onrributod 10 l!Ie In'I'I8SIIino oIlhe myaslheriil1

Ountlon 412; What arIliI;Iolic

TIle ""'*'ogtycoside. amiluJdn. TIle .'_iOgIj'Cosides can ,ntoibll ea" upUlke whic/ll& '&QU,,8(j 101 rhe . . . . . oI~ldlhl...... ~r.n;Uon,

.-.cl cal cause ~ l:*Jdoadoo n. iI •• e ....... dDieI; 01 .... cn.g. buI .......... "¥'Sf. - , , - "'~a«qAillle.

teeth. There was a soli sySlatic murmur consiSlent wilt! mitral irlsulficieocy. His spleen was palpable 2 cenlimelers below the lell OOStaJ margin. The rema;n. der at the physical examination was urvernatkable. !-is past history irduded en episode of v.ooezJ1g ~ ShOlbll!S& 01 breath when he had leee'led peuidllir, lor a sore IIYo8I at age 10.

a.-tlon 411: WhIt tenla..... ~.....:u;lyllU_1

CASE 5 A 36-year-old man was admitted to the hosp~al with fever and ch~ls. WI1ich began 3 weeks earlier. Until that tilT\fl he was well except lor a heart murmur which was asymptomatic. Three months prior to ~ he t\e1o I ,oed a derUI tbscess ~ was treated with stJTgical dl1WlagG of the abscess and erythromycin efhyfslJCCinafe (400 mg orally three times daily !of 10 days). He felt wei unIiI 3 weeks prior 10 admission. when he began to have IeYef as high as 101"F every tlYel1ing. sometimes aa;ompanied by low back pain. He saw his pf1ysician ten days after the onset at the ~ and was again given sf)'ftlfDmyt:itI ~fe (400 mg oraJIy three 6mes daiIy). When . . S\'mpIOITIS did not in1JrOye. he was lIOnitled 10 the hospile' Uporl admissiOl'l. the patif:!n!'s temperalure was 100.•·F. . . pulse 100 8Pt>l. and his BP 135170 fMl Hg. An oral examirlalion revealed carious

seve."

" " - ' flee.... 01 h pIIIotrJI's _~..... 15. ... absceM IlJ'\d _ a I Cllfious \Ieetf\ end ~ .. J)'_ ence 01 11 " nurTUS lWId lOw grade !
s...."'

waaos

Question 414: - . . q h paIiRnt illtAmg trom Rfllkic:M. . G.e to Slae "" i ..naI 8illitliulic be ~ e to employ ~ bebe Ihe O!liOOgical 001P'""" II ..... k:lellir.ed1

"""*'

Ans_ The palienI's I\oslcfy l\Ug{,lE'SlS a hl'I*sensOtMtv 10 k1A, (_ling arereloe. "cram a .... DI a _ioloI dfigJc aa>d< arod be ............ _ . . " . ~ etfi. cacy~ . . a ~ ~ i o.......

Indica

anIiboCItd """""" <:any

~ . . oow....m.-.cl ..... pene• • In addlitw

f"Cl 0 . .

ale

peo>icii'~ ~.

""""t

t>adeJ'Io::i.

dol. Flap(! . _ '... io ~ 1a' . . ~ Oog c:ce odilJOl,

."""0' ..'.' .... _ _ ,·

."

This patienl was treated empirically wilh ~ a60ne because hs pITisldans suspected 1tlal. he had .. Idoc:an:litis, caused by Sl(l~' .5 •• If 01 the yjrjde"'i group. The hislOl)' indicated that the origin 01 the ~te<:tion was the patient's mculh. Tlwee days laler the rlSUl:s from the clinical IIicobODll:igJ' laborarory s1Qled 1tlal. ltYee blood allures. taken af the .,... 01 llO'nission. gew Eote!"""!S "ecati1. susceptible 10 .. I...... ~ ~ geJl/amidn, and Slreplo-

-.

0UHtl0n A.15: The awropialO ,egimen lor !tis patienl'1 Qf\IOIococcal endocardiliI is:

A. IvrtpidIin and fJf'fl0m;Qn B. CBtrriaIDne and g«IlIInlidn C. Vllro:omydn D. VllIlCOmyafl and genlllmidn E. C1indIlmyr:in and gt'fIllll7Dl

The COlleCt _ .. D Or~ ~ """'-*l _• ..-.erococc. aidcc:adrlil_ 'egf'le!' A (.,PiCIIO' If\d lI*'JlalllOUl). buI . . ~ ~

hi ••

'edp&~..

. . . pel . . . . ,

~1oenI'1 l'lIslay

a>d 1IlCo' _

~

d br..... aI bre;Wlj .......

,-sbrJlcfe,_ _

....... . . . . -

_ . IS 1'0 a l l _ 8 II IIOl • CQ"rec! _ _

lleCa.... !he cepl\alDq>al ... do no! have ICIMfy

fIM:rmrr... _ n .. IBclIlllt CIJII6. • a ~ pIaee. !he . . - . .. riok of . .

~

_

~ _ _ C II inconect ~ ........... If'lIedOIIO be _eaIed II ~ V ~ " ~ agansI """" . . . . . d ftWrrgxp § buI In endocArdills • is ~ brIcleridcllll Cl1Iy """'" ~ is used in rorrbnaIion WI1h . . ~ so..dl

U

g.nlarnicin. Th. comllinlll'on il syne'olslic

bec/luse V8f'lCcmycin', efleel on eel WII~ synthesis lacijiUl1es ttllO entry 01 Ihe &rrinogIyc05l
c"'"

.... blC1ericidal. E is InOO"'X:1 lor IWO 'e8$Of'ISo dlw>¥:in .. iY ,,,ains d S!MlrdqOCq aRYl. dIio~.. shot.lId not be ...., ~ is ~ Endocarllire; ....... _ , .. (lUg. _ .. __ leIb> allf'ldocardils.. _ • "wgeIlIIa>.' CXlI_I5 Cl1Iy !IIlm, , , ' " n bIcW& nu I _ no cell ,... ••• ~ Igbed
had 10 be treated, he had to be giYen a 0sec:ono.lirHl" drug. erythromyc;n. when his denlist really woukl have preferred 10 give him penicillin. INote: ~ has !he benefit 01 being able 10 penetnlIe ahS' esses,) (2) A ~ MUd nQI ' been safe 8flOUl1I. because • smaI percentage of patier'ls who Bfe allergic 10 pe,i.c::ilir. also ~ allergy 10 cephalo$pOt'ins. The reaction (bron· chospasm) that lhis patient had could be so lifeltYeatening Ihat1he deotisl OOffedly chose not 10 lake the risk, however small. that this patient might be allergic to both p..lactam categories. (3) That the patient had euooclldilis required that the
CASE 6 A 41·~-ofd female presented 10 her priTIary ITllIdical doc1Or Mh • dlief oomplainl: 01 ;'lSU.I lie and net· \/OUSI'IIBSS worsening 0Yef the past sevenaJ months. Since her last W ~ eum, ....-.r:tI was normal. she has ewpeierad inegulat menstruilI cyckIs. She jj .itIed her job as stres9ullnl attrhIted some of !he nervousness '0 her job. BP 135180 (t2MlO): pulse 135 bpm (6O-eO) and regUlat; rest:Wa!ory rate 01 20(12-18) and \en1pIlfalure 01

99.S"F. Physical exam reveals exophthalmos (abnormal prot'uslon of the eyeball) with weakened e~t,aocular muscles (Rgure A.6). Her silin was W81m a!1d moist

~1cidIll

1)"","'5 __

'CXlI,t-_.aI~ngen­

~""IlefWIIIcoIII'-

Many ~Ies 01 antibiotic seler;:tion Bfe ilustrated by this ptltienl. (I) His h1sto
figure A,6 Patient with e~ophthalmos.

<e-o • . . . - _.. ,

<00<''''''''''<_'''_''

IM:U,1l _ _ . . . . )

Appel'l(lix: Illustrated Case Studies

an
CASE 7

palpable nodules or masses. Pulses were strong blIateraily. Heart sounds were normal. Hand tremors preser1ted as well as sJighI hyperreflexia.

A 32 year-old homeless. HIV-nega~ve man lU'lived 81 'he clinic complaining 01 general malaise and a d1ronic productiIIe cough.

Laboratory TeslS reveal elevated !hyroItine (T.) and slightly decreased Ihyroid·&Iimullllinli hormone (TSH). AI olher 18S1S were wiltW1 normal ~mi\s.

The patient stated thaI he had been Ieeling poorty lor abotIt 5 weeks and thoughl he was losing weight Upon ~ eKalTlinaIion. a sI{;IIty eIlMlled 1e"l)Bl'atu.e and chest congestion were noled; no other apparent irJeg.lIariIies were presenl. Lab tesls were

The woman was treated with ~ lClOmg every 1I1loUrs, and propranolol 40 mg I¥ke daily. OuIIstlon A.16: WI*1I_ at lhelall;Mioog'" dllIaibM 1hlI,1W!id• •" at ao;:Iion at ~ A. t«O.lrlg Ihe~ hoo,IO ............ 8. UiOIiirg ItllI """" ......, at f¥dd tOilO .. c.......-onatltlll.~., . ............. _ .. ~

ordered. including a complete blood count (CSCI. sp.cJ.m ClAIre. and an aQO.fasl beciIi (Af8) stain. A chesI X-ray (F.gure A.7) was oblained and a purified protein derivalive (PPDI was administered. The palienl was k*llo reLm in 2 days lor alolow1Jp IItsit.

fly........

D. UIitIiIioI, at iId'oII ~ lnIClltlll rJyroid gland. E. il~lbiIia, at TSH releeM ~ piIkMary CclmIcl _ _ 8

~~"'b­

.....,df¥oid'..."o..

A_ 1..11:

~ u*og ~or ~

"'. .KonI

,. . . . . . . ,1""'''''.

mclII ~ - . -

mug

'-..ioI'1ll moNIor tor.7

B.f..... C. M) 1;011 D. G

oil

¥ OIl (Gllo,.-

E """" CorTei;l • _ ClC
I••. The Olher IIklI 1IIlecI. "lIY ~1fMfy

............... 0.-... '

_.

agrilRMJCl'lOltl

.ill Tlieedliml"le'f be ....... ged wilt> dU.IICS If'ld !he dl."I.e;l _

.~""'1glWU. oueilion A. 11: Wh~ ;Ire ~ .d,energIc bIocl
flee .... Ihi>8IlodIiol i'"hblI ... ~ d . - Ih'r reid hOll, 0100 ....., 00 IolM 10 Wlitlc It>iI aclMly d dr· ~ It¥oid homo ... ~ bIocl<8rs •• needed 10 ~ "l')fl8'lef>lIO::n .-.:l ~diIo d ~ roldlsrn In lI>e lirll lew ......... d 'llIf~. In ~

adrllflllfgic .ltCeplorS I.' upregulaled (thele is a higrIer popula\lQn In U.. visculll~el in lhe hyP'""IIly'oitI patient th" II Is IlT\flOftanl to block lhese P .ecepilors....., ltIOreby leo1>ce It\e bIooc:l preuure, lVolt> 'Cll.fn 10 e
ThilIIgNer _ Ipn _ _ ...

_._p._.. .

..

Ie .......

af _ _

_---.ThIo~.

of~_~

Agure A,7 CIlesI X-ray 01 palieR.

0ueI!1on A.19: 8;lsed on tt-.e ,;,Idioogs, Ihe plltienlls . . peeled 01 haYiolg:

A. Sb"J*>iX>i;cal pnolU:'llOf'Ila B. M!.oNWderjym ;,~ediool C. Pne\lllOC\'Sli5 caOOli ~ (PCp) D. Pseodcmonas n8l,:lK)n E. AuloirnnYJne deliciclncy syndrome (AlOS)

'_'''''''''''00 _ _ ')

"" 11'1e eOH~1 8flSWtl' is B. 1he o;:he!;l X..ay ",m lung if\I~lla"", could ioclicate Io"ll care"" """""""" III o1he< lung ll,seases. HI>~ver, "' ~"'"' ";!h a poo.itMI AFB SIa",- !he leslS irdcale a myc<:tJaclerUn Infe<:tion. INole: A po&IIrooe AFB stain does no! iOenlily the species cI mycobaclenUm, only "'" QE!fUS. A ~ lUis rJ Mycobaclefi<.rn llA:le'cUosrs III Illis lime is l"(lI corl~med but shouIe appeararaJ 0I1he c/lesl X..ay. but this diagno$i$ is rw:>l deli
sis (TB), C Is incor,ect. PCI' fS s.....n ",Imarlly in r.
inIeclOon.

Two days late, the patient returned to the clinic tor a follow-up examination. The lab resuhs indicated that his sputum cuhure was negative for growth, and the cec showed a slight leukocytosis (increase in white

blood ceMs). [Nole: The PPO is a puritied prOlein derivalive 01 Mycobacterium luberculosis thaI is injected stJbco.Jtaneousty into the voIaI surface 01 the forearm 10 stimu· late a hypersensilivity reaction. If. within 24 to 48 hoors there is an area 01 induration greater than 10 nvn in diameter. it is a positive PPD test and indicates thaI the patienl had been eKPOsed to and infecled wilh Mycobacterium lUberculosis.] The patienrs test was positive. Due to his homeless stalus, it is likely that he came in contact with TB-irllected irlcIividuals. Based on the patient's history and lab informalion, he was starled on a regimen of isoniazid, rilampin, P'fI'IlZinamide, and ethambulol while waiting !of definitive cultures. (Six weeks laler. delinitive culture resuhs demonstrated growth 01 Myoobacterium lubercvbsis.) The patient returned to the c~nic oompIa.inlog 01 blurred vision and an inability to differentiate between green and red colors. Ooolltlon A.20: Whid1 01 lhe drugs he is laking coukt be causing these adver.>e visual syfTllloms? A. Isoniazid

B. Riklmpitl C, E/tlambulol

D. Pyrazinamide

The c<:
CASES A 47·year-old woman complained of recurrent headaches. She described the pain as ul1ilateral. located il1 the lemple, and havil1g a Ihythmic l)( pulsating quality. The headact1es arise spontaneouslyolten awakening her in the rrOddle of lhe night. The headaches are acoompal1ied by nausea, abdominal pain, and spots before lhe eyes. aue..tlon A.21: Whid1 one 01 the following agenls is most likely 10 provide symptomalic rclicllor this patient?

A. Oral S
E. Sumalrflfllrl subculaneously

Coreet M$WeI is E: Sumatffnan a~ered so.t>colaneously is ,apidty absorbed and prOYi1 2 hcus. SO that the headaChe my be rJ longer d..mlioo ltlan the lI
pr!M<Jes re'icl w,'hin 1 to 2 hou<&. The head.1ches described by tho!; p>IlieA peat< ,apidy anJgIl to provide 'eire! lor Lhe acute pain cI he, migmine Illlacks. The llioavaJlabllily 01 the oral form is only aboul 15% due to poor absorption anl, These rrodefately e1fe<:!Ml agenls ale used in mild to moderate headaches. C Propt8J">OiCJ i$ used as a prophylacllc agern. 0 Oral

, ,"" '00 .. I., > • _ ... _

",.

• e - .........._ _.. ,

I >

>UOIUl _ _ ....

>

AppendiX: IlIust,ated Case Sludies

~

OS

ft

P06sibIe

~e&lJtIe(II

oplkn Howeve<.

lhe .\)ent ill moll .nact,ve when gIve btI'OfIl lhe tleadact>e .. esl.Obbhed.

,.A. Raniridne

C.

~)'dmIrof>e(Of
O. Scopc:Umine E. PI>e
CASE 9 A 9 yea.-oId boy was brought to the clinic by his molIle•. He was compIa~.-ag of severe pruritus (ilcht1g) and bl.tties on his arm.

VJe'Mng the c:hild'"s arm. Itlll 00d0J' noticed erythema (II red rash) and smaM ve$ic:les (fluid-filled sacs) anaJlged Iinear1y on the cNfd's ann (F'9JI'e A.8). The dot1oJ <:tllldIed the chld'"s profile and Jloticed no prior hisfory of aRergies 10 medicalion OJ' toods, and no prior IlisIory of skir'I eruptions. The SlaI8d Iler son had not been Villlllio'\g ~ dofil'O OJ' IabIg 81'1 (M!f ltJe.o:uller-fTllllications (orC).

,,1OthaJ

The ttm!Ct _

is C

~..,q

. . . 8I1lI-

hislamine 1h8J is a CQrnpel'liv. iNlibilCI' olllle H, , ~ . _ ill UIv hlsl8l'Wlll I$ • wi! dto . . pru-u rlElw1g) an:! """'"' d ... ~ poduced by' .... 'dea$e d to:\IafI're.1N<;Iito ,~ ~ oIuAcI be caJIicn In ~ de
_led

wed""

swr..- """" naaU>.) A OS n:;cr'a<:l an Hz I

Rao~os OS ..... _"""'fSIl1W • uaed III _ I gesroc:

_1'\>_""",' ...... nDllll!oe<:M 1lQIWIIl~-.iIMIY , ~ ~ ~ inaIancM_ I>ey ere_in w,tIio Ii, _GjjO I" II. 1J"tCOfect.

_

.. h

~iII

__,

",

_

~

~ancI

'*"ll ....

paroc - . . . ••

D. (.I".""•..,.....-

ncI Rloc:aMld lei '" pru-__ irIcuIl!Cl So, ....,••• po. mriI' III _ ~ sOr-. """ ,.. .... &'&(IJIQc

etlettEosio_,..;L,.".._bIaI• • _' a.o:allil

.. _

'''C(antl . . . ~ ~ ) _

~.

FIYe days later the chid .et!Jmed 10 the dinic.. His haflds, lo.earms, and chesl eoythemalous, swollen, and covered with blisters. His motile. ecpIained the poison i¥y was star*lg 10 dea" ~ bUI .-.en her son disobeyed her and wertl if*' .... woods

.,e

...........

Rash and _ . lei on paIillnl's arm.

boJ

had .eoantIy been playing more oulside ~ Ihe yard, due to the Ilol weather, and his rnotIler asked if ltle JastI ClOlJd hIll/ll beencaused bychiggeJs (larvae of miles Ihal attae:hed 10 the $kin). Wdtl Itlll pa6enl's IVstofy of playing 0\.IICI00rs, and Itlll dlar/lOo terislic hili vesic:les. the doctOJ' belMMtd that the dlild had an aIergic oonIaCl I'fVpefsensitMt reaction to poison ivy, and InstJYCted the mother 10 apply c:toehs soaked ~ BurovIs solution (aft.n\hlm acelate) lXltif the Yesides crusted over. The molhef was also told to thinly appIyt"" hydrooOJ'6sone cream (a low poIency steroid) twice pe, day.

The

Question A.22, Thlt hypersensiIivi! ,eaction was no! S 10 wallent stlonger phalll""""4'>g Ihclmp)r, blA Iha palienl IOQuests IOITl8 romody 10 SlOP Iha pt..tIUS (~cNng). wtW;h til Iho following drugs &hooItl be

,-

~""'. Dundon A.23: wticn one "' . . Iooii... ~.".'. g Iheo~ $hIlUId '-'oe bem poNtitleol nea 10 atlBnu-

_ . . ~ ........-.? A. AfIPY hl tr,ckc:atisOl"'aearTI mcoelfequenly 8. OoaIp«dlisollfl~,l8pereddown_ 2 ~ C. HosP\3fiZaIion O. &llaliE'll'_ _ oio.,."..... occlusion E.

AR>lY ice It~

11)'"

lte COI'fect IIJlSMlI ill B DA iflCI'ellse<\l8)' II) '~II, ... ....... Slepin ..... _ia ",IllAeladl nedol8lllll11. _ glucoo<>tictitl, is cc<','o oIy I.IH'd lO.eM CCI'lllitil;Jro ad! as""'" ~ asltn"'8, 1IJlIl .......18 nedo ..... acts by deCle""""O the prOlt..dlon '" !he IT"'8diUors Q! inIIarl'Tm\llll\ It"erl!b\l rl!SUllOg in its artirl\iIm'n!Ily

octic:n.. A is iro.ollItlll:t Hyal is indiC:lIed tor mild iolI\aIm1aliQll ;u>d ;mlalion '" 1hII skin. ThII etoICl"S inIll\rM'1f1l1011 is severe encvgh 10 'equi,,, S)'$lemoc Sl~oIc:IlhII
·"'" ,... _,.,

........ _,)

Case 10 Sp~ • CtNm

co...- SUCfl a

p-adICIl and may _

10 a dBae

ge ..Ill • no! '*'\I ~

CUI'>-

ptolnce C II IIICOJ,eet H05pIla~n1Jon mooN be ,equ;ed ~,. d*l's ~ ..... 1*...... _ ~ C6 , , _e se>o",~ detillf og• .,.. d'ikl • A"Ib.IaIaY _ .. no _ disftsa, _

'Ij)IU'=d.-

,.-.roo.

-..ed en an Q "l ife I bIso5. D ill irco'. a ....ong IDpcal _Cfll INl ......., be a.<Jded ..... ~ ~"-.:id _ lIrge _ _ InlI pc8ti,r bfd<M _ e. lnlI l<JICIty I: I i _ · recI. 101....,. dlIo • SCfM of I a - . . '-"1lf\4lIiCn. ... CIr\ be •.,;1. Ii'll

O.....tlon A.24: v.t.t _ _ of ..... MIl gil

.sr.

ute,. asaooiIled

'kod hlfap(1

~ Pled. . . . ihefaI>II g;.w. (M!Ii • " " ' " pllflOCl is r II _ a ~ (II $ode eIlotcts..tllo:h IIICIude IIypefglj'OefT"OOl. inaNSed susoept,biIi!y ID onI«llOI\ O&1eopc:f05fS. Cur;/'irog's S\'I'O""". C*llfal "'VWI Iystrne (CNS) ell!!Cls. 1I1tK:1'oI)'ll lIiSl... •

bllf'oOIIl Md ,do_, insulriciency. 1o 'void U"H eI\eCII. p'ed'\Ioue " gi\oerl ta a stot pllflOCl

~

and "tepered dc:Mol

hc:..vo..c ,. 'f'9O"TWI.

CASE 10 A SQ-yeafo()kl temale visiled lhe clinic to< Ihe 'irSI

lime. Her chlet complaiot was stomach paio aod .lKler1l sweUiog In her legs. The 1'>UI\30 described her paio as sharp aod IlX:aIized, and stated thaI it had 0CClJrTed ,.equeotly wmg the previous :I week$. One week prior to the clinic visil. she had Slafled IakIlg IoIMl..Oll (ak.ominurnImaooesiu'n l¥i'wide antacid) and it seemed 10 ~ al first, but lhe pain penisled and shof1fy thereaher fie leg sweRiog appeared. Her pasl medical history irduded • prior
episodes of shorloess of brealh and iocreas.d taligue. Her current medications Included digolOrt. hIpro6en. MaaICa, and Iurosemide (1.JISl)(j. She also slated !het she had hean:\ on Ihe _ !hel aspirin milttl be good lor !he heart. so she had ~ 10 t8ke tv.o ~ a day lor her heart condition. The physician ordered • eIectrolyIe panel. digoUl level. and a ttemoeeult test (10 test lhe 51001 for signs 01

cae.

gastrolfttestioal bleeding).

Oueslloo "'.25: Based on the ioiOffnlrlion p'.senlell - . ..nal bB ....,;pila'iog ... SIl:In'i;Kfl p;Wl?

""'*'

A.~

B. Jj, IM!lfi C. NoflSleioilliol anIHnl\arTVnalOrY dfug$ (NSAlDs) D. FtlIOi56l"rNdD E. Aluminum/marlnesium hyd,o"lde combioatioo aotllCid (Maalo~

1he CfI proouC\_ d etid..-.:l~ .... proleCliw rrucx:us

r_..

.... ,oad'I _

(II,.., Gl _ . PldCoogeG t$D

10 decrnse
CirI

CJ.l8f'IioM

GI _ _

Itoer_ lead$

(II ~

u..

~

and Itus

was prllliCfbed

.... NSAIO. ~ 10 clecreese IhI lyr'I"lpI<mS her It....-ilI ...... St>a .... aliso ~ , -xr>cl NSAC. ~ 'Ahd'l e
._lion _ ll'*,e--..,. '8ftXI'''' •

.'

1

....

~

b .... pan

A. O'\Cafacl t:liplfon _~ 10" ~ of

caIlod ... eatlIiec:

lIlY' , _

~

UIeCl III __ Of'

l:¥

n;reaaog ... AI..-.gItl d .... ' - ' CO"$iCUOfl and

wnprJIP,a, Side aIlacts 0'\Cl.dlI _

_Ill

..-.:I

~ ~

l::JkIfell-... anlI ~

_

~

CNS fIIlolca ""ct..Orog boJ 00I1twp .... ,oactl

8 IS looon8Cl HeI'C't!l'C'ft

Il:Dld _

-.

' ..... atar'ISd'>.-.. F1an ... Q8IiIr( hosIay....... "00 ~ ID IcrloIfIlIIIIf>cU ......... ........Iig..im ~ _ _ DCIIo:lfVelI - . t1 mlI;D. D is raxrect. FuO$4lO,Otif Ii a loop diur~ used ID eIirrf. nate lIuId in patienls wiIIl I\uod _ such 1$ . . CHI' C6 pat,anlS •• pa,....eing pulf\'lOf"11fy _ f'utos8rrK1e is , Ia!;I ac:Dng lIiurelic will oilIe effects Ihat indo.de: hypci
include

be

exc"SIii~a

S10m,c" pe,n. E Is inconecl.

..........,., ....... _,. AflpendlJ<: Illustrated Case Stvdies I-WoLOX is an ~ ....... /lyd"o.>.W carlJi. ""lIOn lIIlladd 1hM OS L.ose<J lo treal 003rlt>..o"n ane COl'lblnaIia> arwacid I>as bIlf.:o1 .........., lo cause CMSlipati<:n. dlar'hea. and 8\ll!f1 eNS ette<:ts when used in 'enally e"",p'''''''sed palienls 1m exler>ded "",iods. buI does no! cause sharp stem.""
""'.

Question A.27: Which oIlhe follaHing drugs is NOT an .... .ooeplor antagooisl?

A. CimeIk1ine 8. FamOOdine

C._ D. Nizatidit1e

The doctor hypothesized that the woman might have gastric or duodenal ulcers trom NSAID therapy. and told her to coiled three stool samples to be analyzed lor the preSl!OC(! of blood. The doctor iJlStrUCled the patient to disoontinue using jbtJprofen and aspirin unlit the actual reason lor her pain cook! be diagnosed. She was to return lor a lollow·up visit in a lew days. The doctor sta,ted treatment with an H2 receptor antagonist to prevent any turther 61 irritation. O""$llon A.26: Why has the doctor p,esc,ibed !he H. receptor antagonist?

Answe<: AI H, 'eceplO anle I,om ;n'e<""hng "";th ,he H••eceplCl. thus decreasing Ihe producllon 01 hycm:tlloric acid

by II>e stomaCh. This dec,ease in actd productiro aIows !he SIWl8d1 uIc... 10 heal. They also inlet1E<e in gastrirl-mediated ackl sec<eticn Basal and roclumal acid secreoon is aISdenal ulces in patienls wi'" artrwrtis '~Ion\rlerm NSAID l1lefapy.

-I-- '

, •• • •

-

.

.. '

..

E. RlJflifidin6 The CW'ec1 a-l$weI 0; C. O'nept.orole 0; an

.,,,,,,,,sible

iMibllCl 0I11le H·.K··ATPase (the 'ptOlon ~. 01 the parielal cell). n is use 'ecepIOI artagoNsts. They wry in 1Ilei' side etI8C1 !yOlile and to some extent in IMi, pha,macokineli(;s. Cimelidioo has Ihe mosl side etleclS. which include croluS'Ot'l. d,u,ness, d,a"l",a, muSCle pa,n. and gyne<;omasli3 (beast enlargemet1l) in addilia>. <:i'nelimne is a cytocluorne P·450 enzyme inhibi'or lhal dec'eases lhe metabolism 01 ottle. d.ugs and can lead 10 mug IOxicity. Farnotidine has lew side eftects associ.1led WIth its USG.

Duesllon A.28: Would \'OU llave .ecommended ,hat she cominoo to lake the MAAlOX? ~. Probably noI since she was plaw:l M the H> 'eeeptor an~1gorHst Ihe,aPl' l\fId Ihe antaCid cOUld M"" <:aUSOO ptoblems suc1las consripaOOn and l!iar. ,~.

The doctor next addressed the problem ot edema. The patienrs blood digoxin level was bund to be in a subtherapeulic range. probably accounting lor the ankle edema. The patient was questioned about being noocornpliam (not taking her medication). but she Insisted 1ha.1 she look. her djgoxin every day aod that the swelling in the anktes appeared after she slarted taking MAAtox. Ouestlon A.29: If !he paliem was being IruIh1ul abOul laking he< medication every day. ..tiel <:ouId havo caused !he SIJblhe
I

"

I I

W... ks oIlfe,lltme'l1

FlgureA.10 Cumulative incideooo ot gastric or duodenal ulcers in patients ~iving long-term NSAID therapy.

-

A. Tlle liJrosemi::te was ;"",.easing he< urine output and theteby incrcasi'lg the e1irni'oation ~ digoxin Ifom the B. Aspirin was compeling 10' prolein binding wilh <Jgoxin. I<1adi"ll 10 ioc.eased concool",lions of rroo digom and thus more l,ee digoxin Climinatod by the

'''''''' ,,_.

C. The pallenl is simply lorgelful. and believes she lakeS her medication regularljl. bill trequenIIy misses

<-,'",,_'e'><

')

Case 11

'"

D. The antacid She had beefl taking had been bil'ldlng the 6goJ
The correct

I!I1SW$ is D. c.:.-nbirIalion ~. flyrfi<»OOe l>/lIlICids h.I\'" been I 10 bind cenain .... in Ih

potatoes. but lew vegetables. His other medications included an li/bU1ero1 inhaler, metamuoll, and a daily mUllivltamlo tablet The doctor ordered serum electrolyte levels and II cee with dillef8l111a11Jom lhe lab. Recognizing that the patient had a couple of problems. the doclor decided 10 deal lirSl with 1I1e CfllrTIPs and tatigue.

~

systemic circullllion. The paliet11 I1aIl

no edema pr;or

10 laking MM'-OX. but """eloped il shof1ly 1I11er _ Slarlelll/lliin
«

is lrue then suspension 01 emecill imake shoule co.rtp..l by 0i'iIJiIi"ll 8 carrier syslem in the escenlling 100l) 01 Hen.... II does 001 increase bIooIl clea"ance oIllfuOs by the lo-booxKl, [);gwiin is ~ !han 25% proIein-boo.nl. Even f aspilin IlKlIlispl8ce jn Imm blOOd ptOlelns, "'" """eose in lI>e fme 1f3COOt of digt:»g worse an:11he ;11"1 or taI
CASE 11 A 57-year·old obese male with a history 01 mild asthma and hypertension amvoo at the clinic lor a Ilu shot and annual physical examination.

The doctor noticed 1I1at the patienl had boon placed on I'rydrodllorothionide 8 months earlier lor treatment 01 his high t*lod preSSUre. Throogl1lhc course 01 the ei
~I """"" The doctor pllfformed a physical examination that revealed a BP 01 143'92 mm Hg w~h no other abr\or. mal signs. The patient was questioned aboul his diet anr:l any other medications he had bool'l taking. anr:l he responded that he usuaJly ate a lot 01 meat and

Ouesllon A.30: What coold be causing !he pa1ier'll's tat9Je and r'I'lUScIe cramps?

A. He haS come down wiltI the flu,.midI is responsible lor the tatigue and cramps.

B. The 8IbtJretolls mspoOObIe tor thIl symplOrTlS, ammonly seen in asthmatics on alluten:l/therapy. C. Continued high blood pressure Is ,esponsibIe lor the symptoms (1ha1 is. tlIe paller'll's blood pressure is not controlled witI1lhe thiaooe therapy). D. ThiariOe therapy is causing poIassium depletion aod resulting in !he cramps aod faligue. E. M6tamucil, II bulk lormlng laxalive. is leading to Ilehydration, YItlich gives rise 10 latigue and cr~

The coffeel enswet' is D. ~ is a ttilWde 00"';'; thaI exerts its acllon 81 the distal tubule d the kiIlrley. It VI()fks by irhb/lW'Ig a sodi.m'ctb"ide IranSpor1/lr. which leadS to increased sodi Wl'ltl!f ""creOOn in10 !he lrl"Ie and diurws the elimination 01 sodium is inc'easell. the kidney exchar>ge!l polaSslun tor sod<..... in the transporle< (both a,e monovalenl cal,ons). which ove, an extended period can ""'" to po!assilrn deoletion. II sutlieient quantilies 01 potassium life not obla,ned Itlrough !he diet or by exoget'lll<JS suP\llements, en inIlrviduaI may experience ClsrJ"4lS, latigue, BlId p0ssibly lIfrhvrtmias. A is incor'g these SymolOmS lor """'" a """"'" wiltI no~_ e is incorrocon.1fiCliorl e,perier>ced by aSlhma sulfe'e's ck6ing an aUad<. The rr'll51 COf'flrrU1 side eII:tremcly 1"9'. l.lrd!lf

a""

_cas

_ cira.ms1a'1CeS. Ihe palient will be ~ obvious dis_ kess, and rspid medical treaonent is ~atMl. The parien!"s contimed hypenensioo mighI r"'llJ! .., lUI...e disease. bu1 his C1I'rMt SY"'fJlOI"S are noI indicaIors 01 IlyperlllllSlCO. E .. incoo'ect. Mewno..ci'is lIfI DlC buI< torming I""atlve which. When I~en with water. torms a bull<}' mass thai slrnU!ales GI rmfilily. It has

been known 10 a
<_.0......'.. _... ...-',

."

Appendix: IlIuSlraled Caw ShJ(lieS

teme ~""'. AdVffse side el!eclS 'rduOe nausea, 'o'OIriIing arKl &IOrnaCtl pain. MelamL<:il
fal;g..",

me

p'U8
The lab lesl ,esuUs we'e 'eturned, and lhe dOCIOf notlKl that there were no leukocytosis Of abnormalilies on the cee, but thaI lhe serum e1ectroly1e resullS showed a marked hypokalemia. as was expe<:led. This provided an explanation lor the palielll's cramping and the 1aligue. The doclor p,escribed a polassium wpplemenl tor the patiool. due 10 lhe extern ot his hypokalemia. Next. the dOC10, began 10 address lhe palienl'S uncontrolled hypetlension. Believing him 10 be reasonably dependable and compliant with his diuretic therapy, the doctor realized lhal the patient's current hypertension medication was nOl Yo(lrking. Inslead 01 incraasing lhe dose ot hyd,ochlo'Olhiazide, he fell thai the patient would benem Irom an addiHonaJ antihypertensive medica1iol1 in combination with his preSOOllhe'apy.

Question A.31: Whidl adlitiorIaIl!f\tihypel1ensive medicaIioo> will mosl benefit the patient?

A. An angio1enU> c:onvertiog enzyme (ACE) inhibiIor

B.

N~fQ{Iycem

C. A ~-bIod<e, O. CIondif1e

E. Hydmraz;n" The COn(ICt ~ "' A. ACE inhitlitos llfe "'" effec-

ti"" g'oup of anlih~pe
"8SOOalStrictiorl, ACE iflhIbiIofs slso de<:.-eSS
""""1m

terone secretion, resd\irlg ... less III1d water reabSOlption and tesl potassium wasting. ACE irHbn",s also decrease the lJ<e8kdcwn of 1lf1ld\ole Ueatmenl of aslt'vna patients. ACE iflhIbotos Bfe gm--... ~ w~t 1OIefatOO. arKl are the basI choice lor 1tWs pallel'll. Is InCorrect Nitroglycer,n is "" ",gani<: n~r81e used lor Jts vasodiIaIof ""ron 10 Ueal angona. II is no! indicated lor the tr~ 01 IIypel1er601. C is iocofrOCl. ~s Bfe a group or ......oic8IiOfls used 10 \real hypef1ensiOfl. IIIlgina. gl~ and rc/facIofy migraine headaches. AJtro.>gh """'" Il-bk><:l<efl are ~,-spedlic: blo<:keo-s.!hey ma~ IlIso ha...... 1\> bIocl<...g actiOfl. Use 01 Il-blockers should be in asthmll pati""'•• bflca.ose 1hey may ""perience broncl>oc:oI'Is1ric Sfld an IISItrna 1lI1ad< H their lI>'eceptors are blocked. Also. I\-blocl<ers may cornpHcale "elll1'rl91l at bron<::hospesm l)y decreasing \tie alleo-

e

' ' '<Jed

Iiveness or II> agr;nislS such as ~. The psl$lt suflcred Iforn mile add be used, tlul ~ /'las 8 18aeo- sid-&alleet orotde and ShOUld p'obably be rese",ed !of pe1Jents ... 1Il mote sevee hypeI16'"$ion. e is r.x:.-recl. Hydrlliazine is a direct ""ting VIISOdilll1Of used to ~eat fI'IOderale!y _ere hypel1ensian. HydfBiaz.... is no! a lirst 'ina agent, oue 10 its man~ side eHects, atIIJ is used In combination wilh other "{lents. Since the patienl sulfers only iforn mild hypertensiOfl, wong antihyper1l!flS1\ie lhefap~ wilh tlycJraJllzJna is no! WBf'/lI1led.

,00<.''''''''''''

''

<

e - • _ _ • , .. ,

lCI'<.A>IJI . . _

......

This aooondum provides a current update on important drugs that have been added to the clinical arsenal since the second edition 0/ UppiI'lCOtt"s Illustrated Reviews: PharmaookJgy was published. The addendum is organized by chapter, and eadl drug is presented e~her as a continuation at a preexisting section co.ering similar·acting drugs (!of example, add~ions to the list ot drugs used to treat Parkinson's disaase. below), or as totally new types ot drugs (see the section on th'ombin int1ib~o's, p. 448), Extensive cross-references 10 relBllant pages in the body ot the t!lld allow the reader 10 pIao9 these recently approved drugs in their proper dinical COO1tBllt.

Treatment of Parkinson's Disease V. DRUGS USED IN PARKINSON'S DISEASE

(continued from 1188)

The following a,e new, nonoflrgol dopamine lIgonlsla that have been

apprOYllCllor the treatment 01 Parmson's disease. PramjJexOO
Pramipexo/e {pram i PECKS ole] and ropinlrole [ROH pin i role] are non-ergot agonists at dopamine receptors. They alleviate the motor deficits In both /~naTve patients (patients that have never been treated with /co.Odop8 therapy in early Parkinson's, and may decrease the dose ot lavodopa in advanced Parkinson's. Unlike blOmocriptine (an ergotamine derivative, see p. 87). pramipcxole and ropiniro/(l do not exacerbate pel'ipheral vasospasm. Nausea, hallucinations, Insomnia, diZziness, constipation, and orthostatic hypotension are among the more distressing side-effects 0/ these drugs; dyskinesias are less frequent than with Icvodopa. The dep(.1ldet lCB 0/ pmrnipexoIc 00 renal fUnction lor its elimination cannot be overly stressed. For example, cimetidine (see p. 236), Wtlich inhibits renal tubular secretion ot organic bases, increases the half·lite 01 pramipcxok! by forty percent. The nuoroquinolone antibiotics (see p. 323) have been shown to inhibit the metabolism ot ropinirolc, and enhance the AUC (area urder the oonoentration \IS. time cur.e, see p. 7) by some eigtlty percent. Figures 8.9 and 8. to summarize some properties at pramipexok! and ropinirolc.

BlDoval_y

• _

55 '"

V. Hall-III.

7~

7.5lJ1og

a t\oural

alloln

.... ' .....

'I. gil'" '0

Elo_..

1;11_

lion.. _

I'IerJ

'Inasea ttl 12 hOuIl;." po.li
'0'" _

Figure 8.9 Pharmacokinetic properties ot dopamine agonists at pramipexo/c and ropirJiIOIe.

"'........-._.. c-. ~----"."-.-_ _ _. _ ' " ........ """'"

443

<_.0......'..

" Pharmacolo5w Updale

_..,--

G. Tolcapone

-

.

*

-

-

-

~

.........

~,,",,tiuo,

.............. cI 1 10 5 pen;;fOnI: ++ • ;, cJdw I0Il cI 6 10 15 peoanl; ....... _I0Il cI 1610 25 pen:ent; ........ lCideoiOtclg-..1hon 25~.

Agure 8.10 Sicle elfBCls 01 dopamine agon;SIS pramipexole and ropiniroie.

ToIcaponfJ rroLE ka pone] is a nitrocalechol derivative that represents a new class or anti·Parkinson's drugs, II selectively and reversibly inhibits both peripheral and cenlral catechoH)-methyltranslerase (COMTl (Figure 8. 11). Normally, the melt1y1alion of Ievodopa by COMT 10 3-Q.fnelhyldopa is a minor pathway !of IEMxi:lpa metabolism. However. when peripheral dopamine de<:arborylase activity is inhiMed by cartJidopa, a signilical1t cooc:entralion 01 3-0methyldopa is formed thaI competes with Ievodopa lor actiVe transport into the CNS. Inhibition 01 COMT by lo/capone leads to decreased plasma concentrations of 3-o-melhyldopa, increased central uptake 01 levodopa, and grealer concentralions 01 brain dopamine. Tokapone has been demonstrated to reduce lhe rrequency of the "orHlff" phenomenon. 1. Pharmacoldnetk;" Toicapone. laken ooally, is readily absorbed, Bnd its absorption is not intluenced by lood. It is extensively bound to plasma albumin (>99 percent), and has a smalllllliume or dislribution (0.13 L1kg). The plasma hat1·life is approximately two hours, although inhibition ot COMT may lasl considerably longer due to ~S affinity lor lhe ElnZ)'1OO. ToIcapone is eldensively metabolized, and its metabol~es are eliminated in bolh the urine and teces. Dosage may need to be adjusted in individuals with modefale or severe cintlosis.

2. Adverse ef1eets' Diarrhea is the most common side effect of teJ· capone. As eKpOCfed. leIiI:XIopa-reIaled adverlie effBCls increase when tokapone is added. These include postural hypotension, nausea. sleep disorders, anorexia, dyskinesias, and hallucinations. Most seriously, IUlminating hepatic necrosis is associaled with /Q/capone use. Baseline and Ir9Quer1t, regular detenninations of hepalic serum en:tymes are suggested by lhe manufacturer. Any elevations above normal are cause lor discontinuation. Because of the hepatotox\city, toIcapone should only be used as an adjunct in patients on JevodrJpaIcarbidopa who are experiencing s~tom fluctuations.

T_ -,et;" .-... T'-- ..... ~

Mi"

$

1-0"

I red

....D..

1Ii1

iN

i,

L

... 01 _ _ . . . . . . . . . . . . _

'"

:

u.

11\

-

i' _ ... 01 DI _ _ ... . . .t ._

Agure 8.11 EtlBCl of tolcaponeon dopa conoontration in the central nervous system {CNS). COMT '" catechol-Q-methykranslerase.

.

---.

~

Dope

InCNS

' ..... '''' ..10'.'

,.

Chapter 15 Upcla!e: Drugs Used 10 Treal Epilepr;y

<45

Drugs Used to Treat Epilepsy

15

II. ANnEPILEPTlC DRUGS (c:ontinued fn;Jm page 150) PattiaI seinns aocrJI.WIl tJr!he majority olull,..klly ~ door· derI ~ IIdJls. often recp;ng more than 0tl8 drug kl act#a.. adeqI me ~ control. Three new ~ Iild1 ~ medIanisms 01 aaio'l have 00.. ~ tJr use in J*1W ~ Md, sec:ondariy. g.n.ralll.d ••llur... figure 15.9 summarizes some lherapeulic aduanlages and ~ of I :ted 1Il~ drugs.. 5

_.M

Therapeutic AdvatltajJ!8

-I-

I

01 .. dally

I.nag~

T~ [lye ~ been]l*ld<s GA6A uplake inkl pt85)'OlIPtic ncvtOtI8, pe<mifting more GABA 10 be !lV8ijabie tor leceplor binding,

_

........ dnIg

~ .....d ...

lhus C8U6ing enhanced inhibitory activity. In dinical lrials, tiagabine was ellecllve In decreasing Ihe number 01 seizures In refractory palie<11s with local epileplic disorders.

1. f>tIarmacoklnellc.; TUJgaoos is well absorbed orally (bioavailabil· ity Is 90 percenl), ahhough load slows l1le ralS bUl not 8X1ent of absorption. Bind~ 10 plasma proleins Is 96 percent Tlagabin6 undefgoes two majof metabolic pathways: 1) OIlida1iOt1 oIlIle lhiopheoe mg. and 2) gIoctJror»dation. c:>ny two petOOI1l is 8llcre1ed lrIChanged. The ma;ooty 01 Ihe 8IlCfe1iorl is biiafy (65 peroent). 'Nitll 5QfTlEI 00nary excretion (25 percent). The hall-lile in healthy ..ounloors is SlMlfl kl hours.

.w.e

2.

aflKts; Decreased mantenance doses fTIIlY be necesroary in individuals wilh hepalic impalrmenl. Ac!YerSe sHeets include ~ dizmless"" gasl' .... 'ls I-oal t.piel..

~

~• •

,

-.

...

, ... •

t.a>_ ....

,.,.

-

:. r

~rd"

1"11

JT

•

111; . •. T""I&

J. TDfIlf'8flllll1l

1. Pharmacokinetics: Topiramale is well absorbed, wilh an oral

blGI!v3ilabilily 01

eo pen::ent.

Peak ............ 'lrations 0C(:tJr In aboUt lWO hours. some 30 perce
~

•

•• • • •• • • • • • • • • • • •

•• •

i'o

PYRE a rTIiIIel. a dIei"ical rMaliYe 01 Innose, has S4MIfaI . . . . 1$ aI theoapeulic OOllOBlllraliont; thai: ..... 'bibute to its anliconvulsanl aclivily. These sClionl include blockade 01 Na°-ehMnels, ~eased GABA aaivily al GABA receplOfS. and t*x:kadll 01 some gIulamal& 'ElCel:*l'1. When added 1 O ~ therapy in refractory palienls, kfliramal6 causes II SO pelcel,l or greatet red! ICIion in 1he rurber 01 partial Mizures in appro
----. """'" • ~

--".~

R,q.'._'" ,•• .: ....... '

I.

I~-I

Thenrpeutlc otudvantages FIgure 15.9 Summary 01 Iherapeulic advantages

and dlsadVanlages 01 antiepileplk:

<,...".

<_.0......'.. _... ...-,.

• - - - ....................,.. , """""" .. _ . "" >

Pharmacology Update

2. Adverse etfect.: These are primarily related to eNS and Gl disllltbancaS. They irldude impaired COOCEK1IraliOfl. diZziness. ataxia, diplopia. somnolence, nervousness, and contusion, as well as nausea and weighl loss. Renal stones have been reported in 1.5 percent of patients. Top/ramate is teratogenic in animals, and shoold be avoided during pregnancy. Inducers 01 drug mataboIism such as phenyloin and cartJamazepine decrease lopiramale serum concentralions by approximately 50 percem. Topiramam decreases elhinyl estradiol coocentralklns ot oral conlraceptive preparations, and individuals should supplement tile amount of

elhinyl estradiol. K. Vlgablltrln

--

,~.

AgunI 15.10 Moc:haIlism of action ot vigabatrin.

20

Vlgabatrin [vig a BAT rin] was designed specifically to irreversibly inhibit the enzyme GABA transaminase (Figure 15.10). Inhibition f8SIJlts in increased levels of GABA if1 the brain. Numerous sludies have established lts effectiveness in reducing the number of partial seizures in re\raetory patients. V
Drugs Affecting Blood

V. PLATELET AGGREGATION INHIBITORS

(continued trom p. 197)

Platelets respond to vascular trauma by "activation" processes. which in\oOl-e three Sleps; acl1esiOflto Itle sife of inJury. release 01 intracellular granules and signaling molecules. lollowed by aggregation 01 the platelets. The Last step, aggregation, is mediated by a family 01 membrane gty<:oprotein receptors that can bind adhesive proIeios, such as fibrn:lgen. \IOf1 Wiltebrand ladOf. and libronectin. The roost important is the GP 1Ib11l1a receplor, which ukimalely regulates plalelel-p1alelel intllfadiorl and thrombus Iormalkln. Thus, platelet actil/iltion agents, such as thrornbo>:ane A~. ADP, thrombin, serotonin, and collagen all promole the conlormational change necessary lor the GP 1Ib11l1a receptor to bind ligands, particularly tibrinogen. Fibrinogen simultaneously binds to GP Iib/llta receplors on two separale platelets, resulling in platelel crosslinking and aggregation (Figu.e 20.14). Plalelel aggregalion inhibitors described here block GP IIb11l1a Of ADP receptors, thereby decreasing chemical signals that promote platelet aggragation.

'_ ......10'.'_ ... _'> Chapter 20 Update: Drugs AIfocling 6Iood

'" £'II g

I'lbolo » ,",''' .. -'Y_ .OGfl_, I;l ..... two __

~Iet'

au : '

.....

ooln

~

cn,

;h Figure 20.14 Summary 01 anliplatelel and antilhrombin 898f1tS. O. Abclxlm.b Realizalion 01 lhe key rokl 01 the plalelet GP 1Ibt1l1a reoeplor in stim.Jl8Iing platelet aggregation dirocIed a"erTlplS 10 bIodt lhis reoeplor on &elivaled plalelets. ThIs led 10 lhe deYeIopmem 01 a chimeric monodorIal antibody. abciximab (ab SIH ksih mab) . .....tIicI1 is 0Qnll0S9d 01 Feb fragments 01 a """ririe monoclonal 8I1tibody direc1ed againsl the gIycopro4ein GP 1Itv'llla cornpIall: joined 10 the Cl;lflS18l11 r09ions 01 t'UTIan irm'Iu1ogIctuli. By bir'ol:klg to GP llb!llla. lhe ardlody blocks !he ~dii'9 oIlbinogen (see p. 194) and wn \Wletlrand tador. and CQrl&equenlly. aggr09aliOfl does not ()(:CUr (see Figure 20.16). Abciximab is given inlrilY9f'lOUsIy as an adjUI"CI 10 p8ICUlaneoUS ooronary rtleMlnlion lor f1e pre. & lfi...", 01 c:ardac isch... nic a:Jrlllieaticw.. Ht.priIor aspm is gM!n with iItJo'xio»18b. Atl8r cessalion 01 inlu5ion. plalelet funclion gradually returns teMrards normal. the anltll8lelel eltet1 P'" . r III lor 24 10 48 hoI.n. OpcmallUldion 01 uealll ..... has no! been deltlflTlined. The ma;or acMIrse eIiecl is polalIiaIlor t; eejil og. 8SjlB(' aI'J ~ 8Jbi;Wrnab if; used wifI iDiooagI" IIn5, 01' ~ the pati8nl1'las a diricaII heoll(llltlagic COl diliot I.

E. Ep:l1ibMkSe lind lirofiben

.."

'

_ , . _4 _ _ E I. -~-

•

r..o arqpl

1 1 d"llgs ad ~ 10 iJbciU'uab. bIDc:tJi rg Ile EptiR!aIide [tip" FlH bB 1ydeJ.., tiIoI'IwI {t)e 108 FYE bani ITWr*; the ~asparticIICict seq.oenoe 01 Ii>liliO\IElil. ...t1ich accounIs lor !tlei" spedlic ilrUgOlliY" lS It*! I... OJ ...... These otWlJP()U'ICI$. like abciximab. can decrease the illCidel lOll 01 d.onobolic COI,_!!lWlns asrotia*, wiIh IICU18 coronary Sy,,(1I(l111ElS. Wherl ~ irII'usioo is stopped. flese agen1S are rapilIy cleared rrom !he plasma, but thW etlect can persist lor lou" ho\n. E¢fjOaJide and its met8bdrtes al8 eKC"eted by the klclney. TIfOIfben is 8llcr6led I.W'ldlangecl by !he k01ey. The major adYerse etlect 01 both d'ug5 is bleeding. Fl\iUre 20.15 Sl.IIOOlaril:es some dinicaI ertects 01 the GP 11bt111a reoeplor antagonists.

These

(pl.".

GP Ilb1lIa

,(I(~.

Agure 20.15 Effects 01 ~ 11b!l11a leoepklo' 8flIagOrists 0I'l the iliOdeoa 01 death or nonfillal ~ Warction !clllo¥Iing percuIaneOI.Is transIln1inal

eoronary angioplasly.( NoIe: Dala are rrom 50lMlral studies; thUs reported incidBi ICe 01 COI'tl'Iicalions with slandard therapy Is noIlhe

same lor each d
._ ........ .. -... _,. ,

Pharmacology Updale

F. Clopldogrel Clopidogreilclo PIH doh grell is an analog of ticIopidl'ne (see p. 197). IJke thaI drug, cJopk1ogtcl selectively and ilTeYersi~ blocks ADP binding to platelets. h thus prevents ADP·mediated activalion 01 the gtyooprotein oomplex GPllbIIUa, Ihereby inhibiting platelet aggregation (Figure 20.16). CIopidogreI is extensively metabolized b'I the liver, and its action is doe 10 one 01 these me1abo1ites 1hat has yellO be identified. Elimination oIlhe drug and its metabolites occurs by both the renal and fecal roules, lis primary adverse effect is bleeding. Since clopidogrel can inhibit cy'Iochrome P-450 (see p. 14), il may inlerlere with the metabolism 01 phenytoin, lo/btI'amide, warfarin, f1wastarin and lamoxffen it taken coooomitanlly.

XI, THROMBIN INHIBITORS (continued trom p. 2(6) Thrombocytopenia (a conditiorl in which circulating blood contains an abnormally small !'lJmber 01 platelets) is a common abnormality among hospital patients, and can be caused by a variety 01 lactOfS. Ooe 01 these is associated with the use ot heparin. and is called eilher hcparitHnOOced thrombocytopenia (HIT) Of heparin-associated thfom· bocy10pe0ia (HAT). Two types 01 lhis abnormality ha.....e been identified: HIT type I is a mild decrease of plalelets due to nonimmunologic mechanisms, and is not serious. HIT type II, on the olher hand, irMl/ves immunologic mechanisms. and can cause clinical seqoeIae that range lrom mild to me-threatening. Plalelet counls can drop 50 percent Of more. and thromboembolic COfl1llicBtions can develop. Although HIT is relatively rare, lhe wide use 01 heparin has resutted in a greater recognition 01 its role in thrombocytDpel'1ia. The treatment 01 HIT requires anticoagulation and, llP unlit recently, iow molecular weight heparins (which appear to lead to !ewer clinical problems) have been employed with variable results. Recently, a new agent. lepjrudin, has been approved tor the specillc treatmenl 01 this condition. A, lepirudln FIgure 20.16 Summary 01 antiplalelet and an1ilt1rombin agents.

Lepirudin [Ie pee RUE din] is a polypeptide that is a highly specilic thrombin antagonist One molecule 01 lepirudin binds 10 one motecule 01 thrombin, resuhing in lhe blockade 01 the thrombogenic activity 01 tl1rombin (Figllre 20.16). The drug is produced in yeast cells by recombinant DNA technology. Administered intravenously, lepirvdin is effective in the koolmanl 01 heparin-induced thrornOOCytopenia and olher thromboembolic disorders, and can prevent lurther Ihromboambolic complications. Lepjrudin has a hal'-Iile 01 about one hour. and is believecl10 undergo hydrotysis. The parent drug and its fragments are eliminated in the urine, B~eding is the major adverse ellect ot Ireatmanl with lepirudin, and can be exacerba1ed b'I concommilant thrombolytic thara~, tor example, treatmeflt with stroptokinase or tissue-type plasminogen

acb'vator(,PA

see p. 2(2).

._,,,,ooJ,,,,

,,

<0:-

Chapter 21 Update: Antihypertipidemic OlllQS

Antihyperlipldemic Drugs f. HMG-CoA red\ICtne Inhlbltor1l (oontinuod trom p. 214) These antit"rjperlipidemic agenls inhib~ lHl.lll:M:l. cholesterol synthesis, and deplete the Intracellular supply ot cholesterol. This prompls the cell to increase the number ot specilic cell'Mace LDL receptors that can bind and Internalize circulating LOt..s. Thus the end leW" is 8 reductiorl in plasma cholesterol. both by lowered cholesterol synthesis and by

increased catabolism 01 LOL 1. Atorv8statin

Arorvastatin (a IDR va slah tin) lim~s choIesterollormation by competitively inhibiting the conversion ot HMG·CoA to mevalonate by HMG..coA reductase. Oosa-depen
figure21.12 Summary 01 HMG-CoA reductase Inhibilors.

. ,. . , """""" _ _

.w'

'"

21

<_.0......'.. _... _,. ''0

Pharmacology Update

22

Drugs Affecting the Respiratory System II. Drugs Used to Treat Asthma (conlinued from p. 220)

A new dass 01 antiasthma drugs has recently been ckMlIoped lhat largets lhe formation or fuo<:1ion of leukofrienes (Figure 22.7). These drugs include zilcutOfl (ZYE Joo ton], zafirlukast!zah FUR 100 kastl, and montclukasl [mon TEE 100 kast].

F. Antl-letJkolrlene DnJgs Leukotriene B, (LTB,) and the cysleinylleukotrienes. LTC" LTD,. and LTE., are products of the 5-liporygenase pathway of arachidonic acid malabo/ism. 5-Upmcygenasc Is Iound In cells 01 myeloid origin. such as mast cells, basophils. oosinophils. and neutrophils. LTB, is a poIenl ehemoaltraClanl to netllrophils and eoslnophHs,

eli....

--I~·.l

•

~1IIlD •• •

--.

~ .t!C• •,.,".,.~

lau_lon. E.,

FIgure 22.7 Biochemical palhways of lhe formalion and action of leukollienes and sites of action of leoJ
, ... r", ..,.,

>' ,, _ _ ,)

<.,..." - - -...,...., ......... - _. "" •

'"

Chapter 22 Update: Drugs Affecting the Respiratory System whereas the cysteinyt leukotrienes constrict bronchIolar smooth muscle. Increase endothelial permeability, and promote mucus secretion. [Note: Cysteinyl leukotrienes are the components ot 'slow-reacting substance" (SRS) 01 anaphyla~is and allergy.) bJeuton Is a selective and specitic inhibitor 01 5-Upoxygef1ase. preventirlg the formation 01 both LTB. and the cysteinylleukotrienes. Zafir/tJkast and monte/ukast are selective, reversible Inhibitors 01 the cysteinyt leukotriene-1 receptor, thereby blocking the effects 01 cysteinyt leokotlienes (Figure 22.7). All three drugs are approved for the prophyla>tis 01 asthma. They are no! effective in situations where immed~te bronchodilation is required. Reductions in the doses 01 11adrenergic agonisls and corticosteroids. and improved respiralofy tunction, are among the therapeutic benefits. Monfslukasr is approved lor use in dlildroo si~ years old. and older. 1. Pharmacokinetics' All three drugs are orally active, allhoUgh food impairs the absorption of zafirlukast. Greater than 90 percent 01 each drug is bound to plasma protein. The drugs are extensively metabolized; zi/sulon and its metabolites are e~creted in the urine. whereas zafir/tJkasr and monte/tJkast and their metabolites undergo biWary e~Cfetiofl. 2. Adver5e Effects: Elevations In Serum hepatic enzymes have occurred with all three agents. requiring periodic monitoring and discontinuation when enzyme levels exceed three times the normal. Although rarll, IlOsinophilic vasculilis (Churg-Strass syndrome) has been reportlld wilt1 all aQllnts, partiwlarly wher1 the dose 01 concurrent glucocorticoid is reduced. Other eflects include headache and dyspepsia. Both zafirlukast and zileulon are inhibitors of cytochrome P-450. Both drugs can increasll serum levels of warfarin. MonteJukast has no! been shown to inhibit cytodlrome P-450 (see p. 14). The chewable tablet form or monfelukasr Co<1tains 0.8 mg of phenylalanine; patients with phenylketonuria should bIl so inlormlld. Fl9Ure 22.8 summarizes the drugs that modify the adiofl of Ieukotrienes.

Z.I,r1uk...

to . .

~-

_
AodueIl<>n '" 1l-ad1O""glc "110"1.' UN - ~

31

_'....0'.'•• ~ "100."'0 PEl'ft . " Treotmemtolll.n or ~ k ! II'onpy. I r N _ "S. ~ -

~

'"""*

Monro'uk • .,

Z,"'uto"

............

_,~_...,

~

~

,

Ll

~1

2".10

a.9 .... !U

1.3Yl1:n.!i

CIIltIy

• Figure 22.8 Elleets of leukolriene modifiers in patients with chronic pe.sistent asthma. PEFR '" peak expiralory flow rate.

. . . . . .0 . . .

..... "...---_, -=- .. _. w

'.'> ................. '>

>

'" Insulin and Oral Hypoglycemic Drugs

26

IV, INSULIN PREPARATIONS (continued from p. 260) Most 01 the insulins derived Irom beel end pork have been largely teplacad by lhe human form, synlhesized u1ilizing recombinant DNA technology. For example, lispro insulin is synthesized by recombinant DNA techoology, using a non-pa1hogenic strain 01 E. .l
a,m

Serum insulin levels

1'" ,

~:

m'

•o

-. ...... --. -_.

'''.Regullr InSulin

1 234 !

m

_. I

7

I

'101112

Rate of glucose infusion

ii

E. Lispro insulin Uspro [LIS pro] insulin diIIers from regular insulin in that lysine and proline at pos~iorls 26 and 29 in the B chain are reversed, This results in more rapid absorplion after subcutaneous injEldion than is seen with regula.r insulin, as a consequence, lispro insulin is fIIOfe rapidly-aeting (Figure 26.10). When used before meallirl\ll, lispro insulin shoUld be administered 15 minutes prior to the meal. Peak Iev&ls 01 /ispro insulin are seen at 30 to 90 minules atter injection, as compared 10 50 to 120 minules lor regular insulin. Uspro insvlil1 also has a shoner wrlltion 01 activit)'. Uspro insulin is usually not used alone, but requires a looger acting insulin to assure prope. glucose oontrol. Otherwise no differenc:es Illlist between lispro insulin and regular insulin. Adverse effedS are those reponed lor other insulin preparations. the most irnponant being hypoglycemia.

V. ORAL HYPOGLYCEMIC AGENTS (continued from p. 261) These R!)eIlIS are usefIA in thlItrealment of patients who have non-insulift. dependent diabetes, but cannot be managed by lie! alone. Oral hypo. gycemic agents should not be {jven 10 patieol's with Type 1 diabetes.

j

FlQUffi 26.11 surrmariZes lhll oral antidiabetic drugs.

j

A. Su"onylureas

Figure 26,10 Effect of SlbcuIaneoos aanir"oislration of lispro insulin and regUlar insuUn on (Al sefl.lm insulin COI1alfltrationS, aro (8) the rale 01 glocos8 Inrusiofl r>eoossary to maintain r10mlal bIoocI ~uoose llIwIs in 10 normal

.-,.

Glimepiride [gty MEH ~ rlde] is a new, second generation sultony\-urea. II was the first sullonyllnlR to be l\IlPW'o'OO for C()I"l(UTllI'\t use with insulin, but has no adciIionaI acWantage 0\Illl" the oIher sullonylureas. Elimination is through the urine and feces. Like all sulfonylUI'(las, ~ can cause~, t?,tperlnsulioemia, and ~ht gain. O. Repaglinide Although repaglinide [lett PAG lih nide] is not a sulfonyltJrea, it has actions in C(lfM'lO(\ with this groop of drugs, Repagh'nide binds to the ATP-sensltive polassium channels 01 the pancreatic II cells, causing the lelease of insulin. Repag/inide is Willi absorbed orally, and is taken thraa t;mas a day before meals (its tu:!" 1 hr).

<

( _ ''''' .... 1> ( . . . . . _ _ I )

- . . . . _ _ ' ... >

~""",--o'1,1'<""

Chapter 26 Update: Insulin and Ot'al Hypoglycemic Drugs

453

Combined therapy with me/formin (see p. 261) is belter than monotherapy with either agent in improving glycemic control. Repaglinide is metaboli~ed to Inactive products by the live" and excretion takes place ltuough the bHe. Although the drug can cause hypogtycemia, the incidence of this advelSe effect appears to be lower than that reported fOf the sulfonylureas, Drug iI1teractiOllS haw not been reported, Its future role in the treatment 01 type 2 diabetes remains to be determined. E. Troglitaume and

Roslglita~one

Troglita:rone [tlOh GLI tah ~onel is the fi,st thia~olidinedione approved lor ltle t,eatment of Type 2 diabetic patiertts---partiaJlarly those I'.t1ose hyperglycemia is fIOl controlled despite insulin ltlerapy. Unlike the sullooylureas, /roglirazone acts as an inw/in sens~izer. enhancing insulin's actions in rhe liver and Skeletal muscle. Trogti~ tfeatment mduces ltle inc,eased hepatic 0lJtplJ! of glu· cose common in Type 2 diabetics with hyperglycemia. It also promotes insulin-dependent glucose utili~ation in skeletal muscle. Hype,glycemia. hyperinsulinemia, hypeftfiglyoo,jdemla, and ele-vated glycosylated hemoglobin (HbA ,,> l&\Iels afe impfoved. The d'ug can also countefact Insulin ,esistance. Although insulin is required for its action. /reg/wane does not promole its release from the pancreatic ~ cells, and thus does not reoolt in hyperinsulinemia, It is usually administefed with insulin, and may lowef the dose ot this hormone required lor adequate glucose CQf1trol. Gene,,,, Nama

O",.~on

Fi.... Gene<.1iorl SUlfonylu,,,,

,-

."

~

~

r-.r_

12·;M

• cc

idOoo._,~

OJ

,

at t't

(CUi'" .,VA

•

I'

Gl'jtuldelQ¥l-. _TIIIII Blg....nklM

CClld_"~II"

• at

,

_.!loy

_ _ by 1IYe. 10 both _ .ne! _ . procIuets: •• CItlad byli.l
,-,-

•

""

u

FIgure 26.11 Summary of oral antidiabetic agents.

C· . ' b y _ " ' _ " ' ....: .. ~I>y

- . . , . , _ t 102 . . . . """

...

--..... Ceo..

'., .. ,

II II"

,

..'a. ''''

II ?1>y_Io~_~; ... . 1n _ _ I>y-"';_1102_.day II

••

-~

'I

--

Nol .... tII...,._; •• ore'ad by kldr4y" .... y be uUCl .Ione or 1/1 eomtlI.... lon wttIo ... ~onylu''''

.,

TNazolkllnedlone.

----I.fOgII'-"'"

.........._ by M_t-7O'll.) '0 .... lC!io...... 0b01~" .nl.oct 1-30%1 by ~1dr4y.: ""n p<:>ten..... ..,1Icliur«lc: I>ormone _ : tIIk., """'" • d.y

_5.5

roIe""n,;"

Com~n ..

uetobOIlDd by _ ,,, InSdI¥e pr-.ct: ••ereMcl by _ .....: token 2 to 311n_ • ,,"y

N

)

........ltll ell ...'

tt-GI'

or AOUO" Ihou..)

_ _ ;tl I OIl _ II' • ••• " ... «gIl _

;--.......

OsenI_lMuIln ....._

Iron> Jejunum by

I

I ,

..... '0''''''

> ...... _ , >

'"

Pharmacology Update

1. PtoarmacokJoetlcs: Oral absorption 01 the drug increases when taken with food. It is exlensivel~ bound to sefUm albumin, and has a plasma hatt·l~e 0116 to 34 hoors. Troglilazone is metaboliZed to several inactive metabolites, and can induce cytochrome P-4SO. The primary excretory route is in the laces. The drug is contraindi· cated if! breast·feeding women. 2. Adverse eftolcts: There have beerl deaths due to hepatotoKidly in patients taking IrogNlazone. INafE: The FDA and the manufacturer have restrided the use oIlroglilazooe to patients in hospitals and convalescent homes.] It is strongly recommended th3tliver enz~mes and bilirubin levels 01 patients on the medication be measu.ed initiall~ and periodicall~ thereafter. [Note: A related, less hepatotoKic lhiazolidirnldione, rosiglirazone. has recenll~ been approved b~ the FDA.] Adverse effects that have beef! reported include: upper respiratory inlections, headache, anemia and edema as well as weight gain. Trogli/Bzone increases metabolism 01 oral oontraoeptives. Which ma~ result in O\IUlation and pregnancy. Levels of other drugs such as cydosporine, whidl is metabolized by cytodllOr119 P·450, ma~ also be atfacted.

Steroid Hormones II. Estrogens (oontinued lrom p. 266) E. Anitestrogens (selective estrogen receptor modulators)

5e-Iective estrogen receptor modulators (SEAMs) act as estrogef! agonists in some tissues, but block the action 01 estrogen in others. The first widely used SEAM, lamoxifen (see p. 266), has the anti· estrogenic etfect 01 reducing the risk fOf breast cancet as well as the benelicial estrogen ellects on serum lipids and bone densit~ in women (FIQllr9 27.14). However, tamo"illlnalso has the l.fldesjrable antiestrogen ellect 01 causing hot Ilashes, and the undesirable estrogen effect of increasing the risk lor endometrial cancer and venous thromboembolism in women. Raloxifene, a second-generation SERM, increases women's bone density without increasing the risk lor endometrial cancer..

3. RalOllifene: Lika larnaKi1en, which is also a SEAM (see p 266), ralc»rifena's (ra LOCKS ih loon) actions a'e mediated through the estrogen receptors, and it has both estrogenic and antiestrogenic effects. Its dinical use is basad on its abilit~ to decfease bone resorpiioo and overall bone turnover. However, unlike estrogen and lamoxlfen, it apparenll~ has lillie to no ellect on the eodometrium, and therefore may not predispose to u1l1fine canoer. Rak»r:ifene lowers total cholesterol and LDL in the serum, but has no elfact on HOt. Of lrigl~oeri
'-''''''''''>'---') Chapter'D Update: Steroid Hormones

'"

....n' , •

....

T_

.-

El\rOgInIC

ReduC
'0' bf..s' C
,lJ~L

.. tJ

7

~""'"" rtlle

Cou .. """. menopausa' symp'omillo, G •• mplo

'1>0,

_.118S~'"

)

!ner.... rlsk lOr YInOU.lhfo-

Figure 27.14 Compalisorl of the estrogenic and antiestrogeoic effects of raloldfene and lamoxiferJ .

prote<:ts against cardiovaSCIJlar problems remains to be ascertained_I Raloxifene has been reported to increase the risk 01 thromboembolic episodes. The d
Figure 27.15 Enact of raJoxilene on cumulative incidenoo 01 breast cancer in 7,705

postmenopausal women.

< ..... 0 . . .' . '

.

....... _ , .

~

•

-""', -=- .. _. w

>

'56

32

Quinolones and Urinary Tract Antiseptics II. FLUOROQUINOLONES (continued trom page 327) Four rocen~y approved nuoroquinolones-/eIodIoxacin, lTO\'lIlfaxacin, !Jrepalloxar;in and spar11oxar;ifI--Qt!er greater potency, a broader

( _ Advanlog Em_ actlYlly ~ MRS" I

-----"' 1 1. . ... -Em_ac1MtY _Inst ......

w

.

......=

,

l

•

"

T_ _ _:

--...... '. ,.doI

u •

. .

';

•

.

"

,

ollMth._

'I

•

~'='tt"'iflIoIfWI

•

",",-; he!>aIOlO>XiIy

Adverse

Elrects

Figure 32.7 Summary of therapeutic advantages a~a~e~ectsofq~~.

Spedrum of antimicrobial activity. greater ill ~ ellicacy against resistant organisms, a~ in sorTllI cases, a batter safety prolile tharl older quinolooes. Compared with r;iprofloxacin, these new compounds show increased aetillity against gram-positive organisms. and ralain the bvorabla activity againsl gram·negative microorganisJl'\SGatilloxar;in. clinalloxacin, trovalloxacin and moxilloxacin show inaeased activity agalnSI anaerobes, compared with ciprofloxadn. Clinical evidence, although po-e1iminary, suggests the (;I'lhanr;ed effi· cacy of these drug in the treatmant of almIIIUrlily-ac:quiled a~ n0socomial infections, lor example, respiratory, urinary traet and skin infections, and sexually transmi"ed diseases. Ad~erse etleCls observed with mosl quinoklrlas are mild. Serioos toxicities include photoIoxic:ity (particularty with sparlloxacin), a~ prolongation of the aTc imerval (seen with sparfloxacJn and grepafloxacin). Drugs lhat prolong the QT c inter~al should not be coadministered wilh sparfloxacin and grepafloxacirr. Drug interaetioflS can oc:cu belweefl quinolones and compounds containing multivalent cations (Mg"", AI'-, ca""). Because 01 Its clinical advantages, yet serious side effects. frlMIlIoxacin Is desaibed in detail belo::m. F''9Ure 32.7 shoWs some 1t>erapeotic advantages and adverse e!f1!ClS of quinolones.

F. Trovalloxacin

Troll1lfloxacin [TRO vah IIocks a sinlis a new fluoroquinolone, whict1 has several properties that gi~ it some clinical advan· tagllS. These proplIrties include a long hall-life ot aboull0 hours, which permits OfIOO-a-
..... r.., ..,.,). ,, _ _ ,)

<

e_ • .....-...,' ,,,,,.,

lCI'CUJI . . _ , ... >

'"

Chapter 37 Update: AntMral Drugs

Antiviral Drugs

37

III. DRUGS FOR THE mEATMENT OF HERPESVIRUS INFECTIONS (COI1tinued from p, 368) Herpesviruses are associated with a broad spectrom 01 diseases, for eJ
G, Penciclovir

Pendclovir {pen SIK 10 veer] is an acyclic guanosine nucleoside derivative lt1al is Ilctive against herpes simplex virus Types I and II. and against variceHa-zoster virus, Penciclovir is onty administered topically (Figure 37.8), Penciclavir is mooophosphorylated by viral thymidine kinase, aOO cellular ElllZ)Tlles form the nudeoside triphosphafe, which inhibils herpes DNA polymerase. PencicJt:IvK triphosphate has an intracellular halHife 20 10 30 times longer fhan does acyclovir triphosphate (see p, 365). P8ncicto~ir is negligibly absorbed from topical application. and is welItoleraled. Both healing and pain are shortened approximafely one-half day in duration, compared to placebo-treated subjects,

Figure 37.8 Pencic/ovir is only administered topically.

H. Cidolovir

Cidofovir lsi DOF 0 veer] is approved lor ileatment 01 cyto· megalovirus-induced retinitis in patients with AIDS. CidokNir is a nucleotide analog 01 cytosine, whose pMsptloryIation is flO! dependent on viral enZ)Tlles. Slow elimination 01 the active intracellular metabolite permits prolonged dosage inIetVals, and eliminates the permaneot Ver10US aceess used lor ganciclovir therapy, CidokNir produces significant toxicity to the kidney (Figure 37.9), and is c0ntraindicated in patients with preexisting reoaJ impaIrment, or in those who are laking concurrent nephrotoxic drugs includIng NSAIOs. Neutropenia.. metabolic acidosis, aOO ocular hypotony also OCOJlS. Probenecid IS coadministered with ddolovir to ledUoa the risk 01 nephrotOXIcity, but probenecid itself causes rash. headache, lever and nausea. Figure 'YT.l0 summari2:es some antiviral agents.

~ENAll"PA'R"ENT

Figure 37.9 Renal impairment is the the major toxicity of ddotovir.

< ..... 0 . . . ' . '

.................. , .

""

Pharmacology Update

Acyc/ollif

_"''''10

K'f':-lrIphOopI\at*,

which 1 _....... OtIA poIyn'e
Ii"

; ......

_vir

....... .. oocydoW

......__ to jOnd
... _ .

__ _ •_ -",po.' ' ..... "Ipt _

J",

DHot~

Lami_

c'"

i I :.0...

-0,". vInJ.

-

in: "'-:; k '

'I ' CIlI\I ...

1 " ,_ _

24"

Inl>lbltlon of vlnol ONA po~..-.I .._ lno","""",_ .. ,lie

_

pyttIpho'~ndIn;

1rI1_

of lIIroi OtIA potymo.... ..-.I

- - lnorlKrIpf'"

HopMltI. a (dlronio _ ~ hu",., Jnwnunodofldoncy ...... '1ypO ,

5 _7

'0_111 ~:::==...--;;;:..-

__

0 ........ "'the M2 poolOln Ion

<10--'

In"_A

_lIS ""'itv 10 -.ut. ~U"lArpH ..........,0.

_

I '''''_

..... vhl"""'*'

a_c, -".J

liS.

'

,1,= , ......

..

.....rac.IUar r..ll-l;'" '" CidoIovio ~ is '1·:J(l1'M>u<s.

Rgure37.10 Summary 01 seleded a.ntiviral agents.

IV. TREATMENT OF ACQUIRED IMMUNODEFICIENCY OISEASE (AIOS) (oontinued'rom p. 371) Traatmef1t of human iml'Tll.lOOdelicieoey virus (HIV) irlleclions has b8en radically mod~ied during the past two years by the introduction 01 p0werful antiretroviral drugs, and by the deveIopmDfl1. of melhods to determino the viral burden in plasma. The introduction HIV protease inhibilofs and non..flUCleoside rEl\I(IrSD transcriptase inhibitors has made this breakthrough possible. However, lhe Iong-torrn therapeutic benefits and salety profiles of these agents are stiN bDing evaluated.

0'

f, HIV protease inhibilors (continued 'rom p. 371) These drugs are peptidyl analogs that rlMlrsibly inhibit the proteinase that is essential tor the tinal step ot viral proliteralion. Protease irlhibitors have revolulionlled HIV therapy, reducing infections by opporturlistOc organisms, and prolonging and improving the

lives 01 roost patients.

.

..."

.. ........ _,.

,"' ,.,

Chapter 37 Update: AnliviraJ Drugs

.._.----,--_.....

t. s.qu;navlr lsa KWlN a veer]: TNs drug is taken ornIy. ~ has ~ ,_~y reIom'U8ted ... a sdtiIal ""'4'5'Mlorm Ihal Wrpoves lis billa 3 ti!ioy, aIf'Q.9llhe <Wl'llUll absortJed ,~ !he IowesI fA aI lhe protease il~ibilufs atlltlPi....."atBly 12 fA ltle 00II dose. III ordef to maximize ab5orption. ~ rl88ds to be Iaken with t'igtllal meals.. DistrbJtioo io'*l tissues is good as evidenced by II la,ge volume 01 disllibulion. Elimination 01 saquinavjr is prYnarily by metabotism loIIowed by biliary excretion; its hall-lite is 5 hours. Plasma levels can be sigldicanlly irlcreased when saquinavir Is !XlI ubilled with other antiretroviral agenlS lhat Inhibit ~s metabolism. such as rJelavirrJine (SIHl P.kXM). On the other hand. drugs that enhaoce the metabolism 01 ssquimtvir. soch as rilampin (see p. 333). ritabvtin (see P. 333), and other ~ indu<::ers should be aYOided n possiHe. The most c0mmon achIerse etIecls fA saquinavir Ifealment (5 10 10 percent fA patients) io'ldude e jar:tle. Iatigue. dianhaa, !\aUSeiI, and CIher gastroio1Iestio cistl.wbanoes (F9-e 31.11). Increased IlMlIs fA hepatic Ill'WIOb"ISte,ases NNe been noted..

pel"'.

L

2. R"-W [n TON a ..verI: Tlis Oug tlMlrabIy alters Ihe SUTOgaIe mar1Iers lor HIV illlecb, in bolh antireInMral nai\oe (plUients who have ntl\I9f had HI\' tt-apy) and experienced patients (those who have had ~ HI\' therapy). BioaYailabilily foIIo¥,;ng oral admiolistration is at least 60 percent, and is unaltec:ted by Iood. However, ritonavlr Is lJ'lPi'Ilatabie. and is takeo with chocolate milk or nutritional suppiemoolS to improve palata!);lity. Metabolism and !);Iiary exaetion ale the primary methods 01 eliminatiOfl. Ri,OflllVir has a hall-life 01 3 to 5 hours. O!le 01 its metabolites has equal antiviral adiYity, but its plasma level Is low. Ritt;Inavt' is prio'rIarily an inhblol' 01 cytlXhmme P....SO Isolymes. ~ ... runerous drug interactions (see p. 14). Nausea, vomiting, diarrhea. and astt..... iIf8 among Ihe mont a:w1.TI(llI achIerse ettec:ts). Trtratiorl to !he standard dose is ertec:tive in cliIiW.lioog the gastron:8$IineI side afieds. [tbe: This ITIiII'OBIN8f is not etleclive with other pro-rease inhibiIors.J ~ pareslhesill and h "!all. keq.JBrltly occur. EkMl.1eCI aminotranstefas and triglyceride Ieveb are also

_.

3. lndinaYl, [lI'1 DIN a veer): ClinicaIIriaI:s have delllCl$lated the etfi. ca<:y 01 Indinavir In both antiretrov!ral naive and eMperien<:ed patiEf1ts by using the SlNrogale markers. 'Nhen used in lXlfTbination with reverse transaiplase io1tlibiIors, sustained eHects have been demonstra1ed lor as long as 100 weeb. /ndirlavir is well absabed O'illy. and, 01 aIllhe protease ilH:litors. is the least proteirH)ou'ld at 60 peo... il [Nele: WheIher ~ aoc::ou1lS lor its abilily to leduoe I'tV RNA in tissue and tids such as ~ nodes, S8CJ(tlions 01' semen is t.rinown.] Acil;k: gastric: !XlI"*"'" 1$ 1« ?ry lor absorpIion. AbsoIptiUII is deaeased whefl acluliolislered with meals. allhough a IV1t. IDw-lat Sl"llICJl is permissilIe. MeratQism and hepalk: dearance aa::oum lor eliminatiorl 01 n:fnal'ir; the dosage should lhereb'e be rea ........ Ihe prm ICe 01 hepatic: insutIic:iBl1<:Y. IrIdinaIlir has the shortest hall-lile of the protease W1ibilors at 1.8 hUtn. II is wei IdaIated, with the usual gastn::lfitestinal syrrll'l<J(ns and headadle ptecDiii..ating. Thera is a risk 01

Rg.n37.11 &.ne adYBrse elIeas ollhe HrV pllmnseio~s..

.59

<_

'0...I.,

>< ...... _ _ , >

Pharmac:ology Update

nephrolithiasis and reversible hyperbilil\binemia. Aclequate hydration is i'nportant 10 reduce the irocideoee 01 kidrley stooe formation; patieflls should dmk at least 1.5 liter.> oj water per day. 4. Nelfinavir (ne! FIN II _J: This CWg. when used in combination with zidovudine (AZT. see p. 368) and Iamivudine (3TC. see p. 370). decreases viral load by at least 10C1-Iold, and increases CD4+ oounts. These effOCls hall(! been sustained lor as long as 21 months. Nelfinavir is well absorbed and does not require strict Iood Of fluid conditions; however, it is usually given with Iood. A hydroxylated metabolite appears to be the ac!ill(! agem. The halflite 01 nelfinavir is 5 hours. Diarrhea is Ihe most common side etlect, and can be controlled by !operamide {see p. 244). Like other members of the class. nelfinavir can inNbit !he melabolism oj other drugs, resulting in required aiteratioos ot drug dosages. Of !he prohibition of COI'I'\bined use. 5. Amprenavlr [am PREN II veer}: Like other prOlease inhibitors, amprenavir is used in combination with a least two fi\.lCleoside reverse transcriPlase inhibitors. Its long plasma hatf-lilo permits twioo dally dosing. but the large size and I1UlTIbef of capsules per day (16) day may reduce patient compliance. The drug may be less well tolerated \har1 some other protease inhibitors and it is unclear whether amprenavir offe's any clinical advantages 0Vilf Olher protease int1ibitors.

6. Common lIdIIerse effects of protease Inhibitors: As Protease Inh,bltors

FIgure37.12 Drugs thai shoIJld nol be coadministered with any protease iflhibitor.

e~perience

with the protease if1t1ibitors has grown, two important adverse reactions that are corrwnon to all 01 them have been UOC(l\l(lred. a. Inhibition of cy1ochfOrlle P-45O-dependenl OJlldalions: All of the protease inhibitors inhibit cytochrome P-45D-dependent oxidations. The following drugs should not be coadmirristered with any prOlease inhibitor: 1) antian1lylhmics such as ambdarona or quinidine; 2) antihistamines such as astemizole or terlenadine; 3) antimigaine-ergol derivatives; 4) antWllycobacterial drugs such as rifampin (it decreases protease inhibitor kMIls); 5) benzodiazepines such as midazolamor IriazoIam; or 6) Gl prokinelic agents such as cisapride (Figl.Jre 37.12). b. Upodyslrophy lind hyperglycemia: The protease inhibitors can cause these two disordefS. These eNecls are primarily associated with indif!<111ir and rilonavir. but nellinavir and saquinavir have also been reported 10 hall(! these elfecIs. The ~podyslrophy is characterized by a redistribution oj fat. so that the limbs become skinny. and the tat is deposited along the alxlomen and the upper bad<. The hyperglycemia is associated with either the exacerbation o! existing diabetes, or the iniliaOOn 01 a diabetic condiOOn; !he mechanism is nol known. Fortunately, hypergtycemica is a rare oocorrence. Additionally. signifk:anl e1evaOOns in lrigly<:eride and d1olesterollevels have been reported. The long-Ierm implications 01 these effec1s ale not known. Figure 37.t3 shows some of the precautions in using the protease inhibitors.

'e_"

'-''''-'''>'---')

...' ...·, _

.. _ . w

'"

Chapter 37 Updilte: Antiviral Drugs

....)0' '0""'''' .~d 'o~co'~'

D'ug.

~ . 0 ........

_

• .-cI

>

tn~

"loo,'",mg

_naIdlscomlorl.

_ _ 11

T.... wI1tllllgh-lat meo' '" ""'*' 2 !loll... 01 0 IuW me",

ooomwa, _ _ , .

......... d,...... ,

00_.

".'_,-. ..--_? ? .... ='?

_1'''..0..... _

1Q

r

:.::::..

&.n1gn "",,p.. _ , , _.. ..."....OIhhl.....; Toke 1 ho." bOlor
mly 'ab wlIlI _ milk '" a _lot moal; drinb 1.5 L ol'lq"lcl
tiou_.

d_a. """,ltIng. 0<11' _ ""....01......la _ rash

I _~

",,_

Figure 37.13 Summary of protease intlibitDfS.

G. Non-nucleoside reverse tnmscriplase Inhibitors: These drugs are highly selective. noncompetitive iMibitors 01 HIV-1 reverse trBnscriptase. They do not interfere with the binding 01 primer. template. or nucleoside triptlosphates. They have no effec1 on human DNA potymerases. Their major advanl.a96 is ~r lack 01 efteet on lt1e host blood·lofming eiemerns, and lad< 01 Cfoss·'esis· tance with nucleoside reverse tronsClipta.se inhibitors. 1. NevlllIplne

Nevirapine is more effective than a placebo in redudng the num· ber of copies of viral RNA, and increasing the CD4+ count in individuals wOO have had previous antireirovirallherapy.

a. PI\a"nacoidnetics; NeWapine [roe WE ra peeI1] is....en absortled orally. and ils absorption is no! affected by Iood and antacids. The liJXlPhilic nature ot nevirrlf*le
J

<_ ..... ,.,.< ..... ....--,. Pharmacology Update dosage adjustments are necessary when navlrapine is givan COf1COf11itanlly WIth nucleoside reverse transcriptase inhibitors, such as didanosine (ddt, sea p. 369) or Zidovucine (AZT. see p. 366). Sioca neW8pifIa can increases the metabolism 01 p«)tease inhibitors, dose adjustment ot concurrent protease inhibitor therapy is as follows: ritonavi,-oone; indif18llir and nelfmal'ir-increase dosage: and do not use nevi,apine with saquinavir because 01 saquinavir's low bloavailability. Nevirapine increases the metabolism 01 a number of drugs, such as oral contraceptives. kefoconazole. melhadone. mel'onidazDIe, quinidine. Ihoophy/line. and warfarin

2. Delavlrdine Delavirdine [de Ia VUR deen] has not undergolle as e~lensive clinical trials as did nevirapine, but In one studY, delavirdine added to AZT and deil was more elle<:tlve than the nucleoside reverse transcriplase int1ibilors alone. AS wilh othef members of the class, resistance develops rapidly with monolherapy. a. Pharmacollinetics: Delavirdine is rapidly absorbed afler oral administration, and is Lnlffected by the presence of food. It is extensNely OOund to plasma albumin (96 percent). Delavircfne is exloosively metabolized. and very little is e~creted as the parent comp:;lUnd. Fecal and urinary excretion each account lor approximately on&half tile elimination. b. AdvefSfl effecls: Rash is the most common side eflect of delavirdine: it may occur ill up to 44 percellt 01 the patients. Nausea, dizziness. and headache have also been reported. Delavittline is an inhibitor ot drug metabolism. incl\.lcW'tg that of protease inhibitors. Although ,itonavi, levels are not altered signiticanliy by the presence of delavi'dine. the levels 01 saquinavir and indinavIr are significantly inc;(eased. Fluoxetine and ketocvnazoIe increase cJelavirdine plasma levels. l'
3. Efavlnmr.

Etavirenz (el FA ver ooz] Ileatment resuhs in increases in CD4+ celt counts, and a decrease in viral load. comparable to thaI aelieved by protease inhibitors when used in combination wilt1 nuc:leoside .everse lranscriptase int1ibitors. Following oral administration. etavi,enz is weil distributed. including to the CNS. Most 01 the drug is boU1d to plasma albumin (99 pereeot) at therape.... lic doses. A hall·lile ot {flier 40 heUfS accounts lor its racorn· mended onoo-a-(lay rosing. Mosl adverse etlecls are tolerable, and are associated with tile eNS. including dizziness. headache. vivid dreams, and loss 01 concentration. Nearly halt of Ihe patients e>.parience these complaints. Rash is tile other most common side effect. WIth all incidence of approximately 25 per. cent. SeYere, lite·threatening reactions are rare. Efavirenz is a modest inducer ot cylochrome P-450. The dose of indinavirmay need to be increased when given with elavirenz.

<_.0' ..'.'.< ...... _ , )

<

e- • _"<

,,: "

.....,.,.". .. _

....

Chapler 38 Update: Anlicanoor Drugs H. Other reverse lranscripta5e inhlbitOfS ~ra 8AK a veer) is iI " .... Ple analog available tor d'likten and I!lIUIs wiIh AlDS I'It1O carnoI IOIerale Of I'It1O are Iallin;I QA'Tent nlgi, ....... There may be scme O"OS&fesistance wilh SWlWls resistant 10 AZT WId 3Tc. ~19y 3 pIIlC8lll 01 patienIs 8lHIit drug ieYer, GI SY"$*"'''' malaise, and someIi,ltlS. fBSh. Once foe niYiduaI is sensi1ized. repealed "xpo,;r;o'e restAls in more ~ ~ WId S8WIre r&adicn;., irldt.dr9 ~ WId lesp8b 'I ;;_:: AdriMir(a OEF 0 _ I is a "dpr4ide reYelSell ijxase "i;tIbb res9Ived tor f'106e who hiM! taied o.nenI n::fuIin;j a proasase i'!bb. AdettlWelOttis 11 '!itl:I-=Mr agail61 HlV, hetpes, and hepalitis B m.ses. Sooae 30 peiLWlt d paIients elCtti n'id 10 '"0dlll11e ,qA.'*'«idI,:. Nausea, ~ ashriI, rod inaeased hepaic enzrmes also (lllQ6 odl some ~ 80tl acaeaw lWId adetMi" lIPP63I" 10 be free d acM!rse ~1Ieo"""15 wilh other drugs ODI'.'uol'f ~ in HlV h!rap'f.

"9'

Anticancer Drugs

38

Ill. Antlmetabolltes (conlinued tram p. 384) Antimelabolites lII"e structurally related 10 normal O9lluItlr oomponents. They' generllly Inler\efe with !he tlIIaiabilily 01 nonTIIl ptJflne or P'fOOli. dine rudeolide precursors b'f inhibiting their $'fr'Ithesis. or b'f COIl'4)eIing wi1h tl'wlm in DNA or RNA syrllt is Their maximal cylOIOllic etleds are S~S8 and theJelore oelI-qtde---$pe.

G. Capecttabl".

C'l9"'i'1lbine !cape SrT£ ah beMl is • ncMl 0flII lIuorop'frillioiioe Cll/tlamale. II was appro.«l in 1999 br the hatmenl: 01 tnetilSlatic breasl canoer ltIat is , . 'anl 10 lirsliine thlg5 (tor ~ pedilaxeI(see P. 391) and anhacydinesL and is a.nentl'f abo used br

c

P

h'l

lreatment d c:oIolectal cancer. 1. ~ of Ktion: Qp:dCaboii. Rllf Sill is ~toIcic; it musl wldelgg biDacrivation 10 5-FU in.ri'& After being absootled, the

li'ug t..ndergoes a series d enzymic s1epS, lhe test 01 whictI is ~ 10 5-FU by f1ymOne phosphorylase-- IllU)mlI lhat Is concenlraled primaril'l in tumors (Figure 38.21). Thus. ~ ' s cytoIOKic adiYity is the same lIS lhal 01 5-FU, arc! is tumor·spec:ilic. The most important reactiorl int1ib~ed by 5-FU (and lhUs ~l is Ih'fmid'ylale synthetase (see page 382). Resistance to capedlabine has not been reported at this lime, allt10ugl it will probably be tile same as to 5-FU.

FIgUre 38.21 Melabollc ~Itlwll'l 01 cspec:itabine to 5-FU. S.QFCR. S'-
<_.0...'.'.< ..... _,.

<

•

', IM:I\U . . _ . "" >

Pharmacology Update 2. Phartnilcol
383), with the toxicity OCCtIlTing primarily in the gastrointestiMI Iraer, They indude diarmea tI1at can be SEM:!f8, necrolizing ",teroooI~is, rKlusea, \rOO1~ing, and hyperbilirubinemi3. Dermatologic toxicity indulles palmar·plantar erythrodysesthesia (numbness, painful swelling, dyseslhesialpareslhesia, and erythema ollhe palms 01 tI1e hands and soles of the Ieet.) CapecilabiM should be used cautioosly in patients with hepatic Of renal impairment. The drug is coolraindicaled in individuals wto are hypersensitive to SFU, are pregnanl, or are lactating. H. Gemcitablne

010,' '"' (2'.z-_ _ "")'C)_ . . . dFdCl

Gemcifabine [gem SITE all bean] is an analog of the nocIeosH:le deoxyeytidine; its chemical SlrVCltJre is 2'2'-.dillUOf'Odeoxycytidine (dFdC), Its use is indicaled in lhe first·line lrealmenl 01 locally advanced or melaslatic adenocarcinoma 01 lhe pan<;reas. II has also shoWn some acIM!y against other lUmors, 1. Mechanism of &etlan: Gemcilabine is a substlale lor oexoxycylidine kinase, whid1 phosphorylales i110 dFdCTP (FfQure 38.22). The latter compound i'1hibits DNA sYf1!hesis by iIlc:orporaling inlo sites Ihal would ordinaIily have cyl06ine in the growing strand. Evideflce suggests tI1al DNA repair does 1101 readily OCOJr. Levels oIlhe nalural nucleotide, dCTp,
2. Pharmacokinetics: Gemcitabina is adminis1ered intral'er100sty. It is deamirKlled 10 difluorodeoxyuridine, whid1 is not cytotoxic. and is excreled in the urine.

or

FIgure 38.22 Mech8l1iS of action of gemcitabine. dFdC" 2',2'-.dnluoro-deoxycylidine; dFdCTP " 2',2'-.di!luoroo::leoxVCV!idine tr"iptlosphale

3, Adverse effects: Myelosuppression is the dooo-limiting tox.icity gemcltabine. Other tOlCicities are nausea, vomiting, alopeci3, and rash. Transiel1t eleVations or serum transaminases, proleinurla, and hematuria are oommoo. Resistance to lt1e drug is probably due to its inability to be converted to a nucleofide: the tumor cell produoes increased levels 01 endogenous deoXycytidine lt1at com· pele lor lt1e l
VIII. OTHER CHEMOTHERAPEUTIC AGENTS

(conlinued !rom P. 396)

F. Topotec8n Topofecan (toe poe TEA can) has recently been approved lor the treatmeol 01 metastic ovarian cancer. R is a semj·syntI1etic derivative or an ea~ier drug, eatTfJlOIhedn TopoleCan has a complicated mull}. ring structure containing a lactone ring that is essential lor aClMty. The drug inhibits topoisomerase 1, which is essential in the replication of DNA Tn human cells (FtgUle 38.23). Unlike etoposide, v.t1Kt1 inhib-.s

' ... 'm ....'.'_ .... _ , . Chapter 36 Update: Anlicanoer

<6,

Drugs

the relaled enzyme, topoisomefase II, topoIec8I1 is the first cIri::aIy uselultoposisomerase I Inhibitor, The topoisomerases relieve torsional strain in DNA by caU$ing reversible, single $Iran
n 8uI*''''1IIlo '11lWUttlng from W 1II,.lnclllll 01 h

1. ~rn-=okloetlcs: T<:p:lIeCM is given by IV infusion 0Yef 30 minutes !oJ live oonsecuti'o'e days. ReIlflOl' las may flO! be seen tor Itvee week$. Hydrolysis 01 the Iaaone Jing clestroys me Ikug'$ a<::lMly. Aboul 30 peroent at the drug and it!; metabolites is eIimtnatecl in \he urine; hence, the dose may NNe to be modified With ifIlpaWed ~ II.rOion.

2. Actv_ ettec:ta: The fTlll5l important 01 _ _ etteas are hamalOlogic. Wlduding bone I1\8rKI¥t s u p p r ~neutr0penia .. lid. is the dose-limiling toxicity. Frequent peripheral blood COUfIIS shoukl be peotohued on patients laking Ihis drug. (Note: Jbpo'ocan shoukl not be used ill patjent5 wiltl 8 bas:" iC neutroptjl munt 01 less than 1500~. Doing so (;()ljd .-.. ill illlee::ti""n 8nCl dealh.) Olhef hefl\alologic: complications inc::tuljng lhron'lbOCylClpef'ia and anemia may a£so (lCCd". Nonhematl*lgic etteds inl;U;le 6a"rhea, f"IllUSea, """', iti og. ,.,...,. W, and headadle. Resistance t>as nol yet been described. but in accord \lrilh ohf agenI$. a:pptecan may ~ the p ~ tein (see P. 377). The ~ IS! may 81&0 n'Ua1e.

G.MollOdolllll.,tll:l:¢ •

UonodOllal &ldhdu ani! pIOdi'Olld by hybrid eels oeated from B tymphocyIes fused wiIh r.,WIl0.181'" B ~)'1e \UTIor cell&. The .esdting I¥Jo'ids can be incilIDJalIy doned, and each done wit pr0duce aftibodies (lirected against • sWlgle tltItigetl type. Two . ff1Oi1cxluoal ar1Iibody IypeS have been creaIed that llIe useI~ in ~ Ireametll 01 cen:.er. 1. T...~ In metastalic breast cancer paIients. 0Yef~ sian 0I1'unan epidermall10wth IactDJ I....... protein 2 (HEA2) is seen in 25 10 30 peroent 01 patients. TIlISlIlZlIrIab (Ira STEW zoo mab) is a monoclonal .. ,~ that bn:ls 10 1-ER2 sIles in breast caocer tissue, and inhibits lhe PJol~enItion 01 cells that OYefexpre5S the HER2 proIeh Thus. trasluztmab specifically targets the undeftying getl8tic delect that causes the cancer. The drug can cause rBgres&ion 01 breast cancer and metastases in these ~Is. Trasturom.9b Is 8dr1'Wiislered intriIYenousty; ils metabolism and elimination hlMil not been deSQibecl. The most serious toxlciIy assodaled wiltl IraslUcwmab use is congestive heart failure. Othel" adVerse ellects incIode headache. dizziness, nausea, vomiting, abdominal pain and beck pain. Cautious use 01 the drug is rocomnended in patieflls who are l1ypersensilive 10 il. to Chinese hamster ovary oeU proteins, or to ben~ ak:oI1ol (in which case slerile waler can be used lor preparation of the injection). Extreme caution should be exercised in patieflts with a preexisting cardiac ~ion.

--

dol 1111 hIIbl

<_ .....,.,.< .. _-,. PllaHnacology Update 2. Riluximab: Rifuximab (rih TUCKS ill mab) is a gEll1elically engineered. c:f1imeric lTi(lI1oclonaJ antibody direcled againsl tI1e CD2lJ an~g&n round on !he surtaoos of normal and malignant B 1ymphocytes. CD20 pays a role in the activation process lor cell c:yde iri· tiation and differentiation. The C02Q antigen is expressed on nearty all at the B cell non-HOOgkin's lymphomas, but not in other bone marrow <;ells. The Fab domain of rifu;ximab binds to lha C020 antigen on the B-Iymphocytes, while lhe Fe domain recruits Immuna allacl0r functions that cause lhe lysis 01 the B cells. Rituxirnab is inlused intravenously, and causes a rapid dapelion of B-a!11s (both normal and malignanl). The lata of lt1e antibody has not boon dasalbed. It is important to infuse rituximab slowty. Hypotension, broncilospasm. and angioedema may occur, and must be treatad with dip/1eflhydramlne, acetaminophen, and bronchodilalors if necessary. ctlills and lever Irequently acoompany the firsl infusion. LeuI
39

Anti-inflammatory Drugs

III. NONSTEROIDAL ANTI-mFLAMMATORY DRUGS

(=i~~

The nonsteroidal anli·inllammatory drugs (NSAIOs) are a group 01 chemically diSSimilar aQ6l1ts lhat diller in their antipyratie. analgesic, and anli-inllammalOf)' activities. They act primarily by inhibiting the cyclooxygenasa enzymes. blJt not the Iipoxygenase enzymes (see F'9l'rtl 39.3, P. 403). Cyclooxygenase 2 (COX-2) is a close structural analog 01 COX-1 and,like the latter, catalyzes 1t1e conversion 01 arachidonic acid to prostaglandin PGH 2 via PGG~ (see p. 402). These isozymes are encoded by two different genes. COX-1 is generally regarded 10 be cons1i1utiw and COX·2 inducible. However. this is an OIIl!f1>impilicaboo, since COX-2 is constitulive in the kidney and brain, but Is lndu<::ibIe in othef sites, including those that are inflamed, such as joints. Nearly all NSAIDs haw grealer a selectivity Ief COX-1. They are used primarily for oondifions not considered inflammatOf)' (Ief example, headache and analgesia). Their unwanted side efted 01 causiflQ gastri<; damage Is ascribed to Inhibition of COX-1, resuifing in an inability 10 form pr01eetive prostaglandins (see p. 404). This led to tI1e sealCh lor a COX-2 inhibitor, commonly referrad to as a "safe aspirin", leasoning that ~ COX-1 in the stomach is unaffected by the new drug, then 1I1e gastrointestinal eHeds would be minimiled. The firsl COX-2 inhibifor, Cl11f!Cl»fib, was approved In the Unifad Stales in 1998, and rofecoxib approved in 1999. Interest in this area con~nues high because COX·2 e>.:plession is associaled wilh the development of colon cancer, and also with innammatory processes in the brain that appear to be invol\ied in the development of A1zheime~s disease.

( ""'- .'" _1., • ( ...... ....,.,... , • Chapter 39 Update: Anti-inllamma\ofy Drugs

467

H. Celecoxlb

Ce'e 0000 [681 en COCKS ill] 1$ significanlt'l more selediwllor inhibition at COX-2 lhan at COX·1 (figure 39.16). In laO, at C(lI"(:eI'llr"ti(lns act.ielllCl ill lI:im al' rry,,ib does noI bIoclI COX-l. Urjke the irlhblion at COX-1 by 8$pim (¥rt1ich 1$ rapid and im!YelsIlle), the inhIJi. tion 01 COX·2 is time-dependenl and irevef'Sibie. CMeoo~ib was llpJlI'OYed lor Irealmenl 01 osleOar1hritis and rhet.matoid arttwitis, but no! !of analgesia. [Nole: In some trials. ceIeooXib had analgesic aaMty; in ott-s it was no more eIlectiw th8n the paeeoo. Its abilily to reduce acute pain Is poor.) Unlike aspirin. ceJecoxib r:Ioes noI Olibit platelet aggregation.lnl does r.:Jl increase ~eetill{j ame.

-,.-..--

--

• lat • • •

_......

.-

:t Adverse effedll: Ab(b.liillll pain. Iliarrtlee and dy"P"'llSia are the most OOi,"'IOi.lId\.wM efleets. 0.-. a 12 week period the inci-

AGENTS (oontinuecllroTl p. 415)

In oontrasl 10 !he NSAlD drUgs. remillive (.emissiofHnducin arthritis drugs are sloW-aaing. "These drugs are used primarily lor rtleu1Iatic
ilAI

desa'bed below.

E. Lellunomlde le'kJnomide (Ie FLEW nom ~ is an isoxazole iml1'lK1Ol'l'lOdula· lory agent !hat preterentially causes cell arrest ot the autoimnune lymphocytes ltuougtl lIS 8C1ion on dihydroofolale dehydrogenase (DHOOH). Stimulallon 0' a T cell by an antigen-presenting cell drives the lymphocyte into lis feplicalive cycle. Many enzymes. Il'lCludlng lho!;e required lor dtllXM! p1Jrine. pyrimidine, ANA, and membfane synthesls. afe upregulaled In the G1 phase of 1I1e cycte.

II ·111

"'_11

j

rIim't

os.

V. SLOW-ACTING, ANTl-INFlAMMATORY

-

.

....... ' 8 . . . .

1. Pharmacoklnetk.: CeJ8cn~ib is .eadily absorbed. reaching a peak .... lUllilllalu, in lIbout three hour$. It is IlKlelISi'J9Iy ~ iaKI in the iller by C)1OOln:me P-450 (CYP2C9), and is exaered in the Ieces and ~. Its tIall-lite is abotA eleven hcus. Itus the ~ is usudy I8lo:En on;:e •
dence 01 gastroduodenal ulcers in plItienls taking celsoodl was aboUt dDI.bIe tIlIl iound in plIlients on placebo, and only oneIhi
co~-t_

••_"*",,

COX·21~by:

I Poo

I 81 .....

"

.--

: C .....

Sll.~COX-2

Inhibillon:

._~

<_.0...'.'.< ..... _,.

< <-0 • " " . - . . . _

•

-, >=I\U . . _ . POI >

Pharmacology Updale Dihydroorotate dehydrogenase (DHOOH), \\o+lich catalyws the lormation 01 orotate (a precursor 0I1he pyrimKllnes) lrom dihydroorolate in lhe milochondria. is among lhese (Figure 39.17). INole: Resting lymphocytes can meet lhe" requiremenlS 'or ribonudeotides through the satvage pathway, but cell dMsion requires an 8 to 16·fold expansion 01 the ribonucleotide pool). Inhibition of DHODH deprives the cell 01 the precursor lor uridine monoptlospnate (UMP)-a necessary componenl lor RNA synthesis, and a precursor 01 the thymidine-containing nucleotide required for DNA synthesis. After biotransformation. leflunomide is a reversible inhibilor 01 DHODH. [Note: Leflunomide has also been reported 10 inhibil tyrosine kinases, buI ~ is not known how this mighl inrluence the anti·inflammatory aClion 01 lhe drug.j Leflunomide has been approved for Ihe trealment ot rheumatoid arlhrilis. II not only reduces pain and inflammation associaled with the disease. 001 also apPears to slow the progression 01 structural damage.

2""'. co" • O!I', ._

I I

1. Pharmaa>ldneUcs: LeIIu!omide is well absorbed alter o90 perceol). and has a haW.Jjfe of 14 to 18 days. [Note: Because 01 ~s long haI1.Jife. loading doses ale necessary (see P. 19).) Lefh¥>omide is rapidly COf1Y(!f1ed to the active metabolile. The metabolites are excreled in tile urine and the feces. The active mela.tdite undergoes bi~ary recycling.

~

j D

-j

" .....'... 4

2. Adverse eftl!CtS: The mosl common 01 these are headache. diar-

$'_

rhea. and nausea. Other untoward e'fects are weighlloss, allergic reactions including a flu-like syndrome. skin rash, alopec:ia. and hypokalemia. Leflunomide is teratogenic ,n experimenlal animals, and is therefore contraindicaled in pregnancy. and in women 01 d1i~ng potential. 11 shook! be used with caulion in pa1lenls w"" liver disease, because ~ is cleared by both biliary and renal excretion. Choiestyrarnlle increases the clearance oIle1lunomide. F. Elane«:epl

Figure 39.17 Site 01 action oIleflunomide.

Tumor neaosis 'actor (TNF) plays a key role in the hO$1'S immune sySlem. lis inflammatory and immune regulating aetivioos ale myriad. For example. TNF causes local activation of lhe vascular er1oolhelium. and also release 01 Mric oxide, which causes vasodi· lalalion and increased vasoJlar permeability. Platelel activation and adhesion are also increased by TNF, causing local blood vessel occlusion. These actions 01 TNF resu~ arter i15 binding 10 two dillerenl receplors Ihal are round 011 neulrophils. vascular endolhelial cells, and fibroblasts. These receplors also exist in the serum and synovial fluKl in a soluble form. The largeting of TNF·a rests on the observation that cyIokines produced by macrophages (TNF-a. IL·1. IL·6, IL·8) predominale in the rheomatoid synovUn. Eta~ and in"~imab decrease lt1e acIivity 01 tumor necrosis factor. The former is a fusion protein composed 01 TNF receptors; the laller is a chimeric anlibody directed against TNF"ll. Elanercepl has been approved lor the treatment 0' rheumatoid arthr~is. A recent t"al showed that lhe combination or etanera1p1 and melholrexate pro-

<"'" '''' ..,., • < ...... _ ' "

I )

Chapter 39 Update: Mil-inflammatory Drugs

vided grealef clinical benel~ than melholrexa/e alone. INote: Upon discontinuation 01 elanercept, me SymplOlTlS 01 1lI1hfitis generally reI\.m within a month.]

I, MoIchal~"" 01 action: Etane«:epllee TAN flf sepl] is a geneUcaIy 8llgil-eered Iusion pIOteri (:()IllpO$ed 01 two identical chains 01 the lecorrbinarn tunan TNF-«JCeploI p1S monomer !used with !he F1:: dl:lIrWl at 1'IuTIa'11gG," This nHe tusion PfOIein bO!s two molecule5 01 TNF, and prevents Ihem Irom binding kl cellular 1"""",*"S. "The plOtt*! does not Iisoiltillile bet'I e8f1 TNF-o: and TNF-iJ (IyI1~""""'i). ["'*: Boca... TNF is impoItanl in ~ 1lI1ing 0IIIllAaI ~ fe4IUI es 10 ir'eClioll and ~ lIlere is some WilCeiTl 8Ibc:M the Ionp-IeIITl use 01 etaoeCCfJl.] 2. PfletnlllCOklnetk:s: EIiIrtetcept is given Slbo.rt3l'l8OUSlY twice a week. "The lime kl1T\3.1lin'uTl sennl (:()IlQeI1Iralion afteI a single illjeclioI. is abotA 72 hours. Its meliaI'I t\all-li6e is 115 hours. Data on elimination is not lMtiIable. 3. AdYe1ie etlects; E ~ is wel-1Clerated. No to:o:icities or anlibodles haYs been reported 1-klwe\Ier, it QWl pn;lduce local nIammaIion 81 tte site of i IjeaioI i. Palienls wiltllile-tl1reatering inIection sucI1 as sepsis shoUd not Ieee"" l ltiefaI:lV wiIt1 elallOIOIlJ?f.

G.lnlli.lmab Inflix;mab (in FLICKS ih mab) Is a d1imeric 1060: monoclonal antibody composed 01 human and murine regions. The antibody binds spedlically 10 human TNF·a. thereby neutralizing that cytokine. InflixJmBb has been approved lor Crohn',. disease lor both listulizing and non-tistula disease. {Note: Increased levels 01 TNF-a Bfe Ia.Jfld in fecal samples 01 patients with Crohn's disease.1 It is no! ~ lot mainrenance therapy beyond six weeks. Apprv.oaI tor the Ilealmen! 01 rheu'natic arthritis in combiI ~tion wilh me/tlolrelo:8te is antio;paled in !he near future.

1.

~

InI'Wmab is infused inwaIooenou5Iy (Mlf at least two 1'Q.oIs. It distrhJles in the wsn "ar ~, and has a half.... 01 9.5 days. Its mefaboism and eliminaliotl '-'e not been dl5

.tJed.

2. Moo.'M etlects: Lono-lenTl use 01 illllainab is as'Piated VI'ifl de !I:lI>'Iet'1 01 anli-ntximab allibof I.rIIess ltoe <Wg is used in mmbillalion with me/hotreXale. Infusion reaClions sud1 as 1lMII, ctMI, pruntus, or Uflicaria...,... OCQl(Ted. 1111......... leading 10 pneumonia. ...eHUlitis. and other conditions have also been reported. Whether lIe3trnenl with ~ p1e(isp as kl tym.. ptI01m1, • condition thaI occurs wilh immunosuppressive or inlfnune.attemg M.Jgs. remains 10 be eslaljjsled.

<6,

..... '0' ..1.,

> ....... _ , >

• •_ . - " < ' " ,... ' _

... _ ' ...

>

Pharmacology Update

40

Autacoid and Autacoid Antagonists III. ANTIHISTAMINES (otlrU'ued troI'l'I p..t25) Ae 'efs shol.*l be aware !hal ~ (~. floe moe l'ridel'f s ' f;e H, histamne recepkll anlagtrisI. has been voU1tiriy ..ittJ(hiWn troI'l'I the trIlIt1lel lJof the 1TI8flIAelu"8f. The ..itldlawal was inItituled because 01 the risk 01 life-Ihreatenlng car
used.

F. Fexolenlldine

FexoIenat:Jine is indicated lor the relicr of !he symptoms 01 allergic rhinitis In adults and childran 12 years of age and older. FexoftJn8dne is a teIecIive antagonist althe H, histamine re<:eptor in the periphery or the body, Experhnenlal studies demonstrated that the drug does not aoss the I:llood-brain b8lTier. Fex.oIenadine is rapkIy absorbed following 0faI adrninistrafiof1. Very little of the drug is metlilbolized. witIl 60 peroen1 ekCfllted in the feces. and 11 petcen. In the urine. Its halI·life is about I S hOurS. In patients older Ihan 65 years. the peak concentration was Iwil;:e that 01 normal 1")Iuntee" less Ihan 6S years old. Renal Impalrmenl also results in increased plasma Ie\IeIS. Adverse e«ects are mild and inlreQUer11, and indude~~ and

41

IatiliJue.

Immunosuppressants

I. IMMUNOSUPPRESSANTS Organ tr.-.splantation has be<x:me a fOI./IWle procedure due 10 irnprowd surgical ~. belle, !issue typing. and the availability of drugs Ihat more seIecliYety inhibit rejection 01 lransplanted tissues. and prevent the patienI rrom beooming imrnunoIogicaIl compromised. Earlier drugs were non-selec1ive. and suppressed both !he expansion 01 actio vated T cells and the formation 01 antibodies It1rough inte
'"'"

.. "---"

,"' ,.,

4"

Cflapter 41: Immunosuppressants prine, and the glucccorticoid pro-drug, predSljsone. Patiems trequef1lty succumbed to inlection, Generally, a combinatioo 01 irrrounosuppressant agents are used to pl'evef1t rejection,

a A. Non-selective immunosuppressanls 1. Azathioprine

Azathioprine la zah THIO preen] has been the corne,stone 01 irrmurosuppressive therapy OYIlr the last several decades. II has a nitroimidazoloyt side cI1ain attached to the sullur ot 6-mercaptopurine, which is removed by non-enlymatic 'eduction in the body by glutathione to yield 6omercaptopeJrine (6oMf'). The ~t1er is then converted to the CQlTespond;ng rucleobde, thioinosinic acid (lIMP), by the salvage pathway enzyme, hypoKanthine-guanine phosphoribosyl transferase. The imm.mosuppressant effects of azathioprine are due 10 this t,audulent nucleotide. (See pp. 380-361 tor a discussion at 6oMP's mechanism at action. resistance, pha,macokinetics, and adllfllSe el/ects.) Because 01 their r3¢ proli1eralion in the immJf1fl response, and thei' dependence on.!!l! IlS:Mt synthesis of purines required forceH division.lyn¢ocytes are predominantly affected by the cytotoxic e!t9C\s of azaIhioprine. The dntg has little el/ect 011 suppressing a secondary imm.me response. 2, Mycophe-nolale moIetii

In many centers. azathioprine is being replaced by mycopheno. late mofed/[my koh FEN oil ~te MOrN fe till). An ester. ~ is rapidly hydroly:ted in the gastrointestinal tract to mycophenolic acid, whict1 is QUickly and almost ~etely abSOl'bed. It is a potent, reversible, uncompetitive Inhibitor of inosine monophosphate dehydrogenase, blocking the Q§ flQ'dllo,mation 01 guanosine phosphate (GMP). and thus, like 6oMP, it depriVes the ,apidly prolilerating T and B cells ot a key oomponent of nucleic acids (Figu,e 41.1). Mycophenolic acid is glueuronidated and excn;ted preoominanlly in the urine. Adverse el/ects include pain, diar,hea, letJkopenia, sepsis, and lymphoma, COnoomittan1 adminstration with antacids containing magnesium or aluminum. or with choIesryramine, can decrease the absorption 01 the drug.

B. AnUbodies 1. AntilymphOcyte and anthhymocyle globulin These antibodies are prepared either by immunization of Ia,ge animals with human lymphoid cells (polydonal), or by hybridoma technology, p'oducing monoclonal antibodies. The antlbodies bind 10 the SlJrlace 01 circulating T lymphocytes. The antibodybound cells a,e then opsonized and pIlagocytosed in the liver and spleen, 'esulting in lymphopenia and impaired T-cell ,esponses. They are primarily ~ed to treat the acute pIlase of allograft rejection. The antibodies are administered intramuscularly, or infused intravenously, and thei, hat/-ble extends from three to nine days. Since the humoral antibody mechanism remains aetNe, antibodies can be formed against these Ioreign proteins. Othef adverse allects are chills and lever, leukopenia and thrombocytopenia, and skin 'ashes.

"(X) ·~d 00 00

_ _ ,,"".

P'1*

-

dol,... ;

a

;(X) OH OH ~

"'OflO.... ,_

BlOl:kIn;1he _ 01 (iMP

rIv- ,.pdIy

--

pt'OIM~f_8

..... 01. key p""'U'-

-.quire
Figure 41.1 Mechanism of action of mycophenalale

<_ '0...l.,

>< . . . . . _ , >

<

~

....UY>- .....- - " ' . , """'U . . _ . W >

PIlarma<:oIogy Update

.-

--- =1

puu .... '11

0,_'_'"+

Since initial binding of the muromonab-CD3 to Ihe antigen resutts in cylokine release due to activation of the T Iymphocy1e. it is CUStomary to premedicate the patient with methylprednisolone, diphenhydtamlne. and acetaminophen to allev;ale the cytoklne release syndrome. The arrtlbocly is extensi~ metabolged. and eliminated prer:lominarrtly in the bUe.

b. Adverse effects: Anaphylactoid reactions may occur. Cytokine roIease syndrome may occur on the first dose. The symptoms can range from a mild, flu· like illness, to a life-threatening, shock-like reaction. High fever is commoo. CNS effecls such as Sei2Ures, encephalopathy. cerebral edema. aseplic menin. gitis. and heaclache may occur. Inlections can increase. inchJd· ing some due to cytomegalovirus. Muromonab-CD3 is contraindicated in patients with a hislory of sei2ures. in those with uncompensated hearl failure. as well as in pregnanl women, ex those who are breast feeding.

..... ,01

_",nol

.C:a"'" ~'~'_'I .. II I • •

01I

C. Selective immunosuppressants

:::r

AaI_oI I hOi" l' ~ AT• ..-lnIm .... "Ii' p' "'"

The advenl 01 cycIosporine revolutioni2ed organ transplantation by prolonging organ survival.

t

=~==I , __.01_1 aooc:ocIoill ~

I

-"'~I

\

--e..

1.'IIl,d

Muromonab-CD3 !rnyour oil MCNJ nab] is a morine monoclonal antibody directed againsl the glycopfolein COO antigen of human T cells. Binding 10 the COO protein resu~ in a disruplion 01 T lymphocyte function. because access of arrtigen to the recognition sile is blocked. Thus T lymphocyte participation in the Immune response is decreased. Circulating T cells are depleted. Muromonab-CD3 is indicated lor treatment of acute rejection 01 renal allogrnfts as well as lor steroid-resistant acute allograft rejection in cardiac and hepatic lransplant pa\ieflls. It is also used to deplete T cans lrom donor bone marrow prior 10 transplantatIon.

a. Phannacokinellcs: The antibody is administered intravenously.

.__

2. MUromonllb-COO (0KT31

1

Figure 41.2

Mechanism of action of cycJosporine.

t. Cyclosporine: CycIosporine [SIGH klo spore inn] is a cyclic pep-lide composed 01 11 amino acids (several are methylated on the peptidyl nitrogen) exlr8cted from a soil fungus. Cydosporlne pre!. erentiany suppresses cell-medialed imm.me reactions. whereas humoral immJnity is affected 10 a tar ~ser extent. After dillusing into fhe T cell, cyCIosporifle bindS 10 a cyclophilin to torm a rompie>: whm binds to calcioeurin (FlQure 41.2). The latter is responsible tor dephosphorytating NfATc (cy1osofic Nuclear Factor of Activated T cells). The cyclosporine'calcineurin comple~ cannol carry out this reaction and thus the subsequerrt reactions required lor the synthesis o! a number 01 cy1ok1nes. including Il·2. canroJi occur. The end resutt ot cycJosporine action is to oecrease Il-2. the main stimulus for increase in the number of Ihe T lymphocyles. Cyc/D$por;ne is used to prevem rejection of kidney. liver. and cardiac aJlogeneic transplants (FiQlJre 41.3). Although it can be used alone, il is more effective if glucocorticolds are also administered. and this is the usual practice. Cydosporine is an alternative to merhotrexate tor the treatment of severe. active. iheumatoid arthritis. It can also be used !or patients with recak:::iIrant psoriasis that does not respond to other therapies.

<-''''''''''<---')

<eo- •

'c'.. , .....,.." _ _ .... >

Chapter 41: Immunosuppressanls a. Pharmoookinelics: Cyc/osporine may be given eilh&r orally or by intrilVe!1OlJs infusion. Oral abSOtPbon is variable, ahhough a new preparaoon is more reliable. Inlerpatient variability may be doe to melabolism by a cytochfome P-450 (CYP3A4) present in the gastrointestinal tract. which metaboliles the drug. !NoIe: Grapefruit juice, which lowers the levels 01 this enzyme, increases the i\I11OtJnt of c:ycIosporine absorbed.] Aboul 50 pe, cent of lhe drug is associated with the blood Iraction. Halt 01 this is in the erythrocytes. and tess than one-tenth is bound to the lymphocytes. Cyclosporine is extensiv€oly metabolized, pri· marily by hepatic CYP3A4. [Note: When other drug subslrates lor this enzyme are given concomittanUy, many drug interactions have been reported.] 11 is not dear whether any 01 the 2S or more metabolites have any adivity. Excretion of the metabolites is through lhe biliary route, with onty a small amount of the parent drug appearing in the urine. b. Adverse efllfCts: Many 01 the adverse effects caused by cycJosporine are dose-dependent, and thereklre ~ is irrportant 10 monitor levelS of the drug, although a direct correlation between drug level and toxicity doesn't pertain. Nephrotoxicity is the most common and imporlant adverse effect 01 cycJosporine. II is therefore critical to mDI1~or kid'ley function, Reduction 01 cyclosporine dosage can result in reversal 01 nepl1rotoxicily. Hepalotoxicity can also occur, aflcl therefore liver function should be periodically assessed. Infections in patients taking cycJosporine are common, and may be lifethrealening. Viral infections due to herpes group and cytomegalovirus are prevalent. Lymphoma may occur, presumably due to immunosuppression, a/tl1ough recent evidence has raised a question as 10 whether cycIOSpon'ne itself may prO"" mote lymphoma formation. Anaptlylactic reaetioos can occur on parenteral administration Other loxicities incll.lde: hypertension, hyperkalemia (it is imporlant not to use K'-sparing diurelics in these palientS), tremor, hifSu~sm, glucose Inlolerance, and gum l1ypefpIasia.

2. Taerollmus (FK5D6): Tacrolimus (TACK row lee muss) Is a macrolide that Is isolaled Irom a soil fungus. Its mechanism 01 action is the same as that 01 cycJosporine, excepl that it binds to a differenl irTllTl,lnophilin, FKBP (FK binding protein). TactoIimvs is approved for the prevenlion of rejaetion 01 liver and kidney trans· plants, and is given wilh a glucocorticoid. This drug has found favor over cycJosporine, not only because episodes 01 rejection have been deCreased, but also because lower doses 01 glucooor· tiOOd can be used, reducing the likelihood 01 inteclions. a. Pharmacokinellcs: The oral route is preferable, but, like cyc/osporine, oral absorption is incomplete and variable, ,equiring lailoring 01 doses. Tacrolimus is Irom 10 to 100 times more potent than cyr;/osporine. II is higtlty bound 10 serum proIeins. 11 is also concenlrated in erythrocy1es. Uke cyc/osporine, lacrolimus undergoes hepatic metabolism by the CYP3A4 isozyme and thus !t1e same drug interaclioos occur. Renal excretion is very I<:M': most of the drug and ~s melabolites are found in the feces.

'00

\____

-----Trod_II merlpy

.'-~~~~~~-

o

2

3

•

V.... _lronsPor>\

Figure41.3 Effect 01 cycIosporine on liver transplant survival.

5

..... '0''''''

> ...... _ , )

474

Pharmacology Update b, Adverse effects: TacrDiimus is more toxic than cycIosporine. For example, nephrotoxicity and neurotoxicity (tremor, seizures, hallucinations) tend to be more severe in patients treated with tacrolimus. Other tOllici1ies are the same as those lor cyclospa/ine, except thaI lacro/imus does oot cause hirsutism or gingival hyperplasia. Anapflylactoid reactions to the injection vehicle have been reported. Tho drug it1lefllClions are tho same as those dest::ribed aboIIe lor cycJosporine.

42

Drugs Used to Treat Obesity r.

ANOREXIC AGENTS

Obesity reters 10 presetlOO 01 excess body fat The amount 01 body fal is dllflCtJ~ to measure directly, and is usually detefrnined from body measures that have been shown to correlate with body fat in mast poopIe. Tho body mass index (BMI) is a usetul dinical calculation lor diag10sing obesity because it oorreIates with total body Iat, and Is relatively UIlaffected tl'j heigh\. It can be calculated BMI" (weight in kgY (height in meters)2 determined Itan tables. The normal range for 8MI is betwOO/\ 19.8 and 26.0. Indil/iduals with 8MI between 26.1 and 29.0 are overweight, those who have a 8MI greater than 30 are obese by definition. Obesity is a serious health problem, and its treatment is difficult, because individuals find it hard to adhere to a program 01 dieting and exercise. Currently, two new ll:1oreJdat1ts (appetite suppressants) are available. They are phel1lermine [FEN tur meeo) and sioorramine [SI tl'joo tra moon). both amphetamine-like agents (see p. 103). Of

A. Phentermlne and $ibtttramine

These agents have many properties in common. Both are syrlllathomimetic amines that exert their pIlarmaoologic aetioo by interfering in the reuptake of serotonin and OOfepinephrine into the presynaptic nerve terminal, thereby increasing their brain levels. In the case 01 phentermine,!here is an increased release 01 dopatrino, \\ot1ereas with sibvtmmM1e, the rO\4llake into the presynaptic Ill!t'IIe terminal 01 senr tanin, /\Ofl!pinepIlrine, and toa!esse< extent Oopamrlo,Is hirldered. 1. Pll8rmaco1mellcs: SibtAramine undergoes first pass demethylation to aetM! metabolites, which are turlhef biolranslormed it1 the Iivet' and elfCfeted primarily in the....me. Tho haIf·1ife is about 15 hours.

,_r"" ..,.,>,

,>

Chaptef 42: Drugs Used 10 Treal Obesily

2. Adverse effects and contrllindicaliof>s: These are similar for both drugs. For example, they are both controlled as Schedule IV ageols (they have a low liability for depeIlde!1ce or abose). Heart rale and blood plessure may be increased. and dry mouth, headache, insomnia, and constipation are common pr~ems. Pulmonary hypertension has occurred {rarety} with phenrermine. especially when it is in combination with farlfluramlne. [Note: Thfs combination. referred to as "1en-phen", was widely used as a diel aid. II was nol only reported to cause pulmonary hypertension, but also heart vatve abnormarities. Fenfluramlne has since been withdrawn from the market.] These adverse elfects have not been reported for sibu/ramlne. Sibutramlne should be avoided In patients taking moncamlne oxidase Inhibitors. selective serotonin inhibitors such as fJuoxetine, or serotonin agonists lor migraine, such as sumalrfJran, as well as lithium, dextromelhorpllan. and pentazocine. Drug interactions can occur when slbrilramine is administered with drugs that ifItlib~ CYP3A4, such as /ai/oronazoIe, erythromycin and dmetir:1ine. The increases in sibJ/ramine are smail. and no untoward conSBCpJences have been reported.

II, UPASE INHIBITORS ~ stat] is the first drug in a new Class of r.onsystemicaJly acting anliotlesity drugs know as lipase inhibitors. QrllsUlI is a pentanoic acid ester that inhibits gaslric and parcrealic lipases, thus decreasing the breakdown 01 dietary fat into smaller molecules. Fa! absorption is decreased by about 30 percent The loss of calories is the main cause of weight loss, bot adverse gaslrointestinal eflects associated with the drug may also contribute to a decreased food intake. OrtiS/af is indl· cated in iflvidl.l8ls with a body mass index of 30 or more, or in persons with a 8MI ot 27 or more who have other risk factors. such as high blood pressure. high cholesterol l(!\Iels and diabetes. In dinicaJ trials, individuals treated with «lIsta/1ost an average of 10 percent of their body weight (compared to 6 peroont for the placebo group) wilhin one year (Figure 42.1). Total and low-densfty lipoprotein {lOLl docreased more In the treatmem group than the placebo group. The most corrmon side effects associated willl ortiSfat are gastrointestnal s~toms, such as oily spotting. flatulence with discharge, fecal urgency, and Increased defecation. Orlistaf interferes with !he absorption of the fat-soluble vitamins, II caroleoe and carotenoids. Orllstat is OOIltraindicated in patienls w~h chronic malabsorption syndrome or cholestasis.

Ortista/IOA

.-.~~.

• Figure 42.1

Effect of orlistattreatmenl on body weight.

..... '0''''''

> ................. ' >

'"

Pharmacology Update

Drug Used to Treat Osteoporosis

43

I. OVERVIEW OsIeoporosis is a cordtiCfl 01 skeletal lrag~ity
II. BISPHOSPHONATES Tllese analogs ot pyrophosphate. inclu(j;r)g efid,ona/e [e Ii DRDE nate). ,isedronate [ris ED roo nate]. alBndrcv1
figure 43.1

Chan9£'S in bone morphology SOOIl

m osteoporosis.

"

.... o

...................

,

figure 43.2 Elfeec 01 alendrcv1
A. PhDnnacoklnellcs: Pamidronate is adrrinistered Intravenously. AO 01 the other bisphosphonates are orally IlCtive, although less than ten percent at the administefed oose is absofbed. Food signiticantly interteres with absorption. Bisphosphonates should be administered with si~ to eight ounces ot water at least one hauf betOfe eating bfeak/as!. The bisphosphonales afe rapidly cleared from the plasma. primarily because they avidly bind 10 t¥lroryapame mineral of bone. Once botJnd to bone they are cleared over a period 01 months to years. E~mination from the body is solely It1rough reoat clearance, and the bisphosptlonates should not be given to individu· als with severe .-anal impairment. B. Adverse elfect!: These include diarrhea, nausea. and alx!ominal pain, AlenclrooalB, elkJronate. and risedronate are associated with

'"'"

..

,"' ,., " - - - ' )

Chapte, 44: M>sceIlaneoos Drugs

ontv

member of the class that esophageal ulcers. Etidronale is the causes osteomalacia 1oI1owing long-term. COI1liouous adminisuation. Figure 43.3 shows the relative potencies 0I1hB bisphosphonates.

III_ OTHER THERAPIES

1'MIJdJ .. _

'00

A. Esltogen therapy

.'01 ><11 .......

1QG.1,000

-.

1,0Jl).10.1Xll)

Esf,ogell repacement (see p. 264) is the mosl effective thefapy for the preventiof1 01 postmenopausal bono loss. When initialed in lhe immediate postmenopausal period, estrogen prevents osteoporosis and reduces the ,Isk 01 hip t'ac\u,e. Rak»OSitive breast cance'.

Figure 43.3 Structu'e and antiresorptive activity 01 some bisphosphonales.

B, Calcitonin

In Clinical trials, salmon calcilonin, adminiSlered intranasally. has been effective and well lolerated in postmenopausal women at risk 01 developing osteopor~s. In trials lasting several years the drug reduced bone resorption and improved bone architecture, relieYed pain, and inc,eased function. C. Calcium Calcium intake th'ough diet and, ~ necessary, use 01 SUP\l+emer11, should tOlal 1,000 mg/day. In pos1menopausal women not taking eslrogen, lotal calcium intake shOUld be 1,500 mgtday. In men and women over 65 years 01 age, calcium and vitamin D supplementation have been shown to reduce the risk oIlraclu'e lrom f 3% 10 6% eve, a three year period. This suggests that the benems 01 calcium and vitamin D supplementation is clinically important for preYeIltion 01 lraetures due to bone loss. particula,ly in elderly palients .

Miscellaneous Drugs I. DRUGS FOR ERECTILE DYSFUNCTION Erectile dyslunetion, thaI is, lhe inability 10 maintain penile erection lor lhe successful performance 01 se~ual activity, has both organic and psy. chogenic causes, inclUding as a sequelae to prostatic SlJ'9B')'. Erectile dysfunction is estimated 10 affect up 10 30 million men in lhe United States. Previous therapies have inclUded penile implants, and inlrapenile injectior1s of aJprostadil (see p. 420). SilrJenafil [sit DEN a fill, the Ii,st oral drug app,oved lor the trealmem 01 ereclile dyslunctioo in males, was inlroduced in early 1998.

44

< ....."" ..,., . . . . . . . _ , .

'"

Pharmacologv Update A. Sildenafil

A

In

'l:::'

I

'~

10 --,I B

Sexual stimulation results in smooIh muscle relaxatior1 of the oorpus cavemosum. increasing the inflow of blood (Figure 44.1). 1'he medi· ator 01 this response is nitric OlCide (NO). NO activales guanylyl cyclase. which forms cGMP from GTP. Cyclic-GMP produces smooth muscle relaxaHon. The duration of action 01 cyclic nucleotides is ronlrolled by the action of phosphodieslerase (POE). At least six isozymes or PDE have been charae:terized. Sildenafil inhibits PDE-5. the isozyme responsible lor termination of cGMP in the corpus cavemosum. lhe resutl of the presence 01 sik1enafil is an increased durati
0'

'or

1. Pt\armacokineli<;s: Sildenafil is rapidly absorbed ahe.- oral admin-

Si/dellatil ~",",I"~

Ftgure44.t

A. Chemical mediators leading to efllCIion. B. Effect of sikJenarrr on cGMP levels in the smoolh muscle of the corpus C8\1i!mosum.

istration, and peak plasma levels are achieved within one hwr. Bioavailability is about 40 percent of the oral dosa. Sildanafi/ IlI1tars tissues. and has an apparent lIOIume of distribution of 1.5 LA<.g. Bolh sildenafi/ and its major N-desmethylated metabolite are ,. 95 parcant bound to plasma proteins. Both CYP3A4 (major route) and CYP2C9 (minor roule) ara responsible lor Ihe metabolism of slldenafi/. The major metabolita. N-desmethyl slidenafil, is approximately 50 percent as poIant as siidenafi/ in inhib~· ing PDE5. The major rwle of eliminatIon lor sf/denafil and ~s metabolites is via the bile. Clearance is decreased in older individuals: 'rea plasma concentrations are 40 percant higher in healthy voklnteers ,. 65 years ~d. Severe renal impairment « 30 mUmln) increases the AUC (see p. 7) by two-Iold. Similarly, cirrhosis 01 the liver also slgnilicantly increases the AUG. 2. Adverse Effects: The most frequent adverse etfects reported for si/denafil are headache. lIvshing. dyspepsia. and nasal congeslion. Disturnances in color Yisior1 (loss 01 blue/green discrimination) also occur. probably because 01 inhibition of PDE-S (a phosphodiesterase round in lhe retina that is Important in color vision). The incidence 01 these reactions appears to be dosedependent. Diarrhea. rash. and dizziness have also been reported. SlkJenafil results io mild decreases in blood pressure. Because 01 ~s ability to polentiate the activity of NO. however. there is an absolute contraindication against !he use of concurrent org8r1ic nitrates in any form. Sildanafif was negative in s8\leral el
''''''

..

,"' ,., ) ' ' ' - - ' )

TRADE NAMES

T.- _1or!he_1nlquen1y ""'os p«IGCribed

_

(lql200 dnIgs) "'"

.. CAPITAL l.£T11;R&

MAJOR CITATION

PaO"....-oh<>wnln_ i-
_ ooxt6nGiI«t ........."'" of 11>0 drug Of I
Acetaminophen (TYLENOl), 401{, 412,

412~13

CITATION 'N FIGURES

PRONUNCIATION

Pa\J8 ~_b)' '/'"d0 O'ug lIIlP""S In a figure.

Page"""- "' ilaIics i-
'Sefr Cf05S·rel&rences di'ec11he reader to 100 synonymouS lerm. '500 aJsd' crosstele'ences di'ecl the 'eader 10 related topiCS. (Note: Positional and configuraliOrlal designations in chemical names (l01 example, "3.', '",.', "N••, "'0-1 "'" ignored in a1p1\1100tiZing.) Abac
Abci>
ACCUPAIL

Se9~

AoebUOIOI. 71 I.

n. n. 791

actions. 751 ewneal applicalions, 781 contrairdcatioo, 177 drug eJiminelX.>n. 741 Acetan1inophen (TYLENOl). 4OH. 412.

412-413 actions. 4051 drug i1Iamclions. 140 metabOlism. 4131 tor migraloo. 428 lor Reye's syndlome. 407 Acetazolamide. 2231. 226-227 and e:tIa1lg(IS in urine composiIiOn. 228J.

"',

drug inleractioos. 292 lor glaucoma. 41 &iIe 01 adioo, 224/

Acet0h9Ilemide. 255" 260. 2ro

prq:>erties, 2611 Acety1choline. 351. 39, 39-40 binding. 3&37. 371 degradation. 37, 37' drug iolIeractioos. 236 iI1teraClion wiIh membrane leceplOoS, 21 end muscarinic receptof, 481 as neorotral"'l5"'itler, 32t, 33 telease. 36. 37f &iles 01 ediOn, 36/ Slorage. 35, 37f s1rUC1u"e, 391 syn1llesis. 55. 37f Acqlited irnmI.rIOdeIici syndrome (AIDS), treauoom. :J68.371 ACT11. See Cor1icol:roplo

Actinomyceles. 2901 Soo Daetioomydn ActivaUl
AcycloguaflOU>e. see ~ AcydoYir (ZOVlRAX). 3631. 365, 365--366,

'"

mechanism 01 action. 365. 3661 ~ lale willi, 367/ Acylureldo penicilIio!l. JOI drug elimination, 303 AOAlAT. S6Il Niledpioll Addison's disease, treatment. 274 Adeno!;ine. 1631. 174 antiaJ1tlyllmic elleclS, 1641 Adminstralion muteS, drug. 1-4, 2/

m m·m

Adrenal androgens. prodoc::tiol1, Adrenal cortic:osteroids, drug In!efac\icfls. 270 irIhilliIors. 277 lhe
!>-Adrenergic agents. lor d1nric ObStrudRie pulmonary disease, 222 Adrenelgic agonists, 5!t-70 adverse et1ec1S. 68t lor eSlhma. 218. 218t chM1Clerlstics,59-{l1 diroct-acting, 61-67 mechanism 01 action, 61 SIIes 01 action. 621 indlrect·acting,61.(,8 mecl1anism 01 action. 61 sites 01 ecI01. 62t mechatism 01 aclion, 61 ......ed-aclion. 68-69 mecl1anism 01 ecIioo. 61 sites of aetiOIl. 62/ sites 01 action. 561. 621 speci1ic agents, 551 structules.61/ summary, 69/ !>-Adrenergicagonisl!;.1511 tor asthma. 217/ for ch"CfIic obstructive I"*f"oOnery disease.217f lor COfIQ8SIive hea~ jajllXe. 161 sites 01 eClion, 16 II ",-Adrenergic agc:nists. for rhinilis, 221 specific agents. 2t71 Adrenergic agonls!S, s.pecilic agents albulerol, 55t, 87t, 691. 218, 431-432. ~,

dofIidine. 551. 67, 87. 691, 1801. 189. 189-t9O, 442 dobulamine. 55t, 66, 68, oot. 151 t. 159, 161,1611 lk:pamIl'Ill. 551. 56. 611. 65, 66-66, 001, 691. 1611. 2481

- . - - ""-. " ....._£'""'"

",....,..

c.~,

, - - _ , _ " " : .......""""

479'

. . . . . .0 . . .' . '

.... _ _ ,.

,""". epinephrine, 3, 321. 33, 40-41. S5/. 58/, 58-59. 601, 61. 61. 61 I. 61-63. 63/. 67/.691.72.721. 11a.. 1641. 218, 424 isopocHIeriCJI. S51. S8, S6f. 61. 6' I. Gf.

64-65, 65f.67f. 6G1, 72/. 75

rneIaprtllerenol. S5/. 67. 67. 67~ 691 ~ S5f, 616, ll&-67. 6Ill nor~. 32~ 33, 381, 55. 56/. 56. fi11-5BJ. 58-!ll. 61, 6H. Gf, U. 641. &91. n~ 7lHi pi .." ••••. 47. 551. S8, 60, llOf.61. 6l!i.66.1l9I.1l3,221 ,ilodo... 56t: 6llt

...... _",

_ . r .. 56t:~67.67,67(1l9I.

".9C1*ll:l<ers.

M'eo..

71.eo

Cl·oldI.~bIocI
-""

W58t 71-73

Uoo:lI""UN WId. 721 b~I'*"' ......

I"

SJ-*~71tlllOt

........ '"

II-AcHnergo:tlb:loIrI.. W. 58058. n-7I, 163I,419~ 436,

442

o

COClOiI_ll lin, ••,

,88t."llll

o

on

'l1.

IB2f

_.

353

74'-751.77. 71,

78J.7$~

dcJIwc:Ul. 7". 73, 73. 1801 la!Io'lI;tld, 71( 741. 78.18.791.1791.191 ............... 71( 74,.751. 77.71,76'0791. 171.176,1791.185 nadCtOl, 7". 74/, 15. 76, 781. 179/. 428 ~arrIiI'Ie. 7'. 71 I. 11-72, 721 ~~. 71/. 12, 72. 124 po'ldoIoI, 711. 74/. 77.77.79/.171. In prazOlin. 711, 73, 73, 124. 180/. 189

AI<~~~'ro:I

disaclYarIagei. 4221

~ling

!IQInIS adionI. 3741

in cancer therapy. 381-390 specilic IlgIIIU. 313/ AllEGRA _ F. . . . . . . . . MergiclXlr"jl.lrdMlis b• •' ' ' ' 411 AIergic It*llIi&, _ 278. 424

276, 423-424. 43&-

1Id. . . gic 1IGt"'

-........... -

~

AIoplrtIoI, 402f, 416, 416-417 dru;l illeoaclioo.. 2fj()( 382 1r;Ir~415

0~358

AJoij.244. CUI ~

lXANAXl. 9112421. 438

ildwrM .n.ttI til. 84f 1r;Ir~_wod

~1I1'

TOOlIiblIn

. . - . se.*"'lI-oldI&.gic-ott. ...1Id. . .9C

*'"

. . . . . . . 41.421 .... tlllIdion, 'Jt6I

,

--,'341 ~

71~

_

m. 2121

_~.476

WOI!''''ll- 243
"""- _ 3 ......

~61

_l
",

.....tM.~cu

~41.421

Sl.fI"O'NIO'Y.791 Mleroerglc bloc........ ~ I ilk . . . .

aoet>..,.. '"

lid .lOOOIlUl irJ5Ulic:Ienc:y pmary. . - - . 2 7 4 ~.1I811""'"274 1llr1iMy. III ", .... 274 L• • ' .... 274 '-O.lOOOI ....... opiI; I... ,' ..... See CookOLqllll ...cAIAMYc:»l. See~

ildwrM IIftIcIs, 491 . . . . . b,41

I'!W*lIiPiIiOr .. 1840187 ...... ,841 .t_e/l8ctf.. ll1S. 1851 ","",UIlClOi'''''' tpIIdIe 8QlInI$. I 7$1 IIigoai.... 427f, 428

-'" ...-

AIdosIerOf18. produ;;:Iion,

4" gieI.. L8IIl

d ......gl:, :J$.4,4, 36t. se. Chulio.. yW: ."..,oista. spealIt:

741

e

.

~"'T

"'"

.wg

'"

Ad>• • gic, deIi>..... 33 Ad>eroergic neuron. S5-59 AdI . . .gic ".0........'1 (adl• •o..........s).!iT-

....'"

cIrical .. , . , .. 7SI C1CII1r.dcoIico.. 11I5 . .,

.".." I8nlZOf;lin, 71/. 73, 73, lB01. 189 IWnok:f. 711. 741, ro. 76, 78'-79~ 1791 ~"'dr'erwglc blodI& .. fIIlllCific agera,

AIrQn .1. ,- 'II ~

aoMrH . , . . , 191 0 . . . . . ,760177 Sf**"ll'dI. '75/ ._,.~ ....

proprnrdOl. 7. 71/. 74.741.74-76,75" 761. 78H91, 153J.164f, 171. 1751, 176. '791. IIl5, 190, 3341, 42n 428,

eIlecIs, 1371

modIfa\ij.14O onset ...
AIDS. SeeAcq.Wij(\ ~

1)'.0.....

birding capacily. 11 drug Dindlng 10, 11-12, 121 AlMerOl (VEHTCllIN. f'I:lOVENT1l). 551. 611f. 431 ·432, 441 lor asItwn1I, 218 and lllcolChodilatiOn, 671 AlOClMET. S#l(rMelhykklpa

" 0 . . . ,-...... 1l3f ~oer«:lll~420

AlTACE. SNRon"4IriI (lPA). 1Sl3f. 21:11. 2Q? 202 ~olpiM ,wlOgijl.. 2021 IA4'8ltieI. 2021 AUrinI.m _ ... 438

,n ,-"

............. ~ , 2361, 240, 43D-441 A." ... --.....,111 ......o::to.. 8U. 87, 87. 3153, 363/, :J6). :J64" 364~ 451 AMARYI. _

....

GII.wp;ojdij

AMBlEN. SeeZ....... "

.... ,

;"

ct.'lIII ......,. 345f, 345-348 __

- ellfeatll8ll. $1

AII1MllcdrHnter'Y SM .... '...·M.. .... ,MJicidel ..........346.348 siles 01 acIion. 3461 mixed. 346. 30-348 site. d IOCIion, 3461 syslemlc, 348. 348 IiIes 01 action, 3461 AmlriCan 1111PI'll ~. See Q\agIBs' dOI.aS(t Amikadn. 31 11. 315. 3J5, 433 DdVfIISII 811_. 318 Iher3jlrlUtic llpplieIJtiC014. 3151

<- ,.....,., •• - .... - - , .

,""'.

......,

Ailiilolide. 2231', 233, 233

•

01 acliQn, 22.,

AtrWIe 'iIIfJl181'l.

~ llI\,

10 KId, 3001

61

~eod.~8!HIO.911

AiI, .......... oeeod. 193L 21M, 20If ~.m,2n.373f

in _ _ 1hetIIpy. 395. 395 ~:J14-317

..,.,.. . . . . . 316-317, 3171 'f 'i.. ~ml

.. 51.338

cN;l~""""'

. . . . . lli'Id. 301 • ...1IQ, 2851

lol U'irlaryna 11'. ......... 3281 4A!tM., ~ 8gIIIII'U, 31 If ........ 3111, 315. 315, 31S1; 316, Q3 gBI'Umioo. 51. 311( 31 5. 315, 31 Sf. 316,0 """"'1'<*1, 31 1( 316. 3'6. 317 he'il"'iuo~ 311f. 316. 316 a,,,,*,,,u)dn. 31 1( 31 •. 3 14. 315. 3'5(

Ai'."""r

""

Illb1Imyon (TOOREXI. 51. 311/. 315. 315. 3151, 318. 3161. 431 trAil ,;,1OmeIl .,lbeN:ensullonamidl.t. to< bums, 29\ S·AmInoa.t1lq1alt, In io:1f11lmlTllllllfY bowel ~".,291

AminoealieyIie add. 331/, 335. 335 Amoodarooe. 1631. In, 172 antiarmytmIll:elteets. 16011 doug Or,........... 1601 N,ib"''''' (ELAVL). 96, 119. 1/9; 1191 ~~1WId ~1251

...,"ApiI. (NORVASC). 180( 188, 188 a

Bf'IllIIl" 1861 t .. ' - t ......, 157, 1861 drI4I 1861

aw';

""'*

a ~ 1881 ........tiaIl, fIOI, lU lUabo'Ioi -*"'. 96 •• ~aoMi.,.1WId ~97t

... ,. . . . . . 119. 119; 1191

~""""'1WId ~125'

............ , (AMOXIl, POlYMOX,

TAlUOX. WYMOlQ. 235( 296'. 300. 300

-""

1rBatrrI8I1t,

~_.3112

00ll1. 2ll2, 2821 drug lrrle
spIOfc-.gll'llS. 1931 ~107-11a

IDper"'ell8.3OOI

lol um.y na

~1iO.speok~

3281

AMOXLSeeAi' ' Ai,'JIhellWl'liollll. 55( 61. 67-68, 691. 991. 1001tM IIdArM eIl8clI. 105 del*dtiq . . - _ IIlOI drug~'n 11°.. ,38 .~.-..gagoniIl. 61

" .........."01 ..... ,00 non-- . hdII, ••. 60 ...,,,,, __kil' B, 331. 33'7( 337-339.

""

lol G)pkO
'"

fllf~2991

............. ,09 ~.. I .... lor. 107-101 ....,.,..,.." \09 &Mge&. 110. 1101 Ii'

......

~

... 95

axar

102

epiI

i1,G3

~11O-1I5

d_lgM in •

. . I*;Iod wCMi_aLiol-.1121

".apao.a:~1WId cfsadvanlaglS. 1 161

--""

10 llI;id. 300' 10 pellIcllIlolllSll. 300' lholrllPllutie applice\iorls. 290. 301 leo' urQl)llr>Iet Intuc;lions, 3261 Amprenaylr.460 AinriO
IIdverse el1ecll., 271

.-zI'. <128 137

~.11...13

..-;lIe agent&. «)1 I t!i ... «N, «IS ......." & shock, " I ,...... 62~

ft.

............-.11. Al'W'ROJl. SN

~ ~ . 116/

~,

slabilily

all " ...pI

107'

alIf'C'O ..... 1091 lr1lb::lion, 109

i'bao ......... 115-117

DMoiAI .... ' rouIe, 302 ao dl8l'OOlI..apeujc egenI. 283

"""" ;ql)

'"

m-206

t,.,~218

111·112 '-PINc:ur'o'8I. 112. 112/ V"Il'llf (011$). mlnlmal .,...,.,.". CllfIOIlnlra!lolls (MAC).

j

11, lilt

Anetlhellcl, specilic agenls, Angina peclllfia

\07~ 106f

wI1h ooncomllWlI d$ell&et. trealmei1l.

""

vrilhl1yper1ension, 182~1831. 185 lreetment.73. 7$. n. 78( 173, 175--178, 187, 1861, 189. 198, 204-206. 406

" __Ilin '. co ...." ill enzyme inI'libiIi:n. 1S1( 156-157,<W2 drug.,leoadlOi" «l9 eI!edI. 1561 a~ 186-187 ~ 186,186/ .,.... 186( 186-187 .... CO

,......

1821

~_,

........,. eOI_ ",..

t_,.(,358

ill'tc.ioI~

3611

AiQCJ9IiOC_ ...... 270 A"d,"V'" •. 216e-272 Aildl. . . . spKlfIc ~ 2J53t dBrmct. 263t 270. 27Q, 271 ~ 2631; 271. 211 f'Ill'O ....... 2631; 271, 2T 1 ~. 263( :m. 211 1111 _ _ cypico_. 2631; 271.

.......

m

,..

megaloblllslic, and kll81ll delidency.

sp«*agII1It, lNI

"""""""_".iC8jp.

lor

1>JpioI..... ~ 187

..-;lIeagenil. INt Ai •• / 1 pte '.lClglOI'I01I&pI:ti.... acli tICS CO,'*"*'" see Ailoa....... ~ . 193(

2O:J,

an

p'\4*iM.2021 ~ "",,"od~ _Ilnenl. <109-<111 Aneln"'" rlIIt'oQ5ll. _~ 1:>2

.7.

AnclnlJIic eo;II"ltI. ANSAIO,5eeFlultliproien

..-

chIg io:1Ie
~"''''
_ _ ''

Jar pepIk; "'*~, 236t 240 Arl.ilgto;

22/

.lfJoIelllin II, JarIJrper ......... 181 1IIl"Ciftc~ 1791 ~.IU

Il*ilIc IIliJ"'I5, llO'

....... ""

doolo.gIc. ~

_ol . . . . oU;I . . . ~451

-,-

..s,

~

spedIc: - - - .

289'

"I '•• '''''""",*",440 ape.s, 1»-142, '41-142

-,,.,

~"",I33I

........ 22

.......... i,~polEfICy,2431 SWdd, b f#OQlIr,

392-395

opecIIc.-.ml Anlerior piIuiUory honncnes, 2411, 247-250 actions. 2481 AnIheIml~ic~, 3~

&f*lfic agem. 3591 AntilIf'lClrOO!lI1l, 272 AnU.odIogsn... ~11Ic..,1S cyp/Ol8rQlle .ce4aNl, Z72, 272

..,

finaslertdlI.13. 212, 272 LCafnkls, 272, 3131, 394. 39+395,

m

~
,7S-178

A ~ «ugs., ~ 8gef1IS,

""

fCAROI2EM CD, DUCOR XR). ,63t 173, 1J3, 1731; 175' In. 117, 1801. 187, 187. 181H881 ......t:idoo ell.... 157. 1151. 11'6, .'" 117'

~

'~.lAlW..AT,PAOCAROlA Xl.).

113. 173t, 175( 177.117,187, 181t 181-188, 1881 ~(NTROSTAT).2.4; 175C. 115:176••"" 177,442

poop.dol(1NDEfW.J. 7; 71t 74;141..

7.n. 7Sf.1'61. J8#.19( 16:J#.1601'

171.1151.176, 179' 185. 1!1l. 334( 427' ..:!8. 436-131 ~

(lSOPTIN, IIEAELAN), l00.r; I~16011, 167. 169. 173, '7:J, 1731, 1151, 171.171. lB01, 187, 187, 181,. IMt 189,m A"'I....dety druga, apecIfIc ~ .. ~ (XAIWC). 90. 9a 921-941, 911, 242/, 243. 436 buspiroo&IBVSPAR),93, 93, 94/, 971 cHordazepoJCiclll, 9', 921, 971

,""'. clllnazeI)am (KlONOPlN); 91, 91, 911,

ICICllWde 118l. 163f

1431, 1'*5( 149 dDolLzepall (TRANXENE). 91, 91, 92L 911, 1431, 149 dis,..... (VAlJUMl. so.!Il. 00. 90( 91. 91,92~.91( 103, IDlI, 10Bt.116. '43(, 1451, 149. ZJ9

~

(lSOPTlN. VERel..AN). 16W,

,n.

153f.16C;1. 161. 169. 173, '73. I73/, 177. 180( '81, 187.161" 188( 1118. ~ 163-114, 1641 dIllS ~ 163L 166:170 _""""'n. fIII1f dIllS" 1631. 110-111 ~ 91. 9f. 92. 92f.93t. 91L 137 doIsall. 163L 171( In-l12 hotdIca,.... t3, 9l1l1( 138. 422J dlulY. 1fiG(,13 ~ (ATlVNQ, SIlU93L 91( 1(11( 116. 242L 243. 243t .... "' ... m ...... ,66, 1661 mids""""'- 97( IOlI( , 16 AnIlai"."...,7 I IpeeWe85JWft. 1631 QI.repem, tII2IiQ( 971 AnIIa>1triIiI """'" spedfIc ~ «Rf ~ (REST0ALl. 91. 92.lW~ 34SRM6L 350, 350( 35 f. 351-352, 352, 35:'l, 402t, 414 trlNr;lIIm (tW.ClON). 9f. 92. 921-931, a ...............IOII:lI_.-'32-43l

'75',

m

-"'"

"'." ."

.......-" (AMBlEN). 13. 91911 ~ druga, speciroc agents

~

Alls,402I. 413-414

- - . 205, 24 I t 292-293, 295; 373m". 37ll. 378, 3781,:J78.38O, 3791, 364, 39!1( 402/• • '0, 415. 4 IS.

lldeo....... 163f.1641. 174 erniodllrone. 16lX '63"'64( 11'2172 ~,402f, 414, 4 14 bretyIium, 163f.ll!<1l. '72. 112 dgolIlca SIMI #ho Al".,liattlitd agerts; 159,160'. '63,.'641, 169, 174, In. 213, 320. 352. 395. 410, 4:J9.lor OWIal<, 384-381 ~, specillc epenls, 3731

."

'88.

di/tazflm (CAROIZEM co. DILACOR

--

~1.286

)(R), 163/.173. 113. 173/. 1751. 177, AnIiclIfIO&I' drugS. 313-400 177, lSO/. 187, '87, '87",891 8d'.1lrH elleeu, 3991 disopyrllmldit, 167/. 16&, 169 &m8'\if; pcqnIieI. 2411 disopynImids (IA), 163/ Antbnc:er drugS, speclllc egents, 3731 ftlIlQiQI. 74/, 77, n,78f, 163( In. 171 .~.241/ ....... ""', 170. 110. 1101 bIisornyci'I, 241 L 3731, 378. 31S( 3815, ....... "'" pC), '631 3fl6.387, WI, 39!!i.:lll9' b::aine. 3. " HlIIf, 1171. 164( 169. 169, ....tlCjlolliri, 241( :J13( 31S( 395. ~ 1691.174 Iiclocao. (e), 163/ ca" ....... 241 ( :J13( 3B9, 389:3!10 " .............. end~ 1631 .... .. 241(242;2<1. 316. 37310374( " . '7 t •. 141; '69' I7tl, 1m 171. 387. Si5. 3ll5-396, 3991 ~,241( 373l378C. 3Bll. ,,1ft (111. 1631 3l!lI W, 389( 39!!i, 3Illl1 1M..........' . . . IS7( 168, /Qi;17I. 1721 t'jliiOlIbi •• 37310374( 378( 3l'f;.'J, 383...........,. . (IAJ, 1631 .... , 7 , 11\), fi'l111tl( 111; 1721 deahDll')Gt, 21. 24" 373f.314.( :J17. 3&4•• 1 38:5, DH pre 71 (IC), 1631 ~ 3J:P.374f, 3lI2. 385, 38S1M ...... dol (INOERAI..). 1. 11( 74; 141, 14:1'6. 751:76l. 78,.19( 1l)Y.16
'"

"" 7

• •

"'''''

'"

""

'121.

<.."", ..,.,>< __

~_,)

I,,,.. ""lamlde, 272, 212. m1, 3)4, 390\-395,

3." goserelin, 247/, 250, 25Q m1, 394, 394, 395, 3951

gosereIin """late. 394 ldal\ltllcW'l, 3731, 385 iIOOamlde, 373t, 388. 38lI-389, 3891 ImeoolOll5, 3631, 371, 31 r, 371 I, 3731, 397-398, 3991 ~,2471, 250, 2!(), 3731, 394, 394. 395. 3951, 3991 meo:.:t>Ioretha"*'tl, 241 ~ 3731, 381, 3ll7368, 3881, 3991 6-mercaptopurine, 3731-3741, 3Ef(),:J80.. 381,381/,399'.417 navelJine. m1 padila>.tll, 3731, 391, 391-3$1, 392'.

<8, 2011,213,239.292,295.320,326. 3341,341,411 Antioonvulsive dru(;s. See 8Jso Antie\1ilePtic drugs balbilurates as. 95 IhernpeulX:lr
See Polycyclic

an\idepfes&;Ylts rooeplor spOOfodty. 1211 therapeutic aa-anlageS and disadvantages, 1251

tricy<;tic. Sea Tricyclic antidepnlssarn::s

139,2421,24.2-243,2431 granisellon, 2421, 243, 243 t\llIoperldcl.84. 105, \27.121,127(" 1291.130-131,131(..1321.242/. 24.2·243 t\llIoperidol dec3noale, 3, 13(l Iotazapam (ATlVAN), 92f..93I, 97/. 1081.116,2421.243,2431 melhylp<edoisolone, 219, 24.2/, 243. 275(,,2761 metodopramlde (REGlAN). 1291. 24.2, 242, 24.21. 242·243. 2431 nabilona, 2421. 243 ondansetron, 24.21, 243. 243, 2431 proo::tJlotperazine (COMPAZlNE). 1271. 129, 129/,242.242,2421,

Antlileplic df\og5, 145-150. Sea 8JstJ 8lI'lO>:apine, 119. fl9, 119/, 1251 p/ic:am (VAUUM), 50, 90, 00, 901, 119/, 1251 91.91,92(,,931,97/,103. 108, 390-391,397.3991 HlS/,l16,l43f, 145/,149.239 [l8lOXem.. (PAXIl). 119/. 123, 123, Anlid>olinergics, 1071 125/ ethosu>;lmidlI, 143/, 145/, 149.149 anllernelic poIellCy, 2431 phenelzina, 86, 1191, 123, 123.1251 gabapentin, 143/, 149.14!H50 lor It\m1ic obslrudive pulmonary protriplyline, 119. fl9, 119/, 125/ Iamolriglna, 143/, 149.149-150 dise&e, 222 sertraline (ZOLOFT). 1191, 123, 123. pheoobalbital, 23-24. 901. 94. 95. 97t. pmanesltoelic, Ire \43'. 145/, 148, 1461,213,253. Anllchollnerglcl, lpeclfk: &ge<1IS 343.347,436 lranylcyprooine. 1191. 123, 123. 1251 ~ne{~ATAL},4,40"4I,41f. phenytoin (OILANTlN). 13, 143/, 1451. 1l3Z0d0n8, 96, 119'. 123, 123.1251 4.2,43, 45. 451. 45-48, 461, 491, 64. 146. 146,1461,14&-147,1471. 22(J,22(J1 l!imipramine, 119'. 1251 150. 174. 239. 253, 295. 333, IpIalropium (ATROVENT). 451. 48, 48. \Iflr1laf8l
'"

,."

""""""'"'-

""

""

"'"

( . .t

'0...,.,

> ( ............. , >

a~

B. 284'. 331. 3371. 337_ 339, 3381, 339-340, 356 dolrtmazole,:}.4, 3371, 343, 343 llCXlnalole, 3371. 343, 343 nU
",

f\ucylosine, 2841, 337, 337', 339. 339. 339t. 339-340. 340

grlseofvM1. 201', 337', 342. 342-343,

,.."

ilraoor\a.wIe, 215, 3371, 342, 342, 3421 I<e1oconazole (NIZORALI, 272, ZT7, 211, 334', 3371, 340, 340', 340-341,

,.."

mIconazoIe (MONISTAT), 3371. 343,

m

l'lySlaIil\ 3:SU, 343, 343

Anllgout drugs, specific agents aIopuriool. 200/. 356, 382, 4C2t, 415, 416,41&417 ook:tlldne. 377, 402t, 415, 416. 416, 416/ pmt>ene<;;d, 2OOt. 303, 4021, 4Ollt, 415, 411,417 SIAIinpyrawne, 4021, 4Oll1. 415, 417.

'"

Anlihelmlntllic drugs, speclflc ....ts lvem1ectin, 3591, 360, 3W met>endazoIe. 359. 359, 359', 361/ rOdosarrOdll. 359/, 362, 362 pmziqua1tef, 359/. 300-362, 362, 362 pyt'S(IWl pamoll1e, 359, 3591, 359-360,

''''

1hiabendazoIe, 359t. 360, 360. 361' Ao1ihislarrines, 9Ot. 96, 96, 1071 a,~le" ..1ic potency, 243/

as autacoids,

42I).42S

in oombinalioo therapy, 243 preanesthetic. 108 to< ttWills, 221 specific "Il"flIs. 217t Antihistamines, speclllc ....ts aSlemizoie (HISMANAL), 214, 221, 341.

""

azatadne. 422/ ~lne.422/

carbWlo>:amlne. 4221 oetirlrine,422/ chIorpheriramioe, 221. 422/ cimelidine (TAGAMET), lOB, 147, 147/. 201/, 235/, 236. 236-238, 2371. 326. 340,347,362.419/.440 demasline (TAVlST), 4221 cydizine, 242, 4191, 4221, 424, 424 cyprdIeplaCWle,4221 de>:.dlIorpherifamIn,4221

dimenhy
424,424 diphenhytt>wnine.96, 108, 221. 243, 243/.392. 419f. 4221. 423-424, 424.

""

doo:ylamine. 96, 422/ lamoelernamioe, 4221 trIprolidine, 4221 AnIi~dnfllS,207-216

Anllhyper1ipldemlc drugs, specific . . . .11,2071 atorvaSla&'l, 449 d10Iestymmine (OOESTRAN}, 2071. 212, 212, 212/, 212·213, 215 ce
""

oolesIipQI, 2071, 212. 2 12. 212t. 212-213 llNastaIio1, 2071. 213, 214, 214-215, 4491 gemfibred (LOPIO), 2071. 211. 21 r,

211 I, 211-212, 215 Iovaslatin (MEVACOA), 207t. 214. 214215, 449t rOadn, 2071, 210. 210/, 21 G-21', 2r I, 212.215 prnvaslatin (PAAVACHOL), 207f, 213, 214. 214t. 214-215, 449/ probucol, 2071. 213, 213, 2131, 213-214 simvaslalin (ZOOOA). 2071. 214. 214215,4491 An1illypMeosive dovgs, 179-192 Antihypertensive drug ... specific agents, 179J.l00/ amIodiplne (NORVASC), 157, 180/, 168. 188. 188/ a1eno1ol (lENORMIN). 71t. 751. 11. n, 79t, 176, 179/. 1B5 benazepril, 1791 bomelanide fBUMEX), 1511. 1791,223,<. 224/,221.227-228, 292. 316 C<'(l1opr1l (CAPOTEN), 151/, 179/

ctonidine (CATAPf1ESl, SSt, 67, 61. 69/, 180/, 189.189'190, 442 diaz
,."

enalapril (VASOTEC). 1511. 156. 156,

1571,179f felodpil .... 157, 180/, 188. 188, 188/ fosInopriI, 151/ furosemide (LASlX), 15lf. 179f. 223/, 224,224/,221,227-228, 292, 316, 409. 439-441 hydmchlon)lhi&Zi, 1511. 179/, 183, 183. 223t. 229, 231, 441 isfadipine {DVNAClRC}, 100/, 188, 188, ,~,

I8IleIaloI (NORMODYNEj, 71/, 74/. 78, 78, 1St. 179'. 191 lisi""llri (ZESTRIL. PRIN1VIL). 151 f.

""

tosao1an, 1791, 187, rS1 a-Me1hyldcpa, 180/, 190, 190 metopmlol (LOPRESSOR), 711. 74H51, ll. 78~791, 171. 178, 179/, 185 rninaxidiI (ROGAINE}, 151f. lOOt. 190, 190-191 moexIpriI, 179/ oadoloI (CORGARD), 71f, 74/. 76. 76, 781,1791.428 nicBroipine, 100/, 188. 188. 188f niIedipio ... (ADAlAT. PROCARDlA XL), 173.1731.1751, Ill,ln, 187.1871, 187-188,1881 nisoldIpine. 180f. 188, ItJ8 prazosln (MINIPRESS), 71/, 73, 73. 124, l8Of, 189 propraookll, 7, 711, 74, 74f, 74-76, 75~ 761, 78~791, 163~1641, 171, 175f, 176, l"79t, 185, 190.334/.4271,428.

n,

.,..."

pmpran<:*lI (lNDERAL), 190 Ql*\apIiI (LOTENSIN), 1511. 1791 ,amipl'il (ACCUf'RIL, AtTACE), 179/ sodium nitn:>pfUSSide. 15lf, lOOt. 191,

",

spIrono1aclone,I79I, 183, 183,223J. 224/.232-233, ZJ3, 274, letSlosin (!'1YTAIN). 71/, 73, 73, lOOt.

m

",

1lmoloI (TIMOPTOL, TlMOPTIC). 71/, 741.16, 76, 78~791, 179/ lriamterene (DVAl!DE\, 179/, 223~

2241, ZJ3, 233

vefllJlanIil (ISOPTIN. VERElANj. 163~1641,

160/,

167. 169, 173.113,1731,

·",,,

,~

...1.1 >,

, >

17S~ '",177. ll1tN, 187.187.187.1. 18llt; 189.377 401-411. Soo "'Noo oidII • • •

-

,.....'.,I8ICli,.agerM.

I.,"'"

IIlcJ .00. 413-415 tpecilic . . . . . «11 ~I ~d'u}s.450 ~ and

llI'IlilhymocyI

AntImelllbolite!;.!QI'

cance<. 378484

gklbIJin,471

specilic: 8gefl\S. 3731 AnIi~

"!JI!flI!I

ciaUilicabl, 287, 2f!;7f corr*lNli<:ln8, 26C0, 26C0/ lor pepIic..-r ,5 • 235l; 235-236 ~ ICI, 264-28& , •• ~:z7'9( 279-282 .-.ap,. ..... Iri'.......... 279-218 '" d" ~ dr\IgS, specl/fic: 8QIWltS Il-M...... jjit: bIi:ld<eIS. 581. S8059. 6ll( 73-78, 14H5l; Wllll1631. 176177.178(1112I.1&1(184-117.185. 1851, 1B8f. 409, 419(427(428. 43ll,

_Ie

..,

~~.419/,428,428

"fIOl8ri1e, 419'. 4271. 428, 428, 437 ....tIlyselglde. 419f. 4211. 428. 4a1 ~atl (lMITREXI. 419f. 426, 426••"';.;,4271.437 ~ldilit111Q1!1'1lS.2<W ~ JIllIlflIS., 4S-4&, lIlf lor PwtOnson's cis n,87_ IcrlJ8Plic..-r f .'.2361.239-2.-0 N'Ilin¥ ............ 331-336 tpecilic egerU. 33lf Antlpetklnson'. drugII., _

.U ,.."",

.o.~'0"'" ......

...."'.61(87,87.363. 3631, 363-

IW'Ilimu!lcarin lIlJIlI1lS, 4~ 61(67· 86. 2361. 239-240

brtJmoct1lIine. 611. 67, 87. 671 ecot.JiQ:olp8 (SIN€MET). 611. B4..e6. 65/ deptenyI, 6H. 87. 87. 671 liMldo(re. 8. 611. 64-86. 85~1I6( 141,

,.,

1lI~

.... 443

.qli."".443

........ "'.....

• ' ,*"1. 6lf ....... 'in. 263l, 21&7 An1lptogeslin, SPeCllIc ~ 1I

1s1oi"'. 263(267-268. zn

AlII\* dnJgs, 34W58 AnIlpro1OZOlll '*"Ill, ~ agenls,

345/ ~,34&3461;348, 34lI o;Iilc:Io:Milll--. 345.I.346l347. :uB,

34e .,....... 345I-346t. 348, 34lI ~.34$( 35OI,:l'it 352-3S3 -,II $t4lfd. 345/• .J:53; 3S3L 3!53-3S4 .1"""," i.:laldIl. 201 I, 2351. 236. 2ll2, 282f, 345.1.3401. 347. 347-348, 357 nIlUl1imol<, 3451. 353/, 3.55, 355 palomcmyc:in. 345~1. 348, 348 penl8midin1l, _ 339, 345f. 353/. 356. 370 midin8iselt'Oona1e, 354. 354-355

~,345/. 349, 349:350, 350. 31S(J1.351(432~

~.345/.357

~,147,l6Ot1631-164(167. 167( 167-168, 168. 171. Int. 214,

3301(345/ qI.II'D-. ....... 166 ClI**'oe. 3451. 35Ol. ~ 352 1IOdlI.m Itiboglon, III 345/.356. 3S63S7 .......... 345l. 3531. 3S6, 356 Anlipaeudcmgs.127.'32 aet\orA, 128/ 8<Mll'MefIec:l!I. 1301

""1lIioeo:I..... ~ ~ . . 41 agett. 47 ... '1' 0 III 1*'..... 300, 3llDf

"".-,lOOt: j''''''.

_«Ii"''''

Ai ....,., old dr\IgS, ..-Itlc IIlIJII"'D 1DcIciI.2-47(254 ...... .,.OU18(lEYOXYL).247(253 IIIIlIwMzde, 247( 253, 253-254. 436 ~ 247(, 253. 253-254, 436 1IyfoIOne. 2411. 251. 252/. 4CJ6f lriiodo1tryro'11. 2471. 251, 252/. 4081 Anillut>ereulosis '*"Ill, spec:lflc 8gefI\I amr.osalql;c acid, 331 I, 335, 335

cyo:toseme. 331'. 335, 335 -.ambulcl. 331. 331( 3J4, 334-335, 3361.U1 ........,idIIl,331(33S,335 ~ 141. 141.1.1481.2fI3.283#264(331. 331(332..m. ~ 332333, 3331;3301. 3351; U1 pyqt.ii.,oidIt.l2&l( 331. 334. 334, Df. 335. 437 Ibi,lJlO .. 2ll1t. 253. 2&1(285. 28Sf. 2m(300. 331, 331~.m. 33W34, 3304.. 340-341, 437 AnliwJl
.,NoI.,IicU!lO!S, 129/

~",,1281

and LSD. 105 ........, 132f ___Jd'O* d'uga. opw:Ifk 8gIIfIIS

d"'llI Ul ouir"l.1lOl 127. 12', 127.1. 12& 129--131. 131~132/ dI;lupirle. 127(128, .at, 126/. 130131.131.1.1321 ~. 127. 12'. 127~1281. 130. 131.1.1321 haloperidol. &I. 105, 127. '27. 127~ 129'. 130-131. 131 ~ 132/, 2421. 242243 rIllloperidd ll8aInoal8. 3, 130 1lI0l;lolOopetazine (COMPAZlNE). \27/. 129, 129/. 2..:!. 242. 2..:!/, 243 ~(Pt£I£ACl.oJ,Nj.127.1. 129(130. 13Cl. Q/ I'illC*kICli"l. 127~ 128. '2!lI26( 130131, 132f ~ 127.1.1281. 129. I~ 130,

365-366, 3fiIj~1

_I
~"~;

......-- .... didlw.....'" (clII). 363/.:Bl. 3fl9(3Q-

". 3631. 367. 367 .,oXluotr.

......... 3631;

367.36'

gIIocicbti (DHPG). 363l, 39>. 3Ili6-a67

il1etleu.. 363l, 371. 3", 3711, 373( 3IIl7-3ll8,399f ................. 457

~363'.364.36'365 rimIlilllldine. 363. 3631. 363-364

slaWdine (d4T). 3631. 36Ell. 370. 370 IrifIwidine. 363f. 368, 368 Yk\aIlltlio1Ii (ara-A). 3631. 367. 'Jlj7f. 367)68

, ...... atWle (ddC), 363f, 369(37ll; 370 lIclortudifIe (A2'T). 339. 363L 367, 36a 3158 3M. Df ~<1sadeis

~"""90

--.r.!lQ, 95. 146 1321 ~ 19l!;W' . . oI04i. 0106

An\is:tIizo;lhrdluga. See~
...: : : . : ; . . . , ; ; - ,6,PSAC. See ArO$lIIlIllase

_,.

,.,

~

Am·.... See VidIlrabIne Anti',ohnno&y1l1ll1ni<w. See VIda
ARAV'" see LeIllnotride ~ 163-166. see.-o.podlic

.",..".

lIIrW, __ ,..... 16061.

168. 173

~,"--'I68

_

... 165

-.....c.13, 781. 169. 171, 1721 ~16&I

-

,."....,.

...,

,ibotli&. _lfMn. 203

,....,.iI" 406

~~351.
-_....... .1I••1:H15

......... see AnIIetltwIlIs
Malllu'bh · ... HO;o .. 36J1.3621 . . ', ... 11, 359. 3611 l "'I~'" • 3731, 397. 3lI7. 3lI8I ...a.. ... ,t ClI KIioo\ . , Aapoi..... •. . . . piMfillill2o$II Aapoi\OAAi&. 3012

a_,.II,

.o.spm. 193( 196. I " '!¥. «II( «n

-"". -"",

.. loIO.201( 211. 213

.,.,

•

~do'.,..........iI .......

• •......, _ _ itiyl& 8ftd 2

8ftd~.40

ae::tiDna. 41. 4" ~_.4

don :lepeo ideo Ullec., 47 ~1i$elliCb.. 42-cl. 606 n '"'--ilic ............ 461

.--.220, 220'

"''mOVENT. See Ipatr""*,",,, AaenIIiDn d8ic::lI sy,iilltu, a_'811, 11M AI)opI;aldlp .• '..... ,24 ~.1:H14

......... 9ia-e,.1:H14

,.."""*'" 41l1-42li

~ polenll8l. 1001 dntQ In!e
.......-.".go,

specific 1iQllI'lS. !tIIlnIpe<.Oc II<Mnllogea n

--~971

1CJIGcilt lJluiour.lQl, 96

"""lba
BAVCOl~

8edomIIl..... (BECONASE. V~

VANCE"" 431

ld' ......... II;Ua, 216f

""--'219 dn.gilliol.iIIlia,Z76I --... brtrOlis.221 AlAdI.... 2119 ~ """,*,,_ 276. 2T6 AL«ll ..,.. t'!'P6'...........-nert, 72 BECONASE. see~ ....-.ou51)'Sl1em, 'Z1( 27.,)4, 32J 8e<&zeprl1791 d .....gic ...... · A35-44."JtEJ _. _ I I _ I. . . .,., AJ(l(). see Mz8lIidinII ~_

• •<w

""*"..,.. Alac:,d Aiatldo

...,2411 4*\ACP.. ltiysan:l ~Q2J 3Bll.471

~I • ...,1 ~~~S-

~

'1iL
~~

21•• 3u 221 It• ......,.,.e Dattaga 8ftd b

-""

A!;lhrre•• 31. 450

lIf'C engN. 1781 nhypalflllllDo.. 182~ 1831 - . 3. 48, 62-63. 87« IIl9. 217-

...

~'*' 'G.adl'........ t 3ll2 een ,.....I27'

~.*"'Pb~1 94 8eNod" pil.'~ ~ ~~901

~9OC.lM,9or

~ ...,,.m (ZI1l1AClUAX), 311( 317-320 ~ ft.S3,

..iIio,il:RbiolliClMly. 318, 319' ~~301 . .:ll1

~.,21 A

""

~ (l)()MIIAT Al.l. 45. 451. 45-48, 491

AaI

"E l b ' "I\, 13. oI(loI 1 b "igo..... ~( Q8 .nd~"

0fII811fld Ib'ation ollldioo. 52/ IhEIntpeutic advlO:llageS. 52' Alrilll !brtIaIion. InIaIfNd, 1£41. I T.H14 I\IriIII ~. 1JtIatn'e'1I. 16061. I n-174 ~ nodal_ry. trealme
2 7 2 ' ·...

b.-m...UIo.UU

~UetllCliQ>

,""...

~_.3112 ~ 10 ecid, 30llf

AZMACORT.SIIOIT...'.......... AlT. See lidcM.dire Aaeonam. 298L 307• .:ll1 SInJC:UlI. '3t111 B...-

.'

Ion 11&

""'lic piMfc,. 243f -'lea&. 149

..,,~_8ftd

-.IiIing. 242( 243 ~ ..... 'ibio_.~.243 dI.r.IIIion ClIIICIion, 921 po_ """tie;, 108 1he<3polulic ~ 8ftd ~.97'

g<arTH1eglI.... 283f ~ . 283f

Iorhype
"'ilhchwallWlClloo&. 93/ 8eflztld!ll ........ IPKItIc ..,u.. 89f BIroiII.-IIl'JllnQ:I inleaicn, Ir1I;IInlOOI, 2991 8lprazdam (XAIIIAX). 90, 00. 92~f. &ocibae8', 2981. 3OSI. 309 97( 242( 243. 43ll e..dofen. 50 bJspiroN (BUSPAR). 03. 9194f. 971 BllderiaI pmet~qjtjs. tl8iltmm~ 281 ~. 9', 921. 97/ 8lIaf>o0dll1 chtgs. 282'. 283 ctonazepam (l
Alo
BACmIM ,s...,Trime!hopriln Berbllu<e~. 94-96, 107/. 115-116

Z2O, 218'. 276 speclIlc agents. 217' AlendClI ('l'ENCW.I'N). 7",

""

lldion&. 151 lor 1lIIginII, 176

n. 77. 791.

304. 305f. 321

97/. 143', 149 diazepem {VAliUM}. 50. 90, 00. 90/. 91. 9', 92~f. 911, 103. 108. 1000f. 116, 14;1', 145/, 149. 23lI

<"""""''''''><00 _ _ '>

'"

Index estal:olam, 92f flurazEpam, 91, 9" 92. 92.<931. 971. 137 hy
93" 971 (HAlCION), 91. 92, 92~93f,

lria~m

'"

--

zolpidem (AMBlEN). 93, 93. 971

BenzDlI1iazepr.es, 187, 187

avos,

and neurolepli<: 130 IOf Pal1
~,lor Parl
"'"''''''''"

adrr*11stm1ion mull!, 3 Cak:ium carbofIlIle, 23/lI, 240, 4n C.aIcIum chaooel blDcI<ers. \{;3f

ocetyICtIOIine and, 39-40 tadors aflediOg, 160/ mechanisms lor OOflIroIling, lflO.181 ~ .... ar
"" ""

Brelylium, l{;3f, 172, 172 lis antiarrtly1hmic, 1641 ~ ....,Blr.87,87 ~ effects, 87f Bromphenlramioo, 1he~ adVantages ar
""

f\ror1dIiIis, treatment, 324

67438

BisacodyI, as laxalive, 244. 2441 Bishydroxyalumarin. See also Dicumarol 8dYefse effects, 292 Bismuth (compoundS). 2351 10 e1imnale He!ioohj!gt>r IMllli. 2311

Bismuth subsalicylate. 244, 2441 cosI, 262, 262f Bisp/lQsphOrlates.476 Bladde, carciooma. treatment. 395

BleS!O!IM
"'"'

poIerl1ill1, 100/ drug inte
et1ecl OOIlflllo<:OOe system. 395f

deleminalion.71 Bioequi\Ialelll,l9. 7 BioIrnnsklrmalion, DI epirephrine, 62

aneslhelic solo.J~IY in, 111, 1111 coagulation, 196, 196/

~

drugs affecting, 193-20{; specilic agenlS, 193/ Blood-brain barTier, 6 and NlftlloIics, 281 Blood !low, and drug dis1rb.JIion, 6

Bror>chodiIaIOfS, 431 "",32, 4321 adrtw"lllf9c agooists as. 67f 8rono:::hoI;pasm, lIealmefl1, 62-«3. 67 ~~3811 lWlfV(lSa, treatment, t 22 Bulking agents, 244-245 Bumelarli
8ulim1a

227, 2270228 drug inleractions, 292, 31{; ~ DI acliorI, 22M BUMEX. see 8<>meIlI11ide Bupivacairle, 1081 pham'laooklnelic propertieS, 117/ Bupret'lOf\'lhlOO, 133/, 141. /4' Burl1e Buspiror>e (BUSPAR), 93, S3 a
therapeutic advantages IlI1d dlsadvaOlages. 971

8uIatitaI (FIORINAL), 431 IOf mlgalioe. 428 Bu~q>heI100es, 127f

antiemelic polertCy, 2431 lor dlemDIherapy-induood IlallSea an
in colllbl"ation therapy, 243 Caffei'll!, 99, 99f, 99-100

Cald1onIr1. 4n

a
n

classes, 187-188

drvg Interactions, 51 lorhypertension,187·189 acliorIs,187f

wilhcoooomilantdiseases, 162/ thempetJlicapplications, 188f CalCIum channel bloCkers, ~ltlc "9I!rlls, 180f Ci>Icium gIuCOn8t8. drUg inleradioos,

'"

CaJuses, lleatment, 406 0-,

....

anema wilh, treatmenl, 206 bIadde" lrea!mllfll, 395 metaSlalic, treatmenl, 392, 395 lrealmeo1, 277, 379. 382, 386, 389, 393, 395. 395{ dIemotherapy. see 8JsO A1lticallCOlf

.." principles, 313-378

""""""'' ' ' ' '"

gestational, treatment. 384 lrllll1meflt, 379. 3991

caoreclal, trealmenl, 382, 406 gastric. treatment, 382 head ar
""

oat cell cardnoma, lfootmenl, 396 smalk:el, trealmenl, 392 treatmenl, 3ll6. 396 owlian, treatment, 382, 392, 395 pancrealic, t,eatmenl, 382 prostlllic, trealment, 272. 394 e1lect Ofl endoaine $y$Iem, 3951 trlllliment. 300 CaO!ida iniOClioo, 314 caodidemie, treatment, 342 drug iltoolctions, 340 treatment. 338-339, 343 Candid(asis, See caOOjda infection Caooabiooids

<....... """<00_'_" ~ poIlIro::y, 243f lor ChertlClIhenIpy-.lndueed naISN IWld vomiIiog, 242f, 243 i'l OCfl'tJiNItion 1h8nlP\', 243 C8mabi5, d.pend.'(llI potenIiaI, 100f CIlI ........ 232, 232 Capecirabine, 463

""""

~,Il.8t

~.See~ 151~

17'91

CNW'ATE. SeeSucnlle18 CIlIt&J..... 3S( 4Q 80-41

~.'"

'"


---

Caibeo"~ 29llt.301. 301

8O,.......'_.3C2 _ . _ _ . . .. 303

~1O...,,3OOI

............, ....• • •.. 3011 CllItJi
cana_'."".lf$l8UIIiC:a•••_.,. n i l ..... ~422t

e.t:r.:rk".ord<_ II~""'" 2ZJI dUelic elI8i;:tIo. 225-22J' ~

CefaetDr (CEClOR). 298t ~ ed\Ianlag8llWld

........-."", ........-..,,,

Celadrod (DURICEF), 298/

-_ .. ........-.-

ltIeropeulic ~ and

, _... ~ 226.. 2261

Cad.,' - ~3731, 39S

.. cancar hrllpy. 39&3ge

emelic.-....

2C 1I

',. pol& ..... ::nBt

CAROlJRA. See Do>:aLOein Caimustine, 373', 389. 38W1O emetic pdllftIaI. 2Cl I

Cascara, 244

C8se

51...-, C~2

Caslo< oil, 244, 244' CATAPRES. seeClorildirle CaI8dloIlInira, 69/ C81ecto:lI, Slruet\Jre, 61 f Calecf"ooloO.me1hyllratlSl8nlS8. 444

..,

~aod~N8g8I.

ca..EBREX _ C? "'ib CI'mwib C66-467 CEli.CEPT 588 ~moIetiI celk:)<:l& opedIiclI,'. in 8I,licaoi(llll dn.VJ, 37C, 3761'

.-...,K ..... 204

Cell ..... ~1I.ot/Clo... 2Il'0310

CeIadI. 296~ 306. .:0;

........-.-

C , >i,e.:I>t Cil II,. (Sl.FflAX). 2!l8I

l_apeulic~1fId

........-.........-.-

~

29llt. 31M, 301

'l8Iapeulic -"1Iiog&51f1d

CelooiUd. 2981

--"'"..

1_4**_w••_... _ 296( 306, .:0;

C8IopeI

........-."",

Il'l8fBl** aa""!ll'l end

...... K ..... 204 Celoollloi:llt. lheoilJiEl*: _a~ IWld

........-."",

ilI"

CeUaiOo, •• 29llt. 31M, 301 1cr".. :lOS "6apau1ic_W •• _", _

-"'" _ .. ........-. .., _ ..,

Celu.... 1, 296~ 31M, 301 lheoliOJllt* _all$S end

,

CeloxiIn, 2961,:I>t, 3Cl4, C33 lor Dgi!i( II.......... 31M Ca!bopoOSl, C19. CII, C19M2Ol' .... apauIic .mollall8S and CMIloc~. 151~ See"'DigiIaIiI camiac ........, ....... idioo .. 153--154, 1541 ~. 2961, :I>t• .'Uf, c:JO..431 CaRbl;~. ecefylo::hdne end, 39 'Ilolr1IIlOIUiC ~ and CAROlZEM CO. see DIRiazem ..... ' • .,.

lor urinadYan1ag8S Wid disadVantageI, :KIS, CeluruoimlllX8lil (CEFllN)..... apeuIio:

1heIapeulic ~ 8fld

Ill8lapeulic _altajpi_

C8itl8mazepirle rra>RET0ll, 143( "7,

end

CEClOR.5e9CeflldOr CECA>: _ cehilulen

Ce4amerdole, 296', 306. .:0;

~,8,81

ClitJI<\lot(CAPOTEN),

,......

'-let ..

CEFnN. see CeIurooW'ne axelil C8hIlaUme,2981 IhentpeuIic ~taoes ard

dlsadvarCageS, :KISf <:ehrIaxooa, 298'. 31M. 301. C35 IQr goo IQlmea. 299' lor """911s, 306 Ih8fapeutic IId\tarl1ages and

di_taoes, :KISt

"'** agem.

2981

c......' .. ",80."go;~1or hypef18l1lil:Jl.. 1"110 CenIraI ~ tcNS), 27, 271 in . - ,.. o;x;nIn;lI 01 ...... 30. 31' lIo1eQi(w.. 281 ....-........~81..s2

......... bI'epl_io ... ~

........

e.-- ......... .,-..dep.

......... ...-..

d!IpellClellOl ~ 1001

~

'"

...

depelodooa PliMl_ loot Cenlral ......... 1)'Stem 8IImuIentI,

-.: 110 '9B'1tSo 99f . , . - _ . _ sst; 60-61, 61,17-6ll. Il!l~

lIlH-lllOo'. 103--1 04, lCMt. 105.

'"

CIlWo .., 9!l99( .100, 100( 328. C28 ........."', 3, 56,63. 711, 7tI, J9, !l9~I00t

101, 10'1-101,

102~I03f

-""'.....

... """"""""~ •1191, /OC .iaAio.. • ~ 49, 4S,C!H, 9ll~ 100. 100( 11&10'1,101, IOU

......... oo-n. 1011 I".oboo,

, 119,!19'

It~"

(Slo-BlO, THEQ-Ol.I'l), 99, 99~ lOll, 220, 222. 319-320.

"'.'"

speo;iIif; -oe<*. 21 7f Cep/'oal1oIo.,298t CfIphiIleJ
........-.---

~.30W05 ir.Il (lI!fW3llon, 31M

spedk: 808'1ls, 298/ rwrapevlic advanlapes and dsa
<-,"' ...., > <--....-... ,.

<

<_ •••__

~"

KI'I;UJl . . _

.....

'''','' therapeutic advantages and disa<Mlntages, 3061 Itlitd generation, 304 sptldfic agert1$, 29111 therapeutic advantages and

madYanlages. 3051

'" Cetifizine, lherapeulic adYantagM and dsa
"."..,.,..,

slructOOl, 3041

lor amebiasis, 3451. 345-348

therapeutic advantag
cancer. see 8Ist:! Anticancer dn.gs wrntive,3751

nausea and "omUng wiIh. 241 '. 242

lroalmenl. 241-243. 2421 palIiative,3751 Iiffil generalion princillle$, 373-378 cefam,x~ (DURICEf), 29llI, 305/ prtbIems with, 377-378 C(lfazolin, 291M 3051, 306, 306 lor OIl$loOOs, 3591, 362 oaphadrina, 298f lor giardiasis, 3451, 357 oophalexin (l<EFLEX, KEFTAB), 2981, lor helmintt'k inlections, 359/ lor leishmaniasis, 3451. 356-351 oophalolhin, 298f, 3051 lor leProsy, 335-336 Cfl\lIlapnn, 2981, 30st for malaria. 345/, 349-353 second generation lor .-...malodes. 3591, 359-360 oeli>dor (CEClOR). 2981, 3051 tor t<»an, 2981, 304, .»4, :lOSf C!lIarrMlia inteetion. 2831, 2901 ce1ox1l1n. 2981, 304, 304. 3051, 433 tymphOgrnnuloma venereum, 2901 celuroxime. 298f. 305f t...alment, 290, 312/, 317-318, 318/. celuroxima llXfllj (CEFTIN), 305f 324,3281 !hitd gent!f31ion Chloral h)OOrte, 9Of. 96, 96 oefixime (SUPRA>:), 2981, 3051 ChIorampheniool, 2821, 283, 311 '. ~ C(lfoperamr>e. 204, 298/, 3051, 306,

cephalosporins, specific lIgefltl, 2981

""

'"

'"

C(liotaxima, 2981, 304. 304, 3C6( 306 oeflazidime, 2981, 304. 304, 305/, .,.."

OIlltizoxime, 2981, 3051

celtria>:ona, 298~2991. 304, 304. 3C6/, 306. 3281, 435

moxalac1am, 204. 2981 fourtt> geeoeration oeIepio,Ol, 304, 3051 Coeptlalolhin, 2981

lhernpeutic advanlages and

d:sadvamages, 3051 ceptlaphin, 2961 lhernpeutir; adva ntages and

disadYanli>ges. :lOO1 Cephradine, therapeutic advaotages and d1$l1dvan'ag
==

<:IaS$lficalion,2ff71 drug inleractions. 147, 147f. 2OH. 2601 effact on neonates. 282 me\lIboUsm,15 .aslslaf\Olllo,2851

salely.282 O1lordiazepoxide.9' tor alCohol wiItld
"'"

adver.;e etIaets, 352,

3521

anliinflammalOly eltects, 414 drvg iIlteractions, 350 siIes 01 action, 3461 Ct!loroqUl.... phoSflhate, 432-433 Chloo'oItliazid. 2231. 229-231, 23' hyperuticemia with, 22.

Chlorolrianis&rle, 263. 263. 2631 ChIorphenlramine lor 1Nnilis. 221 lhel'3l'leutir; advanlageS and

disadVanlaQlls, 422f Ctbpromazine, 127, 127,1271,129,1321 actions. 1281 affinities al dopamioorgic recepIOI!>, 1311 lor 1'Iico..ps, \30 rali<> of IeIhalIO alfediw dose, 901 lor sdizqlhrenill, 13\ Ctolorprq)amlda, 2551, 260, 260-261 properties. 261 I ChIorthalidone. 2231. 229. 231, 23' Cholera, treatmenl, 312/ ChoIes1efol, ni;tdn tor, 21 0 ChoIeslyrann (OUESlRAN), 2071. 2'2, 212·213 In COIli*Ia\ion drug therapy, 215 mechanism of Ildion, 212, 212/ Chaloo magnesium salK:ylale, 406 ~.~.37,371

Cl\oliI1
'"

silas 01 action, 361 structures, 391

,,,

Cholinergic "llO"'stl, specific &gen1S, acetylcholine, 21. 32( 33, 351, 36-37. 37f. 39. 39( 39--40, 461, 236 belhanedlol, 351, 391, 40. 40, 236 carbachol, 35', 391, 4(),4G-41 pilocarpine, 35f. 41,.',411,75, CIloIinergic anlagoonisrs, 45-54 for asthma, 220 sites of acbon, 461 spedtic agent$, 451

m

summary.49f CholiI1ef9lc, o:lellnllion. 33 Choli""'ljic neurons. 35-37 ChoIW\eIgic J9OIljlIOrS. 38-39

1ypeS.38' ChoIioe salicyla.te, 406 ChoIioestelllSlllnllblors, dI1.Ig interaclions.51 Cholinesterase lnhlblton, specific

--

IlChoIhiopha.le, 35(, 43, 43 ed
.,,,

..

.<_R ............·-...,_.........,....

,,,,"0....., ........ _ , .

,,,,

• 90

iIlc/kl~, ~

43, 43 f ........ 'iII... ~Q, 42.50-51.311 ~ . 35( Q, 42. 47. 51 ~.351.Q,42

"""""*"..

·o,._ "'~ _••

0 .se..Odo O>orIoc8lcillQ'" ;

kNl,

s

~_,

.... 3fW

1_,. . . 379,3991

0,,,,",, . '........ na"'e"t.339 ()work ClIlIlrI.dvIo

P'*,...., f

anl l781 WIlIhypiIo ~ 1ll2f b_'." 3..a. 221-222 speciIIc-a-u, 2171

••"'**...... ............ ,m

C'.IMIatin. 2981 WiIh~i ...... ' ..

30&-307

CO""lidi .. (TAGAMET). 2351. 23t;, 236238,4191,440 drug~, 147. 1471, 2Olf, 326.

340,347.362 and gaSIftc llCid teQ
CIPffO.

106

see Cipro/Im
Cipn.IIIoxQi (CIPRO). 323. 323, 324.

....... ",.'"

klf meltildllioHesitllanl r.\aOO"'!OC'9ffiI'S

IlenlpMJIIc: app!ica~ 3251

.......... '"

~374f

in '*"01< Jleqpy. 395-396 drug ~.aio.. 242~ 316. 387

llIT18Iie..-_ 241 I "" '" 311. • •'IicKIbioIICtiWy.

(llIA.UI). 235( 311( 317-

5·.·...

COlI. 282. 2821 1O.,iII_O

319f

mAi.236

SiNlOililiolo. aassl<WgI. 12. 12J' ea-al <WgI. 12, 121 ~ -*l, 2Il8( 3lJT, 307-308, :D3I

Q.ARTlN.

.m'iII.........' _ , 302

_ ..............

drug~

.. 300-3111

IIiIIliMy 10 "euld. we. 300t

ClemaslIrlI (T AVlSl), IhBnIpe
""

180( IIlQ 1.1... 442

a.illh.... «e a"nvep"'(TfWIlXENE), 9f. 1431 kif -.ot>d ~ 91 • • iIiepiteptic. 149 donIion of adion. 921 lhenopelAle~ _ diudvanIagea.971

CID6lrklia Ioleclion. IlllalnM11ll. 347 CIosl!iliIm ~ Iofecticn reslstenoe, 304, 321 ~81me<1t

306

C'offlldhl'll pedringem IoIBcllcn, ltllllimenl, 2991 Clot.lormIioo. 1ll:l-194 ~,337/.

edlinII ..... bee" ..... 22lI CI!pIIIin. 3731, ~ 3991

~

.-:1

Cbidio .. /CATAPRESj, 56( 67, 67.619l

••_...... COlO9l.llicJl .. IOU

a.EOCIN-T. SoeCllflllamycin anallo>:&cin, 4561

343, 343 lldrr*lIshioo fOUle. 3-4

a,;,x....." 298/. 300. 3fX) ~1O"""...,:KXlt ~ ~

lV( 128. Ia!l. 131).131. 132/

121!11 11I._,

.,et>!i*A ..,.,.,

IlIlio -j ·0 1311 '-lIc::hI. d.adeobb.. 425f

a.-

ee:.::a.. 71( 711, ~.

JOJ.l01-103

~-'3

dttMdeo

. . -. . loot

drI.g

_'W

llClillnI, 134/. '..01

lor 0llUl/h. 137. 222 eIbey mlll ~ iatIiily.

""

CoclIlr1Io "'_.1Or .......... 4271 CdlJ ....... ..w.416, 4/6 . , . . . eIleo;Is. 4161 1Or~415

_Me ... 10" m

C?

i:

4,207(21~21Z.~3

..........."of .aio'I,212, 2121 Cc**W biIII-.ltl. 236.( ~1 Cth_~.,-,,382,406

k1f1ililur-. '". 1451

c::::lllt*JiIir.0$$7

_

Clindarnyclol (a.EOCIN-T). 311/. 321, 321.43!l d :'........ Wf . .I II a 10, 2lI5t CUNORlL SiN SI.6'ldIc ClcWiminI. 331( 33S..:'J3l> CIOIb_ 207( 211. 211·212 drI.g illrec:*lloa.2fJOl. 3341 Il'IICtI8r'IiIr of.aio'l, 211t Cb'iJII.", 263( 266, 2li5 Cb-u.. h (Kl.CIN(lPW). 91. 1431" . . .Aij. eI'IeclI" 149

63

~of""""1021

-.d'lQ.... ~.io.. remcMIl, 56

""'"

CCM"AZINE. Ste PlilCfbj&ame

""""""

IIiUe _ . 2fi8f ~

__.2fi8f

~"""",,,""r

eo

h"b'leI4, v ....m '-' tIbe

edema

~.2831

(" .....mriIlIln.""''''.·.,

C.... jUles

,,~,,_1rnI!f(,

""'"

Codenl. 133/. 140. 140 absorpliatl. 137

(CAH).

Ir-..em, 229

and~. 182~1831

kidrlIy Iu'll;:liQn IbIng. 225 plIyIldogIcel response$, 154-155. 156/ t'IBI.-ll, 66. 151-162, 188/. 228. 230 specille ager11S. 1511 vvnlrieular tu'!etion curves, 159/ Congestl.......rt 1"lltre drugs, spectllc &geI'Its, 151t smrinone. 1511. 161. 16/.161/ Ilume\aI'lidlI (BWEXI. 1511. 179/. 223~ 2241.221. 227-22&, 292. 316 ",",*"",1 fCAPOTEN). 151~ 179' lligiko
1fggm(I..ANOXlN).151( 156,156, 158. 159.1601; 16Y-I64l169. 17~. In. 188.213. 32ll. 352, 395. 410. 439~,

dclI1uIIlmr'lI. 55( &6, 66, 69l; 151( 159. 161, 1611 • I ,"'CVASOTEC},I51( 156, 156, 15711791' luoir 1511 ........ , (lASlX), 151 ( 1791223t. ~. Z!4( 227. 227-221, 292. 316,

4OlI. 4»4'"

..,

tjJ4 I i ... 151( 157. 1110( 100. 190. ~Ol:foluo"tiazIdI,

~.283f

.

1511. 179( 183,

lea mt, 229. 231.441

.........bklIillSORDll.).151'

iIooIoItlidIclnihle.1S7.175( 176. /16;

,m

~

moo... ili8le. 176

li8ihCl9ll (ZESTFUL PRIMVll). 151 f.

""

me1018zof\e, 151 I, 2231, 231. Z1, milrinooe, 1511. 161, 161

•"'" ,... _,.1 ........ _

,""".

I)

•1.1CI
'" COt.......

,."

O, ~

11I** IIg8IWS,

I..... e ,ale. 268( irr'IplarlIabIe. 2Ii7. 269 01111,261·269 pe
sea

CorllNty 8I1erY ...... ,1:lcA. , .........

co...

$

.. -.~

edll

. , . . . eftMs,.

m,

,,

COt,;. .......' (AClH). ~n 2fl" 2.c9.

--

COt-..alloPiH

1

•

'll hoi"...... ~9f

tor dal......8PJ-inllJced ..usee

-oono. 24U. 243

tor dln:ric~' flI*\'IonarY


drug~1601

P'I4*_

e/irT*I81iOn, Z16I 2751 1or~221

sperik egeru. 2171 ... ei to,..,,' . .. 'Z72J Coi'h ' oklIo, ~ egents bedool ............ (BE(X)NASE.

_--.".

VN«:ENAS€. VAHCEAl).219, 221,2761,431

- , '.....

'"

syrill 1•• :W0

"""'""

ac!ol.oiSlIation roul8, Z76/ e1imlo:l8ljoo, 2761 plopeotlo4. 'n5f

C'oornebtrMrimJ dP!l!... i iIfdoI, ~299'.318/

w

hydo

Z14, 214, 2751 liooI

..,.."

rnefl'Noec:li

274. 214, 2751-2161.

*"*"... 2111. 242/, 243-

"""'" 10. ..

~.V5/

0:10*,,*",.. V5~ 393

plec:li... " (DELTASONE. ORASONE), 219. 275~ 276, 33.". 373f. 393, 393. 397, 3991, 438-

'"

Cyl' -;, n drug.""''''''''' 1..1. 21$. 239. 320, 326. 339. 341. "10

""

_ . 272, 212

~POO1flor"

~, rrealJT1e<W."'"

CyslTIi$. Ir8aIrJ1ent, 3281 CyIluobio1e, 373/, 3B3, 3113-384. 399f ac1ions,3741 ~ P<*fIlial. 3781 ~b;horl" P-450. 14. 141

$I¥Oid hoIll ....... ...:I. 253

~249,2C9

CO"nUM.s..~

~1Di1l6gflii;: l1l!iri1i&.

C$il: 'zo!e(COIRIM).289,289. 2lIl( 290, 2S3-2!il5

~.'-diorl

."",**""

201 1

1or~$_C2ll

""**lioo,,

.....,eu,;.: 290 COugh, re61m1!fl?, 137. 140. 222 spec:;Iic 8(I8'ltS. 2171 COVMAOIN. See Wallarin CoJmarin, drug inter.Clione. 215 Qwnpa. lraatrOOlll, 441-442 CAlXIVAN seelndinltvi, C!OmolyrI (INTAl), 423, 431 Ior.-. 2181, 220, 220 SJlOti* lijjIlIlI$. 2111 ,,**agon1&,211'

""

""

_ ... oce.366 II spBC:ific ~ 363f ~ ... _$EI.oL 3118

~

.. IItIio"""'.See~""

OIcalbftzinll. emetil: pdellliel, 241 1 Oactinomycin, 384, 38' 385. 399/ ll(1iona,3741 emetic pote
mi.

.-ca.... Io.':5T7

0.-0:, 2631. 270. 2lQ. 211

o..dai.., 50 ......

lor rtirlik, 221 .... 1Qi1ie,

II_,.oL 3fi6.

_,.11,

lor ",," ... 'hea. 2991

Ct)Il4I .... II! "

:mlI

, 3311, 335, 33S

Cypd _ _ ... It• ..,..'i;;·;"",.. ""1I3OJil5 ...:I ....."WIegl!S.

••••• ~,••••

It

.

113

--

bhWMI.""53 1lIIiiJ*lo.... 33I1,:os. 335-33& 0ARV0CET..ft.

5ee~

""""'"-,., ~ : m I .382. 3I!l:5, 3

15

3"Ii

Idcn&, :11"1

OAYPAO.5eeO>;aprozin

ddC,

see

Z8IdIabine dell, see Didanosine

be\lImeIhasOne. 2751, 4:)6-439 oortiIlone, 2151. Z16/ de$oo:y<Xl
..

~pcIenbal.

Ol'l h

pl'v'uctim. 272, zrl'

1lUPPft"jnn 01

drug

• •,0iIIl\:: pc*lOqr, 2431 loI---' 218-220 speciIc agenlS, 2171 and

..

(AZMACORT),

Co1iIol. 212, Z14

COt .. • .. Cb, 261-.

...

........"*"" 219• 221, 275l', 276. 276, 2761

'"

c.ep.~eio1lhlOni>osil, Ireatmenl,

~?

............. 356

CyeridlI,~"""l11l' ~ .. «$ 1.'(BuI.I93f.205.5ee

a/Io VI1lWI'i'l8q ~"19(42"

lor mo1ion

~

242. 42"

-""

1t.""'''''l1IIgan ~oaollida.373(

389/, 3991

drug irrIel ...... l$, 395

- " ' potooIilIl, 2.. 11

3Ba 3ll8-389,

198,

201,203 DehydroamoIin&. 3015/. 3Q, 3ot8 . . d .,;on, :M6I ~ ojll

,n

$ 01 ... prodolc1ion.

OB?"~""'. C6? 0El.TASOI'E. see PIa ..... 0ern0d0c)dnII. 311( 31", 314 0EMlLEN. 5ee~_atd

OENAVI'l see P&icldow

eeo.r,oo.,;.,

OEPAI
?!

or.... pl~ 2'75f

see V~ IIcid

~~,61~81.87

• ,"", '''' . .10' . . . . .

&00

,

•

•

COM< . . . . .

.,

.....

'92

'''''''' CU8liDn 01 .aio:1. 92' b Rpiepsy. 91

OiIllxaride Iuooel•• 345t 343, 348 diu; inIeI. . . . . 3'7

~108

sileI al ec:DDn, 3461

IllIio OIlelhIIIlO.t1eo ( ... dc&e. 901 b . . . . . . 14S1

felllPUt ~ lnl

~97' ......... , .. • .. 931

Oesoqccoljo I:

0:.

Die:nlid•• 18ll1. 191, 19' mug i 2W 0I>el'" 1271 0iclL4e0. . (\IOl.TI\RENl. 401 t 41" 4 J' 0'· - .. 2ll8t, 3DO, 300 liIIIbiIly 10 . . . . . • 3IXlf ~ISV.I . .201

mug i

147. 14n 2EfJt (del). 3&3( 3I!l9, 369-310

0idIII

Dideo>c~•.

3m'.

SeeblQlabine

0'" ...." (CAA0lZEM CO. 0Il..A(X)fl XA). 163f, 173, 113, 175t In, 177, 1llOf,

187, 181 ...... 11171 too -.ginll. IllIJI

diu; it'oelnclio:.. 1881

-""

lOt ~"" 1Ot-..po

....

'881 ~

~.419L424

....'..... flIlecb,I29' leo motion ..... 242, 424

-""

.........,.;c~...,

Dme
Dideol.......... See Did8noIine

..

lliIltri:Uion. 11 ~Io""'" 160'. 184, 214,339 .,ludl':'•• end, 63 ITIilChBriIm al ilClio:I, 1581 ~ IIn:lion artilIO, 159f DigiI:I 151t 158, '58

.-ug

3341

~16Of

Digalo;WI(I..ANOXIN), 151t 158, I~ 163f,

."...,

.... 'I'1t'lo"i;~164t 174 lDUOOI;1 ,159

,-.'-1 .....

.................. ,56.160t 169.111I, 213. 320. 352. 3ll5, 410

P

_

-.I6Ot

,.ilIIll. In

~.4'9t428,<J28 ~1117-188

s-
I

1.. 0:. (OHT), 270

"-""

0ip/l0n0z(yllI1lI, 2.... 244, 2441 tor diIIfI'hM, 235 ~187

~ 5eel'tlerJvlDin ~ (PEASANTlNE), 1931; 196,

'" '" DiIo:ltl1,.,1ide,

0is0DIcl . ....-,.. . . . . .

rn: nil'"

Disllll IIlCldit)oirg ~ dfugs, 467 163f, 161, 1m eftec:a. 1671 0iI5riluti0n,'*u;. 1. It Nl, 7-9 .......' ....... 101 "OUne, 9L "11

..., . .' ......,... 25

............

wihIuI~IOI

muglo............ 201'

OiI.on..,. •• 317, 3" ~,in,,,,,,,,,,lilpho . ..

---

ByIill'llie,SS DisDpr~Ie. See

0lLAC0R. See ~

OlLANTIN. See I't'iIJnv':>in

~,1S7

80d c:ha'>Qa6 in urine ,,"'ipOSlIIioo. 233/ lot ~ wilt> co QJI'olanI

diseases. 182'

silas oIlldion, 224/

,,.,. ,....'.,.' ... ",d...

,>

Sf*1lk: IIgeJIta, 1511. 1791,

~

""

41, m~224/. 2261, 22&-227. 233f. 292 .,....illll. 2231-224t 233, 233 bul • • Iidoo (Bl.EX). 15U, 179f, ~t 221. 227.22&, 292, 316

c:hlDoaI'liazJc 223/. 224. 22t-231.

."

d ...... o*b ... 2231.. 229. 231. 231 .....,.• ..", 2241. 221. 22N:28,

".

" ' _ , " (t.ASDC). 15U. 17'91. 2231.. 22<1, 224( 221. 227-22&, 292, 318, 409. 43ll-441 ".,.......,........Iiii.llcis. ISIt 119/. 183. /83, 223/. 229. 231. "1 in:llI,,,'b (l0Z0l). 223/, 231. 231 merriIoI, 223/. 2'33, ZJ3 ~.IS11.?23I.231.231

....... dsclo"e.I791.183. l83,m~ 224/.232'233, 2:)3, V4. zn I)I~. m~m/. 221, 227·228 Iriam.- (DYAZlOE). 119/. 223#2241. 233. 233

.....ee. mI. 233. 233 DobuIllmine, 55/. 66, 00. 691. 1511 Iol"congesw. heart lail\.O"a, 159. 161. 1611

Doc:usa.,tIOdiom, 2441. 24S DOLoeID. See tlilII.oMaI

,.,

Emesis. ct.""ll.~. 241 I.

llII&as. 378 cWg iolEoa:iol.. 242

118IIU.... 24 1-243, 2421

..-c~2411

Iol' KsipoII".ww, •. 429 ~ . -. . . 'g8I

Oo
iof~nausea

....:I_,liIio"" 242·243

DOPA.S&&~

l-QIpL See l.evodope 00J*1 ••,!6f. 6S. &s-66, 691

......

~,.

314

b'*-'" .Kl"._"_''''' 000;",... 96

-"'"

. . . . . . . . . . . .DgiM

n

Oo... ilItJiFiOl, 105" Il15, 242( 243, 243 Ooopelw, 117. 130, 130.242/ 1291 lord'iemolhel~ ........ WId \OOITIltirIg. 20&2-243 In .Iion 1hfInIpy. 2431 d'ug irlWaetIoo'e, 139

....,""*

_,til

pU 1&nlaI¥. 1081 Pffl8nll$1hedc, 108 Dnlg bW'dng. 10 plOleioe, 8-9. 11_12 Dnlg reoepIOrI, 1N~6

_.

"~56

~611

Do;If*I• •gic I'lIIUICIN, n PM<non'a 11'52 IloI-85. Il5f

=•.

Cess IMfIOI"'a.ve. 21.2U lJoM.'MfIOI"'~ - -'1,20-22 Doud'le. PM*" UIoI. 2681 ~4S1

If'Id
13.

"'"

DoMpIn,96.1111.119,119/ ~edYan1age8 and ~nQ1ge5. 125/

l:lol
""

s. . , ".1571 &.111_,271

ENBREl._e ....... £idlc:adiM. •• u" 315 &tOOi,,"'........... tl

270

~

107( 113, 113-114 l*locl,,," pet .....
".••, . IIIveollw ow~~_nl.alioo""'.. 1111 ~ lllMl!Mll'S If'Id ~1161

uplakeQJMI. 112. 1121

Eooxacin, 324, 324, 32&-327

Enoxapm, 1931. 196, 199 IldYefse etleetl. 199 Ertlafl)l!lbA tlsMlMjca i fectioo,. 345-

""

"""~.

....

SdIion,

"'-," &loio"+-'U1

ctugi .......... ,47

I~' l:)Ot. 346 trea........ 341-346 Enl&
0URlC£F. so. C.lsdovd

E..'f- tel illediool, - . . . 290. ::JOlt 301. 31S( 325/. 3611

0YNACFtC- See DpPdIlI. .ee

",.,.....·.'o!l'MY'Mm iItiaiClrl, 361 I

D,srhyIwrin..

..... 66I.CW Iol' 00i 9 r .. ~ .....,. 1611

~

EnIo1IIfri(VASOTa:). 1511. 156, 156.

DYAZIDE. seeT",".l5

DClNNAT""- Soe AIroI*l&

&n""013IS( 348,3461348

E-MYCI\I. S e e ~

'"

Iol' c:ro-. 3121

OIT. Soo Stlrvuclinll [)..cdenllI ulceo:s, If8llIrl'I&r't. 239-241

• • '''''*eflects.l291

~"""51 OolUAA). 71 ( 73,

~

dlemiclll. 8

DoiI4*IlXM •• 242/

_

'" tr--....nl. 201

actionS,3741

~.

n .........,·

...

... 243

See""""""'"

Ed .... oqI_. 351. 43, C3 lor gta.oc:orT-. 41

£<:\1101 ...... __ ,." 95 ~. 337( 3U, 3C3

......

~ Iuraion
226

, _ , . " 223. 229. 4oIO-UI «Iii; drug i

3IS( Q, 43, 433, 4341 Klioo .. 51

ancl~~50 E.e.s.See~ ElIvirenz, 4Q

Etler. . .-..or-.. 2&, 281 B..AVL

see AmilrlpIyIin&

€Iin*Ialion. d'ug, I. 1I. 23-25 by~.23,23f

.......,see

En't>oIi, 1&4.

Il18o PL*nona"

_"."359 ,."2'" .r .-..au,

&.owa:alll'docarditill. ••• "eo.. Fi ....... '7 oct. 3llS .. 111. . . 435

·lI.

£i. . . . . u 'In ........... r 1"1 ..... 311S EHTEX LA. See Pheo •....."Ioe EploIdI' •. 55.( 61, 68, Bill ~ II;lCriiIl. 6\ l'Q'l-CIoW...... ,.... flO

=

......... ""

""--

•

,,0<

,.,.

_1., •• ,, _ _ , >

• 0:-

'" _dai J .143

. _ ,..... 1l0·{II. W

£pi ep .~ .. 33., 55( 6'. 61-63, eIll lor _ -1I4A1J'lbia, 218 alliolio1lalion _ . 3

'"' u-oJc 18Cl8J*JlS, 581. 5805!l

"""'II"".

IInClllfTline 61 MIt! iO&5lhosie. 118 lII1tia!Jhylhmief1iC1S.164/ In ....-00 lOl'lic _ S)'SlIlm. 32/

end iliaD_ '1iWion, fil' end ..... bed>ol, 40 eadooasa.tir enectI, 631

If

E$tfOIliIn repIeceol .... .......".. 2&4, 2651 Esb""",. (PREMARIN). 263. 263-266, 2fI8. 3731. 3liBf " ' - " elJe<;b, 266. 2561 In ca....... lhefapy, 394 tailure rale, 268/ Estr~ 1f>OC1IIc ....... 263t ~ , 263. 26.1, 263t diellAW-oi. 263. 263. ~ 266,

,.. ...

-d;jIES1RACE,

~

263, 26.1, ~ 264-266, 267( 27'0

.n;,l, 263. 263. 263t - . 263, 263. 263t ef'linyl_a::Iid (Tm4.E\IlIN, OEMl.A.EN, lOOVRAl, OVCON, TR~NORINVL TRIPHASL. lOESTRIN·FE. OESOGENj, 263, 263. 263/. 265. 268, 394 me&erenol. 2631. $5, 256

lor llfriur:crn-. 41 rIll/' ,..... 424

....... "

SInIC1ure, 6O~1 /

Eplilibalide. 441

' - _ " '__ . '~eeU"

~ 263, 263. 2631 EQone, 263, 263. 2631 Eliiii ... cepI, 4tl8 ~edcl, 223f. 221, 227-228

EJyivumycin (E.E.S., ERYC. ~.

drug ............. 316 siIe 01 KIion, 22~ EI\aIrtIuW:Il, 331. 331/, 334, 334-31'5, 0437

E'J,,"'' ' Iio..,419l, 42a, <'R 0437 lor .. Iigoaio •• ~,

EAYC.S-~ ERY-TAB. &IIt~

ERV-TAB), 31H, 317. 317. 311-320,

'"

lII'!lWnicfoDial ac1Mly, 317, 3191

<:or*llir"dc8lion$, 282 drugintetll<:titn., 148/. 215 lor ~ 1lI*mCDi. 3121 ..........-: "A"" ..... 290, 3181 lor ...r.y hdlnledioo.. 328f Et,loahr oirot.M.dn1g .............. 1601 ~~0434 Er,h'PC·llill. 1l13( 2OIi,.
-......

,.....

acMtnoe eIIeas. 3351


'

..... "

melatdlsm, 13

E~lheo3j:allic~

and diIllll.-aages. 4221 EI'ler, " ••,...... . . 001 ............ 1111 E'*¥_a::Iid~ l)FM!" EN.

U><MW. """"""'"mlPHASll.., """'" lOESTJUN-FE, 0E90GEN). 263, 2U, 263t; 265. 268 In CifIQir Iherapy, 394 ~26B

Ethionamide. 331/, 335,:ll5 Elhosullimide. 1431. 149, 149 .... selWtei, 145' E ~ lheollj)iO,llic D/Ii I&agiS

.. _""

E!idilW_,476

EblJIa;: (l..OOlNE). 401( q 410 ED".' lOll( 116, 116 Eo? M1e, 373( 396, 39Ii, 399' drug 3B6 &w..... (ESTI'lACE. E.STFlACERM), 263, emelic Pl*N1Iiai, 2411 26.l263( 270 III8CI\llrWm 01 8CIion, 3971 men&InI8I cyde.nd, 256. 2ff11

""""""

e s - . _......

0., 1'D'<:I\IUl ... _

.,,265

. . . ." ... I*h ..... 2&1 £:sa;ol,. 263. 263. 263t

"
Eq..Olin. 263 Eteale dyslI.rdon, 471 t_I ..... 420, 471

'

M "'.-'

"'aIioo...

.....

,-.

"'" '...." :"IX*li_ 3781

EYlSTA see ReIiDIikIr ..

... ,,,

&Iirlg'$d . . . . - . 3 l l O

E

: • r I'

.' "'P'iC poI& .me (EPSP),

~ rtetmenI. C'i( 4J5.4J6 FelllCidoW, 3631, 367, 367, 458 Femiliel co.. lbiooed (mi>:ed) 1I~._.·""lie, 209/. see 1I1so Hypenipop;~I" .."lie,I)?IIIB Femili8l ~0Illi0 i8o'rie. 2Oll( see .elsoHweo""",,Oleio.,1ie, l)pe

•

lIllii'1'lOln, 211

FerniIiiII ~d' I ...,~

i""

See 1JPi1A

2Ql(

,

<;(lillo".. druIllhenlpy, 215, 2151 FemiilII ~. 20llL lIIsoHJpetlpopi............ .",. I Famiial~,

see

209/. See

lI/so~,1)ol)iIV

FllITIiliaI rrOxed ~rtrigIy<:eridam. 2Ollf. See also 1-Weo1ipupl00000.,liIl, .",.

F.,........ " (PEPClDl, 2351, 236. 236-231, 419( 4.40, 440'

F. . . . .,352 F~_Ptlel. .".,. F-o,.e. ' _ '...... 1-442

SoFC.. See R.q1oeine Febrllesez... . 144, 144"1451 1I.... nJenl, 148

FELOENE. see PYolclclw'n FeIodiJline, 180/. 1118. 188 lor COI"'IJ8SWe heart 18be, 157, IIl1lI druIl~18B1

.... ~11lIlf F• •, 401(410 ...epeulic .....,. In;! if 412/ F.IlpfOleo, 401 ( .ta!l, <108-409

cNJ~"'W

IIirapeuIic ..... ~ .... disadvatugM, 4121 F.nUIfIV1,I08f,117, 133f.139, 139 8CIion. 134/ distribulioo, 1':I1

eIlIcM:y and ••, .. '~llbuse 1iebIlify,

''''

cr.-and4nlion 01 8CIion. 139/ lli_

' ...... 108 hnIpeuIica.e __ . . ~1161

FilnoIa .................... 205 F-... ~ drug ODO llIaioldt:ll..... 251 Fetal pr8SflI1taIion,lIbrlom1;II, druIl

.""""'.----_..,

· - .....'., .... _ _ '>

.......odicalioo.. :lSI

Mdp-4.50nre

'."611.

F_. 432 FeJlule".cliI.., 470

is.

-*-.1281 .""'''''6g1cKlMl)l.13O

IorKap:llh _ .

1d0000000_ili

lor ............. ili. 318

Finaslendll. 272. 212 to< bfIrign ptOSlalic hypertrophy. 73 FIOfIINAL See BulaIbiW Recairide. 1631. 110. '10

-""

RODII. See C'l&

•

"""'~ 1dI'1io~llMioo 'CUIIl. 2761 A..-aIn. 2t11£214, 21'-215, U9 drlIg . . . . . . . . 213 ~ . 1191.

1:23. 123

Ihe<,,*,* ....... 1C8ge$ 8IId 6sadvaroges. 125/ Folale 1lt11agOris1s. 289-:296 Folale -.gonia. . IfllICllIc agents,

'or

1ot~.221

~ :J23..327. 456

....j,·'··.... "'" IOOTR1M). 201/. 211!1.

T .ll\lIl, '2H11 eIIBl:I on d oIdI eo I, 282

•'

2t':l!I. 2ll9.( 290. 29:J.2lI5, 2991.•29

. II iCt t>. 2fl5I

agents, 323t

clMbl'in, 456/

323.

""""'d. 2ll9.( 290

11811""'_.291 ~ . 2891. 290, ~

293.

3'151. 35C1. 352·353. 357, 357

324.325.3251.326 llOOl
...... dadiazlnll. 289/. 290-291

~324,~.32S

.... ra"ide, 289£290

' ............ (NOAOXIN). 323, 323. 324,

Sl.......... 2SlO

I(RODll). 324, 324, :!£25.326 SJ:Gi......... 456

....,..... • .... 2e9, 2t':l!I. 2ll9l; 290. 293. 293f, 29', 31st See ~Co­ ~.,"""""

_ ....

""'='"

•• ,.

S.FIlIoroulllCil. 3731, 382. 382-383, 3991 1<:Iillnt.374/ dnJg ;'1Ieo8C\iQ1S. 242 -.wlic: PQIleo iIiii 2" 1I

rnett• •"d-.383I mJ '''PQIleo'''378f ~(PAOZIrC).ll9t. '22,122.123

efIeds. 1231

....

"_'/6011.'" "5t. G( 50, 5{)

lor 1!'liriIiI. 221

plq:lllllils, 21St FUnazBrl, 901, 9'1, 94 Flll"iSolide (NASACORT). 219 8SlhmB, 219

GA8fTRlL_ T-oet:Ir.. GDncicIoYir (DHf'G). 363f. 356, 36&-367. Gao>gliooic bbd
...n1O\2761

AA .............. 27•. 2U

~

FOiSAMAX_"aoo_

227-228, ~1 lhJg ................ 292, 316, -409

~gTI

in C«lCet 1henIpy, 394. 394-395

FLocytosine. 337/. 339. 339-340 lot aypIOOOa:/ll metlioogllil. 284' dnJg irIler....... os, 337. 34ll ~ol""'" 339, 33QI FUlaral:li •• 'ST'JI. 3M, 3I!U

1-"

...

FORTASE_~

Fo6<:amM, 363f. 301, 367. 4.58 FoainopriI. 151/ S.Fu. see S,Fk>orOl¥llCil FlIIOSef'I'Iide (LASIX). 1511. 179'. 2231. 227.

IlnIion of atlion. 9'21 10< sleep disoolle!I, 91 as aleep-1ni:llIo;ef. 137 1hIo1p8Uic ........... 8IId

.......0"""' .. 27'2, 272

3421

~1\oxIIdn (CIPAO). 300. 323.

B,.. 205 F<**: IICid, 379 lor rnegaJobIastic &rremilI. 379 FoIide-stmAaling hoI'rTW;)nIl. 250, :2:50 secoelioll, 250. 2SOI 5-Foi"'• • ill'1d!dolie a::id, See Folino;:

.-on.

lor ~I S81'Clln'II. 429

~ spedk

'"

IIIitlclI ill...etO" !l2.ll3t ~"""22~ Fbbpd.." (MISI.ID). 401( «lI!l &OI!I '01 ..d 22C1 fUMrille, 313( 31991 c4Mj6i1ii1, U3L 149,1$150

I

FUconuoIt. 331£ :Ml~ 342 Pi......, . .

-"

"*'- ..... 13lf

~dllcaocale,"e 1· ......... 130

~

,.205I

will....,.,


- N<"

...

deIiuieo ...

Fluoo
'."6" 3611

FiV ...-••'"

"hI, 1221

. . . . . . . . . . . it).1211 It*apeuIic .... ,1llIJe6 8IId

F'1brW'dysiI., 1901 Fibrinogen. 446 Fbrin. rQle in doning. 1901

Rai'

t

__.....

lItlOCirlylslMaltOq)le. 2891. 291. 291

-...rasalame. 289/. 291, 291 suIliIo~. 2891.

290. 292, 292. 328/ 20. 205. 281. 281£285. 285', 2B7f. 289. 289. 2891, 290. 292( 293. ~ 2'lI3, 293/. 29'. 315lsee-.Cohl 1 _ FolMI,..o;tionilihtiD.. 2891 FulMe I)'I"lfwIIia ~11itJib.. 2891 F<* a::id, 1931, 205 ~.lleltOJPlilll (6ACTRIM}.

••,.........,,«

49,
GaSlrOinlGSlIrIlII drlIgs. 23s.246 GasatinlllSlinallmd 1Ibsoiplio. i\ •

~""*""

..';__".N< ""

C ., ". "1,.56 Ge"....... ~

Gowllbod (l.OPI:l). 207£21 I. 211·212 dnJg inlflf&Ctions. 215 mechIoniIm 01 8C1ion, 211. 211/ GEMZAR 588 Gailocill'lbll ..

General aneMI .......... I071-10flf

W>aIed. lOll ......CQ.. lOBI

ee.- _lheIlc&, '"Ill ·r.. ~ ~(VAlJUM).

50,90, ~~.91. !'H. 921-931. 9n 103, lOB, 1l1lll11l'>. 1"31. 1<16/, 1,.g. 239 llropetidol plus ~rr,t. lOaf

1lflIlumne. Ion 1111. 112.1121, 113. ll:J..ll~,

11.( 1161 10l1L 116, 116 lOB. 10l1L 1161. 111. 13»1351. I:D'. J:m, 139, 13!i11 "'*'ChaIe. 51, 53, 67. Ion 111. 111£ 112. 112/. 113, 113. 11.( 1161

_.'1'1.

ebjlj'

I.

(,.0<'''' ..'.1.

( ..

I.

'''''',

'" isofturane, 1(11/, 1111. 112, 1 \2/, 114, 114,114/, \161 kelamine, 1061, 1161, 117,117 Iorazep.am (ATIVAN), 92~931, 971, 1061, 116,2421,243,2431 meIhohexilal, 106/, 115 methoxyl\Jmne, 1(11/, 114, 114 1Tll'lIphine, 901, 1001, 1081, 117, 13:l~ 135/,135-138,139,1391,141,141f.

'"

1", 1111, 112, 112/,113,114,114/,114-115,116/,

nilrQus oxide, \ 071.

m

pIOpOfOl, 1081, 1161, 117,117 sevolUrane, 1(111, 115, !/5 tNamv\8I, 108/, 115 Ihiopenlal, 9, 901, 94, 95, 971. 108/, 109, 115,1151,115-116, 116/, 4001 Genilallnleclions, treament, 294/ Gemamidn, 311t, 315, 315. 435 ~ e!lects, 316 d'ug interaclions, 51 lherapevlic applicalions, 315/

GesIationaI chori<.x:arcinoma, Irealmem,

""

GHRH, see Growlh hotmone releasing

""""""

Giall!ia.lilD:t!iA iolediQn, 357 lIealmem,347

"'~ ~l 'Mth hypertension, treatment, 185 lfe
Gooadot,opins, 250 Gonoooa::al ophlttalmla. lreatm&nl, 2991 Gonoooa::aI Ulflltuitis, llGUIe. tre3lrOllrll

-"M

oropIlaryogeal, IrOOlrnanI, 2941

trealmenl, 2941, 299/, 324, 3251 Gooorelin, 247f. 250, 250, 3731, 394, 3951 in Cll/'ICEr Itterapy. 394 drug intelaclions, 39S GosereIin acetale, 394

Goo< ctuori<:,416 IrWImel1t, 406. 412, 415-417 specific: agents. 402/ Gouty al1hrills, aeuIe, lrealrOOrrt, 409 Gouty lllled<s. a<:tJIe, uealm8nl, 410, 415-

'"

GP 11llI'I11llleceplor, 446 G.."'H"'O"We ITlicrQo
Grarw:l nlill seizures. See Seizures, toni(:.

""""

GfIllli;.elrQn. 242/, 243, 243 GraI'lJlo<:yte stimulaling lac1Of, tor Kaposi's GIipizide (GlOUCOTflOL), 255/, 260, 260 sarcoma, 429-430 properties, 2611 Grepe.1loxacin, 456 G111OOCQ11iooids, zn..m GrIseofuMn, 3371, 342. 342-343, 3431 lrIha1ed, lor as1tYM, 218~2191 drug Inle
m

""

GLYNASE-

see G¥>uride

Gdd saJrs, 4021, 413-414 Gdd sodium ltIiomalate. 413-414 Gonadal hormone, 250 GooadoU~~hormom (GnRH),

247/,250 &Ctioos, 2481 IlfKIlestosle
Growlh~hormone (GHRH), 2471. 249

actions,2481 Guanethidine, 711, 78, 7&-19 and OOfeplneph
324,3251 Hairy cell leukemia, treatment, 384. 398

HAlCION, See Tri!ll:oIam HaIIucilioge"s, 104-105 dependeoc:epolenlial,lool

HaklgeoalOO hydrocarbon anes1helics, d'ug inlerac:tions, 51 HaIoperiOOI,l21, 127,127/,132/,2421 actions, 128/ allinroes at doparninen;jic feoop!OrS, 1311 anticholinergic aclivillt, 130 enliemelic ellacts, 129/ /01 d>emoI1Ier8Pl'-ind.J<:ed nauSEifl and vomiting, 242·243

andlSD.l05 and parl
aller. 131/ Haloperidol decanoare stmOotsIlalion ffJUIe, 3 metabolism, 130 HaloIhaoo, 107/, 113, 113 blood'gas parlition coefficienl, 1", 111/ charaderislics, 114/ ~ inleractions, 51, 53 eiminalion, 112 melh<.»<arnW>e and, 67 minimal alveolar c:onoentralion, 1", 1111 !he'_ _ 1ic advantages and disOOvan!ages, 116/ uplake OJIVe, 112, 112/ Hansen's disease, Secleprosy Headadte, llllallOOl1l, 400. 412, 437·438 scNzopIuenia reIepse

HearUlum, trea1rTMln1, 237 Heal1 rale, and acetylcholine, 39

Heavy ntelal poisoring, 1re
t1ftIioohaclef Ib'k!Ii inlection, 439

elimination. 239-240 and pepIic ulcer disease, 235-236, 2361 IleIIlill4t>ic inlectiorls ctemoIherapy, 3591

Incidence, 36C1 HemIcl>olinUn, and ac:efY\ChOIitle, 35 Heparin. 193/. 197-199, r99 binding lanlillYOfTbn 111, 198. 1981 drug lnIefaetions, 204, 339, 4061 Hepatic ascites, kio:l'>ey function with, 226 Hepatilis A vinlS, lreatmel11, 365 Hepatitis, IfWlmenI, spedlic agents. 3631 HERCEPnN see Trastuzumab Heroin, 1331, 140,140

acrion,I341

._,.....,., .. _--,.

. . . . . . . . . . . . . . ._ _. ., KI'CAII,I _ _ . . . . .

",

""".

'"

d8pendonce poIiiI ..... 1001'

-'"

....diOll*"... 73, 2'12. 272. 373(

39ol. 39 395,"

",*,**18and, 1"1/, 1"2 ' .... __ ewd, 1"2 ~"'hh ...._~mlTel ..... " . l.pas.."....57

Hllt's-

'*"""'" 81~_""'.".·" ••••••0,.....

.'"

HeIpes ~ ..... ~ l.lfeetmenI.

'"

H&rpes

~~ Yinls ~

2, lr&81menI,

""

Hetpes IIirus inllldion, \felItmenl. 365-

'"

~ lIg8fU.

I'

e'IlinyIll5IradicJI (TF!l.1.£VUN. 1

CW"'*
•

...... '0\191'"-

263/, 26li; 266, 266. :J73I, 3!l1 393-3lM. 3991 do",illleo 18. 263/. 266, 2f:i6 t.llmOXifen (NOLVAOEX). 2631. 266, 266. 373/, 393, 393-394,

.,,,

.lIiptogestil.. 2631. 267-268. ,,>ilep~..

3631

ameltIOI,;.,m, llI"d 0'. ...........

.............. 39 'ile ............. ltagOI· .o.oerse eIIed5, ~'" . . . d lIdiDn, Q3I

H,I:-

IPfICiIic agenIs, .. 191 lheo',,**Di.''-I/M.-cl

_""

~1Iealmllnl,1:30

zn m

263L 267·268. COlli" CIs. 219. 221. 235. 2.(.2'. 243, 243( 27", 274, 21'5( ~ 276, 216, 2761. 2761. 330&1. 362. 3731. 392-3S13, 3ll3,:J!D,

m.

3ll5. 'JE11. 3991• ..:II. ~ ........,oelI __ • (IlECIONASE. VAHCENASE, VANCEAl.). 219. 221. Z761• ..:I1 ~ dipoopioo .. lU. 27'6,

'"

~,27S1,~

diu'etios HIr5/JIis.m, IrOOIrTl8fll. 272

corIisone, 275', Z76' desoxyt::ortico\9fOfl9. 276' dulllroolhaSOn9, 235, 2.. 21. 2.. 3, 2431. 275~Z76/, Z76/. m. 362.

HI$MANAL Soo A51emiZQie

II" 1"""18,~2S Ildions. 0421/ ~04211

H,.............. .......,ii_ _us. .iI_

II .'il18 ..23425. Set! -.0 ""1iI- I If 'il18I ... ' .................. .wo. See_hlil- I • v-*iC ec:id i , ..... 23l>-Z38 b peplic if • 2351 5J*dlic agenta, .. 19t Iii .'='MrM'...... 1nI8ction (N)* o;>lo;mtl$iS). \felIIm8I'1l, 338.

"**

'"

~ePn.247~250,2S0

HIV protease irlIibiIors. 458

HMG-CoA rvdo oct"e .~*"kHS. 449 Hodgkin's diselSe, 3lIO 1169.'... 11, 388, 393, 396. 3991, 409 Hoc*wOrmi ........... _ ....... 369.

""

UOiWo"e... 31 1101"101-, spedlk: . . . .

m

• Idlogeo ... 263L 270. 271, VI d8r8zd. 263( 27'll. 2i'O. 211 . . .", I o"e. 21$31. 271, 271

' ... IClI....... 2631. 271. 271 stam.zolol. 263( 271. 271 \9I5IOSUIlOI19 C)oPioMIU. 2631. 271,

"''''

lludl ...... boi18. V ... 274, 2751 hydnx:o:'iIIone, 21", 274, 275~ ",",,,,,",,, ,,~lOliiioJcw..

"" """'"

219. 2421.

~,2751

...0 ..6dl

l.OE.STI'lfi-FE. O£SOGENI. 263, 2fi3, 2631, 265,

" ~

~383

(OELTASONE. 0RAS0NEl. 219, 2?SI. 27'6, :ntl. :J73I. 393, 393, 397. 3991,":&

'"

trtamc:inok>ne (AZMACOAT). 219. 221.275'. Z76, 276, Z76' <;OI'Iioolropitl (ACTl-I). 2471, 249. 249. 2.. 91 de5m:lp1lMin, 3, 2"7~ 251, 251 _Clgbi", 263. 26.1, 263, 263, 263(

263L 264-266. 2ti6. 266. 267/. 266. 270. 3lM d ...... · .. 2153, 2Ii1. 2631 clefllI • 263, 2Ii1. 2631.

... ...

_Idol (ES'ffiACE. EsmADERM). 2'&3, 263, 2'63( 264-2l56. 267~ 270 IlSIriDl, 263. a53, 2631 estrone,263, 261263/

2m. 54

• d. 2631, 2£6, 268 d. 263, 2Ii1. 2631

gaoedolroPr'H' . 1\11...." .... 18 (GnRH). 2-tU2"81, 2SO. 210 goservtin, 2471, 250, 2:SO. 3731, 3lM.

394, 395. 3951

hl;Im\OO&-.eIea5lno hormone {GHRH}. 247~2481, 20'9 hi5UeIin, 2471. 250. 25() leuptoIide,2"7I, 250. 2SO, 3731. 3lM. 3901. 3ll5. 3ll5I'. 3991 U9i0 .... 1\1 r.... "'OI_~. ... II.·~I\I 00"018 (I.H'lH). 2"U2AS/ , ' ..... 2.. 250, 250 od".oll,de. 247( 2SO. 250 Clll\"Illdn. 20' 7( 250, 251, 25 I

~

n

.. ~,'" 3, 2'63( 267. 267. 266. 2fifII. ~.2631.267.267

.........9

IliigI>owilii l\lliIA'eIics. see Loop

...........

DEMU.£N. lOo'OVRAL OIICON.

~

Ill, 3. 268. 2Ei91

~(PRCNERA).

2631.267.267 nQffilhlrdoone. 263/, 267, 267. 268

OOIgesue1. 263/. 267. 267. 268. 2681 lIOnVllOl5llltin, 2..U2..al, 250

- _... 2"n

_1OlJ, 249, 2'W , ,-nsin,2U/,25O,251.251 50HT.5eo,*",1ii' IeoopIOi tlIcd<eos., b'

....,.1\1. 242( 2.-3

..u- ttoioolic llOi....opi. (ICG), 250 ....... rrm.illClo:!6Ueoq' ....

.....-.. ~-'.II, 2QS bU 3Mo371 ,...,11,

spdic eget'IlS. 3&3f .......... ......... Ddeficieoq Wus prolea!le 1nIlillilofs. 371 Human In&uIin (HUMUUN N), 257 I-Un8n menopausaJ gonadolropln (hMG),

""

H1.JMLl.JN. Se'9 .......... Nl*' HVCAMTlN see T\IIlfMIC*' ~.151t 180( 110, 1~442 b'COI; f,.. r-1 ....... 157 HjGw....... OWide. 151( lT9( 183, 183,.

2231. 229. 231, 441 Hp.i<()IXlCl<M •• tOI COl.9\. 222

1!lGCli:ClM<Ml9,V", 27"'~ .d"liiliAalio" roAe, 2761

--"'" piOp9I'1ie5.. 275'

...

• ,..,. roo ..,., . . . . . . . _

, )

~ .... ,"'~"''' tor c:ougt>. 222

~~ ............. 2"/.~2&5

.1.

..

IIjodi"'Jd~ • • •lIiiollo,.,OIlDfy

IIIJIIfIl,

~

iI'~'" 21'~ 214-215, M9

IIdIIeIae effects, 21st

_.,." ~_.267.267 ~ea.I931

lor ald
fIen\peIJIic l'tto'anli>g8S Wid

-""

llislldIIanlagI97f, .Z!I

* Iin:*.... . . ..." lor pepIic ulcer

.23ll

_dliot.226

,_••,,232

'''''.''27'.277 HJvw<;iok:eI'" _ - - . 228 ~o;aIc::iuria,....... ,. . . 230 HyjMdo:' rele,," I)'plIIIA, Ireau...n~ 213 type lIB, 1r1l81rT18n1. 213 HyperdIcIesI8lClooias. Tr1HI1m8rlt. 210

Hypet\lpillBrris, 207. 206~209/ W1dhypenenslcn, 182~1831 prImery.201

"""'''t.207 ' _ ,..... 21.

...... "'"

-'"

i'f'1peneI ...... 8iI.lIl.""..T.

III

.w_...m..... 211

~415

..... ,. . . .17 ~drugs.-

IJl8Cik agerts. 89~1 Hypoeltunioemia. and drug bird'"O. 11 HypXhromic miaocylio;: enemia. and IoIate defK:iencv. 205

----

oral 255/. 255-282. 260-261 edYe<se e/Ieds, 261 I drug ....1dicnII, 2fIOI

...-II_,ide, 2S5t 26Q, 2I5D. 261/ dbP"4"""idlt.2$5I; 260, 261).261.

''''

type •• 2091

'_I."

1)'plI1l. 1)'plI1Y, 2091 I)'plI V. 2091

215

tr1Nllm8lll.210 lype IIA. lrealm8lll, 212 lype lIB. treatment. 210. 212 1)'plI1Il. Ireatrnenl, 211 !)'pe1Y. _ _ 2100211

,iii""

I)'plIV.....b'. . . 211

tt,perIIllliool Md~I78I

,~ __ ~ ,." ... ,·. ._e ..... 183/ ~.I19

_ _ , . " 73, 75-18. 78t. 173, 188f. 223, :z:3O.Zl1. 441-«2

tr_.sua. . . 181-183 .... 1:0'00",18111 di'e8$", 1821

~

(AOVL. MOT~. «l1t 4ll,

101 409, 440 lteepellic ~ WId di'acMlnIages. 412/ 1dan.tlk*>.37~J115

lOOx..-klne. 368, 36B IFN. $eD ILETIN.

See lnsl*l; l8cptIene

~loipIH_ 2981,.no;;

3Q6.307 Sln-.e.3IJ1f .,.......... 119. "90 1191

...... ~171.172/ .......... 120

""".iI.1",D\lIl56

WId I """"llb

2I5D. 261/

(DIABETA. MICAONASE.. GLYNASE I'f\ESTAB), 255/. 200. 260. 2611 ll'IIlllo<mIl, 2551. 261. 26 I, 261 I repeglinide. 452 f05igIiIazone•• 503 WlIezamide. 255/. 26Q, 2I5D. 261 I 1CItiutamidlo. 255t 26Q, 2l5O. 261 I. ~

...,.

............. (Hl.U..UN HI. 257 2.,',l, 7. 71. 255/. 255-262, 257. 257-258, 2fi8l.25Q( 25&026Q, 200f

r.a..

~

".",

lICIioo ...... 1lf8P8'8lioriII,

isopIIaoe insulin suspen&icn (ILEnN), 2S51,~2S\l

lenIe Iosulir\ 259 pn:lI:JrIg8d lldicn ....... ~

,,,

rapid lldicn insUlin peperelioo .. 2S8

2$51, 2S91 iI'eo*I a.IiCl8i ..... ~ 258

_, _,

...... nun. 255t 259 line ........ 255f Hypoguowdi'oll

po;n.y.

"'*,." 264

,-""

~

Ireaunent. 125

Irller1ercn

lloslerrOde, 373/. 38S, 38&-389. 389/

iJiPe·loo (Gl..OUCX)TAOL.), 255t 26Q,

..... *'c~2551

titpet.ipcpoClllW-re

H'fl'FW\l See TSfUDIln

p_

l"'~ c~_,lk: dNga, apecIfic: ~

tI'P" IB, 2091

. _.. 253

gtolle....id&.452

WCgIitI......... 453 plcp8i-'2611

I)'plI ~ 2091

-". ........ 2.a1

lind ,.p. "'Ill' iI... 63 ......... 75.. 2530254

HtPiW'V\
tfV\lClIl' I he Iu" ....... 247t 2'70:250

121

apecAify. 121 1

~~.-d

di'adYentages. 125/ lMllREX. See s..n.~

Immunceoppressan. '70 IMOOlUM. See l.
371, 371. 458

.., ..... 41»-'10

. . . . . . . . ~1Ind ~'lV

--"'"

~o:IOIllMIiIIiCll~«lU.

401, «J9

......~244.24..,

drug i .... lk:lioo os. .17 lherlIpeuIlc adYa Dg8II WId lliIadYanlages•• ,2/

IrIe~. tree1mllnt, 250 Inllil
..

IrA.oenu B il4ediot .. 1r_1\, 366

u ........ mI

...

s

~HlD'I· t .'

" '"

-!

(FSP).

lNNOVAR, 117 ~","""drugs,

157-161

&peciIc~ 151/

42'. 435-436

~*,I."'lr""""'"

............ 255/, 255-262, 257, 257-258

<_,,,, ..J.,>< __

~_,>

'"

Index administfation rOUle, 2-3 a(\\le<se e1!0C1S, 258, 258/ bioavailabllity,7

jl-bIockersand,n e>
'"

in p!'egnency, 260

Iispm452 prepa18bons, :z58.260 proIOflged aclioo p!'ep8retions. 259

rapid action preparalioos, 2S8 SlandaId vs. irIIensive rrealmefll,

25!J.

260,260' Insulin lire suspension, 255f lNTAL See CromoIyn INTEGRIUN see Eptffibatida ln1erlerons, 363/. 311, 311, 371/, 3131. 397-398, 399f, 458 Inrre·al1e
""

!cf aslhrna, 211/, 220 !cf chronic obsltucWe polmonllry disease, 211', 222 stl\lCMe, 220f

1"",,193/,205 eryl!vopoieIJn and. 206 ISOOIIrbrn
to< g1aurorTlll, 41 and reactivation 01 aceIy\<:llolinease, 43. 43f lsorilltll:l, 263, 263/, 331, 331 f, 332, 332-333. 437 ad'voroo eIf/letS, 333f diSUibl;tion, 332, 332/ drug inlemCliOr'lS, 141,

147~ 148',

334,3J5f !cf 1ullerwlosis, 2841

lsophane insulln suspension (ILEnN), 255/, 258-259 lscproIerenol. 55', 64, 64-65, 69f actions, 66f ard adrenergic receplors. 58, 58/

and amine nitrogen, 61 blockage by [HlIockers, 75 and bnlnl:h<xl;la1ioo, fif' cardiovascular ellacts, 65f as direct-actiog agonist, 61 effed on blood pressure, 72/ structure. 611 ISOPTlN. seeVerapamil ISOROIL See lsooortida IsosorbO:Ie (ISOROIL), 151/ lsosort>ide dinitrllla, 175f, 176, 176 !cf congeslNe hear! lait.lre, 151 onset and duration 0I1IC1ion, 1 nf lsosorbide mon:N'Iirrllle, ooseI 01 action,

'"

Isradipina (OYNACIRC), 180f, 188, ,SS 101 congestive heaf\ 'ai!\Jm, 186f drug Interadions, 188f lor hyper1ension. 188/ m-aronazola, 337/, 342, 342 o:lrug lnlemc:tionS, 215 P«Jl)er1ies,3421 IV(IfTllOCtin, 3591, 360, 300 Kaolin, 244. 244/

Kaposi's sarcoma. lIl!atment. specific agenlS. 363/ K-CUR. seePola$SlU11 KEFl£X. see Gephale>:in KEFTAB. see cephalel
,...,.,

as admnooorticoid inhibilor, V7, 277 as antIandrogan, 272 drug interactions, 334/ mode 01 aclion, 3401 properties, 342' Ke40pr0fen (ORUOIS). 401 I. 408, 408-

..

drug interactions, 417 ther8jlelJ1ic advanlagaS and

disadvaRlageS,412' Kero
*"""

inlection, resislenr:e, 301

K1el15iella pneumonia Inleclion. 3Z7 treatment 304, 315', 3251, 433 KlONOPIN. see Clona~ KLOR-eoN. See PolaSSiunl LabataloI (NORMOOYNE), 71/. 78, 78. 791. 179/ (tug elimination. 7M for trype
IHactam antibiotics dassiticalion, 'lf57' rllSislance 10, 265/ specific agafllS, 29ll, SlrUcIIKe.297/ ll-LacIamase, dn"g interactions, 300 ll-laetamase 1nhibi1ClrS, 307-308 jl-laclamase InhlbilOl'S, specific

.,.m,,'."

cIavulanic lldd, 2981, 300, '2JXJ/, ~11­ 30:2, :¥J7, 301-308, 306, sullaetarn. 298l300, 3001, 302. 307,

""

tazobaClaIl\ 298', 3001, 301-302,

307, :¥J7

laCllJIose. 2441, 245 larTlivudine, 310-371, 371. 458 lamolrigine, 143/, 149,149-15(1 LanopraroIe. 235/. 239, 239 \.ANO)(IN. SceDigoxin

lASlX.

see FUfOSI'lr11ida

lassa lever, lJeatmoot, 365 lal<8li11es,244-245 l;p
Latl........"mde.467 I eg;onena infection, lfealm9rll. 29041, 317.324,3251,326

......

LegioneIlosis. sea LegiooYIaires' Legioma~es' disease, lrea1menl, 316' loliftImaniasis

(,..,..", ..,., > ( " - - ' )

500

Index

thelllohltapy. 345/, 356-351' lrealmOOl, 355 lmIe inslJjn, 259 extant and Ii..oaIiofI 01 action, 259f Lepirudin, 448 It'prosy, Ireatmenl. 331/, 33S-336 Lep!l»llc!ia tM'x'.1'is inIoction, lrea1menl, 2991 l.eu<:o\IorirI, 379, 3791, 3BlJ. S88 8Iso FoIirOc

.""

lor aoerrae, 353 drug interactions, 382. 415 myeIo5uppressive potential, 3781

"'-

tmatmenI, 2991, 300 Uslariosis, lIaalmOOl, 2991 lilhUm, drug Inle
ax:U1e as. 102 epirIephrWIe tn, 63

Local _thetlcs, specific &gents ~ ~ , 108~ 1171 lidocaine, 3, 7, 1081. 1171, 163~1641, 169.169, 1691, 174 procaine. 1081, 1171 pn'lC/line peoio::ilIin G, 302 tetracaine, 1081, 1171

see

3CuII.Ilyrnph<;JbIasl;, trOOtmenl, 381, 390

LOOINE. EIOdolac 8ClIte tymphocytic:, tmatmenl, 3, 376-3n. LOESTRIN'FE. Ethinyl eSlf'8diol

379,386,393,397,3991 acute myelocytic, 1reatmolrl1, 386

acuIe ~ (myelogenous),

-"""'"

chroric ~ , lrOOlmOOI, 384 chroniC 1Tl)'I.lIooenou, tor slcl
....... ""

..,

kellll'oont, speQIic agents. 3631 ~,2471,

250, 250. 3731, 394. 3951,

in cancet Ihefapv, 394 drug inler3ctioos, 395 L.evarrisoIe, drug inleraction'>, 382 Levane<enol, 64. 64

Levodopa,811 and bIoocHlrain barrie<, 8

distribJIim, 8 dopamine synthesis ....th, 85/

drug intera<:tions, 861, 147,240 tor Parkinson's disease, 84-8G l.eYOIloldoe (LEVOXYL), 247f, 253 LEVOXYLS88~

Lidocaine, 1081, 1631, 169,169 as antianhylhmlc, 1641 tor 8fTIlYthmias, 174 efIe<:ts, 1691 with apO'lephrine. 3

-.,

ph1llmllCOkine1ic properties, 1171

Upase~,475

UPITOA see A10lVaslaln

L)sirqIrII (ZESTRIL., PAINIVlL), 1511, 1791 Lispro insulin. 452

.LifiIllI:ia lDllfIPCYIooeoes infection ~,304

see

Logkl,374

lomefloxacin, 324, 324, 325 1.omJsIine, 3731, 389. 389-390 Loop oo,elies., 2231. 227-228 adverse elleds, 2281 and

cttanges in urine composition, 2271.

"''' see

drug in1eracIions, 160, 1601 LQ'OVRAL E1hinyI estrndioI Loperamkle (IMOOIUM), 244. 244, 2441 LOf'I0. s e e ~ LOPflESSOR. MeIoproIol

see

Loratidine (CLARmNj for rtinilis, 221 lherapeutic advantages and <.isadvantages, 4221 Lor82epam tATlVAN), lOllI, 116,2421 lor dlemolherapy..;nojur;ed nausea and vom:ting, 243 in COfrtlinaIion th&rapy, 2431 liImlion 01 action, 921 th&r~ advantages and <.isadvantages. 971 withdrawal reactions, 931 losartan, 179/,181, 187 LOTENSIN, SoeOJinapriI lovaslatin (MEVACORI, ::'(l7f, 214, 214215, 449 LOZOL Soe Indapamidll

-~ OiIt eel carcinoma, t'aatmeflt, 396 smalklaI, " " " ' - ' 392 lreatmenl, 386, 396

Luleinizing hormone, 250 secrelion, 250, 2501 Lulainizing llorrr'IJrle-'aleasing hormone (LHRH),2471 aetior\5, 2481 Lyme disease,trea1menl, 3121

LymphogmrUorna _8\lll\ lreaImenr,

3121 Lymphomas, See aJscl-lodgkin's disease oon-Hodgkin's, 390 lr8ll1ment, 393 ~ caU, trea/mllfl\, 387 1relltmenl, 386, 393 Lvser9c acid dielhyIamidD (LSO), 99', 105 dependence poIenIiaI, 1001 MaalOx Te, drug in1eradions, 370 MACR().8ID, See NiIrolumntoirl MACROOANllN. See N/lrQfurlll1loin Macrolides,317-:129 cIassiI\cation, 287f resislance 10, 285' Mao;roIkIes, specific "genb, 3111 azilhronl)tin (ZlTHFlOMAX). 311 I, 317320,319' d 8 ~ (BIAXlN), 235~ 236, 262, 282/, 3111, 317·320, 3191. 433 erythn:mycin (E£S" ERYC, E·MVClN, ERY-TAB), 1411I, 215, 282, 290, 3111-3121, 317, 317, 317,320, 3181, 319,319',328',435 MaIeritle,2891 lheerl(IazoIo, 359, 359, 3591, 361' conlraindications, 359/ Me<:am;tamine, 451, 491, 50, 50 MechIoreIh;wnin, 3131, 387. 387-388, 36fl',399f emetic poloo1iaI, 241' MecIizine, 419', 424 antiemellc eflects, 1291 lor rTo:.lllon sickneris, 242, 424 1he
see

..--

.... ,.....,., .. -..... ..--,.

."""" ......

.

.,...."..".

..

""'," advanlllglll and dosMlvllrUges. 4121 ~(PfOJERA).2631

MtOm
.~.4IS

U ' .,. . . 34501; 3501• .152. 3Q.353 IWl 1QPid, 346t. 353, 353( 15'-354 M81......

UW.·"·4 am '..... 2641 , . ." . . . :181. 3OS. 333, 33lI Me''''~ .. 250

-

~.

1iq~lIbuse

'abIrv.

""

far migraloD. ~71 oreel and dunllion of actiorI, l':Bl ~,373/.380. 380-381.

,."

1-..

ffl,

2'93

mf

.'oechaiie:"of

..~':1761

551. 6lS. 6647. 69f

1071. 114, 114 MefiJ'l-_ 2«. 244~ 245 Q ~ 180( Il1O, 190

3-0 tAE;"J1dopa. .... HYOFlOCH..ORIDE). 991; 104

lot anenlion delic:lI SViOO'-' 104 Molh)'lpledl-.... ... 2421 adrnini$ll8lion _ . 2761

lot as"""",,. 219

dru;lnter~.417

SibutrllninO MefUIyl oxi
MERIDlA _

phanTlllCClllireti. 265

-,

Met~drug.l.lf.12.15,141

eIIed 01 en.; dl*l on. 13f eirTinIIIion in, 24. 251

moo IKlIherlIPI'~nduc:ed

l\8useB

and \ICIfTVIing. 243 elimioalkln. 2761

prQpefliM. 2751 Mc1tlyIsaIicyIiIG. 4011. 406. 408 MclhybcllnlNres.900104 ~.4191.426

Iof rri;ralne. 4Z1~ 428 Me ... ~.,ide (FlEGlAN). 242. 242.

''''

• iIieo, oelic eIlec:ls, 129/

MeIanu:I, «1-442

Mel>4lo<*<e"ol. 551. 67, 61. fBI and bMd'Ol4 . I, ffll

69

ri<ec)-1CIion ...... 61

Met1oi"w.. 2551. 51. 261

"""'*""-.

2'&11 MeIl'IIdol'oe. 1310.1$ Itvgio ........... 10 eI1icact' and ••• " JlIbuse liIbIIy.

,,,,

~ ~Daneagesard ~4221 ~.

321. 327~ 321-3211 drugl".". . . . . :292 Me....... 2U8f. 300. 300 admil'Isnlion ooulD. res;s1anOll1O. 285 Slabilill' 10 penicllinlo8e. 3001 Mcthimazolo. 247'. 253. 253-254. 436

302

so,

m.

eIIec:II, 1691 29ll( 301. XII

_'_.302

SIabiiIy 1;1 ~ 3001 ~ (MONISTAT), 337( 343, 343 MJCRO.K. See PM m .........q ".,;As IraTI,

,.1Oih'

,,,

""""""'" ...........

U!zpr;rq1m • iIIIdioo.. IIf9Q't&IO 343 MiI;:n;lUde 3lll).392

.,IbloI..

1Or~.~"""",:f73J

~(RITAL.lN

lor

actions. 374/. 3811

•

.~ ... dMei

......

Iof giaIdaM. 357 silIllI 01 ...... 3461 MeIyf1Ip)ne. 217 Io1EVACOR. See llMIstcIIm MeoiIelii ... 163/. 170, 1m lot ~ 171. 1721 drug . _......... 147

Me· adI,

~

338

~!56f.H.

drug lrIll)olldiOl.. 295., 3lW. 410

erne*: ...... 1IiIl. 241 1 and IOlMe cleIitiIOi""l'. 20S

~

435-436

p.. 9 I .... In, 266. 2671 MejMiZCiWe.2'36t MejMdo ... 133f.13l'l13&-139.2« drugiollil!o dicKy..-.d

MelhoU_. 3731. 318, 37&-3lIO, 3991. 4021.41S lot IltutirJi .. 419 ...... ':1741 ~ eIJedf. 378

m.

'h8lapeulic ~ and

......... _mere.

MeIhohexilaI. 1081. , IS

_

Iof ct.'Ioll'I8I~tIllUSeB and ~ 20Q.243 .. ~ tlefIpv. 243, 2431

'1''' ..... 451 ::reel and CUUion 01 KIlian, 521

mlld'Iano&m 01 aaion, 3911 ~101l1.116

lhe.apet.Iic ~ and di$adYMIagIIlS. 971 MmpriIlOnP. 2631. 2IS7.2\S8 as ado'enclcollic:o imtlilor. 'l77 Miglairle~ ch8~.4251

ooncorriIani wllh hypo/1el osioo .. trN\n'eni. IBS 1r1laImIlf'It. 75, 781, 167. QS.428, 4271 spedfiI: 19(1I'IIS. 4191 Milt'. ...... ISI( 161. 161

IoIiW!laloool'licoidll. 2'13-274 prodIdon,272 prope,.... 275/

hlne<4ol,2441.24S ~.

•

. . ..... CO .. """'.{MAC).1Or

"'0--. 111 ,1111

~.See~

-"

.....caN. SeeUiooocp..

~'"

""""'" - ,P.,•• It" ""....... Z3S( 23e, Zl8-23iI. 261. 267, 419~ 420. .cro. 420f

M ? ""OI'l8. 151 ~ 2231". 231. 231 I' •• *(l0Pf'ESS0Fl).71~T7.T1.

791. 1791

Iof"'-" 176 ~

eIIeca. 171

dri;;4 ................ 781 drug '*"*'"On, 74 1 Iof I'Iypetl8IlIiol.. ISS ""'. ..... olol and pildolol. 163/

MeIroni:laloIe.235/. 345/. 347. 347--348 COlI. 282, 2621 drug 1n!oo'adIons. 201' 10 elifTiMtG !:Ill!Ocrtw:!lI' moDi. 236

Uio~..

lUNClCJN). 311( 313, 31.1

'"

~ (Rl:IGAlNE), 15U. IIlO(

110-111

,'_-*

'SlO.

Iof IltutCli .. 419 drug ......... 3110, 4fY1 and gaslric: d . ......"." 2371 MiIt'o.,,~ See~ ~

emeIic: polllnIial. 241 I

~$'I\,4SI

001SIlI8l1ll

duration 01 action, 521

phaornllCiOkinelica.51

<'''''"'....'.,.< ....... _ ... ,. -"'anliJOll$. 521 1791

MONISTATIV. Soo MiconflzClle Moro:.l;unne 0IIil:la5e. 123-1:25

MonoarrWle i

".

1.~tJn il~libi1ool.

I 19/. 123-

tk'ug inIeIa<:IicloI. 86. 861, 138, 2EO'.

'"

~"" ........ trdeIi. 01

opeciIo:: agentS, 2!llIf Moo .......... a,.h'",.56

............

MjUlplasma. 2831

~..-nerw.

MOPP'egil ... ~388 !IoIo!pqlagta'lt I' ............ Jt&, 32-4 hl!lrgII , ilileaiol •• _ , ...... 315/

'_,IeI'"

""

Mo;:wpil.. lOll( 111. 1331.: 135-13. Ildioo\ 13011 clqAo .............. IOOI

''''

. . . . . iMIiily.

I...... e.ro, I.U. 10&2 Cln5el and c:UaIion QI aclion, fUoQlleflllllO dk (.., ex-. 9llI willocllz,,1I, _ , 139

IoIcllionIicN ,_' ~2. .c24 MO I I at SHb4l'Olen MI;uOin "'*'-. ~ 'M\,

4&.W.13ll, I.... m

2lI6f

>ilarrin I( . . . . 2l)(

&-UP. seas III c.,."orine MTX. 5ea Me...... exate ~~356.31561 Muco&aI pI' ..... oe agents. tDr p(lplk: ulger

diIIelllS8, 2361'. 2.1

MUIiclruu oesisla..... g8I'llI. 311. 3111 Mdbiple ~ \te111metI, 90 M,• •,,,,,.,"'. .n Muscarinic bklcI<.Bts. "lll Musc.lIInc: ''''''''*''1. 3BI. 3G-3i Muscle CO'ilIaetioo .. phf.l'ClOgy. 152/. 153-

see

Muade relaxants. NeulOm,l3'Clkr l.*xI<erI Mus<:Uar~. 1reatrne1'(. 90 Myagia. Ir8alrnefIt, 406 Myasthenia gravis. lrealmert. 6B, .33.

.,,,

~"'..;;.

IIt*'cIJIWlI!IOt&, _ - - . JJ7-3C ~ agentI. 3311 .......1tiII,"IUI.... ~ ~",3371

.....",*'- -....c. 337..,)0&2 IlJlll* Igef1ls. 331/

...... ' _ '.... ,71.201.203 an:! . . . . 118I an:l tlWlet*-.oo .. 1lW-183f . . I lEi'" 185 . _ ,...... 7..76,. 186, 196. 198, 202

.. , """"'" -

_

.....

,""'.

NllI'lXlIopsy. lfelItmenl, 1001 NarooIic anaIgesiaI. aug lner&c:tiorII. 138. 1381 twooIIca, dopend&ro;le polOtllial, 100/ NA$ACORT. seeFlunisolide

NaSlIIl1tw igt5laI1 epN!doi"e as. 68 pl'le,,~. . 66 Nausea. see also Emesis lIoolmenll29-t:JJ. ~ Na>etlII.... 373f """ralor lllIIllIi;arJ!I OkN.. 3$" ~11eI1l, 359

Nedooo"oI. 220, ~ 431 tor ashna, 217/ NeIMxlone. 1 19/. 123. 123 1I.8J>8l*:~"'"

t'

-""

M'WlQI" td _ _• - . . - . 290ft 2991. :JJ5f. 325f glol" ~",.,."'3GI 11' 'i1 " • • • "Ioltediol~ _ •••••••

I"

29(( S f Nfl.· ........ "'lO NemaIOde il .......

d'aacseoti1ics" 36" .............. 3!>9J. '59..)NI. 361/ Neomttdn,311( 31&, 316 adY
Or b" )1\111

NIl:1Ione. 2.c2( 243

NEOAAL _

~ (REl..AFE.NI. CO'1 ( . " . 4 I I

Neoo1igo"i .. 35l. U. q drug lo ........... 51. 317 and nllIInlfTLIISGA Ilb::t<Ms. 50 NeJt",*"IJiO<»I. kilny Iurdion cLolng. 22'll

111.16, 16. 17'9t cllr*:lIl ............... 181 tk'ug 7M

NadolCII~.

. . . . . . ' L0456

'"

3121. 3181 Ult! I' ' r r Ql'!llU!IJll'IM lo ......... _.,.".,3121

-I.

1.,

eIlicaq< an:! . ' . iii

•

..........

un .qrg..... lolleclioo. 331.

--=

........,.,..",

...

,-",

SlIeal\loT~

~12S/

dtu;lil. .ae:toI ..

.........._

inIec\kllI. trealmen\, 316. 333. 336 uyrrtw:ter;rn hlleclloll. ~ MII!ri!i!cleriy "NTM:si Iolloclioo .. trealr'r*lt. 332, 3301 ~ium !nl1U inl«lion, 335 Ult! .........

mec:t>atliIm d aclion, 12./ tleoapetllic arMlnlagllS and

_ ...

~

~aWlm i"'I1I°olhAaIll

~ic Moe>ipl~.

<

.,.I&Iioi..

tor "igo_.... 0$28

Nalardn. 20/. 250. ZiO NaUil .. 2ll8( 3OO.:Q) .......... 303

...I.'. ....

... .•.

_.~ ~~ ~-"

" .. h. acid. 323, 323; 327 NaIc:Jlo.. 1331.: '.1-1'*2 aclion, 13ol1 and III'IllSthesia. 111 CO'IJ)eMiolI ..... opioid llIQlrists, ,., I dtu;l lo "",_,.. l.w

_ , ... '" 230. 3119 ~sysIem.~27L21-31

''''lIilllliui. 311 ( 316. 316 ~ e/Ied5, 316 Neun:lleptlInes 117 NeunA
"""'"'".,

adYer.oe etloc1Il. 1301 .,Iiei,__ 129/

~"""'28f

NaI\felU;lne. 1331. lC2, '42

anlLSO.I05

lldion. 13ol1 Nlodl...... .,. 2631. 271. Zll

SI.O'I'ma
see

fWOAO$YN. Naproxen ~en (ANAI'AOX, NAPAQSYNj. .wtf.400~

tk'ug IntIIlracIIons, 406/.•17 tor lIIig"""e. '1271. 'I2Il lI\OrapElu1ic advanIages aod disadvantages•• ,21

132'

Newole9TIc drugs. speclfIc 127/

-v-n'"

dlIorpIOmazifIe.9Of. 127. 127.12U 1281.129-131. t31I'-I32' doz~. 1271, 128. 12l9, 1281. lJO131.13IH321 ~~ne, 127. r21, 1271-1281, I:JJ. 1311-1321

'0'_'"

<00<

><

... , >

lnde~

halOpllridoI, 84,

503 1~

127. '21.

127~

1291.130-131.131$.1321,242/.242-

'"

l\lIlq)e
3, 130

pood1lDopl!Oazine (COMPAZlNEj. 1271. 129. 1291.242,242.2421.243 prornetlazine (PtENEAGAN), 127$. 1291, 130. 130; 4221 rispe'idoi .... 1271. 1:28, '2e, 128/, 130-

131.1321 1hioricla2lne, 127$.1281. 129. 129, 130.

""

see

NICOAETTE. Nil:oline gun t
'"

...,

'(AOAlAT.PACX:AAOIAXL).

/n.

......

01' .M·. bIocIrers, ~

~«52f,

-vna.

-"" 1or1'Tr....

*..oa~

-

~

111111

3Gf, $Jf, 355, .;l'iS

",....... lIlllf, 1Illl,. 188

_of~521

Heo

see NeOn

173. 1151, 117. 181. 187·11ll1 8C1Iio;Q. 1811 lor 18111 dI\Ig i oleo ectiooII, 1881

127, 121. 127~126f, 1321 N
·.~.~~'.U.liO.r·"~ 1011

"""* lie: itlCIlI*Jo'. 38f. 39 W ....

~.

107( 109

cbcauu'n. 61. 51. 521

melDalrine. 45/'. 51. 521 ~6I.51.521 ~6I.51.52J

pipeo:umuI\ 451; 52J Il;lQ,IIOrUn, 4St, 51. 521

""eM. 1781 e4'leca on _ mLl5CIe. 116, 1761 NiWlIes, dIfas on _ nude. 116,

,,.,

'"

Neui........ '

iIl.to8llllgic _

-~"""""

N

--

n,

Wld~.l1l1

55

., 0IlI"nl..--...,.-... 81-8:2

-_. -"

ill c:NlIiioergc~.3S-37

~_","' •• 31-33

SU'\"O'I'I2OY. 32( 32-33

NeW'IIl~ Hoylldoo'" SH

IIClionI. ~'" in <;arolr Itoerapr. 3B9 39lI "'" . . . ~~

-~~318f

NllAU5fAT.see~

NiIn;luooDi&.10n "". n"'l15. 117 blood 'oa pMiIian as!....""'... 111. 1111 d1aradeIMc:s. \l'" ~112

. .~-;;; .......,~..... , N apio .. 461

~

rwoon, 2071. 2111-21 I. 21,

minimaI_~ 111,

NeIo.

choles1eo'oIle\IeII during, 210/ in~~~.215

rlnJg irleiectior •. 212, 215 rnect>anism of adiDn. 210. 2101 Nic4rdipine. Illl1l. 188, /88

'Ofllngina, 1881 lll'Ug in\eIectioo ... 1881 lor hype~fiOO. 1881

f\Iidos.aIricle. 3591. 362, 362

1\lIIloltwle. 113

111 I d.. apeulic lldwnIages lind ~.1161

uptake c:uMl. 112. 1121

Njalidine (AXIO). 2351. 236, 236-238, "191.«0 NIZOAAl.. See I«lIoOOnIIzCIe ""Xerllit 1I!"""*'r5 290/ ~ .,foc:lio"" troatmer1l, 290. 2901 NQl.VAO€J(.

see Tarnw
Non-cIIIectlola ro. tlJI ~'.~39lI beab,.. 1l, 393

NClfH>MXlIic _ . • "'l~13 NofH>W'ootic 1II"'IgIIIe., speclllc ....... olO11 ~ (TYI..ENOL.). lolO. "OIl, olOISf. 401. "/2, 412-41S, 4:!B

......... ........ '"

"'3/.

.. '2... ,2~13

0Idal ~lINgI. olO3-

NQ I

"". ol39. ololOf

lor " ........ ol:i!8 Wld~C11

see*qhcoio,

_~""';;;"_ ... NlIog¥:eril, (NlAU5fAT). 175/. 175171l, 1l6, 4ol2 1071. lIB .to'......diOl' ro.ee. 2." \IJ;Il;Io;lnrin 39. 42. 45/'. 50. 50. 50,( 51. 00.- W'Id 6.nlIiool 01 adiotI, 1 ~ 111. 19' ~«51.52'.107'.1Q1 _>rid.... 45/'. 52( 53. ~ 5J, 531.

speciIc: lIgOf1IS. 2171 dlIoraIllydrile. 9O( 9Il, !l6 pCltfcydJc: lII'bdep I ISanti, 119/. 11~ 121.1201.1251 In<.ydio:ant.dep.'t ~ "2. 119/. 11~ 121, 120~122( 1251, 13!1

~«11(

Ior~b"""'''.~oca .....''''

NTFlO-OUR.

-.",

iII1IiIIisIIIrrilre. 101. 96. 911, 1071. 108. 221. 2"3, 2"31. 419/. 4:10-425

acIicJolf.l001 bbod OC ,bation. 101/ deveodeo polf!o1Ii8I.l001 wil'do....a1 loom. 101 NicoIio ... gum. niClDline

NlcoW'ic acid.

Nc:lrtWbiIura1e sedaliYeI. 9Il NonbIIotlIIu.... IitdallYft., 8P8CHlc

~

fIorI61!

...,2'

Cl~ .. ~ d r u p .

It,

spedfIc ~ "011 ...... 13. lolO. Ii3( 1911, /96; 201 I, 211, 213. 20&01. 2"t "OIL Cl:J, olO304O&, "OU·405,( «171, "27/.

...... ._";;oac

.'2(

.,.

(Io'OLTAAEH). "OIl, "11 ... " cilUliIIII (DOl 06l0I. olOl I. olO3, «1!. olO6, olOll. .. 12f et;Jdolec (l.Ol)I'E). olOl I. «lSI... 10 \eroamaIeI, "011. .121 1et1Clpideo~ 327. "011. ofOI!I, .~m.,~".

..

"'0,

"12' ....b;poob' UWSAIOI. "OIl. ofQ9. olO&ibuproIen (ADVlL MOTRlN). olOl/. ofOI!l 408-401, 412l"O indomelf>aciot, 244. 2W. olOl I. 4OD, G.

olOlll.412l417 kelelpoob' (OAUOIS). olOl I. 4£I!l, .0&olOI,412/."17 ",e'h(k I' \'11118. olO1/. olO6. olOII Il8lIurootOne (AElAFEN), olOl I, "",

m

.'0. pilOl
sulirdac (CLINOAIL), 401/ 0lI09. "1 0,

"'21

<,.o<'m ..,.,. < ................. , . lnde~

1OImetin, 4011, 411, 4", 412/ NOfIDETTE. See EtNnyl eslradic:t NorepioepIlrioe. 33, 551, 64, 64, 691 adf-.gic neurons and. 55 and adrene
a/'Id anWle nitlOgM, 6' in lIIJI
bi"ldiog. 58, 57/ c:ardiovasaJIar eN"""" 641 as direct-acting agonist 61 ellect on blood pmssuro. 72/ g...ar.ethidine and. 79 indirecl-acti1lJ agr.rists and, 6\ metabolism,57f

_."

release. 58, 571 r£!ml'lYaI, 56. 57f ~'pOoeand,78

sites 01 action, 361 stoolge. 56, 57/ struc!u'e,611 synthesis, 55, 57f Non'!Ihindrone, 2631, 267, 267, 268 Nor1Iol
""""

for urinary tr3CI infections, 3251 Not'Qestrel, 2631, 2fJ1, 267, 268 irnpIanl!l, Id.xe rate, 2681 NOfIMOOYNE. l8beta1ol NOFlOXIN. NorIloxacin

see

see

~.see~lleI

Norteslostemn1l progestios, 267 ~ (PAMElOFl). 119, 119,119/

ltle
NORVASC.5eeA,,'bipilte NQRVIR see Ri!onaw Nyslatin, 3371, 343, 343 Clal eel cMinoma, oj lung, treatmen1. 396 Obesity,474 ~
lffl,atmenl, 122 Oc~eoIide, 2471,

2SO, 2SO

OlIoxadn (FlOXINj, 324, 324, 325--326 Oil of winle
"'"

10 elinWIate I-Ir!jqt>artftr ~ 236 and gaslric acid regulation, 2371 OMNICEF see CeldInif PY"YJ'erra VI1!!Uvs in!ection, rreatment, 356, 360, 3611 OndanseIron, 2421, 243, 243 in
Opiales, lor cough, specific agents, 2171 Opioid agonisl-81'118g.:rist. 1~141 Opioid agonisls actions,l341

""""""""

adverse eIIocIs, 1371 moderate, 140 onset and duration oj aclion. 1391 Opioid antagonists, 133-142, 141-142 actiOns,1341

OVCON.

Oplold antagonistS, spectllc agents, ,~,

lIaIol
'"

pen~OCiOO,

1:33...,341, 14/,141 pr'OpOXyIilene (DAAVON COMP 65. DAAVOCEf-N.lOOj, 133/, 135/, 140. 14(), 14B1. 428 sufenlanil, 133/, 139, 139 Oral admiMlI'a1ion, drug, 2, 31 kinetics,2O,211 OralcootraeCplion dtvg inleractions, 147 laJu", rate, 2681 percenl use, 2681 0
OFlASONE. St1e Pred-oisone Organc ritraleS, for angina, 175-176 speciIic agents, 175/ OrIista~ 475 OATHOClONE 0KT3 see MUfOfmIIllb.

COO ORUOIS. see Kelllprolen

0srn<.U: wetics, 2231, Z33 Cstcoar1hritis of ~, rre.almen~ 409 tmIllmenl, 275. 406, 410-411 Osteogcric sarcoma, 379

senile, troa~ 270 lreatme01l, 3

Ovarian carce<, trealmen1, 382, 392, 395

see EhnyI eslnKiol

O>
300, 3X)

stability 10 penicillinase, 3001 OxaproZin (DAYPAO), 401/. 406, 408-409 Oxawpalll. 91 lor alcdlol wilhdrawal, 91 duration of action, 921 1hefapeutic advantages and disa
for rhinitis, 221 Oxytocin, 2471. 250, 251, 251 Padilaxel, 3731, 391. 391-392, 3921, 3991 PAMELOR. Soo NoItripIyline Pamidronale, 476 Pancmalic cancer, 1realmenl, 362 PancurorOom. 45/ ooser and o:lr.nation or action, 521 pharmacol
PNa..a"oiIlObel"oic acid (PABA), 289 struclure, 2901 Paramethasone, prope8lhe1ic netJfOIIS, 28 Parenteral adminisrralion, 2-3 Patkinsonisrn, secondary, 84 Patkinson's disease etiology, 83-84 lreatment, 810M, 443 Paromomycin, 3451, 348, 348 sites or action. 3481 PalOl<etioo (PAXIL). 119/, 123, 123 \heI'apeVIic a""antages and ~antages, 125/ Palen\ duclus 2I10ri0sus, lroalmenl, 406,

""

PAXIL SeeParoxetine Pectin, 244, 2441 PencydoYir. 367, 367. 457-456 Q-Penicilalrine, 4021, 414, 414 Pencillinases, dtvg lr11elaetions, 300 PerOcillin-bindin proteins, 2S8, 302 Penicilin G, 2961. 300 absorpIion, 302

< ..,

'0''''.'

><

,)

< < - - .........."'.... :... _

... _

.... >

,,,',, adIIe<se reacbor>s. 303 bioavailability,7 metaOOlism, J02

505 Pentazocine, 1331, loll, J41 action. 134/ Penlobalbi1al, 901, 94

01 adlon, 95

stability to acid, i!UJ1

o;luratiQn

substitutes tor, 304

prt'anes1helic, 108

Penicillins, 2621, 291, Z97..:Kl3, 3181, 434-

'"

adminislralion mute, 2 anlipseuclomonal, 3001, 301 attver1ie reactions, 303 anliSlaphylococcal, 300, 3001 (\ilIvsion,281/ dislrt:>vOOn. 302, 3031 drug inleraclions, 315, 417 lor entenx:occal eodocatdiIis. 2841 ClCtended specln,lm, 300, :'001 tof lisleriosis, 2991 lIl\lUrlII, 300, 3001 I9SisIance 10. 30 1-302 salely,262 the
'"

a~n, 298/, 300/, 301. 301, 302 calberidllin, 298f. 3OOf. 301, 301. 301 I, "..." cloxacillin, 2981, 300, .m. 3001 dicloxaciIlin, 2981, 300, 300, 3001 melhicilli
'"'

mezlocillin, 2981, 3001, 301. 301, 302 lIl\fcjMin, 298/, 300, 300, 3001, 303

o'aclIin. 298/. 300, 300, 3001 penicillin G, 7, 2981, 300, 300/. J(I2.;J04 penicillin V (PEN-VEE K, V'EETlDS, BETAPEN VK), 2981, 30l1, 3001, 302 pipe
'"'

ticarl:ilin, 29ll1, 3OOf, 301, 301, 301 I, "..." Pencillin V (PEN-VEE K, VEETlDS, BETAPEN VK). 2981. 300 adrrOnislralion rouIe, 302 stabilily 10 add, 3001 f>ooIcjIjum chlysogenum and penicillin formaliOn, 300 Perrlamidine, 345/, 3531 dr\Jo Interactions, 339, 370 tof leishmaniasis, 35'3 Peotan'Ocine iseII>ionate, 354, 3S4-355

therapeutic

a""amages and

disadvantages, 97f PEN-VEE K. Soo Penk:iIin V PEPCIO. Soo Famotidioo Peptic ulcers. treatment. 235-241, 241, m, 2621, 420 specific agents. 2351-2361 Pcp1O-Bismol. see BismJ1h sUlsalicyiate Peripher.l1 al1efial1hrOlTbosis, lroatmoot,

""

I'eriphe
'"

Pemioc:ioos anema. lroatrnen1, 205 PERSANTINE. see~ Pem mal seizures. Abscnc:e seizures pH, and oo.g llbsOrpIion, 4-5, 61 Phatn"lll
see

dcpoodcnce potential, 100/ oploid reccpIOtS and, 133 Phenelzr,e, 1191, 123, 123 drug interactions, B6 therapeuric a""antages and llisadvarl1ageS, 125/ PHENERGAN. Pl'On1I;llharioe Phenlol'min, 261 1'henol.>aIbon of 3<;IK>n, 95 overdose.2J.24 prirridone and, 148, 148/ ralio of lelhallO efleclive dose. 90' tofseizuros,1451

see

II'"oe
and paJ1
"'"'~"••~Vbelll:amine, 7/.711.71_72,721 PtJen1ermlne,474 Phen1olarnine, 711, 72, 72 tof hypertt!nslon, 124 PtJerrytbutazone, 4011. 410, 410-411 adverse e11ec1s. 411' drug hde.aetiolls, 2011, 2001 ~advanlltgeS and

llisadvaotages,4121 PtJerrytep/lrioo (ENTEX LA), 551, 66, 66,

""

and ildronerglc 'OCElIJlO!S, 58 withaneslhesia,l13 as direcl-acting agoooist, 61 as nor>-<:ak><:hOlarnim. 60 in ophlt\a.lrric the
--

ciagoosis. 72 treatment. 72 Phosphodiesterase irllibitors. 1511 IOf coogesliW heart tailure, 161, 161/ Physostigrrine, 35/, 42, 42 and alroplne, 47 drug IntefaCtions, 51 PhytonaOOne. See Vrtamln K Pilocarpine, 35', 41, 41 actions. 41 I tor glaucoma, 75. 227 strue\J..lm,391 Pindolol, 71/, n, 77,791 as antia
<,.o.,~,

,.,.< ... __ ,>

..

""',,

506

---"'" ~trati(ln

_,

302

10 peooicitio _ . 3001 lheolpUl.llic ............ 3011 ~~aMntagesand

-"" -""

"Pipo ..... ~__ If.",*,* .,.... . . . lIrd ~b""""'218

J'lFu",,,,.. 236( 240 ..-.d IIl'I'Ic aid "'9'1 f ,ZPI ..-.dg oio · ... ptCl&' .. 46 lIrd OIIlCepCliS. 38 Ao......."(FEUlEH€).
""*"'....

8ltvao..,...

~.121

PiUlary dI,........ -..enr. 27'll F'IIuitary hOrllaft. 247_2$4 PI;ogue. "Mo'leill. 315 Plasma lIpop,*",,, ~ 206f PIasmro ploteli . , llird'lg or drugs 10, 11·

n f>lMnvv"m !Jl!t:Unm O1Iec1ian, 349 ~reslstant.351 lmlltmeot, 349, 351-353 ptMmrxli''!l\ lite c:ycIe, 3501 f'!asore1" rn 1l'HllI!ri'9 1nl00000, 3t9

~-'" 349

I'Iasmodju!J ~ 1l1Ioc*oo,. 349 1rOlltmenl,

8fwnolljom

""

mu .ofediCIO, 349. 432,

_'."349.351 PIaIeleI ~ 194-196, '95/ PIaIBIet ,1lS-1915 ......... 4016 PlaleIIlcIl........ 1ll&-1t7

awoeva.....,

P'? IMImlblb"apId1'\L~'931 ~447

.,.... 13, 140.'93( 196, '96. 196, 2(lIf, 211. 2'3, 2«. 244( «l1( «Xl ....... ,404~407(.12( WI, 428. 439 110 ··,-~?'i!l,448

~(PERSNmNE).'93(

196, '96

W

"'.«7

• 10

1931, I " '96

~«7

",fIlIell'odolling. '93,1941 C'
PH

t

F'l.A \/IX _

""

--

f>n9umpcysliI CIIlloi pI'l(UnClfIIa. 294 I rNlmet'il, 2f$.29O, 335, 354-355 ~

\II!lMmel", 3121, 3181

2991

pnIlU, . . . . . al _ , .....

"'*'10::• • r.oD:i. 294/

- - . . . 289-29D, 335, 354-355 tr.." ... 31St, <13 PoiIlli_iij. '-'1 mew, . - ,.... 414 ~801icl1lp .... 1'9( 119-121 .,a:t6....,,(1/~ '201 ••.....,...rIic: 8dlr. ages U'd

..

_n,' --..1Or

~

--'"

2"( 245

POl.YMOX. SeeA",add.,

I'OWoiIaIca",,,,,,,,,,"268

'" ""

~nouron,Z8

~ ho<mOilCl1herllpy, 2601,

PoIassk.rnd\annet blOckers, 1631

PoIassilJm.spMng cIu'cIics, ml, 232_

arel changos In urine ca,.,osi1ion. 2321PrllIiOoxIme,351

and

~_,

"3,"31

Pi.'4>oliClls, «3 PfW«>IN _

RcoaglirjdIl

PRAVACHQL Sl!ePr..-1in

Pi_

T'''' (PRAV.-a«:lL). 'lUll, 2'4, 214415,449

c:MI8c:

_

drug i

..... 2141

213

~ 3i59( 1600362.,

362

drugi . . . . . . . . :m ~ ~ , 711, T.J.l3. 11!O1

IDr 1'IJpei......, 124, 1119 PiedlliloQb.. 393 pl

Pledl

_

2T5I (OEl.TASONE, 0RAS0t£).

3731. 3991. 43lJ.43i

IDr asIflma, 219 in canaw 1fIetapy. 393, 393 in eta hOcr.eo..."., 276 drug 33of( 3fP

.'D........

"OjAi_,VS/ F'fugangIonic nouron. Z8

-""

" ••m'.~ . ...'" '~"""''',.e.~ 122 PREVEON _ AdekJr,ow PAl OSEe SeeOmepazolll 345f, 3f9. 3Q 3SO, 3501;

~

..,.."

edwnellllllo*. 350, 3511 P,iliidD.... 143t, 148, '48 m(ht. ,,1481

b ....... l-s1 PAINClPEN. s.eAo,c:CA'

"""""'-

-.-

PtUbe..ecid. 4Cl2( 411, 4 '7 drug II.........., 2EO( 303. 408f

Po$lerior ~ hOi"a...... 2471, ~

'" ""I'llIIdMllianor

'" ~ Ioloi'ley IIn::tilln P'lli'''''......

5

liddecel :f:'?,e,

~dl!ylllo.gIyaIl.

PREMARIN, see ESlrllgelB Premallnbll1hf. d r u g ~ ,

--~~,.--~-"". , lrealmll1ll, 78

1Dr~,415

F'n:lbucoI, rolf. 2'3, 213-214 mec:harliIm of a;IOn. 213, 2131 ~. 1631, ,68, 168 for~,

171,1721

eIIectI, 1671 Pn:>cllIne, 10111 ph'rrnacoIo'Jnclk: properties, 1171 S\IUCIUIe,I17/ PI'(lCiIIoo panicilIin 0, ado'rinlstra1illn rouIll,

""

~,3731,

3!/i6, 396-397, 3991

"."..... "",,"q-*>llIX*Jr'llial, :J76f PAOCAROlA XL S8e ~ III p,w"'peoazr.e (COMPAZINE). 127(, 242, 242. 2421 881iei,IllMcellecls, 129'

In CIlITtIin8Iiort ~. 243

1Dr_,29

a .. ~

Pi";

_-

........ c:ydIl8flCl,

Po.;;

",

.....

'""""'*'

2IS6. 2f)71

26lI

Po< 9 ,. .. 2156-251. 26a

'" cgill ... ..,.ell'Ic sogent&, 263f I'Ijd....

JPI".

'-'"no

Cll ... 263t;267,a37 ...... 3, 268, 2fS1

niDdiDii~Cll'" (PAClVERA).

263l, 267, 261 ,odlliiiCtoCll" 2631, 267. 267, 258 nllIge<eI. 2631. 267, 267,268,2581 PAOGRAFT _ T80llIrruI

-",

~ hclnnone. aQllns, 2481 ~ hoi"QlCI, ac:lions, 2461 Plahc~
''''

jPHENEAGAN), lVI. 130,

< ..,

'0''''.'

><

,)

,"".

'0'

actioos, 128/

antiemcfic ctlocts, 1291 ltIerapeutic advanJages and llisadvamaoos, 4221 Propa!enone, 1631, 110, rTO lor arrhylt'orrias, 171, 1721 effects, 110/ P~fac1ic antibiotics. 286. 2861 P1~"acid

oo.Mltr.tes. 406-409 lher2pOUtic advantages and

disadvamaoes, 412/ Prq>oId, 108/, 117, III therapeutic adIIanlages and disadVantages,1161 Propo>'abu5e liabilify,

"'"

lor migraine, 428 Proprardol (INDERAL), 71/,14,74-76, 79/, 1631, 1751, 1791, 436-437 ac\ionS, 75/ actvf!l'Se eflCC'lS, 76/ lor angina, 176 as antiarrhythmic, 1641, 171 diroiCal applications, 78/ drug Inlcractioos, 334/ elimination,74/ wiIh hyd'ala>:ine, 190 lor hypertension, 165 mclaboism, 7 lor migraine, 4V1, 428 PlOJ)YlltIiou18ci1, 24n 253, 253-254, 436 Pro5IagIanoprost, 4 '9, 419, 4191-420. dinopros~ 419, 419, 4191-4201 dinoptostone, 4.9, 4t9, 419,1.420/

_.

~,235/,

237/, 238. 238-239,

287,267,300,407,419,419/,420,

420,4201

~

metaslatic, treatmenl, 394 trealmefll. 272, 394 effect on endocrioo system, 395/

.,teclions,281 treatment, 2941, 321H Prostatic hyperplasia, berign, treatment. 73,272 PlO5latitis, Prostate, ;,;!eclions PfQIarrWIe S
see

""""

mfeclion (iodi6e positive), lreatment, 3011,315/ resistance, 328

Weus ni@bjIjs;,;!octiorI, 327 treatmenl 2941, 301/, 304. 3251 Proton pump Irhbilors, lor peptic Ike< disease. 235/, 239

Prolon pump Inhlbltors, spedflc agents Iansoprazole, 235/, 239, ZJ9 oroopmzole (PRllOSEC). 2351, 236, m/, 239. 239, 440 ProlriptyIine, 119. rrg,l19/ lhetapeuti<; lIIlvanlageS and disadvantages, 125/ PRQVENTlL AIluterol PRQVERA. Madl'O>(yJ)rOQeSterooo PROZAc. Auoxelioo PrurilJJs, treatmenl, 130,212 E'Wor!omoMs aerugirpsa Infoclion, 430-

see

see see

Purkinje fiber, action poIenlial. 152/ PyeIonepMtis, acute, treatment, 328/ Pyranlel pamo.a1e. 359, 359/, 359-360,

'""

Pyrazina
Pyridosligmine. 35/, 42, 42 PyriOO>6ne, drug interadions, 86/ Pyrilamine, ltIerapeutic advantages and disa""antages, 4221 PyrimeIharnioo, 2891. 290, 290, 345/, 350/,

'"

as folale reduaase Inhib~or. 293 formala1ia,352·353 for IOl
du.ation of action, 92/ fhefapeu1ic a""antages and disadvantages. 97/ withdrawal fCaclions, 931 OUESTRAN. SooCholesty
""

elfocrs. 167/ treatment. 301, 301/, 304, 305/, 307, Ouioidioo suMle. 168 3151,324,325/ Quinioo, 345/, 3501. 352, 352 P second messenger PsyUium soods, 2441, 245 molocules, 34 PTV. PropytIhiooracil AELAFEN. seeNabume!One P1.*TlooaIy edema. acute, treatmenl, 22ll AEMICJ\N see lrtlb!
'"

'"

see

see

,,,-

<

,.0<

'0< ..,., • < ...... .....-....

, •

and hypel'll!rlOOn, 1112~ 183/

,...,," RrTUXAN

see Rituximab

Renal eon'inalion, 23-24, 24/

Ritu:>:imab.466

Renal taiure, acute, !realme"', 233 f\enirl.angioteflsisr1-lCfOne System, and blood pressure, ll!O- I81, 181/

Rive< b&lId"ess, treatment, 360, 361 { Aod
REOPRO see Abciximatl

Ro<.:urorium, 451

FlepagIioide,452 REQUIP 500 Rcpit"'ol9 RE$CflIPTOR see O<.Jl;Mltline

ResJ1pl"e, 7tf, 78, 78 2nd norepineprwine SlOrage, 56 Respiratory ..,lections, 294/ lower, treatment 324 treatmeflt, 300, 325/ spedfic agents. 363/ viral, treatment, 363-365 Respil'atofY syncytial virus, treatmeflt, 365 Respifatoty syslem, drugs alfeeling, 217-

= spaciIic agents, 2171

RESTORIL SooTemazepam REZUUN see TrogIi\anlne Rheumatic fovef, treatment, 406

Rheumaloid ar1hritis acute, !realmCnI, 410 intractable, treatment, 389 treatment. 351, 406. 408, 41().4 I 1. 415-

."

FI>oomatoid ;"lIammations, lreatmenl, 275 Rhinitis causes. 220, 2211 drug troatmenl, specific agents, 2171 treatment. 220-221 RhytIYn method, 01 conIr'aCePtion, failUre mle.268{ Riba~, 3631, 364. 364-365, 458 Ritabutifl, 333 lor Kaposi's sarooma, 429 Ritampin, 331. 331f, 333. 333-334, 437 classification, '2871 drug inleractior1s, WI /, 334. 340-34 t IOf "led idlIin-rosistant Sla!llJlllorJx:m, ~...,

resistance to, 285. 285{ and thyroid hOrn'lOM metabolism, 253

lew tubercuk:lsis. 2841 Rimantadine. 363, 3631, 383-364, 456 Risecnlnate, 467 Rispericlale, 1271, 1'28. 128, 130-131,

_.

""

actions,1281

RITALIN HYDROCHLORIDE. S6e RitoOioo, 55/. 691

RiII'lonaW, 371, 371, 459

312/ onsel 2nd

durar;on ola.cOOn, 521

plIatmaC:>Okmti,51 ~ advantages, 52/ RoloolI
ROGAINE. Soo Mil1O>
Rosio!ililZQOO, 453 RouncII'lOrm Infection, treatment, 359,

""

RU 486. S6eMilepristone SalK:ytales, 403-408 do5e-
disacIvarltagcs,412/

5a1icy1aro salls, ~ advanlages and disadviWl!ageS. 412/ $afl<)'lic acid, 406 Saimeterol xinatoate IOf asthma, 2111, 2/8 and bmnchodilalion. 67/ SalI'l!lI ,ena i"ltedion

fIOI>-lyphold. treatment, 2941 treatment, 289, 291 Sl!!rnm!l!!a Mlbi i"llection, treatmerl~ 2941

SANDIMMUNE see Cydosporine Saqu;navir, 371, 371. 459 SilI'OOII\lI, Soo.alsO Kaposrs sarcoma

5econd messenger systems, 33-34

,.-

absenoe, 144, 144~145/ treatment, 149 classilication, 1441. 144-145 <XlfI1lIex partial, 144, 144~1451 treatment 146-147. 150 tooriIe, 144, 144~145/ treatment. 146 oenern.&zed, 1441, 144-145, f45/ grand mal. Soo $eIZureS, 1al0X:l0nic myoc:Iooi<;, 144, 1441-1451 tteatmenl. 149 partial, 144, 144~1451 treatment, 146-150 petit mal. $ee$eizufes. absence ~ partial, 144, 144... ,45' treatment, 14&-148, 150 lOOlc-o::IoAc, 144, 1441-1451, 146 treatment, 91. 146-f5O treatmeflt, 90-91, 95 SElDANE, see TerIt!oal.tne 5eIective cstn'lglll1 ,ecepIOt rrodlJa\orS,

."

seklgiIine, 811

se.rilente Nu~n, 2551 C1
senna. 244, 244/ SERM,454 Sell I!OOeIi~, 247/. 249, 249 5eroIor*> anlagooists, antiemetic poI00cy,

,."

5et0l00'" ~I<e iohibilcn, 119/, 122-

'"

Ewing's soft lissue, 390

rer:epror specfficify, 121 /

osteogenic, 379 soli tissue, treatment, 384 treatment, 386

Ihcrapeutic 3d'VanlageS and

Schi...... '~ blood. lor maIatiso, 351-.353 tissue. to< malaria, 349-350 SChIzophrenia,127 rates 04 >dapse, 1311 lreatmen~ 129, 131 S<:opolan'W'Ie, 451, 48, 48. 48'"491, 438 antiemeli:: ottocIs, IW/ to< motion sickness, 130, 242 and musc:artoic receplOf, 461 preanesthetic, 108 Sooobarbilal, 901, 94 duration 04 action, 95 lhe
disadvantages, 1251 Strratia 0\fIU"'P5('ll'l irltecllcn, treatmenl, 304,315/,325/ SCtlraline (ZOLOfT). 1191. 123, 123 Iherapeutic lldvaol3ges and disad'Vantages.. 1251 serum lipopotein, 207, 206/ Ilia! Iowc< COl """"ualil)n, 21ll-215 sevofturaoe, 107/. 115, r r5 SllIgefIa it>klctiorI (stOgeIosls), treatment. 291.2941,325/

rn.os

SOOd< blood I'Iow with, 5-fl treatment, 54·6f!. £9 Sibvtramir'le,474 Sickle cell di!;ea~e (anemia) speclfic agent 100', 193/

treatment 206

< "'"

,.....,., ....................

...........--."...,...,..,

I )

,,,",,

~,451,

53, 53, 53/. 1071 IIdYefse elftlda, 53

SiklenaN.476 SMlr 1UIf~. 289/

...

Sirrw8Nlin lZOCXlAl. 'i?a1( 214. 214-215,

*.

e 5tet " '8" i"I"ctcr~

sxtrtxvn·l'D"""tn"ia§ illeaU ..

..-..es CI'L, 176,

""

"-.cMct.l$1 SodiI.o'n ~boi_. 2361, 240 Sodium
Sodium ~Ie, 406 Sodi.m r1tlogll!OOl'lllkl. 345/•

a:Ill.oi$tJllliu,1O!M. 30Z ~i"_,,3OO

S'eIllicl • """",,' , in c;:IfII;8' hlrapIJ, ",.,..

$O!I ~ /l8tOOI'I'IllS. 1ftlatment, 364 Solid IUlT"lOt$. Ir(lalmefII, 388 Somatlc 00lWUII System. 21/. 31, 32/

$le«Iid I ... " ...... 263-278,
c:l"d">Olglo; agoniits In. 36/ Somal
SIA~.

!TltlCharOsm 01 action. 294 Ie>" urinary traeJ inhlction. 31 51

SJ(mtoqvpm ~ inIeclion, tmatmenl. 2991 SVm'n
SUfanlillrnkle. <'89. 289 mechanism 01 action. 292/

lfOlllmenl. 299/ Stn:lpkll
"'"

.liIlOjjOli" 202/

200/

&1"'*'''......:.•;~,IiI._ ...X'...·......M Inlrn, 314 S'lE\O*lOIlfCln. 311 ~ 314, 31., 331 .11Ilecaerial1(llldlUm, 315 • • .......,aic~3151 S'I~.. ' " poaerai;Il, 2411 Sli~ .. 373f

...._-

lorgoo... ,lw. 299' SpeiillCicl&

268I

5Pood

2831" SpiIonoI8dore. 11'9t, 183, U:I3, 2Zll. 232277

lor...,..... n 0l • • ~274 . . 01 Kiion. 2241

Sp:lroo IlOdde, blood. 3!;3

Squ.nouI otI c.dt...,,. 01 he«l ..-.cI red<, tte3tmerl, 3!lZ _,IOOIl,3K1 SCaolfJZdOl. 263f, 271, 211 ~ III1Gcti<> <s. rreatmenI, 3011 &lI]!IlIOlteaioo •• 435

i1lClh1d11lWllSirtant, 299. 300. 3001. 3011.

drug i .... lldiOF.. 40IlI

ifc WI d'\.g ~ -. 147. 1.71. 28JI eI'Itld: on ,1eOl 282 a'lCllDllle ~ 290 ...... ' 0 . . 291

-CI!l*

"'-'"

2

s........... po:MnUltar. loot

ma::haniIitn 01 . . . . Z9Z/

,

S."'ilh4ed~

.,1ieo,0llIic: poltlnCy. 243/ t o r ~""'-"iiBa lind

vllrrOllng. 2421 SWslilulOd~.

~m,291 ~.402~411,.,7

.........

· i*doil ( """., 1.3611 ...., 3eO, 3lI1t Sl.tIl:l.CaneoI (SC) ulliI""ariOl .. 3 ~u"i"alb ..

metabolism. 291

1or~415

--" $IAS

in Inl\lIrro'rIIIo bllwti dlliease. 291

SllIli!olwole. 2ll9I. 292. 292 • •......,.,.0: aw'"1Iion. 290 lor ~ net WetJiuo-. 3ZllI

.....-._.n.""_,.. .". " 1te

""-

SlAasaIazWle, 289/, 29' adr.lilIisl181lOl .. 291

poqlel_ 2021

SpecIIOI.,.:;n. 311 1

"'.233 liwid o'li;lib. .u

anlifTicrobllll acIMry rale. 2931 drug irlCiaclioil'. 293

pneurnorjae ImecIion,

~ollCllan,202.

289. 269. 289/. 290.

SH,,(;o.~

1r1lItment, 294'. 299/

ec:ti'I~1lI1 or c'

........-c........IiQo~ 290

•• .....,.c~290

spodflc >lfQ" 263~2&41 0' "

1.300/

~.2891

s.C.¢ IKlo18. lor mlIIariII. 35Z

S\Qol~243

SbM

s&IIbIIiIyllClpa.....

s............. 289/, 2llll. 290. 292

mechInIIm cI Kiion. 393/

.m 356-357

289( 291

d'\.g~""" .. 341

tabe".2ll8/

eIleo;:ts cI ..... ..-.cI

.~,

SuIe
S' iI:ulIiOl ~ _ • • ej: ' ..

SlOW-+<. see I'I::upUn

1heo~~521

Suttiol/t

s..cr- (CARAFATE). 236l, 241, 24 1

"al.1l, Ill. 95. I.-&. 149 SUM.dne (cM1). 363( 369( 3'7'll, 3JD & \ . " " 17/,11-1" 181-19/

geep ....d.... ~_' ..... 91 SlO-flI). see 'TheoVtJ. e

adicn. 52f

ul . . . . . . . . 291

Sllllllll. . . . . •• 1"~ 145, 1451

Sl
...----

•

'"

SINaET. 5eeCldlldopa SINGUl.AIR _ _

-"" ----"'" --"'"

S!allt•• h

~JiAlk"""'290

~.

~.Il!'" lI l, 109 0fIIeI ..-.cI CUIIDn 01 i

tar~291

~

- .. _.....

tar

-~ ~,242

..

• I 10810, 285/

Sul/onan'lidn, ...-1Ile ~ matenide. 289/. 290

malenide 1ClltaIe, 291 silYtlo" ....8lkzlntI. 289/. 290-291 sua:lnyI$uIIathia>:cle. 2891, 291. 291

suHacetamkle. 289/. ZOO

<,..,. ,....,.,.< ..... _ , .

« ...

M . . . . . .. . . . . . . . . . , . . ' _ ... _ · ... •

s>O llMacIa2Irle. 290 ...."ell ,.a.... 289. 289. 2ll9l. 290. 293, 2931. 294. 31S1. SNaI:!IoCo-

·.M.lrimm'a'" .'.. . .

................,

2lI9t, 291. 291

"Meoq!lQIe,

2tl9I, 2SO, m, 292, 'JZ8I

T~{SEI..DN£)

tor.,.....

dlsadvafllagCS. (I2f SumlIlriplan (IMrTAEX). (I9f. 426. 426421, (37 lOr f'I'I9aine. 4271

221 IOiltOaWn Imm nwl
metastatic. 1l'e81rJlOO\, 395 rel
'

T.......... IOI11 pllalmaooNilelif;:pu"ef'" 1171 TlIiac:rJiii8 tSlNYCl't). 23$( 2113. 2831. 311 L 345-348 dMI" ........ 287/

lIQAll. a_'61t, 164/

- - - . 6 6 , 781.164L In·l73

see

SlJI'RAX. c:eilciI'N &nrr*I. 3451. 353/. ~. 356 SUSTlVAseeElaWenz

~.282

Syrrpa:theIic fII!MlUS S)'Slom. 271. 291. 2930.301

oost, 262. 2821 drug IO'lre
10 (lllminale Hf'i"
anclbloodpmswre. \80.181/ ~ 1le\6Of'I!I. 28 SYNTHAOlO. See~ SyphilII. 1re.,e"l. 2991. 3181 T~473

---

seeCirr.-.s"

T.,ooiIei, (Na..VADEX). 263( 266, 266;

ItlMlr'pIign. 313, 313/ ..,... ellects.31(1

....... 2991

~1lIO""'-:

.., . . . . . 290. 3121

tor Iftwy traeI i*'<:lio: .. 3261 TwaeyclI..... 3111 lleonec:toc:ydi. 31 I f. 31(. 3 14 llo>cycydina (VIBAAMVClN). 147. 311~ 3121, 313. 313, 314. 32111 mi~ (MINOCIN). 3111. 313. 313.

..-.Iic.....

TASMN\_T~"

seeClemaslirle

TIJlOI, 3731 T&lObac:Iam. 2981. 307. 301 ~lratioo roo1e. 3Cl2 drug inIaactio: •• 301

Slllbilitt 10 peooicillit_. 3001 3TG. see l..VrM.dine

~ (SUMYCIN). 1601.213.

235/. 236. 2.a. 282. 262L 283, 2831; 2851.21171.311 I. 31(. 34&346. 3461 T....';:...........'" (THC). 99t 1os.

TEGAETOLSee~ T~(RESTOAll).9f

lUaIIio:'I (II ...... SQI II)' Mllp dsoolleoa. SQ

tor~

_ _ ""

- * v , 243

~,-""ard

clIsalMInIages. 971

foTG.

see6-~

n - ,••. 99, 99'

.... Oa_.twJioi.. 931 Tel. . . . . 396.:B6 TENOAMIN. see A\ooQIoI 425f

~eep."'...... 7 ~nlft. 22L 22-23 ~.35!lf.3ID,36O,

361'

~.I081.IIS

eIIecls. 2301. 230-231

..

ac:liom. 183/ and changes .., lft1e OOf'lllOSiIIOn, 2291.

""

drugio'Ief........ 160, 160( 213, 292

.01 acIio:I, 2241

,-

•.......

Ihefap
n ....."icl. . 253-254

.

,,.,

6- ~ 373L 3IlO. 3ll2. 3&>. 3991 ae::tico'-.3741 1hqlenl/Il.!lOL 94. 1081. 109 as aneslhelic. 95. 115-118 disTribuTion. 9 dn.og k1\e1'ac:1io<1!1, 4Oll1

o"lllaoo ~ aetloo. 95

red.lrt>u\iOn, 115, 1151 It.e.~~and ~97Llltlf

n-idazitle. 121/. 129. 129.132/ ~1281

.. '*J'doeogk:adioCy.13O n ...... oe. 127, 127. 121( 132/

erIIId an d iIcIIell, 282

lOrE

h CllI'lCllII' 1Ie!apr'. 393, .,.,.. T. . . .oo'" ioMdion. lnlll'.1t, 362

ob!IlrUdi¥lI""'' ' .,

'iseare 222 drug illllfac:lio.. 31g..32l), 32&. 3QS

~

T.'11 o"CJpioo_. 2&3L 211. 211

~ad.,....(ia

tor dwtric

tor angina. 183--184

.,,:1'

_'61t, 185 1_'1lI01t, 187. 11161

Iofashna, 100.217/

ThiazId8 dUeli<:$, 157. 223/. 228-231

prrO ........... ml __ dia .. fIlglAIiI;ln. 2101 stW ' .. 340

~laC:h1arrhyf'oTM co.....,........... hpielllli.al,

Torelon~. chaolldOois1ic:s.

214, 320.341

TeslOlIleoone. 269, 269-211

SlJMVCIN. See Telac:,...I"lI

TAVlST.

711. 73,l3, 1I1l1 II)' 1Wel""'..... 1, 189 T8ll;o' foe.56L67,67.691 10:' ......... flH;3, 218 atlCl bodoodil;llil;ln. 67/ drug~_""'...

drug il.-eoaJic:w... 26Ot. 292. 334f s.AIrdIo:: (WNORIl). ~1 I. 409. 410 ~ a
TAGHET.

T ~ (H'l"l'R1N).

nE().Ol.JR. See TheqltlW. e Tl1eop/1.... (Sl().lllO, nE'" "' .... !l9 991,220 """"..,. .

-""

n ...... l6iil15, 121/ ThfeMlwo:m iliecliol, - . . . . . . 360. 0;" Thollbl, iliblo: •. "8 ll'oOrrt>OIy'jc agerItS, 201·204 advclrsl! el\eCls, 202. 203/ oomoarison. 2021

..--.""

"llfldlic: egents. 193/ ~.194

""..... """'' ' ",'\1.

247/

1lIytuid hoolllOOoet., 2S1·2S( ~2S2f

~ 1100"'0'''' 252-253 'fhtrold IiIDmI. I Eali, I6It, 2S4

Thyi .eO colis,

~, . . .

Thyi CIII opOl, 252-253

781. 253-254

_ ,.....'.,... ~IO, 252-253

<e - • .....-....

<-""'-""<---"

'"

acMlfse ettects, 316 ooncentrahQn,3161 !tug Inleractions, 51 tIle
.....

'"

''''''" actions, 2411' Thyroxintl, 247f. 251 DiosynUlesis,2521 IlNg inleraCtioos, 4081 T"'lJ',lbhl,445 Tocartillin, 2981, 301. 3)1 administration route, 302 ~ reaclions. 300 stabiity 10 acid, 3001 10 penicillinase, 300' Iherapeulic applications, 301' Tdopidine, 1931. 196, 196 "TimolOl rnMOPTOL, TlMoPTlC). 7\ I, 76, l6. 7!ll, 17!ll Clinical applications, 781 r:lro!IllIirrination,74' TlMOPTlC. See TlmoIoI TIMoPTOL SeeTtmOlol To:ofibBn,447 Tl!\Sl.I&typIl plasminogen aetiVlltOt (tPA). SooAlleplaoo ToDramycin crOElflEX), 3111, 315, 315,

.".........., .. _

biosynlhesis, 2521 Tranexamic add, 193', 204, 204 Transde<mal p;lll;1l, niwline concenlration, drug interactions, 4OB' 1011 TRI-LEVUN. S
'"

""

TrimelhOprim-sunmethOllaZole, lOr lrilary tracl in1ections, 3281 Trimipramirll!, 119' lhe
T~,

niacin lOt, 210 Tnarncinolorle (AZMACORT), 276, 276 adrniI1is1ration roote. 2761 lOt asthma. 219 elinination, 2761

'"

'" ""

" ...

(,,0(

'0' _""( ", _ _ ,

...

>

, ,

512 INrmacrJI
IiJOWlll rare. 314

-""

lI'ealmefll-inll.loed, 378 T..... Sl!eC8ldumo:artlOtlillle TYlENOL. See .... uamO qlhefl

Typel ct;al lies..

see~"

el·" •.

~...,..~

Type R,W II. . SeeO.h'.......la, ~

Tyra....... ~. 61, E8 as Rhc:l«Ing agonisI, 61 T~ .. ,. . . . oep.~.. ..,.... ;. 56 i'l5Uin.2S5( 2S9 e
la_'''' 1

lIlM

t

.,..

"""""?m il-.::aa~

" ,.... 31& 328f Uf!lInlIylOol, - . ••&l~•• ~.~.,"" UrUtriiI, . _ , 318

lkic IIICid. .. gQI.C. .. 15. .. 151 l.tIo::ofuic . . . . "11 Urilwynaris", J:no13Q.32742S1 I.Ir"-YIrIiCt " ' I pic I, ~Ik

-""

nll!ll .. -*'oe.

292. 327, Wt 327-321

~(WlCAOONmH.

""

"""""- " . Urir"oety ncI olloldiol-. 2901

. _ ,..... 290lt 31s.t 324. 328f

U1....... qlio~ 2511 lIIoknaie. 1931. 201. 2ll3,. 203. 204/ adi ,. ,at,' 'ioJOjjiii4202/ "'...,...... 202/ UI'Icaria, ' _ '.. ll 424

lMliIis. ' _ l l 409 Vagnal illlediols. IrNIr'l1oHlI. 29ol1 V~.458

see

VAl.IUM. OiazllJllllll V~ ae:;,;l (OEPAI
148-149 ~eflec1s. 149/

drugWoll~ 150

loneizures, 1451 VANCENASE. See:Bedo.nelhuone VAN(;ERIL See 6eclomelhasone Vanc:crJll'Cin. 2981. :D1. 308-309, 429: 431,434-435 d9ssillcation.281/ lor methic:ilin...esi$lano: $lallh J1CIc«rI 1$

...... "'"

~

pll1flnlial, 31BI

lflSislanC:8 10. 284, 285/ Varicela-105Ief virus, treatment. 361

VO'IOrEIItine.390.390 V1RACEPT see NeIIlnavir

VascU« lrauma. noomal Ill5JlOll58 10. 193-194 Vasodilatn.1S5-151 Illr hyper\en$iOn, 1go, 191 VMOClI..._ apeclllc egenb, 1511 V-.op um. 2471. 250. 251. 251 VASOTEC. See Enalapril V~ 451. \011 will r Fs:M';", 109 onseI and lUalion at aaion, 52/

V"~allnr""'liul$. ~

~51

412 VIRAMlJNE see NeYioapine

VlSCt!l3lleistwnaniasis, 366 VlSTlDE &ell CltIoIOW ViIarTWl B", SH 81!10 0,.... , ..

"r.

* riI,

de4\citO 1l5 ...... 10 IoItlM dl!1icierlcy.2O!i VIIiHTWl K, 1!Jl', 204 lar I I Iir IQ, 2C
VOLTAAEN. See~

1I.apeuic: -mnlages, 521 VEE'TDS. SeePw....'V

Vcoriling. see aIIioEmesiIi

v~

na',.ll. 129-130 Wa
119.1; 123, 123 ~ Idoa'llageS ard ~125'

V _ "o'*,,*'bJii;m., , ••, . 198

Venoo.e 1h0ll"t:tll5ili., '''''.ll. 198

V£HTOUN. SNAIluErCII

VenIriaAer~ •••••,m'."'1l US-

......'" _",

"w.....'......... 241-242

1"

dnJg io"'~" U. . 196, 201( 2132'39. 295. 320, 326, 334( 341. 411

"ed • ..." at edion. 200. 2(JOI 're~

rda. 22t. 22.zJ

1J'0.112 V-*IcuIa< . . . . . .4 uat~ll. 16ft 112 v.-.tcU8r aJtyantrrh,,"--' 168, 110. 112

Whip..... '" iolltiC1ioi4 '12' ,Ifi't, 359. 3611 \Wm's t..o!IOI. 3llO

"

w.uao.. meh:Id, 0100"· 8j>1iIo,

-

_

164/

treelnWll, 160ft 111-112 Vfi'4*'. (ISOPTIN. VEREI..AN). 163.( 161,173, 17.1 17S(ln. In, 180( 181, 181

actors. 181' eo...8Illlca. 1119 lar~ 1881 1l5.~16"

drugio ...8dO-. 1Sl( Ul!I.377

-"" "'"

lar tTypeoWliliiio4 18l1t lar supr;ll,."Cdar~

VEAEI..N,I, S- V...aparM VlN3RA &ell SitIenaN V1I'lRAMVClN. SH DoIc)qdio1e ~ cf!lMrae olllldioi4 treaImeI't, 3121. 315' Vodarallroe (lII'h'). 3631, 361. 3tm. 367-

'"

Vlgabalrio'l. 446 VIl'CIlISlhe. 313'. 390. 390-391, 3991

doug mler8Ctions, 3ll6. 395 ~ poImlial,:l78f VrcrisIlroe. :l73'. 390. 390-391, 399' doug inleraction$. 384, 391 emetic poIo;ntiaJ. 24"

........ 3&C.3g9/

Iailunl raII!, 2&lf

pelcenl UIil!. 2ll6f

""""S-_

Wu::tajab*gdll,361'

WYMOX. SNAI,.......' XEloo.o. see Ceire jpl- ..

Yaws. ..-.. 299'

-""

Ye!VillXHiio*'<:1io4 ...... ll. 31S'

3m,. 3Jtl, 311l

zakW"bine (OdC). 363( ZNlTIIC. SNRuIillOr.

.. -.""

ZESTRlL SH I..Isirqlot ZlAGEN see Al;Iu;aW Zio:towdFolI (AZT). 363/. 36& 368 36lI,

,

drug ~ 3:5. 361

Zin: ins
lCXX>Fl. See $irrNflSIll~n ZOllingef-Ellisoo synd'ome. "NIm&lI,

m.,.,

ZOLOFT, SH SllfIraiine ~ (AMBlEN). 93. 93 lherape".;c lidYlVltBgOlllIll1d disaclv8nlages. 911

ZOVIRAX, $tHl AeydoYI, lYRO see ZiIeuto'1

'''''0'_'''',

,)

, e-o • _ _ "(M

,

... '

M>'I;Al\.O . . _

.... )

'" Figure Sources Figure 2.5 modified from H. P. Range and M. M. Dale. Pharmacology, Churchill LMngstooe (1987). Figures 6.9, 6.10 and 6.11 modified from A1lwood. CObbold and Ginsburg. British Medical BuUetin 19:132 (1963). Figure 8.10, modified from R. Young, American Family Physician, 59:2155 (1999) Figure 9.5 modified from A. Kales, EKoertpa Medical Congress Series 899:149 (1989). Figure 9.6 from data 01 E. C. Dimilrion. A. J. Parashos. J. S. Gioozepas, Drug Irrvesl. 4:3\6 (1992). Figure 10.4 modified from N. L Benowitz, Science 319:1318 (1988). Figure 16.6 data from Resuhs oIltle Cooperative North Scandinavian Enalapril Survival Study, N. Engl. J. Mecl. 316:60(1988). Figure 17.3 modified from J. A. Bevet1 and J. H. Thompson, Essentials of Pharmaoology. Harper and Row (1983). Figure 17.11 rl'lOdlf~ from J. W. Mason. N. Engl. J. Mell., 329:452 (1993). Figure 19.5 modified from B. J. Mawson, Drug Therapy, NO\'ember p. 157 (1985). Figure 20.14, modified Irom D. J. Schneider. P. B. Tracy. and B. E. Sobel, Hospital Practice. May 15. (1998), P. 107 Figure 20.15. dala from D.A. Vorchheimer. J. J. Badimon. and V. Fusler. Journal American Medical Associalion 281; 1407 (1999) Figure 21.12, modlfied from Knopp. R. H .• N. Engl. J. Med. 34t :498 (1999) Figure 22.7, modified lrom J. M. Drazen, E. Israel, and P. M. O'Bryne, N. Eng!. J. Mad,. 340: 197 (1999). FIgure 22. 8. modilied lrom Ora~n, J. M., Israel, E,. and O'Byrne, P. M .• N. Engl. J. Med .. 340:197 (1999) Figures 21,4 and 21.10 modified from R. H. Knopp, Hospital PraClIce 23:22 (1988). FlQUre 24.2 roodified from D. Caw. HOspital Practice, Sept 30,1992. Figure 24.4 rTlO(l;f~ from S. M. Grunberg and P. J. Heskelh, N. Engl. J. Mell. 329: 1790 (1993). Figures 24.6. 24.7 from data or S. Bilgrami and B. G. Fallon, Postgraduate Medicine, 94:55 (1993). Figures 25.2 and 26.6 modified from B. G. Katzung, Basic and Clinical Pharmacology, Appleton and Lange (1987). Figure 26.4 modified from M. C. Riddle. Postgraduate Med. 92:89 (1992). Figure 26.7 modif~ lrom O. B Crofford, Ann. Rev. Medicine 46:267 (1995). Figure 26.10, from F. Holleman and J. B. L. Hoekstra, N. Engl. J. Med. 337:179 (1997) Figure 26.11 mod~ied from A. E. Kitabchi and M. Bryer·Asl1, Hospital Practice, March 15. 1997. p. 135. Figures V.6 and 27.7 modified from D. R. MisheU. Jr.., N. Eng!. J. Mecl. 320:777 (1989). Figure 27.8 IlXldJ'fied from M. PolanecZky. G, S, Slap, C.F. For1<e. A. R. Rappaport, and S. Sondheimer. N. Engl. J. Med 331 :1201 (1994). Figure 27.15 modijied from CtJmmings, S. R.. et ai, J.A.M.A 281 :2189 (1999) Figure 31.6 modilied from J. Inter. Med Res 2:100 (1974) Figure 32.2 from data or S_ Public HeaRh service.

u.

Figure 33.3 modiHed from data of D. A. Evans, K. A. Maley and V. A. McRusid<, British Medical JoumaI2:485

(1960). Figure 35.3 from W. Peten; and H. A. Folmer, Malaria. RC¥ll Tropicallnstilute. Figure 35.8 from G. Mandel. J. Bennelt R. Dolin. Principles and Practioes or Infeclious Diseases, Churd1ill Livingstone (1995). Figure 36.3 from M. Weber. N. Engl. J. Med., 328:927 (1993) . Figure 36.5 from R. Bratton. R. E. Nessa. Postgraduate MedK:ine. 93: In (1993). Figure 37.2 modified from R. Odin, Science 227:1296 (1985). FlQUre 37.10 modified from Balfour, H. H.. N. Engl. J. Med, 340:1255 (1999) FlQUre 37.13 modified Ifom FteKner. C.. N. Eng!. J. Med. 338:1281 (1998) FlQUre 38.5 modified Ifom N. Karlner and V, Ling. Scientific American, March (1989).

(,.0<

'0'''''' ( ..... _ , ~

>

5" Figure 40.8 mod~ied'rom D. D. DlIbose, A. C. CtJtlip, and W, D. Cutlip. American Family Medicine 51:1496 (1995). F'lIure43.1 photo from Jordan, V. C.. Scientitic Amer1can, October, p. 60 (1996) Agure 43.2 data from Tucci, J. A., Tonino, A. P. and Emkey, A.D, el al., Am. J. Med 101:488 (1996) Figure A.2 H. Lambert, and F. W. EdmJnd, S1i(le Atlas of InfectioUs Disease, Gower Medical Publishing (1~). FIgure A.3 mod~;ed rrom G. S. Rachefefsky, Hospl1al PracliOO, Nov. 15, 1995, Figure A.4 from W. Peters lind H. A. Folmer, Malaria, Royal TropicallnstilUle. Figure A.6 modified'rom H. Kupperman lind I. S. Young, MedCom Famous Teaching in Modern Medicine: Endocrinology, MedCom (1970). Figure A.6!rom T. P. Habit. Clinbll Dermatology, 2nd ed., Mosby (1990). Figure A.9 modified from M. J. Jamieson, KK McHardy, H. M. A. Towler, G, Chessell, K P. Duguid, T. M. MacOonaId, and J. C. Petrie, Essential Clinbll Signs, Churchill Livingstone (1990). Figure A.l0 modified !rom A.S. Taha, N. Hudsoo, C.J. Hawkey, A.J, $wannell, P.N. Trye, J. CotlfeU, S.G. Mann, T.J. Simon, A.D. Sturrock, and R.I. Russell, N. Engl. J. Med 334:1435 (1996).