Essentials of Medical Pharmacology Lafi 09-10

Essentials of Medical

Pharmacology

Majid A. K. Lafi BSc (Hons), MPhil, PhD Department of Pharmacology College of Medicine University of Al-Anbar

ABOUT THE AUTHOR Majid A K Lafi was born in Fallujah, Iraq in 1956, married with five children. He commenced studying at Kettering Technical College, Kettering, England in 1975, and obtained his "A" Level General Certificate of Education (Oxford Board) in 1978; in the same year, started a BSc (Hons) in Pharmacology at the School of Pharmacy, Portsmouth Polytechnic (now University of Portsmouth), Portsmouth, England, he has been awarded the degree in June 1981. Later on he was awarded MPhil in Pharmacology (1984), PhD in Pharmacology (1986) from the same university. I was awarded "Final Diploma" in English from the Institute of Linguists, London, in 1986. Thereafter, in 1987: Lecturer in Pharmacology, Military Medical College, Baghdad; in 1989: Lecturer in Pharmacology, College of Medicine, University of AL-Anbar, Ramadi, Iraq, in 1994: promoted to Assistant Professor of Pharmacology. His research interests in peripheral neuropharmacology (cotransmission at nerve muscle junction), unusual antimicrobial resistance, and medical education (pharmacology curriculum development).

Dr. Majid A K. Lafi

I

PREFACE When starting my carrier teaching pharmacology in Iraq, 3rd year medical school students, I confronted a problem that during the lecture most of the students were over-occupied with writing up what I was saying and not trying to understand what I was trying to deliver to them as core knowledge in pharmacology. With time, I understood that these students were very much concerned with obtaining the lecture material written more than understanding the material itself. After having long talks with them I promised to give them type-written lecture notes prior to delivering the lecture. This appeared to work very well in reassuring them that they would not lose material for "revision" paving the way for winning their attention during the lecture with consistently excellent students' attendance. This gain prompted me to continue improving my lecture notes in pharmacology to suit the need of particularly medical students in Iraq. For several years, students and colleagues have urged me to put this work in a book, only now "after 20 years" I find it is the time to do so. Teaching pharmacology at the College of Medicine, University of AL-Anbar, has been pathophysiology oriented therefore very much attention has been paid to the mechanism(s) of drugs' action. Hence, a brief account on the pathophysiology of major disorders has been mostly included in this book. Over the years of teaching this subject, it is felt that students prefer stating clinical conditions (e.g. indications, adverse effects and contraindications) in a list form rather than in a continuous text. In addition, the inclusion of a summary in a table and/or a figure form at the end of each topic has been found to be useful to recognise the core knowledge should be learned. These strategies have been largely adopted throughout this book. A considerable number of the third year medical students show very poor competence in the medical vocabulary used in delivering the core material of medical pharmacology. This prompted me to make an inclusion of an appropriate glossary at the end of this book to be handy for the reader to refer to. Undoubtedly, there are many occasions of weakness in this book, e.g. the section on antiparasitic agents as it is being very poor, particularly when taking into account the importance of parasitic infections in Iraq. It is hoped that these drawbacks and others will be dealt with in the next issue. This issue is only an initial draft awaiting feedback from students and colleagues. I am very grateful for support and assistance from a number of colleagues and students.

Majid A. K. Lafi October, 2008

CONTENTS

ABOUT THE AUTHOR PREFACE CONTENTS GENERAL PRINCIPLES Pharmacokinetics ……………………………………………………………. Pharmacodynamics ………………………………………………………… AUTONOMIC PHARMACOLOGY Cholinergic Transmission ………………………………………………….. Adrenergic Transmission …………………………………………………. Ocular Pharmacology ……………………………………………………. Drugs Used in Abnormal Micturition ………………………………………. CARDIOVASCULAR PHARMACOLOGY Antihypertensive Drugs ……………………………………………………… Antianginal Drugs …………………………………………………………... Drugs for Congestive Heart Failure …………………………………………. Antiarrhythmic Drugs ………………………………………………………. Diuretics …………………………………………………………………….. Antithrombotic Drugs ……………………………………………………….. Antihyperlipidaemic Drugs …………………………………………………. Drugs for Anaemias ANTIMICROBIAL DRUGS (GENERAL PRINCIPLES) Beta-lactam Antimicrobial Drugs …………………………………………… Sulphonamides, Trimethoprim, and Aminoglycosides ……………………… Tetracyclines, Macrolides, Metronidazole, Chloramphenicol, and others …... Antituberculosis Drugs ……………………………………………………….. Antimicrobial Drugs of Choice ……………………………………………….. Antifungal Drugs ……………………………………………………………… Antiviral Drugs ………………………………………………………………. Antiparasitic Drugs …………………………………………………………. CNS-PHARMACOLOGY (GENERAL PRINCIPLES) Antipsychotic Drugs …………………………………………………………. Drugs for Affective Disorders ……………………………………………….. Antianxiety Drugs …………………………………………………………… Sedative and Hypnotic Drugs ………………………………………………. Drugs for Parkinson s Disease ………………………………………………. Antiepileptic Drugs ………………………………………………………….. Opioids and Narcotic Analgesic Drugs ……………………………………... General Anaesthetic Drugs ………………………………………………….. Local Anaesthetic Drugs ……………………………………………………. Neuromuscular Blocking Drugs ……………………………………………… AUTACOIDS NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) DRUGS AND GASTROINTESTINAL TRACTS DRUGS AND THE RESPIRATORY SYSTEM ENDOCRINE PHARMACOLOGY Hypothalamic and Pituitary Hormones ………………………………………. Sex (Gonadal) Hormones and Inhibitors …………………………………...

III

I II III 1 1 18 24 25 25 33 35 37 46 49 54 61 65 73 77 79 88 96 101 106 110 114 117 121 124 131 135 142 146 153 156 164 170 176 178 182 190 203 212 218 223

Drugs Acting on Uterine Smooth Muscle …………………………………... Adrenocorticosteroids ……………………………………………………... Thyroid and Antithyroid Drugs …………………………………………… Agents that Affect Calcium Metabolism …………………………………… Insulin and Oral Hypoglycaemic Drugs ……………………………………. ANTICANCER DRUGS …………………………………………………… DRUG INTERACTIONS, ADVERSE DRUG REACTIONS AND ANTIDOTES GLOSSARY ……………………………………………………………… INDEX

IV

228 230 236 240 242 250 255 260 280

Essentials of Medical Pharmacology

Majid A. K. Lafi

GENERAL PRINCIPLES of the disease itself may vary from one patient to another, this difference in response is largely accounted for by variations in the metabolic handling of the drug.

Introduction This book is the result of a desire to record and update the material of lectures given upwards of twenty years to medical students. For medical students, the pharmacology course is the first confrontation with medicine and the response of patients to drugs. A drug in the widest sense is a substance used in prevention, cure and diagnosis of disease. The name pharmacon is Greek and means drug. The word drug comes from the French word drogue which means dry herb.

If the serum level of warfarin is measured in these patients a large difference may be found at the two extremes. Thus, some patients were under-treated while others were intoxicated. This phenomenon may be due to a number of factors (in addition to failure to take the prescribed dose of the drug, patient non-compliance). The rate of absorption of the drug, its distribution in various body compartments, tissue and plasma-protein binding, and the rate of metabolism and excretion of the drug all influence the steadystate level of the drug at the site where it is required. Study of these aspects of pharmacology is known as pharmacokinetics.

Pharmacology can be divided into two major parts: 1. Pharmacokinetics means what the body does to the drug . 2. Pharmacodynamics means what the drug does to the body .

Dosage Regimen Dosage regimen is the manner in which a drug is taken concerning dose, frequency, and route of administration that relate to drug level-time relationships in the body. Often, drug level in the body is reflected by plasma drug level that in turn influences the concentration of drug at the site(s) of action that relates to the magnitude of the effect(s) produced. Table 1.1. Basic pharmacological principles in empirical adult therapeutic regimens of some selected drugs. The information in this table is not intended for memorization by students rather as pharmacotherapeutic situations in which skills (critical thinking) are required in applying knowledge and understanding of basic pharmacological principles. The pharmacological principles, presented in this course of pharmacology in a manner coherently complementing each other, represent a core knowledge in which to ground skills in pharmacology as basis in therapeutics. Such knowledge and skills are expected to be learned in sequential increasing in complexity throughout the third year. Therefore, this table is expected to be referred to throughout the year.

In addition, the following topics are also covered: • Toxicology which deals with adverse effects, drug interaction, drug abuse, poisons, antidotes, industrial and environmental pollution, and therapeutic drug monitoring. • Pharmacogenetics which deals with inter-individual differences. • Pharmaceutics (drug delivery, formulation) • Pharmacognosy (plant medicine) • Prescription writing (emphasising on drug names and dosage regimen)

Pharmacokinetics If a fixed dose of a drug is given to a number of patients with a particular disease, e.g. 5 mg of warfarin daily dose in patients with deep venous thrombosis, most will show some therapeutic response as indicated by prothrombin time. A few, however, will not show obvious response, while the occasional patient may develop signs of drug intoxication (bleeding). Although the severity 1

General Principles

Ramadi, 6 October 2009

Table 1.1. Basic pharmacological principles in empirical adult therapeutic regimens of some selected drugs. Drug

Indication

Route

Warfarin t 37 hr Vd 5 L

Deep venous thrombosis

Oral

Theophylline

Asthma

Oral

Induction and maintenance of labour

Slow intravenous injection (over 20-30 min) Intravenous infusion

t 8 hr Vd 35 L

Oxytocin t

minutes Oral (control is too erratic)

Morphine t 2 hr Vd 230 L Ampicillin

Severe pain

Intramuscular Oral

Certain bacterial infections

Oral Intramuscular, intravenous, or infusion Oral

t 1.2 hr Vd 20 L Amoxicillin t 2 hr

Penicilin G t 0.5 hr

Infections due to susceptible microorganisms Infections due -lactamaseproducing amoxicillin resistant organisms

Endocarditis (prophylaxis in dental procedures) Gonorrhoea (Neisseria gonorrhoeae) Certain serious infections

Oral

Oral

Oral Intramuscular Intravenous, or infusion

Intramuscular

Phenobarbital t 4 days Vd 38 L Digoxin

Prophylaxis of recurrent rheumatic fever Syphilis (Treponema pallidum) Epilepsy

Intramuscular

Congestive heart failure

Oral

Intramuscular Oral

Dosage Regimen Individualize dosage according to PT or INR, initially 2-10 mg daily for 3 days, then; average maintenance dose: 2-5 mg at the same time each day Individualize dosage according to clinical responses and monitor serum theophylline levels. Short-acting formulation 500 mg initially, then 100-300 mg 3-4 times daily. Long-acting formulation 150-300 mg twice daily. 5-6 mg/kg (in patients not previously treated with xanthine) 0.2-4 milliunits/min infusion, gradually increased to 20 milliunits/min, if necessary, to produce 3 or 4 contractions within 10-min periods. Not used because of being rapidly destroyed by the proteolytic enzymes in GIT 10 mg when needed Not used because of being rapidly metabolised in the liver. 0.25-1 g every 6 hr 0.5 g every 4-6 hr

250

500 mg every 8 hr

250 500 mg (containing125mg of clavulanic acid, Augmentin ) every 8hr or 875 mg every12h Alternatively amoxicillin 3 g may be taken by mouth together with probenecid 1 g by mouth 4 h before the procedure Amoxicillin 3 g may be taken by mouth together with probenecid 1 g in single dose 300,000 8 million U daily 6 20 million U daily by continuous or intermittent infusion every 2 4h. Up to 60 million U daily have been given in certain serious infections. Procaine Penicillin daily in one or two doses Benzathine 2 Penicillins 1.2 2.4 million U in a single dose every 3 4 wk Benzathine 2 Penicillins 2.4 million U (1.2 million U in each buttock) in a single dose 60-180 mg at night

1.5-2 mg initially over 24 hr, then 0.25-0.5 mg once a day 2

Essentials of Medical Pharmacology

t 39 hr Vd 440 L Amiodarone t 53 days Vd 4200

Captopril t 2.2 hr Vd 57 L Prazosin t 2.9 hr Vd 42 L Aspirin t 0.25 hr Vd 11 L (salicylic acid: t 3 hr to 13-30 hr)

Dopamine t 2 minutes

Cardiac arrhythmia (Atrial fibrillation) Ventricular arrhythmias (recurrent) Ventricular arrhythmias (existing) for not more than 48 hours because of cumulative effect Heart failure Hypertension Hypertension, Benign prostatic hyperplasia (BPH) Transient ischaemic attacks Transient ischaemic attacks Pain, fever Rheumatoid arthritis Osteoarthritis Acute rheumatic fever Renal (D1 -receptor) Cardiac ( 1-receptor) Vascular ( 1-receptor)

Omeprazole t 45 minutes

Majid A. K. Lafi

Oral Oral Intravenous

Oral Oral

6.25 mg initially then 6.25-150 mg daily 25 mg initially then 6.25-150 mg daily

Oral

1 mg 2 to 3 times daily initially, maintenance dose 6 15 mg daily

Oral (Prophylaxis) Oral

81 325 mg daily

Oral

650 mg usual single dose

Oral

2000-6000 mg 3 times daily

Oral Intravenous infusion Intravenous infusion Intravenous infusion

5000-8000 mg daily in divided doses

1300 mg 2 to 4 times daily

<5 µg/kg/min >5 µg/kg/min >10 µg/kg/min Steady-state plasma concentration will be reached in 5 x t = 10 min 20 mg daily, 1 hr before meal (mandatory)

Oral

Insulin

Peptic ulcer Heartburn Active GI bleeding Prostate cancer Central precocious puberty Hypothalamic hypogonadotropic hypogonadism Long term regular use

Intravenous, or infusion

Glucagon

Acute or emergency situations: Diabetic ketoacidosis Hyperosmolar hyperglycemic nonketotic coma Perioperative period Severe infections Pregnancy Hypoglycaemic crisis

Nicotinic acid

Acute overdose of βblockers (heart failure) Pellagra

Goserelin t

l-l.5 mg initially over 24 hr, then 0.06250.5 mg once a day 0.8-1.2 g daily (2 to 4 weeks), then 0.2-0.4 g daily. 0.15g over 30 minutes & 1 g over the 1st day

Intravenous Subcutaneous

8 mg/hr for 72 hrs 3.6 mg every 28 days (i.e. given continuously)

Intravenous tubing (by GnRH pump) Subcutaneous

A portable battery-powered programmable pump allows pulsatile GnRH therapy every 90 minutes. Dosage individualized. Initially, 7 26 units may be given once daily. Suitable for stable biphasic insulin mixtures (e.g. short acting plus long acting) Dosage individualized. For ketoacidosis, regular insulin may be given by direct injection, intermittent infusion, or continuous infusion. One regimen involves an initial bolus injection of 10 20 units followed by a continuous low-dose infusion of 2 10 units/hr, based on hourly blood and urine glucose levels

Intramuscular Subcutaneous Intravenous (bolus) Oral

3

1 mg 5-10 mg 100-500 mg daily.

General Principles

Ramadi, 6 October 2009

(niacin)

Hyperlipidaemia

Oral

250 mg twice daily initially and increasing the dose monthly by 500 to 1000 mg per day to a maximum of 2 6 g daily. This regimen to reduce the intense cutaneous flush produced as an adverse effect. The latter can further be reducing by taking nicotinic acid on a full stomach (end of meal), taking aspirin before dosage, and time-release forms of nicotinic acid can reduce the severity of flushing.

Diclofenac

Pain Dysmenorrhoea

Oral

50 mg 3 times daily

Ankylosing spondylitis

Oral

Osteoarthritis

Oral

Rheumatoid arthritis

Oral

Acute renal colic

Oral

Diclofenac Immediate R (only 50mg) Diclofenac Delayed R (75mg) Extended R (100mg)

Nitroglycern t 1-3 min

Ureteral stone propulsion Relieve acute angina Prevent exercise-induced angina Long-term prophylaxis to decrease the frequency and severity of acute anginal episodes

IV, IM Oral Oral Sublingual Translingual spray

Transmucosal tablet Topical transdermal patch Hypertensive crisis Carbamazepine t 15 hr Vd 98 L

Epilepsy

Continuous Intravenous oral

Trigeminal neuralgia

oral

4

100 125 mg daily in 4-5 divided doses (e.g., 25 mg 4-5 times daily) 100 150 mg daily in divided doses (e.g., 50 mg 2 or 3 times daily, 75 mg twice or 100 mg once daily) 100 150 mg daily in divided doses (e.g., 50 mg 2 or 3 times daily, or 75 mg twice or 100 mg once daily) 50 mg 2 or 3 times daily for 5 days, then on need 75 mg once or twice daily 50 mg 2 or 3 times daily for 15 days Sustained-release tablets, 2.5 9 mg 2 or 4 times per day 0.15 0.6 mg on need for chest pain one or two metered doses (0.4 mg/dose) sprayed onto oral mucosa at onset of anginal pain, to a maximum of 3 doses in 15 min 1 mg every 3 5 hr while awake, placed between upper lip and gum or cheek and gum 5 mg applied once daily, do not rub. 5mcg/min 200 mg twice daily, increased gradually to 600 1200 mg daily if needed, in 3 or 4 divided doses 200 mg daily, increased gradually to 1200 mg if necessary

Essentials of Medical Pharmacology

Majid A. K. Lafi

Pharmacokinetics Dosage Regimen Dose Frequency (Route of administration)

Drug Concentration at Site of Action

Plasma Drug Concentration

Pharmacodynamics

Css

Unacceptable Toxicity

Regimen C MTC Css

Regimen B

Therapeutic Window MEC

Regimen A

Css

Ineffective

Time Fig.1.1. A schematic representation of the approach to the design of dosage regimen. The pharmacokinetics and pharmacodynamics of the drugs are first defined. Then either the plasma drug concentration-time data or the effects produced are used as a feedback to modify the dosage regimen. When a drug is given at fixed time intervals (denoted by arrows), it accumulates within the body until a plateau is reached. With regimen A, the plasma drug concentration is too low therefore therapeutic failure (ineffective) is observed. With regimen B, therapeutic success is achieved although not initially. With regimen C, the therapeutic objective is more quickly achieved but the plasma drug concentration is ultimately too high.

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Ramadi, 6 October 2009

Peak 20

Nausea

Vomiting

CNS stimulation

Unacceptable Toxicity MTC Css

10

Insufficient

Trough 0

8

16 24

48 Time (hr)

bronchodilatatio n 72 96

Therapeutic Window MEC Ineffective

Fig.1.2. Different dosage regimens of theophylline showing the relationship between frequency of dosing and maximum and minimum plasma concentrations when a steady-state theophylline plasma concentration of about 10 µg/ml is desired. Regimen I- intravenous infusion of 25 mg/hr achieves smoothly rising line (dotted with black squares). Regimen II- 8-hourly administration (dark solid thin line) of doses of 200 mg. Regimen III- 24-hourly administration (dark solid thick line) of doses of 600 mg. In each of the 3 regimens, the mean steady-state plasma concentration (Css) is about 10 µg/ml. Note: in regimen III there is a large fluctuation between peak and trough and as estimation of plasma levels of drugs often not available, the former may be reflected clinically by the development of nausea, vomiting and central nervous system (CNS) stimulation as unacceptable toxicity; while trough may be reflected clinically by insufficient bronchodilatation (ineffective). Regimen IV- 12-hourly administration (dotted with black solid circles) of doses of 300 mg with oral slow release formulation to avoid the unacceptable toxicity and the insufficient bronchodilatation may be associated with regimen III. The therapeutic window lies between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC). Therefore, adjustment of dosage regimen may be made depending on the clinical response. This is particularly true for drugs with low therapeutic index like theophylline.

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Essentials of Medical Pharmacology

Majid A. K. Lafi

Unacceptable Toxicity MTC

Css Therapeutic Window

Css MEC 0

3

6

18

12 Time (hr)

24

Fig.1.3. Different dosage regimens for a drug with large therapeutic index such as ampicillin (with t of about 1 hr). Regimen I- 1-hourly (light colour) with low total daily dose and regimen II- 6-hourly (dark colour) with higher total daily dose. Note: The steady-state plasma concentrations (Css) of the two regimens are different and regimen II shows a larger fluctuation between peak and trough comparing with that of regimen I. Both regimens exhibit Css within the therapeutic window, i.e. lies below the level expected to cause unacceptable toxicity. It follows that administering ampicillin 1-hourly would be practically inconvenient (24 times per day) and likely to result in non-compliance and consequently treatment failure. On the other hand, giving the drug 6-hourly with larger doses that attain troughs that lie at a level higher than the minimum effective concentration (MEC) and peaks lie at levels below the minimum toxic concentration (MTC), would lead to a better compliance (as a result of reducing the frequency of dosing, four times daily). This strategy can be adopted only with drugs that show large therapeutic index. In case of drugs that are with low therapeutic index other manoeuvres may be used to improve compliance; for example, sustained release formulation like for theophylline to be given twice daily instead of three times daily.

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General Principles

Ramadi, 6 October 2009

The aforementioned factors are related to the question of whether generic or proprietary (brand) name should be used when prescribing.

Drugs and Medicines It is not always recognised that when prescribing a drug the patient actually receives a medicine. The drug represents only a small proportion of the total weight of the solid dosage form (e.g. tablet, capsule) or injectable dosage form (e.g. ampoule, vial). The dosage form contains other constituents, which may not be inert and may play an important role in facilitating or hindering a drug s absorption. Appropriate pharmaceutical manoeuvres of these materials may allow development of sophisticated delivery systems for delayed or position-released of the drug. The following are some of the factors involved in the production of the solid dosage form, which may influence a drug s absorption.

Absorption of Drugs When a drug is administered orally it has to pass through the gut wall which represents a complex biological barrier (complex lipid membrane) before entering the bloodstream. Dietary substances can pass through this biological barrier by one of the following ways: a. Passive diffusion concentration difference (from high to low) this is being the most important mechanism. b. Active transport e.g. amino acids, or drugs e.g. α-methyldopa that resembles endogenous substances. c. Filtration through pores, limited to molecules of small size e.g. urea. d. Pinocytosis by which small particles are engulfed by cells of the bowel.

1. Diluents e.g. lactose, calcium sulphate. 2. Granulating and binding agents e.g. syrup used for aggregation of powder into granules facilitating compression of tablet. 3. Disintegrating agents are incorporated to produce tablet disintegration in the gastrointestinal tract.

There are a number of factors which influence absorption of drugs: 1. Nature of drug polypeptides e.g. insulin is broken down by intestinal enzymes, benzylpenicillin is destroyed by gastric acid 2. Pharmaceutical formulation (see above) 3. Blood flow maintains continuous absorption by removing drug that passes through membrane. The concentration gradient across the membrane is, thereby, continuously assured. Membrane permeability of drugs also plays an important role in absorption of drugs. When the drug is lipophilic (e.g. ethanol) and thus highly membrane permeable, absorption is controlled or rate limited by perfusion (blood flow). In contrast, with streptomycin and many other polar compounds (like heparin, ipratropium and suxamethonium), absorption is controlled or rate limited by diffusion (penetration, permeability) through the membrane and not in removing the drug from other side of the membrane. Some compounds, e.g. urea, have intermediate permeability properties. At low blood flow rates, the compound has sufficient time to diffuse

moisture Starch Cocoa butter

Swelling body temperature

Melting

Sodium bicarbonate + tartaric acid moisture effervescence

4. Coating material e.g. sugar prevents disintegration before the tablet reaches the stomach or intestine (e.g. omeprazole). 5. Capsules have a gelatine envelope with no granulating excipients. 6. Sustained-release with complex pharmaceutical manoeuvres to control disintegration and dissociation rates, thus regulating the rate of a drug s absorption.

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Essentials of Medical Pharmacology

Majid A. K. Lafi

across the membrane so absorption is perfusion rate-limited. At higher blood flow rates, however, membrane permeability becomes the rate-limiting step, and absorption is insensitive to blood flow.

Because both ionised and unionised solutes readily pass across the capillary wall, the influence of pH on intramuscular and subcutaneous absorption of drugs is likely to be far less significant.

Absorption of drugs in solution from muscle and subcutaneous tissue is normally perfusion rate-limited. An increase in blood flow increases absorption. In this setting, absorption is impeded largely by the capillary wall. At these sites, the capillary wall, a much more loosely knit structure than the epithelial lining of the gastrointestinal tract, allows the rapid passage of all molecules below a molecular weight of about 5000, whether ionised or unionised. This molecular weight range includes essentially all drugs. Streptomycin, a relatively water-soluble polar base, has difficulty penetrating the gastrointestinal mucosa; it is rapidly absorbed from the intramuscular site.

Body fluids Gastric juice Intestine Plasma CSF Urine Prostatic secretions Vaginal secretions Weak acids

pK

pH 1.0 - 3.0 5.0 - 8.0 7.4 7.3 4.0 - 6.8 6.4 -7.4 3.4 - 4.2 Weak bases

Penicillin G Salicylic acid Warfarin

2.7 3.5 Diazepam 5.0 Chlordiazepoxide 7.3 Trimethoprim Phenobarbital 7.8 Lidocaine Theophylline 9.0 Procainamide 10 Amphetamine Permanently ionised (polar) drugs Heparin Streptomycin Ipratropium Tubocurarine Suxamethonium

4. pH and pK. Drugs are usually either weak organic acids (proton donor) or weak organic bases (proton acceptor) existing in equilibrium between undissociated molecules and as ions. This equilibrium depends on the pKa value of the drug and the pH of the surrounding medium. At a pH equals to the pKa the drug is 50% ionised. Thus, a weakly acidic drug (e.g. aspirin) in a medium of low pH (e.g. stomach) will be mainly in its undissociated form; whereas a weakly basic drugs (e.g. amphetamines) in a medium of high pH (e.g. small intestine) will be mainly in its undissociated form. Streptomycin is permanently polar and relatively strongly basic, and its pKa value greatly exceeded the highest pH reached in the intestine. This explains why some drugs (e.g. streptomycin) are very poorly absorbed from the gut, therefore they should be administered parentally. As a general rule, acids tend to ionise in basic (alkaline) media, and bases tend to ionise in acidic media.

Clinical Example Many antibiotics cannot penetrate the prostatic epithelium, therefore not achieving adequate concentration in the prostatic fluid and tissue. Hence, it is difficult to cure bacterial prsotatitis. Trimethoprim is usually effective in the treatment of bacterial prostatitis while penicillin is not. This is because trimethoprim is a basic substance with a pKa of 7.3 and prostatic secretion is relatively acidic (pH 6.4 particularly in inflammatory condition) compared to the plasma (pH 7.4); consequently, trimethoprim is about 50% non-ionised at the plasma and therefore the drug penetrates into prostate. In acidic prostatic fluid trimethoprim is ionised and thus trapped as it cannot diffuse back into plasma. On the other hand, penicillin (acidic substance with a pKa of 2.7) is largely ionised and bound to plasma protein at pH 7.4 and thus cannot penetrate into prostate.

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General Principles

Ramadi, 6 October 2009

5. Gastric emptying- According to what has been described above, it follows that weak acids are absorbed more rapidly from the stomach when the pH of the contents is 1 than when the pH of the contents is closer to 8, and the converse holds for weak bases. However, absorption of acids is always much faster from the more alkaline intestine (pH 5-7) than from the stomach.

oral dose that reaches the general circulation. For example, a 50% bioavailability of a tablet of 10 mg propranolol would mean that a total of 5 mg of propranolol would reach the general circulation. The value of bioavailability may vary widely and being a characteristic of the manufacturing pharmaceutical company and in turn may have clinical implications. For the same proprietary (trade) name, a particular pharmaceutical preparation of a drug may exhibit widely different values of bioavailability due to pharmacokinetic differences in the handling of the drug by the body including concurrent medications. Three major factors are considered below.

These apparently conflicting observations may be reconciled by the following explanation. The surface area and blood flow are important determinants of the rapidity of absorption. The small intestine is favoured on both of these accounts. The total area of the small intestine represented largely by microvilli, has been estimated to be about 200 m2, and an estimated 1 litre of blood passes through the intestinal capillaries each minute. The corresponding estimates for the stomach are only 1 m2 and 150 ml/min. these increases in both surface area and blood flow more than compensate for the decreased fraction of unionised acid in the intestine. In fact, the absorption of all compounds, acids, bases, or neutral compounds, is faster from the small intestine than from the stomach. Therefore, the rate of gastric emptying is a limiting step in the rapidity of drug absorption. Consequently, food, particularly fat, slows stomach emptying. This explains why drugs are frequently recommended to be taken on an empty stomach when a rapid onset of action is desired.

Time for Absorption An orally administered drug is exposed to the gastrointestinal mucosa for no more than 1 to 2 days, and for much less time at the main absorption site, the small intestine. If a drug is poorly permeable, for example, streptomycin, heparin, suxamethonium, and ipratropium, there is insufficient time for complete absorption. There may be insufficient time for complete absorption of the vitamin, riboflavin, and of other substances absorbed by a carrier-mediated transport process. The site of the transport process is usually restricted to a certain part of the gastrointestinal tract. The system for absorbing riboflavin is located in the upper part of the small intestine. At the does taken, the concentration of riboflavin reaching the site of absorption saturates the transport process. The oral bioavailability of riboflavin can be increased by taking the vitamin with small amounts of food. The resultant slowing of stomach emptying both extends the duration and diminishes the rate of delivery of riboflavin and hence its concentration at the absorption site; both factors favour more complete absorption.

The stomach may simply be viewed as a storage organ from which pulses of drug are ejected onto the absorptive sites in the small intestine.

Factors Influencing Bioavailability

There is the situation of a drug, such as griseofulvin (and mebendazole and albendazole), that is sparingly soluble in both gastric and intestinal fluids. There may already be insufficient time for dissolution and absorption when this drug is administered as a tablet. Retaining such a drug in the stomach, by increasing the total time for dissolution, should favour increased

Bioavailability of a drug is the ease (how much of the drug and how fast, completeness of absorption) at which it reaches the general circulation. Drugs that are pharmaceutically formulated (designed) for oral administration may show different bioavailabilities. This is usually measured by the percentage of the 10

Essentials of Medical Pharmacology

Majid A. K. Lafi

acid in a single passage through the liver, resulting in a substantial first-pass effect . Drugs that show a significant first-pass effect in man include aspirin, hydralazine, lidocaine, morphine, nitroglycerin, pentazocine, propoxyphene, and propranolol.

availability. The time available for dissolution within the intestine is probably limited to between 4 and 10 hours. Subsequently, as the intestinal fluid and contents move into the large intestine and water is reabsorbed, the resulting compaction of the solid contents limits further dissolution of drug. An additional 2 to 4 hours in the stomach, where dissolution can occur, would significantly extend the time for dissolution. Fats, particularly, delay stomach emptying, and this delay may be one of the explanations for the observed increase in the availability of griseofulvin when taken with a fatty meal or with fats.

Avoiding the first pass through the liver probably explains the activity of nitroglycerin administered sublingually. Blood perfusing the buccal cavity bypasses the liver and enters directly into the superior vena cava. This anti-anginal drug is almost completely metabolised as it passes through the liver, and any drug swallowed is not systemically available. The metabolites seen in blood are only weakly active.

The rectum has a small surface area and a drug given rectally is not always retained for a sufficient length of time to ensure complete absorption. No time limitation exists for a drug injected into muscle or subcutaneous tissue; complete absorption is anticipated unless destruction occurs at the site of administration.

The rectal route has a definite advantage over the oral route for drugs that are destroyed by gastric acidity or by enzymes in the intestinal wall and microflora. Potentially, the rectal route may also partially reduce first pass hepatic loss. Part of the rectal blood supply, particularly the inferior and middle haemorrhoidal veins, bypasses the hepatic portal circulation and dumps directly into the inferior vena cava. Achieving a reproducible availability, which is important in drug therapy, may be difficult, however, since availability is strongly dependent upon the site of absorption within the rectum.

Competing Reactions Any reactions within the gastrointestinal tract that compete with absorption may reduce the oral bioavailability of a drug. Benzylpenicillin when given orally undergoes substantial hydrolysis by gastric acid; therefore, it is administered by injection. Enzymatic hydrolysis occurs to aspirin forming salicylic acid, active antiinflammatory compound. Tetracycline undergoes complexation with polyvalent metal ions, e.g. Ca++, Al+++, forming unabsorbed insoluble complexes. Decarboxylation occurs to levodopa resulting in loss of activity (product active but not absorbed).

Distribution of Drugs Generally, drugs that are readily absorbed from the gut wall are also readily distributed throughout the body water compartments. This is applicable to most barbiturates; thiopental is highly lipid-soluble and is freely absorbed from the stomach and rectum. When it is administered intravenously, it crosses the biological barriers into the brain producing anaesthesia. Generally, centrally acting drugs have to pass through an additional lipid membrane in the blood brain barrier, and thus, are readily absorbed from the gut. These drugs can easily reach the foetal circulation, being the main offenders in causing foetal abnormalities (e.g. phocomelia caused by thalidomide).

Hepatic Extraction Over hundred years ago, acetylsalicylic acid (aspirin) was synthesised to overcome the bitter taste and the gastrointestinal irritation associated with the parent drug, salicylic acid. Only subsequently was aspirin shown to be also pharmacologically active. Aspirin, a labile ester, is rapidly hydrolysed, particularly by esterases in the liver. In fact, hepatic hydrolysis is so rapid that a significant fraction of aspirin is converted to salicylic

After being absorbed, most drugs bind to tissue and plasma proteins forming

11

General Principles

Ramadi, 6 October 2009

extensively bound to tissues is to have a large apparent volume of distribution (Vd). This is a theoretical volume of fluid, which would be required to contain the total body content of a drug at a concentration equal to the plasma concentration. Drugs which has a large Vd (in litres for 70 kg person) are digoxin (420), nortriptyline (1000), dothiepin (4900), amiodarone (4200) and chloroquine (13000), and drugs with small Vd are warfarin (5), heparin (5), aspirin (11), gentamicin (18), frusemide (21) and amoxicillin (28).

equilibrium with the unbound (free) drug, and the extent of binding varies from drug to drug. If a drug exhibits no appreciable tissue binding, the tissues behave as little more than water compartment in which the drug is dissolved. The pharmacological properties of a drug are greatly influenced by its being highly protein bound; this influence can be seen in the following ways: 1. Its absorption from the gut wall will be facilitated, through capturing the drug molecules by tissues and/or plasma protein molecules leading to maintenance of the concentration gradient across the gut wall.

Serum half-life

2. Since only the unbound form of the drug is the biologically active, it is essential to know the extent of binding for a drug before values given for serum levels reached for the drug in question become meaningful.

Serum half-life (t ) of a drug is the time taken for the serum concentration to halve. Metabolism and/or excretion of the drug determine it. A drug with a short t (e.g. salbutamol) produces a much steadier therapeutic action when given in at least three divided doses daily. On the other hand, a drug with a long t (e.g. digoxin) given as a single daily dose is adequate to maintain a steady response. Drugs with long t will cumulate with repeated and frequent doses and patients receiving such drugs particularly those with low therapeutic index like digoxin and phenytoin should be examined frequently for signs of overdosage.

3. Certain pathological conditions where changes in the concentration of serum proteins, e.g. hypoproteinaemia (which may occur in some renal and/or hepatic dysfunction), a higher level of unbound drug will occur in the serum unless the oral dose is lowered. This should be taken in consideration when dealing with drugs, which are highly protein bound (e.g. diazepam, frusemide, phenytoin and triamterene) and/or have low therapeutic index (e.g. theophylline and digoxin).

Thus, measurements of serum concentrations are performed routinely nowadays; these include anticonvulsants (e.g. phenytoin), antiarrhythmic drugs (e.g. quinidine), theophylline, lithium and aminoglycosides. In certain cases, measuring the response to a drug provides an easy method of monitoring its action (e.g. prothrombin time with anticoagulants like warfarin).

4. Adverse drug interactions may take place on plasma protein binding sites. This is very likely to occur with a highly protein bound drug like warfarin (99% bound) which can be displaced by certain other drugs like phenylbutazone which competes with warfarin on the same binding site. This may result in a small change in binding of warfarin that can greatly lengthen the prothrombin time. This type of drug interaction is clinically more important when the displaced drug has a small volume of distribution.

Metabolism Hepatic enzymes are responsible for the metabolism of most drugs. However, some drugs are metabolised in the plasma (e.g. procaine and suxamethonium are destroyed by pseudocholinesterase in the serum) and tissues (e.g. alcohol is destroyed by enzymes in gastric wall and liver). Metabolism in the liver can take place for those substances, which are lipid soluble and thus can enter the

5. For a drug to be effective therapeutically it has to achieve adequate plasma levels of the unbound form. Drugs vary in the period required to reach equilibrium between the body fluids and tissues. When a drug is 12

Essentials of Medical Pharmacology

Majid A. K. Lafi

liver. Hepatic enzymes are, generally, capable of metabolising endogenous and exogenous substances that are relatively stereotyped. Each enzyme is specific for certain chemical groups, which can occur on a wide range of substances.

Inactive Substance Azathioprine Enalapril Sulphasalazine

Hepatic metabolic processes can be divided into: Phase I metabolism results in a change in drug substance by oxidation, reduction or hydrolysis and in certain cases introduces a chemically active site into it. Oxidation is the most important reaction that is usually achieved by the so-called mixed-function oxidases that are capable of metabolising a variety of compounds.

Talampicillin Acyclovir

Metronidazole

Phase II metabolism involves the union of the drug with one of several polar endogenous molecules (e.g. glucuronide, glycine or acetyl derivative) to form a watersoluble conjugate which is readily eliminated by the kidney or, if the molecular weight more than 300, in the biliary tract. Generally, phase II metabolism inactivates drugs and facilitates their excretion.

Chloramphenicol succinate Chloral hydrate Anistreplase Hexamine

When drugs undergo metabolism, they can be converted from pharmacologically active to inactive substances; this is the most likely event. Further, some pharmacologically active drugs may be converted to another active substance. While some other pharmacologically inactive drugs (prodrugs) can be converted to active ones. Active Drugs Allopurinol Amitriptyline Aspirin Acetaminophen (safe)

Codeine Chloroquine Diazepam

Active Metabolite Mercaptopurine Enalaprilat 5-aminosalicylic acid (mesalazine) plus sulphapyridine (by bacteria in the colon) Ampicillin Acyclovir triphosphate (by viral thymidine kinase) Reducedmetronidazole (by anaerobic bacteria) Chloramphenicol Trichloroethanol Deacylated anistreplase Formaldehyde (by hydrolysis in acidic urine)

Excretion Most drugs are excreted in urine, either as the parent substance or metabolites. Lipid soluble drugs, in addition to being readily absorbed from gut, appear in the glomerular filtrate, but easily pass back into the blood stream by passive diffusion at the proximal tubule. However, many of these drugs are converted by the liver into more polar, lipid insoluble metabolites. These metabolites, and other drugs which are highly polar (e.g. streptomycin), do not pass very readily into glomerular filtrate, but once they are there they have difficulty in diffusing back at the proximal tubule. These substances are usually excreted entirely by the kidney. In addition to passive diffusion, many acidic and basic drugs are actively secreted. The secretion of weakly acidic substances can be inhibited by probenecid, and this substance has been used to prolong the t of penicillin in order to reach higher tissue concentrations without increasing the dose of the antibiotic.

Active Metabolite Alloxanthine (oxypurinol) Nortriptyline Salicylic acid N-acetyl-pbenzoquinoneimine (NABQI, hepatotoxic) Morphine Hydroxychloroquine

Nordiazepam

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General Principles

Ramadi, 6 October 2009

Changes in tubular pH can affect the elimination of these compounds by altering the ratio of ionised to unionised form. Normally the urine is slightly acidic and favours the excretion of weakly basic drugs (e.g. amphetamine, pethidine), while oral sodium bicarbonate will prolong their effects. On the other hand, the excretion of weakly acidic drugs (e.g. for patients who has taken overdose of barbiturates or aspirin) is accelerated by making the urine alkaline (alkaline diuresis) by giving sodium bicarbonate. As the kidney (and cardiac function) and to a lesser extent the liver are important in drug excretion, a serious consideration must be taken with impaired renal and hepatic functions. An elderly patient with congestive heart failure and a raised blood urea is likely to develop digitalis intoxication if digoxin is prescribed in full dose. It is necessary to measure repeatedly the serum level of certain drugs (e.g. gentamicin) when they are given to patients in renal failure.

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Majid A. K. Lafi

The apparent volume of distribution (Vd)

USEFUL NOTES

D C = ------Vd

• Clearance of a drug is the rate of elimination by all routes relative to the concentration of drug in any biological fluid.

D Vd = -----C

Rate of elimination Clearance = -----------------------Concentration

C = plasma concentration of drug D = Total amount of drug in the body

Rate of elimination = Q x Ce - Q x Co

Example: if 10 mg of a drug, thus D = 10 mg, is administered and the plasma concentration is 1.0 mg/L, then the Vd = 10 mg/L = 10 L.

Blood flow = Q Entering drug concentration = Ce Exiting drug concentration = C0

Clinical applications of Vd 1. It is useful to calculate the amount of drug needed to achieve a desired plasma concentration:

Therefore: Q x Ce Q x Co Clearance = ------------------- (ml/min) Ce

Example: if supraventricular arrhythmia of a patient is not responding well due to inadequate plasma levels of digoxin. Assuming the plasma concentration of the drug is C 1 and the desired concentration is C 2, a higher one. It is important to know how additional digoxin should be administered to bring the circulating level of the drug from C1 to C2.

Ce Co = Q x ---------- = Q x ER Ce ER = extraction ratio

Clearance of a drug by an organ (e.g. kidney) means the ability of the kidney to remove the drug from a certain volume of plasma per minute. Similar to renal clearance of creatinine or urea.

D1 = Vd x C1 D1 = amount of drug initially in body D2 = Vd x C2 D2 = amount of drug in the body required to achieve the desired plasma concentration

Dosing rate = Clearance x Css (Q x Ce Q x Co ) = --------------------- x C ss Ce Css = Steady state concentration

Therefore, the additional dosage needed is the difference between the two values: (D2

C1 )

2. Since delivery of drug to the organs of elimination depends not only on blood flow but also on the fraction of the drug in plasma, therefore, the value of Vd of a drug can influence the rate of elimination. Assuming a drug with a large Vd, most of this drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, a drug with a large Vd would

Half-life (t ) is defined as the time required for the amount of drug in the body to decrease by half (50%). t

D1) = Vd (C2

= 0.693 Vd/CL CL = Clearance

15

General Principles

be expected to have a long t extended duration of action.

Ramadi, 6 October 2009

withdrawn, an interval equivalent to 4 t will be required for body stores of the drug to decline by 94%.

and

Clinically, the knowledge of Vd of a drug may be useful when overdosage occurs. Removing a drug by haemodialysis is likely to be of benefit if a major proportion of the total amount of the drug is in the plasma.

• When t is 6-12 hr giving half the priming dose at intervals equal to the t can indeed be a satisfactory solution because dosing every 6-12 hr is reasonable.

Example: For salicylate, which has a small Vd, (12L) haemodialysis is appropriate treatment; while for pethidine, which has a large Vd, (310L) is not appropriate one.

• When t is greater than 24 hr giving half the priming dose every day means that more drug is entering the body than is leaving it each day, and the drug will accumulate indefinitely. Thus, the maintenance dose should be adjusted to replace only that amount of drug that leaves the body in 24 hr, as for warfarin.

Students are expected to be familiar with the following terms. They are advised to make contributions in the discussion sessions on the concepts of these terms. • Therapeutic range, therapeutic window

• When t is less than 3 hr, dosing at intervals equal to the t would be so frequent as to be unacceptable, and the answer is to use continuous intravenous infusion if the t is very short, as for dopamine t , 2 min; steady-state plasma concentration will be reached in 5 x t = 10 min). Benzylpenicillin has a t of less than 1 hr but is effective in a 6-hourly regimen because the drug is very safe that it is possible to give in a dose that achieves a plasma concentration many times in excess of the minimum inhibitory concentration for sensitive organisms.

• Steady state concentrations (Css), plateau (when the quantity of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached. • Time to plateau (When a drug is administered repeatedly in the same dosage, plateau (steady state) will be reached in approximately 4-5 half-lives. • Techniques for reducing fluctuations in drug levels

• First and zero order (saturable) kinetics [clinical implications: (phenytoin, therapeutic index = 2, subtherapeutic plasma concentration with t of 6-24 hr and C ss reached in 2-3 days, while therapeutic plasma concentration with t of 60 hr and Css reached in 2 weeks); alcohol (due to alcohol dehydrogenase being saturable at alcohol blood concentration of about 10 mg/dL), theophylline with therapeutic index <2, salicylates, clarithrmycin, heparin (saturable kinetics, dose-dependent t 60 min. after 75 units per kg and 150 min. after 400 units per kg) versus low molecular weight heparin (LMWH, 1st order kinetics). Rifampicin when given in a dose of more than 300 mg the excretory capacity of the liver becomes saturated, this is an advantage in certain clinical conditions e.g. in tuberculosis).

• Administer drugs by constant IV infusion • Reduce dosage size while increasing dosage number (keeping the daily dose constant) • The priming or loading dose is that dose which will achieve a therapeutic effect in an individual whose body does not already contain the drug. • Loading doses versus maintenance doses (A loading dose is used to rapidly produce a high level of drug equivalent to the plateau level for a similar dose, maintenance dose) • Decline from plateau (When a drug has been administered repeatedly and then 16

Essentials of Medical Pharmacology

Majid A. K. Lafi

Zero-order Kinetics

Therapeutic Range

Dose →

• Bioavailability (How much of the drug and how fast it reaches the general circulation) • pH- logarithm of the reciprocal of the hydrogen ion concentration • pKa- logarithm of the reciprocal of the dissociation constant • Ka- the extent to which a molecule is able to ionise [either to lose a hydrogen ion (acidic groups) or to add a hydrogen ion (basic group)] is given by the dissociation (or ionisation) constant (Ka). • For simplicity purposes drugs can be classified into 3 groups: • Drugs ionised by environmental pH (most drugs) • Drugs incapable of becoming ionised (non-polar) e.g. digoxin, chloramphenicol, steroid hormones such as prednisolone. Effectively lacking any ionisable groups, they are unaffected by environmental pH, are lipid-soluble and so diffuse readily across tissue boundaries. • Permanently ionised drugs (polar) e.g. heparin (acidic), ipratropium, tubocurarine, suxamethonium, and streptomycin (basic).

17

General Principles

Ramadi, 6 October 2009

which is synthesised from ATP by the enzyme adenylate cyclase, which is modulated by β-and α2-adrenoceptor. Subsequently, cAMP activates protein kinase, resulting in phosphorylation of proteins triggering other intracellular effects. Other second messenger systems have been recognised. For example, diacylglcerol (DAG) and inositol trisphosphate (IP3) are the metabolic product of phosphatidyl bisphosphate (PIP2) by the enzyme phospholipase C which is coupled to α1adrenoceptors and cholinergic muscarinic receptors.

Pharmacodynamics Drugs may act by different mechanisms: 1. RECEPTOR INTERACTION Many drugs act by activating or blocking a receptor. Receptors are chemical components mostly on the surface of the cell. 2. ENZYME INHIBITION e.g. monoamine oxidase (deprenyl), cholinesterase (neostigmine), cyclooxygenase (aspirin). 3. CHEMICAL INTERACTION e.g. gastric acid (antacids), urine alkalinizing agent (potassium sodium hydrogen citrate), heparin (protamine sulphate), alkylating agents. 4. PHYSICO-CHEMICAL PROPERTIES e.g. osmotic diuretics, laxatives, volatile anaesthetics.

Tolerance The continual administration of drugs sometimes leads to a progressive decrease in the observed response. This can be called tolerance or desensitisation. This occurs when increasing amounts of opiates (e.g. morphine) are required to achieve the same effect. Tolerance (e.g. for salbutamol) is probably associated with a loss of receptors from the cell surface due to endocytosis or internal uptake. This has been termed downregulation of receptors; i.e. with continued stimulation there will be a lower number of receptors on the cell surface (e.g. with the use of β 2 agonists like salbutamol in asthmatic patients). This type of tolerance is described as pharmacodynamic one. Further, pharmacokinetic tolerance can also be exhibited by some drugs including carbamazepine and alcohol. An alteration in rates of metabolic inactivation with chronic administration of carbamazepine or alcohol can induce hepatic enzymes resulting in an increase in the metabolism of the drug and in turn lead to a decrease in the observed response.

Drug Receptor Interaction Receptor activation is followed by a biological response which is proceeded by: a. Opening of ionic channels (pores) b. Activation of a second messenger Receptor activation can induce an increase in permeability of selected ion, e.g. at the neuromuscular junction acetylcholine is released from the motor endplate and combines with the postsynaptic nicotinic receptor. This results in the opening of ion channels (Na+, K+) and the propagation of an action potential that proceeds skeletal muscle contraction. GABA receptor is another example of receptor coupled to ion channels; it is linked with Cl- channels and when activated leads to enhanced influx of Cl-. In other cells, the binding of a chemical signal (neurotransmitter, chemical mediator) to a receptor (signal detector and transducer) activates enzymatic processes within the cell membrane that eventually result in intracellular response. Second messenger molecules are produced as a result of chemical signal binding to a receptor. These messenger molecules then translate the extracellular signal into an intracellular response. The best-known second messenger is cyclic adenosine monophosphate (cAMP)

Tachyphylaxis

(acute tolerance) is a similar mechanism that develops more rapidly. This clinically can occur to a. Lysergide (LSD) b. Local anaesthetics (lidocaine) repeated administration

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Essentials of Medical Pharmacology

Majid A. K. Lafi

c. Vasopressin causes smooth muscle stimulant effect (in large nonphysiological doses).

Drug receptor interaction can best be studied with isolated tissues, e.g. a gut or blood vessel preparation. The tissue specimen is put into an organ bath in a physiological salt solution (e.g. Kreb s, Tyrode s) and the drug is added. The response to drug administration usually is a contraction that is recorded. Plotting the response in relationship to the logarithm of the dose (concentration) gives a dose-response curve that is a sigmoid (Fig.1.5.).

d. Noradrenaline when attempting to maintain raised blood pressure in some patients with shock (angiotensin II is suitable in this condition). e. Gonadorelins goserelin)

(GnRH

analogues,

e.g.

Clinical Types Antagonism

Supersensitivity means that a certain dose of an agonist (or endogenous mediator) achieves a higher effect. This may be explained by upregulation of receptors (or decreased breakdown) and can occur with long-term use of competitive antagonists (rebound phenomenon after clonidine or β-blockers like propranolol).

of

Drug

a. Chemical antagonism The antagonist combines with the agonist away from the receptor, preventing the action of the agonist at this target receptor or tissue. For example, alkaline antacids neutralise gastric HCl in peptic ulcer; protamine sulphate (base) neutralises the acidic compound heparin preventing its action in overdose.

Examples of receptors are: Muscarinic (M1, 2,3)

b. Physiological antagonism The antagonist is a different agonist that acts on the same tissue as the agonist, but combine with different receptors (from those of the agonist) to produce effects on the tissue that are opposite to those of the agonist, e.g. adrenaline antagonises the effect of endogenous histamine on blood vessels and bronchial smooth muscle when used in the treatment of anaphylactic shock.

Acetylcholine Nicotinic (N1, 2)

¿1,2 Adrenaline

¾1,2 H1 Histamine

c. Pharmacological antagonism When the antagonist competes with the agonist for the specific receptor, combines with the receptor, and prevents the action of the agonist. The antagonist has no intrinsic activity (e.g. diphenhydramine antagonises the action of the endogenous histamine on the specific histamine receptor level as in the treatment of anaphylactic shock). This type of antagonism is further subdivided into:

H2

Agonism and Antagonism Drugs that interact with a receptor and elicit a response are called agonists and compounds that interact with receptors preventing the action are referred to as antagonists. An agonist is a drug that has affinity for a receptor and that has intrinsic activity or efficacy. A competitive antagonist has affinity but lacks intrinsic activity.

• Reversible antagonism This may be demonstrated with many antagonists (Fig. 1.5.). Reversible (competitive) antagonists Increasing the concentration of the agonist can fully overcome the inhibition 19

General Principles

Ramadi, 6 October 2009

by the antagonist (e.g. atropine and tubocurarine antagonising the actions of acetylcholine at muscarinic and nicotinic receptors respectively). Thus, a reversible (competitive) antagonist displaces the dose-response curve parallel to the right but do not change the maximum response.

Full agonist

• Irreversible antagonism When increasing the concentration of the agonist will never fully overcome the inhibition. This is probably due to receptor inactivation (e.g. phenoxybenzamine at αreceptors in blood vessels). Irreversible antagonism can also be observed on the activity of the appropriate enzymes; recovery of the enzyme activity depends on the formation of new enzymes.

Antagonist

Cell with a receptor occupied with a full agonist

Fig.1.4. A schematic representation of drugreceptor interaction. A full agonist can interact with a receptor producing an effect. A partial agonist produces some efficacy on its own and it reduces the efficacy of the full agonist. An antagonist has no efficacy and it inhibits the actions of the full agonist and the partial agonist.

Table 1.2. A selected list of clinically important irreversible antagonists

Site

Partial agonist

Drug

Phenoxybenzamine α-adrenoceptors Cholinesterase DFP (organophosphate) Prostaglandin G/H Aspirin synthase MAO (non-selective) Tranylcypromine & phenelzine* MAO-B Deprenyl (selegiline) H+,K+-ATPase Omeprazole GABA transaminase Vigabatrin ADP receptors Clopidogrel Xanthine oxidase Alloxanthine (oxypurinol) Constitutive β-lactamase Clavulanic acid

Response 100%

A

B

C

D

50%

E

* The selective MAO-A inhibitor moclobamide acts reversibly.

EC

EC

EC

Agonist Concentration (log scale) Fig.1.5. A. Log dose-response curve to a drug (A) on its own. B. The response to the drug (A) in the presence of the drug (B) representing reversible (competitive) antagonism; note there is a shift in the log dose response curve to the right and an increase in EC50 with no reduction in the magnitude of the maximal response. C. The response to the drug (C) on its own. Curves D and E represent the response to the drug (C) in the presence of increasing concentrations of an irreversible antagonist. Note: there is a reduction in maximal response to the drug D.

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important parameters of a drug, characterising its safety is the therapeutic index which can be calculated from animal experiments, it can be expressed as:

Response Full Agonist

LD50 Therapeutic index = ------ED50

Obviously this cannot be calculated in clinical medicine instead, the ratio of a toxic dose (TD) over the effective dose can be utilised, therefore Partial Agonist

TD50 Therapeutic index = ------ED50

Response B

A

C

Agonist scale) Fig.1.6. LogConcentration dose-response (log curves to a full agonist and partial agonist. Note: a partial agonist shows a reduced maximal response compared with that of the full agonist. Therefore, a partial agonist on its own exhibits agonistic activity (efficacy) but it behaves as antagonist on responses mediated by full agonists. This can be demonstrated by the oestrogen receptor partial agonist clomiphene.

Potency

Clinical Studies EC50

In addition to the dose-response relationship of an isolated organ or an individual patient to see the relationship between dose and a quantity of response. Such quantal information can be obtained from a population of individuals in which the dose (plotted on the horizontal axis) is evaluated against the percentage responding to treatment. From this curve, the ED50 value (that is the dose that has a therapeutic effect in 50% of the population) can be obtained. Beside its wanted (therapeutic) effects, a drug can produce unwanted (toxic) effects including death. In testing a new drug, increasing doses are given to a large number of animals and can thereby determine the 50% lethal dose or LD50. One of the most

EC 50

EC50

Agonist Concentration (log scale) Fig.1.7. Log dose-response curves for the drugs (A), (B) and (C). Drug (A) is more potent than drug (B) and (B) is more potent than the drug (C), while both A and B are more efficacious (with more efficacy) than C. Note: The maximal response is a measure of the efficacy while the EC50 is a measure of the potency; i.e. a drug with a higher EC50 is with a lower potency. When substituting morphine for A, codeine for B and aspirin for C it follows that morphine is more potent than codeine, both are more efficacious and more potent than aspirin as analgesic agents.

Clinically, the efficacy of a drug is more important than its potency. 21

General Principles

Ramadi, 6 October 2009

• Irreversible antagonist: (affinity, no efficacy, reduced maximal response, e.g. omeprazole, vigabatrin) • Potency: (activity per unit weight, ED50, e.g. analgesic agents) • Efficacy: (intrinsic activity, measure of maximal response, e.g. analgesic agents) • ED50: (effective dose, half of the maximal response elicited) • LD50: (lethal dose, half of the animals die) • Therapeutic index: (LD50/ED50, measure of safety) • Drug synergism: [summation, 2+2=4; potentiation, 2+2=5 (co-trimoxazole), 0+2=5 (benzerazide + L-DOPA)]

USEFUL NOTES The students are expected to know the concept and definition of the following terms. They are advised to give an example of a drug and a clinical condition, and illustrate by a diagram when appropriate. They may make use of the key words given with each term. • Receptor: (protein molecule, detector and transducer, muscarinic) • Second messenger: (molecule, translate the extracellular signal into a response, e.g. cAMP) • Tolerance: (desensitisation, analgesia, e.g. morphine; asthma, down-regulation, salbutamol) • Tachyphylaxis: (rapid tolerance, local anaesthesia, lidocaine, pH, longer acting local anaesthetic (e.g. bupivacaine) • Idiosyncrasy: [supersensitivity, unpredictable, dose-independent, e.g. chloramphenicol, aplastic anaemia; dosedependent, e.g. isoniazid (INH), hepatitis] • Up-regulation: (supersensitivity, rebound phenomenon, clonidine, or β-adrenoceptor blockers, cardiovascular problem) • Down-regulation: (see tolerance) • Agonism: (affinity and intrinsic activity, efficacy) • Partial agonist: (affinity with some efficacy, reduced maximal response, e.g. clomiphene, buspirone); bupropion: partial nicotinic agonist (basis for smoking cessation?) • Clinical types of antagonism: 1. Chemical (antacids, peptic ulcer) 2. Physiological (exogenous adrenaline, endogenous histamine, acting on different receptors, anaphylactic shock) 3. Pharmacological (diphendydramine, endogenous histamine, acting on the same receptor). • Antagonist: [affinity with little or no e.g. efficacy, reversible (competitive neostigmine, and partial agonist e.g. clomiphene), and irreversible phenoxybenzamine, aspirin] • Competitive (reversible) antagonist: (affinity, no efficacy, maximal response can be attained, dose-response curve shifts to the right, e.g. phentolamine, propranolol) 22

Essentials of Medical Pharmacology

Majid A. K. Lafi

AUTONOMIC PHARMACOLOGY It is the proximal location of the sympathetic ganglion in the sympathetic chain that make them accessible to the procedure of sympathetic blockade with local anaesthetics or sympathectomy, procedures that eliminate regional outflow of nerve impulses and mainly give rise to local vasodilatation. The sites of action of mediators in the autonomic nervous system are the most firmly established:

Introduction The autonomic nervous system, together with both the endocrine system and autacoids (including eicosanoids like prostaglandins and leukotrienes, histamine, 5hydroxytrytptamine, and peptides like angiotensin II and kinins), co-ordinates the regulation and integration of body functions. The endocrine system sends signals to target tissues by varying the levels of blood borne hormones; likewise, autacoids exert regulatory effects on local or distant effector tissues. On the contrary, the autonomic nervous system mediates its influence by rapid transmission of electrical impulses over nerve fibres terminate at effector tissues. The specific effects mediated by neuronal activity are achieved by releasing a chemical transmitter (neuromediator substance) across synaptic junctions delivering an effect on the postsynaptic membrane.

1. Postganglionic parasympathetic nerve endings on smooth muscle, cardiac muscle, and exocrine glands: acetylcholine 2. Postganglionic sympathetic nerve endings on smooth muscle, cardiac muscle, and exocrine glands: noradrenaline (except for sweat glands) An important exception to the generalisation that noradrenaline is the chemical mediator to sympathetically innervated structures are sweat glands, with anatomically sympathetic innervation, activated by cholinergic drugs and inhibited by anticholinergic drugs, such as atropine. Therefore, postganglionic fibres innervating sweat glands are cholinergic rather than adrenergic.

Drugs that produce their primary pharmacological effects through mimicking or inhibiting the functions of the autonomic nervous system are known as autonomic drugs. This chapter is primarily concerned with the fundamental physiology of the autonomic nervous system and emphasising on the role of neurotransmitters in the intertalking between extracellular events and intracellular biochemical events.

3. In all autonomic ganglionic synapses, acetylcholine is the primary neuromediator. The adrenal medulla secretes adrenaline when cholinergic drugs are injected, a response inhibited by ganglionic blocking agents like hexamethonium and mecamylamine. Embryologically, the adrenal medulla can be considered a modified sympathetic ganglion. It is therefore, not surprising that it responds to acetylcholine, the normal ganglionic mediator to both sympathetic and parasympathetic neurones.

The autonomic nervous system consists mostly of the efferent innervation of the viscera with its two major sub-divisions: the sympathetic and parasympathetic systems. The final common pathway is a two-neurone chain: a preganglionic neurone, located in the CNS that projects onto a postganglionic neurone, located in the periphery. In the sympathetic system the postganglionic neurones are generally located near the spinal cord, either paravertebral (sympathetic chain) or prevertabral (celiac ganglion). In contrast, the postganglionic neurones of the parasympathetic system are located in close proximity to their target organ.

4. CNS synapses: acetylcholine, noradrenaline, dopamine, serotonin (5HT), histamine, glutamic and aspartic acids, GABA, glycine, adenosine, and numerous peptides.

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specific cholinesterase is of the non-specific type.

5. Motor fibre terminals: Skeletal neuromuscular junctions acetylcholine is the neuromediator. The postsynaptic cholinergic nicotinic receptors of a subtype termed N2-receptor being more selectively blocked by tubocurarine than ganglionic nicotinic N1-receptors. The latter, however, is more selectively blocked by hexamethonium than the N2-receptors.

Acetyl CoA CAT Choline

Cholinergic Transmission The transmitter is acetylcholine (ACh) which is synthesised intraneurally from activated acetic acid (Acetyl-CoA) and choline. Upon release, it can act on muscarinic or nicotinic receptors and is rapidly broken down by cholinesterase (tissue bound) or pseudocholinesterase (serum). Choline can be re-utilised by being taken up back into the cholinergic neurone by a specific active mechanism.

Acetylcholine Choline + Acetate Cholinesterase ACh Muscarinic Receptors

The term muscarinic was introduced because of the mushroom poison muscarine, a quaternary amine alkaloid. The muscarinic actions are so called because they resemble those of the alkaloid muscarine and are equivalent to the action at parasympathetic postganglionic nerve endings and blocked by atropine and enhanced by anticholinesterase.

Fig.2.1. A simplified representation of a cholinergic neurotransmission function (neuroeffector junction) showing synthesis (choline acetyltransferase, CAT), storage (vesicles), release (exocytotic), postsynaptic site of action (e.g. muscarinic receptors), termination of action (by cholinesterase) of acetylcholine (ACh).

Acetylcholine is synthesised by the cytoplasmic enzyme choline acetyltransferase (CAT). Choline + Acetyl coenzyme A CAT

The compound hemicholinium blocks synthesis of the mediator by interfering with transport of choline across the neuronal membrane. Botulinus toxin blocks the release of acetylcholine.

Acetylcholine + Coenzyme A Cholinesterase Choline + Acetate

Most vascular regions do not receive parasympathetic innervation so that direct control of vascular tone is mediated by variations in sympathetic input to the vessels. Nevertheless, stimulation of muscarinic receptors, possibly located in the vascular endothelium rather than on the smooth muscle, by circulating agonists can dilate blood vessels and cause pronounced hypotension.

Destruction of acetylcholine is accomplished by cholinesterase, which are of two types. Acetylcholinesterase, or specific (or true) cholinesterase, hydrolyses acetyl esters of choline more rapidly than other esters. Pseudocholinesterase is a non-specific cholinesterase. Acetylcholinesterase is localised within neuronal membrane and, surprisingly, also in membranes of red blood cells where its function is unknown. Non24

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cAMP system (e.g. β and α2-adrenoceptors), and the phospholipase C causing the hydrolysis of phosphatidylinositol bisphosphate into diacylglycerol (DAG) and inositol triphosphate (IP3), e.g. α1adrenoceptors.

Several types of muscarinic receptors have been identified. M1 and M3 receptors are activated by ACh (or any muscarinic receptor agonist), the receptor undergoes a conformational change and interact with a G protein, which in turn activates phospholipase C. this leads to the hydrolysis of phosphatidylinositol bisphosphate (PIP2) into the second messengers diacylglycerol (DAG) and inositol trisphosphate (IP3) which cause a cascade of events leading to an increase in intracellular Ca++ can interact to produce cellular response (e.g. smooth muscle contraction). On the contrary, activation of the M2 subtype of muscarinic receptors on the cardiac muscle stimulates a G protein, which inhibits adenylate cyclase and increases K+ conductance, to which the heart responds with a decrease in rate and force of contraction.

Tyrosine DOPA Dopamine Noradrenaline MAO NA

¿2

U1

Adrenergic Transmission The transmitter is noradrenaline (NA) which is synthesised intraneurally from a precursor, the dietary amino acid tyrosine through the steps: tyrosine to DOPA and this in turn converted to dopamine (plays a role of a transmitter on its own right) which undergoes β-hydroxylation yielding noradrenaline. After being released α and β-adrenoceptors are activated postsynaptically and induce the pharmacological action through second messengers e.g. cAMP. The process is quickly terminated by an amine re-uptake (known as amine neuronal uptake, U1) mechanism into the nerve terminal (this can be blocked by cocaine and tricyclic antidepressants). Monoamine oxidase (MAO) or catecholamine-O-methyltransferase (COMT) breaks down a certain quantity and the main metabolite in the urine is vanillinmandelic acid (VMA).

COMT

¿ and ¾ Receptors

Fig.2.2. A simplified representation of noradrenergic synaptic function illustrating synthesis, storage, release, postsynaptic site of action (α and βreceptors), autoregulatory α2-receptors, uptake1 (U1, reuptake of noradrenaline, NA), monoamine oxidase (MAO), and catecholamine-O-methyltransferase (COMT).

Noradrenaline released from postganglionic nerve diffuses across the synaptic membrane and interact with postsynaptically located receptors (on the effector cell) or on the presynaptically located receptors (autoregulatory receptors) modulating its own release. Noradrenergic (adrenergic) receptors can be coupled with adenylate cyclase

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Table 2.1. Transmitter, receptors, primary locations, postreceptor mechanism, stimulant substances and blockers in the autonomic nervous system. Primary location Postganglionic dendrites

cell

body,

Motor end plate

Nerve Heart, nerve, smooth muscle

Glands, smooth muscle, endothelium Postsynaptic effector cells (e.g. smooth muscle) Presynaptic nerve terminals, lipocytes, smooth muscle Postsynaptic effector cells (e.g. heart, lipocytes, juxtaglomerular cells of the kidney) Postsynaptic effector cells (e.g. airway and uterine smooth muscle, cardiac muscle) Presynaptic nerve terminals (e.g. parasympathetic fibres supplying airway smooth muscle) Postsynaptic effector cells, especially Lipocytes Brain, postsynaptic effector cells (e.g. renal vascular beds) Brain, presynaptic nerve terminals, effector tissues especially smooth muscle Brain Brain, cardiovascular system

Transmitter Receptor Acetylcholine N1 -receptor (NN-receptor) Acetylcholine N2-receptor (NM-receptor) Acetylcholine M1 M2

M3 Noradrenaline Adrenaline α1-receptor α2-receptor

β 1-receptor Adrenaline β 2-receptor

β 3-receptor Dopamine D1-receptor

D2-receptor D3-receptor D4-receptor

Postreceptor mechanism +

Na , depolarising channel Na+, depolarising channel

Stimulated by

Blocked by

K ion

Nicotine

Hexamethonium Mecamylamine Trimethaphan

K+ ion

Nicotine

Tubocurarine

Muscarine

Pirenzepine

Muscarine

Gallamine

Muscarine

HHSD

Phenylephrine

Prazosin

Clonidine Methylnoradrenaline

Yohimbine

Dobutamine

Betaxolol

Salbutamol

Butoxamine

+

IP3 , DAG cascade Inhibition of cAMP production, activation of K channel IP3 , DAG cascade IP3 , DAG cascade, ↑ intracellular calcium Inhibition of adenylate cyclase, ↓ cAMP Stimulation of adenylate cyclase, ↑ cAMP Stimulation of adenylate cyclase, ↑ cAMP

Stimulation of adenylate cyclase, ↑ cAMP Stimulation of adenylate cyclase, ↑ cAMP ↑ K conductance; may inhibit adenylate cyclase Inhibition of adenylate cyclase Inhibition of adenylate cyclase

BRL37344

Fenoldopam

Bromocriptine

Quinpirol Clozapine

HHSD: Hexahydrosiladifenidol BRL37344: Sodium-4-(2-[2-hydroxy-{3- chlorophenyl}ethylamino]propyl)phenoxyacetate DAG: Diacylglycerol IP3: Inositol trisphosphate

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Parasympathetic

Somatic motor

Sympathetic

ACh

ACh

ACh ACh

Adrenal medulla

ACh

AD + NA

ACh

ACh

ACh

Nicotinic receptors

Muscarinic receptors

Muscarinic receptors

Striated muscle

NA

DA

Adrenoceptors

Effector Organs

Fig.2.3. A schematic representation of the autonomic nervous system. Note: (1) The parasympathetic ganglia are close to or on the surface of the effector organs and that the postganglionic fibres are usually shorter than preganglionic fibres. (2) The neurotransmitter in all the autonomic ganglia is acetylcholine acting primarily on postsynaptic nicotinic receptors, while the neurotransmitter released from the sympathetic postganglionic neurones is usually noradrenaline (NA), and dopamine (DA) with an exception that acetylcholine (ACh) is released by sympathetic nerves supplying sweat glands. The adrenal medulla releases primarily adrenaline (AD) and noradrenaline (NA).

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Table 2.2. Responses of some effector organs to autonomic nerve impulses, and circulating catecholamines and autonomic drugs.

Effector organ Eye Iris Radial muscle Sphincter muscle Ciliary muscle Heart Sinoatrial node Ectopic pacemakers Contractility (atria) Arterioles Skin, splanchnic Skeletal muscle

Endothelium Platelets Bronchial smooth muscle Gastrointestinal tract Smooth muscle Walls Sphincters Secretion Myenteric plexus Genitourinary smooth muscle Bladder wall Sphincter Uterus, pregnant Penis, seminal vesicles Prostate Skin Pilomotor muscle Sweat glands6 Eccrine (thermoregulatory) Apocrine (stress) Metabolic functions Liver Liver Fat cells

Responses of Parasympathetic Receptor2 Action1

Sympathetic Action

Receptor

…. Contraction (miosis) Contraction

…. M3 M3

Contraction …. [Relaxation]

α1 …. β

Decrease rate …

M2

….

Increase rate Increase rate

Decrease

M2

Increase

β 1, β 2 β 1, β 2 β 1, β 2

…. …. …. …. Releases nitric oxide

α β2 α M4 …. α2 β2

Contracts

M3

Constriction Dilatation [Constriction] Dilatation …. Aggregation Relaxes

Contracts Relaxes Increases Activates

M3 M3 M3 M1

Relaxes Contracts …. Inhibits

Contracts Relaxes Contracts

M3 M3 M3

Erection

M

Relaxes Contracts Relaxes Contracts Ejaculation Contraction

β2 α1 β2 α α α1

…. …. …. …. M3 3

α2 5, β 2 α1 …. α

….

….

Contracts

α1

…. ….

…. ….

Generalised secretion Localised secretion

M α1

Activates gluconeogenesis α/β 2 7 Activates glycogenolysis α/β 2 Activates lipolysis β3 Inhibits lipolysis α2 …. Inhibits potassium uptake …. α1 …. …. Promotes potassium uptake β2 Kidney …. Renin release …. β1 Modified from Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Appleton & Lange, USA. Page 119. …. …. ….

…. …. ….

1

Less important actions are in brackets. Specific receptor type: α = alpha, β = beta, M = muscarinic. Muscarinic receptor subtypes are determined mostly in animal tissues. 3 The endothelium of most blood vessels releases nitric oxide, which causes marked vasodilatation, in response to muscarinic stimuli. These endothelial muscarinic receptors are not innervated and respond only to circulating muscarinic agonists. 4 Vascular smooth muscle in skeletal muscle has sympathetic cholinergic dilator fibres. 5 Probably through presynaptic inhibition of parasympathetic activity. 6 Generalised secretion: thermoregulatory; localised secretion: apocrine (stress, embarrassment). 7 Depends on species.

2

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Table 2.3. A summary of selected clinically important cholinergic drugs and related compounds. Drug Directly Acting Agents Bethanechol

Pilocarpine

Carbachol

Indirectly Acting (Reversible) Agents Physostigmine

Action

Selected therapeutic uses and important remarks

Muscarinic receptors (activation) Muscarinic receptors (activation) Muscarinic & nicotinic NN-receptors (activation)

Atonic bladder (in postpartum or postoperative nonobstructive urinary retention Side-effects: generalised cholinergic stimulation* Narrow (closed) and wide (open) angle glaucoma; it can enter the brain causing CNS-disturbances

Inhibits AChE Atony of bladder and intestine, glaucoma, overdose with anticholinergics (e.g. atropine, phenothiazines and tricyclic antidepressants; it enters the brain, causes generalised cholinergic stimulation*; duration of action (0.5-2 hr) Glaucoma; duration of action (4-6 hr)

Demecarium Neostigmine

Atony of bladder and intestine, overdose with competitive neuromuscular blocking agents (e.g. tubocurarine), myasthenia gravis Side-effects: generalised cholinergic stimulation It poorly enters the CNS; duration of action (0.5-2 hr) In chronic management of myasthenia gravis; duration of action (3-6 hr) In chronic management of myasthenia gravis; duration of action (4-8 hr) In the diagnosis of myasthenia gravis, postoperative paralytic ileus; short duration of action (about 5-15 minutes)

Pyridostigmine Ambenonium Edrophonium

Indirectly Acting (Irreversible) Agents (organophosphate, nerve agent) Isoflurophate (DFP)

Covalently binds to AChE In chronic management of open angle glaucoma (ointment, last for 1 week); it enters CNS, causes generalised cholinergic stimulation* (largely reversed by high dose of atropine); DFP ages in 6-8 hr In chronic management of open angle glaucoma; duration of action (100 hr)

Echothiophate Reactivation of Acetylcholinesterase (AChE) Pralidoxime

Rarely used because of high potency and long duration of action, glaucoma, when used topically shows little or no adverse-effects

Displaces organophosphate regenerating the enzyme

Poisoning with organophosphophorus compounds (before enzyme ageing occurs, i.e. loss of an alkyl group from the phosphorylated enzyme); it can reverse the effect of DFP except for those in CNS; less effective with newer nerve agents (enzyme ageing in seconds). * Generalised cholinergic stimulation: salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhoea, and bronchospasm; if the drug enters the CNS (e.g. physostigmine), it would show CNS disturbances which may lead to convulsion.

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Table 2.4. A summary of selected clinically important cholinergic antagonists (cholinergic blockers or anticholinergic drugs) Drug

Selected therapeutic uses and important remarks*

Antimuscarinic agents

Atropine

In ophthalmology to produce mydriasis & cycloplegia prior to refraction (a single dose lasts for 7 days) In spastic disorders of GI and lower urinary tracts In organophosphate poisoning In premedication prior to surgery, to suppress respiratory secretion in children

Homatropine Tropicamide Scopolamine (hyoscine) Ipratropium Clidinium

Cycloplegic for refraction in children (24 hr duration) Fundus examination (duration of 3 hr) In obstetrics with morphine to produce amnesia and sedation Motion sickness Asthma (inhalation) With chlordiazepoxide (Librax ) in GI disorders like peptic ulcer, nervous dyspepsia, irritable bowel syndrome, spastic colitis, mild ulcerative colitis

Isopropamide Pirenzepine

With trifluoperazine (Stelabid ) in peptic ulcer, visceral spasm Peptic ulcer (inhibits acid secretion), poorly enters the CNS, thus, no or little CNS side-effects Peptic ulcer, irritable bowel syndrome, & urinary disorders of storage (urinary frequency, incontinence, nocturnal enuresis Urinary disorders of storage (as above)

Propantheline Emepronium (Cetiprin ) CNS Agents Benzotropine Procyclidine Benzhexol-HCl Orphenadrine

(Centrally acting antimuscarinic antagonists) Drug induced dystonias and Parkinson s disease

Ganglionic blockers

Mecamylamine Trimethaphan Neuromuscular blockers

Moderately severe to severe hypertension Short-term treatment of hypertension (emergency lowering of blood pressure, when other agents cannot be used) See appropriate section in the chapter on CNS pharmacology (later on)

Nondepolarising (competitive agents) Depolarising agents * Adverse-effects commonly observed with cholinergic antagonists: blurred vision, mydriasis, constipation, urinary retention, tachycardia, and confusion.

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Table 2.5. A summary of selected clinically important adrenergic agonists Drug

Action (receptors)

Selected therapeutic uses and important remarks

Catecholamine* Adrenaline

α1, α2, β1, β 2

Acute asthma, open angle glaucoma, anaphylactic shock, in local anaesthetics to increase duration of action

Noradrenaline Isoprenaline

α1, α2, β1 β1, β 2

Dopamine

dopaminergic

β1 β1

Shock Asthma, severe bradycardia, heart block, sinus bradycardia Shock, decreased renal function Congestive heart failure Congestive heart failure

Phenylephrine

α1

Nasal congestion, hypotension

Methoxamine

α1

Clonidine

α2 (CNS)

Hypotension (during surgery, does not produce cardiac arrhythmias in sensitised heart, i.e. no beta activity) Paroxysmal supraventricular tachycardia Hypertension, withdrawal from opiates or benzodiazepines

Salbutamol Terbutaline Ritodrine

β2

Dobutamine Non-catecholamines♠

Asthma (bronchospasm), premature labour (they have short onset and duration of action)

Salmeterol Formoterol

β2

Asthma (they have slow onset and long duration of action)

Amphetamine

α, β (CNS)

Attention deficit (hyperkinetic) disorder (in children)

α1, α2, β1, β 2 Nasal congestion, asthma (CNS) * Rapid onset of action, brief duration of action, not administered orally, and do not enter the brain. ♠ Longer duration of action, all can be administered orally. Ephedrine

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Table 2.6. A summary of selected clinically important adrenergic antagonists (sympatholytic agents), and other drugs affecting neurotransmission. Drug ¿-adrenoceptor antagonists Phenoxybenzamine

Action (receptors)

Selected therapeutic uses and important remarks

α1, α2

Pheochromocytoma, Raynaud s disease (irreversible block)

(blocking) Phentolamine

α1, α2

Prazosin Terazosin Doxazosin1

α1

Diagnosis of pheochromocytoma (competitive block); it induces reflex tachycardia. (by vasodilatation and blocking autoregulatory α2 receptors) Hypertension [first dose effect, syncope (fainting)] Benign prostatic hyperplasia

Tamsulosin

α1c

Benign prostatic hyperplasia (Not for hypertension) Ureteral colic

¾-adrenoceptor antagonists2 Propranolol

β1, β2

Hypertension, migraine, hyperthyroidism, pheochromocytoma, angina pectoris, myocardial infarction

β1, β2 β1

Glaucoma, hypertension Hypertension

β1, β2 β 1, β 2, α1 β 1, β 2, α1

Hypertension Pheochromocytoma (hypertension) Angina pectoris, cardiomyopathy, (heart failure, hypertension) Higher ratio of β to α blockade than labetolol

Timolol Acebutolol Atenolol Metoprolol Pindolol Labetalol Carvedolol

Drugs affecting neurotransmitter release or re-uptake Reserpine

Guanethidine

Disrupts storage of amines causing depletion of amines

Hypertension (no longer used because of adverse-effects like depression)

Adrenergic neurone blocking agent

Hypertension (no longer used because of adverse-effects, orthostatic hypotension, male sexual dysfunction CNS stimulant (drug abuse)

Cocaine

Neuronal amine reuptake (U1) blocker 1 Doxazosin differs from prazosin and terazosin in having a longer t of about 22 hours. 2 For more details see a special section on β-antagonists in the chapter on Cardiovascular Pharmacology.

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While, contraction of the longitudinal ciliary muscle alters the tension on the trabecular meshwork, opening its pores and thus facilitating outflow of the aqueous humor into the canal of Schlemm. Increased outflow reduces intraocular pressure benefiting patients with glaucoma. It follows that muscarinic blocking drugs like atropine inhibit such effects of muscarinic receptor activation.

Ocular Pharmacology The eye represents a good introduction into system-based pharmacology as this organ comprises multiple autonomic receptors (Fig.2.4.). The structure of the anterior chamber contains several tissues supplied by different autonomic innervations. The iris, a multi-unit smooth muscle, consists of the circular pupillary constrictor muscle (sphincter) which is contracted muscarinic agonists causing miosis (a reduction in pupil size), and the radially oriented pupillary dilator muscle which is contracted by -adrenoceptor agonists causing mydriasis (an increase in pupil size). Muscarinic agonists contract the muscle fibres of the ciliary body. Contraction of the circlar ciliary muscle causes accommodation of focus for near vision.

Activation of -adrenoceptors on the ciliary epithelium facilitates the secretion of aqueous humor. Hence, the use of adrenoceptor blockers like timolol reduces the secretory activity and thus resulting in reduced intraocular pressure, providing a useful pharmacological intervention for the treatment of glaucoma.

Cornea

Canal of Schlemm Trabecular meshwork Dilator ( )

Sphincter (M)

Iris

Sclera

Lens

Ciliary epithelium ( ) Longitudinal ciliary muscle (M)

Circular ciliary muscle (M)

Fig. 2.4. A simplified schematic diagram of the structures of the anterior chamber of the eye illustrating tissues with their autonomic functions and receptors. Aqueous humor is secreted by the ciliary epithelium, flows through the anterior chamber, and exits through the canal of Schlemm (thick arrow).

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Table 2.7. A summary of the important drugs used in glaucoma Drugs or class Cholinergic agents Muscarinic agonists (pilocarpine) Anticholinesterases [physostigmine, DFP (isoflurophate)] -agonists Non-selective Adrenaline 2 -selective Apraclonidine Brimonidine

Nature of action and important remarks Improved drainage of aqueous humour by contracting the longitudinal muscle of the ciliary body leading to opening the trabecular meshwork around Schlemm s canal (drainage channels), causing immediate drop in intraocular pressure (IOP). Therefore, these drugs are used in acute glaucoma in addition to chronic open-angle glaucoma. Enhances aqueous outflow facility (drainage, α-receptors) and/or decreases production of aqueous humour by vasoconstriction of the ciliary body blood vessels leading to reduced IOP. Topical 2% adrenaline solution used in chronic open-angle glaucoma. Contraindicated in closed-angle and acute glaucomas as they dilate the pupil, dilated iris can occlude the outflow drainage pathway at the angle between the cornea and the ciliary body.

¾-blockers Decrease production of aqueous humour by the ciliary body (non-pigmented Timolol Betaxolol epithelium β 2-receptors) leading to reduced IOP. No effect on focusing for near vision or pupil size; (used in chronic open-angle glaucoma, narrow and Cartelol acute glaucoma. Metipranolol Diuretics Carbonic anhydrase Decreases production of aqueous humour by blocking carbonic anhydrase in inhibitors the ciliary body leading to reduced IOP. They are used in chronic glaucoma as Acetazolamide well as in acute closed-angle glaucoma. Osmotic agents Mannitol Reduces IOP in acute closed-angle glaucoma. Increase outflow by acting at the FP receptor and are administered as drops Prostaglandins (PGF2 derivatives: into the conjunctival sac once or twice daily. Adverse effects include latanoprost, irreversible brown pigmentation of the iris and eyelashes, drying of the eyes, unoprostone) and conjunctivitis. Note: For simplicity purposes, open-angle glaucoma = wide-angle glaucoma = chronic simple glaucoma; narrow-angle glaucoma → closed-angle glaucoma → acute glaucoma. Pupillary block glaucoma: adhesion of pupil to the lens which may occur in uveitis.

Table 2.8. A summary of selected mydriatics and cycloplegics Drug Tropicamide

Duration 3-6 hr

Fundus examination

Homatropine

1-3 days

Cycloplegic for refraction* in children

Atropine

7-10 days

For refraction as above; also iridocyclitis** (+ phenylephrine♠)

Use

They may precipitate acute glaucoma in the elderly and predisposed patients * Refraction: determination of the refractive errors of the eye and their correction by glasses ** Iridocyclitis: inflammation of the iris and the ciliary body ♠ In iritis, phenylephrine dilates the pupil, therefore, reducing the possibility of adhesion of the iris to the lens (i.e. pupillary block glaucoma). Cycloplegics reduces contraction of the circular muscle of ciliary body. Myopia: contraction of the circular muscle Phenylephrine and oxymetazoline are ¿-agonists, mydriatic, not cycloplegic; they are contraindicated in patients with closed-angle glaucoma

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a. increasing detrusor muscle contractility b. decreasing outlet resistance

Drugs used in abnormal micturition

2. Urinary disorders of storage (e.g. urinary frequency and incontinence, and nocturnal enuresis) can stem from various dysfunctions. These disorders may be due to detrusor or sphincter problems, sensory disturbances, detrusor muscle irritability (involuntary bladder contractions), secondary to neurological or inflammatory diseases, and stress urinary incontinence (sphincter dysfunction). Treatment of these disorders may be achieved pharmacologically by a. decreasing detrusor contractility b. increasing outlet resistance.

Drugs may be used to alleviate abnormal micturition. The strategy of treatment depends on the nature of disorder and principally may be achieved by two major approaches: a. altering detrusor muscle activity b. altering outlet resistance (bladder neck activity). There are two major disorders of micturition, urinary disorders of emptying and storage are common encounters. 1. Treatment of urinary retention (disorder of emptying) may be achieved pharmacologically by

Detrusor Motor: parasympathetic Sensory: sympathetic

Excitatory M-receptors

Trigone & Sphincter Motor: sympathetic Sensory: sympathetic

¾2 M

Detrusor muscle

¿1 Capsular smooth muscle

Somatic Fig. 2.5. A schematic representation of urinary bladder showing muscarinic (M) receptors being the most important excitatory receptors in the detrusor muscle; while, α1-receptors being the most important ones involved in the bladder neck function. Note: In the bladder neck, although β2-receptors and M-receptors are believed to mediate inhibitory actions, they are clinically not important.

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Table 2.9. A summary of selected drugs used in micturition disorders (neurogenic bladder)

Drug Antimuscarinic agents Propantheline* Emepronium* Tricyclic antidepressants** Imipramine (Tofranil) Amitriptyline (Tryptizol) Nortriptyline (Aventyl) Oestrogens

Parasympathetic agents Bethanechol Carbachol Distigmine ¿1-adrenoceptor antagonists Prazosin (α1) Tamsulosin (α1a) 5¿-reductase inhibitor Finasteride (Proscar)

Nature of actions

Type of micturition disorder

Reduces detrusor instability

Incontinence (enuresis)

Three possible actions may be involved 1. antimuscarinic (detrusor effect) 2. blocking U1-amine re-uptake increasing sympathetic drive at bladder neck and thus outlet resistance 3. by altering sleep pattern

Nocturnal and daytime incontinence (enuresis)

Improve atrophy of urethral epithelium (given locally in vagina or systemically by mouth) Stimulate the detrusor muscle

Incontinence (in menopausal women)

Blocks α1 -receptors at capsular smooth muscle of the prostate easing outlet resistance

Benign prostatic hyperplasia (urinary frequency)

Hypotonic bladder (due to upper motor neurone lesion)

Inhibits conversion of testosterone to Benign prostatic hyperplasia the dihydrotestosterone (reducing (urinary frequency) prostatic volume by 20%, thus reducing outlet resistance resulting in increased urine flow * Propantheline and emepronium are quaternary ammonium compounds, not well absorbed from the GIT (oral bioavailability 5-10%) and their entry into the CNS is limited. On the other hand, atropine and related antimuscarinic drugs are tertiary amines, well absorbed from the GIT and enter the CNS; they therefore have a higher incidence of CNS adverse effects. ** For more details see the section on tricyclic antidepressants in CNS Pharmacology  The popular trade name in Iraq Note: In dynamic disturbances, i.e. seasonal (like in winter), α-receptor antagonists are useful; in static (glandular and usually progressive) disturbances, finasteride is useful.

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ANTIHYPERTENSIVE DRUGS Introduction

The first rule should be to treat the underlying cause in the cases with secondary hypertension with surgical therapy and to attempt normalisation by non-drug therapy. This means elimination of risk factors, obesity, salt and smoking. Dietary measures such as low calorie intake and sodium restrictions should be adhered to.

Hypertension is one of the commonest disorders, defined as a persistent diastolic blood pressure greater than 90 mm Hg that usually associated with increased systolic blood pressure greater than 140 mm Hg. Several factors may result in the development of hypertension; however, the most important is increased peripheral vascular smooth muscle tone leading to increased arteriolar resistance and reduced capacitance of the venous system. Over 90% of hypertensive patients have essential hypertension in which the blood pressure regulating mechanism is responsible for the development of secondary hypertension (<10%).

ARTERIAL BLOOD PRESSURE

Heart rate

=

Treatment of Hypertension It is principally targeted at the major factors influencing blood pressure:

CARDIAC OUTPUT

l

PERIPHERAL RESISTANCE

Filling pressure

Contractility

Blood volume

Venous tone

Fig. 3. 1. A chart showing the important determinants of arterial blood pressure. Drugs can interfere with these various factors resulting in alteration of arterial blood pressure. The principle of the treatment of hypertension is according to a step-up procedure starting with very simple means and adding additional steps if necessary. Essentially, we can use 4 steps as shown below: Prazosin, minoxidil, CNS acting drugs ACE-blockers, Ca-blockers β-blockers or diuretic or both Diet, elimination of stress, physical exercise β-blockers and diuretics are, by most physicians, considered first, either alone or in combination. Of the β-blockers there is not

4 3 2 1

much difference between the different drugs in relation to their blood pressure lowering efficacy (e.g. propranolol, metoprolol,

37

Cardiovascular Pharmacology - Antihypertensive Drugs

CNS

ACE inhibitors Captopril Lisinopril

Renal Tubules Thiazide diuretics Loop diuretics K+sparing diuretics

AT1-receptors Losartan Valsartan

1

Sympathetic Ganglia Trimethaphan

Vasomotor Centre Clonidine Methyldopa

¾1-receptors on Juxtaglomerular Cells Propranolol Atenolol

Kidney Kidney

Ramadi, 6 October 2009

5

Sympathetic 2 Nerves Adrenergic Terminals Guanethidine Reserpine

Anatomical Sites of the Action of Antihypertensive Drugs

SA Node & Myocardium Verapamil Diltiazem

Heart Blood Vessels Vascular Smooth Muscle Hydralazine Minoxidil Nitroprusside Diazoxide Ca channel blockers Thiazides

4

3

¾1-receptors Propranolol Atenolol ¿1-receptors Prazosin Phentolamine

Fig.3.2. The anatomical sites of action of antihypertensive drugs. Several antihypertensive drugs act at more than one site: β-blockers act at sites 3 and 5; thiazides act at sites 4 and 5; and calcium channel blockers act at sites 3 and 4.

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drugs are seldom used because of their anticholinergic side effects.

atenolol, or pindolol). For optimal compliance a preparation should be chosen which could be administered once daily such as atenolol or pindolol. β-blockers can act by a variety of mechanisms such as 1. Reduction in cardiac output 2. Reduction in renin secretion 3. Reduction in sympathetic (central and/or peripheral)

Centrally acting antihypertensive: these include methyldopa and clonidine reduce blood pressure by stimulating postsynaptic α2-receptors in the CNS. Reserpine acts by depleting sympathetic nerve terminals of their transmitter, noradrenaline. All of these drugs act by reducing sympathetic vasoconstrictor tone but also cause an unacceptable high incidence of mental depression and sedation.

outflow

Of the diuretics mostly thiazide have been used such as hydrochlorothiazide, bendrofluazide and chlorthalidone, a thiazide-related compound which has a longer duration of action. These diuretics act by reducing plasma volume and in part by reducing peripheral vascular resistance. The antihypertensive effect is not much enhanced by increasing the dose. The response rate to treatment with β-blockers or diuretics is about 60% and can be increased to about 80% by the combination of a β-blocker and a thiazide.

Adrenergic neurone blocking agents such as guanethidine and bretylium prevent the release of noradrenaline from postganglionic adrenergic neurones, but these drugs cause postural hypotension failure of ejaculation and diarrhoea.

¾-Blockers A special consideration is given to βblockers, as this class of drugs is a frequent encounter in clinical practice. β-blockers are competitive antagonists of catecholamines at the site of β-adrenergic receptors. This antagonist activity is dose-dependent and reversible, since an adequate concentration of catecholamines is enough to dislodge the βblockers from the receptor. β-blockers can be classified pharmacologically according to the following properties:

The next step in non-responders is the addition of a vasodilator such as captopril (ACE-inhibitor) or nifedipine (Ca-blocker). Other drugs that can be considered are the αblocker prazosin or the centrally acting drugs methyldopa and clonidine. In acute hypertension where blood pressure has to be lowered rapidly diazoxide, a thiazide without diuretic action, sodium nitroprusside, and nifedipine can be used (the latter orally, or sublingually). Of mostly historical interest are the following compounds that act by reducing sympathetic tone:

• • • •

β 1-receptor selectivity Intrinsic sympathomimetic activity (ISA) Membrane stabilising activity Pharmacokinetics

¾1-receptor selectivity

1. Ganglionic blocking drugs (e.g. hexamethonium) 2. Centrally acting antihypertensives (clonidine) 3. Adrenergic neurone blockers (e.g. guanethidine)

β-Blockers can be non-selective affecting both β1-receptors and β2-receptors, such as propranolol, pindolol, oxprenolol, timolol, sotalol and nadolol, or β1-receptors selective atenolol, acebutolol and metoprolol having little influence on β2-receptors when employed in low doses. Theoretically, β 1blockers are less likely to cause bronchoconstriction; however, clinically none of the available β 1-blockers is sufficiently selective to be safely used in asthma. The

Ganglionic blockers interrupt impulse transmission in sympathetic (but also parasympathetic) ganglia, e.g. hexamethonium or trimethaphan. These

39

Cardiovascular Pharmacology - Antihypertensive Drugs

principal practical advantage of β 1-receptor selective blockers is in diabetics. These blockers spare β2-receptors that mediate both the symptoms of hypoglycaemia and the counter-regulatory metabolic responses (glycogenolysis and glucagon secretion) that reverse hypoglycaemia.

Intrinsic (ISA)

sympathomimetic

Ramadi, 6 October 2009

difference in hepatic transformation the bioavailability is variable in different βblockers. Some of the metabolites of βblockers are pharmacologically active. Thus, propranolol forms 4-hydroxypropranolol that has β-blocking properties and a shorter plasma t than the parent compound. The degree of hepatic metabolism varies from almost 100% (propranolol, oxprenolol, alprenolol) to moderate breakdown of 5060% of the administered dose (sotalol and pindolol) to virtually no metabolism (atenolol). The elimination of β-blockers therefore varies considerably, e.g. atenolol and practolol are excreted almost entirely by the kidney and their dosage should therefore be reduced in cases with renal insufficiency. On the other hand propranolol and metoprolol are eliminated almost entirely by the liver, therefore, clearance diminishes as hepatic function decreases. Pindolol is partly eliminated by the liver and partly by the kidneys. The plasma t of propranolol and pindolol is about 3 hours but, particularly, in the case of the antihypertensive action their pharmacological effect is much longer than can be expected from plasma levels and successful control of hypertension can be achieved with once daily administration of pindolol, metoprolol and atenolol.

activity

Some β-blockers may also stimulate βreceptors (partial agonists) at the same time as they also block the effect of catecholamines. These drugs are said to be intrinsic sympathomimetic activity (ISA); pindolol, oxprenolol and acebutolol belong to this group. These drugs cause fewer falls in resting heart rate than the β-blockers without ISA, and therefore may be less effective in severe angina pectoris in which reduction in heart rate is particularly desirable. Because of fewer falls in cardiac output, these agents are less likely to produce cold extremities. However, practically all β-blockers including those with ISA, which may offer no advantage, can produce heart failure since patients with heart failure already have high sympathetic drive. Pindolol is a partial agonist on ¾-receptors, at low basal sympathetic flow it has agonistic activity, but at a high sympathetic flow it produces antagonistic activity.

Indications 1. Angina pectoris 2. Arterial hypertension 3. Cardiac arrhythmias (mainly supraventricular) 4. Secondary coronary heart disease (CHD) prevention (after infarction) 5. Migraine 6. Control of excessive β-receptor stimulation in thyrotoxicosis and phaeochromocytoma 7. Glaucoma 8. Adrenergic tremor

Membrane stabilising activity Of the β-blockers propranolol, oxprenolol, and acebutolol have membrane stabilising (quinidine-like, local anaesthetic or cardiac depressant) action (MSA). This effect is probably clinically not important except that when applied topically for glaucoma that these agents will anaesthetise the eye therefore timolol (which does not have an MSA) is used in this condition.

Adverse effects 1. Bronchoconstriction 2. AV-block and depression of cardiac contractility (congestive heart failure) 3. Cold extremities (peripheral vasoconstriction) 4. Hypoglycaemia or interference with recovery from hypoglycaemia

Pharmacokinetics Most β-blockers are well absorbed from the GIT after oral administration. Due to 40

Essentials of Medical Pharmacology

Majid A.K. Lafi

5. Sleep disturbance and nightmares (CNS effect with lipid soluble agents like propranolol) 6. Deleterious effect on plasma lipids (↓ HDL) 7. Impotence

2. Bronchial asthma 3. Diabetes 4. Renal or hepatic impairment 5. Congestive heart failure (unless it is due to tachyarrhythmia treatable with β-blockers) 6. Sinus bradycardia 7. Second and third degree heart block 8. Intermittent claudication 9. Pregnancy (foetal bradycardia and neonatal hypoglycaemia)

Cautions/ Contraindications

1. Abrupt withdrawal of β-blockers (may result in sympathetic overactivity)

Table 3.1. A summary of the pharmacological characteristics of β-blockers Drugs

Non-selective Propranolol1 Pindolol Oxprenolol Timolol Sotalol Nadolol Labetolol Esmolol3 Selective Atenolol1 Acebutolol Metoprolol

ISA

MSA

Lipid solubility

Gut absorpt ion

Liver metabolism

Bioavail ability

CNS Effect

0 + + 0 0 0 +2 0

+ 0 + 0 0 0 + 0

High Moderate + Moderate Low Low Moderate

100% 95% 95%

100% 65% 90%

30 90

+ + +

30%

0

0 + 0

0 + (0)

0

50%

0

+

100%

90%

50 90 30 30 0

Minimal

40 50 50

Minimal +

ISA = intrinsic sympathomimetic (partial agonist) activity MSA = membrane stabilising activity (quinidine-like effect, local anaesthetic effect) 1 The practical points with propranolol is being lipid soluble and undergoes hepatic metabolism while atenolol is being hydrophilic and eliminated by the kidney. 2 Partial agonist effects at 2-receptors. 3 t = 10 minutes. angiotensin (including vasoconstriction, and aldosterone release). In addition, trophic effects on cardiovascular tissues have been attributed to angiotensin II. In contrast to angiotensin AT1-receptor, AT2-receptor mediates antiproliferative actions.

ACE-inhibitors Renin, the enzyme released from the kidneys in response to β1-adrenergic stimulation converts a circulating glycoprotein (angiotensinogen) into the biologically inert angiotensin I which is eventually converted into the highly potent vasoconstrictor angiotensin II by angiotensin converting enzyme (ACE, or kininase II). ACE is located on the luminal surface of the capillary endothelial cells, particularly, in the lungs. Angiotensin II act on two G-protein coupled receptors. Angiotensin AT1-receptor accounts for all the classic actions of

Pressor actions and cardiovascular morbid changes of angiotensin II Neural mechanisms 1. Increased central flow 2. Presynaptic augmentation noradrenaline release

41

of

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Cardiovascular Pharmacology - Antihypertensive Drugs

3. Augmentation of adrenal release 4. Postsynaptic augmentation pressors Vascular mechanisms 1. Direct vasoconstriction 2. Cellular hypertrophy (chronic)

and

Ramadi, 6 October 2009

adrenaline

Indications

of

1. Heart failure (critically part of the management) 2. Arterial hypertension 3. Secondary coronary heart disease prevention (after infarction) 4. Diabetic nephropathy (postponement and diminishing proteinuria probably due to improved intrarenal hemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure; even in the absence of lowering of blood pressure) 5. Vascular changes and cardiac hypertrophy of hypertension (reversal)

other

hyperplasia

Cardiac mechanisms 1. Hypertrophy and fibrosis (associated with congestive heart failure and myocardial infarction) Other volume-related mechanisms 1. Aldosterone release modulation 2. Vasopressin (ADH) release modulation 3. Increased thirst 4. Increased dietary salt intake (salt-craving)

Adverse effects 1. Taste changes 2. Persistent dry cough (bradykinin related) 3. Liver damage 4. Reversible renal impairment in patients with bilateral renal artery stenosis 5. Proteinuria [associated with minimal changes in kidney basal membranes and is reversible after stopping captopril in most but not all cases, an SH-group related autoimmune (vascular) reaction] 6. Hyperkalaemia 7. Agranulocytosis 8. Stomatosis (like aphthous ulcers) 9. Abdominal pain 10.Angioneurotic oedema (may be due to bradykinin accumulation)

The angiotensin converting enzyme (ACE, a non-specific dipeptidase) inhibitors such as captopril act, at least partly, by blocking the vasoconstrictor and aldosterone releasing effects of angiotensin II. Further, bradykinin, a vasodilator is broken down by ACE, which might add to the blood pressure lowering effect. It is believed that either bradykinin or a neurokinin (e.g. substance P) may cause cough. Generally, ACE inhibitors are renally eliminated. Sensitivity to these agents is likely in patients on high dose diuretics or with renovascular hypertension or in the elderly.

ACE inhibitors, the prototype being captopril (t 2hr), have a useful vasodilator with potassium-sparing action being useful in heart failure. Their reduction of mortality in heart failure is, probably, due to their being the only vasodilator that does not reflexly activate the sympathetic system. This absence of reflex tachycardia may be due to downward resetting of the baroreceptors and/or enhanced parasympathetic activity.

Cautions 1. When first administered should be under close observation (because of angioedema and first dose syncope)

Contraindications 1. Pregnancy toxicity)

(because

of

foetal

renal

A newer generation of ACE inhibitors (including enalapril and lisinopril with longer

42

Essentials of Medical Pharmacology

Majid A.K. Lafi

t

than captopril) has been developed with fewer adverse effects compared to those observed with captopril. This is probably due to the lack of the sulphydryl group that is present in captopril. Proteinuria is less likely to be encountered with the newer agents. Most studies have shown little difference in efficacy provided the dose was optimised.

Centrally acting drugs Clonidine (α2-receptor agonist) and methyldopa (false transmitter) exert their effect mainly by stimulating central postsynaptic inhibitory α2-adrenoceptors located on sympathetic neurones leading to a deceased outflow of sympathetic nerve impulses. Methyldopa after being taken up into adrenergic nerves is eventually converted into methylnoradrenaline when released it activates postsynaptic inhibitory α2adrenoceptors more potently than noradrenaline. Methyldopa and clonidine may also exert peripheral inhibitory action on the release of noradrenaline from sympathetic endings. Most of the long list of centrally and peripherally mediated adverse effects of methyldopa may be explained by its action on α2-receptor.

Captopril renogram: The appearance of sudden anuria or azotaemia after the administration of ACE inhibitors is an extremely important sign that may signify renal artery stenosis. An acute dose of ACE inhibitor can be used as a standardised test (captopril renogram) for an acute decrease in GFR, which is usually indicative of renal artery stenosis. Losartan is the first AT1-receptor antagonist to be used clinically. Much lower profile of adverse effects has been reported compared with that of ACE inhibitors. Certainly, it does not cause dry cough, therefore at present, it is used in patients who develop cough with ACE inhibitors.

USEFUL NOTES Postural hypotension is generally produced by vasodilators that have considerable effect on veins. Therefore, postural hypotension is not usually a problem with agents that have little or no vasodilatory effect on veins.

Other vasodilators Hydralazine reduces vascular resistance in all peripheral vascular beds including the kidney. Adverse effects are mainly connected to a lupus erythematosus like syndrome. The incidence is dose related and the syndrome is almost always reversible when hydralazine is stopped. Blood dyscrasias and peripheral neuropathy may occur.

The compensatory baroreceptor-mediated sympathetic discharge induced by the druginduced hypotension causes tachycardia and increased cardiac output, even causing angina pectoris in predisposed subjects. This can be overcome by the use of β-blockers.

Prazosin exerts its vasodilatory effect by blocking postsynaptic α1-receptors. Prazosin may be used in combination with diuretics or β-blockers. Adverse effects are mainly observed initially if a high dose (first dose) is administered and are manifested by hypotension and collapse.

An increase in intravascular capacity, as a result of vasodilatation, usually leads to compensatory increase in blood volume and thus resulting in loss of effect (tolerance). This can be overcome by the use of a diuretic.

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Table 3.3. A summary of selected antihypertensive agents, their adverse effects and important remarks; the site of vasodilatation is predominantly arteriolar (A), venular (V) or combined A & V. Drug

¾-blockers

Drug action

Propranolol Pindolol1

β-blocker β-blocker ISA)

Atenolol1 Labetalol

β-blocker α and β-blocker

(with

Selected adverse effects and important remarks Bronchoconstriction, impotence, cold feet & hands Believed to be suitable in pregnancy (less incidence of sinus bradycardia) & less deleterious effect on lipid profile Bronchoconstriction, impotence, cold feet & hands Bronchoconstriction

Vasodilators Captopril (A&V)

ACE-blocker

Nifedipine (A)

Ca-antagonist

Amlodipine (A)

Ca-antagonist

Diltiazem (A) Verapamil (A)

Ca-antagonist Ca-antagonist

Prazosin (A&V)

α1-blocker

Phenoxybenzamine (A&V)

α1& α2-blocker

Phentolamine (A&V) Hydralazine (A) Nitroprusside (A&V)

α1& α2-blocker Increases cGMP NO-donor

Diazoxide (A) Minoxidil (A)

K-channel agonist K-channel agonist

Metallic taste, renal impairment in bilateral renal stenosis, persistent dry cough, hyperkalaemia, proteinuria, agranulocytosis Hypotension, ankle oedema, tachycardia, headache, constipation; withdraw in ischaemic pain, use with βblocker and diuretics Similar to nifedipine except much longer t (40h) permitting the same benefits as the longest-acting formulations of nifedipine without requiring a special formulation. Hypotension, dizziness, flushing, bradycardia Hypotension, myocardial depression, constipation, dependent oedema Postural hypotension, syncope (no secondary reflex tachycardia) Postural hypotension, secondary reflex tachycardia, nasal congestion, ejaculatory failure; as β-receptors unopposed use β-blocker in phaeochromocytoma Hypotension, tachycardia Reflex tachycardia, fluid retension, SLE-like syndrome Severe postural hypotension, cyanide toxicity, palpitation Diabetogenic, fluid retention (oedema, use a diuretic) Hirsutism, fluid retention, tachycardia (use a diuretic & β-blocker)

Diuretics Hydrochlorothiazide Chlorthalidone Frusemide

Centrally acting Clonidine Methyldopa1

Saluretic Saluretic α2-stimulation α2-stimulation

Hypokalaemia, hyperuricaemia, hyperglycaemia Hypokalaemia, hyperuricaemia, hypotension, ototoxicity

hypercalcaemia, hyperglycaemia,

Sedation, severe withdrawal syndrome Sedation, dry mouth, depression, diarrhoea, oedema, impotence (probably secondary to depression), SLE, Parkinsonism, liver damage (chemical hepatitis), gynaecomastia, haemolytic anaemia2

1

These drugs are suitable in pregnancy Methyldopa combines with a protein in the body so that the body no longer recognises the protein as self and thus forming antibodies (type II reaction) that combine with the antigen and activate complement that damages cells (haemolysis occurs). Similar events may occur with penicillin-induced haemolytic anaemia. 2

45

Cardiovascular Pharmacology - Antianginal Drugs

Ramadi, 6 October 2009

ANTIANGINAL DRUGS Introduction

Antianginal Agents

Angina pectoris (angina, a strangling; pectoris, of the chest) is defined as sudden pain beneath the breastbone, often radiating to the left shoulder and arm. Anginal pain is precipitated when the oxygen supply to the heart is insufficient to meet the heart’s oxygen demand. Most frequently, anginal pain occurs secondary to atherosclerosis of the coronary arteries; hence, angina should be seen as a symptom of a disease and not a disease in its own right.

Three groups of drugs are used in the treatment of classic angina (all of which relieve the pain by decreasing the oxygen need of the heart): 1. Organic nitrates (e.g. nitroglycerin) 2. -adrenoceptor blockers (e.g. propranolol) 3. Calcium antagonists (e.g. nifedipine) Variant angina pectoris is caused by spasm of the coronary arteries. Thus, pain is secondary to insufficient oxygenation of the heart. Unlike classic angina, the symptom of which may occur primarily in response to exertion, variant angina can produce pain at rest or even sleep. Some individuals may have both classic and variant forms of angina pectoris.

Angina pectoris has two major forms: 1. Classic angina (exertional angina or angina of effort) 2. Variant angina (Prinzmetal’s or vasospastic angina)

Objectives of Treatment

Two groups of drugs are employed in the treatment of variant angina (both of which act by decreasing coronary spasm):

Symptomatic treatment of angina pectoris can include the following aspects:

1. Calcium antagonists (e.g. nifedipine) 2. Organic nitrates (e.g. nitroglycerin)

1. Reduction in the workload (oxygen demand) of the heart 2. Coronary vasodilatation (increases oxygen supply to the heart)

Nitrates Nitrates are nitrous acid esters of polyalcohols such as glycerol. The most common is nitroglycerin or glyceryltrinitrate (GTN). GTN has been used to treat angina since 1879 and still remains the drug of choice. It is the same substance that is contained in dynamite. GTN requires glutathione-S-transferase for denitration and donation of NO. The latter enzyme is present in the venous tissue more than the arterial tissue. Therefore, GTN is being more a venular than arteriolar vasodilator. On the other hand, sodium nitroprusside spontaneously (non-enzymatically) release NO in aqueous solution. It is considered as both venular and arteriolar vasodilator. Biologically, constitutive nitric oxide synthase (cNOS) producing nitric oxide (NO) which diffuses freely into the adjacent vascular smooth muscle cells, in turn, causing

In normal subjects, as cardiac demand rises, coronary arteries dilate, thereby keeping oxygen supply and oxygen demand in balance. In subjects with coronary artery disease (CAD), the diseased arteries are unable to dilate; hence, blood flow cannot increase to meet increased oxygen demand resulting in anginal pain. Since the underlying cause of classic angina is physical obstruction of the coronary vasodilatation and hence no increase in cardiac oxygen supply. Therefore, the primary way by which decreasing oxygen demand can relieve the pain of classic angina.

46

Essentials of Medical Pharmacology

Majid A.K. Lafi

an increase in intracellular cGMP and hence vasodilatation.

of benefit to patients suffering from angina pectoris, but in cardiac insufficiency inhibition of normal sympathetic drive may induce failure. They should not be used in variant (spastic) angina, where it might aggravate coronary vasoconstriction.

The beneficial effect of nitrates is exerted in part by its venodilator effect that results in blood pooling on the venous side thus reducing venous return, central venous pressure and cardiac preload. Dilatation of coronary arteries is probably less important. This means that the clinical effect of nitrates has to do with energy and oxygen sparing properties (through reduction of cardiac work). But a fall in blood pressure induces a rise in heart rate.

Table 3.4. Different types of nitrates Preparation Nitroglycerin (glyceryl trinitrate) Isosorbide dinitrate Pentaerythritol tetranitrate Amyl nitrite (inhalant) Na nitroprusside 0B

Organ nitrates are rapidly broken down in the liver (oral bioavailability is less than 10%) to mononitrates. Therefore, organic nitrates are mostly given sublingually where they are easily absorbed through the buccal mucosa. Other routes of administration are transdermal absorption when applied as an ointment to the skin.

Duration 1B

Dose 2B

1-30 min

0.5 mg

2-60 min 10 min to 5 hr (oral)

5-10 mg

1-5 min

20 mg

20 mg

Instantaneously (i.v)

Calcium Channel Blockers Myocardial cell depolarisation is accomplished by a rapid inward current of sodium ions (Phase 0). This is followed by a plateau (Phase 2) during which there is a slow inward movement of calcium ions through separate membrane channels. Calcium channels have voltage-dependent gates on the outside and enzyme dependent gates on the inside. The inward current of calcium ions triggers the release of stored intracellular calcium, which couples the excitation process with muscular contraction. Therefore, calcium blockers inhibit calcium movement, which weakens the contractile process and affects automaticity and conduction, mainly from the atrium to the ventricle. Ca-blockers do not appear to affect calcium dependent neural activity. Presently, the most commonly used Ca-blockers are nifedipine, diltiazem, and verapamil.

Adverse effects 1. Throbbing headache (through dilatation of extra-cranial arteries) 2. Methaemoglobinaemia (It is due to transformation of ferrous iron to ferric iron of haemoglobin. Only with large doses of nitrates there is a significant production of methaemoglobin which has low affinity for O2 and which may be responsible for hypoxia. This adverse effect can be useful in cyanide poisoning since methaemoglobin has a high affinity for the CN- ion that will be detached from cytochrome; thus, cyanmethaemoglobin is formed which can be detoxified with sodium thiosulphate). Tolerance develops to both the therapeutic effect and the adverse effects. Tolerance to headache comes rather quickly but the therapeutic effect to angina pectoris largely remains.

Nifedipine, the prototype of the dihydroperidines and unlike verapamil, has negligible effects on cardiac conduction and a major action to lower peripheral vascular resistance. Hence, in addition to decreasing coronary spasm, it may be used to decrease afterload and to lower blood pressure. Because of the pronounced vasodilatory effect, its use is associated with side effects of headache, reflex tachycardia. Nifedipine (t½ 2h) is eliminated by the liver, and it has a bioavailability approaching 50%.

-Blockers By blockade of 1-receptors, -blockers slow heart rate and by opposing the response to stress and exercise in ischemic heart disease they have an ‘oxygen sparing’ effect. This is 47

Cardiovascular Pharmacology - Antianginal Drugs

Ramadi, 6 October 2009

Amlodipine is characterised by a much longer t½ (40 h) permitting the same benefits as the longest-acting formulations of nifedipine without requiring a special formulation. This makes amlodipine not suitable for emergency reduction of blood pressure where dose adjustment is required. There is less reflex tachycardia with amlodipine, presumably because its long t½ produces minimal peaks and troughs in plasma concentrations.

3 to 5 hours that mandates dosing 3 to 4 times per day. Diltiazem has pharmacological properties that are essentially intermediate between those of nifedipine and verapamil. It has less effect on cardiac conduction than verapamil and less vasodilatation than nifedipine. Similarly to the other calcium antagonists, diltiazem is eliminated by the liver, with a t½ of about 4 hours. It has an active metabolite that probably contributes little to its activity.

Dihydropyridines may differ in their potency in different vascular beds. Such difference in potency is claimed for nimodipine to be particularly selective for cerebral blood vessels and hence is preferred for prevention of ischaemic neurological damage following subarachnoid haemorrhage.

Indications 1. Supraventricular arrhythmias (verapamil, not nifedipine) 2. Angina pectoris (especially variant angina) 3. Hypertrophic cardiomyopathy 4. Acute arterial hypertension 5. Raynaud’s disease (nifedipine) 6. Prevention of ischaemic neurological damage following subarachnoid haemorrhage (nimodipine) 7. Migraine

Verapamil is used most frequently for its ability to slow conduction through the AV node and, as such, has become the agent of choice in most cases of supraventricular tachyarrhythmias. In addition, it has been used successfully in all forms of angina and can be an effective antihypertensive drug. For use in this latter setting, the effects on cardiac conduction may be unwanted.

Cautions 1. Combination of verapamil with drugs that also depress nodal tissues such as digoxin and -blockers (risk of asystol).

Verapamil is eliminated by the liver, and has a substantial first-pass effect. Its bioavailability is only about 20%, and a t½ of

Table 3.5. A summary of the pharmacological effects of calcium channel blockers Drug 5B

Coronary vasodilatation 6B

Peripheral vasodilatation

Negative Inotropy

7B

Slow AV Conduction

8B

3B

Nifedipine +++ +++ Diltiazem +++ + Verapamil +++ ++ + Mild, ++ moderate, +++ pronounced, - negligible

+ +

9B

4B

+ ++

Cardiac Sodium Channels + ++ 10B

Table 3.6. Aim of therapy: to achieve oxygen demand-supply balance in the myocardium in angina pectoris determinants of myocardial oxygen consumption. ( increase, decrease and no change) Parameter

Nitroglycerin A

Nifedipine B

Heart rate Contractility Preload Afterload Coronary Tone arteries Flow

48

Propranolol C

Combination of B and C

Essentials of Medical Pharmacology

Majid A.K. Lafi

DRUGS FOR CONGESTIVE HEART FAILURE increase in sympathetic tone may lead to useful and harmful consequences.

Congestive Heart Failure Congestive heart failure is characterised by an inability of the heart to pump blood in amounts that are sufficient to meet the metabolic needs of tissues. This is primarily due to a reduction in the contractile force of cardiac muscle, hence, a reduction in cardiac output seen in CHF. The underlying mechanisms responsible for this reduction in muscle contractility are still not clearly understood.

1. Positive chronotropic and inotropic effects that may lead to increased cardiac output and in turn improved tissue perfusion. 2. Elevation of venous tone that increases venous return to the heart and thus increases filling of the heart (according to Starling’s law) and in turn enhances cardiac output. However, an excessive increase in venous tone may lead to pulmonary and peripheral oedema and certainly these effects are undesirable. 3. Elevation in arteriolar tone which, on one hand, increases perfusion of vital organs (an effect which is highly desirable); on the other hand, an increase in arteriolar pressure will require the heart to pump against greater resistance. Because of the inability (low reserve) of the heart to increase the contractile force to meet this challenge (increase in arteriolar pressure), cardiac output may decline; an effect which is certainly undesirable.

Physiological Changes to Reduced Cardiac Output In response to reduced ability of the heart to pump blood in sufficient amount to meet the body requirement, the body undergoes certain adaptive physiological changes in order to improve tissue perfusion; however, some of these changes aggravate existing problems of CHF.

Water retention and increased blood volume

Cardiac dilatation Reduced contractility of the cardiac muscle lowers the amount of blood ejected during systole (reduced stroke volume), resulting in a rise in end-systolic volume. Further, increased preload increases diastolic filling, which causes even further expansion of the heart. This increase in heart size helps to improve cardiac output. According to Starling’s law, the force of ventricular contraction is a function of ventricular muscle fibre length.

Water retention may result from: 1. Reduced cardiac output leads to reduced renal blood flow which in turn leads to reduced urine production and thus water retention. 2. Reduced renal blood flow will induce the kidney to release renin that enhances the production of angiotensin; the latter in turn promotes the production of aldosterone. Aldosterone acts on the kidney causing reabsorption of sodium and water.

Increased sympathetic discharge

Cardiac Inotropic Drugs

As the heart fails the cardiac output decreases resulting in a fall in arterial blood pressure which is detected by baroreceptors and relayed to the vasomotor centre; the latter causes an increase in sympathetic discharge to the heart, veins, and arterioles. This

In 1775 Dr William Withering, an English physician from Birmingham, learnt that a dropsical women (his patient), whom he thought she would die, recovered a few weeks later. He enquired into the cause of her 49

Cardiovascular Pharmacology - Inotropic Drugs

Ramadi, 6 October 2009

recovery, and found that she took a herb tea containing foxglove (Digitalis lanata). He began to investigate its properties, trying it on the poor of Birmingham, whom he used to see without fee each day. Ten years later (1785), Withering wrote an accurate account in which he defined the type of patient who might benefit from it, standardised his foxglove leaf preparations with dosage schedules. This account would still serve today after more than 200 years.

Mechanism of Action The cellular mechanism of action seems to be related to an increase in the labile calcium fraction in the sarcoplasmatic reticulum of the myocardial cell by inhibiting the Na-K ATPase. Another effect of digitalis on the heart is indirect through activation of the vagus. The excitatory effect of digitalis on the heart shortens the action potential (QTinterval) and therefore, shortens the refractory period in the atria and the ventricles. The diuretic action of digitalis is almost entirely due to its effect on cardiac output and the consequent improvement of glomerular filtration pressure.

The cardiac glycosides consist of two parts: a glycone and an aglycone. The glycone is a sugar that has no cardiac action, but makes the glycosides more soluble and is essential for fixation to the cardiac muscle fibres. The aglycone contains the active principle that is a steroid (similar to bile and sex hormones) to which a lactone ring with a double bond is attached.

Pharmacokinetics Absorption of different cardiac glycosides varies considerably; digoxin and digitoxin have a high bioavailability. The bioavailability of the lanatosides is poor and should, therefore, be given intravenously.

O

OH CH3 O

The choice of digitalis preparation depends mainly on pharmacokinetic difference and not so much on specific inotropic action on cardiac muscle and cardiac toxicity that is rather similar with various cardiac glycosides. The below table shows the important pharmacokinetic properties of digoxin and digitoxin.

CH3 OH

Sugars O 3 sugars digitoxoses

Steroid Nucleus

Lactone Ring

The inotropic drug of first choice, which can be used for most conditions, is a preparation that can be administered both i.v. and orally. These requirements are met by digoxin that is excreted unchanged by the kidney function, a factor which has to be considered especially with the age-related reduction of glomerular filtration and hence the risk of intoxication. Digitoxin is mostly metabolised in the liver by microsomal enzymes the activity of which is increased by barbiturates and phenytoin.

Fig.3.3 . Structure of the cardiac digoxin

Cardiac glycosides are mainly derived from plant products such as the purple foxglove (digitalis purpurea: digitoxin) or the white foxglove (digitalis lanata: digoxin) or Strophantus gratus: ouabain. Digitalis has very little effect on the normal heart. There is marginal slowing of sinus rhythm, but in higher doses AV-block and ventricular extrasystoles (VES) may be induced. The actions of digitalis on the heart are: 1. Positive inotropic (increases force of contraction) 2. Negative chronotropic (reduces heart rate, vagal) 3. Negative dromotropic (slows AV conduction, vagal) 50

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(Na-pump) Na/K-ATPase K

Glycosides

+

Inhibition of (Na-pump)

Na+ Ca

Intracellular Na+

++

Na/Ca-exchange Intracellular Ca++ Myocardial Cell Contraction Fig.3.4 . A schematic representation of inotropic action of glycosides like digoxin

Table 3.7. Pharmacokinetic parameters of digoxin and digitoxin Drug 0B

Onset (min) i.v. oral

Plateau 1B

Dose (mg)

Therapeutic serum level

Bioavail -ability

Renal excretion 80%

2B

Digoxin

15

45

7 days

0.25

0.5-2.0 ng/ml

75%

Digitoxin

-

120

2 weeks

0.1

14-26 ng/ml

>90 20% Digitoxin Oral

Digoxin (Oral) (i.v.) 3B

Total digitalising dose (mg) administered in divided doses

4B

5B

0.75-1.25

0.8-1.0

6B

7B

8B

9B

1.2-1.6

Indications Therapeutic Control

1. Atrial fibrillation (vagal effect on the AVnode) 2. Paroxysmal supraventricular tachycardia (vagal effect on the SA and AV-nodes) 3. Cardiac failure

Digoxin is the glycoside marketed in Iraq. Therefore, the following account holds for digoxin. The maintenance dosage should be adjusted individually according to the clinical response. Determination of plasma concentrations can be used additionally since there is considerable variation in the response pattern of the patient (i.e. depending on age, electrolyte and thyroid status). Blood samples should be taken a minimum of 6 hours after the last dose in order to avoid the absorption peak. In patients with atrial fibrillation (without AV-block) dosage can usually be adjusted according to heart rate.

Adverse effects 1. Abnormal cardiac rhythm (e.g. ventricular ectopic beats) 2. GI effects (e.g. anorexia, vomiting, and diarrhoea) 3. Visual effects (e.g. disturbances of colour vision, photophobia and blurring) 4. Gynaecomastia 5. Mental effects (e.g. confusion, agitation, nightmare and acute psychoses) 51

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metabolised by COMT. It has a very brief duration of action.

Cautions/ contraindications

Dobutamine

1. Hypokalaemia 2. Hypercalcaemia 3. AV-block II – III (unless treated with pacemaker) 4. Impaired renal function (age-related) 5. Hypothyroidism 6. Conditions may lead to increased Nainflux (e.g. electrical cardioversion, acute myocardial infarction)

Dobutamine is a new synthetic drug that is a 1-receptor agonist showing greater inotropic than chronotropic effects on the heart. It also has some -receptor activity (but less than that with dopamine). It may be useful in shock and in low output heart failure (in the absence of severe hypertension).

Dopexamine Note: Acute digoxin poisoning produces nausea, vomiting and hyperkalaemia.

Cardiac insufficiency can be treated not only by cardiac glycosides but also by other inotropic drugs such as catecholamines, glucagon, dopamine, isoprenaline, dobutamine, dopexamine, xanthines and phosphodiesterase inhibitors.

This synthetic catecholamine is claimed to have positive inotropic action (being a cardiac 2-receptor agonist). It also exhibits some D1-receptor agonistic activity (thus, renal vasodilatation). This agent also appears to have inhibitory activity on noradrenaline reuptake, hence, increasing the synaptic availability of noradrenaline and thus, the stimulation of cardiac 1-receptor. It is useful in low output heart condition.

Dopamine

Bipyridine derivatives

Dopamine occurs as the natural precursor of noradrenaline; in low doses, it stimulates D1receptors causing renal, mesenteric and coronary vasodilatation. Hence, dopamine may lead to an increase in glomerular filtration rate and urine production. At higher doses, dopamine progressively increases heart rate and force by directly stimulating 1-adrenoceptors and indirectly releasing neuronal noradrenaline, which in turn activates Further, still 1-adrenoceptors. higher doses stimulate -adrenoceptors, causing a rise in blood pressure with a decrease in blood flow to vital organs including the kidneys.

The representative agents of this group are amrinone and milrinone. They produce their inotropic activity by selectively inhibiting phosphodiesterase III (cAMP phosphodiesterase) resulting in an increase in tissue cAMP and presumably not cGMP. Catecholamines and xanthine derivatives [caffeine, theophylline ethylenediamine (aminophylline)], however, enhance the availability of both cAMP and cGMP. Bipyridine derivatives appear to have a superior feature that they produce smaller positive chronotropic effects compared to catecholamines and xanthine derivatives and hence lower potential to cause arrhythmias. In chronic heart failure, it is essential for inotropic agents used that they do not have positive chronotropic effects because these effects reduce the energetic efficiency of the failing heart by adding an additional burden.

Other Inotropic Drugs

Isoprenaline It is a potent non-selective -receptor agonist with no or little -receptor actions. It reduces peripheral resistance, mean and diastolic blood pressure but systolic blood pressure and renal blood flow may rise due to increased cardiac output. Isoprenaline is

Diuretics Diuretics are used, alone or with other agents like glycosides, in congestive heart failure to reduce blood volume. Hence, these agents 52

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can decrease pulmonary and peripheral oedema, and in turn reduce cardiac dilatation. (For a detailed account see the section on diuretics) Thiazides (Hydrochlorothiazide) Loop diuretics (Frusemide, bumetanide) Potassium-sparing agents (spironolactone, triamterene)

Vasodilators A new approach to the treatment of cardiac insufficiency is by using vasodilator drugs in order to ‘unload’ the failing ventricle. The response to vasodilator therapy can be considered under two headings: to reduce Preload Afterload Vasodilatation of peripheral arterioles reduces left ventricular work, i.e. afterload, as systolic ventricular wall tension, a major component of myocardial oxygen consumption, is reduced. This leads to a secondary increase in cardiac output. A vasodilatation on the venous side will increase the volume of blood held in this part and will shift blood from the pulmonary veins to the systemic venous compartment. A consequent fall in left ventricular filling pressure, i.e. preload will favour an improved coronary blood flow (as a result of reduced diastolic ventricular wall tension, thus, reduced mechanical compression on coronary arteries). Vasodilator drugs used for this purpose include: ACE-inhibitor (captopril, critical part of the management) Arterial dilators (hydralazine) Venous dilators (nitrates) For a detailed account see the section on antihypertensive agents.

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ANTIARRHYTHMIC DRUGS arrhythmias. Further, cardiac cells that do not normally produce automaticity, e.g. atrial and ventricular muscle, can develop automaticity.

Some Pathophysiology A cardiac arrhythmia (dysrrhythmia) is an abnormality in the rate or regularity of the heart beat. In this section, tachyarrhytmias (arrhythmias that increase heart rate) are considered. Mild arrhythmias may occur without substantial effects on cardiac output: however, very severe arrhythmias can bring the heart into a halt that no blood is pumped at all. Thus, arrhythmias can be associated with a high degree of morbidity and mortality.

In the SA node, an increased sympathetic drive may increase automaticity to the degree that results in tachycardia; however, an increase in parasympathetic drive may decrease automaticity to the degree that results in bradycardia. Upon injury or an increase in sympathetic drive, Purkinje fibres can undergo a sufficient degree of increase in automaticity that these fibres can escape control by the SA node; thus, serious arrhythmias may result.

Drug treatment of cardiac arrhythmias must not be initiated without good indications, and the risk versus benefit ratio must be carefully considered since the drugs are toxic. It is not always necessary to restore sinus rhythm. The indications for antiarrhythmic treatment depend on both the patient s symptoms and the prognostic implications of the arrhythmia. The presence or absence of underlying heart disease is of major importance. Thus a patient with previous myocardial infarction and mild symptoms from recurrent ventricular arrhythmias merits treatment, while the same symptoms in another patient with a normal heart may not.

In certain conditions, contractile cardiac cells like atrial or ventricular cells can be made capable of spontaneously firing action potentials at a rate exceeding that of the SA node thus resulting in arrhythmias.

Alteration in conduction AV block It is reduced conduction through the AV node may result in varying degree of AV block. If the conduction of impulse is delayed, but not prevented, then this is described as a first degree block. Further, in second degree block, some impulses pass through the AV node, but others do not. While, in third degree block, all traffic through the AV node stops.

Cardiac arrhythmias may arise from two main disturbances in: 1. Automaticity 2. Conduction

Reentrant activation

There are several factors that may results in disturbances in automaticity and/or conduction including hypoxia, electrolyte imbalance (hypokalaemia), cardiac surgery, reduced coronary blood flow, myocardial infarction, and some drugs (e.g. digoxin).

Arrhythmias can be produced by recirculating activation of impulses, which can occur as a result of cardiac tissue injury (myocardial infarction). These reentrant impulses are capable of establishing localised, selfsustaining circuits causing repetitive cardiac stimulation. Specific drugs can stop these reentrant impulses, and thus suppression of arrhythmias.

Alterations in automaticity Cardiac cells like those of the SA node, AV node, and His-Purkinje system, are normally capable of automaticity (spontaneously firing action potentials); if the normal discharge of these cells changes, they can produce

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proved ineffective then digitalis can be used to reduce the passage of impulses from the atria to the ventricles.

Common arrhythmias Supraventricular arrhythmias

Ventricular arrhythmias

Arrhythmias that arise in areas of the heart located above the ventricles. Generally, these arrhythmias are not dangerous unless the atrial impulses can express an impact on the ventricular function by passing through the AV node, resulting in excitation of the ventricles. Thus, when dealing with supraventricular arrhythmias, the treatment is primarily directed at blocking impulse conduction through the AV node.

Ventricular arrhythmias are very likely to cause disruption to cardiac output, thus, they are far more serious than supraventricular ones. Hence, treatment should be directed at completely abolishing of the ventricular arrhythmias.

Premature ventricular contractions Ectopic ventricular foci (single focus or multiple foci) produce premature ventricular contractions (PVCs) that are beats occur before they should do in the cardiac cycle. PVCs are treated only when there is a presence of a concurrent cardiac disease like acute myocardial infarction, as in this condition PVCs predispose the patient to ventricular fibrillation (PVCs are not usually treated) the drug of choice is lidocaine; alternatively, procainamide may also be useful.

Supraventricular tachycardia Supraventricular tachycardia (SVT) can be initiated by ectopic focus located in the atria or in the AV node. Heart rate is increased to between 150-250 beats/min. SVT may be treated by vagotonic manoeuvres, however, if not successful a drug therapy (i.v. verapamil) can then be instituted.

Atrial flutter

Ventricular tachycardia

Atrial flutter is caused by an ectopic atrial focus discharging at a rate of 250-350 times/min. However, the ventricular rate is considerably less than this as the AV node cannot conduct impulses at such high rate. DC cardioversion is the treatment of choice in this arrhythmia. If DC cardioversion is ineffective then drug therapy is pursued; digitalis is the drug of choice, however, verapamil or propranolol can also be effective upon acute attacks. Prophylactic use of quinidine can prevent recurrence of atrial flutter.

Ventricular tachycardia arises from a single, rapidly firing ventricular ectopic focus. The focus drives the ventricle at a rate of 150-250 beats/min. because the ventricles cannot pump efficiently at these rates, immediate treatment must be started. DC cardioversion is the treatment of choice, if cardioversion is ineffective, lidocaine must be administered. If the latter is also ineffective then use bretylium. Ventricular fibrillation

Atrial fibrillation

Multiple ventricular ectopic foci with asynchronous discharge initiate uncoordinated (chaotic) contractions resulting in cessation1 of the pumping action of the heart. In the absence of blood flow the patient becomes unconscious and cyanotic. The heart function should soon be restored otherwise death of the patient will follow. DC

Atrial fibrillation is initiated by multiple ectopic foci firing in random order, and each focus stimulates only a small area of smooth muscle. This uncoordinated excitation leads to a highly irregular atrial rhythm traverse through AV node, ventricular rate will increase, otherwise, it will remain near normal. Treatment of atrial fibrillation is the same as that for atrial flutter; DC cardioversion is the preferred choice, if

1

If not already done, give oxygen and establish i.v. line; continue cardiopulmonary resuscitation care.

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Cardiovascular Pharmacology - Antiarrhythmic Drugs

cardioversion should counteract fibrillation and if cardioversion is not effective then administer lignocaine, and if the latter proved to be ineffective then use bretylium.

Ramadi, 6 October 2009

Class Ia This sub-group includes quinidine, procainamide and disopyramide, which are useful for the control of broad spectrum of arrhythmias, both ventricular and supraventricular. These drugs have very similar effects on supraventricular and ventricular arrhythmias. All have been used successfully for the prophylactic treatment of arrhythmias including atrial fibrillation and flutter after DC conversion. If administered alone they may produce an acceleration of the heart rate (ventricular rate). This is due, in part, by the drug-induced reduction of atrial rate and hence reduction of impulses blocked in the AV node (at higher atrial rates, there is a traffic jam at the AV node when this jam eased, the traffic passes much easier). The other reason is because of vagolytic properties, which accelerates AV-conduction. Therefore, these drugs are commonly administered together with digitalis in the treatment of atrial fibrillation and flutter. The Ia drugs are also effective in ventricular ectopic beats and in prophylaxis of recurrent ventricular tachycardia or fibrillation.

Digitalis produced arrhythmias Digitalis-induced arrhythmias can be produced from a combination of increased automaticity in atrial and ventricular tissue together with decreased conduction through the AV node. Thus, digitalis glycosides by both disturbing automaticity and conduction, they can produce varying degrees of AV block, and also the dangerous ventricular arrhythmias. If drug treatment is required then the drugs of choice are lidocaine and phenytoin. In these patients, DC cardioversion may precipitate ventricular fibrillation because the latter increase sensitivity to digitalis.

Antiarrhythmic Drugs The most widely used classification is that by Vaughan-Williams, based on electrophysiological actions of the drugs. This has limitations when applied clinically but it is useful for the discussion of antiarrhythmic agents. The currently available drugs are divided into four main classes.

Quinidine Quinine has been prescribed for palpitations since the 18th century. It was largely replaced by its d-isomer, quinidine. Quinidine is administered orally, it is usually prescribed as a long-acting preparation (e.g. Kinidin Durules , two to four tablets every 12 hours). This produces reasonably constant blood levels for about 12 hours. As with all antiarrhythmic therapy, it is advisable, where possible, to adjust the dosage according to serum drug levels.

Class I Class I Drugs block the fast inward sodium current, responsible for the rapid upstroke (Phase 0) and conduction of the normal action potential. This is also known as a local anaesthetic or membrane-stabilising action. In addition, all class I agents depress abnormal automaticity by slowing the rate of the abnormal phase 4 (diastolic) depolarisation.

Adverse-effects 1. Hypotension 2. Bizarre ventricular arrhythmias 3. Cinchonism (tinnitus, deafness, blurred vision, diplopia, diarrhoea, headache, confusion) 4. Thrombocytopenia 5. Fever

Class I drugs include some of the longest available and well tested antiarrhythmics, like quinidine and lidocaine, but also new agents such as flecainide. Class I drugs have been further sub-divided into Ia which prolong, Ib which shorten, Ic which have no effect on action potential duration.

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Table 3.8. A summary of antiarrhythmic drugs based on Vaughan-Williams classification

Class

I. Sodium Channel Blockers

Action

Indications

Slow impulse conduction*

a. Quinidine Procainamide Disopyramide

Prolong action potential duration & refractoriness

b. Lignocaine

Shorten action potential duration & refractoriness

Mexiletine Phenytoin Tocainide c. Lorcainide Flecainide

II. ¾-adrenergic Blockers

No or little effect on action potential duration & refractoriness Decrease background sympathetic tone in the heart, reduce automatic discharge (phase 4)

Ventricular arrhythmias that are supraventricular in origin As for propranolol

Propranolol Esmolol**

III. Potassium Channel Blockers

Prolong repolarisation

Amiodarone

Ventricular arrhythmias that are resistant to lignocaine As for amiodarone As for amiodarone

Sotalol Bretylium

IV. Calcium Channel Blockers Verapamil

Decrease the slow inward calcium current (phase 2), & prolong conduction & refractoriness (SA & AV nodes) Ventricular arrhythmias that are supraventricular in origin As for verapamil

Diltiazem

Others Digoxin Adenosine

Broad spectrum (for chronic use) Broad spectrum (for acute use) Broad spectrum (less safe) Ventricular arrhythmias, digitalis-induced tachyarrhythmias Ventricular arrhythmias Digitalis-induced tachyarrhythmias Ventricular arrhythmias Ventricular arrhythmias Ventricular arrhythmias

Decreases AV nodal conduction (by increasing vagal activity) Decreases AV nodal conduction

Ventricular arrhythmias that are supraventricular in origin As for digoxin

* These drugs restrict the rapid inflow of sodium during phase 0 and thus slow the maximum rate of depolarisation (membrane stabilising activity) in cells with abnormal activity; while in normal cells they produce the described actions for class Ia, b & c. ** Esmolol is a short-acting β 1-selective agent, hence, it could be used in some patients with contraindications to other β-blocking agents. Underlined drugs are ones with which good familiarity has been attained in Iraq. Note: This classification shows that drugs in class 1b are not effective for supraventricular arrhythmias, whereby they all may have some effect in ventricular arrhythmias.

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achieved widespread acceptance as first-line pharmacological therapy for serious ventricular arrhythmias in acute myocardial infarction. Because of extensive first-pass metabolism in the liver and its metabolites are believed to contribute to central nervous system toxicity, lignocaine must be administered parenterally and never given orally.

Interactions Quinidine interacts with digoxin to produce a significant elevation (50-100%) of the serum digoxin level. This seems to be a result of a combination of displacement of digoxin from tissues and a decrease in renal clearance of digoxin.

Procainamide Adverse effects Procainamide is related to the local anaesthetic procaine that exhibits similar actions but has a longer duration of action. It may be administered orally or intravenously. Because of its short t it has to be given every 3-4 hours or by a sustained release preparation.

1. Hypotension 2. Blurred vision 3. Sleepiness 4. Slurred speech 5. Paraesthesiae (numbness, often perioral) 6. Sweating 7. Confusion 8. Convulsions

Adverse effects

Mexiletine and Tocainide 1. Hypotension 2. GI disturbances 3. Hallucinations 4. Hypersensitivity reactions (reversible lupus erythematosus and agranulocytosis)

Mexiletine and tocainide are chemically very similar to lignocaine. They can be given by mouth. As lignocaine, they are most useful in the treatment of ventricular arrhythmias, and usually, a patient who responds well to lidocaine will also respond to oral therapy with mexiletine or tocainide. Both compounds have shown to be of value in some patients with chronic recurrent ventricular tachyarrythmias.

Disopyramide Disopyramide is now the most used drug of this sub-class. It is effective in ventricular and supraventricular arrhythmias. It is given orally and intravenously and is well absorbed.

Adverse effects of these drugs are similar to those listed for lignocaine. In addition, GI symptoms, particularly nausea, are a common complaint.

Adverse effects 1. Anticholinergic effects (dry mouth, blurred vision, glaucoma, micturition hesitancy and retention. 2. GI disturbances 3. Hypersensitivity reactions (rash and agranulocytosis) 4. Hypotension and cardiac failure (negative inotropic effect) 5. Tachyarrhythmias

Class Ic Lorcainide and Flecainide These drugs are very effective in suppressing both supraventricular and ventricular tachyarrythmias but they also have considerable negative inotropic properties and markedly prolong intracardiac conduction time, even in therapeutic concentration.

Class Ib Lignocaine Lignocaine (lidocaine, xylocaine) is the oldest and best known in this group. It has 58

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Majid A.K. Lafi

Class II

Amiodarone

The mechanism of the acute antiarrhythmic effect of the β-receptor blocking agents is due to direct antagonism of the arrhythmogenic actions of endogenous catecholamines, it is also possible that the class I activity (membrane stabilising properties) in high concentration may play some role.

Apart from its ability to prolong the duration of the cardiac action potential amiodarone is also a smooth muscle relaxant, a noncompetitive β-receptor blocker, and demonstrate some degree of class I and class IV activity, at least in vitro. It is a very useful antiarrhythmic drug in the therapy and prophylaxis of most types of arrhythmias that poorly respond to other drugs.

Propranolol

Pharmacokinetics

Propranolol is often effective both in the treatment and in prophylaxis against supraventricular tachycardia, where they probably act largely by prolonging refractoriness and slowing conduction in the AV node. In atrial fibrillation and flutter (particularly if due to exercise, emotions or thyrotoxicosis) β-receptor blocking agents can be useful in slowing the ventricular response by their effect on the AV node. βblocking agents have some value in the therapy of ventricular tachyarrhythmias though they are not generally regarded as first-line drugs. β-blockers may also be useful in Wolff-Parkinson-White syndrome.

The administration of amiodarone (usually by mouth) is complicated by a variable bioavailability (20-80%), long t (54 days) after multiple dosing, and very large apparent volume of distribution (70 l/kg). Adverse effects 1. Hypotension 2. Bradycardia, heart block 3. Corneal micro-deposits (causing visual haloes & photophobia) 4. Hypothyroidism (blocks conversion of T4 to T3 , compensatory increase in thyroidstimulating hormone, affecting 2-20% of patients) and Hyperthyroidism (due to iodine content of the drug)1 5. Photosensitivity reactions (it may cause a bluish discolouration on exposed areas of the skin) 6. Pulmonary alveolitis 7. hepatitis

Cardiac adverse effects: Heart block and cardiac failure. For detailed adverse effects, see the appropriate section in antihypertensive drugs. Interactions 1. Concomitant i.v. Administration of βblockers with calcium antagonists (those affect conduction, e.g. verapamil and diltiazem) increases the risk of bradycardia and AV block. 2. In the presence of depressed myocardial contractility, the combination of oral or i.v. β-blockers and calcium antagonists (e.g. nifedipine and verapamil) may produce hypotension or heart failure.

Interactions 1. With digoxin (by displacing it from tissue binding sites and interfering with its elimination) and with warfarin (by inhibiting its metabolism) hence increasing the effects of both these drugs. 2. The depressant effect of amiodarone on SA and AV node is enhanced by β-blockers and calcium antagonists.

Class III

Sotalol

The class III agents are believed to produce their antiarrhythmic activity through blocking potassium channels (thus lengthening of refractoriness). The best known drug of this class is amiodarone.

1 Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 616.

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Cardiovascular Pharmacology - Antiarrhythmic Drugs

Sotalol is a non-selective β-blocker with marked class III activity. Unlike other βblocking agents, the prolongation of the duration of the action potential is apparent at once (within minutes, if administered i.v.), and this drug is showing promise in clinical trials in the treatment of supraventricular and ventricular arrhythmias.

Ramadi, 6 October 2009

Interactions 1. The depressant effect of verapamil on AV node and on myocardial contractility is enhanced by β-blockers.

Diltiazem Diltiazem appears to have pharmacological and antiarrhythmic properties that are very similar to those of verapamil.

Bretylium Bretylium is employed acutely and only against severe ventricular arrhythmias; its antiarrhythmic activity, prolongation of effective refractory period, may be mediated by blocking potassium channels. It can cause bradycardia and severe hypotension, probably by virtue of its adrenergic neurone blocking action.

Nifedipine Nifedipine in therapeutic concentrations acts almost solely as a vasodilator. It has no clinically useful antiarrhythmic action, although an antiarrhythmic effect can be demonstrated in vitro.

Class IV

Others

The increase in the slow inward flow of calcium ions through the L-channel (L-large) results in enhanced contractility of myocardial cells, enhanced automatic activity of pacemaker cells (SA node), and shortens conduction and refractoriness in the AV node. Calcium antagonists inhibit calcium influx through the L-channel resulting in depressed rate of discharge of the SA node and prolonged conduction and refractoriness in the AV node.

Digitalis Digitalis glycosides are presented in detail in the section on drugs for congestive heart failure. Digitalis decreases AV nodal conduction (by increasing vagal activity), and hence it is employed only against supraventricular arrhythmias. It is ineffective against arrhythmias originating in the ventricles.

Adenosine

Verapamil

Adenosine is an endogenous purine nucleotide that slows AV nodal conduction, and dilates coronary and peripheral arteries. It is rapidly inactivated by circulating adenosine deaminase; its t is several seconds. It must be administered i.v. by a bolus injection. It may be useful in supraventricular tachycardias, including Wolff-ParkinsonWhite syndrome. Its adverse effects are dyspnoea, facial flushing, chest pain, and transient bradyarrhythmias may occur. It is not suitable in asthmatic patients or those with second or third degree AV block.

Verapamil is the prototype for this class of drugs and it is of first choice for the shortterm therapy of supraventricular tachycardia. It is well absorbed when taken by mouth, but undergoes very extensive first-pass metabolism in the liver; therefore, its bioavailability in oral therapy is only 2040%. Adverse effects 1. Heart failure (particularly, impaired ventricular function)

in already

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DIURETICS order to avoid hypopotassaemia (hypokalaemia) potassium supplements may be necessary or the combination with a potassium sparing diuretic like amiloride. A fixed combination of hydrochlorothiazide and amiloride is available (Moduretic).

Introduction Glomerular filtration rate (GFR) is 125 ml/min; the extracellular fluid volume is 12.5 l, this fluid volume is filtered within a period of 1.5 hours but only 100 ml of urine are produced during the same time, therefore, tubular reabsorption is over 99%. Reabsorption is mainly achieved by active transport of electrolytes (Na+, Cl-, K+, HCO3and solutes like urea, creatinine etc.). the action of diuretics is concerned with selectively blocking the active transport mechanisms of Na+, Cl-, and HCO3-. Normally the volume of urine is determined by the solutes delivered to the tubules therefore, also water, electrolytes and other solutes such as glucose and urea act as diuretics.

Thiazides are used to relieve oedema due to cardiac failure, in which glomerular filtration is reduced resulting in increased reabsorption of sodium from the renal tubules (hence, reduced renal excretion of sodium). In small doses the thiazides are used in hypertension to lower blood pressure. Thiazides can be combined with other antihypertensive drugs such as β-blockers and ACE inhibitors. The antihypertensive action has to do partly with a reduced plasma volume and partly with a reduced responsiveness of the vascular smooth muscle. Thiazides are administered as tablets.

Indications for Diuretics 1. Oedema 2. Ascites, hydrothorax 3. Hypertension 4. Glaucoma (acetazolamide) 5. Renal calculus (thiazides) 6. Hypercalcaemia (loop diuretics)

Thiazides analogues Indapamide is a lipid soluble, non-thiazide diuretic that has long duration of action. It is often used in advanced renal failure to stimulate additional diuresis on top of that achieved by loop diuretics. Indapamide is metabolised and excreted by GI tract and the kidneys. Therefore, it is less likely to accumulate in patients with renal failure and may be useful in their treatment.

Thiazide Diuretics The parent compound is chlorothiazide, a substance derived from the sulphonamides. There are about 13 related compounds with similar action but more potent than chlorothiazide, e.g. hydrochlorothiazide, and chlorthalidone. Thiazides act primarily at the distal convoluted tubule to decrease the reabsorption

Loop Diuretics Loop diuretics such as frusemide, bumetanide, and ethacrynic acid are more potent and have a greater efficacy than any other diuretics. They inhibit the Na+/K+/Clcotransport of the luminal membrane in the ascending part of the loop of Henle leading to excretion of a higher percentage of filtered salt: 30% as compared to 10% for thiazides. Loop diuretics and thiazides are secreted in the proximal tubules, and since uric acid is excreted by the same mechanism; both drugs cause retention of urate. Loop diuretics also

of Na+ by inhibition of a Na+/Cl- cotransport system on the luminal membrane. They also promote excretion of K+, reduce uric acid and Ca++ excretion, increase blood sugar and are weak carbonic anhydrase inhibitors. Reduction of serum potassium is dangerous in patients being treated with digitalis. In 61

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condition with a low GFR (shock, crush injury). Mannitol increases renal blood flow because it dilates the afferent arterioles. Mannitol can also be used in cerebral oedema and elevated intraocular pressure. Since it produces hyperosmolarity in the systemic circulation, hence, drawing water by osmotic force from the extracellular space (from cerebral circulation). Very high level of mannitol, like in renal failure, may lead to pulmonary oedema (as a result of overloading the heart) and cerebral dehydration. Mannitol must be given i.v. as 10 or 25% solution. It is excreted outside the body only by kidney. Thus, if there is renal failure, mannitol is not eliminated; in this condition, haemodialysis is indicated.

cause potassium loss but they increase calcium excretion. Like thiazide diuretics, they possess diabetogenic activity. The greatest danger with loop diuretics is excessive diuresis with circulatory collapse and hypokalaemia. Ototoxicity can occur particularly in conjunction with aminoglycosides.

Potassium Sparing Diuretics These include triamterene and amiloride possess moderate natriuretic effects but their major importance is in inhibiting potassium excretion in the distal tubule. These drugs are not very efficient when used alone but may be useful in the combination with thiazides.

Alteration of Urine pH

Spironolactone is a competitive antagonist of aldosterone. This diuretic is mostly used for its potassium sparing action. Because spironolactone contains a steroid moiety it may produce anti-androgen like adverse effects, e.g. gynaecomastia, and erectile impotence.

Alkalinisation of Urine This may be achieved by sodium bicarbonate or potassium citrate for the following therapeutic objectives:

Xanthines like theophylline and caffeine have a combined effect on renal haemodynamics and tubular reabsorption.

1. Increases the elimination of salicylates and phenobarbital 2. Reduces irritation of an inflamed urinary tract 3. Discourage the growth of certain organisms like E coli.

Acetazolamide

Acidification of Urine

Acetazolamide (Diamox) is a carbonic anhydrase inhibitor that acts principally on the eye and the kidney. It reduces absorption of sodium bicarbonate in the proximal tubule and gives rise to hyperchloraemic acidosis as an adverse effect. Because it causes acidosis it is mostly used for glaucoma (topical preparation is now available). Acetazolamide may benefit some cases with atypical absence and other seizures in children.

This may be achieved by ammonium chloride (after food to avoid vomiting), ascorbic acid, CaCl2 by mouth for the following therapeutic objectives:

Minor Diuretics

1. Test for renal tubular (failure of acidification of urine, ammonium chloride) 2. Increase elimination of amphetamine, phencyclidine and dexfenfluramine.

Osmotic Diuretics These are solutes that increase diuresis because reabsorption is absent (mannitol) or limited (urea). Mannitol is mainly used in

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Table 3.9. A summary of selected actions, indications and adverse effects of the most commonly used diuretics. Diuretic Actions High Potency Inhibits NaCl reabsorption (thick Diuretics ascending loop), hypercalciuria (used in Frusemide hypercalcaemia, not used in the elderly)

Indications Oedematous Conditions (due to congestive heart failure, nephrotic syndrome, impaired renal function) Hypertension Acute pulmonary oedema Acute hypercalcaemia

Inhibits distal tubular NaCl reabsorption, hypocalciuric (used in idiopathic hypercalciuria, renal stone)

Oedematous Conditions Hypertension Idiopathic hypercalciuria Renal stone Nephrogenic diabetes insipidus (paradoxic use)

Inhibit Na+/K+ exchange distal tubule, also Na+/H+ exchange

Nephrogenic diabetes insipidus with kaliuretic (potassium-losing) diuretics

Aldosterone receptor antagonist

Primary hyperaldosteronism Oedematous Conditions Hypertension Hypokalaemia Hirsutism Polycystic ovarian syndrome Glaucomas Altitudes sickness Metabolic alkalosis Oedematous Conditions Epilepsies Oliguric phase of acute renal failure Elevated intracranial pressure Cerebral oedema Elevated intraocular pressure (when cannot be lowered by other means) Drug overdose

Medium Potency Diuretics Hydrochlorothiazide

Potassium Sparing Low potency Diuretics Amiloride Triamterene Low Potency Diuretics Spironolactone

Low Potency Carbonic anhydrase inhibitor Diuretics Inhibits NaHCO3 Acetazolamide reabsorption (proximal tubule) Osmotic diuretic, Osmotic increases tubular fluid Diuretics osmolarity leading to Mannitol increasing urine flow; dilates afferent arterioles

Adverse effects Hypokalaemia Hyperuricaemia Hyperglycaemia Hypotension, Ototoxicity Allergy (sulphonamide) Nephritis (interstitial) Hypokalaemia Hyperuricaemia Hypercalcaemia Hyperglycaemia Thrombocytopenic purpura Impotence Allergy (Sulpha) Hyperkalaemia Acidosis

Hyperkalaemia, Gynaecomastia, Impotence

Hyperchloraemic metabolic acidosis Neuropathy Allergy (sulphonamide) Cerebral dehydration Pulmonary oedema Contraindicated in anuria and congestive heart failure

Diuretics may alter renal haemodynamics and/or renal tubular function: For example mannitol is a vasodilator & saluretic (↑ perfusion, GFR and volume of urine); NSAIDs (e.g. aspirin) may reduce both thus antidiuretics ; ACE inhibitors (e.g. captopril) may alter GFR; saluretics (e.g. thiazides) directly, while alcohol indirectly (↓ ADH secretion) increase urine production; digoxin increases cardiac output thus renal perfusion. 63

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Acetazolamide inhibits

Mannitol & Xanthines increase filtration pressure

Carbonic anhydrase promotes reabsorption NaHCO3

Organic acid & base secretary system

Proximal tubule

Chlorothiazide, Hydrochlorothiazide, Chlorthalidone & Indapamide inhibit reabsorption of NaCl

Ascending Distal Loop of Henle convoluted tubule

Amiloride & Triamterene inhibit

Na/K exchange Late distal & collecting tubule

H+ Na+ Glucose Amino acids

K+ H+ K+

HCO3

Na+ K+ Cl-

Na+ Cl-

Na+

H2O

-

Inhibited by PGE2 Inhibited by Aspirin NSAIDs

H2O

Antagonism

Na/K-ATPase (cotransport system) Promoted by Frusemide Bumetanide Ethacrynic acid

Aldosterone

Blocked by Spironolactone

ADH

Enhanced by Desmopressim Chlorpropamide Carbamazepine Thiazides Reduced by Demeclocycline

Fig.3.5. A simplified schematic representation of the sites of transport of solutes and water, and action of diuretic agents. In the proximal tubule, acetazolamide blocks carbonic anhydrase reducing the availability of HCO3- in both the luminal space and inside the tubular cells; as a result less HCO3- and Na+ are reabsorbed, and less H+ is excreted. In the thick ascending part the loop of Henle, loop diuretics like frusemide inhibit Na/K-ATPase, which usually facilitates the reabsorption of Na+/K+/2Cl-. Prostaglandins (e.g. PGE2) are believed to be the endogenous inhibitors of this Na/KATPase; NSAIDs (e.g. aspirin) are believed to produce their antidiuretic effect, at least in part, through inhibition of synthesis of the inhibitory prostaglandins, resulting in enhanced reabsorption of salt. In the distal convoluted tubule, thiazide-related agents inhibit reabsorption of NaCl. In the late distal tubule, amiloride and triamterene inhibit Na/K exchange mechanism. While inside the renal tubular cell, spironolactone blocks the cytoplasmic aldosterone receptor resulting in reduced aldosterone nuclear activity, which usually leads to the production of certain mRNA and consequently in the cytoplasm increasing the production of specific proteins that enhance the permeability to Na+ and K+.

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ANTITHROMBOTIC DRUGS Introduction

(cyclooxygenase 1, COX-1) by irreversibly acylating the active site of the enzyme; therefore, aspirin permanently inhibits prostaglandin G/H synthase in platelets. Because platelets are non-nucleated, they cannot regenerate the enzyme as can nucleated cells. Thus, thromboxane production is halted until entry of new platelets into the circulation (platelet life-span 8 days). This irreversible action is unique to acetylsalicylic acid (aspirin) among NSAIDs. This is probably why aspirin, unlike other NSAIDs, at low doses (75-100 mg/day) can continuously produce antiplatelet activity.

Haemostasis is the spontaneous arrest of bleeding. Thrombosis is the process of pathological intravascular clotting. Haemostasis and thrombosis depend on a multifactorial balance between mechanisms of clot formation and dissolution (fibrinolysis). This balance depends on three major components: 1. Vessel wall 2. Blood a. Platelets b. Cagulation cascade c. Fibrinolytic system 3. Flow

Dipyridamole

Vessel wall controls vasoconstriction, formation of von Willebrand s factor (VIII), platelet adhesion, and regulation of coagulation and fibrinolysis.

Dipyridamole is a coronary vasodilator, hence, used prophylactically in the treatment of angina pectoris.dipyridamole reversibly inhibits platelet phosphodiesterase leading to increased platelet cyclic AMP concentration, thus, resulting in increased platelet cyclic AMP concentration, thus, resulting in reduced platelet reactivity (antithrombotic action: decreasing platelet reactivity to thrombogenic surfaces). It is usually given in combination with aspirin.

2a. Platelets

Dextrans

Platelets serve as trauma plugs, procoagulant agents, and promoters of healing. Platelet plug formation starts with a process of platelet adhesion, aggregation (ADP and thromboxane A2) and thrombinrecruitment with creation of a fibrin mesh and clot retraction. There are drugs like aspirin, dipyridamole, dextrans, and ticlopidine that inhibit platelet activity; hence, they are called antiplatelet drugs.

Dextrans alter platelet function and prolong the bleeding time. Dextran 70 carries an advantage over other antiplatelet drugs, in that it reduces the incidence of postoperative venous thromboembolism if it is given during or just after surgery.

Antiplatelet drugs

Ticlopidine and clopidogrel interfere with a variety of platelet activities including irreversibly blocking ADP receptors and thus inhibiting the binding of fibrinogen to platelets. The former carries a risk of producing neutropenia (2.4%), and thrombocytopenia. However, clopidogrel lacks the neutropenic effect; this makes it

These three alterations which favour intravascular clot formation are also called Virchow s triad, after the German pathologist Rudolf Virchow. 1. Vessel wall

ADP-receptor blockers

Aspirin Aspirin blocks the synthesis of thromboxane A2 from arachidonic acid in platelets by inhibition of prostaglandin G/H synthase 65

Cardiovascular Pharmacology Antithrombotic Drugs

superior to ticlopidine. Recently, clopidogrel gained a popular use in a fixed combination with lower dose of aspirin in enteric-coated dosage form in patients who cannot tolerate aspirin on its own.

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coagulation factors have been recognised in addition to a tissue factor (III) and calcium (IV). It is convenient to divide these factors into three groups. a. Vitamin-K dependent factors: II, VII, IX and X b. Contact activation factors: XI and XII c. Thrombin-sensitive factors: I, V, VIII, XIII.

2b. Coagulation system The 15 coagulation factors are described by Roman numerals. Twelve plasma protein Serotonin ADP

TXA2

PLATELET

Granule

Dipyridamole

TXA2

+

TXA2 Synthase PGH

-

Aspirin PDE

cAMP

Degradation

DAG IP3

PGH Synthase

AA PIP2

ATP PLC

AC

PLA2

Prostacyclin (PGI2)

Thromboxane A2 (TXA2)

Endothelial cell

Another platelet

Fig.3.6. Autacoids that influence platelet activation and recruitment, and site of action of antiplatelet drugs like aspirin and dipyridamole. TXA2 is thromboxane A2; PGH is prostaglandin G/H; AA is arachidonic acid; PLA2 is phospholipase A2; PLC is phospholipase C; AC is adenylate cyclase; PIP2 is phosphatidyl-4, 5-bisphosphate; IP3 is inositol 1,4,5trisphosphate; DAG is 1,2-diacyglycerol; PDE is phosphodiesterase. Note: aspirin (being uniquely) irreversibly inhibits PGH synthase by acylating the active site of the enzyme, eventually resulting in inhibition of the production of TXA2 that activates TXA2-receptor located on the outside of platelet membrane. In turn, resulting in hydrolysis of PIP2 and thus production of IP3 and DAG both of which promote the excitability of platelet. Other NSAIDs block PGH synthase but in a reversible manner (i.e. not permanently), hence, the natural substrate still has the chance to be acted upon by the enzyme. It is worth noting that platelets adhere to exposed collagen in the subendothelial layer of injured blood vessels.

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Thrombin

Majid A.K. Lafi

Collagen

Irreversibly inhibited by Aspirin

PAF

Irreversibly blocked by Ticlopidine Clopidogrel ADP

AA PGH Synthase

TXA2

PLATELET GP IIb/IIIa

Blocked by Abciximab (Super aspirin)

Fig.3.7. Autacoids that influence platelet activation and aggregation, and site of action of antiplatelet drugs like aspirin and ticlopidine. PAF is platelet activating factor; TXA2 is thromboxane A2; PGH is prostaglandin G/H; AA is arachidonic acid; ADP is adenosine diphosphate. ADP activates ADP-receptor located on the outside of platelet membrane resulting in activation of GP (glycoprotein) IIb/IIIa receptor. In turn, fibrinogen can interact with the activated receptor forming a bridge between two platelets resulting in aggregation.

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Coagulation factors circulate in inactive forms (zymogens). Coagulation entails a series of proteolytic reactions by which the clotting factors become an active protease, designated by a lower case, like Xa. Each clotting factor activates the next in a chain reaction until an insoluble fibrin clot is formed.

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Heparin increases clotting time but bleeding time is little affected and the risk of haemorrhage is not great. The best way to give heparin is by i.v. drip or intermittent i.v. injection. The action of heparin (acidic) can be terminated by an injection of protamine sulphate (basic) which binds to the heparin molecule.

Clotting is initiated either by an intrinsic or extrinsic pathway. Both systems converge to generate thrombin, which in turn cleaves fibrinogen to form a fibrin gel. Thrombin is central to all coagulation processes and it is therefore not surprising that generation of thrombin is the focus of important regulatory controls.

Adverse effects: haemorrhagic conditions and thrombocytopenia In recently years, low molecular weight heparins (LMWHs) have been introduced into clinical practice. Whereas, conventional or unfractionated heparin (UFH) produces its anticoagulant effect by inhibiting both thrombin and factor Xa, LMWHs inactivate only factor Xa. The major advantage of LMWHs is that they have a longer t , hence, they can be given once or, at the most, twice daily in a fixed dose without the need for laboratory monitoring. They are believed to have less incidence of producing haemorrhage and thrombocytopenia.

The most important natural inhibitors of coagulation is antithrombin III, which normally is present in excess amounts in plasma. Patients with an antithrombin III deficiency have a high incidence of recurrent thromboembolic diseases. Protein C and S, vitamin K (Koagulation vitamin) dependent proteins also are important inhibitors of coagulation and stimulators of fibrinolysis. Deficiency of protein C or S is also associated with a high risk of thrombosis.

No Heparin

Anticoagulants

Active clotting factors

Heparin Antithrombin III (Slow conversion)

Heparin is a natural anticoagulant produced mainly in mast cells and found in many tissues. Heparin was discovered by a medical student, J. Mclean, working at Johns Hopkin Medical School in 1916. To his astonishment, the extract of liver that he had kept longest not only failed to speed up but actually impaired clotting. It is now understood that heparin binds to antithrombin III causing a rapid anticoagulant effect (by a factor of 1000-fold).

Inactive factors With Heparin Active clotting factors Antithrombin III plus heparin Rapid conversion (immediately)

Heparin is the strongest organic acid in the body and in solution carries electronegative charge. Heparin exhibits a first-order and zero-order kinetics, the effect of which is that the plasma biological effect t alters disproportionately with dose, being 60 min after 75 units per kg and 150 min after 400 units per kg.

Inactive factors

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2. Pharmacodynamic (increased anticoagulant effect): aspirin (high dose), cephalosporin (3rd generation), heparin

Warfarin The coumarin anticoagulants including warfarin act by antagonising the cofactor functions of vitamin K, primarily inhibiting liver synthesis of prothrombin and some thromboplastin components, particularly factor VII. Initially, these drugs were used as rodenticides. The maixmal effect is produced in 1-2 days. The effect of the coumarin anticoagulants can be antagonised by vitamin K, a structural analogue. Peak absorption for warfarin occurs within two hours and the t is 42 hours. Warfarin is highly protein bound and it is only the free drug that is pharmacologically active.

• Decreased prothrombin time 1. Pharmacokinetic a.Hepatic enzyme induction: barbiturates, carbamazepine, rifampicin b.Impaired absorption and increased elimination of warfarin: cholestyramine, cholestipol (long term treatment may cause impaired vitamin K absorption and enhance anticoagulant effect) 2. Pharmacodynamic (reduced anticoagulant effect): oral contraceptive (oestrogens increase the synthesis of some vitamin K dependent clotting factors), vitamin K

Indications

2c. Fibrinolytic system

1. Deep venous thrombosis 2. Pulmonary embolism 3. Atrial fibrillation (in rheumatic valvular disease with cerebral and peripheral arterial embolism) 4. Acute myocadial infarction 5. Transient ischaemic attacks 6. Hip fracture 7. Disseminated intravascular coagulation (DIC)

Fibrin must be enzymatically digested by the serine protease, which is activated by a plasma or tissue activating factor (pPA and tPA). Plasmin digests fibrin to release a number of fibrin degradation products (fibrin split products) which also are anticoagulants. The conversion of plasminogen to plasmin can be inhibited by tranexamic acid and aminocaproic acid; while the action of plasmin is inhibited by aprotinin.

Adverse effects

Fibrinolytics

1. Haemorrhagic conditions (skin, GI and urinary tract) 2. Teratogenic (therefore, a pregnant women should be put on heparin during the course of pregnancy) 3. Warfarin skin necrosis (in patients with deficiency in protein C and S which are vit. K-dependent antithrombotic factors that can be suppressed by warfarin predisposing to venous thromboembolism and skin necrosis).

Streptokinase is a protein (not an enzyme on its own) synthesized by streptococci that combines with plasminogen to produce an activator complex that in turn converts plasminogen to the proteolytic enzyme plasmin. Plasmin is inactivated by circulating inhibitors like α-2-macroglobulin. These inhibitors are rapidly consumed at high doses of streptokinase. It is administered by intravenous infusion. Streptokinse is associated with bleeding and allergic reactions.

Interactions • Increased prothrombin time 1. Pharmacokinetic (hepatic enzyme inhibition): cimetidine, sulphonamides, mefenamic acid, erythromycin, metronidazole, ciprofloxacin, chloramphenicol,

Anistreplase is the p-anisoylated derivative of the Lys-plasminogen streptokinase activator complex that consists of a combination of purified human plasminogen and a bacterial streptokinase that has been acylated to protect the active site of the enzyme (prodrug). Activation of anistreplase 69

Cardiovascular Pharmacology Antithrombotic Drugs

occurs with the release of the anisoyl group by deacylation, which is a non-enzymatic first order process with a t in vitro in human blood of about 2 hours. Therefore, this product (unlike streptokinase on its own) allows for rapid intravenous injection, greater activity on plasminogen associated with clots than on free plasminogen in the blood. Anistreplase is associated with bleeding and allergic reactions.

Ramadi, 6 October 2009

than with heparin, thus, this form of therapy is only available in specialised centres.

Antifibrinolytic agents Antifibrinolytics (antiplasmins) inhibit plasmin activation like tranexamic acid that is used when haemorrhage cannot be controlled as in:

Alteplase is a tissue plasminogen activator (tPA) that preferentially activates plasminogen that is bound to fibrin, which theoretically limits fibrinolysis to the formed thrombus avoiding systemic activation. Alteplase produced by means of recombinant DNA technology. Alteplase is associated with bleeding; no serious or life-threatening allergic reactions have been reported. The fibrinolytics are indicated in acute myocardial infarction and thromboembolic conditions such as pulmonary embolism. These drugs carry a high risk of antigenicity and also haemorrhage that occurs more often

1. Prostatectomy 2. Haemophiliacs extraction 3. Menorrhagia

undergoing

Antifibrinolytic agents are contraindicated in thromboembolic disorders. Aprotinin, however, inhibits the action of plasmin hence it is useful in hyperplasminaemia. Note: Desmopressin may be useful in haemophilia (it is believed to promote the activity of von Willebrand s factor).

Plasminogen Fibrinolytics Plasminogen activators

dental

pPA, tPA Streptokinase Anistreplase Alteplase

Inhibited by antifibrinolytics, tranexamic acid & aminocaproic acid Plasmin

Inhibited by aprotinin

Stabilised fibrin

Fibrin degradation product

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Table 3.10. A summary of the drugs used in coagulation disorders, their mode of action and clinical uses. Drug Group Drug Anticoagulants (parenteral) Heparin

Mode of Action

Therapeutic Action

With antithrombin III inhibit both thrombin and factor Xa [antidote: protamine; onset: rapid in minutes; duration: hours; assessment: KCCT* 1.5-2.5 times the control

Prevention of venous thrombosis

Haemorrhage, thrombocytopenia

With antithrombin III inhibit only factor Xa (No assessment is usually required)

Prevention of venous thrombosis

Less risk above

Inhibits synthesis of vitamin Kdependent clotting factors [antidote: vitamin K1 ; onset: slow in hours; duration: days; assessment: prothrombin time**]

Prevention of venous thrombosis

Haemorrhage, teratogenic, many interactions

Aspirin

Irreversibly inhibits prostaglandin G/H synthase, hence, inhibition of TXA2 resulting in inhibition of aggregation

Prevention of arterial thrombosis

Dipyridamole

Inhibits platelet phosphodiesterase resulting in more cAMP resulting in inhibition of aggregation Irreversibly block ADP receptors thus inhibiting ADP-mediated aggregation

Prevention of arterial thrombosis

LMWHs

(oral) Warfarin

Adverse effects

of the

Antiplaltelets

Prevention of arterial thrombosis

Ticlopidine

Neutropenia (2.4%)

Clopidogrel

Lacks the above adverse effect

Abciximab

Dextrans

Blocks GP IIb/IIIa Receptors inhibiting the final step in platelet aggregation Alters platelet function & prolong bleeding time

71

Prevention of arterial thrombosis + ↓ postoperative venous thromboembolism

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Thrombolytics Streptokinase (i.v. infusion) Anistreplase (prodrug, i.v. rapid injection)

Activates synthesis of plasmin resulting in fibrin degradation

Acute myocardial infarction (AMI) Pulmonary embolism

Haemorrhage Antigenicity

Alteplase (i.v. infusion)

Activates preferentially fibrinbound plasminogen thus plasmin production confined to clot.

Acute myocardial infarction (AMI) Pulmonary embolism

Haemorrhage

Inhibit conversion of plasminogen to plasmin resulting in formation of clot Directly inhibits plasmin resulting in promotion of clot.

Arresting perfused bleeding

Antithrombolytics Tranexamic acid Aminocaproic acid

Arresting perfused bleeding in hyperplasminaemic conditions * KCCT: kaolin-cephalin clotting time also known as activated partial thromboplastin time (APTT), primarily monitors the intrinsic system. ** Prothrombin time is also expressed as the International Normalised Ratio, INR), primarily monitors the extrinsic system.

Aprotinin

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ANTIHYPERLIPIDAEMIC DRUGS

Introduction

Adverse effects

Elevated cholesterol concentrations are one of the major contributing factors in the development of atherosclerosis. Cholesterol enters the circulation from two major sources, absorption from food (exogenous pathway). It leaves the circulation when it is taken up by the liver to form bile acids, or taken up by other cells to form steroid hormones or inserted into membranes. When present in excess, it is taken up by fibroblasts and scavenger cells in regenerating tissues, as well as fat cells. As lipids are insoluble in aqueous solution, transport of cholesterol within the plasma is by way of lipoprotein particles.

1. Disturbances in liver function tests 2. Elevation of muscle enzymes (creatine phosphokinase)

Bile Acid Binding Resins Cholestyramine and colestipole are ion exchange resins that bind cholesterol and prevent its GI absorption of bile acids, (which is largely reabsorbed by enterohepatic circulation). Thus, they promote the liver to uptake cholesterol from plasma for the synthesis of bile acids hence reduction in plasma cholesterol.

Hyperlipidaemias can be primary and/or secondary depending on their causes. Primary ones can be due to a single gene defect and/or environmental factors. While, secondary hyperlipidaemias are due to a metabolic disorder like diabetes millets, hypothyroidism, primary biliary cirrhosis, or excessive alcohol intake. Management of secondary hyperlipidaemias can be achieved by dietary intervention, and treatment to control the primary cause of the hyperlipidaemia.

These drugs are hypercholesterolaemia.

useful

in

Adverse effects 1. GI disturbances 2. Deficiency of vitamin A, D, K, and folic acid (therefore, supplement of these lipid soluble substances may be needed)

Cautions/ contraindications

Antilipid drugs are used to prevent myocardial infarction and other atherosclerotic disorders such as stroke and peripheral vascular disease. They are used prophylactically to reduce formation of atherosclerotic plaque and subsequent narrowing of lumen in coronary arteries.

1. Complete biliary obstruction 2. Pregnancy

Fibrates Fibrates (clofibrate and gemfibrozil) are derived from fibric acid and all appear to have the same mode of action. These drug are believed to mediate their antilipid effect though the following possible mechanisms:

Statins Lovastatin and simvastatin inhibit the ratelimiting enzyme in endogenous cholesterol synthesis hydroxy-methyl-glutaryl coenzyme A (HMG CoA) reductase. This leads to increase the expression of LDL receptors in the liver (that transport cholesterol out of the plasma) resulting in reduced concentration of circulating cholesterol.

1. Increase cholesterol secreted in the bile, thus, increased faecal loss. 2. Increase extrahepatic lipoprotein lipase activity; thus, triglyceride lowering effect may be due to increased efficiency of

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Cardiovascular Pharmacology - Antihyperlipidaemic Drugs

removal of VLDL, as well as reduced VLDL secretion by the liver.

Ramadi, 6 October 2009

Adverse effects

Fibrates are effective in hypertriglyceridaemia and to a lesser extent hypercholesterolaemia.

1. Intense cutaneous flush (prevented by prior administration of aspirin) 2. Pruritus 3. Hyperuricaemia and gout (it inhibits tubular secretion of uric acid) 4. Hyperglycaemia (it induces glycogenolysis) 5. Hepatotoxicity

Adverse effects 1. G I disturbances 2. Pruritus 3. Impotence 4. Increase gall stone

Antioxidants Probucol has gained a renewed interest because of its antioxidant properties. Probucol inhibits the oxidation of cholesterol. Oxidation of cholesterol-rich LDL promotes the ingestion of LDL by macrophages. These macrophages, being loaded with cholesterol, become foam cells that adhere to the vascular endothelium and are the basis for plaque formation. Thus, preventing oxidation of cholesterol may reduce formation of atherosclerosis.

The use of clofibrate has declined in recent years; this is due to a high incidence of mortality associated with malignancy or complications due to postcolecystectomy and pancreatitis. However, gemfibrozil has gained the reputation to have a lower incidence of mortality, and thus it has largely replaced clofibrate.

Cautions/ contraindications

Probucol can be effective in hypercholesterolaemia in which other antihyperlipidaemic drugs are ineffective.

1. Hepatic and renal dysfunction 2. Pregnancy

Adverse effects Nicotinic Acid 1. GI disturbances 2. Reduce HDL levels 3. prolongation of QT interval (caution with digitalis)

Nicotinic acid (niacin) is a water-soluble vitamin, when given in gram doses, it potently inhibits lipolysis in adipose tissue. Thus, decreasing the production of triglycerides that are essential components for the production of very low-density lipoprotein (VLDL). Further, low-density lipoprotein (LDL, cholesterol-rich lipoprotein) is derived from VLDL in the plasma. Therefore, a reduction in the production of VLDL will lead in a reduction in plasma LDL concentration. Nicotinic acid is effective in hyperlipidaemias in which both VLDL and LDL are elevated.

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Table 3.11. A summary of antihyperlipidaemic drugs, their possible mode of action and adverse effects. Drug Group Statins Simvastatin Lovastatin

Mode of Action Inhibit HMG CoA reductase reducing hepatic cholesterol synthesis →↑ LDL receptor expression →↑ cholesterol transport out of plasma →↓ circulating cholesterol. Bile Acids Binding 1.Reduce reabsorption of lipids & bile acids Resins 2.Promote hepatic uptake of Cholestyramine cholesterol for synthesis of Colestipole bile acids Fibrates 1.↑ extrahepatic lipoprotein Clofibrate lipase activity →↓ Gemfibrozil triglycerides (→ free fatty acids) 2.↑ cholesterol secretion in bile →↑ faecal loss Inhibits lipolysis in adipose tissue Nicotinic Acid →↓ production of free fatty acids →↓ hepatic production of triglycerides Inhibit oxidation of cholesterol-rich Antioxidants Probucol LDL →↓ ingestion of LDL by macrophages →↓ formation of foam cells →↓ formation of plaque

75

Adverse effects Disturbances in liver function tests Elevation of muscle enzymes (creatine phosphokinase)

GI disturbances ↓ intestinal absorption of lipid soluble vitamins (A, D & K) and folic acid GI disturbances Pruritus Impotence 1-2% increase in incidence of gallstones Pancreatitis Cutaneous flush Pruritus Hyperuricaemia Diabetogenic GI disturbances Reduce HDL levels

the

Cardiovascular Pharmacology - Antihyperlipidaemic Drugs

Statins inhibit HMG CoA reductase

Ramadi, 6 October 2009

Enterohepatic circulation

C

Diet CE (0.4 g/d)

Synthesis

_

_ _

Bile acids (total pool, 3-5g)

Free cholesterol pool

Bile acids C CE

Chylomicron

C C C

C TG CE

VLDL

TG CE

Chylomicron remnants bind to LDL (APO B-100, E) receptors on liver where they are endocytosed.

INTESTINE Capillaries

C Bile (0.6 acids g/d) (0.4 g/d)

Faeces

C CE EXTRAHEPATIC TISSUE

Chylomicron remnants

HDL

Extrahepatic tissues like adipose

Nicotinic acid inhibits lipolysis

Free fatty acids

Triglycerides

TG IDL

C

(VLDL remnant)

C

Lipoprotein lipase

Fibrates promotes

C CE C

Extracellular lipoprotein lipae degrades triacylglycerol in chylomicron and VLDL

LDL

Fig.3.8. A simplified schematic representation of transport of cholesterol between the tissues in humans. (C, free cholesterol; CE, cholesteryl ester; TG, triacylglycerol; VLDL, very low density lipoprotein; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. Intestinal mucosa secretes TG-rich chylomicrons (produced primarily from dietary lipids); liver secretes TG-rich very low density lipoprotein particles.

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DRUGS FOR ANAEMIAS A subject is said to be anaemic if the total haemoglobin content per unit of blood volume usually measured as g Hb/dl, is

below normal range .Anaemia can be caused by several conditions including iatrogenic causes (Table.3.10).

___________________________________________________________

Table 3.12. A summary of common types of anaemias, their major causes and treatment Type of Major Causes of Anaemia Anaemia Iron deficiency* 1. Acute or chronic blood loss (hypochromic 2. Insufficient intake during periods of microcytic) accelerated growth in children, or in heavily menstruating or pregnant women (depletion of iron stores & inadequate intake) Megaloblastic Folic acid deficiency caused by: (macrocytic) a.Increased demand as in pregnancy & lactation b.Poor intestinal absorption c.Hepatic enzyme inducers d.Dihydrofolate reductase inhibitors (e.g. trimethoprim) Vitamin B12** deficiency caused by: 1. Failure of gastric parietal cells to produce intrinsic factor (pernicious anaemia) 2. Low dietary levels (dietary deficiency, less commonly)

Treatment Iron supplement

Folic acid supplement

Vitamin B12 (parenterally) Vitamin B12 (orally)

*Iron deficiency anaemia represents over 95% of anaemias, thus, iron therapy is most widely needed. **Cyanocobalamin, or hydroxocobalamin Note :Megaloblastic anaemia should not be treated by folic acid alone but rather with a

combination of folic acid and vitamin B12. This is because folic acid alone reverses the haematological abnormality therefore masking the vitamin B12 deficiency which may progress to severe neurological dysfunction.

3. Abnormalities of the GIT where the proportion of dietary iron absorbed may be decreased as in malabsorption syndromes. 4. Premature babies, as they are both with low iron stores, and babies weaned late; there is very little iron in human milk and even less in cow s milk. 5. Early treatment of severe pernicious anaemia with vitamin B12, as the initial high rate of red cell formation may cause exhaustion of the iron stores.

INDICATIONS FOR IRON THERAPY 1. Iron deficiency due to dietary lack or chronic blood loss 2. Pregnancy [The extra iron required by mother and foetus totals 1000 mg, mainly in the latter half of pregnancy. The foetus takes iron from the mother even if she is iron deficient. In pregnancy, dietary iron is seldom adequate; therefore, iron and folic acid should be given to pregnant women from the fourth month.

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(which may occur in excessive parenteral iron therapy or after a hundred or more blood transfusions as in treatment of thalassaemia). Desferrioxamine is an iron chelating agent, which may be administered orally (for acute iron overdose to chelate the iron present in the GIT as desferrioxamine is not absorbed from the GIT), intramuscularly or by intravenous infusion to remove systemic excess iron. After chelating iron to desferrioxamine, the latter becomes ferrioxamine and is excreted through the kidney.

Adverse effects Off these anti-anaemic drugs only iron containing preparations can produce GI disturbances (by local irritation) as adverse effects. There are no known adverse effects of folic acid or vitamin B12.

Desferrioxamine Occasionally removal of iron from the body may be desirable in conditions like acute iron overdose (poisoning) and haemosiderosis Gut lumen

Gastric mucosal cell

Fe++

Blood Fe++ + apoferritin

Excess ferritin shedded and excreted via faeces

Ferritin + labile Fe+++

Fe+++ in transferrin (transport globulin)

Erythrocyte precursors (80%, haem) Muscle (myoglobulin) Iron containing enzyme (cytochrome P450)

In the body irons is stored as ferritin that aggregates

In the blood the state of iron stores is indicated by: 1. amount of ferritin 2. serum iron concentration (low in iron deficiency) 3. binding capacity of ferritin (high in iron deficiency)

Haemosiderin in the cells of Liver Bone marrow Spleen

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ANTIMICROBIAL DRUGS (GENERAL PRINCIPLES) difficult to treat. Drugs poorly penetrate the eye (as in bacterial endophathalmitis, intravitreal therapy is recommended because of blood-ocular barrier), prostate, and bone, and infections in these sites and sites where there is considerable tissue necrosis (as in burn, penetration problem) require higher dosages of antimicrobials. Higher doses are also required when infection involves avascular tissues, as in bacterial endocarditis. Clindamycin and lincomycin penetrate deep tissues and are useful in the therapy of osteomyelitis caused by staphylococci and Bacteroides fragilis.

Introduction In 1877, Pasteur and Joubert observed that anthrax bacilli grew rapidly when inoculated into sterile urine but failed to multiply and soon died if one of the common bacteria of the air was introduced in the urine at the same time. They commented that life destroys life among the lower species even more than among higher animals and plants. In 1928, Alexander Fleming, while investigating staphylococcus variants at St. Mary s Hospital in London, observed that a mould contaminating one of his cultures caused lysis to the bacteria in its vicinity. Fleming called the antibacterial substance penicillin because the mould belonged to the genus penicillium. In 1941, at Oxford University, Florey and co-workers managed to prepare enough of penicillin to treat for 24 hours with a remarkable result one patient desperately ill with staphylococcal and streptococcal infections resistant to all available antimicrobials.

The in vitro bacterial sensitivity to a certain drug cannot always determine its therapeutic suitability. In severe infections caused by extended spectrum β-lactamases (ESBLs) producing bacteria that in vitro may appear susceptible to the 3rd generation cephalosporins but in vivo with poor therapeutic outcome. In addition, its pharmacokinetic properties may determine its suitability depending on the site of infection. Thus, cephalosporins (except 3rd generation, SC3), aminoglycosides, clindamycin, lincomycin, and amphotericin B do not reach the cerebrospinal fluid (CSF) in sufficient amounts to counter infection in the brain or meninges. When these drugs are indicated they have to be given intrathecally.

Antibacterial Spectrum Two methods are used to determine bacterial sensitivity to antibiotics, in the first organisms are inoculated into plates of culture medium that contain diminishing drug concentration. After incubation the lowest concentration that inhibits bacterial growth (minimal inhibitory concentration, MIC) can be determined. Generally, bacteria are considered sensitive when the MIC is lower than the concentration that can be achieved in blood. The second (KirbyBauer) method employs standardised drugimpregnated filter paper discs onto the surface of a seeded agar plate and measuring the zone of growth inhibition.

Biliary and urinary tracts On the other hand, ampicillin, amoxicillin, ceftriaxone, tetracyclines (concentrations in bile exceed those in serum tenfold) and rifampicin achieve high concentrations in the bile and hence may be suitable for the treatment of biliary tract infections. For this reason, typhoid carriers are treated by ampicillin and not by chloramphenicol which is not suitable in this condition. Nitrofurantoin achieves therapeutic levels only in the urine and should be used only in urinary tract infection (UTI); whereas, erythromycin is only partly excreted in

Site of Infection The desired peak concentration of a drug at the site of infection should equal at least 4 times the MIC. Deep-seated infections are 79

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urine and is therefore unsuitable for the treatment of UTI. It should be noted that practically all antimicrobial drugs that are used in the treatment of UTI share a common pharmacokinetic property, that is eliminated largely unchanged through urinary excretion. Therefore, they can reach the offending microorganisms from the circulation as well as from the lumen of the urinary tract. This is why a sub-MIC blood level of gentamicin is generally effective in the treatment of UTI but not effective in the treatment of burn for the same offending microorganism (e.g. Pseudomonas aeruginosa).

pH The antibacterial potency of an antibiotic in vivo may vary and be quite different than in vitro. The low pH in abscess cavities, pleural space, CSF, and urine may reduce the antimicrobial activity of gentamicin (weak base), erythromycin, and clindamycin. The use of sodium bicarbonate (alkalinisation of urine) as a soothing agent also promotes the antibacterial activity of aminoglycosides (e.g.

Substrate

Sulphonamides Trimethoprim

gentamicin). Acidification of urine with ascorbic acid increases the antibacterial activity of cloxacillin and tetracycline, and is essential for the action of hexamine mandelate (mandelamine, which is in acidic urine slowly hydrolysed to formaldehyde and ammonia) and nitrofurantoin. It is worth noting that certain microorganisms such as Proteus species and Pseudomonas aeruginosa grow better in alkaline media. While others such as Escherichia coli (the growth of which discouraged by alkalinisation of urine) and Mycobacterium tuberculosis grow better in acidic media.

Blood level Measurement of blood levels of antibiotics is useful particularly in non-responding patients and with antibiotics with high toxicity such as aminoglycosides (e.g. gentamicin). Antimicrobials may induce hypersensitivity reactions (which are not dose-related); toxic and irritative effects (which are dose-related).

Penicillins Cephalosporins Imipenem Aztreonam

1

Cell Wall

4 Enzyme

Tetracycline Chloramphenicol Erythromycin DNA Clindamycin Na fusidate mRNA Spectinomycin (Aminoglcosides)

Ciprofloxacin Rifampicin Nalidixic acid Metronidazole 2

Protein

Cell Membrane

5 Polymixin B Amphotericin B

DNA

3 Rough Endoplasmic Reticulum

Fig.4.1. A schematic representation of the principal five different antibacterial mechanisms of action: 1. Intermediary metabolism block (competitive substrate inhibition, enzyme inhibition) e.g. sulphonamides and trimethoprim. 2. Nucleic acid metabolism (block RNA and DNA), e.g. rifampicin. 3. Protein synthesis block by inhibition of ribosomal function, e.g. tetracycline. 4. Cell wall damage by impairment of peptidoglycan synthesis, e.g. penicillin, this gives rise to swelling and rupture. 5. Cytoplasmic membrane damage by disorganising the cell membrane structure resulting in an increase in membrane permeability, e.g. polymixin B. 80

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Table 4.1. A classification of the most important antimicrobial agents according to their mode of action. Drug Sulphonamide

Mode of Action Folic acid synthesis inhibition

Trimethoprim

Folinic acid synthesis inhibition Cell wall damage

Penicillins Cephalosporins Imipenem Vancomycin Aztreonam Tetracyclines Chloramphenicol Erythromycin Clindamycin Spectinomycin Aminoglycosides Polymixin B Amphotericin B Nystatin Rifampicin Ciprofloxacin Metronidazole Nalidixic acid

Protein synthesis inhibition

Activity Bacteriostatic (When combined Bactericidal) Bacteriostatic Bactericidal

Bacteriostatic

Membrane damage

Nucleic acid synthesis inhibition

Bactericidal Bactericidal

Bactericidal

certain sites of infections may show resistance to antimicrobial agents (failure of treatment), as in meningococcal meningitis due to low penetration of antimicrobials through the blood brain barrier resulting in insufficient drug concentration in the spinal cerebral fluid. Or perhaps the bacterial population may exist in a fibrotic tissue (like that may occur in tuberculosis) and not being reached by antimicrobials because of low perfusion to the site of infection. This can also be true when the bacterial population is in a site with low tissue viability and considerable necrotic debris as in burn wounds. Antibiotic resistance can also be observed for bacteria growing in biofilms. Bacterial biofilms are frequent problematic infections, like those associated with cystic fibrosis, chronic bronchitis, osteomylitis, and foreign-body associated infections. Bacteria growing in

Bacterial Drug Resistance The origin of drug resistance may be nongenetic or genetic. 1. Nongenetic Origin: Bacteria may be sensitive to certain antibiotics in vitro but may appear to be resistant in vivo. This may be true with infections with intracellular microorganisms such as in brucellosis, salmonellosis, and tuberculosis. In these cases, drugs may fail to reach the intracellular site of action and therefore resulting in failure of treatment. Active replication of bacteria is usually required for the action of most antibiotics. Consequently, bacteria that are metabolically inactive, i.e. being dormant as may occur in tuberculosis, can exhibit resistance to antimicrobial agents. Further, 81

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• Transduction: Plasmid DNA is enclosed in a bacterial virus (bacteriophage) and transferred by the virus to another bacterium of the same species (as in the case of staphylococci). • Transformation: Naked DNA passes from one cell of a species to another cell thus altering its genotype. • Transposition: A transfer of short DNA sequences (transposons, transposable elements) occurs between one plasmid and another or between a plasmid and a portion of the bacterial chromosome within a bacterial cell.

biofilms are more resistant than those under a planktonic way of life to the action of phagocytic cells antibacterial activity as well as the action of antibiotics. 2. Genetic Origin: Most drug-resistant microbes emerge as a result of genetic change and subsequent selection processes by antimicrobial drugs. a. Chromosomal Resistance: This develops as a result of spontaneous mutation, the presence of the antimicrobial drug serves as a selecting mechanism to suppress susceptible organisms and favour the growth of drug-resistant mutants. Antibiotic resistance can arise from a number of mechanisms involving mutation of chromosomal genes. Such mechanisms, usually involving mutations in genes encoding drug targets or systems that affect drug accumulation, are defined as endogenous resistance mechanisms, to distinguish them from the exogenous resistance mechanisms that are typically mediated by the acquisition of plasmids and transposons.

Selection and Emergence of Drug Resistance The use of antimicrobial agents promotes the emergence of drug resistant mutants. However, it should be stressed that although antimicrobials promote drug resistance, they are not usually mutagenic and do not directly cause the genetic changes that are responsible for reduced drug sensitivity. Spontaneous mutation and conjugation are random events whose incidence is independent of drug use. Antimicrobial agents simply serve to make conditions favourable for selection and emergence (overgrowth) of those microorganisms that possess drug resistance.

b. Extrachromosomal Resistance: Bacteria often contain extrachromosomal genetic elements called plasmids. R factors are a class of plasmids that carry genes for resistance to one and often several antimicrobial drugs and heavy metals. Plasmid genes for antimicrobial resistance often control the formation of enzymes capable of destroying the antimicrobial drugs. Genetic material and plasmids can be transferred by the following mechanisms: • Conjugation: A unilateral transfer of genetic material between bacteria of the same or different genera occurs during a mating (conjugation) process. Plasmid or other DNA is transferred through these protein tubules from the donor to the recipient cell. A series of closely linked genes, each determining resistance to one drug, may thus be transferred from a resistance to a susceptible bacterium. This is the commonest method by which multidrug resistance spreads among different genera of gram-negative bacteria.

It is worth recalling the two main aspects of the ecology of microorganisms: 1. Microorganisms release chemicals that are toxic to other microorganisms. 2. Microorganisms within one ecological niche (location, e.g. intestine, genitourinary tract, skin) competes with one another for available nutrients. In the absence of drugs, these different microorganisms in a one location will serve to keep one another in check. Further, if all these microorganisms are drug sensitive, then the use of antimicrobial agents will be equally detrimental to all members of the population and, thus, will not promote the growth of any individual. On the other hand, if there is a drug resistant microorganism

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present, antimicrobial will favour the overgrowth of that microorganism. Therefore, the introduction of antimicrobial agents will kill sensitive microorganisms (pathogenic and/or non-pathogenic commensals) resulting in:

vulvovaginitis that often due to fungi). Opportunistic infections can occur if the patient develops an impaired immune response due to the disease or other drugs (anticancer drugs, immunosuppressive drugs).

1. Elimination of toxic substances (produced by those microorganisms) 2. Removal of competition for available nutrients

Host Factors There are two factors, host defences and site of infection, which are unique to the selection of antimicrobial agents. Other host factors like age, pregnancy, and previous drug reactions, are same as those considered when prescribing any other medication.

Thereby making conditions even more favourable for the drug-resistant microorganism to flourish. In absence of antimicrobial agents, it appears that drug resistance is of no benefit to microorganisms; it is only when antimicrobial agents are used, these agents will favour overgrowth of those microorganisms that are resistant.

Host defences The immune system plus the phagocytic cells (macrophages, leukocytes), together form the host defences. These defences are essential for antimicrobial therapy to be successful. It should be stressed that, usually, antimicrobial therapy used for the treatment of infection do not produce cure on its own. The objective of antibiotic treatment is to suppress microbial growth to the point at which the balance is tipped in favour of the host. Bactericidal agents are preferred when treating immunocompromised hosts, and even these agents may prove inadequate.

Therefore, emergence of resistance can be avoided if unnecessary use of antibiotics can be prevented, particularly broad-spectrum and if antibiotics are properly selected on the basis of in vitro testing and if high enough concentrations are used. Moreover, if proper drug combination are used, e.g. rifampicin and isoniazid (INH) as in mycobacterial infection.

Antibiotic-resistant cells may be present in susceptible bacterial populations and can emerge under selective pressure.

The objective of antibiotic treatment is to suppress microbial growth to the point at which the balance is tipped in favour of the host defences without which drugs cannot combat infections.

Superinfections More than 300 species of microorganisms normally inhabit the body (normal flora). With the depression of non-pathogenic commensals, drug resistant pathogenic bacteria or foreign organisms can more easily initiate superinfection, particularly in the gastrointestinal tract (e.g. psedomembranous colitis, nowadays known as antibiotic-associated colitis, after clindamycin due to Clostridium difficile infection), upper respiratory tract (pneumonia and sepsis caused by staphylococci, Gram negative bacilli, and Candida albicans) or genitourinary tract (itching and

Site of Infection It is essential that an antimicrobial agent must be present at the site of infection in a concentration greater than the MIC. The MIC can be difficult to achieve for infections at certain sites because of impeded drug penetration. In meningitis, because of the blood brain barrier (BBB), certain drugs cannot achieve the MIC. In order to 83

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example, sulphonamides can reach levels in milk that are sufficient to cause kernicterus in nursing newborns. As a general rule drugs including antibiotics should be avoided by breast-feeding women.

overcome this problem the following may be considered: 1. Select a drug that can readily cross the BBB. 2. Inject antibiotic intrathecally (directly into the subarachnoid space)

Previous allergic reactions

In infected abscesses, poor vascularity and the presence of pus and other material hinder access to drugs. In this condition surgical drainage is indicated.

Severe allergic reactions are more common with penicillins than with any other group of drugs. As a general guideline, patients with a history of allergy to penicillins should not receive them again except in life-threatening infections for which no suitable alternative is available.

Further, in the presence of foreign material (like cardiac pacemakers, prosthetic joints or heart valves, synthetic vascular shunts, renal stones) present a special local problem. Phagocytic cells respond to these materials in an attempt to destroy them. This will distract phagocytes and make them less effective to deal with bacteria. Therefore, bacterial vegitations that difficult to penetrate by drugs result in such sites of infection as in endocarditis. When treating such infections, recurrence and failure are common. Frequently, the infection can be eliminated only by removing the foreign object.

Genetic factors Genetically determined unwanted drug reactions can be observed with some antimicrobial agents. Sulphonamides can cause haemolysis in glucose-6-phosphate dehydrogenase deficient patients. The rate of hepatic inactivation of drugs can also be determined genetically. There are slow and fast drug metabolisers. For example, without adjusting the dose, when giving isoniazid to slow metabolisers it will accumulate to toxic levels producing peripheral neuropathy. On the other hand, in fast metabolisers, isoniazid level may remain subtherapeutic while the high level of its metabolites may cause hepatitis.

Age Infants and the elderly are unusually vulnerable to drug toxicity due to poorly developed kidney and liver function. For example, the use of sulphonamides in newborns can produce kernicterus (a severe neurological disorder caused by displacement of bilirubin from plasma proteins). In the young, the tetracyclines bind to developing teeth causing discolouration, therefore, tetracyclines are contraindicated in children under 8 years of age.

Therapy with Combination

Antimicrobial

Antimicrobial agents are either bactericidal or bacteriostatic. When used concurrently these agents may act in an additive, synergistic or antagonistic manner. A more than additive response (synergistic) can be expected when two bacteriostatic drugs are combined (e.g. trimethoprim plus sulphamethoxazole). Bactericidal drugs act maximally on rapidly multiplying bacteria therefore the combination of a bactericidal (e.g. penicillin) and a bacteriostatic (e.g. tetracycline) may act antagonistically. There is only one clinically important and well established report of antagonism (early 1950s); stating that penicillin alone produced 80% cure-rate in meningococcal meningitis

Pregnancy and lactation Several antimicrobial agents can cross the placenta, posing risk to the developing foetus. The well-known example is tetracyclines that can stain immature teeth. Further, the consumption of aminoglycosides (e.g. streptomycin) in pregnancy can lead to foetal deafness. Drugs can enter breast milk; for 84

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aminoglycoside to reduce bacterial protein synthesis.

while addition of oxytetracycline (penicillin plus oxytetracycline) produced 20% cure rate in meningococcal meningitis. However, there is now a long list of clinically useful combinations of bactericidal and bacteriostatic drugs including penicillins with tetracycline in pelvic infections, and well accepted combination of streptomycin with tetracycline in brucellosis etc. It may be justified to say that the concept of prohibiting the combination of bactericidal with bacteriostatic agents is a myth.

Disadvantages combination

of

antibacterial

1. Increased risk of toxic and allergic reactions 2. Possible antagonism of antimicrobial actions 3. Increased risk of superinfection 4. Selection and emergence of drug resistant bacteria 5. Increased cost to the patient

Indications for use of antimicrobial combination 1. Initial therapy of severe infection of unknown aetiology in neutropenic host until the infecting organism has been identified. 2. Mixed infections (e.g. brain abscesses, pelvic infections, infections resulting from perforation of abdominal organs) 3. Prevention of resistance: Although the combination of antimicrobial agents usually promote emergence of resistance but in some cases such as infection with Mycobacterium tuberculosis, where combination is used specifically to suppress the emergence of resistant bacteria. 4. Decreased toxicity: The addition of flucytosine to amphotericin B in the treatment of fungal meningitis makes it possible to reduce the dose of amphotericin B, thus, reduced risk of renal damage. 5. Enhanced antibacterial action: In enterococcal endocarditis, the combination of penicillin and an aminoglycoside is used. Penicillin weakens bacterial cell wall providing better access for the

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Within one ecological location (e.g. skin) Produce Kill 1. microorganisms bbr toxic compounds br other organisms (pathogenic & nonpathogenic) 2. microorganisms compete with each other for nutrients In drug-free Conditions Organisms keep one another in check (no overgrowth of a certain organism)

When using antimicrobial agents kill Antimicrobial agents bbr sensitive organisms

Selection 1. Elimination of toxic substances 2. Removal of competition for nutrients

Emergence Overgrowth of resistant organisms (including G ve non-pathogenic commensals)

Transfer resistance to pathogens Extrachromosomal (Plasmid mediated) (conjugation, transduction, transformation, transposition, transfection)

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Table 4.2. Classification of the important antimicrobial drugs based on principal therapeutic objectives by susceptible organisms. Susceptible Organisms

Antibacterial Drugs Narrow Spectrum Agents Penicillin G Penicillinase-Resistant Penicillin Erythromycin Clindamycin Vancomycin Sodium fusidate Cephalosporins (1st & 2nd generation) Aminoglycosides

Primarily gram positive cocci and gram positive bacilli

Primarily gram positive cocci

Metronidazole Isoniazid (Rifampicin) Ethambutol Pyrazinamide Dapsone Broad Spectrum Agents Broad spectrum penicillins (e.g. ampicillin, amoxicillin) Cephalosporins (3rd generation, e.g. cefotaxime) Tetracyclines Chloramphenicol Trimethoprim Sulphonamides Ciprofloxacin Imipenem

87

Primarily gram aerobes Anaerobic bacilli

negative

Mycobacteria

Gram positive cocci and gram negative bacilli

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BETA-LACTAM ANTIMICROBIAL DRUGS

Bacterial resistance to penicillins determined primarily by three factors:

PENICILLINS In 1929, Alexander Fleming reported his discovery of penicillin. In 1941, Florey and co-workers managed to prepare enough of penicillin to treat for 24 hours with a remarkable result one patient seriously ill with staphylococcal and streptococcal infections resistant to all available antimicrobials. Ten years later, virtually unlimited amounts of penicillin G were available for clinical use. Since then numerous semisynthetic penicillins were developed, which are superior to penicillin G because they possess the advantages of being stable to acid pH, resistant to β-lactamase, and active against both gram-positive and gram-negative bacteria.

is

1. Inability of a penicillin to reach its site of action 2. Inactivation of a penicillin by bacterial enzymes (penicillinases) 3. Alteration in target PBPs The bacterial cell envelope primarily consists of rigid cell wall plus an outer membrane. The cell wall itself doses not represent a diffusion barrier to penicillins. However, in gram negative bacteria, the outer membrane is complex in nature and does not allow penetration of many penicillins (this is not the case with gram positive bacteria). Therefore, some penicillins are ineffective against gram negative bacteria because they are unable to reach their sites of action is not a problem.

Mechanism of Action

The principal mechanism of acquired resistance to penicillins is production of penicillinases, which are enzymes that cleave β-lactam ring, and therapy makes penicillins inactive. Penicillinases are classified within a larger enzyme family known as β-lactamases, more than 100 different β-lactamases have been identified. These enzymes differ in their abilities to inactivate specific β-lactam antibiotics. Some of these enzymes, like those produced by Staphylococcus aureus, Haemophilus species, and E coli, are relatively narrow in substrate specificity and will hydrolyse penicillins and not cephalosporins. On the other hand, other βlactamases, like those produced by Pseudomonas aeruginosa and Enterobacter species, are much broader in spectrum and will hydrolyse both penicillins and cephalosporins. Carbapenems such as imipenem, which are highly resistant to hydrolysis by penicillinases and cephalosporinases, are hydrolysed by metallo-¾-lactamase.

The penicillins weaken the cell wall, causing bacteria to take up water and rupture. Hence, penicillins are usually bactericidal. This action can be achieved by following two possible processes: 1. Inhibition of transpeptidases 2. Disinhibition (activation) of autolysins Transpeptidases are bacterial enzymes essential for cell wall synthesis; the autolysins are bacterial enzymes that cleave bonds in the cell wall. Thus, penicillins can simultaneously inhibit synthesis of cell wall and promote its active destruction. Penicillin binding proteins (PBPs, penicillin receptors) have been isolated from bacteria. These binding proteins are located on the outer surface of the cytoplasmic membrane and are thought to be the receptors through which the penicillins act to inhibit transpeptidases and disinhibit autolysins.

Bacterial Resistance to Penicillins

Penicillinases are made by both gram negative and gram positive organisms. Gram positive bacteria produce larger amount of penicillinases and then release them into 88

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penicillin derivative introduced by this time.

surrounding medium. On the other hand, gram negative bacteria produce penicillinases in relatively small amounts and, rather than exporting them to the environment, secrete them into the periplasmic space (i.e., the space that lies external to the cytoplasmic membrane but within the confines of the cell envelope), see Fig.4.2.

Cell envelope

PBP

Penicillins Large amount of penicillinase

PBP (receptor)

Inside of bacterial cell

Periplasmic space

G +ve bacteria

PBP

PBP

was

To date there are no known strains of S aureus that produce β-lactamases capable of inactivating methicillin or related penicillinases-resistant penicillins. However, there are strains of S aureus that are resistant to these drugs. This resistance to methicillin appears to be due to the production of altered penicillin binding proteins (PBPs, receptors) to which the penicillinase-resistant penicillins are unable to bind. At present, vancomycin is the drug of choice for use against methicillin-resistant S aureus (MRSA).

Transfer of resistance was discussed earlier in this chapter. It is of particular importance with Staphylococcus aureus. When penicillin was introduced by Florey in the early 1940s, all strains of Staphylococcus aureus were sensitive to the drug. However, by 1960, about 80% of S aureus (hospital) isolates showed penicillin resistance. Luckily, a

Inner membrane

lactamases

G –ve bacteria Small amount of penicillinase Penicillins

&&

Outer membrane

Cell wall

Fig.4.2. A simplified schematic representation showing the factors that influence the activity of penicillins. Note: a penicillin agent has to reach its site of action, penicillin-binding protein (PBP, receptor). This can be hindered by mainly two ways: 1. Penicillins being unable to penetrate the outer membrane (particularly in gram negative, G ve, bacteria) 2. Penicillins being inactivated by penicillinases (as indicated by solid dots).

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Chemistry of Penicillins

as sodium and potassium salts that are quite water-soluble.

All members of penicillin-family have a common dicyclic nucleus, which is composed of the β-lactam and thiozolidine rings (Fig.4.3). Variation in the side chain confers differences in antibacterial activity, absorption, excretion and protein binding. The common nucleus means that a patient, who is hypersensitive to one penicillin is sensitive to all others. Penicillins also show type II reaction (autoallergy).

Pharmacokinetics Benzylpenicillin (crystalline penicillin) is rapidly absorbed from the gut but is inactivated to a major degree by gastric acid; thus, it is not active when given orally. When given parenterally, it is rapidly distributed throughout the body but does not readily pass into the cerebrospinal fluid unless the meninges are inflamed. Benzylpenicillin is rapidly excreted (t 30 minutes) via the urine mainly unchanged. Not only is filtered at the glomerulus (10%) but is also actively secreted (90%) by the kidney tubules.

Side chain S R

N C C  B  A C N O

β-lactamase

C  C

Administration may be as often as 12 times daily to maintain therapeutic blood levels. The frequency of administration can be decreased by delaying absorption from the site of administration by using less soluble preparations.

CH 3 CH3 COOH-

Procaine benzylpenicillin may give antibacterial blood levels for up to 24 hours after a single dose. it is often combined with benzylpenicillin so that high initial levels of penicillin are quickly reached. Further, benzathine benzylpenicillin can give significant blood levels for a week or more after a single dose. it is also possible to block the excretion of penicillin via renal tubules by drugs such as probenecid; a practice used in the treatment of some infections (e.g. rectal and genital gonorrhoea, amoxicillin 3 g orally once plus probenecid 1 g orally once).

Salt formation

Fig. 4.3. A simplified representation of the core structure of penicillin. Benzylpenicillin (penicillin G) when the side chain (R) is benzyl group. The ring marked A is the thiozolidine ring and the ring marked B is the β-lactam ring. The penicillins are susceptible to bacterial metabolism and inactivation by amidases and lactamases at the points shown.

NARROW SPECTRUM PENICILLINS

Acid resistant penicillins: phenoxymethylpenicillin (penicillin V) and phenethicillin that are inactivated by penicillinases.

Penicillinase Sensitive Penicillins Benzylpenicillin

Penicillinase Resistant Penicillins (Antistaphylococcal Penicillins)

Benzylpenicillin (penicillin G) was the first available and the most active. Despite the introduction of many newer antibiotics, penicillin G remains a drug of choice for a wide variety of infections. It is active against gram positive and gram negative cocci, and gram positive bacilli. Penicillin G is available

Penicillin resistant penicillins include methicillin, cloxacillin, dicloxacillin, and nafcillin. These penicillins have a side chain that protects the β-lactam ring from being broken down by penicillinases. In penicillin allergic patients, other antistaphyloccocal agents may be used, such as 1st generation 90

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cephalosporins, clindamycin (or lincomycin), or vancomycin. While, ampicillin, amoxicillin, carbenicillin and tetracycline are not effective against penicillinases-producing staphylococci.

Haemophilus influenzae. Ampicillin achieves therapeutic concentrations in the cerebrospinal fluid only during inflammation. On the other hand, amoxicillin does not reach adequate concentrations in the central nervous system and is not appropriate for meningitis therapy. It is now recognised that penicillinase producing strains of Haemophilus influenzae are emerging, therefore, chloramphenicol is added to the initial regimen until ampicillin sensitivity of the pathogen has been determined. It is also as first or second choice agent for treating infections caused by Listeria monocytogenes. Escherichia coli, Salmonella, and Shigella.

Methicillin resistant staphylococcal strains are also resistant to other penicillinases resistant penicillins, and cephalosporins. This resistance appears to be due to the production of altered PBPs to which methicillin unable to bind. They should be treated by vancomycin, ciprofloxacin, co-trimoxazole, sodium fusidate or (rifampicin).

Beta-lactamase inhibitors

The most common adverse effects with ampicillin are rashes and diarrhoea, which occur more frequently with ampicillin than with any other penicillin.

Clavulanic acid (an irreversible antagonist to β-lactamase) is added to amoxicillin inhibiting the inactivation of amoxicillin. This fixed combination is known as coamoxiclav (augmentin ). Sulbactam is another β-lactamase inhibitor and usually combined with ampicillin, while tazobactam is combined with piperacillin.

Amoxicillin Amoxicillin (t 1.7 hour) is similar to ampicillin in structure and actions. However, ampicillin is more sensitive to gastric acid and more affected by food. Thus, when the two drugs are administered orally in equivalent doses, blood levels of amoxicillin are greater than those of ampicillin. Diarrhoea is less associated with amoxicillin than ampicillin, perhaps because more ampicillin remains unabsorbed in the intestine. Therefore, when oral therapy is indicated amoxicillin is usually preferred.

BROAD SPECTRUM PENICILLINS (AMINOPENICILLINS) Aminopenicillins (e.g. ampicillin and amoxicillin) are penicillins with modification of the side chain leading to a broadened antibacterial activity. They have the same antibacterial spectrum as benzylpenicillin with increased activity against certain gramnegative bacilli, including Haemophilus influenzae, Escherichia coli, Salmonella and Shigella. This increased spectrum of activity is largely due to an increased ability to penetrate the gram negative cell envelope. All aminopenicillins are sensitive to penicillinases; hence, they are ineffective against most infections caused by Staphylococcus aureus.

EXTENDED SPECTRUM PENICILLINS (ANTIPSEUDOMONAL PENICILLINS) Antipseudomonal penicillins are ticarcillin, piperacillin, carbenicillin, azlocillin, and mezlocillin. The antibacterial spectrum of these drugs includes those organisms that are susceptible to the aminopenicillins plus Pseudomonas aeruginosa, Enterobacter species, Proteus (indole positive), Bacteroides fragilis, and many Klebsiella. Some Pseudomonas aeruginosa developed resistance to ticarcillin. Generally, ticarcillinresistant strains are resistant to new drugs.

Ampicillin Ampicillin (t 1.3 hour) was the first broad spectrum penicillin to be introduced to clinical practice. It is a drug of first choice for meningitis and other infections caused by 91

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2. Seizures (in patients with renal failure, penicillin in high doses can cause seizures, perhaps due to salt disturbances) 3. Gastrointestinal disturbances (large doses of penicillins given orally may lead to gastrointestinal upset, nausea, vomiting, and diarrhoea) 4. Neutropenia (with nafcillin) 5. Hepatitis (with oxacillin) 6. Pseudomembranous colitis (more likely with ampicillin) 7. Secondary infections (e.g. vaginal candidiasis) 8. Skin rashes (that are not allergic in nature, with ampicillin and amoxicillin)

Systemic pseudomonal infections are best treated with an antipseudomonal penicillin plus an aminoglycoside or ceftazidime, for synergistic effect. All the extended spectrum penicillins are susceptible to penicillinases; therefore, they are ineffective against most strains of Staphylococcus aureus. All these antipseudomonal penicillins except mezlocillin, inhibit platelet aggregation, and although seldom, promoting bleeding.

ADVERSE EFFECTS 1. Hypersensitivity reactions: including a. Anaphylactic shock, very rare, 0.05% of recipients) b. Interstitial nephritis (autoimmune reaction to a penicillin-protein complex) c. Eosinophilia d. Haemolytic anaemia

Cautions 1. Renal impairment (penicillins with potassium salt, to avoid hyperkalaemia) 2. Heart failure (penicillins with sodium salt, to avoid oedema)

Table 2.3. A summary of the classification of penicillins and their antimicrobial activity Penicillin Class Narrow spectrum penicillins (penicillinase sensitive)

Narrow spectrum penicillins (penicillinase resistant) (antistaphylococcal penicillins) Broad spectrum penicillins (Aminopenicillins) (good permeability) (penicillinase sensitive) Extended spectrum penicillins (antipseudomonal)

(extended permeability) (penicillinase sensitive)

Drug Benzylpenicillin Crystaline penicillin G Aqueous procaine penicillin G Benzathine penicillin G Penicillin V Methicillin Cloxacillin Dicloxacillin Nafcillin Ampicillin Amoxicillin

Carboxypenicillins Ticarcillin Carbenicillin Ureidopenicillins Piperacillin Azlocillin Mezlocillin

Antimicrobial activity Streptococcus species Neisseria species Many anaerobes Spirochaetes (e.g. Treponema pallidum) Staphylococcus aureus

Haemophilus influenzae Escherichia coli Proteus mirabilis Enterococci Neisseria gonorrhoea Same as broad spectrum penicillins plus Pseudomonas aeruginosa, Enterobacter species, Proteus (indole positive) Bacteroiodes fragilis, Many Klebsiella

adverse effects. Because cephalosporins are resistant to many β-lactamases (penicillinases) they usually have a broader spectrum of activity than penicillins. They are

CEPHALOSPORINS Cephalosporins resemble penicillins in terms of chemistry, mechanism of action and 92

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inactivated by other β-lactamases called cephalosporinases. It is worth noting that cephalosporins are not effective against enterococci (as in endocarditis where a penicillin plus an aminoglycoside are effective) and Listeria monocytogenes (as in meningitis where amoxicillin is effective). For simplicity purposes, cephalosporins are classified into four generations depending on their spectrum of antibacterial activity, stability to β-lactamases and ability to penetrate the blood brain barrier.

The 1st generation cephalosporins are rarely the drug of first choice for any infection. They do not penetrate the blood brain barrier and therefore cannot be used to treat meningitis.

SECOND GENERATION (INTERMEDIATE SPECTRUM) CEPHALOSPORINS

FIRST GENERATION (NARROW SPECTRUM) CEPHALOSPORINS

This is a heterogeneous group of drugs with marked individual differences in antibacterial activity, pharmacokinetics, and toxicity. As a general rule they are active against bacteria affected by 1st generation cephalosporins with some extension to cover gram negative organisms; for example cephalothin-resistant Klebsiella are sensitive. However, they appear to be less active against gram positive bacteria than the 1 st generation cephalosporins.

This group includes cephalexin (Keflex ) that is orally active and cephalothin (Keflin ) that should be administered parenterally. In Iraq, best familiarity with 1st generation cephalosporins have been made with these two agents. Generally, these drugs are very active against gram positive cocci including pneumococci, streptococci, and staphylococci (except methicillin-resistant strains). They have moderate activity against Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, but with poor activity against Pseudomonas aeruginosa, Proteus (indole positive), Enterobacter and Bacteroides fragilis.

This group comprises a large number of drugs including cefuroxime (oral and parenteral) that is used to treat communityacquired pneumonia, particularly in cases where β-lactamase-producing Haemophilus influenzae or Klebsiella pneumoniae is the offending organism. Cefoxitin (parenteral) is another member of this group, particularly useful in mixed anaerobic infections as peritonitis.

Pharmacokinetics THIRD GENERATION (BROAD SPECTRUM) CEPHALOSPORINS

Oral and parenteral 1st generation cephalosporins are excreted mainly by the kidney through glomerular filtration and tubular secretion into the urine. By blocking tubular secretion, probenecid may increase serum levels markedly. Therefore, dose adjustments must be made for impaired renal function.

This group includes cefotaxime (Claforan ), ceftriaxone, ceftazidime, ceftizoxime, cefixime (Suprax ), and cefoperazone. This group is characterised by their extended coverage of gram-negative bacteria and better ability to cross the blood brain barrier. The 3rd generation cephalosporins are more active against Citrobacter, Serratia marcescens, and Providencia in addition to β-lactamase producing strains of Neisseria and Haemophilus.

Indications 1. Urinary tract infections 2. Minor staphylococcal lesions 3. Minor polymicrobial infections (e.g. cellulitis or soft tissue abscess) 93

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warfarin) that may be prevented by concurrent administration of vitamin K. 4. Superinfection (secondary infection): particularly with 2nd and 3rd generation drugs being not effective against some gram positive organisms, and fungi. Hence, proliferation of these organisms may lead to superinfection.

Of this group, ceftazidime and cefoperazone have considerable activity against Pseudomonas aeruginosa. Like the 1st and 2 nd generations, this group is not active against Enterobacter species (producing constitutive chromosomal β-lactamase). Cefixime shows little or no activity against pneumococci and Staphylococcus aureus. It is note worthy that of the 3rd generation cephalosporins cefoperazone and ceftriaxone are excreted largely from the biliary tract and therefore their dosage not influenced by renal impairment. For more details of pharmacokinetics see table 4.4.

OTHER BETA-LACTAM DRUGS These are structurally related to penicillins and cephalosporins. Some schools of thought list them as the 4th generation cephalosporins; however, it decided to put them as a separate miscellaneous group.

FOURTH GENERATION (EXTENDED-BROAD SPECTRUM) CEPHALOSPORINS

Aztreonam is a monocyclic β-lactam (monobactam) with antibacterial activity similar to that of antipseudomonal aminoglycosides.

The representative drug of the 4th generation cephalosporins is cefepime. Its pharmacology is very much similar to that of the 3rd generation cephalosporins, but it is characterised by being more resistant to hydrolysis by chromosomal β-lactamases and therefore active against Enterobacter. Otherwise, it shows similar antibacterial activity to that of the 3rd generation drugs, such as being effective against Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae and Enterobacteriaceae.

Imipenem (of the group carbapenems) is the drug of choice in the treatment of Enterobacter infections, as it is resistant to the β-lactamase produced by these organisms. Imipenem is also effective against Pseudomonas aeruginosa but these organisms may rapidly develop resistance to imipenem; for this reason a concurrent use of aminoglycoside is recommended. It is recommended for serious infections (such as neonatal sepsis) caused by extended spectrum β-lactamases (ESBLs) producing bacteria; it has been found to be more effective (markedly less mortality) than the 3rd generation cephalosporins. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Therefore, it is coadministered (fixed combination) with an inhibitor of renal dehydropeptidase, cilastatin.

ADVERSE EFFECTS 1. Hypersensitivity reactions: (identical to that of penicillins) including anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and haemolytic anaemia; cross-allergenicity between penicillins and cephalosporins is about 5-10%. 2. Renal toxicity including interstitial nephritis and tubular necrosis (particularly the 1st generation drugs) 3. Bleeding tendencies (particularly with 3rd generation drugs) due to increased prothrombin time (similar action to

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Table 4.4. A summary of the pharmacology of cephalosporins1 including classification, antibacterial activity, and some pharmacokinetic properties.

Cephalosporin class

Drugs

1st Generation (Narrow spectrum)

Cephalexin Cephalothin Cephazolin2

2nd Generation (Intermediate spectrum) 3rd Generation (Broad spectrum)

Antibacterial

90 50

Pneumococci, Streptococci, Staphylococci Haemophilus influenzae Klebsiella pneumoniae Mixed anaerobic infections (B. fragilis) Citrobacter Serratia marcescens Providencia Neisseria Haemophilus Pseudomonas aeruginosa

Cefuroxime Cefoxitin Cefotaxime (Claforan )

50

Ceftriaxone3 5

Cefoperazone Ceftazidime Ceftizoxime Cefixime6

_4 30 90 90 50

th

4 Generation (Extended Broad spectrum)

Antibacterial activity (specific organisms)

Enterobacter plus those sensitive to the 3rd generation drugs

Cefepime7

1

Cephalosporins are ineffective against methicillin-resistant Staphylococcus aureus (MRSA), Listeria monocytogenes, Clostridium difficile and the enterococci. 2 Cefazolin has a longer duration of action and a similar spectrum of activity compared to other 1st generation drugs. It exhibits good penetration into bone. 3 Ceftriaxone (t 7-8 hours) can be injected once every 24 hours. A single daily 1 g dose is sufficient for most serious infections, with 4 g once daily recommended for treatment of meningitis. Almost all the remaining agents in this group (t ≤ 2 hours) can be injected every 6-8 hours in dosages between 2 and 12 g/d, depending on severity of infection. 4 Renal inactivation is similar to that of cefoperazone. 5 Cefoperazone and ceftriaxone are excreted mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency. 6 Cefixime is available in oral dosage form (200 mg twice daily or 400 mg once daily) for respiratory and urinary tract infections. 7 Cefepime is in many respects similar to the 3rd generation cephalosporins but is more resistant to hydrolysis by chromosomal β-lactamases and some extended spectrum β-lactamases that inactivate many of the 3rd generation cephalosporins. 95

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SULPHONAMIDES, TRIMETHOPRIM, AND AMINOGLYCOSIDES Resistance to sulphonamides has developed in many strains. Sulphonamides are well absorbed except for sulphaloxate, which has been used for preoperative bowel preparation and for gut infection.

SULPHONAMIDES Sulphonamides are structural analogues of paminobenzoic acid (PABA). The action is bacteriostatic and reversible in the presence of PABA. The susceptible microorganisms require PABA to form folate. Animals are not susceptible to sulphonamides because they do not synthesise folate but absorb it from the gastrointestinal tract.

PABA + Pteridine

Silver sulphadiazine (flamazine , 1% cream) is used topically for prophylaxis and treatment of infected burns, leg ulcers and pressure sores because of its wide antibacterial spectrum including pseudomonads. Sulphadiazine enters CSF more readily than others; thus, it is useful prophylactically in meningococcal meningitis. These days, ciprofloxacin has replaced sulphadiazine, and rifampicin.

Sulphonamides block here

Dihydropteroate synthase

Dihydrofolate (Folic acid) Dihydrofolate reductase

Adverse Effects

From GIT in animals

1. Allergic reactions [rash, fever, hepatitis, granulocytopenia, thrombocytopenia, aplastic anaemia, haemolytic reaction (in G6PD deficient patients), StevensJohnson syndrome (erythema multiforme bullosa, particularly serious and potentially fatal type of skin and mucous membrane eruption), and polyarteritis nodosa etc.] 2. Crystalluria, haematuria (Sulphonamides may precipitate in urine particularly at neutral or acidic pH, resulting in crystalluria, haematuria, or even obstruction. This problem may be overcome by administration of sodium bicarbonate to alkalinise the urine and fluids to maintain adequate hydration. 3. Kernicterus (when taken at end of pregnancy ) 4. Diarrhoea 5. Psychosis

Trimethoprim blocks here

Tetrahydrofolate (Folinic acid)

DNA + RNA

Resistance to Sulphonamides Bacterial resistance to sulphonamides may develop by mutation or plasmid-mediated through the following possible ways: 1. Bacterial PABA over-production (through production of a folic-acid synthesising enzyme, dihydropteroate synthase, that has low affinity for sulphonamides) 2. Reduced permeability to sulphonamides

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cause megaloblastic anaemia due to interference with conversion of folic acid to folinic acid (a trimethoprim effect). Therefore, it is advised not to give cotrimoxazole in pregnancy because of the possible teratogenic effects of inducing folate deficiency.

CO-TRIMOXAZOLE (TrimethoprimSulphamethoxazole) Trimethoprim inhibits dihydrofolate reductase and so prevents reduction of dihydrofolic acid to folinic acid (tetrahydrofolate). Although this is also an essential step in human metabolism, trimethoprim is much more active on the bacterial enzyme and so can seriously disrupt production of DNA and RNA without harming human host. When trimethoprim is given in combination with sulphamethoxazole, a sulphonamide that prevents the conversion of PABA to dihydrofolic acid, two sequential metabolic steps are thus affected. The combination is probably truly bactericidal unlike the bacteriostatic effects of the individual drugs and may show a synergistic effect.

Because of the disturbing adverse effects with sulphonamides, the use of trimethoprim alone is now increasing. Trimethoprim alone is useful in urinary and respiratory tract infection.

CO-TRIMOXAZOLE • A fixed-combination of trimethoprim and sulphamethoxazole • Useful in UTI, chronic bronchitis, pneumonia, typhoid, and shigella infections • Adverse effects: Largely due to the sulphonamide1. Allergic reactions (including rash, granulocytopenia, aplastic anaemia and Stevens-Johnson syndrome) 2. Crystalluria, haematuria 3. Kernicterus 4. Diarrhoea and psychosis

The ratio of trimethoprim and sulphamethoxazole is 1:5. The latter was chosen because of having a similar t to trimethoprim (about 10 hours). This combination is known as co-trimoxazole (Septrin , Metheprim ). Co-trimoxazole has special value in the treatment of: 1. Urinary tract infection (UTI) 2. Chronic bronchitis (particularly when due to H influenzae) 3. Pneumonia 4. Shigella infection 5. Typhoid and Paratyphoid (but ciprofloxacin is now preferred) 6. Brucellosis

Others due to trimethoprim1. Megaloblastic anaemia 2. Teratogenic effect

AMINOGLYCOSIDES

Resistance to Trimethoprim

1. Reduced influx of trimethoprim 2. Overproduction of dihydrofolate reductase 3. Modified reductase with reduced drug binding

These antibiotics were isolated from soil bacteria of Streptomyces species and include the antipseudomonal agents such as gentamicin, tobramycin, netilmicin, and amikacin. Netilmicin and amikacin may be used against gentamicin-resistant strains. They are used primarily in serious infections due to aerobic gram-negative bacilli. The principal target organisms are

Adverse effects of co-trimoxazole are similar to those of sulphonamides. In addition, co-trimoxazole in high dose may

1. Pseudomonas aeruginosa 2. Enterobacteriaceae (e.g. E coli, Klebsiella, Serratia, Proteus mirabilis).

Bacterial resistance to trimethoprim may be achieved by:

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sufficient to produce systemic toxicity. Aminoglycosides are eliminated almost exclusively without undergoing metabolism by the kidneys through glomerular filtration into the urine, where levels of 10-50 ³g/ml may be reached.

The aminoglycosides are not effective against anaerobic organisms and are often given in combination with other antimicrobials.

Streptomycin Streptomycin is used in the treatment of

Selection of an Aminoglycoside

1. Endocarditis [due to Streptococcus viridans or enterococci (Streptococcus faecalis) in combination with benzylpenicillin] 2. Brucellosis (in combination with tetracycline) 3. Tuberculosis (as an alternative in combination with other drugs)

Selection among these drugs depends largely upon patterns of resistance in a given hospital or community. In settings where resistance is uncommon, gentamicin is usually preferred because it is the less costly. However, in settings where resistance to gentamicin (and tobramycin) is common, amikacin may be preferred for initial therapy.

Neomycin

Interpatient Variation

Neomycin is no longer recommended for the treatment of bacillary enteric infections, as it may cause superinfections. It is too toxic to be used for systemic infections. However, it is used for topical infections.

Patients can exhibit large variations in serum levels of aminoglycosides even when they receive the same aminoglycoside dosage (in mg/kg of body weight). In one study, it was noted that in order to produce equivalent serum aminoglycoside levels, the required doses of the drugs ranged from as little as 0.5 mg/kg in one patient to a high of 25.8 mg/kg in another (i.e. a difference in dosage of more 50 fold).

Resistance to Aminoglycosides So far, there are three recognised mechanisms that may be responsible for bacterial resistance to aminoglycosides: 1. Enzyme inactivation of aminoglycosides (transferase enzymes inactivate aminoglycosides by adenylation, acetylation, or phosphorylation; these enzymes are largely plasmid-transmitted) 2. Impaired influx of aminoglycosides into the cell 3. Alteration of ribosomal receptor protein (the receptor protein on the 30S ribosomal subunit may be deleted or modified through mutation)

This interpatient variation can be due to various factors, e.g. age, percent body fat, and pathophysiological conditions like kidney function, fever, oedema, and dehydration.

Nephrotoxicity Aminoglycosides bind tightly to renal tissue, achieving levels in the renal tubular cells that are up to 50 times higher than those in serum do. Aminoglycosides are known to cause injury to the cells of proximal tubules (the mechanism not established) presents as acute tubular necrosis; this nephrotoxicity is usually with prominent symptoms as proteinuria, cast in urine, production of dilute urine, and elevation in serum creatinine and blood urea nitrogen (BUN). Therefore, monitoring levels of serum creatinine and BUN may help in detection of aminoglycoside-induced nephrotoxicity.

Pharmacokinetics Aminoglycosides are not easily absorbed from the gastrointestinal; it has been estimated that only about 1% of an oral dose is absorbed. Therefore, they have to be given parenterally (i.m. and i.v.) for systemic infection with close monitoring of the blood level to avoid toxicity. However, when aminoglycosides are used for wound irrigation, they may be absorbed in amounts 98

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The risk of nephrotoxicity is increased in the elderly, in patients with renal dysfunction, and in concurrent use of other nephrotoxic agents (e.g. cephalosporins, amphotericin B, polymixins, vancomycin and methoxyflurane). Luckily, cells of the

proximal tubules regenerate fairly quickly, therefore damage to the kidney usually reverses after stopping the aminoglycoside use.

Table 4.5. A summary of pharmacokinetic properties and dosages of the principal aminoglycosides Agent

Gentamicin Tobramycin Netilmicin Amikacin

Total daily dosage (mg/kg) Adults

Children

3-5 3-5 4-6.5 15

6-7.5 6-7.5 5.5-8 15

Dosing interval (hr) 8 8 8 8 or 12

t

in adults (hr)

Target serum levels* (³g/ml)

Normal

Anuric

Peak

Trough

2-3 2 2-3.4 2-2.5

40-50 55-60 >30 55-150

6-10 6-10 6-10 20-30

1-2 1-2 1-2 4-8

* Note: Levels of aminoglycosides must be kept within a narrow range, and because of interpatient variability, the above standard doses cannot be relied upon to produce predictable levels, dosage must be carefully adjusted for each patient.

When possible, aminoglycosides should not be used for more than 10 days. Further, concurrent administration of aminoglycosides with other potentially ototoxic agents (e.g. frusemide, ethacrynic acid) should be avoided.

Ototoxicity Aminoglycosides penetrate easily to the perilymph of the inner ear, and there is a direct relationship between levels achieved in the perilymph and production of ototoxicity manifests as impairment of hearing and balance. Damage to hair cells within the cochlea results in loss of hearing, while disruption of balance is caused by damage to hair cells of vestibular apparatus.

Other adverse effects and interactions Aminoglycosides can cross the placenta and may have toxic effects on the developing foetus. They are also known to produce curare-like effects (neuromuscular block); thus, they can intensify neuromuscular blockade produced by tubocurarine and other skeletal muscle relaxants. Therefore, when using aminoglycosides together with the muscle relaxants, extreme caution must be taken to avoid respiratory arrest.

Upon giving aminoglycosides, patients should be monitored for early signs of cochlear or vestibular damage. By using audiometric testing, decreased acuity in the high-frequency range indicates loss of hearing. Auditory toxicity can also present as tinnitus or a sense of fullness in the ear. Further, damage to the vestibular system may manifest as nausea, unsteadiness, and vertigo.

Cautions

When ototoxicity is detected, aminoglycosides should be withdrawn or administered in reduced doses. If toxicity is moderate, symptoms reverse following withdrawal of aminoglycosides; however, when ototoxicity is extensive, symptoms may be permanent and even can be with complete hearing loss.

Aminoglycosides should never be mixed together with penicillins (or any β-lactam drug) in the same syringe or in the same i.v. solution because penicillins (when present in high concentrations) interact chemically with aminoglycosides rendering the latter inactive.

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Postantibiotic Effect Postantibiotic effect is the antibacterial activity that persists beyond the time that measurable drug is present. This phenomenon was first observed with anti-mycobacterial drugs like rifampicin and then termed the lag-period effect . This postantibiotic effect is being significant and well documented with aminoglycosides and quinolones. Therefore, a given total daily amount of aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses. Further, the single large dose scheme produces much higher peak concentrations, which saturate an uptake mechanism into the cortex; thus, resulting in less total aminoglycoside accumulation that is thought to cause renal damage and in turn less renal toxicity. The difference in renal toxicity is a predictable consequence of the different patterns of concentration (due to different dosage regimens) and the saturable uptake mechanism in the proximal renal tubular cells.

AMINOGLYCOSIDES • Useful primarily in serious infections due to aerobic gram-negative bacteria (e.g. Pseudomonas aeruginosa) • Have to be given parenterally • Unchanged excreted renally • Adverse effects: 1. Nephrotoxicity 2. Ototoxicity 3. Neuromuscular block 4. Low therapeutic index

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TETRACYCLINES, MACROLIDES, METRONIDAZOLE, CHLORAMPHENICOL, AND OTHERS 3. Opportunistic infections (e.g. candidiasis) 4. Tooth discoloration (tetracyclines are selectively taken up in the teeth and growing bones in the foetus and of children, given rise to inhibition of growth of bones and discoloration of teeth) 5. Inhibition of bone growth 6. Elevated blood urea (the antianabolic effect, inhibition of protein synthesis, cause blood urea to rise that is of a particular importance in uraemic patients) 7. Fatty liver 8. Photosensitisation (exposure to sunlight results in darkening of skin)

TETRACYCLINES Tetracyclines (1948) are a family of broadspectrum antibiotics with only minor differences. Tetracyclines have a 4-ring structure with small side-chains. The earliest members were chlortetracycline, oxytetracycline and tetracycline. The most recent ones are doxycycline and minocycline, which have good absorption and long t (16 h). Tetracyclines are bacteriostatic; they interfere with protein synthesis.

Resistance to Tetracycline

Caution

Bacterial resistance to tetracycline may be conferred by three possible mechanisms:

When passing the date of expiry, particularly tetracycline, becomes nephrotoxic therefore should not be used.

1. Decreased intracellular accumulation due to either impaired influx or increased efflux by an active transport protein pump 2. Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome 3. Enzyme inactivation of tetracycline

MACROLIDES ERYTHROMYCIN

Indications

Erythromycin is one of the macrolides, which are termed after their macrocyclic lactone ring to which different sugars are attached. It was isolated in 1952 from a streptomyces strain found in the Philippine soil.

Their uses include infections with 1. Clamydiae (e.g. psittacosis, trachoma, pelvic inflammatory diseases, lymphogranuloma venereum) 2. Mycoplasma (pneumonia) 3. Rickettsia (Q fever, typhus) 4. Vibrio cholerae (cholera) 5. Haemophilus influenzae (e.g. bronchitis) 6. Brucella (brucellosis)

Absorption is best with erythromycin estolate, even if there is food in the stomach. Erythromycin is partly inactivated by gastric acid. The t (2h) is dose dependent and elimination is almost exclusively in the bile and faeces.

For a summary of pharmacokinetic properties see Table 4.6.

Erythromycin is active against gram-positive bacteria and spirochaetes. It is used instead of penicillin in patients allergic to penicillin and infections resistant to penicillin.

Adverse effects 1. GIT disturbances 2. Disorder of epithelial surfaces (sore mouth and throat, black hairy tongue, odynophagia and perianal soreness) 101

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Table 4.6. A summary of pharmacokinetic properties of tetracyclines Group

Agent

Short-acting

Tetracycline Oxytetracycline Demeclocycline

Low Low Moderate

75 60 65

↓ ↓ ↓

Renal Renal Renal

8 9 15

50-100 50-65 40-60

Doxycycline Minocycline

High High

90-100 90-100

(No change)

Hepatic Hepatic

12-22 12-22

12-22 12-22

Intermediateacting Long-acting

t

Note: Tetracycline may achieve toxic levels in renal dysfunction, therefore, it is not suitable in such condition. Doxycycline does not accumulate in renal dysfunction, does not interact with food, and is given once or twice daily, while tetracycline should be given four times daily. These make doxycycline superior to tetracycline.

2. Gastrointestinal disturbances (particularly diarrhoea, occur in up to 28%) 3. Hepatic enzyme inhibition (unlike azithromycin, erythromycin and clarithromycin inhibit the metabolic inactivation of some drugs like warfarin, carbamazepine, theophylline, disopyramide, increasing their effects)

Resistance to Macrolides Resistance to erythromycin may be conferred by the following: 1. Decreased cellular influx or increased active efflux 2. Production of esterases that hydrolyse macrolides 3. Alteration of the ribosomal binding site

CLARITHROMYCIN Indications 1. Penicillin-allergic patients (alternative to penicillin when infections due to grampositive bacteria) 2. Pneumonia (due to Mycoplasma pneumoniae) 3. Legionnaires disease (Legionnella species, 1st choice drug) 4. Diphtheria (Corynebacterium diphtheriae) 5. Whooping cough (Bordetella pertussis) 6. Gastroenteritis (due to Campylobacter jejuni) 7. Acne

Adverse Effects 1. Cholestatic hepatitis (with abdominal pain and fever that may be confused with viral hepatitis, due to estolate; this is probably an allergic reaction, thus the estolate should not be given to a patient with liver disease. 102

Clarithromycin acts like erythromycin and also exhibits a similar antibacterial activity to the latter agent, being mainly active against gram-positive organisms. It should be noted that the t of clarithromycin is remarkably does-dependent (t 3 hours after 250 mg, 9 hours after 1200 mg). Unlike erythromycin, it is rapidly and completely absorbed from the gastrointestinal tract. Of oral clarithromycin dose, 60% is inactivated by metabolism that is saturable and the remainder is eliminated in the urine. It is useful largely in respiratory tract infection including atypical pneumonias and soft tissue infections. It exhibits fewer gastrointestinal tract adverse effects (7%) than that of erythromycin (28%). Clarithromycin, like erythromycin, also inhibits the metabolic inactivation of some drugs (See above).

Essentials of Medical Pharmacology

Majid A. K. Lafi

2. Metallic taste 3. Peripheral neuropathy 4. Ataxia 5. Insomnia 6. Convulsion 7. Darkening of urine 8. Disulfiram-like reaction (when alcohol is consumed concurrently with metronidazole)

AZITHROMYCIN Azithromycin is a new macrolide agent that acts like erythromycin (inhibits protein synthesis) but with a broader spectrum of antibacterial activity than erythromycin. The extension of activity includes a number of important gram-negative like Haemophilus influenzae and Neisseria gonorrhoeae, and also Chlamydiae. However, it is less effective against gram-positive organisms than erythromycin. Azithromycin is rapidly absorbed and tolerated orally. Azithromycin does inhibit cytochrome P450 enzymes therefore, unlike erythromycin clarithromycin, is relatively free of the interactions.

CHLORAMPHENICOL Chloramphenicol (1948, chloromycetin) was originally obtained from a streptomyces strain from Venezuela but is now synthesised. It readily penetrates the blood brain barrier (BBB). Chloramphenicol has a wide range of antibacterial activity including. infections due to

well not and and drug

1. Typhoid (Salmonella typhi and Salmonella paratyphi) 2. Meningitis (Haemophilus influenzae) 3. Whooping Cough (Bordetella pertussis)

METRONIDAZOLE Metronidazole has for many years been successfully employed to treat protozoal infections but the outstanding activity against anaerobes has been found useful particularly in bacteroides infections, and since the recognition of toxicity from lincomycin, has been widely used in treatment of septic infections of the chest, abdomen and pelvis. Metronidazole is a prodrug activated by anaerobic bacteria and not aerobic ones. It is bactericidal agent and resistance is not a problem.

Adverse Effects

Indications 1. Septic infections 2. Antibiotic-associated enterocolitis (pseudomembraneous colitis due to Clostridium difficile) 3. Urogenital tract trichomoniasis 4. Amoebiasis (Entamoeba histolytica) 5. Giardiasis (Giardia lamblia) 6. Acute ulcerative gingivitis and dental infections 7. Vaginitis (Gardnerella vaginalis)

Adverse Effects 1. Gastrointestinal diarrhoea)

disturbances

(nausea,

103

1. Reversible bone marrow depression (dose-related) 2. Aplastic anaemia (pancytopenia and bone marrow aplasia, occurs with an incidence of 1 in 35,000 and is not related to dose; it occurs with oral, i.v., or even ophthalmic use of the drug. This reaction develops weeks or months after termination of the treatment.) 3. Grey baby syndrome (circulatory collapse, vomiting and fall in body temperature; this depends on the lower capacity to conjugate chloramphenicol in the liver in infants.) 4. Acute haemolytic anaemia in G6PD deficient patients Note: The onset of action of chloramphenicol when given orally is more rapid than when given intravenously. This is because the i.v. formulation of chloramphenicol (usually with succinate) has to be broken down in the liver to release chloramphenicol before it acts, while the capsule (usually with palmitate) form acts directly.

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Adverse Effects LINCOSAMIDES 1. Flu-like illness 2. Hepatitis 3. Thrombocytopaenia 4. Rashes 5. Pink urine

CLINDAMYCIN AND LINCOMYCIN Clindamycin is more effective and better absorbed from the gastrointestinal tract. These drugs are effective against the following:

NITROFURANTOIN AND NALIDIXIC ACID

1. Bacteroides fragilis (first choice against gastrointestinal strains) 2. Anaerobic streptococcal infections (as an alternative) 3. Clostridium perfringens (as an alternative) 4. Staphylococcal infections (as an alternative)

These drugs are urinary tract disinfectant used for the treatment of infections with 1. Escherichia coli 2. Streptococcus faecalis 3. Proteus species Nalidixic acid also has some place in the treatment of infection with Shigella (in paediatric practice).

Adverse Effects 1. Antibiotic-associated enterocolitis (hence, these drugs should not be used indiscriminately; metronidazole is indicated to treat this condition)

Adverse Effects 1. Peripheral neuropathy (with nitrofurantoin) 2. Convulsions (with nalidixic acid)

The use of metronidazole is now preferred to that of clindamycin or lincomycin, for the treatment of anaerobic infections. Metronidazole appears to be superior because it can achieve adequate concentrations in the CSF and has not been reported to cause antibiotic-associated colitis.

SODIUM FUSIDATE Sodium fusidate is an antistaphylococcal agent, useful in severe infections caused by β-lactamase producing and methicillin resistant Staphylococcus aureus (MRSA) including osteomyelitis. It is readily absorbed from the gut and distributes widely in body tissues including bone. It is largely metaboilised and only very little is excreted in the urine. It is available as i.v. , oral, ointment and gel preparations.

RIFAMPICIN It has a broad-spectrum antibacterial activity, particularly, against mycobacterial species, and gram-positive organisms including staphylococci. With rifampicin, the rapid emergence of resistance dictates that they must always be used in combination with unrelated antimicrobial agents. It is largely reserved for mycobacterial infections. Its use in MRSA infections may be justified.

VANCOMYCIN Vancomycin is an antibiotic produced by Streptococcus orientalis, glycopeptide and is water-soluble and very stable. It inhibits cell wall synthesis. It is useful when given orally in antibiotic-associated enterocolitis, and i.v. for systemic infections. It readily crosses the BBB if there is meningeal inflammation. 104

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urinary or gastrointestinal tracts, skin, soft tissues, and bones. They have also been used in the treatment of gonorrhoea and septicaemia.

Vacomycin is largely (90%) eliminated renally by being excreted by glomerular filtration. Therefore, in renal insufficiency, surprisingly high blood levels may be reached.

Adverse Effects

Indications 1. Methicillin-resistant Staphylococcus aureus (MRSA, first choice drug) 2. Enterococcal endocarditis in patients with serious penicillin allergy (in combination with gentamicin) 3. Meningitis suspected or known to be caused by a highly penicillin-resistant strains of pneumococcus (MIC > 1 µg/ml) 4. Antibiotic-associated enterocolitis (due to Clostridium difficile, administered orally)

Adverse Effects 1. Chills and fever 2. Ototoxicity (tinnitus and deafness may reverse upon withdrawal of vancomycin) 3. Nephrotoxicity 4. Red man or Red neck (a maculopapular rash possibly due to histamine release may occur upon rapid i.v. infusion)

Caution

1. Crystalluria (Therefore, adequate amount of water should be taken) 2. Cartilage deterioration (reversible arthropathy in immature animals, although such effects have not been observed in humans, prudence dictates that these drugs are contraindicated in children and in women who are pregnant or nursing. However, some authorities would state that fluoroquinolones should be used with caution in children and adolescents 1 3. Inhibition of Drug Metabolism (inhibits the metabolism of theophylline and warfarin, therefore, both of which should be monitored carefully when concurrently administered with ciprofloxacin)

Cautions 1. Oral absorption of fluoroquinolones is impaired by divalent cations including those in antacids. 2. Interacts with theophylline (inhibit hepatic metabolism of theophylline and therefore can potentiate its effects).

Administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities.

FLUOROQUINOLONES These are synthetic bactericidal agents chemically related to nalidixic acid. The prototype of this group is ciprofloxacin and norfloxacin. They can easily penetrate the BBB and thus can be used as an alternative to the 3rd generation cephalosporins. Nowadays, the use of these drugs has picked up a great popularity as broad-spectrum antibacterial drugs.

Indications They have been found effective in the treatment of infections of the respiratory,

1

Laurence, D. R., Bennett, P. N. & Brown, M.J. (1997) Clinical Pharmacology. 8th edition, page 212. 105

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ANTIMYCOBACTERIAL DRUGS ANTITUBERCULOSIS DRUGS

As treatment is prolonged, if only one antituberculous drug is used there is a high risk that a drug-resistant mutants (due to spontaneous mutation, that exist in all large bacterial populations) will emerge. However, the possibility of bacilli to develop resistance to more than one drug is very low. Therefore, treatment of two or more drugs reduces the risk of developing drug-resistance. Further, drug-combination therapy also serves to reduce the incidence of relapse. A strategy for drug-combination targeting in the course of treatment of tuberculosis is presented in Fig.4.4.

Introduction The objective of antituberculous therapy is to eliminate symptoms of active disease, and to prevent relapse, and emergence of drug resistance. To achieve these goals, the following should be accomplished: 1. Killing the Actively Multiplying Tubercle Bacilli: Elimination of the actively multiplying population, which have been estimated to form about 95% of the total tubercle bacilli, and the intracellular ones within the initial phase (1st 2-3 months) of treatment.

The regimen currently recommended for the treatment of uncomplicated tuberculosis in AL-Anbar as follows:

2. Eradicating the Remaining Problematic Tubercle Bacilli: Eradicating the problematic proportion of the tubercle bacilli which is characterised by usually being at resting state but occasionally exhibits spurts of metabolic activity ; these bacilli represent, at least in part, what are described as persisters , i.e. semidormant bacilli that metabolise slowly or intermittently. It is believed that only during these spurts of activity (which have been estimated to last for about 2 minutes at a time) that drugs can kill these bugs. Therefore, the continuation (2nd) phase is directed at capturing these moments of activity. The 2nd phase usually takes 4-6 months; at the end of which this proportion of the tubercle bacilli should be eradicated (if the treatment is successful).

6-Month Regimen First 2 months (Initial Phase)

Following 4 months (Continuation Phase)

Isoniazid (INH) + rifampicin + pyrazinamide + ethambutol or streptomycin (2HRPE) Isoniazid + rifampicin (4HR)

The regimen currently recommended for the treatment of complicated tuberculosis (e.g. relapse and treatment failure cases) in ALAnbar as follows:

8-Month Regimen First 2 months (Initial Phase)

Further 1 or 2 Months

Success of treatment is indicated by an absence of observable tubercle bacilli in sputum (direct smear) and by failure of sputum cultures to yield any colonies of the bacilli. When sputum test results have become negative, usually within 2-6 months, therapy should continue for additional 4-6 months.

Five months (Continuation Phase)

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Isoniazid + rifampicin + pyrazinamide + ethambutol + streptomycin (2HRZES) Isoniazid + rifampicin + pyrazinamide + ethambutol (1HRZE) Isoniazid + rifampicin + ethambutol (5HRE)

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Most modern regimens for the treatment of tuberculosis include isoniazid, rifampicin, and pyrazinamide, since

Therefore, it is an essential feature of the antituberculosis regimen is that practically all drugs should be given once daily (not divided doses). For a summary of the pharmacology of antituberculosis drugs see Table 4.7.

•

Isoniazid rapidly kills large numbers of actively growing bacteria including those with only occasional spurts of activity. • Rifampicin kills actively growing bacilli including the problematic ones with only spurts of metabolic activity; and also kills intracellular bacilli. • Pyrazinamide that is converted to the active pyrazinoic acid by the activity of intrabacterial pyrazinamidase, an enzyme is most effective in an acidic environment such as the interior of cells. Thus, it is effective uniquely in zones of acute inflammation and against quiescent bacilli within macrophages (persisters, semidormant bacilli that are often within cells).

Isoniazid, pyrazinamide, and ethambutol are considered to be specific antimycobacterial drugs. Therefore, they are used in therapeutic trials for diagnostic purposes. Isoniazid is highly selective for mycobacteria; the drug can kill tubercle bacilli at concentrations 10,000 times lower than those needed to affect gram-positive bacteria.

ANTILEPROSY DRUGS Leprosy (Hansen s disease) is caused by Mycobacterium leprae. The WHO recommends that all patients receive treatment with multiple drugs.

Also, it is worth noting that: •

Ethambutol is a specific drug against mycobacteria. Generally, it is used when resistance to isoniazid and rifampicin is suspected. • Streptomycin has relatively low sterilising activity, perhaps, because of its inability to penetrate cells and not being effective against intracellular bacilli.

Dapsone (t is 27 hr, aminodiphenylsulfone) has been and remains a mainstay of therapy that requires a minimum duration of two years. The absorption of dapsone is slow but complete from the gastrointestinal tract and the drug sustains a steady blood level because it undergoes intestinal reabsorption from the bile. It is excreted in the urine. Dapsone is associated with methemoglobinemia, agranulocytosis, haemolytic anaemia, drug rash, and anorexia as adverse effects. Dapsone causes more haemolytic anaemia in slow acetylators, whereas rapid acetylators may need higher doses to control leprosy.

In general, a 6-month regimen cures the patient rapidly and these drugs are usually well tolerated. In Ramadi, this regimen has been found as the most successful one with the highest cure-rate (85%).

Rifampicin is used in combination with dapsone in the treatment of leprosy. Rifampicin in a dosage of 600 mg daily is safe and effective when given once monthly. This long interval makes acceptable the directly observed therapy with rifampicin which the above regimens require.

Postantibiotic Effect After a culture of Mycobacterium tuberculosis had been exposed to certain drugs for sometime, it took several days (the lag-period , postantibiotic effect) before growth occurred. Therefore, 600 mg of rifampicin given once daily is therapeutically superior to the same dose divided into two parts administered at 12 hours interval.

Clofazimine (t is 70 days) is a phenazine dye and it has a leprostatic action. It is absorbed from the gastrointestinal tract and 107

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accumulates in tissues. Hence, dosage regimen is possible if individual doses are given in a gap separated by four weeks.

discolouration of the skin that may persist for months after the drug has been stopped.

Clofazimine is given for dapsoneresistant leprosy or when patients are intolerant to dapsone. Clofazimine therapy is associated with reddish to nearly black

Table 4.7. A summary of the pharmacology of the currently used antituberculosis drugs. Drug Isoniazid (INH)

Action Powerfully anti-TB; inhibits formation of mycolic acid in bacterial cell wall. Bacteriostatic-cidal

Rifampicin

Inhibits RNA polymerase in bacteria. Resistance develops rapidly if used on its own.

Pyrazinamide

Converted to pyrazinoic acid by intrabacterial pyrazinamidase (most effective in acidic environment) Concentrated in tubercle bacilli, mode of action not known. Resistance develops slowly. Effective against strains resistant to rifampicin and streptomycin.

Ethambutol

Streptomycin

Thiacetazone

See aminoglycosides (not effective in acidic environment) Low efficacy, delays emergence of INH resistance

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Toxicity Insomnia Muscle twitching Peripheral neuropathy (responds to vit. B6) Hepatitis Flu-like illness Hepatitis Thrombocytopenia Rashes Pink urine Hepatotoxicity (10%) Gouty attacks

Peripheral neuropathy Colour blindness Pruritus Joint pains Abdominal pain Confusion Hallucination Contraindicated in pregnancy Nephrotoxicity Ototoxicity Neuromuscular block Hepatotoxicity

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Actively multiplying population

Intracellular population

Isoniazid Rifampicin Streptomycin Ethambutol

Population with spurts of metabolic activity

Rifampicin Pyrazinamid

Isoniazid Rifampicin

This population is usually killed within the 2nd phase of therapy (4-6 months)

These 2 populations are usually killed within the 1st phase of therapy (1st 2-3 months), requiring combined isoniazid, rifampicin, pyrazinamide, & streptomycin or ethambutol.

Dormant population

Not reached by drugs

Eradication decreases relapse & resistance

Fig. 4.4. A simplified representation of the strategy of the treatment of tuberculous infections (pulmonary), different phases of treatment, antituberculous drugs, and duration of treatment are indicated. Note: The actively (rapidly) metabolising bacilli are believed to be killed within a few days: however, the intracellular bacilli (including semidormant bacilli, quiescent but with spurts of metabolic activity) are more difficult to be dealt with. Rifampicin and pyrazinamide are effective in killing the latter population within the initial phase of treatment. The continuation phase of treatment (isoniazid + rifampicin) is directed at least 4-month treatment, hopefully, to achieve eradication of bacilli and therefore decrease the possibility of relapse and drug-resistance.

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ANTIMICROBIAL DRUGS OF CHOICE Table 4.8. Antimicrobial drugs of choice; modified from Laurence, D. R., Bennett, P. N., and Brown, M. J. (1997) Clinical Pharmacology, 8th edition, page 194. * Resistance may be a problem; sensitivity test should be done. ** Suggested alternatives do not necessarily represent all options. CS = a cephalosporin Co-amoxiclav = fixed combination of amoxicillin plus clavulanic acid ± With or without FQ = a fluoroquinolone (e.g. ciprofloxacin)

Infecting organism

Drug(s) of 1st choice

Alternative drugs**

Gram-positive cocci *Enterococcus Endocarditis or other severe infections

Benzylpenicillin or amoxicillin + gentamicin, or streptomycin

Vancomycin + gentamicn or streptomycin

Uncomplicated Urinary tract infections

amoxicillin

Trimethoprim or nitrofurantoin

Non-penicillinase producing

Benzylpenicillin

CS; vancomycin; imipenem; erythromycin

Penicillinase producing

Cloxacillin

CS; vancomycin; co-amoxiclav; erythromycin; clindamycin; FQ

Methicillin-resistant

Vancomycin ± gentamicin ± rifampicin

Co-trimoxazole; a tetracycline; FQ; rifampicin; Na fusidate

Streptococcus pyogenes

Benzylpenicillin or phenoxymethylpenicillin or amoxicillin

Erythromycin; CS; vancomycin; (clindamycin, for necrotic infection of the superficial and deep fascia)

Benzylpenicillin ± gentamicin

Vancomycin; CS

Amoxicillin

Trimethoprim; nitrofurantoin; FQ

*Staphylococcus aureus or epidermidis

(Group A, and Groups C and G) Streptococcus (Group B)

Streptococcus, viridans group (endocarditis) Streptococcus faecalis (enterococci) UTI

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Benzylpenicillin or amoxicillin + gentamicin or streptomycin Benzylpenicillin

Vancomycin + gentamicin or streptomycin

Benzylpenicillin or amoxicillin

Erythromycin; CS; vancomycin; rifampicin (or chloramphenicol for meningitis)

Moraxella (Branhamella) catarrhalis

Co-amoxiclav

Erythromycin or a tetracycline

*Neisseria gonorrhoeae (gonococcus)

Amoxicillin (+ probenecid) or FQ or ceftriaxone

Spectinomycin; cefixime or cefotaxime

Neisseria meningitis (meningococcus)

benzylpenicillin

Chloramphenicol; cefotaxime

Bacillus anthracis (anthrax)

Benzylpenicillin

Erythromycin; a tetracycline

Clostridium perfringens

Benzylpenicillin

Metronidazole; clindamycin

Benzylpenicillin

A tetracycline

Erythromycin

Benzylpenicillin

Amoxicillin ± gentamicin

Erythromycin + gentamicin

Oropharyngeal strains

Benzylpenicillin

Metronidazole; clindamycin

Gastrointestinal strains

Metronidazole

Co-amoxiclav; clindamycin; imipenem; chloramphenicol Tetracycline

Endocarditis

Streptococcus, anaerobic *Streptococcus

pneumoniae (pneumococcus)

Metronidazole

Gram-negative cocci

Gram-positive bacilli

(gas gangrene)

Clostridium tetani (tetanus) Corynebacterium diphtheriae (diphtheria) Listeria monocytogenes (listeriosis)

Enteric gram-negative bacilli *Bacteroides

Erythromycin or FQ *Campylobacter jejuni *Enterobacteriaceae e.g. *Enterobacter aerogenes *Escherichia coli *Klebsiella pneumoniae *Proteus species FQ or an oral CS Lower urinary tract

Amoxicillin or trimethoprim

Septicaemia

Gentamicin or cefotaxime

FQ; imipenem

*Helicobacter pylori (peptic ulcer)

Amoxicillin + clarithromycin + metronidazole (plus omeprazole)

Amoxicillin + metronidazole + bismuth chelate; or tetracycline + clarithromycin + bismuth chelate

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*Salmonella typhi (typhoid fever)

Ceftriaxone; FQ

Chloramphenicol; co-trimoxazole; amoxicillin

*Other Salmonella

FQ

Amoxicillin; co-trimoxazole; chloramphenicol

*Shigella

FQ

Trimethoprim; ampicillin (paediatric: nalidixic acid)

*Yersinia enterocolitica

Co-trimoxazole

FQ, gentamicin; tetracycline

*Bordetella pertussis (whooping cough)

Erythromycin

Ampicillin

*Brucella (brucellosis)

Tetracycline + streptomycin or gentamicin

Co-trimoxazole; rifampicin + tetracycline

Calymmatobacterium granulomatis (granuloma inguinale) *Fusobacterium

A tetracycline

Streptomycin or gentamicin or co-trimoxazole

Benzylpenicillin

Metronidazole or clindamycin

Gardeneralla vaginalis (anaerobic vaginosis)

Metronidazole (oral)

Topical clindamycin or metronidazole; oral clindamycin

*Haemophilus ducreyi (chancroid) *Haemophilus influenzae Meningitis, epiglotitis, arthritis or other serious infections Upper respiratory infections and bronchitis Legionella pneumophila (legionnaire s disease)

Erythromycin

FQ

Cefotaxime or ceftriaxone or amoxicillin

Chloramphenicol

Co-trimoxazole or amoxicillin

Co-amoxiclav; CS (3r generation)

Pasteurella multocida (from animal bites) *Pseudomonas aeruginosa Urinary tract infection

benzylpenicillin

Co-amoxiclav or CS

FQ

Ticarcillin; piperacillin; mezlocillin

Other infections

FQ; ticarcillin; mezlocillin; piperacillin; gentamicin; amikacin Tetracycline

Ceftazidime; imipenem

Other gram-negative bacilli

Vibrio cholerae (cholera)

Erythromycin ± rifampicin

FQ

Acid-fast bacilli *Mycobacterium tuberculosis Isoniazid + rifampicin + 112

Other antitubercular agents include cycloserine, thiacetazone, ethionamide,

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Pulmonary (1st 2 months)

pyrazinamide ± ethambutol (or streptomycin) (2HRPE)

kanamycin, amikacin, capreomycin, ciprofloxacin, and ofloxacin.

(next 4 months)

Isoniazid + rifampicin (4HR)

Ethionamide or cycloserine

Mycobacterium leprae (leprosy)

Dapsone + rifampicin ± clofazimine

Actinomycetes Actinomyces israelii (actinomycosis) Nocardia

Benzylpenicillin

A tetracycline

Co-trimoxazole

Amikacin; minocycline; imipenem

Chlamydiae Chlamydia psittaci (psittacosis, ornithosis)

Tetracycline

Chlamydia trachomatis Trachoma

Azithromycin

Tetracycline (oral plus oral); a sulphonamide (topical plus oral)

Inclusion conjunctivitis

Erythromycin (oral or i.v.)

A sulphonamide

Pneumonia

Erythromycin

A sulphonamide

Urethritis, cervicitis

Doxycycline or azithromycin

Erythromycin or ofloxacin

Lymphogranuloma venereum Chlamydia pneumoniae (TWAR strain)

Tetracycline

Erythromycin

Tetracycline

Erythromycin

Mycoplasma pneumoniae

Erythromycin or tetracycline

Clarithromycin; azithromycin

Ureaplasma urealyticum

Erythromycin

Tetracycline; clarithromycin

Tetracycline

Chloramphenicol; FQ

Borrelia burgdorferi (Lyme disease)

Doxycycline or amoxicillin

Ceftriaxone or cefotaxime or benzylpenicillin

Borrelia recurrentis (relapsing fever) Leptospira (leptospirosis)

Tetracycline

Benzylpenicillin

Benzylpenicillin

Tetracycline

Treponema pallidum (syphilis) Treponema pertenue (yaws)

Benzylpenicillin

Tetracycline or ceftriaxone

Benzylpenicillin

Tetracycline

Chloramphenicol

Mycoplasma

Rickettsia Q fever, typhus

Spirochaetes

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ANTIFUNGAL DRUGS 1. Drugs used to treat superficial mycoses (fungal infections) a. Polyene antibiotics (e.g. nystatin and amphotericin B) b. Imidazoles (e.g. ketoconazole, clotrimazole, miconazole, and econazole) c. Others (e.g. griseofulvin, flucytosine)

Introduction Superficial fungal infections occur much more frequently than system fungal infections. The superficial mycoses are caused by two groups of organisms: 1. Candida species 2. Dermatophytes

2. Drugs used to treat systemic mycoses a. Amphotericin B b. Flucytosine c. Ketoconazole d. Miconazole

Superficial infection with dermatopytes is more common than superficial candidiasis. Candidal infections usually occur in mucous membranes or moist skin. However, candidal chronic infections may occur in scalp, skin, and nails. Dermatophytoses are generally confined to the skin, hair, and nails.

POLYENE ANTIBIOTICS Nystatin Nystatin derived from Streptomyces cultures from the soil of Virginia and its name derived from the New York State Department of Health that was responsible for its culture. It is used topically for the treatment yeast-like fungi such as Candida albicans, also for vaginal infections. It is too toxic to be used systemically.

Systemic mycoses can be classified into two types: 1. Opportunistic infections 2. Non-opportunistic infections The opportunistic mycoses, e.g. candidiasis, aspergillosis, cryptococcosis, mucormycosis, occur primarily in debilitated or immunocompromised host. While, non-opportunistic infections may occur in any subject; these infections are relatively uncommon and include sporotrichosis, blastomycosis, histoplasmosis, and coccidiodomycosis. These infections often pose a therapeutic problem because of their resistance to drugs, consequently requiring a long duration with high dose therapy with drugs that often exhibit high toxicities.

Amphotericin Amphotericin B is a polyene compound that remains the drug of choice for most serious systemic fungal infections. It has serious toxic effects, primarily nephrotoxicity. It must be given intravenously; in meningitis due to fungal infection; it has to be given intrathecally to achieve adequate concentration in the CSF.

Antifungal Drugs

IMIDAZOLES

The antifungal drugs are classified into two main groups:

The imidazole antifungal agents constitute members which are used for 114

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superficial and systemic infections like ketoconazole, and to a lesser extent miconazole (rarely used systemic infections because of high toxicity); and clotrimazole and econazole are used for superficial infections and for topical application only. The imidazole agents are useful for both dermatophytic and candidal infections.

Miconazole

Ketoconazole

Econazole

Ketoconazole is the only imidazole antifungal drug that can be administered by mouth for treatment of superficial mycoses; it is active against a variety of fungal infections, dermatophytic infections and candidiasis of the skin, mouth, and vagina. Its oral absorption is variable, and only partially excreted in the urine. It carries a potential for hepatic toxicity; therefore, a regular assessment of hepatic function should be made. Because it blocks steroid synthesis, it is useful in Cushing s syndrome, and may lead to hypoadrenalism and reduction in testosterone levels (antiandrogenic activity).

Econazole is an imidazole antifungal agent applied topically only. The drug is effective in Tinea infection and for superficial candidiasis.

Miconazole is an imidazole antifungal agent available for topical and systemic administration. Because of high toxicity, the drug rarely used systemically; thus, it is a drug of first choice for dermatophytic infections, and cutaneous and vaginal candidiasis.

OTHERS Griseofulvin Griseofulvin is an antibiotic, isolated from Penicillium griseofulvin in 1939, which is active when given orally but not topically. Its only use is in the systemic treatment of dermatophytosis. The absorbed drug has an affinity for diseased skin and is deposited there, bound to keratin, making keratin resistant to fungal growth. Thus, new growth of hair or nails is free of infection. Therefore, it must be administered for 2-6 weeks for skin and hair infections. It is a hepatic enzyme inducer.

It follows that because of the serious toxicity associated with its systemic use, oral ketoconazole is reserved for fungal infections that have failed to respond to topical agents like clotrimazole and miconazole. A topical preparation of ketoconazole is now available but its use is approved only for dermatophytic infections but not for candidiasis.

Flucytosine Flucytosine is available for oral or parenteral use. It is mainly used in a synergistic combination with amphotericin against Cryptococcus neoformans. High plasma levels that often occur with renal impairment are associated with bone marrow toxicity, and monitoring of plasma concentration is therefore advised.

Clotrimazole Clotrimazole is a synthetic imidazole derivative that is topically active against dermatophytic infections and candidiasis of the skin, mouth and vagina.

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Table 4.9. A summary of drugs of choice for superficial and systemic mycoses. Infection or organism Superficial infections

Drug of choice

Alternative Drugs

Dermatophytoses

Miconazole (topical) Clotrimazole (topical)

Tolnaftate (topical) Griseofulvin (oral) Ketoconazole (oral)

Tinea unguium (nail ringworm) Tinea capitis (scalp ringworm) Tinea pedis (athlete s foot)

(These are acid sensitive; thus, benzoic acid ointment, salicylic acid 4.65%, boric acid 2.87% in alcohol and ethyl acetate as paint)

Candidiasis of Skin and vagina

Clotrimazole (topical) Miconazole (topical)

Nystatin (topical) Ketoconazole (oral)

Mouth

Clotrimazole (topical)

Nystatin (topical) Ketoconazole (oral)

Intestine

Nystatin (oral)

Systemic infections Aspergillus species

Amphotericin B

None

Blastomyces dermatitidis

Amphotericin B

Ketoconazole

Candida species

Amphotericin B

Ketoconazole

Coccidioides immitis

Amphotericin B

Ketoconazole

Histoplasma capsulatum

Amphotericin B

Ketoconazole

Cryptococcus neoformans

Amphotericin B

Ketoconazole

Mucur species

Amphotericin B

None

Paracoccidioides brasiliensis

Ketoconazole

Amphotericin B

Potassium iodide; amphotericin B

Ketoconazole

Sporothrix schenkii

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ANTIVIRAL DRUGS with persistent HIV-1 replication despite ongoing therapy retroviral infections. Local injection site reactions are the most common side effects associated with enfuvirtide therapy.

Introduction Viruses are obligatory intracellular parasites with no growth or reproduction in vitro except in some very specialised laboratory techniques. Viruses cannot produce energy (ATP) and protein and are entirely dependent on the host. The process of viral replication includes:

Amantadine Amantadine acts by inhibiting the uncoating of the viral RNA of influenza A within host cells, therefore, preventing its replication. Amantadine is of value in the prophylaxis of infection with influenza A virus. It stimulates the CNS and can cause convulsion. Amantadine is also used in the treatment of Parkinsonism.

1. Viral penetration into host cells (blocked by enfuvirtide (HIV), γ-globulins, nonspecific) 2. Viral uncoating (blocked by amantadine, influenza A) 3. Early protein synthesis (blocked by fomivirsen, CMV) 4. Nucleic acid synthesis (replication of DNA or RNA, interfered with by purine analogues like acyclovir, pyrimidine analogues like idoxuridine, and reverse transcriptase inhibitors like zidovudine, AZT) 5. Late protein synthesis and processing (interfered with by protease inhibitors like ritonavir) 6. Assembly (maturation) of viral components 7. Release from the cell

Fomivirsen Fomivirsen binds to target mRNA resulting in inhibition of immediate early region 2 protein synthesis, thus inhibiting virus replication. Fomivirsen is injected

intravitreally for the treatment of CMV retinitis in patients with AIDS and is indicated for patients who are intolerant of or unresponsive to alternative therapies. Iritis and vitreitis as well as increased intraocular pressure and changes in vision are associated with fomivirsen therapy.

Attempts to find antiviral drugs have been very successful and their use is complicated as the virus reaches a peak titre before symptoms are observed. Therefore, a drug used to prevent viral replication is best used prophylactically rather than left till gross symptoms occur. There are a few agents, mostly in the developmental stage, which show promise of antiviral activity.

Idoxuridine Idoxuridine is a pyrimidine analogue and is preferentially incorporated in viral DNA producing material. It is very toxic and cannot be used systemically. As it is not specific for viral DNA, idoxuridine causes bone marrow depression and leucopenia.

Antiviral Drugs Enfuvirtide

Acyclovir

Enfuvirtide is a fusion inhibitor that blocks entry into the cell by preventing the

Acyclovir is a guanine analogue that is activated within herpes infected cells. Under the influence of virus thymidine kinase acyclovir is converted into active acyclovir triphosphate. This competes with

conformational changes required for the fusion of the viral and cellular membranes. It is useful in combination with other antiretroviral agents in patients 117

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deoxyguanosine triphosphate as a substrate for viral DNA blocks replication. It is much more active against herpes DNA polymerase than that of the normal host cell, making it a highly selective antiviral agent.

Didanosine Didanosine is also a reverse transcriptase inhibitor. It may increase CD4+ counts in patients with HIV infection. Adverse effects include pancreatitis and peripheral neuropathy.

Acyclovir is active against herpes simplex virus and to a lesser extent varicella-zoster virus. It has been the drug of first choice for severe infections caused by these viruses. It can be administered topically in the eye, on the skin, orally (though poorly absorbed), or intravenously (slowly). Acyclovir is particularly useful in immunocompromised patients. It has low toxicity.

HIV Protease Inhibitors The process of HIV replication involves the production of protein and also a protease that cleaves the protein into component parts that eventually reassembled into virus particles. Protease inhibitors interfere with this essential process. Protease inhibitors have been shown to reduce viral RNA, increase CD4+ counts and improve survival compared with that observed with placebo. The representative agent of this group is ritonavir.

Famciclovir Famciclovir is similar to acyclovir except that it is well absorbed from the gut. It is a prodrug, converting to penciclovir that has a similar spectrum of activity to that of acyclovir.

Ganciclovir

Others

Ganciclovir is similar to acyclovir in its mode of action but it has a broader antiviral spectrum of activity. It is useful for the treatment of serious cytomegalovirus (CMV) infections in immunocompromised patients. However, it has dose-dependent bone marrow depression effects. Therefore, its use limited to life- or sight-threatening CMV (CMV retinitis) infection in immunocompromised patients.

Tribavirin Tribavirin is an example of antimicrobial agents that are used by inhalation (aerosol or nebulised solution) for respiratory tract infections, to avoid systemic adverse effects. It is a synthetic nucleoside useful for severe respiratory syncytial virus bronchiolitis in infants and children.

Interferons HIV Reverse Transcriptase Inhibitors

Interferons are produced by infected host cells that contain replicating viruses. They appear to protect other cells from attacks not only by the offending virus but also other viruses, irrespective of their nucleic acid composition. Interferons are expensive to produce from human white blood cells but recently have been extracted from clones of bacterial cells obtained by genetic engineering.

Zidovudine Zidovudine (azidothymidine, AZT) is a reverse transcriptase inhibitor, has been shown to prolong the life and wellbeing of patients with human immunodeficiency virus (HIV) infection. HIV replicates by converting its single stranded RNA into double stranded DNA that is incorporated into host DNA (this is the reverse of the normal cellular transcription of nucleic acids).

Interferonα2 is the most commonly used, available as subtype interferon α2a and α2b. These differ in a single amino acid but are therapeutically equivalent. They are used in the treatment of hepatitis B and hepatitis C. 118

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immune response against virulent organisms, e.g. influenza, adenovirus, polio, measles, rubella, yellow fever, smallpox.

Viral Vaccines Viral vaccines are composed of killed or attenuated organisms that will induce an

Table 4.10. A summary of drugs of choice for viral infections Organism Herpes Varicella-zoster Chickenpox

Drug of Choice

Acyclovir

Important Remarks Phosphorylated acyclovir (by virus specific thymidine kinase) inhibits DNA polymerase & thus prevents viral DNA formation. Use in immunocompromised (i.v.)

Zoster (shingles)

Acyclovir

In immunocompetent (oral) In immunocompromised (i.v.)

Herpes simplex Ocular keratitis

Acyclovir

(ointment)

Labial (fever blisters)

Acyclovir

(cream and/or oral)

Genital

Acyclovir

(cream and/or oral)

Encephalitis

Acyclovir

(i.v.)

Disseminated

Acyclovir

(i.v.)

Human Deficiency (HIV)

Immuno- Zidovudine Virus Didanosine Ritonavir

Hepatitis B, C or D

Interferon α2a & α2b

Influenza A

Amantadine

Cytomegalovirus (CMV)

Ganciclovir

Respiratory Syncytial Virus Coryza (common cold)

Tribavirin Zinc

Reverse transcriptase inhibitor Reverse transcriptase inhibitor Viral protease inhibitor (Protection of foetuses from becoming infected by the virus in HIV-infected pregnant mothers) 1. Induces enzymes that degrade viral RNA (in uninfected cells) 2. Indirectly stimulates the immune system Interferes with the uncoating and release of viral genome into host cell. It is useful for prevention & treatment (debilitated persons) Similar to acyclovir in action, useful in CMVinfected immunocompromised patients; it may produce bone marrow depression. (Inhalational) Lozenges containing duration of symptoms.

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zinc

shortens

the

Antimicrobial Drugs - Antiviral Drugs

Blocked by

enfuvirtide (HIV), γ-globulins (non-specific)

Ramadi, 09 October, 2009

Blocked by amantadine (Influenza A)

Viral uptake Uncoating

Blocked by fomivirsen (CMV)

Early protein synthesis

Host cell

Nucleic acid synthesis

Late protein synthesis & processing Packaging & assembly

Viral release

Fig.4.5. The major sites of action of antiviral agents

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Blocked by purine analogues (acyclovir), pyrimidine analogues (idoxuridine), & reverse transcriptase inhibitors (zidovudine, AZT) Blocked by protease inhibitors (ritonavir, HIV)

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Majid A. K. Lafi

ANTIPARASITIC DRUGS

Table 4.11. Drugs of choice for treatment and prevention of malaria

Plasmodial strain P vivax P falciparum (chloroquinesensitive) P falciparum (chloroquineresistant)

Drugs of choice for Prevention of relapse Primaquine* NA**

Treatment of acute attack Chloroquine Chloroquine

Quinine plus pyrimethamine/ sulfadoxine or tetracycline; or i.v. quinine infusion

NA

Prophylaxis Chloroquine Chloroquine

Chloroquine plus pyrimethamine/ sulfadoxine + proguanil; or chloroquine plus doxycycline

* Primaquine is given following control of the acute attack. ** Not applicable, malaria caused by P falciparum does not relapse following successful treatment of the acute attack.

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Table 4.12. Drugs of choice for protozoal infections

Amoebiasis

Causative protozoan and important remarks Entamoeba histoltyica

Bowel lumen

(to eradicate cyst give)

Disease

Drugs of choice

Diloxanide

Tissue-invading

Metronidazole In severe cases, to lessen the risk of opportunistic infection, perforation, & peritonitis, give

Tetracycline

Treatment of tissue-invading amoebiasis should be followed by a luminal amoebicide to eradicate the source, give

Diloxanide

Giardiasis

Giardia lamblia

Leishmaniasis Visceral

Leishmania species

Metronidazole Tinidazole Primaquine Mepacrine

Resistant cases may benefit from combining antimonials with allopurinol, pentamidine of amphotericin B.

Na stibogluconate Meglumine antimoniate

Cutaneous

Mild lesions heal spontaneously; antimonials or stibogluconate may be injected intralesionally.

Pneumocystosis (HIV-infection)

Pneumocystis carinii

Co-trimoxazole

Intolerant or resistant cases may benefit from

Pentamidine

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Toxoplasmosis

Trichomoniasis Trypanosomiasis African (Sleeping sickness)

American (Chaga s disease)

Majid A. K. Lafi

Toxoplasma gondii

Pyrimethamine plus sulphonamide; or tetracycline

(Self-limiting, treat immunocompromised or prior to pregnancy) Trichomonas vaginalis

Metronidazole

Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense For early phase For later phase

Pentamidine, suramin Melarsoprol

Trypanosoma cruzi

Nifurtimox

Table 4.13. Drugs of choice for parasitic worms Worm Class Nematodes (round worms) Intestinal

(In immunocompromised ) Cestodes (Tapeworms) Trematodes (Flukes) Hydatid cysts (when surgery is contraindicated or when cysts rupture or spill during surgery)

Common Name Pinworm

Official Name Enterobius vermicularis

Drug of Choice Pyrantel pamoate; Mebendazole; Piperazine

Giant round worm

Ascaris lumbricoides

Mebendazole; Pyrantel pamoate; Piperazine citrate; Levamisole

Hookworm

Ancylostoma duodenale

Bephenium; Mebendazole; Pyrantel pamoate

Threadworm

Strongyloides stercoralis

Thiabendazole

Beef tapeworm Pork tapeworm Blood flukes Intestinal Urinary

Schistosoma species mansoni & japonicum haematobium Echinococcus granulosus

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Niclosamide; Praziquantel Praziquantel

Albendazole & mebendazole or praziquantel

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Ramadi, 9 October 2009

CNS-PHARMACOLOGY (GENERAL PRINCIPLES) potential by increasing Na+ permeability of the cell membrane (decreasing negativity inside the cell resulting in reduced value as measured by -mV). An IPSP lowers the resting membrane potential (hyperpolarisation) by increasing Cl- influx (increasing negativity inside the cell and thus increased value as measured by mV).

Introduction The resting membrane potential of the neurone in the CNS is about (-70 mV). The neurone can be affected by excitatory or inhibitory actions which give rise to an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP). An EPSP raises the resting membrane

Benzodiazepines Barbiturates Valproic acid Vigabatrin

Lamotrigine

Inhibitory neurone

Excitatory neurone

mV 0

Ethosuximide Carbamazepine Phenytoin

Action potential

Threshold potential

-60 EPSP

EPSP Resting potential

-70 IPSP Hyperpolarisation

Fig. 5.1. A simplified representation of polysynapses in the CNS showing excitatory and inhibitory neurones modulating the excitability of a primary neurone. The excitatory transmitter (e.g. glutamate) produces EPSP (excitatory postsynaptic potential) which may raise the resting potential high enough to reach the threshold and then fire an action potential. While, inhibitory transmitters (e.g. GABA) produces IPSP (inhibitory postsynaptic potential) which lowers the resting potential making it at a distance from the threshold potential (hyperpolarisation); therefore, reducing the possibility of firing action potential.

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Transmission of electrical impulses in the neurones of the CNS mainly takes place by the action of chemical transmitter substances, neurotransmitters, which are released from presynaptic nerve endings and act on

postsynaptic membranes. In addition to distinctly released neurotransmitters there are a number of putative (suggested) neurotransmitters and neuromodulators with more diffuse actions.

Table 5.1. A summary of the possible sites of drug action in the CNS

Mechanism 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Action potential Synthesis Storage Metabolism Release Reuptake Degradation Receptor Conductance Second messenger

Drug

Specific Drug Actions

Blocks action potential Synthesis of false transmitter Depletes transmitters Blocks amine breakdown Reduces transmitter release Increase transmitter availability Blocks acetylcholinesterase Blocks postsynaptic effects Hyperpolarisation Blocks phosphodiesterase

Catecholamines

Besides the principle actions of drugs on various mechanisms, many drugs are employed because they have a specific action on one of the functions in the CNS. There are essentially three different anatomical sites in the brain to which specific function can be assigned ( Table 5.2.). There is a complex range of interrelationships, e.g. the locus caeruleus interconnects the reticular formation, hypothalamus and cortex.

The CNS contains separate neuronal systems that involve catecholamines like dopamine, noradrenaline, and adrenaline. Each system is anatomically distinct and serves separate functions.

Serotonin Serotonin (5-hydroxytryptamine, 5HT) is the chemical transmitter in the tryptaminergic systems that are found mainly in the pons and upper brain stem.

Table 5.2. An overview of the functional organisation of the brain Site Cerebral cortex Limbic system Brain stem

Action

Tetrodotoxin Methyldopa Reserpine MAO-inhibitor Ca-antagonist Cocaine Tacrine Phenothiazines Benzodiazepine Methylxanthines

Functions Motor, sensory, thought

Peptides A large number of neuromodulatory peptides have been identified as endorphinpeptides. These peptides share actions that originally were ascribed to opioids.

Emotions, visceral control Wakefulness, vasomotor & respiratory control

Other peptides: vasoactive intestinal peptide (VIP), glucagon, substance P. These substances are synthesised in the rough endoplasmic reticulum of the nerve cell body as a propeptide that is cleaved into its active form and stored in secretory vesicles.

Acetylcholine Acetylcholine (ACh) is a central neurotransmitter acting with a mixture of nicotinic and muscarinic receptors. 125

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Apparently, there is no reuptake mechanism for peptides.

GABA

It is now well established that a neurone may synthesise and release one or more than one neurotransmitter (cotransmission). This is particularly true for neuropeptides.

GABA (gamma-aminobutyric acid) mediates inhibitory actions on local interneurones. Benzodiazepines potentiate the effect of GABA by interacting with GABA-receptor complex (Fig. 5.2).

Glucose

Glutamic acid

GABA vesicle

GABA

BNZ

GABA

Barbiturate -

Cl

Postsynaptic membrane -

Cl channel Fig. 5.2. A simplified schematic representation of synthesis, storage, and release of GABA from GABAergic neurone. When released GABA acts postsynaptically on a specific site that located on GABA receptor complex enhancing entry of Cl- through Cl- channel. Note: Benzodiazepines and barbiturates act allosterically on specific sites located nearby the GABA site on the GABA receptor complex to enhance the action of GABA.

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glutamate receptor complex to enhance the excitatory effect of glutamate (Fig. 5.3).

Glycine Glycine is another amino acid with inhibitory action (increases Cl- conductance and results in hyperpolarisation) in the spinal cord. However, glycine acts allosterically on

so-called acidic amino acid receptors, glutamate receptor system , causing dislodging of Mg++ and letting Na+ and Ca++ enter, and K+ leave the cell. Glycine can also bind to this receptor system allosterically enhancing the action of glutamate and aspartate (Fig. 5.3.).

Glutamate and Aspartate Glutamate and aspartate are excitatory neuromodulators act on specific sites on the

Glycine (allosteric)

Glutamate

Agonist (NMDA +

Na ++ Ca

++

Mg Postsynaptic membrane

+

K

Fig. 5.3. A simplified schematic representation of acidic amino acid receptor system. Glutamate or aspartate (or N-methyl-D-aspartate, NMDA) can activate the ligand specific site on the receptor system leading to deployment of Mg++ and letting Na+ and Ca++ enter, and K+ leaves the cell. Allosterically, glycine enhances the action of the acidic amino acids. Mg++ ions block the channel in the resting state. Depolarisation by ligand or voltage gating dislodging Mg++. Glycine enhances the action of glutamate to open the channel.

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Table 5.3. A summary of selected central transmitters and neuromodulators, their functions, agonists and antagonists

Transmitter

Site

Function Dysfunction

Receptor Agonists

Antagonists

Mechanism

Motor control: Nicotinic stimulation Memory: Muscarinic stimulation ↓ : Alzheimer s disease ↑ (relative): Parkinsonism

Nicotine

Dihydro-βerythroidine

Muscarine

Atropine

Muscarine

Atropine

Excitatory: ↑ cation conductance. Excitatory: ↓ K+ conductance; ↑ IP3, DAG Inhibitory: ↑ K+ conductance, ↓ cAMP

Substantia nigra Substantia nigra Pituitary gland Mesolimbic system Mesolimbic system Mesocortical system

↓ : Parkinsonism ↑ : Chorea

D1: SKF 38393

Phenothiazines SCH 23390

(Inhibitory): ↑ cAMP

D2: quinpirole

Phenothiazines Butyrophenones

Inhibitory (presynaptic): ↓ Ca2+ (postsynaptic):↑ K+ conductance, ↓ cAMP.

( (

↓ : Depression ↓:Obsessive-compulsive

5HT1A: LSD

Metergoline Spiperone

Inhibitory: ↑ K+ conductance, ↓ cAMP

5HT2A: LSD

Ketanserine

Excitatory: ↓ K+ conductance; ↑ IP3, DAG

5HT3: 2-methyl-5HT Phenylbiguanide

Ondansetrone

Excitatory: ↑ cation conductance

Prazosin

Excitatory: ↓ K+ conductance; ↑ IP3, DAG

Yohimbine

Inhibitory (presynaptic): ↓ Ca2+ conductance. Inhibitory:↑ K+ efflux;↓ cAMP

Spinal cord CNS cortex

Basal ganglia

) )

Amygdala Hypothalamus Pons (raphe nuclei) Mesolimbic system

Locus caeruleus & diffuse terminals to hypothalamus & cortex

↓ : Hyperprolactinaemia ↑ : Schizophrenia ↑ : Arousal ↓ : Negative symptoms

disorder ↑ : Anxiety ↑ : Decreased appetite ↑ : Sleep ↑ : Arousal*

Arousal, mood ↓ : Depression ↑ : Mania Decrease in pressure by stimulation

(α1): Phenylephrine

blood α2 -

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(α2): Clonidine

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TransSite mitter GABA Basal ganglia

Majid A. K. Lafi

Function Dysfunction ↓ : Huntington s disease

Most inhibitory ↓ : Convulsions interneurones Amygdala

↓ : Anxiety

Glycine Spinal interneurones & Inhibitory some brain stem interneurones Relay neurones at all levels

Excitatory

Receptor Agonists

Antagonists

Type A: Muscimol

Bicuculline,

Type B: Baclofen

2-OH saclofen

Taurine

Strychnine

Ionotropic

2-Amino5phosphonovalerate

N-Methyl-Daspartate (NMDA): NMDA

picrotoxin

Metabotropic

Hypothalamus & diffuse terminals to all parts of the brain

Endings of primary afferent neurones Pain transmission (ascending) pathways Primary afferents Spinal cord Thalamus Pain inhibiting (modulating, descending) pathways Midbrain Medulla

Arousal

Nociception (algesia, tachykinins)

Antinociception (analgesia, opioid peptides)

: quisqualate

MCPG

H1: 2(m-Fphenyl) histamine H2: Dimaprit

Mepyramine

NK1:

CP99994

Ranitidine

Substance P Methylester

µ (Mu): ¾-Endorphin δ (Delta): Enkephalins

κ (Kappa): Dynorphin

Naloxone Naloxone Naloxone

Mechanism Inhibitory: conductance.

↑

Inhibitory (presynaptic): ↓ Ca2+ Inhibitory (postsynaptic):↑ in K+ conductance. Inhibitory: ↑ Clconductance Excitatory: ↑ cation conductance, (Ca2+).

Inhibitory (presynaptic): ↓ Ca2+ Conductance; ↓ cAMP. Excitatory: ↓ K+ conductance, ↑ IP3, DAG. Excitatory: ↓ K+ conductance; ↑ IP3, DAG Excitatory: ↓ K+ conductance; ↑ cAMP Excitatory: ↓ K+ conductance, ↑ IP3, DAG

Inhibitory (presynaptic): ↓ Ca2+ conductance, ↓ cAMP Inhibitory (postynaptic): ↑ K+ conductance, ↓ cAMP

NA: Noradrenaline; DA: Dopamine; 5HT: 5-hydroxytryptamine (serotonin); ACh: Acetylcholine; GABA: Gamma aminobutyric acid; ↓: Deficiency; ↑: Access. * Fluoxetine (5HT reuptake inhibitor) may produce arousal, insomnia, and reduced appetite. MCPG: α-methyl-4-carboxyphenylglycine NK: Neurokinin

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Cl-

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Table 5.4. A summary of the targets for selected centrally acting drugs Cellular Target

Drug Group/Drug

Membrane lipid Cyclooxygenase Voltage-dependent sodium channel Voltage-dependent sodium channel L-type voltage-dependent calcium channel

General anaesthetic drugs NSAIDs Local anaesthetics Phenytoin, carbamazepine Calcium channel blockers

Opioid receptors Opioid receptors GABA receptor complex GABA receptor complex GABA receptor complex GABA transaminase

Opioid analgesics Opioid antagonists Benzodiazepines (BNZ) Flumazenil ( BNZ-receptor antagonist) Barbiturates Sodium valproate

Acetylcholinesterase Adrenergic receptors Adrenergic receptors

Tacrine Clonidine (α2-agonist) Mianserin (tetracyclic antidepressant, α2antagonist?) Lecithin (ACh precursor) Antihistamine

Cholinoceptors Histamine receptors Dopamine receptors Adenosine receptors Monoamine oxidase

Antipsychotic drugs Caffeine Phenelzine, tranylcypromine, isocarboxazid & deprenyl L-DOPA L-tryptophan

Dopamine synthesis Serotonin synthesis Noradrenaline reuptake Serotonin reuptake

Viloxazine (bicyclic antidepressant) Clomipramine (tricyclic antidepressant) & fluoxetine Amantadine Lithium

Dopamine reuptake Phosphatidylinositol bisphosphate (PIP2) breakdown cAMP breakdown

Caffeine

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ANTIPSYCHOTIC DRUGS other evidence has lead to the development of the dopamine theory of schizophrenia.

Introduction Antipsychotics are usually employed for the treatment of major psychoses such as schizophrenia. The term neuroleptic is often used for antipsychosis. They cause psychomotor slowing, emotional quietening and in higher doses, psychic indifference to the environment. It may have a sedative effect but it is not a hypnotic.

It has been known that the sympathomimetic drug amphetamine produces a psychosis rather similar to paranoid schizophrenia and this effect was shown to be related to increased release of dopamine and that he effects of this can be reduced by dopamine receptors blockade. Further experimental work suggested that in schizophrenia the dopaminergic neurone is in fact working normally and from post mortem receptors binding studies on human schizophrenia brain tissues that the density of dopamine receptors is higher than normal. In addition, there is a positive relationship between the receptor blocking activity of antipsychotic agents and their clinical effectiveness.

One of the first drugs to be used for its antipsychotic properties was reserpine (Rauwolfia alkaloid), which also reduces blood pressure. It is no longer used, partly because more effective drugs have been developed and partly because reserpine has serious side effects including the production of depressive conditions and suicidal tendencies. The central pharmacological actions of reserpine are due to the disruption of noradrenaline and dopamine storage sites in nerve terminals leading to reduced-release of these neurotransmitters.

Normally there is a balance of dopamine in the limbic system and the substantia nigra. An increased dopaminergic activity in the former gives rise to active schizophrenia and a decrease in the latter gives rise to extrapyramidal symptoms such as Parkinson s disease (Fig.5.4).

A variety of drugs are currently used in the treatment of schizophrenia, which is characterised by added features to personality known, as positive symptoms like: • Hallucination (e.g visual, olfactory and auditory) • Delusions (false unshakable belief of morbid origin not consistent with the patient s social, cultural and educational background) • Thought disorders (organisation, stream of thought; content of thought, such that it drifts away from the point)

There is a long list of antipsychotics of different groups. Within the scope of the objectives of this chapter, it is not possible to go through the pharmacology of each drug separately. Therefore, it is decided to present the essential details in Table 5.6.

Indications of antipsychotics 1. Treatment of acute and chronic schizophrenia 2. Prophylaxis of schizophrenia 3. Treatment and prophylaxis of mania 4. Psychotic depression (depression with psychotic symptoms) 5. Other psychoses (e.g. paranoid psychosis, morbid jealousy, erotomania) 6. Anxiety 7. Organic psychoses (delirium, dementia including Alzheimer s psychotic features)

Schizophrenia may also be characterised by absence of features of personality known, as negative symptoms like: • Apathy (lack of feeling or emotion; indifference) • Being withdrawn (retreat from external reality; reduced ability to relate to people) All of these drugs have in common the ability to block central dopamine receptors. This and 131

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8. Movements disorders (Huntington s chorea, Sydenham s chorea, tics, stuttering) 9. Anorexia nervosa 10.Management of aggressive people (therapeutic restraining, chlorpromazine) 11.Personality disorder (very touchy person, small doses of antipsychotics) 12.Irritable bowel syndrome (trifluoperazine) 13.Peptic ulcer (sulpiride) Vomiting (prochlorperazine) 14.Intractable hiccup (chlorpromazine) 15.Neuroleptanalgesia (droperidol + Fentanyl) 16.Chronic pain (chlorpromazine + fentanyl) 17.Hypertensive crisis of MAO inhibitors (cheese effect)

12.Poikelothermia (disturbance in the setpoint, hypothermia and hyperthermia) 13.Eye (cornea: opacity; retina: pigmentation) 14.Iris (miosis: thioridazine; chlorpromazine: mydriasis)

Onset of Action Generally, the antipsychotic effects of neuroleptics, in the presence of adequate dosages and serum drug concentrations, take several weeks or longer to appear. This delay may be due to an inhibition of presynaptic (autoregulatory) dopamine receptors by neuroleptics leading to an enhanced release of dopamine that counteracts the postsynaptic receptor blockade. As tolerance develops to this autoregulatory receptor phenomenon, postsynaptic blockade becomes more effective. This probably also explains why only a few Parkinsonian-like side effects appear acutely in normal or psychotic subjects given neuroleptics.

Adverse effects 1. Acute dystonic reactions (use anticholinergic, e.g. benzhexol; diphenhydramine; diazepam) 2. Parkinson s syndrome 3. Akathisia (motor restlessness, severe sense of agitation), use less potent antipsychotics, β-blockers, or a benzodiazepine 4. Tardive dyskinesia (oral-facial involuntary movements, 10-30%), no satisfactory treatment 5. Anticholinergic (e.g. glaucoma, dry mouth, urinary retention, confusion in the elderly) 6. Endocrine (e.g. hyperprolactinaemia, gynaecomastia, galactorrhoea, amenorrhoea, erectile impotence) 7. Postural hypotension (α-antagonist activity) 8. Sedation (antihistamine effect) 9. Neuroleptic malignant syndrome (hyperpyrexia, disturbed consciousness, muscular rigidity, myoglobinaemia, use dantrolene, bromocriptine) 10.Proconvulsant (lower seizure threshold, particularly phenothiazines) 11.Cardiotoxicity (quinidine-like activity)

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However, antipsychotics have rapid onset of actions for the following indications: severe anxiety, acute mania, acute psychotic states (for sedation and restraining), intractable hiccup. Note: Antipsychotics are used as therapeutic restraints in severe schizophrenia (to restrain aggressive over-excited persons) by an effect on the basal ganglia leading to generalised dystonia. For this purpose, usually a large dose and potent agent is required (e.g. fluphenazine, or chlorpromazine).

Essentials of Medical Pharmacology

Majid A. K. Lafi

Parkinsonism Hypokinesia Dystonic syndrome Hyperprolactinaemia

Schizophrenia Dyskineasia-Chorea Tardive dyskinesia Nausea

Dopamine

Dopamine

Fig. 5.4. A simplified representation of dopamine balance in the CNS with the possible clinical consequences. If the balance is tilted in favour of dopamine then CNS disorders like schizophrenia, dyskinesia-chorea, and tardive dyskinesia may be produced; however, if the balance tilted against dopamine then CNS disorders like Parkinsonism and dystonic syndromes.

Table 5.5. Antipsychotics may produce the following extrapyramidal reactions, range of onset time and features are also listed.

Reaction Acute dystonia

Onset Hours to 5 days

Parkinsonism

5

30 days

Akathesia

5

60 days

Tarditive dyskinesia

Months to years

Features Spasm of tongue, neck, face & back Tremor, shuffling gait, drooling, stooped posture, instability Compulsive, repetitive motions; agitation Lip-smacking, worm-like tongue movement, fly-catching

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Table 5.6. A summary of selected antipsychotics used in schizophrenia and related disorders Antipsychotics

Adverse Effects

Remarks about Uses

(mg)

Phenothiazines Chlorpromazine (Largactil) Fluphenazine (Modecate) Trifluoperazine (Stelazine)

100

+++

++

++

++

Useful in violent patients Severe anxiety (short term) Intractable hiccup Antiemetic

+

Maintenance therapy Therapeutic restraining

2

++

+++

+

5

+

+++

+

100

++

+

+++

++

useful in elderly due to low incidence of EP effects

2

+

+++

+

+

Rapid control of acute mania & other psychoses

2

+

+++

+

+

Neuroleptanalgesia

Pimozide

2

+

+

+

+

Thioxanthenes Flupenthixol

3

++

+++

+

++

Benzamides Sulpiride

50

-

+

+

+

100

+++

+

+++

+++

5

++

-

++

1

+

+

+

Thioridazine (Melleril) Butyrophenone Haloperidol (Serenace) Droperidol

Dibenzodiazepine

Clozapine* Theinobenzodiazepine

Olanzapine Benzisoxide Risperidone**

+

++

Retarded schizophrenia (-ve symptoms)

Retarded & monodelusional disorders (e.g. paranoid) Apathetic & withdrawn patients Avoid in manic or hyperactive patients Useful in ve symptoms Useful in resistant schizophrenia, lower seizure threshold, (may cause agranulocytosis, 1-2%) Useful in mania, Less incidence of blood dyscrasia Useful in ve symptoms

* Clozapine is a selective D4 receptor antagonist. ** Risperidone is an antagonist at both D2 and 5HT 2 receptors.

Note: A general rule the more potent antipsychotic drug is expected to produce more EP effects, with less anticholinergic and less sedative actions.

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DRUGS FOR AFFECTIVE DISORDERS

inhibition of biogenic amine reuptake or degradation, in isolation, can correct the fundamental biochemical abnormalities of depression. It has been hypothesised that antidepressants increase the efficiency of transmission through 5HT and/or noradrenaline pathways but by different molecular mechanism.

Antidepressants Affective (mood) disorders are characterised by severe disturbance of mood and range from depression (unipolar affective disorder) to manic-depressive illness (bipolar affective disorder). These disorders are associated with multiple derangements of normal biological processes, neuroendocrine circadian rhythms. In severe forms, patients develop psychotic symptoms and become detached from reality, thus, these disorders represent extreme expressions (depression and manicdepressive states) of otherwise normal emotional swings, suggesting major alterations in normal biological function (Fig.5.5).

There are two major isoenzymes of MAO: types A and B. A is selectively inhibited by clorgyline and primarily degrades 5HT. B is selectively inhibited by deprenyl (used as protective therapy in Parkinson s disease) primarily degrades dopamine. The available MAO inhibitors used for treating depression are relatively nonselective for A or B isoenzymes. It has been proposed that MAO inhibitors (type A only) produce an improvement in transmission of 5HT pathways.

Typical Symptoms of Depression Depression is characterised by: • Sadness • Anhedonia (loss of interest pleasure in activities) • Crying spells • Emotional liability • Feeling of guilt • Worthlessness and hopelessness

There is a delay in onset of antidepressant effect (7-21 days). This delay may represent the time required to overcome compensatory mechanism. Hence, the initial increase in neurotransmission appears to produce, over time, a compensatory decrease in receptor activity (down-regulation of receptors). Antidepressants like selective noradrenaline reuptake inhibitors, those with mixed action on noradrenaline and 5HT.

and

Depression requiring medical treatment, is usually associated with biological abnormalities (vegetative signs, which include decreased appetite, weight loss, GI disturbances, fatigue, difficulty in concentrating, early morning awakening, and loss of libido. It is well recognised that depression may impair the immune system and may lead to increased susceptibility to infection and risk of cancer.

Tricyclic Antidepressants (TCAs) and Related Compounds These drugs are generally believed to produce their antidepressant activity by virtue of their ability to block the neuronal amine (5HT and noradrenaline) reuptake. This in turn may lead to enhanced availability of the amines in synaptic junctions, and thus, facilitates aminergic neurotransmission (i.e. correction of the disturbed balance of amines).

Two major groups of antidepressant drugs (tricyclic and related monoamine reuptake inhibiting compounds and MAO-A inhibitors) are used in the treatment of depression. No single biochemical effect can explain the mechanism of action of these antidepressant drugs. It is unlikely that

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scope of this volume. Therefore, it is decided to present a summary of the pharmacology of these agents in Table 5.8 and Table 5.9.

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7. 8. 9. 10. 11. 12.

Indications 1. Depression (unipolar, bipolar and reactive depression) 2. Prophylaxis of depression (seasonal depression) 3. Obsessive-compulsive disorder (clomipramine, fluoxetine) 4. Phobias (an unusual or morbid fear from a condition, e.g. agoraphobia, clomipramine) 5. Anxiety (superior to diazepam because no risk of addiction, suitable for long term therapy, amitriptyline) 6. Nocturnal enuresis

13. 14. 15. 16.

Premature ejaculation Neurogenic pain Chronic pain (in cancer) Peripheral neuropathy Migraine headache Rumination disorder (in man , the regurgitation of food after almost every meal, part of it being vomited and the rest swallowed; a condition seen in infants) Attention deficit (hyperkinetic) disorder (hyperactive child) Alcoholism (as secondary to depression) Eating disorders (bulimia nervosa, fluoxetine) Sleep disorders (narcolepsy, imipramine; hypersomnia, imipramine)

Depression Mania

Amines

Amines

Fig.5.5. A simplified representation the Amine Hypothesis that proposes depression is somehow associated with underactivity of functional amine (5HT and noradrenaline)-dependent neurotransmission. While, mania may be explained by overactivity of amine-dependent neurotransmission. Note: Much of the evidence for the amine hypothesis of depression was available in the early 1950s when reserpine was used in the treatment of hypertension and schizophrenia. In hypertensive and schizophrenic patients as well as normal subjects, reserpine could produce depression and suicidal tendency that were major problems with reserpine. Reserpine interferes with aminergic neurotransmission by inhibiting the vesicular storage of amines like 5HT and noradrenaline, consequently, reducing release and hence synaptic availability of the biogenic amine neurotransmitters.

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Reuptake

MAO inhibitors lie in two major groups: Irreversible MAO Inhibitors

The tricyclic antidepressant clomipramine is to certain extent selective amine reuptake inhibitor for serotonin (5HT) than noradrenaline. In recent years, a new group of drugs has emerged which characterised to be selective for serotonin reuptake. This group includes fluoxetine, paroxetine and sertraline. So there is no substantial evidence that this group provides a greater therapeutic efficacy than the older drugs. However, the SSRIs offer an advantage of their lack of antimuscarinic adverse effects.

1. Hydrazine • Phenelzine (Nardil) • Isocarboxazid (Marplan) (Leg oedema and hepatitis as adverse effects) 2. Non-hydrazine • Tranylcypromine (Parnate) (Insomnia, and addiction as adverse effects) Reversible MAO Inhibitors Moclobamide is a reversible inhibitor of MAO-A. Therefore, as tyramine is metabolised by both forms of MAO, if tyramine-containing food is consumed, tyramine is metabolised by MAO-B enzymes as well as being able to reverse the inhibition of MAO-A. Unless very large quantities of tyramine are ingested, this appears to prevent the typical hypertensive reaction seen with conventional MAOIs and tyraminecontaining foods.

A selected list of adverse effects and the possible mode of action for the TCAs and other antidepressants are presented in Table 5.9.

MAO Inhibitors MAO inhibitors were the first to be found to have antidepressant action. In 1951, iproniazid, which was then used as antituberculosis drug, was observed to elevate mood. This effect was attributed to the ability of the drug to inhibit the enzyme monoamine oxidase (MAO). The termination of the synaptic action of monoamines, such as 5HT and noradrenaline, is primarily achieved by neuronal amine-reuptake pump and the activity of MAO located intraneurally. Upon blocking MAO, the vesicular storage and consequently release and synaptic availability of the monoamine neurotransmitter is increased. In fact, this is the opposite to what happens with reserpine that reduces monoamine vesicular storage and consequently reduces release of the amine transmitter. Hence, depression may be associated with the use of reserpine.

Indications for MAO Inhibitors They have no superiority to TCAs or related agents. However, it has been suggested that MAO inhibitors may be more effective in reactive and atypical depression. Onset of action occurs in 1 to 2 weeks and persists as long as 2 to 3 weeks after stopping the treatment. A summary of the adverse effects and their possible mode of action for MAO inhibitors is presented in Table 5.7.

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Table 5.7. A summary of the following adverse effects, the possible mode of action of MAO inhibitors Adverse effects Possible Mode of Action Hypertensive crisis (cheese Inhibit the metabolism of dietary tyramine leading to effect) enhanced systemic tyramine that causes the release of endogenous neural noradrenaline resulting in enhanced vascular α-receptor activity. Therefore, patients must carry a card stating details of treatment. Hypotension Sympathetic ganglionic block Others similar to that of TCAs •

MAOIs have anxiolytic properties; they are considered as second line drugs

CAUTION: Concomitant use of MAO inhibitors and tricyclic antidepressants may result in mutual enhancement of effects with possibility of hyperpyrexia, hypertension, seizure and death.

Antimanic Drugs

Lithium

Mania is characterised by elevated, expansive or irritable mood, accelerated speech, racing thoughts with flight of ideas, increased activity and reduced sleep. Patients may develop grandiose ideas, act recklessly with overspending, and show increased sexual drive and activity. Impaired judgement (lack of insight) is usually associated with the illness; therefore, the patient and his family should be protected by hospitalisation of the patient.

Patients with mania are at risk of physiological exhaustion and require special attention to nutrition, hydration, and rest. Lithium carbonate and a neuroleptic (or a sedative-hypnotic like diazepam) should be initiated. The additional tranquilliser is necessary because the onset of the antimanic effect of lithium is usually delayed. Further, patients with bipolar disease usually require maintenance therapy with lithium to prevent relapse into mania or depression. Those who do not respond to lithium respond to carbamazepine or sodium valproate (see antiepileptic drugs).

The antipsychotic drugs, lithium and benzodiazepines all are important in the management of mania. Antipsychotics (e.g. chlorpromazine, haloperidol) are preferred to control the acute stages; if more sedation is desired (particularly when using haloperidol) then add a benzodiazepine (e.g. diazepam). Lithium is initiated, as it is the drug of choice for long-term use to prevent relapse of manic attacks, i.e. prophylactic use.

It has been suggested that lithium produces its antimanic activity at least in part by virtue of inhibition of hydrolysis of phosphatidylinositol bisphosphate leading to reduced production of the second messenger diacylglycerol (DAG).

Adverse Effects 1. GI disturbances vomiting, diarrhoea)

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2. Nontoxic goitre (hypothyroidism, inhibits iodine uptake and thyroid hormone release, affecting 5-15% of patients on long term treatment1) 3. Polyuria 4. Diabetes insipidus 5. Renal tubular impairment (failure to concentrate urine after fluid deprivation and failure to acidify urine after ingestion of ammonium chloride) 6. Leucocytosis 7. CNS toxic encephalopathy (may lead to coma)

Interactions 1. With thiazide that increases lithium renal distal tubular reabsorption leading to lithium toxicity. Note: Lithium exhibits a low therapeutic index, and haemodialysis is indicated in toxicity (apparent volume of distribution is 55 litre). 1

Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 616.

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Table 5.8. A summary of tricyclic antidepressants and related compounds, and other antidepressants Drug

Class

Important Remarks WITH SEDATIVE ACTION (useful in depression associated with agitation, or anxiety, and insomnia)

Amitriptyline (Tryptizol)

Tricyclic

More cardiotoxic (sudden death) than others Useful in nocturnal enuresis and anxiety

Dothiepin (Prothiaden)

Tri-

Most widely prescribed in the U.K. Improved adverse effects profile

Mianserin

Tetra-

α2-receptor antagonist (↑ release of transmitter1) Less cardiac risk ; (it does not affect amine reuptake)

Trazodone2

Other

Probably as for mianserin?

Trimipramine (Surmontil)

TriWITH MINIMAL SEDATIVE ACTION (useful in depression associated with retardation, hypersomnia)

Clomipramine (Anafranil) Fluoxetine (Prozac )

Tri-

5HT reuptake inhibitor Useful in obsessive-compulsive patients

SSRI

Selective 5HT reuptake inhibitor Useful in obsessive-compulsive patients

Imipramine (Tofranil) Maprotiline (Ludiomil)

Tri-

Useful in nocturnal enuresis

Tetra-

Proconvulsant activity (fit) Useful in heart disease

Nortriptyline (Aventyl)

Tri-

Useful in nocturnal enuresis

Viloxazine

Bi-

Noradrenaline reuptake inhibitor

Flupenthixol

Thioxanthene

Antidepressant neuroleptic

α2-adrenoceptors generally mediate inhibition on the excitability of neurones and therefore reducing transmitter release. These receptors are termed autoreceptors (or presynaptic receptors) when inhibited by α2-receptor antagonists like mianserin and probably trazodone the release of neurotransmitter is enhanced (inhibiting inhibitory mechanism). 2 Trazodone may produce priapism and may decrease appetite as adverse effects. Therefore, its use is largely restricted to female patients. 1

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Table 5.9. A summary of adverse effects that may be encountered with the use of TCAs and other antidepressants.

Group/Drug

TCAs

Overdosage with TCAs & other antidepressants

Mode of Action

Adverse Effects

Muscarinic antagonism (especially amitriptyline, thus, avoid in the elderly, prostatism, narrow angle glaucoma) promoting sympathetic noradrenergic transmission by reuptake inhibition; while muscarinic antagonism may cause dryness in the axilla and groin regions. H1-receptor antagonism (especially doxepine, tolerance develops) ¿1-receptor antagonism3 (thus, useful in premature ejaculation) Increased catecholamine activity (cardiac overstimulation) ( Sympathomimetic) Quinidine-like action (unrelated to receptor antagonism)

Dry mouth, blurred vision, glaucoma, constipation, delayed bladder emptying, and confusion

Lowering seizure threshold in epileptic patients Shift of mood from depression to hypomania in bipolar illness Deriving from anticholinergic toxicity

Trazodone

Quinidine-like action α2-receptor antagonist (↑ release of transmitter)

SSRIs Fluoxetine

↑ synaptic availability of 5HT at certain sites in the CNS

Diaphoresis (excessive apocrine sweating, face, palm & sole, nonthermoregulatory sweating, cold sweat)

Sedation

Orthostatic hypotension Ejaculatory delay Cardiac arrhythmia Adrenergic tremor Cardiac toxicity (most serious adverse effect of TCAs, thus, avoid in patients with conduction defects and heart disease Seizure recurrence Hypomania Dilated seizure

pupil,

fever,

coma,

Cardiac toxicity Sedation, nausea, decreased appetite, priapism ( 1-blocking effect) Arousal, insomnia, decreased appetite

Caution: TCAs in a patient with bipolar illness, usually presenting as depression without history of mania, can precipitate acute mania or rapid cycling.

3

(Frohlich, D. F. (1993) Rypins Basic Science Review, 16th edition, Page 661; Mycek, M. J., Harvey, R. A. & Champe, P. C. (2000) Lippincott s Illustrated Reviews Pharmacology, 2nd edition, Page 121)

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ANTIANXIETY DRUGS system (affect), the median fore-brain bundle (reward and punishment systems) and hypothalamus.

Introduction Anxiety, fear for no adequate reason, is the most prevalent symptom in mental illnesses, but it also occurs normally and may have adaptive value. Normal anxiety, marked by dissatisfaction, unhappiness, or apprehension, is of short duration and usually event-related (e.g. as a part of the hypoglycaemic alarm, sitting an examination) and not under the subject s control. Normal subjects, under severe stress may experience periods of increased muscle tension, exaggeration of the discomfort of minor aches and pains, irritability, or sadness. There is evidence suggests that pathological anxiety is not an exaggeration of normal anxiety, because of considerable overlap in the symptoms of anxiety disorders and depressive states. However, the treatments of normal anxiety and pathological anxiety involve the same drugs.

Both BNZ and barbiturates modulate GABA type receptor complex resulting in increased chloride channel ion current. Binding of BNZ increase the frequency of chloride channel openings, whereas binding of a barbiturate like pentobarbital prolongs the duration of the chloride channel open time. The sedative, muscle relaxant, or anticonvulsant effects of BNZ show tolerance fairly rapidly upon prolonged usage, where relief of anxiety does not show tolerance. It has been suggested that a type 1 benzodiazepine receptor may be responsible for the anxiolytic actions of these drugs and a type 2 benzodiazepine receptor may be involved in other central actions. Type 3 benzodiazepine receptor has been proposed to be found in peripheral organs, e.g. stomach and heart. Serotonergic (5HT) innervation to the amygdala has been investigated with BNZ treatment which show reduced activity suggesting 5HT activity in the amygdala may be anxiety-promoting, and its interruption by a benzodiazepine drug could explain the antianxiety effect.

In the past, several drugs had been used for the treatment of anxiety; alcohol, opioids, or barbiturates. In the 1950s, meprobamate was introduced as a more selective antianxiety drug, but later it was found to have barbiturate-like actions. In the late 1960s, benzodiazepines were introduced as the first drugs to relieve anxiety without producing sedative effects. Buspirone, a more recent drug, may effectively treat anxiety with fewer side effects. The antianxiety drugs are also known as anxiolytics and have been known as minor tranquillisers (and neuroleptics as major tranquillisers).

Further evidence which lends support for the theory of the involvement of 5HT in promoting anxiety comes from the development of the second-generation antianxiety drugs like buspirone (5HT partial agonist) which affects 5HT mechanisms. Thus, it is conceivable that GABA- and 5HT modulating brain systems are involved, each having greater or lesser control according to the type of anxiety that predominates in a particular patient.

Benzodiazepines The benzodiazepines (BNZ) or barbiturates bind to GABA type A receptor/chloride channel complex (Fig.5.2.). This GABA neurotransmitter-receptor system in the CNS is the major inhibitory biochemical pathway in the mammalian brain, particularly in the amygdala region and spinal cord. BNZ may act chiefly on the brain reticular activating system (reducing sensory input), the limbic

Flumazenil A benzodiazepine receptor competitive antagonist (partial agonist) Flumazenil with a t of 1 hour, therefore, repeated i.v. doses or infusion may be needed in heavily sedated patients. Flumazenil finds use in the termination of agonist (BNZ) effect in 142

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conditions like after endoscopies, and diagnosis and treatment of BNZ-overdose.

6. Paradoxical effects (agitation, overactivity, insomnia may be observed in children and elderly)

Inverse Agonists

Benzodiazepines should be avoided with alcohol as additive effects occur. Tolerance occurs with chronic use and there is a crosstolerance within the sedative-hypnotic drugs and also with ethanol. Several days (a week or more) after withdrawal seizures, rebound insomnia, and inhibition of control of aggression (disinhibition of aggression) may occur. Benzodiazepine should be avoided in pregnancy as far as possible as diazepam is known to be teratogenic in mice. A summary of the important pharmacological characteristics of BNZ is presented in Table 5.10.

Substances known as β-carbolines bind to the benzodiazepine receptor causing stimulation, anxiety, increased muscle tone and convulsions. These substances are called inverse agonist. Note: These substances produce their effects not by inhibiting the action of BNZ, rather, they appear to operate a mechanism via a benzodiazepine site that is not already in operation.

Indications for BNZ 1. Anxiety (generalised anxiety disorder, GAD) 2. Panic anxiety disorder (attack form, lasting minutes or hours, with intense fear of eminent death; high dose of BNZ, or alprazolam) 3. Phobias 4. Insomnia (a benzodiazepine with short t , e.g. midazolam, is preferred when there is no anxiety otherwise it may produce rebound anxiety) 5. Muscle relaxant (tetanus, infantile spasm; BNZ, meprobamate, or barbiturate) 6. Epilepsy (status epilepticus, diazepam i.v., lorazepam i.m., thiopental, chlormethiazole; maintenance therapy, clonazepam) 7. Premedication in anaesthesia 8. Before endoscopy (midazolam) 9. Alcohol withdrawal (BNZ, chlormethiazole)

Buspirone Buspirone is a new generation of antianxiety agents. It is believed to produce its effect by its property as a partial 5HT-receptor agonist as explained above. Unlike benzodiazepines, buspirone has no hypnotic, muscle relaxant or antiepileptic effect. The onset of its antianxiety action is delayed for 2 or more weeks. It causes little or no depression on psychomotor function. It does not benefit benzodiazepine withdrawal symptoms.

Barbiturates An account on barbiturates is presented in the following section (Sedatives and Hypnotics) and also in the section on Antiepileptic Drugs.

Adverse Effects

Others

1. Sleepiness (therefore, operating machines should be avoided) 2. Impaired psychomotor function 3. Amnesia 4. Dependence 5. Hangover (delayed drowsiness; a benzodiazepine with short t , e.g. midazolam, is preferred, less hangover particularly in the elderly)

1. ¾-blockers (e.g. propranolol) can be used where there are somatic symptoms like tremor and tachycardia. 2. Antidepressants (e.g. amitriptyline can be useful where there is depression with anxiety) 3. Antipsychotics (for their sedative action, e.g. trifluoperazine)

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Table 5.10. A summary of the pharmacology of selected benzodiazepines Drug

Anxiolytic Action

Plasma t h

Metabolites (t h)

Alprazolam (Xanax)

16

Inactive

Chlordiazepoxide (Librium)

20

Clobazam (Frisium)

35

Active (42)

Clonazepam (Rivotril)

25

Inactive

Clorazepate (Tranxene )

Prodrug

Nordiazepam (80)

Diazepam (Valium)

43

Nordiazepam (80)

RO LA

Highly lipid soluble so quickly effective (orally), but slowly effective i.m.; short-acting as anticonvulsant i.v. (rectally, in children)

Lorazepam (Ativan)

20

Inactive

IO SA

Slowly absorbed & distributed (lower lipid solubility; thus, slower onset & offset of effect than diazepam & midazolam); quickly effective i.m., used for status epilepticus

Midazolam (Hypnovel)

3

Inactive

RO SA

Injected as adjunct in anaesthesia for endoscopies, dentistry etc; quickly effective i.m; given sublingually in status epilepticus.

Nitrazepam (Mogadon)

30

Inactive

Superseded because of long t , more sedative-hypnotic, abuse potential in Iraq; 1st choice in infantile spasm

Triazolam (Halcion )

3

Active (7)

Amnesia; psychiatric reactions; very rapid oral absorption

Important Remarks Has antidepressant activity; used in panic disorders, agoraphobia

Desmethyldiazepam

[nordiazepam (80)]

IO LA

Steady-state effect for about 3 days; low lipid solubility; slowly effective i.m.; less sedative (good anxiolytic) Used in epilepsy as well as anxiety Broad spectrum antiepileptic; useful in absence and myoclonus In stomach converted by hydrolysis to nordiazepam

Modified from Laurence, D. R., Bennett, P. N., and Brown, M. J. (1997) Clinical Pharmacology, 8th edition, page 318. R: rapid; I: intermediate; O: onset; S: short; L: long; A: action; note these generally apply to the anxiolytic action of these agents. For other actions the classification may be different, e.g. as anticonvulsant diazepam is shorter acting than lorazepam.

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Majid A. K. Lafi

Lorazepam, when given i.v., diffuses into the CNS more slowly so that the onset (15 min) and offset of effect are smoother compared to that of diazepam and midazolam both are more lipid soluble with rapid onset of action (2 min). Therefore, at sedative dose lorazepam acts longer and may produce more amnesia for which it may be superior to diazepam and midazolam. Lorazepam has a plasma t of 20 h with a single step metabolism (conjugation) suggesting that it is not seriously accumulative. This is probably why it has a substantial capacity to induce dependence and withdrawal of the drug can be troublesome for which diazepam therapy is used. Lorazepam is metabolised by conjugation (inactive metabolites), a process is less influenced by age than is oxidation of other benzodiazepines like diazepam. Cimetidine (hepatic enzyme inhibitor) does not increase plasma concentrations of lorazepam, while it may increase concentrations of diazepam and chlordiazepoxide by as much as 50%. Clonazepam, unlike diazepam, can be effective in the treatment (chronic use) of epilepsy. This is probably with diazepam tolerance to the antiepileptic action develops rapidly.

2.

3.

4.

Long t drugs/metabolites are appropriate for anxiety. Short t drugs/metabolites are appropriate for insomnia.

•

Sedative action: premedication for surgery, dental surgery (with local anaesthetic), cardioversion, endoscopies and anxiety with agitation; sedative action reduces attention; also amnesia is desired. • Hypnotic action: insomnia

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SEDATIVE AND HYPNOTIC DRUGS without adverse effects such as drowsiness and hangover, and with all hypnotics there is a risk of addiction. Finally, there is no hypnotic that gives you physiological sleep as hypnotics usually cut down on the important component rapid eye movement (REM) sleep that should make up 20% of sleeping time.

Introduction To date, the physiology of sleep is still not fully understood. However, several anatomical centres are believed to be involved, as shown in the following schematic diagram (Fig.5.6). In sleep control centres, the important factor is inhibition produced by excitatory inputs that come from two major sources (reticular activating system). Both of which stimulate the reticular formation (wake centre) that in turn inhibits raphe nuclei (sleep centre):

Sedatives and Hypnotics A sedative should reduce anxiety with little or no effect on mental or motor functions. A hypnotic drug induces more marked depression on CNS function than a sedative and this can be achieved with most drugs, simply by increasing the dose. Most of the sedatives and hypnotics give a graded CNS depression, dose-related (Fig.5.7.).

1. Afferent input from sensory nerves (e.g. tactile, visual, auditory) 2. Impulses from the limbic system (e.g. emotions)

Individual sedative-hypnotic drugs differ in their dose-response to the four principle actions (Fig. 5.7.). The steep dose-response curve, for example, for a barbiturate agent would show that sedation, anaesthesia, and undesirable clinical effects (e.g. respiratory depression) fall in a narrow dose range (thus, low therapeutic index). Whereas a benzodiazepine agent would show that sedation, hypnosis, and undesirable clinical effects fall in a wide dose range (thus, a large therapeutic index) that makes the drug attractive as a sedative.

Reticular Activating System The reticular activating system is a network of neurones that extends from the spinal cord through the medulla and pons to the thalamus and hypothalamus. It receives impulses from all parts of the body, evaluates the significance of the impulses, and decides which impulses to transmit to the cerebral cortex. It also excites or inhibits motor nerves that control both reflex and voluntary movement. Stimulation of these neurones produces wakefulness and mental alertness; depression causes sedation and loss of consciousness.

Sedative-hypnotic drugs can be classified into the following chemical groups:

This means that one is able to sleep when one does not suffer pain or other discomfort, moreover it is possible to fall asleep if you are not bothered about distracting feelings from the limbic system. Also other excitatory stimuli from coffee, tea and nicotine must be considered. Hypnotics produce a state similar to physiological sleep in that the patient is rousable by external stimuli while sleep induced by anaesthetics is not rousable by external stimuli.

1. Benzodiazepines 2. Barbiturates 3. Carbamates (meprobamate) 4. Alcohols (ethanol, chloral hydrate) 5. Cyclic ethers (paraldehyde)

Benzodiazepines This class of drugs has been covered in the section on anxiolytics. Benzodiazepines are generally considered superior to barbiturates in that being characterised by:

Thus, before prescribing a sleeping pill, one should exclude other wakeful stimuli. Unfortunately, there is no sleeping pill

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Majid A. K. Lafi

B

Cortex

Sleep Raphe Nuclei

Limbic System

+ Sensory Input

GABA Raphe Nuclei

-

+

5HT

Sleep Centre NA

Reticular Formation Wake Centre

Locus Caeruleus Nuclei

Fig.5.6. A simplified schematic representation of the sleep centre. Note: Two major stimulatory inputs coming via afferent sensory pathway (e.g tactile, visual and auditory) and input arriving from the limbic system (A). It is believed that in the raphe nuclei (sleep centre) the release of 5HT from serotonergic neurones mediates sleep. The inhibition of these serotonergic neurones by GABAergic (interneurone) activity leading to inhibition of the sleep centre, thus, wakefulness predominates. This probably explains the stimulatory effects (arousal state) of noradrenaline, 5HT, and histamine acting through the (reticular formation) interconnected with the locus caeruleus and then in turn with the sleep centre (B). 5HT in the mesolimbic system is suggested to produce arousal (it inhibits sleep as the case with the SSRI fluoxetine producing arousal and insomnia); while, in raphe nuclei it is suggested to produce sleep.

Coma -

Barbiturates

Anaesthesia -

Benzodiazepines

Hypnosis Sedation Anxiolysis -

Increasing dose Fig.5.7. A graph showing that sedative-hypnotic drugs like barbiturates (e.g. thiopental) exhibit a steep linear dose-response relationship; i.e. the dose required to produce anaesthesia and coma is close to that producing hypnosis. This type of drugs is described as having a low therapeutic index (low safety). On the other hand, drugs like benzodiazepines (e.g. diazepam) exhibit a non-linear dose-response relationship; i.e. the dose required to produce anaesthesia is very much greater than that required to produce sedation and hypnosis. This type of drugs is said to have a high therapeutic index (high safety).

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Nonbenzodiazepine Hypnotics that Act at the GABAABenzodiazepine Receptor

A list of adverse effects for barbiturates is presented in the section on Antiepileptic Drugs. It would suffice here to mention that barbiturates are characterised by:

Although structurally unrelated to the benzodiazepines, these drugs, represented by zopiclone, zolpidem and zaleplon, act on the same BNZ1 subtype of benzodiazepine receptors; their effects can be blocked by flumazenil, the receptor antagonist. They are largely effective in insomnia, have low tendency for tolerance, rebound insomnia, withdrawal symptoms and abuse potential.

1. Low therapeutic index 2. Risk for addiction

Addiction Addiction is a general term that describes the following clinical conditions that may be observed in a patient taking addictive drug:

Barbiturates

Addiction 1. Compulsion1 to use the drug 2. Using the drug taking the priority to other life activities 3. Symptoms appear upon withdrawal 4. When abstinence2 occurs, reusing the treatment leads to withdrawal symptoms more rapidly. 5. Tolerance leads to take more of the drug (higher dose), hence, withdrawal symptoms are more likely and consequently taking the drug more frequently.

Barbiturates (1903) are derivatives of barbituric acid, which is synthesised from malonic acid and urea. Barbiturates are today mostly used as antiepileptic drugs and for induction of general anaesthesia. They are too toxic to be used as sedatives or hypnotics. Phenobarbital is used as antiepileptic and thiopental for i.v. anaesthesia. Barbiturates exert a general depressant activity on cellular functions (reduce glucose oxidation), depress synaptic transmission by increasing membrane stability and by increasing GABA activity. In the brain, barbiturates predominantly depress the reticular activating system (reticular formation). The long acting phenobarbital (t : 80 hours) is more ionised and less lipid soluble than the ultrashort acting thiopental (initial t : 5 min, terminal t : 11 hr). High lipid solubility makes the drug penetrates the CNS rapidly. After entry into the CNS, thiopental is rapidly redistributed to other parts of the body that is the main reason for their ultrashort action.

Carbamates Meprobamate is a representative of the carbamate group, introduced in 1952. It has anxiolytic-sedative actions, anticonvulsant activity, and central muscle relaxant effect. It has hepatic enzyme induction activity. These days, its use is very much reduced, as this group is largely inferior to the benzodiazepines, and does not have any superiority over barbiturates. In fact, carbamates have a tendency to induce tolerance and dependence after prolonged use, and withdrawal symptoms may be precipitated if their use is terminated abruptly. Generally, its use is restricted in patients who do not respond to benzodiazepines.

Barbiturates rapidly induce tolerance since most of their effectiveness is lost with continued administration over a 2-week period and this explains why patients increase the dose. This makes the patient dependent since withdrawal induces abstinence symptoms. This tolerance depends on a metabolic factor (induction of liver enzymes) and pharmacodynamic factors (biological adaptation, see similar effects for morphine, section on Narcotic Analgesics).

1

An irresistible impulse to perform some act contrary to one s better judgement or will. 2 A refraining from the use of or indulgence in drugs. 148

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5. Vomiting (Following oral or i.v. administration, therefore, this action appears to be partly central, besides local gastric irritation. Note: Because the emetic blood alcohol level is below that which induces coma, death from acute alcoholism is rare. When it occurs, it is usually due to suffocation from inhaled vomit.) 6. Hypoglycaemia (Alcohol inhibits gluconeogenesis, particularly, when heavy drinking with a meal that enhanceinsulin response to carbohydrate intake.) 7. Hyperuricaemia: Gout may be precipitated by a. Increased metabolism of adenine nucleotides (e.g. ATP) leading to the production of uric acid. b. At high alcohol level, raised blood lactate compete for renal tubular elimination resulting in reduced excretion of urate 8. Actions on sexual functions: Ethanol produces CNS disinhibition, thus, increasing libido and erection (provokes the desire).

Alcohols Ethyl alcohol behaves like general anaesthetics on the CNS. It has been suggested that the acute effect of alcohol is to block NMDA (N-methyl-D-aspartate) receptors for which the normal agonist is glutamate, the main excitatory transmitter in the brain. Preseumably as a compensatory mechanism, alcohol chronic exposure increases the number of NMDA receptors and also 'L type' calcium channels, while the action of the (inhibitory) GABA neurotransmitter is reduced. Anxiety, insomnia and craving that accompanies sudden withdrawal of alcohol may explain why resumption of drinking brings about relief, and thus perpetuating dependence.

Ethanol is hardly used as a therapeutic compound; however, it has important toxicological interest. The main effects of ethanol are on the CNS. It acts as hypnotic and anaesthetic; and it disinhibits behaviour, which appears as stimulation (an effect on the higher centres). Peripheral actions include vasodilatation, stimulation of gastric acid. The diuretic effect is due to a central action, inhibition on the release of the posterior pituitary hormone ADH.

Chronic Alcohol Consumption Chronic alcohol consumption may lead to: 1. Hepatic enzyme induction: This leads to increased metabolism of testosterone, 2. Direct toxic effect on Leydig cells: This leads to reduced production of testosterone. 3. Testicular atrophy: Both 1 and 2 (above) result in testicular atrophy leading to feminisation (takes away the performance). 4. Foetal alcohol syndrome: teratogenic effects.

Ethanol is considered to be as a rich source of calories that 1 g of ethanol produces 7 calories. The alcoholic are prone to having a variety of pathological conditions, e.g. gastritis, hepatic cirrhosis, brain damage (loss of memory, mental changes). The following list represents the important actions of ethanol. 1. Cutaneous vasodilatation (feeling of warmth, as a result of depressing the vasomotor centre, risk of rapid hypothermia) 2. Increased blood pressure (probably due to centrally mediated sympathetic stimulation) 3. Diuretic action (decreases the release of ADH from the posterior pituitary gland) 4. Gastric mucosa (erosion and petechial haemorrhages due to allowing back diffusion of acid from the gastric mucosa)

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Withdrawal of Alcohol This may be encountered when an ill or injured alcoholic is admitted to hospital. The possible sequence of events may appear as: 1. Withdrawal syndrome (in 6 hours, craving for alcohol, tremor, and sympathetic overactivity)

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2. Acute psychotic attack (delirium tremens3): (in 72 hours, seizures, agitation, anxiety, and excessive sympathetic autonomic activity.

Drugs used in treatment 1. Benzodiazepine (chlordiazepoxide, large dose for sedative action) 2. ¾-adrenoceptor blocker (propranolol for sympatholytic action) 3. Butyrophenone neuroleptic4 (haloperidol for its antipsychotic action)

Chloral Hydrate Chloral hydrate (1869) is the first synthetic hypnotic agent to be used clinically. It is usually given orally in solution. Because of its unpalatable taste a capsule is available. It is irritant to the stomach. Chloral hydrate is a prodrug, rapidly metabolised by alcohol dehydrogenase into the active hypnotic trichloroethanol. The latter undergoes conjugation with glucuronic acid to an inert form that is excreted in the urine. Therefore, avoid in serious hepatic or renal failure. Choral hydrate aggravates peptic ulcer.

Interactions As chloral hydrate is metabolised by the enzyme alcohol dehydrogenase that is also responsible for the conversion of ethanol to acetaldehyde, therefore, resulting in an increase in plasma concentration of alcohol; hence, the action of ethanol is potentiated by chloral hydrate.

3

An acute mental disturbance marked by delirium with trembling and great excitement, and attended by anxiety, mental distress, sweating, GI symptoms, and precordial pain. It is also seen in opium addiction. 4 Phenothiazines (e.g. fluphenazine and chlorpromazine) should be avoided in this condition as they are proconvulsant (lower threshold for convulsion). 150

Cyclic Ethers Paraldehyde (1882) for a long time had been used as a hypnotic (oral and injection) for control of mania, alcohol withdrawal, tetanus, and status epilepticus. These days, paraldehyde is obsolete except for status epilepticus. This is because of many major disadvantages such as unpleasant taste and smell, irritant to the stomach, causes painful muscle cramps when injected i.m., dissolves plastic syringes.

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Table 5.11. Comparison between benzodiazepines and barbiturates Nature of comparison Relatively safe Maximal ability to suppress CNS function Respiratory depressant ability Suicide potential Ability to cause physical dependence Ability to cause tolerance Abuse potential Ability to induce drug metabolism Number of drug interactions Safety in intermittent porphyria Effects increased by other CNS depressants Availability of antagonist

Benzodiazepines High Low Low Low Low Low Low Low Few ? Yes Yes

Barbiturates Low High High High High High High High Many No Yes No

Table 5.12. Barbiturates: prototypes and their clinically important pharmacological characteristics.

Sub-group

Prototype

Ultra-short acting

Thiopental (Pentothol ) Secobarbital (Seconal ) Phenobarbital (Luminal )

Short acting Long acting

Action Onset Duration minutes hours

Lipid solubility

Typical Indication

High

0.5

0.2

Induction of anesthesia; convulsion

Moderate

10-15

3-4

Insomnia

Low

60

10-12

Epilepsy

Therapeutic Coverage Anxiolytic Sedative Hypnotic Buspirone Neuroleptics, Meprobamate Benzodiazepines Barbiturates

Anaesthetic

Coma

Fig. 5.8. A simplified schematic representation of anxiolytic, sedative, hypnotic drugs and their most common therapeutic coverage. Buspirone is used for its anxiolytic action; while neuroleptics (major tranquillisers, e.g. chlorpromazine) are used for their anxiolytic-sedative actions, likewise is meprobamate. Further, benzodiazepines (e.g. diazepam) are used for therapeutic coverage including anxiolytic, sedative and hypnotic actions. Furthermore, the therapeutic objective of barbiturates (e.g. thiopental) is extended further to include their anaesthetic action. Of the major adverse effects of the CNS depressant agents are coma and depression of the respiratory and vasomotor centres; this is most apparent with barbiturates then to a much lesser extent with benzodiazepines.

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Useful Notes • Psychotic states (manic or endogenous depressive illness and schizophrenia) • Psychoneurosis [anxiety, phobias, (exogenous) reactive depression, obsessivecompulsive disorders, and hysteria) • Neuroleptics are effective in positive symptoms, e.g. aggression, hyperactivity, delusions and hallucinations. But negative symptoms, e.g. apathy, respond less well. • In addition to schizophrenia, neuroleptics are also useful in a. Severe anxiety b. Acute mania c. Acute psychotic states d. Therapeutic restraining e. Intractable hiccup • Endogenous depression: TCA + ECT (increase postsynaptic response, if severe state) plus phenothiazine. Benzodiazepines are contraindicated except for alprazolam. • Insomnia of depression (characteristically, early waking) relieved by a sedative antidepressant drug. • Reactive (exogenous) depression (commonly associated with anxiety) is treated with anxiolytic-sedative or a TCA or MAO inhibitor. • Acute behavioural disturbances: a neuroleptic or benzodiazepine, orally, i.m. • Appetite disorders: anorexia (decrease appetite) and bulimia (increased appetite)

anticholinesterase tacrine and the ACh precursor lecithin. • Excessive sex drive in men reduced by oestrogens or by antiandrogen (cyproterone).

PSYCHOSTIMULATS These (amphetamines e.g. dexamphetamine, methylphenidate, and pemoline) increase the level of alertness and/or motivation. Indications: Narcolepsy, attention deficit disorder in children, anorectic (reduce appetite). Adverse effects: tolerance, insomnia, dependence, nausea & vomiting, increase distractibility, paranoid schizophrenia like symptoms.

PSYCHODYSLEPTICS Psychodysleptics (hallucinogens) produce mental changes that resemble those of some psychotic states. They are usually used for nonmedical purposes. • Lysergide (LSD) • Cocaine • Cannabis

a. Anorexia nervosa treated by chlorpromazine (& cyproheptadine) b. Bulimia treated by dexfenfluramine, fluoxetine, TCA. • Narcolepsy benefited by activating noradrenegic mechanisms with amphetamines (dexamphetamine, methylphenidate, mazindol or caffeine). • Attention deficit (hyperkinetic) disorder in children responds to adrenergic activation by dexamphetamine (or methylphenidate or pemoline). • Nocturnal enuresis: TCA (imipramine), desmopressin (ADH) intranasal metered aerosol (for a holiday). • Organic brain syndromes and senile dementia of Alzheimer type may be improved by the centrally acting

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DRUGS FOR PARKINSON S DISEASE Introduction

Brain dopamine (DA) receptors operate through secondary messenger systems. DA1receptors binding Gs-protein coupled to adenylate cyclase leading to increased cAMP production. DA2-receptors coupled to adenylate cyclase but through an inhibitory Gi-protein that decreases cAMP production. DA2-receptors are also found to be coupled to a mechanism inhibiting the hydrolysis of phosphatidyl inositol bisphosphate (PI2) leading to reduced production of diacylglycerol (DAG) and inositol trisphosphate (IP3). Further, activation of D2receptors hyperpolarises neurones by increasing potassium conductance of both brainstem dopamine neurones and that receive dopamine terminals. Blockade of DA2-receptors by neuroleptic drugs or metoclopramide is associated with their ability to produce Parkinsonism in patients taking such drugs

Parkinson s disease is a progressive disorder of voluntary movement that affects 1% to 2% of the population (in the western world) over 60 years of age has an average onset age in the 50s and 60s. Clinical symptoms of Parkinson s disease manifested by most patients include: 1. Resting tremor 2. Rigidity (increased resistance to passive stretching of muscle) 3. Hypokinesia1 (slowness in initiating and carrying out voluntary movements) 4. Impaired postural reflexes (with a tendency to fall backwards or forwards easily) 1

Slowness of movements is variably called bradykinesia, hypokinesia or akinesia

Normal

Substantia nigra Dopamine (inhibitory)

Corpus striatum Acetylcholine (excitatory)

Putamen GABA (inhibitory)

Parkinsonism DA

ACh

GABA

ACh

GABA

Huntington’s disease DA

Fig. 5.9. A simplified schematic representation of nigrostriatal system of the basal ganglia. The dopaminergic neurotransmission exerts inhibitory actions on the cholinergic neurones of the corpus striatum; the latter exerts excitatory effects on the GABAergic neurones of the putamen. Normally, there is a balance between the dopaminergic and the cholinergic pathways, which is important in the extrapyramidal control of motor activity at the level of the substantia nigra and the corpus striatum. A decrease in the dopaminergic activity (degenerative loss) is believed to be the underlying cause for Parkinson s disease; while, a decrease in the GABAergic activity is believed to be responsible for Huntington s disease. It follows that an increase in dopaminergic activity may result in GABAergic underactivity and hence choreoathetosis (a condition characterised by choreic and athetoid movements ).

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effects, particularly emetic effects from about 80% to less than 15%.

Therapeutic Objectives 1. Promoting dopaminergic activity that may be achieved by the use of certain drugs targeted at different dopaminergic mechanisms. This approach improves certain parkinsonian features like hypokinesia and rigidity, with little effect on tremor. 2. Reducing cholinergic activity by antimuscarinic drugs that, at least, partially redressing the imbalance created by decreased dopaminergic activity. This approach improves tremor, sailorrhoea (excessive secretion of saliva), rigidity, with little effect on hypokinesia.

At present, two fixed combined preparations are available. • Co-careldopa (carbidopa + levodopa, Sinemet) • Co-beneldopa (benserazide + levodopa, Madopar)

Dopaminergic Drugs Levodopa Levodopa (L-DOPA) is the normal physiological precursor of dopamine synthesis, being converted to dopamine by the enzyme dopa decarboxylase. Unlike dopamine, levodopa readily crosses the blood brain barrier (BBB). When levodopa is used alone, it is readily taken up and converted to dopamine by peripheral and central nervous tissues. The peripheral conversion of levodopa is undesirable as it results in peripheral adverse effects, particularly cardiovascular and emetic effects. This problem has been overcome by the concurrent administration of a levodopa decarboxylase inhibitor like carbidopa and benserazide that cannot cross the BBB. The enzyme inhibitor peripherally prevents the (extracerebral) conversion of levodopa to dopamine; therefore the required dose of levodopa is reduced to about 25%. This consequently reduces peripheral adverse

Adverse Effects 1. Postural hypotension ( ) 2. Nausea (effect DA-receptor on the CTZ, reduced by prior administration of domperidone that minimally crosses the BBB) 3. Dyskinesia (extra movements; choreoathetosis, choreic involuntary movements, involving head, lip, tongue; peak dose effect, reduced by the use of slow-release preparations) 4. Mental changes (psychosis, hallucinations; depression) 5. Wearing-off (effect of each dose becomes shorter, i.e. reduced duration of action) 6. End of Dose Akinesia (end of dosage interval; may respond to giving smaller doses of levodopa more frequently) 7. On-Off phenomenon: Severe swings in performance ranging from extra movements (dyskinesia) to complete lack of movement (total akinesia). These swings in performance often do not appear to be directly related to time of drug administration. A summary of the pharmacology of the drugs used in the treatment of Parkinson s disease is presented in Table 5.13.

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Table 5.13. A summary of the drugs used in the treatment of Parkinson s disease. Approach Drug

Adverse Effects and Important Remarks

Action

Enhance Dopamine Activity Levodopa [+ carbidopa (Sinemet)]

Dopamine precursor [+ extracerebral decarboxylase inhibitor]

Postural hypotension Nausea Dyskinesia Psychosis Decreasing hypokinesia, rigidity, less effective on tremor

Bromocriptine (Parlodel) Lysuride Pergolide Apomorphine

Dopamine agonist

Postural hypotension Nausea Dyskinesia Psychosis

Selegiline* (Deprenyl)

MAO-B inhibitor

Amantadine

↑ dopamine synthesis & release ↓ reuptake

Increases likelihood of adverse effects caused by levodopa or dopamine agonists. Used as adjunct with levodopa (dose reduced by about 50%); improves end-ofdose akinesia1.

Confusion or agitation Benefits wears off, after about 3 months of treatment Used alone when early, and adjunct when disease progresses

Reduce Cholinergic Activity Benzhexol (trihexiphenidyl-HCl, Artane) Procyclidine Orphenadrine Benztropine

CNS (loss of memory, confusion) and HALLUCINATION →DRUG ABUSE Peripherally (dry mouth, decreased sweating, constipation, urinary retention etc.) Decreasing tremor, rigidity, less effective on hypokinesia

Muscarinic antagonist

* The claim that selegiline delays progress of the disease has lead to its use as protective therapy. This claim stemmed initially from the theory that it inhibits the oxidation (by the brain MAO-B) of the protoxin MPTP to MPP+ which results in death of dopaminergic neurones (thus, protecting the surviving dopamine neurones). However, this claim has not been supported by subsequent trials; indeed, one

study has shown an increased mortality in patients receiving selegiline2.

1 2

Laurence, D. R., Bennett, P. N. and Brown, M. J. (1997) Clinical Pharmacology. 8th edition, Page 367. Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 459. 155

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ANTIEPILEPTIC DRUGS seizure (e.g. head injury, tumour, hypoglycaemia, meningeal infection, or perhaps, rapid withdrawal of alcohol from an alcoholic). This is known as secondary epilepsy and is usually reversible. Status epilepticus, in which the episodes of tonicclonic seizure occur without intervening recovery of consciousness, is serious and may be fatal unless treated rapidly.

Introduction Epilepsy1 is a syndrome characterised by sudden transient alterations in brain function leading to motor, sensory, autonomic or psychic syndrome, often accompanied by unconsciousness. Seizures2 may result in abnormal perceptions if the parietal or occipital cortex is involved. However, seizures may result in abnormal movements (convulsions) if the motor cortex is involved.

Patients are treated with antiepileptic drugs. Patients with primary epilepsy are treated often for life, whereas those with secondary epilepsy are treated with antiepileptic drugs until the cause of the seizure is corrected. It is generally accepted that a patient having recurrent seizures should receive antiepileptic treatment that will be stopped only if two years elapse without any seizure. For classification of seizures see Table 5.14. and for a summary of antiepileptics and their indications (Table 5. 15).

In epilepsy, the abnormal neuronal discharge is usually localised to a specific area of the brain, known as the primary focus that usually does not show any anatomical abnormality. The functional abnormality of these foci may be triggered by different environmental factors, e.g. changes in blood gases, electrolytes, pH, glucose level. A focal cortical seizure may spread to involve the cortex and a generalised (tonic-clonic) seizure with unconsciousness, convulsions and incontinence. When the spread from the initial focus is slow, the initial focal symptoms give rise to a warning (or aura) of the impending fit. However, if the spread of the focal seizure over the cortex is rapid an aura may be absent.

Mode of Action Antiepileptic drugs inhibit the repetitive neuronal firing or its spread by one of the following three possible ways: 1. Modifying cell membrane permeability to ions like Na+ (e.g. carbamazepine, phenytoin) and Ca++ (e.g. ethosuximide) 2. Promoting the action of endogenous inhibitory neurotransmitters such as GABA producing hyperpolarisation (e.g. benzodiazepines, barbiturates, valproic acid, vigabatrin) 3. Inhibiting excitatory neurotransmitters like glutamate and aspartate (e.g. lamotrigine).

In the absence of anatomical cause (e.g. trauma or tumour) for the seizure, it is called idiopathic or primary epilepsy. However, when there is an apparent cause for the 1

Reference to the disease can be found as early as 2080 BC in the code of Hammurabi, King of Babylon. Hippocrates in about 400 BC opposed the supernatural explanation of epilepsy and correctly attributed it to abnormal cerebral function. 2 An attack of epilepsy variably called fit.

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Table 5.14. Classification of seizure, frequency, and clinical manifestations. Frequency (%) PARTIAL (FOCAL) SEIZURES Simple partial (10%)

Clinical Manifestations

No impairment of consciousness; focal motor, sensory (e.g, olfactory hallucination), speech, psychic (e.g. delusion), and autonomic disturbances (e.g. tachycardia).

Complex partial (35%)

Impaired consciousness; complex sensory hallucinations, mental distortions, and motor dysfunctions (chewing movements).

Partial seizures secondarily generalised

(10%) Start as simple partial or partial complex and marsh to tonic clonic fit

GENERALISED SEIZURES Tonic-clonic (30%) (Grand mal)

Loss of consciousness, falling, rigidity extension of trunk and limbs (tonic phase), rhythmic contraction of arms and legs (clonic)

Absence (10%) (Petit mal) Myoclonic, atonic (4%) (Atypical absence)

Impaired consciousness with staring spells, with or without eye blinks Myclonic jerks (shock-like contractions), loss of muscle tone, falling (drop attack, Salaam attack)

Other Seizures (1-8%) frequency repetitive firing in neurones in culture (for more details see phenytoin below).

Antiepileptic Drugs All central depressant drugs like anaesthetic and hypnotics act as anticonvulsants and will suppress epileptoform convulsions. Antiepileptic drugs are special selection of anticonvulsants that are capable of suppressing epileptic seizures in doses that produce little or no sedation. An overview of the pharmacology of the important antiepileptic drugs is presented in Table 5.16.

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic secondary) 4. Trigeminal neuralgia1 5. Postherpetic neuralgia 6. Diabetic neuropathy2 1

(primary

&

Paroxysmal pain which extends along the course of one or more nerves. Many varieties of neuralgia are distinguished according to the part affected or to the cause, as trigeminal, brachial, facial, occipital, supraorbital, etc., or postherpetic, anaemic, diabetic, gouty, malarial, syphilitic, etc. 2 A chronic, symmetrical sensory polyneuropathy affecting first the nerves of the lower limbs and often affecting autonomic nerves; pathologically, there is segmental demyelination of the peripheral nerves. An uncommon, acute form is marked by severe pain, weakness, and wasting of proximal and distal muscles, peripheral sensory impairment, and loss of tendon reflexes. With

Carbamazepine Carbamazepine is a tricyclic compound closely related to imipramine and other antidepressants. Carbamazepine was originally developed for the treatment of bipolar depression. However, it was first used in the treatment of trigeminal neuralgia and only later its anticonvulsant action has been recognised. The mechanism responsible for its anticonvulsant action appears to be related to its capability to block sodium channels at therapeutic concentrations and inhibits high157

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7. Cerebellar ataxia (failure of muscular coordination due to a disease of the cerebellum) 8. Nocturnal enuresis 9. Affective disorder (unipolar depression and mania, treatment and prophylaxis) 10.Resistant schizophrenia 11.Diabetes insipidus 12.Hyperkinetic child 13.Dementia (organic loss of intellectual function) 14.Emotional incontinence (uncontrolled emotional acts, e.g. laughing) 15.Aggressive behaviour 16.Migraine (prophylaxis) 17.Impulse dyscontrol syndrome

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depolarised (i.e. has more positive resting potential) cells that will recover from block Table 5.15. A summary of antiepileptic drugs and their indications Type of Epilepsy Partial (including secondarily generalised)

Antiepileptic Drug

Tonic-clonic

Carbamazepine Phenytoin Phenobarbital Primidone Valproic acid Lamotrigine ( as adjunct)

Absence

Ethosuximide Valproic acid Clonazepam Lamotrigine ACTH

Myclonic

Valproic acid Clonazepam ACTH

Febrile

Diazepam Phenobarbital Valproic acid

Status Epilepticus

Phenytoin (i.v.) Diazepam (i.v.) Phenobarbital (i.v.)

Adverse Effects Dose related (predictable) 1. Diplopia 2. drowsiness 3. Orofacial dyskinesia 4. Cardiac arrhythmias (AV depression) 5. Impairs cognition 6. Osteomalacia and folate deficiency (due to hepatic enzyme induction; with first few weeks, t 35 hours becomes 20 hours) Non-dose related (Idiosyncratic) 7. Agranulocytosis 8. Aplastic anaemia 9. Hepatotoxicity 10.Stevens-Johnson syndrome (severe form of erythema multiforme in which there is involvement of the oronasal and anogenital mucosa, the eyes, and viscera)

Carbamazepine Phenytoin Phenobarbital Primidone Valproic acid Lamotrigine Vigabatrin

Bold prints: preferred drugs In pregnancy: carbamazepine and phenobarbital are most suitable.

Phenytoin Phenytoin (1938) is a nonsedative hydantoin compound. It appears to produce its anticonvulsant action through its capability, at therapeutic concentrations, to block sodium channels and inhibit sustained highfrequency repetitive firing in neurones in culture. Like carbamazepine, phenytoin appears to exert selective inhibition on

very slowly if at all. In doing so, phenytoin increases refractory period in depolarised (sick) cells. This apparently selective action has been attributed to what is known as the use-dependent effect 3; therapeutically useful sodium channel blocking (local anaesthetic, membrane stabilising) drugs

autonomic involvement there may be orthostatic hypotension, nocturnal diarrhoea, retention of urine, impotence, and small diameter of the pupils with sluggish reaction to light.

3

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Page 551 & 562. 158

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have a high affinity for activated channels or inactivated channels but very low affinity for rested channels. Bearing in mind that an ionchannel is usually in one of three possible states:

Rested

indicator of plasma concentrations. As shown above in a, the t value cannot help the prescriber to decide the dosage regimen with reasonable safety; therefore in such condition, serial plasma concentration measurement has been recommended].

Activated

Inactivated It follows that in sick cells with abnormally high firing activity, the most likely ionchannel states would be the activated and inactivated ones. Consequently, these sodium channel-blocking drugs would preferentially bind to these channels that are in depolarised cells resulting in increased refractory period and therefore decreasing cell excitability. Indeed, this hypothesis of use-dependent effect is applied for calcium channel blocking drugs as well.

Pharmacokinetics 1. Saturation (zero-order) kinetics [At subtherapeutic (low) blood levels, phenytoin metabolism is directly proportional to the rate at which the drug is presented to the liver, i.e. first-order metabolism, the t of phenytoin is 6-24 hours. However, at therapeutic (high) blood levels the metabolic machinery becomes saturated (said to have reached zero-order kinetics), the t may reach 60 hours. Phenytoin is the most clinically important example of the drugs exhibiting zero-order kinetics. This is because it is characterised by: a. Its overall t ranges from 6-60 hours, and considering the time to reach a steady-state plasma concentration after dose increment (about 5 × t ) ranges from 2 days to 2 weeks. Consequently, the knowledge of its t is clinically not meaningful, as it is not possible to determine (reasonably) reliably the time to reach the therapeutic steadystate concentration. b. Being a drug with low therapeutic index, it should not be given without a reliable 159

2. Hepatic enzyme induction and enzyme inhibition [phenytoin is a potent hepatic enzyme inducer influencing its own metabolism as well as other drugs and dietary and naturally occurring substances such as vitamin D, folate, adrenal and gonadal steroids, thyroxine. Other drugs whose hepatic metabolism significantly increased including other antiepileptic drugs, e.g. carbamazepine, warfarin, tricyclic antidepressants, and doxycycline. It follows that hepatic enzyme inducing drugs can affect each other when administered concurrently; for example, phenobarbital, carbamazepine, rifampicin may lower phenytoin concentrations. Likewise, hepatic enzyme inhibiting drugs such as valproate, cimetidine, cotrimoxazole, isoniazid, chloramphenicol, erythromycin etc. can interact with phenytoin, and other antiepileptic drugs, causing an increase in plasma concentrations, hence increasing the possibility of toxicity].

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic (primary secondary) 4. Status epilepticus 5. Digitalis-induced arrhythmias 6. Trigeminal neuralgia (see above)

&

Adverse Effects Dose related (predictable) 1. Ataxia, nystagmus, orofacial dyskinesia 2. Drowsiness 3. Impairment of cognitive function 4. Gingival hyperplasia (may be due to inhibition of collagen catabolism) 5. Coarsening of facial features 6. Hirsutism

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7. Megaloblastic anaemia (probably due to folate deficiency as a result of hepatic enzyme induction by phenytoin) 8. Osteomalacia (due to vitamin D deficiency as a result of increased hepatic metabolism after years of therapy) 9. Teratogenic 10.Peripheral neuropathy 11.Rashes Non-dose related (idiosyncratic) 12.Hepatotoxicity

1. Dyspepsia, nausea, vomiting 2. Coagulation disorder (due to inhibition of platelet aggregation) 3. Alopecia (hair loss) 4. Increased appetite (results in weight gain) 5. Teratogenic (spina bifida) 6. Acute pancrititis 7. Hepatitis

Overdose

Barbiturates

1. Cerebellar dysfunctions 2. Coma and apnoea (may be for a long time because of zero-kinetics, maintain respiration, no antidote)

An account on barbiturates has been given in the section on sedatives and hypnotics (above). The most widely used antiepileptic member of barbiturates is phenobarbital (t 100 hours). Other members like methylphenobarbital and primidone (a prodrug) that is largely metabolised to phenobarbital. Barbiturates are potent hepatic enzyme inducers.

Valproic Acid (Sodium Valproate) Valproic acid was incidentally found to have antiepileptic activity when it was used as a solvent in the search for antiepileptic drugs. The mechanism of action of valproic acid as antiepileptic drug is not conclusively settled. However, much of the evidence now points out to its capability to block sustained high-frequency repetitive firing of neurons in culture at therapeutically relevant concentrations. Its action against partial seizures may be a consequence of this effect on sodium channel. Blockade of NMDA receptor-mediated excitation may also be important Valproic acid is a hepatic enzyme inhibitor; and it is 90% plasma protein bound with apparent volume of distribution of 9 L.

Adverse Effects

Indications 1. 2. 3. 4. 5.

Simple partial seizures Complex partial seizures Anaesthesia (e.g. thiopental) Anxiety (rarely used these days) Insomnia (rarely used these days)

Adverse Effects 1. 2. 3. 4. 5.

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic 4. Absence 5. Myoclonic seizures 6. Affective disorders 7. Huntington s chorea 8. Peripheral neuropathy 9. Hyperkinetic child 10.Prophylaxis of migraine 11.Tardive dyskinesia 12.Impulse dyscontrol syndrome

Sedation Impaired cognition Addiction risk Enzyme induction Low therapeutic index

Benzodiazepines A detailed account on benzodiazepines has been given in the section on anxiolytics (above). Of this group, clonazepam (Rivotril, t 25 hours) is widely used as a broad-spectrum antiepileptic drug. It has the reputation to have less sedative action than most other members of benzodiazepines do. Clonazepam and diazepam are useful in status epilepticus; in this medical emergency, they should be administered i.v. slowly (30 seconds), while i.m.

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administration is not appropriate as peak plasma concentration can be delayed as long as 2 hours making these drugs useless for the urgent control required in this medical emergency. However, lorazepam is more rapidly absorbed when administered i.m.

Adverse Effects 1. Gastric upset (Nausea, vomiting) 2. Allergic reactions (Rash, Stevens-Johnson syndrome, SLE) 3. Hepatic enzyme inhibition

Ethosuximide Lamotrigine Ethosuximide was introduced as a specific anti-absence seizure drug. To date, it remains the drug of first choice for absence seizure. The mechanism of action of ethosuximide is believed to be mediated through inhibiting the low-threshold (T-type) Ca2+ currents in the thalamic neurones; these currents are suggested to be responsible for generating the rhythmic cortical discharge of an absence seizure4. Therefore, it is useful only in absence seizure.

Lamotrigine (1993) is a voltage dependent sodium channel blocker. This action results in reduced release of excitatory amino acids like glutamate and aspartate. It is believed to have less frequent adverse effects (compared with that of carbamazepine). It finds use in partial and generalised seizures, as an adjuvant or monotherapy.

4

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Page 567.

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Table 5.16. A summary of the pharmacology of selected antiepileptic drugs Drug Group Drug Carbamazepine

Mechanism of Action Reduces repetitive neural firing (inhibits voltage-sensitive Na+ channel)

Phenytoin

Reduces repetitive neural firing (inhibits voltage-sensitive Na+ channel)

Partial Tonic-clonic Status epilepticus

Na valproate

Reduces repetitive neural firing (inhibits voltage-sensitive Na+ channel)

Partial Tonic-clonic Absence Myclonic Febrile

Barbiturates Phenobarbital (t 100 hr) Methylphenobarbital Primidone (prodrug)

Potentiates GABA effects on Cl- influx

Partial Tonic-clonic Status epilepticus Febrile convulsion

Benzodiazepines Diazepam Lorazepam Clonazepam

GABA Clchannel receptor complex

Lamotrigine

Selected Adverse Effects and Important Remarks

Partial Tonic-clonic

Osteomalacia and folate deficiency (due to hepatic enzyme induction; with first few weeks, t 35 hours becomes 20 hours) Cardiac arrhythmias (AV depression) Impairs cognition (Idiosyncratic) Agranulocytosis Aplastic anaemia Hepatotoxicity Impairs cognition Gingival hyperplasia Coarsening of facial features Hirsutism Megaloblastic anaemia (probably due to folate deficiency as a result of hepatic enzyme induction by phenytoin) Osteomalacia (due to vitamin D deficiency as a result of increased hepatic metabolism after years of therapy) Teratogenic Peripheral neuropathy Rashes (idiosyncratic) Hepatotoxicity Coagulation disorder (due to inhibition of platelet aggregation) Alopecia (hair loss) Increased appetite (results in weight gain) Teratogenic (spina bifida) Acute pancrititis Hepatitis Hepatic enzyme inhibition

Status epilepticus Absence Myoclonic

Clonazepam

Ethosuximide

Indication

Inhibits lowthreshold (T-type) Ca2+ currents Inhibits release of glutamate & aspartate

Absence Partial Generalised seizures

162

Sedation Impaired cognition Addiction risk Enzyme induction Low therapeutic index Sleepiness Impaired psychomotor function Amnesia Dependence Gastric upset (Nausea, vomiting) Allergic reactions (Rash, StevensJohnson syndrome, SLE) Hepatic enzyme inhibition

Same as carbamazepine but probably less frequently.

Essentials of Medical Pharmacology

Vigabatrin

Inhibits GABA transaminase (irreversibly)

Majid A. K. Lafi

Partial seizures

Sedation Weight gain Confusion, agitation & psychoses

A SUMMARY OF THE DRUGS USED IN MOVEMENT DISORDERS

Hypokinetic Movement Disorders disease. • Idiopathic Parkinson s Primary agents: carbidopa/ levodopa; bromocriptine; pergolide. Secondary agents: benzhexol; benztropine; amantadine; selegiline Hyperkinetic Movement Disorders • Tics e.g. Tourette s syndrome, which begins in childhood and is associated with vocalization, abnormal gestures, and frequently with obsessive-compulsive personality. Neuroleptic drugs e.g. haloperidol can be useful. • Myclonus (e.g. Salaam attack, infantile myclonus seizure). Benzodiazepines (clonazepam); carbidopa/5-HTP (for anoxic myclonus); baclofen (a GABA-B agonist); tetracosactrin • Essential tremor (or known as adrenergic or intentional tremor, or familial tremor). Propranolol; primidone; clonidine may be considered (advise to decrease intake of tea, coffee and smoking) • Parkinsonian tremor (rest tremor) Anticholinergics (e.g. benzhexol) • Dystonia (disordered tonicity of muscle, acute sustained contraction of muscle) may begin and remain focal, affecting only one area of the body, but can also begin focally and evolve in generalised dystonia. Two very common forms of focal dystonias involve forced eyelid closure (blepharospasm) or twisting of the neck to one side (torticolis), frequently in combination with pulling of the neck backwards (retrocollis). Trismus (clinching of teeth, lockjaw) and opisthatonus (contraction of the muscle of the back) may also be encountered. A high dose of anticholinergic drugs (e.g. benzhexol, diphenhydramine) is useful. Generalised dystonia patients surprisingly

tolerate high doses of anticholinergics with substantial improvement. If anticholinergics are not available a benzodiazepine may do. • Dyskinesia-Chorea: Dyskinesias generally refer to choreic drug side effects, whereas choreas occur in the course of natural disease. The common dyskinesia is that arising in the natural history of Parkinson s disease treated with levodopa. This dopa-dyskinesia can also be seen with direct dopamine agonist. No satisfactory treatment is available at present. • Tardive Dyskinesia: Tardive dyskinesia is a choreic movement disorder arising late in the course of neuroleptic treatment. This dyskinesia is suggested to be due to hypersensitivity (upregulation) of dopamine receptor, particularly of the substantia nigra leading to reduced GABAergic activity in the corpus striatum resulting in choreic movement. No effective specific treatment is available, however, stop giving the antipsychotics may be useful, otherwise reserpine can be used in the disabling cases; the less severe cases may respond paradoxically to carbidopa/levodopa or to clonidine treatment. • Huntington s chorea: Chorea occurs in the course of Huntington s disease, an autosomal dominantly inherited neurodegenerative disorder. The marked loss of GABA neurone in the brains of Huntington s disease patients suggests similarities to tardive dyskinesia. Neuroleptic drugs or reserpine may help.

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OPIOIDS AND NARCOTIC ANALGESIC DRUGS

The actions of opioids can be explained by action on specific opioid receptors in the CNS (Table 5. 17), thalamus, limbic system, hypothalamus, substantia gelatinosa of the spinal cord, nucleus tractus etc. The receptor type most responsible for analgesic properties has been designated the (mu) µ-receptor. The opioid receptors respond to natural morphinelike substances, which are peptides and act as neuromodulators. These are called enkephalins and endorphins. Endogenous analgesics like enkephalins can be detected in the CSF after certain pain-relieving procedures such as acupuncture, placebo medication and transcutaneous electrical stimulation. The endorphins are long-chain polypeptides, which also exhibit opiate activity; the best known is ¾-endorphin that is mainly found in the hypothalamus and the pituitary gland. Opioid peptides seem to be involved in many physiological functions including regulation of temperature, behaviour, gastrointestinal motility, appetite, thirst etc.

Introduction Opium is the dried latex (milky fluid) obtained from the unripe capsules of opium poppy, papaver somniferum. Opium contains 25 different alkaloids; the most important of which are morphine (15%), codeine (2%) and papaverine (1%). Papaverine is distinct from opium, it is not an analgesic and it is a potent relaxant of smooth muscle whereas the opioids induce smooth muscle contraction. Opium was initially used for its antitussive actions that were recognised. The semisynthetic opiate heroin (diacetylmorphine) was produced in 1844 with the hope of curing morphine addicts, but it was soon appreciated that it was not a cure, but on the contrary a more potent narcotic. The search for agents with analgesic qualities of morphine but without the side effects of dependence and tolerance continued and resulted in methadone and pethidine (mepiridine), which however have little advantage.

Opioids relieve pain by raising the pain threshold at the spinal cord level, and also by altering the brain s perception of pain. With morphine, the patient is still aware of the presence of pain, but the sensation is not unpleasant. It is believed that morphine acts at µ-receptors in the substantia gelatinosa of the spinal cord, decreasing the release of substance P (and probably other excitatory transmitters from terminals carrying nociceptive stimuli) which modulates pain perception in the spinal cord.

Mechanism of Action Although much remains to be learned about the neurotransmitters involved in both the afferent nociceptive pathways (primary afferent nerve fibres) and descending antinociceptive pathways, prime candidates for the afferent pathways include peptidergic neurotransmitters (e.g. substance P, somatostatin, vasoactive intestinal polypeptide, cholecystokinin, and calcitonin gene-related peptides). The descending antinociceptive pathways appear to inhibit or modulate the process of pain transmission through the afferent (spinal) nociceptive pathways. This process of modulating transmission of pain is the essential part of the gate theory of pain. Several neurotransmitters have been suggested to be involved in pain modulation, e.g. noradrenaline and serotonin, as well as endogenous opioid peptides.

Classification of Narcotic Analgesics Opiates can be classified into three groups: 1. Pure agonists: dextropropoxyphene, codeine, pethidine (meperidine), methadone, morphine, heroin, fentanyl 2. Mixed agonists/antagonists & partial agonist: pentazocine, nalorphine 3. Antagonists: naloxone, naltrexone

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Table 5.17. A summary of responses to stimulation of the three major types of opioid receptors. Receptor Types Kappa (µ) Spinal analgesia Dysphoria/sedation Respiratory depression Miosis

Mu (³) Sigma (-) Spinal and supraspinal Dysphoria analgesia Psychotomimetic reactions* Respiratory depression Respiratory stimulation Euphoria/sedation Mydriasis Physical dependence Decreased GI motility Miosis * e.g. anxiety, strange thoughts, nightmares, hallucinations Table 5.18. Drug actions at opioid receptors Agents Pure opioid agonists: morphine, codeine etc. Mixed acting opioids: pentazocine Partial agonists nalorphine Pure opioid antagonist: naloxone, naltrexone

Mu (³) Agonist

Antagonist Weak agonist Antagonist

Agonist

Agonist

-

-

Antagonist

Antagonist

8. Respiratory depression (reduced sensitivity to CO2) 9. Miosis 10. Decreased release of LH and FSH 11. Increased release of prolactin and ADH

Principle Pharmacological Effects Desirable effects 1. 2. 3. 4. 5. 6.

Receptor Types Kappa (µ) Sigma (-) Agonist No action

Effective analgesia Sedation Sleep Euphoria Depression of Cough Relief of anxiety

Tolerance and Dependence Tolerance is characterised by decreased intensity and shortened duration of all the usual pharmacological effects of morphine. It may occur in individuals who have become socially habituated to the drug, or in patients who require continuous therapy for chronic pain (like in cancer). The pharmacokinetic parameters of morphine do not alter with its repeated use. A negative feedback system resulting in decreased production of endogenous opioid peptides may be implicated (pharmacodynamic tolerance, Fig.5.10). Different opioids exhibit crosstolerance.

Undesirable effects 1. Tolerance and dependence 2. Bronchoconstriction (due to histamine release) 3. Nausea and vomiting 4. Dysphoria 5. Depression of cough reflex 6. Spasmogenic effects (GI spasm, sphincter of Oddi spasm) 7. Constipation

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Upon repeated dosage, cellular adaptation to the exogenously applied morphine occurs; i.e. neurotransmission (particularly the postsynaptic opioid activity that is responsible for modulating various essential biological activities) becomes dependent on the exogenous morphine. A sudden withdrawal (abstinence) of the exogenous morphine cannot be immediately compensated for, consequently results in disturbance in the regulation of these biological activities such as cardiovascular functions.

Reversal of Narcotic Effects Naloxone is the pure antagonist and the drug of choice for the treatment of narcotic overdose, or for reversing the depressant effects of narcotic agents on the neonates. The normal dose may be repeated once or twice at frequent intervals if respiratory function does not improve or relapse. It would appear that all the pharmacological actions of the narcotic agents are reversed by naloxone. If naloxone is administered to a person who has been abusing opioids, he will develop a withdrawal syndrome, but nothing happens if given to a normal person.

Withdrawal (Abstinence) Syndrome

Indications for morphine

The development of dependence to morphine can be demonstrated when the drug is suddenly withdrawn after repeated dosage. Various physical and physiological phenomena may develop, the severity of which are related to the total amount administered. Symptoms and signs include restlessness and irritability, frequent yawning, excessive sweating, gooseling of skin (piloerection), hyperpnoe, dilated pupils, tachycardia, lachrymartion and salivation, painful muscle cramps and intense and uncontrolled vomiting, diarrhoea and urination. Mild symptoms have been reported after only 48 hours therapy. Although withdrawal from opioids is unpleasant, the syndrome is rarely dangerous; on the contrary, withdrawal from other CNS depressants (e.g. alcohol, barbiturates) can be lethal.

1. Severe pain euphoria in the dying 2. Myocardial infarction (MI) or dyspnoea in acute left ventricular failure and pulmonary oedema (see later notes) 3. Premedication for surgery

Contraindications 1. Chronic obstructive lung disease 2. Liver failure 3. Raised intracranial pressure (including head injury)

Morphine and the Cardiovascular System Morphine exerts the following actions on the cardiovascular system.

Treatment of Withdrawal Syndrome

1. Decreases sympathetic vascular reflexes resulting in veno-arteriolar dilatation 2. Stimulates vagal centre leading to decreased heart rate 3. Releases histamine resulting in vasodilatation 4. Tranquillising action, thus decreasing mental distress 5. Decreases central sensitivity to afferent stimuli from the congested lung leading to decreased respiratory distress

The following drugs are essential in the treatment of the withdrawal syndrome. 1. Methadone addictive) 2. Diazepam 3. Clonidine

(oral,

long

acting,

less

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THEREFORE, MORPHINE IS USEFUL IN DYSPNOEA DUE TO ACUTE LEFT VENTRICULAR FAILURE AND PULMONARY OEDEMA

Exogenous opioids

Pethidine versus Morphine 1. Pethidine is not useful in suppressing cough 2. Pethidine does not constipate; however, like morphine, it produces spasm of the sphincter of Oddi. 3. Pethidine is widely used in obstetrics because it does not delay labour like morphine that produces this effect centrally by reducing co-operation rather than by an action on the uterus. However, pethidine enters the foetus and can depress respiration at birth; therefore, the availability of naloxone can be essential as an antidote. 4. Pethidine is less likely to cause urinary retention which has at least partly for morphine due to the central sedation causing the patient to ignore afferent messages from a full bladder. 5. Unlike morphine, pethidine has little hypnotic effect. 6. Pethidine has shorter duration (2-3 hr) of analgesia. 7. Because of unfavourable cardiovascular effects (a transient rise in systemic arterial pressure, systemic vascular resistance and heart rate) pethidine could not be recommended for the relief of pain in myocardial infarction patients. Unlike morphine, pethidine is not considered as a venolytic agent. 8. Pethidine has considerable antimuscarinic effects that may be a problem if tachycardia would be a problem. This antimuscarinic activity is responsible for its mydriatic action (while morphine produces miosis).

167

-ve opioid Presynaptic nerve

opioid

¿2

Postsynaptic nerve

-ve

Fig. 5.10. A simplified diagrammatic representation of the effect of exogenously administered opioids (e.g. morphine) on post and presynaptic opioid receptors. Opioid-like substances are endogenously released from peptideergic nerves; therefore, when giving the first dose of an exogenous opioid the observed response would appear to be due to the exogenous opioid. This response is super-added to the basal endogenous opioid activity. As the exogenous opioid causes negative feedback effect on the release of the endogenous opioid; thus, upon subsequent administration of the opioid the effect of a particular (first) dose will be reduced (i.e. pharmacodynamic tolerance develops, a larger dose is required to produce the same effect). In this condition biological adaptation (dependence on exogenous substance) is said to have taken place. Upon withdrawal (abstinence) of the exogenous opioid, the postsynaptic opioid activity (which is responsible for modulating various essential biological activities such as regulation of cardiovascular functions) is reduced. This cannot be immediately compensated by the reduced availability of the endogenous opioid.

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Table 5.19. A summary of the pharmacology of selected narcotic analgesics and their antagonists. Narcotic agent

t (hr) 2

Duration of analgesia (hr) 3-6

Codeine (methylmorphine)

3

4

Pethidine (meperidine)

5

2-3

Methadone

8

24

Dextropropoxyphene

5

4-6

Tramadol

6

Fentanyl

3

Morphine

Activates mu (µ) & kappa (κ) receptors; it produces analgesia, euphoria, miosis, sedation. Respiratory depression, orthostatic hypotension, cough, suppression, constipation, biliary colic, urinary retention, emesis & elevation of intracranial pressure; USES: moderate-to-severe pain, MI or dyspnoea associated with acute left ventricular failure and pulmonary oedema, & premedication for surgery. Useful in mild-to-moderate pain (codeine 30 mg is equianalgesic to 325 mg of aspirin or paracetamol), used in combination with nonopioid analgesics (e.g. aspirin) to produce greater analgesic action; & as cough suppressant (10 mg); Adverse-effects: sedation and constipation. Used primarily for its analgesic effect, preferred for obstetrical analgesia; it is less likely to cause smooth muscle spasm than morphine, thus, less constipation & urinary retention. Not preferred in MI or dyspnoea associated with acute left ventricular failure and pulmonary oedema. Synthetic, good absorption from GIT, long duration of action, used to cover opioid withdrawal & for chronic pain in palliative care. Rapidly absorbed from GIT, used for its analgesic action (similar to codeine), structurally similar to methadone Synthetic, rapidly absorbed from GIT, as effective as pethidine for postoperative pain and as morphine for moderate chronic pain, less likely to constipate, depress respiration and addict. Eighty times more potent than morphine; & more efficacious, used in surgery.

0.5-1

Increases cardiac work and oxygen demand, thus, not suitable in MI; less respiratory depression than morphine; because of sigma (-) receptor (psychotomimetic) effects, it has a low potential for abuse. It can precipitate an abstinence syndrome in a patient physically dependent on a pure opioid agonist.

Mixed agonist/antagonist Pentazocine

Principal features

5

Used to reverse depression.

Nalorphine (Partial agonist) Opioid antagonists

Naloxone

1.25

1-2

Naltrexone

4

1-3 days

narcotic

induced

respiratory

Blocks opioid actions; precipitates an immediate withdrawal reaction in a patient dependent on opioids; Useful in: 1. Opioid overdose 2. Reversal of postoperative opioid depression 3. Reversal of neonatal respiratory depression Similar to naloxone; but can be given orally; useful in former opioid addicts to prevent relapse (prevents opioid-induced euphoria, long duration of action).

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When combining amphetamines with morphine-like agents lead to increased analgesia, and decreased sedation. When combining antiemetics with morphine-like agents lead to suppression of nausea and vomiting. When combining CNS depressants, phenothiazines, and antidepressants with morphine-like agents leads to increased respiratory depression.

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GENERAL ANAESTHETIC DRUGS Introduction

Diaphragmatic paralysis can be induced by muscle relaxants (e.g. tubocurarine), however, an overdose with inhalational anaesthetics may produce this effect in stage IV.

Objectives: analgesia, amnesia-hypnosis (unconsciousness), muscle relaxation (loss of reflexes), and physiological homeostasis. General anaesthesia is said to be achieved when the above four objectives are met, and during which there is loss of sensation and consciousness (the subject is not rousable by external stimuli). This can be obtained by inhalation of a volatile anaesthetic agent(s) or intravenous administration of a drug or a combination of them. The order of depression in the CNS is:

Inhalational Anaesthetics Inhalation of anaesthetic drug produces a depth of anaesthesia that depends on the partial pressure of the anaesthetic agent, which will be dependent on: 1. Partial pressure of anaesthetic agent (concentration) in the inspired air 2. Solubility of anaesthetic agent in blood 3. Pulmonary ventilation (The rate of rise of anaesthetic gas tension in arterial blood is directly dependent on both the rate and depth of respiration) 4. Cardiac output (An increase in cardiac output leads to an increase in pulmonary blood flow; thus, blood capacity increases and tension rises slowly. Therefore in circulatory shock, decreased pulmonary blood flow and increased ventilation may speed up the induction of anaesthesia with some anaesthetics particularly those with high blood solubility.

Cortical centres r basal ganglia r spinal cord r medulla According to Guedel (1920) the degree of nervous depression can be divided into four different stages, as may be observed with ether, equivalent to the cumulative effect on the above-mentioned CNS-centres. Stage I: Analgesia, and amnesia from start of induction to loss of consciousness. Stage II: Excitation (delirium or confusion, but definitely the patient is amnesic), from loss of consciousness to reestablishment of regular respiration.

An anaesthetic drug with high blood solubility, such as ether and methoxyflurane, may require a long time for induction, since the blood, which acts as a reservoir, can dissolve a large amount of gas. Halothane, which has a lower solubility in blood, will equilibrate rapidly and the partial pressure of this gas in blood therefore rises quickly. Further, nitrous oxide (N2O), which has a much lower solubility will achieve a quicker induction. Nitrous oxide is the commonly used inhalational anaesthetic that is a gas at ambient temperatures and pressure. All of the other inhalational anaesthetics are liquids at room temperature and pressure, require vapourisation before use.

Stage III: Surgical anaesthesia, from the beginning of regular respiration to respiratory arrest. This stage is divided into four planes, which have been described in terms of changes in ocular movements, eye reflexes, and pupil size; these under specified conditions may represent signs of increasing depth of anaesthesia. In practice, the most important indications that surgical anaesthesia has been achieved are loss of eyelash reflex and establishment of a respiratory pattern that is regular in rate and depth.

Minimum alveolar anaesthetic concentration (MAC) is defined as that concentration of anaesthetic agent in alveolar or end-expired gas that is present when 50%

Stage IV: Overdosage (stage of medullary depression or paralysis) from onset of diaphragmatic paralysis to cardiac arrest. 170

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of the subjects do not respond when exposed to the skin incision (MAC=1.0, equivalent to effective dose in 50% of patients). The value of MAC is reduced in the elderly. In general, however, the dose-response relationship for

inhaled anaesthetics is steep. Over 95% of patients may exhibit a state of anaesthesia at 1.1 MAC.

Inspired r Face mask r Alveoli r Pulmonary r Arterial Gas upper airways PAa membrane blood PAi PAfm PApm PAab

Metabolised

CNS bbr Other bbbrs tissue tissue PAcns PAt

Fig.5.11 A schematic representation of pathways for uptake, distribution, and elimination of inhalational anaesthetic agents. PA = partial pressure of agent A; other subscripts refer to anatomical regions. Note elimination of the anaesthetic agents is usually achieved by the reverse of uptake of the agent (reverse arrows to expired air are not shown).

Table 5.20. Shows the values of MAC and PC in tissues of selected general anaesthetic agents. Note: nitrous oxide is poor anaesthetic compared with other inhalational agents.

Anaesthetic Agent Nitrous oxide

MAC*

Blood/Gas PC

Brain/Gas

Metabolism

PC

101.0

0.47

0.5

None

Desflurane

6-7

0.42

1.3

<0.05%

Enflurane

1.7

1.9

3.2

8%

Isoflurane

1.3

1.4

4.7

<2%

Halothane

0.75

2.3

8.2

>40%

Methoxyflurane

0.16

10.2

31.0

>70% (fluoride)

Important remarks Rapid onset & recovery; incomplete anaesthetic Low volatility; poor induction; rapid recovery Medium rate of onset & recovery Medium rate of onset & recovery Medium rate of onset & recovery Slow onset & recovery Nephrotoxic

* Expressed as partial pressure of agent (in alveolar space) divided by standard total atmospheric pressure (×100) that produces immobility in 50% of patients exposed to a noxious stimuli; PC = partition coefficient (reflecting solubility of agent in tissue).

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cellular threshold for firing. This in turn results in a decrease in neuronal activity1.

Note: An inhalational anaesthetic agent with low solubility in blood shows fast induction time and also recovery time (e.g. nitrous oxide), and an agent with relatively high solubility in blood shows slower induction and recovery time (e.g. halothane).

Ether Ether (diethyl ether) as an anaesthetic agent was first clinically demonstrated by William Morton (Massachusetts General Hospital, Boston, 1846).

The elimination of anaesthetic gases occurs mainly by the lungs and therefore the depth of the anaesthesia is easily controlled by assisted breathing (anaesthetic machine).

Ether is a volatile liquid with an unpleasant odour. It is highly flammable and explosive, therefore, cautery should not be used in operation; for this property it is now obsolete. Otherwise, it is a safe drug because it stimulates respiration and there is a wide margin between the dose to induce surgical anaesthesia and that to cause medullary paralysis.

Elimination of the anaesthetic is also dependent on the amount of drug bound to fat tissue in the body. The biological t of most anaesthetics is about 1 hour but total elimination of metabolites may require several days.

Ether anaesthesia is associated with release of endogenous catecholamines. It therefore induces bronchial dilatation and therefore can be used in patients with severe asthma. It produces good muscle relaxation, but induction is unpleasant, and nausea and vomiting may occur frequently upon emergence.

Second Gas Effect The MAC of an inhalational anaesthetic can be reduced by a concurrent use of another inhalational agent; thus, a concurrent use of nitrous oxide with halothane would reduce the MAC for halothane and also the presence of the latter would reduce the MAC for nitrous oxide. It has been suggested that the presence of agent (gas) facilitates the uptake (transport into the pulmonary blood) of the other agent. Therefore, it is called the second gas effect. This effect is utilised for using reduced inspired partial pressure for certain agents, particularly, nitrous oxide which has a high MAC (>100%) which is practically difficult to achieve. Further, a reduction in MAC can also be achieved by the use of adjuvant drugs like narcotic analgesics or sedative-hypnotics.

Ethyl Chloride is a liquid like ether and divinyl ether. It has a boiling point below normal room temperature and can be used both for induction and refrigeration anaesthesia when sprayed from a bottle onto the skin. Like divinyl ether, it is hepatotoxic.

Nitrous Oxide Nitrous oxide (N2O) is the oldest anaesthetic compound known. Horace Wells (Massachusetts General Hospital, Boston, 1845) was the first to describe the importance of its anaesthetic property in clinical practice. Today, it is the most commonly used inhalation anaesthetic agent despite its weak anaesthetic properties: even at its maximum safe concentration of 75% it still requires some supplementation to produce adequate surgical anaesthesia and skeletal muscle relaxation. Nitrous oxide is an inert gas,

Mechanism of Action Anaesthetic agents appear to concentrate in hydrophobic regions of cell membranes, causing the membrane to swell and altering the crystalline structure of the membrane. It has been suggested that most general anaesthetic agents have a common neurophysiological action that increasing the

1

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 7th edition, Page 415. 172

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which is compressed to a liquid, and stored in steel cylinders, coloured blue for identification. Nitrous oxide returns to the gaseous state when released from the cylinder. The gas is colourless and tasteless but has a faintly sweet odour. Nitrous oxide is sometimes called laughing gas. It induces euphoria and a dreamy state but its effect is mostly one of analgesia. Nitrous oxide does not depress respiration and in the absence of hypoxia there is no effect on the heart.

Methoxyflurane Methoxyflurane is the most potent inhalation anaesthetic with very good skeletal muscle relaxing properties. Its disadvantage is prolonged induction and emergence. Otherwise its properties are similar to halothane.

Intravenous Anaesthetics

Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anaemia. This is of a particular importance for staff working in poorly ventilated dental operating rooms.

Barbiturates Barbiturates are used mainly for induction of anaesthesia since the ultra-short acting barbiturates act rapidly without fear of an unpleasant mask and smell of inhalational anaesthetic agents. In sufficient amounts, these drugs can accomplish all the anaesthetic stages but they may cause serious cardiovascular suppression, therefore they are mainly used in combination with inhalational agents such as nitrous oxide and oxygen. Cerebral metabolism, O2 consumption are reduced with barbiturates in proportion to the cerebral suppression and also cerebral blood flow (CBF).

Halothane Halothane (1956), a fluorinated nonflammable hydrocarbon, is a clear, colourless, potent, volatile liquid, which gives smooth induction and comfortable recovery. Anaesthesia can be induced with concentration of 4-5% halothane in oxygen (as a loading dose analogous to that with digoxin priming). For maintenance a concentration of halothane should be reduced. For convenience a hypnotic dose of an i.v. anaesthetic is often used prior to halothane administration. Muscle relaxation is not always sufficient with halothane and can be supplemented by muscle relaxant drugs such as suxamethonium. The neuromuscular blocking actions of dtubocurarine are potentiated and is therefore advisable to use a reduced dose of this component.

Thiopental sodium Thiopental is the most commonly used intravenous anaesthetic in Iraq, usually in combination with inhaled general anaesthetics. The pharmacology of barbiturates is discussed in the sections on sedatives and hypnotics, and antiepiletic drugs. It is worth noting thiopental is useful in abreaction2. Degradation takes place mainly in the liver. For distribution and redistribution of thiopental see (Fig.5.12).

Cautions 1. Postpartum haemorrhage: Halothane causes relaxation of smooth muscle including the uterine muscle, which may give rise to postpartum haemorrhage. 2. Myocardial depressant properties and may induce bradycardia. 3. Respiratory depressant, as indicated by the reduced response to various levels of carbon dioxide. 4. Liver toxicity (halothane) has been observed especially after repeated administration. 173

Adverse Effects 1. Cardiac and respiratory depression 2. Bronchospasm

2

The reliving of an experience in such a way that previously repressed emotions associated with it are released.

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Propofol Methohexital Propofol as intravenous anaesthetic is very much similar to thiopental. However, it produces anaesthesia with a more rapid recovery than that obtained with thiopental. Further, in the immediate postoperative period after propofol patients feel better as compared with other intravenous anaesthetics. Perhaps, the major advantage of propofol is that it has a useful antiemetic action. This probably is responsible for the observation that postoperative vomiting is uncommon with propofol.

It is another ultra-short acting barbiturate with similar pharmacological properties but differs chemically from thiopental in that it contains no sulphur.

Ketamine Ketamine is a phencyclidine (hallucinogen) derivative and an antagonist of the NMDAreceptor. It (is a mirror image of thiopental) produces cardiovascular stimulation and increases cerebral blood flow. It is known to produce dissociative anaesthesia (the patient seems awake but dissociated from the environment, responds to verbal commands but does not respond to painful stimuli). Emergence reaction characterised by hallucination is a frequent encounter with ketamine, diazepam is used to conteract this effect.

Etomidate Etomidate is a potent hypnotic (5 minutes) used for induction of anaesthesia. Its major advantages over other agents that it causes minimal cardiovascular and respiratory depressant effects. This drug has no analgesic actions; therefore, premedication with opioid may be required. It is known as an inhibitor of steroidogenesis.

Dose % 100-

Blood

Preanaesthetic Medication

Muscle

The objectives of the drugs that may be required as adjunct to the anaesthetic agents are:

Brain

50 -

1. Allay anxiety (e.g. diazepam) 2. Reduction of secretion (e.g. oropharyngeal surgery, atropine) 3. Reduction of parasympathetic preponderance ( children tend to show parasympathetic hyperresponsiveness, thus, antimuscarinic may be used in paediatric surgery) 4. Relax muscles (muscle relaxants) 5. Rapid induction of anaesthesia (shortacting barbiturate) 6. Prevent postsurgical nausea and vomiting (antiemetics)

Fat

1.0 -

0.1

0.5

1

4

16

64

256

Time (min) Fig.5.12. Redistribution of thiopental after intravenous bolus administration (the time axis is not linear). Note: The ultra-short acting thiopental rapidly crosses the blood brain barrier because of high lipid solubility (1 min.). Then, they diffuse out of the brain to other highly vascular (highly perfused tissues like skeletal muscle) and subsequently to poorly perfused adipose tissue. It is because of this rapid removal from the CNS that a single dose is so short acting. Metabolism is much slower than redistributed.

Other Agents 1. Midazolam (slow onset and recovery; flumazenil reversal available; used in balanced anaesthesia and conscious

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sedation; cardiovascular stability; marked amnesia. 2. Fentanyl (slow onset and recovery; naloxone reversal available; used in balanced anaesthesia and conscious sedation; marked analgesia).

Neuroleptanaesthesia When a neuroleptic drug (like droperidol) and a narcotic analgesic drug (like fentanyl that is 80 times more potent that morphine, shorter onset and duration of action), are administered together to produce a

physiological state with somnolence (sleepiness), indifference, analgesia, amnesia, and patients are responsive to commands. This state is called neuroleptanalgesia that is useful for several diagnostic or minor surgical procedures like bronchoscopy, painful dressing, cystoscopy etc. Neuroleptanalgesia can be converted to neuroleptanaesthesia by the concurrent administration of 65% nitrous oxide in oxygen.

Table 5.21. A summary of the pharmacology of selected general anaesthetic agents Effect on CVS Resp.

Adverse Effects and Important Remarks

INDUCTION (i.v.)

Thiopental

Ketamine

YES

YES

NO

YES

YES

NO

↓

↑

↓

Contraindicated in porphyria

NO

Increases cerebral blood flow. Contraindicated in open eye surgery, neurosurgery (brain), preeclampsia (hypertension); hypertensive, hallucinogenic, emergence delirium

MAINTENANCE (inhalational)

Halothane

YES

YES*

YES*

↓

↓

Nitrous oxide

YES*

YES

NO

Variable

Variable

* Not adequate

175

Dysrhythmogenic (sensitises heart), hepatotoxicity (avoid repeated administration in short period, 90 days), malignant hyperthermia; postpartum haemorage, Myocardial depressant properties (bradycardia), Respiratory depression Megaloblastic anaemia (prolonged exposure →↓ methionine synthase activity)

CNS-Pharmacology - Local Anaesthetics

Ramadi, 10 October 2009

LOCAL ANAESTHETIC DRUGS Introduction

Lidocaine

The first local anaesthetic agent was cocaine (obtained from the leaves of the South American shrub E. Coca) that was introduced into clinical practice by Koller in 1884 as an ophthalmic anaesthetic. Cocaine has powerful central stimulating side effects and induces dependence. The central stimulant effect is manifested in restlessness and excitement and eventually convulsions. This effect is shared by other nitrogen containing local anaesthetics. The central action of cocaine is also related to the ability to potentiate noradrenaline, this action is not shared by other local anaesthetics. When applied to the cornea cocaine anaesthetises the surface and induces mydriasis (enlargement of the pupil). Because of its adverse effects cocaine is not used in clinical medicine.

Lignocaine (lidocaine) is most common type of local anaesthetic agents in clinical practice and it is effective in all five forms of local anaesthesia: 1. Surface (e.g. lignocaine; proparacaine, Alcaine eye drops (0.5%); cinchocaine, Nupercainal ointment (1%), Proctosedyl ointment (0.5%). 2. Infiltration (e.g. lignocaine 0.25-0.5% with adrenaline) 3. Nerve block ( lignocaine 1-2% with adrenaline, e.g. pudendal nerve block as for episiotomy1) 4. Epidural (peridural) nerve block (lignocaine 1-2% with adrenaline) requires high skills. 5. Spinal nerve block (lignocaine) with the following disadvantages: a.headache due to CSF leakage b.hypotension due to block of the sympathetic nervous system c.potential of introducing bacteria

Procaine is the first synthetic local anaesthetic was introduced in 1905 and remained the dominant local anaesthetic for the next 50 years. Procaine is an example of a local anaesthetic with an ester-bond and therefore rapidly broken down by plasma cholinesterase. Procaine still had a considerable potential for producing adverse effects like local irritation and tissue damage in addition to systemic toxicity. At present, it is only used as an amide (procainamide) for cardiac arrhythmias and in procaine penicillin (that should not be given intravenously) for slow release of penicillin.

Mechanism of Action It is believed that the mechanism of action of local anaesthetics is primarily effected by blockade of voltage-gated sodium channels. These agents block sodium channels in a voltage- and time-dependent manner. Local anaesthetics exert their effect on excitable nerve axons and neuronal cell bodies (like the membrane of cardiac muscle) mostly when these cells with high firing activity and thus at more positive membrane potential. It is noted earlier (page 150) that local anaesthetics have a much higher affinity for the activated and inactivated states (usedependence) than the rested state of sodium channels. It follows that the effect of a given concentration of a local anaesthetic is more

The continued effort to find a better local anaesthetic agent lead to the synthesis of lignocaine (1943) by L fgren. To date, lignocaine (lidocaine, xylocaine) is still considered the prototype local anaesthetic agent. Although the development of new local anaesthetic agents continues but none showed significant reduction in toxicity as compared with that of the current agents. This is probably because the most serious toxicity of local anaesthetic agents is produced by the therapeutic effect on the brain and the cardiovascular system.

1

Episiotomy: surgical incision into the perineum and vagina for obstetrical purposes.

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marked in rapidly firing axons than in resting neurones2.

The onset of local anaesthesia is sometimes accelerated by the use of solutions saturated with carbon dioxide. The high tissue level of CO2 results in intracellular acidosis (CO2 crosses membrane readily), which results in intracellular accumulation (trapping) of cationic form of the local anaesthetic. It must be noted that the cationic (ionised) form is thought to be the most active form at the local anaesthetic receptor site located within the voltage-dependent sodium channel; this is probably because the cationic form cannot readily leave the closed channels. Further, this local anaesthetic receptor is not accessible from the external side of the cell membrane. Unlike, the cationic drug form, the uncharged form can rapidly penetrate biological membranes.

Adverse Effects 1. Seizures and convulsions (use diazepam) 2. Cardiovascular depression

Combination with Vasoconstrictors Vasoconstrictor substances such as adrenaline reduces systemic absorption of local anaesthetics resulting in enhanced neuronal uptake of the drug and reduced systemic toxic effects of the drug. Such combination should not be given for the digits. Nowadays, the vasoconstrictor agent preferred to be used is a vasopressin receptor agonist like felypressin; vasopressin is supposed to be safer in patients with coronary artery disease.

Table 5.22. A summary of the pharmacology of selected local anaesthetic agents for infiltration anaesthesia. Time course of action

Agent

Tachyphylaxis

Procaine* Tetracaine*

Repeated injection of local anaesthetics during spinal and epidural anaesthesias (and for infiltration in tissue where there is pus) results in rapid loss of effectiveness (tachyphylaxis). This is probably a consequence of local extracellular acidosis. Local anaesthetics are weak bases and marketed as hydrochloride salts (pH 4 to 6) for reasons of solubility and stability. After injection, the salts are buffered in the tissue to physiological pH, thereby providing sufficient free base for diffusion through axonal membranes. However, repeated injections deplete the local available buffer. The ensuing acidosis increases the extracellular cationic form, which diffuses poorly into axons. The clinical result is apparent tachyphylaxis, especially in areas of limited buffer reserve, such as the cerebrospinal fluid. Therefore, an agent with a long duration of action like bupivacaine is preferred in this condition to avoid repeating the dose.

Lidocaine

Onset (min) 2-5 15 <2 5 1-15

Duration (hr) 0.25-1 2-3 0.5-1 2-4 2-6

Potency

1 4 16 -

Bupivacaine Ropivacaine *Ester type local anesthetics are metabolized to paminobenzoic acid derivatives that are responsible for allergic reactions in a small percentage of the population.

• Local anaesthetics have higher affinity for neurones with high rate of firing (use-dependence effect). • Local anaesthetics have to penetrate the neurone (thus, uncharged form is required) and from the inside of the cell bind to the receptor site (thus, cationic form is required). • Cationic form cannot readily leave closed sodium channels, thus, it is the most active form at the local anaesthetic receptor.

2

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 7th edition, page 428. 177

CNS Pharmacology - Neuromuscular Blocking Drugs

Ramadi, 10 October 2009

NEUROMUSCULAR BLOCKING DRUGS sites that normally combine with acetylcholine. This drug-receptor interaction does not produce any change in membrane permeability, so that depolarisation and muscle contraction are prevented. Flaccid paralysis of all skeletal muscles can be produced by the intravenous administration of large doses of a neuromuscular blocking agent, such as tubocurarine However, not all skeletal musculature is equally sensitive to the action of these drugs. The muscles that produce fine movements (e.g., the extraocular muscles, fingers, and muscles of the head, face, and neck) are most sensitive to these drugs. Muscles of the trunk, abdomen, and extremities are relaxed next, and the respiratory muscles (i.e., the intercostals and the diaphragm) are the most resistant to the action of tubocurarine.

Introduction Neuromuscular blocking agents act at nicotinic receptors of the muscle endplate. There are two types: 1. Competitive (non-depolarising) blockers (e.g. tubocurarine) 2. Depolarising agents (e.g. suxamethonium) Skeletal muscle relaxation may be achieved by other mechanism as well. Centrally acting agents, such as diazepam, produce relaxation primarily by actions within the central nervous system. Dantrolene, in contrast, acts within the muscle fibre to interfere with excitation-contraction coupling. It appears that two molecules of acetylcholine (ACh) are required for the ion channel to open, one acting on each of the α-subunits. Binding of a nondepolarising antagonist to either of these subunits therefore prevents influx of sodium ions.

Normal function is restored when the blocker is eliminated or a large quantity of acetylcholine can displace the drug from it binding sites. Therefore, administration of an acetylcholinesterase blocker, such as physostigmine (which crosses the BBB and used in glaucoma) and neostigmine (which does not cross the BBB and used in myasthenia gravis), can restore muscle contraction.

Unlike curare, suxamethonium (also known as succinylcholine) mimics ACh in stimulating the nicotinic receptor and produces paralysis similar to that produced (cholinergic crisis) by an excess of ACh.

Other non-depolarising drugs are gallamine, pancuronium, alcuronium and atracurium. Atracurium is noteworthy because it is metabolised by plasma esterases (hepatic enzymes) and spontaneous degradation, thus suitable in renal impairmenand does not depend on the major route of elimination by the kidneys, which applies to tubocurarine and the others. For a summary of the pharmacology of the important neuromuscular blocking agents see Table 5.21.

Competitive Neuromuscular Blockers Curare is the name applied to various rude extracts obtained from strychnos plants and which have been used by South American Indians as an arrow poison, paralysing wild animals used for food. Since curare reached the western world in containers such as bamboo tubes, the pure chemical substance has been called tubocurarine. Tubocurarine is a quaternary ammonium compound, i.e. a big molecule that is not absorbed from the GI tract and does not pass the blood brain barrier (BBB). The mechanism of action is to produce competitive blockade by occupying receptor 178

Adverse Remarks

Effects

and

Important

1. Release histamine from mast cells; this can give rise to cutaneous flushing, hypotension and bronchospasm.

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Majid A. K. Lafi

2. Aminoglycoside antibiotics like gentamicin and streptomycin and the general anaesthetic halothane increase neuromuscular block.

When this drug is injected intravenously, it produces a considerable muscular fasciculation for several seconds before paralysis. Many patients will later experience muscle soreness. The muscles remain paralysed for about five minutes and resume their function in another 5 minutes.

Depolarising Neuromuscular Blockers Suxamethonium consists of two acetylcholine molecules joined together.

H3C

O O CH3 \ || || / Cl-.H3C-N+CH2CH2OCCH2CH2COCH2CH2N+-CH2.Cl\ H3C CH3 Suxamethonium (Succinylcholine) The action of suxamethonium is inhibited by prior administration of a non-depolarising blocker such as tubocurarine. When suxamethonium is used to facilitate endotracheal intubation, a sufficient interval should be allowed for it to wear off before a non-depolarising blocker is given; this is to make sure that there is no complication with suxamethonium.

Suxamethonium is known to produce a dual block; its action pharmacologically characterised by two phases: Phase I. A sustained depolarisation, which is not reversed by cholinesterase inhibitors. Phase II. This phase is sub-divided into: 1. Although repolarisation occurs, the membrane cannot be depolarised again (i.e. there is desensitisation) 2. Later, the blockade can be reversed by acetylcholinesterase inhibitors (e.g. edrophonium)

Neostigmine is not an antidote to suxamethonium during depolarisation; rather, it tends to enhance early paralysis. The depth and phase of blockade can be assessed by peripheral nerve stimulation. Edrophonium, a short acting acetylcholinesterase inhibitor, can be used to determine the phase of blockade. If the paralysis (blockade) in phase IIb, as described above, then edrophonium would reverse paralysis; otherwise, it would fail to do so.

Suxamethonium (t for effect is of about 10 minutes) is rapidly hydrolysed by plasma pseudocholinesterase (hepatic enzyme) to choline and succinylmonocholine. The latter is then hydrolysed to succinic acid and choline. The t of suxamethonium is increased by neostigmine, which inhibits the enzyme, and in patients with hepatic disease or severe malnutrition whose plasma enzyme levels may be lower than normal. The patients with quantitative or qualitative differences in plasma cholinesterase, because of a genetic abnormality (about 1 in 2500 of the population), suxamethonium can produce apnoea for hours (scoline apnoea). Malignant hyperthermia may occur as an adverse effect to suxamethonium. There is no antidote for suxamethonium.

Suxamethonium can also contribute to certain other problems. In the absence of atropine, stimulation of ganglionic receptors may elicit bradycardia. Life threatening hyperkalaemia1 caused by the release of potassium from muscle as a result of suxamethonium-induced depolarisation, which may produce cardiac 1

Usually K+ is found in high concentration intracellularly, during depolarisation the intracellular K+ is less than that during resting state; in addition, in extensive trauma, intracellular K+ is released raising the extracellular K+ resulting in hyperkalaemia. 179

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Ramadi, 10 October 2009

status epilepticus, tetanus and convulsant drug poisoning. 5. Diagnosis of myasthenia gravis: a small dose of tubocurarine can induce paralysis in myasthenic subjects but not in nonmyasthenic subjects.

arrest particularly in patients who already have raised plasma potassium after extensive trauma (burns, spinal cord transection, crush injury). The development of malignant hyperthermia, a fulminant and often fatal disorder characterised by myoglobinuria and a rapid increase in temperature, is enhanced when suxamethonium is used with potent inhalational anaesthetics. Avoid in liver disease and burnt patient.

Other Muscle Relaxants Some drugs may relax muscle by acting on spinal neurones to depress polysynaptic pathways. Such relaxants also act on higher centres, such as the benzodiazepines, which are used to relieve anxiety or to induce sleep.

Non-depolarising agents (like tubocurarine) are not suitable to be used to facilitate intubation because if the anaesthetist fails to introduce the tube then it is difficult to reverse the effect of the non-depolarising agent (tubocurarine), as the duration of action is much longer than suxamethonium. Therefore, both the short onset and duration of action are advantageous with suxamethonium.

Baclofen mimics GABA at the so-called GABA-B receptors. Baclofen is useful in treating spasticity associated with multiple sclerosis and in conditions related to spinal cord injury. Dantrolene acts on skeletal muscle beyond the neuromuscular junction. It reduces the availability of calcium ions for muscle contraction. The drug has become the agent of choice for reducing heat production by muscle in anaesthetic induced malignant hyperthermia.

Suxamethonium can in low doses achieve muscle relaxation (not for endotracheal intubation) with minimal effect on the diaphragm; the patient is kept on spontaneous respiration.

Therapeutic Uses of Neuromuscular Blocking Agents 1. Muscle relaxation during surgery is produced by agents such as tubocurarine, resulting in reduced inhalational anaesthetic required to achieve anaesthesia. 2. Facilitation of mechanical ventilation (by tubocurarine) is used to reduce resistance to mechanical ventilation by suppressing spontaneous respiratory movements, which can fight against the rhythm of the respirator. 3. Endotracheal intubation can be facilitated by suxamethonium through suppressing gag reflexes. 4. In convulsion: suxamethonium (adjunct to electroconvulsive therapy, ECT) is used to prevent injury due to the violence of the fit. Also useful in similar conditions like

180

Orphenadrine is promoted for the relief of acute muscle spasm caused by local trauma or strain.

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Majid A. K. Lafi

Table 5.23. A summary of the pharmacology of muscle relaxants Action (min) Onset Duration

Adverse Effects & Important Remarks

Non-depolarising Agents* d-Tubocurarine

3-5

30-60

Release histamine, causes ganglion blockade; causes transient hypotension, erythematous rash & rarely bronchospasm.

Gallamine

2-5

15-30

Causes tachycardia due to atropine-like effect (vagal block) on the heart. It does not release histamine. It crosses the placenta.

0.75

<60

Causes minimal releases of histamine, minimal effect on blood pressure; suitable for intubation.

Pancuronium

Alcuronium

(curare-like)

Atracurium

1.0

15-35

Metabolised by plasma esterases (hepatic enzymes) and spontaneous degradation, thus suitable in renal impairment; it causes release of histamine.

Depolarising Agents Suxamethonium

0.5

4-6

Causes bradycardia. Pre-treatment with atropine is essential. Avoid in liver disease and burnt patient.

* Non-depolarising agents, except atracurium, should be reduced or avoided (e.g. gallamine) when GFR < 20.

Recurarisation? To be given in the discussion

Scoline apnoea? To be given in the discussion

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Autacoids

Ramadi, 10 October 2009

AUTACOIDS Histamine is released from the tissue mast cells and basophils by an energy-dependent mechanism, in response to immunological and non-immunological stimuli (trauma, toxins). Other constituents of the intracellular storage granules are released with histamine. These include heparin, eosinophil and neutrophil chemotactic factors, neutral proteases, and other enzymes. In addition to newly synthesised mediators like prostaglandins D2 , leukotrienes C4 and D4, and platelet activating factor are also released. This leads to a vasodilatation and a fall in blood pressure (shock), itching, redness, oedema and bronchoconstriction. If generalised the release of histamine causes anaphylactic shock.

Histamine Histamine is a tissue (histos) amine the first of its kind to be detected and synthesised in 1906. It is found in mast cells and basophils in the stomach and CNS. Histamine is formed by decarboxylation of the amino acid Lhistidine, a reaction is catalysed by histadine decarboxylase. It is broken down by deamination in the presence of diamine oxidase or by methylation of the imidazole ring in the presence of histamine-Nmethyltransferase. Histamine breakdown products make up 97% and unchanged histamine 3% in the urine. Various foods contain histamine, and some intestinal bacteria can form it, but histamine from these sources is rapidly metabolised and is not stored in tissues.

Certain chemical compounds can release histamine. An intracutaneous morphine injection in man produces localised erythema and oedema. Curare alkaloids cause a similar response and histamine is believed to cause episodes of bronchial constriction that accompanied intravenous injections of curare.

In addition to the metabolic products, some histamine is excreted as N-acetylhistamine. Acetylation occurs in bacteria in the intestine, and the acetylated product reflects metabolism of ingested histamine or histamine formed within the gut. It has been estimated that in a normal person 2 to 3 mg of histamine is released daily from tissues. Allergic or chemically induced release of histamine from mast cells or basophils greatly increases urinary excretion of histamine.

Allergy and Anaphylaxis Histamine is a major mediator of acute allergic reactions in humans. Release of histamine from mast cells in the skin and mucosa can cause cutaneous and laryngeal oedema, bronchoconstriction and hypotension.

Histamine release

The two major factors involved in the circulatory effects of histamine are arteriolar dilatation and increased capillary permeability. These factors act in concert to promote loss of plasma from the circulation and development of tissue oedema.

Histamine is stored in mast cells in tissues and basophils in blood. Some organs, the socalled shock organs contain large numbers of mast cells and lethal quantities of histamine. The organs are mainly the skin, the gastrointestinal tract (GIT) and the lung. In the stomach histamine is present in nonmast cells stores. Histamine is also associated with neural elements. The neural pool (CNS neurotransmitter) differs from mast cell histamine in having a more rapid turnover rate and resistance to agents that release histamine from mast cells.

Injection of a low concentration of histamine intracutaneously in humans produces the triple response of Lewis : localised erythema at the injection site, localised oedema (or weal), and diffuse erythema (or flare) at some distance from the injection site. The flare involves neural mechanism known as axon reflex mediated through sensorimotor nerves (C-fibres) which release 182

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Majid A.K. Lafi

tachykinins like substance P, neurokinin A, and calcitonin gene related peptide (CGRP). These phenomena are inhibited by antihistaminic drugs of the H1-receptor class. In some sensitive persons, only scratching of the skin gives rise to a triple response.

The concentration of histamine is particularly high in the acid-secreting part of the stomach. Histamine is believed to be localised in enterochromaffin-like (ECL) cells in the lamina propria. Its release is stimulated by the vagus nerve (via M1-receptors located on ECL cells) and hormonally by the polypeptide gastrin. Histamine stimulates gastric secretion through H2-receptors on parietal cells. Gastrin, an extremely potent stimulant of gastric acid secretion, is also inhibited by H2-antagonists. A similar finding for cholinergic stimulation of gastric secretion indicates that histamine may be final common mediator of secretion. The effects of acetylcholine and histamine can be abolished by orally applied antagonists that reach parietal cells via the blood.

Gastric secretion Histamine is a potent stimulant of gastric acid secretion and pepsin secretion. A subcutaneous injection of a very low dose will increase gastric secretion without causing other effects. This response is used as a test for complete achlorhydria.

Table 6.1. A summary of selected actions of histamine System/ tissue Cardiovascular Vascular Arterioles Precapillary sphincters Heart Respiratory Bronchiolar smooth muscle Exocrine Stomach Gall bladder smooth muscle Intestinal smooth muscle Cutaneous nerve ending CNS Adrenal medulla Basophils Mast cells Eosinophils Neutrophils

Receptor H1, H2 H1, H2

Response Decrease systemic blood pressure Decrease in total peripheral resistance

H2

Relaxation; activation of H2 receptors (in vascular smooth muscle) causes dilatation that develops more slowly and is more sustained. Relaxation & permeability; H1 receptors have a higher affinity for histamine and mediate an endothelium NO dependent dilatation that is relatively rapid in onset and short-lived. Increased heart rate

H1

Asthma, decreased lung capacity Contraction

H1 H2 H1

Increased nasal & bronchial mucus secretion Acid and pepsin secretion Contraction

H1

Cramps and diarrhoea (contraction)

H1

Pain and itching

H1

H1 H1 H2*

Arousal, emesis Adrenaline secretion Inhibition of IgE-dependent degranulation, and thus inhibition of histamine release H4 Activation of H4 receptors on eosinophils induces a cellular shape change, chemotaxis, and upregulation of adhesion molecules such as CD11b/CD18 and ICAM-1 suggesting that the histamine released from mast cells acts at H4 receptors to recruit eosinophils. Skin H1 Induce weal and flare reaction (reddening due to dilatation & increased permeability of the capillaries, & axon reflex) Presynaptic H3 Inhibition of the release of histamine and other transmitters; H3 antagonists promote wakefulness; conversely, H3 agonists promote sleep. * In humans, this negative feed-back mechanism is shown in mast cells in skin and basophils while in lung is not. It appears that histamine may modulate the intensity of the allergic reaction in the skin and blood. 183

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Ramadi, 28 May 2005

and blood pressure was lowered. One of the substances was more soluble in ether and was, therefore, referred to as PGE, the other more soluble in phosphate (fosfate in Swedish) buffer and was therefore, called PGF. It is now recognised that PG s constitute one group of a larger family of endogenous compounds known as eicosanoids (eicosa, containing 20 carbon atoms), which form a diverse group of oxygenated unsaturated C-20 fatty acids. Most eicosanoids are synthesised from arachidonic acid, which is a major component of mammalian membrane phospholipids.

Antihistamines There is a long list of H1-receptor antagonists, however, there is no evidence that on antihistamine is superior to another. They may differ in the duration of action and incidence of sedative and anticholinergic effects. Further, patients may vary widely in their response to individual agents. Antihistamines find a wide use for the symptomatic relief of rhinorrhoea and sneezing and itching of the nose, ear and eye associated with hay fever; they are not so effective in relieving nasal congestion. They are also useful in other conditions like prevention of urticaria and treatment of allergic skin reactions, insect bites and druginduced allergies.

Synthesis The first step in prostaglandin synthesis is the release of arachidonic acid by phospholipases within the cell membrane. Various stimuli, including bradykinin, immunoglobulins, microbial products, thrombin, lectins, and physical trauma (mechanical distortion of the membrane) can activate tissue phospholipases by a process that is dependent on calcium from extracellular and intracellular stores. The availability of arachidonic acid is limited by two opposing reactions 1) its liberation from and 2) its reacylation back into membrane phospholipids.

Because of their sedative effects, antihistamines may induce drowsiness and, therefore, they may impair driving performance and the ability to handle machinery. Further, this sedative effect may be potentiated by alcohol and other CNS depressants. Antihistamines may induce adverse effects that are characteristic of anticholinergic action like dry mouth, blurred vision, constipation, tachycardia, urinary retention, and may precipitate glaucoma in susceptible patients. Recently, a number of H1-receptor antagonist with little or no sedative effects have been introduced.

Prostaglandins are 20-carbon carboxylic acids containing a five-membered ring. They also have one, two, or three double bonds in the side chains. Biological activity requires a carboxyl group at carbon position 1 (C-1), a double bond at C-13 and a β-hydroxyl at C15. The number of double bonds is indicated by the subscript for example, PGE1, PGE2.

H2-receptor antagonists have also been developed and found a place in clinical use for over three decades. This has been largely in the treatment of peptic ulcer, e.g. cimetidine and ranitidine.

Inhibition of Synthesis

Prostaglandins and Related Autacoids

Both glucocorticoids and non-steroidal antiinflammatory drugs (NSAIDs) block prostaglandin synthesis. The non-steroidal compounds inhibit cyclooxygenase, the enzyme that converts the precursor arachidonic acid to the endoperoxides PGG2 and PGH2. The steroids including the naturally occurring hydrocortisone and synthetic analogues increase intracellularly the expression of lipocortin 1 which inhibits the activity of phospholipase A2 enzyme

Introduction Prostaglandins (PG) were extracted from semen by ULF von Euler in 1930. He found that when components from this fluid were injected into animals, the uterus contracted 184

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Majid A.K. Lafi

resulting in reduced release of arachidonic acid from membrane phospholipids.

Table 6.2. A summary of selected clinically important antihistamines.

Antihistamine

Actions & Indications

Adverse effects & Other remarks

H1-antagonist (Sedative) Antazoline HCl (Antistine ) Chlorpheniramine maleate (Histadine ) Clemastine (Tavegyl ) Cyproheptadine (Periactin ) Dexchlorpheniramine maleate (Polaramine ) Dimethinendene maleate (Fenistil ) Diphenhydramine HCl (Allermine ) Promethazine (Phenergan ) Triprolidine HCl (Actidil )

All block H1-receptors Variably block 5-HT receptors, α-receptors & muscarinic receptors.

Drowsiness Impair psychomotor function Antimuscarinic effects (dry mouth, blurred vision, constipation, tachycardia, urinary retention, precipitating glaucoma)

H1-antagonist (Non or less sedative) Acrivastin

2 hr

Cetirizine Loratidine

7 hr 15 hr

Allergic rhinitis Hay fever Urticaria Conjunctivitis Anaphylactic shock Motion sickness For sedation (especially in children)

5 days

in

They lack antimuscarinic activity.

t Rapid onset duration

&

Fexofenadine

Astemizole

Individual variation response to the agents

Slow onset & duration of action

short

Stimulates appetite (weight gain) Lower risk of arrhythmia (unlike its parent compound terfenadine) long Unsuitable for treatment of acute allergic symptoms; for maintenance in allergic

rhinitis and chronic urticaria H2-antagonists Cimetidine, Ranitidine, Famotidine & Nizatidine

influence second messenger system through modification of guanylate cyclase eventually through mobilisation of Ca2+ from intracellular stores. It is also evident that eicosanoid-dependent mechanisms act within the neurone of origin and externally at nerve endings to modulate autonomic transmission. Thus, it appears that eicosanoids have intracellular actions in addition to the effects that achieved at the cell membrane.

Mechanism of Action Prostaglandins are not stored (with the exception of the seminal fluid. They are synthesised in response to diverse membrane stimuli and then enter the extracellular space and act locally. The newly formed prostaglandins affect target tissues through specific membrane receptors and appear to involve second messengers. Eicosanoids may

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Prostaglandins affect the cell of origin and neighbouring cells by binding to specific membrane receptors linked via G proteins to adenylate cyclases, guanylate cyclases, and lipases.

Biological Responses Vasodilatation induced by PGE2 and PGI2 helps maintain renal perfusion in clinical states of decreased cardiac output. Another important function of prostaglandins is on the prenatal circulation. The maintenance of a patent ductus arteriosus by the continued production of PGI2 is necessary for the fettle circulation. Cyclooxygenase inhibitors are sometimes used to used to promote closure when the ductus remains patent after birth. PGI2 relaxes whereas PGF2α contracts smooth muscle. PGI2 is produced by endothelial cells, while TXA2 in platelets.

Breakdown The most important step in the breakdown of prostaglandins is initiated by the rapid inactivation through oxidation of the 15-OH prostaglandin dehydrogenase, an enzyme widely distributed in the body. The greatest activity of this enzyme is in the lung, kidney, and liver. The strategic location of this enzyme in the lung prevents the persistence of prostaglandins in the systemic circulation. PGE2 and TXA2 are rapidly converted nonenzymatically to the inactive products 6-keto PGF1 and TXB2 respectively, which are further oxidised by prostaglandin dehydrogenase.

Prostaglandins are believed to have a protective role in the stomach. PGE2 and PGI2 inhibit stimulation of gastric acid and pepsin secretion. Aspirin, other cyclooxygenase inhibitors and glucocorticoids are contraindicated in peptic ulcer disease because inhibition of prostaglandin synthesis leads to enhanced acid and pepsin secretion. On the other hand, stable prostaglandin analogues, e.g. misoprostol, are currently used in acid-peptic disease (given concurrently with nonsteroidal anti-inflammatory drugs in susceptible patients).

HO 1 COOH

5

PGF2¿

15 HO

OH

17

O

In the reproductive system, prostaglandinrelated mechanisms are involved in implantation. Prostaglandins also participate in the regulation of cyclic events in the ovary and uterus. Prostaglandin-dependent mechanisms are involved in luteinizing hormone (LH) release, ovulation, and termination of corpus luteum function (luteolysis). The importance of prostaglandins to the normal birth process as in the initiation of parturition is well recognised. An additional physiological role has been suggested for uterine prostaglandins in endometrial changes that lead to menstruation.

COOH

PGE2 HO

OH

HO COOH

PGD2 O

OH

Fig.6.1. The chemical structures of selected primary prostaglandins, prostaglandin F2α (PGF2α), prostaglandin E2 (PGE2), and prostaglandin D2 (PGD2).

Dysmenorrhoea has been shown to be related to a high menstrual release of prostaglandins, a finding that led to the use of aspirin-like drugs in its treatment. Prostaglandins and their analogues have been used to induce labour and to terminate

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pregnancy from the second trimester. To avoid gastrointestinal side-effects induced by oral or intravenous administration, therefore, local vaginal or intra-amniotic administration is preferred (PGE2 and PGF2α).

Leukotrienes Leukotrienes C4 (LTC 4) and D4 (LTD4) are active components of the slow-reacting substances of anaphylaxis (SRS-A). These mediators are formed primarily by mast cells, monocytes and eosinophils. They are recognised for their prominent bronchoconstrictive effect, which is probably involved in asthma. In addition, LTC4 and LTD4 contract gastrointestinal and vascular smooth muscle and are approximately 100 times more potent than histamine in increasing permeability within the microcirculation and may contribute to development of oedema in inflammation.

Aspirin and other NSAIDs can arrest premature labour, but they are contraindicated since prostaglandin inhibition may give rise to premature closure of the ductus arteriosus and hence pulmonary hypertension.

Phospholipid Phospholipase A2 Blocked by glucocorticoids Arachidonic acid

Cytochrom P450

Cyclooxygenases* COX1,COX2 Prostaglandin G/H synthase

Blocked by aspirin

5-lipooxygenase Blocked by zileuton

Epoxide

leukotrienes [Endoperoxidase]]

Blocked by montelukast

Intermediate Prostaglandins (PGG2 & PGH2)

Prostacyclin synthase

Thromboxane synthase

Prostacyclin (PGI2)

Leukotriene receptors

Thromboxane A2 (TXA2) PGE2

PGF2

PGD2

* Note: cyclooxygenase is termed prostaglandin G/H synthase which is present in at least two forms 1) cyclooxygenase-1 (COX-1) which is constitutive (noninducible) and present in many tissues including platelets, stomach and kidney; and cyclooxygenase-2 (COX-2) which is induced by cytokines and endotoxins at sites of inflammation, e.g. joints. Aspirin appears to block nonselectively both COX-1 and COX-2, whereas rofecoxib is claimed to be a relatively selective COX-2 antagonist.

Fig.6.2. Pathways of synthesis of major eicosanoids of pharmacological interests.

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Table 6.3. A simplified list of effects of eicosanoids (prostanoids, prostacyclin, and thromboxane) including a selected list of therapeutically useful prostaglandins.

Effect Pain-promotion

Parturition Primary dysmenorrhoea pyrexia Protection (Cytogastric) Pressure

Prostaglandin 9P plus Eicosanoid Nature of action Lowers threshold of response to stimuli, e.g. PGE2, PGI2 histamine, serotonin, bradykinin, & mechanical PGE2, PGF2¿ Contraction of pregnant uterus → painful menstruation PGF2¿ PGE2 PGI2 PGE2, PGF2¿ PGE2, PGI2

Patency Pulmonary

TXA2 , PGF2¿ PGI2 TXA2 PGE2* PGE2,PGI2

Inflammation

PGD2, PGF2¿, TXA2 PGE2, PGI2

Platelets

LTC4 GIT motility Ureteral activity Reproductive system

PGE2, PGF2¿ PGF2¿ PGE2, PGI2 PGE2 PGF2¿

↑ the temperature set-point in the hypothalamus ↓ acid secretion ↑ mucus secretion & viscosity (in both the stomach and intestine) Renal vascular dilatation, ↑ GFR, natriuresis, & diuresis Renal vasoconstriction ↓ aggregation ↑ aggregation Maintaining the ductus arteriosus patent Bronchodilatation, vasodilatation Bronchconstriction Promote oedema & leukocyte infiltration ↑ vascular permeability & leukocyte infiltration (asthma) ↑ motility ↑ ureteral activity (including pacemaker activity in renal pelvis, ureteral colic) Relaxation of nonpregnant uterus Contraction of pregnant uterus Contraction of pregnant or nonpregnant uterus, lysis of corpus luteum

Prostaglandin analogues

Indications & important remarks

Dinoprost, dinoprostone, carboprost, misoprostol

Directly contracts the uterine smooth muscle inducing labour from the 12th week through the 2nd trimester of pregnancy. Useful in patients with gastric ulcer who have to take aspirin or glucocorticoids. Useful in erectile impotence (injected into the corpus cavernosum of the penis)

Misoprostol Alprostadil

* PGE2 is useful in maintaining the ductus patent This can be desirable in certain newborns with congenital heart defects (anomalies). For example, the great arteries are transpositioned in a way that the left ventricle pumping into the pulmonary artery while the right ventricle pumping into the aorta. This leads to two unlinked circulations. Thus, keeping the ductus open helps mixing the two circulations resulting in some oxygenated blood will circulate for a few hours until surgical intervention made possible. 188

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Clinically, cyproheptadine is useful in the treatment of the smooth muscle manifestations of carcinoid tumour. It is also useful for increasing appetite, probably, through an action on the CNS.

Serotonin (5-Hydroxytryptamine) Serotonin (5-Hydroxytryptamine, 5-HT), like histamine, is widely distributed in nature, in plant and animal tissues. Biologically, it is synthesised from the amino acid tryptophan by hydroxylation of the indole ring followed by the decarboxylation of the amino acid. The free 5-HT is then either stored or undergo inactivation. The latter is largely achieved by monoamine oxidase (which also inactivates other amines like catecholamines). In humans, over 90% of 5-HT in the body is found in enterochromaffin cells in the gastrointestinal tract. 5-HT is also found in blood platelets that are equipped with active carrier mechanism to concentrate the amine.

Ketanserine blocks both 5-HT2-receptor, and α1-receptor. Its clinical use is limited to the treatment of hypertension, and vasospastic conditions. Ondansetron (5-HT3-receptor antagonist) useful in the prevention of nausea and vomiting associated with cancer chemotherapy.

In the CNS, 5-HT serves as a neurotransmitter in tryptominergic (serotonergic) neurones that synthesise, store, release, re-uptake and inactivate 5HT. Of the major locations in the brain, serotonergic neurones are found in the raphe nuclei of the brain stem, where it is believed to play an important role in the biology of sleep. Serotonergic neurones are also implicated in temperature regulation, perception of pain, and regulation of blood pressure. Recent evidence suggests the involvement of 5-HT in conditions like depression, anxiety, and migraine. Peripherally, serotonergic neurones are found in the enteric nervous system of the gastrointestinal tract and around blood vessels.

5-HT receptor agonists Sumatriptan is a new 5-HT analogue and found to be a 5-HT1d agonist. It is useful in the treatment of acute migraine and cluster headache attacks.

5-HT receptor antagonists Cyproheptadine (Periactin) has both 5-HT receptor and H1-receptor antagonistic activity. In addition, it has substantial antimuscarinic effects and causes sedation. 189

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Table 6.4. A selected list of the actions of Tissue /organ Cardiovascular system Vessels (generally, except) Skeletal muscle & heart Heart Chemosensitive nerve endings* (located in coronary vessels) Gastrointestinal tract Smooth muscle

Action Vasoconstriction Vasodilatation Reflex bradycardia mediated by vagal outflow to the heart (& consequently hypotension ↑ tone and peristalsis (severe diarrhoea may occur in carcinoid tumour)

Respiratory tract Bronchiolar smooth muscle

Bronchoconstriction (may be evident in carcinoid tumour)

Nervous system Pain & itch sensory nerve endings CNS**

5-HT in some organs in the body.

Potent stimulant (as in insect & plant stings) Sleep, temperature regulation, perception of pain , blood pressure regulation, affect state, migraine, appetite

* Activation of 5-HT3 receptors on these afferent vagal nerve endings is associated with the chemoreceptor reflex. Several agents can activate the chemoreceptor reflex, nicotinic cholinoceptor agonists and digoxin. ** For more details see the chapter on CNS pharmacology. Peripherally, 5-HT is pain stimulant (promoter), while, centrally it is involved with perception of pain.

Table 6.5. A summary of the pharmacology of selected 5-HT receptor agonists and antagonists used therapeutically.

Agent Sumatriptan Cyproheptadine Ketanserine Ondansetron Tropisetron

Indications and remarks Acute migraine, 5-HT 1d receptor agonist Carcinoid tumour (smooth muscle manifestation), for increasing appetite, 5-HT receptor antagonist Hypertention, 5-HT2 & α-receptor antagonist Nausea & vomiting (cancer chemotherapy), 5-HT 3- receptor antagonist

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NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Introduction

Pyrexia

Several drugs from diverse structural classes share analgesic, antipyretic, antiinflammatory and spasmolytic activity. Collectively they have been termed nonsteroidal anti-inflammatory drugs (NSAIDs) compared to Glucocorticoids. The mechanism for their actions is their ability to inhibit the enzyme cyclooxygenase and thereby decrease the conversion of arachidonic acid to prostaglandins, thromboxane A2 or prostacyclin.

In contrast to analgesia, the site of antipyretic action of NSAIDs is central in the hypothalamus. In fever the temperatureregulating system maintains temperature at a higher level (the temperature set point is raised, upward setting) than normal. The stimulus for the set shift to a higher level is due to the action of an endogenous pyrogen, interleukin 1, on neurones of the thermoregulatory system in the hypothalamus where it releases prostaglandin E2. Aspirin does not affect the release of interleukin 1, rather it reduces the effect of the pyrogen. Therapeutic doses of aspirin affect neither normal body temperature nor elevated temperatures (hyperthermias), associated with exercise, drugs, or hypothalamic lesions, to which pyrogen does not contribute. Although the role of fever in combating infection is not clearly understood, antipyretic agents are best utilised only when body temperature is dangerously high.

Therapeutic Uses Pain Prostaglandins sensitise nociceptors (pain receptors) which can be stimulated by various substances, such as bradykinin, histamine, serotonin, thromboxanes, and leukotrienes and mechanical or thermal stimuli. The signals are transmitted to the spinal cord by either small (1-5 µm) myelinated afferent nerve fibres (A-delta) or unmyelinated Cfibres (0.5-1 µm). These primary afferent fibres synapse in the dorsal horn of the spinal cord. All the NSAIDs, including, aspirin, inhibit the enzyme cyclooxygenase which is responsible for converting arachidonic acid to prostaglandins resulting in reduced sensitisation of nociceptors. Hence, unlike the action of narcotic analgesics (e.g. morphine) which act centrally, the predominant analgesic action of NSAIDs is peripheral. NSAIDs are most effective in alleviating pain of mild to moderate intensity, though they may be more effective than narcotic analgesics in alleviating pain associated with prostaglandin-stimulated smooth muscle motility, as in primary dysmenorrhoea, and diarrhoea associated with irritable bowel syndrome and ureteral colic.

Inflammation Prostaglandins are important mediators of inflammation (by promoting oedema and leukocyte infiltration). Thus, a reduction of prostaglandins at sites of inflammation should be beneficial. In rheumatic fever administration of large daily doses of aspirin lowers fever and relieves joint symptoms. In arthritic diseases NSAIDs reduce inflammation, swelling, although they are not usually considered to alter the progression of the disease. Although all NSAIDs appear to have the same mechanism of action, differences between them are largely due to differing concentrations in different tissues, and different rate of absorption and elimination from the body. There is some evidence of substantial differences in their effects in patients. This may be explained in the light of the findings that various NSAIDs possess other actions that are related to inflammation, 191

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e.g. inhibition of lipoxygenases (LOX, diclofenac, indomethacin), superoxide production and leukocyte migration. Recently, a good body of evidence suggests that the inflammatory prostanoids are the products of the activity of COX-2 (cyclooxygenase-2) and therefore a number of allegedly relatively selective COX-2 inhibitors have been introduced to the market (e.g. meloxicam). These are supposed to be effective as anti-inflammatory agents with substantially reduced adverse effects (that are largely result from inhibiting the biologically beneficial COX-1). At present, therefore, no particular NSAID is preferred but selection might depend on factors such as the patient s age, renal function and previous experiences (familiarity) with particular NSAIDs.

oxidative enzymes, to accumulate. Other drugs that induce these enzymes, e.g. anticonvulsants and alcohol, enhance metabolism to toxic metabolite in overdosage. The metabolite (NABQI) oxidises thiol (SH-) groups of important enzymes, causing cell death. Therefore, hepatic and renal tubular necrosis may occur in paracetamol overdosage. Paracetamol has few adverse effects in normal dosage, but may occasionally cause gastrointestinal upsets. It causes hepatotoxicity in overdosage, particularly in patients who have their hepatic oxidative enzymes induced by other agents. Usage of 4 g or more of paracetamol per day for 12 months has been associated with chronic liver disease.

These drugs are usually effective in the treatment of arthritic patients (rheumatoid arthritis, lupus erythmatosus, osteoarthritis, ankylosing spondylitis, and gout). However, some patients will require treatment with more toxic drugs such as methotrexate and other immunsuppressive drugs, antimalarial drugs (e.g. chloroquine and hydroxychloroquine), gold salts, penicillamine and sulphasalazine, or glucocorticoids (see later section on diseasemodifying drugs).

Therefore, in overdosage the level of the products of phase I metabolism can be too high to be handled by the machinery of phase II metabolism resulting in accumulation of toxic level of metabolites. This may also occur in normal doses if drugs like phenytoin and barbiturates induce the hepatic oxidative enzyme. Therefore, alcoholics are more prone to develop hepatic toxicity when taken paracetamol. Paracetamol Minor

Paracetamol (Acetaminophen)

Phase I Oxidative enzyme

Paracetamol has analgesic and antipyretic properties, and because it has little antiinflammatory activity in arthritis. Some authorities would not list paracetamol with the NSAIDs but as a separate agent .

Major Glucuronide Sulphate

Toxic products (NABQI) Phase II Glutathione

Paracetamol inhibits prostaglandin synthesis in the brain but hardly at all in the periphery, therefore, it does not affect platelet function.

Conjugated products (Pharmacologically inactive)

It is well absorbed, and almost entirely metabolised by the liver with an excretion t of about 4 hours. In normal doses, it is mainly metabolised by conjugation with glutathione, glucuronide and sulphate, but these pathways are saturated at higher doses, and allow a toxic metabolite (N-acetyl-benzoquinone, NABQI), which is formed by the hepatic

Fig. 7.1. A schematic representation of the metabolic inactivation of paracetamol. Note: Paracetamol is largely converted to paracetamol glucuronide and sulphate. Upon depletion of glutathione the toxic products (NABQI) will accumulate. This makes paracetamol with a high potential of toxicity at a time it is one of the most commonly used drugs. 192

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after birth. Although surgical closure is an established therapy, cyclooxygenase inhibitors can also be effective. Indomethacin promotes closure of the patent ductus arteriosus and alleviates the associated symptoms of cardiac failure in the neonates.

Paracetamol poisoning N-acetylcysteine (20% solution) is given intravenously (infusion). Therapy is most effective if given within 8 hours of the overdose. Glutathione itself poorly penetrates cells but N-acetylcysteine (i.v.) and methionine (orally) are effective precursors for the synthesis of glutathione.

Adverse-effects All NSAIDs have antiplatelet effects, resulting in increased bleeding time. Therefore, care should be taken with their use in the immediate peri-operative period and also in patients who are, or who are likely to become, thrombocytopenic.

Aspirin and Other NSAIDs Aspirin (acetylsalicylic acid) is a derivative of salicylic acid (which can be produced from the glycoside salicin from the bark of the willow tree (Salix), and was introduced into medicine in 1899. Since that time it has become one of the most cheapest and most easily available and widely used drugs in the world. Aspirin is the prototype agent of NSAIDs. It is well absorbed from both the stomach and upper intestine. Absorption from the stomach is favoured by the presence of the salicylate (pKa = 3.5) predominantly in the unionised form, whilst the large absorbing surface of the small intestine will facilitate uptake and is probably more important.

They also all cause dyspepsia or, on occasions, upper gastrointestinal bleeding as an adverse effect. Chronic use of NSAIDs in therapeutic doses very rarely produces renal damage (analgesic nephropathy). The incidence of adverse effects increases with increasing dosage but there is little evidence that any of the NSAIDs, in equal antiinflammatory doses to aspirin, produces less major gastrointestinal bleeding episodes than aspirin. However, there is some claim that among the NSAIDs, ibuprofen has the least gastric effect particularly in the elderly. Enteric coated preparation of aspirin (or suppository preparation of indomethacin) is used successfully to reduce its gastric effects, but some of the gastric effects are systemic rather than local.

Aspirin is rapidly distributed throughout the body and readily crosses most cellular barrier. The drug undergoes extensive biotransformation. Aspirin undergoes hydrolysis resulting in removal of the acetyl group, the remaining salicylate ion is inactivated mainly by conjugation with glycine. At low doses, the latter reaction follows first-order kinetics with a t of about 4 hours but at higher doses and overdose the reaction follows zero-order kinetics. Thus, in aspirin overdose the offending substance is salicylate. The kidney eliminates the unchanged drug and its metabolites (salicylic acid) and their excretion is facilitated when the urine is alkaline.

They can displace oral anticoagulants, sulphonylureas, hydantoins, and sulphonamides from binding sites of plasma proteins leading to drug-drug interaction.

Salicylism A serious adverse effect of aspirin when given in high doses is salicylism: tinnitus, decrease hearing, vertigo and confusion. Aspirin is a common cause of severe rhinitis, urticaria, angioedema, asthma or shock.

Low dose aspirin (300 mg/day) is recommended as prophylactic therapy in coronary artery disease based on its antiplatelet action; some schools recommend much lower dose than that stated above. The ductus arteriosus normally constricts during the first day of life, resulting in functional closure. In some neonates, it remains paten

Reye s syndrome In children under the age of 12 the use aspirin has been implicated in some cases Reye s syndrome (a serious disorder encephalopathy, liver damage); therefore,

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children recovering from febrile viral infection (respiratory, varicella) paracetamol should be preferred in this condition.

It is worth noting that indomethacin is the most toxic member of NSAIDs. It exerts powerful anti-inflammatory activity, but it is a less efficient analgesic for pain of nonspecific origin. Its long-term use should be restricted to the management of rheumatoid arthritis, ankylosing spondylitis and recently has gained popularity as a spasmolytic agent in ureteral colic. Indomethacin therapy may lead to headache and psychosis.

Overdosage Overdosage of aspirin may result initially in respiratory alkalosis (directly by increasing stimulation of respiratory centre and indirectly by increasing production of CO2). This alkalosis may be compensated by renal loss of bicarbonate (with Na+, K+, and H2O) which may result in dehydration and hypokalaemia. However, metabolic acidosis may ensue as a result from the following:

Disease conditions like renal and cardiovascular disorders lead to decreased renal blood flow, and liver cirrhosis, nephrosis, heart failure and diuretics lead to decreased blood volume. Thus, such conditions increase vasoconstrictors like angiotensin II, catecholamines and vasopressin The effect (vasoconstriction) of these agents on renal blood flow is normally antagonised intrarenally by local synthesis of vasodilator prostaglandins. When NSAIDs are administered in such conditions the inhibition of intrarenal prostaglandin synthesis let go the actions of the vasoconstrictors unopposed.

a. accumulation of lactic acid and pyruvic acid resulting from interference with Kreb s cycle enzymes b. stimulation of lipid metabolism resulting in ketone bodies c. late toxic respiratory depression causing CO2 retention. In children under 4 years, metabolic acidosis may develop without respiratory alkalosis.

Table 7.1. Adverse effects of NSAIDs (related to inhibition of prostaglandin synthesis) System Gastrointestinal

Effects Erosive gastritis (peptic ulceration)

Remarks Inhibition of PGE2, which suppresses gastric acid secretion, helps maintain mucosal barrier and regulate microcirculation. Antiplatelet Prolonged bleeding time, Inhibition of synthesis of thromboxane A2 gastrointestinal blood loss by platelets Renal Fluid retention, diminished Inhibition of synthesis of renal sodium excretion, prerenal prostaglandins involved in regulation of azotaemia*, hyperkalaemia, renal blood flow, glomerular filtration, and oliguria, & anuria renal sodium and water excretion; also (oedema & hypertension) involved in mediation of renin release. Allergic Bronchospasm, urticaria, Inhibition of cyclooxygenase pathway, rhinitis, polyposis allowing lipooxygenase pathway to dominate in susceptible individuals Uterine Delayed parturition, Loss of contractile effects of dystocia** prostaglandins on uterine muscle * Azotaemia: an excess of urea or other nitrogen bodies in the blood ** Dystocia: abnormal labour or childbirth

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Antipyretic Analgesic

Anti-inflammatory Gastric irritation

Indomethacin Diclofenac Ibuprofen Mefenamic Paracetamol Piroxicam Meloxicam acid Aspirin Celecoxib Aspirin (high dose) (low dose) Fig. 7.2. A simplified representation of agents which have largely analgesic activity (e.g. paracetamol and low dose of aspirin); on the other extreme, agents which have high antiinflammatory efficacy (e.g. indomethacin and high dose aspirin). While, ibuprofen and diclofenac are considered to have moderate anti-inflammatory activity coinciding with less gastric toxicity than that may be produced by indomethacin and high-dose aspirin.

Selection of NSAIDs In the following respects ibuprofen may be superior to aspirin.

Older Agents (aspirin, ibuprofen) • Cost (low) • Follow-up advantage (salicylate blood level, aspirin)

•

It does not potentiate the effect of the hypoglycaemic drugs or warfarin. • It exhibits a lower incidence of gastric irritation.

Newer Agents (Celecoxib) • Easier dosage schedules • Better compliance • Lower incidence of gastric irritation

Some patients derive benefit from a particular one NSAID agent and not from another. This variability in response may be related to one or more of the following: • The NSAID per se • Individual differences in metabolism of the drug • Placebo effect

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Table 7.2. Half-lives and dosing schedules of NSAIDs NSAIDs With short t Aspirin Diclofenac (Voltaren ) Ketoprofen

t (hr)

Daily doses Number of (mg) Doses/day

0.25

2000-4000

3-4

1

75-150

2-3

2

100-200

1-2

Ibuprofen (Brufen )

2

1200-2400

2-3

Indomethacin (Indocid )

4

50-150

3-4

4

1000-2000

3-4

Mefenamic acid (Ponstan ) With long t Diflunisal (Dolobid )

13

1000

2

Naproxen

14

375-1000

2

Sulindac

8

200-400

2

57

10-20

1

68

100-300

1-2

Piroxicam (Feldene ) Phenylbutazone

Rofecoxib (Dioxx )

Inhibits LOX The concomitant administration of ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin. Inhibits LOX, phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation. Particularly useful in gout and ankylosing spondylitis

Inhibits phospholipase A2

Its elimination depends on renal and hepatic functions, hence, diflunisal's dosage should be limited in patients with significant renal impairment.

The enterohepatic cycling prolongs the duration of action to 12 16 hr.

Do not inhibit platelet aggregation; reduce renal function and thromboresistance of the vessel wall (↓ endothelial PGI2).

COX-2 antagonists Meloxicam (Mobic ) Celecoxib (Celebrex )

Important notes

20

7.5-15

10

200-400

17

1

12.5-25

1

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It was voluntarily withdrawn on September 30, 2004 due to mounting evidence linking it to increased risk of cardiovascular problems.

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inflammatory actions. Its onset of action is slow and its toxicity is substantial.

Disease-Modifying Antirheumatic Drugs Control studies have firmly shown that rheumatoid arthritis results in marked systemic effects in addition to the joint disease that reduces mobility and quality of life. Certain drugs might arrest or at least slow structural damage to joints. These are known as disease-modifying antirheumatic drugs (DMARDs, and also variably called slow-acting antirheumatic drugs and remission-inducing drugs). Toxic effects of DMARDs limit their use and make them second line drugs in the treatment of rheumatic diseases. While the first line drugs (NSAIDs) being less toxic are expected to relieve pain, inflammation and muscle stiffness (symptomatic only).

Antimalarial Drugs Hydroxychloroquine Hydroxychloroquine is indicated when treatment with NSAIDs has been unsuccessful. Because full therapeutic effects take 3 to 6 months to develop concurrent therapy with anti-inflammatory drugs (e.g. glucocorticoids) is indicated. The antiinflammatory action of hydroxychloroquine and chloroquine is probably due to its ability to block phospholipase A2. The most serious of hydroxychloroquine is retinal damage that can be irreversible and can produce blindness.

In recent years, some schools suggest the early introduction of DMARDs, once the diagnosis of rheumatoid arthritis is confirmed. This is because their ability to slow the progress of the disease although they may not influence the ultimate degree of deformity and disability.

Gold Salts Gold salts (Sodium aurothiomalate by deep intramuscular injection or auranofin by mouth) produce analgesic, anti-inflammatory and immunosuppressant actions. The t of elimination from plasma is 22 days, steady state concentration is reached only after 3 months and the therapeutic response within 4 months. For intramuscular preparations, the dosing interval can be lengthened from one week to reach one month that can be continued indefinitely. Oral preparation is administered once or twice daily.

Immunosuppressive Drugs Methotrexate Methotrexate (a folic acid antagonist) is the fastest acting of the DMARDs. Its effects may be seen in 6 to 8 weeks. Unlike cyclophosphamide and azathioprine, methotrexate does not induce neoplastic disease. Major toxicities are hepatic fibrosis, bone marrow suppression, and gastrointestinal ulceration. It is now recognised that methotrexate toxicity can be reduced without decreasing its efficacy in rheumatoid arthritis by giving leucovorin 24 hours after each weekly dose of methotrexate or by the use of daily folic acid.

Gold salts have a number of toxicities that can limit their use. 1. Intense pruritus, rashes, and stomatitis (lesions of the oral mucosa) 2. Renal toxicity (manifested as proteinuria) 3. Severe blood dyscrasias (thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia) 4. Encephalitis, hepatitis, peripheral neuritis, profound hypotension

Azathioprine Azathioprine (Imuran ) is a purine antagonist. Its antiarthritic benefit is probably derived from its immunosuppressive and anti-

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Drugs Used in Gout Penicillamine Gout is a recurrent inflammatory disorder characterised by hyperuricaemia and by episodes of severe joint pain, typically in the large toe. Hyperuricaemia can occur through two mechanisms:

The mechanism of action of penicillamine in rheumatoid arthritis is unclear. However, it reduces rheumatoid factor and the concentration of immune complexes in plasma and synovial fluid. Because of serious toxicity, penicillamine is usually prescribed for patients who have not responded to gold therapy.

1. Excessive uric acid production 2. Impaired uric acid excretion Acute attacks are precipitated by crystallisation of sodium urate within the synovial space. Deposition of urate crystals promotes inflammation by triggering a complex series of events. The most important feature of the inflammatory process is infiltration of leukocytes. Being in the synovial cavity, leukocytes phagocytise urate crystals and then break down, causing release of destructive lysosomal enzymes, prostaglandins, and interleukin-1. When hyperuricaemia is chronic (with urate pool that may be 15-26 times normal), large and gritty deposits, known as tophi, may form in the affected joints. Renal damage may also result from deposition of urate in the kidney.

Penicillamine can produce toxicities that can limit its use. 1. Proteinuria is encountered in 20% of patients. 2. Immune complex nephritis (4% of patients) 3. Severe blood dyscrasias (thrombocytopenia, leucopenia, aplastic anaemia) 4. Various autoimmune diseases (including myasthenia gravis, lupus erythematosus, haemolytic anaemia, and thyroiditis)

Sulphasalazine

Drug Therapy of Gout

Sulphasalazine is now recognised that sulphasalazine produces two primary metabolites; 5-acetylsalicylic acid that is active in inflammatory bowel disease (ulcerative colitis) and sulphapyridine that is active in rheumatoid arthritis. The mechanism of action is undetermined. Major adverse effects are gastrointestinal upset, dizziness and photosensitivity.

The aims of drug therapy to: 1. Suppress the symptoms (antiinflammatory drugs, e.g. indomethacin, diclofenac and piroxicam; colchicine; glucocorticoids) 2. Prevent urate synthesis (e.g. allopurinol) 3. Promote elimination of urate (uricosurics, e.g. probenecid, sulphinpyrazone)

Glucocorticoids Full account on glucocorticoids is presented in the chapter on Endocrine Pharmacology. Glucocorticoids may be useful for certain serious extra-articular manifestations such as pericarditis or eye involvement or during periods of exacerbation. Intra-articular glucocorticoids are often helpful to alleviate painful symptoms and are preferable to increasing the dosage of systemic administration.

Anti-inflammatory Drugs This broad group of drugs is covered largely above (NSAIDs) and adrenal corticosteroids (in the chapter on Endocrine Pharmacology); therefore, the following account will cover colchicine.

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3. Bone marrow depression 4. Peripheral neuritis and myopathy

Colchicine Colchicine is an anti-inflammatory agent whose effects are specific for gout. Colchicine is not an analgesic and will not relieve pain in conditions other than gout. Colchicine (t 1 hour) is readily absorbed following oral administration. The drug is excreted primarily in the faeces; it enters the intestine via the bile and intestinal secretions.

Intravenous administration will obviate most gastrointestinal toxicity of colchicine. Diarrhoea from colchicine can be treated with opioids.

Mode of Action

Acute intoxication with large doses (nontherapeutic) of colchicine may result in

The drug is believed to relieve or prevent episodes of gout through its ability to inhibit leukocyte infiltration. In the absence of leukocytes, there is no phagocytosis of uric acid and no subsequent release of lysosomal enzymes. Colchicine disrupts microtubules, the structures required for cellular motility. Since integrity of microtubules is essential for cell division, colchicine is toxic to any tissue that has a large proportion of proliferating cells. Disruption of cell division is responsible for the gastrointestinal toxicity of colchicine.

1. Burning throat pain 2. Bloody diarrhoea 3. Shock 4. Haematuria 5. Oliguria

Allopurinol Both allopurinol (Zyloric ) and its major metabolite (alloxanthine) inhibit production of uric acid. Therefore, these compounds act to reduce hyperuricaemia through inhibiting xanthine oxidase, an enzyme essential for uric acid production. Allopurinol (t 2 hours) is readily absorbed from the gut and, in the liver, undergoes rapid conversion to alloxanthine by xanthine oxidase. Since alloxanthine has a long plasma t (25 hours) and is an irreversible inhibitor of xanthine oxidase, the therapeutic effects of allopurinol are long lasting. Thus, allopurinol requires only once-a-day dosing.

Indications of Colchicine 1. Treatment of acute gouty arthritis 2. Prophylaxis of gouty attacks (When taken, 0.5 to 1.0 mg/day, during the asymptomatic intercritical period it can decrease the frequency and intensity of acute attacks) 3. Abortion of an impending attack (During prophylactic use of colchicine, patients may experience prodromal signs of a developing gouty attack. If a large amount of colchicine, 0.5 mg every 2 hours, is taken immediately, the attack may be prevented. Therefore, patients suffering chronic gout are advised to have colchicine tablets always with them) 4. Prevention and treatment of attacks of acute familial Mediterranean fever

Indications of Allopurinol 1. Chronic tophaceous gout 2. Secondary hyperuricaemia (hyperuricaemia may occur secondary to treatment with anticancer drugs; uric acid level is elevated because of the break down of DNA that occurs following cell death. It also may occur secondary to certain blood dyscrasias (e.g. polycythemia vera, myeloid metaplasia, leukaemia).

Adverse effects of colchicine 1. Nausea, vomiting, diarrhoea and abdominal pain (due to injury to the rapidly proliferating cells of the gastrointestinal epithelium) 2. Hair loss 199

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Adverse effects of Allopurinol Probenecid may exacerbate acute episodes of gout, and hence treatment should be delayed until the acute attack has been controlled.

1. Precipitation of acute gout (Early in treatment deployment of uric acid from tissues to plasma occurs, resulting in acute attack. This can be prevented by the concurrent use of colchicine) 2. Hypersensitivity syndrome (characterised by rash, fever, eosinophilia, and dysfunction of the liver and kidneys) 3. Drug interactions (Allopurinol inhibits hepatic metabolism of probenecid, oral anticoagulants such as warfarin, mercaptopurines and cyclophosphamide.

Probenecid is generally well tolerated but gastrointestinal disturbances (nausea, vomiting, and anorexia)

Sulphinpyrazone The action of sulphinpyrazone is similar to that of probenecid. It is a uricosuric agent and is employed to reduce hyperuricaemia in patients with chronic gout. Like probenecid, it may precipitate an acute gouty attack; concurrent use of colchicine or indomethacin will decrease the risk of such an episode.

Drugs that increase the renal excretion of uric acid

Sulphinpyrazone is well tolerated but with some possibility of gastrointestinal disturbances (nausea and abdominal pain). It can exacerbate gastrointestinal ulcers, therefore, the drug is contraindicated in the presence of current ulceration.

Probenecid

Probenecid acts on the renal tubules to inhibit reabsorption of uric acid; this promotes excretion of uric acid and thereby reduces hyperuricaemia. By lowering plasma level, probenecid prevents formation of new tophi and facilitates regression of tophi that are already present. Table 7.3. A summary of the uses of anti-arthritic drugs Disease Rheumatoid arthritis Ankylosing spondylitis Degenerative joint disease (osteoarthritis) Systemic lupus erythematosus Gout

Anti-arthritic drugs used Salicylate, other NSAIDs, gold salts, steroids, anti-malarials, penicillamine, cytostatics (methotrexate, azathioprine) Other NSAIDs, salicylates Paracetamol, Salicylates, other NSAIDs Salicylates, anti-malarials, steroids, penicillamine, cytostatics Colchicine, other NSAIDs, allopurinol, sulphinpyrazone, probenecid

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ATP r ADP r Adenine r Hypoxanthine Allopurinol inhibits

Arthropathy Nephropathy Urate stone Tophi

Guanine Xanthine oxidase

Xanthine

Tissue deposition of urate crystals Urinary excretion

Uric acid

Phagocytosis Lactic acid

Promote Probenecid Sulphinpyrazone Aspirin (high dose)

Colchicine inhibits

↓ Tissue pH

Fig. 7.3. A simplified schematic representation of the biochemical events involved in the pathogenicity of gout. Specific drugs can be targeted at inhibiting the synthesis of uric acid (e.g. allopurinol) and/or increasing the renal excretion of uric acid (uricosurics, e.g. probenecid, sulphinpyrazone, and high dose of aspirin). Colchicine inhibits the phagocytic activity and therefore reducing the production of lactic acid, consequently, reducing the crystallisation of uric acid in the synovium.

Table 7.4. A summary of the pharmacology of drugs used in gout Drug Group/ Drug

Mode of Action

Main Indications

Important Adverse Effects

Drugs in Gout Colchicine

Disrupts microtubules in phagocytic cells

Prophylaxis & treatment of gouty attacks

Vomiting Diarrhoea Abdominal pain

Allopurinol

Inhibits xanthine oxidase

Chronic tophaceous gout Secondary hyperuricaemia

Precipitation of acute gout Drug interactions

Uricosurics Probenecid

Sulphinpyrazone

Inhibit renal tubular reabsorption of uric acid

Inhibit renal tubular reabsorption of uric acid

Chronic tophaceous gout

Precipitation of acute gout GI disturbances (vomiting & anorexia)

Chronic tophaceous gout

Precipitation of acute gout GI disturbances (nausea & abdominal pain) Avoid in current ulceration

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Table 7.5. A summary of the pharmacology of NSAIDs and related agents Drug Group/ Drug Paracetamol (Acetaminophen)

Main Indications

Inhibits prostaglandin synthesis in the brain

Pain Pyrexia

Salicylates Aspirin Non-salicylates Ibuprofen Diclofenac Mefenamic acid Indomethacin Naproxen Piroxicam COX-2 antagonist Meloxicam Celecoxib Rofecoxib

Inhibits prostaglandin synthesis in the brain and peripherally (by inhibiting prostaglandin G/H synthase). Differences in effects on patients between these drugs may be due to other modes of action, e.g. inhibiting lipoxygenase, leukocyte migration (diclofenac, indomethacin).

Moderate Pain Pyrexia Inflammatory conditions (e.g. rheumatoid arthritis & gout) Spasmodic conditions (e.g. dysmenorrhoea, ureteral & intestinal colics) Thromboembolic disorders

Salicylism: (tinnitus & vertigo due to high level of salicylic acid) Reye s syndrome (with aspirin & children) Gastric distress Bleeding Hypersensitivity reactions (e.g. urticaria & bronchospasm) Fluid retention Delayed parturition

Methotrexate

Folic acid antagonist (folinic acid rescue)**

Rheumatoid arthritis

Azathioprine

Purine antagonist

SLE

Bone marrow depression GI ulceration

Inhibit Phospholipase A2

Rheumatoid arthritis SLE

Mode of Action

Important Adverse Effects GI upsets In overdose:

Hepatotoxicity

DMARDs* Immunosuppressive Drugs

Antimalarials Hydroxychloroquine

Chloroquine

Gold Salts

Undetermined (analgesic, antiinflammatory & immunosuppressive)

Rheumatoid arthritis

Penicillamine

Undetermined (reduces rheumatoid factor & the concentration of immune complexes in plasma & synovial fluid

Rheumatoid arthritis SLE

Retinal damage Intense pruritus Stomatitis Renal toxicity (proteinuria) Blood dyscrasias Renal toxicity (proteinuria in 20% of patients, immune complex nephritis in 4%)

Blood dyscrasias

GI upsets Dizziness Photosensitivity Useful for extra-articular manifestations (e.g. pericarditis) or during period Glucocorticoids of exacerbation (systemic and intra-articular administration) * DMARDs: Disease-modifying antirheumatic drugs ** Its toxicity can be reduced without decreasing its efficacy in rheumatoid arthritis by giving folinic acid after each weekly dose of methotrexate or by the use of daily folic acid. Sulphasalazine

Undetermined

Rheumatoid arthritis

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DRUGS AND GASTROINTESTINAL TRACTS

a. sucralfate b. bismuth compounds (e.g. bismuth subcitrate) c. prostaglandins (e.g. misoprostol) d. antimicrobial agents (eradicating Helicobacter pylori)

Anti-peptic Ulcer Drugs Peptic ulcer is influenced by several factors including 1. Helicobacter pylori 2. Hyperacidity 3. Gastric emptying 4. Stress

Recently, a good body of evidence points out that peptic ulcer, particularly duodenal ulcer, is very much influenced by a local bacterial infection with Helicobacter pylori. The eradication of this bacterium by appropriate anti-bacterial agents has made a great success in the treatment of peptic ulcer. This new approach has substantially reduced the relapse rate, particularly with duodenal ulcer, that has been a major problem as it often meant a re-treatment with anti-ulcer drugs.

For many decades, the treatment of peptic ulcer was largely aimed at • Directly neutralising gastric acidity by the use of antacids, e.g. sodium bicarbonate. • Inhibiting secretion of HCl and this may be achieved by

Use of non-steroidal (NSAIDs) cigarette (male sex, blood predisposing factors of peptic ulcer.

a. H2-receptor antagonists (e.g. cimetidine) b. M1-receptor antagonists (e.g. pirenzepine) c. Proton pump inhibitors (e.g. omeprazole). • Enhancement of mucosal resistance by different drugs

anti-inflammatory drugs smoking, and heredity group O) are also for increased incidence

Table 8.1. A summary of selected drugs used in the treatment of peptic ulcer, indicating the mechanism of action, selected adverse effects and important remarks. Drug group

Mechanism of action

Selected adverse-effects and important remarks

H2-antagonists

Block H2-receptors → ↓ H+ secretion

Cimetidine

Gynaecomastia, impotence (antiandrogenic), inhibits hepatic enzymes (Ranitidine is 50%, famotidine GI disturbances (constipation is 25%, nizatidine is 10% & diarrhoea) , no metabolised, the remainder is antiandrogenic, or inhibition renally excreted unchanged) on hepatic enzymes Block M1-receptor (block Dry mouth, constipation, visual transmission in disturbance, mental confusion parasympathetic enteric (relative selectivity in inhibiting gastric acid secretion at low ganglia)

Ranitidine Famotidine Nizatidine M1-antagonists Pirenzepine

doses)

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Drug group Proton inhibitors Omeprazole Lansoprazole

Mechanism of action pump Inhibit H+, K+-ATPase leading to decrease H+ secretion (irreversible inhibition)

Antacids

Selected adverse-effects and important remarks GIT disturbances, hepatic enzyme inhibition, potential for gastric neoplasia (carcinoid tumour); 1st line therapy for Zollinger-Ellison syndrome, & ulcerative reflux oesophagitis; 2nd line therapy for peptic ulcer; (destroyed by acid in stomach thus made as entericcoated granules )

Neutralise secreted H+

NaHCO3

Not used routinely to treat ulcers; used to treat acidosis and alkalinise urine; high risk of sodium loading; release CO2

Mg(OH)2

Diarrhoea, cause Mg toxicity (CNS depression) in patients with renal impairment. Constipation, it can cause hypophosphotaemia, thus, it is used to treat hyperphosphotaemia.

Al (OH)3

Constipation, it may cause acid rebound or milk-alkali syndrome (hypercalcaemia without hypercalciuria with only mild alkalosis); release CO2

CaCO3

Mucosa protecting agents 1. Sucralfate

with proteins forms a protective layer 2. decreases back-diffusion of H+ 3. binds to pepsin and bile salts Chelates with protein in the ulcer crate, thus, protecting from H+, pepsin and bile. It also possesses anti-H pylori activity.

Constipation, dry mouth, skin rash; inactivated by antacids, thus, avoid antacids.

Prostaglandins (Misoprostol)

1. ↑mucus & bicarbonate secretion 2. Maintenance of blood flow 3. ↓ H+ back diffusion 4. ↑ mucosal cell replication 5. ↓ gastric acid secretion

Diarrhoea, & abdominal pain, spotting & dysmenorrhoea; Contraindicated in pregnancy (it is abortifacient); used in combination with NSAIDs or glucocorticoids.

Antimicrobial agents

Eradicating H. pylori

Combined antimicrobial therapy. (see chapter on antimicrobial agents)

Bismuth chelates

Anticholinergics and Compound Preparations

Constipation, black encephalopathy

stools,

Librax: Clidinium + chlordiazepoxide; useful in peptic ulcer, nervous dyspepsia, irritable bowel syndrome, and mild ulcerative colitis

Anticholinergic drug + a sedative (a barbiturate, benzodiazepine, or phenothiazine) or NSAID

Stelabid: Isopropamide + trifluoperazine; useful in peptic ulcer, and visceral spasm

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Propantheline (an anticholinergic) alone is useful in peptic ulcer and irritable bowel syndrome. This drug is also used in micturition disorders (unstable detrusor contractions).

3. drug-induced constipation (by opiates, anticholinergics, sedatives) 4. prior to GI surgery or radiology, and other conditions

Drugs and Irritable Bowel Syndrome

The use of laxatives can cause hypokalaemia, malabsorption and dependence. For a summary of the pharmacology of laxatives see Table 8.2.

Usually associated with abdominal pain, constipation or diarrhoea. Useful drugs: bulk purgatives (bran), sedatives (benzodiazepine), mebeverine (a direct smooth muscle relaxant) or NSAIDs.

HIGH FIBRE DIET IS OFTEN SUFFICIENT TO REGULATE BOWEL MOTION

Drugs and Ulcerative Colitis

CONSTIPATION IN INFANTS CAN BE RELIEVED SIMPLY BY INCREASING SUGAR CONTENT IN MILK

Prednisolone (suppositories, and enema) is useful in mild attacks of ulcerative colitis; it may be given orally in severe cases. When stools with blood and pus, sulphasalazine can be useful. Sulphasalazine is broken down into 5-aminosalicylic acid (mesalazine) and sulphapyridine by bacteria in the colon. In effect the sulphapyridine component contributes to a mechanism for delivering 5-aminosalicylic acid to the colon. Mesalazine is also formulated in a way to delay its release until it reaches the colon. Mesalazine is used for the maintenance of remission of ulcerative colitis in patients unable to tolerate sulphasalazine. Sulphasalazine has been widely used in ulcerative colitis and Crohn s disease, and in rheumatoid arthritis for which it was originally introduced in 1930s; mesalazine is considered to be the active moiety in ulcerative colitis, but not however in rheumatoid arthritis.

vagus

parietal cell HCl

ACh M3 H2

ECL cell M1

Histamine

Gastrin Fig. 8.1. Histamine release from enterochromaffin-like (ECL) cells is stimulated by ACh (vagal, via activation of M1-receptors) and gastrin (via activation of gastrin receptors) on ECL cells, in turn histamine activates H2receptors located on parietal cells resulting in release of gastric acid. Further, ACh and gastrin stimulate their corresponding receptors located on parietal cells evoking the release of gastric acid. The muscarinic receptors on parietal cells are believed to be M3 subtype.

Laxatives (Purgatives) The terms laxative, purgative and cathartic are all more or less mean an agent that causes evacuation of the bowel. Laxatives are indicated in 1. when straining may be dangerous (as in angina) 2. painful anal conditions 205

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Pirenzepine blocks ganglionic M1-receptor reducing Acetylcholine

Cimetidine Ranitidine Famotidine

Misoprostol stimulates prostaglandin receptor PGI2 & E2

Block H2-receptor Histamine

Gs

+

Adenylate cyclase

Gastrin

Gi

_

ATP ++

Inactive product

Ca

PDE

cAMP

+

Caffeine blocks here

+

+

Protein kinase (activated)

PARIETAL CELL

+ -

Cl Ion channel

LUMEN OF ClSTOMACH Antimicrobilas

Ca++

K

+

K

+

H

+

Omeprazole blocks here

+

H pump H+, K+-ATPase K

+

+

H

Antacids

Bismuth chelates

Sucralfate

Mucosal Protection H. pylori bacilli

Eradication Ulcer crate

Gastric mucosa

Fig. 8.2. A simplified schematic representation of the nature and site of action of antipeptic ulcer drugs illustrating the receptors and intracellular events involved in the release of HCl in the gastric lumen, and the major drugs that alter these events. Other agents that act in the gastric lumen are also included. Note: Pirenzepine blocks ganglionic M1-receptor resulting in reduced vagal discharge, thus, reduced activation of M3-receptors that are located on the parietal cells. PDE: phosphodiesterase; +: stimulatory; -: inhibitory.

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Table 8.2. A summary of selected drugs used as laxatives (purgatives), their mode of action and adverse effects with important remarks. Drug group Bulk forming Bran Ispaghula husk methylcellulose Osmotic agents

Mode of action

Selected adverse effects and important remarks Promote large, soft, solid Obstruction of bowel, 2 stool encouraging normal l/day of fluid must be reflex bowel activity taken Increase the bulk and reduce viscosity of intestinal contents to promote a fluid stool

Magnesium sulphate Lactulose

Stimulants (irritants) Senna, Cascara Bisacodyl

Hypermagnesaemia renal failure

in

In addition, lactulose is fermented to lactic and acetic acids inhibiting the growth of colonic ammonia-producing organisms, thus, useful in hepatic encephalopathy. Increase intestinal motility by various mechanisms Gripping pain Stimulates sensory ending in Rectal irritation colon directly from the prolonged use lumen suppositories

from of

Na picosulphate Glycerol Castor oil (drastic)

Faecal softeners (Lubricants) Liquid paraffin

Mild stimulant as a suppository Undergoes hydrolysis into Avoid in pregnant ricinolic acid that stimulates women. Evacuates bowel peristalsis. of gas for X-ray examination. Softening powers of the oil Useful if fissure and in the colon promote the haemorrhoids; passage of softer faeces. Reduces absorption of (help reduce straining) fat-soluble vitamins

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Table 8.3. A summary of selected antidiarrhoeal drugs, their mode of action, adverse effects and important remarks

Drug group Oral Rehydration Therapy (ORT)

Antimotility Drugs (Opioid-like Drugs)

Diphenoxylate (Lomotil)

Loperamide (Vacontil)

Codeine Adsorbents Kaolin & Pectin

Antimicrobial agents

Mode of action

Selected adverse effects and important remarks Prevention & treatment of Can be life-saving in fluid & electrolyte loss as acute diarrhoea in infants glucose-coupled sodium & children. transport continues during diarrhoea & thus REMARKABLY SAFE replacement of water & electrolyte losses in the stool. Reduce peristalsis & Contraindication: in increase segmentation infectious diarrhoea & contractions delaying children under 2 years; passage of contents & thus more water is Caution: in ulcerative absorbed (actions blocked colitis by naloxone) Mixed with low dose of CNS side effects: nausea, atropine to discourage vomiting, abdominal abuse) pain, sedation Overdosage: respiratory depression Given on its own as it has Nausea, vomiting, low potential for abuse. abdominal cramp; poorly absorbed from GIT Sedation, respiratory depression Believed to act through removal of bacterial toxins by adsorbing Suspension: Kaolin 900 toxins from stomach & mg, Pectin 20 mg/5ml intestine (a physical (100 ml) phenomenon) Only in severe cases of enteritis, specific agents may be used.

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7. Postpartum lactation stimulation (to increase milk production in nursing mothers)

Vomiting and Antiemetics Vomiting is co-ordinated by the activity of vomiting centre which is located in the medulla oblongata in close proximity to other visceral centres, e.g. for respiration, salivation, vagal and vascular control which give rise to prodromal sensations of vomiting.

Adverse Effects 1. Extrapyramidal effects (dystonias, akathisia, parkinsonian features) 2. Endocrine (e.g. hyperprolactinaemia, gynaecomastia, galactorrhoea, amenorrhoea, erectile impotence) 3. Tardive dyskinesia (Long-term use of metoclopramide may cause tardive dyskinesia in the elderly)

Antiemetic and Prokinetic Drugs Metoclopramide (Plasil) is a derivative of procainamide but has negligible cardiac and local anaesthetic effects and is a powerful antiemetic (35x more powerful than chlorpromazine). In addition to its central action (dopamine antagonist) has prokinetic effects on the GIT. It increases the tone of the oesophageal (cardiac) sphincter and increases peristalsis and thus emptying. Postganglionic stimulation and release of acetylcholine mediate this action. This action is mediated by stimulating intrinsic sensory neurones in the myenteric plexus (local reflex pathway) via 5HT 4-receptor agonism, and vagal and central 5-HT3-receptor antagonism. . Domperidone is a D2-receptor antagonist with a pharmacological profile similar to metoclopramide except that it poorly crosses the blood brain barrier; thus fewer dystonic reactions than with metocopramide, and hence domperidone is well tolerated.

Phenothiazines, chlorpromazine (Largactil) and prochlorperazine (Stemetil) act mainly on the vomiting centre and CTZ. Hyoscine anticholinergic, useful in motion sickness, atropine is less specific. If given prophylactically together with morphine, it should be remembered that the emetic action of morphine outlasts the antiemetic effect of a single dose of hyoscine. Table 8.4. A summary of antiemetic agents Drug group D2-receptor antagonists Metoclopramide Domperidone Phenothiazines Chlorpromazine Prochlorperazine 5HT3-receptor antagonists Ondansetron Antimuscarinics Hyoscine Cyclizine* Promethazine* Others Cisapride Cinnarzine Glucocorticoids Benzodiazepine

Indications 1. Gastroesophageal reflux disease (GERD) (for the treatment of symptomatic GERD but none are effective for treatment of erosive esophagitis where antisecretory agents are the main stay of treatment of heartburn due to their superior efficacy and safety) 2. Impaired gastric emptying (delayed gastric emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis) 3. Nonulcer dyspepsia 4. Postoperative vomiting 5. Radiation sickness (and drug induced toxicity including cytotoxic drugs) 6. Oesophagitis (hiatus hernia, and endoscopy)

Site of action

CTZ & gut Vomiting centre & CTZ

CTZ & gut Vomiting centre & gut

Vomiting centre & gut

* In addition to being antimuscarinic, it also has antihistaminic and antidopamine activities.

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Antihistamines act on vomiting centre and vestibular nuclei.

Vitamin B6 is alleged to be effective in postoperative emesis where metoclopramide is poorly or not effective.

Cisapride is related to metoclopramide but it does not have dopamine receptor antagonistic activity. Cisapride acts peripherally on the gut as a prokinetic agent via 5HT 4-receptor agonism and 5HT3-receptor antagonism .

Metoclopramide Domperidone Cisapride

Metoclopramide Domperidone Cisapride

(õ)

(ó) 5HT 3 receptor

ACh

NANC

(ó) (õ)

5HT

5HT 4 receptor 5HT

ACh Gut smooth muscle

Fig. 8.3. A schematic representation of the possible sites of prokinetic agents.

(ó) inhibitory, (õ) excitatory

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Centrally acting emetics Chemoreceptor trigger zone (CTZ)

Vertigo: prochlorperazine Motion sickness: hyoscine, cyclizine Meniere s syndrome: cinnarizine

Vestibular system (Labyrinthine disorder)

VOMITING CENTRE

Radiation Urea Oestrogen Bromocriptine L-DOPA Apomorphine Morphine Ergot alkaloid Digoxin Cortical centre (Intracrainal pressure)

Anti-ischaemic agents Spasmolytics

Cisapride (Prokinetic)

Pain receptors Myocardial infarction Appendicitis Genital, urinary, renal, intestinal & biliary t act

Gut distension or chemical irritation of the gut Peripherally acting emetics: Emetine (Ipecacuanha) Ammonium chloride NaCl, CuSO4, ZnSO4

Fig. 8.3. A schematic representation of the sites and factors involved in the mediation of emesis, and the major drugs influencing this act.

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DRUGS AND THE RESPIRATORY SYSTEM BRONCHIAL ASTHMA

¾2-agonists

Asthma is dependent on a large number of factors such as allergy, air pollution, smoking and infections. Allergic asthma is often termed extrinsic . Asthma is characterised by bronchial hyperreactivity with variable airways obstruction. Some patients exhibit wheeze and breathlessness that is not attributable to any allergic reaction. They are considered to have intrinsic asthma. The underlying mechanism remains uncertain. The most likely cause is local release of bronchoconstrictors, such as leukotrienes. Other possible causes involve an abnormality of the bronchial smooth muscle or its innervation (decreased β2-receptor sensitivity, increased activity of cholinergic innervation, and the involvement of sensory-motorinflammatory nerves). The factors that produce airways obstruction in asthma probably are:

The most commonly used bronchodilators are the specific β2-receptor agonists salbutamol and terbutaline. These are usually administered by metered aerosol and have a rapid onset of action (peak action after 15 minutes) and duration of 4 hours. Salbutamol and terbutaline are also available in tablets for oral administration and the duration of action is the same. The inhaler is convenient but administration may be difficult in the severely dyspnoic patient or in a younger child. For these, salbutamol can be more reliably administered if diluted in saline and given over a few minutes by an air-driven nebulizer. Recently, a new generation of β 2-receptor agonists have been introduced into clinical practice. They are known as long acting β 2receptor agonists (inhaled), e.g. salmeterol and formoterol, which have slow onset of action and long duration of action (12 hours). They are useful in nocturnal asthma and exercise-induced asthma, and claimed to be effective in poorly controlled asthma.

1. Bronchial constriction 2. Mucous plugging 3. Oedema of bronchial mucosa 4. Vascular congestion 5. Cellular infiltration

Adverse-effects With these multiple possible factors involved, it is clear that bronchial relaxation is just one possible approach that can be achieved therapeutically.

Adrenaline stimulates α, β1 and β 2-receptors, and produces transient hypertension, pallor, and urinary retention (in patients with benign prostatic hypertrophy). Tremors, palpitations, tachycardia, and, rarely, arrhythmias are potential adverse effects of β-receptor stimulation. Central nervous system stimulation or headache is common, and vomiting frequently follows administration to children.

Sympathomimetics The oldest sympathomimetic drug used in the western world is adrenaline which has both α and β-receptors stimulating properties. Formerly it was used by subcutaneous (s.c.) injection. Because of extensive side effects (blood pressure elevation and tachycardia, it is hardly used today except in acute allergic bronchoconstriction associated with hypersensitivity reactions where it is given s.c. the only advantage here is that it reduces vascular congestion by virtue of its αadrenergic action which is a characteristic feature of the allergic reaction.

In high doses, all ¾2-receptor agonists can cause significant hypokalaemia.

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Benefits and toxicity are related to serum concentration which should be within 5-20 µg/ml. Dosage must be adjusted individually because of great pharmacokinetic variations. The risk of toxicity increases progressively as serum concentrations approach 20 µg/ml. Toxic symptoms are nausea, headache, insomnia, tremor, anxiety. At higher level: cardiac arrhythmias, convulsions and coma may occur.

Leukotriene modifiers Zileuton inhibits lipoxygenase

Leukotriene receptor antagonists Montelukast and zafirlukast, competitively prevent the bronchoconstrictor effects of cysteinyl-leukotrienes (C4, D4 and E4) by blocking their common cysLTl receptor. Zafirlukast and montelukast improve symptoms and pulmonary function tests, decrease nighttime symptoms, and decrease the use of β 2-agonist drugs. They are effective with oral administration, can be taken once or twice daily, can be used with bronchodilators and corticosteroids, and produce a high degree of patient adherence and satisfaction. However, they are less effective than low doses of inhaled glucocorticoid.

Cautions The t is increased in heart failure, liver cirrhosis, and viral infection. It should be given with caution in patients with epilepsy or fever, in the elderly and during breastfeeding.

Drug interactions Ciprofloxacin, cimetidine, erythromycin, and oral contraceptives inhibit the metabolism of theophylline and therefore can potentiate its effects. While rifampicin, phenytoin, barbiturates, carbamazepine can reduce plasma concentrations of theophylline by virtue of inducing hepatic enzyme activity.

Theophylline Theophylline (t , 8 hr) acts mainly by inhibiting the enzyme phosphodiesterase and thereby reduces the breakdown of cAMP. In this way it produces increased levels of cAMP within the cells and thus enhances bronchial smooth muscle relaxation. It also inhibits degranulation of mast cells. It is used both for acute bronchodilatation (given intravenously, i.v.) and chronic prophylaxis (given usually orally e.g. phyllocontin, sustained release capsule).

Sodium cromoglycate Sodium cromoglycate (cromolyn Na) is administered as an inhaled dry powder. Although its cellular mechanism of action is not fully understood, it blocks allergeninduced bronchoconstriction. For many years, it was thought to act by inhibiting the release of mediators from mast cells. However, recent evidence suggests that the late allergic responses and bronchial hyperreactivity are also inhibited, and indicating effects of cromoglycate on other inflammatory cells and also on local sensorimotor (also known as inflammatory, and peptidergic) nerves which function by way of axon reflexes.

Aminophylline is the ethylenendiamine salt of theophylline which is sufficiently soluble for i.v. administration. Aminophylline should not be administered rapidly i.v. (appropriate duration: 10-20 minutes) because it may cause hypotension and tachycardia. Further, it should not be administered intramuscularly (i.m.) as the injection is extremely painful. A loading dose may be administered, if patients have not recently received theophylline therapy, within 48 hours. However, if patients have recently received theophylline, a loading dose should not be administered because toxic concentrations are then likely to be reached.

It is not effective at terminating an existing attack (bronchoconstriction), rather, it prevents bronchoconstriction as opposed to inducing bronchodilatation. It is largely useful in extrinsic (allergic) asthma including exercise-induced asthma. The clinical response to cromoglycate may be delayed by several weeks. When used, cromoglycate

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lozenges). Therefore, it is advisable to wash the mouth with water after each administration to avoid such a problem.

may reduce the need for corticosteroids allowing a lower dose of steroids to be used.

Ketotifen Ipratropium bromide

Ketotifen is histamine H1-receptor antagonist, and appear to have some antiasthma actions. Its only noteworthy adverse effect is sedation that affects 10-15% of adults during the first week of treatment.

For hundreds of years, leaves from Datura stromonium have been used in the treatment of asthma; recently, the use of antimuscarinic agents in asthma has gained a greater popularity particularly after the advent of a more selective quaternary ammonium derivative of atropine, ipratropium bromide. Its selectivity, being poorly absorbed and does not enter the central nervous system readily, allows high availability to airway muscarinic receptors.

Corticosteroids Corticosteroids are becoming a main stay in the treatment of asthma. This is not surprising considering that corticosteroids are potent anti-inflammatory agents and asthma is an inflammatory disease. Their precise mechanism(s) of action is still not clearly understood; but it is likely to include a reduction in the synthesis and secretion of a number of inflammatory mediators (e.g. prostanoids and leukotrienes) and cytokines (for further details see the appropriate section in the chapter on endocrine pharmacology).

Ipratropium has been suggested to be as an alternative in patients who fail to respond adequately to β2-agonists (exhibiting adverse effects such as tremor or tachycardia). Or in combination regimen where there is failure to single-drug regimens. Ipratropium has a slow onset of action and duration of 6 hours.

Inhaled corticosteroids are used as long-term suppressive treatment of asthma; beclomethasone is the one at present marketed in Iraq. Systemically, corticosteroids are also used in asthma, i.v. preparations include hydrocortisone, dexamethasone, and methylprednisolone, while the most common oral corticosteroid preparation is prednisolone.

Over-exposure of the airway smooth muscle to β 2-agonists (in terms of frequency and magnitude of dose) is believed to contribute to reduced therapeutic effect of β 2-agonists (tolerance), a phenomenon known as downregulation . Thus, the use of the anticholinergic agent ipratropium as an alternative to single therapy or as a combination with a β 2-agonist (reduced dose) may help reduce the possibility of the development of refractoriness to β2-agonists.

Administering corticosteroids by inhalation gives the advantage of being local, thus, reduced systemic adverse effects. In addition, beclomethasone is reduced systemic adverse effects. In addition, beclomethasone is superior to others when given by inhalation. It is absorbed into the bronchial mucosa, and then into the circulation. After being administered by inhalation, a sizeable proportion is also swallowed and the absorbed, with beclomethasone, this proportion is largely metabolised during the first pass in the liver (first pass effect), consequently, little or none reaches the systemic circulation. This is not the case with the other oral corticosteroids (e.g. prednisolone). Administering corticosteroids by inhalation carries the risk of candidiasis infection of the mouth (treat with nystatin

Antihistamines Antihistamines of the H1-type are not effective unless bronchospasm is part of an acute allergic reaction like anaphylactic shock.

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Table 9.1. A summary of selected drugs used in asthma

Drug (class) β 2-agonists Short-acting: Salbutamol Terbutaline Long-acting: Salmeterol Formoterol Leukotriene antagonists Montelukast Zafirlukast

Nature of action Bronchodilator and Anti-inflammatory

Zileuton

Inhibits lipooxygenase

Methylxanthines Theophylline (Aminophylline)

Inhibits phosphodiesterase, Bronchodilator and Anti-inflammatory

Sodium cromoglycate Corticosteroids

Important remarks Risk of tolerance Aerosol, nebulising solution, oral (tablets), i.v. Aerosol

Prevent bronchoconstriction by blocking cysLTl receptor

Orally effective, once or twice daily

Anti-inflammatory

Risk of hepatotoxicity Orally effective, multiple daily dosing is required Oral (theophylline) and (aminophylline) i.v. (aminophylline) Low therapeutic index Aerosol, prophylactic use, not useful in acute attacks

Anti-inflammatory

Beclomethasone Hydrocortisone Methylprednisolone

(low potency) (intermediate potency)

Dexamethasone

(high potency)

Prednisolone

(intermediate potency)

Ipratropium bromide

Blocks muscarinic receptors Bronchodilator Anti-inflammatory

Aerosol, prophylactic use, not useful in acute attacks i.v., useful in acute attack i.v. i.v. Most commonly used oral corticosteroid Aerosol, nebulising solution

depressant effect on the respiratory centre and are relatively non-addicting (in comparison with morphine and methadone. Cough suppressants are useful when sleep is disturbed by a dry (non-productive) cough. They are harmful in patients with bronchiectasis and bronchitis, since they may dry (leading to sputum retention). They are generally not needed in acute bronchitis and pneumonia. Usually antitussive treatment has to be an adjunct to antibiotic and bronchodilator therapy.

COUGH MEDICINES Antitussives The most important antitussive drugs are morphine-related agents including codeine (methylmorphine), noscapine, pholcodine and dextromethorphan that have a central action. They are thought to produce their antitussive activity primarily by raising the threshold of the medullary cough centre to afferent cough impulses. These have little

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Adverse effects of codeine occur rarely if low doses are used. The most common adverse effects are nausea, sedation and anorexia. With higher doses constipation and biliary colic may be a problem. Dextromethorphan and noscapine have few side effects and no addictive properties. For more details about the morphine-related agents see later section on narcotic analgesics (CNS Pharmacology).

Decongestants Various decongestants may be found in cold medicines: these are especially antihistamines and sympathomimetics. The anti-histaminics are included not only with the aim to counteract allergy swelling but also due to their anticholinergic effect on the nasal mucosa. This drying effect may be desirable against excessive thin nasal secretions (rhinorrhea) but hazardous particularly in lower respiratory tract involvement since this drying effect may lead to mucous plugging of small bronchi (sometimes inducing cough). Antihistamines are best effective in seasonal rhinitis and conjunctivitis (hay fever), in which these drugs relieve the sneezing, rhinorrhea, and itching of eyes, nose, and throat. Sympathomimietics can produce side effects due to cardiac stimulation with palpitations and increased blood pressure. Topical corticosteroid nasal preparations such as beclomethasone, fluticasone or triamcinolone are also used for nasal allergy symptoms.

Expectorants Expectorants reduce the viscosity of respiratory tract secretions and facilitate the removal of accumulated mucus and phlegm by ciliary action and coughing. They are thought to achieve this effect by stimulating the flow of thin, watery secretions within the respiratory tract, possibly by a reflex involving the vagus nerve and initiated by an effect of the expectorant on the stomach following oral administration. By increasing respiratory tract secretions, expectorants may also soothe dry, irritated tissues and in so doing reduce the urge to cough. They may also make a dry, unproductive cough more productive.

RESPIRATORY STIMULANTS Respiratory stimulants (analeptics) such as nikethamide and doxapram are of little value in the treatment of respiratory failure induced by barbiturates over-dosage ( or other CNS depressants). In such cases the sooner the patient is attached to a respirator the better. They are indicated in some acute respiratory failure , in an attempt, to obviate tracheal intubation and mechanical ventilation.

However, there is still no scientific evidence that expectorants (or demulcents) are of any therapeutic value, but may have a useful placebo effect. The sub-emetic doses of ammonium chloride, and ipecacuanha contained in many cough mixtures do not promote expectoration. There is a long list of substances that are claimed to have expectorant, mucolytic, or demulcent actions, e.g. acetylcysteine, glyceryl guaiacolate, bromhexine, and sodium citrate.

Adverse-effects: sweating, anxiety, nausea and vomiting, cardiac arrhythmias, hypertension and these drugs have low therapeutic index and can readily induce convulsions and coma.

Warm steam from a vaporiser is much more effective.

Contraindications: respiratory failure due to neurological or muscular disorder or due to drug toxicity, status asthmaticus, and ischaemic heart disease.

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Table 9.2. A summary of selected drugs used in cough medicines, and some centrally acting respiratory stimulants. Drug (class)

Nature of Important remarks action Raising the Useful when sleep is disturbed by dry Antitussives Codeine threshold of the cough Noscapine medullary cough Harmful in patients with bronchiectasis and Pholcodeine centre to afferent bronchitis (promoting sputum retention) Dextromethorphan cough impulses Butamirate citrate Centrally acting Unrelated to the opium alkaloids (Sinecod ) Possibly by: Expectorants ( demulcents, Expectorants Ammonium chloride Stimulating the flow of thin, mucolytics) Ipecacuanha watery secretions within Bromhexine airways, thus, soothing dry Warm steam is more effective! Acetylcysteine irritated tissues & making a Glyceryl guaiacolate dry (unproductive) cough Sodium citrate more productive. Allergic rhinitis and conjunctivitis Decongestants Antihistamines may Antihistamines (Hay fever: rhinorrhoea, sneezing possibly act by: (Sedative) and itching of eyes, nose, and 1.counteracting allergy throat) Chlorpheniramine swelling Mepyramine 2.also anticholinergic Diphenhydramine For rhinorrhoea associated with effect against Triprolidine common colds and allergies excessive nasal Promethasine secretions (Non or less sedative) They can be hazardous in lower Cetirizine respiratory tract involvement Loratidine since they may lead to mucous Astemizole plugging of small bronchi. Sympathomimetics Ephedrine Pseudoephedrine Phenylpropanolamine

Respiratory stimulants (Analeptics) Nikethamide Doxapram

Cause vasoconstriction by activating vascular α-adrenoceptors

Topical decongestants should not be used for longer than 3 days to prevent rebound nasal congestion (rhinitis medicamentosa).

In high doses, they can cause hypertension, headache, palpitations, cardiac arrhythmias and psychiatric disorders. Cautions: hypertension, hyperthyroidism, coronary heart disease Stimulate the medullary Useful in some cases of acute respiratory centres respiratory failure Contraindications: ischaemic heart disease, status asthmaticus, severe hypertension and thyrotoxicosis Low therapeutic index

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HYPOTHALAMIC AND PITUITARY HORMONES Introduction

Thyrotropin (TSH) is a glycoprotein acts on the thyroid to cause cellular hyperplasia, increased uptake of iodine and secretion of thyroxin (T4) and triidothyronine (T3). The amount released is controlled by circulating hormone levels acting on the hypothalamic release of thyrotropin-releasing hormone (protirelin, TRH). TSH may be used clinically to assess the power of thyroid gland to respond to pituitary stimulation.

Various physiological activities, such as metabolism, growth, and certain aspects of reproduction are under neuroendocrine control. The hypothalamus is connected to the pituitary gland by a stalk composed of neurosecretory fibres and portal venous system transporting substances from the hypothalamus to the anterior pituitary gland; this system is called the hypothalamichypophyseal portal venous system. Further, the hormones of the posterior lobe are synthesised in the hypothalamus and transported through the neurosecretory fibres in the stalk of the pituitary to the posterior lobe. The latter serves as a store from which the hormones are released to the circulation. The intermediate lobe of the pituitary gland releases hormones that have melanocytestimulating activity. In animals, the role of these hormones is clear, serving as adaptive mechanisms for skin colour changes. However, in human the role of these hormones is still not clear.

Growth Hormone (Somatropin, GH) GH is released from the anterior pituitary in response to growth hormone releasing hormone produced by the hypothalamus. Somatropin acts on all tissues to promote their growth. Administration causes an acceleration of bone growth but not bone age, unlike the sex hormones that cause both an acceleration of bone growth and an increase in bone age with premature fusion of the epiphysis. GH is extremely species specific and the therapeutic uses are limited. As it is a polypeptide it must be given parenterally. Somatropin is useful in the treatment of GH deficiency in children. Before starting somatotropin therapy, it is essential to check that there is normal thyroid function. The actions of somatropin appear to last much longer than the t (25 minutes) of somatotropin. This is because the latter induces the release from the liver of somatomedins (insulin-like growth factors) that are responsible for the subsequent somatropin-like actions. Somatropin is a diabetogenic hormone causing a rise in the blood glucose, and glucose tolerance falls.

The control of secretion is a feedback system in which falling levels of circulating adenohypophyseal hormones provoke the secretion of the appropriate releasing hormone. Generally, hormones including the hypothalamic hormones have the following clinical applications: 1. Replacement therapy for hormone deficiency conditions 2. Pharmacological therapy (pharmacological doses producing a hormonal action that is not present at physiological blood levels) 3. Diagnostic (stimulation tests to diagnose hypo- or hyperfunctional endocrine states.

Overproduction of somatotropin is usually causes gigantism if the epiphyses have not united and acromegaly after they have united.

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Prolactin is a peptide hormone with a structure resembles that of growth hormone (GH). It is the principal hormone responsible for lactation (milk production). In hypothalamic destruction, prolactin levels may be elevated as a result of impaired transport of prolactin-inhibiting hormone (dopamine) to the pituitary. In symptomatic hyperprolactinaemia, inhibition of prolactin secretion can be achieved with bromocriptine and other dopamine agonists, e.g. bromocriptine and pergolide. In contrast, drugs decreasing dopaminergic activity by the hypothalamus cause an impressive increase in prolactin secretion rate (e.g. the phenothiazines, reserpine, methyldopa, and metoclopramide).

Gonadotropin-Releasing Hormone (GnRH) Pharmaceutical GnRH is synthetic (e.g. leuprolide and goserelin). Pulsatile (every 14 hours) intravenous administration stimulates follicle-stimulating hormone (FSH) and luteinising hormone (LH) secretion. On the other hand, GnRH given continuously or GnRH analogues administered in depot formulations inhibit gonadotropin release.

Indications of GnRH 1. Hypothalamic hypogonadotropic hypogonadism (infertility in both sexes, pulsatile administration of GnRH driven by a portable batterypowered programmable pump, stimulates pituitary function) 2. Prostatic cancer, uterine fibroids, endometriosis, polycystic ovary syndrome, and precocious puberty (GnRH analogue agonists, e.g. triptoreline, leuprolide and goserelin, suppress pituitary function when administered continuously)

Indications of Dopamine Agonists 1. Prolactin-secreting adenomas (bromocriptine reduces both tumour size and serum prolactin levels in about 85% of patients for 6 months) 2. Amenorrhoea and Galactorrhoea (bromocriptine is useful in the treatment of hyperprolactinaemiainduced disorders like amenorrhoea, galactorrhoea, infertility, and hypogonadism) 3. Physiological lactation (bromocriptine is useful in the prevention of breast engorgement when breast feeding is not desired, e.g. when loss of baby) 4. Acromegaly (some acromegalic patients respond to bromocriptine) 5. Parkinson s disease (see appropriate section in CNS pharmacology) 6. Hirsutism in women (due to hyperprolactinaemia; in the adrenal cortex, prolactin increases dehydroepiandrosterone sulphate, and thus, increases androgen synthesis)

Gonadotropins Effective secretion of gonadotropins does not begin till puberty that they initiate. They also control and regulate the development of the gonads and secondary sex characters.

Follicle-Stimulating Hormone (FSH) It stimulates the formation of the ovarian follicle, in the female and spermatogenesis in the male.

Luteinising Hormone (LH) In the female, this hormone is concerned with the maturation of the ovarian follicle, ovulation and the formation of the corpus luteum. In the male, it stimulates the interstitial cells of the testes to secrete androgens. Note: Opioids decrease the release of both FSH and LH.

Adrenocorticotropic Hormone (Corticotropin, ACTH) ACTH is a polypeptide and its function is to stimulate the synthesis and release of adrenocorticosteroids, particularly, cortisol (hydrocortisone). The control of the secretion

Prolactin

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of ACTH is by the hypothalamic feedback system involving corticotropin-releasing hormone. If the blood level of adrenal corticosteroid is high, the secretion of ACTH is depressed and vice versa. Any nervous stimulation, trauma, endotoxin, stress or anxiety may also release ACTH releasing hormone. Insulin hypoglycaemia is used as test of anterior pituitary function, ACTH and growth hormone are released. In the normal person there appears to be a diurnal variation in corticosteroid release with high levels in the early morning and low levels in the late evening due to a similar variation in ACTH release.

labour. Oxytocin also plays an important role in process of milk ejection.

ACTH is given therapeutically to obtain adrenocortical effects or to stimulate an inactive adrenal cortex. It does not cause muscle wasting as it stimulates both the secretions of androgens and glucocorticoids. Cortisol, given on its own, can cause muscle wasting, as the catabolic action is now predominant. ACTH is not active by mouth and, as it is a peptide, may cause sensitivity reactions. Synthetic ACTH known as tetracosactrin has replaced ACTH for clinical use (See section on adrenocorticoids).

ADH is an octapeptide differing in only two amino acids when compared with oxytocin. The major action of vasopressin is to reduce water clearance by the kidney. In the absence of vasopressin the distal convoluted tubules and collecting ducts are virtually impermeable to water. Vasopressin also constricts vascular smooth muscle and causes a rise in blood pressure, bronchoconstriction, intestinal colic and stimulation of the bladder, though larger doses are necessary than to produce antidiuretic effect.

The major use of oxytocin is to induce labour for which it is given by slow intravenous infusion. It cannot be given by mouth as it is destroyed, but can be given intramuscularly, subcutaneously or sublingually, control by these routes is not likely to be so effective as by intravenous methods.

Vasopressin (Antidiuretic Hormone, ADH)

Clinically, vasopressin is used mainly to control the urine output in pituitary diabetes insipidus in which there is insufficient production of the natural hormone. As no reabsorption then occurs in the collecting tubules, the daily urine output may be as much as 10-20 litres. It is inactive by mouth and given parenterally or intranasally.

Posterior Pituitary Hormones The posterior lobe or neurohypophysis produces two hormones, oxytocin and vasopressin. These are formed in the neurones of the supraoptic and paraventricular nuclei of the hypothalamus. They are also released by various physical and mental stresses such as haemorrhage, sucking and coitus. The afferent pathways are to the cell bodies and not the neurosecretory terminals and there is evidence of differential secretion.

Indications of Vasopressins 1. Diabetes insipidus 2. Local anaesthesia (as a vasoconstrictor in conjunction with local anaesthetics, instead of adrenaline, being safer) 3. Child nocturnal enuresis (on holidays, given intranasally) 4. Bleeding oesophageal varices (i.v. infusion)

Oxytocin Oxytocin causes a rapid increase in the tone and motility of the uterus particularly in the presence of oestrogens, probably by an effect on electrical and contractile activity. The sensitivity of the uterus is maximal at term and plays a part in the normal process of

Diabetes Insipidus Pituitary diabetes insipidus is usually reflects reduced level of ADH release. It responds to

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ADH, felypressin and desmopressin (ADH agonists). The oral hypoglycaemic agent chlorpropamide is effective in partial pituitary diabetes insipidus, because it acts on the kidney potentiating the effect of ADH on the renal tubule. Different clinical conditions and iatrogenically (e.g. demeclocycline, lithium) can produce nephrogenic diabetes insipidus. It may respond paradoxically to diuretic agents like thiazides (including diazoxide).

Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) In SIADH, there is an abnormal level of release of ADH that may lead to chronic (dilutional) hypokalaemia. Demeclocycline (a tetracycline) produces a state of unresponsiveness to ADH by an action on the renal tubule; it is therapeutically useful in this condition.

Table 10.1. A summary of the use of (vasopressins) and drugs used in ADH-related disorders. Agent Demeclocycline

Action Reduces ADH renal action

Vasopressin

Vasopressin receptor (V1 & V2) agonist

Desmopressin

V2-receptor agonist (devoid of presser Pituitary diabetes insipidus effect, H2O-channel (aquaporin) Nocturnal enuresis Haemophilia (promote the effect of von Willbrand s factor, VIII)

Chlorpropamide

Potentiates ADH action

Partial pituitary insipidus

diabetes

Carbamazepine

Potentiates ADH action

Partial pituitary insipidus

diabetes

Thiazides

Paradoxical

Nephrogenic insipidus

diabetes

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Use SIADH Pituitary diabetes insipidus Local anaesthesia Nocturnal enuresis Bleeding oesophageal varices

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Table 10.2. A summary of hypothalamic-pituitary-peripheral organ hormones and their end effects. Hypothalamus Clinical uses CRH

TRH

Anterior pituitary (+) ACTH Tetracosactrin

Peripheral target Adrenal cortex

(ACTH analogue) (+) TSH

Effects (release of) Glucocorticoids Mineralocorticoids Androgens

Thyroid

Thyroxine

Ovary

(formation of ovarian follicle) (Oestrogen)

Testis

Spermatogenesis

Ovary

Maturation of ovarian follicle, ovulation & formation of corpus luteum (Oestrogen, Progesterone)

Testis

Testosterone

Breast

(enlargement, formation)

Gonads

(Antagonises Gn action, thus anovulatory infertility (FSH-LH) Erectile impotence (LH-effect) Male infertility (FSH-effect)

Adrenal cortex Liver

Androgens, thus hirsutism in women Somatomedin Both GH & somatomedin promote protein synthesis, cell proliferation & growth formation.

(+) FSH GnRH 1. Hypothalamic hypogonadotropic hypogonadism (infertility in both sexes, pulsatile (+) LH administration of agonist, e.g. triptoreline, leuprolide & goserelin) 2. Prostatic cancer, uterine fibroid, endometriosis, polycystic ovary syndrome, & central precocious puberty (given continuously) Dopamine (DA2-receptor agonists)* (-) Prolactin 1. Prolactin secreting adenomas (agonist, e.g. bromocriptine) 2. Amenorrhoea, galactorrhoea, infertility, & hypogonadism 3. Physiological lactation 4. Acromegaly 5. Parkinsonism 6. Hirsutism (due to hyperprolactinaemia, adrenal androgens are increased by prolactin) GHRH (+) GH Somatropin (GH analogue) 1. Childhood pituitary insufficiency Somatostatin (-) GH Octreotide (somatostatin analogue) 1. Acromegaly 2. Carcinoid tumour

milk

(+) Stimulates the release of (-) inhibits the release of * Drugs decreasing dopaminergic activity by the hypothalamus cause an impressive increase in prolactin secretion rate (e.g. the phenothiazines, reserpine, methyldopa, and metoclopramide). DA-antagonists like metoclopramide are used to increase milk production in conditions like nursing mothers with low milk production.

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SEX (GONADAL) HORMONES AND INHIBITORS leading to increased pituitary secretion of gonadotropins; thus, they are used to induce ovulation in patients with anovulatory infertility.

Non-pituitary Gonadotropins Human chorionic gonadotropin Human chorionic gonadotropin (hCG, Pregnyl ) is mainly luteinising, secreted by the placenta and is found in the urine shortly after the start of pregnancy. It is the basis of such pregnancy diagnostic tests as the Ascheim-Zondek. It is also secreted by various tumours such as hydatidiform mole, chorionepithelioma and testicular teratoma.

Oestrogen receptors Oestrogens binds to specific nuclear receptor that is a member of superfamily of receptors, including those for thyroxine and vitamin D. the oestrogen-receptor complex interacts with nuclear chromatin producing transcription of specific mRNA responsible for the expression of specific proteins that mediate certain biological functions depending on target tissues.

Serum gonadotropin Serum gonadotropin (PMSG, Humegon ) is found in the serum of pregnant mares and is of endometrial origion. It has mainly follicle stimulating action and some luteinising action.

Indications of Oestrogens 1. Oral contraception 2. Uterine dysfunction 3. Menopausal and postmenopausal symptoms (e.g. hot flushes, age-related loss of bone, and atrophic vaginitis; oestrogen replacement therapy; oestrogen provides a protective effect against cardiovascular disease by decreasing LDL and increasing HDL levels in plasma)

Menotropins Menotropins (human menopausal gonadotropins, hMG, Pergonal ) are partially metabolised human FSH and LH extracted from the urine of postmenopausal women. They must be given by injection and have been found to be of use in the treatment of cryptorchism (failure of testes to descend into the scrotum), infertility, and delayed puberty.

Adverse Effects 1. Nausea and vomiting 2. Menstrual disorders 3. Breast enlargement 4. Thromboembolic disorders 5. Oedema 6. Hypertension 7. Endometrial cancer 8. Decreased lactation 9. Increased binding globulins cortisol, thyroxine, iron)

Oestrogens, Progestins, Androgens & inhibitors Oestrogens The most important oestrogen produced by the ovaries is oestradiol that is partly converted by the liver to less active oestrone and oestriol. This means that natural oestrogens are not very active when given orally whereas synthetic oestrogens on the other hand (ethinyl oestradiol and stilboestrol) are active orally. Plasma oestrogen inhibits FSH and LH release by an action on the hypothalamus. Clomiphene and cyclofenil and tamoxifen block oestrogen receptors at the hypothalamus

(for

Progestins The main natural one secreted by the corpus luteum is hydroxyprogesterone that like oestrogen is relatively inactive when given orally because it is rapidly metabolised in the liver. Plasma progesterone inhibits LH release by an action on the hypothalamus.

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Table 10.3. Selected oestrogens and their indications Oestrogen

Table 10.4. Selected progestins and their indications

Indications

Progestin

Indications

Oestradiol (IM)*

Primary amenorrhoea

Allyloestrenol

Habitual abortion

Oestriol (oral)

Postmenopausal vaginal & vulval conditions

Hydroxyprogesterone caproate (Primolut Depot , oily)

Habitual abortion

Stilboestrol (oral)

Menopausal symptoms Amenorrhoea Prostatic cancer

Medroxyprogesterone acetate (Depo-Provera , IM)

Ethinyloestradiol Mestranol

Oral contraceptive Oral contraceptive

Endometriosis Dysfunctional uterine bleeding Secondary amenorrhoea Contraception

Norethisterone (Primolut N , oral)*

Endometriosis Dysfunctional uterine bleeding Dysmenorrhoea Postponement of menstruation Fasting in Ramadan, & pilgrimage (Haj)

* Oestradiol is largely inactivated by first pass metabolism when administered orally.

Indications of Progestins 1. Oral contraception 2. Uterine dysfunction 3. Habitual abortion 4. Postponement of menstruation

Norgestrel Oral contraceptive * Also available in tablet form; the indcation limits the use of certain dosage forms.

Adverse Effects of Progestins

Oral Contraception

1. Weight gain 2. Irregular menstruation 3. Adverse changes in lipoprotein levels (↑LDL & ↓HDL) 4. Adverse effects on foetus (virilisation) 5. Abnormal glucose tolerance (diabetogenic)

Combined oestrogen-progestin oral contraceptive pills are the most common. The principle is suppression of the release of pituitary gonadotropins, by action on the hypothalamus inhibiting the release of GnRH and thus the pituitary that results in impaired follicular maturation and inhibition of ovulation. This effect is dose-related, therefore, occasional ovulation is more likely with 20-30 µg than with 50 µg oestrogen pills. In addition, there are peripheral effects on cervical mucus becomes more viscous and hinders the movement of the spermatozoa, and the state of the endometrium is disturbed so that implantation is less likely to occur. The oestrogen usually is ethinyloestradiol and various synthetic progestogens such as norgestrel. One tablet is taken during 21 days followed by a 7-day interval during which withdrawal bleeding occurs.

Note: A progestin with least androgenic activity is preferred to avoid adverse effects (musculinisation) on female foetus. This is particularly true when used in habitual abortion. Note: An oestrogen alone can inhibit ovulation; however, oestrogen can cause thromboembolism and endometrial cancer, adding a progestin can lessen the possibility of the unwanted latter effects. Oral contraceptives contain higher doses of oestrogen than those used in oestrogen replacement therapy do.

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2. Stroke 3. Myocardial infarction 4. Hypertension 5. Hepatic function impairment 6. Decreased glucose tolerance (insulin antagonism)

hypothalamic receptors and does not cause liver injury. Drugs with antiandrogenic activity are spironolactone, ketoconazole, digoxin and cimetidine.

Progestin Only Contraceptive

Male hypogonadism, and for libido and potency, when fertility is desired testosterone should be replaced by gonadotropin therapy. Danazol is a partial (impeded) androgen agonist, danazol inhibits pituitary gonadotropin secretion leading to secondary endometrial atrophy; thus, it is useful in endometriosis (ectopic growth of the endometrium), precocious puberty, gynaecomastia and menorrhagia.

Indications of Androgens

Progestin alone is also used as oral and parenteral contraceptive. It is less reliable than combined preparations; inhibits ovulation in up to 40% of cycles, makes it more difficult for sperm to penetrate cervical mucus and prevents implantation as a result of inducing premature endometrial secretary phase. They are used as alternatives when oestrogens are contraindicated or not tolerated, and in heavy smokers (in whom oestrogen significantly increases the risk endometrial cancer).

Mesterolone (androgen) 1. Acts intratesticularly (essential for the action of FSH in spermatogenesis) 2. Has less hypothalamic negative feedback 3. Is useful in infertility 4. It does not cause liver injury

It should be stressed that progestin only (contraceptive) pill is useful in lactating women. It has the advantage of being a contraceptive on its own, and unlike oestrogen, progestins spare lactation that itself also has contraceptive actions.

Cyproterone Androgens

It is an antiandrogen with progestogenic activity. It causes reversible inhibition of spermatogenesis and infertility, probably by blocking gonadotropin release via activating the inhibitory hypothalamic progestogen receptors, and reduces male sexual function, at least in part, by competing with testosterone for target receptors.

The most important androgen is testosterone that is produced by interstitial cells of the testes. LH stimulates its synthesis. It is necessary for male sexual function. Circulating testosterone inhibits LH secretion and only in large doses it reduces plasma FSH (hypothalamic feedback inhibition of pituitary gonadotropin secretion). Thus, suppression of spermatogenesis is a side effect of testosterone therapy. Inhibin, a factor of testicular origin (Sertoli cells) inhibits FSH secretion. Androgens also have anabolic action, promoting growth, developing and maintaining muscle mass and preventing osteoporosis. Testosterone itself is only weakly active because of hepatic breakdown. Testosterone derivatives, fluoxymesterone and mesterolone are androgenic substances, active when given by mouth that is used in replacement therapy. Mesterolone is less effective on

Indications of Cyproterone 1. Severe hypersexuality 2. Sexual deviation in men 3. Severe hirsutism in females

Anabolic Steroids They are synthetic androgen like nandrolone phenpropionate (Durabolin ) and nandrolone decanoate (Deca-Durabolin ). These agents are not acted upon by 5αreductase, thus, are not converted to dihydrotestosterone, therefore, less virilising; 225

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Ramadi, 11 October 2009

this makes anabolic steroids superior to testosterone and hence have been introduced as anabolic agents. They are useful in aplastic anaemia (preferred agent is oxymethalone), severe wasting, and osteoporosis. The most important adverse effects of anabolic steroids include liver cancer.

• In males 1. Priapism 2. Impotence 3. Gynaecomastia 4. Decreased spermatogenesis • In children 1. Premature closure of the epiphyseal plates 2. Abnormal sexual maturation

Adverse Effects of Androgens • In females 1. Musculinisation with acne, growth of facial hair, deepening of the voice, male pattern baldness, and excessive muscle development. 2. Menstrual irregularities

• •

Increase LDL/HDL ratio Oedema (fluid retention)

Table 10.5. A summary of agents used in oral contraception Agent Oestrogens

Progestins

Mode of Action Inhibit hypothalamic release of GnRH → ↓ pituitary Gn → ↓ follicular maturation & ovulation 1. Inhibit ovulation in 40% of cycles 2. Slow movements of spermatozoa 3. → Endometrial disturbance (premature secretary phase) → inhibit implantation

Important Remarks Decrease LDL/HDL ratio Adverse effects: Thromboembolism Endometrial cancer Adverse effects: Break-through bleeding Adverse changes in lipoprotein levels (↑ LDL/HDL ratio) Abnormal glucose tolerance (diabetogenic) Useful when: 1. Oestrogen not tolerated 2. Heavy smokers 3. Lactating women

Progestin only Oral Parenteral

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Table 10.6. A summary of sex hormones and their antagonists Agent Non-pituitary

Primary Action

Chorionic gonadotropin

(LH-agonist, Pregnyl )

Serum gonadotropin

(PMSGn, FSH & LH, Humegon )

Menotropins

Oestrogens

(postmenopausal urine, FSH & LH, Pergonal ) Reduce Gn release

Oestradiol (IM) Oestriol (oral) Stilboestrol (oral) Ethinyloestradiol (oral) Mestranol (oral)

(Antagonists) Clomiphene Cyclofenil Tamoxifen

Cryptorchism (failure of testes to descend into the scrotum) Infertility Delayed puberty Contraceptive pill Menstrual disorders Menopausal symptoms (hot flushes) Postmenopausal symptoms (osteoporosis) Prostatic cancer Ovarian failure (replacement)

Oestrogen receptor Partial agonist Partial agonist Antagonist

Anovulatory infertility Male infertility

Reduce LH release

Contraceptive pill Menstrual disorders Endometriosis Ovarian failure (replacement) Habitual abortion*

Androgenic & anabolic effects (-ve hypothalamic & pituitary feedback)

Male hypogonadism Increase libido & potency (Use Gn when fertility is desired)

Progestins Hydroxyprogesterone caproate Medroxyprogesterone acetate Norethisterone Norgesterol (oral)

Use

Androgens Testosterone propionate (IM) Methyltestosterone (oral) Nandrolone phenpropionate Nandrolone decanoate

Anabolic (largely)

Severe wasting Osteoporosis Aplastic anaemia

Mesterolone

Acts intratesticularly promoting the action of FSH in spermatogenesis

Infertility

Danazol

Androgen partial agonist

Gynaecomastia Precocious puberty Menorrhagia

Reduces Gn release (endometrial atrophy)

Endometriosis

Androgen receptor antagonist

Hirsutism Hypersexuality (sexual deviation in men) Prostatic cancer

Progestogenic activity due to the acetate form (reduces Gn release)

Male contraceptive (?)

Finasteride Ketoconazole Spironolactone

5-α reductase inhibitor Antiandrogen (synthesis inhibitor)

Benign prostatic hyperplasia Cushing s syndrome Prostatic cancer

Flutamide Spironolactone

Androgen receptor antagonist

Prostatic cancer

Androgen antagonists Cyproterone acetate

* With least androgenic activity to avoid musculinisation of female foetus.

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Endocrine Pharmacology - Drugs Acting on Uterine Smooth Muscle

Ramadi, 11 October 2009

DRUGS ACTING ON UTERINE SMOOTH MUSCLE 2. Coitus 3. Suckling 4. Emotional stimuli 5. Some drugs (e.g. nicotine)

Introduction Uterine contractions are rhythmical or sustained as shown in Fig.10.1. For induction of labour rhythmic contractions are important and after delivery sustained contractions in order to minimise bleeding.

morphine

&

During pregnancy, a specific enzyme oxytocinase exists for its degradation. Oxytocin has a vasodilator action and hence a side effect is hypotension, thus it should not be given in ischaemic heart disease. With large doses an ADH-like activity can be observed with water retention. Oxytocin is used to induce labour at term. Oxytocin nasal spray may be used to facilitate breastfeeding.

Normally uterine smooth muscle is stimulated by α1-adrenoceptors and inhibited by β 2-adrenoceptors. At term, oxytocin stimulation is very important. Oxytocin probably partly acts by local liberation of prostaglandin E2. Uterine stimulant drugs used in obstetrics are: 1. Oxytocin (for induction of labour at term) 2. Prostaglandin E2 (for induction of labour before term, i.e. in abortion) 3. Ergometrine (after delivery)

Adverse Effects of Oxytocin 1. Uterine rupture 2. Rebound atonia 3. Hypotension (hence, caution in ischaemic heart disease) 4. Water intoxication (upon prolonged administration that characterised by headache, nausea, vomiting, confusion and coma; this is because oxytocin has weak antidiuretic properties and acts like vasopressin to increase tubular reabsorption of water.)

Oxytocin

Sustained Rhythmic

Prostaglandins PGF2α and PGE2 induce labour at any time during pregnancy and therefore are used mainly as abortifacient. Prostaglandin synthesis inhibitors such as indomethacin and aspirin can prolong labour but can induce premature closure of the ductus arteriosus and lead to pulmonary hypertension in the baby.

Fig. 10.1. A schematic representation of the effect of oxytocin. Note: Oxytocin increases the rhythmic contractions.

Oxytocin Oxytocin (Pitocin , Syntocin ) is an octapeptide, released from the posterior pituitary where it is stored after being synthesised in the paraventricular and supraoptic nuclei. Oxytocin is now available as a synthetic drug. The release of oxytocin is governed by neuronal mechanisms elicited by:

Adverse Effects 1. Abdominal cramps (both PGF2α and PGE2) 2. Bronchospasm (PGF2α)

1. Cervical dilatation

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Ergometrine

Uterine Relaxants (Tocolytics)

Ergometrine is only used in the 3rd stage of labour and postpartum haemorrhage. Ergometrine is synonymous to ergonovine and acts through α and dopamine receptors. Its action is more prolonged than oxytocin and may last 3-6 hours.

Uterine relaxation can be brought about by β2-receptor agonists such as terbutaline, salbutamol or ritodrine. These drugs are used to prevent preterm labour. Uterine contractions can also be reduced for the prevention of dysmenorrhoic pain (uterine cramps). For this purpose non-steroidal antiinflammatory drugs (NSAIDs) can be used such as ibuprofen, indomethacin and naproxen. Naproxen can be given 3-4 times daily prior to the expected menstrual period. It has been shown that prostaglandin levels are increased in patients with dysmenorrhoic pain. NSAIDs not to be used during pregnancy (risk for closure of patent ductus arteriosus). General anaesthetics, particularly halothane relaxes uterine smooth muscle. Papaverine and amyl nitrite relax the cervix.

Adverse Effects of Ergometrine 1. Nausea 2. Hypertension 3. Decrease lactation (being ergot alkaloid, it interferes on the level of the hypothalamus, like bromocriptine, reducing the release of prolactin and thus decrease lactation)

Table 10.7. A summary of selected drugs acting on uterine smooth muscle Agent Oxytocin

Action Indication Via oxytocin receptors → Induction of labour at term PGE2 → contraction

Adverse Effects Uterine rupture Rebound atonia Hypotension Water intoxication

PGE2, PGF2¿

Uterine contraction

Abdominal cramps ( PGF2α and PGE2) Bronchospasm (PGF2α)

Ergometrine (Ergonovine)

Via α1-receptors contraction

→ Postpartum haemorrhage

Salbutamol Terbutaline Ritodrine

Via β2-receptors relaxation

→ Prevention preterm labour

NSAIDs

Reduce PGs production → Dysmenorrhoic pain ↓ uterine contraction

Induction of labour (before term, abortion)

229

Nausea Hypertension Decrease lactation of See appropriate section.

See appropriate section.

Endocrine Pharmacology - Adrenocorticosteroids

Ramadi, 11 October 2009

ADRENOCORTICOSTEROIDS Fig.10.2. The mechanism of action of cortisol is illustrated in Fig.10.3.

Introduction All hormones released from the adrenal cortex are steroids and known as corticosteroids. The adrenal cortex consists of three distinct layers of secretary cells.

Diurnal rhythm of cortisol levels reflects ACTH release with peak level at about 8:00 hours and trough at midnight. Feedback inhibition of ACTH release and ACTH-RH (corticotropin releasing hormone) is mediated by circulating cortisol. About 95% of cortisol is bound in circulation to corticosteroid binding globulin (CBG, transcortin). The level of CBG also varies with maximum binding at midnight and minimum at about 8:00 hours.

1. Zona glomerulosa (outermost layer, secrets mineralocorticoids) 2. Zona fasciculata (middle layer, secretes glucocorticoids) 3. Zona reticularis (inner layer, secretes small amounts of glucocorticoids and gonadocorticoids)

Therapeutic Uses of Glucocorticoids

Mineralocorticoids

Replacement Therapy

Aldosterone is responsible for maintenance of sodium homeostasis in the blood by increasing sodium reabsorption in the kidney. It also increases water retention and promotes the loss of potassium and hydrogen ions. Aldosterone secretion is controlled by the renin-angiotensin system and by blood sodium and potassium concentration.

Replacement in adrenocortical insufficiency disorders (including Addison s disease, and adrenal crisis) in which physiological concentrations (low doses) are required. The preferred agent in this condition is cortisone acetate.

Pharmacotherapy

Excessive aldosterone secretion (hyperaldosteronism as in Conn s syndrome) is characterised by sodium retention (and hypertension), potassium loss (and muscular weakness). The aldosterone receptor antagonist spironolactone may be useful in this condition.

Cortcosteroids are used for the treatment of adrenal disorders and also for diagnostic purposes; they are more frequently used for nonadrenal disorders, e.g. suppression of inflammatory responses, given systemically (usually in high doses) or topically. The following are some therapeutic indications for the use of glucocorticoids.

Impaired aldosterone secretion, exhibited in Addison s disease, contributes to hyponatraemia, hypovolaemia and hypotension. The use of the aldosterone receptor agonist fludrocortisone is recommended in this condition.

1. Allergic reactions (e.g. drug reactions, angioneurotic oedema, allergic rhinitis, contact dermatitis, asthma, bee stings, urticaria etc.) 2. Collagen-vascular disorders [e.g. Systemic lupus erythematosus (SLE), rheumatoid arthritis, temporal arteritis) 3. Ocular diseases (e.g. acute uveitis, allergic conjunctivitis, choroditis) 4. Gastrointestinal diseases (e.g. ulcerative colitis)

Glucocorticoids The main glucocorticoids secreted by the zona fasiculata are cortisol (hydrocortisone), cortisone, and corticosterone, with cortisol the only one secreted in significant amount. They affect every cell in the body. A summary of the actions of cortisol is made in 230

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5. Haematological disorders (e.g. idiopathic thrombocytopenic purpura, acquired haemolytic anaemia, leukaemia) 6. Infections (e.g. gram-negative septicaemia, to suppress excessive inflammation) 7. Inflammatory conditions of bone joints (e.g. arthritis, tenosynovitis) 8. Neurological disorders (e.g. cerebral oedema, as in cerebrovascular accidents, anaphylactic shock, and following brain surgery, use dexamethasone) 9. Organ transplant (prevention and treatment of rejection)

10.Pulmonary diseases [e.g. bronchial asthma (oral inhalation, beclomethasone; systemic, oral prednisolone; acute severe asthma, hydrocortisone), prevention of infant respiratory distress syndrome (dexamethasone), sarcoidosis, aspiration pneumonia) 11.Minimal change (idiopathic) nephrotic syndrome (intermittent administration, prednisolone) 12.Skin diseases (e.g. atopic dermatitis) 13.(Myclonic seizures) 14.Diagnosis (hypothalamic-pituitaryadrenal function; dexamethasone test)

Table 10.8. A summary of the distinguishing characteristics of adrenocorticosteroids Agent

Plasma t (min)

Biological

t (hr)

Glucocorticoid* Effects Relative potency

Equivalent dose (mg)

Mineralocorticoid** Effects

Short-acting Cortisone acetate*** 30 12-18 0.8 25.0 1.0 Hydrocortiosone 12-18 1.0 20.0 1.0 (Cortisol) Intermediate-acting Prednisone*** 18-36 4.0 5.0 0.3 Prednisolone 60-120 18-36 5.0 5.0 0.3 Methylprednisolone 18-36 5.0 4.0 minimal Triamcinolone 18-36 5.0 4.0 none Long-acting Dexamethasone 190 36-54 30.0 0.75 minimal Betamethasone 36-54 30.0 0.75 minimal Fludrocortisone 15.0 150 Aldosterone none 500 * Antiiflammatory, immunosuppressant, and metabolic effects ** Sodium or water retention, potassium depletion *** cortisone and prednisone are inactive; when administered systemically, in the liver converted to the pharmacologically active hydrocotisone (cortisol) and prednisolone respectively. addition to producing glucocorticoid activity, it also produces androgenic activity. For this reason, tetracosactrin is gaining a good use in asthmatic children with the advantage of avoiding growth retardation.

Synthetic Corticotropin Synthetic corticotropin (ACTH) with short amino acid chains (without amino acids 2539 to which serious allergy is attributed) have been developed. Tetracosactrin is composed of the active first 24 amino acids of natural human corticotropin with t of 10 minutes. It is used for diagnosis purposes and also for glucocorticoid activity. Further, it is superior to glucocorticoids because in

High plasma concentration of any glucocorticoid agent inhibits release of corticotropin releasing hormone and therefore corticotropin. In the absence of corticotropin the cells of the inner cortex atrophy resulting in reduced production of 231

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androgens and hence reduced anabolic processes. This is probably why retardation of growth in children is associated with the use of glucocorticoids in children (in conditions like severe chronic rheumatic disease). It follows that the use of corticotropin like tetracosactrin (although it has to be given i.m.) in children can be superior to the use of glucocorticoids as the former is less likely to suppress growth in children. A long-term use of tetracosactrin, like in myclonus seizure in children, carries the risk of hirsutism.

6. Peptic ulcer (in 2% of cases) 7. Diabetes (insulin antagonism) 8. Cataracts (↑ frequency, glucose → sorbitol, hyperglyacemic toxicity) 9. Euphoria 10.Psychoses 11.Muscle wasting (↓protein anabolism, ↑protein catabolism) 12.Osteoporosis (↓ bone protein matrix) 13.Cushing-like syndrome (Moon face, buffalo hump, lemon stick, hypertension, bruising etc.; This may occur even with skin preparations particularly in children, thin stratum corneum epidermis, high % content, and potent glucocorticoids). 14.Aseptic necrosis (vasoconstriction) 15.Telangiectasia (prolonged use of topical preparation; local skin atrophy; spider-like proliferation of capillaries; abuse potential) 16.Increased appetite 17.Hypothalamic-pituitary-adrenal suppression (abrupt withdrawal results in acute adrenal insufficiency syndrome)

However, tetracosactrin is inactive when taken orally and has to be given parenterally like other peptide hormones. This makes its use largely limited for diagnostic purposes, as a test of the capacity of the adrenal cortex to produce cortisol. The plasma cortisol concentration is measured before and after an intramuscular injection of tetracosactrin.

Prednisolone has a biological t lasting serveral hours, intermediate between those of cortisol and the long-acting glucocorticoids like dexamethasone. It is this intermediate duration of action that makes it suitable for the alternate day administration regimens, which have been found to reduce the risk of cushingnoid features, adrenocortical insufficiency and growth retardation in children, yet provide adequate corticosteroid coverage in some disorders such as asthma, minimal change nephrotic syndrome and idiopathic thrombocytopenic purpura.

Inhibition of Synthesis of Adrenal Steroid Hormones Inhibitors of synthesis of adrenal steroid hormones are used in both diagnosis of adrenal disease and controlling excessive production of corticosteroids as in Cushing s syndrome (pituitary hyperfunction) or primary adrenocortical hyperfunction.

Metyrapone Metyrapone inhibits cortisol production by blocking the enzyme, steroid 11βhydroxylase that converts 11deoxyprecursors into cortisol, leading to increased release of ACTH. It is used diagnostically in the functional assessment of pituitary-adrenal axis (metyrapone test).

Adverse Effects of Adrenal Corticosteroids 1. 2. 3. 4.

Infection (increased risk) Oedema (Na+ & H2O retention) Hypertension (Na+ & H2O retention) Glaucoma (raised intraocular pressure; Na+ & H2O retention) 5. Pseudotumour cerebri (benign intracranial hypertension; a condition caused by cerebral oedema, marked by raised intracranial pressure; Na+ & H2O retention)

Aminoglutethimide Aminoglutethimide inhibits the synthesis of all active steroid hormones by blocking the conversion of cholesterol to pregnenolone. Aminoglutethimide is useful therapeutically in the treatment of breast cancer (reducing 232

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oestrogen production) concurrently administered with dexamethasone.

Ketoconazole Ketoconazole is mainly used as antifungal agent, mediating this effect by inhibiting synthesis of ergosterol in fungi. However, in man it blocks synthesis of steroids in gonads and adrenal cortex. Ketoconazole is useful in Cushing s syndrome and prostatic cancer.

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(ADDISONS)

MSH ACTH

DEPRESSION PSYCHOSIS Hallucination Euphoria CNS electrolyte changes (probably)

Ramadi, 11 October 2009

GLUCOCORTICOID ACTIONS Diabetes Muscle Wasting Protein anabolism

Insulin antagonism Gluconeogenesis (lipolysis)

Protein catabolism

FAT DEPOSITION Face, shoulder, abdomen

Na+ Mineralocorticoid

K+ Ca++

CORTISOL (Hydrocortisone)

INFECTION Leukocytes Macrophages Lymphocytes Antibodies

HYPERTENSION

Ca++

Gastric ulcer (2%)

Blood Pressure Vasoconstriction mediated by catecholamines

Vit D Osteoporosis Bone protein matrix Back Pain

CUSHING SYNDROME Moon face, buffalo hump, lemon stick, hypertension, bruising, osteoporosis (IATROGENIC)

Intraocular pressure

Aseptic necrosis Telangiectesia

Cataracts

Antiinflammatory Immunosuppressive

Immunological response

Fig. 10.2. A summary of the major actions of cortisol, actions described briefly clockwise. 1. 2.

Has protein-catabolising, gluconeogenic, and hyperglycaemic (insulin antagonism) actions. Causes shift from carbohydrate catabolism to lipid catabolism as energy source, and fat deposition as in Cushing s syndrome. 3. High blood concentration causes leucopenia and marked atrophy of lymphatic tissue (antiiflammatory and immunosuppressive actions). 4. In conjunction with adrenaline, mediates normal recovery from injury produced by inflammatory agents. 5. Maintains normal blood pressure by aiding noradrenaline and adrenaline to have their full effect, causing vasoconstriction; aseptic necrosis as a result of vasoconstriction; telangiectasia as a result of local skin atrophy. 6. May cause an increase in intraocular pressure (glaucoma) and cataracts (increase frequency, glucose toxicity). 7. By inhibiting synthesis of cytoprotective prostaglandins, gastric acid secretion may be increased. 8. Decreased bone protein matrix as a result of protein catabolism. 9. Inhibits intestinal calcium absorption by inhibiting the action of vitamin D. 10. Its mineralocorticoid actions lead to reabsorption of sodium and water and losing potassium and calcium. 11. Its secretion is controlled by a negative feedback mechanism involving ACTH from the adenohypophysis, except in stress response; its secretion is increased in response to stress. 12. Causes a state of euphoria, and hallucination. 234

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Multiple stimuli (e.g. bradykinin)

AA

CORTISOL

+ Steroid receptor

Phospholipids Phospholipase A2

_ Lipocortin 1

GRE

HSP90

Eicosanoids

mRNA

NFµB mRNA

HSP90 +

iNOS COX-2 Chemokines Cytokines

mRNA

DNA

HSP90

mRNA

Rough ER NFµB active

NFµB

Rough ER

Glucocorticoids

IµB Multiple stimuli IµB

NFµB inactive

s lipocortin 1 + q COX-2

Fig. 10.3. A relatively recent concept of the cellular mechanisms responsible for mediating the major actions of cortisol. The adrenocortical steroid cortisol enters their target cells, and bind to the glucocorticoid (steroid) receptor in the cytoplasm. This receptor is usually bound to what is known as the heat shock protein HSP90. When cortisol binds to the receptor, the HSP90 changes conformation and dissociates from the receptor. Thence, the cortisolreceptor complex enters the nucleus; this complex interacts with promoter regions of several genes through coordination with the so-called the glucocorticoid response elements (GRE) switching on or off certain transcription processes. Thus, by expression of a protein called IκB which inactivates the transcription factor nuclear factor kappa B (NFκB). The latter is stimulated by a variety of proinflammatory mediators to turn on the production of inflammatory mediators like inducible nitric oxide synthase (iNOS), inducible cyclooxygenase (COX-2), chemokines and cytokines. Similarly, cortisol nuclear action may lead to an increase in the production of lipocortin 1 which inhibits phospholipase A2 leading to an increase in the production of lipocortin 1 which inhibits phospholipase A2 leading to reduced production of arachidonic acid (AA) and in turn reduced synthesis of eicosanoids (prostanoids and leukotrienes). These products usually would contribute to increased vascular permeability resulting in oedema, leukocyte migration, fibrin deposition. (+) stimulatory; (-) inhibitory; ER: endoplasmic reticulum.

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Endocrine Pharmacology - Thyroid & Antithyroid Drugs

Ramadi, 11 October 2009

THYROID AND ANTITHYROID DRUGS Introduction

Adverse Effects of T3 and T4

Tetraiodothyronine (T4), thyroxine containing 4 iodine atoms; approximately 20 times more abundant than triiodothyronine (T3). Its major importance is as a precursor to T3 contains three iodine atoms; considered being the principal thyroid hormone. T 3 binds efficiently to nuclear receptors in target cells.

Cardiac effects

The thyroid gland stores considerable amounts of a preliminary form of its hormones prior to secreting them. Before being stored in the colloid of follicles, T3 and T4 are attached to globulin molecules, forming thyroglobulin and enter the bloodstream. Once in the stream, T3 and T4 attach to plasma globulins and travel as a hormone-globulin complex. T 3 and T4 detach from plasma globulin as they come near the target cells.

Non-cardiac effects

1. 2. 3. 4. 5. 6.

Tachycardia Angina Myocardial infarction Congestive heart failure Arrhythmia Sudden death

7. Tremor 8. Restlessness 9. Heat intolerance 10.Diarrhoea

Antithyroid Drugs Hyperthyroidism is associated with a number of disease conditions, including 1. Graves disease 2. Goitre 3. Toxic adenoma 4. Thyroiditis

Actions of Thyroid Hormones 1. Stimulation of metabolism (heat intolerance, increased appetite with weight loss, raised metabolic rate in hyperthyroidism; coma and hypothermia) 2. Promotion of growth and development (dwarfism and mental deficiency in cretinism) 3. Sensitisation to sympathetic effects and catecholamines (tachycardia, tremor, hyperactive reflexes in hyperthyroidism)

The aim of drug therapy of hyperthyroidism is to reduce synthesis and/or release of thyroid hormones (Fig.10.4.). The thionamides, carbimazole (with active metabolite methimazole) and propylthiuracil are concentrated in the thyroid gland where they inhibit synthesis of the thyroid hormones. They inhibit both the oxidation of iodide ions required for iodination of the tyrosyl residues (tyrosines) and the condensation (coupling) of iodotyrosines to triiodothyronine (T3) and thyroxine (T4). These drugs do not affect the release of the thyroid hormones already stored on the thyroglobulin; thus, their effect would not appear until exhaustion of the preformed thyroglobulin has taken place. Therefore, a delay of 1-2 months is expected before a clinical effect is observed.

Indications of T3 and T4 T4 is a standard treatment of hypothyroidism [cretinism (congenital), myxoedema (acquired), panhypopituitarism]. T 3 is used in the initial treatment of myxoedema coma. T4 may reduce the size of the goitres (puberty goitre, Hashimoto s autoimmune thyroiditis and endemic iodine deficiency) that have not responded to iodine alone.

Dietary iodine reaches the circulation as iodide. The latter is taken up (a process being stimulated by TSH and inhibited by perchlorate) and concentrated in the thyroid 236

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Majid A. K. Lafi

gland for the synthesis of thyroid hormones. However, high doses of iodide, unlike the thionamides, inhibit the release of hormones from thyroglobulins. The latter effect is responsible for its rapid effect; therefore, it is useful in combination with a thionamide agent in the treatment of thyrotoxic crisis. Iodine is also found to reduce vascularity. In thyrotoxicosis, the effects of iodine last only for two weeks; therefore, it is useful for preoperative preparation of the patient for thyroidectomy.

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Table 10.9. A summary of antithyroid drugs

Agent Thionamides

Mode of Action Blockade of both iodination of tyrosyl residues, & condensation of iodotyrosines. Delay of 1-2 months before hyperthyroidism begins to respond

Carbimazole

Propythiouracil Potassium perchlorate

Iodine (Lugol s solution)

Adverse Effects

Rashes Bone marrow depression Drug fever Arthralgia Rashes Bone marrow depression Prevents trapping and Bone marrow depression concentration of iodine in the thyroid gland. Inhibits bot iodination of Allergic reactions

tyrosyl residues and release of hormones from thyroglobulin 131

I and 125I

¾-adrenergic blockers

Concentrated in thyroid gland Under or over treatment by thyroid trap. Isotopes irradiate and destroy thyroid cells. β-Blockers are useful therapeutically to control tremor and tachycardia in thyrotoxicosis.

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PLASMA

Majid A. K. Lafi

COLLOID

THYROID CELL

Amino acids

Tyrosine Thyroglobulin

Synthesis of thyroglobulin

Tyrosine

Carbimazole -ve Propylthiouracil Peroxidase High dose iodide 2II2 I Iodination Tyrosine I I Tyrosine I

2IIodide uptake (Inhibited by perchlorate)

Condensation

Thyroxine Triiodothyronine

Release of hormones from thyroglobulin -ve High dose iodide

-ve Carbimazole Propylthiouracil

I Tyrosine I I Tyrosine I

Fig. 10.4. A simplified representation of the biosynthesis of the thyroid hormones and the sites of action of the major antithyroid drugs. Note: Tyrosine represents tyrosyl residue.

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Endocrine Pharmacology - Agents that Affect Calcium Metabolism

Ramadi, 11 October 2009

AGENTS THAT AFFECT CALCIUM METABOLISM Calcitonin

Vitamin D

This hormone is produced by the thyroid gland in the parafollicular cells. It influences the processing of calcium by bone cells through decreasing blood calcium levels and promoting conservation of hard bone matrix (inhibition of osteoclastic bone resorption,). The parathyroid hormone acts as a physiological antagonist to calcitonin to maintain calcium homeostasis.

Dietary vitamin D2 and vitamin D3 are inactive, in the liver converted to 25hydroxycholecalciferol (25-HCC) which is a major circulating metabolite but inactive. When low plasma calcium and high phosphate, PTH release is stimulated and in the kidney helps to convert 25-HCC to 1, 25dihydroxycholecalciferol (1, 25-DHCC) that is a powerfully active hormone.

Calcitonin inhibits osteoclastic bone resorption.

Activated vitamin D increases calcium absorption in the gut. In the bone, it potentiates calcium deposition in bone and used for mineralisation of new bone (increasing osteoblastic activity). Further, it plays a minor role in the kidney by increasing tubular reabsorption of calcium.

Indications of Calcitonin 1. Hypercalcaemia 2. Paget s disease of bone 3. Postmenopausal osteoporosis (treatment or prevention)

Indications of Vitamin D 1. Rickets 2. Osteomalacia 3. Hypocalcaemia 4. Hypoparathyroidism

Adverse Effects of Calcitonin 1. Skin rashes 2. GI disturbances 3. Glucose intolerance

Adverse Effects of Vitamin D Parathyroid Hormone (PTH)

1. Hypercalcaemia

PTH is released from the parathyroid glands, 4 or 5 parathyroid glands imbedded in the posterior surface of the thyroid s lateral lobes. PTH is a biological antagonist to calcitonin and acts to maintain calcium homeostasis. It acts on bone, kidney, and intestinal cells. It causes more bone to be dissolved (bone resorption, osteoclast, yielding calcium and phosphate, which enters the blood stream). It also causes phosphate to be secreted by the kidney cell into the urine to be excreted. Further, it causes increased intestinal absorption of calcium by activating vitamin D.

For selected other agents affecting calcium metabolism see Table 10.10.

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Table 10.10. A summary of agents affecting calcium metabolism and bone mineral homeostasis Agent Vitamin D

Mode of Action 1. ↑ intestinal calcium & phosphate absorption 2. ↓ renal calcium & phosphate excretion 3. ↑ calcium & phosphate osteoclastic resorption in bone 4. ↑ osteoblastic bone formation

Uses Rickets Osteomalacia Hypocalcaemia Hypoparathyroidism

Calcitonin

Inhibits osteoclastic bone resorption

Paget s disease of bone Postmenopausal osteoporosis Hypercalcaemia of pregnancy Paget s disease of bone Osteoporosis Hypercalcaemia (due to cancer) Hypercalcaemia Hypercalcaemia

Bisphosphonates (Etidronate &

↓ osteoclastic bone resorption

pamidronate)

Frusemide EDTA* Thiazides

Calcium Oestrogen

Fluoride

↑ renal calcium excretion Chelator of divalent & trivalent metals (renally excreted) ↓ renal calcium excretion (oral & parenteral)

Idiopathic hypercalciuria Hypocalcaemia

↓ the bone resorbing action of Prevention & treatment of postmenopausal osteoporosis parathyroid hormone Stabilises hydroxyapatite crystals Prophylaxis of dental caries

* EDTA (Ethylenediaminetetraacetic acid) is indicated chiefly for the chelation of heavy metals like lead, but it may also have place in poisoning by zinc, manganese etc. When used in the treatment of lead poisoning, the drug is administered as calcium disodium salt to prevent potentially life-threatening depletion of calcium.

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INSULIN AND ORAL HYPOGLYCAEMIC DRUGS 5. Thyroid hormone: hyperthyroidism → hyperglycaemia 6. Iatrogenic diabetes: corticosteroids, thiazide diuretics, and oral contraceptive pills, diazoxide (used in insulinoma)

Introduction The term diabetes mellitus encompasses a group of pancreatic endocrine-based disease states of differing aetiology and severity. Diabetes is derived from the Greek word meaning syphon, to signify the copious urine production in individuals with this affliction. The urine from some types of diabetic patients tasted sweet [a common, if unsavory, diagnostic procedure; when the blood glucose concentration falls below the renal threshold (180 mg/dL) glycosuria (sweetness) disappears] whereas that from other types was tasteless, led to the first distinction between diabetes mellitus and diabetes insipidus.

The differentiation between the two major types of diabetes mellitus Type I diabetes (IDDM): ketosis prone, juvenile onset, growth onset It is a catabolic disorder in which circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic β-cells fail to respond to all insulinogenic stimuli. Therapy for IDDM: insulin, diet, and exercise

Twenty-five percent have Type I (insulin dependent diabetes mellitus, IDDM), 70% have Type II (non-insulin dependent diabetes mellitus, NIDD, insulin resistant ) and 5% secondary diabetes.

Type II (NIDDM): ketosis resistant, adult onset, maturity onset Circulating endogenous insulin is sufficient to prevent ketoacidosis but is often either subnormal or relatively inadequate because of tissue insensitivity. There is also a concurrent deficiency of the pancreatic β-cells response to glucose. These defects are further aggravated by increased hyperglycaemia. However, hypoglycaemic drugs and other therapeutic measures ameliorate these defects.

Secondary diabetes may be recognised in the following clinical conditions: 1. Growth hormone: in acromegaly 30% of patients are diabetics 2. ACTH and adrenocortical hormones: ACTH and cortisol (stress and physical injury) lead to increased glucose level by gluconeogenesis, and decreased utilisation of glucose by peripheral tissues, thus, a. Cushing s syndrome → diabetes mellitus b. Addison s disease → hypoglycaemia c. Hypopituitarism → hypoglycaemia

Therapy for NIDDM: diet, weight reduction, exercise, oral hypoglycaemic agents sulphonylureas, biguanides, and insulin.

Insulin

3. Adrenaline: a. Increases glycogenolysis (α & β2receptor activation) b. Decrease insulin secretion (α-receptor stimulation) Thus, phaeochromocytoma may result in hyperglycaemia. 4. Gestational diabetes: hyperglycaemia

pregnancy

Insulin is a polypeptide of 51 amino acids (molecular weight 6000) synthesised in the pancreatic β-cells as a single chain polypeptide precursor, proinsulin (molecular weight 9000). Insulin is formed by enzymatic cleavage through a trypsin like enzyme that removes a large connecting peptide (Cpeptide, molecular weight 3000). Zinc is present in the granules of β-cells forming an

→

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insoluble complex with insulin and constitutes a natural storage form. Insulin obtained from cattle and pigs is rather similar to human insulin and consequently these have a relatively low antigenicity when administered to patients (particularly pig insulin). In man the average insulin content of the pancreas is about 200 units and the daily secretion amounts to approximately 3040 units.

increase in the density of insulin receptors (up-regulation) resulting in increased responsiveness to insulin. It appears that patients with NIDDM produce abnormally high amounts of insulin and yet they are insulin resistant. Upon dieting, obese NIDDM patients may have reduced insulin secretion resulting in increased insulin receptor density, thus, regaining insulin responsiveness.

Insulin secretion is mainly related to the concentration of blood glucose. Other factors that influence insulin release are:

Action of Insulin Insulin increases the transport of glucose through the plasma membranes of most tissues (muscle, adipose tissue, but not the brain, red blood cells and tubular cells of the kidney). It acts like a key to the cell-door. Insulin favours glycogen formation, inhibits glycogenolysis and stimulates protein synthesis. It also suppresses lipolysis and makes glucose available for synthesis into fatty acids and triglycerides. Insulin increases potassium uptake that leads to a lowered plasma concentration (hypokalaemia). Insulin increases renal conservation of sodium by increasing renal tubular reabsorption. Administration of high dosage of insulin and glucose are effective for the temporary relief of hyperkalaemia in uraemia. The cellular basis for insulin action is by stimulation of specific receptors that probably reduce intracellular cAMP. For a summary of the actions of insulin see Table 10.11.

Stimulation 1. Glucose, amino acids 2. Free fatty acids 3. Ketone bodies 4. Sympathetic nervous receptor involvement) 5. β-receptor agonists 6. cholinergic agonists 7. Sulphonylureas 8. Meglitinides

system

(β-

Inhibition 1. Insulin 2. Somatostatin (a universal inhibition of secretory cells) 3. α2-adrenoceptor agonists 4. β-receptor antagonists 5. Thiazides 6. Frusemide 7. Diazoxide

Insulin is an anabolic hormone, mainly in the liver, muscle, and adipose tissue.

Insulin Receptors

Pharmacokinetics

Insulin binds to tyrosine kinase, a receptor on the surface of the target cell; after they interact, the insulin-receptor complex enters the cell. The density of insulin receptors on the surface of the target cells varies inversely with the concentration of insulin to which they are exposed. As the concentration of insulin increases the density of insulin receptors decreases resulting in decreased responsiveness to insulin ( insulin resistance ). This is known as downregulation phenomenon, whereas a decrease in insulin concentration may lead to an

Insulin must be given parenterally by injection (s.c., i.m. or i.v.). The t of insulin in the plasma is about 10 minutes, but the biological effects of the hormones reach their maximum much later since insulin is bound to the tissues. After release insulin, reaches the liver through the portal vein and there about 40% is removed from the circulation. Therefore, in order to secure an appropriate action, slow release preparations have been developed. Several compounds can be added to increase the duration of insulin action, these are zinc, protamine (Table 10.12.). 243

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Table 10.11. A summary of the metabolic effects of insulin. Note: Anabolic processes are increased while catabolic processes are decreased. Tissue Liver

Anabolic Effects (increased anabolism) Glycogen synthesis Amino acid uptake Protein synthesis

Adipose

Glucose uptake Glycerol synthesis Fatty acids synthesis Triglyceride synthesis

Muscle

Glucose uptake Glucose utilisation Glycogen synthesis Glucose oxidation Amino acid uptake Protein synthesis

Anticatabolic Effects (decreased catabolism) Glucose production Gluconeogenesis Glycogenolysis Ketogenesis (probable an indirect effect due to decreased delivery of substrate) Lipolysis Free fatty acids and glycerol release

Glycogenolysis Amino acid release Protein catabolism

3. Local fat atrophy (This is also a frequent encounter that hard to explain in terms of the defined actions of insulin, and is most likely caused by stimulation of lipolysis by contaminants, possibly glucagon, in the insulin preparations.)

Adverse Effects of Insulin 1. Hypoglycaemia: It is the major adverse reaction. It is caused by excessive insulin dosage, a missed or late meal or by excessive exercise. Therefore, the diabetic should always carry quick-acting oral glucose tablets. The unconscious patient should be given 20 ml of 50% dextrose i.v., together with glucagon. Prolonged severe hypoglycaemia reactions may require 10-20% dextrose infusions over 24-48 hours or longer, together with highdose steroids, e.g. dexamethasone (2 mg i.m. 4 hourly) and 20% mannitol i.v. over 20 minutes, to reduce cerebral oedema. Unfortunately, if treatment is delayed, some diabetics may develop irreversible brain damage and death may occur.

4. Insulin allergy (An immediate type hypersensitivity, characterised by local or systemic urticaria, or even in severe cases anaphylaxis may result. This sensitivity is often due to non-insulin minor protein contaminants, or to one of the components added to insulin in its formulation (protamine, Zn++, phenol.) 5. Immune insulin resistance (antigenic, a high titre of circulating IgG anti-insulin antibodies develops) 6. Peripheral oedema (Na+ retention is primarily responsible for oedema that usually disappears spontaneously within several days)

2. Local fat hypertrophy (This is presumably caused by the action of insulin to promote triglyceride accumulation in fat cells.)

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Table 10.12. A summary of the pharmacokinetic parameters of selected insulin preparation Insulin Preparation Onset ULTRA-SHORT ACTING Lispro insulin, Aspart insulin (Insulin analogues) SHORT-ACTING Insulin injection (Regular, soluble) Prompt insulin zinc suspension (Semilente) INTERMEDIATE-ACTING Isophane insulin suspension (NPH) Insulin zinc suspension (Lente) LONG-ACTING Protamine zinc insulin suspension Extended zinc insulin suspension (Ultralente)

Action (hr) Peak Duration

0.25

0.5-1.5

3-4

0.5-1 1

2-3

5-7 14

1-1.5 1-2

8-12 8-18

18-24 18-24

4 4-8

10-30

36 36 plus

Human insulin is now being manufactured either by the genetic manipulation of Escherichia coli (recombinant or biosynthetic human insulin). Isophane insulin is also known as neutral protamine Hagedorn, NPH, is a suspension of crystalline zinc insulin combined at neutral pH with the positively charged polypeptide, protamine. Lente insulin is a mixture of 30% semilente insulin and 70% ultralente insulin providing a relatively rapid absorption, with a prolonged action making it the most commonly used among the lente series of insulin.

cells, voltage-gated Ca++-channels open in response to depolarisation allowing more calcium to enter the cell. Consequently, increased intracellular calcium results in increased insulin release. Further, chronic administration of sulphonylurea drugs reduces serum glucagon concentration. It has been suggested that sulphonylureas produce this effect through increasing the release of both insulin and somatostatin, which inhibit α-cell secretion. In addition, sulphonylureas may exert extra-pancreatic actions by increasing binding of insulin to tissue receptors, thus, potentiating insulin action. An intracellular (post-receptor) site of action for sulphonylureas have also been implicated.

Oral Hypoglycaemic Drugs Therapy with oral hypoglycaemic drugs is usually effective only in type II diabetic patients who fail to respond satisfactorily to dietary measures alone.

Sulphonylurea Drugs Sulphonylureas have been successfully used for over 30 years. They include tolbutamide, chlorpropamide, glibenclamide, and glibezide, for more details see Table 10.13. They appear to have stimulatory effects on βcells to increase basal and glucose-stimulated insulin secretion. It has been suggested that sulphonylureas block ATP-gated K+channels in the pancreatic β-cells, and thus, causing depolarisation of the cell resulting in increased excitability of the cell, and hence, increased release of insulin. Similar mechanisms of action have been proposed for glucose in promoting the release insulin. After entry into the β-cell, glucose increases the production of ATP leading to closure of the ATP-gated K+-channel and depolarisation of the β-cell occurs. As in most secretory

Sulphonylurea drugs may produce their hypoglycaemic action by: 1. Blocking causing enhanced 2. Promotes 3. Reducing

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K+-channels in the ¾-cells depolarisation and thus release of insulin. insulin exocytosis serum glucagon levels.

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4. Increasing binding of insulin to target tissue receptors.

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1. Direct stimulation of glycolysis in tissues, thus, increased glucose removal from circulation. 2. Reduced hepatic gluconeogenesis 3. Inhibiting glucose absorption from the gastrointestinal tract 4. Reducing plasma glucagon levels

Adverse Effects of Sulphonylureas 1. Hypoglycaemia 2. Gastrointestinal disturbances 3. Haematological disturbances (transient leucopenia, thrombocytopenia) occur in less than 1% of patients, particularly, with chlorpropamide. 4. Disulfiram-like reaction (particularly with chlorpropamide)

The use of metformin is restricted to type II patients who appear to develop resistance to sulphonylureas, although insulin is generally thought to be a better alternative.

Adverse Effects of Biguanides 1. Gastrointestinal disturbances (anorexia, nausea, vomiting, abdominal discomfort, diarrhoea; occur in 20% of patients and are often transient.) 2. Reducing vitamin B12 absorption 3. Lactic acidosis

Sulphonylureas are contraindicated in hepatic and renal insufficiency. Interactions with other drugs that compete with serum binding sites (phenylbutazone or salicylates).

Meglitinides Alpha-Glucosidase Inhibitors Meglitinides are relatively a new generation of oral antidiabetic agents, acting primarily via stimulating insulin release by closing ATP-sensitive potassium channels in pancreatic cells. In effect, they Amplify the insulin secretory response to a glucose load with virtually no effect in the presence of normoglycemia. Unlike the sulfonylureas,

The prototype of this is acarbose that is an oligosaccharide analogue that binds with 1000 times more ability than natural carbohydrates to the intestinal disaccharidases like α-glucosidase. This inhibition of α-glucosidase reduces the postprandial rise of glucose resulting in an insulin sparing action.

they have no direct effect on insulin exocytosis. They affect only postprandial insulin profiles. Dosing is recommended immediately before having a meal, and thus omit dose when skipping a meal. Suitable in

Biguanides are contraindicated in renal disease, hepatic disease, alcoholism, or conditions predisposing to tissue anoxia (e.g. chronic obstructive pulmonary disease), because of increased risk of lactic acidosis in the presence of these conditions.

individuals with sulfur or sulfonylurea allergy. This class of antidiabetics are represented by repaglinide and nateglinide.

Biguanides Aldose Reductase Inhbitors

Biguanides are more appropriately described as euglycaemic rather than hypoglycaemic drugs. This is because glucose is not lowered in normal subjects after an overnight fast, but their postprandial blood glucose levels are lower during biguanide administration. There are several possible mechanisms proposed for the antihyperglycaemic action of biguanides.

The conversion of glucose to fructose and in turn to sorbitol is believed to contribute to the toxic effects of hyperglycaemia (glucose toxicity). Therefore, aldose reductase inhibitors like tolrestat are targeted at inhibiting cellular conversion of glucose to

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fructose and consequently reducing glucose toxicity in tissues like the eye and the kidney.

Glucagon Glucagon is useful in insulin hypoglycaemic crisis (1 mg, i.m., s.c.) while in acute overdose of β-blockers (5-10 mg i.v. for positive inotropic and positive chronotropic effects).

Glitazones This recent group of antidiabetic drugs is believed to produce its hypoglycaemic activity primarily by increasing tissue sensitivity to insulin. This class of drugs is represented by pioglitazone and rosiglitazone that have been recommended for insulinresistant patients who are receiving insulin.

Table 10.13. A summary of parenteral and oral antidiabetic drugs. Drug

Mode of Antidiabetic Action

Adverse Effects and Important Remarks

PARENTERAL

Insulin

Acts like a key to cell-door promoting the transport of glucose through the plasma membranes of most tissues. Insulin is an anabolic hormone, mainly in the liver, muscle, and adipose tissue

Hypoglycaemia Local fat hypertrophy Local fat atrophy Insulin allergy Immune insulin resistance Peripheral oedema

Blocking ATP-sensitive K+channels in the β-cells causing depolarisation and thus enhanced release of insulin. Promote insulin exocytosis Reducing serum glucagon levels. Increasing binding of insulin to target tissue receptors.

Hypoglycaemia GI disturbances Haematological disturbances (chlorpropamide) Disulfiram-like reaction (chlorpropamide)

ORAL Sulphonylureas

Tolbutamide (Orinase )

Chlorpropamide

4

24

2-3 daily doses, safe, inactivated by hepatic oxidation

8

1 daily dose at breakfast, less safe, avoid in elderly, renal & hepatic failure [largely excreted changed, & unchanged (20-30%) by the kidney]

72

(Diabinase )

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Glibenclamide (Daonil )

Glipizide

10

24

3

8

Repaglinide

Nateglinide

1-2 daily dosing

Blocking ATP sensitive K+channels in the β-cells causing depolarisation and thus enhanced release of insulin.

Meglitinides

1

1

3

3

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It affects only postprandial insulin profiles. Omit dose if skip a meal. Suitable in

individuals with sulfur or sulfonylurea allergy. tmax 1 hr,

Amplifies the insulin secretory response to a glucose load with virtually no effect in the presence of normoglycemia

tmax <1 hr, 1-10 minutes before meal, useful in isolated

postprandial hyperglycemia, least hypoglycaemic action, dose

titration is not required.

Biguanides

Metformin (Glucophage®)

5

12

Direct stimulation of glycolysis in tissues Reduced hepatic gluconeogenesis Inhibiting glucose absorption from the GIT

Reducing plasma glucagon levels

Aldose Reductase Inhibitors Tolrestat

Glitazones

Lactic acidosis

Inhibition of α-glucosidase reduces the postprandial rise of glucose resulting in an insulin sparing action.

¿-Glucosidase Inhibitors

Acarbose

GI disturbances (anorexia, nausea, vomiting, abdominal discomfort, diarrhoea; 20% of cases) Reducing vitamin B12 absorption (megaloblastic anaemia)

2

Flatulence (20-30%, caused by lower bowel undigested carbohydrate) Inhibit aldose reductase →↓ intracellular conversion of glucose to sorbitol →↓ fructose →↓ glucose toxicity Sensitise tissue to insulin

Useful in insulin resistant patients Weight gain Oedema

Pioglitazone Rosiglitazone In pregnancy: Sulphonylureas can traverse the placenta and act on the islet cells of the pancreas of the foetus to deplete them of insulin, thus, the infant is born hypoglycaemic; insulin does not pass through the placenta; there is a greater demand for insulin in pregnancy than can be provided by sulphonylureas. Therefore, a pregnant diabetic woman is usually switched from oral hypoglycaemic drugs to insulin.

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ATP-sensitive K+ channel

Sulphonylureas Promote Meglitinides

K+

Block

ATP

Depolarize

Prevents

Diazoxide

Glucose transporter

Ca++

Glucose

Voltagesensitive Ca++ channel

Sulphonylureas Promote

Insulin exocytosis

Fig. 10.5 . A simplified representation of control of insulin release from the pancreatic cell by glucose, sulfonylureas, meglitinides, diazoxide. In the resting cell with normal (low) ATP levels, potassium exists via ATP-sensitive K+ channels, maintaining the intracellular potential at a fully polarized, negative level (low excitability). Insulin release is minimal. When glucose concentration rises, ATP production increases, potassium channels close resulting in depolarization of the cell. As in other excitable cells like muscle and nerve ones, voltage-sensitive Ca++ channels open in response to depolarization, allowing more Ca++ to enter the cell. Increased intracellular free Ca++ results in increased insulin secretion. Insulin secretagogues close the ATP-sensitive K+ channel, thereby depolarizing the membrane and causing increased insulin release by promoting the action of the effect of hyperglycaemia (glucose → ATP → closure of ATP-sensitive K+ channels). On the other hand, diazoxide appears to interacts with the ATP-sensitive K+ channel and either prevents its closure or prolongs the open time. Sulphonylureas appear to have an independent additional secretagogue action through promoting the insulin exocytotic process.

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ANTICANCER DRUGS vary in their ability to do so, e.g. cisplatin does not induce drug resistance.

Introduction The principle of treating cancer with drugs has some similarities with antibiotic treatment of bacterial infection. The objective is to reduce the number of hostile cells but the difference is that natural defenses of the body is much weaker in case of malignant cells as compared to the immunological mechanisms in infections. Therefore, it is essential to kill tumour cells with cancer chemotherapy whereas it may be enough to reduce the number of bacteria with antibiotics.

Resistance is delayed when combination therapy is used. Combination therapy may also have the advantage of synergism (1+1=3) rather than the additive effect (1+1=2). Therefore, these days a combination of 2-6 drugs is given in intermittent pulses to achieve total tumour cell kill, giving time in between for normal cells to recover. Optimum synergism can be achieved by selecting the appropriate combination of:

Cell cycle specificity

1. Drugs which are effective when used alone 2. Drugs with different mechanisms when used alone 3. Synchronising the active cell cycle 4. Drugs with differing toxicities (giving drugs that do not suppress bone marrow in between courses of those that do. The normal tissue toxicity that limits further escalation of dose is the dose-limiting toxicity and this is the maximum tolerated dose. Hence, drug with different doselimiting toxicity is preferred in combination) 5. Empirically by trial and error

In addition to the differences in biochemical mechanisms of action, anticancer agents differ in the point in the cell cycle at which they inhibit cell growth and replication. Those drugs, which kill a cell whether it is cyclic or at rest are said to be cycle-non specific, e.g. glucocorticoids. While other agents kill only cells that are actively cycling, usually because their site of action is restricted to one part of the cell cycle, and are therefore called cyclespecific, e.g. antimetabolite drugs and spindle poisons. Further, some agents can be cycleactive phase-non-specific, e.g. alkylating agents.

All cytotoxic drugs with antitumour activity probably exert their effects by impairing the synthesis or function of nucleic acids (DNA). Cells most susceptible to cytotoxic drugs are those with a mitotic rate. Most tumour cells grow rapidly but the turnover rate of bone marrow cells, intestinal mucosa and epidermis, including hair follicles is as rapid and therefore these cells are susceptible to cytotoxic drugs. This explains the side effects: infections, bleeding, enteritis, and alopecia.

Drug Resistance Drug resistance is a feature typical not only to bacterial cells but also to tumour cells because of emergence of resistant cell variants; multiple drug resistance is now becoming a major problem. Drug resistance is believed to be mediated through the development of an active extrusion process of the anticancer agents from the cancer cell. It has been suggested that an ATP-dependent membrane efflux pump acting via a protein called P-glycoprotein, developed as a protective mechanism against environmental toxins. Anticancer agents appear to induce the expression of P-glycoprotein; however, they

Examples for Combination Therapy Non-Hodgkin s Lymphoma

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A combination of four drugs is used in one regimen for the treatment of non-Hodgkin s lymphoma. This combination is known as CHOP, the latter stands for cyclophosphamide, hydroxydonorubicin (doxorubicin), Oncovin (vincristine), and prednisone. It is worth noting that:

The most common agents of this group are cyclophosphamide, busulphan, chlorambucil, and platinum compounds like cisplatin. Generally, these agents cause nausea and vomiting, and bone marrow depression; male infertility and premature menopause may also occur. However, a specific toxicity may appear with cyclophosphamide, which causes haemorrhagic cyctitis, and busulphan, which causes pulmonary fibrosis.

1. These drugs produce cytotoxicity by different mode of action. 2. The first three agents are capable of inducing complete response when given alone. 3. None of these agents would be expected to exhibit cross-resistance.

Antimetabolites These cytotoxic agents are structural analogues of normal metabolites, being incorporated in the S-phase of cell cycle and, thus, deceiving bodily processes.

Acute Myeloid Leukaemia For this type of leukaemia (AML) usually two drugs are used daunorubicin and cytarabine.

Methotrexate

Adjuvant Use

Methotrexate is a folic acid antagonist, competitively inhibits dihydrofolate reductase, thus, preventing the conversion of folic acid to folinic acid (the coenzyme responsible for the synthesis of amino and nucleic acids). When a maximum effect is desired, a special manoeuvre is followed with the use of methotrexate. A potentially fatal dose of methotrexate is administered and followed 24 hours later by a dose of tetrahydrofolic (folinic) acid as calcium folinate (Ca leucovorin) to terminate the action of methotrexate. This is known as folinic acid rescue . Because it is life saving, if folinic acid not given, the patient will die. It appears that bone marrow cells recover better than tumour cells, thus, some degree of useful selectivity is utilised.

Adjuvant use of anticancer drugs after definite surgical resection, e.g. in breast cancer, fluorouracil, adriamycin (doxorubicin), and cyclophosphamide.

Anticancer Drugs 1. Alkylating agents 2. Antimetabolites 3. Cytotoxic antibiotics 4. Spindle poisons 5. Biological agents 6. Hormones (or antagonists) 7. Miscellaneous agents

Alkylating agents

Methotrexate is predominantly renally excreted; therefore, patients with impairment require dose adjustment. Methotrexate can precipitate in the distal renal tubule when urine is acidic, therefore, a prior hydration and alkalinisation of urine are essential. Further, cytotoxic agents including methotrexate cause tumour lysis syndrome (characterised by metabolic derangements including hyperuricaemia)

These compounds which can introduce an alkyl group to DNA in the N-7 position of guanine during cell division. Thus, these agents cause either DNA strand breakage or c cross-linking of the two strands so that normal synthesis is prevented. Alkylating agents are mostly for treatment of leukaemias and solid tumours. The original agents were called nitrogen mustards.

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Purine Antagonists Vinca Alkaloids Azathioprine (Imuran ), mercaptopurine, thioguanine,

Vinca alkaloids comprise alkaloids extracted from the plant periwinkle, represented by vincristine and vinblastine. They inhibit microtubule assembly and cause cell cycle arrest in mitosis at the M-phase.

Pyrimidine Antagonists Cytarabine, fluorouracil, and fludarabine interfere with the production of essential metabolites. Cytarabine is particularly useful in acute myeloid leukaemia. This drug is usually given by continuous intravenous infusion over 5 to 7 days. With this regimen better therapeutic effects and less adverse effects are observed compared with that when given in bolus doses.

Taxanes This subgroup is represented paclitaxel; they act by stabilising microtubules and thereby preventing their disassembly.

Epipodophylotoxins This subgroup is represented by etoposide; they interact with topoisomerase II. This enzyme is capable of producing and repairing DNA-double strand breaks. Etoposide enhance DNA cleavage by inhibiting reunion activity of this enzyme leading to DNA fragmentation and ultimately cell death.

Adverse Effects of Antimetabolites 1. Gastrointestinal upsets stomatitis, & ulceration) 2. Bone marrow depression

(e.g.

Renal impairment increases their toxicity, particularly, methtrexate. Salicylates block active excretion of methotrexate by renal tubules, in addition, salicylates displace methotrexate from plasma binding proteins.

Adverse Effects 1. Bone marrow depression 2. Alopecia 3. Peripheral neuropathy (which limits the total dose of vincristine)

Cytotoxic Antibiotics These agents interfere with DNA and RNA replication and protein synthesis. They are represented by bleomycin, dactinomycin, adriamycin, doxorubicin, plicamycin, and daunorubicin.

Biological Agents Interferons and more recently interleukins are used in hairy cell leukaemia and Kaposi s sarcoma.

Adverse Effects Hormones (or Antagonists) 1. Gastrointestinal upsets 2. Bone marrow depression 3. Alopecia 4. Cardiomyopathy (doxorubicin) 5. Pulmonary fibrosis (bleomycin)

Hormones can also be used in malignant disease arising from tissues such as the mammary gland, uterus and prostate whose normal growth is dependent on hormones. Tamoxifen is an antioestrogen compound especially useful in postmenopausal breast cancer. Androgens are useful in some premenopausal breast cancer. Cyproterone (antiandrogen) is useful in prostatic cancer.

Spindle Poisons This group includes a number of drugs collectively being plant alkaloids. These are divided into three subgroups according to their cytotoxic mode of action.

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ability to suppress cell division, particularly in lymphocytes, it supprsses both cellular immunity and antibody formation. Glucocorticoids are useful in acute leukaemias, Hodgkin s and other lymphomas. They induce rapid remission and control complications like hypercalcaemia, haemolysis, and increased intracranial pressure.

lymphokine genes, thus inhibiting the production of lymphokines by T lymphocytes that mediate specific recognition of alien molecules. Therefore, cyclosporin A does not have an effect on non-specific functions, like that of granulocytes, that are responsible for phagocytosis and metabolism of foreign substances. Further, cyclosporin A does not depress haemopoiesis. These drugs have also been used to cause immunosuppression in autoimmune, collagen and connective tissue diseases which include inflammatory bowel disease, rheumatoid arthritis, chronic active hepatitis, systemic lupus erythematosus (SLE), glomerulonephritis, nephrotic syndrome, some haemolytic anaemias and thrombocytopenias, uveitis, myasthenia gravis, polyarteritis, polymyositis, systemic sclerosis.

Miscellaneous Compounds Crisantapase (asparginase) deprives tumour cells, which are dependent upon a supply of the amino acid aspargine (and not being able to synthesise it themselves). The use of asparginase is largely limited to acute lymphoblastic leukaemia. Other agents like hydroxyurea that has antitumour activity by inhibiting formation of deoxyribonucleotides.

Immunostimulant Therapy

Immunotherapy

The principle of immunotherapy is to increase the body s own defense system such as generation of antibodies and interferon.

Immunosuppressive Therapy Cytotoxic cancer chemotherapeutic drugs have also been used in organ transplantation in order to prevent rejection, e.g. glucocorticoids (prednisolone), azathioprine (antimetabolite, Imuran ), alkylating agents (e.g. cyclophosphamide and chlorambucil), cyclosporin A, and antilymphocyte immunoglobulin. Except cyclosporin A, all these agents cause non-specific immunosuppression so that the general defenses of the body against infections are impaired.

The importance of the immune system for the development of cancer comes from the observation that immunodeficient patient and patients who are immunosuppressed by drugs such as azathioprine for organ transplantation easily develop cancer. This is probably due to the immunosuppression, induced by cytotoxic agents, abolishes what little natural immune resistance that there may be to a tumour. Agents that increase immunological responses are bacterial vaccines such as BCG (Bacille Calmette-Guerin) instilled in the urinary bladder for bladder cancer, and the immunostimulant levamisole (anthelminthic) which appears to enhance the function of phagocytes and T lymphocytes when this is subnormal. Levamisole is also useful in immune deficiency states.

Cyclosporin A is a polypeptide obtained from a soil fungus of Norway (1969). This drug has a selective and reversible action against T lymphocyte, which are the cells that play a central role in the induction of immune responses. This selectivity of action is believed to be due to inhibiting the transcription of interleukin-2 and other

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Table 11.5. A summary of the pharmacology of anticancer drugs

Drug Group

Mode of Action

Important Remarks

Alkylating Agents Cyclophosphamide Busulphan Chlorambucil Platinum compounds (cisplatin)

Cycle-active phase non-specific; they introduce alkyl groups to DNA causing either DNA strand breakage or crosslinking of the two strands, thus, preventing normal synthesis.

Useful in leukaemias & solid tumours; specific adverse effects: [cyclophosphamide: haemorrhagic cystitis], [busulphan: pulmonary fibrosis], [cisplatin: nephrotoxicity)

Antimetabolites

Cycle & phase specific

Methotrexate

Dihydrofolate inhibitor

Distal renal tubular toxicity

Azathioprine Mercaptopurine Thioguanine

Purine antagonists

[mercaptopurine & thioguanine for haematological malignancies]

Cytarabine Fludarabine Cytotoxic Antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Spindle Poisons Vinca Alkaloids Vincristine Vinblastine

Pyrimidine antagonists

Taxanes Paclitaxel Epipodophylotoxins Etoposide Biological Agents Interferon α2 Interleukin 2 Hormones (or Antagonists) Glucocorticoids

Inhibit microtubule disassembly

Tamoxifen

Antioestrogen

Breast cancer

Goserelin Flutamide Cyproterone

GnRH agonist Antiandrogen Antiandrogen

Prostatic cancer

Deprives tumour cells of aspargine

Acute lymphoblastic leukaemia

Inhibits DNA formation

For myeloid proliferative disorder

Miscellaneous Agents Crisantapase (asparginase) Hydroxyurea

Interfere with DNA & RNA replication and protein synthesis.

Cycle & phase specific Inhibit microtubule assembly

[bleomycin: pulmonary fibrosis], [doxorubicin: cardiomyopathy]

[vincristine: peripheral neuropathy], [vinblastine: bone marrow depression] [paclitexal: reaction]

hypersensitivity

Inhibit topoisomerase II, inhibit reunion activity of this enzyme Hairy cell leukaemia sarcoma

Kaposi s

Cycle-non-specific

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DRUG INTERACTIONS, ADVERSE DRUG REACTIONS AND ANTIDOTES bear clinical implication manifested reduced therapeutic efficacy.

DRUG INTERACTIONS Interactions between drugs can occur when two drugs or more agents are administered concurrently. This may lead to altered pharmacological or therapeutic effects of the drugs in question. The changes due to such interactions could be either a decrease in the desired effect, increased plasma levels of the free drug or prolongation of t of the drug. Such drug interactions are classified into two main types: pharmacokinetic and pharmacodynamic ones.

by

2. Hepatic enzyme induction Most drugs undergo hepatic phase I metabolism by mixed function oxidases (cytochrome P450 oxidase) found in the endoplasmic reticulum. Certain drugs can enhance mixed function oxidase enzyme activity. Such hepatic enzyme inducers include all barbiturates, rifampicin, carbamezapine, phenytoin, chronic acohol consumption. Thus, hepatic enzyme inducers decrease plasma levels of drugs like warfarin, see page 66.

PHARMACOKINETIC INTERACTIONS

• Increased drug systemic availability

Drug incompatibility of ampicillin, chlorpromazine with dextran solutions, i.v., takes place as a result of drug breakdown or chemical complex formation. Tetracycline combines with cations like calcium present in dairy product (like yogurt) and some antacids or aluminium presents in antacids forming insoluble complexes which are not absorbed giving reduced systemic delivery of the drug. Pharmacokinetic interactions can also increase systemic availability of drugs.

1. Competitive protein binding Drug interactions influence the distribution of drugs as a result of competitive plasma protein binding. An increase in plasma free drug concentration due to displacement of plasma protein bound drug can result in changes in pharmacological effects. For example, the strongly bound drug clofibrate displaces warfarin that may result in haemorrhage due to enhanced inhibition of prothrombin synthesis in the live.

• Decreased drug systemic availability

2. Inhibition of drug metabolism 1. Impaired gastrointestinal absorption Drug clearance can be reduced by inhibition of drug metabolism resulting in accumulation and prolonged t . Such excessive accumulation a drug can lead to adverse effects. For example, the oxidative metabolism of the low therapeutic index drugs like warfarin, theophylline and phenytoin can be inhibited by cimetidine, erythromycin and ciprofloxacin. Such interactions can lead to complications with adverse effects particularly with drugs characterized by low therapeutic index. These complications can be controlled by monitoring plasma drug concentration (known as therapeutic drug monitoring,

The antihyperlipidaemic agent cholestyramine, an ion exchange resin, binds to drugs like thyroxine and digoxin and hence blocking their absorption. As mentioned above antacids interact with tetracycline, and kaolin-pectin with digoxin resulting in reduced intestinal absorption. There a number of factors which influence absorption of drugs (see section on absorption of drugs, page 7) that can reduce delivery of drugs to the systemic system and hence resulting in reduced both peak plasma concentration and steady state concentration (Css). Consequently, this type of interaction may

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TDM) and altering the dosage regimen accordingly.

Ramadi, 11 October 2009

excessive effect. For example, an antihypertensive agent like the calcium channel blocker nifedipine, when used in elevated arterial blood pressure, can lead to hypotension as an adverse reaction by virtue of excessive pharmacological action as a vasodilator. The magnitude of the adverse reaction is further extended when drugs are taken during pregnancy, lactation or the presence of co-morbid conditions, e.g. the coexistence of arterial hypertension and asthma in the same patient will render the antihypertensive agent propranolol to be contraindicated in this patient.

3. Inhibition of renal elimination Clearance of drugs can be reduced by inhibiting renal elimination. For example, penicillin undergoes renal elimination largely by renal tubular secretion (into the tubular lumen) which is inhibited by probenicid. This interaction is advantageous as it results in accumulation of penicillin (characterized by high therapeutic index) in blood and prolonging its t . This can be desirable in certain clinical conditions where therapeutically high blood penicillin levels are required. Such interaction can be undesirable in other clinical conditions, e.g. quinidine can inhibit the renal elimination of digoxin and thus may result in cardiac arrhythmias if quinidine is administered concomitantly with digoxin.

The known pharmacological actions of drugs can be altered (decreased or increased) by interaction of a number of factors, e.g. pharmacokinetic and pharmacodynamic ones, see above. Such alterations can be predicted and controlled. To achieve this, therapeutic drug monitoring approach can be used as a guide for appropriate dosage regimen adjustment. This approach is essential particularly when using drugs characterized by having low therapeutic index, i.e. with low margin of safety such as digoxin, phenytoin, lithium, procainamide, and theophylline.

PHARMACODYNAMIC INTERACTIONS Pharmacodynamic interactions are those in which the responsiveness of the target organ or receptor or the physiological system is modified by concomitant administration of the second agent. This type of interaction can lead to a physiological change in the intra or extra cellular environment. For example, hypokalaemia induced by diuretics can promote digitalis toxicity; while the diuretic effect of diuretics can be antagonized by NSAIDs like aspirin. Further, pharmacodynamic interaction can be expressed by chemical inactivation as in the neutralization of heparin's action by protamine heparin binding. Pharmacodynamic interaction may also be expressed as a drug can enhance the action of another drug through different mechanism(s); for example, alcohol enhances the CNS depression of sedatives and hypnotics.

For simplicity purposes, adverse drug reactions are generally clinically viewed in the following five types: Type A: (Augmented) reactions are the most frequently encountered in clinical practice when enough of the drug is given because they are due to excess of normal, predictable, dose-related, pharmacodynamic effects, e.g. postural hypotension, hypoglycaemia, and hypokalaemia. Type B: (Bizarre) reactions are encountered only in some people. They are not due to excess of the normal pharmacodynamic effects of the drug, are not dose-related and are due to unusual attributes of the patient interacting with the drug. These effects are usually unpredictable but with mostly known incidence. These reactions include unwanted effects due to inherited metabolic abnormalities (idiosyncrasy) and abnormal immune responses. These account for most drug fatalities, for example, chloramphenicol can produce aplastic anaemia (a life threatening morbidity).

ADVERSE DRUG REACTIONS All drugs are associated with unavoidable unwanted effects, usually as an extension of its normal pharmacological effects, i.e. 256

Essentials of Medical Pharmacology

Majid A.K. Lafi

2. Abnormal immune response: This can be manifested as specific hypersensitivity reactions shown by individuals to a particular drug. These reactions are the resultant of the interaction of drug or metabolite (or an excipient substance in the formulation) with patient and disease, and subsequent reexposure. Four types of hypersensitivity reactions to drugs are generally described:

Type C: (Chronic) reactions due to long-term exposure, e.g. analgesic nephropathy, dyskinesias with levodopa. Type D: (Delayed) effects following prolonged exposure, e.g. carcinogenesis or short-term exposure at a critical time, e.g. teratogenesis.

A.Type I reactions: that occurring within minutes (anaphylactic/immediate) when a sensitized individual is reexposed to antigen, resulting from interaction of IgE and the antigen. This gives rise to clinical manifestations including urticaria and bronchospasm as with penicillins. B. Type II reactions: some drugs can stimulate antibody production as a result of their molecular characteristics by combining with a protein in the body so that the body no longer recognises the protein as self and thus forming antibodies that combine with the antigen and activate complement that damages cells (haemolysis occurs) as in penicillin and methyldopa induced haemolytic anaemia. Further, hydralazine and procainamide can chemically alter nuclear material that can stimulate formation of antinuclear antibody and may cause lupus erythematosus. Furthermore, thrombocytopenia due to quinidine and agranulocytosis due to a number of other drugs which can be explained on the basis of autoimmune reactions. C.Type III reactions: serum sickness to a drug is associated with IgG immunoglobulins. For example, penicillin is well known to cause serum sickness as a result of deposition of circulating drug antibody complex on endothelial cell surface of tissues, which release histamine that can produce anaphylaxis characterized by hypotension, urticaria, wheezing and rhinorrhoea. These reactions also include glomerulonephritis, vasculitis, and pulmonary disease. D. Type IV reactions: contact dermatitis is cell mediated allergy arising out of topical application of a drug. Antigen-specific receptors develop on T-lymphocytes. Subsequent administration leads to a local or tissue allergic reaction.

Type E: (Ending of use) reactions, upon abrupt discontinuation of chronic therapy, e.g. of adrenal steroid causing rebound adrenocortical insufficiency, of -blockers causing propranolol withdrawal syndrome, of alcohol causing alcohol withdrawal syndrome. Adverse and toxic reactions of drugs can be produced by actions unrelated to the normal (wanted) pharmacological actions of the drugs as describe above. These types of reactions may further be classified according to the nature of action into the following: 1. Cytotoxic reactions: some drugs can undergo metabolic activation to reactive metabolites. Such a process usually takes place in the microsomal mixed function oxidase system of the hepatic enzymes. These reactive metabolites may covalently bind to the tissue macromolecules causing tissue damage. For example, isoniazid is largely metabolized by acetylation to acetylisoniazid which in turn undergoes hydrolysis producing acetylhydrazine. Further metabolism of the latter by mixed function oxidase system results in reactive metabolites that covalently bind to hepatic macromolecule causing hepatic necrosis. Hence, a concomitant administration of hepatic enzyme inducers like phenobarbital with isoniazid can result in liver damage. This explanation is also applicable to paracetamol overdose induced hepatic and renal necrosis, see page 191. Usually these reactive metabolites are removed by hepatic glutathione. When glutathione is exhausted the reactive metabolites bind to hepatic macromolecules resulting in hepatic damage. Glutathione itself poorly penetrates cells but Nacetylcysteine (i.v.) and methionine (orally) are effective precursors for the synthesis of glutathione.

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other of the enzymes that convert the various porphyrins to haem is deficient and thus porphyria is characterized by overproduction, accumulation and excretion of intermediates of haem biosynthesis. Porphyria is life threatening and is precipitated by a variety of drugs, hormones and other agents. Porphyria exacerbation can be shown by barbiturates, chlordiazopoxide, chorpropamide, oestrogen, griseofulvin, phenytoin and rifampicin. During an attack there is increased urinary excretion of delta-aminolaevulinic acid and porphobilinogen.

3. Derangement in the metabolic functions: Drug toxicity can be associated with enzymatic defects such as deficiency of glucose-6-phosphate dehydrogenase (G6PD) can induce haemolytic anaemia with a number of drugs such as primaquine, dapsone, nalidixic acid, nitrofurantoin and probenicid. Another drug toxicity associated with enzymatic defects is observed in different porphyrias which may be erythropoietic or of hepatic origin acquired by disturbances in haem biosynthesis. Porphyrins are tetrapyrrole intermediates formed from delta-aminolaevulinic acid and porphobilinogen, the ferrous ion complex of porphobilinogen (haem) serves as prosthetic group for haemoprotein like haemoglobin. However, in people with porphyria one or

Table 11.1. Selected specific antidotes, poison(s), modes of action and important remarks. Antidote

Poison(s)

Mode of action & remarks

N-acetylcysteine

Paracetamol

Methionine Pralidoxime (2PAM)

Paracetamol Cholinesterase inhibitors, e.g. organophosphorus insecticides Cholinesterase inhibitors, e.g. organophosphorus insecticides

Atropine

Atropine Propranolol

Isoprenaline Glucagon

Benzhexol Desferrioxamine Digoxin-specific antibody fragments (FAB) Calcium

-blocker poisoning -adrenoceptor agonists, ephedrine, theophylline, thyroxine -blocker poisoning -blocker poisoning

Drug-induced movement disorders Iron Digitalis glycosides

Calcium channel blockers

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Replenishes depleted glutathione stores. Best results if given within 8 10 hrs of overdose. It can be given successfully orally (Mucomyst) and intravenously. Replenishes depleted glutathione stores Competitively reactivates cholinesterase

Blocks muscarinic cholinoceptors. A test dose of 1 2 mg (for adult) is given intravenously and repeated until symptoms of atropinism appear (tachycardia, dilated pupils). Dose may be repeated every 10 15 minutes, with decrease of secretions as therapeutic objective. Vagal block accelerates heart rate. Blocks -adrenoceptors

Competes for -adrenoceptors Bypasses blockade of the -adrenoceptor; stimulates cyclic AMP formation with positive cardiac inotropic effect via stimulation of glucagon receptors. 5 10 mg intravenously bolus may reverse hypotension and bradycardia that was resistant to -agonist drugs. Blocks muscarinic cholinoceptors; alternatively use diazepam Chelates ferrous ions Binds free glycoside in plasma, complex excreted in urine, indicated in serious arrhythmias, hyperkalaemia. One vial binds 0.5 mg digoxin. It provides a rapid increase in extracellular calcium that helps overcome calcium channel

Essentials of Medical Pharmacology

Dimercaprol (BAL) Penicillamine Sodium edetate Ethanol

calcium

Majid A.K. Lafi

Arsenic, copper, gold, lead, inorganic mercury Copper, gold, lead, elemental mercury (vapour), zinc Lead Ethylene glycol, methanol

Flumazenil Naloxone Folinic acid (Leucovorin) (Folinic acid rescue, 24 h later) Neostigmine

Benzodiazepines Opioids Folic acid antagonists e.g. methotrexate, trimethoprim

Phenoxybenzamine

hypertension due to adrenoceptor agonists, e.g. with MAOI, clonidine, ergotamine. As above

Phentolamine Vitamine K1 Protamine sulphate Oxygen

Antimuscarinic drugs

Coumarin (warfarin) and indandione anticoagulants Heparin Carbon monoxide

Sodium bicarbonate

Membrane-stabilizing cardiotoxic drugs (tricyclic antidepressants, quinidine, etc)

Sodium bicarbonate

Aspirin (salicylate, moderate intoxications)

Sodium nitrite plus sodium thiosulphate

Cyanide

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blockade. Chelates metal ions Chelates metal ions Chelates lead ions Competes for alcohol and acetaldehyde dehydrogenases, preventing formation of toxic metabolites Competes for benzodiazepine receptors Competes for opioid receptors Bypasses block in folate metabolism

Inhibits acetylcholinesterase, causing acetylcholine to accumulate at cholinoceptors Competes for -adrenoceptors (long-acting)

Competes for -adrenoceptors (short-acting) Replenishes vitamin K Binds ionically to neutralise Competitively displaces carbon monoxide from binding sites on haemoglobin. Give 100% by high-flow nonrebreathing mask. It provides a rapid increase in extracellular sodium that helps overcome sodium channel blockade.1 2 mEq/kg IV bolus usually reverses cardiotoxic effects (including wide QRS, hypotension). Give cautiously in heart failure to avoid sodium overload. It is given to alkalinize the urine and promote salicylate excretion by trapping the salicylate in its ionized, polar form. For severe poisoning ( with severe acidosis, coma, and serum salicylate level > 100 mg/dL), emergency haemodialysis is preferred to remove the salicylate more quickly and restore acid-base balance and fluid status. Sodium nitrite rapidly converts haemoglobin to methaemoglobin that binds CN, and thiosulphate promotes the formation of less toxic thiocyanate.

Glossary and Abbreviations

Ramadi, 11 October 2009

GLOSSARY AND ABBREVIATIONS Incomplete list of vocabulary adapted by and large from Dorland's Medical Dictionary (2000) W.B. Saunders 1, 25-DHCC: 1, 25-dihydroxycholecalciferol. 25-HCC: 25-hydroxycholecalciferol. Abortifacient: 1. causing abortion. 2. an agent which causes abortion. Abreaction: the reliving of an experience in such a way that previously repressed emotions associated with it are released. (Thiopental) Abscess: a localized collection of pus buried in tissues, organs, or confined spaces. Absence: the seizure seen in absence epilepsy, consisting of a sudden momentary break in consciousness of thought or activity, often accompanied by automatisms or clonic movements, especially of the eyelids. On the electroencephalogram it is characterized by a specific symmetrical spike and wave type occurring at three cycles per second. Abstinence: a refraining from the use of or indulgence in food, stimulants, or sexual intercourse. ACE: angiotensin converting enzyme ACh: acetylcholine. Achlorhydria: absence of hydrochloric acid from maximally stimulated gastric secretions; a result of gastric mucosal atrophy. Acne: an inflammatory disease of the pilosebaceous unit, the specific type usually being indicated by a modifying term; frequently used alone to designate common acne, or a. vulgaris. Acromegaly: a chronic disease of adults caused by hypersecretion of growth hormone, characterized by enlargement of many parts of the skeleton, especially distal portions such as the nose, ears, jaws, fingers, and toes. ACTH: (corticotrophin) adrenocorticotropic hormone. Acute intermittent porphyria: hereditary hepatic porphyria manifested by recurrent attacks of abdominal pain, gastrointestinal dysfunction, and neurological disturbances and by excessive amounts of aminolevulinic acid and porphobilinogen in the urine; it is due to an abnormality of pyrrole metabolism transmitted as an autosomal dominant trait. (Barbiturates) Acute: having a short and relatively severe course. Addiction: 1. the state of being given up to some habit or compulsion. 2. strong physiological and psychological dependence on a drug or other psychoactive substance. Addison s disease: a chronic type of adrenocortical insufficiency, characterized by hypotension, weight loss, anorexia, weakness, and a bronzelike hyperpigmentation of the skin. It is

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due to tuberculosis- or autoimmune-induced destruction of the adrenal cortex, which results in deficiency of aldosterone and cortisol and is fatal in the absence of replacement therapy. ADH: (vasopressin) antidiuretic hormone. Adjunct: an accessory or auxiliary agent or measure. Adjuvant: 1. assisting or aiding. 2. a substance that aids another, such as an auxiliary remedy. 3. in immunology, a non-specific stimulator of the immune response, such as BCG vaccine. Adrenal crisis: acute onset of adrenocortical insufficiency or sudden worsening of Addison's disease; manifestations include anorexia, vomiting, abdominal pain, apathy, confusion, extreme weakness, renal loss of sodium and water, and hypotension progressing to shock and, if untreated, death. Adrenergic tremor: (enhanced physiological tremor) a tremor that may appear in normal individuals under conditions of stress, such as cold, excitement, hunger, or exercise; it represents an intensification of physiological tremor to detectable levels. Affect: the external expression of emotion attached to ideas or mental representations of objects. Agitation: excessive, purposeless cognitive and motor activity or restlessness, usually associated with a state of tension or anxiety Agoraphobia: intense, irrational fear of open spaces, characterized by marked fear of being alone or of being in public places where escape would be difficult or help might be unavailable. Agranulocytosis: 1. any condition involving greatly decreased numbers of granulocytes 2. more specifically, a symptom complex characterized by marked decrease in the number of circulating granulocytes; severe neutropenia results in lesions of the throat, other mucous membranes, gastrointestinal tract, and skin; in most cases it is caused by sensitization to drugs, chemicals, or radiation affecting the bone marrow and depressing granulopoiesis. Akathesia: a condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. Akinesia: see hypokinesia Alcoholism: a disorder characterized by a pathological pattern of alcohol use that causes a serious impairment in social or occupational functioning. Algesia: 1. pain sense. 2. excessive sensitivity to

Essentials of Medical Pharmacology

Majid A.K. Lafi

pain, a type of hyperesthesia. Allergic rhinitis: a general term used to denote any allergic reaction of the nasal mucosa; it may occur perennially (nonseasonal allergic rhinitis) or seasonally (hay fever). Alopecia: lack or loss of the hair from skin areas where it normally is present. Altitudes sickness: the condition resulting from difficulty in adjusting to diminished oxygen pressure at high altitudes. It may take the form of mountain sickness, high-altitude pulmonary oedema, or cerebral oedema. Alzheimer s disease: a progressive degenerative disease of the brain of unknown aetiology, characterized by diffuse atrophy throughout the cerebral cortex with distinctive lesions called senile plaques and clumps of fibrils called neurofibrillary tangles. There is a loss of choline acetyltransferase activity in the cortex, and many of the degenerating neurons seem to be cholinergic neurons projecting from the substantia innominata to the cortex. The first signs of the disease are slight memory disturbance or changes in personality; deterioration progresses to profound dementia over 5 to 10 years. Women are affected twice as often as men, and onset may occur at any age. Amenorrhoea: absence or abnormal stoppage of the menses. (Oestrogens) AML: Acute Myeloid Leukaemia Amnesia: lack or loss of memory; inability to remember past experiences. Amoebiasis: he state of being infected with amoebae, especially with Entamoeba histolytica. Anaemia: a reduction below normal in the concentration of erythrocytes or hemoglobin in the blood, measured per cu mm or by volume of packed red cells per 100 mL of blood; it occurs when the equilibrium is disturbed between blood loss (through bleeding or destruction) and blood production. Analgesia: 1. absence of sensibility to pain; absence of pain on noxious stimulation. 2. the relief of pain without loss of consciousness. Anaphylactic shock: a type I hypersensitivity reaction in which exposure of a sensitized individual to a specific antigen or hapten results in urticaria, pruritus, and angioedema, followed by vascular collapse and shock and often accompanied by life-threatening respiratory distress. Angina pectoris: a paroxysmal thoracic pain, often radiating to the arms, particularly the left, sometimes accompanied by a feeling of suffocation and impending death; it is most often due to ischemia of the myocardium and precipitated by effort or excitement. Angioedema: a vascular reaction involving the deep dermis or subcutaneous or submucosal tissues, representing localized edema caused by dilatation and increased permeability of capillaries, and characterized by development of giant wheals.

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Angioneurotic oedema: see angioedema Ankylosing spondylitis: a form of degenerative joint disease that affects the spine. It is a systemic illness of unknown etiology, affecting young persons predominantly, and producing pain and stiffness as a result of inflammation of the sacroiliac, intervertebral, and costovertebral joints; paraspinal calcification, with ossification and ankylosis of the spinal joints, may cause complete rigidity of the spine and thorax. Anorexia nervosa: an eating disorder primarily affecting females, usually with onset in adolescence, characterized by refusal to maintain a normal minimal body weight, intense fear of gaining weight or becoming obese, and a disturbance of body image resulting in a feeling of being fat or having fat in certain areas even when extremely emaciated, undue reliance on body weight or shape for self-evaluation, and amenorrhea. Associated features often include denial of the illness and resistance to psychotherapy, depressive symptoms, markedly decreased libido, and obsessions or peculiar behaviour regarding food, such as hoarding. Anorexia: lack or loss of the appetite for food. Antibiotic-associated enterocolitis: that in which treatment with antibiotics alters the bowel flora and results in diarrhea or pseudomembranous enterocolitis. Called also pseudomembranous colitis and antibiotic-associated colitis. Antigenicity: the property of being able to induce a specific immune response or the degree to which a substance is able to stimulate an immune response. Antinociception: having an analgesic effect; reducing sensitivity to painful stimuli. Antipsychotic: effective in the treatment of psychosis, or an agent that so acts. Antrectomy: surgical excision of an antrum, as resection of the pyloric antrum of the stomach. Anuria: complete suppression of urinary secretion by the kidneys. Anxiety: the unpleasant emotional state consisting of psychophysiological responses to anticipation of unreal or imagined danger, ostensibly resulting from unrecognized intrapsychic conflict. Physiological concomitants include increased heart rate, altered respiration rate, sweating, trembling, weakness, and fatigue; psychological concomitants include feelings of impending danger, powerlessness, apprehension, and tension. Apathetic: indifferent; undemonstrative. Apathy: lack of feeling or emotion; indifference. Aphthous ulcer: a small ulcer, such as the round lesion with a grayish exudate surrounded by a red halo characteristic of recurrent aphthous stomatitis Aplastic anaemia: any of a diverse group of anaemias characterized by bone marrow failure with reduction of hematopoietic cells and their replacement by fat, resulting in pancytopenia, often accompanied by granulocytopenia and

Glossary and Abbreviations

Ramadi, 11 October 2009

thrombocytopenia. It may be hereditary; it may be secondary to causes such as toxic, radiant, or immunologic injury to bone marrow stem cells or their microenvironment; it may be associated with various diseases; or it may be idiopathic. Appetite: a natural longing or desire, especially the natural and recurring desire for food. Arousal: 1. a state of responsiveness to sensory stimulation or excitability. 2. the act or state of waking from or as if from sleep. 3. the act of stimulating to readiness or to action. Ascites: effusion and accumulation of serous fluid in the abdominal cavity. Aseptic necrosis: increasing sclerosis and cystic changes in the head of the femur which sometimes follow traumatic dislocation of the hip. A similar condition sometimes develops in the head of the humerus after shoulder dislocation. Asthma: recurrent attacks of paroxysmal dyspnea, with airway inflammation and wheezing due to spasmodic contraction of the bronchi. Asystol: absence of a heartbeat Ataxia: failure of muscular coordination; irregularity of muscular action. Atonia: see atony. Atonic bladder: a condition marked by a dilated, poorly contracting urinary bladder without evidence of a lesion of the central nervous system. Atony: lack of normal tone or strength, such as in a muscle deprived of its innervation. Atopic dermatitis: a chronic type seen in those with a hereditary susceptibility to pruritus; it may be accompanied by allergic rhinitis, hay fever, and asthma. Attention deficit (hyperkinetic) disorder: a childhood mental disorder characterized by inattention (such as distractibility, forgetfulness, not finishing tasks, and not appearing to listen), by hyperactivity and impulsivity (such as fidgeting and squirming, difficulty in remaining seated, excessive running or climbing, feelings of restlessness, difficulty awaiting one's turn, interrupting others, and excessive talking) or by both types of behaviour. Autoallergy: autoimmunity. Azotaemia: an excess of urea or other nitrogen bodies in the blood (NSAIDs) BBB: blood brain barrier. BCG: Bacille Calmette-Guerin Benign prostatic hyperplasia: see prostatism. Bilateral renal stenosis: see renal artery stenosis. Bioequivalence: the quality of being bioequivalent. Bioequivalent: having the same strength and similar bioavailability in the same dosage form as another specimen of a given drug substance. Bipolar affective disorder: pertaining to mood disorders in which both depressive episodes and manic or hypomanic episodes occur. Bizarre: peculiar, weird, absurd. Bleeding oesophageal varices: pertaining to

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bleeding of varicosities of the branches of the azygos vein which anastomose with tributaries of the portal vein in the lower oesophagus, occurring in patients with portal hypertension. Blood dyscrasia: a pathologic condition of the blood, usually referring to disorders of the cellular elements of the blood. Blurred vision: fuzzy image. Blush: sudden, brief erythema of the face and neck, resulting from vascular dilatation due to emotion or heat. Bonchoconstriction: constriction or narrowing the lumina of the air passages of the lungs, typically as a result of bronchial smooth muscle contraction. BPH : Benign prostatic hyperplasia. Bradycardia: slowness of the heartbeat, as evidenced by slowing of the pulse rate to less than 60. Bradykinesia: see hypokinesia Bronchiectasis: chronic dilatation of the bronchi marked by fetid breath and paroxysmal coughing, with the expectoration of mucopurulent matter. Brucellosis: in humans, a generalized infection caused by species of Brucella, transmitted by contact with the natural animal reservoirs, including cattle, sheep, goats, swine, deer, and rabbits, or their infected products or tissue. It involves primarily the reticuloendothelial system and is characterized by fever, sweating, weakness, malaise, and weight loss. Bulimia nervosa: an eating disorder occurring predominantly in females, with onset usually in adolescence or early adulthood and characterized by episodic binge eating followed by behaviours designed to prevent weight gain, including purging, fasting, and excessive exercise. BUN: blood urea nitrogen CAD: coronary artery disease Calculus: an abnormal concretion occurring within the body and usually composed of mineral salts. Carcinoid tumour: a yellow circumscribed tumor arising from enterochromaffin cells, usually in the small intestine, appendix, stomach, or colon and less commonly in the bronchus. Cardiomyopathy: a general diagnostic term designating primary noninflammatory disease of the heart muscle, often of obscure or unknown etiology and not the result of ischemic, hypertensive, congenital, valvular, or pericardial disease. Cardioversion: the restoration of normal rhythm of the heart by electrical shock. Cataracts: a partial or complete opacity on or in the lens or lens capsule of the eye, especially one impairing vision or causing blindness. Cathartic: 1. causing emptying of the bowels. 2. an agent that causes emptying of the bowels, such as by increasing bulk or stimulating peristaltic action. Called also evacuant and purgative. 3. producing emotional catharsis.

Essentials of Medical Pharmacology

Majid A.K. Lafi

CBF: cerebral blood flow. CBG: corticosteroid binding globulin. Cellulitis: an acute, diffuse, spreading, edematous, suppurative inflammation of the deep subcutaneous tissues and sometimes muscle, sometimes with abscess formation; the skin is warm and tender. Central precocious puberty: precocious puberty due to premature hypothalamic-pituitary-gonadal maturation; it is always isosexual and involves not only development of secondary sex characters but also development of the gonads. Increases in height and weight and osseous maturation are accelerated, and early closing of the epiphyses leads to short stature. CGRP: calcitonin gene related peptide. Cheese effect: cheese contains substantial amounts of sympathomimetics, most commonly tyramine, which acts by releasing tissue-stored noradrenaline. For example, degradation of the protein 'casein' by resident bacteria in well matured cheese can produce tyramine from the amino acid tyrosine, hence use of the term 'cheese effect' to describe provocation of a hypertensive crisis by orally administered sympathomimetics. CHF: Congestive heart failure Chickenpox: (varicella) a highly contagious infectious disease caused by human herpesvirus 3, usually affecting children, spread by direct contact or the respiratory route via droplet nuclei, and characterized by the appearance on the skin and mucous membranes of successive crops of typical pruritic vesicular lesions that are easily broken and become scabbed, and generally accompanied by mild constitutional symptoms. Cholinergic crisis: muscular weakness resulting from depolarization block due to overdosage of anticholinesterase agents used for myasthenia gravis; similar to but different from myasthenic crisis. CHOP: cyclophosphamide, hydroxydonorubicin (doxorubicin), Oncovin (vincristine), and prednisone. Chorea: the ceaseless occurrence of a wide variety of rapid, highly complex, jerky movements that appear to be well coordinated but are performed involuntarily. (Drugs and movement disorders) Chorionepithelioma: an epithelial malignancy of trophoblastic cells, formed by the abnormal proliferation of cuboidal and syncytial cells of the placental epithelium, without the production of chorionic villi. Chronic bronchitis: a type of chronic obstructive pulmonary disease in which there is bronchial irritation with increased secretions and a productive cough for at least three months, two years in succession; it is usually accompanied by pulmonary emphysema. The most common cause is long-term inhalation of irritants. Chronic: persisting over a long period of time. Chronotropic: affecting the time or rate, as the

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rate of contraction of the heart. Cinchonism: poisoning by the injudicious use of cinchona bark or its alkaloids, characterized by nausea, vomiting, headache, tinnitus, deafness, symptoms of cerebral congestion, vertigo, and visual disturbances. Closed-angle glaucoma: glaucoma caused by closure of the anterior angle by contact between the iris and the inner surface of the trabecular meshwork; called also closed-angle g., narrowangle g., and pupillary block g. CMV: cytomegalovirus CNS: central nervous system. Coitus: sexual connection per vaginam between male and female. Cold sweat: a sweat produced by the apocrine sweat glands, located on the palms of the hands and a few other areas, respond to adrenoceptor stimulants with increased sweat production. These are the apocrine nonthermoregulatory glands usually associated with psychological stress, e.g. an embarrassing situation. Collapse: 1. a state of extreme prostration and depression, with failure of circulation. 2. abnormal falling in of the walls of any part or organ. Compulsion: a persistent and irresistible impulse to perform an irrational or apparently useless act. 2. a compulsive act or ritual; a repetitive and stereotyped action, such as hand-washing, touching, counting, and checking, that is engaged in for an unknown or unconscious purpose. COMT: catechol-O-methyltransferase Concomitant: accompanying; accessory; joined with another. Confusion: disturbed orientation in regard to time, place, or person, sometimes accompanied by disordered consciousness. Congestion: excessive or abnormal accumulation of fluid, as of blood in a part. Congestive heart failure: (CHF) a clinical syndrome due to heart disease, characterized by breathlessness and abnormal sodium and water retention, often resulting in oedema. The congestion may occur in the lungs or peripheral circulation or both, depending on whether the heart failure is right-sided or general. Conjunctivitis: inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. Constipation: infrequent or difficult evacuation of the faeces. Contraception: the prevention of conception or impregnation. Convulsion: a violent involuntary contraction or series of contractions of the voluntary muscles. COX: cyclooxgenase. Cretinism: a chronic condition due to congenital severe hypothyroidism; manifestations begin in late infancy and include arrested physical development (dwarfism), mental retardation, dystrophy of the

Glossary and Abbreviations

Ramadi, 11 October 2009

bones and soft parts, and lowered basal metabolism. Crohn s disease: a chronic granulomatous inflammatory disease of unknown aetiology, involving any part of the gastrointestinal tract from mouth to anus, but commonly involving the terminal ileum with scarring and thickening of the bowel wall; it frequently leads to intestinal obstruction and fistula and abscess formation and has a high rate of recurrence after treatment. Cryptorchism: failure of testes to descend to into the scrotum. (Non-pituitary gonadotropins) Crystalluria CSF: cerebrospinal fluid. Css: steady-state concentration. CTZ: chemoreceptor trigger zone. Cushing s syndrome: a complex of symptoms caused by hyperadrenocorticism due either to a neoplasm of the adrenal cortex or adenohypophysis, or to excessive intake of glucocorticoids. Symptoms may include adiposity of the face, neck, and trunk; kyphosis from osteoporosis of the spine; hypertension; diabetes mellitus; amenorrhea and hypertrichosis in females; impotence in males; dusky complexion with purple striae; polycythemia; and muscular wasting and weakness. Cushing-like syndrome: a complex of symptoms caused by hyperadrenocorticism due either to a neoplasm of the adrenal cortex or adenohypophysis, or to excessive intake of glucocorticoids. Symptoms may include adiposity of the face, neck, and trunk; kyphosis from osteoporosis of the spine; hypertension; diabetes mellitus; amenorrhoea and hypertrichosis in females; impotence in males; dusky complexion with purple striae; polycythaemia; and muscular wasting and weakness. Cycloplegia: paralysis of the ciliary muscle; paralysis of accommodation. Cystic fibrosis: cystic fibrosis of the pancreas, an autosomal recessive disorder of infants, children, and young adults in which there is widespread dysfunction of the exocrine glands, with signs of chronic pulmonary disease (due to excess mucus production in the respiratory tract), pancreatic deficiency, abnormally high levels of electrolytes in the sweat, and occasionally biliary cirrhosis. DAG: diacylglycerol Deep venous thrombosis: DVT; thrombosis of one or more of the deep veins of the lower limb, characterized by swelling, warmth, and erythema, frequently a precursor of a pulmonary embolism. Deleterious: hurtful; injurious. Delirium tremens: (alcohol withdrawal delirium) delirium caused by cessation or reduction in alcohol consumption, typically in alcoholics with 10 years or more of heavy drinking. Clinical manifestations include autonomic hyperactivity, such as tachycardia, sweating, and hypertension; a

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coarse, irregular tremor, and delusions, vivid hallucinations; and wild, agitated behaviour. The onset is usually 2 or 3 days after cessation of drinking; the delirium and other withdrawal symptoms usually resolve in 3 or 4 days. Delirium: an acute, transient disturbance of consciousness accompanied by a change in cognition and having a fluctuating course. Delusion of jealousy: a delusional belief that one's spouse or lover is unfaithful based on erroneous inferences drawn from innocent events imagined to be evidence and often resulting in confrontation with the accused. It is one of the subtypes of delusional disorder. Delusion: a false belief that is firmly maintained in spite of undeniable and obvious proof or evidence to the contrary and in spite of the fact that other members of the culture do not share the belief. Dementia: a general loss of cognitive abilities, including impairment of memory as well as one or more of the following: aphasia, apraxia, agnosia, or disturbed planning, organizing, and abstract thinking abilities. Demulcent: 1. soothing; bland; allaying the irritation of inflamed or abraded surfaces. 2. a soothing, mucilaginous, or oily medicine or application. Dependent oedema: oedema affecting most seriously the lowermost or dependent parts of the body. Depression: 1. a hollow or depressed area; downward or inward displacement. 2. a lowering or decrease of functional activity. 3. a mental state of depressed mood characterized by feelings of sadness, despair, and discouragement. Depression ranges from normal feelings of ''the blues'' through dysthymic disorder to major depressive disorder. It in many ways resembles the grief and mourning that follow bereavement; there are often feelings of low self-esteem, guilt, and self-reproach, withdrawal from interpersonal contact, and somatic symptoms such as eating and sleep disturbances. Dermatophytoses: any superficial fungal infection caused by a dermatophyte and involving the stratum corneum of the skin, hair, and nails, including onychomycosis and the various forms of tinea. Diabetes insipidus: any of several types of polyuria in which the volume of urine exceeds 3 litres per day, causing dehydration and great thirst, as well as sometimes emaciation and great hunger. Diabetic neuropathy: any of several clinical types of peripheral neuropathy occurring with diabetes mellitus; there are sensory, motor, autonomic, and mixed varieties. The most common kind is a chronic, symmetrical sensory polyneuropathy affecting first the nerves of the lower limbs and often affecting autonomic nerves; pathologically, there is a segmental demyelination of the

Essentials of Medical Pharmacology

Majid A.K. Lafi

peripheral nerves. An uncommon acute form is the ischemic variety, accompanied by severe pain, weakness, and wasting of proximal and distal muscles, peripheral sensory impairment, and loss of tendon reflexes. With autonomic involvement there may be orthostatic hypotension, nocturnal diarrhea, retention of urine, impotence, and small diameter of the pupils with sluggish reaction to light. Diabetogenic: producing diabetes Diaphoresis: sweating, especially of a profuse type. Diarrhoea: abnormal frequency and liquidity of faecal discharges. DIC: Disseminated intravascular coagulation Diphtheria: an acute infectious disease caused by toxigenic strains of Corynebacterium diphtheriae, acquired by contact with an infected person or a carrier; it is usually confined to the upper respiratory tract, and characterized by the formation of a tough false membrane attached firmly to the underlying tissue that will bleed if forcibly removed. In the most serious infections the membrane begins in the faucial area on one tonsil and may spread to the other tonsil, uvula, soft palate, and pharyngeal wall, followed by the larynx, trachea, and bronchial tree, where it may cause bronchial obstruction and death by hypoxia. Diplopia: the perception of two images of a single object. Disinhibition: 1. removal of inhibitions, as reduction of the inhibitory function of the cerebral cortex by drugs such as ethyl alcohol or reduction in the severity of superego controls in psychotherapy. 2. in experimental psychology, the revival of an extinguished conditioned response by exposure to an unconditioned stimulus. Dissociative anaesthesia: loss of sensitivity to pain, heat, and cold without loss of other tactile senses. Disulfiram-like reaction: a syndrome occurring after inhalation or ingestion of disulfiram followed by drinking an alcoholic beverage, marked by intense flushing, rapid pulse and pounding heart, panting respiration, and impaired taste, unpleasant breath and perspiration, which may be followed by nausea, vomiting, and a precipitous fall in blood pressure; the extent and severity of the symptoms depend on the amount of calcium cyanamide and alcohol in the system. The reactions are due to the inhibition by disulfiram of one or more of the enzymes required for oxidation of acetaldehyde formed from alcohol, resulting in the accumulation of acetaldehyde and the altered vascular reaction to it. Dizziness: a disturbed sense of relationship to space; a sensation of unsteadiness with a feeling of movement within the head. DMARD: disease-modifying antirheumatic drug. Dosage: the determination and regulation of the

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size, frequency, and number of doses. Dromotropic: affecting the conductivity of a nerve fiber Dropsical: oedematous. Drowsiness: sleepiness. Drug Abuse: a substance use disorder characterized by the use of a mood or behaviouraltering substance in a maladaptive pattern resulting in significant impairment or distress, such as failure to fulfil social or occupational obligations or recurrent use in situations in which it is physically dangerous to do so or which end in legal problems, but without fulfilling the criteria for substance dependence (q.v.). Specific disorders are named for their aetiology, eg., alcohol abuse, anabolic steroid abuse. Ductus arteriosus: arterial duct: a fetal blood vessel connecting the left pulmonary artery directly to the descending aorta. Dysfunctional uterine bleeding: bleeding from the uterus when no organic uterine lesions are present. Dysmenorrhoea: Painful menstruation (NSAIDs) Dyspepsia: impairment of the power or function of digestion; usually applied to epigastric discomfort following meals. Dysphoria: disquiet; restlessness; malaise (Opioids and narcotic analgesics) Dyspnoea: breathlessness or shortness of breath; difficult or laboured breathing. Dystocia: abnormal labour or childbirth (NSAIDs) Dystonia: dyskinetic movements due to disordered tonicity of muscle. ECL: enterochromaffin-like. ECT: electroconvulsive therapy. Ectopic beats: a heart beat originating at some point other than the sinus node. Emotion: a strong feeling state, such as excitement, distress, happiness, sadness, love, hate, fear, or anger, arising subjectively and directed toward a specific object, with physiological, somatic, and behavioural components. In psychoanalytic theory, it is a state of tension associated with an instinctual drive. The external manifestation of emotion is called affect; a pervasive and sustained emotional state, mood. Empirical: based on experience. Encephalopathy: any degenerative disease of the brain. Endemic: present or usually prevalent in a population or geographical area at all times; said of a disease or agent. and proliferative Endocarditis: exudative inflammatory alterations of the endocardium, usually characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary

Glossary and Abbreviations

Ramadi, 11 October 2009

disorder or as a complication of or in association with another disease. Endometrial cancer: carcinoma characterized by glandular patterns that resemble those of the endometrium, occurring in the uterine fundus and in the ovaries. Endometriosis: a condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. (Progestins, danazol) Endophathalmitis: nflammation involving the ocular cavities and their adjacent structures. Enema: a liquid injected or to be injected into the rectum Enuresis: urinary incontinence after the age at which urinary control should have been achieved; often used alone with specific reference to that occurring during sleep at night (bed-wetting; nocturnal enuresis) Eosinophilia: 1. the formation and accumulation of an abnormally large number of eosinophils in the blood. 2. the condition of being readily stained with eosin. EP: extrapyramidal. Epidural (peridural) nerve block. regional anaesthesia produced by injection of the anaesthetic agent between the vertebral spines and beneath the ligamentum flavum into the epidural space. Epilepsy: any of a group of syndromes characterized by paroxysmal transient disturbances of the brain function that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system. Epileptoform: 1. resembling epilepsy or its manifestations. 2. occurring in severe or sudden paroxysms. Episiotomy: surgical incision into the perineum and vagina to prevent traumatic tearing during delivery. EPSP: excitatory postsynaptic potential. Erotomania: 1. a disorder in which the subject believes that a person, usually older and of higher social status, is deeply in love with them; failure of the object of the delusion to respond to the subject's advances are rationalized, and pursuit and harassment of the object of the delusion may occur. 2. occasionally, hypersexuality. ESBLs: extended spectrum -lactamases Essential tremor: a hereditary tremor with onset at varying ages, usually at about 50 years of age, beginning with a fine rapid tremor (as distinct from that of parkinsonism) of the hands, followed by tremor of the arms, tongue, head, legs, and trunk; it is aggravated by emotional factors, is accentuated by volitional movement, and in some cases is

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temporarily improved by alcohol. Euphoria: bodily comfort; well being; absence of pain or distress. In psychiatry, an abnormal or exaggerated sense of well being, particularly common in the manic state. (Opioids and narcotic analgesics, glucocorticoids) Excipient: any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; called also vehicle. Expectorant: 1. promoting the ejection, by spitting, of mucus or other fluids from the lungs and trachea. 2. an agent that promotes the ejection of mucus or exudate from the lungs, bronchi, and trachea; sometimes extended to all remedies that quiet cough (antitussives). Extrasystole: a weak systole, usually premature, not associated with pulsation of a peripheral artery Extremity: an upper or lower limb ( a hand or foot) Febrile: 1. pertaining to fever. 2. characterized by fever. Fever: elevation of body temperature above the normal Fibrosis: the formation of fibrous tissue, as in repair or replacement of parenchymatous elements. Flush: 1.transient, episodic redness of the face and neck caused by certain diseases, ingestion of certain drugs or other substances, heat, emotional factors, or physical exertion. 2. to wash out with fluid. Foetal alcohol syndrome: a syndrome of altered prenatal growth and morphogenesis occurring in infants born of women who were chronically alcoholic during pregnancy; it includes maxillary hypoplasia, prominence of the forehead and mandible, short palpebral fissures, microphthalmia, epicanthal folds, severe growth retardation, mental retardation, and microcephaly. Foetal: of or pertaining to a foetus; pertaining to in utero development after the embryonic period. FSH: follicle-stimulating hormone. GABA: γ-aminobutyric acid. GAD: generalised anxiety disorder. Gastroenteritis: an acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Gastroparesis: paralysis of the stomach. GERD: gastroesophageal reflux disease. Gestational diabetes: diabetes mellitus with onset or first recognition during pregnancy; this category does not include diabetics who become pregnant or women who become lactosuric. GFR: glomerular filtration rate. GH: (somatropin) growth hormone.

Essentials of Medical Pharmacology

Majid A.K. Lafi

Gigantism: abnormal overgrowth; excessive size and stature. Gingivitis: inflammation of the gingivae. GIT: gastrointestinal tract Glaucoma: a group of eye diseases characterized by an increase in intraocular pressure that causes pathological changes in the optic disk and typical defects in the field of vision. Glycogenolysis: the breakdown of glycogen to glucose by hydrolysis (as in digestion or within lysosomes) or phosphorolysis (as in mobilization of glycogen as a fuel). Gn: gonadotropin. GnRH: gonadotropin-releasing hormone. Goitre: an enlargement of the thyroid gland, causing a swelling in the front part of the neck. Gout: a group of disorders of purine metabolism, manifested by various combinations of (1) hyperuricaemia; (2) recurrent acute inflammatory arthritis induced by crystals of monosodium urate monohydrate; (3) tophaceous deposits of these crystals in and around the joints of the extremities, which may lead to crippling destruction of joints; and (4) uric acid urolithiasis. Granulocytopenia: reduction in the number of granular leukocytes in the blood. Graves disease: a syndrome of diffuse hyperplasia of the thyroid, with a female predominance; it usually has an autoimmune aetiology and has been linked to autoimmune thyroiditis. Characteristics include hyperthyroidism, usually with goitre and ophthalmic symptoms (Graves' orbitopathy). Grey baby syndrome: a potentially fatal condition seen in neonates, particularly premature infants, due to a reaction to chloramphenicol, characterized by an ashen gray cyanosis, listlessness, weakness, and hypotension. GTN: glyceryltrinitrate Gynaecomastia: excessive growth of the male mammary glands, in some cases including development to the stage at which milk is produced, usually associated with metabolic derangements that lead to oestrogen accumulation, testosterone deficiency, and hyperprolactinaemia. A mild form may develop transiently during normal puberty. Habitual abortion: the spontaneous expulsion of a dead or nonviable foetus in three or more consecutive pregnancies, at about the same period of development. Haematuria: blood in the urine Haemophilia: a hemorrhagic diathesis occurring in two main forms: haemophilia A, deficiency of coagulation factor VIII; and haemophilia B, deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but at different loci, and are characterized by

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subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. Haemorrhoids: a varicose dilatation of a vein of the superior or inferior hemorrhoidal plexus, resulting from a persistent increase in venous pressure. Hallucination: a sense perception without a source in the external world; a perception of an external stimulus object in the absence of such an object. Hangover: extended beyond. Hashimoto s autoimmune thyroiditis: a progressive type of autoimmune thyroiditis with lymphocytic infiltration of the gland and circulating antithyroid antibodies; patients have goitre and gradually develop hypothyroidism. It has a familial predisposition, usually affects women, and sometimes precedes the onset of Graves' disease or is manifested after the major symptoms subside. Hay fever: a type of allergic rhinitis that occurs at the same time every year, marked by acute conjunctivitis with lacrimation and itching, swelling of the nasal mucosa, sneezing, and often asthmatic symptoms. hCG: human chorionic gonadotropin. Heart block: impairment of conduction of an impulse in heart excitation; often applied specifically to atrioventricular block. Hepatotoxicity: the quality or property of exerting a destructive or poisonous effect upon liver cells. Herpes simplex: a group of acute infections caused by human herpesviruses 1 and 2, characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane, and occurring as a primary infection or recurring because of reactivation of a latent infection. Type 1 infections usually involve nongenital regions of the body, whereas in type 2 infections the lesions are primarily seen on the genital and surrounding areas, although there is overlap between the two types. Hiatus hernia: a condition of incompetent gastrooesophageal sphincters. Hiccup: an involuntary spasmodic contraction of the diaphragm, causing a beginning inspiration that is suddenly checked by closure of the glottis, causing a characteristic sound. Hirsutism: abnormal hairiness, especially an adult male pattern of hair distribution in women. hMG: human menopausal gonadotropin. Huntington s chorea: a rare hereditary disease characterised by chronic progressive chorea and mental deterioration terminating in dementia; the age of onset is variable but usually occurs in the fourth decade of life. Death usually follows within 15 years. It is transmitted as an autosomal dominant trait. (Drugs and movement disorders) Huntington s chorea: an autosomal dominant

Glossary and Abbreviations

Ramadi, 11 October 2009

disease characterized by chronic progressive chorea and mental deterioration terminating in dementia; the age of onset is variable but usually in the fourth decade of life, with death within 15 years. Huntington s disease: see Huntington s chorea Hydatidiform mole: an abnormal pregnancy resulting from a pathological ovum, with proliferation of the epithelial covering of the chorionic villi and dissolution and cystic cavitation of the avascular stroma of the villi. Hydrothorax: a pleural effusion containing serous fluid. Hyperactive child: see Attention deficit (hyperkinetic) disorder Hypercalcaemia: an excess of calcium in the blood; manifestations include fatigability, muscle weakness, depression, anorexia, nausea, and constipation. Hypercalciuria: excess of calcium in the urine. Hyperchloraemic acidosis: metabolic acidosis accompanied by elevated plasma chloride. Hyperglycaemia: abnormally increased glucose in the blood, such as in diabetes mellitus. Hyperkinetic child: see Attention deficit (hyperkinetic) disorder an abnormally high Hypermagnesaemia: magnesium content of the blood; manifestations include lethargy, weakness, electrocardiographic abnormalities and, as levels increase, loss of deep tendon reflexes, somnolence, and coma. Hyperplasia: abnormal multiplication or increase in the number of normal cells in normal arrangement in a tissue. Hyperplasminaemia: abnormally increased plasmin in the blood. Hyperprolactinaemia: increased levels of prolactin in the blood; in women it is associated with amenorrhea and galactorrhoea, and in men it has been reported to cause hypogonadism, impotence, and in some cases gynaecomastia. It is often associated with microadenoma of the adenohypophysis. Hypersexuality: abnormally increased sexual desire or activity; nymphomania; satyriasis. Hypersomnia: excessive sleeping or sleepiness, as in any of a group of sleep disorders with a variety of physical and psychogenic causes. Hypertension: high arterial blood pressure; various criteria for its threshold have been suggested, ranging from 140 mm Hg systolic and 90 mm Hg diastolic to as high as 200 mm Hg systolic and 110 mm Hg diastolic. Hypertension may have no known cause (essential or idiopathic h.) or be associated with other primary diseases (secondary h.). Hypertensive crisis: dangerously high blood pressure of acute onset. Hyperthermia of anaesthesia: see malignant hyperthermia.

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Hyperthyroidism: a condition caused by excessive production of iodinated thyroid hormones. Hypertrophy: the enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells. Hyperuricaemia: excess of uric acid or urates in the blood; it is a prerequisite for the development of gout and may lead to renal disease. Hypoadrenalism: adrenal insufficiency. Hypoglycaemia: an abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache; when chronic and severe it may cause central nervous system manifestations that in rare cases can even be fatal. Hypokalaemia: abnormally low potassium concentration in the blood; it may result from excessive potassium loss by the renal or the gastrointestinal route, from decreased intake, or from transcellular shifts. It may be manifested clinically by neuromuscular disorders ranging from weakness to paralysis, by electrocardiographic abnormalities (depression of the T wave and elevation of the U wave), by renal disease, and by gastrointestinal disorders. Hypokinesia: (bradykinesia, akinesia) slowness of movements (Drugs and movement disorders) Hypomania: an abnormality of mood resembling mania (persistent elevated or expansive mood, hyperactivity, inflated self-esteem, etc.) but of lesser intensity. Hypophosphotaemia: an abnormally decreased amount of phosphates in the blood; manifestations include haemolysis, lassitude, weakness, and convulsions. Hypotension: abnormally low blood pressure. Hypothalamic hypogonadotropic hypogonadism: that due to lack of gonadotropin secretion; it is caused by lack of secretion of gonadotropin-releasing hormone. Hypothyroidism: deficiency of thyroid activity, characterized by decrease in basal metabolic rate, fatigue, and lethargy; if untreated, it progresses to myxoedema. In adults it is more common in women than men, and in infants it can lead to cretinism. Hypothyroidism: deficiency of thyroid activity, characterized by decrease in basal metabolic rate, fatigue, and lethargy; if untreated, it progresses to myxoedema. In adults it is more common in women than men, and in infants it can lead to cretinism. Hypotonic bladder: a condition of diminished tone of the detrusor muscle of the urinary bladder. Hypoxia: reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. i.m.: intramuscular. i.v.: intravenous.

Essentials of Medical Pharmacology

Majid A.K. Lafi

IDDM: insulin dependent diabetes mellitus. Idiopathic: of unknown cause or spontaneous origin; of the nature of an idiopathy. Ileus: obstruction of the intestines. Immune insulin resistance: see insulin resistance. Impulse dyscontrol syndrome: a pattern of episodic, abnormal, and often violent and uncontrollable social behaviour with little or no provocation; it may result from diseases of the limbic system or the temporal lobe or may accompany abuse of alcohol or some other psychoactive substance. Incontinence: 1. inability to control excretory functions, such as defecation (fecal i.) or urination (urinary i. ). Infant respiratory distress syndrome: dyspnoea with cyanosis in the newborn, heralded by such prodromal signs as dilatation of the alae nasi, expiratory grunt, and retraction of the suprasternal notch or costal margins, caused by a deficiency in surfactant. It is usually seen in premature infants, children of diabetic mothers, or infants delivered by caesarean section, although sometimes there is no apparent predisposing cause. Infertility: diminished or absent capacity to produce offspring; the term does not denote complete inability to produce offspring as does sterility. Inotropic: affecting the force or energy of muscular contractions. INR: international normalized ratio. Insomnia: inability to sleep; abnormal wakefulness. Insulin resistance: impairment of normal biological responses to insulin, which may result from abnormalities in the beta-cell products, binding of insulin to antagonists such as antiinsulin antibodies, defects in or reduced numbers of receptors, or defects in the insulin action cascade in the target cell. It can also be caused by excessive quantities of growth hormone, adrenocortical steroids, or some other regulators, or by chronic hyperinsulinaemia secondary to hyperphagia. Incidence is increased with conditions such as obesity, diabetes mellitus, acromegaly, uraemia, and certain rare, possibly genetic, autoimmune disorders. Insulinogenic: pertaining to, characterized by, or promoting insulinogenesis. Insulinoma: an islet cell tumor of pancreatic beta cells; although usually benign, such tumours secrete excessive amounts of insulin and are among the most important causes of hypoglycemia. Intermittent claudication: a complex of symptoms characterized by pain, tension, and weakness in a limb when walking is begun, intensification of the condition until walking becomes impossible, and disappearance of the symptoms after a period of rest. It is seen in occlusive arterial diseases of the limbs, such as

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thromboangiitis obliterans, and in compression of the cauda equina. Intermittent: occurring at separated intervals; having periods of cessation of activity. Intractable: resistant to cure, relief, or control. IPSP: inhibitory postsynaptic potential. Iritis: inflammation of the iris, usually marked by pain, congestion in the ciliary region, photophobia, contraction of the pupil, and discoloration of the iris. Iron deficiency: deficiency of iron in the system, usually caused by blood loss, low dietary levels of iron, or a disease condition that inhibits iron uptake. Irritable bowel syndrome: irritable colon syndrome, a chronic noninflammatory disease characterized by abdominal pain, altered bowel habits consisting of diarrhea or constipation or both, and no detectable pathologic change; a variant form is characterized by painless diarrhea. It is a common disorder with a psychophysiological basis. ISA: intrinsic sympathomimetic activity Kaliuretic: 1. pertaining to, characterized by, or promoting kaliuresis. 2. an agent that promotes kaliuresis (potassium losing). Kernicterus: a condition associated with high levels of bilirubin in the blood, nearly always with severe neural symptoms, usually seen in infants as a sequela of icterus gravis neonatorum. Lactic acidosis: a metabolic acidosis occurring as a result of excess lactic acid in the blood, due to conditions causing impaired cellular respiration. It occurs most commonly in disorders in which O2 is inadequately delivered to tissues, e.g., shock, septicemia, or extreme hypoxemia, but it can also result from exogenous or endogenous metabolic defects. Initially manifesting as hyperventilation, it progresses to mental confusion and coma. Legionnaires disease: a bacterial disease caused by infection with Legionella pneumophila, and not spread by person-to-person contact; it is characterized by pneumonia, high fever, gastrointestinal pain, headache, and sometimes involvement of the kidneys, liver, or nervous system. Leucocytosis: a transient increase in the number of leukocytes in the blood; seen normally with strenuous exercise and pathologically accompanying haemorrhage, fever, infection, or inflammation. LH: luteinizing hormone. Libido: 1. sexual desire. 2. the psychic energy derived from instinctive biological drives; in early freudian theory it was restricted to the sexual drive, then expanded to include all expressions of love and pleasure, but the concept has evolved to include also the death instinct. LOX: lipoxygenase. LSD: lysergide.

Glossary and Abbreviations

Ramadi, 11 October 2009

Lupus erythematosus: a group of connective tissue disorders primarily affecting women aged 20 to 40 years, comprising a spectrum of clinical forms in which cutaneous disease may occur with or without systemic involvement. Luteolysis: degeneration of corpus luteum. Lymphogranuloma venereum: a sexually transmitted infection usually seen in warm climates, due to strains of Chlamydia trachomatis, characterized by a primary cutaneous or mucosal lesion at the site of infection, which may be a papular, ulcerative, herpetiform, or erosive lesion or urethritis or endocervicitis that heals spontaneously and may go unnoticed, followed by acute unilateral or bilateral lymphadenopathy. Malaise: a vague feeling of bodily discomfort. Malignant hyperthermia: an autosomal dominantly inherited condition, occurring in patients undergoing general anaesthesia, and causing a sudden, rapid rise in body temperature, associated with signs of increased muscle metabolism, such as tachycardia, tachypnoea, sweating, and cyanosis, usually, muscle rigidity. Called also hyperthermia of anaesthesia and malignant hyperpyrexia. (General anaesthetic agents, antipsychotic neuroleptic drugs, dantroline) Mania: a phase of bipolar disorder characterized by expansiveness, euphoria, agitation, hyperexcitability, hyperactivity, and increased speed of thought and speech (flight of ideas). Manic-depressive illness: older term for bipolar disorder, see bipolar affective disorder. MAO: monoamine oxidase. Megaloblastic: any anaemia characterized by the presence of megaloblasts in the bone marrow, such as pernicious anaemia. Meningitis: inflammation of the meninges, usually by either a bacterium (bacterial m.) or a virus (viral m.). Menopausal symptoms: including transient vaginal bleeding, hot flushes, and vaginal dryness. Menopausal: pertaining to or associated with the menopause. Menopause: cessation of menstruation in the human female, occurring usually between the age of 48 and 50. Menorrhagia: excessive uterine bleeding at the regular intervals of menstruation, the period of flow being greater than usual duration. (Progestins) Menstrual disorder: a derangement or abnormality of function related to menstruation. Metabolic alkalosis: any of the various kinds of acidosis in which the acid-base status of the body shifts toward the acid side because of loss of base or retention of acids other than carbonic acid (fixed or nonvolatile acids), in contrast to respiratory acidosis. Metallic: pertaining to, consisting of, or of the nature of metal.

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Methemoglobinemia: the presence of excessive methemoglobin in the blood, resulting in cyanosis and headache, dizziness, fatigue, ataxia, dyspnea, tachycardia, nausea, vomiting, and drowsiness, which can progress to stupor, coma, and occasionally death. It may be either chemicalor drug-induced (acquired or toxic m.) or hereditary (congenital or hereditary m.). MIC: minimum inhibitory concentration Micturition: urination. Migraine: an often familial symptom complex of periodic attacks of vascular headache, usually temporal and unilateral in onset, commonly associated with irritability, nausea, vomiting, constipation or diarrhoea, and often photophobia. Attacks are preceded by constriction of the cranial arteries, often with resultant prodromal sensory (especially ocular) symptoms and the spreading depression of Le o; the migraines themselves commence with the vasodilatation that follows. Two primary types are distinguished, m. with aura and m. without aura; the variety without an aura is more common. Milk-alkali syndrome: a syndrome characterized by hypercalcaemia without hypercalciuria or hypophosphataemia, with only mild alkalosis, normal serum phosphatase, severe renal insufficiency with hyperazotaemia, and calcinosis, attributed to ingestion of milk and absorbable alkali for long periods of time. Miosis: contraction of the pupil. Mood: a pervasive and sustained emotion that, when extreme, can colour one's whole view of life and markedly affect behaviour. Mood is generally used to refer to either elation or depression. Morbid jealousy: preoccupation with gloomy or distrustful feelings or thoughts, see delusion of jealousy. Morbid: 1. pertaining to, affected with, or inducing disease; diseased. 2. unhealthy or unwholesome. 3. characterized by preoccupation with gloomy or unwholesome feelings or thoughts. Morbidity: 1. a diseased condition or state. 2. the incidence or prevalence of a disease or of all diseases in a population. Mortality: 1. the quality of being mortal. 2. the mortality rate. Motion sickness: sickness caused by motion experienced in any kind of travel, such as sea sickness, train sickness, car sickness, and air sickness. MRSA: Methicillin Resistant Staphylococcus Aureus. MSA: membrane stabilising activity. Mucolytic: destroying or dissolving mucin; an agent that so acts. Myasthenia gravis: a disorder of neuromuscular function due to the presence of antibodies to acetylcholine receptors at the neuromuscular

Essentials of Medical Pharmacology

Majid A.K. Lafi

junction; characteristics include muscular fatigue and exhaustion tending to fluctuate in severity, without sensory disturbance or atrophy. It may be restricted to one muscle group or become generalized with severe weakness and sometimes ventilatory insufficiency. It may affect any muscle of the body, but especially those of the eye, face, lips, tongue, throat, and neck. Mydriasis: 1. physiologic dilatation of the pupil. 2. morbid dilatation of the pupil. 3. dilatation of the pupil effected by a drug. Myocardial infarction: (MI) gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. Myoclonic: relating to or marked by myoclonus. Myoclonus: shocklike contractions of a portion of a muscle, an entire muscle, or a group of muscles, restricted to one area of the body or appearing synchronously or asynchronously in several areas. It may be part of a disease process (e.g., epileptic or post-anoxic myoclonus) or be a normal physiological response (e.g., nocturnal myoclonus). Myxoedema: 1. a condition characterized by dry, waxy swelling of the skin, with abnormal deposits of glycosaminoglycans in skin (mucinosis) and other tissues, associated with primary hypothyroidism. The oedema is nonpitting, and there are distinctive facial changes including swollen lips and a thickened nose. 2. hypothyroidism in adults. NABQI: N-acetyl-benzoquinone. Narcolepsy: recurrent, uncontrollable, brief episodes of sleep often associated with hypnagogic or hypnopompic hallucinations, cataplexy, and sleep paralysis. Narcotic: 1. pertaining to or producing narcosis. 2. an agent that produces insensibility or stupor, applied especially to the opioids, i.e., to any natural or synthetic drug that has morphine-like actions. Necrosis: the sum of the morphological changes indicative of cell death and caused by the progressive degradative action of enzymes; it may affect groups of cells or part of a structure or an organ. Negative symptoms: (retarded schizophrenia) minus personality features including apathy, flattening of affect and poverty of speech. Neonatal: pertaining to the first four weeks after birth. Nephrogenic diabetes insipidus: diabetes insipidus caused by failure of the renal tubules to reabsorb water in response to antidiuretic hormone, without disturbance in the renal filtration and solute excretion rates; the condition does not respond to exogenous vasopressin. It may be inherited as an X-linked trait or be acquired as a result of drug therapy or systemic disease.

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Nephrotic syndrome: general name for any of a group of diseases involving defective kidney glomeruli, characterized by massive proteinuria and lipiduria with varying degrees of oedema, hypoalbuminaemia, and hyperlipidaemia Nerve block: that is, injection of the anaesthetic agent close to the nerves whose conductivity is to be cut off. Neuralgia: see trigeminal neuralgia. Neurogenic: 1. forming nervous tissue. 2. originating in the nervous system or from a lesion in the nervous system. Neuroleptanaesthesia: a state of neuroleptanalgesia and unconsciousness, produced by the combined administration of a narcotic analgesic and a neuroleptic agent, together with the inhalation of nitrous oxide and oxygen. Neuroleptanalgesia: a state of quiescence, altered awareness, and analgesia produced by the administration of a combination of a narcotic analgesic and a neuroleptic agent. Neuroleptic: a term coined to refer to the effects on cognition and behaviour of the original antipsychotic agents, which produced a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients caused a reduction in confusion and agitation and normalization of psychomotor activity. The term is outdated as a synonym for antipsychotic agents because newer agents do not necessarily have such effects. Neuromuscular block: a failure in neuromuscular transmission that can be induced pharmacologically or may result from pathological disturbance at the myoneural junction. Neuropathy: a functional disturbance or pathological change in the peripheral nervous system, sometimes limited to noninflammatory lesions as opposed to those of neuritis; the aetiology may be known or unknown. Neutropenia: a decrease in the number of neutrophils in the blood NIDD: non-insulin dependent diabetes mellitus. Nightmare: a terrifying dream; an anxiety attack during dreaming, accompanied by mild autonomic reactions and usually awakening the dreamer, who recalls the dream but is oriented. Nociception: pain sense. Nociceptor: a receptor for pain caused by injury to body tissues; the injury may be from physical stimuli such as mechanical, thermal, or electrical stimuli, or from chemical stimuli such as the presence of a toxin or an excess of a nontoxic substance. Most nociceptors are in either the skin (cutaneous nociceptor) or the walls of viscera (visceral nociceptor). Nocturnal: pertaining to, occurring at, or active at night. NSAID: non-steroidal anti-inflammatory drug. Nystagmus: an involuntary, rapid, rhythmic

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movement of the eyeball, which may be horizontal, vertical, rotatory, or mixed, i.e., of two varieties. Obsessive-compulsive disorder: an anxiety disorder characterized by recurrent obsessions or compulsions, which are severe enough to interfere significantly with personal or social functioning. Performing compulsive rituals may release tension temporarily, and resisting them causes increased tension. Odynophagia: pain on swallowing (tetracycline) Oliguria: excretion of a diminished amount of urine in relation to the fluid intake, usually defined as less than 400 mL per 24 hours. Oliguric: pertaining to or characterized by oliguria. Open-angle glaucoma: any glaucoma in which the angle of the anterior chamber remains open, but filtration is gradually diminished because of the tissues of the angle; called also chronic g., simple g., and wide-angle g. Opportunistic infections: superinfection. Organic brain syndrome: former term for a constellation of psychological or behavioural signs and symptoms associated with brain dysfunction of unknown or unspecified aetiology and grouped according to symptoms. Organic psychoses: a psychotic disorder with a known or presumed organic aetiology. Orofacial dyskinesia: see tardive dyskinesia. Orthostatic hypotension: a fall in blood pressure associated with dizziness, blurred vision, and sometimes syncope, occurring upon standing or when standing motionless in a fixed position; it can be acquired or idiopathic. Orthostatic: pertaining to or standing erect (Antihypertensive drugs) Osteoarthritis: a noninflammatory degenerative joint disease seen mainly in older persons, characterized by degeneration of the articular cartilage, hypertrophy of bone at the margins, and changes in the synovial membrane. It is accompanied by pain, usually after prolonged activity, and stiffness, particularly in the morning or with inactivity. inadequate or delayed Osteomalacia: mineralization of osteoid in mature cortical and spongy bone; it is the adult equivalent of rickets and accompanies that disorder in children. Osteomyelitis: inflammation of bone caused by infection, usually by a pyogenic organism, although any infectious agent may be involved. It may remain localized or may spread through the bone to involve the marrow, cortex, cancellous tissue, and periosteum. Ototoxic: causing damage to the vestibulocochlear nerve or the organs of hearing and balance. Ototoxicity: the quality of causing damage to the vestibulocochlear nerve or the organs of hearing and balance PABA: p-aminobenzoic acid.

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Paget s disease of bone: a disease of bone marked by repeated episodes of increased bone resorption followed by excessive attempts at repair, resulting in weakened deformed bones of increased mass. Pain: a more or less localized sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. It serves as a protective mechanism insofar as it induces the sufferer to remove or withdraw from the source. Palliative care: treatment designed to relieve pain and distress, but not attempting a cure. Palpitation: a subjective sensation of an unduly rapid or irregular heart beat Pancytopaenia: deficiency of all cellular elements of the blood. Panhypopituitarism: generalized or particularly severe hypopituitarism, which in its complete form leads to absence of gonadal function and insufficiency of thyroid and adrenal cortical function. Panic: acute, extreme anxiety with disorganization of personality and function. Paradox: a statement which seems to be, though it may not be, absurd or self-contradictory. Paradoxical: occurring at variance with the normal rule. Paraesthesiae: (numbness) abnormal perception, feeling, or sensation. Paralytic ileus: ileus resulting from inhibition of bowel motility, which may be produced by numerous causes, most frequently by peritonitis. Paranoid psychosis: a type of psychosis characterized by preoccupation with one or more systematized delusions or with frequent auditory hallucinations but without disorganized speech, disorganized or catatonic behaviour, or flat or inappropriate affect. Paranoid schizophrenia: a type of schizophrenia characterized by preoccupation with one or more systematized delusions or with frequent auditory hallucinations but without disorganized speech, disorganized or catatonic behaviour, or flat or inappropriate affect. Parenteral: not through the alimentary canal but rather by injection through some other route, such as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, or intravenous. Parkinson s disease: a group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. Parkinsonism: see Parkinson s disease. Paroxysm: 1. a sudden recurrence or intensification of symptoms Paroxysmal: recurring in paroxysms PBPs: penicillin binding proteins Pellagra: a clinical deficiency syndrome due to deficiency of niacin (or failure to convert tryptophan to niacin) and characterized by dermatitis, inflammation of mucous membranes,

Essentials of Medical Pharmacology

Majid A.K. Lafi

diarrhoea, and psychic disturbances. The dermatitis occurs on the portions of the body exposed to light or trauma. Mental symptoms include depression, irritability, anxiety, confusion, disorientation, delusions, and hallucinations. Peptic: pertaining to pepsin or to digestion; related to the action of gastric juices. Peripheral neuropathy: Some conditions that are actually polyneuropathies are called neuropathies. Peritonitis: inflammation of the peritoneum, with exudations of serum, fibrin, cells, and pus, usually accompanied by abdominal pain and tenderness, constipation, vomiting, and moderate fever. Personality disorder: a category of mental disorders characterized by enduring, inflexible, and maladaptive personality traits that deviate markedly from cultural expectations, are selfperpetuating, pervade a broad range of situations, and either generate subjective distress or result in significant impairments in social, occupational, or other functioning. Onset is by adolescence or early adulthood. Pheochromocytoma: a usually benign, wellencapsulated, lobular, vascular tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. Because of increased secretion of adrenaline and noradrenaline, hypertension is a cardinal symptom; it may be persistent or intermittent. During severe attacks, there may be headache; sweating; palpitation and tremor; pallor or flushing of the face; nausea and vomiting; pain in the chest and abdomen; and paresthesias of the extremities. Phlegm: abnormally thick mucus secreted by the mucosa of the respiratory passages during certain infectious processes. Phobia: a persistent, irrational, intense fear of a specific object, activity, or situation (the phobic stimulus), fear that is recognized as being excessive or unreasonable by the individual himself. Phocomelia: a type of meromelia characterized by absence of the proximal portion of a limb or limbs, the hands or feet being attached to the trunk of the body by a single small, irregularly shaped bone. Photophobia: abnormal visual intolerance of light. Photosensitivity reactions: an abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280 400 nm. Physiological lactation: normal; not pathological secretion of milk. Pituitary diabetes insipidus: iabetes insipidus due to injury of the neurohypophyseal system, with a deficient quantity of antidiuretic hormone being released or produced, causing failure of renal tubular reabsorption of water. It may be inherited, acquired, or idiopathic. Plankton: a collective name for the minute freefloating organisms, vegetable and animal, which

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live in practically all natural waters. Planktonic: pertaining to plankton. PMSG: (serum gonadotropin) pregnant mare serum gonadotropin. Poikelothermia: variable or irregular body temperature. Polyarteritis nodosa: a form of systemic necrotizing vasculitis involving the small and medium-sized arteries with signs and symptoms resulting from infarction and scarring of the affected organ system. Polyarteritis: multiple inflammatory and destructive arterial lesions. Polycystic ovarian syndrome: (PCOS) a clinical symptom complex associated with polycystic ovaries and characterized by oligomenorrhea or amenorrhea, anovulation (hence infertility), and hirsutism. Both hyperestrogenism (from peripheral conversion of androgen) and hyperandrogenism are present. Polymyositis: a chronic, progressive inflammatory disease of skeletal muscle, occurring in both children and adults, and characterized by symmetrical weakness of the limb girdles, neck, and pharynx, usually associated with pain and tenderness, and sometimes preceded or followed by manifestations typical of scleroderma, arthritis, systemic lupus erythematosus, or Sj gren's syndrome. It is also sometimes associated with malignancy, and may be accompanied by characteristic skin lesions. Polyuria: the passage of a large volume of urine in a given period, a characteristic of diabetes. Porphyria: see acute intermittent porphyria. Positive symptoms: added features to personality including hallucinations, delusions and thought disorder. Postherpetic neuralgia: persistent burning pain and hyperesthesia along the distribution of a cutaneous nerve following an attack of herpes zoster; it may last for a few weeks or many months. Postmenopausal osteoporosis: that occurring in women within 3 to 20 years after menopause, affecting trabecular bone more than cortical bone, and manifested mainly by vertebral fractures of the painful crush type, hip fracture, Colles' fracture, and increased tooth loss. Postmortem: occurring or performed after death; pertaining to the period after death. Postural: pertaining to posture or position (Antihypertensive drugs) Precocious puberty: onset of sexual maturation at an earlier age than normal, defined as two standard deviations below the mean, or before age 8 in girls and 9 in boys. Premature ejaculation: ejaculation consistently occurring either prior to, upon, or immediately after penetration and before it is desired, taking into account factors such as age, novelty of the specific situation, and recent frequency of the

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sexual act. Premature labour: expulsion of a viable infant before the normal end of gestation, usually applied to interruption of pregnancy between the twentieth and the thirty-seventh completed weeks after the onset of the last menstrual period. Preterm labour: labour at any time before the thirty-seventh completed week (259 days) of gestation. Priapism: persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. Primary amenorrhoea: failure of menstruation to occur at puberty. Primary hyperaldosteronism: that arising from oversecretion of aldosterone by an adrenal cortical adenoma, characterized typically by hypokalemia, alkalosis, muscular weakness, polyuria, polydipsia, and hypertension. Called also Conn's syndrome. prn: (p.r.n.) abbreviation for L. pro re na´ta, according as circumstances may require (as needed). Proconvulsant: an agent that promote the initiation of convulsions. Prokinetic: pertaining to gastrointestinal motilityenhancing activity. Prolactin-secreting adenomas: a pituitary adenoma made up of lactotrophs that secretes excessive amounts of prolactin; this may delay puberty in either sex, cause galactorrhoeaamenorrhoea syndrome in women, or decrease libido and fertility in men. Prophylaxis: intervention aimed at the prevention of disease; called also preventive treatment, prophylactic treatment, and protective therapy. Prostatectomy: surgical removal of the prostate or of a part of it. Prostatism: a symptom complex resulting from compression or obstruction of the urethra, due most commonly to nodular hyperplasia of the prostate. Proteinuria: the presence of an excess of serum proteins in the urine; called also albuminuria. Pruritus: 1. an unpleasant cutaneous sensation that provokes the desire to rub or scratch the skin to obtain relief. Called also itching. 2. any of various conditions marked by this sensation, the specific site or type being indicated by a modifying term. Pseudomembranous colitis: see antibioticassociated enterocolitis. Pseudotumour cerebri: a condition caused by venous sinus occlusion and cerebral oedema associated with a number of pathologic conditions, marked by raised intracranial pressure with normal cerebrospinal fluid, headache, nausea, vomiting, and papilloedema, but without neurological signs except occasional abducens paralysis.

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Psittacosis: human infection by Chlamydia psittaci, generally acquired by inhalation of dried bird excreta containing the pathogen; it may also be acquired by handling feathers or tissues of infected birds, through an open skin lesion, or from the bite of an infected bird. It may be asymptomatic, have mild influenzalike symptoms, or manifest as a severe, highly fatal pneumonia. Psychodysleptic: inducing a dreamlike or delusional state of mind. Psychosis: 1. a mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour, usually without apparent awareness on the part of the patient of the incomprehensibility of his behaviour. 2. the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g., manicdepressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. Psychotic depression: in the strict sense, major depressive disorder with psychotic features, such as hallucinations, delusions, mutism, or stupor. However, this term is commonly used in a broader sense to cover all severe depressions causing gross impairment of social or occupational functioning, i.e., as a rough equivalent of major depressive disorder or of endogenous depression. PT: prothrombine time. PTH: parathyroid hormone. Puberty: the period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. Pulmonary embolism: the closure of the pulmonary artery or one of its branches by an embolus, sometimes associated with pulmonary infarction. Purgative: see cathartic. Purpura: 1. any of a group of conditions characterized by ecchymoses or other small haemorrhages in the skin, mucous membranes, or serosal surfaces; possible causes include blood disorders, vascular abnormalities, and trauma. 2. any of several conditions similar to the traditional purpura group, which may be caused by decreased platelet counts, platelet abnormalities, vascular defects, or reactions to drugs. PVCs: premature ventricular contractions Pyrogen: a fever-producing substance. Rash: a temporary eruption on the skin, as in urticaria; a drug eruption or viral exanthema. Raynaud s disease: a primary or idiopathic vascular disorder characterized by bilateral attacks of Raynaud's phenomenon; it affects females more often than males. Called also Raynaud's gangrene.

Essentials of Medical Pharmacology

Majid A.K. Lafi

Rebound: a reversed response on the withdrawal of a stimulus. Reflux oesophagitis: serious and sometimes lifethreatening type of gastroesophageal reflux disease that involves damage to the esophageal mucosa, often with erosion, ulceration, and infiltration by neutrophils or eosinophils. Refraction: the act or process of refracting; specifically the determination of the refractive errors of the eye and their correction by glasses. Regimen: a strictly regulated scheme of medication, diet, exercise, or other activity designed to achieve certain ends. Relapse: the return of a disease after its apparent cessation. Renal artery stenosis: RAS; narrowing of one or both renal arteries, caused by atherosclerosis or by fibrous dysplasia or hyperplasia, so that renal function is impaired; increased renin release by the affected kidney causes renovascular hypertension, and bilateral stenosis may result in chronic renal failure. Resting tremor: a tremor occurring when a limb or other body part is at rest; it may be normal, as in some physiologic tremors, or abnormal, as in parkinsonian tremors. Retarded schizophrenia: see negative symptoms. Reye s syndrome: a rare, acute, sometimes fatal disease of childhood, characterized by recurrent vomiting and elevated serum transaminase levels, with distinctive changes in the liver and other viscera; an encephalopathic phase may follow with acute brain swelling, disturbances of consciousness, and seizures. It most often occurs as a sequel of chickenpox or a viral upper respiratory infection. Rheumatoid arthritis: a chronic systemic disease primarily of the joints, usually polyarticular, marked by inflammatory changes in the synovial membranes and articular structures and by muscle atrophy and rarefaction of the bones. In late stages deformity and ankylosis develop. The cause is unknown, but autoimmune mechanisms and virus infection have been postulated. Rhinorrhoea: the free discharge of a thin nasal mucus. Rickets: an interruption in the development and mineralization of the growth plate of bone, with radiographic abnormalities, osteomalacia, bone pain, fatigability, growth retardation, and often hypotonia, convulsions, and tetany. Rigidity: stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. s.c.: subcutaneous. Salicylism: the commonly occurring toxic effects of excessive dosage with salicylic acid or its salts, usually marked by tinnitus, nausea, and vomiting. Salmonellosis: any disease caused by infection

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with a species of Salmonella; in humans it is most often manifested as food poisoning with acute gastroenteritis, vomiting, diarrhoea, and rarely septicaemia, or as typhoid or paratyphoid fever. Recurrent fevers and diarrhoea with more serious gastrointestinal symptoms are seen in immunocompromised patients. Sarcoidosis: a chronic, progressive, systemic granulomatous reticulosis of unknown aetiology, characterized by hard tubercles in almost any organ or tissue, including the skin, lungs, lymph nodes, liver, spleen, eyes, and small bones of the hands and feet. SC3: third generation cephalosporin. Schizophrenia: a mental disorder or heterogeneous group of disorders (the schizophrenias or schizophrenic disorders) comprising most major psychotic disorders and characterized by disturbances in form and content of thought (loosening of associations, delusions, and hallucinations), mood (blunted, flattened, or inappropriate affect), sense of self and relationship to the external world (loss of ego boundaries, dereistic thinking, and autistic withdrawal), and behaviour (bizarre, apparently purposeless, and stereotyped activity or inactivity). Secondary amenorrhoea: cessation of menstruation after it has once been established at puberty. Sedation: the production of a sedative effect; the act or process of calming. Senile dementia: that occurring in older persons, usually over the age of 65; since most cases are due to Alzheimer's disease, the term is sometimes used as a synonym of d. of the Alzheimer type, late onset. Sepsis: 1. the presence in the blood or other tissues of pathogenic microorganisms or their toxins. 2. septicemia. Septic: pertaining to sepsis Serum sickness: a hypersensitivity reaction to the administration of foreign serum or serum proteins characterized by fever, urticaria, arthralgia, edema, and lymphadenopathy. It is caused by the formation of circulating antigen-antibody complexes that are deposited in tissues and trigger tissue injury mediated by complement and polymorphonuclear leukocytes. Serum sickness is classed with the Arthus reaction and other immune complex diseases as a type III hypersensitivity reaction (Gell and Coombs classification). Although serum sickness is now rare because of the replacement of most animal-derived antisera with human immune globulins, an identical illness (serum sickness like reaction or syndrome) can be produced by hypersensitivity reactions to penicillin and other drugs. Sexual deviation: sexual behaviour or fantasy outside that which is morally, biologically, or legally sanctioned, often specifically one of the

Glossary and Abbreviations

Ramadi, 11 October 2009

paraphilias. Sexual dysfunction: any of a group of sexual disorders characterized by disturbance either of sexual desire or of the psychophysiological changes that usually characterize sexual response. Included are sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders, substance-induced sexual dysfunction, and sexual dysfunction due to a general medical condition. Shingles: (herpes zoster) an acute infectious, usually self-limited, disease believed to represent activation of latent human herpesvirus 3 in those who have been rendered partially immune after a previous attack of chickenpox. It involves the sensory ganglia and their areas of innervation, is characterized by severe neuralgic pain along the distribution of the affected nerve and crops of clustered vesicles over the area of the corresponding dermatome, and is usually unilateral and confined to single or adjacent dermatomes. Postherpetic neuralgia may be a complication. In immunocompromised patients it may disseminate and be fatal. Called also acute posterior ganglionitis, shingles, zona, and zoster. Shock: 1. a sudden disturbance of mental or physical equilibrium. 2. a condition of profound hemodynamic and metabolic disturbance characterized by failure of the circulatory system to maintain adequate perfusion of vital organs. It may result from inadequate blood volume (hypovolemic shock); inadequate cardiac function (cardiogenic shock); or inadequate vasomotor tone (neurogenic shock and septic shock). SIADH: syndrome of inappropriate secretion of antidiuretic hormone. Sinus bradycardia: a slow sinus rhythm, with a heart rate of less than 60 beats per minute in an adult; it is common in young adults and in athletes but is also a manifestation of some disorders. SLE: systemic lupus erythematosus Slurred speech: speech in which the words are uncompleted Sneezing: expelling air forcibly and spasmodically through the nose and mouth. 2. an involuntary, sudden, violent, and audible expulsion of air through the mouth and nose. Spasm: 1. a sudden, violent, involuntary contraction of a muscle or a group of muscles, attended by pain and interference with function, producing involuntary movement and distortion. 2. a sudden but transitory constriction of a passage, canal, or orifice. Spasmodic: of the nature of a spasm. Spinal nerve block: 1. regional anaesthesia produced by injection of a local anesthetic into the subarachnoid space around the spinal cord; anaesthesia Called also intraspinal a. or block and subarachnoid anaesthesia or block. 2. loss of sensation due to a spinal lesion.

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Status epilepticus: a continuous series of generalized tonic-clonic seizures without return to consciousness, a life-threatening emergency. Stevens-Johnson syndrome: a sometimes fatal form of erythema multiforme presenting with a flulike prodrome, and characterized by systemic as well as more severe mucocutaneous lesions. The oronasal and anogenital mucous membranes may become involved with a characteristic gray or white pseudomembrane, and hemorrhagic crusts often occur on the lips. Ocular lesions vary, often with injected conjunctivitis, iritis, uveitis, corneal vesicles, erosions, and perforation, which may result in corneal opacities and blindness. Pulmonary, gastrointestinal, cardiac, and renal involvement also occurs. Stomatitis: inflammation of the oral mucosa, due to local or systemic factors, which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. Subarachnoid haemorrhage: intracranial hemorrhage into the subarachnoid space. Superinfection: (suprainfection, opportunistic infection, secondary infection) a new infection occurring in a patient having a preexisting infection, such as bacterial superinfection in viral respiratory disease or infection of a chronic hepatitis B carrier with hepatitis D virus. Superinfection can complicate the course of antimicrobial therapy when the new infection is by organisms resistant to the drugs in use. Suppository: a medicated mass adapted for introduction into the rectal, vaginal, or urethral orifice of the body; suppository bases are solid at room temperature but melt or dissolve at body temperature. Sydenham s chorea: an acute, usually self-limited disorder of early life, usually between the ages of 5 and 15 or during pregnancy, and closely linked with rheumatic fever. It is characterized by involuntary movements that gradually become severe, affecting all motor activities including gait, arm movements, and speech. A mild psychic component is usually present. Syncope: a temporary suspension of consciousness due to generalized cerebral ischemia; a faint. Synergistic: 1. acting together. 2. enhancing the effect of another force or agent. Systemic lupus erythematosus: (SLE) a chronic, remitting, relapsing, inflammatory, often febrile multisystemic disorder of connective tissue, acute or insidious in onset, characterized principally by involvement of the skin joints, kidneys, and serosal membranes. It is of unknown etiology, but it is thought to represent a failure of regulatory mechanisms of the autoimmune system, as suggested by the high level of numerous autoantibodies against nuclear and cytoplasmic cellular components. It is marked by a wide variety of abnormalities, including arthritis and arthralgias,

Essentials of Medical Pharmacology

Majid A.K. Lafi

nephritis, central nervous system manifestations, pleurisy, pericarditis, leukopenia or thrombocytopenia, hemolytic anemia, elevated erythrocyte sedimentation rate, and positive LEcell preparations. Systemic sclerosis: a systemic disorder of the connective tissue characterized by induration and thickening of the skin, by abnormalities involving both the microvasculature (telangiectasia) and larger vessels (Raynaud's phenomenon), and by fibrotic degenerative changes in various body organs, including the heart, lungs, kidneys, and gastrointestinal tract. It may remain confined to the face and hands for long periods or may be progressive and spread diffusely to become generalized. t : half life. T3: triiodothyronine. T4: Tetraiodothyronine. Tachycardia: excessive rapidity in the action of the heart; the term is usually applied to a heart rate above 100 beats per minute in an adult and is often qualified by the locus of origin as well as by whether it is paroxysmal or nonparoxysmal. Tarditive dyskinesia: (orofacial dyskinesia) an iatrogenic extrapyramidal disorder caused by longterm use of antipsychotic drugs; it is characterized by oral-lingual-buccal dyskinesias that usually resemble continual chewing motions with intermittent darting movements of the tongue; there may also be choreoathetoid movements of the extremities. It is more common in women than in men and in the elderly than in the young, and incidence is related to drug dosage and duration of treatment. In some patients symptoms disappear within a few months after the drugs are withdrawn; in others symptoms may persist indefinitely. TCA: tricyclic antidepressant. TDM: therapeutic drug monitoring. Telangiectasia: permanent dilation of preexisting small blood vessels (capillaries, arterioles, venules), creating focal red lesions, usually in the skin or mucous membranes. Tenosynovitis: inflammation of a tendon sheath. Teratogenic: tending to produce congenital anomalies. Testicular teratoma: a type of germ cell tumour derived from pluripotent cells and made up of elements of different types of tissue from one or more of the three germ cell layers in the testis. Tetanus: 1. an acute, often fatal infectious disease caused by the bacillus Clostridium tetani, which produces the neurotoxin tetanospasmin; it usually enters the body through a contaminated puncture wound (such as from a metal nail, wood splinter, or insect bite), although other portals of entry include burns, surgical wounds, cutaneous ulcers, injection sites of drug abusers, the umbilical stump of neonates (t. neonatorum), and the postpartum uterus. 2. physiological tetanus; a state of

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sustained muscular contraction without periods of relaxation caused by repetitive stimulation of the motor nerve trunk at frequencies so high that individual muscle twitches are fused and cannot be distinguished from one another. Thalassaemia: a heterogeneous group of hereditary hemolytic anemias that have in common a decreased rate of synthesis of one or more hemoglobin polypeptide chains and are classified according to the chain involved (a, b, d); the two major categories are a- and b-thalassemia. Homozygous forms are manifested by profound anemia or death in utero, and heterozygous forms by erythrocyte anomalies ranging from mild to severe. Therapeutic restraining: the use of drug therapy to control of a subject, as of a violently psychotic or irrational person. Thought disorders: a disturbance in the thought process that is most narrowly defined as disorganized thinking with altered associations, as is characteristic of schizophrenia. The term is often used much more broadly to include any disturbance of thought, such as confusion, hallucinations, or delusions, which affects possession, quantity, or content of thought. Throbbing: beating; attended with a rhythmic beating sensation. Thrombocytopenia: decrease in the number of platelets, such as in thrombocytopenic purpura. Thrombocytopenic purpura: any form of purpura in which the platelet count is decreased; it may be either primary (idiopathic) or secondary. (see purpura) Thromboembolism: obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel. Thyroiditis: inflammation of the thyroid gland. Thyrotoxicosis: the condition caused by excessive quantities of thyroid hormones (see hyperthyroidism); it may be due to overproduction by the thyroid gland as in Graves' disease, overproduction originating outside the thyroid, or loss of storage function and leakage from the gland. TIA: Transient ischaemic attack. Tics: an involuntary, compulsive, rapid, repetitive, stereotyped movement or vocalization, experienced as irresistible although it can be suppressed for some length of time; occurrence is exacerbated by stress and diminished during sleep or engrossing activities. Tics may be psychogenic or neurogenic in origin and are subclassified as either simple, such as eye blinking, shoulder shrugging, coughing, grunting, snorting, or barking, or complex, such as facial gestures, grooming motions. Tinnitus: a noise in the ears, such as ringing, buzzing, roaring, or clicking. It is usually

Glossary and Abbreviations

Ramadi, 11 October 2009

subjective in type. Tocolytic: pertaining to inhibition of uterine contractions. Tocolytic: uterine relaxant. Toxic adenoma: hyperthyroidism arising in a multinodular goiter, usually of long standing. Trachoma: a chronic infectious disease of the conjunctiva and cornea, producing photophobia, pain, and lacrimation, caused by a strain of Chlamydia trachomatis. Tranquilliser: a drug with a calming, soothing effect; currently it is usually used to denote a minor tranquilliser. Transient ischaemic attacks: (TIA) a brief attack (from a few minutes to an hour) of cerebral dysfunction of vascular origin, with no persistent neurological deficit; TIAs are most commonly associated with occlusive vascular disease, especially in the distribution of the carotid and vertebral-basilar systems. TRH: (protirelin) thyrotropin-releasing hormone. Trigeminal neuralgia: Paroxysmal pain that extends along the course of one or more nerves. Many varieties of neuralgia are distinguished according to the part affected or to the cause, as trigeminal, brachial, facial, occipital, supraorbital, etc., or postherpatic, anaemic, diabetic, gouty, malarial, syphilitic, etc. (carbamazepine) TSH: (thyrotropin) Thyroid-stimulating hormone. Tuberculosis: any of the infectious diseases of humans or other animals caused by species of Mycobacterium and characterized by the formation of tubercles and caseous necrosis in the tissues. The usual causative species are M. tuberculosis and M. bovis. Type I reaction: that occurring within minutes when a sensitized individual is reexposed to antigen, resulting from interaction of IgE and the antigen; clinical manifestations can range from localized dermatitis, urticaria, or angioedema to allergic rhinitis or asthma to systemic anaphylaxis. The first exposure to the antigen induces the production of IgE antibodies that bind to receptors on mast cells and basophils. Upon subsequent exposure the antigen cross-links receptor-bound IgE molecules, triggering production and release of a diverse array of mediators that act on other cells, producing symptoms such as bronchospasm, edema, mucous secretion, and inflammation. (penicillin) Type II reaction: tissue or cell damage resulting from the interaction of antibodies and antigens on cell surfaces; specific IgG or IgM against cell surface or extracellular matrix antigens or cell surface receptors binds and causes damage at the site of binding by any of several mechanisms involving either complement activation and lysis or opsonization mediated by receptors for Fc or C3b leading to phagocytosis and destruction by macrophages and neutrophils. Examples of

278

disorders caused by such tissue damage include myasthenia gravis, hemolytic anemia, Goodpasture's syndrome, and Rh incompatibility and transfusion reactions. Type III reaction: local or general inflammatory response due to formation of circulating antigenantibody complexes and their deposition in tissues; the complexes activate complement and other inflammatory mediators, initiating processes including increased vascular permeability, stimulation of mast cell degranulation and neutrophil chemotaxis and accumulation, and aggregation of platelets, and resulting in tissue damage. Ensuing diseases, called also immune complex diseases, can be roughly classified as being due to persistent infection, to autoimmunity, or to inhalation of antigenic material; examples include serum sickness, Arthus reaction, subacute bacterial endocarditis, systemic lupus erythematosus, and farmer's lung. Type IV reaction: a reaction of cell-mediated immunity, the immune response being initiated by antigen-specific T lymphocytes; in contrast to the reactions of immediate hypersensitivity, reactions take one or more days to develop and can be transferred by lymphocytes but not by serum. Reactions are mediated by T lymphocytes both through release of cytokines and through direct cytolysis. In the former mechanism, release of vasoactive and chemotactic cytokines is triggered by contact between the T cells and specific antigens on antigen-presenting cells; the cytokines attract and activate non antigen-specific monocytes and macrophages, resulting in local erythema and induration, and leading to granuloma formation and necrosis if the eliciting stimulus cannot be eliminated. A common example is the tuberculin reaction elicited in skin testing for tuberculosis. In direct cytolysis, sometimes called cell-mediated cytotoxicity, cytotoxic T lymphocytes interact with foreign antigens presented by class I MHC molecules on cell surfaces, causing lysis of these foreign cells, as in allograft rejection. Type IV reactions can be induced by intracellular parasites, such as certain viruses, mycobacteria, and fungi, foreign tissue, tumour cells, soluble proteins, and haptens. The term is often equated with delayed hypersensitivity reaction, although the latter is sometimes restricted to cytokine-mediated reactions (as contrasted with direct cytolysis). U: unit. Ulcerative colitis: chronic, recurrent ulceration in the colon, chiefly of the mucosa and submucosa, of unknown cause; it is manifested clinically by cramping abdominal pain, rectal bleeding, and loose discharges of blood, pus, and mucus with scanty fecal particles. Complications include hemorrhoids, abscesses, fistulas, perforation of the colon, pseudopolyps, and carcinoma.

Essentials of Medical Pharmacology

Majid A.K. Lafi

Unipolar affective disorder: that unaccompanied by episodes of mania or hypomania, as in major depressive disorder. Ureteral colic: colicky pains due to obstruction of the ureter. Urinary frequency: urination at short intervals without increase in daily volume of urinary output, due to reduced bladder capacity. Urinary retention: accumulation of urine within the bladder because of inability to urinate. Urolithiasis: 1. the formation of urinary calculi (stones). 2. the diseased condition associated with the presence of urinary calculi. Urticaria: a vascular reaction in the upper dermis, usually transient, consisting of localized oedema caused by dilatation and increased capillary permeability, with development of wheals. Uterine fibroids: a benign tumour derived from smooth muscle of the uterus. Uterine rupture: forcible tearing of the uterus. Uveitis: an inflammation of part or all of the uvea, commonly involving the other tunics of the eye (sclera, cornea, and retina). Vagotomy: interruption of the impulses carried by the vagus nerve or nerves. Vertigo: an illusory sense that either the environment or one's own body is revolving; it may result from diseases of the inner ear or may be due to disturbances of the vestibular centers or pathways in the central nervous system. Visual haloes: the seeing of coloured rings around an individual light source; indicative of glaucoma. Vulvovaginitis: inflammation of the vulva and vagina, or of the vulvovaginal glands. Whooping Cough: an acute, highly contagious infection of the respiratory tract, usually affecting young children and caused by Bordetella pertussis; similar illnesses are caused by B. parapertussis and B. bronchiseptica. Wolff-Parkinson-White syndrome: the association of paroxysmal tachycardia (or atrial fibrillation) and preexcitation, in which the electrocardiogram displays a short P R interval and a wide QRS complex which characteristically shows an early QRS vector (delta wave); sometimes used synonymously with preexcitation s. Called also WPW s. Zollinger-Ellison syndrome: a triad comprising (1) intractable, sometimes fulminating, and in many ways atypical peptic ulcers; (2) extreme gastric hyperacidity; and (3) gastrin-secreting, non beta islet cell tumours of the pancreas, which may be single or multiple, small or large, benign or malignant.

279

Essentials of Medical

Pharmacology

Majid A. K. Lafi BSc (Hons), MPhil, PhD Department of Pharmacology College of Medicine University of Al-Anbar

ABOUT THE AUTHOR Majid A K Lafi was born in Fallujah, Iraq in 1956, married with five children. He commenced studying at Kettering Technical College, Kettering, England in 1975, and obtained his "A" Level General Certificate of Education (Oxford Board) in 1978; in the same year, started a BSc (Hons) in Pharmacology at the School of Pharmacy, Portsmouth Polytechnic (now University of Portsmouth), Portsmouth, England, he has been awarded the degree in June 1981. Later on he was awarded MPhil in Pharmacology (1984), PhD in Pharmacology (1986) from the same university. I was awarded "Final Diploma" in English from the Institute of Linguists, London, in 1986. Thereafter, in 1987: Lecturer in Pharmacology, Military Medical College, Baghdad; in 1989: Lecturer in Pharmacology, College of Medicine, University of AL-Anbar, Ramadi, Iraq, in 1994: promoted to Assistant Professor of Pharmacology. His research interests in peripheral neuropharmacology (cotransmission at nerve muscle junction), unusual antimicrobial resistance, and medical education (pharmacology curriculum development).

Dr. Majid A K. Lafi

I

PREFACE When starting my carrier teaching pharmacology in Iraq, 3rd year medical school students, I confronted a problem that during the lecture most of the students were over-occupied with writing up what I was saying and not trying to understand what I was trying to deliver to them as core knowledge in pharmacology. With time, I understood that these students were very much concerned with obtaining the lecture material written more than understanding the material itself. After having long talks with them I promised to give them type-written lecture notes prior to delivering the lecture. This appeared to work very well in reassuring them that they would not lose material for "revision" paving the way for winning their attention during the lecture with consistently excellent students' attendance. This gain prompted me to continue improving my lecture notes in pharmacology to suit the need of particularly medical students in Iraq. For several years, students and colleagues have urged me to put this work in a book, only now "after 20 years" I find it is the time to do so. Teaching pharmacology at the College of Medicine, University of AL-Anbar, has been pathophysiology oriented therefore very much attention has been paid to the mechanism(s) of drugs' action. Hence, a brief account on the pathophysiology of major disorders has been mostly included in this book. Over the years of teaching this subject, it is felt that students prefer stating clinical conditions (e.g. indications, adverse effects and contraindications) in a list form rather than in a continuous text. In addition, the inclusion of a summary in a table and/or a figure form at the end of each topic has been found to be useful to recognise the core knowledge should be learned. These strategies have been largely adopted throughout this book. A considerable number of the third year medical students show very poor competence in the medical vocabulary used in delivering the core material of medical pharmacology. This prompted me to make an inclusion of an appropriate glossary at the end of this book to be handy for the reader to refer to. Undoubtedly, there are many occasions of weakness in this book, e.g. the section on antiparasitic agents as it is being very poor, particularly when taking into account the importance of parasitic infections in Iraq. It is hoped that these drawbacks and others will be dealt with in the next issue. This issue is only an initial draft awaiting feedback from students and colleagues. I am very grateful for support and assistance from a number of colleagues and students.

Majid A. K. Lafi October, 2008

CONTENTS

ABOUT THE AUTHOR PREFACE CONTENTS GENERAL PRINCIPLES Pharmacokinetics ……………………………………………………………. Pharmacodynamics ………………………………………………………… AUTONOMIC PHARMACOLOGY Cholinergic Transmission ………………………………………………….. Adrenergic Transmission …………………………………………………. Ocular Pharmacology ……………………………………………………. Drugs Used in Abnormal Micturition ………………………………………. CARDIOVASCULAR PHARMACOLOGY Antihypertensive Drugs ……………………………………………………… Antianginal Drugs …………………………………………………………... Drugs for Congestive Heart Failure …………………………………………. Antiarrhythmic Drugs ………………………………………………………. Diuretics …………………………………………………………………….. Antithrombotic Drugs ……………………………………………………….. Antihyperlipidaemic Drugs …………………………………………………. Drugs for Anaemias ANTIMICROBIAL DRUGS (GENERAL PRINCIPLES) Beta-lactam Antimicrobial Drugs …………………………………………… Sulphonamides, Trimethoprim, and Aminoglycosides ……………………… Tetracyclines, Macrolides, Metronidazole, Chloramphenicol, and others …... Antituberculosis Drugs ……………………………………………………….. Antimicrobial Drugs of Choice ……………………………………………….. Antifungal Drugs ……………………………………………………………… Antiviral Drugs ………………………………………………………………. Antiparasitic Drugs …………………………………………………………. CNS-PHARMACOLOGY (GENERAL PRINCIPLES) Antipsychotic Drugs …………………………………………………………. Drugs for Affective Disorders ……………………………………………….. Antianxiety Drugs …………………………………………………………… Sedative and Hypnotic Drugs ………………………………………………. Drugs for Parkinson s Disease ………………………………………………. Antiepileptic Drugs ………………………………………………………….. Opioids and Narcotic Analgesic Drugs ……………………………………... General Anaesthetic Drugs ………………………………………………….. Local Anaesthetic Drugs ……………………………………………………. Neuromuscular Blocking Drugs ……………………………………………… AUTACOIDS NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) DRUGS AND GASTROINTESTINAL TRACTS DRUGS AND THE RESPIRATORY SYSTEM ENDOCRINE PHARMACOLOGY Hypothalamic and Pituitary Hormones ………………………………………. Sex (Gonadal) Hormones and Inhibitors …………………………………...

III

I II III 1 1 18 24 25 25 33 35 37 46 49 54 61 65 73 77 79 88 96 101 106 110 114 117 121 124 131 135 142 146 153 156 164 170 176 178 182 190 203 212 218 223

Drugs Acting on Uterine Smooth Muscle …………………………………... Adrenocorticosteroids ……………………………………………………... Thyroid and Antithyroid Drugs …………………………………………… Agents that Affect Calcium Metabolism …………………………………… Insulin and Oral Hypoglycaemic Drugs ……………………………………. ANTICANCER DRUGS …………………………………………………… DRUG INTERACTIONS, ADVERSE DRUG REACTIONS AND ANTIDOTES GLOSSARY ……………………………………………………………… INDEX

IV

228 230 236 240 242 250 255 260 280

Essentials of Medical Pharmacology

Majid A. K. Lafi

GENERAL PRINCIPLES of the disease itself may vary from one patient to another, this difference in response is largely accounted for by variations in the metabolic handling of the drug.

Introduction This book is the result of a desire to record and update the material of lectures given upwards of twenty years to medical students. For medical students, the pharmacology course is the first confrontation with medicine and the response of patients to drugs. A drug in the widest sense is a substance used in prevention, cure and diagnosis of disease. The name pharmacon is Greek and means drug. The word drug comes from the French word drogue which means dry herb.

If the serum level of warfarin is measured in these patients a large difference may be found at the two extremes. Thus, some patients were under-treated while others were intoxicated. This phenomenon may be due to a number of factors (in addition to failure to take the prescribed dose of the drug, patient non-compliance). The rate of absorption of the drug, its distribution in various body compartments, tissue and plasma-protein binding, and the rate of metabolism and excretion of the drug all influence the steadystate level of the drug at the site where it is required. Study of these aspects of pharmacology is known as pharmacokinetics.

Pharmacology can be divided into two major parts: 1. Pharmacokinetics means what the body does to the drug . 2. Pharmacodynamics means what the drug does to the body .

Dosage Regimen Dosage regimen is the manner in which a drug is taken concerning dose, frequency, and route of administration that relate to drug level-time relationships in the body. Often, drug level in the body is reflected by plasma drug level that in turn influences the concentration of drug at the site(s) of action that relates to the magnitude of the effect(s) produced. Table 1.1. Basic pharmacological principles in empirical adult therapeutic regimens of some selected drugs. The information in this table is not intended for memorization by students rather as pharmacotherapeutic situations in which skills (critical thinking) are required in applying knowledge and understanding of basic pharmacological principles. The pharmacological principles, presented in this course of pharmacology in a manner coherently complementing each other, represent a core knowledge in which to ground skills in pharmacology as basis in therapeutics. Such knowledge and skills are expected to be learned in sequential increasing in complexity throughout the third year. Therefore, this table is expected to be referred to throughout the year.

In addition, the following topics are also covered: • Toxicology which deals with adverse effects, drug interaction, drug abuse, poisons, antidotes, industrial and environmental pollution, and therapeutic drug monitoring. • Pharmacogenetics which deals with inter-individual differences. • Pharmaceutics (drug delivery, formulation) • Pharmacognosy (plant medicine) • Prescription writing (emphasising on drug names and dosage regimen)

Pharmacokinetics If a fixed dose of a drug is given to a number of patients with a particular disease, e.g. 5 mg of warfarin daily dose in patients with deep venous thrombosis, most will show some therapeutic response as indicated by prothrombin time. A few, however, will not show obvious response, while the occasional patient may develop signs of drug intoxication (bleeding). Although the severity 1

General Principles

Ramadi, 6 October 2009

Table 1.1. Basic pharmacological principles in empirical adult therapeutic regimens of some selected drugs. Drug

Indication

Route

Warfarin t 37 hr Vd 5 L

Deep venous thrombosis

Oral

Theophylline

Asthma

Oral

Induction and maintenance of labour

Slow intravenous injection (over 20-30 min) Intravenous infusion

t 8 hr Vd 35 L

Oxytocin t

minutes Oral (control is too erratic)

Morphine t 2 hr Vd 230 L Ampicillin

Severe pain

Intramuscular Oral

Certain bacterial infections

Oral Intramuscular, intravenous, or infusion Oral

t 1.2 hr Vd 20 L Amoxicillin t 2 hr

Penicilin G t 0.5 hr

Infections due to susceptible microorganisms Infections due -lactamaseproducing amoxicillin resistant organisms

Endocarditis (prophylaxis in dental procedures) Gonorrhoea (Neisseria gonorrhoeae) Certain serious infections

Oral

Oral

Oral Intramuscular Intravenous, or infusion

Intramuscular

Phenobarbital t 4 days Vd 38 L Digoxin

Prophylaxis of recurrent rheumatic fever Syphilis (Treponema pallidum) Epilepsy

Intramuscular

Congestive heart failure

Oral

Intramuscular Oral

Dosage Regimen Individualize dosage according to PT or INR, initially 2-10 mg daily for 3 days, then; average maintenance dose: 2-5 mg at the same time each day Individualize dosage according to clinical responses and monitor serum theophylline levels. Short-acting formulation 500 mg initially, then 100-300 mg 3-4 times daily. Long-acting formulation 150-300 mg twice daily. 5-6 mg/kg (in patients not previously treated with xanthine) 0.2-4 milliunits/min infusion, gradually increased to 20 milliunits/min, if necessary, to produce 3 or 4 contractions within 10-min periods. Not used because of being rapidly destroyed by the proteolytic enzymes in GIT 10 mg when needed Not used because of being rapidly metabolised in the liver. 0.25-1 g every 6 hr 0.5 g every 4-6 hr

250

500 mg every 8 hr

250 500 mg (containing125mg of clavulanic acid, Augmentin ) every 8hr or 875 mg every12h Alternatively amoxicillin 3 g may be taken by mouth together with probenecid 1 g by mouth 4 h before the procedure Amoxicillin 3 g may be taken by mouth together with probenecid 1 g in single dose 300,000 8 million U daily 6 20 million U daily by continuous or intermittent infusion every 2 4h. Up to 60 million U daily have been given in certain serious infections. Procaine Penicillin daily in one or two doses Benzathine 2 Penicillins 1.2 2.4 million U in a single dose every 3 4 wk Benzathine 2 Penicillins 2.4 million U (1.2 million U in each buttock) in a single dose 60-180 mg at night

1.5-2 mg initially over 24 hr, then 0.25-0.5 mg once a day 2

Essentials of Medical Pharmacology

t 39 hr Vd 440 L Amiodarone t 53 days Vd 4200

Captopril t 2.2 hr Vd 57 L Prazosin t 2.9 hr Vd 42 L Aspirin t 0.25 hr Vd 11 L (salicylic acid: t 3 hr to 13-30 hr)

Dopamine t 2 minutes

Cardiac arrhythmia (Atrial fibrillation) Ventricular arrhythmias (recurrent) Ventricular arrhythmias (existing) for not more than 48 hours because of cumulative effect Heart failure Hypertension Hypertension, Benign prostatic hyperplasia (BPH) Transient ischaemic attacks Transient ischaemic attacks Pain, fever Rheumatoid arthritis Osteoarthritis Acute rheumatic fever Renal (D1 -receptor) Cardiac ( 1-receptor) Vascular ( 1-receptor)

Omeprazole t 45 minutes

Majid A. K. Lafi

Oral Oral Intravenous

Oral Oral

6.25 mg initially then 6.25-150 mg daily 25 mg initially then 6.25-150 mg daily

Oral

1 mg 2 to 3 times daily initially, maintenance dose 6 15 mg daily

Oral (Prophylaxis) Oral

81 325 mg daily

Oral

650 mg usual single dose

Oral

2000-6000 mg 3 times daily

Oral Intravenous infusion Intravenous infusion Intravenous infusion

5000-8000 mg daily in divided doses

1300 mg 2 to 4 times daily

<5 µg/kg/min >5 µg/kg/min >10 µg/kg/min Steady-state plasma concentration will be reached in 5 x t = 10 min 20 mg daily, 1 hr before meal (mandatory)

Oral

Insulin

Peptic ulcer Heartburn Active GI bleeding Prostate cancer Central precocious puberty Hypothalamic hypogonadotropic hypogonadism Long term regular use

Intravenous, or infusion

Glucagon

Acute or emergency situations: Diabetic ketoacidosis Hyperosmolar hyperglycemic nonketotic coma Perioperative period Severe infections Pregnancy Hypoglycaemic crisis

Nicotinic acid

Acute overdose of βblockers (heart failure) Pellagra

Goserelin t

l-l.5 mg initially over 24 hr, then 0.06250.5 mg once a day 0.8-1.2 g daily (2 to 4 weeks), then 0.2-0.4 g daily. 0.15g over 30 minutes & 1 g over the 1st day

Intravenous Subcutaneous

8 mg/hr for 72 hrs 3.6 mg every 28 days (i.e. given continuously)

Intravenous tubing (by GnRH pump) Subcutaneous

A portable battery-powered programmable pump allows pulsatile GnRH therapy every 90 minutes. Dosage individualized. Initially, 7 26 units may be given once daily. Suitable for stable biphasic insulin mixtures (e.g. short acting plus long acting) Dosage individualized. For ketoacidosis, regular insulin may be given by direct injection, intermittent infusion, or continuous infusion. One regimen involves an initial bolus injection of 10 20 units followed by a continuous low-dose infusion of 2 10 units/hr, based on hourly blood and urine glucose levels

Intramuscular Subcutaneous Intravenous (bolus) Oral

3

1 mg 5-10 mg 100-500 mg daily.

General Principles

Ramadi, 6 October 2009

(niacin)

Hyperlipidaemia

Oral

250 mg twice daily initially and increasing the dose monthly by 500 to 1000 mg per day to a maximum of 2 6 g daily. This regimen to reduce the intense cutaneous flush produced as an adverse effect. The latter can further be reducing by taking nicotinic acid on a full stomach (end of meal), taking aspirin before dosage, and time-release forms of nicotinic acid can reduce the severity of flushing.

Diclofenac

Pain Dysmenorrhoea

Oral

50 mg 3 times daily

Ankylosing spondylitis

Oral

Osteoarthritis

Oral

Rheumatoid arthritis

Oral

Acute renal colic

Oral

Diclofenac Immediate R (only 50mg) Diclofenac Delayed R (75mg) Extended R (100mg)

Nitroglycern t 1-3 min

Ureteral stone propulsion Relieve acute angina Prevent exercise-induced angina Long-term prophylaxis to decrease the frequency and severity of acute anginal episodes

IV, IM Oral Oral Sublingual Translingual spray

Transmucosal tablet Topical transdermal patch Hypertensive crisis Carbamazepine t 15 hr Vd 98 L

Epilepsy

Continuous Intravenous oral

Trigeminal neuralgia

oral

4

100 125 mg daily in 4-5 divided doses (e.g., 25 mg 4-5 times daily) 100 150 mg daily in divided doses (e.g., 50 mg 2 or 3 times daily, 75 mg twice or 100 mg once daily) 100 150 mg daily in divided doses (e.g., 50 mg 2 or 3 times daily, or 75 mg twice or 100 mg once daily) 50 mg 2 or 3 times daily for 5 days, then on need 75 mg once or twice daily 50 mg 2 or 3 times daily for 15 days Sustained-release tablets, 2.5 9 mg 2 or 4 times per day 0.15 0.6 mg on need for chest pain one or two metered doses (0.4 mg/dose) sprayed onto oral mucosa at onset of anginal pain, to a maximum of 3 doses in 15 min 1 mg every 3 5 hr while awake, placed between upper lip and gum or cheek and gum 5 mg applied once daily, do not rub. 5mcg/min 200 mg twice daily, increased gradually to 600 1200 mg daily if needed, in 3 or 4 divided doses 200 mg daily, increased gradually to 1200 mg if necessary

Essentials of Medical Pharmacology

Majid A. K. Lafi

Pharmacokinetics Dosage Regimen Dose Frequency (Route of administration)

Drug Concentration at Site of Action

Plasma Drug Concentration

Pharmacodynamics

Css

Unacceptable Toxicity

Regimen C MTC Css

Regimen B

Therapeutic Window MEC

Regimen A

Css

Ineffective

Time Fig.1.1. A schematic representation of the approach to the design of dosage regimen. The pharmacokinetics and pharmacodynamics of the drugs are first defined. Then either the plasma drug concentration-time data or the effects produced are used as a feedback to modify the dosage regimen. When a drug is given at fixed time intervals (denoted by arrows), it accumulates within the body until a plateau is reached. With regimen A, the plasma drug concentration is too low therefore therapeutic failure (ineffective) is observed. With regimen B, therapeutic success is achieved although not initially. With regimen C, the therapeutic objective is more quickly achieved but the plasma drug concentration is ultimately too high.

5

General Principles

Ramadi, 6 October 2009

Peak 20

Nausea

Vomiting

CNS stimulation

Unacceptable Toxicity MTC Css

10

Insufficient

Trough 0

8

16 24

48 Time (hr)

bronchodilatatio n 72 96

Therapeutic Window MEC Ineffective

Fig.1.2. Different dosage regimens of theophylline showing the relationship between frequency of dosing and maximum and minimum plasma concentrations when a steady-state theophylline plasma concentration of about 10 µg/ml is desired. Regimen I- intravenous infusion of 25 mg/hr achieves smoothly rising line (dotted with black squares). Regimen II- 8-hourly administration (dark solid thin line) of doses of 200 mg. Regimen III- 24-hourly administration (dark solid thick line) of doses of 600 mg. In each of the 3 regimens, the mean steady-state plasma concentration (Css) is about 10 µg/ml. Note: in regimen III there is a large fluctuation between peak and trough and as estimation of plasma levels of drugs often not available, the former may be reflected clinically by the development of nausea, vomiting and central nervous system (CNS) stimulation as unacceptable toxicity; while trough may be reflected clinically by insufficient bronchodilatation (ineffective). Regimen IV- 12-hourly administration (dotted with black solid circles) of doses of 300 mg with oral slow release formulation to avoid the unacceptable toxicity and the insufficient bronchodilatation may be associated with regimen III. The therapeutic window lies between the minimum effective concentration (MEC) and the minimum toxic concentration (MTC). Therefore, adjustment of dosage regimen may be made depending on the clinical response. This is particularly true for drugs with low therapeutic index like theophylline.

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Essentials of Medical Pharmacology

Majid A. K. Lafi

Unacceptable Toxicity MTC

Css Therapeutic Window

Css MEC 0

3

6

18

12 Time (hr)

24

Fig.1.3. Different dosage regimens for a drug with large therapeutic index such as ampicillin (with t of about 1 hr). Regimen I- 1-hourly (light colour) with low total daily dose and regimen II- 6-hourly (dark colour) with higher total daily dose. Note: The steady-state plasma concentrations (Css) of the two regimens are different and regimen II shows a larger fluctuation between peak and trough comparing with that of regimen I. Both regimens exhibit Css within the therapeutic window, i.e. lies below the level expected to cause unacceptable toxicity. It follows that administering ampicillin 1-hourly would be practically inconvenient (24 times per day) and likely to result in non-compliance and consequently treatment failure. On the other hand, giving the drug 6-hourly with larger doses that attain troughs that lie at a level higher than the minimum effective concentration (MEC) and peaks lie at levels below the minimum toxic concentration (MTC), would lead to a better compliance (as a result of reducing the frequency of dosing, four times daily). This strategy can be adopted only with drugs that show large therapeutic index. In case of drugs that are with low therapeutic index other manoeuvres may be used to improve compliance; for example, sustained release formulation like for theophylline to be given twice daily instead of three times daily.

7

General Principles

Ramadi, 6 October 2009

The aforementioned factors are related to the question of whether generic or proprietary (brand) name should be used when prescribing.

Drugs and Medicines It is not always recognised that when prescribing a drug the patient actually receives a medicine. The drug represents only a small proportion of the total weight of the solid dosage form (e.g. tablet, capsule) or injectable dosage form (e.g. ampoule, vial). The dosage form contains other constituents, which may not be inert and may play an important role in facilitating or hindering a drug s absorption. Appropriate pharmaceutical manoeuvres of these materials may allow development of sophisticated delivery systems for delayed or position-released of the drug. The following are some of the factors involved in the production of the solid dosage form, which may influence a drug s absorption.

Absorption of Drugs When a drug is administered orally it has to pass through the gut wall which represents a complex biological barrier (complex lipid membrane) before entering the bloodstream. Dietary substances can pass through this biological barrier by one of the following ways: a. Passive diffusion concentration difference (from high to low) this is being the most important mechanism. b. Active transport e.g. amino acids, or drugs e.g. α-methyldopa that resembles endogenous substances. c. Filtration through pores, limited to molecules of small size e.g. urea. d. Pinocytosis by which small particles are engulfed by cells of the bowel.

1. Diluents e.g. lactose, calcium sulphate. 2. Granulating and binding agents e.g. syrup used for aggregation of powder into granules facilitating compression of tablet. 3. Disintegrating agents are incorporated to produce tablet disintegration in the gastrointestinal tract.

There are a number of factors which influence absorption of drugs: 1. Nature of drug polypeptides e.g. insulin is broken down by intestinal enzymes, benzylpenicillin is destroyed by gastric acid 2. Pharmaceutical formulation (see above) 3. Blood flow maintains continuous absorption by removing drug that passes through membrane. The concentration gradient across the membrane is, thereby, continuously assured. Membrane permeability of drugs also plays an important role in absorption of drugs. When the drug is lipophilic (e.g. ethanol) and thus highly membrane permeable, absorption is controlled or rate limited by perfusion (blood flow). In contrast, with streptomycin and many other polar compounds (like heparin, ipratropium and suxamethonium), absorption is controlled or rate limited by diffusion (penetration, permeability) through the membrane and not in removing the drug from other side of the membrane. Some compounds, e.g. urea, have intermediate permeability properties. At low blood flow rates, the compound has sufficient time to diffuse

moisture Starch Cocoa butter

Swelling body temperature

Melting

Sodium bicarbonate + tartaric acid moisture effervescence

4. Coating material e.g. sugar prevents disintegration before the tablet reaches the stomach or intestine (e.g. omeprazole). 5. Capsules have a gelatine envelope with no granulating excipients. 6. Sustained-release with complex pharmaceutical manoeuvres to control disintegration and dissociation rates, thus regulating the rate of a drug s absorption.

8

Essentials of Medical Pharmacology

Majid A. K. Lafi

across the membrane so absorption is perfusion rate-limited. At higher blood flow rates, however, membrane permeability becomes the rate-limiting step, and absorption is insensitive to blood flow.

Because both ionised and unionised solutes readily pass across the capillary wall, the influence of pH on intramuscular and subcutaneous absorption of drugs is likely to be far less significant.

Absorption of drugs in solution from muscle and subcutaneous tissue is normally perfusion rate-limited. An increase in blood flow increases absorption. In this setting, absorption is impeded largely by the capillary wall. At these sites, the capillary wall, a much more loosely knit structure than the epithelial lining of the gastrointestinal tract, allows the rapid passage of all molecules below a molecular weight of about 5000, whether ionised or unionised. This molecular weight range includes essentially all drugs. Streptomycin, a relatively water-soluble polar base, has difficulty penetrating the gastrointestinal mucosa; it is rapidly absorbed from the intramuscular site.

Body fluids Gastric juice Intestine Plasma CSF Urine Prostatic secretions Vaginal secretions Weak acids

pK

pH 1.0 - 3.0 5.0 - 8.0 7.4 7.3 4.0 - 6.8 6.4 -7.4 3.4 - 4.2 Weak bases

Penicillin G Salicylic acid Warfarin

2.7 3.5 Diazepam 5.0 Chlordiazepoxide 7.3 Trimethoprim Phenobarbital 7.8 Lidocaine Theophylline 9.0 Procainamide 10 Amphetamine Permanently ionised (polar) drugs Heparin Streptomycin Ipratropium Tubocurarine Suxamethonium

4. pH and pK. Drugs are usually either weak organic acids (proton donor) or weak organic bases (proton acceptor) existing in equilibrium between undissociated molecules and as ions. This equilibrium depends on the pKa value of the drug and the pH of the surrounding medium. At a pH equals to the pKa the drug is 50% ionised. Thus, a weakly acidic drug (e.g. aspirin) in a medium of low pH (e.g. stomach) will be mainly in its undissociated form; whereas a weakly basic drugs (e.g. amphetamines) in a medium of high pH (e.g. small intestine) will be mainly in its undissociated form. Streptomycin is permanently polar and relatively strongly basic, and its pKa value greatly exceeded the highest pH reached in the intestine. This explains why some drugs (e.g. streptomycin) are very poorly absorbed from the gut, therefore they should be administered parentally. As a general rule, acids tend to ionise in basic (alkaline) media, and bases tend to ionise in acidic media.

Clinical Example Many antibiotics cannot penetrate the prostatic epithelium, therefore not achieving adequate concentration in the prostatic fluid and tissue. Hence, it is difficult to cure bacterial prsotatitis. Trimethoprim is usually effective in the treatment of bacterial prostatitis while penicillin is not. This is because trimethoprim is a basic substance with a pKa of 7.3 and prostatic secretion is relatively acidic (pH 6.4 particularly in inflammatory condition) compared to the plasma (pH 7.4); consequently, trimethoprim is about 50% non-ionised at the plasma and therefore the drug penetrates into prostate. In acidic prostatic fluid trimethoprim is ionised and thus trapped as it cannot diffuse back into plasma. On the other hand, penicillin (acidic substance with a pKa of 2.7) is largely ionised and bound to plasma protein at pH 7.4 and thus cannot penetrate into prostate.

9

General Principles

Ramadi, 6 October 2009

5. Gastric emptying- According to what has been described above, it follows that weak acids are absorbed more rapidly from the stomach when the pH of the contents is 1 than when the pH of the contents is closer to 8, and the converse holds for weak bases. However, absorption of acids is always much faster from the more alkaline intestine (pH 5-7) than from the stomach.

oral dose that reaches the general circulation. For example, a 50% bioavailability of a tablet of 10 mg propranolol would mean that a total of 5 mg of propranolol would reach the general circulation. The value of bioavailability may vary widely and being a characteristic of the manufacturing pharmaceutical company and in turn may have clinical implications. For the same proprietary (trade) name, a particular pharmaceutical preparation of a drug may exhibit widely different values of bioavailability due to pharmacokinetic differences in the handling of the drug by the body including concurrent medications. Three major factors are considered below.

These apparently conflicting observations may be reconciled by the following explanation. The surface area and blood flow are important determinants of the rapidity of absorption. The small intestine is favoured on both of these accounts. The total area of the small intestine represented largely by microvilli, has been estimated to be about 200 m2, and an estimated 1 litre of blood passes through the intestinal capillaries each minute. The corresponding estimates for the stomach are only 1 m2 and 150 ml/min. these increases in both surface area and blood flow more than compensate for the decreased fraction of unionised acid in the intestine. In fact, the absorption of all compounds, acids, bases, or neutral compounds, is faster from the small intestine than from the stomach. Therefore, the rate of gastric emptying is a limiting step in the rapidity of drug absorption. Consequently, food, particularly fat, slows stomach emptying. This explains why drugs are frequently recommended to be taken on an empty stomach when a rapid onset of action is desired.

Time for Absorption An orally administered drug is exposed to the gastrointestinal mucosa for no more than 1 to 2 days, and for much less time at the main absorption site, the small intestine. If a drug is poorly permeable, for example, streptomycin, heparin, suxamethonium, and ipratropium, there is insufficient time for complete absorption. There may be insufficient time for complete absorption of the vitamin, riboflavin, and of other substances absorbed by a carrier-mediated transport process. The site of the transport process is usually restricted to a certain part of the gastrointestinal tract. The system for absorbing riboflavin is located in the upper part of the small intestine. At the does taken, the concentration of riboflavin reaching the site of absorption saturates the transport process. The oral bioavailability of riboflavin can be increased by taking the vitamin with small amounts of food. The resultant slowing of stomach emptying both extends the duration and diminishes the rate of delivery of riboflavin and hence its concentration at the absorption site; both factors favour more complete absorption.

The stomach may simply be viewed as a storage organ from which pulses of drug are ejected onto the absorptive sites in the small intestine.

Factors Influencing Bioavailability

There is the situation of a drug, such as griseofulvin (and mebendazole and albendazole), that is sparingly soluble in both gastric and intestinal fluids. There may already be insufficient time for dissolution and absorption when this drug is administered as a tablet. Retaining such a drug in the stomach, by increasing the total time for dissolution, should favour increased

Bioavailability of a drug is the ease (how much of the drug and how fast, completeness of absorption) at which it reaches the general circulation. Drugs that are pharmaceutically formulated (designed) for oral administration may show different bioavailabilities. This is usually measured by the percentage of the 10

Essentials of Medical Pharmacology

Majid A. K. Lafi

acid in a single passage through the liver, resulting in a substantial first-pass effect . Drugs that show a significant first-pass effect in man include aspirin, hydralazine, lidocaine, morphine, nitroglycerin, pentazocine, propoxyphene, and propranolol.

availability. The time available for dissolution within the intestine is probably limited to between 4 and 10 hours. Subsequently, as the intestinal fluid and contents move into the large intestine and water is reabsorbed, the resulting compaction of the solid contents limits further dissolution of drug. An additional 2 to 4 hours in the stomach, where dissolution can occur, would significantly extend the time for dissolution. Fats, particularly, delay stomach emptying, and this delay may be one of the explanations for the observed increase in the availability of griseofulvin when taken with a fatty meal or with fats.

Avoiding the first pass through the liver probably explains the activity of nitroglycerin administered sublingually. Blood perfusing the buccal cavity bypasses the liver and enters directly into the superior vena cava. This anti-anginal drug is almost completely metabolised as it passes through the liver, and any drug swallowed is not systemically available. The metabolites seen in blood are only weakly active.

The rectum has a small surface area and a drug given rectally is not always retained for a sufficient length of time to ensure complete absorption. No time limitation exists for a drug injected into muscle or subcutaneous tissue; complete absorption is anticipated unless destruction occurs at the site of administration.

The rectal route has a definite advantage over the oral route for drugs that are destroyed by gastric acidity or by enzymes in the intestinal wall and microflora. Potentially, the rectal route may also partially reduce first pass hepatic loss. Part of the rectal blood supply, particularly the inferior and middle haemorrhoidal veins, bypasses the hepatic portal circulation and dumps directly into the inferior vena cava. Achieving a reproducible availability, which is important in drug therapy, may be difficult, however, since availability is strongly dependent upon the site of absorption within the rectum.

Competing Reactions Any reactions within the gastrointestinal tract that compete with absorption may reduce the oral bioavailability of a drug. Benzylpenicillin when given orally undergoes substantial hydrolysis by gastric acid; therefore, it is administered by injection. Enzymatic hydrolysis occurs to aspirin forming salicylic acid, active antiinflammatory compound. Tetracycline undergoes complexation with polyvalent metal ions, e.g. Ca++, Al+++, forming unabsorbed insoluble complexes. Decarboxylation occurs to levodopa resulting in loss of activity (product active but not absorbed).

Distribution of Drugs Generally, drugs that are readily absorbed from the gut wall are also readily distributed throughout the body water compartments. This is applicable to most barbiturates; thiopental is highly lipid-soluble and is freely absorbed from the stomach and rectum. When it is administered intravenously, it crosses the biological barriers into the brain producing anaesthesia. Generally, centrally acting drugs have to pass through an additional lipid membrane in the blood brain barrier, and thus, are readily absorbed from the gut. These drugs can easily reach the foetal circulation, being the main offenders in causing foetal abnormalities (e.g. phocomelia caused by thalidomide).

Hepatic Extraction Over hundred years ago, acetylsalicylic acid (aspirin) was synthesised to overcome the bitter taste and the gastrointestinal irritation associated with the parent drug, salicylic acid. Only subsequently was aspirin shown to be also pharmacologically active. Aspirin, a labile ester, is rapidly hydrolysed, particularly by esterases in the liver. In fact, hepatic hydrolysis is so rapid that a significant fraction of aspirin is converted to salicylic

After being absorbed, most drugs bind to tissue and plasma proteins forming

11

General Principles

Ramadi, 6 October 2009

extensively bound to tissues is to have a large apparent volume of distribution (Vd). This is a theoretical volume of fluid, which would be required to contain the total body content of a drug at a concentration equal to the plasma concentration. Drugs which has a large Vd (in litres for 70 kg person) are digoxin (420), nortriptyline (1000), dothiepin (4900), amiodarone (4200) and chloroquine (13000), and drugs with small Vd are warfarin (5), heparin (5), aspirin (11), gentamicin (18), frusemide (21) and amoxicillin (28).

equilibrium with the unbound (free) drug, and the extent of binding varies from drug to drug. If a drug exhibits no appreciable tissue binding, the tissues behave as little more than water compartment in which the drug is dissolved. The pharmacological properties of a drug are greatly influenced by its being highly protein bound; this influence can be seen in the following ways: 1. Its absorption from the gut wall will be facilitated, through capturing the drug molecules by tissues and/or plasma protein molecules leading to maintenance of the concentration gradient across the gut wall.

Serum half-life

2. Since only the unbound form of the drug is the biologically active, it is essential to know the extent of binding for a drug before values given for serum levels reached for the drug in question become meaningful.

Serum half-life (t ) of a drug is the time taken for the serum concentration to halve. Metabolism and/or excretion of the drug determine it. A drug with a short t (e.g. salbutamol) produces a much steadier therapeutic action when given in at least three divided doses daily. On the other hand, a drug with a long t (e.g. digoxin) given as a single daily dose is adequate to maintain a steady response. Drugs with long t will cumulate with repeated and frequent doses and patients receiving such drugs particularly those with low therapeutic index like digoxin and phenytoin should be examined frequently for signs of overdosage.

3. Certain pathological conditions where changes in the concentration of serum proteins, e.g. hypoproteinaemia (which may occur in some renal and/or hepatic dysfunction), a higher level of unbound drug will occur in the serum unless the oral dose is lowered. This should be taken in consideration when dealing with drugs, which are highly protein bound (e.g. diazepam, frusemide, phenytoin and triamterene) and/or have low therapeutic index (e.g. theophylline and digoxin).

Thus, measurements of serum concentrations are performed routinely nowadays; these include anticonvulsants (e.g. phenytoin), antiarrhythmic drugs (e.g. quinidine), theophylline, lithium and aminoglycosides. In certain cases, measuring the response to a drug provides an easy method of monitoring its action (e.g. prothrombin time with anticoagulants like warfarin).

4. Adverse drug interactions may take place on plasma protein binding sites. This is very likely to occur with a highly protein bound drug like warfarin (99% bound) which can be displaced by certain other drugs like phenylbutazone which competes with warfarin on the same binding site. This may result in a small change in binding of warfarin that can greatly lengthen the prothrombin time. This type of drug interaction is clinically more important when the displaced drug has a small volume of distribution.

Metabolism Hepatic enzymes are responsible for the metabolism of most drugs. However, some drugs are metabolised in the plasma (e.g. procaine and suxamethonium are destroyed by pseudocholinesterase in the serum) and tissues (e.g. alcohol is destroyed by enzymes in gastric wall and liver). Metabolism in the liver can take place for those substances, which are lipid soluble and thus can enter the

5. For a drug to be effective therapeutically it has to achieve adequate plasma levels of the unbound form. Drugs vary in the period required to reach equilibrium between the body fluids and tissues. When a drug is 12

Essentials of Medical Pharmacology

Majid A. K. Lafi

liver. Hepatic enzymes are, generally, capable of metabolising endogenous and exogenous substances that are relatively stereotyped. Each enzyme is specific for certain chemical groups, which can occur on a wide range of substances.

Inactive Substance Azathioprine Enalapril Sulphasalazine

Hepatic metabolic processes can be divided into: Phase I metabolism results in a change in drug substance by oxidation, reduction or hydrolysis and in certain cases introduces a chemically active site into it. Oxidation is the most important reaction that is usually achieved by the so-called mixed-function oxidases that are capable of metabolising a variety of compounds.

Talampicillin Acyclovir

Metronidazole

Phase II metabolism involves the union of the drug with one of several polar endogenous molecules (e.g. glucuronide, glycine or acetyl derivative) to form a watersoluble conjugate which is readily eliminated by the kidney or, if the molecular weight more than 300, in the biliary tract. Generally, phase II metabolism inactivates drugs and facilitates their excretion.

Chloramphenicol succinate Chloral hydrate Anistreplase Hexamine

When drugs undergo metabolism, they can be converted from pharmacologically active to inactive substances; this is the most likely event. Further, some pharmacologically active drugs may be converted to another active substance. While some other pharmacologically inactive drugs (prodrugs) can be converted to active ones. Active Drugs Allopurinol Amitriptyline Aspirin Acetaminophen (safe)

Codeine Chloroquine Diazepam

Active Metabolite Mercaptopurine Enalaprilat 5-aminosalicylic acid (mesalazine) plus sulphapyridine (by bacteria in the colon) Ampicillin Acyclovir triphosphate (by viral thymidine kinase) Reducedmetronidazole (by anaerobic bacteria) Chloramphenicol Trichloroethanol Deacylated anistreplase Formaldehyde (by hydrolysis in acidic urine)

Excretion Most drugs are excreted in urine, either as the parent substance or metabolites. Lipid soluble drugs, in addition to being readily absorbed from gut, appear in the glomerular filtrate, but easily pass back into the blood stream by passive diffusion at the proximal tubule. However, many of these drugs are converted by the liver into more polar, lipid insoluble metabolites. These metabolites, and other drugs which are highly polar (e.g. streptomycin), do not pass very readily into glomerular filtrate, but once they are there they have difficulty in diffusing back at the proximal tubule. These substances are usually excreted entirely by the kidney. In addition to passive diffusion, many acidic and basic drugs are actively secreted. The secretion of weakly acidic substances can be inhibited by probenecid, and this substance has been used to prolong the t of penicillin in order to reach higher tissue concentrations without increasing the dose of the antibiotic.

Active Metabolite Alloxanthine (oxypurinol) Nortriptyline Salicylic acid N-acetyl-pbenzoquinoneimine (NABQI, hepatotoxic) Morphine Hydroxychloroquine

Nordiazepam

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General Principles

Ramadi, 6 October 2009

Changes in tubular pH can affect the elimination of these compounds by altering the ratio of ionised to unionised form. Normally the urine is slightly acidic and favours the excretion of weakly basic drugs (e.g. amphetamine, pethidine), while oral sodium bicarbonate will prolong their effects. On the other hand, the excretion of weakly acidic drugs (e.g. for patients who has taken overdose of barbiturates or aspirin) is accelerated by making the urine alkaline (alkaline diuresis) by giving sodium bicarbonate. As the kidney (and cardiac function) and to a lesser extent the liver are important in drug excretion, a serious consideration must be taken with impaired renal and hepatic functions. An elderly patient with congestive heart failure and a raised blood urea is likely to develop digitalis intoxication if digoxin is prescribed in full dose. It is necessary to measure repeatedly the serum level of certain drugs (e.g. gentamicin) when they are given to patients in renal failure.

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Majid A. K. Lafi

The apparent volume of distribution (Vd)

USEFUL NOTES

D C = ------Vd

• Clearance of a drug is the rate of elimination by all routes relative to the concentration of drug in any biological fluid.

D Vd = -----C

Rate of elimination Clearance = -----------------------Concentration

C = plasma concentration of drug D = Total amount of drug in the body

Rate of elimination = Q x Ce - Q x Co

Example: if 10 mg of a drug, thus D = 10 mg, is administered and the plasma concentration is 1.0 mg/L, then the Vd = 10 mg/L = 10 L.

Blood flow = Q Entering drug concentration = Ce Exiting drug concentration = C0

Clinical applications of Vd 1. It is useful to calculate the amount of drug needed to achieve a desired plasma concentration:

Therefore: Q x Ce Q x Co Clearance = ------------------- (ml/min) Ce

Example: if supraventricular arrhythmia of a patient is not responding well due to inadequate plasma levels of digoxin. Assuming the plasma concentration of the drug is C 1 and the desired concentration is C 2, a higher one. It is important to know how additional digoxin should be administered to bring the circulating level of the drug from C1 to C2.

Ce Co = Q x ---------- = Q x ER Ce ER = extraction ratio

Clearance of a drug by an organ (e.g. kidney) means the ability of the kidney to remove the drug from a certain volume of plasma per minute. Similar to renal clearance of creatinine or urea.

D1 = Vd x C1 D1 = amount of drug initially in body D2 = Vd x C2 D2 = amount of drug in the body required to achieve the desired plasma concentration

Dosing rate = Clearance x Css (Q x Ce Q x Co ) = --------------------- x C ss Ce Css = Steady state concentration

Therefore, the additional dosage needed is the difference between the two values: (D2

C1 )

2. Since delivery of drug to the organs of elimination depends not only on blood flow but also on the fraction of the drug in plasma, therefore, the value of Vd of a drug can influence the rate of elimination. Assuming a drug with a large Vd, most of this drug is in the extraplasmic space and is unavailable to the excretory organs. Therefore, a drug with a large Vd would

Half-life (t ) is defined as the time required for the amount of drug in the body to decrease by half (50%). t

D1) = Vd (C2

= 0.693 Vd/CL CL = Clearance

15

General Principles

be expected to have a long t extended duration of action.

Ramadi, 6 October 2009

withdrawn, an interval equivalent to 4 t will be required for body stores of the drug to decline by 94%.

and

Clinically, the knowledge of Vd of a drug may be useful when overdosage occurs. Removing a drug by haemodialysis is likely to be of benefit if a major proportion of the total amount of the drug is in the plasma.

• When t is 6-12 hr giving half the priming dose at intervals equal to the t can indeed be a satisfactory solution because dosing every 6-12 hr is reasonable.

Example: For salicylate, which has a small Vd, (12L) haemodialysis is appropriate treatment; while for pethidine, which has a large Vd, (310L) is not appropriate one.

• When t is greater than 24 hr giving half the priming dose every day means that more drug is entering the body than is leaving it each day, and the drug will accumulate indefinitely. Thus, the maintenance dose should be adjusted to replace only that amount of drug that leaves the body in 24 hr, as for warfarin.

Students are expected to be familiar with the following terms. They are advised to make contributions in the discussion sessions on the concepts of these terms. • Therapeutic range, therapeutic window

• When t is less than 3 hr, dosing at intervals equal to the t would be so frequent as to be unacceptable, and the answer is to use continuous intravenous infusion if the t is very short, as for dopamine t , 2 min; steady-state plasma concentration will be reached in 5 x t = 10 min). Benzylpenicillin has a t of less than 1 hr but is effective in a 6-hourly regimen because the drug is very safe that it is possible to give in a dose that achieves a plasma concentration many times in excess of the minimum inhibitory concentration for sensitive organisms.

• Steady state concentrations (Css), plateau (when the quantity of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached. • Time to plateau (When a drug is administered repeatedly in the same dosage, plateau (steady state) will be reached in approximately 4-5 half-lives. • Techniques for reducing fluctuations in drug levels

• First and zero order (saturable) kinetics [clinical implications: (phenytoin, therapeutic index = 2, subtherapeutic plasma concentration with t of 6-24 hr and C ss reached in 2-3 days, while therapeutic plasma concentration with t of 60 hr and Css reached in 2 weeks); alcohol (due to alcohol dehydrogenase being saturable at alcohol blood concentration of about 10 mg/dL), theophylline with therapeutic index <2, salicylates, clarithrmycin, heparin (saturable kinetics, dose-dependent t 60 min. after 75 units per kg and 150 min. after 400 units per kg) versus low molecular weight heparin (LMWH, 1st order kinetics). Rifampicin when given in a dose of more than 300 mg the excretory capacity of the liver becomes saturated, this is an advantage in certain clinical conditions e.g. in tuberculosis).

• Administer drugs by constant IV infusion • Reduce dosage size while increasing dosage number (keeping the daily dose constant) • The priming or loading dose is that dose which will achieve a therapeutic effect in an individual whose body does not already contain the drug. • Loading doses versus maintenance doses (A loading dose is used to rapidly produce a high level of drug equivalent to the plateau level for a similar dose, maintenance dose) • Decline from plateau (When a drug has been administered repeatedly and then 16

Essentials of Medical Pharmacology

Majid A. K. Lafi

Zero-order Kinetics

Therapeutic Range

Dose →

• Bioavailability (How much of the drug and how fast it reaches the general circulation) • pH- logarithm of the reciprocal of the hydrogen ion concentration • pKa- logarithm of the reciprocal of the dissociation constant • Ka- the extent to which a molecule is able to ionise [either to lose a hydrogen ion (acidic groups) or to add a hydrogen ion (basic group)] is given by the dissociation (or ionisation) constant (Ka). • For simplicity purposes drugs can be classified into 3 groups: • Drugs ionised by environmental pH (most drugs) • Drugs incapable of becoming ionised (non-polar) e.g. digoxin, chloramphenicol, steroid hormones such as prednisolone. Effectively lacking any ionisable groups, they are unaffected by environmental pH, are lipid-soluble and so diffuse readily across tissue boundaries. • Permanently ionised drugs (polar) e.g. heparin (acidic), ipratropium, tubocurarine, suxamethonium, and streptomycin (basic).

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General Principles

Ramadi, 6 October 2009

which is synthesised from ATP by the enzyme adenylate cyclase, which is modulated by β-and α2-adrenoceptor. Subsequently, cAMP activates protein kinase, resulting in phosphorylation of proteins triggering other intracellular effects. Other second messenger systems have been recognised. For example, diacylglcerol (DAG) and inositol trisphosphate (IP3) are the metabolic product of phosphatidyl bisphosphate (PIP2) by the enzyme phospholipase C which is coupled to α1adrenoceptors and cholinergic muscarinic receptors.

Pharmacodynamics Drugs may act by different mechanisms: 1. RECEPTOR INTERACTION Many drugs act by activating or blocking a receptor. Receptors are chemical components mostly on the surface of the cell. 2. ENZYME INHIBITION e.g. monoamine oxidase (deprenyl), cholinesterase (neostigmine), cyclooxygenase (aspirin). 3. CHEMICAL INTERACTION e.g. gastric acid (antacids), urine alkalinizing agent (potassium sodium hydrogen citrate), heparin (protamine sulphate), alkylating agents. 4. PHYSICO-CHEMICAL PROPERTIES e.g. osmotic diuretics, laxatives, volatile anaesthetics.

Tolerance The continual administration of drugs sometimes leads to a progressive decrease in the observed response. This can be called tolerance or desensitisation. This occurs when increasing amounts of opiates (e.g. morphine) are required to achieve the same effect. Tolerance (e.g. for salbutamol) is probably associated with a loss of receptors from the cell surface due to endocytosis or internal uptake. This has been termed downregulation of receptors; i.e. with continued stimulation there will be a lower number of receptors on the cell surface (e.g. with the use of β 2 agonists like salbutamol in asthmatic patients). This type of tolerance is described as pharmacodynamic one. Further, pharmacokinetic tolerance can also be exhibited by some drugs including carbamazepine and alcohol. An alteration in rates of metabolic inactivation with chronic administration of carbamazepine or alcohol can induce hepatic enzymes resulting in an increase in the metabolism of the drug and in turn lead to a decrease in the observed response.

Drug Receptor Interaction Receptor activation is followed by a biological response which is proceeded by: a. Opening of ionic channels (pores) b. Activation of a second messenger Receptor activation can induce an increase in permeability of selected ion, e.g. at the neuromuscular junction acetylcholine is released from the motor endplate and combines with the postsynaptic nicotinic receptor. This results in the opening of ion channels (Na+, K+) and the propagation of an action potential that proceeds skeletal muscle contraction. GABA receptor is another example of receptor coupled to ion channels; it is linked with Cl- channels and when activated leads to enhanced influx of Cl-. In other cells, the binding of a chemical signal (neurotransmitter, chemical mediator) to a receptor (signal detector and transducer) activates enzymatic processes within the cell membrane that eventually result in intracellular response. Second messenger molecules are produced as a result of chemical signal binding to a receptor. These messenger molecules then translate the extracellular signal into an intracellular response. The best-known second messenger is cyclic adenosine monophosphate (cAMP)

Tachyphylaxis

(acute tolerance) is a similar mechanism that develops more rapidly. This clinically can occur to a. Lysergide (LSD) b. Local anaesthetics (lidocaine) repeated administration

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Essentials of Medical Pharmacology

Majid A. K. Lafi

c. Vasopressin causes smooth muscle stimulant effect (in large nonphysiological doses).

Drug receptor interaction can best be studied with isolated tissues, e.g. a gut or blood vessel preparation. The tissue specimen is put into an organ bath in a physiological salt solution (e.g. Kreb s, Tyrode s) and the drug is added. The response to drug administration usually is a contraction that is recorded. Plotting the response in relationship to the logarithm of the dose (concentration) gives a dose-response curve that is a sigmoid (Fig.1.5.).

d. Noradrenaline when attempting to maintain raised blood pressure in some patients with shock (angiotensin II is suitable in this condition). e. Gonadorelins goserelin)

(GnRH

analogues,

e.g.

Clinical Types Antagonism

Supersensitivity means that a certain dose of an agonist (or endogenous mediator) achieves a higher effect. This may be explained by upregulation of receptors (or decreased breakdown) and can occur with long-term use of competitive antagonists (rebound phenomenon after clonidine or β-blockers like propranolol).

of

Drug

a. Chemical antagonism The antagonist combines with the agonist away from the receptor, preventing the action of the agonist at this target receptor or tissue. For example, alkaline antacids neutralise gastric HCl in peptic ulcer; protamine sulphate (base) neutralises the acidic compound heparin preventing its action in overdose.

Examples of receptors are: Muscarinic (M1, 2,3)

b. Physiological antagonism The antagonist is a different agonist that acts on the same tissue as the agonist, but combine with different receptors (from those of the agonist) to produce effects on the tissue that are opposite to those of the agonist, e.g. adrenaline antagonises the effect of endogenous histamine on blood vessels and bronchial smooth muscle when used in the treatment of anaphylactic shock.

Acetylcholine Nicotinic (N1, 2)

¿1,2 Adrenaline

¾1,2 H1 Histamine

c. Pharmacological antagonism When the antagonist competes with the agonist for the specific receptor, combines with the receptor, and prevents the action of the agonist. The antagonist has no intrinsic activity (e.g. diphenhydramine antagonises the action of the endogenous histamine on the specific histamine receptor level as in the treatment of anaphylactic shock). This type of antagonism is further subdivided into:

H2

Agonism and Antagonism Drugs that interact with a receptor and elicit a response are called agonists and compounds that interact with receptors preventing the action are referred to as antagonists. An agonist is a drug that has affinity for a receptor and that has intrinsic activity or efficacy. A competitive antagonist has affinity but lacks intrinsic activity.

• Reversible antagonism This may be demonstrated with many antagonists (Fig. 1.5.). Reversible (competitive) antagonists Increasing the concentration of the agonist can fully overcome the inhibition 19

General Principles

Ramadi, 6 October 2009

by the antagonist (e.g. atropine and tubocurarine antagonising the actions of acetylcholine at muscarinic and nicotinic receptors respectively). Thus, a reversible (competitive) antagonist displaces the dose-response curve parallel to the right but do not change the maximum response.

Full agonist

• Irreversible antagonism When increasing the concentration of the agonist will never fully overcome the inhibition. This is probably due to receptor inactivation (e.g. phenoxybenzamine at αreceptors in blood vessels). Irreversible antagonism can also be observed on the activity of the appropriate enzymes; recovery of the enzyme activity depends on the formation of new enzymes.

Antagonist

Cell with a receptor occupied with a full agonist

Fig.1.4. A schematic representation of drugreceptor interaction. A full agonist can interact with a receptor producing an effect. A partial agonist produces some efficacy on its own and it reduces the efficacy of the full agonist. An antagonist has no efficacy and it inhibits the actions of the full agonist and the partial agonist.

Table 1.2. A selected list of clinically important irreversible antagonists

Site

Partial agonist

Drug

Phenoxybenzamine α-adrenoceptors Cholinesterase DFP (organophosphate) Prostaglandin G/H Aspirin synthase MAO (non-selective) Tranylcypromine & phenelzine* MAO-B Deprenyl (selegiline) H+,K+-ATPase Omeprazole GABA transaminase Vigabatrin ADP receptors Clopidogrel Xanthine oxidase Alloxanthine (oxypurinol) Constitutive β-lactamase Clavulanic acid

Response 100%

A

B

C

D

50%

E

* The selective MAO-A inhibitor moclobamide acts reversibly.

EC

EC

EC

Agonist Concentration (log scale) Fig.1.5. A. Log dose-response curve to a drug (A) on its own. B. The response to the drug (A) in the presence of the drug (B) representing reversible (competitive) antagonism; note there is a shift in the log dose response curve to the right and an increase in EC50 with no reduction in the magnitude of the maximal response. C. The response to the drug (C) on its own. Curves D and E represent the response to the drug (C) in the presence of increasing concentrations of an irreversible antagonist. Note: there is a reduction in maximal response to the drug D.

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important parameters of a drug, characterising its safety is the therapeutic index which can be calculated from animal experiments, it can be expressed as:

Response Full Agonist

LD50 Therapeutic index = ------ED50

Obviously this cannot be calculated in clinical medicine instead, the ratio of a toxic dose (TD) over the effective dose can be utilised, therefore Partial Agonist

TD50 Therapeutic index = ------ED50

Response B

A

C

Agonist scale) Fig.1.6. LogConcentration dose-response (log curves to a full agonist and partial agonist. Note: a partial agonist shows a reduced maximal response compared with that of the full agonist. Therefore, a partial agonist on its own exhibits agonistic activity (efficacy) but it behaves as antagonist on responses mediated by full agonists. This can be demonstrated by the oestrogen receptor partial agonist clomiphene.

Potency

Clinical Studies EC50

In addition to the dose-response relationship of an isolated organ or an individual patient to see the relationship between dose and a quantity of response. Such quantal information can be obtained from a population of individuals in which the dose (plotted on the horizontal axis) is evaluated against the percentage responding to treatment. From this curve, the ED50 value (that is the dose that has a therapeutic effect in 50% of the population) can be obtained. Beside its wanted (therapeutic) effects, a drug can produce unwanted (toxic) effects including death. In testing a new drug, increasing doses are given to a large number of animals and can thereby determine the 50% lethal dose or LD50. One of the most

EC 50

EC50

Agonist Concentration (log scale) Fig.1.7. Log dose-response curves for the drugs (A), (B) and (C). Drug (A) is more potent than drug (B) and (B) is more potent than the drug (C), while both A and B are more efficacious (with more efficacy) than C. Note: The maximal response is a measure of the efficacy while the EC50 is a measure of the potency; i.e. a drug with a higher EC50 is with a lower potency. When substituting morphine for A, codeine for B and aspirin for C it follows that morphine is more potent than codeine, both are more efficacious and more potent than aspirin as analgesic agents.

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• Irreversible antagonist: (affinity, no efficacy, reduced maximal response, e.g. omeprazole, vigabatrin) • Potency: (activity per unit weight, ED50, e.g. analgesic agents) • Efficacy: (intrinsic activity, measure of maximal response, e.g. analgesic agents) • ED50: (effective dose, half of the maximal response elicited) • LD50: (lethal dose, half of the animals die) • Therapeutic index: (LD50/ED50, measure of safety) • Drug synergism: [summation, 2+2=4; potentiation, 2+2=5 (co-trimoxazole), 0+2=5 (benzerazide + L-DOPA)]

USEFUL NOTES The students are expected to know the concept and definition of the following terms. They are advised to give an example of a drug and a clinical condition, and illustrate by a diagram when appropriate. They may make use of the key words given with each term. • Receptor: (protein molecule, detector and transducer, muscarinic) • Second messenger: (molecule, translate the extracellular signal into a response, e.g. cAMP) • Tolerance: (desensitisation, analgesia, e.g. morphine; asthma, down-regulation, salbutamol) • Tachyphylaxis: (rapid tolerance, local anaesthesia, lidocaine, pH, longer acting local anaesthetic (e.g. bupivacaine) • Idiosyncrasy: [supersensitivity, unpredictable, dose-independent, e.g. chloramphenicol, aplastic anaemia; dosedependent, e.g. isoniazid (INH), hepatitis] • Up-regulation: (supersensitivity, rebound phenomenon, clonidine, or β-adrenoceptor blockers, cardiovascular problem) • Down-regulation: (see tolerance) • Agonism: (affinity and intrinsic activity, efficacy) • Partial agonist: (affinity with some efficacy, reduced maximal response, e.g. clomiphene, buspirone); bupropion: partial nicotinic agonist (basis for smoking cessation?) • Clinical types of antagonism: 1. Chemical (antacids, peptic ulcer) 2. Physiological (exogenous adrenaline, endogenous histamine, acting on different receptors, anaphylactic shock) 3. Pharmacological (diphendydramine, endogenous histamine, acting on the same receptor). • Antagonist: [affinity with little or no e.g. efficacy, reversible (competitive neostigmine, and partial agonist e.g. clomiphene), and irreversible phenoxybenzamine, aspirin] • Competitive (reversible) antagonist: (affinity, no efficacy, maximal response can be attained, dose-response curve shifts to the right, e.g. phentolamine, propranolol) 22

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AUTONOMIC PHARMACOLOGY It is the proximal location of the sympathetic ganglion in the sympathetic chain that make them accessible to the procedure of sympathetic blockade with local anaesthetics or sympathectomy, procedures that eliminate regional outflow of nerve impulses and mainly give rise to local vasodilatation. The sites of action of mediators in the autonomic nervous system are the most firmly established:

Introduction The autonomic nervous system, together with both the endocrine system and autacoids (including eicosanoids like prostaglandins and leukotrienes, histamine, 5hydroxytrytptamine, and peptides like angiotensin II and kinins), co-ordinates the regulation and integration of body functions. The endocrine system sends signals to target tissues by varying the levels of blood borne hormones; likewise, autacoids exert regulatory effects on local or distant effector tissues. On the contrary, the autonomic nervous system mediates its influence by rapid transmission of electrical impulses over nerve fibres terminate at effector tissues. The specific effects mediated by neuronal activity are achieved by releasing a chemical transmitter (neuromediator substance) across synaptic junctions delivering an effect on the postsynaptic membrane.

1. Postganglionic parasympathetic nerve endings on smooth muscle, cardiac muscle, and exocrine glands: acetylcholine 2. Postganglionic sympathetic nerve endings on smooth muscle, cardiac muscle, and exocrine glands: noradrenaline (except for sweat glands) An important exception to the generalisation that noradrenaline is the chemical mediator to sympathetically innervated structures are sweat glands, with anatomically sympathetic innervation, activated by cholinergic drugs and inhibited by anticholinergic drugs, such as atropine. Therefore, postganglionic fibres innervating sweat glands are cholinergic rather than adrenergic.

Drugs that produce their primary pharmacological effects through mimicking or inhibiting the functions of the autonomic nervous system are known as autonomic drugs. This chapter is primarily concerned with the fundamental physiology of the autonomic nervous system and emphasising on the role of neurotransmitters in the intertalking between extracellular events and intracellular biochemical events.

3. In all autonomic ganglionic synapses, acetylcholine is the primary neuromediator. The adrenal medulla secretes adrenaline when cholinergic drugs are injected, a response inhibited by ganglionic blocking agents like hexamethonium and mecamylamine. Embryologically, the adrenal medulla can be considered a modified sympathetic ganglion. It is therefore, not surprising that it responds to acetylcholine, the normal ganglionic mediator to both sympathetic and parasympathetic neurones.

The autonomic nervous system consists mostly of the efferent innervation of the viscera with its two major sub-divisions: the sympathetic and parasympathetic systems. The final common pathway is a two-neurone chain: a preganglionic neurone, located in the CNS that projects onto a postganglionic neurone, located in the periphery. In the sympathetic system the postganglionic neurones are generally located near the spinal cord, either paravertebral (sympathetic chain) or prevertabral (celiac ganglion). In contrast, the postganglionic neurones of the parasympathetic system are located in close proximity to their target organ.

4. CNS synapses: acetylcholine, noradrenaline, dopamine, serotonin (5HT), histamine, glutamic and aspartic acids, GABA, glycine, adenosine, and numerous peptides.

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specific cholinesterase is of the non-specific type.

5. Motor fibre terminals: Skeletal neuromuscular junctions acetylcholine is the neuromediator. The postsynaptic cholinergic nicotinic receptors of a subtype termed N2-receptor being more selectively blocked by tubocurarine than ganglionic nicotinic N1-receptors. The latter, however, is more selectively blocked by hexamethonium than the N2-receptors.

Acetyl CoA CAT Choline

Cholinergic Transmission The transmitter is acetylcholine (ACh) which is synthesised intraneurally from activated acetic acid (Acetyl-CoA) and choline. Upon release, it can act on muscarinic or nicotinic receptors and is rapidly broken down by cholinesterase (tissue bound) or pseudocholinesterase (serum). Choline can be re-utilised by being taken up back into the cholinergic neurone by a specific active mechanism.

Acetylcholine Choline + Acetate Cholinesterase ACh Muscarinic Receptors

The term muscarinic was introduced because of the mushroom poison muscarine, a quaternary amine alkaloid. The muscarinic actions are so called because they resemble those of the alkaloid muscarine and are equivalent to the action at parasympathetic postganglionic nerve endings and blocked by atropine and enhanced by anticholinesterase.

Fig.2.1. A simplified representation of a cholinergic neurotransmission function (neuroeffector junction) showing synthesis (choline acetyltransferase, CAT), storage (vesicles), release (exocytotic), postsynaptic site of action (e.g. muscarinic receptors), termination of action (by cholinesterase) of acetylcholine (ACh).

Acetylcholine is synthesised by the cytoplasmic enzyme choline acetyltransferase (CAT). Choline + Acetyl coenzyme A CAT

The compound hemicholinium blocks synthesis of the mediator by interfering with transport of choline across the neuronal membrane. Botulinus toxin blocks the release of acetylcholine.

Acetylcholine + Coenzyme A Cholinesterase Choline + Acetate

Most vascular regions do not receive parasympathetic innervation so that direct control of vascular tone is mediated by variations in sympathetic input to the vessels. Nevertheless, stimulation of muscarinic receptors, possibly located in the vascular endothelium rather than on the smooth muscle, by circulating agonists can dilate blood vessels and cause pronounced hypotension.

Destruction of acetylcholine is accomplished by cholinesterase, which are of two types. Acetylcholinesterase, or specific (or true) cholinesterase, hydrolyses acetyl esters of choline more rapidly than other esters. Pseudocholinesterase is a non-specific cholinesterase. Acetylcholinesterase is localised within neuronal membrane and, surprisingly, also in membranes of red blood cells where its function is unknown. Non24

Essentials of Medical Pharmacology

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cAMP system (e.g. β and α2-adrenoceptors), and the phospholipase C causing the hydrolysis of phosphatidylinositol bisphosphate into diacylglycerol (DAG) and inositol triphosphate (IP3), e.g. α1adrenoceptors.

Several types of muscarinic receptors have been identified. M1 and M3 receptors are activated by ACh (or any muscarinic receptor agonist), the receptor undergoes a conformational change and interact with a G protein, which in turn activates phospholipase C. this leads to the hydrolysis of phosphatidylinositol bisphosphate (PIP2) into the second messengers diacylglycerol (DAG) and inositol trisphosphate (IP3) which cause a cascade of events leading to an increase in intracellular Ca++ can interact to produce cellular response (e.g. smooth muscle contraction). On the contrary, activation of the M2 subtype of muscarinic receptors on the cardiac muscle stimulates a G protein, which inhibits adenylate cyclase and increases K+ conductance, to which the heart responds with a decrease in rate and force of contraction.

Tyrosine DOPA Dopamine Noradrenaline MAO NA

¿2

U1

Adrenergic Transmission The transmitter is noradrenaline (NA) which is synthesised intraneurally from a precursor, the dietary amino acid tyrosine through the steps: tyrosine to DOPA and this in turn converted to dopamine (plays a role of a transmitter on its own right) which undergoes β-hydroxylation yielding noradrenaline. After being released α and β-adrenoceptors are activated postsynaptically and induce the pharmacological action through second messengers e.g. cAMP. The process is quickly terminated by an amine re-uptake (known as amine neuronal uptake, U1) mechanism into the nerve terminal (this can be blocked by cocaine and tricyclic antidepressants). Monoamine oxidase (MAO) or catecholamine-O-methyltransferase (COMT) breaks down a certain quantity and the main metabolite in the urine is vanillinmandelic acid (VMA).

COMT

¿ and ¾ Receptors

Fig.2.2. A simplified representation of noradrenergic synaptic function illustrating synthesis, storage, release, postsynaptic site of action (α and βreceptors), autoregulatory α2-receptors, uptake1 (U1, reuptake of noradrenaline, NA), monoamine oxidase (MAO), and catecholamine-O-methyltransferase (COMT).

Noradrenaline released from postganglionic nerve diffuses across the synaptic membrane and interact with postsynaptically located receptors (on the effector cell) or on the presynaptically located receptors (autoregulatory receptors) modulating its own release. Noradrenergic (adrenergic) receptors can be coupled with adenylate cyclase

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Table 2.1. Transmitter, receptors, primary locations, postreceptor mechanism, stimulant substances and blockers in the autonomic nervous system. Primary location Postganglionic dendrites

cell

body,

Motor end plate

Nerve Heart, nerve, smooth muscle

Glands, smooth muscle, endothelium Postsynaptic effector cells (e.g. smooth muscle) Presynaptic nerve terminals, lipocytes, smooth muscle Postsynaptic effector cells (e.g. heart, lipocytes, juxtaglomerular cells of the kidney) Postsynaptic effector cells (e.g. airway and uterine smooth muscle, cardiac muscle) Presynaptic nerve terminals (e.g. parasympathetic fibres supplying airway smooth muscle) Postsynaptic effector cells, especially Lipocytes Brain, postsynaptic effector cells (e.g. renal vascular beds) Brain, presynaptic nerve terminals, effector tissues especially smooth muscle Brain Brain, cardiovascular system

Transmitter Receptor Acetylcholine N1 -receptor (NN-receptor) Acetylcholine N2-receptor (NM-receptor) Acetylcholine M1 M2

M3 Noradrenaline Adrenaline α1-receptor α2-receptor

β 1-receptor Adrenaline β 2-receptor

β 3-receptor Dopamine D1-receptor

D2-receptor D3-receptor D4-receptor

Postreceptor mechanism +

Na , depolarising channel Na+, depolarising channel

Stimulated by

Blocked by

K ion

Nicotine

Hexamethonium Mecamylamine Trimethaphan

K+ ion

Nicotine

Tubocurarine

Muscarine

Pirenzepine

Muscarine

Gallamine

Muscarine

HHSD

Phenylephrine

Prazosin

Clonidine Methylnoradrenaline

Yohimbine

Dobutamine

Betaxolol

Salbutamol

Butoxamine

+

IP3 , DAG cascade Inhibition of cAMP production, activation of K channel IP3 , DAG cascade IP3 , DAG cascade, ↑ intracellular calcium Inhibition of adenylate cyclase, ↓ cAMP Stimulation of adenylate cyclase, ↑ cAMP Stimulation of adenylate cyclase, ↑ cAMP

Stimulation of adenylate cyclase, ↑ cAMP Stimulation of adenylate cyclase, ↑ cAMP ↑ K conductance; may inhibit adenylate cyclase Inhibition of adenylate cyclase Inhibition of adenylate cyclase

BRL37344

Fenoldopam

Bromocriptine

Quinpirol Clozapine

HHSD: Hexahydrosiladifenidol BRL37344: Sodium-4-(2-[2-hydroxy-{3- chlorophenyl}ethylamino]propyl)phenoxyacetate DAG: Diacylglycerol IP3: Inositol trisphosphate

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Parasympathetic

Somatic motor

Sympathetic

ACh

ACh

ACh ACh

Adrenal medulla

ACh

AD + NA

ACh

ACh

ACh

Nicotinic receptors

Muscarinic receptors

Muscarinic receptors

Striated muscle

NA

DA

Adrenoceptors

Effector Organs

Fig.2.3. A schematic representation of the autonomic nervous system. Note: (1) The parasympathetic ganglia are close to or on the surface of the effector organs and that the postganglionic fibres are usually shorter than preganglionic fibres. (2) The neurotransmitter in all the autonomic ganglia is acetylcholine acting primarily on postsynaptic nicotinic receptors, while the neurotransmitter released from the sympathetic postganglionic neurones is usually noradrenaline (NA), and dopamine (DA) with an exception that acetylcholine (ACh) is released by sympathetic nerves supplying sweat glands. The adrenal medulla releases primarily adrenaline (AD) and noradrenaline (NA).

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Table 2.2. Responses of some effector organs to autonomic nerve impulses, and circulating catecholamines and autonomic drugs.

Effector organ Eye Iris Radial muscle Sphincter muscle Ciliary muscle Heart Sinoatrial node Ectopic pacemakers Contractility (atria) Arterioles Skin, splanchnic Skeletal muscle

Endothelium Platelets Bronchial smooth muscle Gastrointestinal tract Smooth muscle Walls Sphincters Secretion Myenteric plexus Genitourinary smooth muscle Bladder wall Sphincter Uterus, pregnant Penis, seminal vesicles Prostate Skin Pilomotor muscle Sweat glands6 Eccrine (thermoregulatory) Apocrine (stress) Metabolic functions Liver Liver Fat cells

Responses of Parasympathetic Receptor2 Action1

Sympathetic Action

Receptor

…. Contraction (miosis) Contraction

…. M3 M3

Contraction …. [Relaxation]

α1 …. β

Decrease rate …

M2

….

Increase rate Increase rate

Decrease

M2

Increase

β 1, β 2 β 1, β 2 β 1, β 2

…. …. …. …. Releases nitric oxide

α β2 α M4 …. α2 β2

Contracts

M3

Constriction Dilatation [Constriction] Dilatation …. Aggregation Relaxes

Contracts Relaxes Increases Activates

M3 M3 M3 M1

Relaxes Contracts …. Inhibits

Contracts Relaxes Contracts

M3 M3 M3

Erection

M

Relaxes Contracts Relaxes Contracts Ejaculation Contraction

β2 α1 β2 α α α1

…. …. …. …. M3 3

α2 5, β 2 α1 …. α

….

….

Contracts

α1

…. ….

…. ….

Generalised secretion Localised secretion

M α1

Activates gluconeogenesis α/β 2 7 Activates glycogenolysis α/β 2 Activates lipolysis β3 Inhibits lipolysis α2 …. Inhibits potassium uptake …. α1 …. …. Promotes potassium uptake β2 Kidney …. Renin release …. β1 Modified from Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Appleton & Lange, USA. Page 119. …. …. ….

…. …. ….

1

Less important actions are in brackets. Specific receptor type: α = alpha, β = beta, M = muscarinic. Muscarinic receptor subtypes are determined mostly in animal tissues. 3 The endothelium of most blood vessels releases nitric oxide, which causes marked vasodilatation, in response to muscarinic stimuli. These endothelial muscarinic receptors are not innervated and respond only to circulating muscarinic agonists. 4 Vascular smooth muscle in skeletal muscle has sympathetic cholinergic dilator fibres. 5 Probably through presynaptic inhibition of parasympathetic activity. 6 Generalised secretion: thermoregulatory; localised secretion: apocrine (stress, embarrassment). 7 Depends on species.

2

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Table 2.3. A summary of selected clinically important cholinergic drugs and related compounds. Drug Directly Acting Agents Bethanechol

Pilocarpine

Carbachol

Indirectly Acting (Reversible) Agents Physostigmine

Action

Selected therapeutic uses and important remarks

Muscarinic receptors (activation) Muscarinic receptors (activation) Muscarinic & nicotinic NN-receptors (activation)

Atonic bladder (in postpartum or postoperative nonobstructive urinary retention Side-effects: generalised cholinergic stimulation* Narrow (closed) and wide (open) angle glaucoma; it can enter the brain causing CNS-disturbances

Inhibits AChE Atony of bladder and intestine, glaucoma, overdose with anticholinergics (e.g. atropine, phenothiazines and tricyclic antidepressants; it enters the brain, causes generalised cholinergic stimulation*; duration of action (0.5-2 hr) Glaucoma; duration of action (4-6 hr)

Demecarium Neostigmine

Atony of bladder and intestine, overdose with competitive neuromuscular blocking agents (e.g. tubocurarine), myasthenia gravis Side-effects: generalised cholinergic stimulation It poorly enters the CNS; duration of action (0.5-2 hr) In chronic management of myasthenia gravis; duration of action (3-6 hr) In chronic management of myasthenia gravis; duration of action (4-8 hr) In the diagnosis of myasthenia gravis, postoperative paralytic ileus; short duration of action (about 5-15 minutes)

Pyridostigmine Ambenonium Edrophonium

Indirectly Acting (Irreversible) Agents (organophosphate, nerve agent) Isoflurophate (DFP)

Covalently binds to AChE In chronic management of open angle glaucoma (ointment, last for 1 week); it enters CNS, causes generalised cholinergic stimulation* (largely reversed by high dose of atropine); DFP ages in 6-8 hr In chronic management of open angle glaucoma; duration of action (100 hr)

Echothiophate Reactivation of Acetylcholinesterase (AChE) Pralidoxime

Rarely used because of high potency and long duration of action, glaucoma, when used topically shows little or no adverse-effects

Displaces organophosphate regenerating the enzyme

Poisoning with organophosphophorus compounds (before enzyme ageing occurs, i.e. loss of an alkyl group from the phosphorylated enzyme); it can reverse the effect of DFP except for those in CNS; less effective with newer nerve agents (enzyme ageing in seconds). * Generalised cholinergic stimulation: salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhoea, and bronchospasm; if the drug enters the CNS (e.g. physostigmine), it would show CNS disturbances which may lead to convulsion.

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Table 2.4. A summary of selected clinically important cholinergic antagonists (cholinergic blockers or anticholinergic drugs) Drug

Selected therapeutic uses and important remarks*

Antimuscarinic agents

Atropine

In ophthalmology to produce mydriasis & cycloplegia prior to refraction (a single dose lasts for 7 days) In spastic disorders of GI and lower urinary tracts In organophosphate poisoning In premedication prior to surgery, to suppress respiratory secretion in children

Homatropine Tropicamide Scopolamine (hyoscine) Ipratropium Clidinium

Cycloplegic for refraction in children (24 hr duration) Fundus examination (duration of 3 hr) In obstetrics with morphine to produce amnesia and sedation Motion sickness Asthma (inhalation) With chlordiazepoxide (Librax ) in GI disorders like peptic ulcer, nervous dyspepsia, irritable bowel syndrome, spastic colitis, mild ulcerative colitis

Isopropamide Pirenzepine

With trifluoperazine (Stelabid ) in peptic ulcer, visceral spasm Peptic ulcer (inhibits acid secretion), poorly enters the CNS, thus, no or little CNS side-effects Peptic ulcer, irritable bowel syndrome, & urinary disorders of storage (urinary frequency, incontinence, nocturnal enuresis Urinary disorders of storage (as above)

Propantheline Emepronium (Cetiprin ) CNS Agents Benzotropine Procyclidine Benzhexol-HCl Orphenadrine

(Centrally acting antimuscarinic antagonists) Drug induced dystonias and Parkinson s disease

Ganglionic blockers

Mecamylamine Trimethaphan Neuromuscular blockers

Moderately severe to severe hypertension Short-term treatment of hypertension (emergency lowering of blood pressure, when other agents cannot be used) See appropriate section in the chapter on CNS pharmacology (later on)

Nondepolarising (competitive agents) Depolarising agents * Adverse-effects commonly observed with cholinergic antagonists: blurred vision, mydriasis, constipation, urinary retention, tachycardia, and confusion.

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Table 2.5. A summary of selected clinically important adrenergic agonists Drug

Action (receptors)

Selected therapeutic uses and important remarks

Catecholamine* Adrenaline

α1, α2, β1, β 2

Acute asthma, open angle glaucoma, anaphylactic shock, in local anaesthetics to increase duration of action

Noradrenaline Isoprenaline

α1, α2, β1 β1, β 2

Dopamine

dopaminergic

β1 β1

Shock Asthma, severe bradycardia, heart block, sinus bradycardia Shock, decreased renal function Congestive heart failure Congestive heart failure

Phenylephrine

α1

Nasal congestion, hypotension

Methoxamine

α1

Clonidine

α2 (CNS)

Hypotension (during surgery, does not produce cardiac arrhythmias in sensitised heart, i.e. no beta activity) Paroxysmal supraventricular tachycardia Hypertension, withdrawal from opiates or benzodiazepines

Salbutamol Terbutaline Ritodrine

β2

Dobutamine Non-catecholamines♠

Asthma (bronchospasm), premature labour (they have short onset and duration of action)

Salmeterol Formoterol

β2

Asthma (they have slow onset and long duration of action)

Amphetamine

α, β (CNS)

Attention deficit (hyperkinetic) disorder (in children)

α1, α2, β1, β 2 Nasal congestion, asthma (CNS) * Rapid onset of action, brief duration of action, not administered orally, and do not enter the brain. ♠ Longer duration of action, all can be administered orally. Ephedrine

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Table 2.6. A summary of selected clinically important adrenergic antagonists (sympatholytic agents), and other drugs affecting neurotransmission. Drug ¿-adrenoceptor antagonists Phenoxybenzamine

Action (receptors)

Selected therapeutic uses and important remarks

α1, α2

Pheochromocytoma, Raynaud s disease (irreversible block)

(blocking) Phentolamine

α1, α2

Prazosin Terazosin Doxazosin1

α1

Diagnosis of pheochromocytoma (competitive block); it induces reflex tachycardia. (by vasodilatation and blocking autoregulatory α2 receptors) Hypertension [first dose effect, syncope (fainting)] Benign prostatic hyperplasia

Tamsulosin

α1c

Benign prostatic hyperplasia (Not for hypertension) Ureteral colic

¾-adrenoceptor antagonists2 Propranolol

β1, β2

Hypertension, migraine, hyperthyroidism, pheochromocytoma, angina pectoris, myocardial infarction

β1, β2 β1

Glaucoma, hypertension Hypertension

β1, β2 β 1, β 2, α1 β 1, β 2, α1

Hypertension Pheochromocytoma (hypertension) Angina pectoris, cardiomyopathy, (heart failure, hypertension) Higher ratio of β to α blockade than labetolol

Timolol Acebutolol Atenolol Metoprolol Pindolol Labetalol Carvedolol

Drugs affecting neurotransmitter release or re-uptake Reserpine

Guanethidine

Disrupts storage of amines causing depletion of amines

Hypertension (no longer used because of adverse-effects like depression)

Adrenergic neurone blocking agent

Hypertension (no longer used because of adverse-effects, orthostatic hypotension, male sexual dysfunction CNS stimulant (drug abuse)

Cocaine

Neuronal amine reuptake (U1) blocker 1 Doxazosin differs from prazosin and terazosin in having a longer t of about 22 hours. 2 For more details see a special section on β-antagonists in the chapter on Cardiovascular Pharmacology.

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While, contraction of the longitudinal ciliary muscle alters the tension on the trabecular meshwork, opening its pores and thus facilitating outflow of the aqueous humor into the canal of Schlemm. Increased outflow reduces intraocular pressure benefiting patients with glaucoma. It follows that muscarinic blocking drugs like atropine inhibit such effects of muscarinic receptor activation.

Ocular Pharmacology The eye represents a good introduction into system-based pharmacology as this organ comprises multiple autonomic receptors (Fig.2.4.). The structure of the anterior chamber contains several tissues supplied by different autonomic innervations. The iris, a multi-unit smooth muscle, consists of the circular pupillary constrictor muscle (sphincter) which is contracted muscarinic agonists causing miosis (a reduction in pupil size), and the radially oriented pupillary dilator muscle which is contracted by -adrenoceptor agonists causing mydriasis (an increase in pupil size). Muscarinic agonists contract the muscle fibres of the ciliary body. Contraction of the circlar ciliary muscle causes accommodation of focus for near vision.

Activation of -adrenoceptors on the ciliary epithelium facilitates the secretion of aqueous humor. Hence, the use of adrenoceptor blockers like timolol reduces the secretory activity and thus resulting in reduced intraocular pressure, providing a useful pharmacological intervention for the treatment of glaucoma.

Cornea

Canal of Schlemm Trabecular meshwork Dilator ( )

Sphincter (M)

Iris

Sclera

Lens

Ciliary epithelium ( ) Longitudinal ciliary muscle (M)

Circular ciliary muscle (M)

Fig. 2.4. A simplified schematic diagram of the structures of the anterior chamber of the eye illustrating tissues with their autonomic functions and receptors. Aqueous humor is secreted by the ciliary epithelium, flows through the anterior chamber, and exits through the canal of Schlemm (thick arrow).

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Table 2.7. A summary of the important drugs used in glaucoma Drugs or class Cholinergic agents Muscarinic agonists (pilocarpine) Anticholinesterases [physostigmine, DFP (isoflurophate)] -agonists Non-selective Adrenaline 2 -selective Apraclonidine Brimonidine

Nature of action and important remarks Improved drainage of aqueous humour by contracting the longitudinal muscle of the ciliary body leading to opening the trabecular meshwork around Schlemm s canal (drainage channels), causing immediate drop in intraocular pressure (IOP). Therefore, these drugs are used in acute glaucoma in addition to chronic open-angle glaucoma. Enhances aqueous outflow facility (drainage, α-receptors) and/or decreases production of aqueous humour by vasoconstriction of the ciliary body blood vessels leading to reduced IOP. Topical 2% adrenaline solution used in chronic open-angle glaucoma. Contraindicated in closed-angle and acute glaucomas as they dilate the pupil, dilated iris can occlude the outflow drainage pathway at the angle between the cornea and the ciliary body.

¾-blockers Decrease production of aqueous humour by the ciliary body (non-pigmented Timolol Betaxolol epithelium β 2-receptors) leading to reduced IOP. No effect on focusing for near vision or pupil size; (used in chronic open-angle glaucoma, narrow and Cartelol acute glaucoma. Metipranolol Diuretics Carbonic anhydrase Decreases production of aqueous humour by blocking carbonic anhydrase in inhibitors the ciliary body leading to reduced IOP. They are used in chronic glaucoma as Acetazolamide well as in acute closed-angle glaucoma. Osmotic agents Mannitol Reduces IOP in acute closed-angle glaucoma. Increase outflow by acting at the FP receptor and are administered as drops Prostaglandins (PGF2 derivatives: into the conjunctival sac once or twice daily. Adverse effects include latanoprost, irreversible brown pigmentation of the iris and eyelashes, drying of the eyes, unoprostone) and conjunctivitis. Note: For simplicity purposes, open-angle glaucoma = wide-angle glaucoma = chronic simple glaucoma; narrow-angle glaucoma → closed-angle glaucoma → acute glaucoma. Pupillary block glaucoma: adhesion of pupil to the lens which may occur in uveitis.

Table 2.8. A summary of selected mydriatics and cycloplegics Drug Tropicamide

Duration 3-6 hr

Fundus examination

Homatropine

1-3 days

Cycloplegic for refraction* in children

Atropine

7-10 days

For refraction as above; also iridocyclitis** (+ phenylephrine♠)

Use

They may precipitate acute glaucoma in the elderly and predisposed patients * Refraction: determination of the refractive errors of the eye and their correction by glasses ** Iridocyclitis: inflammation of the iris and the ciliary body ♠ In iritis, phenylephrine dilates the pupil, therefore, reducing the possibility of adhesion of the iris to the lens (i.e. pupillary block glaucoma). Cycloplegics reduces contraction of the circular muscle of ciliary body. Myopia: contraction of the circular muscle Phenylephrine and oxymetazoline are ¿-agonists, mydriatic, not cycloplegic; they are contraindicated in patients with closed-angle glaucoma

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a. increasing detrusor muscle contractility b. decreasing outlet resistance

Drugs used in abnormal micturition

2. Urinary disorders of storage (e.g. urinary frequency and incontinence, and nocturnal enuresis) can stem from various dysfunctions. These disorders may be due to detrusor or sphincter problems, sensory disturbances, detrusor muscle irritability (involuntary bladder contractions), secondary to neurological or inflammatory diseases, and stress urinary incontinence (sphincter dysfunction). Treatment of these disorders may be achieved pharmacologically by a. decreasing detrusor contractility b. increasing outlet resistance.

Drugs may be used to alleviate abnormal micturition. The strategy of treatment depends on the nature of disorder and principally may be achieved by two major approaches: a. altering detrusor muscle activity b. altering outlet resistance (bladder neck activity). There are two major disorders of micturition, urinary disorders of emptying and storage are common encounters. 1. Treatment of urinary retention (disorder of emptying) may be achieved pharmacologically by

Detrusor Motor: parasympathetic Sensory: sympathetic

Excitatory M-receptors

Trigone & Sphincter Motor: sympathetic Sensory: sympathetic

¾2 M

Detrusor muscle

¿1 Capsular smooth muscle

Somatic Fig. 2.5. A schematic representation of urinary bladder showing muscarinic (M) receptors being the most important excitatory receptors in the detrusor muscle; while, α1-receptors being the most important ones involved in the bladder neck function. Note: In the bladder neck, although β2-receptors and M-receptors are believed to mediate inhibitory actions, they are clinically not important.

35

Autonomic Pharmacology

Ramadi, 6 October 2009

Table 2.9. A summary of selected drugs used in micturition disorders (neurogenic bladder)

Drug Antimuscarinic agents Propantheline* Emepronium* Tricyclic antidepressants** Imipramine (Tofranil) Amitriptyline (Tryptizol) Nortriptyline (Aventyl) Oestrogens

Parasympathetic agents Bethanechol Carbachol Distigmine ¿1-adrenoceptor antagonists Prazosin (α1) Tamsulosin (α1a) 5¿-reductase inhibitor Finasteride (Proscar)

Nature of actions

Type of micturition disorder

Reduces detrusor instability

Incontinence (enuresis)

Three possible actions may be involved 1. antimuscarinic (detrusor effect) 2. blocking U1-amine re-uptake increasing sympathetic drive at bladder neck and thus outlet resistance 3. by altering sleep pattern

Nocturnal and daytime incontinence (enuresis)

Improve atrophy of urethral epithelium (given locally in vagina or systemically by mouth) Stimulate the detrusor muscle

Incontinence (in menopausal women)

Blocks α1 -receptors at capsular smooth muscle of the prostate easing outlet resistance

Benign prostatic hyperplasia (urinary frequency)

Hypotonic bladder (due to upper motor neurone lesion)

Inhibits conversion of testosterone to Benign prostatic hyperplasia the dihydrotestosterone (reducing (urinary frequency) prostatic volume by 20%, thus reducing outlet resistance resulting in increased urine flow * Propantheline and emepronium are quaternary ammonium compounds, not well absorbed from the GIT (oral bioavailability 5-10%) and their entry into the CNS is limited. On the other hand, atropine and related antimuscarinic drugs are tertiary amines, well absorbed from the GIT and enter the CNS; they therefore have a higher incidence of CNS adverse effects. ** For more details see the section on tricyclic antidepressants in CNS Pharmacology  The popular trade name in Iraq Note: In dynamic disturbances, i.e. seasonal (like in winter), α-receptor antagonists are useful; in static (glandular and usually progressive) disturbances, finasteride is useful.

36

Essentials of Medical Pharmacology

Majid A.K. Lafi

ANTIHYPERTENSIVE DRUGS Introduction

The first rule should be to treat the underlying cause in the cases with secondary hypertension with surgical therapy and to attempt normalisation by non-drug therapy. This means elimination of risk factors, obesity, salt and smoking. Dietary measures such as low calorie intake and sodium restrictions should be adhered to.

Hypertension is one of the commonest disorders, defined as a persistent diastolic blood pressure greater than 90 mm Hg that usually associated with increased systolic blood pressure greater than 140 mm Hg. Several factors may result in the development of hypertension; however, the most important is increased peripheral vascular smooth muscle tone leading to increased arteriolar resistance and reduced capacitance of the venous system. Over 90% of hypertensive patients have essential hypertension in which the blood pressure regulating mechanism is responsible for the development of secondary hypertension (<10%).

ARTERIAL BLOOD PRESSURE

Heart rate

=

Treatment of Hypertension It is principally targeted at the major factors influencing blood pressure:

CARDIAC OUTPUT

l

PERIPHERAL RESISTANCE

Filling pressure

Contractility

Blood volume

Venous tone

Fig. 3. 1. A chart showing the important determinants of arterial blood pressure. Drugs can interfere with these various factors resulting in alteration of arterial blood pressure. The principle of the treatment of hypertension is according to a step-up procedure starting with very simple means and adding additional steps if necessary. Essentially, we can use 4 steps as shown below: Prazosin, minoxidil, CNS acting drugs ACE-blockers, Ca-blockers β-blockers or diuretic or both Diet, elimination of stress, physical exercise β-blockers and diuretics are, by most physicians, considered first, either alone or in combination. Of the β-blockers there is not

4 3 2 1

much difference between the different drugs in relation to their blood pressure lowering efficacy (e.g. propranolol, metoprolol,

37

Cardiovascular Pharmacology - Antihypertensive Drugs

CNS

ACE inhibitors Captopril Lisinopril

Renal Tubules Thiazide diuretics Loop diuretics K+sparing diuretics

AT1-receptors Losartan Valsartan

1

Sympathetic Ganglia Trimethaphan

Vasomotor Centre Clonidine Methyldopa

¾1-receptors on Juxtaglomerular Cells Propranolol Atenolol

Kidney Kidney

Ramadi, 6 October 2009

5

Sympathetic 2 Nerves Adrenergic Terminals Guanethidine Reserpine

Anatomical Sites of the Action of Antihypertensive Drugs

SA Node & Myocardium Verapamil Diltiazem

Heart Blood Vessels Vascular Smooth Muscle Hydralazine Minoxidil Nitroprusside Diazoxide Ca channel blockers Thiazides

4

3

¾1-receptors Propranolol Atenolol ¿1-receptors Prazosin Phentolamine

Fig.3.2. The anatomical sites of action of antihypertensive drugs. Several antihypertensive drugs act at more than one site: β-blockers act at sites 3 and 5; thiazides act at sites 4 and 5; and calcium channel blockers act at sites 3 and 4.

38

Essentials of Medical Pharmacology

Majid A.K. Lafi

drugs are seldom used because of their anticholinergic side effects.

atenolol, or pindolol). For optimal compliance a preparation should be chosen which could be administered once daily such as atenolol or pindolol. β-blockers can act by a variety of mechanisms such as 1. Reduction in cardiac output 2. Reduction in renin secretion 3. Reduction in sympathetic (central and/or peripheral)

Centrally acting antihypertensive: these include methyldopa and clonidine reduce blood pressure by stimulating postsynaptic α2-receptors in the CNS. Reserpine acts by depleting sympathetic nerve terminals of their transmitter, noradrenaline. All of these drugs act by reducing sympathetic vasoconstrictor tone but also cause an unacceptable high incidence of mental depression and sedation.

outflow

Of the diuretics mostly thiazide have been used such as hydrochlorothiazide, bendrofluazide and chlorthalidone, a thiazide-related compound which has a longer duration of action. These diuretics act by reducing plasma volume and in part by reducing peripheral vascular resistance. The antihypertensive effect is not much enhanced by increasing the dose. The response rate to treatment with β-blockers or diuretics is about 60% and can be increased to about 80% by the combination of a β-blocker and a thiazide.

Adrenergic neurone blocking agents such as guanethidine and bretylium prevent the release of noradrenaline from postganglionic adrenergic neurones, but these drugs cause postural hypotension failure of ejaculation and diarrhoea.

¾-Blockers A special consideration is given to βblockers, as this class of drugs is a frequent encounter in clinical practice. β-blockers are competitive antagonists of catecholamines at the site of β-adrenergic receptors. This antagonist activity is dose-dependent and reversible, since an adequate concentration of catecholamines is enough to dislodge the βblockers from the receptor. β-blockers can be classified pharmacologically according to the following properties:

The next step in non-responders is the addition of a vasodilator such as captopril (ACE-inhibitor) or nifedipine (Ca-blocker). Other drugs that can be considered are the αblocker prazosin or the centrally acting drugs methyldopa and clonidine. In acute hypertension where blood pressure has to be lowered rapidly diazoxide, a thiazide without diuretic action, sodium nitroprusside, and nifedipine can be used (the latter orally, or sublingually). Of mostly historical interest are the following compounds that act by reducing sympathetic tone:

• • • •

β 1-receptor selectivity Intrinsic sympathomimetic activity (ISA) Membrane stabilising activity Pharmacokinetics

¾1-receptor selectivity

1. Ganglionic blocking drugs (e.g. hexamethonium) 2. Centrally acting antihypertensives (clonidine) 3. Adrenergic neurone blockers (e.g. guanethidine)

β-Blockers can be non-selective affecting both β1-receptors and β2-receptors, such as propranolol, pindolol, oxprenolol, timolol, sotalol and nadolol, or β1-receptors selective atenolol, acebutolol and metoprolol having little influence on β2-receptors when employed in low doses. Theoretically, β 1blockers are less likely to cause bronchoconstriction; however, clinically none of the available β 1-blockers is sufficiently selective to be safely used in asthma. The

Ganglionic blockers interrupt impulse transmission in sympathetic (but also parasympathetic) ganglia, e.g. hexamethonium or trimethaphan. These

39

Cardiovascular Pharmacology - Antihypertensive Drugs

principal practical advantage of β 1-receptor selective blockers is in diabetics. These blockers spare β2-receptors that mediate both the symptoms of hypoglycaemia and the counter-regulatory metabolic responses (glycogenolysis and glucagon secretion) that reverse hypoglycaemia.

Intrinsic (ISA)

sympathomimetic

Ramadi, 6 October 2009

difference in hepatic transformation the bioavailability is variable in different βblockers. Some of the metabolites of βblockers are pharmacologically active. Thus, propranolol forms 4-hydroxypropranolol that has β-blocking properties and a shorter plasma t than the parent compound. The degree of hepatic metabolism varies from almost 100% (propranolol, oxprenolol, alprenolol) to moderate breakdown of 5060% of the administered dose (sotalol and pindolol) to virtually no metabolism (atenolol). The elimination of β-blockers therefore varies considerably, e.g. atenolol and practolol are excreted almost entirely by the kidney and their dosage should therefore be reduced in cases with renal insufficiency. On the other hand propranolol and metoprolol are eliminated almost entirely by the liver, therefore, clearance diminishes as hepatic function decreases. Pindolol is partly eliminated by the liver and partly by the kidneys. The plasma t of propranolol and pindolol is about 3 hours but, particularly, in the case of the antihypertensive action their pharmacological effect is much longer than can be expected from plasma levels and successful control of hypertension can be achieved with once daily administration of pindolol, metoprolol and atenolol.

activity

Some β-blockers may also stimulate βreceptors (partial agonists) at the same time as they also block the effect of catecholamines. These drugs are said to be intrinsic sympathomimetic activity (ISA); pindolol, oxprenolol and acebutolol belong to this group. These drugs cause fewer falls in resting heart rate than the β-blockers without ISA, and therefore may be less effective in severe angina pectoris in which reduction in heart rate is particularly desirable. Because of fewer falls in cardiac output, these agents are less likely to produce cold extremities. However, practically all β-blockers including those with ISA, which may offer no advantage, can produce heart failure since patients with heart failure already have high sympathetic drive. Pindolol is a partial agonist on ¾-receptors, at low basal sympathetic flow it has agonistic activity, but at a high sympathetic flow it produces antagonistic activity.

Indications 1. Angina pectoris 2. Arterial hypertension 3. Cardiac arrhythmias (mainly supraventricular) 4. Secondary coronary heart disease (CHD) prevention (after infarction) 5. Migraine 6. Control of excessive β-receptor stimulation in thyrotoxicosis and phaeochromocytoma 7. Glaucoma 8. Adrenergic tremor

Membrane stabilising activity Of the β-blockers propranolol, oxprenolol, and acebutolol have membrane stabilising (quinidine-like, local anaesthetic or cardiac depressant) action (MSA). This effect is probably clinically not important except that when applied topically for glaucoma that these agents will anaesthetise the eye therefore timolol (which does not have an MSA) is used in this condition.

Adverse effects 1. Bronchoconstriction 2. AV-block and depression of cardiac contractility (congestive heart failure) 3. Cold extremities (peripheral vasoconstriction) 4. Hypoglycaemia or interference with recovery from hypoglycaemia

Pharmacokinetics Most β-blockers are well absorbed from the GIT after oral administration. Due to 40

Essentials of Medical Pharmacology

Majid A.K. Lafi

5. Sleep disturbance and nightmares (CNS effect with lipid soluble agents like propranolol) 6. Deleterious effect on plasma lipids (↓ HDL) 7. Impotence

2. Bronchial asthma 3. Diabetes 4. Renal or hepatic impairment 5. Congestive heart failure (unless it is due to tachyarrhythmia treatable with β-blockers) 6. Sinus bradycardia 7. Second and third degree heart block 8. Intermittent claudication 9. Pregnancy (foetal bradycardia and neonatal hypoglycaemia)

Cautions/ Contraindications

1. Abrupt withdrawal of β-blockers (may result in sympathetic overactivity)

Table 3.1. A summary of the pharmacological characteristics of β-blockers Drugs

Non-selective Propranolol1 Pindolol Oxprenolol Timolol Sotalol Nadolol Labetolol Esmolol3 Selective Atenolol1 Acebutolol Metoprolol

ISA

MSA

Lipid solubility

Gut absorpt ion

Liver metabolism

Bioavail ability

CNS Effect

0 + + 0 0 0 +2 0

+ 0 + 0 0 0 + 0

High Moderate + Moderate Low Low Moderate

100% 95% 95%

100% 65% 90%

30 90

+ + +

30%

0

0 + 0

0 + (0)

0

50%

0

+

100%

90%

50 90 30 30 0

Minimal

40 50 50

Minimal +

ISA = intrinsic sympathomimetic (partial agonist) activity MSA = membrane stabilising activity (quinidine-like effect, local anaesthetic effect) 1 The practical points with propranolol is being lipid soluble and undergoes hepatic metabolism while atenolol is being hydrophilic and eliminated by the kidney. 2 Partial agonist effects at 2-receptors. 3 t = 10 minutes. angiotensin (including vasoconstriction, and aldosterone release). In addition, trophic effects on cardiovascular tissues have been attributed to angiotensin II. In contrast to angiotensin AT1-receptor, AT2-receptor mediates antiproliferative actions.

ACE-inhibitors Renin, the enzyme released from the kidneys in response to β1-adrenergic stimulation converts a circulating glycoprotein (angiotensinogen) into the biologically inert angiotensin I which is eventually converted into the highly potent vasoconstrictor angiotensin II by angiotensin converting enzyme (ACE, or kininase II). ACE is located on the luminal surface of the capillary endothelial cells, particularly, in the lungs. Angiotensin II act on two G-protein coupled receptors. Angiotensin AT1-receptor accounts for all the classic actions of

Pressor actions and cardiovascular morbid changes of angiotensin II Neural mechanisms 1. Increased central flow 2. Presynaptic augmentation noradrenaline release

41

of

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Cardiovascular Pharmacology - Antihypertensive Drugs

3. Augmentation of adrenal release 4. Postsynaptic augmentation pressors Vascular mechanisms 1. Direct vasoconstriction 2. Cellular hypertrophy (chronic)

and

Ramadi, 6 October 2009

adrenaline

Indications

of

1. Heart failure (critically part of the management) 2. Arterial hypertension 3. Secondary coronary heart disease prevention (after infarction) 4. Diabetic nephropathy (postponement and diminishing proteinuria probably due to improved intrarenal hemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure; even in the absence of lowering of blood pressure) 5. Vascular changes and cardiac hypertrophy of hypertension (reversal)

other

hyperplasia

Cardiac mechanisms 1. Hypertrophy and fibrosis (associated with congestive heart failure and myocardial infarction) Other volume-related mechanisms 1. Aldosterone release modulation 2. Vasopressin (ADH) release modulation 3. Increased thirst 4. Increased dietary salt intake (salt-craving)

Adverse effects 1. Taste changes 2. Persistent dry cough (bradykinin related) 3. Liver damage 4. Reversible renal impairment in patients with bilateral renal artery stenosis 5. Proteinuria [associated with minimal changes in kidney basal membranes and is reversible after stopping captopril in most but not all cases, an SH-group related autoimmune (vascular) reaction] 6. Hyperkalaemia 7. Agranulocytosis 8. Stomatosis (like aphthous ulcers) 9. Abdominal pain 10.Angioneurotic oedema (may be due to bradykinin accumulation)

The angiotensin converting enzyme (ACE, a non-specific dipeptidase) inhibitors such as captopril act, at least partly, by blocking the vasoconstrictor and aldosterone releasing effects of angiotensin II. Further, bradykinin, a vasodilator is broken down by ACE, which might add to the blood pressure lowering effect. It is believed that either bradykinin or a neurokinin (e.g. substance P) may cause cough. Generally, ACE inhibitors are renally eliminated. Sensitivity to these agents is likely in patients on high dose diuretics or with renovascular hypertension or in the elderly.

ACE inhibitors, the prototype being captopril (t 2hr), have a useful vasodilator with potassium-sparing action being useful in heart failure. Their reduction of mortality in heart failure is, probably, due to their being the only vasodilator that does not reflexly activate the sympathetic system. This absence of reflex tachycardia may be due to downward resetting of the baroreceptors and/or enhanced parasympathetic activity.

Cautions 1. When first administered should be under close observation (because of angioedema and first dose syncope)

Contraindications 1. Pregnancy toxicity)

(because

of

foetal

renal

A newer generation of ACE inhibitors (including enalapril and lisinopril with longer

42

Essentials of Medical Pharmacology

Majid A.K. Lafi

t

than captopril) has been developed with fewer adverse effects compared to those observed with captopril. This is probably due to the lack of the sulphydryl group that is present in captopril. Proteinuria is less likely to be encountered with the newer agents. Most studies have shown little difference in efficacy provided the dose was optimised.

Centrally acting drugs Clonidine (α2-receptor agonist) and methyldopa (false transmitter) exert their effect mainly by stimulating central postsynaptic inhibitory α2-adrenoceptors located on sympathetic neurones leading to a deceased outflow of sympathetic nerve impulses. Methyldopa after being taken up into adrenergic nerves is eventually converted into methylnoradrenaline when released it activates postsynaptic inhibitory α2adrenoceptors more potently than noradrenaline. Methyldopa and clonidine may also exert peripheral inhibitory action on the release of noradrenaline from sympathetic endings. Most of the long list of centrally and peripherally mediated adverse effects of methyldopa may be explained by its action on α2-receptor.

Captopril renogram: The appearance of sudden anuria or azotaemia after the administration of ACE inhibitors is an extremely important sign that may signify renal artery stenosis. An acute dose of ACE inhibitor can be used as a standardised test (captopril renogram) for an acute decrease in GFR, which is usually indicative of renal artery stenosis. Losartan is the first AT1-receptor antagonist to be used clinically. Much lower profile of adverse effects has been reported compared with that of ACE inhibitors. Certainly, it does not cause dry cough, therefore at present, it is used in patients who develop cough with ACE inhibitors.

USEFUL NOTES Postural hypotension is generally produced by vasodilators that have considerable effect on veins. Therefore, postural hypotension is not usually a problem with agents that have little or no vasodilatory effect on veins.

Other vasodilators Hydralazine reduces vascular resistance in all peripheral vascular beds including the kidney. Adverse effects are mainly connected to a lupus erythematosus like syndrome. The incidence is dose related and the syndrome is almost always reversible when hydralazine is stopped. Blood dyscrasias and peripheral neuropathy may occur.

The compensatory baroreceptor-mediated sympathetic discharge induced by the druginduced hypotension causes tachycardia and increased cardiac output, even causing angina pectoris in predisposed subjects. This can be overcome by the use of β-blockers.

Prazosin exerts its vasodilatory effect by blocking postsynaptic α1-receptors. Prazosin may be used in combination with diuretics or β-blockers. Adverse effects are mainly observed initially if a high dose (first dose) is administered and are manifested by hypotension and collapse.

An increase in intravascular capacity, as a result of vasodilatation, usually leads to compensatory increase in blood volume and thus resulting in loss of effect (tolerance). This can be overcome by the use of a diuretic.

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Majid A.K. Lafi

Table 3.3. A summary of selected antihypertensive agents, their adverse effects and important remarks; the site of vasodilatation is predominantly arteriolar (A), venular (V) or combined A & V. Drug

¾-blockers

Drug action

Propranolol Pindolol1

β-blocker β-blocker ISA)

Atenolol1 Labetalol

β-blocker α and β-blocker

(with

Selected adverse effects and important remarks Bronchoconstriction, impotence, cold feet & hands Believed to be suitable in pregnancy (less incidence of sinus bradycardia) & less deleterious effect on lipid profile Bronchoconstriction, impotence, cold feet & hands Bronchoconstriction

Vasodilators Captopril (A&V)

ACE-blocker

Nifedipine (A)

Ca-antagonist

Amlodipine (A)

Ca-antagonist

Diltiazem (A) Verapamil (A)

Ca-antagonist Ca-antagonist

Prazosin (A&V)

α1-blocker

Phenoxybenzamine (A&V)

α1& α2-blocker

Phentolamine (A&V) Hydralazine (A) Nitroprusside (A&V)

α1& α2-blocker Increases cGMP NO-donor

Diazoxide (A) Minoxidil (A)

K-channel agonist K-channel agonist

Metallic taste, renal impairment in bilateral renal stenosis, persistent dry cough, hyperkalaemia, proteinuria, agranulocytosis Hypotension, ankle oedema, tachycardia, headache, constipation; withdraw in ischaemic pain, use with βblocker and diuretics Similar to nifedipine except much longer t (40h) permitting the same benefits as the longest-acting formulations of nifedipine without requiring a special formulation. Hypotension, dizziness, flushing, bradycardia Hypotension, myocardial depression, constipation, dependent oedema Postural hypotension, syncope (no secondary reflex tachycardia) Postural hypotension, secondary reflex tachycardia, nasal congestion, ejaculatory failure; as β-receptors unopposed use β-blocker in phaeochromocytoma Hypotension, tachycardia Reflex tachycardia, fluid retension, SLE-like syndrome Severe postural hypotension, cyanide toxicity, palpitation Diabetogenic, fluid retention (oedema, use a diuretic) Hirsutism, fluid retention, tachycardia (use a diuretic & β-blocker)

Diuretics Hydrochlorothiazide Chlorthalidone Frusemide

Centrally acting Clonidine Methyldopa1

Saluretic Saluretic α2-stimulation α2-stimulation

Hypokalaemia, hyperuricaemia, hyperglycaemia Hypokalaemia, hyperuricaemia, hypotension, ototoxicity

hypercalcaemia, hyperglycaemia,

Sedation, severe withdrawal syndrome Sedation, dry mouth, depression, diarrhoea, oedema, impotence (probably secondary to depression), SLE, Parkinsonism, liver damage (chemical hepatitis), gynaecomastia, haemolytic anaemia2

1

These drugs are suitable in pregnancy Methyldopa combines with a protein in the body so that the body no longer recognises the protein as self and thus forming antibodies (type II reaction) that combine with the antigen and activate complement that damages cells (haemolysis occurs). Similar events may occur with penicillin-induced haemolytic anaemia. 2

45

Cardiovascular Pharmacology - Antianginal Drugs

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ANTIANGINAL DRUGS Introduction

Antianginal Agents

Angina pectoris (angina, a strangling; pectoris, of the chest) is defined as sudden pain beneath the breastbone, often radiating to the left shoulder and arm. Anginal pain is precipitated when the oxygen supply to the heart is insufficient to meet the heart’s oxygen demand. Most frequently, anginal pain occurs secondary to atherosclerosis of the coronary arteries; hence, angina should be seen as a symptom of a disease and not a disease in its own right.

Three groups of drugs are used in the treatment of classic angina (all of which relieve the pain by decreasing the oxygen need of the heart): 1. Organic nitrates (e.g. nitroglycerin) 2. -adrenoceptor blockers (e.g. propranolol) 3. Calcium antagonists (e.g. nifedipine) Variant angina pectoris is caused by spasm of the coronary arteries. Thus, pain is secondary to insufficient oxygenation of the heart. Unlike classic angina, the symptom of which may occur primarily in response to exertion, variant angina can produce pain at rest or even sleep. Some individuals may have both classic and variant forms of angina pectoris.

Angina pectoris has two major forms: 1. Classic angina (exertional angina or angina of effort) 2. Variant angina (Prinzmetal’s or vasospastic angina)

Objectives of Treatment

Two groups of drugs are employed in the treatment of variant angina (both of which act by decreasing coronary spasm):

Symptomatic treatment of angina pectoris can include the following aspects:

1. Calcium antagonists (e.g. nifedipine) 2. Organic nitrates (e.g. nitroglycerin)

1. Reduction in the workload (oxygen demand) of the heart 2. Coronary vasodilatation (increases oxygen supply to the heart)

Nitrates Nitrates are nitrous acid esters of polyalcohols such as glycerol. The most common is nitroglycerin or glyceryltrinitrate (GTN). GTN has been used to treat angina since 1879 and still remains the drug of choice. It is the same substance that is contained in dynamite. GTN requires glutathione-S-transferase for denitration and donation of NO. The latter enzyme is present in the venous tissue more than the arterial tissue. Therefore, GTN is being more a venular than arteriolar vasodilator. On the other hand, sodium nitroprusside spontaneously (non-enzymatically) release NO in aqueous solution. It is considered as both venular and arteriolar vasodilator. Biologically, constitutive nitric oxide synthase (cNOS) producing nitric oxide (NO) which diffuses freely into the adjacent vascular smooth muscle cells, in turn, causing

In normal subjects, as cardiac demand rises, coronary arteries dilate, thereby keeping oxygen supply and oxygen demand in balance. In subjects with coronary artery disease (CAD), the diseased arteries are unable to dilate; hence, blood flow cannot increase to meet increased oxygen demand resulting in anginal pain. Since the underlying cause of classic angina is physical obstruction of the coronary vasodilatation and hence no increase in cardiac oxygen supply. Therefore, the primary way by which decreasing oxygen demand can relieve the pain of classic angina.

46

Essentials of Medical Pharmacology

Majid A.K. Lafi

an increase in intracellular cGMP and hence vasodilatation.

of benefit to patients suffering from angina pectoris, but in cardiac insufficiency inhibition of normal sympathetic drive may induce failure. They should not be used in variant (spastic) angina, where it might aggravate coronary vasoconstriction.

The beneficial effect of nitrates is exerted in part by its venodilator effect that results in blood pooling on the venous side thus reducing venous return, central venous pressure and cardiac preload. Dilatation of coronary arteries is probably less important. This means that the clinical effect of nitrates has to do with energy and oxygen sparing properties (through reduction of cardiac work). But a fall in blood pressure induces a rise in heart rate.

Table 3.4. Different types of nitrates Preparation Nitroglycerin (glyceryl trinitrate) Isosorbide dinitrate Pentaerythritol tetranitrate Amyl nitrite (inhalant) Na nitroprusside 0B

Organ nitrates are rapidly broken down in the liver (oral bioavailability is less than 10%) to mononitrates. Therefore, organic nitrates are mostly given sublingually where they are easily absorbed through the buccal mucosa. Other routes of administration are transdermal absorption when applied as an ointment to the skin.

Duration 1B

Dose 2B

1-30 min

0.5 mg

2-60 min 10 min to 5 hr (oral)

5-10 mg

1-5 min

20 mg

20 mg

Instantaneously (i.v)

Calcium Channel Blockers Myocardial cell depolarisation is accomplished by a rapid inward current of sodium ions (Phase 0). This is followed by a plateau (Phase 2) during which there is a slow inward movement of calcium ions through separate membrane channels. Calcium channels have voltage-dependent gates on the outside and enzyme dependent gates on the inside. The inward current of calcium ions triggers the release of stored intracellular calcium, which couples the excitation process with muscular contraction. Therefore, calcium blockers inhibit calcium movement, which weakens the contractile process and affects automaticity and conduction, mainly from the atrium to the ventricle. Ca-blockers do not appear to affect calcium dependent neural activity. Presently, the most commonly used Ca-blockers are nifedipine, diltiazem, and verapamil.

Adverse effects 1. Throbbing headache (through dilatation of extra-cranial arteries) 2. Methaemoglobinaemia (It is due to transformation of ferrous iron to ferric iron of haemoglobin. Only with large doses of nitrates there is a significant production of methaemoglobin which has low affinity for O2 and which may be responsible for hypoxia. This adverse effect can be useful in cyanide poisoning since methaemoglobin has a high affinity for the CN- ion that will be detached from cytochrome; thus, cyanmethaemoglobin is formed which can be detoxified with sodium thiosulphate). Tolerance develops to both the therapeutic effect and the adverse effects. Tolerance to headache comes rather quickly but the therapeutic effect to angina pectoris largely remains.

Nifedipine, the prototype of the dihydroperidines and unlike verapamil, has negligible effects on cardiac conduction and a major action to lower peripheral vascular resistance. Hence, in addition to decreasing coronary spasm, it may be used to decrease afterload and to lower blood pressure. Because of the pronounced vasodilatory effect, its use is associated with side effects of headache, reflex tachycardia. Nifedipine (t½ 2h) is eliminated by the liver, and it has a bioavailability approaching 50%.

-Blockers By blockade of 1-receptors, -blockers slow heart rate and by opposing the response to stress and exercise in ischemic heart disease they have an ‘oxygen sparing’ effect. This is 47

Cardiovascular Pharmacology - Antianginal Drugs

Ramadi, 6 October 2009

Amlodipine is characterised by a much longer t½ (40 h) permitting the same benefits as the longest-acting formulations of nifedipine without requiring a special formulation. This makes amlodipine not suitable for emergency reduction of blood pressure where dose adjustment is required. There is less reflex tachycardia with amlodipine, presumably because its long t½ produces minimal peaks and troughs in plasma concentrations.

3 to 5 hours that mandates dosing 3 to 4 times per day. Diltiazem has pharmacological properties that are essentially intermediate between those of nifedipine and verapamil. It has less effect on cardiac conduction than verapamil and less vasodilatation than nifedipine. Similarly to the other calcium antagonists, diltiazem is eliminated by the liver, with a t½ of about 4 hours. It has an active metabolite that probably contributes little to its activity.

Dihydropyridines may differ in their potency in different vascular beds. Such difference in potency is claimed for nimodipine to be particularly selective for cerebral blood vessels and hence is preferred for prevention of ischaemic neurological damage following subarachnoid haemorrhage.

Indications 1. Supraventricular arrhythmias (verapamil, not nifedipine) 2. Angina pectoris (especially variant angina) 3. Hypertrophic cardiomyopathy 4. Acute arterial hypertension 5. Raynaud’s disease (nifedipine) 6. Prevention of ischaemic neurological damage following subarachnoid haemorrhage (nimodipine) 7. Migraine

Verapamil is used most frequently for its ability to slow conduction through the AV node and, as such, has become the agent of choice in most cases of supraventricular tachyarrhythmias. In addition, it has been used successfully in all forms of angina and can be an effective antihypertensive drug. For use in this latter setting, the effects on cardiac conduction may be unwanted.

Cautions 1. Combination of verapamil with drugs that also depress nodal tissues such as digoxin and -blockers (risk of asystol).

Verapamil is eliminated by the liver, and has a substantial first-pass effect. Its bioavailability is only about 20%, and a t½ of

Table 3.5. A summary of the pharmacological effects of calcium channel blockers Drug 5B

Coronary vasodilatation 6B

Peripheral vasodilatation

Negative Inotropy

7B

Slow AV Conduction

8B

3B

Nifedipine +++ +++ Diltiazem +++ + Verapamil +++ ++ + Mild, ++ moderate, +++ pronounced, - negligible

+ +

9B

4B

+ ++

Cardiac Sodium Channels + ++ 10B

Table 3.6. Aim of therapy: to achieve oxygen demand-supply balance in the myocardium in angina pectoris determinants of myocardial oxygen consumption. ( increase, decrease and no change) Parameter

Nitroglycerin A

Nifedipine B

Heart rate Contractility Preload Afterload Coronary Tone arteries Flow

48

Propranolol C

Combination of B and C

Essentials of Medical Pharmacology

Majid A.K. Lafi

DRUGS FOR CONGESTIVE HEART FAILURE increase in sympathetic tone may lead to useful and harmful consequences.

Congestive Heart Failure Congestive heart failure is characterised by an inability of the heart to pump blood in amounts that are sufficient to meet the metabolic needs of tissues. This is primarily due to a reduction in the contractile force of cardiac muscle, hence, a reduction in cardiac output seen in CHF. The underlying mechanisms responsible for this reduction in muscle contractility are still not clearly understood.

1. Positive chronotropic and inotropic effects that may lead to increased cardiac output and in turn improved tissue perfusion. 2. Elevation of venous tone that increases venous return to the heart and thus increases filling of the heart (according to Starling’s law) and in turn enhances cardiac output. However, an excessive increase in venous tone may lead to pulmonary and peripheral oedema and certainly these effects are undesirable. 3. Elevation in arteriolar tone which, on one hand, increases perfusion of vital organs (an effect which is highly desirable); on the other hand, an increase in arteriolar pressure will require the heart to pump against greater resistance. Because of the inability (low reserve) of the heart to increase the contractile force to meet this challenge (increase in arteriolar pressure), cardiac output may decline; an effect which is certainly undesirable.

Physiological Changes to Reduced Cardiac Output In response to reduced ability of the heart to pump blood in sufficient amount to meet the body requirement, the body undergoes certain adaptive physiological changes in order to improve tissue perfusion; however, some of these changes aggravate existing problems of CHF.

Water retention and increased blood volume

Cardiac dilatation Reduced contractility of the cardiac muscle lowers the amount of blood ejected during systole (reduced stroke volume), resulting in a rise in end-systolic volume. Further, increased preload increases diastolic filling, which causes even further expansion of the heart. This increase in heart size helps to improve cardiac output. According to Starling’s law, the force of ventricular contraction is a function of ventricular muscle fibre length.

Water retention may result from: 1. Reduced cardiac output leads to reduced renal blood flow which in turn leads to reduced urine production and thus water retention. 2. Reduced renal blood flow will induce the kidney to release renin that enhances the production of angiotensin; the latter in turn promotes the production of aldosterone. Aldosterone acts on the kidney causing reabsorption of sodium and water.

Increased sympathetic discharge

Cardiac Inotropic Drugs

As the heart fails the cardiac output decreases resulting in a fall in arterial blood pressure which is detected by baroreceptors and relayed to the vasomotor centre; the latter causes an increase in sympathetic discharge to the heart, veins, and arterioles. This

In 1775 Dr William Withering, an English physician from Birmingham, learnt that a dropsical women (his patient), whom he thought she would die, recovered a few weeks later. He enquired into the cause of her 49

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recovery, and found that she took a herb tea containing foxglove (Digitalis lanata). He began to investigate its properties, trying it on the poor of Birmingham, whom he used to see without fee each day. Ten years later (1785), Withering wrote an accurate account in which he defined the type of patient who might benefit from it, standardised his foxglove leaf preparations with dosage schedules. This account would still serve today after more than 200 years.

Mechanism of Action The cellular mechanism of action seems to be related to an increase in the labile calcium fraction in the sarcoplasmatic reticulum of the myocardial cell by inhibiting the Na-K ATPase. Another effect of digitalis on the heart is indirect through activation of the vagus. The excitatory effect of digitalis on the heart shortens the action potential (QTinterval) and therefore, shortens the refractory period in the atria and the ventricles. The diuretic action of digitalis is almost entirely due to its effect on cardiac output and the consequent improvement of glomerular filtration pressure.

The cardiac glycosides consist of two parts: a glycone and an aglycone. The glycone is a sugar that has no cardiac action, but makes the glycosides more soluble and is essential for fixation to the cardiac muscle fibres. The aglycone contains the active principle that is a steroid (similar to bile and sex hormones) to which a lactone ring with a double bond is attached.

Pharmacokinetics Absorption of different cardiac glycosides varies considerably; digoxin and digitoxin have a high bioavailability. The bioavailability of the lanatosides is poor and should, therefore, be given intravenously.

O

OH CH3 O

The choice of digitalis preparation depends mainly on pharmacokinetic difference and not so much on specific inotropic action on cardiac muscle and cardiac toxicity that is rather similar with various cardiac glycosides. The below table shows the important pharmacokinetic properties of digoxin and digitoxin.

CH3 OH

Sugars O 3 sugars digitoxoses

Steroid Nucleus

Lactone Ring

The inotropic drug of first choice, which can be used for most conditions, is a preparation that can be administered both i.v. and orally. These requirements are met by digoxin that is excreted unchanged by the kidney function, a factor which has to be considered especially with the age-related reduction of glomerular filtration and hence the risk of intoxication. Digitoxin is mostly metabolised in the liver by microsomal enzymes the activity of which is increased by barbiturates and phenytoin.

Fig.3.3 . Structure of the cardiac digoxin

Cardiac glycosides are mainly derived from plant products such as the purple foxglove (digitalis purpurea: digitoxin) or the white foxglove (digitalis lanata: digoxin) or Strophantus gratus: ouabain. Digitalis has very little effect on the normal heart. There is marginal slowing of sinus rhythm, but in higher doses AV-block and ventricular extrasystoles (VES) may be induced. The actions of digitalis on the heart are: 1. Positive inotropic (increases force of contraction) 2. Negative chronotropic (reduces heart rate, vagal) 3. Negative dromotropic (slows AV conduction, vagal) 50

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Majid A.K. Lafi

(Na-pump) Na/K-ATPase K

Glycosides

+

Inhibition of (Na-pump)

Na+ Ca

Intracellular Na+

++

Na/Ca-exchange Intracellular Ca++ Myocardial Cell Contraction Fig.3.4 . A schematic representation of inotropic action of glycosides like digoxin

Table 3.7. Pharmacokinetic parameters of digoxin and digitoxin Drug 0B

Onset (min) i.v. oral

Plateau 1B

Dose (mg)

Therapeutic serum level

Bioavail -ability

Renal excretion 80%

2B

Digoxin

15

45

7 days

0.25

0.5-2.0 ng/ml

75%

Digitoxin

-

120

2 weeks

0.1

14-26 ng/ml

>90 20% Digitoxin Oral

Digoxin (Oral) (i.v.) 3B

Total digitalising dose (mg) administered in divided doses

4B

5B

0.75-1.25

0.8-1.0

6B

7B

8B

9B

1.2-1.6

Indications Therapeutic Control

1. Atrial fibrillation (vagal effect on the AVnode) 2. Paroxysmal supraventricular tachycardia (vagal effect on the SA and AV-nodes) 3. Cardiac failure

Digoxin is the glycoside marketed in Iraq. Therefore, the following account holds for digoxin. The maintenance dosage should be adjusted individually according to the clinical response. Determination of plasma concentrations can be used additionally since there is considerable variation in the response pattern of the patient (i.e. depending on age, electrolyte and thyroid status). Blood samples should be taken a minimum of 6 hours after the last dose in order to avoid the absorption peak. In patients with atrial fibrillation (without AV-block) dosage can usually be adjusted according to heart rate.

Adverse effects 1. Abnormal cardiac rhythm (e.g. ventricular ectopic beats) 2. GI effects (e.g. anorexia, vomiting, and diarrhoea) 3. Visual effects (e.g. disturbances of colour vision, photophobia and blurring) 4. Gynaecomastia 5. Mental effects (e.g. confusion, agitation, nightmare and acute psychoses) 51

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metabolised by COMT. It has a very brief duration of action.

Cautions/ contraindications

Dobutamine

1. Hypokalaemia 2. Hypercalcaemia 3. AV-block II – III (unless treated with pacemaker) 4. Impaired renal function (age-related) 5. Hypothyroidism 6. Conditions may lead to increased Nainflux (e.g. electrical cardioversion, acute myocardial infarction)

Dobutamine is a new synthetic drug that is a 1-receptor agonist showing greater inotropic than chronotropic effects on the heart. It also has some -receptor activity (but less than that with dopamine). It may be useful in shock and in low output heart failure (in the absence of severe hypertension).

Dopexamine Note: Acute digoxin poisoning produces nausea, vomiting and hyperkalaemia.

Cardiac insufficiency can be treated not only by cardiac glycosides but also by other inotropic drugs such as catecholamines, glucagon, dopamine, isoprenaline, dobutamine, dopexamine, xanthines and phosphodiesterase inhibitors.

This synthetic catecholamine is claimed to have positive inotropic action (being a cardiac 2-receptor agonist). It also exhibits some D1-receptor agonistic activity (thus, renal vasodilatation). This agent also appears to have inhibitory activity on noradrenaline reuptake, hence, increasing the synaptic availability of noradrenaline and thus, the stimulation of cardiac 1-receptor. It is useful in low output heart condition.

Dopamine

Bipyridine derivatives

Dopamine occurs as the natural precursor of noradrenaline; in low doses, it stimulates D1receptors causing renal, mesenteric and coronary vasodilatation. Hence, dopamine may lead to an increase in glomerular filtration rate and urine production. At higher doses, dopamine progressively increases heart rate and force by directly stimulating 1-adrenoceptors and indirectly releasing neuronal noradrenaline, which in turn activates Further, still 1-adrenoceptors. higher doses stimulate -adrenoceptors, causing a rise in blood pressure with a decrease in blood flow to vital organs including the kidneys.

The representative agents of this group are amrinone and milrinone. They produce their inotropic activity by selectively inhibiting phosphodiesterase III (cAMP phosphodiesterase) resulting in an increase in tissue cAMP and presumably not cGMP. Catecholamines and xanthine derivatives [caffeine, theophylline ethylenediamine (aminophylline)], however, enhance the availability of both cAMP and cGMP. Bipyridine derivatives appear to have a superior feature that they produce smaller positive chronotropic effects compared to catecholamines and xanthine derivatives and hence lower potential to cause arrhythmias. In chronic heart failure, it is essential for inotropic agents used that they do not have positive chronotropic effects because these effects reduce the energetic efficiency of the failing heart by adding an additional burden.

Other Inotropic Drugs

Isoprenaline It is a potent non-selective -receptor agonist with no or little -receptor actions. It reduces peripheral resistance, mean and diastolic blood pressure but systolic blood pressure and renal blood flow may rise due to increased cardiac output. Isoprenaline is

Diuretics Diuretics are used, alone or with other agents like glycosides, in congestive heart failure to reduce blood volume. Hence, these agents 52

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can decrease pulmonary and peripheral oedema, and in turn reduce cardiac dilatation. (For a detailed account see the section on diuretics) Thiazides (Hydrochlorothiazide) Loop diuretics (Frusemide, bumetanide) Potassium-sparing agents (spironolactone, triamterene)

Vasodilators A new approach to the treatment of cardiac insufficiency is by using vasodilator drugs in order to ‘unload’ the failing ventricle. The response to vasodilator therapy can be considered under two headings: to reduce Preload Afterload Vasodilatation of peripheral arterioles reduces left ventricular work, i.e. afterload, as systolic ventricular wall tension, a major component of myocardial oxygen consumption, is reduced. This leads to a secondary increase in cardiac output. A vasodilatation on the venous side will increase the volume of blood held in this part and will shift blood from the pulmonary veins to the systemic venous compartment. A consequent fall in left ventricular filling pressure, i.e. preload will favour an improved coronary blood flow (as a result of reduced diastolic ventricular wall tension, thus, reduced mechanical compression on coronary arteries). Vasodilator drugs used for this purpose include: ACE-inhibitor (captopril, critical part of the management) Arterial dilators (hydralazine) Venous dilators (nitrates) For a detailed account see the section on antihypertensive agents.

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ANTIARRHYTHMIC DRUGS arrhythmias. Further, cardiac cells that do not normally produce automaticity, e.g. atrial and ventricular muscle, can develop automaticity.

Some Pathophysiology A cardiac arrhythmia (dysrrhythmia) is an abnormality in the rate or regularity of the heart beat. In this section, tachyarrhytmias (arrhythmias that increase heart rate) are considered. Mild arrhythmias may occur without substantial effects on cardiac output: however, very severe arrhythmias can bring the heart into a halt that no blood is pumped at all. Thus, arrhythmias can be associated with a high degree of morbidity and mortality.

In the SA node, an increased sympathetic drive may increase automaticity to the degree that results in tachycardia; however, an increase in parasympathetic drive may decrease automaticity to the degree that results in bradycardia. Upon injury or an increase in sympathetic drive, Purkinje fibres can undergo a sufficient degree of increase in automaticity that these fibres can escape control by the SA node; thus, serious arrhythmias may result.

Drug treatment of cardiac arrhythmias must not be initiated without good indications, and the risk versus benefit ratio must be carefully considered since the drugs are toxic. It is not always necessary to restore sinus rhythm. The indications for antiarrhythmic treatment depend on both the patient s symptoms and the prognostic implications of the arrhythmia. The presence or absence of underlying heart disease is of major importance. Thus a patient with previous myocardial infarction and mild symptoms from recurrent ventricular arrhythmias merits treatment, while the same symptoms in another patient with a normal heart may not.

In certain conditions, contractile cardiac cells like atrial or ventricular cells can be made capable of spontaneously firing action potentials at a rate exceeding that of the SA node thus resulting in arrhythmias.

Alteration in conduction AV block It is reduced conduction through the AV node may result in varying degree of AV block. If the conduction of impulse is delayed, but not prevented, then this is described as a first degree block. Further, in second degree block, some impulses pass through the AV node, but others do not. While, in third degree block, all traffic through the AV node stops.

Cardiac arrhythmias may arise from two main disturbances in: 1. Automaticity 2. Conduction

Reentrant activation

There are several factors that may results in disturbances in automaticity and/or conduction including hypoxia, electrolyte imbalance (hypokalaemia), cardiac surgery, reduced coronary blood flow, myocardial infarction, and some drugs (e.g. digoxin).

Arrhythmias can be produced by recirculating activation of impulses, which can occur as a result of cardiac tissue injury (myocardial infarction). These reentrant impulses are capable of establishing localised, selfsustaining circuits causing repetitive cardiac stimulation. Specific drugs can stop these reentrant impulses, and thus suppression of arrhythmias.

Alterations in automaticity Cardiac cells like those of the SA node, AV node, and His-Purkinje system, are normally capable of automaticity (spontaneously firing action potentials); if the normal discharge of these cells changes, they can produce

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proved ineffective then digitalis can be used to reduce the passage of impulses from the atria to the ventricles.

Common arrhythmias Supraventricular arrhythmias

Ventricular arrhythmias

Arrhythmias that arise in areas of the heart located above the ventricles. Generally, these arrhythmias are not dangerous unless the atrial impulses can express an impact on the ventricular function by passing through the AV node, resulting in excitation of the ventricles. Thus, when dealing with supraventricular arrhythmias, the treatment is primarily directed at blocking impulse conduction through the AV node.

Ventricular arrhythmias are very likely to cause disruption to cardiac output, thus, they are far more serious than supraventricular ones. Hence, treatment should be directed at completely abolishing of the ventricular arrhythmias.

Premature ventricular contractions Ectopic ventricular foci (single focus or multiple foci) produce premature ventricular contractions (PVCs) that are beats occur before they should do in the cardiac cycle. PVCs are treated only when there is a presence of a concurrent cardiac disease like acute myocardial infarction, as in this condition PVCs predispose the patient to ventricular fibrillation (PVCs are not usually treated) the drug of choice is lidocaine; alternatively, procainamide may also be useful.

Supraventricular tachycardia Supraventricular tachycardia (SVT) can be initiated by ectopic focus located in the atria or in the AV node. Heart rate is increased to between 150-250 beats/min. SVT may be treated by vagotonic manoeuvres, however, if not successful a drug therapy (i.v. verapamil) can then be instituted.

Atrial flutter

Ventricular tachycardia

Atrial flutter is caused by an ectopic atrial focus discharging at a rate of 250-350 times/min. However, the ventricular rate is considerably less than this as the AV node cannot conduct impulses at such high rate. DC cardioversion is the treatment of choice in this arrhythmia. If DC cardioversion is ineffective then drug therapy is pursued; digitalis is the drug of choice, however, verapamil or propranolol can also be effective upon acute attacks. Prophylactic use of quinidine can prevent recurrence of atrial flutter.

Ventricular tachycardia arises from a single, rapidly firing ventricular ectopic focus. The focus drives the ventricle at a rate of 150-250 beats/min. because the ventricles cannot pump efficiently at these rates, immediate treatment must be started. DC cardioversion is the treatment of choice, if cardioversion is ineffective, lidocaine must be administered. If the latter is also ineffective then use bretylium. Ventricular fibrillation

Atrial fibrillation

Multiple ventricular ectopic foci with asynchronous discharge initiate uncoordinated (chaotic) contractions resulting in cessation1 of the pumping action of the heart. In the absence of blood flow the patient becomes unconscious and cyanotic. The heart function should soon be restored otherwise death of the patient will follow. DC

Atrial fibrillation is initiated by multiple ectopic foci firing in random order, and each focus stimulates only a small area of smooth muscle. This uncoordinated excitation leads to a highly irregular atrial rhythm traverse through AV node, ventricular rate will increase, otherwise, it will remain near normal. Treatment of atrial fibrillation is the same as that for atrial flutter; DC cardioversion is the preferred choice, if

1

If not already done, give oxygen and establish i.v. line; continue cardiopulmonary resuscitation care.

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Cardiovascular Pharmacology - Antiarrhythmic Drugs

cardioversion should counteract fibrillation and if cardioversion is not effective then administer lignocaine, and if the latter proved to be ineffective then use bretylium.

Ramadi, 6 October 2009

Class Ia This sub-group includes quinidine, procainamide and disopyramide, which are useful for the control of broad spectrum of arrhythmias, both ventricular and supraventricular. These drugs have very similar effects on supraventricular and ventricular arrhythmias. All have been used successfully for the prophylactic treatment of arrhythmias including atrial fibrillation and flutter after DC conversion. If administered alone they may produce an acceleration of the heart rate (ventricular rate). This is due, in part, by the drug-induced reduction of atrial rate and hence reduction of impulses blocked in the AV node (at higher atrial rates, there is a traffic jam at the AV node when this jam eased, the traffic passes much easier). The other reason is because of vagolytic properties, which accelerates AV-conduction. Therefore, these drugs are commonly administered together with digitalis in the treatment of atrial fibrillation and flutter. The Ia drugs are also effective in ventricular ectopic beats and in prophylaxis of recurrent ventricular tachycardia or fibrillation.

Digitalis produced arrhythmias Digitalis-induced arrhythmias can be produced from a combination of increased automaticity in atrial and ventricular tissue together with decreased conduction through the AV node. Thus, digitalis glycosides by both disturbing automaticity and conduction, they can produce varying degrees of AV block, and also the dangerous ventricular arrhythmias. If drug treatment is required then the drugs of choice are lidocaine and phenytoin. In these patients, DC cardioversion may precipitate ventricular fibrillation because the latter increase sensitivity to digitalis.

Antiarrhythmic Drugs The most widely used classification is that by Vaughan-Williams, based on electrophysiological actions of the drugs. This has limitations when applied clinically but it is useful for the discussion of antiarrhythmic agents. The currently available drugs are divided into four main classes.

Quinidine Quinine has been prescribed for palpitations since the 18th century. It was largely replaced by its d-isomer, quinidine. Quinidine is administered orally, it is usually prescribed as a long-acting preparation (e.g. Kinidin Durules , two to four tablets every 12 hours). This produces reasonably constant blood levels for about 12 hours. As with all antiarrhythmic therapy, it is advisable, where possible, to adjust the dosage according to serum drug levels.

Class I Class I Drugs block the fast inward sodium current, responsible for the rapid upstroke (Phase 0) and conduction of the normal action potential. This is also known as a local anaesthetic or membrane-stabilising action. In addition, all class I agents depress abnormal automaticity by slowing the rate of the abnormal phase 4 (diastolic) depolarisation.

Adverse-effects 1. Hypotension 2. Bizarre ventricular arrhythmias 3. Cinchonism (tinnitus, deafness, blurred vision, diplopia, diarrhoea, headache, confusion) 4. Thrombocytopenia 5. Fever

Class I drugs include some of the longest available and well tested antiarrhythmics, like quinidine and lidocaine, but also new agents such as flecainide. Class I drugs have been further sub-divided into Ia which prolong, Ib which shorten, Ic which have no effect on action potential duration.

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Table 3.8. A summary of antiarrhythmic drugs based on Vaughan-Williams classification

Class

I. Sodium Channel Blockers

Action

Indications

Slow impulse conduction*

a. Quinidine Procainamide Disopyramide

Prolong action potential duration & refractoriness

b. Lignocaine

Shorten action potential duration & refractoriness

Mexiletine Phenytoin Tocainide c. Lorcainide Flecainide

II. ¾-adrenergic Blockers

No or little effect on action potential duration & refractoriness Decrease background sympathetic tone in the heart, reduce automatic discharge (phase 4)

Ventricular arrhythmias that are supraventricular in origin As for propranolol

Propranolol Esmolol**

III. Potassium Channel Blockers

Prolong repolarisation

Amiodarone

Ventricular arrhythmias that are resistant to lignocaine As for amiodarone As for amiodarone

Sotalol Bretylium

IV. Calcium Channel Blockers Verapamil

Decrease the slow inward calcium current (phase 2), & prolong conduction & refractoriness (SA & AV nodes) Ventricular arrhythmias that are supraventricular in origin As for verapamil

Diltiazem

Others Digoxin Adenosine

Broad spectrum (for chronic use) Broad spectrum (for acute use) Broad spectrum (less safe) Ventricular arrhythmias, digitalis-induced tachyarrhythmias Ventricular arrhythmias Digitalis-induced tachyarrhythmias Ventricular arrhythmias Ventricular arrhythmias Ventricular arrhythmias

Decreases AV nodal conduction (by increasing vagal activity) Decreases AV nodal conduction

Ventricular arrhythmias that are supraventricular in origin As for digoxin

* These drugs restrict the rapid inflow of sodium during phase 0 and thus slow the maximum rate of depolarisation (membrane stabilising activity) in cells with abnormal activity; while in normal cells they produce the described actions for class Ia, b & c. ** Esmolol is a short-acting β 1-selective agent, hence, it could be used in some patients with contraindications to other β-blocking agents. Underlined drugs are ones with which good familiarity has been attained in Iraq. Note: This classification shows that drugs in class 1b are not effective for supraventricular arrhythmias, whereby they all may have some effect in ventricular arrhythmias.

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achieved widespread acceptance as first-line pharmacological therapy for serious ventricular arrhythmias in acute myocardial infarction. Because of extensive first-pass metabolism in the liver and its metabolites are believed to contribute to central nervous system toxicity, lignocaine must be administered parenterally and never given orally.

Interactions Quinidine interacts with digoxin to produce a significant elevation (50-100%) of the serum digoxin level. This seems to be a result of a combination of displacement of digoxin from tissues and a decrease in renal clearance of digoxin.

Procainamide Adverse effects Procainamide is related to the local anaesthetic procaine that exhibits similar actions but has a longer duration of action. It may be administered orally or intravenously. Because of its short t it has to be given every 3-4 hours or by a sustained release preparation.

1. Hypotension 2. Blurred vision 3. Sleepiness 4. Slurred speech 5. Paraesthesiae (numbness, often perioral) 6. Sweating 7. Confusion 8. Convulsions

Adverse effects

Mexiletine and Tocainide 1. Hypotension 2. GI disturbances 3. Hallucinations 4. Hypersensitivity reactions (reversible lupus erythematosus and agranulocytosis)

Mexiletine and tocainide are chemically very similar to lignocaine. They can be given by mouth. As lignocaine, they are most useful in the treatment of ventricular arrhythmias, and usually, a patient who responds well to lidocaine will also respond to oral therapy with mexiletine or tocainide. Both compounds have shown to be of value in some patients with chronic recurrent ventricular tachyarrythmias.

Disopyramide Disopyramide is now the most used drug of this sub-class. It is effective in ventricular and supraventricular arrhythmias. It is given orally and intravenously and is well absorbed.

Adverse effects of these drugs are similar to those listed for lignocaine. In addition, GI symptoms, particularly nausea, are a common complaint.

Adverse effects 1. Anticholinergic effects (dry mouth, blurred vision, glaucoma, micturition hesitancy and retention. 2. GI disturbances 3. Hypersensitivity reactions (rash and agranulocytosis) 4. Hypotension and cardiac failure (negative inotropic effect) 5. Tachyarrhythmias

Class Ic Lorcainide and Flecainide These drugs are very effective in suppressing both supraventricular and ventricular tachyarrythmias but they also have considerable negative inotropic properties and markedly prolong intracardiac conduction time, even in therapeutic concentration.

Class Ib Lignocaine Lignocaine (lidocaine, xylocaine) is the oldest and best known in this group. It has 58

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Majid A.K. Lafi

Class II

Amiodarone

The mechanism of the acute antiarrhythmic effect of the β-receptor blocking agents is due to direct antagonism of the arrhythmogenic actions of endogenous catecholamines, it is also possible that the class I activity (membrane stabilising properties) in high concentration may play some role.

Apart from its ability to prolong the duration of the cardiac action potential amiodarone is also a smooth muscle relaxant, a noncompetitive β-receptor blocker, and demonstrate some degree of class I and class IV activity, at least in vitro. It is a very useful antiarrhythmic drug in the therapy and prophylaxis of most types of arrhythmias that poorly respond to other drugs.

Propranolol

Pharmacokinetics

Propranolol is often effective both in the treatment and in prophylaxis against supraventricular tachycardia, where they probably act largely by prolonging refractoriness and slowing conduction in the AV node. In atrial fibrillation and flutter (particularly if due to exercise, emotions or thyrotoxicosis) β-receptor blocking agents can be useful in slowing the ventricular response by their effect on the AV node. βblocking agents have some value in the therapy of ventricular tachyarrhythmias though they are not generally regarded as first-line drugs. β-blockers may also be useful in Wolff-Parkinson-White syndrome.

The administration of amiodarone (usually by mouth) is complicated by a variable bioavailability (20-80%), long t (54 days) after multiple dosing, and very large apparent volume of distribution (70 l/kg). Adverse effects 1. Hypotension 2. Bradycardia, heart block 3. Corneal micro-deposits (causing visual haloes & photophobia) 4. Hypothyroidism (blocks conversion of T4 to T3 , compensatory increase in thyroidstimulating hormone, affecting 2-20% of patients) and Hyperthyroidism (due to iodine content of the drug)1 5. Photosensitivity reactions (it may cause a bluish discolouration on exposed areas of the skin) 6. Pulmonary alveolitis 7. hepatitis

Cardiac adverse effects: Heart block and cardiac failure. For detailed adverse effects, see the appropriate section in antihypertensive drugs. Interactions 1. Concomitant i.v. Administration of βblockers with calcium antagonists (those affect conduction, e.g. verapamil and diltiazem) increases the risk of bradycardia and AV block. 2. In the presence of depressed myocardial contractility, the combination of oral or i.v. β-blockers and calcium antagonists (e.g. nifedipine and verapamil) may produce hypotension or heart failure.

Interactions 1. With digoxin (by displacing it from tissue binding sites and interfering with its elimination) and with warfarin (by inhibiting its metabolism) hence increasing the effects of both these drugs. 2. The depressant effect of amiodarone on SA and AV node is enhanced by β-blockers and calcium antagonists.

Class III

Sotalol

The class III agents are believed to produce their antiarrhythmic activity through blocking potassium channels (thus lengthening of refractoriness). The best known drug of this class is amiodarone.

1 Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 616.

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Cardiovascular Pharmacology - Antiarrhythmic Drugs

Sotalol is a non-selective β-blocker with marked class III activity. Unlike other βblocking agents, the prolongation of the duration of the action potential is apparent at once (within minutes, if administered i.v.), and this drug is showing promise in clinical trials in the treatment of supraventricular and ventricular arrhythmias.

Ramadi, 6 October 2009

Interactions 1. The depressant effect of verapamil on AV node and on myocardial contractility is enhanced by β-blockers.

Diltiazem Diltiazem appears to have pharmacological and antiarrhythmic properties that are very similar to those of verapamil.

Bretylium Bretylium is employed acutely and only against severe ventricular arrhythmias; its antiarrhythmic activity, prolongation of effective refractory period, may be mediated by blocking potassium channels. It can cause bradycardia and severe hypotension, probably by virtue of its adrenergic neurone blocking action.

Nifedipine Nifedipine in therapeutic concentrations acts almost solely as a vasodilator. It has no clinically useful antiarrhythmic action, although an antiarrhythmic effect can be demonstrated in vitro.

Class IV

Others

The increase in the slow inward flow of calcium ions through the L-channel (L-large) results in enhanced contractility of myocardial cells, enhanced automatic activity of pacemaker cells (SA node), and shortens conduction and refractoriness in the AV node. Calcium antagonists inhibit calcium influx through the L-channel resulting in depressed rate of discharge of the SA node and prolonged conduction and refractoriness in the AV node.

Digitalis Digitalis glycosides are presented in detail in the section on drugs for congestive heart failure. Digitalis decreases AV nodal conduction (by increasing vagal activity), and hence it is employed only against supraventricular arrhythmias. It is ineffective against arrhythmias originating in the ventricles.

Adenosine

Verapamil

Adenosine is an endogenous purine nucleotide that slows AV nodal conduction, and dilates coronary and peripheral arteries. It is rapidly inactivated by circulating adenosine deaminase; its t is several seconds. It must be administered i.v. by a bolus injection. It may be useful in supraventricular tachycardias, including Wolff-ParkinsonWhite syndrome. Its adverse effects are dyspnoea, facial flushing, chest pain, and transient bradyarrhythmias may occur. It is not suitable in asthmatic patients or those with second or third degree AV block.

Verapamil is the prototype for this class of drugs and it is of first choice for the shortterm therapy of supraventricular tachycardia. It is well absorbed when taken by mouth, but undergoes very extensive first-pass metabolism in the liver; therefore, its bioavailability in oral therapy is only 2040%. Adverse effects 1. Heart failure (particularly, impaired ventricular function)

in already

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DIURETICS order to avoid hypopotassaemia (hypokalaemia) potassium supplements may be necessary or the combination with a potassium sparing diuretic like amiloride. A fixed combination of hydrochlorothiazide and amiloride is available (Moduretic).

Introduction Glomerular filtration rate (GFR) is 125 ml/min; the extracellular fluid volume is 12.5 l, this fluid volume is filtered within a period of 1.5 hours but only 100 ml of urine are produced during the same time, therefore, tubular reabsorption is over 99%. Reabsorption is mainly achieved by active transport of electrolytes (Na+, Cl-, K+, HCO3and solutes like urea, creatinine etc.). the action of diuretics is concerned with selectively blocking the active transport mechanisms of Na+, Cl-, and HCO3-. Normally the volume of urine is determined by the solutes delivered to the tubules therefore, also water, electrolytes and other solutes such as glucose and urea act as diuretics.

Thiazides are used to relieve oedema due to cardiac failure, in which glomerular filtration is reduced resulting in increased reabsorption of sodium from the renal tubules (hence, reduced renal excretion of sodium). In small doses the thiazides are used in hypertension to lower blood pressure. Thiazides can be combined with other antihypertensive drugs such as β-blockers and ACE inhibitors. The antihypertensive action has to do partly with a reduced plasma volume and partly with a reduced responsiveness of the vascular smooth muscle. Thiazides are administered as tablets.

Indications for Diuretics 1. Oedema 2. Ascites, hydrothorax 3. Hypertension 4. Glaucoma (acetazolamide) 5. Renal calculus (thiazides) 6. Hypercalcaemia (loop diuretics)

Thiazides analogues Indapamide is a lipid soluble, non-thiazide diuretic that has long duration of action. It is often used in advanced renal failure to stimulate additional diuresis on top of that achieved by loop diuretics. Indapamide is metabolised and excreted by GI tract and the kidneys. Therefore, it is less likely to accumulate in patients with renal failure and may be useful in their treatment.

Thiazide Diuretics The parent compound is chlorothiazide, a substance derived from the sulphonamides. There are about 13 related compounds with similar action but more potent than chlorothiazide, e.g. hydrochlorothiazide, and chlorthalidone. Thiazides act primarily at the distal convoluted tubule to decrease the reabsorption

Loop Diuretics Loop diuretics such as frusemide, bumetanide, and ethacrynic acid are more potent and have a greater efficacy than any other diuretics. They inhibit the Na+/K+/Clcotransport of the luminal membrane in the ascending part of the loop of Henle leading to excretion of a higher percentage of filtered salt: 30% as compared to 10% for thiazides. Loop diuretics and thiazides are secreted in the proximal tubules, and since uric acid is excreted by the same mechanism; both drugs cause retention of urate. Loop diuretics also

of Na+ by inhibition of a Na+/Cl- cotransport system on the luminal membrane. They also promote excretion of K+, reduce uric acid and Ca++ excretion, increase blood sugar and are weak carbonic anhydrase inhibitors. Reduction of serum potassium is dangerous in patients being treated with digitalis. In 61

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condition with a low GFR (shock, crush injury). Mannitol increases renal blood flow because it dilates the afferent arterioles. Mannitol can also be used in cerebral oedema and elevated intraocular pressure. Since it produces hyperosmolarity in the systemic circulation, hence, drawing water by osmotic force from the extracellular space (from cerebral circulation). Very high level of mannitol, like in renal failure, may lead to pulmonary oedema (as a result of overloading the heart) and cerebral dehydration. Mannitol must be given i.v. as 10 or 25% solution. It is excreted outside the body only by kidney. Thus, if there is renal failure, mannitol is not eliminated; in this condition, haemodialysis is indicated.

cause potassium loss but they increase calcium excretion. Like thiazide diuretics, they possess diabetogenic activity. The greatest danger with loop diuretics is excessive diuresis with circulatory collapse and hypokalaemia. Ototoxicity can occur particularly in conjunction with aminoglycosides.

Potassium Sparing Diuretics These include triamterene and amiloride possess moderate natriuretic effects but their major importance is in inhibiting potassium excretion in the distal tubule. These drugs are not very efficient when used alone but may be useful in the combination with thiazides.

Alteration of Urine pH

Spironolactone is a competitive antagonist of aldosterone. This diuretic is mostly used for its potassium sparing action. Because spironolactone contains a steroid moiety it may produce anti-androgen like adverse effects, e.g. gynaecomastia, and erectile impotence.

Alkalinisation of Urine This may be achieved by sodium bicarbonate or potassium citrate for the following therapeutic objectives:

Xanthines like theophylline and caffeine have a combined effect on renal haemodynamics and tubular reabsorption.

1. Increases the elimination of salicylates and phenobarbital 2. Reduces irritation of an inflamed urinary tract 3. Discourage the growth of certain organisms like E coli.

Acetazolamide

Acidification of Urine

Acetazolamide (Diamox) is a carbonic anhydrase inhibitor that acts principally on the eye and the kidney. It reduces absorption of sodium bicarbonate in the proximal tubule and gives rise to hyperchloraemic acidosis as an adverse effect. Because it causes acidosis it is mostly used for glaucoma (topical preparation is now available). Acetazolamide may benefit some cases with atypical absence and other seizures in children.

This may be achieved by ammonium chloride (after food to avoid vomiting), ascorbic acid, CaCl2 by mouth for the following therapeutic objectives:

Minor Diuretics

1. Test for renal tubular (failure of acidification of urine, ammonium chloride) 2. Increase elimination of amphetamine, phencyclidine and dexfenfluramine.

Osmotic Diuretics These are solutes that increase diuresis because reabsorption is absent (mannitol) or limited (urea). Mannitol is mainly used in

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Table 3.9. A summary of selected actions, indications and adverse effects of the most commonly used diuretics. Diuretic Actions High Potency Inhibits NaCl reabsorption (thick Diuretics ascending loop), hypercalciuria (used in Frusemide hypercalcaemia, not used in the elderly)

Indications Oedematous Conditions (due to congestive heart failure, nephrotic syndrome, impaired renal function) Hypertension Acute pulmonary oedema Acute hypercalcaemia

Inhibits distal tubular NaCl reabsorption, hypocalciuric (used in idiopathic hypercalciuria, renal stone)

Oedematous Conditions Hypertension Idiopathic hypercalciuria Renal stone Nephrogenic diabetes insipidus (paradoxic use)

Inhibit Na+/K+ exchange distal tubule, also Na+/H+ exchange

Nephrogenic diabetes insipidus with kaliuretic (potassium-losing) diuretics

Aldosterone receptor antagonist

Primary hyperaldosteronism Oedematous Conditions Hypertension Hypokalaemia Hirsutism Polycystic ovarian syndrome Glaucomas Altitudes sickness Metabolic alkalosis Oedematous Conditions Epilepsies Oliguric phase of acute renal failure Elevated intracranial pressure Cerebral oedema Elevated intraocular pressure (when cannot be lowered by other means) Drug overdose

Medium Potency Diuretics Hydrochlorothiazide

Potassium Sparing Low potency Diuretics Amiloride Triamterene Low Potency Diuretics Spironolactone

Low Potency Carbonic anhydrase inhibitor Diuretics Inhibits NaHCO3 Acetazolamide reabsorption (proximal tubule) Osmotic diuretic, Osmotic increases tubular fluid Diuretics osmolarity leading to Mannitol increasing urine flow; dilates afferent arterioles

Adverse effects Hypokalaemia Hyperuricaemia Hyperglycaemia Hypotension, Ototoxicity Allergy (sulphonamide) Nephritis (interstitial) Hypokalaemia Hyperuricaemia Hypercalcaemia Hyperglycaemia Thrombocytopenic purpura Impotence Allergy (Sulpha) Hyperkalaemia Acidosis

Hyperkalaemia, Gynaecomastia, Impotence

Hyperchloraemic metabolic acidosis Neuropathy Allergy (sulphonamide) Cerebral dehydration Pulmonary oedema Contraindicated in anuria and congestive heart failure

Diuretics may alter renal haemodynamics and/or renal tubular function: For example mannitol is a vasodilator & saluretic (↑ perfusion, GFR and volume of urine); NSAIDs (e.g. aspirin) may reduce both thus antidiuretics ; ACE inhibitors (e.g. captopril) may alter GFR; saluretics (e.g. thiazides) directly, while alcohol indirectly (↓ ADH secretion) increase urine production; digoxin increases cardiac output thus renal perfusion. 63

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Acetazolamide inhibits

Mannitol & Xanthines increase filtration pressure

Carbonic anhydrase promotes reabsorption NaHCO3

Organic acid & base secretary system

Proximal tubule

Chlorothiazide, Hydrochlorothiazide, Chlorthalidone & Indapamide inhibit reabsorption of NaCl

Ascending Distal Loop of Henle convoluted tubule

Amiloride & Triamterene inhibit

Na/K exchange Late distal & collecting tubule

H+ Na+ Glucose Amino acids

K+ H+ K+

HCO3

Na+ K+ Cl-

Na+ Cl-

Na+

H2O

-

Inhibited by PGE2 Inhibited by Aspirin NSAIDs

H2O

Antagonism

Na/K-ATPase (cotransport system) Promoted by Frusemide Bumetanide Ethacrynic acid

Aldosterone

Blocked by Spironolactone

ADH

Enhanced by Desmopressim Chlorpropamide Carbamazepine Thiazides Reduced by Demeclocycline

Fig.3.5. A simplified schematic representation of the sites of transport of solutes and water, and action of diuretic agents. In the proximal tubule, acetazolamide blocks carbonic anhydrase reducing the availability of HCO3- in both the luminal space and inside the tubular cells; as a result less HCO3- and Na+ are reabsorbed, and less H+ is excreted. In the thick ascending part the loop of Henle, loop diuretics like frusemide inhibit Na/K-ATPase, which usually facilitates the reabsorption of Na+/K+/2Cl-. Prostaglandins (e.g. PGE2) are believed to be the endogenous inhibitors of this Na/KATPase; NSAIDs (e.g. aspirin) are believed to produce their antidiuretic effect, at least in part, through inhibition of synthesis of the inhibitory prostaglandins, resulting in enhanced reabsorption of salt. In the distal convoluted tubule, thiazide-related agents inhibit reabsorption of NaCl. In the late distal tubule, amiloride and triamterene inhibit Na/K exchange mechanism. While inside the renal tubular cell, spironolactone blocks the cytoplasmic aldosterone receptor resulting in reduced aldosterone nuclear activity, which usually leads to the production of certain mRNA and consequently in the cytoplasm increasing the production of specific proteins that enhance the permeability to Na+ and K+.

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ANTITHROMBOTIC DRUGS Introduction

(cyclooxygenase 1, COX-1) by irreversibly acylating the active site of the enzyme; therefore, aspirin permanently inhibits prostaglandin G/H synthase in platelets. Because platelets are non-nucleated, they cannot regenerate the enzyme as can nucleated cells. Thus, thromboxane production is halted until entry of new platelets into the circulation (platelet life-span 8 days). This irreversible action is unique to acetylsalicylic acid (aspirin) among NSAIDs. This is probably why aspirin, unlike other NSAIDs, at low doses (75-100 mg/day) can continuously produce antiplatelet activity.

Haemostasis is the spontaneous arrest of bleeding. Thrombosis is the process of pathological intravascular clotting. Haemostasis and thrombosis depend on a multifactorial balance between mechanisms of clot formation and dissolution (fibrinolysis). This balance depends on three major components: 1. Vessel wall 2. Blood a. Platelets b. Cagulation cascade c. Fibrinolytic system 3. Flow

Dipyridamole

Vessel wall controls vasoconstriction, formation of von Willebrand s factor (VIII), platelet adhesion, and regulation of coagulation and fibrinolysis.

Dipyridamole is a coronary vasodilator, hence, used prophylactically in the treatment of angina pectoris.dipyridamole reversibly inhibits platelet phosphodiesterase leading to increased platelet cyclic AMP concentration, thus, resulting in increased platelet cyclic AMP concentration, thus, resulting in reduced platelet reactivity (antithrombotic action: decreasing platelet reactivity to thrombogenic surfaces). It is usually given in combination with aspirin.

2a. Platelets

Dextrans

Platelets serve as trauma plugs, procoagulant agents, and promoters of healing. Platelet plug formation starts with a process of platelet adhesion, aggregation (ADP and thromboxane A2) and thrombinrecruitment with creation of a fibrin mesh and clot retraction. There are drugs like aspirin, dipyridamole, dextrans, and ticlopidine that inhibit platelet activity; hence, they are called antiplatelet drugs.

Dextrans alter platelet function and prolong the bleeding time. Dextran 70 carries an advantage over other antiplatelet drugs, in that it reduces the incidence of postoperative venous thromboembolism if it is given during or just after surgery.

Antiplatelet drugs

Ticlopidine and clopidogrel interfere with a variety of platelet activities including irreversibly blocking ADP receptors and thus inhibiting the binding of fibrinogen to platelets. The former carries a risk of producing neutropenia (2.4%), and thrombocytopenia. However, clopidogrel lacks the neutropenic effect; this makes it

These three alterations which favour intravascular clot formation are also called Virchow s triad, after the German pathologist Rudolf Virchow. 1. Vessel wall

ADP-receptor blockers

Aspirin Aspirin blocks the synthesis of thromboxane A2 from arachidonic acid in platelets by inhibition of prostaglandin G/H synthase 65

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superior to ticlopidine. Recently, clopidogrel gained a popular use in a fixed combination with lower dose of aspirin in enteric-coated dosage form in patients who cannot tolerate aspirin on its own.

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coagulation factors have been recognised in addition to a tissue factor (III) and calcium (IV). It is convenient to divide these factors into three groups. a. Vitamin-K dependent factors: II, VII, IX and X b. Contact activation factors: XI and XII c. Thrombin-sensitive factors: I, V, VIII, XIII.

2b. Coagulation system The 15 coagulation factors are described by Roman numerals. Twelve plasma protein Serotonin ADP

TXA2

PLATELET

Granule

Dipyridamole

TXA2

+

TXA2 Synthase PGH

-

Aspirin PDE

cAMP

Degradation

DAG IP3

PGH Synthase

AA PIP2

ATP PLC

AC

PLA2

Prostacyclin (PGI2)

Thromboxane A2 (TXA2)

Endothelial cell

Another platelet

Fig.3.6. Autacoids that influence platelet activation and recruitment, and site of action of antiplatelet drugs like aspirin and dipyridamole. TXA2 is thromboxane A2; PGH is prostaglandin G/H; AA is arachidonic acid; PLA2 is phospholipase A2; PLC is phospholipase C; AC is adenylate cyclase; PIP2 is phosphatidyl-4, 5-bisphosphate; IP3 is inositol 1,4,5trisphosphate; DAG is 1,2-diacyglycerol; PDE is phosphodiesterase. Note: aspirin (being uniquely) irreversibly inhibits PGH synthase by acylating the active site of the enzyme, eventually resulting in inhibition of the production of TXA2 that activates TXA2-receptor located on the outside of platelet membrane. In turn, resulting in hydrolysis of PIP2 and thus production of IP3 and DAG both of which promote the excitability of platelet. Other NSAIDs block PGH synthase but in a reversible manner (i.e. not permanently), hence, the natural substrate still has the chance to be acted upon by the enzyme. It is worth noting that platelets adhere to exposed collagen in the subendothelial layer of injured blood vessels.

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Thrombin

Majid A.K. Lafi

Collagen

Irreversibly inhibited by Aspirin

PAF

Irreversibly blocked by Ticlopidine Clopidogrel ADP

AA PGH Synthase

TXA2

PLATELET GP IIb/IIIa

Blocked by Abciximab (Super aspirin)

Fig.3.7. Autacoids that influence platelet activation and aggregation, and site of action of antiplatelet drugs like aspirin and ticlopidine. PAF is platelet activating factor; TXA2 is thromboxane A2; PGH is prostaglandin G/H; AA is arachidonic acid; ADP is adenosine diphosphate. ADP activates ADP-receptor located on the outside of platelet membrane resulting in activation of GP (glycoprotein) IIb/IIIa receptor. In turn, fibrinogen can interact with the activated receptor forming a bridge between two platelets resulting in aggregation.

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Coagulation factors circulate in inactive forms (zymogens). Coagulation entails a series of proteolytic reactions by which the clotting factors become an active protease, designated by a lower case, like Xa. Each clotting factor activates the next in a chain reaction until an insoluble fibrin clot is formed.

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Heparin increases clotting time but bleeding time is little affected and the risk of haemorrhage is not great. The best way to give heparin is by i.v. drip or intermittent i.v. injection. The action of heparin (acidic) can be terminated by an injection of protamine sulphate (basic) which binds to the heparin molecule.

Clotting is initiated either by an intrinsic or extrinsic pathway. Both systems converge to generate thrombin, which in turn cleaves fibrinogen to form a fibrin gel. Thrombin is central to all coagulation processes and it is therefore not surprising that generation of thrombin is the focus of important regulatory controls.

Adverse effects: haemorrhagic conditions and thrombocytopenia In recently years, low molecular weight heparins (LMWHs) have been introduced into clinical practice. Whereas, conventional or unfractionated heparin (UFH) produces its anticoagulant effect by inhibiting both thrombin and factor Xa, LMWHs inactivate only factor Xa. The major advantage of LMWHs is that they have a longer t , hence, they can be given once or, at the most, twice daily in a fixed dose without the need for laboratory monitoring. They are believed to have less incidence of producing haemorrhage and thrombocytopenia.

The most important natural inhibitors of coagulation is antithrombin III, which normally is present in excess amounts in plasma. Patients with an antithrombin III deficiency have a high incidence of recurrent thromboembolic diseases. Protein C and S, vitamin K (Koagulation vitamin) dependent proteins also are important inhibitors of coagulation and stimulators of fibrinolysis. Deficiency of protein C or S is also associated with a high risk of thrombosis.

No Heparin

Anticoagulants

Active clotting factors

Heparin Antithrombin III (Slow conversion)

Heparin is a natural anticoagulant produced mainly in mast cells and found in many tissues. Heparin was discovered by a medical student, J. Mclean, working at Johns Hopkin Medical School in 1916. To his astonishment, the extract of liver that he had kept longest not only failed to speed up but actually impaired clotting. It is now understood that heparin binds to antithrombin III causing a rapid anticoagulant effect (by a factor of 1000-fold).

Inactive factors With Heparin Active clotting factors Antithrombin III plus heparin Rapid conversion (immediately)

Heparin is the strongest organic acid in the body and in solution carries electronegative charge. Heparin exhibits a first-order and zero-order kinetics, the effect of which is that the plasma biological effect t alters disproportionately with dose, being 60 min after 75 units per kg and 150 min after 400 units per kg.

Inactive factors

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2. Pharmacodynamic (increased anticoagulant effect): aspirin (high dose), cephalosporin (3rd generation), heparin

Warfarin The coumarin anticoagulants including warfarin act by antagonising the cofactor functions of vitamin K, primarily inhibiting liver synthesis of prothrombin and some thromboplastin components, particularly factor VII. Initially, these drugs were used as rodenticides. The maixmal effect is produced in 1-2 days. The effect of the coumarin anticoagulants can be antagonised by vitamin K, a structural analogue. Peak absorption for warfarin occurs within two hours and the t is 42 hours. Warfarin is highly protein bound and it is only the free drug that is pharmacologically active.

• Decreased prothrombin time 1. Pharmacokinetic a.Hepatic enzyme induction: barbiturates, carbamazepine, rifampicin b.Impaired absorption and increased elimination of warfarin: cholestyramine, cholestipol (long term treatment may cause impaired vitamin K absorption and enhance anticoagulant effect) 2. Pharmacodynamic (reduced anticoagulant effect): oral contraceptive (oestrogens increase the synthesis of some vitamin K dependent clotting factors), vitamin K

Indications

2c. Fibrinolytic system

1. Deep venous thrombosis 2. Pulmonary embolism 3. Atrial fibrillation (in rheumatic valvular disease with cerebral and peripheral arterial embolism) 4. Acute myocadial infarction 5. Transient ischaemic attacks 6. Hip fracture 7. Disseminated intravascular coagulation (DIC)

Fibrin must be enzymatically digested by the serine protease, which is activated by a plasma or tissue activating factor (pPA and tPA). Plasmin digests fibrin to release a number of fibrin degradation products (fibrin split products) which also are anticoagulants. The conversion of plasminogen to plasmin can be inhibited by tranexamic acid and aminocaproic acid; while the action of plasmin is inhibited by aprotinin.

Adverse effects

Fibrinolytics

1. Haemorrhagic conditions (skin, GI and urinary tract) 2. Teratogenic (therefore, a pregnant women should be put on heparin during the course of pregnancy) 3. Warfarin skin necrosis (in patients with deficiency in protein C and S which are vit. K-dependent antithrombotic factors that can be suppressed by warfarin predisposing to venous thromboembolism and skin necrosis).

Streptokinase is a protein (not an enzyme on its own) synthesized by streptococci that combines with plasminogen to produce an activator complex that in turn converts plasminogen to the proteolytic enzyme plasmin. Plasmin is inactivated by circulating inhibitors like α-2-macroglobulin. These inhibitors are rapidly consumed at high doses of streptokinase. It is administered by intravenous infusion. Streptokinse is associated with bleeding and allergic reactions.

Interactions • Increased prothrombin time 1. Pharmacokinetic (hepatic enzyme inhibition): cimetidine, sulphonamides, mefenamic acid, erythromycin, metronidazole, ciprofloxacin, chloramphenicol,

Anistreplase is the p-anisoylated derivative of the Lys-plasminogen streptokinase activator complex that consists of a combination of purified human plasminogen and a bacterial streptokinase that has been acylated to protect the active site of the enzyme (prodrug). Activation of anistreplase 69

Cardiovascular Pharmacology Antithrombotic Drugs

occurs with the release of the anisoyl group by deacylation, which is a non-enzymatic first order process with a t in vitro in human blood of about 2 hours. Therefore, this product (unlike streptokinase on its own) allows for rapid intravenous injection, greater activity on plasminogen associated with clots than on free plasminogen in the blood. Anistreplase is associated with bleeding and allergic reactions.

Ramadi, 6 October 2009

than with heparin, thus, this form of therapy is only available in specialised centres.

Antifibrinolytic agents Antifibrinolytics (antiplasmins) inhibit plasmin activation like tranexamic acid that is used when haemorrhage cannot be controlled as in:

Alteplase is a tissue plasminogen activator (tPA) that preferentially activates plasminogen that is bound to fibrin, which theoretically limits fibrinolysis to the formed thrombus avoiding systemic activation. Alteplase produced by means of recombinant DNA technology. Alteplase is associated with bleeding; no serious or life-threatening allergic reactions have been reported. The fibrinolytics are indicated in acute myocardial infarction and thromboembolic conditions such as pulmonary embolism. These drugs carry a high risk of antigenicity and also haemorrhage that occurs more often

1. Prostatectomy 2. Haemophiliacs extraction 3. Menorrhagia

undergoing

Antifibrinolytic agents are contraindicated in thromboembolic disorders. Aprotinin, however, inhibits the action of plasmin hence it is useful in hyperplasminaemia. Note: Desmopressin may be useful in haemophilia (it is believed to promote the activity of von Willebrand s factor).

Plasminogen Fibrinolytics Plasminogen activators

dental

pPA, tPA Streptokinase Anistreplase Alteplase

Inhibited by antifibrinolytics, tranexamic acid & aminocaproic acid Plasmin

Inhibited by aprotinin

Stabilised fibrin

Fibrin degradation product

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Table 3.10. A summary of the drugs used in coagulation disorders, their mode of action and clinical uses. Drug Group Drug Anticoagulants (parenteral) Heparin

Mode of Action

Therapeutic Action

With antithrombin III inhibit both thrombin and factor Xa [antidote: protamine; onset: rapid in minutes; duration: hours; assessment: KCCT* 1.5-2.5 times the control

Prevention of venous thrombosis

Haemorrhage, thrombocytopenia

With antithrombin III inhibit only factor Xa (No assessment is usually required)

Prevention of venous thrombosis

Less risk above

Inhibits synthesis of vitamin Kdependent clotting factors [antidote: vitamin K1 ; onset: slow in hours; duration: days; assessment: prothrombin time**]

Prevention of venous thrombosis

Haemorrhage, teratogenic, many interactions

Aspirin

Irreversibly inhibits prostaglandin G/H synthase, hence, inhibition of TXA2 resulting in inhibition of aggregation

Prevention of arterial thrombosis

Dipyridamole

Inhibits platelet phosphodiesterase resulting in more cAMP resulting in inhibition of aggregation Irreversibly block ADP receptors thus inhibiting ADP-mediated aggregation

Prevention of arterial thrombosis

LMWHs

(oral) Warfarin

Adverse effects

of the

Antiplaltelets

Prevention of arterial thrombosis

Ticlopidine

Neutropenia (2.4%)

Clopidogrel

Lacks the above adverse effect

Abciximab

Dextrans

Blocks GP IIb/IIIa Receptors inhibiting the final step in platelet aggregation Alters platelet function & prolong bleeding time

71

Prevention of arterial thrombosis + ↓ postoperative venous thromboembolism

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Thrombolytics Streptokinase (i.v. infusion) Anistreplase (prodrug, i.v. rapid injection)

Activates synthesis of plasmin resulting in fibrin degradation

Acute myocardial infarction (AMI) Pulmonary embolism

Haemorrhage Antigenicity

Alteplase (i.v. infusion)

Activates preferentially fibrinbound plasminogen thus plasmin production confined to clot.

Acute myocardial infarction (AMI) Pulmonary embolism

Haemorrhage

Inhibit conversion of plasminogen to plasmin resulting in formation of clot Directly inhibits plasmin resulting in promotion of clot.

Arresting perfused bleeding

Antithrombolytics Tranexamic acid Aminocaproic acid

Arresting perfused bleeding in hyperplasminaemic conditions * KCCT: kaolin-cephalin clotting time also known as activated partial thromboplastin time (APTT), primarily monitors the intrinsic system. ** Prothrombin time is also expressed as the International Normalised Ratio, INR), primarily monitors the extrinsic system.

Aprotinin

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ANTIHYPERLIPIDAEMIC DRUGS

Introduction

Adverse effects

Elevated cholesterol concentrations are one of the major contributing factors in the development of atherosclerosis. Cholesterol enters the circulation from two major sources, absorption from food (exogenous pathway). It leaves the circulation when it is taken up by the liver to form bile acids, or taken up by other cells to form steroid hormones or inserted into membranes. When present in excess, it is taken up by fibroblasts and scavenger cells in regenerating tissues, as well as fat cells. As lipids are insoluble in aqueous solution, transport of cholesterol within the plasma is by way of lipoprotein particles.

1. Disturbances in liver function tests 2. Elevation of muscle enzymes (creatine phosphokinase)

Bile Acid Binding Resins Cholestyramine and colestipole are ion exchange resins that bind cholesterol and prevent its GI absorption of bile acids, (which is largely reabsorbed by enterohepatic circulation). Thus, they promote the liver to uptake cholesterol from plasma for the synthesis of bile acids hence reduction in plasma cholesterol.

Hyperlipidaemias can be primary and/or secondary depending on their causes. Primary ones can be due to a single gene defect and/or environmental factors. While, secondary hyperlipidaemias are due to a metabolic disorder like diabetes millets, hypothyroidism, primary biliary cirrhosis, or excessive alcohol intake. Management of secondary hyperlipidaemias can be achieved by dietary intervention, and treatment to control the primary cause of the hyperlipidaemia.

These drugs are hypercholesterolaemia.

useful

in

Adverse effects 1. GI disturbances 2. Deficiency of vitamin A, D, K, and folic acid (therefore, supplement of these lipid soluble substances may be needed)

Cautions/ contraindications

Antilipid drugs are used to prevent myocardial infarction and other atherosclerotic disorders such as stroke and peripheral vascular disease. They are used prophylactically to reduce formation of atherosclerotic plaque and subsequent narrowing of lumen in coronary arteries.

1. Complete biliary obstruction 2. Pregnancy

Fibrates Fibrates (clofibrate and gemfibrozil) are derived from fibric acid and all appear to have the same mode of action. These drug are believed to mediate their antilipid effect though the following possible mechanisms:

Statins Lovastatin and simvastatin inhibit the ratelimiting enzyme in endogenous cholesterol synthesis hydroxy-methyl-glutaryl coenzyme A (HMG CoA) reductase. This leads to increase the expression of LDL receptors in the liver (that transport cholesterol out of the plasma) resulting in reduced concentration of circulating cholesterol.

1. Increase cholesterol secreted in the bile, thus, increased faecal loss. 2. Increase extrahepatic lipoprotein lipase activity; thus, triglyceride lowering effect may be due to increased efficiency of

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Cardiovascular Pharmacology - Antihyperlipidaemic Drugs

removal of VLDL, as well as reduced VLDL secretion by the liver.

Ramadi, 6 October 2009

Adverse effects

Fibrates are effective in hypertriglyceridaemia and to a lesser extent hypercholesterolaemia.

1. Intense cutaneous flush (prevented by prior administration of aspirin) 2. Pruritus 3. Hyperuricaemia and gout (it inhibits tubular secretion of uric acid) 4. Hyperglycaemia (it induces glycogenolysis) 5. Hepatotoxicity

Adverse effects 1. G I disturbances 2. Pruritus 3. Impotence 4. Increase gall stone

Antioxidants Probucol has gained a renewed interest because of its antioxidant properties. Probucol inhibits the oxidation of cholesterol. Oxidation of cholesterol-rich LDL promotes the ingestion of LDL by macrophages. These macrophages, being loaded with cholesterol, become foam cells that adhere to the vascular endothelium and are the basis for plaque formation. Thus, preventing oxidation of cholesterol may reduce formation of atherosclerosis.

The use of clofibrate has declined in recent years; this is due to a high incidence of mortality associated with malignancy or complications due to postcolecystectomy and pancreatitis. However, gemfibrozil has gained the reputation to have a lower incidence of mortality, and thus it has largely replaced clofibrate.

Cautions/ contraindications

Probucol can be effective in hypercholesterolaemia in which other antihyperlipidaemic drugs are ineffective.

1. Hepatic and renal dysfunction 2. Pregnancy

Adverse effects Nicotinic Acid 1. GI disturbances 2. Reduce HDL levels 3. prolongation of QT interval (caution with digitalis)

Nicotinic acid (niacin) is a water-soluble vitamin, when given in gram doses, it potently inhibits lipolysis in adipose tissue. Thus, decreasing the production of triglycerides that are essential components for the production of very low-density lipoprotein (VLDL). Further, low-density lipoprotein (LDL, cholesterol-rich lipoprotein) is derived from VLDL in the plasma. Therefore, a reduction in the production of VLDL will lead in a reduction in plasma LDL concentration. Nicotinic acid is effective in hyperlipidaemias in which both VLDL and LDL are elevated.

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Table 3.11. A summary of antihyperlipidaemic drugs, their possible mode of action and adverse effects. Drug Group Statins Simvastatin Lovastatin

Mode of Action Inhibit HMG CoA reductase reducing hepatic cholesterol synthesis →↑ LDL receptor expression →↑ cholesterol transport out of plasma →↓ circulating cholesterol. Bile Acids Binding 1.Reduce reabsorption of lipids & bile acids Resins 2.Promote hepatic uptake of Cholestyramine cholesterol for synthesis of Colestipole bile acids Fibrates 1.↑ extrahepatic lipoprotein Clofibrate lipase activity →↓ Gemfibrozil triglycerides (→ free fatty acids) 2.↑ cholesterol secretion in bile →↑ faecal loss Inhibits lipolysis in adipose tissue Nicotinic Acid →↓ production of free fatty acids →↓ hepatic production of triglycerides Inhibit oxidation of cholesterol-rich Antioxidants Probucol LDL →↓ ingestion of LDL by macrophages →↓ formation of foam cells →↓ formation of plaque

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Adverse effects Disturbances in liver function tests Elevation of muscle enzymes (creatine phosphokinase)

GI disturbances ↓ intestinal absorption of lipid soluble vitamins (A, D & K) and folic acid GI disturbances Pruritus Impotence 1-2% increase in incidence of gallstones Pancreatitis Cutaneous flush Pruritus Hyperuricaemia Diabetogenic GI disturbances Reduce HDL levels

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Statins inhibit HMG CoA reductase

Ramadi, 6 October 2009

Enterohepatic circulation

C

Diet CE (0.4 g/d)

Synthesis

_

_ _

Bile acids (total pool, 3-5g)

Free cholesterol pool

Bile acids C CE

Chylomicron

C C C

C TG CE

VLDL

TG CE

Chylomicron remnants bind to LDL (APO B-100, E) receptors on liver where they are endocytosed.

INTESTINE Capillaries

C Bile (0.6 acids g/d) (0.4 g/d)

Faeces

C CE EXTRAHEPATIC TISSUE

Chylomicron remnants

HDL

Extrahepatic tissues like adipose

Nicotinic acid inhibits lipolysis

Free fatty acids

Triglycerides

TG IDL

C

(VLDL remnant)

C

Lipoprotein lipase

Fibrates promotes

C CE C

Extracellular lipoprotein lipae degrades triacylglycerol in chylomicron and VLDL

LDL

Fig.3.8. A simplified schematic representation of transport of cholesterol between the tissues in humans. (C, free cholesterol; CE, cholesteryl ester; TG, triacylglycerol; VLDL, very low density lipoprotein; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; HDL, high density lipoprotein. Intestinal mucosa secretes TG-rich chylomicrons (produced primarily from dietary lipids); liver secretes TG-rich very low density lipoprotein particles.

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DRUGS FOR ANAEMIAS A subject is said to be anaemic if the total haemoglobin content per unit of blood volume usually measured as g Hb/dl, is

below normal range .Anaemia can be caused by several conditions including iatrogenic causes (Table.3.10).

___________________________________________________________

Table 3.12. A summary of common types of anaemias, their major causes and treatment Type of Major Causes of Anaemia Anaemia Iron deficiency* 1. Acute or chronic blood loss (hypochromic 2. Insufficient intake during periods of microcytic) accelerated growth in children, or in heavily menstruating or pregnant women (depletion of iron stores & inadequate intake) Megaloblastic Folic acid deficiency caused by: (macrocytic) a.Increased demand as in pregnancy & lactation b.Poor intestinal absorption c.Hepatic enzyme inducers d.Dihydrofolate reductase inhibitors (e.g. trimethoprim) Vitamin B12** deficiency caused by: 1. Failure of gastric parietal cells to produce intrinsic factor (pernicious anaemia) 2. Low dietary levels (dietary deficiency, less commonly)

Treatment Iron supplement

Folic acid supplement

Vitamin B12 (parenterally) Vitamin B12 (orally)

*Iron deficiency anaemia represents over 95% of anaemias, thus, iron therapy is most widely needed. **Cyanocobalamin, or hydroxocobalamin Note :Megaloblastic anaemia should not be treated by folic acid alone but rather with a

combination of folic acid and vitamin B12. This is because folic acid alone reverses the haematological abnormality therefore masking the vitamin B12 deficiency which may progress to severe neurological dysfunction.

3. Abnormalities of the GIT where the proportion of dietary iron absorbed may be decreased as in malabsorption syndromes. 4. Premature babies, as they are both with low iron stores, and babies weaned late; there is very little iron in human milk and even less in cow s milk. 5. Early treatment of severe pernicious anaemia with vitamin B12, as the initial high rate of red cell formation may cause exhaustion of the iron stores.

INDICATIONS FOR IRON THERAPY 1. Iron deficiency due to dietary lack or chronic blood loss 2. Pregnancy [The extra iron required by mother and foetus totals 1000 mg, mainly in the latter half of pregnancy. The foetus takes iron from the mother even if she is iron deficient. In pregnancy, dietary iron is seldom adequate; therefore, iron and folic acid should be given to pregnant women from the fourth month.

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(which may occur in excessive parenteral iron therapy or after a hundred or more blood transfusions as in treatment of thalassaemia). Desferrioxamine is an iron chelating agent, which may be administered orally (for acute iron overdose to chelate the iron present in the GIT as desferrioxamine is not absorbed from the GIT), intramuscularly or by intravenous infusion to remove systemic excess iron. After chelating iron to desferrioxamine, the latter becomes ferrioxamine and is excreted through the kidney.

Adverse effects Off these anti-anaemic drugs only iron containing preparations can produce GI disturbances (by local irritation) as adverse effects. There are no known adverse effects of folic acid or vitamin B12.

Desferrioxamine Occasionally removal of iron from the body may be desirable in conditions like acute iron overdose (poisoning) and haemosiderosis Gut lumen

Gastric mucosal cell

Fe++

Blood Fe++ + apoferritin

Excess ferritin shedded and excreted via faeces

Ferritin + labile Fe+++

Fe+++ in transferrin (transport globulin)

Erythrocyte precursors (80%, haem) Muscle (myoglobulin) Iron containing enzyme (cytochrome P450)

In the body irons is stored as ferritin that aggregates

In the blood the state of iron stores is indicated by: 1. amount of ferritin 2. serum iron concentration (low in iron deficiency) 3. binding capacity of ferritin (high in iron deficiency)

Haemosiderin in the cells of Liver Bone marrow Spleen

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ANTIMICROBIAL DRUGS (GENERAL PRINCIPLES) difficult to treat. Drugs poorly penetrate the eye (as in bacterial endophathalmitis, intravitreal therapy is recommended because of blood-ocular barrier), prostate, and bone, and infections in these sites and sites where there is considerable tissue necrosis (as in burn, penetration problem) require higher dosages of antimicrobials. Higher doses are also required when infection involves avascular tissues, as in bacterial endocarditis. Clindamycin and lincomycin penetrate deep tissues and are useful in the therapy of osteomyelitis caused by staphylococci and Bacteroides fragilis.

Introduction In 1877, Pasteur and Joubert observed that anthrax bacilli grew rapidly when inoculated into sterile urine but failed to multiply and soon died if one of the common bacteria of the air was introduced in the urine at the same time. They commented that life destroys life among the lower species even more than among higher animals and plants. In 1928, Alexander Fleming, while investigating staphylococcus variants at St. Mary s Hospital in London, observed that a mould contaminating one of his cultures caused lysis to the bacteria in its vicinity. Fleming called the antibacterial substance penicillin because the mould belonged to the genus penicillium. In 1941, at Oxford University, Florey and co-workers managed to prepare enough of penicillin to treat for 24 hours with a remarkable result one patient desperately ill with staphylococcal and streptococcal infections resistant to all available antimicrobials.

The in vitro bacterial sensitivity to a certain drug cannot always determine its therapeutic suitability. In severe infections caused by extended spectrum β-lactamases (ESBLs) producing bacteria that in vitro may appear susceptible to the 3rd generation cephalosporins but in vivo with poor therapeutic outcome. In addition, its pharmacokinetic properties may determine its suitability depending on the site of infection. Thus, cephalosporins (except 3rd generation, SC3), aminoglycosides, clindamycin, lincomycin, and amphotericin B do not reach the cerebrospinal fluid (CSF) in sufficient amounts to counter infection in the brain or meninges. When these drugs are indicated they have to be given intrathecally.

Antibacterial Spectrum Two methods are used to determine bacterial sensitivity to antibiotics, in the first organisms are inoculated into plates of culture medium that contain diminishing drug concentration. After incubation the lowest concentration that inhibits bacterial growth (minimal inhibitory concentration, MIC) can be determined. Generally, bacteria are considered sensitive when the MIC is lower than the concentration that can be achieved in blood. The second (KirbyBauer) method employs standardised drugimpregnated filter paper discs onto the surface of a seeded agar plate and measuring the zone of growth inhibition.

Biliary and urinary tracts On the other hand, ampicillin, amoxicillin, ceftriaxone, tetracyclines (concentrations in bile exceed those in serum tenfold) and rifampicin achieve high concentrations in the bile and hence may be suitable for the treatment of biliary tract infections. For this reason, typhoid carriers are treated by ampicillin and not by chloramphenicol which is not suitable in this condition. Nitrofurantoin achieves therapeutic levels only in the urine and should be used only in urinary tract infection (UTI); whereas, erythromycin is only partly excreted in

Site of Infection The desired peak concentration of a drug at the site of infection should equal at least 4 times the MIC. Deep-seated infections are 79

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urine and is therefore unsuitable for the treatment of UTI. It should be noted that practically all antimicrobial drugs that are used in the treatment of UTI share a common pharmacokinetic property, that is eliminated largely unchanged through urinary excretion. Therefore, they can reach the offending microorganisms from the circulation as well as from the lumen of the urinary tract. This is why a sub-MIC blood level of gentamicin is generally effective in the treatment of UTI but not effective in the treatment of burn for the same offending microorganism (e.g. Pseudomonas aeruginosa).

pH The antibacterial potency of an antibiotic in vivo may vary and be quite different than in vitro. The low pH in abscess cavities, pleural space, CSF, and urine may reduce the antimicrobial activity of gentamicin (weak base), erythromycin, and clindamycin. The use of sodium bicarbonate (alkalinisation of urine) as a soothing agent also promotes the antibacterial activity of aminoglycosides (e.g.

Substrate

Sulphonamides Trimethoprim

gentamicin). Acidification of urine with ascorbic acid increases the antibacterial activity of cloxacillin and tetracycline, and is essential for the action of hexamine mandelate (mandelamine, which is in acidic urine slowly hydrolysed to formaldehyde and ammonia) and nitrofurantoin. It is worth noting that certain microorganisms such as Proteus species and Pseudomonas aeruginosa grow better in alkaline media. While others such as Escherichia coli (the growth of which discouraged by alkalinisation of urine) and Mycobacterium tuberculosis grow better in acidic media.

Blood level Measurement of blood levels of antibiotics is useful particularly in non-responding patients and with antibiotics with high toxicity such as aminoglycosides (e.g. gentamicin). Antimicrobials may induce hypersensitivity reactions (which are not dose-related); toxic and irritative effects (which are dose-related).

Penicillins Cephalosporins Imipenem Aztreonam

1

Cell Wall

4 Enzyme

Tetracycline Chloramphenicol Erythromycin DNA Clindamycin Na fusidate mRNA Spectinomycin (Aminoglcosides)

Ciprofloxacin Rifampicin Nalidixic acid Metronidazole 2

Protein

Cell Membrane

5 Polymixin B Amphotericin B

DNA

3 Rough Endoplasmic Reticulum

Fig.4.1. A schematic representation of the principal five different antibacterial mechanisms of action: 1. Intermediary metabolism block (competitive substrate inhibition, enzyme inhibition) e.g. sulphonamides and trimethoprim. 2. Nucleic acid metabolism (block RNA and DNA), e.g. rifampicin. 3. Protein synthesis block by inhibition of ribosomal function, e.g. tetracycline. 4. Cell wall damage by impairment of peptidoglycan synthesis, e.g. penicillin, this gives rise to swelling and rupture. 5. Cytoplasmic membrane damage by disorganising the cell membrane structure resulting in an increase in membrane permeability, e.g. polymixin B. 80

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Table 4.1. A classification of the most important antimicrobial agents according to their mode of action. Drug Sulphonamide

Mode of Action Folic acid synthesis inhibition

Trimethoprim

Folinic acid synthesis inhibition Cell wall damage

Penicillins Cephalosporins Imipenem Vancomycin Aztreonam Tetracyclines Chloramphenicol Erythromycin Clindamycin Spectinomycin Aminoglycosides Polymixin B Amphotericin B Nystatin Rifampicin Ciprofloxacin Metronidazole Nalidixic acid

Protein synthesis inhibition

Activity Bacteriostatic (When combined Bactericidal) Bacteriostatic Bactericidal

Bacteriostatic

Membrane damage

Nucleic acid synthesis inhibition

Bactericidal Bactericidal

Bactericidal

certain sites of infections may show resistance to antimicrobial agents (failure of treatment), as in meningococcal meningitis due to low penetration of antimicrobials through the blood brain barrier resulting in insufficient drug concentration in the spinal cerebral fluid. Or perhaps the bacterial population may exist in a fibrotic tissue (like that may occur in tuberculosis) and not being reached by antimicrobials because of low perfusion to the site of infection. This can also be true when the bacterial population is in a site with low tissue viability and considerable necrotic debris as in burn wounds. Antibiotic resistance can also be observed for bacteria growing in biofilms. Bacterial biofilms are frequent problematic infections, like those associated with cystic fibrosis, chronic bronchitis, osteomylitis, and foreign-body associated infections. Bacteria growing in

Bacterial Drug Resistance The origin of drug resistance may be nongenetic or genetic. 1. Nongenetic Origin: Bacteria may be sensitive to certain antibiotics in vitro but may appear to be resistant in vivo. This may be true with infections with intracellular microorganisms such as in brucellosis, salmonellosis, and tuberculosis. In these cases, drugs may fail to reach the intracellular site of action and therefore resulting in failure of treatment. Active replication of bacteria is usually required for the action of most antibiotics. Consequently, bacteria that are metabolically inactive, i.e. being dormant as may occur in tuberculosis, can exhibit resistance to antimicrobial agents. Further, 81

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• Transduction: Plasmid DNA is enclosed in a bacterial virus (bacteriophage) and transferred by the virus to another bacterium of the same species (as in the case of staphylococci). • Transformation: Naked DNA passes from one cell of a species to another cell thus altering its genotype. • Transposition: A transfer of short DNA sequences (transposons, transposable elements) occurs between one plasmid and another or between a plasmid and a portion of the bacterial chromosome within a bacterial cell.

biofilms are more resistant than those under a planktonic way of life to the action of phagocytic cells antibacterial activity as well as the action of antibiotics. 2. Genetic Origin: Most drug-resistant microbes emerge as a result of genetic change and subsequent selection processes by antimicrobial drugs. a. Chromosomal Resistance: This develops as a result of spontaneous mutation, the presence of the antimicrobial drug serves as a selecting mechanism to suppress susceptible organisms and favour the growth of drug-resistant mutants. Antibiotic resistance can arise from a number of mechanisms involving mutation of chromosomal genes. Such mechanisms, usually involving mutations in genes encoding drug targets or systems that affect drug accumulation, are defined as endogenous resistance mechanisms, to distinguish them from the exogenous resistance mechanisms that are typically mediated by the acquisition of plasmids and transposons.

Selection and Emergence of Drug Resistance The use of antimicrobial agents promotes the emergence of drug resistant mutants. However, it should be stressed that although antimicrobials promote drug resistance, they are not usually mutagenic and do not directly cause the genetic changes that are responsible for reduced drug sensitivity. Spontaneous mutation and conjugation are random events whose incidence is independent of drug use. Antimicrobial agents simply serve to make conditions favourable for selection and emergence (overgrowth) of those microorganisms that possess drug resistance.

b. Extrachromosomal Resistance: Bacteria often contain extrachromosomal genetic elements called plasmids. R factors are a class of plasmids that carry genes for resistance to one and often several antimicrobial drugs and heavy metals. Plasmid genes for antimicrobial resistance often control the formation of enzymes capable of destroying the antimicrobial drugs. Genetic material and plasmids can be transferred by the following mechanisms: • Conjugation: A unilateral transfer of genetic material between bacteria of the same or different genera occurs during a mating (conjugation) process. Plasmid or other DNA is transferred through these protein tubules from the donor to the recipient cell. A series of closely linked genes, each determining resistance to one drug, may thus be transferred from a resistance to a susceptible bacterium. This is the commonest method by which multidrug resistance spreads among different genera of gram-negative bacteria.

It is worth recalling the two main aspects of the ecology of microorganisms: 1. Microorganisms release chemicals that are toxic to other microorganisms. 2. Microorganisms within one ecological niche (location, e.g. intestine, genitourinary tract, skin) competes with one another for available nutrients. In the absence of drugs, these different microorganisms in a one location will serve to keep one another in check. Further, if all these microorganisms are drug sensitive, then the use of antimicrobial agents will be equally detrimental to all members of the population and, thus, will not promote the growth of any individual. On the other hand, if there is a drug resistant microorganism

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present, antimicrobial will favour the overgrowth of that microorganism. Therefore, the introduction of antimicrobial agents will kill sensitive microorganisms (pathogenic and/or non-pathogenic commensals) resulting in:

vulvovaginitis that often due to fungi). Opportunistic infections can occur if the patient develops an impaired immune response due to the disease or other drugs (anticancer drugs, immunosuppressive drugs).

1. Elimination of toxic substances (produced by those microorganisms) 2. Removal of competition for available nutrients

Host Factors There are two factors, host defences and site of infection, which are unique to the selection of antimicrobial agents. Other host factors like age, pregnancy, and previous drug reactions, are same as those considered when prescribing any other medication.

Thereby making conditions even more favourable for the drug-resistant microorganism to flourish. In absence of antimicrobial agents, it appears that drug resistance is of no benefit to microorganisms; it is only when antimicrobial agents are used, these agents will favour overgrowth of those microorganisms that are resistant.

Host defences The immune system plus the phagocytic cells (macrophages, leukocytes), together form the host defences. These defences are essential for antimicrobial therapy to be successful. It should be stressed that, usually, antimicrobial therapy used for the treatment of infection do not produce cure on its own. The objective of antibiotic treatment is to suppress microbial growth to the point at which the balance is tipped in favour of the host. Bactericidal agents are preferred when treating immunocompromised hosts, and even these agents may prove inadequate.

Therefore, emergence of resistance can be avoided if unnecessary use of antibiotics can be prevented, particularly broad-spectrum and if antibiotics are properly selected on the basis of in vitro testing and if high enough concentrations are used. Moreover, if proper drug combination are used, e.g. rifampicin and isoniazid (INH) as in mycobacterial infection.

Antibiotic-resistant cells may be present in susceptible bacterial populations and can emerge under selective pressure.

The objective of antibiotic treatment is to suppress microbial growth to the point at which the balance is tipped in favour of the host defences without which drugs cannot combat infections.

Superinfections More than 300 species of microorganisms normally inhabit the body (normal flora). With the depression of non-pathogenic commensals, drug resistant pathogenic bacteria or foreign organisms can more easily initiate superinfection, particularly in the gastrointestinal tract (e.g. psedomembranous colitis, nowadays known as antibiotic-associated colitis, after clindamycin due to Clostridium difficile infection), upper respiratory tract (pneumonia and sepsis caused by staphylococci, Gram negative bacilli, and Candida albicans) or genitourinary tract (itching and

Site of Infection It is essential that an antimicrobial agent must be present at the site of infection in a concentration greater than the MIC. The MIC can be difficult to achieve for infections at certain sites because of impeded drug penetration. In meningitis, because of the blood brain barrier (BBB), certain drugs cannot achieve the MIC. In order to 83

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example, sulphonamides can reach levels in milk that are sufficient to cause kernicterus in nursing newborns. As a general rule drugs including antibiotics should be avoided by breast-feeding women.

overcome this problem the following may be considered: 1. Select a drug that can readily cross the BBB. 2. Inject antibiotic intrathecally (directly into the subarachnoid space)

Previous allergic reactions

In infected abscesses, poor vascularity and the presence of pus and other material hinder access to drugs. In this condition surgical drainage is indicated.

Severe allergic reactions are more common with penicillins than with any other group of drugs. As a general guideline, patients with a history of allergy to penicillins should not receive them again except in life-threatening infections for which no suitable alternative is available.

Further, in the presence of foreign material (like cardiac pacemakers, prosthetic joints or heart valves, synthetic vascular shunts, renal stones) present a special local problem. Phagocytic cells respond to these materials in an attempt to destroy them. This will distract phagocytes and make them less effective to deal with bacteria. Therefore, bacterial vegitations that difficult to penetrate by drugs result in such sites of infection as in endocarditis. When treating such infections, recurrence and failure are common. Frequently, the infection can be eliminated only by removing the foreign object.

Genetic factors Genetically determined unwanted drug reactions can be observed with some antimicrobial agents. Sulphonamides can cause haemolysis in glucose-6-phosphate dehydrogenase deficient patients. The rate of hepatic inactivation of drugs can also be determined genetically. There are slow and fast drug metabolisers. For example, without adjusting the dose, when giving isoniazid to slow metabolisers it will accumulate to toxic levels producing peripheral neuropathy. On the other hand, in fast metabolisers, isoniazid level may remain subtherapeutic while the high level of its metabolites may cause hepatitis.

Age Infants and the elderly are unusually vulnerable to drug toxicity due to poorly developed kidney and liver function. For example, the use of sulphonamides in newborns can produce kernicterus (a severe neurological disorder caused by displacement of bilirubin from plasma proteins). In the young, the tetracyclines bind to developing teeth causing discolouration, therefore, tetracyclines are contraindicated in children under 8 years of age.

Therapy with Combination

Antimicrobial

Antimicrobial agents are either bactericidal or bacteriostatic. When used concurrently these agents may act in an additive, synergistic or antagonistic manner. A more than additive response (synergistic) can be expected when two bacteriostatic drugs are combined (e.g. trimethoprim plus sulphamethoxazole). Bactericidal drugs act maximally on rapidly multiplying bacteria therefore the combination of a bactericidal (e.g. penicillin) and a bacteriostatic (e.g. tetracycline) may act antagonistically. There is only one clinically important and well established report of antagonism (early 1950s); stating that penicillin alone produced 80% cure-rate in meningococcal meningitis

Pregnancy and lactation Several antimicrobial agents can cross the placenta, posing risk to the developing foetus. The well-known example is tetracyclines that can stain immature teeth. Further, the consumption of aminoglycosides (e.g. streptomycin) in pregnancy can lead to foetal deafness. Drugs can enter breast milk; for 84

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Majid A. K. Lafi

aminoglycoside to reduce bacterial protein synthesis.

while addition of oxytetracycline (penicillin plus oxytetracycline) produced 20% cure rate in meningococcal meningitis. However, there is now a long list of clinically useful combinations of bactericidal and bacteriostatic drugs including penicillins with tetracycline in pelvic infections, and well accepted combination of streptomycin with tetracycline in brucellosis etc. It may be justified to say that the concept of prohibiting the combination of bactericidal with bacteriostatic agents is a myth.

Disadvantages combination

of

antibacterial

1. Increased risk of toxic and allergic reactions 2. Possible antagonism of antimicrobial actions 3. Increased risk of superinfection 4. Selection and emergence of drug resistant bacteria 5. Increased cost to the patient

Indications for use of antimicrobial combination 1. Initial therapy of severe infection of unknown aetiology in neutropenic host until the infecting organism has been identified. 2. Mixed infections (e.g. brain abscesses, pelvic infections, infections resulting from perforation of abdominal organs) 3. Prevention of resistance: Although the combination of antimicrobial agents usually promote emergence of resistance but in some cases such as infection with Mycobacterium tuberculosis, where combination is used specifically to suppress the emergence of resistant bacteria. 4. Decreased toxicity: The addition of flucytosine to amphotericin B in the treatment of fungal meningitis makes it possible to reduce the dose of amphotericin B, thus, reduced risk of renal damage. 5. Enhanced antibacterial action: In enterococcal endocarditis, the combination of penicillin and an aminoglycoside is used. Penicillin weakens bacterial cell wall providing better access for the

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Within one ecological location (e.g. skin) Produce Kill 1. microorganisms bbr toxic compounds br other organisms (pathogenic & nonpathogenic) 2. microorganisms compete with each other for nutrients In drug-free Conditions Organisms keep one another in check (no overgrowth of a certain organism)

When using antimicrobial agents kill Antimicrobial agents bbr sensitive organisms

Selection 1. Elimination of toxic substances 2. Removal of competition for nutrients

Emergence Overgrowth of resistant organisms (including G ve non-pathogenic commensals)

Transfer resistance to pathogens Extrachromosomal (Plasmid mediated) (conjugation, transduction, transformation, transposition, transfection)

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Table 4.2. Classification of the important antimicrobial drugs based on principal therapeutic objectives by susceptible organisms. Susceptible Organisms

Antibacterial Drugs Narrow Spectrum Agents Penicillin G Penicillinase-Resistant Penicillin Erythromycin Clindamycin Vancomycin Sodium fusidate Cephalosporins (1st & 2nd generation) Aminoglycosides

Primarily gram positive cocci and gram positive bacilli

Primarily gram positive cocci

Metronidazole Isoniazid (Rifampicin) Ethambutol Pyrazinamide Dapsone Broad Spectrum Agents Broad spectrum penicillins (e.g. ampicillin, amoxicillin) Cephalosporins (3rd generation, e.g. cefotaxime) Tetracyclines Chloramphenicol Trimethoprim Sulphonamides Ciprofloxacin Imipenem

87

Primarily gram aerobes Anaerobic bacilli

negative

Mycobacteria

Gram positive cocci and gram negative bacilli

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BETA-LACTAM ANTIMICROBIAL DRUGS

Bacterial resistance to penicillins determined primarily by three factors:

PENICILLINS In 1929, Alexander Fleming reported his discovery of penicillin. In 1941, Florey and co-workers managed to prepare enough of penicillin to treat for 24 hours with a remarkable result one patient seriously ill with staphylococcal and streptococcal infections resistant to all available antimicrobials. Ten years later, virtually unlimited amounts of penicillin G were available for clinical use. Since then numerous semisynthetic penicillins were developed, which are superior to penicillin G because they possess the advantages of being stable to acid pH, resistant to β-lactamase, and active against both gram-positive and gram-negative bacteria.

is

1. Inability of a penicillin to reach its site of action 2. Inactivation of a penicillin by bacterial enzymes (penicillinases) 3. Alteration in target PBPs The bacterial cell envelope primarily consists of rigid cell wall plus an outer membrane. The cell wall itself doses not represent a diffusion barrier to penicillins. However, in gram negative bacteria, the outer membrane is complex in nature and does not allow penetration of many penicillins (this is not the case with gram positive bacteria). Therefore, some penicillins are ineffective against gram negative bacteria because they are unable to reach their sites of action is not a problem.

Mechanism of Action

The principal mechanism of acquired resistance to penicillins is production of penicillinases, which are enzymes that cleave β-lactam ring, and therapy makes penicillins inactive. Penicillinases are classified within a larger enzyme family known as β-lactamases, more than 100 different β-lactamases have been identified. These enzymes differ in their abilities to inactivate specific β-lactam antibiotics. Some of these enzymes, like those produced by Staphylococcus aureus, Haemophilus species, and E coli, are relatively narrow in substrate specificity and will hydrolyse penicillins and not cephalosporins. On the other hand, other βlactamases, like those produced by Pseudomonas aeruginosa and Enterobacter species, are much broader in spectrum and will hydrolyse both penicillins and cephalosporins. Carbapenems such as imipenem, which are highly resistant to hydrolysis by penicillinases and cephalosporinases, are hydrolysed by metallo-¾-lactamase.

The penicillins weaken the cell wall, causing bacteria to take up water and rupture. Hence, penicillins are usually bactericidal. This action can be achieved by following two possible processes: 1. Inhibition of transpeptidases 2. Disinhibition (activation) of autolysins Transpeptidases are bacterial enzymes essential for cell wall synthesis; the autolysins are bacterial enzymes that cleave bonds in the cell wall. Thus, penicillins can simultaneously inhibit synthesis of cell wall and promote its active destruction. Penicillin binding proteins (PBPs, penicillin receptors) have been isolated from bacteria. These binding proteins are located on the outer surface of the cytoplasmic membrane and are thought to be the receptors through which the penicillins act to inhibit transpeptidases and disinhibit autolysins.

Bacterial Resistance to Penicillins

Penicillinases are made by both gram negative and gram positive organisms. Gram positive bacteria produce larger amount of penicillinases and then release them into 88

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penicillin derivative introduced by this time.

surrounding medium. On the other hand, gram negative bacteria produce penicillinases in relatively small amounts and, rather than exporting them to the environment, secrete them into the periplasmic space (i.e., the space that lies external to the cytoplasmic membrane but within the confines of the cell envelope), see Fig.4.2.

Cell envelope

PBP

Penicillins Large amount of penicillinase

PBP (receptor)

Inside of bacterial cell

Periplasmic space

G +ve bacteria

PBP

PBP

was

To date there are no known strains of S aureus that produce β-lactamases capable of inactivating methicillin or related penicillinases-resistant penicillins. However, there are strains of S aureus that are resistant to these drugs. This resistance to methicillin appears to be due to the production of altered penicillin binding proteins (PBPs, receptors) to which the penicillinase-resistant penicillins are unable to bind. At present, vancomycin is the drug of choice for use against methicillin-resistant S aureus (MRSA).

Transfer of resistance was discussed earlier in this chapter. It is of particular importance with Staphylococcus aureus. When penicillin was introduced by Florey in the early 1940s, all strains of Staphylococcus aureus were sensitive to the drug. However, by 1960, about 80% of S aureus (hospital) isolates showed penicillin resistance. Luckily, a

Inner membrane

lactamases

G –ve bacteria Small amount of penicillinase Penicillins

&&

Outer membrane

Cell wall

Fig.4.2. A simplified schematic representation showing the factors that influence the activity of penicillins. Note: a penicillin agent has to reach its site of action, penicillin-binding protein (PBP, receptor). This can be hindered by mainly two ways: 1. Penicillins being unable to penetrate the outer membrane (particularly in gram negative, G ve, bacteria) 2. Penicillins being inactivated by penicillinases (as indicated by solid dots).

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Chemistry of Penicillins

as sodium and potassium salts that are quite water-soluble.

All members of penicillin-family have a common dicyclic nucleus, which is composed of the β-lactam and thiozolidine rings (Fig.4.3). Variation in the side chain confers differences in antibacterial activity, absorption, excretion and protein binding. The common nucleus means that a patient, who is hypersensitive to one penicillin is sensitive to all others. Penicillins also show type II reaction (autoallergy).

Pharmacokinetics Benzylpenicillin (crystalline penicillin) is rapidly absorbed from the gut but is inactivated to a major degree by gastric acid; thus, it is not active when given orally. When given parenterally, it is rapidly distributed throughout the body but does not readily pass into the cerebrospinal fluid unless the meninges are inflamed. Benzylpenicillin is rapidly excreted (t 30 minutes) via the urine mainly unchanged. Not only is filtered at the glomerulus (10%) but is also actively secreted (90%) by the kidney tubules.

Side chain S R

N C C  B  A C N O

β-lactamase

C  C

Administration may be as often as 12 times daily to maintain therapeutic blood levels. The frequency of administration can be decreased by delaying absorption from the site of administration by using less soluble preparations.

CH 3 CH3 COOH-

Procaine benzylpenicillin may give antibacterial blood levels for up to 24 hours after a single dose. it is often combined with benzylpenicillin so that high initial levels of penicillin are quickly reached. Further, benzathine benzylpenicillin can give significant blood levels for a week or more after a single dose. it is also possible to block the excretion of penicillin via renal tubules by drugs such as probenecid; a practice used in the treatment of some infections (e.g. rectal and genital gonorrhoea, amoxicillin 3 g orally once plus probenecid 1 g orally once).

Salt formation

Fig. 4.3. A simplified representation of the core structure of penicillin. Benzylpenicillin (penicillin G) when the side chain (R) is benzyl group. The ring marked A is the thiozolidine ring and the ring marked B is the β-lactam ring. The penicillins are susceptible to bacterial metabolism and inactivation by amidases and lactamases at the points shown.

NARROW SPECTRUM PENICILLINS

Acid resistant penicillins: phenoxymethylpenicillin (penicillin V) and phenethicillin that are inactivated by penicillinases.

Penicillinase Sensitive Penicillins Benzylpenicillin

Penicillinase Resistant Penicillins (Antistaphylococcal Penicillins)

Benzylpenicillin (penicillin G) was the first available and the most active. Despite the introduction of many newer antibiotics, penicillin G remains a drug of choice for a wide variety of infections. It is active against gram positive and gram negative cocci, and gram positive bacilli. Penicillin G is available

Penicillin resistant penicillins include methicillin, cloxacillin, dicloxacillin, and nafcillin. These penicillins have a side chain that protects the β-lactam ring from being broken down by penicillinases. In penicillin allergic patients, other antistaphyloccocal agents may be used, such as 1st generation 90

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cephalosporins, clindamycin (or lincomycin), or vancomycin. While, ampicillin, amoxicillin, carbenicillin and tetracycline are not effective against penicillinases-producing staphylococci.

Haemophilus influenzae. Ampicillin achieves therapeutic concentrations in the cerebrospinal fluid only during inflammation. On the other hand, amoxicillin does not reach adequate concentrations in the central nervous system and is not appropriate for meningitis therapy. It is now recognised that penicillinase producing strains of Haemophilus influenzae are emerging, therefore, chloramphenicol is added to the initial regimen until ampicillin sensitivity of the pathogen has been determined. It is also as first or second choice agent for treating infections caused by Listeria monocytogenes. Escherichia coli, Salmonella, and Shigella.

Methicillin resistant staphylococcal strains are also resistant to other penicillinases resistant penicillins, and cephalosporins. This resistance appears to be due to the production of altered PBPs to which methicillin unable to bind. They should be treated by vancomycin, ciprofloxacin, co-trimoxazole, sodium fusidate or (rifampicin).

Beta-lactamase inhibitors

The most common adverse effects with ampicillin are rashes and diarrhoea, which occur more frequently with ampicillin than with any other penicillin.

Clavulanic acid (an irreversible antagonist to β-lactamase) is added to amoxicillin inhibiting the inactivation of amoxicillin. This fixed combination is known as coamoxiclav (augmentin ). Sulbactam is another β-lactamase inhibitor and usually combined with ampicillin, while tazobactam is combined with piperacillin.

Amoxicillin Amoxicillin (t 1.7 hour) is similar to ampicillin in structure and actions. However, ampicillin is more sensitive to gastric acid and more affected by food. Thus, when the two drugs are administered orally in equivalent doses, blood levels of amoxicillin are greater than those of ampicillin. Diarrhoea is less associated with amoxicillin than ampicillin, perhaps because more ampicillin remains unabsorbed in the intestine. Therefore, when oral therapy is indicated amoxicillin is usually preferred.

BROAD SPECTRUM PENICILLINS (AMINOPENICILLINS) Aminopenicillins (e.g. ampicillin and amoxicillin) are penicillins with modification of the side chain leading to a broadened antibacterial activity. They have the same antibacterial spectrum as benzylpenicillin with increased activity against certain gramnegative bacilli, including Haemophilus influenzae, Escherichia coli, Salmonella and Shigella. This increased spectrum of activity is largely due to an increased ability to penetrate the gram negative cell envelope. All aminopenicillins are sensitive to penicillinases; hence, they are ineffective against most infections caused by Staphylococcus aureus.

EXTENDED SPECTRUM PENICILLINS (ANTIPSEUDOMONAL PENICILLINS) Antipseudomonal penicillins are ticarcillin, piperacillin, carbenicillin, azlocillin, and mezlocillin. The antibacterial spectrum of these drugs includes those organisms that are susceptible to the aminopenicillins plus Pseudomonas aeruginosa, Enterobacter species, Proteus (indole positive), Bacteroides fragilis, and many Klebsiella. Some Pseudomonas aeruginosa developed resistance to ticarcillin. Generally, ticarcillinresistant strains are resistant to new drugs.

Ampicillin Ampicillin (t 1.3 hour) was the first broad spectrum penicillin to be introduced to clinical practice. It is a drug of first choice for meningitis and other infections caused by 91

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2. Seizures (in patients with renal failure, penicillin in high doses can cause seizures, perhaps due to salt disturbances) 3. Gastrointestinal disturbances (large doses of penicillins given orally may lead to gastrointestinal upset, nausea, vomiting, and diarrhoea) 4. Neutropenia (with nafcillin) 5. Hepatitis (with oxacillin) 6. Pseudomembranous colitis (more likely with ampicillin) 7. Secondary infections (e.g. vaginal candidiasis) 8. Skin rashes (that are not allergic in nature, with ampicillin and amoxicillin)

Systemic pseudomonal infections are best treated with an antipseudomonal penicillin plus an aminoglycoside or ceftazidime, for synergistic effect. All the extended spectrum penicillins are susceptible to penicillinases; therefore, they are ineffective against most strains of Staphylococcus aureus. All these antipseudomonal penicillins except mezlocillin, inhibit platelet aggregation, and although seldom, promoting bleeding.

ADVERSE EFFECTS 1. Hypersensitivity reactions: including a. Anaphylactic shock, very rare, 0.05% of recipients) b. Interstitial nephritis (autoimmune reaction to a penicillin-protein complex) c. Eosinophilia d. Haemolytic anaemia

Cautions 1. Renal impairment (penicillins with potassium salt, to avoid hyperkalaemia) 2. Heart failure (penicillins with sodium salt, to avoid oedema)

Table 2.3. A summary of the classification of penicillins and their antimicrobial activity Penicillin Class Narrow spectrum penicillins (penicillinase sensitive)

Narrow spectrum penicillins (penicillinase resistant) (antistaphylococcal penicillins) Broad spectrum penicillins (Aminopenicillins) (good permeability) (penicillinase sensitive) Extended spectrum penicillins (antipseudomonal)

(extended permeability) (penicillinase sensitive)

Drug Benzylpenicillin Crystaline penicillin G Aqueous procaine penicillin G Benzathine penicillin G Penicillin V Methicillin Cloxacillin Dicloxacillin Nafcillin Ampicillin Amoxicillin

Carboxypenicillins Ticarcillin Carbenicillin Ureidopenicillins Piperacillin Azlocillin Mezlocillin

Antimicrobial activity Streptococcus species Neisseria species Many anaerobes Spirochaetes (e.g. Treponema pallidum) Staphylococcus aureus

Haemophilus influenzae Escherichia coli Proteus mirabilis Enterococci Neisseria gonorrhoea Same as broad spectrum penicillins plus Pseudomonas aeruginosa, Enterobacter species, Proteus (indole positive) Bacteroiodes fragilis, Many Klebsiella

adverse effects. Because cephalosporins are resistant to many β-lactamases (penicillinases) they usually have a broader spectrum of activity than penicillins. They are

CEPHALOSPORINS Cephalosporins resemble penicillins in terms of chemistry, mechanism of action and 92

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inactivated by other β-lactamases called cephalosporinases. It is worth noting that cephalosporins are not effective against enterococci (as in endocarditis where a penicillin plus an aminoglycoside are effective) and Listeria monocytogenes (as in meningitis where amoxicillin is effective). For simplicity purposes, cephalosporins are classified into four generations depending on their spectrum of antibacterial activity, stability to β-lactamases and ability to penetrate the blood brain barrier.

The 1st generation cephalosporins are rarely the drug of first choice for any infection. They do not penetrate the blood brain barrier and therefore cannot be used to treat meningitis.

SECOND GENERATION (INTERMEDIATE SPECTRUM) CEPHALOSPORINS

FIRST GENERATION (NARROW SPECTRUM) CEPHALOSPORINS

This is a heterogeneous group of drugs with marked individual differences in antibacterial activity, pharmacokinetics, and toxicity. As a general rule they are active against bacteria affected by 1st generation cephalosporins with some extension to cover gram negative organisms; for example cephalothin-resistant Klebsiella are sensitive. However, they appear to be less active against gram positive bacteria than the 1 st generation cephalosporins.

This group includes cephalexin (Keflex ) that is orally active and cephalothin (Keflin ) that should be administered parenterally. In Iraq, best familiarity with 1st generation cephalosporins have been made with these two agents. Generally, these drugs are very active against gram positive cocci including pneumococci, streptococci, and staphylococci (except methicillin-resistant strains). They have moderate activity against Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, but with poor activity against Pseudomonas aeruginosa, Proteus (indole positive), Enterobacter and Bacteroides fragilis.

This group comprises a large number of drugs including cefuroxime (oral and parenteral) that is used to treat communityacquired pneumonia, particularly in cases where β-lactamase-producing Haemophilus influenzae or Klebsiella pneumoniae is the offending organism. Cefoxitin (parenteral) is another member of this group, particularly useful in mixed anaerobic infections as peritonitis.

Pharmacokinetics THIRD GENERATION (BROAD SPECTRUM) CEPHALOSPORINS

Oral and parenteral 1st generation cephalosporins are excreted mainly by the kidney through glomerular filtration and tubular secretion into the urine. By blocking tubular secretion, probenecid may increase serum levels markedly. Therefore, dose adjustments must be made for impaired renal function.

This group includes cefotaxime (Claforan ), ceftriaxone, ceftazidime, ceftizoxime, cefixime (Suprax ), and cefoperazone. This group is characterised by their extended coverage of gram-negative bacteria and better ability to cross the blood brain barrier. The 3rd generation cephalosporins are more active against Citrobacter, Serratia marcescens, and Providencia in addition to β-lactamase producing strains of Neisseria and Haemophilus.

Indications 1. Urinary tract infections 2. Minor staphylococcal lesions 3. Minor polymicrobial infections (e.g. cellulitis or soft tissue abscess) 93

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warfarin) that may be prevented by concurrent administration of vitamin K. 4. Superinfection (secondary infection): particularly with 2nd and 3rd generation drugs being not effective against some gram positive organisms, and fungi. Hence, proliferation of these organisms may lead to superinfection.

Of this group, ceftazidime and cefoperazone have considerable activity against Pseudomonas aeruginosa. Like the 1st and 2 nd generations, this group is not active against Enterobacter species (producing constitutive chromosomal β-lactamase). Cefixime shows little or no activity against pneumococci and Staphylococcus aureus. It is note worthy that of the 3rd generation cephalosporins cefoperazone and ceftriaxone are excreted largely from the biliary tract and therefore their dosage not influenced by renal impairment. For more details of pharmacokinetics see table 4.4.

OTHER BETA-LACTAM DRUGS These are structurally related to penicillins and cephalosporins. Some schools of thought list them as the 4th generation cephalosporins; however, it decided to put them as a separate miscellaneous group.

FOURTH GENERATION (EXTENDED-BROAD SPECTRUM) CEPHALOSPORINS

Aztreonam is a monocyclic β-lactam (monobactam) with antibacterial activity similar to that of antipseudomonal aminoglycosides.

The representative drug of the 4th generation cephalosporins is cefepime. Its pharmacology is very much similar to that of the 3rd generation cephalosporins, but it is characterised by being more resistant to hydrolysis by chromosomal β-lactamases and therefore active against Enterobacter. Otherwise, it shows similar antibacterial activity to that of the 3rd generation drugs, such as being effective against Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae and Enterobacteriaceae.

Imipenem (of the group carbapenems) is the drug of choice in the treatment of Enterobacter infections, as it is resistant to the β-lactamase produced by these organisms. Imipenem is also effective against Pseudomonas aeruginosa but these organisms may rapidly develop resistance to imipenem; for this reason a concurrent use of aminoglycoside is recommended. It is recommended for serious infections (such as neonatal sepsis) caused by extended spectrum β-lactamases (ESBLs) producing bacteria; it has been found to be more effective (markedly less mortality) than the 3rd generation cephalosporins. Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in low urinary concentrations. Therefore, it is coadministered (fixed combination) with an inhibitor of renal dehydropeptidase, cilastatin.

ADVERSE EFFECTS 1. Hypersensitivity reactions: (identical to that of penicillins) including anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and haemolytic anaemia; cross-allergenicity between penicillins and cephalosporins is about 5-10%. 2. Renal toxicity including interstitial nephritis and tubular necrosis (particularly the 1st generation drugs) 3. Bleeding tendencies (particularly with 3rd generation drugs) due to increased prothrombin time (similar action to

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Table 4.4. A summary of the pharmacology of cephalosporins1 including classification, antibacterial activity, and some pharmacokinetic properties.

Cephalosporin class

Drugs

1st Generation (Narrow spectrum)

Cephalexin Cephalothin Cephazolin2

2nd Generation (Intermediate spectrum) 3rd Generation (Broad spectrum)

Antibacterial

90 50

Pneumococci, Streptococci, Staphylococci Haemophilus influenzae Klebsiella pneumoniae Mixed anaerobic infections (B. fragilis) Citrobacter Serratia marcescens Providencia Neisseria Haemophilus Pseudomonas aeruginosa

Cefuroxime Cefoxitin Cefotaxime (Claforan )

50

Ceftriaxone3 5

Cefoperazone Ceftazidime Ceftizoxime Cefixime6

_4 30 90 90 50

th

4 Generation (Extended Broad spectrum)

Antibacterial activity (specific organisms)

Enterobacter plus those sensitive to the 3rd generation drugs

Cefepime7

1

Cephalosporins are ineffective against methicillin-resistant Staphylococcus aureus (MRSA), Listeria monocytogenes, Clostridium difficile and the enterococci. 2 Cefazolin has a longer duration of action and a similar spectrum of activity compared to other 1st generation drugs. It exhibits good penetration into bone. 3 Ceftriaxone (t 7-8 hours) can be injected once every 24 hours. A single daily 1 g dose is sufficient for most serious infections, with 4 g once daily recommended for treatment of meningitis. Almost all the remaining agents in this group (t ≤ 2 hours) can be injected every 6-8 hours in dosages between 2 and 12 g/d, depending on severity of infection. 4 Renal inactivation is similar to that of cefoperazone. 5 Cefoperazone and ceftriaxone are excreted mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency. 6 Cefixime is available in oral dosage form (200 mg twice daily or 400 mg once daily) for respiratory and urinary tract infections. 7 Cefepime is in many respects similar to the 3rd generation cephalosporins but is more resistant to hydrolysis by chromosomal β-lactamases and some extended spectrum β-lactamases that inactivate many of the 3rd generation cephalosporins. 95

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SULPHONAMIDES, TRIMETHOPRIM, AND AMINOGLYCOSIDES Resistance to sulphonamides has developed in many strains. Sulphonamides are well absorbed except for sulphaloxate, which has been used for preoperative bowel preparation and for gut infection.

SULPHONAMIDES Sulphonamides are structural analogues of paminobenzoic acid (PABA). The action is bacteriostatic and reversible in the presence of PABA. The susceptible microorganisms require PABA to form folate. Animals are not susceptible to sulphonamides because they do not synthesise folate but absorb it from the gastrointestinal tract.

PABA + Pteridine

Silver sulphadiazine (flamazine , 1% cream) is used topically for prophylaxis and treatment of infected burns, leg ulcers and pressure sores because of its wide antibacterial spectrum including pseudomonads. Sulphadiazine enters CSF more readily than others; thus, it is useful prophylactically in meningococcal meningitis. These days, ciprofloxacin has replaced sulphadiazine, and rifampicin.

Sulphonamides block here

Dihydropteroate synthase

Dihydrofolate (Folic acid) Dihydrofolate reductase

Adverse Effects

From GIT in animals

1. Allergic reactions [rash, fever, hepatitis, granulocytopenia, thrombocytopenia, aplastic anaemia, haemolytic reaction (in G6PD deficient patients), StevensJohnson syndrome (erythema multiforme bullosa, particularly serious and potentially fatal type of skin and mucous membrane eruption), and polyarteritis nodosa etc.] 2. Crystalluria, haematuria (Sulphonamides may precipitate in urine particularly at neutral or acidic pH, resulting in crystalluria, haematuria, or even obstruction. This problem may be overcome by administration of sodium bicarbonate to alkalinise the urine and fluids to maintain adequate hydration. 3. Kernicterus (when taken at end of pregnancy ) 4. Diarrhoea 5. Psychosis

Trimethoprim blocks here

Tetrahydrofolate (Folinic acid)

DNA + RNA

Resistance to Sulphonamides Bacterial resistance to sulphonamides may develop by mutation or plasmid-mediated through the following possible ways: 1. Bacterial PABA over-production (through production of a folic-acid synthesising enzyme, dihydropteroate synthase, that has low affinity for sulphonamides) 2. Reduced permeability to sulphonamides

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cause megaloblastic anaemia due to interference with conversion of folic acid to folinic acid (a trimethoprim effect). Therefore, it is advised not to give cotrimoxazole in pregnancy because of the possible teratogenic effects of inducing folate deficiency.

CO-TRIMOXAZOLE (TrimethoprimSulphamethoxazole) Trimethoprim inhibits dihydrofolate reductase and so prevents reduction of dihydrofolic acid to folinic acid (tetrahydrofolate). Although this is also an essential step in human metabolism, trimethoprim is much more active on the bacterial enzyme and so can seriously disrupt production of DNA and RNA without harming human host. When trimethoprim is given in combination with sulphamethoxazole, a sulphonamide that prevents the conversion of PABA to dihydrofolic acid, two sequential metabolic steps are thus affected. The combination is probably truly bactericidal unlike the bacteriostatic effects of the individual drugs and may show a synergistic effect.

Because of the disturbing adverse effects with sulphonamides, the use of trimethoprim alone is now increasing. Trimethoprim alone is useful in urinary and respiratory tract infection.

CO-TRIMOXAZOLE • A fixed-combination of trimethoprim and sulphamethoxazole • Useful in UTI, chronic bronchitis, pneumonia, typhoid, and shigella infections • Adverse effects: Largely due to the sulphonamide1. Allergic reactions (including rash, granulocytopenia, aplastic anaemia and Stevens-Johnson syndrome) 2. Crystalluria, haematuria 3. Kernicterus 4. Diarrhoea and psychosis

The ratio of trimethoprim and sulphamethoxazole is 1:5. The latter was chosen because of having a similar t to trimethoprim (about 10 hours). This combination is known as co-trimoxazole (Septrin , Metheprim ). Co-trimoxazole has special value in the treatment of: 1. Urinary tract infection (UTI) 2. Chronic bronchitis (particularly when due to H influenzae) 3. Pneumonia 4. Shigella infection 5. Typhoid and Paratyphoid (but ciprofloxacin is now preferred) 6. Brucellosis

Others due to trimethoprim1. Megaloblastic anaemia 2. Teratogenic effect

AMINOGLYCOSIDES

Resistance to Trimethoprim

1. Reduced influx of trimethoprim 2. Overproduction of dihydrofolate reductase 3. Modified reductase with reduced drug binding

These antibiotics were isolated from soil bacteria of Streptomyces species and include the antipseudomonal agents such as gentamicin, tobramycin, netilmicin, and amikacin. Netilmicin and amikacin may be used against gentamicin-resistant strains. They are used primarily in serious infections due to aerobic gram-negative bacilli. The principal target organisms are

Adverse effects of co-trimoxazole are similar to those of sulphonamides. In addition, co-trimoxazole in high dose may

1. Pseudomonas aeruginosa 2. Enterobacteriaceae (e.g. E coli, Klebsiella, Serratia, Proteus mirabilis).

Bacterial resistance to trimethoprim may be achieved by:

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sufficient to produce systemic toxicity. Aminoglycosides are eliminated almost exclusively without undergoing metabolism by the kidneys through glomerular filtration into the urine, where levels of 10-50 ³g/ml may be reached.

The aminoglycosides are not effective against anaerobic organisms and are often given in combination with other antimicrobials.

Streptomycin Streptomycin is used in the treatment of

Selection of an Aminoglycoside

1. Endocarditis [due to Streptococcus viridans or enterococci (Streptococcus faecalis) in combination with benzylpenicillin] 2. Brucellosis (in combination with tetracycline) 3. Tuberculosis (as an alternative in combination with other drugs)

Selection among these drugs depends largely upon patterns of resistance in a given hospital or community. In settings where resistance is uncommon, gentamicin is usually preferred because it is the less costly. However, in settings where resistance to gentamicin (and tobramycin) is common, amikacin may be preferred for initial therapy.

Neomycin

Interpatient Variation

Neomycin is no longer recommended for the treatment of bacillary enteric infections, as it may cause superinfections. It is too toxic to be used for systemic infections. However, it is used for topical infections.

Patients can exhibit large variations in serum levels of aminoglycosides even when they receive the same aminoglycoside dosage (in mg/kg of body weight). In one study, it was noted that in order to produce equivalent serum aminoglycoside levels, the required doses of the drugs ranged from as little as 0.5 mg/kg in one patient to a high of 25.8 mg/kg in another (i.e. a difference in dosage of more 50 fold).

Resistance to Aminoglycosides So far, there are three recognised mechanisms that may be responsible for bacterial resistance to aminoglycosides: 1. Enzyme inactivation of aminoglycosides (transferase enzymes inactivate aminoglycosides by adenylation, acetylation, or phosphorylation; these enzymes are largely plasmid-transmitted) 2. Impaired influx of aminoglycosides into the cell 3. Alteration of ribosomal receptor protein (the receptor protein on the 30S ribosomal subunit may be deleted or modified through mutation)

This interpatient variation can be due to various factors, e.g. age, percent body fat, and pathophysiological conditions like kidney function, fever, oedema, and dehydration.

Nephrotoxicity Aminoglycosides bind tightly to renal tissue, achieving levels in the renal tubular cells that are up to 50 times higher than those in serum do. Aminoglycosides are known to cause injury to the cells of proximal tubules (the mechanism not established) presents as acute tubular necrosis; this nephrotoxicity is usually with prominent symptoms as proteinuria, cast in urine, production of dilute urine, and elevation in serum creatinine and blood urea nitrogen (BUN). Therefore, monitoring levels of serum creatinine and BUN may help in detection of aminoglycoside-induced nephrotoxicity.

Pharmacokinetics Aminoglycosides are not easily absorbed from the gastrointestinal; it has been estimated that only about 1% of an oral dose is absorbed. Therefore, they have to be given parenterally (i.m. and i.v.) for systemic infection with close monitoring of the blood level to avoid toxicity. However, when aminoglycosides are used for wound irrigation, they may be absorbed in amounts 98

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The risk of nephrotoxicity is increased in the elderly, in patients with renal dysfunction, and in concurrent use of other nephrotoxic agents (e.g. cephalosporins, amphotericin B, polymixins, vancomycin and methoxyflurane). Luckily, cells of the

proximal tubules regenerate fairly quickly, therefore damage to the kidney usually reverses after stopping the aminoglycoside use.

Table 4.5. A summary of pharmacokinetic properties and dosages of the principal aminoglycosides Agent

Gentamicin Tobramycin Netilmicin Amikacin

Total daily dosage (mg/kg) Adults

Children

3-5 3-5 4-6.5 15

6-7.5 6-7.5 5.5-8 15

Dosing interval (hr) 8 8 8 8 or 12

t

in adults (hr)

Target serum levels* (³g/ml)

Normal

Anuric

Peak

Trough

2-3 2 2-3.4 2-2.5

40-50 55-60 >30 55-150

6-10 6-10 6-10 20-30

1-2 1-2 1-2 4-8

* Note: Levels of aminoglycosides must be kept within a narrow range, and because of interpatient variability, the above standard doses cannot be relied upon to produce predictable levels, dosage must be carefully adjusted for each patient.

When possible, aminoglycosides should not be used for more than 10 days. Further, concurrent administration of aminoglycosides with other potentially ototoxic agents (e.g. frusemide, ethacrynic acid) should be avoided.

Ototoxicity Aminoglycosides penetrate easily to the perilymph of the inner ear, and there is a direct relationship between levels achieved in the perilymph and production of ototoxicity manifests as impairment of hearing and balance. Damage to hair cells within the cochlea results in loss of hearing, while disruption of balance is caused by damage to hair cells of vestibular apparatus.

Other adverse effects and interactions Aminoglycosides can cross the placenta and may have toxic effects on the developing foetus. They are also known to produce curare-like effects (neuromuscular block); thus, they can intensify neuromuscular blockade produced by tubocurarine and other skeletal muscle relaxants. Therefore, when using aminoglycosides together with the muscle relaxants, extreme caution must be taken to avoid respiratory arrest.

Upon giving aminoglycosides, patients should be monitored for early signs of cochlear or vestibular damage. By using audiometric testing, decreased acuity in the high-frequency range indicates loss of hearing. Auditory toxicity can also present as tinnitus or a sense of fullness in the ear. Further, damage to the vestibular system may manifest as nausea, unsteadiness, and vertigo.

Cautions

When ototoxicity is detected, aminoglycosides should be withdrawn or administered in reduced doses. If toxicity is moderate, symptoms reverse following withdrawal of aminoglycosides; however, when ototoxicity is extensive, symptoms may be permanent and even can be with complete hearing loss.

Aminoglycosides should never be mixed together with penicillins (or any β-lactam drug) in the same syringe or in the same i.v. solution because penicillins (when present in high concentrations) interact chemically with aminoglycosides rendering the latter inactive.

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Postantibiotic Effect Postantibiotic effect is the antibacterial activity that persists beyond the time that measurable drug is present. This phenomenon was first observed with anti-mycobacterial drugs like rifampicin and then termed the lag-period effect . This postantibiotic effect is being significant and well documented with aminoglycosides and quinolones. Therefore, a given total daily amount of aminoglycoside may have better efficacy when administered as a single large dose than when administered as multiple smaller doses. Further, the single large dose scheme produces much higher peak concentrations, which saturate an uptake mechanism into the cortex; thus, resulting in less total aminoglycoside accumulation that is thought to cause renal damage and in turn less renal toxicity. The difference in renal toxicity is a predictable consequence of the different patterns of concentration (due to different dosage regimens) and the saturable uptake mechanism in the proximal renal tubular cells.

AMINOGLYCOSIDES • Useful primarily in serious infections due to aerobic gram-negative bacteria (e.g. Pseudomonas aeruginosa) • Have to be given parenterally • Unchanged excreted renally • Adverse effects: 1. Nephrotoxicity 2. Ototoxicity 3. Neuromuscular block 4. Low therapeutic index

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TETRACYCLINES, MACROLIDES, METRONIDAZOLE, CHLORAMPHENICOL, AND OTHERS 3. Opportunistic infections (e.g. candidiasis) 4. Tooth discoloration (tetracyclines are selectively taken up in the teeth and growing bones in the foetus and of children, given rise to inhibition of growth of bones and discoloration of teeth) 5. Inhibition of bone growth 6. Elevated blood urea (the antianabolic effect, inhibition of protein synthesis, cause blood urea to rise that is of a particular importance in uraemic patients) 7. Fatty liver 8. Photosensitisation (exposure to sunlight results in darkening of skin)

TETRACYCLINES Tetracyclines (1948) are a family of broadspectrum antibiotics with only minor differences. Tetracyclines have a 4-ring structure with small side-chains. The earliest members were chlortetracycline, oxytetracycline and tetracycline. The most recent ones are doxycycline and minocycline, which have good absorption and long t (16 h). Tetracyclines are bacteriostatic; they interfere with protein synthesis.

Resistance to Tetracycline

Caution

Bacterial resistance to tetracycline may be conferred by three possible mechanisms:

When passing the date of expiry, particularly tetracycline, becomes nephrotoxic therefore should not be used.

1. Decreased intracellular accumulation due to either impaired influx or increased efflux by an active transport protein pump 2. Ribosome protection due to production of proteins that interfere with tetracycline binding to the ribosome 3. Enzyme inactivation of tetracycline

MACROLIDES ERYTHROMYCIN

Indications

Erythromycin is one of the macrolides, which are termed after their macrocyclic lactone ring to which different sugars are attached. It was isolated in 1952 from a streptomyces strain found in the Philippine soil.

Their uses include infections with 1. Clamydiae (e.g. psittacosis, trachoma, pelvic inflammatory diseases, lymphogranuloma venereum) 2. Mycoplasma (pneumonia) 3. Rickettsia (Q fever, typhus) 4. Vibrio cholerae (cholera) 5. Haemophilus influenzae (e.g. bronchitis) 6. Brucella (brucellosis)

Absorption is best with erythromycin estolate, even if there is food in the stomach. Erythromycin is partly inactivated by gastric acid. The t (2h) is dose dependent and elimination is almost exclusively in the bile and faeces.

For a summary of pharmacokinetic properties see Table 4.6.

Erythromycin is active against gram-positive bacteria and spirochaetes. It is used instead of penicillin in patients allergic to penicillin and infections resistant to penicillin.

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Table 4.6. A summary of pharmacokinetic properties of tetracyclines Group

Agent

Short-acting

Tetracycline Oxytetracycline Demeclocycline

Low Low Moderate

75 60 65

↓ ↓ ↓

Renal Renal Renal

8 9 15

50-100 50-65 40-60

Doxycycline Minocycline

High High

90-100 90-100

(No change)

Hepatic Hepatic

12-22 12-22

12-22 12-22

Intermediateacting Long-acting

t

Note: Tetracycline may achieve toxic levels in renal dysfunction, therefore, it is not suitable in such condition. Doxycycline does not accumulate in renal dysfunction, does not interact with food, and is given once or twice daily, while tetracycline should be given four times daily. These make doxycycline superior to tetracycline.

2. Gastrointestinal disturbances (particularly diarrhoea, occur in up to 28%) 3. Hepatic enzyme inhibition (unlike azithromycin, erythromycin and clarithromycin inhibit the metabolic inactivation of some drugs like warfarin, carbamazepine, theophylline, disopyramide, increasing their effects)

Resistance to Macrolides Resistance to erythromycin may be conferred by the following: 1. Decreased cellular influx or increased active efflux 2. Production of esterases that hydrolyse macrolides 3. Alteration of the ribosomal binding site

CLARITHROMYCIN Indications 1. Penicillin-allergic patients (alternative to penicillin when infections due to grampositive bacteria) 2. Pneumonia (due to Mycoplasma pneumoniae) 3. Legionnaires disease (Legionnella species, 1st choice drug) 4. Diphtheria (Corynebacterium diphtheriae) 5. Whooping cough (Bordetella pertussis) 6. Gastroenteritis (due to Campylobacter jejuni) 7. Acne

Adverse Effects 1. Cholestatic hepatitis (with abdominal pain and fever that may be confused with viral hepatitis, due to estolate; this is probably an allergic reaction, thus the estolate should not be given to a patient with liver disease. 102

Clarithromycin acts like erythromycin and also exhibits a similar antibacterial activity to the latter agent, being mainly active against gram-positive organisms. It should be noted that the t of clarithromycin is remarkably does-dependent (t 3 hours after 250 mg, 9 hours after 1200 mg). Unlike erythromycin, it is rapidly and completely absorbed from the gastrointestinal tract. Of oral clarithromycin dose, 60% is inactivated by metabolism that is saturable and the remainder is eliminated in the urine. It is useful largely in respiratory tract infection including atypical pneumonias and soft tissue infections. It exhibits fewer gastrointestinal tract adverse effects (7%) than that of erythromycin (28%). Clarithromycin, like erythromycin, also inhibits the metabolic inactivation of some drugs (See above).

Essentials of Medical Pharmacology

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2. Metallic taste 3. Peripheral neuropathy 4. Ataxia 5. Insomnia 6. Convulsion 7. Darkening of urine 8. Disulfiram-like reaction (when alcohol is consumed concurrently with metronidazole)

AZITHROMYCIN Azithromycin is a new macrolide agent that acts like erythromycin (inhibits protein synthesis) but with a broader spectrum of antibacterial activity than erythromycin. The extension of activity includes a number of important gram-negative like Haemophilus influenzae and Neisseria gonorrhoeae, and also Chlamydiae. However, it is less effective against gram-positive organisms than erythromycin. Azithromycin is rapidly absorbed and tolerated orally. Azithromycin does inhibit cytochrome P450 enzymes therefore, unlike erythromycin clarithromycin, is relatively free of the interactions.

CHLORAMPHENICOL Chloramphenicol (1948, chloromycetin) was originally obtained from a streptomyces strain from Venezuela but is now synthesised. It readily penetrates the blood brain barrier (BBB). Chloramphenicol has a wide range of antibacterial activity including. infections due to

well not and and drug

1. Typhoid (Salmonella typhi and Salmonella paratyphi) 2. Meningitis (Haemophilus influenzae) 3. Whooping Cough (Bordetella pertussis)

METRONIDAZOLE Metronidazole has for many years been successfully employed to treat protozoal infections but the outstanding activity against anaerobes has been found useful particularly in bacteroides infections, and since the recognition of toxicity from lincomycin, has been widely used in treatment of septic infections of the chest, abdomen and pelvis. Metronidazole is a prodrug activated by anaerobic bacteria and not aerobic ones. It is bactericidal agent and resistance is not a problem.

Adverse Effects

Indications 1. Septic infections 2. Antibiotic-associated enterocolitis (pseudomembraneous colitis due to Clostridium difficile) 3. Urogenital tract trichomoniasis 4. Amoebiasis (Entamoeba histolytica) 5. Giardiasis (Giardia lamblia) 6. Acute ulcerative gingivitis and dental infections 7. Vaginitis (Gardnerella vaginalis)

Adverse Effects 1. Gastrointestinal diarrhoea)

disturbances

(nausea,

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1. Reversible bone marrow depression (dose-related) 2. Aplastic anaemia (pancytopenia and bone marrow aplasia, occurs with an incidence of 1 in 35,000 and is not related to dose; it occurs with oral, i.v., or even ophthalmic use of the drug. This reaction develops weeks or months after termination of the treatment.) 3. Grey baby syndrome (circulatory collapse, vomiting and fall in body temperature; this depends on the lower capacity to conjugate chloramphenicol in the liver in infants.) 4. Acute haemolytic anaemia in G6PD deficient patients Note: The onset of action of chloramphenicol when given orally is more rapid than when given intravenously. This is because the i.v. formulation of chloramphenicol (usually with succinate) has to be broken down in the liver to release chloramphenicol before it acts, while the capsule (usually with palmitate) form acts directly.

Tetracyclines, Macrolides, Metronidazole, Chloramphenicol, and Others

Ramadi, 24 February 2007

Adverse Effects LINCOSAMIDES 1. Flu-like illness 2. Hepatitis 3. Thrombocytopaenia 4. Rashes 5. Pink urine

CLINDAMYCIN AND LINCOMYCIN Clindamycin is more effective and better absorbed from the gastrointestinal tract. These drugs are effective against the following:

NITROFURANTOIN AND NALIDIXIC ACID

1. Bacteroides fragilis (first choice against gastrointestinal strains) 2. Anaerobic streptococcal infections (as an alternative) 3. Clostridium perfringens (as an alternative) 4. Staphylococcal infections (as an alternative)

These drugs are urinary tract disinfectant used for the treatment of infections with 1. Escherichia coli 2. Streptococcus faecalis 3. Proteus species Nalidixic acid also has some place in the treatment of infection with Shigella (in paediatric practice).

Adverse Effects 1. Antibiotic-associated enterocolitis (hence, these drugs should not be used indiscriminately; metronidazole is indicated to treat this condition)

Adverse Effects 1. Peripheral neuropathy (with nitrofurantoin) 2. Convulsions (with nalidixic acid)

The use of metronidazole is now preferred to that of clindamycin or lincomycin, for the treatment of anaerobic infections. Metronidazole appears to be superior because it can achieve adequate concentrations in the CSF and has not been reported to cause antibiotic-associated colitis.

SODIUM FUSIDATE Sodium fusidate is an antistaphylococcal agent, useful in severe infections caused by β-lactamase producing and methicillin resistant Staphylococcus aureus (MRSA) including osteomyelitis. It is readily absorbed from the gut and distributes widely in body tissues including bone. It is largely metaboilised and only very little is excreted in the urine. It is available as i.v. , oral, ointment and gel preparations.

RIFAMPICIN It has a broad-spectrum antibacterial activity, particularly, against mycobacterial species, and gram-positive organisms including staphylococci. With rifampicin, the rapid emergence of resistance dictates that they must always be used in combination with unrelated antimicrobial agents. It is largely reserved for mycobacterial infections. Its use in MRSA infections may be justified.

VANCOMYCIN Vancomycin is an antibiotic produced by Streptococcus orientalis, glycopeptide and is water-soluble and very stable. It inhibits cell wall synthesis. It is useful when given orally in antibiotic-associated enterocolitis, and i.v. for systemic infections. It readily crosses the BBB if there is meningeal inflammation. 104

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urinary or gastrointestinal tracts, skin, soft tissues, and bones. They have also been used in the treatment of gonorrhoea and septicaemia.

Vacomycin is largely (90%) eliminated renally by being excreted by glomerular filtration. Therefore, in renal insufficiency, surprisingly high blood levels may be reached.

Adverse Effects

Indications 1. Methicillin-resistant Staphylococcus aureus (MRSA, first choice drug) 2. Enterococcal endocarditis in patients with serious penicillin allergy (in combination with gentamicin) 3. Meningitis suspected or known to be caused by a highly penicillin-resistant strains of pneumococcus (MIC > 1 µg/ml) 4. Antibiotic-associated enterocolitis (due to Clostridium difficile, administered orally)

Adverse Effects 1. Chills and fever 2. Ototoxicity (tinnitus and deafness may reverse upon withdrawal of vancomycin) 3. Nephrotoxicity 4. Red man or Red neck (a maculopapular rash possibly due to histamine release may occur upon rapid i.v. infusion)

Caution

1. Crystalluria (Therefore, adequate amount of water should be taken) 2. Cartilage deterioration (reversible arthropathy in immature animals, although such effects have not been observed in humans, prudence dictates that these drugs are contraindicated in children and in women who are pregnant or nursing. However, some authorities would state that fluoroquinolones should be used with caution in children and adolescents 1 3. Inhibition of Drug Metabolism (inhibits the metabolism of theophylline and warfarin, therefore, both of which should be monitored carefully when concurrently administered with ciprofloxacin)

Cautions 1. Oral absorption of fluoroquinolones is impaired by divalent cations including those in antacids. 2. Interacts with theophylline (inhibit hepatic metabolism of theophylline and therefore can potentiate its effects).

Administration with another ototoxic or nephrotoxic drug, such as an aminoglycoside, increases the risk of these toxicities.

FLUOROQUINOLONES These are synthetic bactericidal agents chemically related to nalidixic acid. The prototype of this group is ciprofloxacin and norfloxacin. They can easily penetrate the BBB and thus can be used as an alternative to the 3rd generation cephalosporins. Nowadays, the use of these drugs has picked up a great popularity as broad-spectrum antibacterial drugs.

Indications They have been found effective in the treatment of infections of the respiratory,

1

Laurence, D. R., Bennett, P. N. & Brown, M.J. (1997) Clinical Pharmacology. 8th edition, page 212. 105

Antimicrobial Drugs - Antimycobacterial Drugs

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ANTIMYCOBACTERIAL DRUGS ANTITUBERCULOSIS DRUGS

As treatment is prolonged, if only one antituberculous drug is used there is a high risk that a drug-resistant mutants (due to spontaneous mutation, that exist in all large bacterial populations) will emerge. However, the possibility of bacilli to develop resistance to more than one drug is very low. Therefore, treatment of two or more drugs reduces the risk of developing drug-resistance. Further, drug-combination therapy also serves to reduce the incidence of relapse. A strategy for drug-combination targeting in the course of treatment of tuberculosis is presented in Fig.4.4.

Introduction The objective of antituberculous therapy is to eliminate symptoms of active disease, and to prevent relapse, and emergence of drug resistance. To achieve these goals, the following should be accomplished: 1. Killing the Actively Multiplying Tubercle Bacilli: Elimination of the actively multiplying population, which have been estimated to form about 95% of the total tubercle bacilli, and the intracellular ones within the initial phase (1st 2-3 months) of treatment.

The regimen currently recommended for the treatment of uncomplicated tuberculosis in AL-Anbar as follows:

2. Eradicating the Remaining Problematic Tubercle Bacilli: Eradicating the problematic proportion of the tubercle bacilli which is characterised by usually being at resting state but occasionally exhibits spurts of metabolic activity ; these bacilli represent, at least in part, what are described as persisters , i.e. semidormant bacilli that metabolise slowly or intermittently. It is believed that only during these spurts of activity (which have been estimated to last for about 2 minutes at a time) that drugs can kill these bugs. Therefore, the continuation (2nd) phase is directed at capturing these moments of activity. The 2nd phase usually takes 4-6 months; at the end of which this proportion of the tubercle bacilli should be eradicated (if the treatment is successful).

6-Month Regimen First 2 months (Initial Phase)

Following 4 months (Continuation Phase)

Isoniazid (INH) + rifampicin + pyrazinamide + ethambutol or streptomycin (2HRPE) Isoniazid + rifampicin (4HR)

The regimen currently recommended for the treatment of complicated tuberculosis (e.g. relapse and treatment failure cases) in ALAnbar as follows:

8-Month Regimen First 2 months (Initial Phase)

Further 1 or 2 Months

Success of treatment is indicated by an absence of observable tubercle bacilli in sputum (direct smear) and by failure of sputum cultures to yield any colonies of the bacilli. When sputum test results have become negative, usually within 2-6 months, therapy should continue for additional 4-6 months.

Five months (Continuation Phase)

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Isoniazid + rifampicin + pyrazinamide + ethambutol + streptomycin (2HRZES) Isoniazid + rifampicin + pyrazinamide + ethambutol (1HRZE) Isoniazid + rifampicin + ethambutol (5HRE)

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Most modern regimens for the treatment of tuberculosis include isoniazid, rifampicin, and pyrazinamide, since

Therefore, it is an essential feature of the antituberculosis regimen is that practically all drugs should be given once daily (not divided doses). For a summary of the pharmacology of antituberculosis drugs see Table 4.7.

•

Isoniazid rapidly kills large numbers of actively growing bacteria including those with only occasional spurts of activity. • Rifampicin kills actively growing bacilli including the problematic ones with only spurts of metabolic activity; and also kills intracellular bacilli. • Pyrazinamide that is converted to the active pyrazinoic acid by the activity of intrabacterial pyrazinamidase, an enzyme is most effective in an acidic environment such as the interior of cells. Thus, it is effective uniquely in zones of acute inflammation and against quiescent bacilli within macrophages (persisters, semidormant bacilli that are often within cells).

Isoniazid, pyrazinamide, and ethambutol are considered to be specific antimycobacterial drugs. Therefore, they are used in therapeutic trials for diagnostic purposes. Isoniazid is highly selective for mycobacteria; the drug can kill tubercle bacilli at concentrations 10,000 times lower than those needed to affect gram-positive bacteria.

ANTILEPROSY DRUGS Leprosy (Hansen s disease) is caused by Mycobacterium leprae. The WHO recommends that all patients receive treatment with multiple drugs.

Also, it is worth noting that: •

Ethambutol is a specific drug against mycobacteria. Generally, it is used when resistance to isoniazid and rifampicin is suspected. • Streptomycin has relatively low sterilising activity, perhaps, because of its inability to penetrate cells and not being effective against intracellular bacilli.

Dapsone (t is 27 hr, aminodiphenylsulfone) has been and remains a mainstay of therapy that requires a minimum duration of two years. The absorption of dapsone is slow but complete from the gastrointestinal tract and the drug sustains a steady blood level because it undergoes intestinal reabsorption from the bile. It is excreted in the urine. Dapsone is associated with methemoglobinemia, agranulocytosis, haemolytic anaemia, drug rash, and anorexia as adverse effects. Dapsone causes more haemolytic anaemia in slow acetylators, whereas rapid acetylators may need higher doses to control leprosy.

In general, a 6-month regimen cures the patient rapidly and these drugs are usually well tolerated. In Ramadi, this regimen has been found as the most successful one with the highest cure-rate (85%).

Rifampicin is used in combination with dapsone in the treatment of leprosy. Rifampicin in a dosage of 600 mg daily is safe and effective when given once monthly. This long interval makes acceptable the directly observed therapy with rifampicin which the above regimens require.

Postantibiotic Effect After a culture of Mycobacterium tuberculosis had been exposed to certain drugs for sometime, it took several days (the lag-period , postantibiotic effect) before growth occurred. Therefore, 600 mg of rifampicin given once daily is therapeutically superior to the same dose divided into two parts administered at 12 hours interval.

Clofazimine (t is 70 days) is a phenazine dye and it has a leprostatic action. It is absorbed from the gastrointestinal tract and 107

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accumulates in tissues. Hence, dosage regimen is possible if individual doses are given in a gap separated by four weeks.

discolouration of the skin that may persist for months after the drug has been stopped.

Clofazimine is given for dapsoneresistant leprosy or when patients are intolerant to dapsone. Clofazimine therapy is associated with reddish to nearly black

Table 4.7. A summary of the pharmacology of the currently used antituberculosis drugs. Drug Isoniazid (INH)

Action Powerfully anti-TB; inhibits formation of mycolic acid in bacterial cell wall. Bacteriostatic-cidal

Rifampicin

Inhibits RNA polymerase in bacteria. Resistance develops rapidly if used on its own.

Pyrazinamide

Converted to pyrazinoic acid by intrabacterial pyrazinamidase (most effective in acidic environment) Concentrated in tubercle bacilli, mode of action not known. Resistance develops slowly. Effective against strains resistant to rifampicin and streptomycin.

Ethambutol

Streptomycin

Thiacetazone

See aminoglycosides (not effective in acidic environment) Low efficacy, delays emergence of INH resistance

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Toxicity Insomnia Muscle twitching Peripheral neuropathy (responds to vit. B6) Hepatitis Flu-like illness Hepatitis Thrombocytopenia Rashes Pink urine Hepatotoxicity (10%) Gouty attacks

Peripheral neuropathy Colour blindness Pruritus Joint pains Abdominal pain Confusion Hallucination Contraindicated in pregnancy Nephrotoxicity Ototoxicity Neuromuscular block Hepatotoxicity

Essentials of Medical Pharmacology

Majid A. K. Lafi

Actively multiplying population

Intracellular population

Isoniazid Rifampicin Streptomycin Ethambutol

Population with spurts of metabolic activity

Rifampicin Pyrazinamid

Isoniazid Rifampicin

This population is usually killed within the 2nd phase of therapy (4-6 months)

These 2 populations are usually killed within the 1st phase of therapy (1st 2-3 months), requiring combined isoniazid, rifampicin, pyrazinamide, & streptomycin or ethambutol.

Dormant population

Not reached by drugs

Eradication decreases relapse & resistance

Fig. 4.4. A simplified representation of the strategy of the treatment of tuberculous infections (pulmonary), different phases of treatment, antituberculous drugs, and duration of treatment are indicated. Note: The actively (rapidly) metabolising bacilli are believed to be killed within a few days: however, the intracellular bacilli (including semidormant bacilli, quiescent but with spurts of metabolic activity) are more difficult to be dealt with. Rifampicin and pyrazinamide are effective in killing the latter population within the initial phase of treatment. The continuation phase of treatment (isoniazid + rifampicin) is directed at least 4-month treatment, hopefully, to achieve eradication of bacilli and therefore decrease the possibility of relapse and drug-resistance.

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ANTIMICROBIAL DRUGS OF CHOICE Table 4.8. Antimicrobial drugs of choice; modified from Laurence, D. R., Bennett, P. N., and Brown, M. J. (1997) Clinical Pharmacology, 8th edition, page 194. * Resistance may be a problem; sensitivity test should be done. ** Suggested alternatives do not necessarily represent all options. CS = a cephalosporin Co-amoxiclav = fixed combination of amoxicillin plus clavulanic acid ± With or without FQ = a fluoroquinolone (e.g. ciprofloxacin)

Infecting organism

Drug(s) of 1st choice

Alternative drugs**

Gram-positive cocci *Enterococcus Endocarditis or other severe infections

Benzylpenicillin or amoxicillin + gentamicin, or streptomycin

Vancomycin + gentamicn or streptomycin

Uncomplicated Urinary tract infections

amoxicillin

Trimethoprim or nitrofurantoin

Non-penicillinase producing

Benzylpenicillin

CS; vancomycin; imipenem; erythromycin

Penicillinase producing

Cloxacillin

CS; vancomycin; co-amoxiclav; erythromycin; clindamycin; FQ

Methicillin-resistant

Vancomycin ± gentamicin ± rifampicin

Co-trimoxazole; a tetracycline; FQ; rifampicin; Na fusidate

Streptococcus pyogenes

Benzylpenicillin or phenoxymethylpenicillin or amoxicillin

Erythromycin; CS; vancomycin; (clindamycin, for necrotic infection of the superficial and deep fascia)

Benzylpenicillin ± gentamicin

Vancomycin; CS

Amoxicillin

Trimethoprim; nitrofurantoin; FQ

*Staphylococcus aureus or epidermidis

(Group A, and Groups C and G) Streptococcus (Group B)

Streptococcus, viridans group (endocarditis) Streptococcus faecalis (enterococci) UTI

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Benzylpenicillin or amoxicillin + gentamicin or streptomycin Benzylpenicillin

Vancomycin + gentamicin or streptomycin

Benzylpenicillin or amoxicillin

Erythromycin; CS; vancomycin; rifampicin (or chloramphenicol for meningitis)

Moraxella (Branhamella) catarrhalis

Co-amoxiclav

Erythromycin or a tetracycline

*Neisseria gonorrhoeae (gonococcus)

Amoxicillin (+ probenecid) or FQ or ceftriaxone

Spectinomycin; cefixime or cefotaxime

Neisseria meningitis (meningococcus)

benzylpenicillin

Chloramphenicol; cefotaxime

Bacillus anthracis (anthrax)

Benzylpenicillin

Erythromycin; a tetracycline

Clostridium perfringens

Benzylpenicillin

Metronidazole; clindamycin

Benzylpenicillin

A tetracycline

Erythromycin

Benzylpenicillin

Amoxicillin ± gentamicin

Erythromycin + gentamicin

Oropharyngeal strains

Benzylpenicillin

Metronidazole; clindamycin

Gastrointestinal strains

Metronidazole

Co-amoxiclav; clindamycin; imipenem; chloramphenicol Tetracycline

Endocarditis

Streptococcus, anaerobic *Streptococcus

pneumoniae (pneumococcus)

Metronidazole

Gram-negative cocci

Gram-positive bacilli

(gas gangrene)

Clostridium tetani (tetanus) Corynebacterium diphtheriae (diphtheria) Listeria monocytogenes (listeriosis)

Enteric gram-negative bacilli *Bacteroides

Erythromycin or FQ *Campylobacter jejuni *Enterobacteriaceae e.g. *Enterobacter aerogenes *Escherichia coli *Klebsiella pneumoniae *Proteus species FQ or an oral CS Lower urinary tract

Amoxicillin or trimethoprim

Septicaemia

Gentamicin or cefotaxime

FQ; imipenem

*Helicobacter pylori (peptic ulcer)

Amoxicillin + clarithromycin + metronidazole (plus omeprazole)

Amoxicillin + metronidazole + bismuth chelate; or tetracycline + clarithromycin + bismuth chelate

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*Salmonella typhi (typhoid fever)

Ceftriaxone; FQ

Chloramphenicol; co-trimoxazole; amoxicillin

*Other Salmonella

FQ

Amoxicillin; co-trimoxazole; chloramphenicol

*Shigella

FQ

Trimethoprim; ampicillin (paediatric: nalidixic acid)

*Yersinia enterocolitica

Co-trimoxazole

FQ, gentamicin; tetracycline

*Bordetella pertussis (whooping cough)

Erythromycin

Ampicillin

*Brucella (brucellosis)

Tetracycline + streptomycin or gentamicin

Co-trimoxazole; rifampicin + tetracycline

Calymmatobacterium granulomatis (granuloma inguinale) *Fusobacterium

A tetracycline

Streptomycin or gentamicin or co-trimoxazole

Benzylpenicillin

Metronidazole or clindamycin

Gardeneralla vaginalis (anaerobic vaginosis)

Metronidazole (oral)

Topical clindamycin or metronidazole; oral clindamycin

*Haemophilus ducreyi (chancroid) *Haemophilus influenzae Meningitis, epiglotitis, arthritis or other serious infections Upper respiratory infections and bronchitis Legionella pneumophila (legionnaire s disease)

Erythromycin

FQ

Cefotaxime or ceftriaxone or amoxicillin

Chloramphenicol

Co-trimoxazole or amoxicillin

Co-amoxiclav; CS (3r generation)

Pasteurella multocida (from animal bites) *Pseudomonas aeruginosa Urinary tract infection

benzylpenicillin

Co-amoxiclav or CS

FQ

Ticarcillin; piperacillin; mezlocillin

Other infections

FQ; ticarcillin; mezlocillin; piperacillin; gentamicin; amikacin Tetracycline

Ceftazidime; imipenem

Other gram-negative bacilli

Vibrio cholerae (cholera)

Erythromycin ± rifampicin

FQ

Acid-fast bacilli *Mycobacterium tuberculosis Isoniazid + rifampicin + 112

Other antitubercular agents include cycloserine, thiacetazone, ethionamide,

Essentials of Medical Pharmacology

Majid A. K. Lafi

Pulmonary (1st 2 months)

pyrazinamide ± ethambutol (or streptomycin) (2HRPE)

kanamycin, amikacin, capreomycin, ciprofloxacin, and ofloxacin.

(next 4 months)

Isoniazid + rifampicin (4HR)

Ethionamide or cycloserine

Mycobacterium leprae (leprosy)

Dapsone + rifampicin ± clofazimine

Actinomycetes Actinomyces israelii (actinomycosis) Nocardia

Benzylpenicillin

A tetracycline

Co-trimoxazole

Amikacin; minocycline; imipenem

Chlamydiae Chlamydia psittaci (psittacosis, ornithosis)

Tetracycline

Chlamydia trachomatis Trachoma

Azithromycin

Tetracycline (oral plus oral); a sulphonamide (topical plus oral)

Inclusion conjunctivitis

Erythromycin (oral or i.v.)

A sulphonamide

Pneumonia

Erythromycin

A sulphonamide

Urethritis, cervicitis

Doxycycline or azithromycin

Erythromycin or ofloxacin

Lymphogranuloma venereum Chlamydia pneumoniae (TWAR strain)

Tetracycline

Erythromycin

Tetracycline

Erythromycin

Mycoplasma pneumoniae

Erythromycin or tetracycline

Clarithromycin; azithromycin

Ureaplasma urealyticum

Erythromycin

Tetracycline; clarithromycin

Tetracycline

Chloramphenicol; FQ

Borrelia burgdorferi (Lyme disease)

Doxycycline or amoxicillin

Ceftriaxone or cefotaxime or benzylpenicillin

Borrelia recurrentis (relapsing fever) Leptospira (leptospirosis)

Tetracycline

Benzylpenicillin

Benzylpenicillin

Tetracycline

Treponema pallidum (syphilis) Treponema pertenue (yaws)

Benzylpenicillin

Tetracycline or ceftriaxone

Benzylpenicillin

Tetracycline

Chloramphenicol

Mycoplasma

Rickettsia Q fever, typhus

Spirochaetes

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ANTIFUNGAL DRUGS 1. Drugs used to treat superficial mycoses (fungal infections) a. Polyene antibiotics (e.g. nystatin and amphotericin B) b. Imidazoles (e.g. ketoconazole, clotrimazole, miconazole, and econazole) c. Others (e.g. griseofulvin, flucytosine)

Introduction Superficial fungal infections occur much more frequently than system fungal infections. The superficial mycoses are caused by two groups of organisms: 1. Candida species 2. Dermatophytes

2. Drugs used to treat systemic mycoses a. Amphotericin B b. Flucytosine c. Ketoconazole d. Miconazole

Superficial infection with dermatopytes is more common than superficial candidiasis. Candidal infections usually occur in mucous membranes or moist skin. However, candidal chronic infections may occur in scalp, skin, and nails. Dermatophytoses are generally confined to the skin, hair, and nails.

POLYENE ANTIBIOTICS Nystatin Nystatin derived from Streptomyces cultures from the soil of Virginia and its name derived from the New York State Department of Health that was responsible for its culture. It is used topically for the treatment yeast-like fungi such as Candida albicans, also for vaginal infections. It is too toxic to be used systemically.

Systemic mycoses can be classified into two types: 1. Opportunistic infections 2. Non-opportunistic infections The opportunistic mycoses, e.g. candidiasis, aspergillosis, cryptococcosis, mucormycosis, occur primarily in debilitated or immunocompromised host. While, non-opportunistic infections may occur in any subject; these infections are relatively uncommon and include sporotrichosis, blastomycosis, histoplasmosis, and coccidiodomycosis. These infections often pose a therapeutic problem because of their resistance to drugs, consequently requiring a long duration with high dose therapy with drugs that often exhibit high toxicities.

Amphotericin Amphotericin B is a polyene compound that remains the drug of choice for most serious systemic fungal infections. It has serious toxic effects, primarily nephrotoxicity. It must be given intravenously; in meningitis due to fungal infection; it has to be given intrathecally to achieve adequate concentration in the CSF.

Antifungal Drugs

IMIDAZOLES

The antifungal drugs are classified into two main groups:

The imidazole antifungal agents constitute members which are used for 114

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superficial and systemic infections like ketoconazole, and to a lesser extent miconazole (rarely used systemic infections because of high toxicity); and clotrimazole and econazole are used for superficial infections and for topical application only. The imidazole agents are useful for both dermatophytic and candidal infections.

Miconazole

Ketoconazole

Econazole

Ketoconazole is the only imidazole antifungal drug that can be administered by mouth for treatment of superficial mycoses; it is active against a variety of fungal infections, dermatophytic infections and candidiasis of the skin, mouth, and vagina. Its oral absorption is variable, and only partially excreted in the urine. It carries a potential for hepatic toxicity; therefore, a regular assessment of hepatic function should be made. Because it blocks steroid synthesis, it is useful in Cushing s syndrome, and may lead to hypoadrenalism and reduction in testosterone levels (antiandrogenic activity).

Econazole is an imidazole antifungal agent applied topically only. The drug is effective in Tinea infection and for superficial candidiasis.

Miconazole is an imidazole antifungal agent available for topical and systemic administration. Because of high toxicity, the drug rarely used systemically; thus, it is a drug of first choice for dermatophytic infections, and cutaneous and vaginal candidiasis.

OTHERS Griseofulvin Griseofulvin is an antibiotic, isolated from Penicillium griseofulvin in 1939, which is active when given orally but not topically. Its only use is in the systemic treatment of dermatophytosis. The absorbed drug has an affinity for diseased skin and is deposited there, bound to keratin, making keratin resistant to fungal growth. Thus, new growth of hair or nails is free of infection. Therefore, it must be administered for 2-6 weeks for skin and hair infections. It is a hepatic enzyme inducer.

It follows that because of the serious toxicity associated with its systemic use, oral ketoconazole is reserved for fungal infections that have failed to respond to topical agents like clotrimazole and miconazole. A topical preparation of ketoconazole is now available but its use is approved only for dermatophytic infections but not for candidiasis.

Flucytosine Flucytosine is available for oral or parenteral use. It is mainly used in a synergistic combination with amphotericin against Cryptococcus neoformans. High plasma levels that often occur with renal impairment are associated with bone marrow toxicity, and monitoring of plasma concentration is therefore advised.

Clotrimazole Clotrimazole is a synthetic imidazole derivative that is topically active against dermatophytic infections and candidiasis of the skin, mouth and vagina.

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Table 4.9. A summary of drugs of choice for superficial and systemic mycoses. Infection or organism Superficial infections

Drug of choice

Alternative Drugs

Dermatophytoses

Miconazole (topical) Clotrimazole (topical)

Tolnaftate (topical) Griseofulvin (oral) Ketoconazole (oral)

Tinea unguium (nail ringworm) Tinea capitis (scalp ringworm) Tinea pedis (athlete s foot)

(These are acid sensitive; thus, benzoic acid ointment, salicylic acid 4.65%, boric acid 2.87% in alcohol and ethyl acetate as paint)

Candidiasis of Skin and vagina

Clotrimazole (topical) Miconazole (topical)

Nystatin (topical) Ketoconazole (oral)

Mouth

Clotrimazole (topical)

Nystatin (topical) Ketoconazole (oral)

Intestine

Nystatin (oral)

Systemic infections Aspergillus species

Amphotericin B

None

Blastomyces dermatitidis

Amphotericin B

Ketoconazole

Candida species

Amphotericin B

Ketoconazole

Coccidioides immitis

Amphotericin B

Ketoconazole

Histoplasma capsulatum

Amphotericin B

Ketoconazole

Cryptococcus neoformans

Amphotericin B

Ketoconazole

Mucur species

Amphotericin B

None

Paracoccidioides brasiliensis

Ketoconazole

Amphotericin B

Potassium iodide; amphotericin B

Ketoconazole

Sporothrix schenkii

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ANTIVIRAL DRUGS with persistent HIV-1 replication despite ongoing therapy retroviral infections. Local injection site reactions are the most common side effects associated with enfuvirtide therapy.

Introduction Viruses are obligatory intracellular parasites with no growth or reproduction in vitro except in some very specialised laboratory techniques. Viruses cannot produce energy (ATP) and protein and are entirely dependent on the host. The process of viral replication includes:

Amantadine Amantadine acts by inhibiting the uncoating of the viral RNA of influenza A within host cells, therefore, preventing its replication. Amantadine is of value in the prophylaxis of infection with influenza A virus. It stimulates the CNS and can cause convulsion. Amantadine is also used in the treatment of Parkinsonism.

1. Viral penetration into host cells (blocked by enfuvirtide (HIV), γ-globulins, nonspecific) 2. Viral uncoating (blocked by amantadine, influenza A) 3. Early protein synthesis (blocked by fomivirsen, CMV) 4. Nucleic acid synthesis (replication of DNA or RNA, interfered with by purine analogues like acyclovir, pyrimidine analogues like idoxuridine, and reverse transcriptase inhibitors like zidovudine, AZT) 5. Late protein synthesis and processing (interfered with by protease inhibitors like ritonavir) 6. Assembly (maturation) of viral components 7. Release from the cell

Fomivirsen Fomivirsen binds to target mRNA resulting in inhibition of immediate early region 2 protein synthesis, thus inhibiting virus replication. Fomivirsen is injected

intravitreally for the treatment of CMV retinitis in patients with AIDS and is indicated for patients who are intolerant of or unresponsive to alternative therapies. Iritis and vitreitis as well as increased intraocular pressure and changes in vision are associated with fomivirsen therapy.

Attempts to find antiviral drugs have been very successful and their use is complicated as the virus reaches a peak titre before symptoms are observed. Therefore, a drug used to prevent viral replication is best used prophylactically rather than left till gross symptoms occur. There are a few agents, mostly in the developmental stage, which show promise of antiviral activity.

Idoxuridine Idoxuridine is a pyrimidine analogue and is preferentially incorporated in viral DNA producing material. It is very toxic and cannot be used systemically. As it is not specific for viral DNA, idoxuridine causes bone marrow depression and leucopenia.

Antiviral Drugs Enfuvirtide

Acyclovir

Enfuvirtide is a fusion inhibitor that blocks entry into the cell by preventing the

Acyclovir is a guanine analogue that is activated within herpes infected cells. Under the influence of virus thymidine kinase acyclovir is converted into active acyclovir triphosphate. This competes with

conformational changes required for the fusion of the viral and cellular membranes. It is useful in combination with other antiretroviral agents in patients 117

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deoxyguanosine triphosphate as a substrate for viral DNA blocks replication. It is much more active against herpes DNA polymerase than that of the normal host cell, making it a highly selective antiviral agent.

Didanosine Didanosine is also a reverse transcriptase inhibitor. It may increase CD4+ counts in patients with HIV infection. Adverse effects include pancreatitis and peripheral neuropathy.

Acyclovir is active against herpes simplex virus and to a lesser extent varicella-zoster virus. It has been the drug of first choice for severe infections caused by these viruses. It can be administered topically in the eye, on the skin, orally (though poorly absorbed), or intravenously (slowly). Acyclovir is particularly useful in immunocompromised patients. It has low toxicity.

HIV Protease Inhibitors The process of HIV replication involves the production of protein and also a protease that cleaves the protein into component parts that eventually reassembled into virus particles. Protease inhibitors interfere with this essential process. Protease inhibitors have been shown to reduce viral RNA, increase CD4+ counts and improve survival compared with that observed with placebo. The representative agent of this group is ritonavir.

Famciclovir Famciclovir is similar to acyclovir except that it is well absorbed from the gut. It is a prodrug, converting to penciclovir that has a similar spectrum of activity to that of acyclovir.

Ganciclovir

Others

Ganciclovir is similar to acyclovir in its mode of action but it has a broader antiviral spectrum of activity. It is useful for the treatment of serious cytomegalovirus (CMV) infections in immunocompromised patients. However, it has dose-dependent bone marrow depression effects. Therefore, its use limited to life- or sight-threatening CMV (CMV retinitis) infection in immunocompromised patients.

Tribavirin Tribavirin is an example of antimicrobial agents that are used by inhalation (aerosol or nebulised solution) for respiratory tract infections, to avoid systemic adverse effects. It is a synthetic nucleoside useful for severe respiratory syncytial virus bronchiolitis in infants and children.

Interferons HIV Reverse Transcriptase Inhibitors

Interferons are produced by infected host cells that contain replicating viruses. They appear to protect other cells from attacks not only by the offending virus but also other viruses, irrespective of their nucleic acid composition. Interferons are expensive to produce from human white blood cells but recently have been extracted from clones of bacterial cells obtained by genetic engineering.

Zidovudine Zidovudine (azidothymidine, AZT) is a reverse transcriptase inhibitor, has been shown to prolong the life and wellbeing of patients with human immunodeficiency virus (HIV) infection. HIV replicates by converting its single stranded RNA into double stranded DNA that is incorporated into host DNA (this is the reverse of the normal cellular transcription of nucleic acids).

Interferonα2 is the most commonly used, available as subtype interferon α2a and α2b. These differ in a single amino acid but are therapeutically equivalent. They are used in the treatment of hepatitis B and hepatitis C. 118

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immune response against virulent organisms, e.g. influenza, adenovirus, polio, measles, rubella, yellow fever, smallpox.

Viral Vaccines Viral vaccines are composed of killed or attenuated organisms that will induce an

Table 4.10. A summary of drugs of choice for viral infections Organism Herpes Varicella-zoster Chickenpox

Drug of Choice

Acyclovir

Important Remarks Phosphorylated acyclovir (by virus specific thymidine kinase) inhibits DNA polymerase & thus prevents viral DNA formation. Use in immunocompromised (i.v.)

Zoster (shingles)

Acyclovir

In immunocompetent (oral) In immunocompromised (i.v.)

Herpes simplex Ocular keratitis

Acyclovir

(ointment)

Labial (fever blisters)

Acyclovir

(cream and/or oral)

Genital

Acyclovir

(cream and/or oral)

Encephalitis

Acyclovir

(i.v.)

Disseminated

Acyclovir

(i.v.)

Human Deficiency (HIV)

Immuno- Zidovudine Virus Didanosine Ritonavir

Hepatitis B, C or D

Interferon α2a & α2b

Influenza A

Amantadine

Cytomegalovirus (CMV)

Ganciclovir

Respiratory Syncytial Virus Coryza (common cold)

Tribavirin Zinc

Reverse transcriptase inhibitor Reverse transcriptase inhibitor Viral protease inhibitor (Protection of foetuses from becoming infected by the virus in HIV-infected pregnant mothers) 1. Induces enzymes that degrade viral RNA (in uninfected cells) 2. Indirectly stimulates the immune system Interferes with the uncoating and release of viral genome into host cell. It is useful for prevention & treatment (debilitated persons) Similar to acyclovir in action, useful in CMVinfected immunocompromised patients; it may produce bone marrow depression. (Inhalational) Lozenges containing duration of symptoms.

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shortens

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Blocked by

enfuvirtide (HIV), γ-globulins (non-specific)

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Blocked by amantadine (Influenza A)

Viral uptake Uncoating

Blocked by fomivirsen (CMV)

Early protein synthesis

Host cell

Nucleic acid synthesis

Late protein synthesis & processing Packaging & assembly

Viral release

Fig.4.5. The major sites of action of antiviral agents

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Blocked by purine analogues (acyclovir), pyrimidine analogues (idoxuridine), & reverse transcriptase inhibitors (zidovudine, AZT) Blocked by protease inhibitors (ritonavir, HIV)

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Majid A. K. Lafi

ANTIPARASITIC DRUGS

Table 4.11. Drugs of choice for treatment and prevention of malaria

Plasmodial strain P vivax P falciparum (chloroquinesensitive) P falciparum (chloroquineresistant)

Drugs of choice for Prevention of relapse Primaquine* NA**

Treatment of acute attack Chloroquine Chloroquine

Quinine plus pyrimethamine/ sulfadoxine or tetracycline; or i.v. quinine infusion

NA

Prophylaxis Chloroquine Chloroquine

Chloroquine plus pyrimethamine/ sulfadoxine + proguanil; or chloroquine plus doxycycline

* Primaquine is given following control of the acute attack. ** Not applicable, malaria caused by P falciparum does not relapse following successful treatment of the acute attack.

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Table 4.12. Drugs of choice for protozoal infections

Amoebiasis

Causative protozoan and important remarks Entamoeba histoltyica

Bowel lumen

(to eradicate cyst give)

Disease

Drugs of choice

Diloxanide

Tissue-invading

Metronidazole In severe cases, to lessen the risk of opportunistic infection, perforation, & peritonitis, give

Tetracycline

Treatment of tissue-invading amoebiasis should be followed by a luminal amoebicide to eradicate the source, give

Diloxanide

Giardiasis

Giardia lamblia

Leishmaniasis Visceral

Leishmania species

Metronidazole Tinidazole Primaquine Mepacrine

Resistant cases may benefit from combining antimonials with allopurinol, pentamidine of amphotericin B.

Na stibogluconate Meglumine antimoniate

Cutaneous

Mild lesions heal spontaneously; antimonials or stibogluconate may be injected intralesionally.

Pneumocystosis (HIV-infection)

Pneumocystis carinii

Co-trimoxazole

Intolerant or resistant cases may benefit from

Pentamidine

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Toxoplasmosis

Trichomoniasis Trypanosomiasis African (Sleeping sickness)

American (Chaga s disease)

Majid A. K. Lafi

Toxoplasma gondii

Pyrimethamine plus sulphonamide; or tetracycline

(Self-limiting, treat immunocompromised or prior to pregnancy) Trichomonas vaginalis

Metronidazole

Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense For early phase For later phase

Pentamidine, suramin Melarsoprol

Trypanosoma cruzi

Nifurtimox

Table 4.13. Drugs of choice for parasitic worms Worm Class Nematodes (round worms) Intestinal

(In immunocompromised ) Cestodes (Tapeworms) Trematodes (Flukes) Hydatid cysts (when surgery is contraindicated or when cysts rupture or spill during surgery)

Common Name Pinworm

Official Name Enterobius vermicularis

Drug of Choice Pyrantel pamoate; Mebendazole; Piperazine

Giant round worm

Ascaris lumbricoides

Mebendazole; Pyrantel pamoate; Piperazine citrate; Levamisole

Hookworm

Ancylostoma duodenale

Bephenium; Mebendazole; Pyrantel pamoate

Threadworm

Strongyloides stercoralis

Thiabendazole

Beef tapeworm Pork tapeworm Blood flukes Intestinal Urinary

Schistosoma species mansoni & japonicum haematobium Echinococcus granulosus

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Niclosamide; Praziquantel Praziquantel

Albendazole & mebendazole or praziquantel

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CNS-PHARMACOLOGY (GENERAL PRINCIPLES) potential by increasing Na+ permeability of the cell membrane (decreasing negativity inside the cell resulting in reduced value as measured by -mV). An IPSP lowers the resting membrane potential (hyperpolarisation) by increasing Cl- influx (increasing negativity inside the cell and thus increased value as measured by mV).

Introduction The resting membrane potential of the neurone in the CNS is about (-70 mV). The neurone can be affected by excitatory or inhibitory actions which give rise to an excitatory postsynaptic potential (EPSP) or an inhibitory postsynaptic potential (IPSP). An EPSP raises the resting membrane

Benzodiazepines Barbiturates Valproic acid Vigabatrin

Lamotrigine

Inhibitory neurone

Excitatory neurone

mV 0

Ethosuximide Carbamazepine Phenytoin

Action potential

Threshold potential

-60 EPSP

EPSP Resting potential

-70 IPSP Hyperpolarisation

Fig. 5.1. A simplified representation of polysynapses in the CNS showing excitatory and inhibitory neurones modulating the excitability of a primary neurone. The excitatory transmitter (e.g. glutamate) produces EPSP (excitatory postsynaptic potential) which may raise the resting potential high enough to reach the threshold and then fire an action potential. While, inhibitory transmitters (e.g. GABA) produces IPSP (inhibitory postsynaptic potential) which lowers the resting potential making it at a distance from the threshold potential (hyperpolarisation); therefore, reducing the possibility of firing action potential.

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Transmission of electrical impulses in the neurones of the CNS mainly takes place by the action of chemical transmitter substances, neurotransmitters, which are released from presynaptic nerve endings and act on

postsynaptic membranes. In addition to distinctly released neurotransmitters there are a number of putative (suggested) neurotransmitters and neuromodulators with more diffuse actions.

Table 5.1. A summary of the possible sites of drug action in the CNS

Mechanism 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

Action potential Synthesis Storage Metabolism Release Reuptake Degradation Receptor Conductance Second messenger

Drug

Specific Drug Actions

Blocks action potential Synthesis of false transmitter Depletes transmitters Blocks amine breakdown Reduces transmitter release Increase transmitter availability Blocks acetylcholinesterase Blocks postsynaptic effects Hyperpolarisation Blocks phosphodiesterase

Catecholamines

Besides the principle actions of drugs on various mechanisms, many drugs are employed because they have a specific action on one of the functions in the CNS. There are essentially three different anatomical sites in the brain to which specific function can be assigned ( Table 5.2.). There is a complex range of interrelationships, e.g. the locus caeruleus interconnects the reticular formation, hypothalamus and cortex.

The CNS contains separate neuronal systems that involve catecholamines like dopamine, noradrenaline, and adrenaline. Each system is anatomically distinct and serves separate functions.

Serotonin Serotonin (5-hydroxytryptamine, 5HT) is the chemical transmitter in the tryptaminergic systems that are found mainly in the pons and upper brain stem.

Table 5.2. An overview of the functional organisation of the brain Site Cerebral cortex Limbic system Brain stem

Action

Tetrodotoxin Methyldopa Reserpine MAO-inhibitor Ca-antagonist Cocaine Tacrine Phenothiazines Benzodiazepine Methylxanthines

Functions Motor, sensory, thought

Peptides A large number of neuromodulatory peptides have been identified as endorphinpeptides. These peptides share actions that originally were ascribed to opioids.

Emotions, visceral control Wakefulness, vasomotor & respiratory control

Other peptides: vasoactive intestinal peptide (VIP), glucagon, substance P. These substances are synthesised in the rough endoplasmic reticulum of the nerve cell body as a propeptide that is cleaved into its active form and stored in secretory vesicles.

Acetylcholine Acetylcholine (ACh) is a central neurotransmitter acting with a mixture of nicotinic and muscarinic receptors. 125

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Apparently, there is no reuptake mechanism for peptides.

GABA

It is now well established that a neurone may synthesise and release one or more than one neurotransmitter (cotransmission). This is particularly true for neuropeptides.

GABA (gamma-aminobutyric acid) mediates inhibitory actions on local interneurones. Benzodiazepines potentiate the effect of GABA by interacting with GABA-receptor complex (Fig. 5.2).

Glucose

Glutamic acid

GABA vesicle

GABA

BNZ

GABA

Barbiturate -

Cl

Postsynaptic membrane -

Cl channel Fig. 5.2. A simplified schematic representation of synthesis, storage, and release of GABA from GABAergic neurone. When released GABA acts postsynaptically on a specific site that located on GABA receptor complex enhancing entry of Cl- through Cl- channel. Note: Benzodiazepines and barbiturates act allosterically on specific sites located nearby the GABA site on the GABA receptor complex to enhance the action of GABA.

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glutamate receptor complex to enhance the excitatory effect of glutamate (Fig. 5.3).

Glycine Glycine is another amino acid with inhibitory action (increases Cl- conductance and results in hyperpolarisation) in the spinal cord. However, glycine acts allosterically on

so-called acidic amino acid receptors, glutamate receptor system , causing dislodging of Mg++ and letting Na+ and Ca++ enter, and K+ leave the cell. Glycine can also bind to this receptor system allosterically enhancing the action of glutamate and aspartate (Fig. 5.3.).

Glutamate and Aspartate Glutamate and aspartate are excitatory neuromodulators act on specific sites on the

Glycine (allosteric)

Glutamate

Agonist (NMDA +

Na ++ Ca

++

Mg Postsynaptic membrane

+

K

Fig. 5.3. A simplified schematic representation of acidic amino acid receptor system. Glutamate or aspartate (or N-methyl-D-aspartate, NMDA) can activate the ligand specific site on the receptor system leading to deployment of Mg++ and letting Na+ and Ca++ enter, and K+ leaves the cell. Allosterically, glycine enhances the action of the acidic amino acids. Mg++ ions block the channel in the resting state. Depolarisation by ligand or voltage gating dislodging Mg++. Glycine enhances the action of glutamate to open the channel.

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Table 5.3. A summary of selected central transmitters and neuromodulators, their functions, agonists and antagonists

Transmitter

Site

Function Dysfunction

Receptor Agonists

Antagonists

Mechanism

Motor control: Nicotinic stimulation Memory: Muscarinic stimulation ↓ : Alzheimer s disease ↑ (relative): Parkinsonism

Nicotine

Dihydro-βerythroidine

Muscarine

Atropine

Muscarine

Atropine

Excitatory: ↑ cation conductance. Excitatory: ↓ K+ conductance; ↑ IP3, DAG Inhibitory: ↑ K+ conductance, ↓ cAMP

Substantia nigra Substantia nigra Pituitary gland Mesolimbic system Mesolimbic system Mesocortical system

↓ : Parkinsonism ↑ : Chorea

D1: SKF 38393

Phenothiazines SCH 23390

(Inhibitory): ↑ cAMP

D2: quinpirole

Phenothiazines Butyrophenones

Inhibitory (presynaptic): ↓ Ca2+ (postsynaptic):↑ K+ conductance, ↓ cAMP.

( (

↓ : Depression ↓:Obsessive-compulsive

5HT1A: LSD

Metergoline Spiperone

Inhibitory: ↑ K+ conductance, ↓ cAMP

5HT2A: LSD

Ketanserine

Excitatory: ↓ K+ conductance; ↑ IP3, DAG

5HT3: 2-methyl-5HT Phenylbiguanide

Ondansetrone

Excitatory: ↑ cation conductance

Prazosin

Excitatory: ↓ K+ conductance; ↑ IP3, DAG

Yohimbine

Inhibitory (presynaptic): ↓ Ca2+ conductance. Inhibitory:↑ K+ efflux;↓ cAMP

Spinal cord CNS cortex

Basal ganglia

) )

Amygdala Hypothalamus Pons (raphe nuclei) Mesolimbic system

Locus caeruleus & diffuse terminals to hypothalamus & cortex

↓ : Hyperprolactinaemia ↑ : Schizophrenia ↑ : Arousal ↓ : Negative symptoms

disorder ↑ : Anxiety ↑ : Decreased appetite ↑ : Sleep ↑ : Arousal*

Arousal, mood ↓ : Depression ↑ : Mania Decrease in pressure by stimulation

(α1): Phenylephrine

blood α2 -

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TransSite mitter GABA Basal ganglia

Majid A. K. Lafi

Function Dysfunction ↓ : Huntington s disease

Most inhibitory ↓ : Convulsions interneurones Amygdala

↓ : Anxiety

Glycine Spinal interneurones & Inhibitory some brain stem interneurones Relay neurones at all levels

Excitatory

Receptor Agonists

Antagonists

Type A: Muscimol

Bicuculline,

Type B: Baclofen

2-OH saclofen

Taurine

Strychnine

Ionotropic

2-Amino5phosphonovalerate

N-Methyl-Daspartate (NMDA): NMDA

picrotoxin

Metabotropic

Hypothalamus & diffuse terminals to all parts of the brain

Endings of primary afferent neurones Pain transmission (ascending) pathways Primary afferents Spinal cord Thalamus Pain inhibiting (modulating, descending) pathways Midbrain Medulla

Arousal

Nociception (algesia, tachykinins)

Antinociception (analgesia, opioid peptides)

: quisqualate

MCPG

H1: 2(m-Fphenyl) histamine H2: Dimaprit

Mepyramine

NK1:

CP99994

Ranitidine

Substance P Methylester

µ (Mu): ¾-Endorphin δ (Delta): Enkephalins

κ (Kappa): Dynorphin

Naloxone Naloxone Naloxone

Mechanism Inhibitory: conductance.

↑

Inhibitory (presynaptic): ↓ Ca2+ Inhibitory (postsynaptic):↑ in K+ conductance. Inhibitory: ↑ Clconductance Excitatory: ↑ cation conductance, (Ca2+).

Inhibitory (presynaptic): ↓ Ca2+ Conductance; ↓ cAMP. Excitatory: ↓ K+ conductance, ↑ IP3, DAG. Excitatory: ↓ K+ conductance; ↑ IP3, DAG Excitatory: ↓ K+ conductance; ↑ cAMP Excitatory: ↓ K+ conductance, ↑ IP3, DAG

Inhibitory (presynaptic): ↓ Ca2+ conductance, ↓ cAMP Inhibitory (postynaptic): ↑ K+ conductance, ↓ cAMP

NA: Noradrenaline; DA: Dopamine; 5HT: 5-hydroxytryptamine (serotonin); ACh: Acetylcholine; GABA: Gamma aminobutyric acid; ↓: Deficiency; ↑: Access. * Fluoxetine (5HT reuptake inhibitor) may produce arousal, insomnia, and reduced appetite. MCPG: α-methyl-4-carboxyphenylglycine NK: Neurokinin

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Table 5.4. A summary of the targets for selected centrally acting drugs Cellular Target

Drug Group/Drug

Membrane lipid Cyclooxygenase Voltage-dependent sodium channel Voltage-dependent sodium channel L-type voltage-dependent calcium channel

General anaesthetic drugs NSAIDs Local anaesthetics Phenytoin, carbamazepine Calcium channel blockers

Opioid receptors Opioid receptors GABA receptor complex GABA receptor complex GABA receptor complex GABA transaminase

Opioid analgesics Opioid antagonists Benzodiazepines (BNZ) Flumazenil ( BNZ-receptor antagonist) Barbiturates Sodium valproate

Acetylcholinesterase Adrenergic receptors Adrenergic receptors

Tacrine Clonidine (α2-agonist) Mianserin (tetracyclic antidepressant, α2antagonist?) Lecithin (ACh precursor) Antihistamine

Cholinoceptors Histamine receptors Dopamine receptors Adenosine receptors Monoamine oxidase

Antipsychotic drugs Caffeine Phenelzine, tranylcypromine, isocarboxazid & deprenyl L-DOPA L-tryptophan

Dopamine synthesis Serotonin synthesis Noradrenaline reuptake Serotonin reuptake

Viloxazine (bicyclic antidepressant) Clomipramine (tricyclic antidepressant) & fluoxetine Amantadine Lithium

Dopamine reuptake Phosphatidylinositol bisphosphate (PIP2) breakdown cAMP breakdown

Caffeine

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ANTIPSYCHOTIC DRUGS other evidence has lead to the development of the dopamine theory of schizophrenia.

Introduction Antipsychotics are usually employed for the treatment of major psychoses such as schizophrenia. The term neuroleptic is often used for antipsychosis. They cause psychomotor slowing, emotional quietening and in higher doses, psychic indifference to the environment. It may have a sedative effect but it is not a hypnotic.

It has been known that the sympathomimetic drug amphetamine produces a psychosis rather similar to paranoid schizophrenia and this effect was shown to be related to increased release of dopamine and that he effects of this can be reduced by dopamine receptors blockade. Further experimental work suggested that in schizophrenia the dopaminergic neurone is in fact working normally and from post mortem receptors binding studies on human schizophrenia brain tissues that the density of dopamine receptors is higher than normal. In addition, there is a positive relationship between the receptor blocking activity of antipsychotic agents and their clinical effectiveness.

One of the first drugs to be used for its antipsychotic properties was reserpine (Rauwolfia alkaloid), which also reduces blood pressure. It is no longer used, partly because more effective drugs have been developed and partly because reserpine has serious side effects including the production of depressive conditions and suicidal tendencies. The central pharmacological actions of reserpine are due to the disruption of noradrenaline and dopamine storage sites in nerve terminals leading to reduced-release of these neurotransmitters.

Normally there is a balance of dopamine in the limbic system and the substantia nigra. An increased dopaminergic activity in the former gives rise to active schizophrenia and a decrease in the latter gives rise to extrapyramidal symptoms such as Parkinson s disease (Fig.5.4).

A variety of drugs are currently used in the treatment of schizophrenia, which is characterised by added features to personality known, as positive symptoms like: • Hallucination (e.g visual, olfactory and auditory) • Delusions (false unshakable belief of morbid origin not consistent with the patient s social, cultural and educational background) • Thought disorders (organisation, stream of thought; content of thought, such that it drifts away from the point)

There is a long list of antipsychotics of different groups. Within the scope of the objectives of this chapter, it is not possible to go through the pharmacology of each drug separately. Therefore, it is decided to present the essential details in Table 5.6.

Indications of antipsychotics 1. Treatment of acute and chronic schizophrenia 2. Prophylaxis of schizophrenia 3. Treatment and prophylaxis of mania 4. Psychotic depression (depression with psychotic symptoms) 5. Other psychoses (e.g. paranoid psychosis, morbid jealousy, erotomania) 6. Anxiety 7. Organic psychoses (delirium, dementia including Alzheimer s psychotic features)

Schizophrenia may also be characterised by absence of features of personality known, as negative symptoms like: • Apathy (lack of feeling or emotion; indifference) • Being withdrawn (retreat from external reality; reduced ability to relate to people) All of these drugs have in common the ability to block central dopamine receptors. This and 131

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8. Movements disorders (Huntington s chorea, Sydenham s chorea, tics, stuttering) 9. Anorexia nervosa 10.Management of aggressive people (therapeutic restraining, chlorpromazine) 11.Personality disorder (very touchy person, small doses of antipsychotics) 12.Irritable bowel syndrome (trifluoperazine) 13.Peptic ulcer (sulpiride) Vomiting (prochlorperazine) 14.Intractable hiccup (chlorpromazine) 15.Neuroleptanalgesia (droperidol + Fentanyl) 16.Chronic pain (chlorpromazine + fentanyl) 17.Hypertensive crisis of MAO inhibitors (cheese effect)

12.Poikelothermia (disturbance in the setpoint, hypothermia and hyperthermia) 13.Eye (cornea: opacity; retina: pigmentation) 14.Iris (miosis: thioridazine; chlorpromazine: mydriasis)

Onset of Action Generally, the antipsychotic effects of neuroleptics, in the presence of adequate dosages and serum drug concentrations, take several weeks or longer to appear. This delay may be due to an inhibition of presynaptic (autoregulatory) dopamine receptors by neuroleptics leading to an enhanced release of dopamine that counteracts the postsynaptic receptor blockade. As tolerance develops to this autoregulatory receptor phenomenon, postsynaptic blockade becomes more effective. This probably also explains why only a few Parkinsonian-like side effects appear acutely in normal or psychotic subjects given neuroleptics.

Adverse effects 1. Acute dystonic reactions (use anticholinergic, e.g. benzhexol; diphenhydramine; diazepam) 2. Parkinson s syndrome 3. Akathisia (motor restlessness, severe sense of agitation), use less potent antipsychotics, β-blockers, or a benzodiazepine 4. Tardive dyskinesia (oral-facial involuntary movements, 10-30%), no satisfactory treatment 5. Anticholinergic (e.g. glaucoma, dry mouth, urinary retention, confusion in the elderly) 6. Endocrine (e.g. hyperprolactinaemia, gynaecomastia, galactorrhoea, amenorrhoea, erectile impotence) 7. Postural hypotension (α-antagonist activity) 8. Sedation (antihistamine effect) 9. Neuroleptic malignant syndrome (hyperpyrexia, disturbed consciousness, muscular rigidity, myoglobinaemia, use dantrolene, bromocriptine) 10.Proconvulsant (lower seizure threshold, particularly phenothiazines) 11.Cardiotoxicity (quinidine-like activity)

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However, antipsychotics have rapid onset of actions for the following indications: severe anxiety, acute mania, acute psychotic states (for sedation and restraining), intractable hiccup. Note: Antipsychotics are used as therapeutic restraints in severe schizophrenia (to restrain aggressive over-excited persons) by an effect on the basal ganglia leading to generalised dystonia. For this purpose, usually a large dose and potent agent is required (e.g. fluphenazine, or chlorpromazine).

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Parkinsonism Hypokinesia Dystonic syndrome Hyperprolactinaemia

Schizophrenia Dyskineasia-Chorea Tardive dyskinesia Nausea

Dopamine

Dopamine

Fig. 5.4. A simplified representation of dopamine balance in the CNS with the possible clinical consequences. If the balance is tilted in favour of dopamine then CNS disorders like schizophrenia, dyskinesia-chorea, and tardive dyskinesia may be produced; however, if the balance tilted against dopamine then CNS disorders like Parkinsonism and dystonic syndromes.

Table 5.5. Antipsychotics may produce the following extrapyramidal reactions, range of onset time and features are also listed.

Reaction Acute dystonia

Onset Hours to 5 days

Parkinsonism

5

30 days

Akathesia

5

60 days

Tarditive dyskinesia

Months to years

Features Spasm of tongue, neck, face & back Tremor, shuffling gait, drooling, stooped posture, instability Compulsive, repetitive motions; agitation Lip-smacking, worm-like tongue movement, fly-catching

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Table 5.6. A summary of selected antipsychotics used in schizophrenia and related disorders Antipsychotics

Adverse Effects

Remarks about Uses

(mg)

Phenothiazines Chlorpromazine (Largactil) Fluphenazine (Modecate) Trifluoperazine (Stelazine)

100

+++

++

++

++

Useful in violent patients Severe anxiety (short term) Intractable hiccup Antiemetic

+

Maintenance therapy Therapeutic restraining

2

++

+++

+

5

+

+++

+

100

++

+

+++

++

useful in elderly due to low incidence of EP effects

2

+

+++

+

+

Rapid control of acute mania & other psychoses

2

+

+++

+

+

Neuroleptanalgesia

Pimozide

2

+

+

+

+

Thioxanthenes Flupenthixol

3

++

+++

+

++

Benzamides Sulpiride

50

-

+

+

+

100

+++

+

+++

+++

5

++

-

++

1

+

+

+

Thioridazine (Melleril) Butyrophenone Haloperidol (Serenace) Droperidol

Dibenzodiazepine

Clozapine* Theinobenzodiazepine

Olanzapine Benzisoxide Risperidone**

+

++

Retarded schizophrenia (-ve symptoms)

Retarded & monodelusional disorders (e.g. paranoid) Apathetic & withdrawn patients Avoid in manic or hyperactive patients Useful in ve symptoms Useful in resistant schizophrenia, lower seizure threshold, (may cause agranulocytosis, 1-2%) Useful in mania, Less incidence of blood dyscrasia Useful in ve symptoms

* Clozapine is a selective D4 receptor antagonist. ** Risperidone is an antagonist at both D2 and 5HT 2 receptors.

Note: A general rule the more potent antipsychotic drug is expected to produce more EP effects, with less anticholinergic and less sedative actions.

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DRUGS FOR AFFECTIVE DISORDERS

inhibition of biogenic amine reuptake or degradation, in isolation, can correct the fundamental biochemical abnormalities of depression. It has been hypothesised that antidepressants increase the efficiency of transmission through 5HT and/or noradrenaline pathways but by different molecular mechanism.

Antidepressants Affective (mood) disorders are characterised by severe disturbance of mood and range from depression (unipolar affective disorder) to manic-depressive illness (bipolar affective disorder). These disorders are associated with multiple derangements of normal biological processes, neuroendocrine circadian rhythms. In severe forms, patients develop psychotic symptoms and become detached from reality, thus, these disorders represent extreme expressions (depression and manicdepressive states) of otherwise normal emotional swings, suggesting major alterations in normal biological function (Fig.5.5).

There are two major isoenzymes of MAO: types A and B. A is selectively inhibited by clorgyline and primarily degrades 5HT. B is selectively inhibited by deprenyl (used as protective therapy in Parkinson s disease) primarily degrades dopamine. The available MAO inhibitors used for treating depression are relatively nonselective for A or B isoenzymes. It has been proposed that MAO inhibitors (type A only) produce an improvement in transmission of 5HT pathways.

Typical Symptoms of Depression Depression is characterised by: • Sadness • Anhedonia (loss of interest pleasure in activities) • Crying spells • Emotional liability • Feeling of guilt • Worthlessness and hopelessness

There is a delay in onset of antidepressant effect (7-21 days). This delay may represent the time required to overcome compensatory mechanism. Hence, the initial increase in neurotransmission appears to produce, over time, a compensatory decrease in receptor activity (down-regulation of receptors). Antidepressants like selective noradrenaline reuptake inhibitors, those with mixed action on noradrenaline and 5HT.

and

Depression requiring medical treatment, is usually associated with biological abnormalities (vegetative signs, which include decreased appetite, weight loss, GI disturbances, fatigue, difficulty in concentrating, early morning awakening, and loss of libido. It is well recognised that depression may impair the immune system and may lead to increased susceptibility to infection and risk of cancer.

Tricyclic Antidepressants (TCAs) and Related Compounds These drugs are generally believed to produce their antidepressant activity by virtue of their ability to block the neuronal amine (5HT and noradrenaline) reuptake. This in turn may lead to enhanced availability of the amines in synaptic junctions, and thus, facilitates aminergic neurotransmission (i.e. correction of the disturbed balance of amines).

Two major groups of antidepressant drugs (tricyclic and related monoamine reuptake inhibiting compounds and MAO-A inhibitors) are used in the treatment of depression. No single biochemical effect can explain the mechanism of action of these antidepressant drugs. It is unlikely that

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scope of this volume. Therefore, it is decided to present a summary of the pharmacology of these agents in Table 5.8 and Table 5.9.

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7. 8. 9. 10. 11. 12.

Indications 1. Depression (unipolar, bipolar and reactive depression) 2. Prophylaxis of depression (seasonal depression) 3. Obsessive-compulsive disorder (clomipramine, fluoxetine) 4. Phobias (an unusual or morbid fear from a condition, e.g. agoraphobia, clomipramine) 5. Anxiety (superior to diazepam because no risk of addiction, suitable for long term therapy, amitriptyline) 6. Nocturnal enuresis

13. 14. 15. 16.

Premature ejaculation Neurogenic pain Chronic pain (in cancer) Peripheral neuropathy Migraine headache Rumination disorder (in man , the regurgitation of food after almost every meal, part of it being vomited and the rest swallowed; a condition seen in infants) Attention deficit (hyperkinetic) disorder (hyperactive child) Alcoholism (as secondary to depression) Eating disorders (bulimia nervosa, fluoxetine) Sleep disorders (narcolepsy, imipramine; hypersomnia, imipramine)

Depression Mania

Amines

Amines

Fig.5.5. A simplified representation the Amine Hypothesis that proposes depression is somehow associated with underactivity of functional amine (5HT and noradrenaline)-dependent neurotransmission. While, mania may be explained by overactivity of amine-dependent neurotransmission. Note: Much of the evidence for the amine hypothesis of depression was available in the early 1950s when reserpine was used in the treatment of hypertension and schizophrenia. In hypertensive and schizophrenic patients as well as normal subjects, reserpine could produce depression and suicidal tendency that were major problems with reserpine. Reserpine interferes with aminergic neurotransmission by inhibiting the vesicular storage of amines like 5HT and noradrenaline, consequently, reducing release and hence synaptic availability of the biogenic amine neurotransmitters.

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Reuptake

MAO inhibitors lie in two major groups: Irreversible MAO Inhibitors

The tricyclic antidepressant clomipramine is to certain extent selective amine reuptake inhibitor for serotonin (5HT) than noradrenaline. In recent years, a new group of drugs has emerged which characterised to be selective for serotonin reuptake. This group includes fluoxetine, paroxetine and sertraline. So there is no substantial evidence that this group provides a greater therapeutic efficacy than the older drugs. However, the SSRIs offer an advantage of their lack of antimuscarinic adverse effects.

1. Hydrazine • Phenelzine (Nardil) • Isocarboxazid (Marplan) (Leg oedema and hepatitis as adverse effects) 2. Non-hydrazine • Tranylcypromine (Parnate) (Insomnia, and addiction as adverse effects) Reversible MAO Inhibitors Moclobamide is a reversible inhibitor of MAO-A. Therefore, as tyramine is metabolised by both forms of MAO, if tyramine-containing food is consumed, tyramine is metabolised by MAO-B enzymes as well as being able to reverse the inhibition of MAO-A. Unless very large quantities of tyramine are ingested, this appears to prevent the typical hypertensive reaction seen with conventional MAOIs and tyraminecontaining foods.

A selected list of adverse effects and the possible mode of action for the TCAs and other antidepressants are presented in Table 5.9.

MAO Inhibitors MAO inhibitors were the first to be found to have antidepressant action. In 1951, iproniazid, which was then used as antituberculosis drug, was observed to elevate mood. This effect was attributed to the ability of the drug to inhibit the enzyme monoamine oxidase (MAO). The termination of the synaptic action of monoamines, such as 5HT and noradrenaline, is primarily achieved by neuronal amine-reuptake pump and the activity of MAO located intraneurally. Upon blocking MAO, the vesicular storage and consequently release and synaptic availability of the monoamine neurotransmitter is increased. In fact, this is the opposite to what happens with reserpine that reduces monoamine vesicular storage and consequently reduces release of the amine transmitter. Hence, depression may be associated with the use of reserpine.

Indications for MAO Inhibitors They have no superiority to TCAs or related agents. However, it has been suggested that MAO inhibitors may be more effective in reactive and atypical depression. Onset of action occurs in 1 to 2 weeks and persists as long as 2 to 3 weeks after stopping the treatment. A summary of the adverse effects and their possible mode of action for MAO inhibitors is presented in Table 5.7.

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Table 5.7. A summary of the following adverse effects, the possible mode of action of MAO inhibitors Adverse effects Possible Mode of Action Hypertensive crisis (cheese Inhibit the metabolism of dietary tyramine leading to effect) enhanced systemic tyramine that causes the release of endogenous neural noradrenaline resulting in enhanced vascular α-receptor activity. Therefore, patients must carry a card stating details of treatment. Hypotension Sympathetic ganglionic block Others similar to that of TCAs •

MAOIs have anxiolytic properties; they are considered as second line drugs

CAUTION: Concomitant use of MAO inhibitors and tricyclic antidepressants may result in mutual enhancement of effects with possibility of hyperpyrexia, hypertension, seizure and death.

Antimanic Drugs

Lithium

Mania is characterised by elevated, expansive or irritable mood, accelerated speech, racing thoughts with flight of ideas, increased activity and reduced sleep. Patients may develop grandiose ideas, act recklessly with overspending, and show increased sexual drive and activity. Impaired judgement (lack of insight) is usually associated with the illness; therefore, the patient and his family should be protected by hospitalisation of the patient.

Patients with mania are at risk of physiological exhaustion and require special attention to nutrition, hydration, and rest. Lithium carbonate and a neuroleptic (or a sedative-hypnotic like diazepam) should be initiated. The additional tranquilliser is necessary because the onset of the antimanic effect of lithium is usually delayed. Further, patients with bipolar disease usually require maintenance therapy with lithium to prevent relapse into mania or depression. Those who do not respond to lithium respond to carbamazepine or sodium valproate (see antiepileptic drugs).

The antipsychotic drugs, lithium and benzodiazepines all are important in the management of mania. Antipsychotics (e.g. chlorpromazine, haloperidol) are preferred to control the acute stages; if more sedation is desired (particularly when using haloperidol) then add a benzodiazepine (e.g. diazepam). Lithium is initiated, as it is the drug of choice for long-term use to prevent relapse of manic attacks, i.e. prophylactic use.

It has been suggested that lithium produces its antimanic activity at least in part by virtue of inhibition of hydrolysis of phosphatidylinositol bisphosphate leading to reduced production of the second messenger diacylglycerol (DAG).

Adverse Effects 1. GI disturbances vomiting, diarrhoea)

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(nausea,

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Majid A. K. Lafi

2. Nontoxic goitre (hypothyroidism, inhibits iodine uptake and thyroid hormone release, affecting 5-15% of patients on long term treatment1) 3. Polyuria 4. Diabetes insipidus 5. Renal tubular impairment (failure to concentrate urine after fluid deprivation and failure to acidify urine after ingestion of ammonium chloride) 6. Leucocytosis 7. CNS toxic encephalopathy (may lead to coma)

Interactions 1. With thiazide that increases lithium renal distal tubular reabsorption leading to lithium toxicity. Note: Lithium exhibits a low therapeutic index, and haemodialysis is indicated in toxicity (apparent volume of distribution is 55 litre). 1

Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 616.

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Table 5.8. A summary of tricyclic antidepressants and related compounds, and other antidepressants Drug

Class

Important Remarks WITH SEDATIVE ACTION (useful in depression associated with agitation, or anxiety, and insomnia)

Amitriptyline (Tryptizol)

Tricyclic

More cardiotoxic (sudden death) than others Useful in nocturnal enuresis and anxiety

Dothiepin (Prothiaden)

Tri-

Most widely prescribed in the U.K. Improved adverse effects profile

Mianserin

Tetra-

α2-receptor antagonist (↑ release of transmitter1) Less cardiac risk ; (it does not affect amine reuptake)

Trazodone2

Other

Probably as for mianserin?

Trimipramine (Surmontil)

TriWITH MINIMAL SEDATIVE ACTION (useful in depression associated with retardation, hypersomnia)

Clomipramine (Anafranil) Fluoxetine (Prozac )

Tri-

5HT reuptake inhibitor Useful in obsessive-compulsive patients

SSRI

Selective 5HT reuptake inhibitor Useful in obsessive-compulsive patients

Imipramine (Tofranil) Maprotiline (Ludiomil)

Tri-

Useful in nocturnal enuresis

Tetra-

Proconvulsant activity (fit) Useful in heart disease

Nortriptyline (Aventyl)

Tri-

Useful in nocturnal enuresis

Viloxazine

Bi-

Noradrenaline reuptake inhibitor

Flupenthixol

Thioxanthene

Antidepressant neuroleptic

α2-adrenoceptors generally mediate inhibition on the excitability of neurones and therefore reducing transmitter release. These receptors are termed autoreceptors (or presynaptic receptors) when inhibited by α2-receptor antagonists like mianserin and probably trazodone the release of neurotransmitter is enhanced (inhibiting inhibitory mechanism). 2 Trazodone may produce priapism and may decrease appetite as adverse effects. Therefore, its use is largely restricted to female patients. 1

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Table 5.9. A summary of adverse effects that may be encountered with the use of TCAs and other antidepressants.

Group/Drug

TCAs

Overdosage with TCAs & other antidepressants

Mode of Action

Adverse Effects

Muscarinic antagonism (especially amitriptyline, thus, avoid in the elderly, prostatism, narrow angle glaucoma) promoting sympathetic noradrenergic transmission by reuptake inhibition; while muscarinic antagonism may cause dryness in the axilla and groin regions. H1-receptor antagonism (especially doxepine, tolerance develops) ¿1-receptor antagonism3 (thus, useful in premature ejaculation) Increased catecholamine activity (cardiac overstimulation) ( Sympathomimetic) Quinidine-like action (unrelated to receptor antagonism)

Dry mouth, blurred vision, glaucoma, constipation, delayed bladder emptying, and confusion

Lowering seizure threshold in epileptic patients Shift of mood from depression to hypomania in bipolar illness Deriving from anticholinergic toxicity

Trazodone

Quinidine-like action α2-receptor antagonist (↑ release of transmitter)

SSRIs Fluoxetine

↑ synaptic availability of 5HT at certain sites in the CNS

Diaphoresis (excessive apocrine sweating, face, palm & sole, nonthermoregulatory sweating, cold sweat)

Sedation

Orthostatic hypotension Ejaculatory delay Cardiac arrhythmia Adrenergic tremor Cardiac toxicity (most serious adverse effect of TCAs, thus, avoid in patients with conduction defects and heart disease Seizure recurrence Hypomania Dilated seizure

pupil,

fever,

coma,

Cardiac toxicity Sedation, nausea, decreased appetite, priapism ( 1-blocking effect) Arousal, insomnia, decreased appetite

Caution: TCAs in a patient with bipolar illness, usually presenting as depression without history of mania, can precipitate acute mania or rapid cycling.

3

(Frohlich, D. F. (1993) Rypins Basic Science Review, 16th edition, Page 661; Mycek, M. J., Harvey, R. A. & Champe, P. C. (2000) Lippincott s Illustrated Reviews Pharmacology, 2nd edition, Page 121)

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ANTIANXIETY DRUGS system (affect), the median fore-brain bundle (reward and punishment systems) and hypothalamus.

Introduction Anxiety, fear for no adequate reason, is the most prevalent symptom in mental illnesses, but it also occurs normally and may have adaptive value. Normal anxiety, marked by dissatisfaction, unhappiness, or apprehension, is of short duration and usually event-related (e.g. as a part of the hypoglycaemic alarm, sitting an examination) and not under the subject s control. Normal subjects, under severe stress may experience periods of increased muscle tension, exaggeration of the discomfort of minor aches and pains, irritability, or sadness. There is evidence suggests that pathological anxiety is not an exaggeration of normal anxiety, because of considerable overlap in the symptoms of anxiety disorders and depressive states. However, the treatments of normal anxiety and pathological anxiety involve the same drugs.

Both BNZ and barbiturates modulate GABA type receptor complex resulting in increased chloride channel ion current. Binding of BNZ increase the frequency of chloride channel openings, whereas binding of a barbiturate like pentobarbital prolongs the duration of the chloride channel open time. The sedative, muscle relaxant, or anticonvulsant effects of BNZ show tolerance fairly rapidly upon prolonged usage, where relief of anxiety does not show tolerance. It has been suggested that a type 1 benzodiazepine receptor may be responsible for the anxiolytic actions of these drugs and a type 2 benzodiazepine receptor may be involved in other central actions. Type 3 benzodiazepine receptor has been proposed to be found in peripheral organs, e.g. stomach and heart. Serotonergic (5HT) innervation to the amygdala has been investigated with BNZ treatment which show reduced activity suggesting 5HT activity in the amygdala may be anxiety-promoting, and its interruption by a benzodiazepine drug could explain the antianxiety effect.

In the past, several drugs had been used for the treatment of anxiety; alcohol, opioids, or barbiturates. In the 1950s, meprobamate was introduced as a more selective antianxiety drug, but later it was found to have barbiturate-like actions. In the late 1960s, benzodiazepines were introduced as the first drugs to relieve anxiety without producing sedative effects. Buspirone, a more recent drug, may effectively treat anxiety with fewer side effects. The antianxiety drugs are also known as anxiolytics and have been known as minor tranquillisers (and neuroleptics as major tranquillisers).

Further evidence which lends support for the theory of the involvement of 5HT in promoting anxiety comes from the development of the second-generation antianxiety drugs like buspirone (5HT partial agonist) which affects 5HT mechanisms. Thus, it is conceivable that GABA- and 5HT modulating brain systems are involved, each having greater or lesser control according to the type of anxiety that predominates in a particular patient.

Benzodiazepines The benzodiazepines (BNZ) or barbiturates bind to GABA type A receptor/chloride channel complex (Fig.5.2.). This GABA neurotransmitter-receptor system in the CNS is the major inhibitory biochemical pathway in the mammalian brain, particularly in the amygdala region and spinal cord. BNZ may act chiefly on the brain reticular activating system (reducing sensory input), the limbic

Flumazenil A benzodiazepine receptor competitive antagonist (partial agonist) Flumazenil with a t of 1 hour, therefore, repeated i.v. doses or infusion may be needed in heavily sedated patients. Flumazenil finds use in the termination of agonist (BNZ) effect in 142

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conditions like after endoscopies, and diagnosis and treatment of BNZ-overdose.

6. Paradoxical effects (agitation, overactivity, insomnia may be observed in children and elderly)

Inverse Agonists

Benzodiazepines should be avoided with alcohol as additive effects occur. Tolerance occurs with chronic use and there is a crosstolerance within the sedative-hypnotic drugs and also with ethanol. Several days (a week or more) after withdrawal seizures, rebound insomnia, and inhibition of control of aggression (disinhibition of aggression) may occur. Benzodiazepine should be avoided in pregnancy as far as possible as diazepam is known to be teratogenic in mice. A summary of the important pharmacological characteristics of BNZ is presented in Table 5.10.

Substances known as β-carbolines bind to the benzodiazepine receptor causing stimulation, anxiety, increased muscle tone and convulsions. These substances are called inverse agonist. Note: These substances produce their effects not by inhibiting the action of BNZ, rather, they appear to operate a mechanism via a benzodiazepine site that is not already in operation.

Indications for BNZ 1. Anxiety (generalised anxiety disorder, GAD) 2. Panic anxiety disorder (attack form, lasting minutes or hours, with intense fear of eminent death; high dose of BNZ, or alprazolam) 3. Phobias 4. Insomnia (a benzodiazepine with short t , e.g. midazolam, is preferred when there is no anxiety otherwise it may produce rebound anxiety) 5. Muscle relaxant (tetanus, infantile spasm; BNZ, meprobamate, or barbiturate) 6. Epilepsy (status epilepticus, diazepam i.v., lorazepam i.m., thiopental, chlormethiazole; maintenance therapy, clonazepam) 7. Premedication in anaesthesia 8. Before endoscopy (midazolam) 9. Alcohol withdrawal (BNZ, chlormethiazole)

Buspirone Buspirone is a new generation of antianxiety agents. It is believed to produce its effect by its property as a partial 5HT-receptor agonist as explained above. Unlike benzodiazepines, buspirone has no hypnotic, muscle relaxant or antiepileptic effect. The onset of its antianxiety action is delayed for 2 or more weeks. It causes little or no depression on psychomotor function. It does not benefit benzodiazepine withdrawal symptoms.

Barbiturates An account on barbiturates is presented in the following section (Sedatives and Hypnotics) and also in the section on Antiepileptic Drugs.

Adverse Effects

Others

1. Sleepiness (therefore, operating machines should be avoided) 2. Impaired psychomotor function 3. Amnesia 4. Dependence 5. Hangover (delayed drowsiness; a benzodiazepine with short t , e.g. midazolam, is preferred, less hangover particularly in the elderly)

1. ¾-blockers (e.g. propranolol) can be used where there are somatic symptoms like tremor and tachycardia. 2. Antidepressants (e.g. amitriptyline can be useful where there is depression with anxiety) 3. Antipsychotics (for their sedative action, e.g. trifluoperazine)

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Table 5.10. A summary of the pharmacology of selected benzodiazepines Drug

Anxiolytic Action

Plasma t h

Metabolites (t h)

Alprazolam (Xanax)

16

Inactive

Chlordiazepoxide (Librium)

20

Clobazam (Frisium)

35

Active (42)

Clonazepam (Rivotril)

25

Inactive

Clorazepate (Tranxene )

Prodrug

Nordiazepam (80)

Diazepam (Valium)

43

Nordiazepam (80)

RO LA

Highly lipid soluble so quickly effective (orally), but slowly effective i.m.; short-acting as anticonvulsant i.v. (rectally, in children)

Lorazepam (Ativan)

20

Inactive

IO SA

Slowly absorbed & distributed (lower lipid solubility; thus, slower onset & offset of effect than diazepam & midazolam); quickly effective i.m., used for status epilepticus

Midazolam (Hypnovel)

3

Inactive

RO SA

Injected as adjunct in anaesthesia for endoscopies, dentistry etc; quickly effective i.m; given sublingually in status epilepticus.

Nitrazepam (Mogadon)

30

Inactive

Superseded because of long t , more sedative-hypnotic, abuse potential in Iraq; 1st choice in infantile spasm

Triazolam (Halcion )

3

Active (7)

Amnesia; psychiatric reactions; very rapid oral absorption

Important Remarks Has antidepressant activity; used in panic disorders, agoraphobia

Desmethyldiazepam

[nordiazepam (80)]

IO LA

Steady-state effect for about 3 days; low lipid solubility; slowly effective i.m.; less sedative (good anxiolytic) Used in epilepsy as well as anxiety Broad spectrum antiepileptic; useful in absence and myoclonus In stomach converted by hydrolysis to nordiazepam

Modified from Laurence, D. R., Bennett, P. N., and Brown, M. J. (1997) Clinical Pharmacology, 8th edition, page 318. R: rapid; I: intermediate; O: onset; S: short; L: long; A: action; note these generally apply to the anxiolytic action of these agents. For other actions the classification may be different, e.g. as anticonvulsant diazepam is shorter acting than lorazepam.

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Majid A. K. Lafi

Lorazepam, when given i.v., diffuses into the CNS more slowly so that the onset (15 min) and offset of effect are smoother compared to that of diazepam and midazolam both are more lipid soluble with rapid onset of action (2 min). Therefore, at sedative dose lorazepam acts longer and may produce more amnesia for which it may be superior to diazepam and midazolam. Lorazepam has a plasma t of 20 h with a single step metabolism (conjugation) suggesting that it is not seriously accumulative. This is probably why it has a substantial capacity to induce dependence and withdrawal of the drug can be troublesome for which diazepam therapy is used. Lorazepam is metabolised by conjugation (inactive metabolites), a process is less influenced by age than is oxidation of other benzodiazepines like diazepam. Cimetidine (hepatic enzyme inhibitor) does not increase plasma concentrations of lorazepam, while it may increase concentrations of diazepam and chlordiazepoxide by as much as 50%. Clonazepam, unlike diazepam, can be effective in the treatment (chronic use) of epilepsy. This is probably with diazepam tolerance to the antiepileptic action develops rapidly.

2.

3.

4.

Long t drugs/metabolites are appropriate for anxiety. Short t drugs/metabolites are appropriate for insomnia.

•

Sedative action: premedication for surgery, dental surgery (with local anaesthetic), cardioversion, endoscopies and anxiety with agitation; sedative action reduces attention; also amnesia is desired. • Hypnotic action: insomnia

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SEDATIVE AND HYPNOTIC DRUGS without adverse effects such as drowsiness and hangover, and with all hypnotics there is a risk of addiction. Finally, there is no hypnotic that gives you physiological sleep as hypnotics usually cut down on the important component rapid eye movement (REM) sleep that should make up 20% of sleeping time.

Introduction To date, the physiology of sleep is still not fully understood. However, several anatomical centres are believed to be involved, as shown in the following schematic diagram (Fig.5.6). In sleep control centres, the important factor is inhibition produced by excitatory inputs that come from two major sources (reticular activating system). Both of which stimulate the reticular formation (wake centre) that in turn inhibits raphe nuclei (sleep centre):

Sedatives and Hypnotics A sedative should reduce anxiety with little or no effect on mental or motor functions. A hypnotic drug induces more marked depression on CNS function than a sedative and this can be achieved with most drugs, simply by increasing the dose. Most of the sedatives and hypnotics give a graded CNS depression, dose-related (Fig.5.7.).

1. Afferent input from sensory nerves (e.g. tactile, visual, auditory) 2. Impulses from the limbic system (e.g. emotions)

Individual sedative-hypnotic drugs differ in their dose-response to the four principle actions (Fig. 5.7.). The steep dose-response curve, for example, for a barbiturate agent would show that sedation, anaesthesia, and undesirable clinical effects (e.g. respiratory depression) fall in a narrow dose range (thus, low therapeutic index). Whereas a benzodiazepine agent would show that sedation, hypnosis, and undesirable clinical effects fall in a wide dose range (thus, a large therapeutic index) that makes the drug attractive as a sedative.

Reticular Activating System The reticular activating system is a network of neurones that extends from the spinal cord through the medulla and pons to the thalamus and hypothalamus. It receives impulses from all parts of the body, evaluates the significance of the impulses, and decides which impulses to transmit to the cerebral cortex. It also excites or inhibits motor nerves that control both reflex and voluntary movement. Stimulation of these neurones produces wakefulness and mental alertness; depression causes sedation and loss of consciousness.

Sedative-hypnotic drugs can be classified into the following chemical groups:

This means that one is able to sleep when one does not suffer pain or other discomfort, moreover it is possible to fall asleep if you are not bothered about distracting feelings from the limbic system. Also other excitatory stimuli from coffee, tea and nicotine must be considered. Hypnotics produce a state similar to physiological sleep in that the patient is rousable by external stimuli while sleep induced by anaesthetics is not rousable by external stimuli.

1. Benzodiazepines 2. Barbiturates 3. Carbamates (meprobamate) 4. Alcohols (ethanol, chloral hydrate) 5. Cyclic ethers (paraldehyde)

Benzodiazepines This class of drugs has been covered in the section on anxiolytics. Benzodiazepines are generally considered superior to barbiturates in that being characterised by:

Thus, before prescribing a sleeping pill, one should exclude other wakeful stimuli. Unfortunately, there is no sleeping pill

1. High therapeutic index 146

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A

Majid A. K. Lafi

B

Cortex

Sleep Raphe Nuclei

Limbic System

+ Sensory Input

GABA Raphe Nuclei

-

+

5HT

Sleep Centre NA

Reticular Formation Wake Centre

Locus Caeruleus Nuclei

Fig.5.6. A simplified schematic representation of the sleep centre. Note: Two major stimulatory inputs coming via afferent sensory pathway (e.g tactile, visual and auditory) and input arriving from the limbic system (A). It is believed that in the raphe nuclei (sleep centre) the release of 5HT from serotonergic neurones mediates sleep. The inhibition of these serotonergic neurones by GABAergic (interneurone) activity leading to inhibition of the sleep centre, thus, wakefulness predominates. This probably explains the stimulatory effects (arousal state) of noradrenaline, 5HT, and histamine acting through the (reticular formation) interconnected with the locus caeruleus and then in turn with the sleep centre (B). 5HT in the mesolimbic system is suggested to produce arousal (it inhibits sleep as the case with the SSRI fluoxetine producing arousal and insomnia); while, in raphe nuclei it is suggested to produce sleep.

Coma -

Barbiturates

Anaesthesia -

Benzodiazepines

Hypnosis Sedation Anxiolysis -

Increasing dose Fig.5.7. A graph showing that sedative-hypnotic drugs like barbiturates (e.g. thiopental) exhibit a steep linear dose-response relationship; i.e. the dose required to produce anaesthesia and coma is close to that producing hypnosis. This type of drugs is described as having a low therapeutic index (low safety). On the other hand, drugs like benzodiazepines (e.g. diazepam) exhibit a non-linear dose-response relationship; i.e. the dose required to produce anaesthesia is very much greater than that required to produce sedation and hypnosis. This type of drugs is said to have a high therapeutic index (high safety).

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Nonbenzodiazepine Hypnotics that Act at the GABAABenzodiazepine Receptor

A list of adverse effects for barbiturates is presented in the section on Antiepileptic Drugs. It would suffice here to mention that barbiturates are characterised by:

Although structurally unrelated to the benzodiazepines, these drugs, represented by zopiclone, zolpidem and zaleplon, act on the same BNZ1 subtype of benzodiazepine receptors; their effects can be blocked by flumazenil, the receptor antagonist. They are largely effective in insomnia, have low tendency for tolerance, rebound insomnia, withdrawal symptoms and abuse potential.

1. Low therapeutic index 2. Risk for addiction

Addiction Addiction is a general term that describes the following clinical conditions that may be observed in a patient taking addictive drug:

Barbiturates

Addiction 1. Compulsion1 to use the drug 2. Using the drug taking the priority to other life activities 3. Symptoms appear upon withdrawal 4. When abstinence2 occurs, reusing the treatment leads to withdrawal symptoms more rapidly. 5. Tolerance leads to take more of the drug (higher dose), hence, withdrawal symptoms are more likely and consequently taking the drug more frequently.

Barbiturates (1903) are derivatives of barbituric acid, which is synthesised from malonic acid and urea. Barbiturates are today mostly used as antiepileptic drugs and for induction of general anaesthesia. They are too toxic to be used as sedatives or hypnotics. Phenobarbital is used as antiepileptic and thiopental for i.v. anaesthesia. Barbiturates exert a general depressant activity on cellular functions (reduce glucose oxidation), depress synaptic transmission by increasing membrane stability and by increasing GABA activity. In the brain, barbiturates predominantly depress the reticular activating system (reticular formation). The long acting phenobarbital (t : 80 hours) is more ionised and less lipid soluble than the ultrashort acting thiopental (initial t : 5 min, terminal t : 11 hr). High lipid solubility makes the drug penetrates the CNS rapidly. After entry into the CNS, thiopental is rapidly redistributed to other parts of the body that is the main reason for their ultrashort action.

Carbamates Meprobamate is a representative of the carbamate group, introduced in 1952. It has anxiolytic-sedative actions, anticonvulsant activity, and central muscle relaxant effect. It has hepatic enzyme induction activity. These days, its use is very much reduced, as this group is largely inferior to the benzodiazepines, and does not have any superiority over barbiturates. In fact, carbamates have a tendency to induce tolerance and dependence after prolonged use, and withdrawal symptoms may be precipitated if their use is terminated abruptly. Generally, its use is restricted in patients who do not respond to benzodiazepines.

Barbiturates rapidly induce tolerance since most of their effectiveness is lost with continued administration over a 2-week period and this explains why patients increase the dose. This makes the patient dependent since withdrawal induces abstinence symptoms. This tolerance depends on a metabolic factor (induction of liver enzymes) and pharmacodynamic factors (biological adaptation, see similar effects for morphine, section on Narcotic Analgesics).

1

An irresistible impulse to perform some act contrary to one s better judgement or will. 2 A refraining from the use of or indulgence in drugs. 148

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5. Vomiting (Following oral or i.v. administration, therefore, this action appears to be partly central, besides local gastric irritation. Note: Because the emetic blood alcohol level is below that which induces coma, death from acute alcoholism is rare. When it occurs, it is usually due to suffocation from inhaled vomit.) 6. Hypoglycaemia (Alcohol inhibits gluconeogenesis, particularly, when heavy drinking with a meal that enhanceinsulin response to carbohydrate intake.) 7. Hyperuricaemia: Gout may be precipitated by a. Increased metabolism of adenine nucleotides (e.g. ATP) leading to the production of uric acid. b. At high alcohol level, raised blood lactate compete for renal tubular elimination resulting in reduced excretion of urate 8. Actions on sexual functions: Ethanol produces CNS disinhibition, thus, increasing libido and erection (provokes the desire).

Alcohols Ethyl alcohol behaves like general anaesthetics on the CNS. It has been suggested that the acute effect of alcohol is to block NMDA (N-methyl-D-aspartate) receptors for which the normal agonist is glutamate, the main excitatory transmitter in the brain. Preseumably as a compensatory mechanism, alcohol chronic exposure increases the number of NMDA receptors and also 'L type' calcium channels, while the action of the (inhibitory) GABA neurotransmitter is reduced. Anxiety, insomnia and craving that accompanies sudden withdrawal of alcohol may explain why resumption of drinking brings about relief, and thus perpetuating dependence.

Ethanol is hardly used as a therapeutic compound; however, it has important toxicological interest. The main effects of ethanol are on the CNS. It acts as hypnotic and anaesthetic; and it disinhibits behaviour, which appears as stimulation (an effect on the higher centres). Peripheral actions include vasodilatation, stimulation of gastric acid. The diuretic effect is due to a central action, inhibition on the release of the posterior pituitary hormone ADH.

Chronic Alcohol Consumption Chronic alcohol consumption may lead to: 1. Hepatic enzyme induction: This leads to increased metabolism of testosterone, 2. Direct toxic effect on Leydig cells: This leads to reduced production of testosterone. 3. Testicular atrophy: Both 1 and 2 (above) result in testicular atrophy leading to feminisation (takes away the performance). 4. Foetal alcohol syndrome: teratogenic effects.

Ethanol is considered to be as a rich source of calories that 1 g of ethanol produces 7 calories. The alcoholic are prone to having a variety of pathological conditions, e.g. gastritis, hepatic cirrhosis, brain damage (loss of memory, mental changes). The following list represents the important actions of ethanol. 1. Cutaneous vasodilatation (feeling of warmth, as a result of depressing the vasomotor centre, risk of rapid hypothermia) 2. Increased blood pressure (probably due to centrally mediated sympathetic stimulation) 3. Diuretic action (decreases the release of ADH from the posterior pituitary gland) 4. Gastric mucosa (erosion and petechial haemorrhages due to allowing back diffusion of acid from the gastric mucosa)

149

Withdrawal of Alcohol This may be encountered when an ill or injured alcoholic is admitted to hospital. The possible sequence of events may appear as: 1. Withdrawal syndrome (in 6 hours, craving for alcohol, tremor, and sympathetic overactivity)

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2. Acute psychotic attack (delirium tremens3): (in 72 hours, seizures, agitation, anxiety, and excessive sympathetic autonomic activity.

Drugs used in treatment 1. Benzodiazepine (chlordiazepoxide, large dose for sedative action) 2. ¾-adrenoceptor blocker (propranolol for sympatholytic action) 3. Butyrophenone neuroleptic4 (haloperidol for its antipsychotic action)

Chloral Hydrate Chloral hydrate (1869) is the first synthetic hypnotic agent to be used clinically. It is usually given orally in solution. Because of its unpalatable taste a capsule is available. It is irritant to the stomach. Chloral hydrate is a prodrug, rapidly metabolised by alcohol dehydrogenase into the active hypnotic trichloroethanol. The latter undergoes conjugation with glucuronic acid to an inert form that is excreted in the urine. Therefore, avoid in serious hepatic or renal failure. Choral hydrate aggravates peptic ulcer.

Interactions As chloral hydrate is metabolised by the enzyme alcohol dehydrogenase that is also responsible for the conversion of ethanol to acetaldehyde, therefore, resulting in an increase in plasma concentration of alcohol; hence, the action of ethanol is potentiated by chloral hydrate.

3

An acute mental disturbance marked by delirium with trembling and great excitement, and attended by anxiety, mental distress, sweating, GI symptoms, and precordial pain. It is also seen in opium addiction. 4 Phenothiazines (e.g. fluphenazine and chlorpromazine) should be avoided in this condition as they are proconvulsant (lower threshold for convulsion). 150

Cyclic Ethers Paraldehyde (1882) for a long time had been used as a hypnotic (oral and injection) for control of mania, alcohol withdrawal, tetanus, and status epilepticus. These days, paraldehyde is obsolete except for status epilepticus. This is because of many major disadvantages such as unpleasant taste and smell, irritant to the stomach, causes painful muscle cramps when injected i.m., dissolves plastic syringes.

Essentials of Medical Pharmacology

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Table 5.11. Comparison between benzodiazepines and barbiturates Nature of comparison Relatively safe Maximal ability to suppress CNS function Respiratory depressant ability Suicide potential Ability to cause physical dependence Ability to cause tolerance Abuse potential Ability to induce drug metabolism Number of drug interactions Safety in intermittent porphyria Effects increased by other CNS depressants Availability of antagonist

Benzodiazepines High Low Low Low Low Low Low Low Few ? Yes Yes

Barbiturates Low High High High High High High High Many No Yes No

Table 5.12. Barbiturates: prototypes and their clinically important pharmacological characteristics.

Sub-group

Prototype

Ultra-short acting

Thiopental (Pentothol ) Secobarbital (Seconal ) Phenobarbital (Luminal )

Short acting Long acting

Action Onset Duration minutes hours

Lipid solubility

Typical Indication

High

0.5

0.2

Induction of anesthesia; convulsion

Moderate

10-15

3-4

Insomnia

Low

60

10-12

Epilepsy

Therapeutic Coverage Anxiolytic Sedative Hypnotic Buspirone Neuroleptics, Meprobamate Benzodiazepines Barbiturates

Anaesthetic

Coma

Fig. 5.8. A simplified schematic representation of anxiolytic, sedative, hypnotic drugs and their most common therapeutic coverage. Buspirone is used for its anxiolytic action; while neuroleptics (major tranquillisers, e.g. chlorpromazine) are used for their anxiolytic-sedative actions, likewise is meprobamate. Further, benzodiazepines (e.g. diazepam) are used for therapeutic coverage including anxiolytic, sedative and hypnotic actions. Furthermore, the therapeutic objective of barbiturates (e.g. thiopental) is extended further to include their anaesthetic action. Of the major adverse effects of the CNS depressant agents are coma and depression of the respiratory and vasomotor centres; this is most apparent with barbiturates then to a much lesser extent with benzodiazepines.

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Useful Notes • Psychotic states (manic or endogenous depressive illness and schizophrenia) • Psychoneurosis [anxiety, phobias, (exogenous) reactive depression, obsessivecompulsive disorders, and hysteria) • Neuroleptics are effective in positive symptoms, e.g. aggression, hyperactivity, delusions and hallucinations. But negative symptoms, e.g. apathy, respond less well. • In addition to schizophrenia, neuroleptics are also useful in a. Severe anxiety b. Acute mania c. Acute psychotic states d. Therapeutic restraining e. Intractable hiccup • Endogenous depression: TCA + ECT (increase postsynaptic response, if severe state) plus phenothiazine. Benzodiazepines are contraindicated except for alprazolam. • Insomnia of depression (characteristically, early waking) relieved by a sedative antidepressant drug. • Reactive (exogenous) depression (commonly associated with anxiety) is treated with anxiolytic-sedative or a TCA or MAO inhibitor. • Acute behavioural disturbances: a neuroleptic or benzodiazepine, orally, i.m. • Appetite disorders: anorexia (decrease appetite) and bulimia (increased appetite)

anticholinesterase tacrine and the ACh precursor lecithin. • Excessive sex drive in men reduced by oestrogens or by antiandrogen (cyproterone).

PSYCHOSTIMULATS These (amphetamines e.g. dexamphetamine, methylphenidate, and pemoline) increase the level of alertness and/or motivation. Indications: Narcolepsy, attention deficit disorder in children, anorectic (reduce appetite). Adverse effects: tolerance, insomnia, dependence, nausea & vomiting, increase distractibility, paranoid schizophrenia like symptoms.

PSYCHODYSLEPTICS Psychodysleptics (hallucinogens) produce mental changes that resemble those of some psychotic states. They are usually used for nonmedical purposes. • Lysergide (LSD) • Cocaine • Cannabis

a. Anorexia nervosa treated by chlorpromazine (& cyproheptadine) b. Bulimia treated by dexfenfluramine, fluoxetine, TCA. • Narcolepsy benefited by activating noradrenegic mechanisms with amphetamines (dexamphetamine, methylphenidate, mazindol or caffeine). • Attention deficit (hyperkinetic) disorder in children responds to adrenergic activation by dexamphetamine (or methylphenidate or pemoline). • Nocturnal enuresis: TCA (imipramine), desmopressin (ADH) intranasal metered aerosol (for a holiday). • Organic brain syndromes and senile dementia of Alzheimer type may be improved by the centrally acting

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DRUGS FOR PARKINSON S DISEASE Introduction

Brain dopamine (DA) receptors operate through secondary messenger systems. DA1receptors binding Gs-protein coupled to adenylate cyclase leading to increased cAMP production. DA2-receptors coupled to adenylate cyclase but through an inhibitory Gi-protein that decreases cAMP production. DA2-receptors are also found to be coupled to a mechanism inhibiting the hydrolysis of phosphatidyl inositol bisphosphate (PI2) leading to reduced production of diacylglycerol (DAG) and inositol trisphosphate (IP3). Further, activation of D2receptors hyperpolarises neurones by increasing potassium conductance of both brainstem dopamine neurones and that receive dopamine terminals. Blockade of DA2-receptors by neuroleptic drugs or metoclopramide is associated with their ability to produce Parkinsonism in patients taking such drugs

Parkinson s disease is a progressive disorder of voluntary movement that affects 1% to 2% of the population (in the western world) over 60 years of age has an average onset age in the 50s and 60s. Clinical symptoms of Parkinson s disease manifested by most patients include: 1. Resting tremor 2. Rigidity (increased resistance to passive stretching of muscle) 3. Hypokinesia1 (slowness in initiating and carrying out voluntary movements) 4. Impaired postural reflexes (with a tendency to fall backwards or forwards easily) 1

Slowness of movements is variably called bradykinesia, hypokinesia or akinesia

Normal

Substantia nigra Dopamine (inhibitory)

Corpus striatum Acetylcholine (excitatory)

Putamen GABA (inhibitory)

Parkinsonism DA

ACh

GABA

ACh

GABA

Huntington’s disease DA

Fig. 5.9. A simplified schematic representation of nigrostriatal system of the basal ganglia. The dopaminergic neurotransmission exerts inhibitory actions on the cholinergic neurones of the corpus striatum; the latter exerts excitatory effects on the GABAergic neurones of the putamen. Normally, there is a balance between the dopaminergic and the cholinergic pathways, which is important in the extrapyramidal control of motor activity at the level of the substantia nigra and the corpus striatum. A decrease in the dopaminergic activity (degenerative loss) is believed to be the underlying cause for Parkinson s disease; while, a decrease in the GABAergic activity is believed to be responsible for Huntington s disease. It follows that an increase in dopaminergic activity may result in GABAergic underactivity and hence choreoathetosis (a condition characterised by choreic and athetoid movements ).

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effects, particularly emetic effects from about 80% to less than 15%.

Therapeutic Objectives 1. Promoting dopaminergic activity that may be achieved by the use of certain drugs targeted at different dopaminergic mechanisms. This approach improves certain parkinsonian features like hypokinesia and rigidity, with little effect on tremor. 2. Reducing cholinergic activity by antimuscarinic drugs that, at least, partially redressing the imbalance created by decreased dopaminergic activity. This approach improves tremor, sailorrhoea (excessive secretion of saliva), rigidity, with little effect on hypokinesia.

At present, two fixed combined preparations are available. • Co-careldopa (carbidopa + levodopa, Sinemet) • Co-beneldopa (benserazide + levodopa, Madopar)

Dopaminergic Drugs Levodopa Levodopa (L-DOPA) is the normal physiological precursor of dopamine synthesis, being converted to dopamine by the enzyme dopa decarboxylase. Unlike dopamine, levodopa readily crosses the blood brain barrier (BBB). When levodopa is used alone, it is readily taken up and converted to dopamine by peripheral and central nervous tissues. The peripheral conversion of levodopa is undesirable as it results in peripheral adverse effects, particularly cardiovascular and emetic effects. This problem has been overcome by the concurrent administration of a levodopa decarboxylase inhibitor like carbidopa and benserazide that cannot cross the BBB. The enzyme inhibitor peripherally prevents the (extracerebral) conversion of levodopa to dopamine; therefore the required dose of levodopa is reduced to about 25%. This consequently reduces peripheral adverse

Adverse Effects 1. Postural hypotension ( ) 2. Nausea (effect DA-receptor on the CTZ, reduced by prior administration of domperidone that minimally crosses the BBB) 3. Dyskinesia (extra movements; choreoathetosis, choreic involuntary movements, involving head, lip, tongue; peak dose effect, reduced by the use of slow-release preparations) 4. Mental changes (psychosis, hallucinations; depression) 5. Wearing-off (effect of each dose becomes shorter, i.e. reduced duration of action) 6. End of Dose Akinesia (end of dosage interval; may respond to giving smaller doses of levodopa more frequently) 7. On-Off phenomenon: Severe swings in performance ranging from extra movements (dyskinesia) to complete lack of movement (total akinesia). These swings in performance often do not appear to be directly related to time of drug administration. A summary of the pharmacology of the drugs used in the treatment of Parkinson s disease is presented in Table 5.13.

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Table 5.13. A summary of the drugs used in the treatment of Parkinson s disease. Approach Drug

Adverse Effects and Important Remarks

Action

Enhance Dopamine Activity Levodopa [+ carbidopa (Sinemet)]

Dopamine precursor [+ extracerebral decarboxylase inhibitor]

Postural hypotension Nausea Dyskinesia Psychosis Decreasing hypokinesia, rigidity, less effective on tremor

Bromocriptine (Parlodel) Lysuride Pergolide Apomorphine

Dopamine agonist

Postural hypotension Nausea Dyskinesia Psychosis

Selegiline* (Deprenyl)

MAO-B inhibitor

Amantadine

↑ dopamine synthesis & release ↓ reuptake

Increases likelihood of adverse effects caused by levodopa or dopamine agonists. Used as adjunct with levodopa (dose reduced by about 50%); improves end-ofdose akinesia1.

Confusion or agitation Benefits wears off, after about 3 months of treatment Used alone when early, and adjunct when disease progresses

Reduce Cholinergic Activity Benzhexol (trihexiphenidyl-HCl, Artane) Procyclidine Orphenadrine Benztropine

CNS (loss of memory, confusion) and HALLUCINATION →DRUG ABUSE Peripherally (dry mouth, decreased sweating, constipation, urinary retention etc.) Decreasing tremor, rigidity, less effective on hypokinesia

Muscarinic antagonist

* The claim that selegiline delays progress of the disease has lead to its use as protective therapy. This claim stemmed initially from the theory that it inhibits the oxidation (by the brain MAO-B) of the protoxin MPTP to MPP+ which results in death of dopaminergic neurones (thus, protecting the surviving dopamine neurones). However, this claim has not been supported by subsequent trials; indeed, one

study has shown an increased mortality in patients receiving selegiline2.

1 2

Laurence, D. R., Bennett, P. N. and Brown, M. J. (1997) Clinical Pharmacology. 8th edition, Page 367. Walker, R. and Edwards, C. (1999) Clinical Pharmacy and Therapeutics. 2nd edition, Page 459. 155

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ANTIEPILEPTIC DRUGS seizure (e.g. head injury, tumour, hypoglycaemia, meningeal infection, or perhaps, rapid withdrawal of alcohol from an alcoholic). This is known as secondary epilepsy and is usually reversible. Status epilepticus, in which the episodes of tonicclonic seizure occur without intervening recovery of consciousness, is serious and may be fatal unless treated rapidly.

Introduction Epilepsy1 is a syndrome characterised by sudden transient alterations in brain function leading to motor, sensory, autonomic or psychic syndrome, often accompanied by unconsciousness. Seizures2 may result in abnormal perceptions if the parietal or occipital cortex is involved. However, seizures may result in abnormal movements (convulsions) if the motor cortex is involved.

Patients are treated with antiepileptic drugs. Patients with primary epilepsy are treated often for life, whereas those with secondary epilepsy are treated with antiepileptic drugs until the cause of the seizure is corrected. It is generally accepted that a patient having recurrent seizures should receive antiepileptic treatment that will be stopped only if two years elapse without any seizure. For classification of seizures see Table 5.14. and for a summary of antiepileptics and their indications (Table 5. 15).

In epilepsy, the abnormal neuronal discharge is usually localised to a specific area of the brain, known as the primary focus that usually does not show any anatomical abnormality. The functional abnormality of these foci may be triggered by different environmental factors, e.g. changes in blood gases, electrolytes, pH, glucose level. A focal cortical seizure may spread to involve the cortex and a generalised (tonic-clonic) seizure with unconsciousness, convulsions and incontinence. When the spread from the initial focus is slow, the initial focal symptoms give rise to a warning (or aura) of the impending fit. However, if the spread of the focal seizure over the cortex is rapid an aura may be absent.

Mode of Action Antiepileptic drugs inhibit the repetitive neuronal firing or its spread by one of the following three possible ways: 1. Modifying cell membrane permeability to ions like Na+ (e.g. carbamazepine, phenytoin) and Ca++ (e.g. ethosuximide) 2. Promoting the action of endogenous inhibitory neurotransmitters such as GABA producing hyperpolarisation (e.g. benzodiazepines, barbiturates, valproic acid, vigabatrin) 3. Inhibiting excitatory neurotransmitters like glutamate and aspartate (e.g. lamotrigine).

In the absence of anatomical cause (e.g. trauma or tumour) for the seizure, it is called idiopathic or primary epilepsy. However, when there is an apparent cause for the 1

Reference to the disease can be found as early as 2080 BC in the code of Hammurabi, King of Babylon. Hippocrates in about 400 BC opposed the supernatural explanation of epilepsy and correctly attributed it to abnormal cerebral function. 2 An attack of epilepsy variably called fit.

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Table 5.14. Classification of seizure, frequency, and clinical manifestations. Frequency (%) PARTIAL (FOCAL) SEIZURES Simple partial (10%)

Clinical Manifestations

No impairment of consciousness; focal motor, sensory (e.g, olfactory hallucination), speech, psychic (e.g. delusion), and autonomic disturbances (e.g. tachycardia).

Complex partial (35%)

Impaired consciousness; complex sensory hallucinations, mental distortions, and motor dysfunctions (chewing movements).

Partial seizures secondarily generalised

(10%) Start as simple partial or partial complex and marsh to tonic clonic fit

GENERALISED SEIZURES Tonic-clonic (30%) (Grand mal)

Loss of consciousness, falling, rigidity extension of trunk and limbs (tonic phase), rhythmic contraction of arms and legs (clonic)

Absence (10%) (Petit mal) Myoclonic, atonic (4%) (Atypical absence)

Impaired consciousness with staring spells, with or without eye blinks Myclonic jerks (shock-like contractions), loss of muscle tone, falling (drop attack, Salaam attack)

Other Seizures (1-8%) frequency repetitive firing in neurones in culture (for more details see phenytoin below).

Antiepileptic Drugs All central depressant drugs like anaesthetic and hypnotics act as anticonvulsants and will suppress epileptoform convulsions. Antiepileptic drugs are special selection of anticonvulsants that are capable of suppressing epileptic seizures in doses that produce little or no sedation. An overview of the pharmacology of the important antiepileptic drugs is presented in Table 5.16.

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic secondary) 4. Trigeminal neuralgia1 5. Postherpetic neuralgia 6. Diabetic neuropathy2 1

(primary

&

Paroxysmal pain which extends along the course of one or more nerves. Many varieties of neuralgia are distinguished according to the part affected or to the cause, as trigeminal, brachial, facial, occipital, supraorbital, etc., or postherpetic, anaemic, diabetic, gouty, malarial, syphilitic, etc. 2 A chronic, symmetrical sensory polyneuropathy affecting first the nerves of the lower limbs and often affecting autonomic nerves; pathologically, there is segmental demyelination of the peripheral nerves. An uncommon, acute form is marked by severe pain, weakness, and wasting of proximal and distal muscles, peripheral sensory impairment, and loss of tendon reflexes. With

Carbamazepine Carbamazepine is a tricyclic compound closely related to imipramine and other antidepressants. Carbamazepine was originally developed for the treatment of bipolar depression. However, it was first used in the treatment of trigeminal neuralgia and only later its anticonvulsant action has been recognised. The mechanism responsible for its anticonvulsant action appears to be related to its capability to block sodium channels at therapeutic concentrations and inhibits high157

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7. Cerebellar ataxia (failure of muscular coordination due to a disease of the cerebellum) 8. Nocturnal enuresis 9. Affective disorder (unipolar depression and mania, treatment and prophylaxis) 10.Resistant schizophrenia 11.Diabetes insipidus 12.Hyperkinetic child 13.Dementia (organic loss of intellectual function) 14.Emotional incontinence (uncontrolled emotional acts, e.g. laughing) 15.Aggressive behaviour 16.Migraine (prophylaxis) 17.Impulse dyscontrol syndrome

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depolarised (i.e. has more positive resting potential) cells that will recover from block Table 5.15. A summary of antiepileptic drugs and their indications Type of Epilepsy Partial (including secondarily generalised)

Antiepileptic Drug

Tonic-clonic

Carbamazepine Phenytoin Phenobarbital Primidone Valproic acid Lamotrigine ( as adjunct)

Absence

Ethosuximide Valproic acid Clonazepam Lamotrigine ACTH

Myclonic

Valproic acid Clonazepam ACTH

Febrile

Diazepam Phenobarbital Valproic acid

Status Epilepticus

Phenytoin (i.v.) Diazepam (i.v.) Phenobarbital (i.v.)

Adverse Effects Dose related (predictable) 1. Diplopia 2. drowsiness 3. Orofacial dyskinesia 4. Cardiac arrhythmias (AV depression) 5. Impairs cognition 6. Osteomalacia and folate deficiency (due to hepatic enzyme induction; with first few weeks, t 35 hours becomes 20 hours) Non-dose related (Idiosyncratic) 7. Agranulocytosis 8. Aplastic anaemia 9. Hepatotoxicity 10.Stevens-Johnson syndrome (severe form of erythema multiforme in which there is involvement of the oronasal and anogenital mucosa, the eyes, and viscera)

Carbamazepine Phenytoin Phenobarbital Primidone Valproic acid Lamotrigine Vigabatrin

Bold prints: preferred drugs In pregnancy: carbamazepine and phenobarbital are most suitable.

Phenytoin Phenytoin (1938) is a nonsedative hydantoin compound. It appears to produce its anticonvulsant action through its capability, at therapeutic concentrations, to block sodium channels and inhibit sustained highfrequency repetitive firing in neurones in culture. Like carbamazepine, phenytoin appears to exert selective inhibition on

very slowly if at all. In doing so, phenytoin increases refractory period in depolarised (sick) cells. This apparently selective action has been attributed to what is known as the use-dependent effect 3; therapeutically useful sodium channel blocking (local anaesthetic, membrane stabilising) drugs

autonomic involvement there may be orthostatic hypotension, nocturnal diarrhoea, retention of urine, impotence, and small diameter of the pupils with sluggish reaction to light.

3

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Page 551 & 562. 158

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have a high affinity for activated channels or inactivated channels but very low affinity for rested channels. Bearing in mind that an ionchannel is usually in one of three possible states:

Rested

indicator of plasma concentrations. As shown above in a, the t value cannot help the prescriber to decide the dosage regimen with reasonable safety; therefore in such condition, serial plasma concentration measurement has been recommended].

Activated

Inactivated It follows that in sick cells with abnormally high firing activity, the most likely ionchannel states would be the activated and inactivated ones. Consequently, these sodium channel-blocking drugs would preferentially bind to these channels that are in depolarised cells resulting in increased refractory period and therefore decreasing cell excitability. Indeed, this hypothesis of use-dependent effect is applied for calcium channel blocking drugs as well.

Pharmacokinetics 1. Saturation (zero-order) kinetics [At subtherapeutic (low) blood levels, phenytoin metabolism is directly proportional to the rate at which the drug is presented to the liver, i.e. first-order metabolism, the t of phenytoin is 6-24 hours. However, at therapeutic (high) blood levels the metabolic machinery becomes saturated (said to have reached zero-order kinetics), the t may reach 60 hours. Phenytoin is the most clinically important example of the drugs exhibiting zero-order kinetics. This is because it is characterised by: a. Its overall t ranges from 6-60 hours, and considering the time to reach a steady-state plasma concentration after dose increment (about 5 × t ) ranges from 2 days to 2 weeks. Consequently, the knowledge of its t is clinically not meaningful, as it is not possible to determine (reasonably) reliably the time to reach the therapeutic steadystate concentration. b. Being a drug with low therapeutic index, it should not be given without a reliable 159

2. Hepatic enzyme induction and enzyme inhibition [phenytoin is a potent hepatic enzyme inducer influencing its own metabolism as well as other drugs and dietary and naturally occurring substances such as vitamin D, folate, adrenal and gonadal steroids, thyroxine. Other drugs whose hepatic metabolism significantly increased including other antiepileptic drugs, e.g. carbamazepine, warfarin, tricyclic antidepressants, and doxycycline. It follows that hepatic enzyme inducing drugs can affect each other when administered concurrently; for example, phenobarbital, carbamazepine, rifampicin may lower phenytoin concentrations. Likewise, hepatic enzyme inhibiting drugs such as valproate, cimetidine, cotrimoxazole, isoniazid, chloramphenicol, erythromycin etc. can interact with phenytoin, and other antiepileptic drugs, causing an increase in plasma concentrations, hence increasing the possibility of toxicity].

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic (primary secondary) 4. Status epilepticus 5. Digitalis-induced arrhythmias 6. Trigeminal neuralgia (see above)

&

Adverse Effects Dose related (predictable) 1. Ataxia, nystagmus, orofacial dyskinesia 2. Drowsiness 3. Impairment of cognitive function 4. Gingival hyperplasia (may be due to inhibition of collagen catabolism) 5. Coarsening of facial features 6. Hirsutism

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Ramadi, 10 October 2009

7. Megaloblastic anaemia (probably due to folate deficiency as a result of hepatic enzyme induction by phenytoin) 8. Osteomalacia (due to vitamin D deficiency as a result of increased hepatic metabolism after years of therapy) 9. Teratogenic 10.Peripheral neuropathy 11.Rashes Non-dose related (idiosyncratic) 12.Hepatotoxicity

1. Dyspepsia, nausea, vomiting 2. Coagulation disorder (due to inhibition of platelet aggregation) 3. Alopecia (hair loss) 4. Increased appetite (results in weight gain) 5. Teratogenic (spina bifida) 6. Acute pancrititis 7. Hepatitis

Overdose

Barbiturates

1. Cerebellar dysfunctions 2. Coma and apnoea (may be for a long time because of zero-kinetics, maintain respiration, no antidote)

An account on barbiturates has been given in the section on sedatives and hypnotics (above). The most widely used antiepileptic member of barbiturates is phenobarbital (t 100 hours). Other members like methylphenobarbital and primidone (a prodrug) that is largely metabolised to phenobarbital. Barbiturates are potent hepatic enzyme inducers.

Valproic Acid (Sodium Valproate) Valproic acid was incidentally found to have antiepileptic activity when it was used as a solvent in the search for antiepileptic drugs. The mechanism of action of valproic acid as antiepileptic drug is not conclusively settled. However, much of the evidence now points out to its capability to block sustained high-frequency repetitive firing of neurons in culture at therapeutically relevant concentrations. Its action against partial seizures may be a consequence of this effect on sodium channel. Blockade of NMDA receptor-mediated excitation may also be important Valproic acid is a hepatic enzyme inhibitor; and it is 90% plasma protein bound with apparent volume of distribution of 9 L.

Adverse Effects

Indications 1. 2. 3. 4. 5.

Simple partial seizures Complex partial seizures Anaesthesia (e.g. thiopental) Anxiety (rarely used these days) Insomnia (rarely used these days)

Adverse Effects 1. 2. 3. 4. 5.

Indications 1. Simple partial epilepsy 2. Complex partial epilepsy 3. Generalised tonic-clonic 4. Absence 5. Myoclonic seizures 6. Affective disorders 7. Huntington s chorea 8. Peripheral neuropathy 9. Hyperkinetic child 10.Prophylaxis of migraine 11.Tardive dyskinesia 12.Impulse dyscontrol syndrome

Sedation Impaired cognition Addiction risk Enzyme induction Low therapeutic index

Benzodiazepines A detailed account on benzodiazepines has been given in the section on anxiolytics (above). Of this group, clonazepam (Rivotril, t 25 hours) is widely used as a broad-spectrum antiepileptic drug. It has the reputation to have less sedative action than most other members of benzodiazepines do. Clonazepam and diazepam are useful in status epilepticus; in this medical emergency, they should be administered i.v. slowly (30 seconds), while i.m.

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administration is not appropriate as peak plasma concentration can be delayed as long as 2 hours making these drugs useless for the urgent control required in this medical emergency. However, lorazepam is more rapidly absorbed when administered i.m.

Adverse Effects 1. Gastric upset (Nausea, vomiting) 2. Allergic reactions (Rash, Stevens-Johnson syndrome, SLE) 3. Hepatic enzyme inhibition

Ethosuximide Lamotrigine Ethosuximide was introduced as a specific anti-absence seizure drug. To date, it remains the drug of first choice for absence seizure. The mechanism of action of ethosuximide is believed to be mediated through inhibiting the low-threshold (T-type) Ca2+ currents in the thalamic neurones; these currents are suggested to be responsible for generating the rhythmic cortical discharge of an absence seizure4. Therefore, it is useful only in absence seizure.

Lamotrigine (1993) is a voltage dependent sodium channel blocker. This action results in reduced release of excitatory amino acids like glutamate and aspartate. It is believed to have less frequent adverse effects (compared with that of carbamazepine). It finds use in partial and generalised seizures, as an adjuvant or monotherapy.

4

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 9th edition, Page 567.

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Table 5.16. A summary of the pharmacology of selected antiepileptic drugs Drug Group Drug Carbamazepine

Mechanism of Action Reduces repetitive neural firing (inhibits voltage-sensitive Na+ channel)

Phenytoin

Reduces repetitive neural firing (inhibits voltage-sensitive Na+ channel)

Partial Tonic-clonic Status epilepticus

Na valproate

Reduces repetitive neural firing (inhibits voltage-sensitive Na+ channel)

Partial Tonic-clonic Absence Myclonic Febrile

Barbiturates Phenobarbital (t 100 hr) Methylphenobarbital Primidone (prodrug)

Potentiates GABA effects on Cl- influx

Partial Tonic-clonic Status epilepticus Febrile convulsion

Benzodiazepines Diazepam Lorazepam Clonazepam

GABA Clchannel receptor complex

Lamotrigine

Selected Adverse Effects and Important Remarks

Partial Tonic-clonic

Osteomalacia and folate deficiency (due to hepatic enzyme induction; with first few weeks, t 35 hours becomes 20 hours) Cardiac arrhythmias (AV depression) Impairs cognition (Idiosyncratic) Agranulocytosis Aplastic anaemia Hepatotoxicity Impairs cognition Gingival hyperplasia Coarsening of facial features Hirsutism Megaloblastic anaemia (probably due to folate deficiency as a result of hepatic enzyme induction by phenytoin) Osteomalacia (due to vitamin D deficiency as a result of increased hepatic metabolism after years of therapy) Teratogenic Peripheral neuropathy Rashes (idiosyncratic) Hepatotoxicity Coagulation disorder (due to inhibition of platelet aggregation) Alopecia (hair loss) Increased appetite (results in weight gain) Teratogenic (spina bifida) Acute pancrititis Hepatitis Hepatic enzyme inhibition

Status epilepticus Absence Myoclonic

Clonazepam

Ethosuximide

Indication

Inhibits lowthreshold (T-type) Ca2+ currents Inhibits release of glutamate & aspartate

Absence Partial Generalised seizures

162

Sedation Impaired cognition Addiction risk Enzyme induction Low therapeutic index Sleepiness Impaired psychomotor function Amnesia Dependence Gastric upset (Nausea, vomiting) Allergic reactions (Rash, StevensJohnson syndrome, SLE) Hepatic enzyme inhibition

Same as carbamazepine but probably less frequently.

Essentials of Medical Pharmacology

Vigabatrin

Inhibits GABA transaminase (irreversibly)

Majid A. K. Lafi

Partial seizures

Sedation Weight gain Confusion, agitation & psychoses

A SUMMARY OF THE DRUGS USED IN MOVEMENT DISORDERS

Hypokinetic Movement Disorders disease. • Idiopathic Parkinson s Primary agents: carbidopa/ levodopa; bromocriptine; pergolide. Secondary agents: benzhexol; benztropine; amantadine; selegiline Hyperkinetic Movement Disorders • Tics e.g. Tourette s syndrome, which begins in childhood and is associated with vocalization, abnormal gestures, and frequently with obsessive-compulsive personality. Neuroleptic drugs e.g. haloperidol can be useful. • Myclonus (e.g. Salaam attack, infantile myclonus seizure). Benzodiazepines (clonazepam); carbidopa/5-HTP (for anoxic myclonus); baclofen (a GABA-B agonist); tetracosactrin • Essential tremor (or known as adrenergic or intentional tremor, or familial tremor). Propranolol; primidone; clonidine may be considered (advise to decrease intake of tea, coffee and smoking) • Parkinsonian tremor (rest tremor) Anticholinergics (e.g. benzhexol) • Dystonia (disordered tonicity of muscle, acute sustained contraction of muscle) may begin and remain focal, affecting only one area of the body, but can also begin focally and evolve in generalised dystonia. Two very common forms of focal dystonias involve forced eyelid closure (blepharospasm) or twisting of the neck to one side (torticolis), frequently in combination with pulling of the neck backwards (retrocollis). Trismus (clinching of teeth, lockjaw) and opisthatonus (contraction of the muscle of the back) may also be encountered. A high dose of anticholinergic drugs (e.g. benzhexol, diphenhydramine) is useful. Generalised dystonia patients surprisingly

tolerate high doses of anticholinergics with substantial improvement. If anticholinergics are not available a benzodiazepine may do. • Dyskinesia-Chorea: Dyskinesias generally refer to choreic drug side effects, whereas choreas occur in the course of natural disease. The common dyskinesia is that arising in the natural history of Parkinson s disease treated with levodopa. This dopa-dyskinesia can also be seen with direct dopamine agonist. No satisfactory treatment is available at present. • Tardive Dyskinesia: Tardive dyskinesia is a choreic movement disorder arising late in the course of neuroleptic treatment. This dyskinesia is suggested to be due to hypersensitivity (upregulation) of dopamine receptor, particularly of the substantia nigra leading to reduced GABAergic activity in the corpus striatum resulting in choreic movement. No effective specific treatment is available, however, stop giving the antipsychotics may be useful, otherwise reserpine can be used in the disabling cases; the less severe cases may respond paradoxically to carbidopa/levodopa or to clonidine treatment. • Huntington s chorea: Chorea occurs in the course of Huntington s disease, an autosomal dominantly inherited neurodegenerative disorder. The marked loss of GABA neurone in the brains of Huntington s disease patients suggests similarities to tardive dyskinesia. Neuroleptic drugs or reserpine may help.

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OPIOIDS AND NARCOTIC ANALGESIC DRUGS

The actions of opioids can be explained by action on specific opioid receptors in the CNS (Table 5. 17), thalamus, limbic system, hypothalamus, substantia gelatinosa of the spinal cord, nucleus tractus etc. The receptor type most responsible for analgesic properties has been designated the (mu) µ-receptor. The opioid receptors respond to natural morphinelike substances, which are peptides and act as neuromodulators. These are called enkephalins and endorphins. Endogenous analgesics like enkephalins can be detected in the CSF after certain pain-relieving procedures such as acupuncture, placebo medication and transcutaneous electrical stimulation. The endorphins are long-chain polypeptides, which also exhibit opiate activity; the best known is ¾-endorphin that is mainly found in the hypothalamus and the pituitary gland. Opioid peptides seem to be involved in many physiological functions including regulation of temperature, behaviour, gastrointestinal motility, appetite, thirst etc.

Introduction Opium is the dried latex (milky fluid) obtained from the unripe capsules of opium poppy, papaver somniferum. Opium contains 25 different alkaloids; the most important of which are morphine (15%), codeine (2%) and papaverine (1%). Papaverine is distinct from opium, it is not an analgesic and it is a potent relaxant of smooth muscle whereas the opioids induce smooth muscle contraction. Opium was initially used for its antitussive actions that were recognised. The semisynthetic opiate heroin (diacetylmorphine) was produced in 1844 with the hope of curing morphine addicts, but it was soon appreciated that it was not a cure, but on the contrary a more potent narcotic. The search for agents with analgesic qualities of morphine but without the side effects of dependence and tolerance continued and resulted in methadone and pethidine (mepiridine), which however have little advantage.

Opioids relieve pain by raising the pain threshold at the spinal cord level, and also by altering the brain s perception of pain. With morphine, the patient is still aware of the presence of pain, but the sensation is not unpleasant. It is believed that morphine acts at µ-receptors in the substantia gelatinosa of the spinal cord, decreasing the release of substance P (and probably other excitatory transmitters from terminals carrying nociceptive stimuli) which modulates pain perception in the spinal cord.

Mechanism of Action Although much remains to be learned about the neurotransmitters involved in both the afferent nociceptive pathways (primary afferent nerve fibres) and descending antinociceptive pathways, prime candidates for the afferent pathways include peptidergic neurotransmitters (e.g. substance P, somatostatin, vasoactive intestinal polypeptide, cholecystokinin, and calcitonin gene-related peptides). The descending antinociceptive pathways appear to inhibit or modulate the process of pain transmission through the afferent (spinal) nociceptive pathways. This process of modulating transmission of pain is the essential part of the gate theory of pain. Several neurotransmitters have been suggested to be involved in pain modulation, e.g. noradrenaline and serotonin, as well as endogenous opioid peptides.

Classification of Narcotic Analgesics Opiates can be classified into three groups: 1. Pure agonists: dextropropoxyphene, codeine, pethidine (meperidine), methadone, morphine, heroin, fentanyl 2. Mixed agonists/antagonists & partial agonist: pentazocine, nalorphine 3. Antagonists: naloxone, naltrexone

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Table 5.17. A summary of responses to stimulation of the three major types of opioid receptors. Receptor Types Kappa (µ) Spinal analgesia Dysphoria/sedation Respiratory depression Miosis

Mu (³) Sigma (-) Spinal and supraspinal Dysphoria analgesia Psychotomimetic reactions* Respiratory depression Respiratory stimulation Euphoria/sedation Mydriasis Physical dependence Decreased GI motility Miosis * e.g. anxiety, strange thoughts, nightmares, hallucinations Table 5.18. Drug actions at opioid receptors Agents Pure opioid agonists: morphine, codeine etc. Mixed acting opioids: pentazocine Partial agonists nalorphine Pure opioid antagonist: naloxone, naltrexone

Mu (³) Agonist

Antagonist Weak agonist Antagonist

Agonist

Agonist

-

-

Antagonist

Antagonist

8. Respiratory depression (reduced sensitivity to CO2) 9. Miosis 10. Decreased release of LH and FSH 11. Increased release of prolactin and ADH

Principle Pharmacological Effects Desirable effects 1. 2. 3. 4. 5. 6.

Receptor Types Kappa (µ) Sigma (-) Agonist No action

Effective analgesia Sedation Sleep Euphoria Depression of Cough Relief of anxiety

Tolerance and Dependence Tolerance is characterised by decreased intensity and shortened duration of all the usual pharmacological effects of morphine. It may occur in individuals who have become socially habituated to the drug, or in patients who require continuous therapy for chronic pain (like in cancer). The pharmacokinetic parameters of morphine do not alter with its repeated use. A negative feedback system resulting in decreased production of endogenous opioid peptides may be implicated (pharmacodynamic tolerance, Fig.5.10). Different opioids exhibit crosstolerance.

Undesirable effects 1. Tolerance and dependence 2. Bronchoconstriction (due to histamine release) 3. Nausea and vomiting 4. Dysphoria 5. Depression of cough reflex 6. Spasmogenic effects (GI spasm, sphincter of Oddi spasm) 7. Constipation

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Upon repeated dosage, cellular adaptation to the exogenously applied morphine occurs; i.e. neurotransmission (particularly the postsynaptic opioid activity that is responsible for modulating various essential biological activities) becomes dependent on the exogenous morphine. A sudden withdrawal (abstinence) of the exogenous morphine cannot be immediately compensated for, consequently results in disturbance in the regulation of these biological activities such as cardiovascular functions.

Reversal of Narcotic Effects Naloxone is the pure antagonist and the drug of choice for the treatment of narcotic overdose, or for reversing the depressant effects of narcotic agents on the neonates. The normal dose may be repeated once or twice at frequent intervals if respiratory function does not improve or relapse. It would appear that all the pharmacological actions of the narcotic agents are reversed by naloxone. If naloxone is administered to a person who has been abusing opioids, he will develop a withdrawal syndrome, but nothing happens if given to a normal person.

Withdrawal (Abstinence) Syndrome

Indications for morphine

The development of dependence to morphine can be demonstrated when the drug is suddenly withdrawn after repeated dosage. Various physical and physiological phenomena may develop, the severity of which are related to the total amount administered. Symptoms and signs include restlessness and irritability, frequent yawning, excessive sweating, gooseling of skin (piloerection), hyperpnoe, dilated pupils, tachycardia, lachrymartion and salivation, painful muscle cramps and intense and uncontrolled vomiting, diarrhoea and urination. Mild symptoms have been reported after only 48 hours therapy. Although withdrawal from opioids is unpleasant, the syndrome is rarely dangerous; on the contrary, withdrawal from other CNS depressants (e.g. alcohol, barbiturates) can be lethal.

1. Severe pain euphoria in the dying 2. Myocardial infarction (MI) or dyspnoea in acute left ventricular failure and pulmonary oedema (see later notes) 3. Premedication for surgery

Contraindications 1. Chronic obstructive lung disease 2. Liver failure 3. Raised intracranial pressure (including head injury)

Morphine and the Cardiovascular System Morphine exerts the following actions on the cardiovascular system.

Treatment of Withdrawal Syndrome

1. Decreases sympathetic vascular reflexes resulting in veno-arteriolar dilatation 2. Stimulates vagal centre leading to decreased heart rate 3. Releases histamine resulting in vasodilatation 4. Tranquillising action, thus decreasing mental distress 5. Decreases central sensitivity to afferent stimuli from the congested lung leading to decreased respiratory distress

The following drugs are essential in the treatment of the withdrawal syndrome. 1. Methadone addictive) 2. Diazepam 3. Clonidine

(oral,

long

acting,

less

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THEREFORE, MORPHINE IS USEFUL IN DYSPNOEA DUE TO ACUTE LEFT VENTRICULAR FAILURE AND PULMONARY OEDEMA

Exogenous opioids

Pethidine versus Morphine 1. Pethidine is not useful in suppressing cough 2. Pethidine does not constipate; however, like morphine, it produces spasm of the sphincter of Oddi. 3. Pethidine is widely used in obstetrics because it does not delay labour like morphine that produces this effect centrally by reducing co-operation rather than by an action on the uterus. However, pethidine enters the foetus and can depress respiration at birth; therefore, the availability of naloxone can be essential as an antidote. 4. Pethidine is less likely to cause urinary retention which has at least partly for morphine due to the central sedation causing the patient to ignore afferent messages from a full bladder. 5. Unlike morphine, pethidine has little hypnotic effect. 6. Pethidine has shorter duration (2-3 hr) of analgesia. 7. Because of unfavourable cardiovascular effects (a transient rise in systemic arterial pressure, systemic vascular resistance and heart rate) pethidine could not be recommended for the relief of pain in myocardial infarction patients. Unlike morphine, pethidine is not considered as a venolytic agent. 8. Pethidine has considerable antimuscarinic effects that may be a problem if tachycardia would be a problem. This antimuscarinic activity is responsible for its mydriatic action (while morphine produces miosis).

167

-ve opioid Presynaptic nerve

opioid

¿2

Postsynaptic nerve

-ve

Fig. 5.10. A simplified diagrammatic representation of the effect of exogenously administered opioids (e.g. morphine) on post and presynaptic opioid receptors. Opioid-like substances are endogenously released from peptideergic nerves; therefore, when giving the first dose of an exogenous opioid the observed response would appear to be due to the exogenous opioid. This response is super-added to the basal endogenous opioid activity. As the exogenous opioid causes negative feedback effect on the release of the endogenous opioid; thus, upon subsequent administration of the opioid the effect of a particular (first) dose will be reduced (i.e. pharmacodynamic tolerance develops, a larger dose is required to produce the same effect). In this condition biological adaptation (dependence on exogenous substance) is said to have taken place. Upon withdrawal (abstinence) of the exogenous opioid, the postsynaptic opioid activity (which is responsible for modulating various essential biological activities such as regulation of cardiovascular functions) is reduced. This cannot be immediately compensated by the reduced availability of the endogenous opioid.

CNS Pharmacology - Narcotic Analgesic Drugs

Ramadi, 1 March 2008

Table 5.19. A summary of the pharmacology of selected narcotic analgesics and their antagonists. Narcotic agent

t (hr) 2

Duration of analgesia (hr) 3-6

Codeine (methylmorphine)

3

4

Pethidine (meperidine)

5

2-3

Methadone

8

24

Dextropropoxyphene

5

4-6

Tramadol

6

Fentanyl

3

Morphine

Activates mu (µ) & kappa (κ) receptors; it produces analgesia, euphoria, miosis, sedation. Respiratory depression, orthostatic hypotension, cough, suppression, constipation, biliary colic, urinary retention, emesis & elevation of intracranial pressure; USES: moderate-to-severe pain, MI or dyspnoea associated with acute left ventricular failure and pulmonary oedema, & premedication for surgery. Useful in mild-to-moderate pain (codeine 30 mg is equianalgesic to 325 mg of aspirin or paracetamol), used in combination with nonopioid analgesics (e.g. aspirin) to produce greater analgesic action; & as cough suppressant (10 mg); Adverse-effects: sedation and constipation. Used primarily for its analgesic effect, preferred for obstetrical analgesia; it is less likely to cause smooth muscle spasm than morphine, thus, less constipation & urinary retention. Not preferred in MI or dyspnoea associated with acute left ventricular failure and pulmonary oedema. Synthetic, good absorption from GIT, long duration of action, used to cover opioid withdrawal & for chronic pain in palliative care. Rapidly absorbed from GIT, used for its analgesic action (similar to codeine), structurally similar to methadone Synthetic, rapidly absorbed from GIT, as effective as pethidine for postoperative pain and as morphine for moderate chronic pain, less likely to constipate, depress respiration and addict. Eighty times more potent than morphine; & more efficacious, used in surgery.

0.5-1

Increases cardiac work and oxygen demand, thus, not suitable in MI; less respiratory depression than morphine; because of sigma (-) receptor (psychotomimetic) effects, it has a low potential for abuse. It can precipitate an abstinence syndrome in a patient physically dependent on a pure opioid agonist.

Mixed agonist/antagonist Pentazocine

Principal features

5

Used to reverse depression.

Nalorphine (Partial agonist) Opioid antagonists

Naloxone

1.25

1-2

Naltrexone

4

1-3 days

narcotic

induced

respiratory

Blocks opioid actions; precipitates an immediate withdrawal reaction in a patient dependent on opioids; Useful in: 1. Opioid overdose 2. Reversal of postoperative opioid depression 3. Reversal of neonatal respiratory depression Similar to naloxone; but can be given orally; useful in former opioid addicts to prevent relapse (prevents opioid-induced euphoria, long duration of action).

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When combining amphetamines with morphine-like agents lead to increased analgesia, and decreased sedation. When combining antiemetics with morphine-like agents lead to suppression of nausea and vomiting. When combining CNS depressants, phenothiazines, and antidepressants with morphine-like agents leads to increased respiratory depression.

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GENERAL ANAESTHETIC DRUGS Introduction

Diaphragmatic paralysis can be induced by muscle relaxants (e.g. tubocurarine), however, an overdose with inhalational anaesthetics may produce this effect in stage IV.

Objectives: analgesia, amnesia-hypnosis (unconsciousness), muscle relaxation (loss of reflexes), and physiological homeostasis. General anaesthesia is said to be achieved when the above four objectives are met, and during which there is loss of sensation and consciousness (the subject is not rousable by external stimuli). This can be obtained by inhalation of a volatile anaesthetic agent(s) or intravenous administration of a drug or a combination of them. The order of depression in the CNS is:

Inhalational Anaesthetics Inhalation of anaesthetic drug produces a depth of anaesthesia that depends on the partial pressure of the anaesthetic agent, which will be dependent on: 1. Partial pressure of anaesthetic agent (concentration) in the inspired air 2. Solubility of anaesthetic agent in blood 3. Pulmonary ventilation (The rate of rise of anaesthetic gas tension in arterial blood is directly dependent on both the rate and depth of respiration) 4. Cardiac output (An increase in cardiac output leads to an increase in pulmonary blood flow; thus, blood capacity increases and tension rises slowly. Therefore in circulatory shock, decreased pulmonary blood flow and increased ventilation may speed up the induction of anaesthesia with some anaesthetics particularly those with high blood solubility.

Cortical centres r basal ganglia r spinal cord r medulla According to Guedel (1920) the degree of nervous depression can be divided into four different stages, as may be observed with ether, equivalent to the cumulative effect on the above-mentioned CNS-centres. Stage I: Analgesia, and amnesia from start of induction to loss of consciousness. Stage II: Excitation (delirium or confusion, but definitely the patient is amnesic), from loss of consciousness to reestablishment of regular respiration.

An anaesthetic drug with high blood solubility, such as ether and methoxyflurane, may require a long time for induction, since the blood, which acts as a reservoir, can dissolve a large amount of gas. Halothane, which has a lower solubility in blood, will equilibrate rapidly and the partial pressure of this gas in blood therefore rises quickly. Further, nitrous oxide (N2O), which has a much lower solubility will achieve a quicker induction. Nitrous oxide is the commonly used inhalational anaesthetic that is a gas at ambient temperatures and pressure. All of the other inhalational anaesthetics are liquids at room temperature and pressure, require vapourisation before use.

Stage III: Surgical anaesthesia, from the beginning of regular respiration to respiratory arrest. This stage is divided into four planes, which have been described in terms of changes in ocular movements, eye reflexes, and pupil size; these under specified conditions may represent signs of increasing depth of anaesthesia. In practice, the most important indications that surgical anaesthesia has been achieved are loss of eyelash reflex and establishment of a respiratory pattern that is regular in rate and depth.

Minimum alveolar anaesthetic concentration (MAC) is defined as that concentration of anaesthetic agent in alveolar or end-expired gas that is present when 50%

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of the subjects do not respond when exposed to the skin incision (MAC=1.0, equivalent to effective dose in 50% of patients). The value of MAC is reduced in the elderly. In general, however, the dose-response relationship for

inhaled anaesthetics is steep. Over 95% of patients may exhibit a state of anaesthesia at 1.1 MAC.

Inspired r Face mask r Alveoli r Pulmonary r Arterial Gas upper airways PAa membrane blood PAi PAfm PApm PAab

Metabolised

CNS bbr Other bbbrs tissue tissue PAcns PAt

Fig.5.11 A schematic representation of pathways for uptake, distribution, and elimination of inhalational anaesthetic agents. PA = partial pressure of agent A; other subscripts refer to anatomical regions. Note elimination of the anaesthetic agents is usually achieved by the reverse of uptake of the agent (reverse arrows to expired air are not shown).

Table 5.20. Shows the values of MAC and PC in tissues of selected general anaesthetic agents. Note: nitrous oxide is poor anaesthetic compared with other inhalational agents.

Anaesthetic Agent Nitrous oxide

MAC*

Blood/Gas PC

Brain/Gas

Metabolism

PC

101.0

0.47

0.5

None

Desflurane

6-7

0.42

1.3

<0.05%

Enflurane

1.7

1.9

3.2

8%

Isoflurane

1.3

1.4

4.7

<2%

Halothane

0.75

2.3

8.2

>40%

Methoxyflurane

0.16

10.2

31.0

>70% (fluoride)

Important remarks Rapid onset & recovery; incomplete anaesthetic Low volatility; poor induction; rapid recovery Medium rate of onset & recovery Medium rate of onset & recovery Medium rate of onset & recovery Slow onset & recovery Nephrotoxic

* Expressed as partial pressure of agent (in alveolar space) divided by standard total atmospheric pressure (×100) that produces immobility in 50% of patients exposed to a noxious stimuli; PC = partition coefficient (reflecting solubility of agent in tissue).

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cellular threshold for firing. This in turn results in a decrease in neuronal activity1.

Note: An inhalational anaesthetic agent with low solubility in blood shows fast induction time and also recovery time (e.g. nitrous oxide), and an agent with relatively high solubility in blood shows slower induction and recovery time (e.g. halothane).

Ether Ether (diethyl ether) as an anaesthetic agent was first clinically demonstrated by William Morton (Massachusetts General Hospital, Boston, 1846).

The elimination of anaesthetic gases occurs mainly by the lungs and therefore the depth of the anaesthesia is easily controlled by assisted breathing (anaesthetic machine).

Ether is a volatile liquid with an unpleasant odour. It is highly flammable and explosive, therefore, cautery should not be used in operation; for this property it is now obsolete. Otherwise, it is a safe drug because it stimulates respiration and there is a wide margin between the dose to induce surgical anaesthesia and that to cause medullary paralysis.

Elimination of the anaesthetic is also dependent on the amount of drug bound to fat tissue in the body. The biological t of most anaesthetics is about 1 hour but total elimination of metabolites may require several days.

Ether anaesthesia is associated with release of endogenous catecholamines. It therefore induces bronchial dilatation and therefore can be used in patients with severe asthma. It produces good muscle relaxation, but induction is unpleasant, and nausea and vomiting may occur frequently upon emergence.

Second Gas Effect The MAC of an inhalational anaesthetic can be reduced by a concurrent use of another inhalational agent; thus, a concurrent use of nitrous oxide with halothane would reduce the MAC for halothane and also the presence of the latter would reduce the MAC for nitrous oxide. It has been suggested that the presence of agent (gas) facilitates the uptake (transport into the pulmonary blood) of the other agent. Therefore, it is called the second gas effect. This effect is utilised for using reduced inspired partial pressure for certain agents, particularly, nitrous oxide which has a high MAC (>100%) which is practically difficult to achieve. Further, a reduction in MAC can also be achieved by the use of adjuvant drugs like narcotic analgesics or sedative-hypnotics.

Ethyl Chloride is a liquid like ether and divinyl ether. It has a boiling point below normal room temperature and can be used both for induction and refrigeration anaesthesia when sprayed from a bottle onto the skin. Like divinyl ether, it is hepatotoxic.

Nitrous Oxide Nitrous oxide (N2O) is the oldest anaesthetic compound known. Horace Wells (Massachusetts General Hospital, Boston, 1845) was the first to describe the importance of its anaesthetic property in clinical practice. Today, it is the most commonly used inhalation anaesthetic agent despite its weak anaesthetic properties: even at its maximum safe concentration of 75% it still requires some supplementation to produce adequate surgical anaesthesia and skeletal muscle relaxation. Nitrous oxide is an inert gas,

Mechanism of Action Anaesthetic agents appear to concentrate in hydrophobic regions of cell membranes, causing the membrane to swell and altering the crystalline structure of the membrane. It has been suggested that most general anaesthetic agents have a common neurophysiological action that increasing the

1

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 7th edition, Page 415. 172

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which is compressed to a liquid, and stored in steel cylinders, coloured blue for identification. Nitrous oxide returns to the gaseous state when released from the cylinder. The gas is colourless and tasteless but has a faintly sweet odour. Nitrous oxide is sometimes called laughing gas. It induces euphoria and a dreamy state but its effect is mostly one of analgesia. Nitrous oxide does not depress respiration and in the absence of hypoxia there is no effect on the heart.

Methoxyflurane Methoxyflurane is the most potent inhalation anaesthetic with very good skeletal muscle relaxing properties. Its disadvantage is prolonged induction and emergence. Otherwise its properties are similar to halothane.

Intravenous Anaesthetics

Prolonged exposure to nitrous oxide decreases methionine synthase activity and may lead to megaloblastic anaemia. This is of a particular importance for staff working in poorly ventilated dental operating rooms.

Barbiturates Barbiturates are used mainly for induction of anaesthesia since the ultra-short acting barbiturates act rapidly without fear of an unpleasant mask and smell of inhalational anaesthetic agents. In sufficient amounts, these drugs can accomplish all the anaesthetic stages but they may cause serious cardiovascular suppression, therefore they are mainly used in combination with inhalational agents such as nitrous oxide and oxygen. Cerebral metabolism, O2 consumption are reduced with barbiturates in proportion to the cerebral suppression and also cerebral blood flow (CBF).

Halothane Halothane (1956), a fluorinated nonflammable hydrocarbon, is a clear, colourless, potent, volatile liquid, which gives smooth induction and comfortable recovery. Anaesthesia can be induced with concentration of 4-5% halothane in oxygen (as a loading dose analogous to that with digoxin priming). For maintenance a concentration of halothane should be reduced. For convenience a hypnotic dose of an i.v. anaesthetic is often used prior to halothane administration. Muscle relaxation is not always sufficient with halothane and can be supplemented by muscle relaxant drugs such as suxamethonium. The neuromuscular blocking actions of dtubocurarine are potentiated and is therefore advisable to use a reduced dose of this component.

Thiopental sodium Thiopental is the most commonly used intravenous anaesthetic in Iraq, usually in combination with inhaled general anaesthetics. The pharmacology of barbiturates is discussed in the sections on sedatives and hypnotics, and antiepiletic drugs. It is worth noting thiopental is useful in abreaction2. Degradation takes place mainly in the liver. For distribution and redistribution of thiopental see (Fig.5.12).

Cautions 1. Postpartum haemorrhage: Halothane causes relaxation of smooth muscle including the uterine muscle, which may give rise to postpartum haemorrhage. 2. Myocardial depressant properties and may induce bradycardia. 3. Respiratory depressant, as indicated by the reduced response to various levels of carbon dioxide. 4. Liver toxicity (halothane) has been observed especially after repeated administration. 173

Adverse Effects 1. Cardiac and respiratory depression 2. Bronchospasm

2

The reliving of an experience in such a way that previously repressed emotions associated with it are released.

CNS Pharmacology - General Anaesthetic Drugs

Ramadi, 10 October 2009

Propofol Methohexital Propofol as intravenous anaesthetic is very much similar to thiopental. However, it produces anaesthesia with a more rapid recovery than that obtained with thiopental. Further, in the immediate postoperative period after propofol patients feel better as compared with other intravenous anaesthetics. Perhaps, the major advantage of propofol is that it has a useful antiemetic action. This probably is responsible for the observation that postoperative vomiting is uncommon with propofol.

It is another ultra-short acting barbiturate with similar pharmacological properties but differs chemically from thiopental in that it contains no sulphur.

Ketamine Ketamine is a phencyclidine (hallucinogen) derivative and an antagonist of the NMDAreceptor. It (is a mirror image of thiopental) produces cardiovascular stimulation and increases cerebral blood flow. It is known to produce dissociative anaesthesia (the patient seems awake but dissociated from the environment, responds to verbal commands but does not respond to painful stimuli). Emergence reaction characterised by hallucination is a frequent encounter with ketamine, diazepam is used to conteract this effect.

Etomidate Etomidate is a potent hypnotic (5 minutes) used for induction of anaesthesia. Its major advantages over other agents that it causes minimal cardiovascular and respiratory depressant effects. This drug has no analgesic actions; therefore, premedication with opioid may be required. It is known as an inhibitor of steroidogenesis.

Dose % 100-

Blood

Preanaesthetic Medication

Muscle

The objectives of the drugs that may be required as adjunct to the anaesthetic agents are:

Brain

50 -

1. Allay anxiety (e.g. diazepam) 2. Reduction of secretion (e.g. oropharyngeal surgery, atropine) 3. Reduction of parasympathetic preponderance ( children tend to show parasympathetic hyperresponsiveness, thus, antimuscarinic may be used in paediatric surgery) 4. Relax muscles (muscle relaxants) 5. Rapid induction of anaesthesia (shortacting barbiturate) 6. Prevent postsurgical nausea and vomiting (antiemetics)

Fat

1.0 -

0.1

0.5

1

4

16

64

256

Time (min) Fig.5.12. Redistribution of thiopental after intravenous bolus administration (the time axis is not linear). Note: The ultra-short acting thiopental rapidly crosses the blood brain barrier because of high lipid solubility (1 min.). Then, they diffuse out of the brain to other highly vascular (highly perfused tissues like skeletal muscle) and subsequently to poorly perfused adipose tissue. It is because of this rapid removal from the CNS that a single dose is so short acting. Metabolism is much slower than redistributed.

Other Agents 1. Midazolam (slow onset and recovery; flumazenil reversal available; used in balanced anaesthesia and conscious

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sedation; cardiovascular stability; marked amnesia. 2. Fentanyl (slow onset and recovery; naloxone reversal available; used in balanced anaesthesia and conscious sedation; marked analgesia).

Neuroleptanaesthesia When a neuroleptic drug (like droperidol) and a narcotic analgesic drug (like fentanyl that is 80 times more potent that morphine, shorter onset and duration of action), are administered together to produce a

physiological state with somnolence (sleepiness), indifference, analgesia, amnesia, and patients are responsive to commands. This state is called neuroleptanalgesia that is useful for several diagnostic or minor surgical procedures like bronchoscopy, painful dressing, cystoscopy etc. Neuroleptanalgesia can be converted to neuroleptanaesthesia by the concurrent administration of 65% nitrous oxide in oxygen.

Table 5.21. A summary of the pharmacology of selected general anaesthetic agents Effect on CVS Resp.

Adverse Effects and Important Remarks

INDUCTION (i.v.)

Thiopental

Ketamine

YES

YES

NO

YES

YES

NO

↓

↑

↓

Contraindicated in porphyria

NO

Increases cerebral blood flow. Contraindicated in open eye surgery, neurosurgery (brain), preeclampsia (hypertension); hypertensive, hallucinogenic, emergence delirium

MAINTENANCE (inhalational)

Halothane

YES

YES*

YES*

↓

↓

Nitrous oxide

YES*

YES

NO

Variable

Variable

* Not adequate

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Dysrhythmogenic (sensitises heart), hepatotoxicity (avoid repeated administration in short period, 90 days), malignant hyperthermia; postpartum haemorage, Myocardial depressant properties (bradycardia), Respiratory depression Megaloblastic anaemia (prolonged exposure →↓ methionine synthase activity)

CNS-Pharmacology - Local Anaesthetics

Ramadi, 10 October 2009

LOCAL ANAESTHETIC DRUGS Introduction

Lidocaine

The first local anaesthetic agent was cocaine (obtained from the leaves of the South American shrub E. Coca) that was introduced into clinical practice by Koller in 1884 as an ophthalmic anaesthetic. Cocaine has powerful central stimulating side effects and induces dependence. The central stimulant effect is manifested in restlessness and excitement and eventually convulsions. This effect is shared by other nitrogen containing local anaesthetics. The central action of cocaine is also related to the ability to potentiate noradrenaline, this action is not shared by other local anaesthetics. When applied to the cornea cocaine anaesthetises the surface and induces mydriasis (enlargement of the pupil). Because of its adverse effects cocaine is not used in clinical medicine.

Lignocaine (lidocaine) is most common type of local anaesthetic agents in clinical practice and it is effective in all five forms of local anaesthesia: 1. Surface (e.g. lignocaine; proparacaine, Alcaine eye drops (0.5%); cinchocaine, Nupercainal ointment (1%), Proctosedyl ointment (0.5%). 2. Infiltration (e.g. lignocaine 0.25-0.5% with adrenaline) 3. Nerve block ( lignocaine 1-2% with adrenaline, e.g. pudendal nerve block as for episiotomy1) 4. Epidural (peridural) nerve block (lignocaine 1-2% with adrenaline) requires high skills. 5. Spinal nerve block (lignocaine) with the following disadvantages: a.headache due to CSF leakage b.hypotension due to block of the sympathetic nervous system c.potential of introducing bacteria

Procaine is the first synthetic local anaesthetic was introduced in 1905 and remained the dominant local anaesthetic for the next 50 years. Procaine is an example of a local anaesthetic with an ester-bond and therefore rapidly broken down by plasma cholinesterase. Procaine still had a considerable potential for producing adverse effects like local irritation and tissue damage in addition to systemic toxicity. At present, it is only used as an amide (procainamide) for cardiac arrhythmias and in procaine penicillin (that should not be given intravenously) for slow release of penicillin.

Mechanism of Action It is believed that the mechanism of action of local anaesthetics is primarily effected by blockade of voltage-gated sodium channels. These agents block sodium channels in a voltage- and time-dependent manner. Local anaesthetics exert their effect on excitable nerve axons and neuronal cell bodies (like the membrane of cardiac muscle) mostly when these cells with high firing activity and thus at more positive membrane potential. It is noted earlier (page 150) that local anaesthetics have a much higher affinity for the activated and inactivated states (usedependence) than the rested state of sodium channels. It follows that the effect of a given concentration of a local anaesthetic is more

The continued effort to find a better local anaesthetic agent lead to the synthesis of lignocaine (1943) by L fgren. To date, lignocaine (lidocaine, xylocaine) is still considered the prototype local anaesthetic agent. Although the development of new local anaesthetic agents continues but none showed significant reduction in toxicity as compared with that of the current agents. This is probably because the most serious toxicity of local anaesthetic agents is produced by the therapeutic effect on the brain and the cardiovascular system.

1

Episiotomy: surgical incision into the perineum and vagina for obstetrical purposes.

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marked in rapidly firing axons than in resting neurones2.

The onset of local anaesthesia is sometimes accelerated by the use of solutions saturated with carbon dioxide. The high tissue level of CO2 results in intracellular acidosis (CO2 crosses membrane readily), which results in intracellular accumulation (trapping) of cationic form of the local anaesthetic. It must be noted that the cationic (ionised) form is thought to be the most active form at the local anaesthetic receptor site located within the voltage-dependent sodium channel; this is probably because the cationic form cannot readily leave the closed channels. Further, this local anaesthetic receptor is not accessible from the external side of the cell membrane. Unlike, the cationic drug form, the uncharged form can rapidly penetrate biological membranes.

Adverse Effects 1. Seizures and convulsions (use diazepam) 2. Cardiovascular depression

Combination with Vasoconstrictors Vasoconstrictor substances such as adrenaline reduces systemic absorption of local anaesthetics resulting in enhanced neuronal uptake of the drug and reduced systemic toxic effects of the drug. Such combination should not be given for the digits. Nowadays, the vasoconstrictor agent preferred to be used is a vasopressin receptor agonist like felypressin; vasopressin is supposed to be safer in patients with coronary artery disease.

Table 5.22. A summary of the pharmacology of selected local anaesthetic agents for infiltration anaesthesia. Time course of action

Agent

Tachyphylaxis

Procaine* Tetracaine*

Repeated injection of local anaesthetics during spinal and epidural anaesthesias (and for infiltration in tissue where there is pus) results in rapid loss of effectiveness (tachyphylaxis). This is probably a consequence of local extracellular acidosis. Local anaesthetics are weak bases and marketed as hydrochloride salts (pH 4 to 6) for reasons of solubility and stability. After injection, the salts are buffered in the tissue to physiological pH, thereby providing sufficient free base for diffusion through axonal membranes. However, repeated injections deplete the local available buffer. The ensuing acidosis increases the extracellular cationic form, which diffuses poorly into axons. The clinical result is apparent tachyphylaxis, especially in areas of limited buffer reserve, such as the cerebrospinal fluid. Therefore, an agent with a long duration of action like bupivacaine is preferred in this condition to avoid repeating the dose.

Lidocaine

Onset (min) 2-5 15 <2 5 1-15

Duration (hr) 0.25-1 2-3 0.5-1 2-4 2-6

Potency

1 4 16 -

Bupivacaine Ropivacaine *Ester type local anesthetics are metabolized to paminobenzoic acid derivatives that are responsible for allergic reactions in a small percentage of the population.

• Local anaesthetics have higher affinity for neurones with high rate of firing (use-dependence effect). • Local anaesthetics have to penetrate the neurone (thus, uncharged form is required) and from the inside of the cell bind to the receptor site (thus, cationic form is required). • Cationic form cannot readily leave closed sodium channels, thus, it is the most active form at the local anaesthetic receptor.

2

Katzung, B. G. (1998) Basic & Clinical Pharmacology. 7th edition, page 428. 177

CNS Pharmacology - Neuromuscular Blocking Drugs

Ramadi, 10 October 2009

NEUROMUSCULAR BLOCKING DRUGS sites that normally combine with acetylcholine. This drug-receptor interaction does not produce any change in membrane permeability, so that depolarisation and muscle contraction are prevented. Flaccid paralysis of all skeletal muscles can be produced by the intravenous administration of large doses of a neuromuscular blocking agent, such as tubocurarine However, not all skeletal musculature is equally sensitive to the action of these drugs. The muscles that produce fine movements (e.g., the extraocular muscles, fingers, and muscles of the head, face, and neck) are most sensitive to these drugs. Muscles of the trunk, abdomen, and extremities are relaxed next, and the respiratory muscles (i.e., the intercostals and the diaphragm) are the most resistant to the action of tubocurarine.

Introduction Neuromuscular blocking agents act at nicotinic receptors of the muscle endplate. There are two types: 1. Competitive (non-depolarising) blockers (e.g. tubocurarine) 2. Depolarising agents (e.g. suxamethonium) Skeletal muscle relaxation may be achieved by other mechanism as well. Centrally acting agents, such as diazepam, produce relaxation primarily by actions within the central nervous system. Dantrolene, in contrast, acts within the muscle fibre to interfere with excitation-contraction coupling. It appears that two molecules of acetylcholine (ACh) are required for the ion channel to open, one acting on each of the α-subunits. Binding of a nondepolarising antagonist to either of these subunits therefore prevents influx of sodium ions.

Normal function is restored when the blocker is eliminated or a large quantity of acetylcholine can displace the drug from it binding sites. Therefore, administration of an acetylcholinesterase blocker, such as physostigmine (which crosses the BBB and used in glaucoma) and neostigmine (which does not cross the BBB and used in myasthenia gravis), can restore muscle contraction.

Unlike curare, suxamethonium (also known as succinylcholine) mimics ACh in stimulating the nicotinic receptor and produces paralysis similar to that produced (cholinergic crisis) by an excess of ACh.

Other non-depolarising drugs are gallamine, pancuronium, alcuronium and atracurium. Atracurium is noteworthy because it is metabolised by plasma esterases (hepatic enzymes) and spontaneous degradation, thus suitable in renal impairmenand does not depend on the major route of elimination by the kidneys, which applies to tubocurarine and the others. For a summary of the pharmacology of the important neuromuscular blocking agents see Table 5.21.

Competitive Neuromuscular Blockers Curare is the name applied to various rude extracts obtained from strychnos plants and which have been used by South American Indians as an arrow poison, paralysing wild animals used for food. Since curare reached the western world in containers such as bamboo tubes, the pure chemical substance has been called tubocurarine. Tubocurarine is a quaternary ammonium compound, i.e. a big molecule that is not absorbed from the GI tract and does not pass the blood brain barrier (BBB). The mechanism of action is to produce competitive blockade by occupying receptor 178

Adverse Remarks

Effects

and

Important

1. Release histamine from mast cells; this can give rise to cutaneous flushing, hypotension and bronchospasm.

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Majid A. K. Lafi

2. Aminoglycoside antibiotics like gentamicin and streptomycin and the general anaesthetic halothane increase neuromuscular block.

When this drug is injected intravenously, it produces a considerable muscular fasciculation for several seconds before paralysis. Many patients will later experience muscle soreness. The muscles remain paralysed for about five minutes and resume their function in another 5 minutes.

Depolarising Neuromuscular Blockers Suxamethonium consists of two acetylcholine molecules joined together.

H3C

O O CH3 \ || || / Cl-.H3C-N+CH2CH2OCCH2CH2COCH2CH2N+-CH2.Cl\ H3C CH3 Suxamethonium (Succinylcholine) The action of suxamethonium is inhibited by prior administration of a non-depolarising blocker such as tubocurarine. When suxamethonium is used to facilitate endotracheal intubation, a sufficient interval should be allowed for it to wear off before a non-depolarising blocker is given; this is to make sure that there is no complication with suxamethonium.

Suxamethonium is known to produce a dual block; its action pharmacologically characterised by two phases: Phase I. A sustained depolarisation, which is not reversed by cholinesterase inhibitors. Phase II. This phase is sub-divided into: 1. Although repolarisation occurs, the membrane cannot be depolarised again (i.e. there is desensitisation) 2. Later, the blockade can be reversed by acetylcholinesterase inhibitors (e.g. edrophonium)

Neostigmine is not an antidote to suxamethonium during depolarisation; rather, it tends to enhance early paralysis. The depth and phase of blockade can be assessed by peripheral nerve stimulation. Edrophonium, a short acting acetylcholinesterase inhibitor, can be used to determine the phase of blockade. If the paralysis (blockade) in phase IIb, as described above, then edrophonium would reverse paralysis; otherwise, it would fail to do so.

Suxamethonium (t for effect is of about 10 minutes) is rapidly hydrolysed by plasma pseudocholinesterase (hepatic enzyme) to choline and succinylmonocholine. The latter is then hydrolysed to succinic acid and choline. The t of suxamethonium is increased by neostigmine, which inhibits the enzyme, and in patients with hepatic disease or severe malnutrition whose plasma enzyme levels may be lower than normal. The patients with quantitative or qualitative differences in plasma cholinesterase, because of a genetic abnormality (about 1 in 2500 of the population), suxamethonium can produce apnoea for hours (scoline apnoea). Malignant hyperthermia may occur as an adverse effect to suxamethonium. There is no antidote for suxamethonium.

Suxamethonium can also contribute to certain other problems. In the absence of atropine, stimulation of ganglionic receptors may elicit bradycardia. Life threatening hyperkalaemia1 caused by the release of potassium from muscle as a result of suxamethonium-induced depolarisation, which may produce cardiac 1

Usually K+ is found in high concentration intracellularly, during depolarisation the intracellular K+ is less than that during resting state; in addition, in extensive trauma, intracellular K+ is released raising the extracellular K+ resulting in hyperkalaemia. 179

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Ramadi, 10 October 2009

status epilepticus, tetanus and convulsant drug poisoning. 5. Diagnosis of myasthenia gravis: a small dose of tubocurarine can induce paralysis in myasthenic subjects but not in nonmyasthenic subjects.

arrest particularly in patients who already have raised plasma potassium after extensive trauma (burns, spinal cord transection, crush injury). The development of malignant hyperthermia, a fulminant and often fatal disorder characterised by myoglobinuria and a rapid increase in temperature, is enhanced when suxamethonium is used with potent inhalational anaesthetics. Avoid in liver disease and burnt patient.

Other Muscle Relaxants Some drugs may relax muscle by acting on spinal neurones to depress polysynaptic pathways. Such relaxants also act on higher centres, such as the benzodiazepines, which are used to relieve anxiety or to induce sleep.

Non-depolarising agents (like tubocurarine) are not suitable to be used to facilitate intubation because if the anaesthetist fails to introduce the tube then it is difficult to reverse the effect of the non-depolarising agent (tubocurarine), as the duration of action is much longer than suxamethonium. Therefore, both the short onset and duration of action are advantageous with suxamethonium.

Baclofen mimics GABA at the so-called GABA-B receptors. Baclofen is useful in treating spasticity associated with multiple sclerosis and in conditions related to spinal cord injury. Dantrolene acts on skeletal muscle beyond the neuromuscular junction. It reduces the availability of calcium ions for muscle contraction. The drug has become the agent of choice for reducing heat production by muscle in anaesthetic induced malignant hyperthermia.

Suxamethonium can in low doses achieve muscle relaxation (not for endotracheal intubation) with minimal effect on the diaphragm; the patient is kept on spontaneous respiration.

Therapeutic Uses of Neuromuscular Blocking Agents 1. Muscle relaxation during surgery is produced by agents such as tubocurarine, resulting in reduced inhalational anaesthetic required to achieve anaesthesia. 2. Facilitation of mechanical ventilation (by tubocurarine) is used to reduce resistance to mechanical ventilation by suppressing spontaneous respiratory movements, which can fight against the rhythm of the respirator. 3. Endotracheal intubation can be facilitated by suxamethonium through suppressing gag reflexes. 4. In convulsion: suxamethonium (adjunct to electroconvulsive therapy, ECT) is used to prevent injury due to the violence of the fit. Also useful in similar conditions like

180

Orphenadrine is promoted for the relief of acute muscle spasm caused by local trauma or strain.

Essentials of Medical Pharmacology

Majid A. K. Lafi

Table 5.23. A summary of the pharmacology of muscle relaxants Action (min) Onset Duration

Adverse Effects & Important Remarks

Non-depolarising Agents* d-Tubocurarine

3-5

30-60

Release histamine, causes ganglion blockade; causes transient hypotension, erythematous rash & rarely bronchospasm.

Gallamine

2-5

15-30

Causes tachycardia due to atropine-like effect (vagal block) on the heart. It does not release histamine. It crosses the placenta.

0.75

<60

Causes minimal releases of histamine, minimal effect on blood pressure; suitable for intubation.

Pancuronium

Alcuronium

(curare-like)

Atracurium

1.0

15-35

Metabolised by plasma esterases (hepatic enzymes) and spontaneous degradation, thus suitable in renal impairment; it causes release of histamine.

Depolarising Agents Suxamethonium

0.5

4-6

Causes bradycardia. Pre-treatment with atropine is essential. Avoid in liver disease and burnt patient.

* Non-depolarising agents, except atracurium, should be reduced or avoided (e.g. gallamine) when GFR < 20.

Recurarisation? To be given in the discussion

Scoline apnoea? To be given in the discussion

181

Autacoids

Ramadi, 10 October 2009

AUTACOIDS Histamine is released from the tissue mast cells and basophils by an energy-dependent mechanism, in response to immunological and non-immunological stimuli (trauma, toxins). Other constituents of the intracellular storage granules are released with histamine. These include heparin, eosinophil and neutrophil chemotactic factors, neutral proteases, and other enzymes. In addition to newly synthesised mediators like prostaglandins D2 , leukotrienes C4 and D4, and platelet activating factor are also released. This leads to a vasodilatation and a fall in blood pressure (shock), itching, redness, oedema and bronchoconstriction. If generalised the release of histamine causes anaphylactic shock.

Histamine Histamine is a tissue (histos) amine the first of its kind to be detected and synthesised in 1906. It is found in mast cells and basophils in the stomach and CNS. Histamine is formed by decarboxylation of the amino acid Lhistidine, a reaction is catalysed by histadine decarboxylase. It is broken down by deamination in the presence of diamine oxidase or by methylation of the imidazole ring in the presence of histamine-Nmethyltransferase. Histamine breakdown products make up 97% and unchanged histamine 3% in the urine. Various foods contain histamine, and some intestinal bacteria can form it, but histamine from these sources is rapidly metabolised and is not stored in tissues.

Certain chemical compounds can release histamine. An intracutaneous morphine injection in man produces localised erythema and oedema. Curare alkaloids cause a similar response and histamine is believed to cause episodes of bronchial constriction that accompanied intravenous injections of curare.

In addition to the metabolic products, some histamine is excreted as N-acetylhistamine. Acetylation occurs in bacteria in the intestine, and the acetylated product reflects metabolism of ingested histamine or histamine formed within the gut. It has been estimated that in a normal person 2 to 3 mg of histamine is released daily from tissues. Allergic or chemically induced release of histamine from mast cells or basophils greatly increases urinary excretion of histamine.

Allergy and Anaphylaxis Histamine is a major mediator of acute allergic reactions in humans. Release of histamine from mast cells in the skin and mucosa can cause cutaneous and laryngeal oedema, bronchoconstriction and hypotension.

Histamine release

The two major factors involved in the circulatory effects of histamine are arteriolar dilatation and increased capillary permeability. These factors act in concert to promote loss of plasma from the circulation and development of tissue oedema.

Histamine is stored in mast cells in tissues and basophils in blood. Some organs, the socalled shock organs contain large numbers of mast cells and lethal quantities of histamine. The organs are mainly the skin, the gastrointestinal tract (GIT) and the lung. In the stomach histamine is present in nonmast cells stores. Histamine is also associated with neural elements. The neural pool (CNS neurotransmitter) differs from mast cell histamine in having a more rapid turnover rate and resistance to agents that release histamine from mast cells.

Injection of a low concentration of histamine intracutaneously in humans produces the triple response of Lewis : localised erythema at the injection site, localised oedema (or weal), and diffuse erythema (or flare) at some distance from the injection site. The flare involves neural mechanism known as axon reflex mediated through sensorimotor nerves (C-fibres) which release 182

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Majid A.K. Lafi

tachykinins like substance P, neurokinin A, and calcitonin gene related peptide (CGRP). These phenomena are inhibited by antihistaminic drugs of the H1-receptor class. In some sensitive persons, only scratching of the skin gives rise to a triple response.

The concentration of histamine is particularly high in the acid-secreting part of the stomach. Histamine is believed to be localised in enterochromaffin-like (ECL) cells in the lamina propria. Its release is stimulated by the vagus nerve (via M1-receptors located on ECL cells) and hormonally by the polypeptide gastrin. Histamine stimulates gastric secretion through H2-receptors on parietal cells. Gastrin, an extremely potent stimulant of gastric acid secretion, is also inhibited by H2-antagonists. A similar finding for cholinergic stimulation of gastric secretion indicates that histamine may be final common mediator of secretion. The effects of acetylcholine and histamine can be abolished by orally applied antagonists that reach parietal cells via the blood.

Gastric secretion Histamine is a potent stimulant of gastric acid secretion and pepsin secretion. A subcutaneous injection of a very low dose will increase gastric secretion without causing other effects. This response is used as a test for complete achlorhydria.

Table 6.1. A summary of selected actions of histamine System/ tissue Cardiovascular Vascular Arterioles Precapillary sphincters Heart Respiratory Bronchiolar smooth muscle Exocrine Stomach Gall bladder smooth muscle Intestinal smooth muscle Cutaneous nerve ending CNS Adrenal medulla Basophils Mast cells Eosinophils Neutrophils

Receptor H1, H2 H1, H2

Response Decrease systemic blood pressure Decrease in total peripheral resistance

H2

Relaxation; activation of H2 receptors (in vascular smooth muscle) causes dilatation that develops more slowly and is more sustained. Relaxation & permeability; H1 receptors have a higher affinity for histamine and mediate an endothelium NO dependent dilatation that is relatively rapid in onset and short-lived. Increased heart rate

H1

Asthma, decreased lung capacity Contraction

H1 H2 H1

Increased nasal & bronchial mucus secretion Acid and pepsin secretion Contraction

H1

Cramps and diarrhoea (contraction)

H1

Pain and itching

H1

H1 H1 H2*

Arousal, emesis Adrenaline secretion Inhibition of IgE-dependent degranulation, and thus inhibition of histamine release H4 Activation of H4 receptors on eosinophils induces a cellular shape change, chemotaxis, and upregulation of adhesion molecules such as CD11b/CD18 and ICAM-1 suggesting that the histamine released from mast cells acts at H4 receptors to recruit eosinophils. Skin H1 Induce weal and flare reaction (reddening due to dilatation & increased permeability of the capillaries, & axon reflex) Presynaptic H3 Inhibition of the release of histamine and other transmitters; H3 antagonists promote wakefulness; conversely, H3 agonists promote sleep. * In humans, this negative feed-back mechanism is shown in mast cells in skin and basophils while in lung is not. It appears that histamine may modulate the intensity of the allergic reaction in the skin and blood. 183

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and blood pressure was lowered. One of the substances was more soluble in ether and was, therefore, referred to as PGE, the other more soluble in phosphate (fosfate in Swedish) buffer and was therefore, called PGF. It is now recognised that PG s constitute one group of a larger family of endogenous compounds known as eicosanoids (eicosa, containing 20 carbon atoms), which form a diverse group of oxygenated unsaturated C-20 fatty acids. Most eicosanoids are synthesised from arachidonic acid, which is a major component of mammalian membrane phospholipids.

Antihistamines There is a long list of H1-receptor antagonists, however, there is no evidence that on antihistamine is superior to another. They may differ in the duration of action and incidence of sedative and anticholinergic effects. Further, patients may vary widely in their response to individual agents. Antihistamines find a wide use for the symptomatic relief of rhinorrhoea and sneezing and itching of the nose, ear and eye associated with hay fever; they are not so effective in relieving nasal congestion. They are also useful in other conditions like prevention of urticaria and treatment of allergic skin reactions, insect bites and druginduced allergies.

Synthesis The first step in prostaglandin synthesis is the release of arachidonic acid by phospholipases within the cell membrane. Various stimuli, including bradykinin, immunoglobulins, microbial products, thrombin, lectins, and physical trauma (mechanical distortion of the membrane) can activate tissue phospholipases by a process that is dependent on calcium from extracellular and intracellular stores. The availability of arachidonic acid is limited by two opposing reactions 1) its liberation from and 2) its reacylation back into membrane phospholipids.

Because of their sedative effects, antihistamines may induce drowsiness and, therefore, they may impair driving performance and the ability to handle machinery. Further, this sedative effect may be potentiated by alcohol and other CNS depressants. Antihistamines may induce adverse effects that are characteristic of anticholinergic action like dry mouth, blurred vision, constipation, tachycardia, urinary retention, and may precipitate glaucoma in susceptible patients. Recently, a number of H1-receptor antagonist with little or no sedative effects have been introduced.

Prostaglandins are 20-carbon carboxylic acids containing a five-membered ring. They also have one, two, or three double bonds in the side chains. Biological activity requires a carboxyl group at carbon position 1 (C-1), a double bond at C-13 and a β-hydroxyl at C15. The number of double bonds is indicated by the subscript for example, PGE1, PGE2.

H2-receptor antagonists have also been developed and found a place in clinical use for over three decades. This has been largely in the treatment of peptic ulcer, e.g. cimetidine and ranitidine.

Inhibition of Synthesis

Prostaglandins and Related Autacoids

Both glucocorticoids and non-steroidal antiinflammatory drugs (NSAIDs) block prostaglandin synthesis. The non-steroidal compounds inhibit cyclooxygenase, the enzyme that converts the precursor arachidonic acid to the endoperoxides PGG2 and PGH2. The steroids including the naturally occurring hydrocortisone and synthetic analogues increase intracellularly the expression of lipocortin 1 which inhibits the activity of phospholipase A2 enzyme

Introduction Prostaglandins (PG) were extracted from semen by ULF von Euler in 1930. He found that when components from this fluid were injected into animals, the uterus contracted 184

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resulting in reduced release of arachidonic acid from membrane phospholipids.

Table 6.2. A summary of selected clinically important antihistamines.

Antihistamine

Actions & Indications

Adverse effects & Other remarks

H1-antagonist (Sedative) Antazoline HCl (Antistine ) Chlorpheniramine maleate (Histadine ) Clemastine (Tavegyl ) Cyproheptadine (Periactin ) Dexchlorpheniramine maleate (Polaramine ) Dimethinendene maleate (Fenistil ) Diphenhydramine HCl (Allermine ) Promethazine (Phenergan ) Triprolidine HCl (Actidil )

All block H1-receptors Variably block 5-HT receptors, α-receptors & muscarinic receptors.

Drowsiness Impair psychomotor function Antimuscarinic effects (dry mouth, blurred vision, constipation, tachycardia, urinary retention, precipitating glaucoma)

H1-antagonist (Non or less sedative) Acrivastin

2 hr

Cetirizine Loratidine

7 hr 15 hr

Allergic rhinitis Hay fever Urticaria Conjunctivitis Anaphylactic shock Motion sickness For sedation (especially in children)

5 days

in

They lack antimuscarinic activity.

t Rapid onset duration

&

Fexofenadine

Astemizole

Individual variation response to the agents

Slow onset & duration of action

short

Stimulates appetite (weight gain) Lower risk of arrhythmia (unlike its parent compound terfenadine) long Unsuitable for treatment of acute allergic symptoms; for maintenance in allergic

rhinitis and chronic urticaria H2-antagonists Cimetidine, Ranitidine, Famotidine & Nizatidine

influence second messenger system through modification of guanylate cyclase eventually through mobilisation of Ca2+ from intracellular stores. It is also evident that eicosanoid-dependent mechanisms act within the neurone of origin and externally at nerve endings to modulate autonomic transmission. Thus, it appears that eicosanoids have intracellular actions in addition to the effects that achieved at the cell membrane.

Mechanism of Action Prostaglandins are not stored (with the exception of the seminal fluid. They are synthesised in response to diverse membrane stimuli and then enter the extracellular space and act locally. The newly formed prostaglandins affect target tissues through specific membrane receptors and appear to involve second messengers. Eicosanoids may

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Prostaglandins affect the cell of origin and neighbouring cells by binding to specific membrane receptors linked via G proteins to adenylate cyclases, guanylate cyclases, and lipases.

Biological Responses Vasodilatation induced by PGE2 and PGI2 helps maintain renal perfusion in clinical states of decreased cardiac output. Another important function of prostaglandins is on the prenatal circulation. The maintenance of a patent ductus arteriosus by the continued production of PGI2 is necessary for the fettle circulation. Cyclooxygenase inhibitors are sometimes used to used to promote closure when the ductus remains patent after birth. PGI2 relaxes whereas PGF2α contracts smooth muscle. PGI2 is produced by endothelial cells, while TXA2 in platelets.

Breakdown The most important step in the breakdown of prostaglandins is initiated by the rapid inactivation through oxidation of the 15-OH prostaglandin dehydrogenase, an enzyme widely distributed in the body. The greatest activity of this enzyme is in the lung, kidney, and liver. The strategic location of this enzyme in the lung prevents the persistence of prostaglandins in the systemic circulation. PGE2 and TXA2 are rapidly converted nonenzymatically to the inactive products 6-keto PGF1 and TXB2 respectively, which are further oxidised by prostaglandin dehydrogenase.

Prostaglandins are believed to have a protective role in the stomach. PGE2 and PGI2 inhibit stimulation of gastric acid and pepsin secretion. Aspirin, other cyclooxygenase inhibitors and glucocorticoids are contraindicated in peptic ulcer disease because inhibition of prostaglandin synthesis leads to enhanced acid and pepsin secretion. On the other hand, stable prostaglandin analogues, e.g. misoprostol, are currently used in acid-peptic disease (given concurrently with nonsteroidal anti-inflammatory drugs in susceptible patients).

HO 1 COOH

5

PGF2¿

15 HO

OH

17

O

In the reproductive system, prostaglandinrelated mechanisms are involved in implantation. Prostaglandins also participate in the regulation of cyclic events in the ovary and uterus. Prostaglandin-dependent mechanisms are involved in luteinizing hormone (LH) release, ovulation, and termination of corpus luteum function (luteolysis). The importance of prostaglandins to the normal birth process as in the initiation of parturition is well recognised. An additional physiological role has been suggested for uterine prostaglandins in endometrial changes that lead to menstruation.

COOH

PGE2 HO

OH

HO COOH

PGD2 O

OH

Fig.6.1. The chemical structures of selected primary prostaglandins, prostaglandin F2α (PGF2α), prostaglandin E2 (PGE2), and prostaglandin D2 (PGD2).

Dysmenorrhoea has been shown to be related to a high menstrual release of prostaglandins, a finding that led to the use of aspirin-like drugs in its treatment. Prostaglandins and their analogues have been used to induce labour and to terminate

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pregnancy from the second trimester. To avoid gastrointestinal side-effects induced by oral or intravenous administration, therefore, local vaginal or intra-amniotic administration is preferred (PGE2 and PGF2α).

Leukotrienes Leukotrienes C4 (LTC 4) and D4 (LTD4) are active components of the slow-reacting substances of anaphylaxis (SRS-A). These mediators are formed primarily by mast cells, monocytes and eosinophils. They are recognised for their prominent bronchoconstrictive effect, which is probably involved in asthma. In addition, LTC4 and LTD4 contract gastrointestinal and vascular smooth muscle and are approximately 100 times more potent than histamine in increasing permeability within the microcirculation and may contribute to development of oedema in inflammation.

Aspirin and other NSAIDs can arrest premature labour, but they are contraindicated since prostaglandin inhibition may give rise to premature closure of the ductus arteriosus and hence pulmonary hypertension.

Phospholipid Phospholipase A2 Blocked by glucocorticoids Arachidonic acid

Cytochrom P450

Cyclooxygenases* COX1,COX2 Prostaglandin G/H synthase

Blocked by aspirin

5-lipooxygenase Blocked by zileuton

Epoxide

leukotrienes [Endoperoxidase]]

Blocked by montelukast

Intermediate Prostaglandins (PGG2 & PGH2)

Prostacyclin synthase

Thromboxane synthase

Prostacyclin (PGI2)

Leukotriene receptors

Thromboxane A2 (TXA2) PGE2

PGF2

PGD2

* Note: cyclooxygenase is termed prostaglandin G/H synthase which is present in at least two forms 1) cyclooxygenase-1 (COX-1) which is constitutive (noninducible) and present in many tissues including platelets, stomach and kidney; and cyclooxygenase-2 (COX-2) which is induced by cytokines and endotoxins at sites of inflammation, e.g. joints. Aspirin appears to block nonselectively both COX-1 and COX-2, whereas rofecoxib is claimed to be a relatively selective COX-2 antagonist.

Fig.6.2. Pathways of synthesis of major eicosanoids of pharmacological interests.

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Table 6.3. A simplified list of effects of eicosanoids (prostanoids, prostacyclin, and thromboxane) including a selected list of therapeutically useful prostaglandins.

Effect Pain-promotion

Parturition Primary dysmenorrhoea pyrexia Protection (Cytogastric) Pressure

Prostaglandin 9P plus Eicosanoid Nature of action Lowers threshold of response to stimuli, e.g. PGE2, PGI2 histamine, serotonin, bradykinin, & mechanical PGE2, PGF2¿ Contraction of pregnant uterus → painful menstruation PGF2¿ PGE2 PGI2 PGE2, PGF2¿ PGE2, PGI2

Patency Pulmonary

TXA2 , PGF2¿ PGI2 TXA2 PGE2* PGE2,PGI2

Inflammation

PGD2, PGF2¿, TXA2 PGE2, PGI2

Platelets

LTC4 GIT motility Ureteral activity Reproductive system

PGE2, PGF2¿ PGF2¿ PGE2, PGI2 PGE2 PGF2¿

↑ the temperature set-point in the hypothalamus ↓ acid secretion ↑ mucus secretion & viscosity (in both the stomach and intestine) Renal vascular dilatation, ↑ GFR, natriuresis, & diuresis Renal vasoconstriction ↓ aggregation ↑ aggregation Maintaining the ductus arteriosus patent Bronchodilatation, vasodilatation Bronchconstriction Promote oedema & leukocyte infiltration ↑ vascular permeability & leukocyte infiltration (asthma) ↑ motility ↑ ureteral activity (including pacemaker activity in renal pelvis, ureteral colic) Relaxation of nonpregnant uterus Contraction of pregnant uterus Contraction of pregnant or nonpregnant uterus, lysis of corpus luteum

Prostaglandin analogues

Indications & important remarks

Dinoprost, dinoprostone, carboprost, misoprostol

Directly contracts the uterine smooth muscle inducing labour from the 12th week through the 2nd trimester of pregnancy. Useful in patients with gastric ulcer who have to take aspirin or glucocorticoids. Useful in erectile impotence (injected into the corpus cavernosum of the penis)

Misoprostol Alprostadil

* PGE2 is useful in maintaining the ductus patent This can be desirable in certain newborns with congenital heart defects (anomalies). For example, the great arteries are transpositioned in a way that the left ventricle pumping into the pulmonary artery while the right ventricle pumping into the aorta. This leads to two unlinked circulations. Thus, keeping the ductus open helps mixing the two circulations resulting in some oxygenated blood will circulate for a few hours until surgical intervention made possible. 188

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Clinically, cyproheptadine is useful in the treatment of the smooth muscle manifestations of carcinoid tumour. It is also useful for increasing appetite, probably, through an action on the CNS.

Serotonin (5-Hydroxytryptamine) Serotonin (5-Hydroxytryptamine, 5-HT), like histamine, is widely distributed in nature, in plant and animal tissues. Biologically, it is synthesised from the amino acid tryptophan by hydroxylation of the indole ring followed by the decarboxylation of the amino acid. The free 5-HT is then either stored or undergo inactivation. The latter is largely achieved by monoamine oxidase (which also inactivates other amines like catecholamines). In humans, over 90% of 5-HT in the body is found in enterochromaffin cells in the gastrointestinal tract. 5-HT is also found in blood platelets that are equipped with active carrier mechanism to concentrate the amine.

Ketanserine blocks both 5-HT2-receptor, and α1-receptor. Its clinical use is limited to the treatment of hypertension, and vasospastic conditions. Ondansetron (5-HT3-receptor antagonist) useful in the prevention of nausea and vomiting associated with cancer chemotherapy.

In the CNS, 5-HT serves as a neurotransmitter in tryptominergic (serotonergic) neurones that synthesise, store, release, re-uptake and inactivate 5HT. Of the major locations in the brain, serotonergic neurones are found in the raphe nuclei of the brain stem, where it is believed to play an important role in the biology of sleep. Serotonergic neurones are also implicated in temperature regulation, perception of pain, and regulation of blood pressure. Recent evidence suggests the involvement of 5-HT in conditions like depression, anxiety, and migraine. Peripherally, serotonergic neurones are found in the enteric nervous system of the gastrointestinal tract and around blood vessels.

5-HT receptor agonists Sumatriptan is a new 5-HT analogue and found to be a 5-HT1d agonist. It is useful in the treatment of acute migraine and cluster headache attacks.

5-HT receptor antagonists Cyproheptadine (Periactin) has both 5-HT receptor and H1-receptor antagonistic activity. In addition, it has substantial antimuscarinic effects and causes sedation. 189

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Table 6.4. A selected list of the actions of Tissue /organ Cardiovascular system Vessels (generally, except) Skeletal muscle & heart Heart Chemosensitive nerve endings* (located in coronary vessels) Gastrointestinal tract Smooth muscle

Action Vasoconstriction Vasodilatation Reflex bradycardia mediated by vagal outflow to the heart (& consequently hypotension ↑ tone and peristalsis (severe diarrhoea may occur in carcinoid tumour)

Respiratory tract Bronchiolar smooth muscle

Bronchoconstriction (may be evident in carcinoid tumour)

Nervous system Pain & itch sensory nerve endings CNS**

5-HT in some organs in the body.

Potent stimulant (as in insect & plant stings) Sleep, temperature regulation, perception of pain , blood pressure regulation, affect state, migraine, appetite

* Activation of 5-HT3 receptors on these afferent vagal nerve endings is associated with the chemoreceptor reflex. Several agents can activate the chemoreceptor reflex, nicotinic cholinoceptor agonists and digoxin. ** For more details see the chapter on CNS pharmacology. Peripherally, 5-HT is pain stimulant (promoter), while, centrally it is involved with perception of pain.

Table 6.5. A summary of the pharmacology of selected 5-HT receptor agonists and antagonists used therapeutically.

Agent Sumatriptan Cyproheptadine Ketanserine Ondansetron Tropisetron

Indications and remarks Acute migraine, 5-HT 1d receptor agonist Carcinoid tumour (smooth muscle manifestation), for increasing appetite, 5-HT receptor antagonist Hypertention, 5-HT2 & α-receptor antagonist Nausea & vomiting (cancer chemotherapy), 5-HT 3- receptor antagonist

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NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDs) Introduction

Pyrexia

Several drugs from diverse structural classes share analgesic, antipyretic, antiinflammatory and spasmolytic activity. Collectively they have been termed nonsteroidal anti-inflammatory drugs (NSAIDs) compared to Glucocorticoids. The mechanism for their actions is their ability to inhibit the enzyme cyclooxygenase and thereby decrease the conversion of arachidonic acid to prostaglandins, thromboxane A2 or prostacyclin.

In contrast to analgesia, the site of antipyretic action of NSAIDs is central in the hypothalamus. In fever the temperatureregulating system maintains temperature at a higher level (the temperature set point is raised, upward setting) than normal. The stimulus for the set shift to a higher level is due to the action of an endogenous pyrogen, interleukin 1, on neurones of the thermoregulatory system in the hypothalamus where it releases prostaglandin E2. Aspirin does not affect the release of interleukin 1, rather it reduces the effect of the pyrogen. Therapeutic doses of aspirin affect neither normal body temperature nor elevated temperatures (hyperthermias), associated with exercise, drugs, or hypothalamic lesions, to which pyrogen does not contribute. Although the role of fever in combating infection is not clearly understood, antipyretic agents are best utilised only when body temperature is dangerously high.

Therapeutic Uses Pain Prostaglandins sensitise nociceptors (pain receptors) which can be stimulated by various substances, such as bradykinin, histamine, serotonin, thromboxanes, and leukotrienes and mechanical or thermal stimuli. The signals are transmitted to the spinal cord by either small (1-5 µm) myelinated afferent nerve fibres (A-delta) or unmyelinated Cfibres (0.5-1 µm). These primary afferent fibres synapse in the dorsal horn of the spinal cord. All the NSAIDs, including, aspirin, inhibit the enzyme cyclooxygenase which is responsible for converting arachidonic acid to prostaglandins resulting in reduced sensitisation of nociceptors. Hence, unlike the action of narcotic analgesics (e.g. morphine) which act centrally, the predominant analgesic action of NSAIDs is peripheral. NSAIDs are most effective in alleviating pain of mild to moderate intensity, though they may be more effective than narcotic analgesics in alleviating pain associated with prostaglandin-stimulated smooth muscle motility, as in primary dysmenorrhoea, and diarrhoea associated with irritable bowel syndrome and ureteral colic.

Inflammation Prostaglandins are important mediators of inflammation (by promoting oedema and leukocyte infiltration). Thus, a reduction of prostaglandins at sites of inflammation should be beneficial. In rheumatic fever administration of large daily doses of aspirin lowers fever and relieves joint symptoms. In arthritic diseases NSAIDs reduce inflammation, swelling, although they are not usually considered to alter the progression of the disease. Although all NSAIDs appear to have the same mechanism of action, differences between them are largely due to differing concentrations in different tissues, and different rate of absorption and elimination from the body. There is some evidence of substantial differences in their effects in patients. This may be explained in the light of the findings that various NSAIDs possess other actions that are related to inflammation, 191

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e.g. inhibition of lipoxygenases (LOX, diclofenac, indomethacin), superoxide production and leukocyte migration. Recently, a good body of evidence suggests that the inflammatory prostanoids are the products of the activity of COX-2 (cyclooxygenase-2) and therefore a number of allegedly relatively selective COX-2 inhibitors have been introduced to the market (e.g. meloxicam). These are supposed to be effective as anti-inflammatory agents with substantially reduced adverse effects (that are largely result from inhibiting the biologically beneficial COX-1). At present, therefore, no particular NSAID is preferred but selection might depend on factors such as the patient s age, renal function and previous experiences (familiarity) with particular NSAIDs.

oxidative enzymes, to accumulate. Other drugs that induce these enzymes, e.g. anticonvulsants and alcohol, enhance metabolism to toxic metabolite in overdosage. The metabolite (NABQI) oxidises thiol (SH-) groups of important enzymes, causing cell death. Therefore, hepatic and renal tubular necrosis may occur in paracetamol overdosage. Paracetamol has few adverse effects in normal dosage, but may occasionally cause gastrointestinal upsets. It causes hepatotoxicity in overdosage, particularly in patients who have their hepatic oxidative enzymes induced by other agents. Usage of 4 g or more of paracetamol per day for 12 months has been associated with chronic liver disease.

These drugs are usually effective in the treatment of arthritic patients (rheumatoid arthritis, lupus erythmatosus, osteoarthritis, ankylosing spondylitis, and gout). However, some patients will require treatment with more toxic drugs such as methotrexate and other immunsuppressive drugs, antimalarial drugs (e.g. chloroquine and hydroxychloroquine), gold salts, penicillamine and sulphasalazine, or glucocorticoids (see later section on diseasemodifying drugs).

Therefore, in overdosage the level of the products of phase I metabolism can be too high to be handled by the machinery of phase II metabolism resulting in accumulation of toxic level of metabolites. This may also occur in normal doses if drugs like phenytoin and barbiturates induce the hepatic oxidative enzyme. Therefore, alcoholics are more prone to develop hepatic toxicity when taken paracetamol. Paracetamol Minor

Paracetamol (Acetaminophen)

Phase I Oxidative enzyme

Paracetamol has analgesic and antipyretic properties, and because it has little antiinflammatory activity in arthritis. Some authorities would not list paracetamol with the NSAIDs but as a separate agent .

Major Glucuronide Sulphate

Toxic products (NABQI) Phase II Glutathione

Paracetamol inhibits prostaglandin synthesis in the brain but hardly at all in the periphery, therefore, it does not affect platelet function.

Conjugated products (Pharmacologically inactive)

It is well absorbed, and almost entirely metabolised by the liver with an excretion t of about 4 hours. In normal doses, it is mainly metabolised by conjugation with glutathione, glucuronide and sulphate, but these pathways are saturated at higher doses, and allow a toxic metabolite (N-acetyl-benzoquinone, NABQI), which is formed by the hepatic

Fig. 7.1. A schematic representation of the metabolic inactivation of paracetamol. Note: Paracetamol is largely converted to paracetamol glucuronide and sulphate. Upon depletion of glutathione the toxic products (NABQI) will accumulate. This makes paracetamol with a high potential of toxicity at a time it is one of the most commonly used drugs. 192

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after birth. Although surgical closure is an established therapy, cyclooxygenase inhibitors can also be effective. Indomethacin promotes closure of the patent ductus arteriosus and alleviates the associated symptoms of cardiac failure in the neonates.

Paracetamol poisoning N-acetylcysteine (20% solution) is given intravenously (infusion). Therapy is most effective if given within 8 hours of the overdose. Glutathione itself poorly penetrates cells but N-acetylcysteine (i.v.) and methionine (orally) are effective precursors for the synthesis of glutathione.

Adverse-effects All NSAIDs have antiplatelet effects, resulting in increased bleeding time. Therefore, care should be taken with their use in the immediate peri-operative period and also in patients who are, or who are likely to become, thrombocytopenic.

Aspirin and Other NSAIDs Aspirin (acetylsalicylic acid) is a derivative of salicylic acid (which can be produced from the glycoside salicin from the bark of the willow tree (Salix), and was introduced into medicine in 1899. Since that time it has become one of the most cheapest and most easily available and widely used drugs in the world. Aspirin is the prototype agent of NSAIDs. It is well absorbed from both the stomach and upper intestine. Absorption from the stomach is favoured by the presence of the salicylate (pKa = 3.5) predominantly in the unionised form, whilst the large absorbing surface of the small intestine will facilitate uptake and is probably more important.

They also all cause dyspepsia or, on occasions, upper gastrointestinal bleeding as an adverse effect. Chronic use of NSAIDs in therapeutic doses very rarely produces renal damage (analgesic nephropathy). The incidence of adverse effects increases with increasing dosage but there is little evidence that any of the NSAIDs, in equal antiinflammatory doses to aspirin, produces less major gastrointestinal bleeding episodes than aspirin. However, there is some claim that among the NSAIDs, ibuprofen has the least gastric effect particularly in the elderly. Enteric coated preparation of aspirin (or suppository preparation of indomethacin) is used successfully to reduce its gastric effects, but some of the gastric effects are systemic rather than local.

Aspirin is rapidly distributed throughout the body and readily crosses most cellular barrier. The drug undergoes extensive biotransformation. Aspirin undergoes hydrolysis resulting in removal of the acetyl group, the remaining salicylate ion is inactivated mainly by conjugation with glycine. At low doses, the latter reaction follows first-order kinetics with a t of about 4 hours but at higher doses and overdose the reaction follows zero-order kinetics. Thus, in aspirin overdose the offending substance is salicylate. The kidney eliminates the unchanged drug and its metabolites (salicylic acid) and their excretion is facilitated when the urine is alkaline.

They can displace oral anticoagulants, sulphonylureas, hydantoins, and sulphonamides from binding sites of plasma proteins leading to drug-drug interaction.

Salicylism A serious adverse effect of aspirin when given in high doses is salicylism: tinnitus, decrease hearing, vertigo and confusion. Aspirin is a common cause of severe rhinitis, urticaria, angioedema, asthma or shock.

Low dose aspirin (300 mg/day) is recommended as prophylactic therapy in coronary artery disease based on its antiplatelet action; some schools recommend much lower dose than that stated above. The ductus arteriosus normally constricts during the first day of life, resulting in functional closure. In some neonates, it remains paten

Reye s syndrome In children under the age of 12 the use aspirin has been implicated in some cases Reye s syndrome (a serious disorder encephalopathy, liver damage); therefore,

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children recovering from febrile viral infection (respiratory, varicella) paracetamol should be preferred in this condition.

It is worth noting that indomethacin is the most toxic member of NSAIDs. It exerts powerful anti-inflammatory activity, but it is a less efficient analgesic for pain of nonspecific origin. Its long-term use should be restricted to the management of rheumatoid arthritis, ankylosing spondylitis and recently has gained popularity as a spasmolytic agent in ureteral colic. Indomethacin therapy may lead to headache and psychosis.

Overdosage Overdosage of aspirin may result initially in respiratory alkalosis (directly by increasing stimulation of respiratory centre and indirectly by increasing production of CO2). This alkalosis may be compensated by renal loss of bicarbonate (with Na+, K+, and H2O) which may result in dehydration and hypokalaemia. However, metabolic acidosis may ensue as a result from the following:

Disease conditions like renal and cardiovascular disorders lead to decreased renal blood flow, and liver cirrhosis, nephrosis, heart failure and diuretics lead to decreased blood volume. Thus, such conditions increase vasoconstrictors like angiotensin II, catecholamines and vasopressin The effect (vasoconstriction) of these agents on renal blood flow is normally antagonised intrarenally by local synthesis of vasodilator prostaglandins. When NSAIDs are administered in such conditions the inhibition of intrarenal prostaglandin synthesis let go the actions of the vasoconstrictors unopposed.

a. accumulation of lactic acid and pyruvic acid resulting from interference with Kreb s cycle enzymes b. stimulation of lipid metabolism resulting in ketone bodies c. late toxic respiratory depression causing CO2 retention. In children under 4 years, metabolic acidosis may develop without respiratory alkalosis.

Table 7.1. Adverse effects of NSAIDs (related to inhibition of prostaglandin synthesis) System Gastrointestinal

Effects Erosive gastritis (peptic ulceration)

Remarks Inhibition of PGE2, which suppresses gastric acid secretion, helps maintain mucosal barrier and regulate microcirculation. Antiplatelet Prolonged bleeding time, Inhibition of synthesis of thromboxane A2 gastrointestinal blood loss by platelets Renal Fluid retention, diminished Inhibition of synthesis of renal sodium excretion, prerenal prostaglandins involved in regulation of azotaemia*, hyperkalaemia, renal blood flow, glomerular filtration, and oliguria, & anuria renal sodium and water excretion; also (oedema & hypertension) involved in mediation of renin release. Allergic Bronchospasm, urticaria, Inhibition of cyclooxygenase pathway, rhinitis, polyposis allowing lipooxygenase pathway to dominate in susceptible individuals Uterine Delayed parturition, Loss of contractile effects of dystocia** prostaglandins on uterine muscle * Azotaemia: an excess of urea or other nitrogen bodies in the blood ** Dystocia: abnormal labour or childbirth

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Antipyretic Analgesic

Anti-inflammatory Gastric irritation

Indomethacin Diclofenac Ibuprofen Mefenamic Paracetamol Piroxicam Meloxicam acid Aspirin Celecoxib Aspirin (high dose) (low dose) Fig. 7.2. A simplified representation of agents which have largely analgesic activity (e.g. paracetamol and low dose of aspirin); on the other extreme, agents which have high antiinflammatory efficacy (e.g. indomethacin and high dose aspirin). While, ibuprofen and diclofenac are considered to have moderate anti-inflammatory activity coinciding with less gastric toxicity than that may be produced by indomethacin and high-dose aspirin.

Selection of NSAIDs In the following respects ibuprofen may be superior to aspirin.

Older Agents (aspirin, ibuprofen) • Cost (low) • Follow-up advantage (salicylate blood level, aspirin)

•

It does not potentiate the effect of the hypoglycaemic drugs or warfarin. • It exhibits a lower incidence of gastric irritation.

Newer Agents (Celecoxib) • Easier dosage schedules • Better compliance • Lower incidence of gastric irritation

Some patients derive benefit from a particular one NSAID agent and not from another. This variability in response may be related to one or more of the following: • The NSAID per se • Individual differences in metabolism of the drug • Placebo effect

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Table 7.2. Half-lives and dosing schedules of NSAIDs NSAIDs With short t Aspirin Diclofenac (Voltaren ) Ketoprofen

t (hr)

Daily doses Number of (mg) Doses/day

0.25

2000-4000

3-4

1

75-150

2-3

2

100-200

1-2

Ibuprofen (Brufen )

2

1200-2400

2-3

Indomethacin (Indocid )

4

50-150

3-4

4

1000-2000

3-4

Mefenamic acid (Ponstan ) With long t Diflunisal (Dolobid )

13

1000

2

Naproxen

14

375-1000

2

Sulindac

8

200-400

2

57

10-20

1

68

100-300

1-2

Piroxicam (Feldene ) Phenylbutazone

Rofecoxib (Dioxx )

Inhibits LOX The concomitant administration of ibuprofen antagonizes the irreversible platelet inhibition induced by aspirin. Inhibits LOX, phospholipase A and C, reduce neutrophil migration, and decrease T cell and B cell proliferation. Particularly useful in gout and ankylosing spondylitis

Inhibits phospholipase A2

Its elimination depends on renal and hepatic functions, hence, diflunisal's dosage should be limited in patients with significant renal impairment.

The enterohepatic cycling prolongs the duration of action to 12 16 hr.

Do not inhibit platelet aggregation; reduce renal function and thromboresistance of the vessel wall (↓ endothelial PGI2).

COX-2 antagonists Meloxicam (Mobic ) Celecoxib (Celebrex )

Important notes

20

7.5-15

10

200-400

17

1

12.5-25

1

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It was voluntarily withdrawn on September 30, 2004 due to mounting evidence linking it to increased risk of cardiovascular problems.

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inflammatory actions. Its onset of action is slow and its toxicity is substantial.

Disease-Modifying Antirheumatic Drugs Control studies have firmly shown that rheumatoid arthritis results in marked systemic effects in addition to the joint disease that reduces mobility and quality of life. Certain drugs might arrest or at least slow structural damage to joints. These are known as disease-modifying antirheumatic drugs (DMARDs, and also variably called slow-acting antirheumatic drugs and remission-inducing drugs). Toxic effects of DMARDs limit their use and make them second line drugs in the treatment of rheumatic diseases. While the first line drugs (NSAIDs) being less toxic are expected to relieve pain, inflammation and muscle stiffness (symptomatic only).

Antimalarial Drugs Hydroxychloroquine Hydroxychloroquine is indicated when treatment with NSAIDs has been unsuccessful. Because full therapeutic effects take 3 to 6 months to develop concurrent therapy with anti-inflammatory drugs (e.g. glucocorticoids) is indicated. The antiinflammatory action of hydroxychloroquine and chloroquine is probably due to its ability to block phospholipase A2. The most serious of hydroxychloroquine is retinal damage that can be irreversible and can produce blindness.

In recent years, some schools suggest the early introduction of DMARDs, once the diagnosis of rheumatoid arthritis is confirmed. This is because their ability to slow the progress of the disease although they may not influence the ultimate degree of deformity and disability.

Gold Salts Gold salts (Sodium aurothiomalate by deep intramuscular injection or auranofin by mouth) produce analgesic, anti-inflammatory and immunosuppressant actions. The t of elimination from plasma is 22 days, steady state concentration is reached only after 3 months and the therapeutic response within 4 months. For intramuscular preparations, the dosing interval can be lengthened from one week to reach one month that can be continued indefinitely. Oral preparation is administered once or twice daily.

Immunosuppressive Drugs Methotrexate Methotrexate (a folic acid antagonist) is the fastest acting of the DMARDs. Its effects may be seen in 6 to 8 weeks. Unlike cyclophosphamide and azathioprine, methotrexate does not induce neoplastic disease. Major toxicities are hepatic fibrosis, bone marrow suppression, and gastrointestinal ulceration. It is now recognised that methotrexate toxicity can be reduced without decreasing its efficacy in rheumatoid arthritis by giving leucovorin 24 hours after each weekly dose of methotrexate or by the use of daily folic acid.

Gold salts have a number of toxicities that can limit their use. 1. Intense pruritus, rashes, and stomatitis (lesions of the oral mucosa) 2. Renal toxicity (manifested as proteinuria) 3. Severe blood dyscrasias (thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia) 4. Encephalitis, hepatitis, peripheral neuritis, profound hypotension

Azathioprine Azathioprine (Imuran ) is a purine antagonist. Its antiarthritic benefit is probably derived from its immunosuppressive and anti-

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Drugs Used in Gout Penicillamine Gout is a recurrent inflammatory disorder characterised by hyperuricaemia and by episodes of severe joint pain, typically in the large toe. Hyperuricaemia can occur through two mechanisms:

The mechanism of action of penicillamine in rheumatoid arthritis is unclear. However, it reduces rheumatoid factor and the concentration of immune complexes in plasma and synovial fluid. Because of serious toxicity, penicillamine is usually prescribed for patients who have not responded to gold therapy.

1. Excessive uric acid production 2. Impaired uric acid excretion Acute attacks are precipitated by crystallisation of sodium urate within the synovial space. Deposition of urate crystals promotes inflammation by triggering a complex series of events. The most important feature of the inflammatory process is infiltration of leukocytes. Being in the synovial cavity, leukocytes phagocytise urate crystals and then break down, causing release of destructive lysosomal enzymes, prostaglandins, and interleukin-1. When hyperuricaemia is chronic (with urate pool that may be 15-26 times normal), large and gritty deposits, known as tophi, may form in the affected joints. Renal damage may also result from deposition of urate in the kidney.

Penicillamine can produce toxicities that can limit its use. 1. Proteinuria is encountered in 20% of patients. 2. Immune complex nephritis (4% of patients) 3. Severe blood dyscrasias (thrombocytopenia, leucopenia, aplastic anaemia) 4. Various autoimmune diseases (including myasthenia gravis, lupus erythematosus, haemolytic anaemia, and thyroiditis)

Sulphasalazine

Drug Therapy of Gout

Sulphasalazine is now recognised that sulphasalazine produces two primary metabolites; 5-acetylsalicylic acid that is active in inflammatory bowel disease (ulcerative colitis) and sulphapyridine that is active in rheumatoid arthritis. The mechanism of action is undetermined. Major adverse effects are gastrointestinal upset, dizziness and photosensitivity.

The aims of drug therapy to: 1. Suppress the symptoms (antiinflammatory drugs, e.g. indomethacin, diclofenac and piroxicam; colchicine; glucocorticoids) 2. Prevent urate synthesis (e.g. allopurinol) 3. Promote elimination of urate (uricosurics, e.g. probenecid, sulphinpyrazone)

Glucocorticoids Full account on glucocorticoids is presented in the chapter on Endocrine Pharmacology. Glucocorticoids may be useful for certain serious extra-articular manifestations such as pericarditis or eye involvement or during periods of exacerbation. Intra-articular glucocorticoids are often helpful to alleviate painful symptoms and are preferable to increasing the dosage of systemic administration.

Anti-inflammatory Drugs This broad group of drugs is covered largely above (NSAIDs) and adrenal corticosteroids (in the chapter on Endocrine Pharmacology); therefore, the following account will cover colchicine.

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3. Bone marrow depression 4. Peripheral neuritis and myopathy

Colchicine Colchicine is an anti-inflammatory agent whose effects are specific for gout. Colchicine is not an analgesic and will not relieve pain in conditions other than gout. Colchicine (t 1 hour) is readily absorbed following oral administration. The drug is excreted primarily in the faeces; it enters the intestine via the bile and intestinal secretions.

Intravenous administration will obviate most gastrointestinal toxicity of colchicine. Diarrhoea from colchicine can be treated with opioids.

Mode of Action

Acute intoxication with large doses (nontherapeutic) of colchicine may result in

The drug is believed to relieve or prevent episodes of gout through its ability to inhibit leukocyte infiltration. In the absence of leukocytes, there is no phagocytosis of uric acid and no subsequent release of lysosomal enzymes. Colchicine disrupts microtubules, the structures required for cellular motility. Since integrity of microtubules is essential for cell division, colchicine is toxic to any tissue that has a large proportion of proliferating cells. Disruption of cell division is responsible for the gastrointestinal toxicity of colchicine.

1. Burning throat pain 2. Bloody diarrhoea 3. Shock 4. Haematuria 5. Oliguria

Allopurinol Both allopurinol (Zyloric ) and its major metabolite (alloxanthine) inhibit production of uric acid. Therefore, these compounds act to reduce hyperuricaemia through inhibiting xanthine oxidase, an enzyme essential for uric acid production. Allopurinol (t 2 hours) is readily absorbed from the gut and, in the liver, undergoes rapid conversion to alloxanthine by xanthine oxidase. Since alloxanthine has a long plasma t (25 hours) and is an irreversible inhibitor of xanthine oxidase, the therapeutic effects of allopurinol are long lasting. Thus, allopurinol requires only once-a-day dosing.

Indications of Colchicine 1. Treatment of acute gouty arthritis 2. Prophylaxis of gouty attacks (When taken, 0.5 to 1.0 mg/day, during the asymptomatic intercritical period it can decrease the frequency and intensity of acute attacks) 3. Abortion of an impending attack (During prophylactic use of colchicine, patients may experience prodromal signs of a developing gouty attack. If a large amount of colchicine, 0.5 mg every 2 hours, is taken immediately, the attack may be prevented. Therefore, patients suffering chronic gout are advised to have colchicine tablets always with them) 4. Prevention and treatment of attacks of acute familial Mediterranean fever

Indications of Allopurinol 1. Chronic tophaceous gout 2. Secondary hyperuricaemia (hyperuricaemia may occur secondary to treatment with anticancer drugs; uric acid level is elevated because of the break down of DNA that occurs following cell death. It also may occur secondary to certain blood dyscrasias (e.g. polycythemia vera, myeloid metaplasia, leukaemia).

Adverse effects of colchicine 1. Nausea, vomiting, diarrhoea and abdominal pain (due to injury to the rapidly proliferating cells of the gastrointestinal epithelium) 2. Hair loss 199

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Adverse effects of Allopurinol Probenecid may exacerbate acute episodes of gout, and hence treatment should be delayed until the acute attack has been controlled.

1. Precipitation of acute gout (Early in treatment deployment of uric acid from tissues to plasma occurs, resulting in acute attack. This can be prevented by the concurrent use of colchicine) 2. Hypersensitivity syndrome (characterised by rash, fever, eosinophilia, and dysfunction of the liver and kidneys) 3. Drug interactions (Allopurinol inhibits hepatic metabolism of probenecid, oral anticoagulants such as warfarin, mercaptopurines and cyclophosphamide.

Probenecid is generally well tolerated but gastrointestinal disturbances (nausea, vomiting, and anorexia)

Sulphinpyrazone The action of sulphinpyrazone is similar to that of probenecid. It is a uricosuric agent and is employed to reduce hyperuricaemia in patients with chronic gout. Like probenecid, it may precipitate an acute gouty attack; concurrent use of colchicine or indomethacin will decrease the risk of such an episode.

Drugs that increase the renal excretion of uric acid

Sulphinpyrazone is well tolerated but with some possibility of gastrointestinal disturbances (nausea and abdominal pain). It can exacerbate gastrointestinal ulcers, therefore, the drug is contraindicated in the presence of current ulceration.

Probenecid

Probenecid acts on the renal tubules to inhibit reabsorption of uric acid; this promotes excretion of uric acid and thereby reduces hyperuricaemia. By lowering plasma level, probenecid prevents formation of new tophi and facilitates regression of tophi that are already present. Table 7.3. A summary of the uses of anti-arthritic drugs Disease Rheumatoid arthritis Ankylosing spondylitis Degenerative joint disease (osteoarthritis) Systemic lupus erythematosus Gout

Anti-arthritic drugs used Salicylate, other NSAIDs, gold salts, steroids, anti-malarials, penicillamine, cytostatics (methotrexate, azathioprine) Other NSAIDs, salicylates Paracetamol, Salicylates, other NSAIDs Salicylates, anti-malarials, steroids, penicillamine, cytostatics Colchicine, other NSAIDs, allopurinol, sulphinpyrazone, probenecid

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ATP r ADP r Adenine r Hypoxanthine Allopurinol inhibits

Arthropathy Nephropathy Urate stone Tophi

Guanine Xanthine oxidase

Xanthine

Tissue deposition of urate crystals Urinary excretion

Uric acid

Phagocytosis Lactic acid

Promote Probenecid Sulphinpyrazone Aspirin (high dose)

Colchicine inhibits

↓ Tissue pH

Fig. 7.3. A simplified schematic representation of the biochemical events involved in the pathogenicity of gout. Specific drugs can be targeted at inhibiting the synthesis of uric acid (e.g. allopurinol) and/or increasing the renal excretion of uric acid (uricosurics, e.g. probenecid, sulphinpyrazone, and high dose of aspirin). Colchicine inhibits the phagocytic activity and therefore reducing the production of lactic acid, consequently, reducing the crystallisation of uric acid in the synovium.

Table 7.4. A summary of the pharmacology of drugs used in gout Drug Group/ Drug

Mode of Action

Main Indications

Important Adverse Effects

Drugs in Gout Colchicine

Disrupts microtubules in phagocytic cells

Prophylaxis & treatment of gouty attacks

Vomiting Diarrhoea Abdominal pain

Allopurinol

Inhibits xanthine oxidase

Chronic tophaceous gout Secondary hyperuricaemia

Precipitation of acute gout Drug interactions

Uricosurics Probenecid

Sulphinpyrazone

Inhibit renal tubular reabsorption of uric acid

Inhibit renal tubular reabsorption of uric acid

Chronic tophaceous gout

Precipitation of acute gout GI disturbances (vomiting & anorexia)

Chronic tophaceous gout

Precipitation of acute gout GI disturbances (nausea & abdominal pain) Avoid in current ulceration

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Table 7.5. A summary of the pharmacology of NSAIDs and related agents Drug Group/ Drug Paracetamol (Acetaminophen)

Main Indications

Inhibits prostaglandin synthesis in the brain

Pain Pyrexia

Salicylates Aspirin Non-salicylates Ibuprofen Diclofenac Mefenamic acid Indomethacin Naproxen Piroxicam COX-2 antagonist Meloxicam Celecoxib Rofecoxib

Inhibits prostaglandin synthesis in the brain and peripherally (by inhibiting prostaglandin G/H synthase). Differences in effects on patients between these drugs may be due to other modes of action, e.g. inhibiting lipoxygenase, leukocyte migration (diclofenac, indomethacin).

Moderate Pain Pyrexia Inflammatory conditions (e.g. rheumatoid arthritis & gout) Spasmodic conditions (e.g. dysmenorrhoea, ureteral & intestinal colics) Thromboembolic disorders

Salicylism: (tinnitus & vertigo due to high level of salicylic acid) Reye s syndrome (with aspirin & children) Gastric distress Bleeding Hypersensitivity reactions (e.g. urticaria & bronchospasm) Fluid retention Delayed parturition

Methotrexate

Folic acid antagonist (folinic acid rescue)**

Rheumatoid arthritis

Azathioprine

Purine antagonist

SLE

Bone marrow depression GI ulceration

Inhibit Phospholipase A2

Rheumatoid arthritis SLE

Mode of Action

Important Adverse Effects GI upsets In overdose:

Hepatotoxicity

DMARDs* Immunosuppressive Drugs

Antimalarials Hydroxychloroquine

Chloroquine

Gold Salts

Undetermined (analgesic, antiinflammatory & immunosuppressive)

Rheumatoid arthritis

Penicillamine

Undetermined (reduces rheumatoid factor & the concentration of immune complexes in plasma & synovial fluid

Rheumatoid arthritis SLE

Retinal damage Intense pruritus Stomatitis Renal toxicity (proteinuria) Blood dyscrasias Renal toxicity (proteinuria in 20% of patients, immune complex nephritis in 4%)

Blood dyscrasias

GI upsets Dizziness Photosensitivity Useful for extra-articular manifestations (e.g. pericarditis) or during period Glucocorticoids of exacerbation (systemic and intra-articular administration) * DMARDs: Disease-modifying antirheumatic drugs ** Its toxicity can be reduced without decreasing its efficacy in rheumatoid arthritis by giving folinic acid after each weekly dose of methotrexate or by the use of daily folic acid. Sulphasalazine

Undetermined

Rheumatoid arthritis

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DRUGS AND GASTROINTESTINAL TRACTS

a. sucralfate b. bismuth compounds (e.g. bismuth subcitrate) c. prostaglandins (e.g. misoprostol) d. antimicrobial agents (eradicating Helicobacter pylori)

Anti-peptic Ulcer Drugs Peptic ulcer is influenced by several factors including 1. Helicobacter pylori 2. Hyperacidity 3. Gastric emptying 4. Stress

Recently, a good body of evidence points out that peptic ulcer, particularly duodenal ulcer, is very much influenced by a local bacterial infection with Helicobacter pylori. The eradication of this bacterium by appropriate anti-bacterial agents has made a great success in the treatment of peptic ulcer. This new approach has substantially reduced the relapse rate, particularly with duodenal ulcer, that has been a major problem as it often meant a re-treatment with anti-ulcer drugs.

For many decades, the treatment of peptic ulcer was largely aimed at • Directly neutralising gastric acidity by the use of antacids, e.g. sodium bicarbonate. • Inhibiting secretion of HCl and this may be achieved by

Use of non-steroidal (NSAIDs) cigarette (male sex, blood predisposing factors of peptic ulcer.

a. H2-receptor antagonists (e.g. cimetidine) b. M1-receptor antagonists (e.g. pirenzepine) c. Proton pump inhibitors (e.g. omeprazole). • Enhancement of mucosal resistance by different drugs

anti-inflammatory drugs smoking, and heredity group O) are also for increased incidence

Table 8.1. A summary of selected drugs used in the treatment of peptic ulcer, indicating the mechanism of action, selected adverse effects and important remarks. Drug group

Mechanism of action

Selected adverse-effects and important remarks

H2-antagonists

Block H2-receptors → ↓ H+ secretion

Cimetidine

Gynaecomastia, impotence (antiandrogenic), inhibits hepatic enzymes (Ranitidine is 50%, famotidine GI disturbances (constipation is 25%, nizatidine is 10% & diarrhoea) , no metabolised, the remainder is antiandrogenic, or inhibition renally excreted unchanged) on hepatic enzymes Block M1-receptor (block Dry mouth, constipation, visual transmission in disturbance, mental confusion parasympathetic enteric (relative selectivity in inhibiting gastric acid secretion at low ganglia)

Ranitidine Famotidine Nizatidine M1-antagonists Pirenzepine

doses)

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Drug group Proton inhibitors Omeprazole Lansoprazole

Mechanism of action pump Inhibit H+, K+-ATPase leading to decrease H+ secretion (irreversible inhibition)

Antacids

Selected adverse-effects and important remarks GIT disturbances, hepatic enzyme inhibition, potential for gastric neoplasia (carcinoid tumour); 1st line therapy for Zollinger-Ellison syndrome, & ulcerative reflux oesophagitis; 2nd line therapy for peptic ulcer; (destroyed by acid in stomach thus made as entericcoated granules )

Neutralise secreted H+

NaHCO3

Not used routinely to treat ulcers; used to treat acidosis and alkalinise urine; high risk of sodium loading; release CO2

Mg(OH)2

Diarrhoea, cause Mg toxicity (CNS depression) in patients with renal impairment. Constipation, it can cause hypophosphotaemia, thus, it is used to treat hyperphosphotaemia.

Al (OH)3

Constipation, it may cause acid rebound or milk-alkali syndrome (hypercalcaemia without hypercalciuria with only mild alkalosis); release CO2

CaCO3

Mucosa protecting agents 1. Sucralfate

with proteins forms a protective layer 2. decreases back-diffusion of H+ 3. binds to pepsin and bile salts Chelates with protein in the ulcer crate, thus, protecting from H+, pepsin and bile. It also possesses anti-H pylori activity.

Constipation, dry mouth, skin rash; inactivated by antacids, thus, avoid antacids.

Prostaglandins (Misoprostol)

1. ↑mucus & bicarbonate secretion 2. Maintenance of blood flow 3. ↓ H+ back diffusion 4. ↑ mucosal cell replication 5. ↓ gastric acid secretion

Diarrhoea, & abdominal pain, spotting & dysmenorrhoea; Contraindicated in pregnancy (it is abortifacient); used in combination with NSAIDs or glucocorticoids.

Antimicrobial agents

Eradicating H. pylori

Combined antimicrobial therapy. (see chapter on antimicrobial agents)

Bismuth chelates

Anticholinergics and Compound Preparations

Constipation, black encephalopathy

stools,

Librax: Clidinium + chlordiazepoxide; useful in peptic ulcer, nervous dyspepsia, irritable bowel syndrome, and mild ulcerative colitis

Anticholinergic drug + a sedative (a barbiturate, benzodiazepine, or phenothiazine) or NSAID

Stelabid: Isopropamide + trifluoperazine; useful in peptic ulcer, and visceral spasm

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Propantheline (an anticholinergic) alone is useful in peptic ulcer and irritable bowel syndrome. This drug is also used in micturition disorders (unstable detrusor contractions).

3. drug-induced constipation (by opiates, anticholinergics, sedatives) 4. prior to GI surgery or radiology, and other conditions

Drugs and Irritable Bowel Syndrome

The use of laxatives can cause hypokalaemia, malabsorption and dependence. For a summary of the pharmacology of laxatives see Table 8.2.

Usually associated with abdominal pain, constipation or diarrhoea. Useful drugs: bulk purgatives (bran), sedatives (benzodiazepine), mebeverine (a direct smooth muscle relaxant) or NSAIDs.

HIGH FIBRE DIET IS OFTEN SUFFICIENT TO REGULATE BOWEL MOTION

Drugs and Ulcerative Colitis

CONSTIPATION IN INFANTS CAN BE RELIEVED SIMPLY BY INCREASING SUGAR CONTENT IN MILK

Prednisolone (suppositories, and enema) is useful in mild attacks of ulcerative colitis; it may be given orally in severe cases. When stools with blood and pus, sulphasalazine can be useful. Sulphasalazine is broken down into 5-aminosalicylic acid (mesalazine) and sulphapyridine by bacteria in the colon. In effect the sulphapyridine component contributes to a mechanism for delivering 5-aminosalicylic acid to the colon. Mesalazine is also formulated in a way to delay its release until it reaches the colon. Mesalazine is used for the maintenance of remission of ulcerative colitis in patients unable to tolerate sulphasalazine. Sulphasalazine has been widely used in ulcerative colitis and Crohn s disease, and in rheumatoid arthritis for which it was originally introduced in 1930s; mesalazine is considered to be the active moiety in ulcerative colitis, but not however in rheumatoid arthritis.

vagus

parietal cell HCl

ACh M3 H2

ECL cell M1

Histamine

Gastrin Fig. 8.1. Histamine release from enterochromaffin-like (ECL) cells is stimulated by ACh (vagal, via activation of M1-receptors) and gastrin (via activation of gastrin receptors) on ECL cells, in turn histamine activates H2receptors located on parietal cells resulting in release of gastric acid. Further, ACh and gastrin stimulate their corresponding receptors located on parietal cells evoking the release of gastric acid. The muscarinic receptors on parietal cells are believed to be M3 subtype.

Laxatives (Purgatives) The terms laxative, purgative and cathartic are all more or less mean an agent that causes evacuation of the bowel. Laxatives are indicated in 1. when straining may be dangerous (as in angina) 2. painful anal conditions 205

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Pirenzepine blocks ganglionic M1-receptor reducing Acetylcholine

Cimetidine Ranitidine Famotidine

Misoprostol stimulates prostaglandin receptor PGI2 & E2

Block H2-receptor Histamine

Gs

+

Adenylate cyclase

Gastrin

Gi

_

ATP ++

Inactive product

Ca

PDE

cAMP

+

Caffeine blocks here

+

+

Protein kinase (activated)

PARIETAL CELL

+ -

Cl Ion channel

LUMEN OF ClSTOMACH Antimicrobilas

Ca++

K

+

K

+

H

+

Omeprazole blocks here

+

H pump H+, K+-ATPase K

+

+

H

Antacids

Bismuth chelates

Sucralfate

Mucosal Protection H. pylori bacilli

Eradication Ulcer crate

Gastric mucosa

Fig. 8.2. A simplified schematic representation of the nature and site of action of antipeptic ulcer drugs illustrating the receptors and intracellular events involved in the release of HCl in the gastric lumen, and the major drugs that alter these events. Other agents that act in the gastric lumen are also included. Note: Pirenzepine blocks ganglionic M1-receptor resulting in reduced vagal discharge, thus, reduced activation of M3-receptors that are located on the parietal cells. PDE: phosphodiesterase; +: stimulatory; -: inhibitory.

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Table 8.2. A summary of selected drugs used as laxatives (purgatives), their mode of action and adverse effects with important remarks. Drug group Bulk forming Bran Ispaghula husk methylcellulose Osmotic agents

Mode of action

Selected adverse effects and important remarks Promote large, soft, solid Obstruction of bowel, 2 stool encouraging normal l/day of fluid must be reflex bowel activity taken Increase the bulk and reduce viscosity of intestinal contents to promote a fluid stool

Magnesium sulphate Lactulose

Stimulants (irritants) Senna, Cascara Bisacodyl

Hypermagnesaemia renal failure

in

In addition, lactulose is fermented to lactic and acetic acids inhibiting the growth of colonic ammonia-producing organisms, thus, useful in hepatic encephalopathy. Increase intestinal motility by various mechanisms Gripping pain Stimulates sensory ending in Rectal irritation colon directly from the prolonged use lumen suppositories

from of

Na picosulphate Glycerol Castor oil (drastic)

Faecal softeners (Lubricants) Liquid paraffin

Mild stimulant as a suppository Undergoes hydrolysis into Avoid in pregnant ricinolic acid that stimulates women. Evacuates bowel peristalsis. of gas for X-ray examination. Softening powers of the oil Useful if fissure and in the colon promote the haemorrhoids; passage of softer faeces. Reduces absorption of (help reduce straining) fat-soluble vitamins

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Table 8.3. A summary of selected antidiarrhoeal drugs, their mode of action, adverse effects and important remarks

Drug group Oral Rehydration Therapy (ORT)

Antimotility Drugs (Opioid-like Drugs)

Diphenoxylate (Lomotil)

Loperamide (Vacontil)

Codeine Adsorbents Kaolin & Pectin

Antimicrobial agents

Mode of action

Selected adverse effects and important remarks Prevention & treatment of Can be life-saving in fluid & electrolyte loss as acute diarrhoea in infants glucose-coupled sodium & children. transport continues during diarrhoea & thus REMARKABLY SAFE replacement of water & electrolyte losses in the stool. Reduce peristalsis & Contraindication: in increase segmentation infectious diarrhoea & contractions delaying children under 2 years; passage of contents & thus more water is Caution: in ulcerative absorbed (actions blocked colitis by naloxone) Mixed with low dose of CNS side effects: nausea, atropine to discourage vomiting, abdominal abuse) pain, sedation Overdosage: respiratory depression Given on its own as it has Nausea, vomiting, low potential for abuse. abdominal cramp; poorly absorbed from GIT Sedation, respiratory depression Believed to act through removal of bacterial toxins by adsorbing Suspension: Kaolin 900 toxins from stomach & mg, Pectin 20 mg/5ml intestine (a physical (100 ml) phenomenon) Only in severe cases of enteritis, specific agents may be used.

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7. Postpartum lactation stimulation (to increase milk production in nursing mothers)

Vomiting and Antiemetics Vomiting is co-ordinated by the activity of vomiting centre which is located in the medulla oblongata in close proximity to other visceral centres, e.g. for respiration, salivation, vagal and vascular control which give rise to prodromal sensations of vomiting.

Adverse Effects 1. Extrapyramidal effects (dystonias, akathisia, parkinsonian features) 2. Endocrine (e.g. hyperprolactinaemia, gynaecomastia, galactorrhoea, amenorrhoea, erectile impotence) 3. Tardive dyskinesia (Long-term use of metoclopramide may cause tardive dyskinesia in the elderly)

Antiemetic and Prokinetic Drugs Metoclopramide (Plasil) is a derivative of procainamide but has negligible cardiac and local anaesthetic effects and is a powerful antiemetic (35x more powerful than chlorpromazine). In addition to its central action (dopamine antagonist) has prokinetic effects on the GIT. It increases the tone of the oesophageal (cardiac) sphincter and increases peristalsis and thus emptying. Postganglionic stimulation and release of acetylcholine mediate this action. This action is mediated by stimulating intrinsic sensory neurones in the myenteric plexus (local reflex pathway) via 5HT 4-receptor agonism, and vagal and central 5-HT3-receptor antagonism. . Domperidone is a D2-receptor antagonist with a pharmacological profile similar to metoclopramide except that it poorly crosses the blood brain barrier; thus fewer dystonic reactions than with metocopramide, and hence domperidone is well tolerated.

Phenothiazines, chlorpromazine (Largactil) and prochlorperazine (Stemetil) act mainly on the vomiting centre and CTZ. Hyoscine anticholinergic, useful in motion sickness, atropine is less specific. If given prophylactically together with morphine, it should be remembered that the emetic action of morphine outlasts the antiemetic effect of a single dose of hyoscine. Table 8.4. A summary of antiemetic agents Drug group D2-receptor antagonists Metoclopramide Domperidone Phenothiazines Chlorpromazine Prochlorperazine 5HT3-receptor antagonists Ondansetron Antimuscarinics Hyoscine Cyclizine* Promethazine* Others Cisapride Cinnarzine Glucocorticoids Benzodiazepine

Indications 1. Gastroesophageal reflux disease (GERD) (for the treatment of symptomatic GERD but none are effective for treatment of erosive esophagitis where antisecretory agents are the main stay of treatment of heartburn due to their superior efficacy and safety) 2. Impaired gastric emptying (delayed gastric emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis) 3. Nonulcer dyspepsia 4. Postoperative vomiting 5. Radiation sickness (and drug induced toxicity including cytotoxic drugs) 6. Oesophagitis (hiatus hernia, and endoscopy)

Site of action

CTZ & gut Vomiting centre & CTZ

CTZ & gut Vomiting centre & gut

Vomiting centre & gut

* In addition to being antimuscarinic, it also has antihistaminic and antidopamine activities.

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Antihistamines act on vomiting centre and vestibular nuclei.

Vitamin B6 is alleged to be effective in postoperative emesis where metoclopramide is poorly or not effective.

Cisapride is related to metoclopramide but it does not have dopamine receptor antagonistic activity. Cisapride acts peripherally on the gut as a prokinetic agent via 5HT 4-receptor agonism and 5HT3-receptor antagonism .

Metoclopramide Domperidone Cisapride

Metoclopramide Domperidone Cisapride

(õ)

(ó) 5HT 3 receptor

ACh

NANC

(ó) (õ)

5HT

5HT 4 receptor 5HT

ACh Gut smooth muscle

Fig. 8.3. A schematic representation of the possible sites of prokinetic agents.

(ó) inhibitory, (õ) excitatory

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Centrally acting emetics Chemoreceptor trigger zone (CTZ)

Vertigo: prochlorperazine Motion sickness: hyoscine, cyclizine Meniere s syndrome: cinnarizine

Vestibular system (Labyrinthine disorder)

VOMITING CENTRE

Radiation Urea Oestrogen Bromocriptine L-DOPA Apomorphine Morphine Ergot alkaloid Digoxin Cortical centre (Intracrainal pressure)

Anti-ischaemic agents Spasmolytics

Cisapride (Prokinetic)

Pain receptors Myocardial infarction Appendicitis Genital, urinary, renal, intestinal & biliary t act

Gut distension or chemical irritation of the gut Peripherally acting emetics: Emetine (Ipecacuanha) Ammonium chloride NaCl, CuSO4, ZnSO4

Fig. 8.3. A schematic representation of the sites and factors involved in the mediation of emesis, and the major drugs influencing this act.

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DRUGS AND THE RESPIRATORY SYSTEM BRONCHIAL ASTHMA

¾2-agonists

Asthma is dependent on a large number of factors such as allergy, air pollution, smoking and infections. Allergic asthma is often termed extrinsic . Asthma is characterised by bronchial hyperreactivity with variable airways obstruction. Some patients exhibit wheeze and breathlessness that is not attributable to any allergic reaction. They are considered to have intrinsic asthma. The underlying mechanism remains uncertain. The most likely cause is local release of bronchoconstrictors, such as leukotrienes. Other possible causes involve an abnormality of the bronchial smooth muscle or its innervation (decreased β2-receptor sensitivity, increased activity of cholinergic innervation, and the involvement of sensory-motorinflammatory nerves). The factors that produce airways obstruction in asthma probably are:

The most commonly used bronchodilators are the specific β2-receptor agonists salbutamol and terbutaline. These are usually administered by metered aerosol and have a rapid onset of action (peak action after 15 minutes) and duration of 4 hours. Salbutamol and terbutaline are also available in tablets for oral administration and the duration of action is the same. The inhaler is convenient but administration may be difficult in the severely dyspnoic patient or in a younger child. For these, salbutamol can be more reliably administered if diluted in saline and given over a few minutes by an air-driven nebulizer. Recently, a new generation of β 2-receptor agonists have been introduced into clinical practice. They are known as long acting β 2receptor agonists (inhaled), e.g. salmeterol and formoterol, which have slow onset of action and long duration of action (12 hours). They are useful in nocturnal asthma and exercise-induced asthma, and claimed to be effective in poorly controlled asthma.

1. Bronchial constriction 2. Mucous plugging 3. Oedema of bronchial mucosa 4. Vascular congestion 5. Cellular infiltration

Adverse-effects With these multiple possible factors involved, it is clear that bronchial relaxation is just one possible approach that can be achieved therapeutically.

Adrenaline stimulates α, β1 and β 2-receptors, and produces transient hypertension, pallor, and urinary retention (in patients with benign prostatic hypertrophy). Tremors, palpitations, tachycardia, and, rarely, arrhythmias are potential adverse effects of β-receptor stimulation. Central nervous system stimulation or headache is common, and vomiting frequently follows administration to children.

Sympathomimetics The oldest sympathomimetic drug used in the western world is adrenaline which has both α and β-receptors stimulating properties. Formerly it was used by subcutaneous (s.c.) injection. Because of extensive side effects (blood pressure elevation and tachycardia, it is hardly used today except in acute allergic bronchoconstriction associated with hypersensitivity reactions where it is given s.c. the only advantage here is that it reduces vascular congestion by virtue of its αadrenergic action which is a characteristic feature of the allergic reaction.

In high doses, all ¾2-receptor agonists can cause significant hypokalaemia.

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Benefits and toxicity are related to serum concentration which should be within 5-20 µg/ml. Dosage must be adjusted individually because of great pharmacokinetic variations. The risk of toxicity increases progressively as serum concentrations approach 20 µg/ml. Toxic symptoms are nausea, headache, insomnia, tremor, anxiety. At higher level: cardiac arrhythmias, convulsions and coma may occur.

Leukotriene modifiers Zileuton inhibits lipoxygenase

Leukotriene receptor antagonists Montelukast and zafirlukast, competitively prevent the bronchoconstrictor effects of cysteinyl-leukotrienes (C4, D4 and E4) by blocking their common cysLTl receptor. Zafirlukast and montelukast improve symptoms and pulmonary function tests, decrease nighttime symptoms, and decrease the use of β 2-agonist drugs. They are effective with oral administration, can be taken once or twice daily, can be used with bronchodilators and corticosteroids, and produce a high degree of patient adherence and satisfaction. However, they are less effective than low doses of inhaled glucocorticoid.

Cautions The t is increased in heart failure, liver cirrhosis, and viral infection. It should be given with caution in patients with epilepsy or fever, in the elderly and during breastfeeding.

Drug interactions Ciprofloxacin, cimetidine, erythromycin, and oral contraceptives inhibit the metabolism of theophylline and therefore can potentiate its effects. While rifampicin, phenytoin, barbiturates, carbamazepine can reduce plasma concentrations of theophylline by virtue of inducing hepatic enzyme activity.

Theophylline Theophylline (t , 8 hr) acts mainly by inhibiting the enzyme phosphodiesterase and thereby reduces the breakdown of cAMP. In this way it produces increased levels of cAMP within the cells and thus enhances bronchial smooth muscle relaxation. It also inhibits degranulation of mast cells. It is used both for acute bronchodilatation (given intravenously, i.v.) and chronic prophylaxis (given usually orally e.g. phyllocontin, sustained release capsule).

Sodium cromoglycate Sodium cromoglycate (cromolyn Na) is administered as an inhaled dry powder. Although its cellular mechanism of action is not fully understood, it blocks allergeninduced bronchoconstriction. For many years, it was thought to act by inhibiting the release of mediators from mast cells. However, recent evidence suggests that the late allergic responses and bronchial hyperreactivity are also inhibited, and indicating effects of cromoglycate on other inflammatory cells and also on local sensorimotor (also known as inflammatory, and peptidergic) nerves which function by way of axon reflexes.

Aminophylline is the ethylenendiamine salt of theophylline which is sufficiently soluble for i.v. administration. Aminophylline should not be administered rapidly i.v. (appropriate duration: 10-20 minutes) because it may cause hypotension and tachycardia. Further, it should not be administered intramuscularly (i.m.) as the injection is extremely painful. A loading dose may be administered, if patients have not recently received theophylline therapy, within 48 hours. However, if patients have recently received theophylline, a loading dose should not be administered because toxic concentrations are then likely to be reached.

It is not effective at terminating an existing attack (bronchoconstriction), rather, it prevents bronchoconstriction as opposed to inducing bronchodilatation. It is largely useful in extrinsic (allergic) asthma including exercise-induced asthma. The clinical response to cromoglycate may be delayed by several weeks. When used, cromoglycate

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lozenges). Therefore, it is advisable to wash the mouth with water after each administration to avoid such a problem.

may reduce the need for corticosteroids allowing a lower dose of steroids to be used.

Ketotifen Ipratropium bromide

Ketotifen is histamine H1-receptor antagonist, and appear to have some antiasthma actions. Its only noteworthy adverse effect is sedation that affects 10-15% of adults during the first week of treatment.

For hundreds of years, leaves from Datura stromonium have been used in the treatment of asthma; recently, the use of antimuscarinic agents in asthma has gained a greater popularity particularly after the advent of a more selective quaternary ammonium derivative of atropine, ipratropium bromide. Its selectivity, being poorly absorbed and does not enter the central nervous system readily, allows high availability to airway muscarinic receptors.

Corticosteroids Corticosteroids are becoming a main stay in the treatment of asthma. This is not surprising considering that corticosteroids are potent anti-inflammatory agents and asthma is an inflammatory disease. Their precise mechanism(s) of action is still not clearly understood; but it is likely to include a reduction in the synthesis and secretion of a number of inflammatory mediators (e.g. prostanoids and leukotrienes) and cytokines (for further details see the appropriate section in the chapter on endocrine pharmacology).

Ipratropium has been suggested to be as an alternative in patients who fail to respond adequately to β2-agonists (exhibiting adverse effects such as tremor or tachycardia). Or in combination regimen where there is failure to single-drug regimens. Ipratropium has a slow onset of action and duration of 6 hours.

Inhaled corticosteroids are used as long-term suppressive treatment of asthma; beclomethasone is the one at present marketed in Iraq. Systemically, corticosteroids are also used in asthma, i.v. preparations include hydrocortisone, dexamethasone, and methylprednisolone, while the most common oral corticosteroid preparation is prednisolone.

Over-exposure of the airway smooth muscle to β 2-agonists (in terms of frequency and magnitude of dose) is believed to contribute to reduced therapeutic effect of β 2-agonists (tolerance), a phenomenon known as downregulation . Thus, the use of the anticholinergic agent ipratropium as an alternative to single therapy or as a combination with a β 2-agonist (reduced dose) may help reduce the possibility of the development of refractoriness to β2-agonists.

Administering corticosteroids by inhalation gives the advantage of being local, thus, reduced systemic adverse effects. In addition, beclomethasone is reduced systemic adverse effects. In addition, beclomethasone is superior to others when given by inhalation. It is absorbed into the bronchial mucosa, and then into the circulation. After being administered by inhalation, a sizeable proportion is also swallowed and the absorbed, with beclomethasone, this proportion is largely metabolised during the first pass in the liver (first pass effect), consequently, little or none reaches the systemic circulation. This is not the case with the other oral corticosteroids (e.g. prednisolone). Administering corticosteroids by inhalation carries the risk of candidiasis infection of the mouth (treat with nystatin

Antihistamines Antihistamines of the H1-type are not effective unless bronchospasm is part of an acute allergic reaction like anaphylactic shock.

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Table 9.1. A summary of selected drugs used in asthma

Drug (class) β 2-agonists Short-acting: Salbutamol Terbutaline Long-acting: Salmeterol Formoterol Leukotriene antagonists Montelukast Zafirlukast

Nature of action Bronchodilator and Anti-inflammatory

Zileuton

Inhibits lipooxygenase

Methylxanthines Theophylline (Aminophylline)

Inhibits phosphodiesterase, Bronchodilator and Anti-inflammatory

Sodium cromoglycate Corticosteroids

Important remarks Risk of tolerance Aerosol, nebulising solution, oral (tablets), i.v. Aerosol

Prevent bronchoconstriction by blocking cysLTl receptor

Orally effective, once or twice daily

Anti-inflammatory

Risk of hepatotoxicity Orally effective, multiple daily dosing is required Oral (theophylline) and (aminophylline) i.v. (aminophylline) Low therapeutic index Aerosol, prophylactic use, not useful in acute attacks

Anti-inflammatory

Beclomethasone Hydrocortisone Methylprednisolone

(low potency) (intermediate potency)

Dexamethasone

(high potency)

Prednisolone

(intermediate potency)

Ipratropium bromide

Blocks muscarinic receptors Bronchodilator Anti-inflammatory

Aerosol, prophylactic use, not useful in acute attacks i.v., useful in acute attack i.v. i.v. Most commonly used oral corticosteroid Aerosol, nebulising solution

depressant effect on the respiratory centre and are relatively non-addicting (in comparison with morphine and methadone. Cough suppressants are useful when sleep is disturbed by a dry (non-productive) cough. They are harmful in patients with bronchiectasis and bronchitis, since they may dry (leading to sputum retention). They are generally not needed in acute bronchitis and pneumonia. Usually antitussive treatment has to be an adjunct to antibiotic and bronchodilator therapy.

COUGH MEDICINES Antitussives The most important antitussive drugs are morphine-related agents including codeine (methylmorphine), noscapine, pholcodine and dextromethorphan that have a central action. They are thought to produce their antitussive activity primarily by raising the threshold of the medullary cough centre to afferent cough impulses. These have little

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Adverse effects of codeine occur rarely if low doses are used. The most common adverse effects are nausea, sedation and anorexia. With higher doses constipation and biliary colic may be a problem. Dextromethorphan and noscapine have few side effects and no addictive properties. For more details about the morphine-related agents see later section on narcotic analgesics (CNS Pharmacology).

Decongestants Various decongestants may be found in cold medicines: these are especially antihistamines and sympathomimetics. The anti-histaminics are included not only with the aim to counteract allergy swelling but also due to their anticholinergic effect on the nasal mucosa. This drying effect may be desirable against excessive thin nasal secretions (rhinorrhea) but hazardous particularly in lower respiratory tract involvement since this drying effect may lead to mucous plugging of small bronchi (sometimes inducing cough). Antihistamines are best effective in seasonal rhinitis and conjunctivitis (hay fever), in which these drugs relieve the sneezing, rhinorrhea, and itching of eyes, nose, and throat. Sympathomimietics can produce side effects due to cardiac stimulation with palpitations and increased blood pressure. Topical corticosteroid nasal preparations such as beclomethasone, fluticasone or triamcinolone are also used for nasal allergy symptoms.

Expectorants Expectorants reduce the viscosity of respiratory tract secretions and facilitate the removal of accumulated mucus and phlegm by ciliary action and coughing. They are thought to achieve this effect by stimulating the flow of thin, watery secretions within the respiratory tract, possibly by a reflex involving the vagus nerve and initiated by an effect of the expectorant on the stomach following oral administration. By increasing respiratory tract secretions, expectorants may also soothe dry, irritated tissues and in so doing reduce the urge to cough. They may also make a dry, unproductive cough more productive.

RESPIRATORY STIMULANTS Respiratory stimulants (analeptics) such as nikethamide and doxapram are of little value in the treatment of respiratory failure induced by barbiturates over-dosage ( or other CNS depressants). In such cases the sooner the patient is attached to a respirator the better. They are indicated in some acute respiratory failure , in an attempt, to obviate tracheal intubation and mechanical ventilation.

However, there is still no scientific evidence that expectorants (or demulcents) are of any therapeutic value, but may have a useful placebo effect. The sub-emetic doses of ammonium chloride, and ipecacuanha contained in many cough mixtures do not promote expectoration. There is a long list of substances that are claimed to have expectorant, mucolytic, or demulcent actions, e.g. acetylcysteine, glyceryl guaiacolate, bromhexine, and sodium citrate.

Adverse-effects: sweating, anxiety, nausea and vomiting, cardiac arrhythmias, hypertension and these drugs have low therapeutic index and can readily induce convulsions and coma.

Warm steam from a vaporiser is much more effective.

Contraindications: respiratory failure due to neurological or muscular disorder or due to drug toxicity, status asthmaticus, and ischaemic heart disease.

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Table 9.2. A summary of selected drugs used in cough medicines, and some centrally acting respiratory stimulants. Drug (class)

Nature of Important remarks action Raising the Useful when sleep is disturbed by dry Antitussives Codeine threshold of the cough Noscapine medullary cough Harmful in patients with bronchiectasis and Pholcodeine centre to afferent bronchitis (promoting sputum retention) Dextromethorphan cough impulses Butamirate citrate Centrally acting Unrelated to the opium alkaloids (Sinecod ) Possibly by: Expectorants ( demulcents, Expectorants Ammonium chloride Stimulating the flow of thin, mucolytics) Ipecacuanha watery secretions within Bromhexine airways, thus, soothing dry Warm steam is more effective! Acetylcysteine irritated tissues & making a Glyceryl guaiacolate dry (unproductive) cough Sodium citrate more productive. Allergic rhinitis and conjunctivitis Decongestants Antihistamines may Antihistamines (Hay fever: rhinorrhoea, sneezing possibly act by: (Sedative) and itching of eyes, nose, and 1.counteracting allergy throat) Chlorpheniramine swelling Mepyramine 2.also anticholinergic Diphenhydramine For rhinorrhoea associated with effect against Triprolidine common colds and allergies excessive nasal Promethasine secretions (Non or less sedative) They can be hazardous in lower Cetirizine respiratory tract involvement Loratidine since they may lead to mucous Astemizole plugging of small bronchi. Sympathomimetics Ephedrine Pseudoephedrine Phenylpropanolamine

Respiratory stimulants (Analeptics) Nikethamide Doxapram

Cause vasoconstriction by activating vascular α-adrenoceptors

Topical decongestants should not be used for longer than 3 days to prevent rebound nasal congestion (rhinitis medicamentosa).

In high doses, they can cause hypertension, headache, palpitations, cardiac arrhythmias and psychiatric disorders. Cautions: hypertension, hyperthyroidism, coronary heart disease Stimulate the medullary Useful in some cases of acute respiratory centres respiratory failure Contraindications: ischaemic heart disease, status asthmaticus, severe hypertension and thyrotoxicosis Low therapeutic index

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HYPOTHALAMIC AND PITUITARY HORMONES Introduction

Thyrotropin (TSH) is a glycoprotein acts on the thyroid to cause cellular hyperplasia, increased uptake of iodine and secretion of thyroxin (T4) and triidothyronine (T3). The amount released is controlled by circulating hormone levels acting on the hypothalamic release of thyrotropin-releasing hormone (protirelin, TRH). TSH may be used clinically to assess the power of thyroid gland to respond to pituitary stimulation.

Various physiological activities, such as metabolism, growth, and certain aspects of reproduction are under neuroendocrine control. The hypothalamus is connected to the pituitary gland by a stalk composed of neurosecretory fibres and portal venous system transporting substances from the hypothalamus to the anterior pituitary gland; this system is called the hypothalamichypophyseal portal venous system. Further, the hormones of the posterior lobe are synthesised in the hypothalamus and transported through the neurosecretory fibres in the stalk of the pituitary to the posterior lobe. The latter serves as a store from which the hormones are released to the circulation. The intermediate lobe of the pituitary gland releases hormones that have melanocytestimulating activity. In animals, the role of these hormones is clear, serving as adaptive mechanisms for skin colour changes. However, in human the role of these hormones is still not clear.

Growth Hormone (Somatropin, GH) GH is released from the anterior pituitary in response to growth hormone releasing hormone produced by the hypothalamus. Somatropin acts on all tissues to promote their growth. Administration causes an acceleration of bone growth but not bone age, unlike the sex hormones that cause both an acceleration of bone growth and an increase in bone age with premature fusion of the epiphysis. GH is extremely species specific and the therapeutic uses are limited. As it is a polypeptide it must be given parenterally. Somatropin is useful in the treatment of GH deficiency in children. Before starting somatotropin therapy, it is essential to check that there is normal thyroid function. The actions of somatropin appear to last much longer than the t (25 minutes) of somatotropin. This is because the latter induces the release from the liver of somatomedins (insulin-like growth factors) that are responsible for the subsequent somatropin-like actions. Somatropin is a diabetogenic hormone causing a rise in the blood glucose, and glucose tolerance falls.

The control of secretion is a feedback system in which falling levels of circulating adenohypophyseal hormones provoke the secretion of the appropriate releasing hormone. Generally, hormones including the hypothalamic hormones have the following clinical applications: 1. Replacement therapy for hormone deficiency conditions 2. Pharmacological therapy (pharmacological doses producing a hormonal action that is not present at physiological blood levels) 3. Diagnostic (stimulation tests to diagnose hypo- or hyperfunctional endocrine states.

Overproduction of somatotropin is usually causes gigantism if the epiphyses have not united and acromegaly after they have united.

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Prolactin is a peptide hormone with a structure resembles that of growth hormone (GH). It is the principal hormone responsible for lactation (milk production). In hypothalamic destruction, prolactin levels may be elevated as a result of impaired transport of prolactin-inhibiting hormone (dopamine) to the pituitary. In symptomatic hyperprolactinaemia, inhibition of prolactin secretion can be achieved with bromocriptine and other dopamine agonists, e.g. bromocriptine and pergolide. In contrast, drugs decreasing dopaminergic activity by the hypothalamus cause an impressive increase in prolactin secretion rate (e.g. the phenothiazines, reserpine, methyldopa, and metoclopramide).

Gonadotropin-Releasing Hormone (GnRH) Pharmaceutical GnRH is synthetic (e.g. leuprolide and goserelin). Pulsatile (every 14 hours) intravenous administration stimulates follicle-stimulating hormone (FSH) and luteinising hormone (LH) secretion. On the other hand, GnRH given continuously or GnRH analogues administered in depot formulations inhibit gonadotropin release.

Indications of GnRH 1. Hypothalamic hypogonadotropic hypogonadism (infertility in both sexes, pulsatile administration of GnRH driven by a portable batterypowered programmable pump, stimulates pituitary function) 2. Prostatic cancer, uterine fibroids, endometriosis, polycystic ovary syndrome, and precocious puberty (GnRH analogue agonists, e.g. triptoreline, leuprolide and goserelin, suppress pituitary function when administered continuously)

Indications of Dopamine Agonists 1. Prolactin-secreting adenomas (bromocriptine reduces both tumour size and serum prolactin levels in about 85% of patients for 6 months) 2. Amenorrhoea and Galactorrhoea (bromocriptine is useful in the treatment of hyperprolactinaemiainduced disorders like amenorrhoea, galactorrhoea, infertility, and hypogonadism) 3. Physiological lactation (bromocriptine is useful in the prevention of breast engorgement when breast feeding is not desired, e.g. when loss of baby) 4. Acromegaly (some acromegalic patients respond to bromocriptine) 5. Parkinson s disease (see appropriate section in CNS pharmacology) 6. Hirsutism in women (due to hyperprolactinaemia; in the adrenal cortex, prolactin increases dehydroepiandrosterone sulphate, and thus, increases androgen synthesis)

Gonadotropins Effective secretion of gonadotropins does not begin till puberty that they initiate. They also control and regulate the development of the gonads and secondary sex characters.

Follicle-Stimulating Hormone (FSH) It stimulates the formation of the ovarian follicle, in the female and spermatogenesis in the male.

Luteinising Hormone (LH) In the female, this hormone is concerned with the maturation of the ovarian follicle, ovulation and the formation of the corpus luteum. In the male, it stimulates the interstitial cells of the testes to secrete androgens. Note: Opioids decrease the release of both FSH and LH.

Adrenocorticotropic Hormone (Corticotropin, ACTH) ACTH is a polypeptide and its function is to stimulate the synthesis and release of adrenocorticosteroids, particularly, cortisol (hydrocortisone). The control of the secretion

Prolactin

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of ACTH is by the hypothalamic feedback system involving corticotropin-releasing hormone. If the blood level of adrenal corticosteroid is high, the secretion of ACTH is depressed and vice versa. Any nervous stimulation, trauma, endotoxin, stress or anxiety may also release ACTH releasing hormone. Insulin hypoglycaemia is used as test of anterior pituitary function, ACTH and growth hormone are released. In the normal person there appears to be a diurnal variation in corticosteroid release with high levels in the early morning and low levels in the late evening due to a similar variation in ACTH release.

labour. Oxytocin also plays an important role in process of milk ejection.

ACTH is given therapeutically to obtain adrenocortical effects or to stimulate an inactive adrenal cortex. It does not cause muscle wasting as it stimulates both the secretions of androgens and glucocorticoids. Cortisol, given on its own, can cause muscle wasting, as the catabolic action is now predominant. ACTH is not active by mouth and, as it is a peptide, may cause sensitivity reactions. Synthetic ACTH known as tetracosactrin has replaced ACTH for clinical use (See section on adrenocorticoids).

ADH is an octapeptide differing in only two amino acids when compared with oxytocin. The major action of vasopressin is to reduce water clearance by the kidney. In the absence of vasopressin the distal convoluted tubules and collecting ducts are virtually impermeable to water. Vasopressin also constricts vascular smooth muscle and causes a rise in blood pressure, bronchoconstriction, intestinal colic and stimulation of the bladder, though larger doses are necessary than to produce antidiuretic effect.

The major use of oxytocin is to induce labour for which it is given by slow intravenous infusion. It cannot be given by mouth as it is destroyed, but can be given intramuscularly, subcutaneously or sublingually, control by these routes is not likely to be so effective as by intravenous methods.

Vasopressin (Antidiuretic Hormone, ADH)

Clinically, vasopressin is used mainly to control the urine output in pituitary diabetes insipidus in which there is insufficient production of the natural hormone. As no reabsorption then occurs in the collecting tubules, the daily urine output may be as much as 10-20 litres. It is inactive by mouth and given parenterally or intranasally.

Posterior Pituitary Hormones The posterior lobe or neurohypophysis produces two hormones, oxytocin and vasopressin. These are formed in the neurones of the supraoptic and paraventricular nuclei of the hypothalamus. They are also released by various physical and mental stresses such as haemorrhage, sucking and coitus. The afferent pathways are to the cell bodies and not the neurosecretory terminals and there is evidence of differential secretion.

Indications of Vasopressins 1. Diabetes insipidus 2. Local anaesthesia (as a vasoconstrictor in conjunction with local anaesthetics, instead of adrenaline, being safer) 3. Child nocturnal enuresis (on holidays, given intranasally) 4. Bleeding oesophageal varices (i.v. infusion)

Oxytocin Oxytocin causes a rapid increase in the tone and motility of the uterus particularly in the presence of oestrogens, probably by an effect on electrical and contractile activity. The sensitivity of the uterus is maximal at term and plays a part in the normal process of

Diabetes Insipidus Pituitary diabetes insipidus is usually reflects reduced level of ADH release. It responds to

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ADH, felypressin and desmopressin (ADH agonists). The oral hypoglycaemic agent chlorpropamide is effective in partial pituitary diabetes insipidus, because it acts on the kidney potentiating the effect of ADH on the renal tubule. Different clinical conditions and iatrogenically (e.g. demeclocycline, lithium) can produce nephrogenic diabetes insipidus. It may respond paradoxically to diuretic agents like thiazides (including diazoxide).

Syndrome of Inappropriate Secretion of Antidiuretic Hormone (SIADH) In SIADH, there is an abnormal level of release of ADH that may lead to chronic (dilutional) hypokalaemia. Demeclocycline (a tetracycline) produces a state of unresponsiveness to ADH by an action on the renal tubule; it is therapeutically useful in this condition.

Table 10.1. A summary of the use of (vasopressins) and drugs used in ADH-related disorders. Agent Demeclocycline

Action Reduces ADH renal action

Vasopressin

Vasopressin receptor (V1 & V2) agonist

Desmopressin

V2-receptor agonist (devoid of presser Pituitary diabetes insipidus effect, H2O-channel (aquaporin) Nocturnal enuresis Haemophilia (promote the effect of von Willbrand s factor, VIII)

Chlorpropamide

Potentiates ADH action

Partial pituitary insipidus

diabetes

Carbamazepine

Potentiates ADH action

Partial pituitary insipidus

diabetes

Thiazides

Paradoxical

Nephrogenic insipidus

diabetes

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Use SIADH Pituitary diabetes insipidus Local anaesthesia Nocturnal enuresis Bleeding oesophageal varices

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Table 10.2. A summary of hypothalamic-pituitary-peripheral organ hormones and their end effects. Hypothalamus Clinical uses CRH

TRH

Anterior pituitary (+) ACTH Tetracosactrin

Peripheral target Adrenal cortex

(ACTH analogue) (+) TSH

Effects (release of) Glucocorticoids Mineralocorticoids Androgens

Thyroid

Thyroxine

Ovary

(formation of ovarian follicle) (Oestrogen)

Testis

Spermatogenesis

Ovary

Maturation of ovarian follicle, ovulation & formation of corpus luteum (Oestrogen, Progesterone)

Testis

Testosterone

Breast

(enlargement, formation)

Gonads

(Antagonises Gn action, thus anovulatory infertility (FSH-LH) Erectile impotence (LH-effect) Male infertility (FSH-effect)

Adrenal cortex Liver

Androgens, thus hirsutism in women Somatomedin Both GH & somatomedin promote protein synthesis, cell proliferation & growth formation.

(+) FSH GnRH 1. Hypothalamic hypogonadotropic hypogonadism (infertility in both sexes, pulsatile (+) LH administration of agonist, e.g. triptoreline, leuprolide & goserelin) 2. Prostatic cancer, uterine fibroid, endometriosis, polycystic ovary syndrome, & central precocious puberty (given continuously) Dopamine (DA2-receptor agonists)* (-) Prolactin 1. Prolactin secreting adenomas (agonist, e.g. bromocriptine) 2. Amenorrhoea, galactorrhoea, infertility, & hypogonadism 3. Physiological lactation 4. Acromegaly 5. Parkinsonism 6. Hirsutism (due to hyperprolactinaemia, adrenal androgens are increased by prolactin) GHRH (+) GH Somatropin (GH analogue) 1. Childhood pituitary insufficiency Somatostatin (-) GH Octreotide (somatostatin analogue) 1. Acromegaly 2. Carcinoid tumour

milk

(+) Stimulates the release of (-) inhibits the release of * Drugs decreasing dopaminergic activity by the hypothalamus cause an impressive increase in prolactin secretion rate (e.g. the phenothiazines, reserpine, methyldopa, and metoclopramide). DA-antagonists like metoclopramide are used to increase milk production in conditions like nursing mothers with low milk production.

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SEX (GONADAL) HORMONES AND INHIBITORS leading to increased pituitary secretion of gonadotropins; thus, they are used to induce ovulation in patients with anovulatory infertility.

Non-pituitary Gonadotropins Human chorionic gonadotropin Human chorionic gonadotropin (hCG, Pregnyl ) is mainly luteinising, secreted by the placenta and is found in the urine shortly after the start of pregnancy. It is the basis of such pregnancy diagnostic tests as the Ascheim-Zondek. It is also secreted by various tumours such as hydatidiform mole, chorionepithelioma and testicular teratoma.

Oestrogen receptors Oestrogens binds to specific nuclear receptor that is a member of superfamily of receptors, including those for thyroxine and vitamin D. the oestrogen-receptor complex interacts with nuclear chromatin producing transcription of specific mRNA responsible for the expression of specific proteins that mediate certain biological functions depending on target tissues.

Serum gonadotropin Serum gonadotropin (PMSG, Humegon ) is found in the serum of pregnant mares and is of endometrial origion. It has mainly follicle stimulating action and some luteinising action.

Indications of Oestrogens 1. Oral contraception 2. Uterine dysfunction 3. Menopausal and postmenopausal symptoms (e.g. hot flushes, age-related loss of bone, and atrophic vaginitis; oestrogen replacement therapy; oestrogen provides a protective effect against cardiovascular disease by decreasing LDL and increasing HDL levels in plasma)

Menotropins Menotropins (human menopausal gonadotropins, hMG, Pergonal ) are partially metabolised human FSH and LH extracted from the urine of postmenopausal women. They must be given by injection and have been found to be of use in the treatment of cryptorchism (failure of testes to descend into the scrotum), infertility, and delayed puberty.

Adverse Effects 1. Nausea and vomiting 2. Menstrual disorders 3. Breast enlargement 4. Thromboembolic disorders 5. Oedema 6. Hypertension 7. Endometrial cancer 8. Decreased lactation 9. Increased binding globulins cortisol, thyroxine, iron)

Oestrogens, Progestins, Androgens & inhibitors Oestrogens The most important oestrogen produced by the ovaries is oestradiol that is partly converted by the liver to less active oestrone and oestriol. This means that natural oestrogens are not very active when given orally whereas synthetic oestrogens on the other hand (ethinyl oestradiol and stilboestrol) are active orally. Plasma oestrogen inhibits FSH and LH release by an action on the hypothalamus. Clomiphene and cyclofenil and tamoxifen block oestrogen receptors at the hypothalamus

(for

Progestins The main natural one secreted by the corpus luteum is hydroxyprogesterone that like oestrogen is relatively inactive when given orally because it is rapidly metabolised in the liver. Plasma progesterone inhibits LH release by an action on the hypothalamus.

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Table 10.3. Selected oestrogens and their indications Oestrogen

Table 10.4. Selected progestins and their indications

Indications

Progestin

Indications

Oestradiol (IM)*

Primary amenorrhoea

Allyloestrenol

Habitual abortion

Oestriol (oral)

Postmenopausal vaginal & vulval conditions

Hydroxyprogesterone caproate (Primolut Depot , oily)

Habitual abortion

Stilboestrol (oral)

Menopausal symptoms Amenorrhoea Prostatic cancer

Medroxyprogesterone acetate (Depo-Provera , IM)

Ethinyloestradiol Mestranol

Oral contraceptive Oral contraceptive

Endometriosis Dysfunctional uterine bleeding Secondary amenorrhoea Contraception

Norethisterone (Primolut N , oral)*

Endometriosis Dysfunctional uterine bleeding Dysmenorrhoea Postponement of menstruation Fasting in Ramadan, & pilgrimage (Haj)

* Oestradiol is largely inactivated by first pass metabolism when administered orally.

Indications of Progestins 1. Oral contraception 2. Uterine dysfunction 3. Habitual abortion 4. Postponement of menstruation

Norgestrel Oral contraceptive * Also available in tablet form; the indcation limits the use of certain dosage forms.

Adverse Effects of Progestins

Oral Contraception

1. Weight gain 2. Irregular menstruation 3. Adverse changes in lipoprotein levels (↑LDL & ↓HDL) 4. Adverse effects on foetus (virilisation) 5. Abnormal glucose tolerance (diabetogenic)

Combined oestrogen-progestin oral contraceptive pills are the most common. The principle is suppression of the release of pituitary gonadotropins, by action on the hypothalamus inhibiting the release of GnRH and thus the pituitary that results in impaired follicular maturation and inhibition of ovulation. This effect is dose-related, therefore, occasional ovulation is more likely with 20-30 µg than with 50 µg oestrogen pills. In addition, there are peripheral effects on cervical mucus becomes more viscous and hinders the movement of the spermatozoa, and the state of the endometrium is disturbed so that implantation is less likely to occur. The oestrogen usually is ethinyloestradiol and various synthetic progestogens such as norgestrel. One tablet is taken during 21 days followed by a 7-day interval during which withdrawal bleeding occurs.

Note: A progestin with least androgenic activity is preferred to avoid adverse effects (musculinisation) on female foetus. This is particularly true when used in habitual abortion. Note: An oestrogen alone can inhibit ovulation; however, oestrogen can cause thromboembolism and endometrial cancer, adding a progestin can lessen the possibility of the unwanted latter effects. Oral contraceptives contain higher doses of oestrogen than those used in oestrogen replacement therapy do.

Adverse Effects of Combined Oral Contraceptive 1. Thromboembolism 224

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2. Stroke 3. Myocardial infarction 4. Hypertension 5. Hepatic function impairment 6. Decreased glucose tolerance (insulin antagonism)

hypothalamic receptors and does not cause liver injury. Drugs with antiandrogenic activity are spironolactone, ketoconazole, digoxin and cimetidine.

Progestin Only Contraceptive

Male hypogonadism, and for libido and potency, when fertility is desired testosterone should be replaced by gonadotropin therapy. Danazol is a partial (impeded) androgen agonist, danazol inhibits pituitary gonadotropin secretion leading to secondary endometrial atrophy; thus, it is useful in endometriosis (ectopic growth of the endometrium), precocious puberty, gynaecomastia and menorrhagia.

Indications of Androgens

Progestin alone is also used as oral and parenteral contraceptive. It is less reliable than combined preparations; inhibits ovulation in up to 40% of cycles, makes it more difficult for sperm to penetrate cervical mucus and prevents implantation as a result of inducing premature endometrial secretary phase. They are used as alternatives when oestrogens are contraindicated or not tolerated, and in heavy smokers (in whom oestrogen significantly increases the risk endometrial cancer).

Mesterolone (androgen) 1. Acts intratesticularly (essential for the action of FSH in spermatogenesis) 2. Has less hypothalamic negative feedback 3. Is useful in infertility 4. It does not cause liver injury

It should be stressed that progestin only (contraceptive) pill is useful in lactating women. It has the advantage of being a contraceptive on its own, and unlike oestrogen, progestins spare lactation that itself also has contraceptive actions.

Cyproterone Androgens

It is an antiandrogen with progestogenic activity. It causes reversible inhibition of spermatogenesis and infertility, probably by blocking gonadotropin release via activating the inhibitory hypothalamic progestogen receptors, and reduces male sexual function, at least in part, by competing with testosterone for target receptors.

The most important androgen is testosterone that is produced by interstitial cells of the testes. LH stimulates its synthesis. It is necessary for male sexual function. Circulating testosterone inhibits LH secretion and only in large doses it reduces plasma FSH (hypothalamic feedback inhibition of pituitary gonadotropin secretion). Thus, suppression of spermatogenesis is a side effect of testosterone therapy. Inhibin, a factor of testicular origin (Sertoli cells) inhibits FSH secretion. Androgens also have anabolic action, promoting growth, developing and maintaining muscle mass and preventing osteoporosis. Testosterone itself is only weakly active because of hepatic breakdown. Testosterone derivatives, fluoxymesterone and mesterolone are androgenic substances, active when given by mouth that is used in replacement therapy. Mesterolone is less effective on

Indications of Cyproterone 1. Severe hypersexuality 2. Sexual deviation in men 3. Severe hirsutism in females

Anabolic Steroids They are synthetic androgen like nandrolone phenpropionate (Durabolin ) and nandrolone decanoate (Deca-Durabolin ). These agents are not acted upon by 5αreductase, thus, are not converted to dihydrotestosterone, therefore, less virilising; 225

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this makes anabolic steroids superior to testosterone and hence have been introduced as anabolic agents. They are useful in aplastic anaemia (preferred agent is oxymethalone), severe wasting, and osteoporosis. The most important adverse effects of anabolic steroids include liver cancer.

• In males 1. Priapism 2. Impotence 3. Gynaecomastia 4. Decreased spermatogenesis • In children 1. Premature closure of the epiphyseal plates 2. Abnormal sexual maturation

Adverse Effects of Androgens • In females 1. Musculinisation with acne, growth of facial hair, deepening of the voice, male pattern baldness, and excessive muscle development. 2. Menstrual irregularities

• •

Increase LDL/HDL ratio Oedema (fluid retention)

Table 10.5. A summary of agents used in oral contraception Agent Oestrogens

Progestins

Mode of Action Inhibit hypothalamic release of GnRH → ↓ pituitary Gn → ↓ follicular maturation & ovulation 1. Inhibit ovulation in 40% of cycles 2. Slow movements of spermatozoa 3. → Endometrial disturbance (premature secretary phase) → inhibit implantation

Important Remarks Decrease LDL/HDL ratio Adverse effects: Thromboembolism Endometrial cancer Adverse effects: Break-through bleeding Adverse changes in lipoprotein levels (↑ LDL/HDL ratio) Abnormal glucose tolerance (diabetogenic) Useful when: 1. Oestrogen not tolerated 2. Heavy smokers 3. Lactating women

Progestin only Oral Parenteral

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Table 10.6. A summary of sex hormones and their antagonists Agent Non-pituitary

Primary Action

Chorionic gonadotropin

(LH-agonist, Pregnyl )

Serum gonadotropin

(PMSGn, FSH & LH, Humegon )

Menotropins

Oestrogens

(postmenopausal urine, FSH & LH, Pergonal ) Reduce Gn release

Oestradiol (IM) Oestriol (oral) Stilboestrol (oral) Ethinyloestradiol (oral) Mestranol (oral)

(Antagonists) Clomiphene Cyclofenil Tamoxifen

Cryptorchism (failure of testes to descend into the scrotum) Infertility Delayed puberty Contraceptive pill Menstrual disorders Menopausal symptoms (hot flushes) Postmenopausal symptoms (osteoporosis) Prostatic cancer Ovarian failure (replacement)

Oestrogen receptor Partial agonist Partial agonist Antagonist

Anovulatory infertility Male infertility

Reduce LH release

Contraceptive pill Menstrual disorders Endometriosis Ovarian failure (replacement) Habitual abortion*

Androgenic & anabolic effects (-ve hypothalamic & pituitary feedback)

Male hypogonadism Increase libido & potency (Use Gn when fertility is desired)

Progestins Hydroxyprogesterone caproate Medroxyprogesterone acetate Norethisterone Norgesterol (oral)

Use

Androgens Testosterone propionate (IM) Methyltestosterone (oral) Nandrolone phenpropionate Nandrolone decanoate

Anabolic (largely)

Severe wasting Osteoporosis Aplastic anaemia

Mesterolone

Acts intratesticularly promoting the action of FSH in spermatogenesis

Infertility

Danazol

Androgen partial agonist

Gynaecomastia Precocious puberty Menorrhagia

Reduces Gn release (endometrial atrophy)

Endometriosis

Androgen receptor antagonist

Hirsutism Hypersexuality (sexual deviation in men) Prostatic cancer

Progestogenic activity due to the acetate form (reduces Gn release)

Male contraceptive (?)

Finasteride Ketoconazole Spironolactone

5-α reductase inhibitor Antiandrogen (synthesis inhibitor)

Benign prostatic hyperplasia Cushing s syndrome Prostatic cancer

Flutamide Spironolactone

Androgen receptor antagonist

Prostatic cancer

Androgen antagonists Cyproterone acetate

* With least androgenic activity to avoid musculinisation of female foetus.

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DRUGS ACTING ON UTERINE SMOOTH MUSCLE 2. Coitus 3. Suckling 4. Emotional stimuli 5. Some drugs (e.g. nicotine)

Introduction Uterine contractions are rhythmical or sustained as shown in Fig.10.1. For induction of labour rhythmic contractions are important and after delivery sustained contractions in order to minimise bleeding.

morphine

&

During pregnancy, a specific enzyme oxytocinase exists for its degradation. Oxytocin has a vasodilator action and hence a side effect is hypotension, thus it should not be given in ischaemic heart disease. With large doses an ADH-like activity can be observed with water retention. Oxytocin is used to induce labour at term. Oxytocin nasal spray may be used to facilitate breastfeeding.

Normally uterine smooth muscle is stimulated by α1-adrenoceptors and inhibited by β 2-adrenoceptors. At term, oxytocin stimulation is very important. Oxytocin probably partly acts by local liberation of prostaglandin E2. Uterine stimulant drugs used in obstetrics are: 1. Oxytocin (for induction of labour at term) 2. Prostaglandin E2 (for induction of labour before term, i.e. in abortion) 3. Ergometrine (after delivery)

Adverse Effects of Oxytocin 1. Uterine rupture 2. Rebound atonia 3. Hypotension (hence, caution in ischaemic heart disease) 4. Water intoxication (upon prolonged administration that characterised by headache, nausea, vomiting, confusion and coma; this is because oxytocin has weak antidiuretic properties and acts like vasopressin to increase tubular reabsorption of water.)

Oxytocin

Sustained Rhythmic

Prostaglandins PGF2α and PGE2 induce labour at any time during pregnancy and therefore are used mainly as abortifacient. Prostaglandin synthesis inhibitors such as indomethacin and aspirin can prolong labour but can induce premature closure of the ductus arteriosus and lead to pulmonary hypertension in the baby.

Fig. 10.1. A schematic representation of the effect of oxytocin. Note: Oxytocin increases the rhythmic contractions.

Oxytocin Oxytocin (Pitocin , Syntocin ) is an octapeptide, released from the posterior pituitary where it is stored after being synthesised in the paraventricular and supraoptic nuclei. Oxytocin is now available as a synthetic drug. The release of oxytocin is governed by neuronal mechanisms elicited by:

Adverse Effects 1. Abdominal cramps (both PGF2α and PGE2) 2. Bronchospasm (PGF2α)

1. Cervical dilatation

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Ergometrine

Uterine Relaxants (Tocolytics)

Ergometrine is only used in the 3rd stage of labour and postpartum haemorrhage. Ergometrine is synonymous to ergonovine and acts through α and dopamine receptors. Its action is more prolonged than oxytocin and may last 3-6 hours.

Uterine relaxation can be brought about by β2-receptor agonists such as terbutaline, salbutamol or ritodrine. These drugs are used to prevent preterm labour. Uterine contractions can also be reduced for the prevention of dysmenorrhoic pain (uterine cramps). For this purpose non-steroidal antiinflammatory drugs (NSAIDs) can be used such as ibuprofen, indomethacin and naproxen. Naproxen can be given 3-4 times daily prior to the expected menstrual period. It has been shown that prostaglandin levels are increased in patients with dysmenorrhoic pain. NSAIDs not to be used during pregnancy (risk for closure of patent ductus arteriosus). General anaesthetics, particularly halothane relaxes uterine smooth muscle. Papaverine and amyl nitrite relax the cervix.

Adverse Effects of Ergometrine 1. Nausea 2. Hypertension 3. Decrease lactation (being ergot alkaloid, it interferes on the level of the hypothalamus, like bromocriptine, reducing the release of prolactin and thus decrease lactation)

Table 10.7. A summary of selected drugs acting on uterine smooth muscle Agent Oxytocin

Action Indication Via oxytocin receptors → Induction of labour at term PGE2 → contraction

Adverse Effects Uterine rupture Rebound atonia Hypotension Water intoxication

PGE2, PGF2¿

Uterine contraction

Abdominal cramps ( PGF2α and PGE2) Bronchospasm (PGF2α)

Ergometrine (Ergonovine)

Via α1-receptors contraction

→ Postpartum haemorrhage

Salbutamol Terbutaline Ritodrine

Via β2-receptors relaxation

→ Prevention preterm labour

NSAIDs

Reduce PGs production → Dysmenorrhoic pain ↓ uterine contraction

Induction of labour (before term, abortion)

229

Nausea Hypertension Decrease lactation of See appropriate section.

See appropriate section.

Endocrine Pharmacology - Adrenocorticosteroids

Ramadi, 11 October 2009

ADRENOCORTICOSTEROIDS Fig.10.2. The mechanism of action of cortisol is illustrated in Fig.10.3.

Introduction All hormones released from the adrenal cortex are steroids and known as corticosteroids. The adrenal cortex consists of three distinct layers of secretary cells.

Diurnal rhythm of cortisol levels reflects ACTH release with peak level at about 8:00 hours and trough at midnight. Feedback inhibition of ACTH release and ACTH-RH (corticotropin releasing hormone) is mediated by circulating cortisol. About 95% of cortisol is bound in circulation to corticosteroid binding globulin (CBG, transcortin). The level of CBG also varies with maximum binding at midnight and minimum at about 8:00 hours.

1. Zona glomerulosa (outermost layer, secrets mineralocorticoids) 2. Zona fasciculata (middle layer, secretes glucocorticoids) 3. Zona reticularis (inner layer, secretes small amounts of glucocorticoids and gonadocorticoids)

Therapeutic Uses of Glucocorticoids

Mineralocorticoids

Replacement Therapy

Aldosterone is responsible for maintenance of sodium homeostasis in the blood by increasing sodium reabsorption in the kidney. It also increases water retention and promotes the loss of potassium and hydrogen ions. Aldosterone secretion is controlled by the renin-angiotensin system and by blood sodium and potassium concentration.

Replacement in adrenocortical insufficiency disorders (including Addison s disease, and adrenal crisis) in which physiological concentrations (low doses) are required. The preferred agent in this condition is cortisone acetate.

Pharmacotherapy

Excessive aldosterone secretion (hyperaldosteronism as in Conn s syndrome) is characterised by sodium retention (and hypertension), potassium loss (and muscular weakness). The aldosterone receptor antagonist spironolactone may be useful in this condition.

Cortcosteroids are used for the treatment of adrenal disorders and also for diagnostic purposes; they are more frequently used for nonadrenal disorders, e.g. suppression of inflammatory responses, given systemically (usually in high doses) or topically. The following are some therapeutic indications for the use of glucocorticoids.

Impaired aldosterone secretion, exhibited in Addison s disease, contributes to hyponatraemia, hypovolaemia and hypotension. The use of the aldosterone receptor agonist fludrocortisone is recommended in this condition.

1. Allergic reactions (e.g. drug reactions, angioneurotic oedema, allergic rhinitis, contact dermatitis, asthma, bee stings, urticaria etc.) 2. Collagen-vascular disorders [e.g. Systemic lupus erythematosus (SLE), rheumatoid arthritis, temporal arteritis) 3. Ocular diseases (e.g. acute uveitis, allergic conjunctivitis, choroditis) 4. Gastrointestinal diseases (e.g. ulcerative colitis)

Glucocorticoids The main glucocorticoids secreted by the zona fasiculata are cortisol (hydrocortisone), cortisone, and corticosterone, with cortisol the only one secreted in significant amount. They affect every cell in the body. A summary of the actions of cortisol is made in 230

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5. Haematological disorders (e.g. idiopathic thrombocytopenic purpura, acquired haemolytic anaemia, leukaemia) 6. Infections (e.g. gram-negative septicaemia, to suppress excessive inflammation) 7. Inflammatory conditions of bone joints (e.g. arthritis, tenosynovitis) 8. Neurological disorders (e.g. cerebral oedema, as in cerebrovascular accidents, anaphylactic shock, and following brain surgery, use dexamethasone) 9. Organ transplant (prevention and treatment of rejection)

10.Pulmonary diseases [e.g. bronchial asthma (oral inhalation, beclomethasone; systemic, oral prednisolone; acute severe asthma, hydrocortisone), prevention of infant respiratory distress syndrome (dexamethasone), sarcoidosis, aspiration pneumonia) 11.Minimal change (idiopathic) nephrotic syndrome (intermittent administration, prednisolone) 12.Skin diseases (e.g. atopic dermatitis) 13.(Myclonic seizures) 14.Diagnosis (hypothalamic-pituitaryadrenal function; dexamethasone test)

Table 10.8. A summary of the distinguishing characteristics of adrenocorticosteroids Agent

Plasma t (min)

Biological

t (hr)

Glucocorticoid* Effects Relative potency

Equivalent dose (mg)

Mineralocorticoid** Effects

Short-acting Cortisone acetate*** 30 12-18 0.8 25.0 1.0 Hydrocortiosone 12-18 1.0 20.0 1.0 (Cortisol) Intermediate-acting Prednisone*** 18-36 4.0 5.0 0.3 Prednisolone 60-120 18-36 5.0 5.0 0.3 Methylprednisolone 18-36 5.0 4.0 minimal Triamcinolone 18-36 5.0 4.0 none Long-acting Dexamethasone 190 36-54 30.0 0.75 minimal Betamethasone 36-54 30.0 0.75 minimal Fludrocortisone 15.0 150 Aldosterone none 500 * Antiiflammatory, immunosuppressant, and metabolic effects ** Sodium or water retention, potassium depletion *** cortisone and prednisone are inactive; when administered systemically, in the liver converted to the pharmacologically active hydrocotisone (cortisol) and prednisolone respectively. addition to producing glucocorticoid activity, it also produces androgenic activity. For this reason, tetracosactrin is gaining a good use in asthmatic children with the advantage of avoiding growth retardation.

Synthetic Corticotropin Synthetic corticotropin (ACTH) with short amino acid chains (without amino acids 2539 to which serious allergy is attributed) have been developed. Tetracosactrin is composed of the active first 24 amino acids of natural human corticotropin with t of 10 minutes. It is used for diagnosis purposes and also for glucocorticoid activity. Further, it is superior to glucocorticoids because in

High plasma concentration of any glucocorticoid agent inhibits release of corticotropin releasing hormone and therefore corticotropin. In the absence of corticotropin the cells of the inner cortex atrophy resulting in reduced production of 231

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androgens and hence reduced anabolic processes. This is probably why retardation of growth in children is associated with the use of glucocorticoids in children (in conditions like severe chronic rheumatic disease). It follows that the use of corticotropin like tetracosactrin (although it has to be given i.m.) in children can be superior to the use of glucocorticoids as the former is less likely to suppress growth in children. A long-term use of tetracosactrin, like in myclonus seizure in children, carries the risk of hirsutism.

6. Peptic ulcer (in 2% of cases) 7. Diabetes (insulin antagonism) 8. Cataracts (↑ frequency, glucose → sorbitol, hyperglyacemic toxicity) 9. Euphoria 10.Psychoses 11.Muscle wasting (↓protein anabolism, ↑protein catabolism) 12.Osteoporosis (↓ bone protein matrix) 13.Cushing-like syndrome (Moon face, buffalo hump, lemon stick, hypertension, bruising etc.; This may occur even with skin preparations particularly in children, thin stratum corneum epidermis, high % content, and potent glucocorticoids). 14.Aseptic necrosis (vasoconstriction) 15.Telangiectasia (prolonged use of topical preparation; local skin atrophy; spider-like proliferation of capillaries; abuse potential) 16.Increased appetite 17.Hypothalamic-pituitary-adrenal suppression (abrupt withdrawal results in acute adrenal insufficiency syndrome)

However, tetracosactrin is inactive when taken orally and has to be given parenterally like other peptide hormones. This makes its use largely limited for diagnostic purposes, as a test of the capacity of the adrenal cortex to produce cortisol. The plasma cortisol concentration is measured before and after an intramuscular injection of tetracosactrin.

Prednisolone has a biological t lasting serveral hours, intermediate between those of cortisol and the long-acting glucocorticoids like dexamethasone. It is this intermediate duration of action that makes it suitable for the alternate day administration regimens, which have been found to reduce the risk of cushingnoid features, adrenocortical insufficiency and growth retardation in children, yet provide adequate corticosteroid coverage in some disorders such as asthma, minimal change nephrotic syndrome and idiopathic thrombocytopenic purpura.

Inhibition of Synthesis of Adrenal Steroid Hormones Inhibitors of synthesis of adrenal steroid hormones are used in both diagnosis of adrenal disease and controlling excessive production of corticosteroids as in Cushing s syndrome (pituitary hyperfunction) or primary adrenocortical hyperfunction.

Metyrapone Metyrapone inhibits cortisol production by blocking the enzyme, steroid 11βhydroxylase that converts 11deoxyprecursors into cortisol, leading to increased release of ACTH. It is used diagnostically in the functional assessment of pituitary-adrenal axis (metyrapone test).

Adverse Effects of Adrenal Corticosteroids 1. 2. 3. 4.

Infection (increased risk) Oedema (Na+ & H2O retention) Hypertension (Na+ & H2O retention) Glaucoma (raised intraocular pressure; Na+ & H2O retention) 5. Pseudotumour cerebri (benign intracranial hypertension; a condition caused by cerebral oedema, marked by raised intracranial pressure; Na+ & H2O retention)

Aminoglutethimide Aminoglutethimide inhibits the synthesis of all active steroid hormones by blocking the conversion of cholesterol to pregnenolone. Aminoglutethimide is useful therapeutically in the treatment of breast cancer (reducing 232

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oestrogen production) concurrently administered with dexamethasone.

Ketoconazole Ketoconazole is mainly used as antifungal agent, mediating this effect by inhibiting synthesis of ergosterol in fungi. However, in man it blocks synthesis of steroids in gonads and adrenal cortex. Ketoconazole is useful in Cushing s syndrome and prostatic cancer.

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(ADDISONS)

MSH ACTH

DEPRESSION PSYCHOSIS Hallucination Euphoria CNS electrolyte changes (probably)

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GLUCOCORTICOID ACTIONS Diabetes Muscle Wasting Protein anabolism

Insulin antagonism Gluconeogenesis (lipolysis)

Protein catabolism

FAT DEPOSITION Face, shoulder, abdomen

Na+ Mineralocorticoid

K+ Ca++

CORTISOL (Hydrocortisone)

INFECTION Leukocytes Macrophages Lymphocytes Antibodies

HYPERTENSION

Ca++

Gastric ulcer (2%)

Blood Pressure Vasoconstriction mediated by catecholamines

Vit D Osteoporosis Bone protein matrix Back Pain

CUSHING SYNDROME Moon face, buffalo hump, lemon stick, hypertension, bruising, osteoporosis (IATROGENIC)

Intraocular pressure

Aseptic necrosis Telangiectesia

Cataracts

Antiinflammatory Immunosuppressive

Immunological response

Fig. 10.2. A summary of the major actions of cortisol, actions described briefly clockwise. 1. 2.

Has protein-catabolising, gluconeogenic, and hyperglycaemic (insulin antagonism) actions. Causes shift from carbohydrate catabolism to lipid catabolism as energy source, and fat deposition as in Cushing s syndrome. 3. High blood concentration causes leucopenia and marked atrophy of lymphatic tissue (antiiflammatory and immunosuppressive actions). 4. In conjunction with adrenaline, mediates normal recovery from injury produced by inflammatory agents. 5. Maintains normal blood pressure by aiding noradrenaline and adrenaline to have their full effect, causing vasoconstriction; aseptic necrosis as a result of vasoconstriction; telangiectasia as a result of local skin atrophy. 6. May cause an increase in intraocular pressure (glaucoma) and cataracts (increase frequency, glucose toxicity). 7. By inhibiting synthesis of cytoprotective prostaglandins, gastric acid secretion may be increased. 8. Decreased bone protein matrix as a result of protein catabolism. 9. Inhibits intestinal calcium absorption by inhibiting the action of vitamin D. 10. Its mineralocorticoid actions lead to reabsorption of sodium and water and losing potassium and calcium. 11. Its secretion is controlled by a negative feedback mechanism involving ACTH from the adenohypophysis, except in stress response; its secretion is increased in response to stress. 12. Causes a state of euphoria, and hallucination. 234

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Multiple stimuli (e.g. bradykinin)

AA

CORTISOL

+ Steroid receptor

Phospholipids Phospholipase A2

_ Lipocortin 1

GRE

HSP90

Eicosanoids

mRNA

NFµB mRNA

HSP90 +

iNOS COX-2 Chemokines Cytokines

mRNA

DNA

HSP90

mRNA

Rough ER NFµB active

NFµB

Rough ER

Glucocorticoids

IµB Multiple stimuli IµB

NFµB inactive

s lipocortin 1 + q COX-2

Fig. 10.3. A relatively recent concept of the cellular mechanisms responsible for mediating the major actions of cortisol. The adrenocortical steroid cortisol enters their target cells, and bind to the glucocorticoid (steroid) receptor in the cytoplasm. This receptor is usually bound to what is known as the heat shock protein HSP90. When cortisol binds to the receptor, the HSP90 changes conformation and dissociates from the receptor. Thence, the cortisolreceptor complex enters the nucleus; this complex interacts with promoter regions of several genes through coordination with the so-called the glucocorticoid response elements (GRE) switching on or off certain transcription processes. Thus, by expression of a protein called IκB which inactivates the transcription factor nuclear factor kappa B (NFκB). The latter is stimulated by a variety of proinflammatory mediators to turn on the production of inflammatory mediators like inducible nitric oxide synthase (iNOS), inducible cyclooxygenase (COX-2), chemokines and cytokines. Similarly, cortisol nuclear action may lead to an increase in the production of lipocortin 1 which inhibits phospholipase A2 leading to an increase in the production of lipocortin 1 which inhibits phospholipase A2 leading to reduced production of arachidonic acid (AA) and in turn reduced synthesis of eicosanoids (prostanoids and leukotrienes). These products usually would contribute to increased vascular permeability resulting in oedema, leukocyte migration, fibrin deposition. (+) stimulatory; (-) inhibitory; ER: endoplasmic reticulum.

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Endocrine Pharmacology - Thyroid & Antithyroid Drugs

Ramadi, 11 October 2009

THYROID AND ANTITHYROID DRUGS Introduction

Adverse Effects of T3 and T4

Tetraiodothyronine (T4), thyroxine containing 4 iodine atoms; approximately 20 times more abundant than triiodothyronine (T3). Its major importance is as a precursor to T3 contains three iodine atoms; considered being the principal thyroid hormone. T 3 binds efficiently to nuclear receptors in target cells.

Cardiac effects

The thyroid gland stores considerable amounts of a preliminary form of its hormones prior to secreting them. Before being stored in the colloid of follicles, T3 and T4 are attached to globulin molecules, forming thyroglobulin and enter the bloodstream. Once in the stream, T3 and T4 attach to plasma globulins and travel as a hormone-globulin complex. T 3 and T4 detach from plasma globulin as they come near the target cells.

Non-cardiac effects

1. 2. 3. 4. 5. 6.

Tachycardia Angina Myocardial infarction Congestive heart failure Arrhythmia Sudden death

7. Tremor 8. Restlessness 9. Heat intolerance 10.Diarrhoea

Antithyroid Drugs Hyperthyroidism is associated with a number of disease conditions, including 1. Graves disease 2. Goitre 3. Toxic adenoma 4. Thyroiditis

Actions of Thyroid Hormones 1. Stimulation of metabolism (heat intolerance, increased appetite with weight loss, raised metabolic rate in hyperthyroidism; coma and hypothermia) 2. Promotion of growth and development (dwarfism and mental deficiency in cretinism) 3. Sensitisation to sympathetic effects and catecholamines (tachycardia, tremor, hyperactive reflexes in hyperthyroidism)

The aim of drug therapy of hyperthyroidism is to reduce synthesis and/or release of thyroid hormones (Fig.10.4.). The thionamides, carbimazole (with active metabolite methimazole) and propylthiuracil are concentrated in the thyroid gland where they inhibit synthesis of the thyroid hormones. They inhibit both the oxidation of iodide ions required for iodination of the tyrosyl residues (tyrosines) and the condensation (coupling) of iodotyrosines to triiodothyronine (T3) and thyroxine (T4). These drugs do not affect the release of the thyroid hormones already stored on the thyroglobulin; thus, their effect would not appear until exhaustion of the preformed thyroglobulin has taken place. Therefore, a delay of 1-2 months is expected before a clinical effect is observed.

Indications of T3 and T4 T4 is a standard treatment of hypothyroidism [cretinism (congenital), myxoedema (acquired), panhypopituitarism]. T 3 is used in the initial treatment of myxoedema coma. T4 may reduce the size of the goitres (puberty goitre, Hashimoto s autoimmune thyroiditis and endemic iodine deficiency) that have not responded to iodine alone.

Dietary iodine reaches the circulation as iodide. The latter is taken up (a process being stimulated by TSH and inhibited by perchlorate) and concentrated in the thyroid 236

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gland for the synthesis of thyroid hormones. However, high doses of iodide, unlike the thionamides, inhibit the release of hormones from thyroglobulins. The latter effect is responsible for its rapid effect; therefore, it is useful in combination with a thionamide agent in the treatment of thyrotoxic crisis. Iodine is also found to reduce vascularity. In thyrotoxicosis, the effects of iodine last only for two weeks; therefore, it is useful for preoperative preparation of the patient for thyroidectomy.

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Table 10.9. A summary of antithyroid drugs

Agent Thionamides

Mode of Action Blockade of both iodination of tyrosyl residues, & condensation of iodotyrosines. Delay of 1-2 months before hyperthyroidism begins to respond

Carbimazole

Propythiouracil Potassium perchlorate

Iodine (Lugol s solution)

Adverse Effects

Rashes Bone marrow depression Drug fever Arthralgia Rashes Bone marrow depression Prevents trapping and Bone marrow depression concentration of iodine in the thyroid gland. Inhibits bot iodination of Allergic reactions

tyrosyl residues and release of hormones from thyroglobulin 131

I and 125I

¾-adrenergic blockers

Concentrated in thyroid gland Under or over treatment by thyroid trap. Isotopes irradiate and destroy thyroid cells. β-Blockers are useful therapeutically to control tremor and tachycardia in thyrotoxicosis.

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PLASMA

Majid A. K. Lafi

COLLOID

THYROID CELL

Amino acids

Tyrosine Thyroglobulin

Synthesis of thyroglobulin

Tyrosine

Carbimazole -ve Propylthiouracil Peroxidase High dose iodide 2II2 I Iodination Tyrosine I I Tyrosine I

2IIodide uptake (Inhibited by perchlorate)

Condensation

Thyroxine Triiodothyronine

Release of hormones from thyroglobulin -ve High dose iodide

-ve Carbimazole Propylthiouracil

I Tyrosine I I Tyrosine I

Fig. 10.4. A simplified representation of the biosynthesis of the thyroid hormones and the sites of action of the major antithyroid drugs. Note: Tyrosine represents tyrosyl residue.

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AGENTS THAT AFFECT CALCIUM METABOLISM Calcitonin

Vitamin D

This hormone is produced by the thyroid gland in the parafollicular cells. It influences the processing of calcium by bone cells through decreasing blood calcium levels and promoting conservation of hard bone matrix (inhibition of osteoclastic bone resorption,). The parathyroid hormone acts as a physiological antagonist to calcitonin to maintain calcium homeostasis.

Dietary vitamin D2 and vitamin D3 are inactive, in the liver converted to 25hydroxycholecalciferol (25-HCC) which is a major circulating metabolite but inactive. When low plasma calcium and high phosphate, PTH release is stimulated and in the kidney helps to convert 25-HCC to 1, 25dihydroxycholecalciferol (1, 25-DHCC) that is a powerfully active hormone.

Calcitonin inhibits osteoclastic bone resorption.

Activated vitamin D increases calcium absorption in the gut. In the bone, it potentiates calcium deposition in bone and used for mineralisation of new bone (increasing osteoblastic activity). Further, it plays a minor role in the kidney by increasing tubular reabsorption of calcium.

Indications of Calcitonin 1. Hypercalcaemia 2. Paget s disease of bone 3. Postmenopausal osteoporosis (treatment or prevention)

Indications of Vitamin D 1. Rickets 2. Osteomalacia 3. Hypocalcaemia 4. Hypoparathyroidism

Adverse Effects of Calcitonin 1. Skin rashes 2. GI disturbances 3. Glucose intolerance

Adverse Effects of Vitamin D Parathyroid Hormone (PTH)

1. Hypercalcaemia

PTH is released from the parathyroid glands, 4 or 5 parathyroid glands imbedded in the posterior surface of the thyroid s lateral lobes. PTH is a biological antagonist to calcitonin and acts to maintain calcium homeostasis. It acts on bone, kidney, and intestinal cells. It causes more bone to be dissolved (bone resorption, osteoclast, yielding calcium and phosphate, which enters the blood stream). It also causes phosphate to be secreted by the kidney cell into the urine to be excreted. Further, it causes increased intestinal absorption of calcium by activating vitamin D.

For selected other agents affecting calcium metabolism see Table 10.10.

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Table 10.10. A summary of agents affecting calcium metabolism and bone mineral homeostasis Agent Vitamin D

Mode of Action 1. ↑ intestinal calcium & phosphate absorption 2. ↓ renal calcium & phosphate excretion 3. ↑ calcium & phosphate osteoclastic resorption in bone 4. ↑ osteoblastic bone formation

Uses Rickets Osteomalacia Hypocalcaemia Hypoparathyroidism

Calcitonin

Inhibits osteoclastic bone resorption

Paget s disease of bone Postmenopausal osteoporosis Hypercalcaemia of pregnancy Paget s disease of bone Osteoporosis Hypercalcaemia (due to cancer) Hypercalcaemia Hypercalcaemia

Bisphosphonates (Etidronate &

↓ osteoclastic bone resorption

pamidronate)

Frusemide EDTA* Thiazides

Calcium Oestrogen

Fluoride

↑ renal calcium excretion Chelator of divalent & trivalent metals (renally excreted) ↓ renal calcium excretion (oral & parenteral)

Idiopathic hypercalciuria Hypocalcaemia

↓ the bone resorbing action of Prevention & treatment of postmenopausal osteoporosis parathyroid hormone Stabilises hydroxyapatite crystals Prophylaxis of dental caries

* EDTA (Ethylenediaminetetraacetic acid) is indicated chiefly for the chelation of heavy metals like lead, but it may also have place in poisoning by zinc, manganese etc. When used in the treatment of lead poisoning, the drug is administered as calcium disodium salt to prevent potentially life-threatening depletion of calcium.

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INSULIN AND ORAL HYPOGLYCAEMIC DRUGS 5. Thyroid hormone: hyperthyroidism → hyperglycaemia 6. Iatrogenic diabetes: corticosteroids, thiazide diuretics, and oral contraceptive pills, diazoxide (used in insulinoma)

Introduction The term diabetes mellitus encompasses a group of pancreatic endocrine-based disease states of differing aetiology and severity. Diabetes is derived from the Greek word meaning syphon, to signify the copious urine production in individuals with this affliction. The urine from some types of diabetic patients tasted sweet [a common, if unsavory, diagnostic procedure; when the blood glucose concentration falls below the renal threshold (180 mg/dL) glycosuria (sweetness) disappears] whereas that from other types was tasteless, led to the first distinction between diabetes mellitus and diabetes insipidus.

The differentiation between the two major types of diabetes mellitus Type I diabetes (IDDM): ketosis prone, juvenile onset, growth onset It is a catabolic disorder in which circulating insulin is virtually absent, plasma glucagon is elevated, and the pancreatic β-cells fail to respond to all insulinogenic stimuli. Therapy for IDDM: insulin, diet, and exercise

Twenty-five percent have Type I (insulin dependent diabetes mellitus, IDDM), 70% have Type II (non-insulin dependent diabetes mellitus, NIDD, insulin resistant ) and 5% secondary diabetes.

Type II (NIDDM): ketosis resistant, adult onset, maturity onset Circulating endogenous insulin is sufficient to prevent ketoacidosis but is often either subnormal or relatively inadequate because of tissue insensitivity. There is also a concurrent deficiency of the pancreatic β-cells response to glucose. These defects are further aggravated by increased hyperglycaemia. However, hypoglycaemic drugs and other therapeutic measures ameliorate these defects.

Secondary diabetes may be recognised in the following clinical conditions: 1. Growth hormone: in acromegaly 30% of patients are diabetics 2. ACTH and adrenocortical hormones: ACTH and cortisol (stress and physical injury) lead to increased glucose level by gluconeogenesis, and decreased utilisation of glucose by peripheral tissues, thus, a. Cushing s syndrome → diabetes mellitus b. Addison s disease → hypoglycaemia c. Hypopituitarism → hypoglycaemia

Therapy for NIDDM: diet, weight reduction, exercise, oral hypoglycaemic agents sulphonylureas, biguanides, and insulin.

Insulin

3. Adrenaline: a. Increases glycogenolysis (α & β2receptor activation) b. Decrease insulin secretion (α-receptor stimulation) Thus, phaeochromocytoma may result in hyperglycaemia. 4. Gestational diabetes: hyperglycaemia

pregnancy

Insulin is a polypeptide of 51 amino acids (molecular weight 6000) synthesised in the pancreatic β-cells as a single chain polypeptide precursor, proinsulin (molecular weight 9000). Insulin is formed by enzymatic cleavage through a trypsin like enzyme that removes a large connecting peptide (Cpeptide, molecular weight 3000). Zinc is present in the granules of β-cells forming an

→

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insoluble complex with insulin and constitutes a natural storage form. Insulin obtained from cattle and pigs is rather similar to human insulin and consequently these have a relatively low antigenicity when administered to patients (particularly pig insulin). In man the average insulin content of the pancreas is about 200 units and the daily secretion amounts to approximately 3040 units.

increase in the density of insulin receptors (up-regulation) resulting in increased responsiveness to insulin. It appears that patients with NIDDM produce abnormally high amounts of insulin and yet they are insulin resistant. Upon dieting, obese NIDDM patients may have reduced insulin secretion resulting in increased insulin receptor density, thus, regaining insulin responsiveness.

Insulin secretion is mainly related to the concentration of blood glucose. Other factors that influence insulin release are:

Action of Insulin Insulin increases the transport of glucose through the plasma membranes of most tissues (muscle, adipose tissue, but not the brain, red blood cells and tubular cells of the kidney). It acts like a key to the cell-door. Insulin favours glycogen formation, inhibits glycogenolysis and stimulates protein synthesis. It also suppresses lipolysis and makes glucose available for synthesis into fatty acids and triglycerides. Insulin increases potassium uptake that leads to a lowered plasma concentration (hypokalaemia). Insulin increases renal conservation of sodium by increasing renal tubular reabsorption. Administration of high dosage of insulin and glucose are effective for the temporary relief of hyperkalaemia in uraemia. The cellular basis for insulin action is by stimulation of specific receptors that probably reduce intracellular cAMP. For a summary of the actions of insulin see Table 10.11.

Stimulation 1. Glucose, amino acids 2. Free fatty acids 3. Ketone bodies 4. Sympathetic nervous receptor involvement) 5. β-receptor agonists 6. cholinergic agonists 7. Sulphonylureas 8. Meglitinides

system

(β-

Inhibition 1. Insulin 2. Somatostatin (a universal inhibition of secretory cells) 3. α2-adrenoceptor agonists 4. β-receptor antagonists 5. Thiazides 6. Frusemide 7. Diazoxide

Insulin is an anabolic hormone, mainly in the liver, muscle, and adipose tissue.

Insulin Receptors

Pharmacokinetics

Insulin binds to tyrosine kinase, a receptor on the surface of the target cell; after they interact, the insulin-receptor complex enters the cell. The density of insulin receptors on the surface of the target cells varies inversely with the concentration of insulin to which they are exposed. As the concentration of insulin increases the density of insulin receptors decreases resulting in decreased responsiveness to insulin ( insulin resistance ). This is known as downregulation phenomenon, whereas a decrease in insulin concentration may lead to an

Insulin must be given parenterally by injection (s.c., i.m. or i.v.). The t of insulin in the plasma is about 10 minutes, but the biological effects of the hormones reach their maximum much later since insulin is bound to the tissues. After release insulin, reaches the liver through the portal vein and there about 40% is removed from the circulation. Therefore, in order to secure an appropriate action, slow release preparations have been developed. Several compounds can be added to increase the duration of insulin action, these are zinc, protamine (Table 10.12.). 243

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Table 10.11. A summary of the metabolic effects of insulin. Note: Anabolic processes are increased while catabolic processes are decreased. Tissue Liver

Anabolic Effects (increased anabolism) Glycogen synthesis Amino acid uptake Protein synthesis

Adipose

Glucose uptake Glycerol synthesis Fatty acids synthesis Triglyceride synthesis

Muscle

Glucose uptake Glucose utilisation Glycogen synthesis Glucose oxidation Amino acid uptake Protein synthesis

Anticatabolic Effects (decreased catabolism) Glucose production Gluconeogenesis Glycogenolysis Ketogenesis (probable an indirect effect due to decreased delivery of substrate) Lipolysis Free fatty acids and glycerol release

Glycogenolysis Amino acid release Protein catabolism

3. Local fat atrophy (This is also a frequent encounter that hard to explain in terms of the defined actions of insulin, and is most likely caused by stimulation of lipolysis by contaminants, possibly glucagon, in the insulin preparations.)

Adverse Effects of Insulin 1. Hypoglycaemia: It is the major adverse reaction. It is caused by excessive insulin dosage, a missed or late meal or by excessive exercise. Therefore, the diabetic should always carry quick-acting oral glucose tablets. The unconscious patient should be given 20 ml of 50% dextrose i.v., together with glucagon. Prolonged severe hypoglycaemia reactions may require 10-20% dextrose infusions over 24-48 hours or longer, together with highdose steroids, e.g. dexamethasone (2 mg i.m. 4 hourly) and 20% mannitol i.v. over 20 minutes, to reduce cerebral oedema. Unfortunately, if treatment is delayed, some diabetics may develop irreversible brain damage and death may occur.

4. Insulin allergy (An immediate type hypersensitivity, characterised by local or systemic urticaria, or even in severe cases anaphylaxis may result. This sensitivity is often due to non-insulin minor protein contaminants, or to one of the components added to insulin in its formulation (protamine, Zn++, phenol.) 5. Immune insulin resistance (antigenic, a high titre of circulating IgG anti-insulin antibodies develops) 6. Peripheral oedema (Na+ retention is primarily responsible for oedema that usually disappears spontaneously within several days)

2. Local fat hypertrophy (This is presumably caused by the action of insulin to promote triglyceride accumulation in fat cells.)

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Table 10.12. A summary of the pharmacokinetic parameters of selected insulin preparation Insulin Preparation Onset ULTRA-SHORT ACTING Lispro insulin, Aspart insulin (Insulin analogues) SHORT-ACTING Insulin injection (Regular, soluble) Prompt insulin zinc suspension (Semilente) INTERMEDIATE-ACTING Isophane insulin suspension (NPH) Insulin zinc suspension (Lente) LONG-ACTING Protamine zinc insulin suspension Extended zinc insulin suspension (Ultralente)

Action (hr) Peak Duration

0.25

0.5-1.5

3-4

0.5-1 1

2-3

5-7 14

1-1.5 1-2

8-12 8-18

18-24 18-24

4 4-8

10-30

36 36 plus

Human insulin is now being manufactured either by the genetic manipulation of Escherichia coli (recombinant or biosynthetic human insulin). Isophane insulin is also known as neutral protamine Hagedorn, NPH, is a suspension of crystalline zinc insulin combined at neutral pH with the positively charged polypeptide, protamine. Lente insulin is a mixture of 30% semilente insulin and 70% ultralente insulin providing a relatively rapid absorption, with a prolonged action making it the most commonly used among the lente series of insulin.

cells, voltage-gated Ca++-channels open in response to depolarisation allowing more calcium to enter the cell. Consequently, increased intracellular calcium results in increased insulin release. Further, chronic administration of sulphonylurea drugs reduces serum glucagon concentration. It has been suggested that sulphonylureas produce this effect through increasing the release of both insulin and somatostatin, which inhibit α-cell secretion. In addition, sulphonylureas may exert extra-pancreatic actions by increasing binding of insulin to tissue receptors, thus, potentiating insulin action. An intracellular (post-receptor) site of action for sulphonylureas have also been implicated.

Oral Hypoglycaemic Drugs Therapy with oral hypoglycaemic drugs is usually effective only in type II diabetic patients who fail to respond satisfactorily to dietary measures alone.

Sulphonylurea Drugs Sulphonylureas have been successfully used for over 30 years. They include tolbutamide, chlorpropamide, glibenclamide, and glibezide, for more details see Table 10.13. They appear to have stimulatory effects on βcells to increase basal and glucose-stimulated insulin secretion. It has been suggested that sulphonylureas block ATP-gated K+channels in the pancreatic β-cells, and thus, causing depolarisation of the cell resulting in increased excitability of the cell, and hence, increased release of insulin. Similar mechanisms of action have been proposed for glucose in promoting the release insulin. After entry into the β-cell, glucose increases the production of ATP leading to closure of the ATP-gated K+-channel and depolarisation of the β-cell occurs. As in most secretory

Sulphonylurea drugs may produce their hypoglycaemic action by: 1. Blocking causing enhanced 2. Promotes 3. Reducing

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K+-channels in the ¾-cells depolarisation and thus release of insulin. insulin exocytosis serum glucagon levels.

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4. Increasing binding of insulin to target tissue receptors.

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1. Direct stimulation of glycolysis in tissues, thus, increased glucose removal from circulation. 2. Reduced hepatic gluconeogenesis 3. Inhibiting glucose absorption from the gastrointestinal tract 4. Reducing plasma glucagon levels

Adverse Effects of Sulphonylureas 1. Hypoglycaemia 2. Gastrointestinal disturbances 3. Haematological disturbances (transient leucopenia, thrombocytopenia) occur in less than 1% of patients, particularly, with chlorpropamide. 4. Disulfiram-like reaction (particularly with chlorpropamide)

The use of metformin is restricted to type II patients who appear to develop resistance to sulphonylureas, although insulin is generally thought to be a better alternative.

Adverse Effects of Biguanides 1. Gastrointestinal disturbances (anorexia, nausea, vomiting, abdominal discomfort, diarrhoea; occur in 20% of patients and are often transient.) 2. Reducing vitamin B12 absorption 3. Lactic acidosis

Sulphonylureas are contraindicated in hepatic and renal insufficiency. Interactions with other drugs that compete with serum binding sites (phenylbutazone or salicylates).

Meglitinides Alpha-Glucosidase Inhibitors Meglitinides are relatively a new generation of oral antidiabetic agents, acting primarily via stimulating insulin release by closing ATP-sensitive potassium channels in pancreatic cells. In effect, they Amplify the insulin secretory response to a glucose load with virtually no effect in the presence of normoglycemia. Unlike the sulfonylureas,

The prototype of this is acarbose that is an oligosaccharide analogue that binds with 1000 times more ability than natural carbohydrates to the intestinal disaccharidases like α-glucosidase. This inhibition of α-glucosidase reduces the postprandial rise of glucose resulting in an insulin sparing action.

they have no direct effect on insulin exocytosis. They affect only postprandial insulin profiles. Dosing is recommended immediately before having a meal, and thus omit dose when skipping a meal. Suitable in

Biguanides are contraindicated in renal disease, hepatic disease, alcoholism, or conditions predisposing to tissue anoxia (e.g. chronic obstructive pulmonary disease), because of increased risk of lactic acidosis in the presence of these conditions.

individuals with sulfur or sulfonylurea allergy. This class of antidiabetics are represented by repaglinide and nateglinide.

Biguanides Aldose Reductase Inhbitors

Biguanides are more appropriately described as euglycaemic rather than hypoglycaemic drugs. This is because glucose is not lowered in normal subjects after an overnight fast, but their postprandial blood glucose levels are lower during biguanide administration. There are several possible mechanisms proposed for the antihyperglycaemic action of biguanides.

The conversion of glucose to fructose and in turn to sorbitol is believed to contribute to the toxic effects of hyperglycaemia (glucose toxicity). Therefore, aldose reductase inhibitors like tolrestat are targeted at inhibiting cellular conversion of glucose to

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fructose and consequently reducing glucose toxicity in tissues like the eye and the kidney.

Glucagon Glucagon is useful in insulin hypoglycaemic crisis (1 mg, i.m., s.c.) while in acute overdose of β-blockers (5-10 mg i.v. for positive inotropic and positive chronotropic effects).

Glitazones This recent group of antidiabetic drugs is believed to produce its hypoglycaemic activity primarily by increasing tissue sensitivity to insulin. This class of drugs is represented by pioglitazone and rosiglitazone that have been recommended for insulinresistant patients who are receiving insulin.

Table 10.13. A summary of parenteral and oral antidiabetic drugs. Drug

Mode of Antidiabetic Action

Adverse Effects and Important Remarks

PARENTERAL

Insulin

Acts like a key to cell-door promoting the transport of glucose through the plasma membranes of most tissues. Insulin is an anabolic hormone, mainly in the liver, muscle, and adipose tissue

Hypoglycaemia Local fat hypertrophy Local fat atrophy Insulin allergy Immune insulin resistance Peripheral oedema

Blocking ATP-sensitive K+channels in the β-cells causing depolarisation and thus enhanced release of insulin. Promote insulin exocytosis Reducing serum glucagon levels. Increasing binding of insulin to target tissue receptors.

Hypoglycaemia GI disturbances Haematological disturbances (chlorpropamide) Disulfiram-like reaction (chlorpropamide)

ORAL Sulphonylureas

Tolbutamide (Orinase )

Chlorpropamide

4

24

2-3 daily doses, safe, inactivated by hepatic oxidation

8

1 daily dose at breakfast, less safe, avoid in elderly, renal & hepatic failure [largely excreted changed, & unchanged (20-30%) by the kidney]

72

(Diabinase )

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Glibenclamide (Daonil )

Glipizide

10

24

3

8

Repaglinide

Nateglinide

1-2 daily dosing

Blocking ATP sensitive K+channels in the β-cells causing depolarisation and thus enhanced release of insulin.

Meglitinides

1

1

3

3

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It affects only postprandial insulin profiles. Omit dose if skip a meal. Suitable in

individuals with sulfur or sulfonylurea allergy. tmax 1 hr,

Amplifies the insulin secretory response to a glucose load with virtually no effect in the presence of normoglycemia

tmax <1 hr, 1-10 minutes before meal, useful in isolated

postprandial hyperglycemia, least hypoglycaemic action, dose

titration is not required.

Biguanides

Metformin (Glucophage®)

5

12

Direct stimulation of glycolysis in tissues Reduced hepatic gluconeogenesis Inhibiting glucose absorption from the GIT

Reducing plasma glucagon levels

Aldose Reductase Inhibitors Tolrestat

Glitazones

Lactic acidosis

Inhibition of α-glucosidase reduces the postprandial rise of glucose resulting in an insulin sparing action.

¿-Glucosidase Inhibitors

Acarbose

GI disturbances (anorexia, nausea, vomiting, abdominal discomfort, diarrhoea; 20% of cases) Reducing vitamin B12 absorption (megaloblastic anaemia)

2

Flatulence (20-30%, caused by lower bowel undigested carbohydrate) Inhibit aldose reductase →↓ intracellular conversion of glucose to sorbitol →↓ fructose →↓ glucose toxicity Sensitise tissue to insulin

Useful in insulin resistant patients Weight gain Oedema

Pioglitazone Rosiglitazone In pregnancy: Sulphonylureas can traverse the placenta and act on the islet cells of the pancreas of the foetus to deplete them of insulin, thus, the infant is born hypoglycaemic; insulin does not pass through the placenta; there is a greater demand for insulin in pregnancy than can be provided by sulphonylureas. Therefore, a pregnant diabetic woman is usually switched from oral hypoglycaemic drugs to insulin.

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ATP-sensitive K+ channel

Sulphonylureas Promote Meglitinides

K+

Block

ATP

Depolarize

Prevents

Diazoxide

Glucose transporter

Ca++

Glucose

Voltagesensitive Ca++ channel

Sulphonylureas Promote

Insulin exocytosis

Fig. 10.5 . A simplified representation of control of insulin release from the pancreatic cell by glucose, sulfonylureas, meglitinides, diazoxide. In the resting cell with normal (low) ATP levels, potassium exists via ATP-sensitive K+ channels, maintaining the intracellular potential at a fully polarized, negative level (low excitability). Insulin release is minimal. When glucose concentration rises, ATP production increases, potassium channels close resulting in depolarization of the cell. As in other excitable cells like muscle and nerve ones, voltage-sensitive Ca++ channels open in response to depolarization, allowing more Ca++ to enter the cell. Increased intracellular free Ca++ results in increased insulin secretion. Insulin secretagogues close the ATP-sensitive K+ channel, thereby depolarizing the membrane and causing increased insulin release by promoting the action of the effect of hyperglycaemia (glucose → ATP → closure of ATP-sensitive K+ channels). On the other hand, diazoxide appears to interacts with the ATP-sensitive K+ channel and either prevents its closure or prolongs the open time. Sulphonylureas appear to have an independent additional secretagogue action through promoting the insulin exocytotic process.

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ANTICANCER DRUGS vary in their ability to do so, e.g. cisplatin does not induce drug resistance.

Introduction The principle of treating cancer with drugs has some similarities with antibiotic treatment of bacterial infection. The objective is to reduce the number of hostile cells but the difference is that natural defenses of the body is much weaker in case of malignant cells as compared to the immunological mechanisms in infections. Therefore, it is essential to kill tumour cells with cancer chemotherapy whereas it may be enough to reduce the number of bacteria with antibiotics.

Resistance is delayed when combination therapy is used. Combination therapy may also have the advantage of synergism (1+1=3) rather than the additive effect (1+1=2). Therefore, these days a combination of 2-6 drugs is given in intermittent pulses to achieve total tumour cell kill, giving time in between for normal cells to recover. Optimum synergism can be achieved by selecting the appropriate combination of:

Cell cycle specificity

1. Drugs which are effective when used alone 2. Drugs with different mechanisms when used alone 3. Synchronising the active cell cycle 4. Drugs with differing toxicities (giving drugs that do not suppress bone marrow in between courses of those that do. The normal tissue toxicity that limits further escalation of dose is the dose-limiting toxicity and this is the maximum tolerated dose. Hence, drug with different doselimiting toxicity is preferred in combination) 5. Empirically by trial and error

In addition to the differences in biochemical mechanisms of action, anticancer agents differ in the point in the cell cycle at which they inhibit cell growth and replication. Those drugs, which kill a cell whether it is cyclic or at rest are said to be cycle-non specific, e.g. glucocorticoids. While other agents kill only cells that are actively cycling, usually because their site of action is restricted to one part of the cell cycle, and are therefore called cyclespecific, e.g. antimetabolite drugs and spindle poisons. Further, some agents can be cycleactive phase-non-specific, e.g. alkylating agents.

All cytotoxic drugs with antitumour activity probably exert their effects by impairing the synthesis or function of nucleic acids (DNA). Cells most susceptible to cytotoxic drugs are those with a mitotic rate. Most tumour cells grow rapidly but the turnover rate of bone marrow cells, intestinal mucosa and epidermis, including hair follicles is as rapid and therefore these cells are susceptible to cytotoxic drugs. This explains the side effects: infections, bleeding, enteritis, and alopecia.

Drug Resistance Drug resistance is a feature typical not only to bacterial cells but also to tumour cells because of emergence of resistant cell variants; multiple drug resistance is now becoming a major problem. Drug resistance is believed to be mediated through the development of an active extrusion process of the anticancer agents from the cancer cell. It has been suggested that an ATP-dependent membrane efflux pump acting via a protein called P-glycoprotein, developed as a protective mechanism against environmental toxins. Anticancer agents appear to induce the expression of P-glycoprotein; however, they

Examples for Combination Therapy Non-Hodgkin s Lymphoma

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A combination of four drugs is used in one regimen for the treatment of non-Hodgkin s lymphoma. This combination is known as CHOP, the latter stands for cyclophosphamide, hydroxydonorubicin (doxorubicin), Oncovin (vincristine), and prednisone. It is worth noting that:

The most common agents of this group are cyclophosphamide, busulphan, chlorambucil, and platinum compounds like cisplatin. Generally, these agents cause nausea and vomiting, and bone marrow depression; male infertility and premature menopause may also occur. However, a specific toxicity may appear with cyclophosphamide, which causes haemorrhagic cyctitis, and busulphan, which causes pulmonary fibrosis.

1. These drugs produce cytotoxicity by different mode of action. 2. The first three agents are capable of inducing complete response when given alone. 3. None of these agents would be expected to exhibit cross-resistance.

Antimetabolites These cytotoxic agents are structural analogues of normal metabolites, being incorporated in the S-phase of cell cycle and, thus, deceiving bodily processes.

Acute Myeloid Leukaemia For this type of leukaemia (AML) usually two drugs are used daunorubicin and cytarabine.

Methotrexate

Adjuvant Use

Methotrexate is a folic acid antagonist, competitively inhibits dihydrofolate reductase, thus, preventing the conversion of folic acid to folinic acid (the coenzyme responsible for the synthesis of amino and nucleic acids). When a maximum effect is desired, a special manoeuvre is followed with the use of methotrexate. A potentially fatal dose of methotrexate is administered and followed 24 hours later by a dose of tetrahydrofolic (folinic) acid as calcium folinate (Ca leucovorin) to terminate the action of methotrexate. This is known as folinic acid rescue . Because it is life saving, if folinic acid not given, the patient will die. It appears that bone marrow cells recover better than tumour cells, thus, some degree of useful selectivity is utilised.

Adjuvant use of anticancer drugs after definite surgical resection, e.g. in breast cancer, fluorouracil, adriamycin (doxorubicin), and cyclophosphamide.

Anticancer Drugs 1. Alkylating agents 2. Antimetabolites 3. Cytotoxic antibiotics 4. Spindle poisons 5. Biological agents 6. Hormones (or antagonists) 7. Miscellaneous agents

Alkylating agents

Methotrexate is predominantly renally excreted; therefore, patients with impairment require dose adjustment. Methotrexate can precipitate in the distal renal tubule when urine is acidic, therefore, a prior hydration and alkalinisation of urine are essential. Further, cytotoxic agents including methotrexate cause tumour lysis syndrome (characterised by metabolic derangements including hyperuricaemia)

These compounds which can introduce an alkyl group to DNA in the N-7 position of guanine during cell division. Thus, these agents cause either DNA strand breakage or c cross-linking of the two strands so that normal synthesis is prevented. Alkylating agents are mostly for treatment of leukaemias and solid tumours. The original agents were called nitrogen mustards.

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Purine Antagonists Vinca Alkaloids Azathioprine (Imuran ), mercaptopurine, thioguanine,

Vinca alkaloids comprise alkaloids extracted from the plant periwinkle, represented by vincristine and vinblastine. They inhibit microtubule assembly and cause cell cycle arrest in mitosis at the M-phase.

Pyrimidine Antagonists Cytarabine, fluorouracil, and fludarabine interfere with the production of essential metabolites. Cytarabine is particularly useful in acute myeloid leukaemia. This drug is usually given by continuous intravenous infusion over 5 to 7 days. With this regimen better therapeutic effects and less adverse effects are observed compared with that when given in bolus doses.

Taxanes This subgroup is represented paclitaxel; they act by stabilising microtubules and thereby preventing their disassembly.

Epipodophylotoxins This subgroup is represented by etoposide; they interact with topoisomerase II. This enzyme is capable of producing and repairing DNA-double strand breaks. Etoposide enhance DNA cleavage by inhibiting reunion activity of this enzyme leading to DNA fragmentation and ultimately cell death.

Adverse Effects of Antimetabolites 1. Gastrointestinal upsets stomatitis, & ulceration) 2. Bone marrow depression

(e.g.

Renal impairment increases their toxicity, particularly, methtrexate. Salicylates block active excretion of methotrexate by renal tubules, in addition, salicylates displace methotrexate from plasma binding proteins.

Adverse Effects 1. Bone marrow depression 2. Alopecia 3. Peripheral neuropathy (which limits the total dose of vincristine)

Cytotoxic Antibiotics These agents interfere with DNA and RNA replication and protein synthesis. They are represented by bleomycin, dactinomycin, adriamycin, doxorubicin, plicamycin, and daunorubicin.

Biological Agents Interferons and more recently interleukins are used in hairy cell leukaemia and Kaposi s sarcoma.

Adverse Effects Hormones (or Antagonists) 1. Gastrointestinal upsets 2. Bone marrow depression 3. Alopecia 4. Cardiomyopathy (doxorubicin) 5. Pulmonary fibrosis (bleomycin)

Hormones can also be used in malignant disease arising from tissues such as the mammary gland, uterus and prostate whose normal growth is dependent on hormones. Tamoxifen is an antioestrogen compound especially useful in postmenopausal breast cancer. Androgens are useful in some premenopausal breast cancer. Cyproterone (antiandrogen) is useful in prostatic cancer.

Spindle Poisons This group includes a number of drugs collectively being plant alkaloids. These are divided into three subgroups according to their cytotoxic mode of action.

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ability to suppress cell division, particularly in lymphocytes, it supprsses both cellular immunity and antibody formation. Glucocorticoids are useful in acute leukaemias, Hodgkin s and other lymphomas. They induce rapid remission and control complications like hypercalcaemia, haemolysis, and increased intracranial pressure.

lymphokine genes, thus inhibiting the production of lymphokines by T lymphocytes that mediate specific recognition of alien molecules. Therefore, cyclosporin A does not have an effect on non-specific functions, like that of granulocytes, that are responsible for phagocytosis and metabolism of foreign substances. Further, cyclosporin A does not depress haemopoiesis. These drugs have also been used to cause immunosuppression in autoimmune, collagen and connective tissue diseases which include inflammatory bowel disease, rheumatoid arthritis, chronic active hepatitis, systemic lupus erythematosus (SLE), glomerulonephritis, nephrotic syndrome, some haemolytic anaemias and thrombocytopenias, uveitis, myasthenia gravis, polyarteritis, polymyositis, systemic sclerosis.

Miscellaneous Compounds Crisantapase (asparginase) deprives tumour cells, which are dependent upon a supply of the amino acid aspargine (and not being able to synthesise it themselves). The use of asparginase is largely limited to acute lymphoblastic leukaemia. Other agents like hydroxyurea that has antitumour activity by inhibiting formation of deoxyribonucleotides.

Immunostimulant Therapy

Immunotherapy

The principle of immunotherapy is to increase the body s own defense system such as generation of antibodies and interferon.

Immunosuppressive Therapy Cytotoxic cancer chemotherapeutic drugs have also been used in organ transplantation in order to prevent rejection, e.g. glucocorticoids (prednisolone), azathioprine (antimetabolite, Imuran ), alkylating agents (e.g. cyclophosphamide and chlorambucil), cyclosporin A, and antilymphocyte immunoglobulin. Except cyclosporin A, all these agents cause non-specific immunosuppression so that the general defenses of the body against infections are impaired.

The importance of the immune system for the development of cancer comes from the observation that immunodeficient patient and patients who are immunosuppressed by drugs such as azathioprine for organ transplantation easily develop cancer. This is probably due to the immunosuppression, induced by cytotoxic agents, abolishes what little natural immune resistance that there may be to a tumour. Agents that increase immunological responses are bacterial vaccines such as BCG (Bacille Calmette-Guerin) instilled in the urinary bladder for bladder cancer, and the immunostimulant levamisole (anthelminthic) which appears to enhance the function of phagocytes and T lymphocytes when this is subnormal. Levamisole is also useful in immune deficiency states.

Cyclosporin A is a polypeptide obtained from a soil fungus of Norway (1969). This drug has a selective and reversible action against T lymphocyte, which are the cells that play a central role in the induction of immune responses. This selectivity of action is believed to be due to inhibiting the transcription of interleukin-2 and other

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Anticancer Drugs

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Table 11.5. A summary of the pharmacology of anticancer drugs

Drug Group

Mode of Action

Important Remarks

Alkylating Agents Cyclophosphamide Busulphan Chlorambucil Platinum compounds (cisplatin)

Cycle-active phase non-specific; they introduce alkyl groups to DNA causing either DNA strand breakage or crosslinking of the two strands, thus, preventing normal synthesis.

Useful in leukaemias & solid tumours; specific adverse effects: [cyclophosphamide: haemorrhagic cystitis], [busulphan: pulmonary fibrosis], [cisplatin: nephrotoxicity)

Antimetabolites

Cycle & phase specific

Methotrexate

Dihydrofolate inhibitor

Distal renal tubular toxicity

Azathioprine Mercaptopurine Thioguanine

Purine antagonists

[mercaptopurine & thioguanine for haematological malignancies]

Cytarabine Fludarabine Cytotoxic Antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Spindle Poisons Vinca Alkaloids Vincristine Vinblastine

Pyrimidine antagonists

Taxanes Paclitaxel Epipodophylotoxins Etoposide Biological Agents Interferon α2 Interleukin 2 Hormones (or Antagonists) Glucocorticoids

Inhibit microtubule disassembly

Tamoxifen

Antioestrogen

Breast cancer

Goserelin Flutamide Cyproterone

GnRH agonist Antiandrogen Antiandrogen

Prostatic cancer

Deprives tumour cells of aspargine

Acute lymphoblastic leukaemia

Inhibits DNA formation

For myeloid proliferative disorder

Miscellaneous Agents Crisantapase (asparginase) Hydroxyurea

Interfere with DNA & RNA replication and protein synthesis.

Cycle & phase specific Inhibit microtubule assembly

[bleomycin: pulmonary fibrosis], [doxorubicin: cardiomyopathy]

[vincristine: peripheral neuropathy], [vinblastine: bone marrow depression] [paclitexal: reaction]

hypersensitivity

Inhibit topoisomerase II, inhibit reunion activity of this enzyme Hairy cell leukaemia sarcoma

Kaposi s

Cycle-non-specific

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DRUG INTERACTIONS, ADVERSE DRUG REACTIONS AND ANTIDOTES bear clinical implication manifested reduced therapeutic efficacy.

DRUG INTERACTIONS Interactions between drugs can occur when two drugs or more agents are administered concurrently. This may lead to altered pharmacological or therapeutic effects of the drugs in question. The changes due to such interactions could be either a decrease in the desired effect, increased plasma levels of the free drug or prolongation of t of the drug. Such drug interactions are classified into two main types: pharmacokinetic and pharmacodynamic ones.

by

2. Hepatic enzyme induction Most drugs undergo hepatic phase I metabolism by mixed function oxidases (cytochrome P450 oxidase) found in the endoplasmic reticulum. Certain drugs can enhance mixed function oxidase enzyme activity. Such hepatic enzyme inducers include all barbiturates, rifampicin, carbamezapine, phenytoin, chronic acohol consumption. Thus, hepatic enzyme inducers decrease plasma levels of drugs like warfarin, see page 66.

PHARMACOKINETIC INTERACTIONS

• Increased drug systemic availability

Drug incompatibility of ampicillin, chlorpromazine with dextran solutions, i.v., takes place as a result of drug breakdown or chemical complex formation. Tetracycline combines with cations like calcium present in dairy product (like yogurt) and some antacids or aluminium presents in antacids forming insoluble complexes which are not absorbed giving reduced systemic delivery of the drug. Pharmacokinetic interactions can also increase systemic availability of drugs.

1. Competitive protein binding Drug interactions influence the distribution of drugs as a result of competitive plasma protein binding. An increase in plasma free drug concentration due to displacement of plasma protein bound drug can result in changes in pharmacological effects. For example, the strongly bound drug clofibrate displaces warfarin that may result in haemorrhage due to enhanced inhibition of prothrombin synthesis in the live.

• Decreased drug systemic availability

2. Inhibition of drug metabolism 1. Impaired gastrointestinal absorption Drug clearance can be reduced by inhibition of drug metabolism resulting in accumulation and prolonged t . Such excessive accumulation a drug can lead to adverse effects. For example, the oxidative metabolism of the low therapeutic index drugs like warfarin, theophylline and phenytoin can be inhibited by cimetidine, erythromycin and ciprofloxacin. Such interactions can lead to complications with adverse effects particularly with drugs characterized by low therapeutic index. These complications can be controlled by monitoring plasma drug concentration (known as therapeutic drug monitoring,

The antihyperlipidaemic agent cholestyramine, an ion exchange resin, binds to drugs like thyroxine and digoxin and hence blocking their absorption. As mentioned above antacids interact with tetracycline, and kaolin-pectin with digoxin resulting in reduced intestinal absorption. There a number of factors which influence absorption of drugs (see section on absorption of drugs, page 7) that can reduce delivery of drugs to the systemic system and hence resulting in reduced both peak plasma concentration and steady state concentration (Css). Consequently, this type of interaction may

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TDM) and altering the dosage regimen accordingly.

Ramadi, 11 October 2009

excessive effect. For example, an antihypertensive agent like the calcium channel blocker nifedipine, when used in elevated arterial blood pressure, can lead to hypotension as an adverse reaction by virtue of excessive pharmacological action as a vasodilator. The magnitude of the adverse reaction is further extended when drugs are taken during pregnancy, lactation or the presence of co-morbid conditions, e.g. the coexistence of arterial hypertension and asthma in the same patient will render the antihypertensive agent propranolol to be contraindicated in this patient.

3. Inhibition of renal elimination Clearance of drugs can be reduced by inhibiting renal elimination. For example, penicillin undergoes renal elimination largely by renal tubular secretion (into the tubular lumen) which is inhibited by probenicid. This interaction is advantageous as it results in accumulation of penicillin (characterized by high therapeutic index) in blood and prolonging its t . This can be desirable in certain clinical conditions where therapeutically high blood penicillin levels are required. Such interaction can be undesirable in other clinical conditions, e.g. quinidine can inhibit the renal elimination of digoxin and thus may result in cardiac arrhythmias if quinidine is administered concomitantly with digoxin.

The known pharmacological actions of drugs can be altered (decreased or increased) by interaction of a number of factors, e.g. pharmacokinetic and pharmacodynamic ones, see above. Such alterations can be predicted and controlled. To achieve this, therapeutic drug monitoring approach can be used as a guide for appropriate dosage regimen adjustment. This approach is essential particularly when using drugs characterized by having low therapeutic index, i.e. with low margin of safety such as digoxin, phenytoin, lithium, procainamide, and theophylline.

PHARMACODYNAMIC INTERACTIONS Pharmacodynamic interactions are those in which the responsiveness of the target organ or receptor or the physiological system is modified by concomitant administration of the second agent. This type of interaction can lead to a physiological change in the intra or extra cellular environment. For example, hypokalaemia induced by diuretics can promote digitalis toxicity; while the diuretic effect of diuretics can be antagonized by NSAIDs like aspirin. Further, pharmacodynamic interaction can be expressed by chemical inactivation as in the neutralization of heparin's action by protamine heparin binding. Pharmacodynamic interaction may also be expressed as a drug can enhance the action of another drug through different mechanism(s); for example, alcohol enhances the CNS depression of sedatives and hypnotics.

For simplicity purposes, adverse drug reactions are generally clinically viewed in the following five types: Type A: (Augmented) reactions are the most frequently encountered in clinical practice when enough of the drug is given because they are due to excess of normal, predictable, dose-related, pharmacodynamic effects, e.g. postural hypotension, hypoglycaemia, and hypokalaemia. Type B: (Bizarre) reactions are encountered only in some people. They are not due to excess of the normal pharmacodynamic effects of the drug, are not dose-related and are due to unusual attributes of the patient interacting with the drug. These effects are usually unpredictable but with mostly known incidence. These reactions include unwanted effects due to inherited metabolic abnormalities (idiosyncrasy) and abnormal immune responses. These account for most drug fatalities, for example, chloramphenicol can produce aplastic anaemia (a life threatening morbidity).

ADVERSE DRUG REACTIONS All drugs are associated with unavoidable unwanted effects, usually as an extension of its normal pharmacological effects, i.e. 256

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2. Abnormal immune response: This can be manifested as specific hypersensitivity reactions shown by individuals to a particular drug. These reactions are the resultant of the interaction of drug or metabolite (or an excipient substance in the formulation) with patient and disease, and subsequent reexposure. Four types of hypersensitivity reactions to drugs are generally described:

Type C: (Chronic) reactions due to long-term exposure, e.g. analgesic nephropathy, dyskinesias with levodopa. Type D: (Delayed) effects following prolonged exposure, e.g. carcinogenesis or short-term exposure at a critical time, e.g. teratogenesis.

A.Type I reactions: that occurring within minutes (anaphylactic/immediate) when a sensitized individual is reexposed to antigen, resulting from interaction of IgE and the antigen. This gives rise to clinical manifestations including urticaria and bronchospasm as with penicillins. B. Type II reactions: some drugs can stimulate antibody production as a result of their molecular characteristics by combining with a protein in the body so that the body no longer recognises the protein as self and thus forming antibodies that combine with the antigen and activate complement that damages cells (haemolysis occurs) as in penicillin and methyldopa induced haemolytic anaemia. Further, hydralazine and procainamide can chemically alter nuclear material that can stimulate formation of antinuclear antibody and may cause lupus erythematosus. Furthermore, thrombocytopenia due to quinidine and agranulocytosis due to a number of other drugs which can be explained on the basis of autoimmune reactions. C.Type III reactions: serum sickness to a drug is associated with IgG immunoglobulins. For example, penicillin is well known to cause serum sickness as a result of deposition of circulating drug antibody complex on endothelial cell surface of tissues, which release histamine that can produce anaphylaxis characterized by hypotension, urticaria, wheezing and rhinorrhoea. These reactions also include glomerulonephritis, vasculitis, and pulmonary disease. D. Type IV reactions: contact dermatitis is cell mediated allergy arising out of topical application of a drug. Antigen-specific receptors develop on T-lymphocytes. Subsequent administration leads to a local or tissue allergic reaction.

Type E: (Ending of use) reactions, upon abrupt discontinuation of chronic therapy, e.g. of adrenal steroid causing rebound adrenocortical insufficiency, of -blockers causing propranolol withdrawal syndrome, of alcohol causing alcohol withdrawal syndrome. Adverse and toxic reactions of drugs can be produced by actions unrelated to the normal (wanted) pharmacological actions of the drugs as describe above. These types of reactions may further be classified according to the nature of action into the following: 1. Cytotoxic reactions: some drugs can undergo metabolic activation to reactive metabolites. Such a process usually takes place in the microsomal mixed function oxidase system of the hepatic enzymes. These reactive metabolites may covalently bind to the tissue macromolecules causing tissue damage. For example, isoniazid is largely metabolized by acetylation to acetylisoniazid which in turn undergoes hydrolysis producing acetylhydrazine. Further metabolism of the latter by mixed function oxidase system results in reactive metabolites that covalently bind to hepatic macromolecule causing hepatic necrosis. Hence, a concomitant administration of hepatic enzyme inducers like phenobarbital with isoniazid can result in liver damage. This explanation is also applicable to paracetamol overdose induced hepatic and renal necrosis, see page 191. Usually these reactive metabolites are removed by hepatic glutathione. When glutathione is exhausted the reactive metabolites bind to hepatic macromolecules resulting in hepatic damage. Glutathione itself poorly penetrates cells but Nacetylcysteine (i.v.) and methionine (orally) are effective precursors for the synthesis of glutathione.

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other of the enzymes that convert the various porphyrins to haem is deficient and thus porphyria is characterized by overproduction, accumulation and excretion of intermediates of haem biosynthesis. Porphyria is life threatening and is precipitated by a variety of drugs, hormones and other agents. Porphyria exacerbation can be shown by barbiturates, chlordiazopoxide, chorpropamide, oestrogen, griseofulvin, phenytoin and rifampicin. During an attack there is increased urinary excretion of delta-aminolaevulinic acid and porphobilinogen.

3. Derangement in the metabolic functions: Drug toxicity can be associated with enzymatic defects such as deficiency of glucose-6-phosphate dehydrogenase (G6PD) can induce haemolytic anaemia with a number of drugs such as primaquine, dapsone, nalidixic acid, nitrofurantoin and probenicid. Another drug toxicity associated with enzymatic defects is observed in different porphyrias which may be erythropoietic or of hepatic origin acquired by disturbances in haem biosynthesis. Porphyrins are tetrapyrrole intermediates formed from delta-aminolaevulinic acid and porphobilinogen, the ferrous ion complex of porphobilinogen (haem) serves as prosthetic group for haemoprotein like haemoglobin. However, in people with porphyria one or

Table 11.1. Selected specific antidotes, poison(s), modes of action and important remarks. Antidote

Poison(s)

Mode of action & remarks

N-acetylcysteine

Paracetamol

Methionine Pralidoxime (2PAM)

Paracetamol Cholinesterase inhibitors, e.g. organophosphorus insecticides Cholinesterase inhibitors, e.g. organophosphorus insecticides

Atropine

Atropine Propranolol

Isoprenaline Glucagon

Benzhexol Desferrioxamine Digoxin-specific antibody fragments (FAB) Calcium

-blocker poisoning -adrenoceptor agonists, ephedrine, theophylline, thyroxine -blocker poisoning -blocker poisoning

Drug-induced movement disorders Iron Digitalis glycosides

Calcium channel blockers

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Replenishes depleted glutathione stores. Best results if given within 8 10 hrs of overdose. It can be given successfully orally (Mucomyst) and intravenously. Replenishes depleted glutathione stores Competitively reactivates cholinesterase

Blocks muscarinic cholinoceptors. A test dose of 1 2 mg (for adult) is given intravenously and repeated until symptoms of atropinism appear (tachycardia, dilated pupils). Dose may be repeated every 10 15 minutes, with decrease of secretions as therapeutic objective. Vagal block accelerates heart rate. Blocks -adrenoceptors

Competes for -adrenoceptors Bypasses blockade of the -adrenoceptor; stimulates cyclic AMP formation with positive cardiac inotropic effect via stimulation of glucagon receptors. 5 10 mg intravenously bolus may reverse hypotension and bradycardia that was resistant to -agonist drugs. Blocks muscarinic cholinoceptors; alternatively use diazepam Chelates ferrous ions Binds free glycoside in plasma, complex excreted in urine, indicated in serious arrhythmias, hyperkalaemia. One vial binds 0.5 mg digoxin. It provides a rapid increase in extracellular calcium that helps overcome calcium channel

Essentials of Medical Pharmacology

Dimercaprol (BAL) Penicillamine Sodium edetate Ethanol

calcium

Majid A.K. Lafi

Arsenic, copper, gold, lead, inorganic mercury Copper, gold, lead, elemental mercury (vapour), zinc Lead Ethylene glycol, methanol

Flumazenil Naloxone Folinic acid (Leucovorin) (Folinic acid rescue, 24 h later) Neostigmine

Benzodiazepines Opioids Folic acid antagonists e.g. methotrexate, trimethoprim

Phenoxybenzamine

hypertension due to adrenoceptor agonists, e.g. with MAOI, clonidine, ergotamine. As above

Phentolamine Vitamine K1 Protamine sulphate Oxygen

Antimuscarinic drugs

Coumarin (warfarin) and indandione anticoagulants Heparin Carbon monoxide

Sodium bicarbonate

Membrane-stabilizing cardiotoxic drugs (tricyclic antidepressants, quinidine, etc)

Sodium bicarbonate

Aspirin (salicylate, moderate intoxications)

Sodium nitrite plus sodium thiosulphate

Cyanide

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blockade. Chelates metal ions Chelates metal ions Chelates lead ions Competes for alcohol and acetaldehyde dehydrogenases, preventing formation of toxic metabolites Competes for benzodiazepine receptors Competes for opioid receptors Bypasses block in folate metabolism

Inhibits acetylcholinesterase, causing acetylcholine to accumulate at cholinoceptors Competes for -adrenoceptors (long-acting)

Competes for -adrenoceptors (short-acting) Replenishes vitamin K Binds ionically to neutralise Competitively displaces carbon monoxide from binding sites on haemoglobin. Give 100% by high-flow nonrebreathing mask. It provides a rapid increase in extracellular sodium that helps overcome sodium channel blockade.1 2 mEq/kg IV bolus usually reverses cardiotoxic effects (including wide QRS, hypotension). Give cautiously in heart failure to avoid sodium overload. It is given to alkalinize the urine and promote salicylate excretion by trapping the salicylate in its ionized, polar form. For severe poisoning ( with severe acidosis, coma, and serum salicylate level > 100 mg/dL), emergency haemodialysis is preferred to remove the salicylate more quickly and restore acid-base balance and fluid status. Sodium nitrite rapidly converts haemoglobin to methaemoglobin that binds CN, and thiosulphate promotes the formation of less toxic thiocyanate.

Glossary and Abbreviations

Ramadi, 11 October 2009

GLOSSARY AND ABBREVIATIONS Incomplete list of vocabulary adapted by and large from Dorland's Medical Dictionary (2000) W.B. Saunders 1, 25-DHCC: 1, 25-dihydroxycholecalciferol. 25-HCC: 25-hydroxycholecalciferol. Abortifacient: 1. causing abortion. 2. an agent which causes abortion. Abreaction: the reliving of an experience in such a way that previously repressed emotions associated with it are released. (Thiopental) Abscess: a localized collection of pus buried in tissues, organs, or confined spaces. Absence: the seizure seen in absence epilepsy, consisting of a sudden momentary break in consciousness of thought or activity, often accompanied by automatisms or clonic movements, especially of the eyelids. On the electroencephalogram it is characterized by a specific symmetrical spike and wave type occurring at three cycles per second. Abstinence: a refraining from the use of or indulgence in food, stimulants, or sexual intercourse. ACE: angiotensin converting enzyme ACh: acetylcholine. Achlorhydria: absence of hydrochloric acid from maximally stimulated gastric secretions; a result of gastric mucosal atrophy. Acne: an inflammatory disease of the pilosebaceous unit, the specific type usually being indicated by a modifying term; frequently used alone to designate common acne, or a. vulgaris. Acromegaly: a chronic disease of adults caused by hypersecretion of growth hormone, characterized by enlargement of many parts of the skeleton, especially distal portions such as the nose, ears, jaws, fingers, and toes. ACTH: (corticotrophin) adrenocorticotropic hormone. Acute intermittent porphyria: hereditary hepatic porphyria manifested by recurrent attacks of abdominal pain, gastrointestinal dysfunction, and neurological disturbances and by excessive amounts of aminolevulinic acid and porphobilinogen in the urine; it is due to an abnormality of pyrrole metabolism transmitted as an autosomal dominant trait. (Barbiturates) Acute: having a short and relatively severe course. Addiction: 1. the state of being given up to some habit or compulsion. 2. strong physiological and psychological dependence on a drug or other psychoactive substance. Addison s disease: a chronic type of adrenocortical insufficiency, characterized by hypotension, weight loss, anorexia, weakness, and a bronzelike hyperpigmentation of the skin. It is

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due to tuberculosis- or autoimmune-induced destruction of the adrenal cortex, which results in deficiency of aldosterone and cortisol and is fatal in the absence of replacement therapy. ADH: (vasopressin) antidiuretic hormone. Adjunct: an accessory or auxiliary agent or measure. Adjuvant: 1. assisting or aiding. 2. a substance that aids another, such as an auxiliary remedy. 3. in immunology, a non-specific stimulator of the immune response, such as BCG vaccine. Adrenal crisis: acute onset of adrenocortical insufficiency or sudden worsening of Addison's disease; manifestations include anorexia, vomiting, abdominal pain, apathy, confusion, extreme weakness, renal loss of sodium and water, and hypotension progressing to shock and, if untreated, death. Adrenergic tremor: (enhanced physiological tremor) a tremor that may appear in normal individuals under conditions of stress, such as cold, excitement, hunger, or exercise; it represents an intensification of physiological tremor to detectable levels. Affect: the external expression of emotion attached to ideas or mental representations of objects. Agitation: excessive, purposeless cognitive and motor activity or restlessness, usually associated with a state of tension or anxiety Agoraphobia: intense, irrational fear of open spaces, characterized by marked fear of being alone or of being in public places where escape would be difficult or help might be unavailable. Agranulocytosis: 1. any condition involving greatly decreased numbers of granulocytes 2. more specifically, a symptom complex characterized by marked decrease in the number of circulating granulocytes; severe neutropenia results in lesions of the throat, other mucous membranes, gastrointestinal tract, and skin; in most cases it is caused by sensitization to drugs, chemicals, or radiation affecting the bone marrow and depressing granulopoiesis. Akathesia: a condition of motor restlessness in which there is a feeling of muscular quivering, an urge to move about constantly, and an inability to sit still, a common extrapyramidal side effect of neuroleptic drugs. Akinesia: see hypokinesia Alcoholism: a disorder characterized by a pathological pattern of alcohol use that causes a serious impairment in social or occupational functioning. Algesia: 1. pain sense. 2. excessive sensitivity to

Essentials of Medical Pharmacology

Majid A.K. Lafi

pain, a type of hyperesthesia. Allergic rhinitis: a general term used to denote any allergic reaction of the nasal mucosa; it may occur perennially (nonseasonal allergic rhinitis) or seasonally (hay fever). Alopecia: lack or loss of the hair from skin areas where it normally is present. Altitudes sickness: the condition resulting from difficulty in adjusting to diminished oxygen pressure at high altitudes. It may take the form of mountain sickness, high-altitude pulmonary oedema, or cerebral oedema. Alzheimer s disease: a progressive degenerative disease of the brain of unknown aetiology, characterized by diffuse atrophy throughout the cerebral cortex with distinctive lesions called senile plaques and clumps of fibrils called neurofibrillary tangles. There is a loss of choline acetyltransferase activity in the cortex, and many of the degenerating neurons seem to be cholinergic neurons projecting from the substantia innominata to the cortex. The first signs of the disease are slight memory disturbance or changes in personality; deterioration progresses to profound dementia over 5 to 10 years. Women are affected twice as often as men, and onset may occur at any age. Amenorrhoea: absence or abnormal stoppage of the menses. (Oestrogens) AML: Acute Myeloid Leukaemia Amnesia: lack or loss of memory; inability to remember past experiences. Amoebiasis: he state of being infected with amoebae, especially with Entamoeba histolytica. Anaemia: a reduction below normal in the concentration of erythrocytes or hemoglobin in the blood, measured per cu mm or by volume of packed red cells per 100 mL of blood; it occurs when the equilibrium is disturbed between blood loss (through bleeding or destruction) and blood production. Analgesia: 1. absence of sensibility to pain; absence of pain on noxious stimulation. 2. the relief of pain without loss of consciousness. Anaphylactic shock: a type I hypersensitivity reaction in which exposure of a sensitized individual to a specific antigen or hapten results in urticaria, pruritus, and angioedema, followed by vascular collapse and shock and often accompanied by life-threatening respiratory distress. Angina pectoris: a paroxysmal thoracic pain, often radiating to the arms, particularly the left, sometimes accompanied by a feeling of suffocation and impending death; it is most often due to ischemia of the myocardium and precipitated by effort or excitement. Angioedema: a vascular reaction involving the deep dermis or subcutaneous or submucosal tissues, representing localized edema caused by dilatation and increased permeability of capillaries, and characterized by development of giant wheals.

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Angioneurotic oedema: see angioedema Ankylosing spondylitis: a form of degenerative joint disease that affects the spine. It is a systemic illness of unknown etiology, affecting young persons predominantly, and producing pain and stiffness as a result of inflammation of the sacroiliac, intervertebral, and costovertebral joints; paraspinal calcification, with ossification and ankylosis of the spinal joints, may cause complete rigidity of the spine and thorax. Anorexia nervosa: an eating disorder primarily affecting females, usually with onset in adolescence, characterized by refusal to maintain a normal minimal body weight, intense fear of gaining weight or becoming obese, and a disturbance of body image resulting in a feeling of being fat or having fat in certain areas even when extremely emaciated, undue reliance on body weight or shape for self-evaluation, and amenorrhea. Associated features often include denial of the illness and resistance to psychotherapy, depressive symptoms, markedly decreased libido, and obsessions or peculiar behaviour regarding food, such as hoarding. Anorexia: lack or loss of the appetite for food. Antibiotic-associated enterocolitis: that in which treatment with antibiotics alters the bowel flora and results in diarrhea or pseudomembranous enterocolitis. Called also pseudomembranous colitis and antibiotic-associated colitis. Antigenicity: the property of being able to induce a specific immune response or the degree to which a substance is able to stimulate an immune response. Antinociception: having an analgesic effect; reducing sensitivity to painful stimuli. Antipsychotic: effective in the treatment of psychosis, or an agent that so acts. Antrectomy: surgical excision of an antrum, as resection of the pyloric antrum of the stomach. Anuria: complete suppression of urinary secretion by the kidneys. Anxiety: the unpleasant emotional state consisting of psychophysiological responses to anticipation of unreal or imagined danger, ostensibly resulting from unrecognized intrapsychic conflict. Physiological concomitants include increased heart rate, altered respiration rate, sweating, trembling, weakness, and fatigue; psychological concomitants include feelings of impending danger, powerlessness, apprehension, and tension. Apathetic: indifferent; undemonstrative. Apathy: lack of feeling or emotion; indifference. Aphthous ulcer: a small ulcer, such as the round lesion with a grayish exudate surrounded by a red halo characteristic of recurrent aphthous stomatitis Aplastic anaemia: any of a diverse group of anaemias characterized by bone marrow failure with reduction of hematopoietic cells and their replacement by fat, resulting in pancytopenia, often accompanied by granulocytopenia and

Glossary and Abbreviations

Ramadi, 11 October 2009

thrombocytopenia. It may be hereditary; it may be secondary to causes such as toxic, radiant, or immunologic injury to bone marrow stem cells or their microenvironment; it may be associated with various diseases; or it may be idiopathic. Appetite: a natural longing or desire, especially the natural and recurring desire for food. Arousal: 1. a state of responsiveness to sensory stimulation or excitability. 2. the act or state of waking from or as if from sleep. 3. the act of stimulating to readiness or to action. Ascites: effusion and accumulation of serous fluid in the abdominal cavity. Aseptic necrosis: increasing sclerosis and cystic changes in the head of the femur which sometimes follow traumatic dislocation of the hip. A similar condition sometimes develops in the head of the humerus after shoulder dislocation. Asthma: recurrent attacks of paroxysmal dyspnea, with airway inflammation and wheezing due to spasmodic contraction of the bronchi. Asystol: absence of a heartbeat Ataxia: failure of muscular coordination; irregularity of muscular action. Atonia: see atony. Atonic bladder: a condition marked by a dilated, poorly contracting urinary bladder without evidence of a lesion of the central nervous system. Atony: lack of normal tone or strength, such as in a muscle deprived of its innervation. Atopic dermatitis: a chronic type seen in those with a hereditary susceptibility to pruritus; it may be accompanied by allergic rhinitis, hay fever, and asthma. Attention deficit (hyperkinetic) disorder: a childhood mental disorder characterized by inattention (such as distractibility, forgetfulness, not finishing tasks, and not appearing to listen), by hyperactivity and impulsivity (such as fidgeting and squirming, difficulty in remaining seated, excessive running or climbing, feelings of restlessness, difficulty awaiting one's turn, interrupting others, and excessive talking) or by both types of behaviour. Autoallergy: autoimmunity. Azotaemia: an excess of urea or other nitrogen bodies in the blood (NSAIDs) BBB: blood brain barrier. BCG: Bacille Calmette-Guerin Benign prostatic hyperplasia: see prostatism. Bilateral renal stenosis: see renal artery stenosis. Bioequivalence: the quality of being bioequivalent. Bioequivalent: having the same strength and similar bioavailability in the same dosage form as another specimen of a given drug substance. Bipolar affective disorder: pertaining to mood disorders in which both depressive episodes and manic or hypomanic episodes occur. Bizarre: peculiar, weird, absurd. Bleeding oesophageal varices: pertaining to

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bleeding of varicosities of the branches of the azygos vein which anastomose with tributaries of the portal vein in the lower oesophagus, occurring in patients with portal hypertension. Blood dyscrasia: a pathologic condition of the blood, usually referring to disorders of the cellular elements of the blood. Blurred vision: fuzzy image. Blush: sudden, brief erythema of the face and neck, resulting from vascular dilatation due to emotion or heat. Bonchoconstriction: constriction or narrowing the lumina of the air passages of the lungs, typically as a result of bronchial smooth muscle contraction. BPH : Benign prostatic hyperplasia. Bradycardia: slowness of the heartbeat, as evidenced by slowing of the pulse rate to less than 60. Bradykinesia: see hypokinesia Bronchiectasis: chronic dilatation of the bronchi marked by fetid breath and paroxysmal coughing, with the expectoration of mucopurulent matter. Brucellosis: in humans, a generalized infection caused by species of Brucella, transmitted by contact with the natural animal reservoirs, including cattle, sheep, goats, swine, deer, and rabbits, or their infected products or tissue. It involves primarily the reticuloendothelial system and is characterized by fever, sweating, weakness, malaise, and weight loss. Bulimia nervosa: an eating disorder occurring predominantly in females, with onset usually in adolescence or early adulthood and characterized by episodic binge eating followed by behaviours designed to prevent weight gain, including purging, fasting, and excessive exercise. BUN: blood urea nitrogen CAD: coronary artery disease Calculus: an abnormal concretion occurring within the body and usually composed of mineral salts. Carcinoid tumour: a yellow circumscribed tumor arising from enterochromaffin cells, usually in the small intestine, appendix, stomach, or colon and less commonly in the bronchus. Cardiomyopathy: a general diagnostic term designating primary noninflammatory disease of the heart muscle, often of obscure or unknown etiology and not the result of ischemic, hypertensive, congenital, valvular, or pericardial disease. Cardioversion: the restoration of normal rhythm of the heart by electrical shock. Cataracts: a partial or complete opacity on or in the lens or lens capsule of the eye, especially one impairing vision or causing blindness. Cathartic: 1. causing emptying of the bowels. 2. an agent that causes emptying of the bowels, such as by increasing bulk or stimulating peristaltic action. Called also evacuant and purgative. 3. producing emotional catharsis.

Essentials of Medical Pharmacology

Majid A.K. Lafi

CBF: cerebral blood flow. CBG: corticosteroid binding globulin. Cellulitis: an acute, diffuse, spreading, edematous, suppurative inflammation of the deep subcutaneous tissues and sometimes muscle, sometimes with abscess formation; the skin is warm and tender. Central precocious puberty: precocious puberty due to premature hypothalamic-pituitary-gonadal maturation; it is always isosexual and involves not only development of secondary sex characters but also development of the gonads. Increases in height and weight and osseous maturation are accelerated, and early closing of the epiphyses leads to short stature. CGRP: calcitonin gene related peptide. Cheese effect: cheese contains substantial amounts of sympathomimetics, most commonly tyramine, which acts by releasing tissue-stored noradrenaline. For example, degradation of the protein 'casein' by resident bacteria in well matured cheese can produce tyramine from the amino acid tyrosine, hence use of the term 'cheese effect' to describe provocation of a hypertensive crisis by orally administered sympathomimetics. CHF: Congestive heart failure Chickenpox: (varicella) a highly contagious infectious disease caused by human herpesvirus 3, usually affecting children, spread by direct contact or the respiratory route via droplet nuclei, and characterized by the appearance on the skin and mucous membranes of successive crops of typical pruritic vesicular lesions that are easily broken and become scabbed, and generally accompanied by mild constitutional symptoms. Cholinergic crisis: muscular weakness resulting from depolarization block due to overdosage of anticholinesterase agents used for myasthenia gravis; similar to but different from myasthenic crisis. CHOP: cyclophosphamide, hydroxydonorubicin (doxorubicin), Oncovin (vincristine), and prednisone. Chorea: the ceaseless occurrence of a wide variety of rapid, highly complex, jerky movements that appear to be well coordinated but are performed involuntarily. (Drugs and movement disorders) Chorionepithelioma: an epithelial malignancy of trophoblastic cells, formed by the abnormal proliferation of cuboidal and syncytial cells of the placental epithelium, without the production of chorionic villi. Chronic bronchitis: a type of chronic obstructive pulmonary disease in which there is bronchial irritation with increased secretions and a productive cough for at least three months, two years in succession; it is usually accompanied by pulmonary emphysema. The most common cause is long-term inhalation of irritants. Chronic: persisting over a long period of time. Chronotropic: affecting the time or rate, as the

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rate of contraction of the heart. Cinchonism: poisoning by the injudicious use of cinchona bark or its alkaloids, characterized by nausea, vomiting, headache, tinnitus, deafness, symptoms of cerebral congestion, vertigo, and visual disturbances. Closed-angle glaucoma: glaucoma caused by closure of the anterior angle by contact between the iris and the inner surface of the trabecular meshwork; called also closed-angle g., narrowangle g., and pupillary block g. CMV: cytomegalovirus CNS: central nervous system. Coitus: sexual connection per vaginam between male and female. Cold sweat: a sweat produced by the apocrine sweat glands, located on the palms of the hands and a few other areas, respond to adrenoceptor stimulants with increased sweat production. These are the apocrine nonthermoregulatory glands usually associated with psychological stress, e.g. an embarrassing situation. Collapse: 1. a state of extreme prostration and depression, with failure of circulation. 2. abnormal falling in of the walls of any part or organ. Compulsion: a persistent and irresistible impulse to perform an irrational or apparently useless act. 2. a compulsive act or ritual; a repetitive and stereotyped action, such as hand-washing, touching, counting, and checking, that is engaged in for an unknown or unconscious purpose. COMT: catechol-O-methyltransferase Concomitant: accompanying; accessory; joined with another. Confusion: disturbed orientation in regard to time, place, or person, sometimes accompanied by disordered consciousness. Congestion: excessive or abnormal accumulation of fluid, as of blood in a part. Congestive heart failure: (CHF) a clinical syndrome due to heart disease, characterized by breathlessness and abnormal sodium and water retention, often resulting in oedema. The congestion may occur in the lungs or peripheral circulation or both, depending on whether the heart failure is right-sided or general. Conjunctivitis: inflammation of the conjunctiva, generally consisting of conjunctival hyperaemia associated with a discharge. Constipation: infrequent or difficult evacuation of the faeces. Contraception: the prevention of conception or impregnation. Convulsion: a violent involuntary contraction or series of contractions of the voluntary muscles. COX: cyclooxgenase. Cretinism: a chronic condition due to congenital severe hypothyroidism; manifestations begin in late infancy and include arrested physical development (dwarfism), mental retardation, dystrophy of the

Glossary and Abbreviations

Ramadi, 11 October 2009

bones and soft parts, and lowered basal metabolism. Crohn s disease: a chronic granulomatous inflammatory disease of unknown aetiology, involving any part of the gastrointestinal tract from mouth to anus, but commonly involving the terminal ileum with scarring and thickening of the bowel wall; it frequently leads to intestinal obstruction and fistula and abscess formation and has a high rate of recurrence after treatment. Cryptorchism: failure of testes to descend to into the scrotum. (Non-pituitary gonadotropins) Crystalluria CSF: cerebrospinal fluid. Css: steady-state concentration. CTZ: chemoreceptor trigger zone. Cushing s syndrome: a complex of symptoms caused by hyperadrenocorticism due either to a neoplasm of the adrenal cortex or adenohypophysis, or to excessive intake of glucocorticoids. Symptoms may include adiposity of the face, neck, and trunk; kyphosis from osteoporosis of the spine; hypertension; diabetes mellitus; amenorrhea and hypertrichosis in females; impotence in males; dusky complexion with purple striae; polycythemia; and muscular wasting and weakness. Cushing-like syndrome: a complex of symptoms caused by hyperadrenocorticism due either to a neoplasm of the adrenal cortex or adenohypophysis, or to excessive intake of glucocorticoids. Symptoms may include adiposity of the face, neck, and trunk; kyphosis from osteoporosis of the spine; hypertension; diabetes mellitus; amenorrhoea and hypertrichosis in females; impotence in males; dusky complexion with purple striae; polycythaemia; and muscular wasting and weakness. Cycloplegia: paralysis of the ciliary muscle; paralysis of accommodation. Cystic fibrosis: cystic fibrosis of the pancreas, an autosomal recessive disorder of infants, children, and young adults in which there is widespread dysfunction of the exocrine glands, with signs of chronic pulmonary disease (due to excess mucus production in the respiratory tract), pancreatic deficiency, abnormally high levels of electrolytes in the sweat, and occasionally biliary cirrhosis. DAG: diacylglycerol Deep venous thrombosis: DVT; thrombosis of one or more of the deep veins of the lower limb, characterized by swelling, warmth, and erythema, frequently a precursor of a pulmonary embolism. Deleterious: hurtful; injurious. Delirium tremens: (alcohol withdrawal delirium) delirium caused by cessation or reduction in alcohol consumption, typically in alcoholics with 10 years or more of heavy drinking. Clinical manifestations include autonomic hyperactivity, such as tachycardia, sweating, and hypertension; a

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coarse, irregular tremor, and delusions, vivid hallucinations; and wild, agitated behaviour. The onset is usually 2 or 3 days after cessation of drinking; the delirium and other withdrawal symptoms usually resolve in 3 or 4 days. Delirium: an acute, transient disturbance of consciousness accompanied by a change in cognition and having a fluctuating course. Delusion of jealousy: a delusional belief that one's spouse or lover is unfaithful based on erroneous inferences drawn from innocent events imagined to be evidence and often resulting in confrontation with the accused. It is one of the subtypes of delusional disorder. Delusion: a false belief that is firmly maintained in spite of undeniable and obvious proof or evidence to the contrary and in spite of the fact that other members of the culture do not share the belief. Dementia: a general loss of cognitive abilities, including impairment of memory as well as one or more of the following: aphasia, apraxia, agnosia, or disturbed planning, organizing, and abstract thinking abilities. Demulcent: 1. soothing; bland; allaying the irritation of inflamed or abraded surfaces. 2. a soothing, mucilaginous, or oily medicine or application. Dependent oedema: oedema affecting most seriously the lowermost or dependent parts of the body. Depression: 1. a hollow or depressed area; downward or inward displacement. 2. a lowering or decrease of functional activity. 3. a mental state of depressed mood characterized by feelings of sadness, despair, and discouragement. Depression ranges from normal feelings of ''the blues'' through dysthymic disorder to major depressive disorder. It in many ways resembles the grief and mourning that follow bereavement; there are often feelings of low self-esteem, guilt, and self-reproach, withdrawal from interpersonal contact, and somatic symptoms such as eating and sleep disturbances. Dermatophytoses: any superficial fungal infection caused by a dermatophyte and involving the stratum corneum of the skin, hair, and nails, including onychomycosis and the various forms of tinea. Diabetes insipidus: any of several types of polyuria in which the volume of urine exceeds 3 litres per day, causing dehydration and great thirst, as well as sometimes emaciation and great hunger. Diabetic neuropathy: any of several clinical types of peripheral neuropathy occurring with diabetes mellitus; there are sensory, motor, autonomic, and mixed varieties. The most common kind is a chronic, symmetrical sensory polyneuropathy affecting first the nerves of the lower limbs and often affecting autonomic nerves; pathologically, there is a segmental demyelination of the

Essentials of Medical Pharmacology

Majid A.K. Lafi

peripheral nerves. An uncommon acute form is the ischemic variety, accompanied by severe pain, weakness, and wasting of proximal and distal muscles, peripheral sensory impairment, and loss of tendon reflexes. With autonomic involvement there may be orthostatic hypotension, nocturnal diarrhea, retention of urine, impotence, and small diameter of the pupils with sluggish reaction to light. Diabetogenic: producing diabetes Diaphoresis: sweating, especially of a profuse type. Diarrhoea: abnormal frequency and liquidity of faecal discharges. DIC: Disseminated intravascular coagulation Diphtheria: an acute infectious disease caused by toxigenic strains of Corynebacterium diphtheriae, acquired by contact with an infected person or a carrier; it is usually confined to the upper respiratory tract, and characterized by the formation of a tough false membrane attached firmly to the underlying tissue that will bleed if forcibly removed. In the most serious infections the membrane begins in the faucial area on one tonsil and may spread to the other tonsil, uvula, soft palate, and pharyngeal wall, followed by the larynx, trachea, and bronchial tree, where it may cause bronchial obstruction and death by hypoxia. Diplopia: the perception of two images of a single object. Disinhibition: 1. removal of inhibitions, as reduction of the inhibitory function of the cerebral cortex by drugs such as ethyl alcohol or reduction in the severity of superego controls in psychotherapy. 2. in experimental psychology, the revival of an extinguished conditioned response by exposure to an unconditioned stimulus. Dissociative anaesthesia: loss of sensitivity to pain, heat, and cold without loss of other tactile senses. Disulfiram-like reaction: a syndrome occurring after inhalation or ingestion of disulfiram followed by drinking an alcoholic beverage, marked by intense flushing, rapid pulse and pounding heart, panting respiration, and impaired taste, unpleasant breath and perspiration, which may be followed by nausea, vomiting, and a precipitous fall in blood pressure; the extent and severity of the symptoms depend on the amount of calcium cyanamide and alcohol in the system. The reactions are due to the inhibition by disulfiram of one or more of the enzymes required for oxidation of acetaldehyde formed from alcohol, resulting in the accumulation of acetaldehyde and the altered vascular reaction to it. Dizziness: a disturbed sense of relationship to space; a sensation of unsteadiness with a feeling of movement within the head. DMARD: disease-modifying antirheumatic drug. Dosage: the determination and regulation of the

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size, frequency, and number of doses. Dromotropic: affecting the conductivity of a nerve fiber Dropsical: oedematous. Drowsiness: sleepiness. Drug Abuse: a substance use disorder characterized by the use of a mood or behaviouraltering substance in a maladaptive pattern resulting in significant impairment or distress, such as failure to fulfil social or occupational obligations or recurrent use in situations in which it is physically dangerous to do so or which end in legal problems, but without fulfilling the criteria for substance dependence (q.v.). Specific disorders are named for their aetiology, eg., alcohol abuse, anabolic steroid abuse. Ductus arteriosus: arterial duct: a fetal blood vessel connecting the left pulmonary artery directly to the descending aorta. Dysfunctional uterine bleeding: bleeding from the uterus when no organic uterine lesions are present. Dysmenorrhoea: Painful menstruation (NSAIDs) Dyspepsia: impairment of the power or function of digestion; usually applied to epigastric discomfort following meals. Dysphoria: disquiet; restlessness; malaise (Opioids and narcotic analgesics) Dyspnoea: breathlessness or shortness of breath; difficult or laboured breathing. Dystocia: abnormal labour or childbirth (NSAIDs) Dystonia: dyskinetic movements due to disordered tonicity of muscle. ECL: enterochromaffin-like. ECT: electroconvulsive therapy. Ectopic beats: a heart beat originating at some point other than the sinus node. Emotion: a strong feeling state, such as excitement, distress, happiness, sadness, love, hate, fear, or anger, arising subjectively and directed toward a specific object, with physiological, somatic, and behavioural components. In psychoanalytic theory, it is a state of tension associated with an instinctual drive. The external manifestation of emotion is called affect; a pervasive and sustained emotional state, mood. Empirical: based on experience. Encephalopathy: any degenerative disease of the brain. Endemic: present or usually prevalent in a population or geographical area at all times; said of a disease or agent. and proliferative Endocarditis: exudative inflammatory alterations of the endocardium, usually characterized by the presence of vegetations on the surface of the endocardium or in the endocardium itself, and most commonly involving a heart valve, but sometimes affecting the inner lining of the cardiac chambers or the endocardium elsewhere. It may occur as a primary

Glossary and Abbreviations

Ramadi, 11 October 2009

disorder or as a complication of or in association with another disease. Endometrial cancer: carcinoma characterized by glandular patterns that resemble those of the endometrium, occurring in the uterine fundus and in the ovaries. Endometriosis: a condition in which tissue more or less perfectly resembling the uterine mucous membrane (the endometrium) and containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity. (Progestins, danazol) Endophathalmitis: nflammation involving the ocular cavities and their adjacent structures. Enema: a liquid injected or to be injected into the rectum Enuresis: urinary incontinence after the age at which urinary control should have been achieved; often used alone with specific reference to that occurring during sleep at night (bed-wetting; nocturnal enuresis) Eosinophilia: 1. the formation and accumulation of an abnormally large number of eosinophils in the blood. 2. the condition of being readily stained with eosin. EP: extrapyramidal. Epidural (peridural) nerve block. regional anaesthesia produced by injection of the anaesthetic agent between the vertebral spines and beneath the ligamentum flavum into the epidural space. Epilepsy: any of a group of syndromes characterized by paroxysmal transient disturbances of the brain function that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system. Epileptoform: 1. resembling epilepsy or its manifestations. 2. occurring in severe or sudden paroxysms. Episiotomy: surgical incision into the perineum and vagina to prevent traumatic tearing during delivery. EPSP: excitatory postsynaptic potential. Erotomania: 1. a disorder in which the subject believes that a person, usually older and of higher social status, is deeply in love with them; failure of the object of the delusion to respond to the subject's advances are rationalized, and pursuit and harassment of the object of the delusion may occur. 2. occasionally, hypersexuality. ESBLs: extended spectrum -lactamases Essential tremor: a hereditary tremor with onset at varying ages, usually at about 50 years of age, beginning with a fine rapid tremor (as distinct from that of parkinsonism) of the hands, followed by tremor of the arms, tongue, head, legs, and trunk; it is aggravated by emotional factors, is accentuated by volitional movement, and in some cases is

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temporarily improved by alcohol. Euphoria: bodily comfort; well being; absence of pain or distress. In psychiatry, an abnormal or exaggerated sense of well being, particularly common in the manic state. (Opioids and narcotic analgesics, glucocorticoids) Excipient: any more or less inert substance added to a prescription in order to confer a suitable consistency or form to the drug; called also vehicle. Expectorant: 1. promoting the ejection, by spitting, of mucus or other fluids from the lungs and trachea. 2. an agent that promotes the ejection of mucus or exudate from the lungs, bronchi, and trachea; sometimes extended to all remedies that quiet cough (antitussives). Extrasystole: a weak systole, usually premature, not associated with pulsation of a peripheral artery Extremity: an upper or lower limb ( a hand or foot) Febrile: 1. pertaining to fever. 2. characterized by fever. Fever: elevation of body temperature above the normal Fibrosis: the formation of fibrous tissue, as in repair or replacement of parenchymatous elements. Flush: 1.transient, episodic redness of the face and neck caused by certain diseases, ingestion of certain drugs or other substances, heat, emotional factors, or physical exertion. 2. to wash out with fluid. Foetal alcohol syndrome: a syndrome of altered prenatal growth and morphogenesis occurring in infants born of women who were chronically alcoholic during pregnancy; it includes maxillary hypoplasia, prominence of the forehead and mandible, short palpebral fissures, microphthalmia, epicanthal folds, severe growth retardation, mental retardation, and microcephaly. Foetal: of or pertaining to a foetus; pertaining to in utero development after the embryonic period. FSH: follicle-stimulating hormone. GABA: γ-aminobutyric acid. GAD: generalised anxiety disorder. Gastroenteritis: an acute inflammation of the lining of the stomach and intestines, characterized by anorexia, nausea, diarrhea, abdominal pain, and weakness, which has various causes, including food poisoning due to infection with such organisms as Escherichia coli, Staphylococcus aureus, and Salmonella species; consumption of irritating food or drink; or psychological factors such as anger, stress, and fear. Gastroparesis: paralysis of the stomach. GERD: gastroesophageal reflux disease. Gestational diabetes: diabetes mellitus with onset or first recognition during pregnancy; this category does not include diabetics who become pregnant or women who become lactosuric. GFR: glomerular filtration rate. GH: (somatropin) growth hormone.

Essentials of Medical Pharmacology

Majid A.K. Lafi

Gigantism: abnormal overgrowth; excessive size and stature. Gingivitis: inflammation of the gingivae. GIT: gastrointestinal tract Glaucoma: a group of eye diseases characterized by an increase in intraocular pressure that causes pathological changes in the optic disk and typical defects in the field of vision. Glycogenolysis: the breakdown of glycogen to glucose by hydrolysis (as in digestion or within lysosomes) or phosphorolysis (as in mobilization of glycogen as a fuel). Gn: gonadotropin. GnRH: gonadotropin-releasing hormone. Goitre: an enlargement of the thyroid gland, causing a swelling in the front part of the neck. Gout: a group of disorders of purine metabolism, manifested by various combinations of (1) hyperuricaemia; (2) recurrent acute inflammatory arthritis induced by crystals of monosodium urate monohydrate; (3) tophaceous deposits of these crystals in and around the joints of the extremities, which may lead to crippling destruction of joints; and (4) uric acid urolithiasis. Granulocytopenia: reduction in the number of granular leukocytes in the blood. Graves disease: a syndrome of diffuse hyperplasia of the thyroid, with a female predominance; it usually has an autoimmune aetiology and has been linked to autoimmune thyroiditis. Characteristics include hyperthyroidism, usually with goitre and ophthalmic symptoms (Graves' orbitopathy). Grey baby syndrome: a potentially fatal condition seen in neonates, particularly premature infants, due to a reaction to chloramphenicol, characterized by an ashen gray cyanosis, listlessness, weakness, and hypotension. GTN: glyceryltrinitrate Gynaecomastia: excessive growth of the male mammary glands, in some cases including development to the stage at which milk is produced, usually associated with metabolic derangements that lead to oestrogen accumulation, testosterone deficiency, and hyperprolactinaemia. A mild form may develop transiently during normal puberty. Habitual abortion: the spontaneous expulsion of a dead or nonviable foetus in three or more consecutive pregnancies, at about the same period of development. Haematuria: blood in the urine Haemophilia: a hemorrhagic diathesis occurring in two main forms: haemophilia A, deficiency of coagulation factor VIII; and haemophilia B, deficiency of coagulation factor IX. Both forms are determined by a mutant gene near the telomere of the long arm of the X chromosome (Xq), but at different loci, and are characterized by

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subcutaneous and intramuscular haemorrhages; bleeding from the mouth, gums, lips, and tongue; haematuria; and haemarthroses. Haemorrhoids: a varicose dilatation of a vein of the superior or inferior hemorrhoidal plexus, resulting from a persistent increase in venous pressure. Hallucination: a sense perception without a source in the external world; a perception of an external stimulus object in the absence of such an object. Hangover: extended beyond. Hashimoto s autoimmune thyroiditis: a progressive type of autoimmune thyroiditis with lymphocytic infiltration of the gland and circulating antithyroid antibodies; patients have goitre and gradually develop hypothyroidism. It has a familial predisposition, usually affects women, and sometimes precedes the onset of Graves' disease or is manifested after the major symptoms subside. Hay fever: a type of allergic rhinitis that occurs at the same time every year, marked by acute conjunctivitis with lacrimation and itching, swelling of the nasal mucosa, sneezing, and often asthmatic symptoms. hCG: human chorionic gonadotropin. Heart block: impairment of conduction of an impulse in heart excitation; often applied specifically to atrioventricular block. Hepatotoxicity: the quality or property of exerting a destructive or poisonous effect upon liver cells. Herpes simplex: a group of acute infections caused by human herpesviruses 1 and 2, characterized by the development of one or more small fluid-filled vesicles with a raised erythematous base on the skin or mucous membrane, and occurring as a primary infection or recurring because of reactivation of a latent infection. Type 1 infections usually involve nongenital regions of the body, whereas in type 2 infections the lesions are primarily seen on the genital and surrounding areas, although there is overlap between the two types. Hiatus hernia: a condition of incompetent gastrooesophageal sphincters. Hiccup: an involuntary spasmodic contraction of the diaphragm, causing a beginning inspiration that is suddenly checked by closure of the glottis, causing a characteristic sound. Hirsutism: abnormal hairiness, especially an adult male pattern of hair distribution in women. hMG: human menopausal gonadotropin. Huntington s chorea: a rare hereditary disease characterised by chronic progressive chorea and mental deterioration terminating in dementia; the age of onset is variable but usually occurs in the fourth decade of life. Death usually follows within 15 years. It is transmitted as an autosomal dominant trait. (Drugs and movement disorders) Huntington s chorea: an autosomal dominant

Glossary and Abbreviations

Ramadi, 11 October 2009

disease characterized by chronic progressive chorea and mental deterioration terminating in dementia; the age of onset is variable but usually in the fourth decade of life, with death within 15 years. Huntington s disease: see Huntington s chorea Hydatidiform mole: an abnormal pregnancy resulting from a pathological ovum, with proliferation of the epithelial covering of the chorionic villi and dissolution and cystic cavitation of the avascular stroma of the villi. Hydrothorax: a pleural effusion containing serous fluid. Hyperactive child: see Attention deficit (hyperkinetic) disorder Hypercalcaemia: an excess of calcium in the blood; manifestations include fatigability, muscle weakness, depression, anorexia, nausea, and constipation. Hypercalciuria: excess of calcium in the urine. Hyperchloraemic acidosis: metabolic acidosis accompanied by elevated plasma chloride. Hyperglycaemia: abnormally increased glucose in the blood, such as in diabetes mellitus. Hyperkinetic child: see Attention deficit (hyperkinetic) disorder an abnormally high Hypermagnesaemia: magnesium content of the blood; manifestations include lethargy, weakness, electrocardiographic abnormalities and, as levels increase, loss of deep tendon reflexes, somnolence, and coma. Hyperplasia: abnormal multiplication or increase in the number of normal cells in normal arrangement in a tissue. Hyperplasminaemia: abnormally increased plasmin in the blood. Hyperprolactinaemia: increased levels of prolactin in the blood; in women it is associated with amenorrhea and galactorrhoea, and in men it has been reported to cause hypogonadism, impotence, and in some cases gynaecomastia. It is often associated with microadenoma of the adenohypophysis. Hypersexuality: abnormally increased sexual desire or activity; nymphomania; satyriasis. Hypersomnia: excessive sleeping or sleepiness, as in any of a group of sleep disorders with a variety of physical and psychogenic causes. Hypertension: high arterial blood pressure; various criteria for its threshold have been suggested, ranging from 140 mm Hg systolic and 90 mm Hg diastolic to as high as 200 mm Hg systolic and 110 mm Hg diastolic. Hypertension may have no known cause (essential or idiopathic h.) or be associated with other primary diseases (secondary h.). Hypertensive crisis: dangerously high blood pressure of acute onset. Hyperthermia of anaesthesia: see malignant hyperthermia.

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Hyperthyroidism: a condition caused by excessive production of iodinated thyroid hormones. Hypertrophy: the enlargement or overgrowth of an organ or part due to an increase in size of its constituent cells. Hyperuricaemia: excess of uric acid or urates in the blood; it is a prerequisite for the development of gout and may lead to renal disease. Hypoadrenalism: adrenal insufficiency. Hypoglycaemia: an abnormally diminished concentration of glucose in the blood, which may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache; when chronic and severe it may cause central nervous system manifestations that in rare cases can even be fatal. Hypokalaemia: abnormally low potassium concentration in the blood; it may result from excessive potassium loss by the renal or the gastrointestinal route, from decreased intake, or from transcellular shifts. It may be manifested clinically by neuromuscular disorders ranging from weakness to paralysis, by electrocardiographic abnormalities (depression of the T wave and elevation of the U wave), by renal disease, and by gastrointestinal disorders. Hypokinesia: (bradykinesia, akinesia) slowness of movements (Drugs and movement disorders) Hypomania: an abnormality of mood resembling mania (persistent elevated or expansive mood, hyperactivity, inflated self-esteem, etc.) but of lesser intensity. Hypophosphotaemia: an abnormally decreased amount of phosphates in the blood; manifestations include haemolysis, lassitude, weakness, and convulsions. Hypotension: abnormally low blood pressure. Hypothalamic hypogonadotropic hypogonadism: that due to lack of gonadotropin secretion; it is caused by lack of secretion of gonadotropin-releasing hormone. Hypothyroidism: deficiency of thyroid activity, characterized by decrease in basal metabolic rate, fatigue, and lethargy; if untreated, it progresses to myxoedema. In adults it is more common in women than men, and in infants it can lead to cretinism. Hypothyroidism: deficiency of thyroid activity, characterized by decrease in basal metabolic rate, fatigue, and lethargy; if untreated, it progresses to myxoedema. In adults it is more common in women than men, and in infants it can lead to cretinism. Hypotonic bladder: a condition of diminished tone of the detrusor muscle of the urinary bladder. Hypoxia: reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. i.m.: intramuscular. i.v.: intravenous.

Essentials of Medical Pharmacology

Majid A.K. Lafi

IDDM: insulin dependent diabetes mellitus. Idiopathic: of unknown cause or spontaneous origin; of the nature of an idiopathy. Ileus: obstruction of the intestines. Immune insulin resistance: see insulin resistance. Impulse dyscontrol syndrome: a pattern of episodic, abnormal, and often violent and uncontrollable social behaviour with little or no provocation; it may result from diseases of the limbic system or the temporal lobe or may accompany abuse of alcohol or some other psychoactive substance. Incontinence: 1. inability to control excretory functions, such as defecation (fecal i.) or urination (urinary i. ). Infant respiratory distress syndrome: dyspnoea with cyanosis in the newborn, heralded by such prodromal signs as dilatation of the alae nasi, expiratory grunt, and retraction of the suprasternal notch or costal margins, caused by a deficiency in surfactant. It is usually seen in premature infants, children of diabetic mothers, or infants delivered by caesarean section, although sometimes there is no apparent predisposing cause. Infertility: diminished or absent capacity to produce offspring; the term does not denote complete inability to produce offspring as does sterility. Inotropic: affecting the force or energy of muscular contractions. INR: international normalized ratio. Insomnia: inability to sleep; abnormal wakefulness. Insulin resistance: impairment of normal biological responses to insulin, which may result from abnormalities in the beta-cell products, binding of insulin to antagonists such as antiinsulin antibodies, defects in or reduced numbers of receptors, or defects in the insulin action cascade in the target cell. It can also be caused by excessive quantities of growth hormone, adrenocortical steroids, or some other regulators, or by chronic hyperinsulinaemia secondary to hyperphagia. Incidence is increased with conditions such as obesity, diabetes mellitus, acromegaly, uraemia, and certain rare, possibly genetic, autoimmune disorders. Insulinogenic: pertaining to, characterized by, or promoting insulinogenesis. Insulinoma: an islet cell tumor of pancreatic beta cells; although usually benign, such tumours secrete excessive amounts of insulin and are among the most important causes of hypoglycemia. Intermittent claudication: a complex of symptoms characterized by pain, tension, and weakness in a limb when walking is begun, intensification of the condition until walking becomes impossible, and disappearance of the symptoms after a period of rest. It is seen in occlusive arterial diseases of the limbs, such as

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thromboangiitis obliterans, and in compression of the cauda equina. Intermittent: occurring at separated intervals; having periods of cessation of activity. Intractable: resistant to cure, relief, or control. IPSP: inhibitory postsynaptic potential. Iritis: inflammation of the iris, usually marked by pain, congestion in the ciliary region, photophobia, contraction of the pupil, and discoloration of the iris. Iron deficiency: deficiency of iron in the system, usually caused by blood loss, low dietary levels of iron, or a disease condition that inhibits iron uptake. Irritable bowel syndrome: irritable colon syndrome, a chronic noninflammatory disease characterized by abdominal pain, altered bowel habits consisting of diarrhea or constipation or both, and no detectable pathologic change; a variant form is characterized by painless diarrhea. It is a common disorder with a psychophysiological basis. ISA: intrinsic sympathomimetic activity Kaliuretic: 1. pertaining to, characterized by, or promoting kaliuresis. 2. an agent that promotes kaliuresis (potassium losing). Kernicterus: a condition associated with high levels of bilirubin in the blood, nearly always with severe neural symptoms, usually seen in infants as a sequela of icterus gravis neonatorum. Lactic acidosis: a metabolic acidosis occurring as a result of excess lactic acid in the blood, due to conditions causing impaired cellular respiration. It occurs most commonly in disorders in which O2 is inadequately delivered to tissues, e.g., shock, septicemia, or extreme hypoxemia, but it can also result from exogenous or endogenous metabolic defects. Initially manifesting as hyperventilation, it progresses to mental confusion and coma. Legionnaires disease: a bacterial disease caused by infection with Legionella pneumophila, and not spread by person-to-person contact; it is characterized by pneumonia, high fever, gastrointestinal pain, headache, and sometimes involvement of the kidneys, liver, or nervous system. Leucocytosis: a transient increase in the number of leukocytes in the blood; seen normally with strenuous exercise and pathologically accompanying haemorrhage, fever, infection, or inflammation. LH: luteinizing hormone. Libido: 1. sexual desire. 2. the psychic energy derived from instinctive biological drives; in early freudian theory it was restricted to the sexual drive, then expanded to include all expressions of love and pleasure, but the concept has evolved to include also the death instinct. LOX: lipoxygenase. LSD: lysergide.

Glossary and Abbreviations

Ramadi, 11 October 2009

Lupus erythematosus: a group of connective tissue disorders primarily affecting women aged 20 to 40 years, comprising a spectrum of clinical forms in which cutaneous disease may occur with or without systemic involvement. Luteolysis: degeneration of corpus luteum. Lymphogranuloma venereum: a sexually transmitted infection usually seen in warm climates, due to strains of Chlamydia trachomatis, characterized by a primary cutaneous or mucosal lesion at the site of infection, which may be a papular, ulcerative, herpetiform, or erosive lesion or urethritis or endocervicitis that heals spontaneously and may go unnoticed, followed by acute unilateral or bilateral lymphadenopathy. Malaise: a vague feeling of bodily discomfort. Malignant hyperthermia: an autosomal dominantly inherited condition, occurring in patients undergoing general anaesthesia, and causing a sudden, rapid rise in body temperature, associated with signs of increased muscle metabolism, such as tachycardia, tachypnoea, sweating, and cyanosis, usually, muscle rigidity. Called also hyperthermia of anaesthesia and malignant hyperpyrexia. (General anaesthetic agents, antipsychotic neuroleptic drugs, dantroline) Mania: a phase of bipolar disorder characterized by expansiveness, euphoria, agitation, hyperexcitability, hyperactivity, and increased speed of thought and speech (flight of ideas). Manic-depressive illness: older term for bipolar disorder, see bipolar affective disorder. MAO: monoamine oxidase. Megaloblastic: any anaemia characterized by the presence of megaloblasts in the bone marrow, such as pernicious anaemia. Meningitis: inflammation of the meninges, usually by either a bacterium (bacterial m.) or a virus (viral m.). Menopausal symptoms: including transient vaginal bleeding, hot flushes, and vaginal dryness. Menopausal: pertaining to or associated with the menopause. Menopause: cessation of menstruation in the human female, occurring usually between the age of 48 and 50. Menorrhagia: excessive uterine bleeding at the regular intervals of menstruation, the period of flow being greater than usual duration. (Progestins) Menstrual disorder: a derangement or abnormality of function related to menstruation. Metabolic alkalosis: any of the various kinds of acidosis in which the acid-base status of the body shifts toward the acid side because of loss of base or retention of acids other than carbonic acid (fixed or nonvolatile acids), in contrast to respiratory acidosis. Metallic: pertaining to, consisting of, or of the nature of metal.

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Methemoglobinemia: the presence of excessive methemoglobin in the blood, resulting in cyanosis and headache, dizziness, fatigue, ataxia, dyspnea, tachycardia, nausea, vomiting, and drowsiness, which can progress to stupor, coma, and occasionally death. It may be either chemicalor drug-induced (acquired or toxic m.) or hereditary (congenital or hereditary m.). MIC: minimum inhibitory concentration Micturition: urination. Migraine: an often familial symptom complex of periodic attacks of vascular headache, usually temporal and unilateral in onset, commonly associated with irritability, nausea, vomiting, constipation or diarrhoea, and often photophobia. Attacks are preceded by constriction of the cranial arteries, often with resultant prodromal sensory (especially ocular) symptoms and the spreading depression of Le o; the migraines themselves commence with the vasodilatation that follows. Two primary types are distinguished, m. with aura and m. without aura; the variety without an aura is more common. Milk-alkali syndrome: a syndrome characterized by hypercalcaemia without hypercalciuria or hypophosphataemia, with only mild alkalosis, normal serum phosphatase, severe renal insufficiency with hyperazotaemia, and calcinosis, attributed to ingestion of milk and absorbable alkali for long periods of time. Miosis: contraction of the pupil. Mood: a pervasive and sustained emotion that, when extreme, can colour one's whole view of life and markedly affect behaviour. Mood is generally used to refer to either elation or depression. Morbid jealousy: preoccupation with gloomy or distrustful feelings or thoughts, see delusion of jealousy. Morbid: 1. pertaining to, affected with, or inducing disease; diseased. 2. unhealthy or unwholesome. 3. characterized by preoccupation with gloomy or unwholesome feelings or thoughts. Morbidity: 1. a diseased condition or state. 2. the incidence or prevalence of a disease or of all diseases in a population. Mortality: 1. the quality of being mortal. 2. the mortality rate. Motion sickness: sickness caused by motion experienced in any kind of travel, such as sea sickness, train sickness, car sickness, and air sickness. MRSA: Methicillin Resistant Staphylococcus Aureus. MSA: membrane stabilising activity. Mucolytic: destroying or dissolving mucin; an agent that so acts. Myasthenia gravis: a disorder of neuromuscular function due to the presence of antibodies to acetylcholine receptors at the neuromuscular

Essentials of Medical Pharmacology

Majid A.K. Lafi

junction; characteristics include muscular fatigue and exhaustion tending to fluctuate in severity, without sensory disturbance or atrophy. It may be restricted to one muscle group or become generalized with severe weakness and sometimes ventilatory insufficiency. It may affect any muscle of the body, but especially those of the eye, face, lips, tongue, throat, and neck. Mydriasis: 1. physiologic dilatation of the pupil. 2. morbid dilatation of the pupil. 3. dilatation of the pupil effected by a drug. Myocardial infarction: (MI) gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. Myoclonic: relating to or marked by myoclonus. Myoclonus: shocklike contractions of a portion of a muscle, an entire muscle, or a group of muscles, restricted to one area of the body or appearing synchronously or asynchronously in several areas. It may be part of a disease process (e.g., epileptic or post-anoxic myoclonus) or be a normal physiological response (e.g., nocturnal myoclonus). Myxoedema: 1. a condition characterized by dry, waxy swelling of the skin, with abnormal deposits of glycosaminoglycans in skin (mucinosis) and other tissues, associated with primary hypothyroidism. The oedema is nonpitting, and there are distinctive facial changes including swollen lips and a thickened nose. 2. hypothyroidism in adults. NABQI: N-acetyl-benzoquinone. Narcolepsy: recurrent, uncontrollable, brief episodes of sleep often associated with hypnagogic or hypnopompic hallucinations, cataplexy, and sleep paralysis. Narcotic: 1. pertaining to or producing narcosis. 2. an agent that produces insensibility or stupor, applied especially to the opioids, i.e., to any natural or synthetic drug that has morphine-like actions. Necrosis: the sum of the morphological changes indicative of cell death and caused by the progressive degradative action of enzymes; it may affect groups of cells or part of a structure or an organ. Negative symptoms: (retarded schizophrenia) minus personality features including apathy, flattening of affect and poverty of speech. Neonatal: pertaining to the first four weeks after birth. Nephrogenic diabetes insipidus: diabetes insipidus caused by failure of the renal tubules to reabsorb water in response to antidiuretic hormone, without disturbance in the renal filtration and solute excretion rates; the condition does not respond to exogenous vasopressin. It may be inherited as an X-linked trait or be acquired as a result of drug therapy or systemic disease.

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Nephrotic syndrome: general name for any of a group of diseases involving defective kidney glomeruli, characterized by massive proteinuria and lipiduria with varying degrees of oedema, hypoalbuminaemia, and hyperlipidaemia Nerve block: that is, injection of the anaesthetic agent close to the nerves whose conductivity is to be cut off. Neuralgia: see trigeminal neuralgia. Neurogenic: 1. forming nervous tissue. 2. originating in the nervous system or from a lesion in the nervous system. Neuroleptanaesthesia: a state of neuroleptanalgesia and unconsciousness, produced by the combined administration of a narcotic analgesic and a neuroleptic agent, together with the inhalation of nitrous oxide and oxygen. Neuroleptanalgesia: a state of quiescence, altered awareness, and analgesia produced by the administration of a combination of a narcotic analgesic and a neuroleptic agent. Neuroleptic: a term coined to refer to the effects on cognition and behaviour of the original antipsychotic agents, which produced a state of apathy, lack of initiative, and limited range of emotion and in psychotic patients caused a reduction in confusion and agitation and normalization of psychomotor activity. The term is outdated as a synonym for antipsychotic agents because newer agents do not necessarily have such effects. Neuromuscular block: a failure in neuromuscular transmission that can be induced pharmacologically or may result from pathological disturbance at the myoneural junction. Neuropathy: a functional disturbance or pathological change in the peripheral nervous system, sometimes limited to noninflammatory lesions as opposed to those of neuritis; the aetiology may be known or unknown. Neutropenia: a decrease in the number of neutrophils in the blood NIDD: non-insulin dependent diabetes mellitus. Nightmare: a terrifying dream; an anxiety attack during dreaming, accompanied by mild autonomic reactions and usually awakening the dreamer, who recalls the dream but is oriented. Nociception: pain sense. Nociceptor: a receptor for pain caused by injury to body tissues; the injury may be from physical stimuli such as mechanical, thermal, or electrical stimuli, or from chemical stimuli such as the presence of a toxin or an excess of a nontoxic substance. Most nociceptors are in either the skin (cutaneous nociceptor) or the walls of viscera (visceral nociceptor). Nocturnal: pertaining to, occurring at, or active at night. NSAID: non-steroidal anti-inflammatory drug. Nystagmus: an involuntary, rapid, rhythmic

Glossary and Abbreviations

Ramadi, 11 October 2009

movement of the eyeball, which may be horizontal, vertical, rotatory, or mixed, i.e., of two varieties. Obsessive-compulsive disorder: an anxiety disorder characterized by recurrent obsessions or compulsions, which are severe enough to interfere significantly with personal or social functioning. Performing compulsive rituals may release tension temporarily, and resisting them causes increased tension. Odynophagia: pain on swallowing (tetracycline) Oliguria: excretion of a diminished amount of urine in relation to the fluid intake, usually defined as less than 400 mL per 24 hours. Oliguric: pertaining to or characterized by oliguria. Open-angle glaucoma: any glaucoma in which the angle of the anterior chamber remains open, but filtration is gradually diminished because of the tissues of the angle; called also chronic g., simple g., and wide-angle g. Opportunistic infections: superinfection. Organic brain syndrome: former term for a constellation of psychological or behavioural signs and symptoms associated with brain dysfunction of unknown or unspecified aetiology and grouped according to symptoms. Organic psychoses: a psychotic disorder with a known or presumed organic aetiology. Orofacial dyskinesia: see tardive dyskinesia. Orthostatic hypotension: a fall in blood pressure associated with dizziness, blurred vision, and sometimes syncope, occurring upon standing or when standing motionless in a fixed position; it can be acquired or idiopathic. Orthostatic: pertaining to or standing erect (Antihypertensive drugs) Osteoarthritis: a noninflammatory degenerative joint disease seen mainly in older persons, characterized by degeneration of the articular cartilage, hypertrophy of bone at the margins, and changes in the synovial membrane. It is accompanied by pain, usually after prolonged activity, and stiffness, particularly in the morning or with inactivity. inadequate or delayed Osteomalacia: mineralization of osteoid in mature cortical and spongy bone; it is the adult equivalent of rickets and accompanies that disorder in children. Osteomyelitis: inflammation of bone caused by infection, usually by a pyogenic organism, although any infectious agent may be involved. It may remain localized or may spread through the bone to involve the marrow, cortex, cancellous tissue, and periosteum. Ototoxic: causing damage to the vestibulocochlear nerve or the organs of hearing and balance. Ototoxicity: the quality of causing damage to the vestibulocochlear nerve or the organs of hearing and balance PABA: p-aminobenzoic acid.

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Paget s disease of bone: a disease of bone marked by repeated episodes of increased bone resorption followed by excessive attempts at repair, resulting in weakened deformed bones of increased mass. Pain: a more or less localized sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. It serves as a protective mechanism insofar as it induces the sufferer to remove or withdraw from the source. Palliative care: treatment designed to relieve pain and distress, but not attempting a cure. Palpitation: a subjective sensation of an unduly rapid or irregular heart beat Pancytopaenia: deficiency of all cellular elements of the blood. Panhypopituitarism: generalized or particularly severe hypopituitarism, which in its complete form leads to absence of gonadal function and insufficiency of thyroid and adrenal cortical function. Panic: acute, extreme anxiety with disorganization of personality and function. Paradox: a statement which seems to be, though it may not be, absurd or self-contradictory. Paradoxical: occurring at variance with the normal rule. Paraesthesiae: (numbness) abnormal perception, feeling, or sensation. Paralytic ileus: ileus resulting from inhibition of bowel motility, which may be produced by numerous causes, most frequently by peritonitis. Paranoid psychosis: a type of psychosis characterized by preoccupation with one or more systematized delusions or with frequent auditory hallucinations but without disorganized speech, disorganized or catatonic behaviour, or flat or inappropriate affect. Paranoid schizophrenia: a type of schizophrenia characterized by preoccupation with one or more systematized delusions or with frequent auditory hallucinations but without disorganized speech, disorganized or catatonic behaviour, or flat or inappropriate affect. Parenteral: not through the alimentary canal but rather by injection through some other route, such as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, or intravenous. Parkinson s disease: a group of neurological disorders characterized by hypokinesia, tremor, and muscular rigidity. Parkinsonism: see Parkinson s disease. Paroxysm: 1. a sudden recurrence or intensification of symptoms Paroxysmal: recurring in paroxysms PBPs: penicillin binding proteins Pellagra: a clinical deficiency syndrome due to deficiency of niacin (or failure to convert tryptophan to niacin) and characterized by dermatitis, inflammation of mucous membranes,

Essentials of Medical Pharmacology

Majid A.K. Lafi

diarrhoea, and psychic disturbances. The dermatitis occurs on the portions of the body exposed to light or trauma. Mental symptoms include depression, irritability, anxiety, confusion, disorientation, delusions, and hallucinations. Peptic: pertaining to pepsin or to digestion; related to the action of gastric juices. Peripheral neuropathy: Some conditions that are actually polyneuropathies are called neuropathies. Peritonitis: inflammation of the peritoneum, with exudations of serum, fibrin, cells, and pus, usually accompanied by abdominal pain and tenderness, constipation, vomiting, and moderate fever. Personality disorder: a category of mental disorders characterized by enduring, inflexible, and maladaptive personality traits that deviate markedly from cultural expectations, are selfperpetuating, pervade a broad range of situations, and either generate subjective distress or result in significant impairments in social, occupational, or other functioning. Onset is by adolescence or early adulthood. Pheochromocytoma: a usually benign, wellencapsulated, lobular, vascular tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. Because of increased secretion of adrenaline and noradrenaline, hypertension is a cardinal symptom; it may be persistent or intermittent. During severe attacks, there may be headache; sweating; palpitation and tremor; pallor or flushing of the face; nausea and vomiting; pain in the chest and abdomen; and paresthesias of the extremities. Phlegm: abnormally thick mucus secreted by the mucosa of the respiratory passages during certain infectious processes. Phobia: a persistent, irrational, intense fear of a specific object, activity, or situation (the phobic stimulus), fear that is recognized as being excessive or unreasonable by the individual himself. Phocomelia: a type of meromelia characterized by absence of the proximal portion of a limb or limbs, the hands or feet being attached to the trunk of the body by a single small, irregularly shaped bone. Photophobia: abnormal visual intolerance of light. Photosensitivity reactions: an abnormal cutaneous response involving the interaction between photosensitizing substances and sunlight or filtered or artificial light at wavelengths of 280 400 nm. Physiological lactation: normal; not pathological secretion of milk. Pituitary diabetes insipidus: iabetes insipidus due to injury of the neurohypophyseal system, with a deficient quantity of antidiuretic hormone being released or produced, causing failure of renal tubular reabsorption of water. It may be inherited, acquired, or idiopathic. Plankton: a collective name for the minute freefloating organisms, vegetable and animal, which

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live in practically all natural waters. Planktonic: pertaining to plankton. PMSG: (serum gonadotropin) pregnant mare serum gonadotropin. Poikelothermia: variable or irregular body temperature. Polyarteritis nodosa: a form of systemic necrotizing vasculitis involving the small and medium-sized arteries with signs and symptoms resulting from infarction and scarring of the affected organ system. Polyarteritis: multiple inflammatory and destructive arterial lesions. Polycystic ovarian syndrome: (PCOS) a clinical symptom complex associated with polycystic ovaries and characterized by oligomenorrhea or amenorrhea, anovulation (hence infertility), and hirsutism. Both hyperestrogenism (from peripheral conversion of androgen) and hyperandrogenism are present. Polymyositis: a chronic, progressive inflammatory disease of skeletal muscle, occurring in both children and adults, and characterized by symmetrical weakness of the limb girdles, neck, and pharynx, usually associated with pain and tenderness, and sometimes preceded or followed by manifestations typical of scleroderma, arthritis, systemic lupus erythematosus, or Sj gren's syndrome. It is also sometimes associated with malignancy, and may be accompanied by characteristic skin lesions. Polyuria: the passage of a large volume of urine in a given period, a characteristic of diabetes. Porphyria: see acute intermittent porphyria. Positive symptoms: added features to personality including hallucinations, delusions and thought disorder. Postherpetic neuralgia: persistent burning pain and hyperesthesia along the distribution of a cutaneous nerve following an attack of herpes zoster; it may last for a few weeks or many months. Postmenopausal osteoporosis: that occurring in women within 3 to 20 years after menopause, affecting trabecular bone more than cortical bone, and manifested mainly by vertebral fractures of the painful crush type, hip fracture, Colles' fracture, and increased tooth loss. Postmortem: occurring or performed after death; pertaining to the period after death. Postural: pertaining to posture or position (Antihypertensive drugs) Precocious puberty: onset of sexual maturation at an earlier age than normal, defined as two standard deviations below the mean, or before age 8 in girls and 9 in boys. Premature ejaculation: ejaculation consistently occurring either prior to, upon, or immediately after penetration and before it is desired, taking into account factors such as age, novelty of the specific situation, and recent frequency of the

Glossary and Abbreviations

Ramadi, 11 October 2009

sexual act. Premature labour: expulsion of a viable infant before the normal end of gestation, usually applied to interruption of pregnancy between the twentieth and the thirty-seventh completed weeks after the onset of the last menstrual period. Preterm labour: labour at any time before the thirty-seventh completed week (259 days) of gestation. Priapism: persistent abnormal erection of the penis, usually without sexual desire, and accompanied by pain and tenderness. It is seen in diseases and injuries of the spinal cord, and may be caused by vesical calculus and certain injuries to the penis. Primary amenorrhoea: failure of menstruation to occur at puberty. Primary hyperaldosteronism: that arising from oversecretion of aldosterone by an adrenal cortical adenoma, characterized typically by hypokalemia, alkalosis, muscular weakness, polyuria, polydipsia, and hypertension. Called also Conn's syndrome. prn: (p.r.n.) abbreviation for L. pro re na´ta, according as circumstances may require (as needed). Proconvulsant: an agent that promote the initiation of convulsions. Prokinetic: pertaining to gastrointestinal motilityenhancing activity. Prolactin-secreting adenomas: a pituitary adenoma made up of lactotrophs that secretes excessive amounts of prolactin; this may delay puberty in either sex, cause galactorrhoeaamenorrhoea syndrome in women, or decrease libido and fertility in men. Prophylaxis: intervention aimed at the prevention of disease; called also preventive treatment, prophylactic treatment, and protective therapy. Prostatectomy: surgical removal of the prostate or of a part of it. Prostatism: a symptom complex resulting from compression or obstruction of the urethra, due most commonly to nodular hyperplasia of the prostate. Proteinuria: the presence of an excess of serum proteins in the urine; called also albuminuria. Pruritus: 1. an unpleasant cutaneous sensation that provokes the desire to rub or scratch the skin to obtain relief. Called also itching. 2. any of various conditions marked by this sensation, the specific site or type being indicated by a modifying term. Pseudomembranous colitis: see antibioticassociated enterocolitis. Pseudotumour cerebri: a condition caused by venous sinus occlusion and cerebral oedema associated with a number of pathologic conditions, marked by raised intracranial pressure with normal cerebrospinal fluid, headache, nausea, vomiting, and papilloedema, but without neurological signs except occasional abducens paralysis.

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Psittacosis: human infection by Chlamydia psittaci, generally acquired by inhalation of dried bird excreta containing the pathogen; it may also be acquired by handling feathers or tissues of infected birds, through an open skin lesion, or from the bite of an infected bird. It may be asymptomatic, have mild influenzalike symptoms, or manifest as a severe, highly fatal pneumonia. Psychodysleptic: inducing a dreamlike or delusional state of mind. Psychosis: 1. a mental disorder characterized by gross impairment in reality testing as evidenced by delusions, hallucinations, markedly incoherent speech, or disorganized and agitated behaviour, usually without apparent awareness on the part of the patient of the incomprehensibility of his behaviour. 2. the term is also used in a more general sense to refer to mental disorders in which mental functioning is sufficiently impaired as to interfere grossly with the patient's capacity to meet the ordinary demands of life. Historically, the term has been applied to many conditions, e.g., manicdepressive psychosis, that were first described in psychotic patients, although many patients with the disorder are not judged psychotic. Psychotic depression: in the strict sense, major depressive disorder with psychotic features, such as hallucinations, delusions, mutism, or stupor. However, this term is commonly used in a broader sense to cover all severe depressions causing gross impairment of social or occupational functioning, i.e., as a rough equivalent of major depressive disorder or of endogenous depression. PT: prothrombine time. PTH: parathyroid hormone. Puberty: the period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. Pulmonary embolism: the closure of the pulmonary artery or one of its branches by an embolus, sometimes associated with pulmonary infarction. Purgative: see cathartic. Purpura: 1. any of a group of conditions characterized by ecchymoses or other small haemorrhages in the skin, mucous membranes, or serosal surfaces; possible causes include blood disorders, vascular abnormalities, and trauma. 2. any of several conditions similar to the traditional purpura group, which may be caused by decreased platelet counts, platelet abnormalities, vascular defects, or reactions to drugs. PVCs: premature ventricular contractions Pyrogen: a fever-producing substance. Rash: a temporary eruption on the skin, as in urticaria; a drug eruption or viral exanthema. Raynaud s disease: a primary or idiopathic vascular disorder characterized by bilateral attacks of Raynaud's phenomenon; it affects females more often than males. Called also Raynaud's gangrene.

Essentials of Medical Pharmacology

Majid A.K. Lafi

Rebound: a reversed response on the withdrawal of a stimulus. Reflux oesophagitis: serious and sometimes lifethreatening type of gastroesophageal reflux disease that involves damage to the esophageal mucosa, often with erosion, ulceration, and infiltration by neutrophils or eosinophils. Refraction: the act or process of refracting; specifically the determination of the refractive errors of the eye and their correction by glasses. Regimen: a strictly regulated scheme of medication, diet, exercise, or other activity designed to achieve certain ends. Relapse: the return of a disease after its apparent cessation. Renal artery stenosis: RAS; narrowing of one or both renal arteries, caused by atherosclerosis or by fibrous dysplasia or hyperplasia, so that renal function is impaired; increased renin release by the affected kidney causes renovascular hypertension, and bilateral stenosis may result in chronic renal failure. Resting tremor: a tremor occurring when a limb or other body part is at rest; it may be normal, as in some physiologic tremors, or abnormal, as in parkinsonian tremors. Retarded schizophrenia: see negative symptoms. Reye s syndrome: a rare, acute, sometimes fatal disease of childhood, characterized by recurrent vomiting and elevated serum transaminase levels, with distinctive changes in the liver and other viscera; an encephalopathic phase may follow with acute brain swelling, disturbances of consciousness, and seizures. It most often occurs as a sequel of chickenpox or a viral upper respiratory infection. Rheumatoid arthritis: a chronic systemic disease primarily of the joints, usually polyarticular, marked by inflammatory changes in the synovial membranes and articular structures and by muscle atrophy and rarefaction of the bones. In late stages deformity and ankylosis develop. The cause is unknown, but autoimmune mechanisms and virus infection have been postulated. Rhinorrhoea: the free discharge of a thin nasal mucus. Rickets: an interruption in the development and mineralization of the growth plate of bone, with radiographic abnormalities, osteomalacia, bone pain, fatigability, growth retardation, and often hypotonia, convulsions, and tetany. Rigidity: stiffness or inflexibility, chiefly that which is abnormal or morbid; rigor. s.c.: subcutaneous. Salicylism: the commonly occurring toxic effects of excessive dosage with salicylic acid or its salts, usually marked by tinnitus, nausea, and vomiting. Salmonellosis: any disease caused by infection

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with a species of Salmonella; in humans it is most often manifested as food poisoning with acute gastroenteritis, vomiting, diarrhoea, and rarely septicaemia, or as typhoid or paratyphoid fever. Recurrent fevers and diarrhoea with more serious gastrointestinal symptoms are seen in immunocompromised patients. Sarcoidosis: a chronic, progressive, systemic granulomatous reticulosis of unknown aetiology, characterized by hard tubercles in almost any organ or tissue, including the skin, lungs, lymph nodes, liver, spleen, eyes, and small bones of the hands and feet. SC3: third generation cephalosporin. Schizophrenia: a mental disorder or heterogeneous group of disorders (the schizophrenias or schizophrenic disorders) comprising most major psychotic disorders and characterized by disturbances in form and content of thought (loosening of associations, delusions, and hallucinations), mood (blunted, flattened, or inappropriate affect), sense of self and relationship to the external world (loss of ego boundaries, dereistic thinking, and autistic withdrawal), and behaviour (bizarre, apparently purposeless, and stereotyped activity or inactivity). Secondary amenorrhoea: cessation of menstruation after it has once been established at puberty. Sedation: the production of a sedative effect; the act or process of calming. Senile dementia: that occurring in older persons, usually over the age of 65; since most cases are due to Alzheimer's disease, the term is sometimes used as a synonym of d. of the Alzheimer type, late onset. Sepsis: 1. the presence in the blood or other tissues of pathogenic microorganisms or their toxins. 2. septicemia. Septic: pertaining to sepsis Serum sickness: a hypersensitivity reaction to the administration of foreign serum or serum proteins characterized by fever, urticaria, arthralgia, edema, and lymphadenopathy. It is caused by the formation of circulating antigen-antibody complexes that are deposited in tissues and trigger tissue injury mediated by complement and polymorphonuclear leukocytes. Serum sickness is classed with the Arthus reaction and other immune complex diseases as a type III hypersensitivity reaction (Gell and Coombs classification). Although serum sickness is now rare because of the replacement of most animal-derived antisera with human immune globulins, an identical illness (serum sickness like reaction or syndrome) can be produced by hypersensitivity reactions to penicillin and other drugs. Sexual deviation: sexual behaviour or fantasy outside that which is morally, biologically, or legally sanctioned, often specifically one of the

Glossary and Abbreviations

Ramadi, 11 October 2009

paraphilias. Sexual dysfunction: any of a group of sexual disorders characterized by disturbance either of sexual desire or of the psychophysiological changes that usually characterize sexual response. Included are sexual desire disorders, sexual arousal disorders, orgasmic disorders, sexual pain disorders, substance-induced sexual dysfunction, and sexual dysfunction due to a general medical condition. Shingles: (herpes zoster) an acute infectious, usually self-limited, disease believed to represent activation of latent human herpesvirus 3 in those who have been rendered partially immune after a previous attack of chickenpox. It involves the sensory ganglia and their areas of innervation, is characterized by severe neuralgic pain along the distribution of the affected nerve and crops of clustered vesicles over the area of the corresponding dermatome, and is usually unilateral and confined to single or adjacent dermatomes. Postherpetic neuralgia may be a complication. In immunocompromised patients it may disseminate and be fatal. Called also acute posterior ganglionitis, shingles, zona, and zoster. Shock: 1. a sudden disturbance of mental or physical equilibrium. 2. a condition of profound hemodynamic and metabolic disturbance characterized by failure of the circulatory system to maintain adequate perfusion of vital organs. It may result from inadequate blood volume (hypovolemic shock); inadequate cardiac function (cardiogenic shock); or inadequate vasomotor tone (neurogenic shock and septic shock). SIADH: syndrome of inappropriate secretion of antidiuretic hormone. Sinus bradycardia: a slow sinus rhythm, with a heart rate of less than 60 beats per minute in an adult; it is common in young adults and in athletes but is also a manifestation of some disorders. SLE: systemic lupus erythematosus Slurred speech: speech in which the words are uncompleted Sneezing: expelling air forcibly and spasmodically through the nose and mouth. 2. an involuntary, sudden, violent, and audible expulsion of air through the mouth and nose. Spasm: 1. a sudden, violent, involuntary contraction of a muscle or a group of muscles, attended by pain and interference with function, producing involuntary movement and distortion. 2. a sudden but transitory constriction of a passage, canal, or orifice. Spasmodic: of the nature of a spasm. Spinal nerve block: 1. regional anaesthesia produced by injection of a local anesthetic into the subarachnoid space around the spinal cord; anaesthesia Called also intraspinal a. or block and subarachnoid anaesthesia or block. 2. loss of sensation due to a spinal lesion.

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Status epilepticus: a continuous series of generalized tonic-clonic seizures without return to consciousness, a life-threatening emergency. Stevens-Johnson syndrome: a sometimes fatal form of erythema multiforme presenting with a flulike prodrome, and characterized by systemic as well as more severe mucocutaneous lesions. The oronasal and anogenital mucous membranes may become involved with a characteristic gray or white pseudomembrane, and hemorrhagic crusts often occur on the lips. Ocular lesions vary, often with injected conjunctivitis, iritis, uveitis, corneal vesicles, erosions, and perforation, which may result in corneal opacities and blindness. Pulmonary, gastrointestinal, cardiac, and renal involvement also occurs. Stomatitis: inflammation of the oral mucosa, due to local or systemic factors, which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae. Subarachnoid haemorrhage: intracranial hemorrhage into the subarachnoid space. Superinfection: (suprainfection, opportunistic infection, secondary infection) a new infection occurring in a patient having a preexisting infection, such as bacterial superinfection in viral respiratory disease or infection of a chronic hepatitis B carrier with hepatitis D virus. Superinfection can complicate the course of antimicrobial therapy when the new infection is by organisms resistant to the drugs in use. Suppository: a medicated mass adapted for introduction into the rectal, vaginal, or urethral orifice of the body; suppository bases are solid at room temperature but melt or dissolve at body temperature. Sydenham s chorea: an acute, usually self-limited disorder of early life, usually between the ages of 5 and 15 or during pregnancy, and closely linked with rheumatic fever. It is characterized by involuntary movements that gradually become severe, affecting all motor activities including gait, arm movements, and speech. A mild psychic component is usually present. Syncope: a temporary suspension of consciousness due to generalized cerebral ischemia; a faint. Synergistic: 1. acting together. 2. enhancing the effect of another force or agent. Systemic lupus erythematosus: (SLE) a chronic, remitting, relapsing, inflammatory, often febrile multisystemic disorder of connective tissue, acute or insidious in onset, characterized principally by involvement of the skin joints, kidneys, and serosal membranes. It is of unknown etiology, but it is thought to represent a failure of regulatory mechanisms of the autoimmune system, as suggested by the high level of numerous autoantibodies against nuclear and cytoplasmic cellular components. It is marked by a wide variety of abnormalities, including arthritis and arthralgias,

Essentials of Medical Pharmacology

Majid A.K. Lafi

nephritis, central nervous system manifestations, pleurisy, pericarditis, leukopenia or thrombocytopenia, hemolytic anemia, elevated erythrocyte sedimentation rate, and positive LEcell preparations. Systemic sclerosis: a systemic disorder of the connective tissue characterized by induration and thickening of the skin, by abnormalities involving both the microvasculature (telangiectasia) and larger vessels (Raynaud's phenomenon), and by fibrotic degenerative changes in various body organs, including the heart, lungs, kidneys, and gastrointestinal tract. It may remain confined to the face and hands for long periods or may be progressive and spread diffusely to become generalized. t : half life. T3: triiodothyronine. T4: Tetraiodothyronine. Tachycardia: excessive rapidity in the action of the heart; the term is usually applied to a heart rate above 100 beats per minute in an adult and is often qualified by the locus of origin as well as by whether it is paroxysmal or nonparoxysmal. Tarditive dyskinesia: (orofacial dyskinesia) an iatrogenic extrapyramidal disorder caused by longterm use of antipsychotic drugs; it is characterized by oral-lingual-buccal dyskinesias that usually resemble continual chewing motions with intermittent darting movements of the tongue; there may also be choreoathetoid movements of the extremities. It is more common in women than in men and in the elderly than in the young, and incidence is related to drug dosage and duration of treatment. In some patients symptoms disappear within a few months after the drugs are withdrawn; in others symptoms may persist indefinitely. TCA: tricyclic antidepressant. TDM: therapeutic drug monitoring. Telangiectasia: permanent dilation of preexisting small blood vessels (capillaries, arterioles, venules), creating focal red lesions, usually in the skin or mucous membranes. Tenosynovitis: inflammation of a tendon sheath. Teratogenic: tending to produce congenital anomalies. Testicular teratoma: a type of germ cell tumour derived from pluripotent cells and made up of elements of different types of tissue from one or more of the three germ cell layers in the testis. Tetanus: 1. an acute, often fatal infectious disease caused by the bacillus Clostridium tetani, which produces the neurotoxin tetanospasmin; it usually enters the body through a contaminated puncture wound (such as from a metal nail, wood splinter, or insect bite), although other portals of entry include burns, surgical wounds, cutaneous ulcers, injection sites of drug abusers, the umbilical stump of neonates (t. neonatorum), and the postpartum uterus. 2. physiological tetanus; a state of

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sustained muscular contraction without periods of relaxation caused by repetitive stimulation of the motor nerve trunk at frequencies so high that individual muscle twitches are fused and cannot be distinguished from one another. Thalassaemia: a heterogeneous group of hereditary hemolytic anemias that have in common a decreased rate of synthesis of one or more hemoglobin polypeptide chains and are classified according to the chain involved (a, b, d); the two major categories are a- and b-thalassemia. Homozygous forms are manifested by profound anemia or death in utero, and heterozygous forms by erythrocyte anomalies ranging from mild to severe. Therapeutic restraining: the use of drug therapy to control of a subject, as of a violently psychotic or irrational person. Thought disorders: a disturbance in the thought process that is most narrowly defined as disorganized thinking with altered associations, as is characteristic of schizophrenia. The term is often used much more broadly to include any disturbance of thought, such as confusion, hallucinations, or delusions, which affects possession, quantity, or content of thought. Throbbing: beating; attended with a rhythmic beating sensation. Thrombocytopenia: decrease in the number of platelets, such as in thrombocytopenic purpura. Thrombocytopenic purpura: any form of purpura in which the platelet count is decreased; it may be either primary (idiopathic) or secondary. (see purpura) Thromboembolism: obstruction of a blood vessel with thrombotic material carried by the blood stream from the site of origin to plug another vessel. Thyroiditis: inflammation of the thyroid gland. Thyrotoxicosis: the condition caused by excessive quantities of thyroid hormones (see hyperthyroidism); it may be due to overproduction by the thyroid gland as in Graves' disease, overproduction originating outside the thyroid, or loss of storage function and leakage from the gland. TIA: Transient ischaemic attack. Tics: an involuntary, compulsive, rapid, repetitive, stereotyped movement or vocalization, experienced as irresistible although it can be suppressed for some length of time; occurrence is exacerbated by stress and diminished during sleep or engrossing activities. Tics may be psychogenic or neurogenic in origin and are subclassified as either simple, such as eye blinking, shoulder shrugging, coughing, grunting, snorting, or barking, or complex, such as facial gestures, grooming motions. Tinnitus: a noise in the ears, such as ringing, buzzing, roaring, or clicking. It is usually

Glossary and Abbreviations

Ramadi, 11 October 2009

subjective in type. Tocolytic: pertaining to inhibition of uterine contractions. Tocolytic: uterine relaxant. Toxic adenoma: hyperthyroidism arising in a multinodular goiter, usually of long standing. Trachoma: a chronic infectious disease of the conjunctiva and cornea, producing photophobia, pain, and lacrimation, caused by a strain of Chlamydia trachomatis. Tranquilliser: a drug with a calming, soothing effect; currently it is usually used to denote a minor tranquilliser. Transient ischaemic attacks: (TIA) a brief attack (from a few minutes to an hour) of cerebral dysfunction of vascular origin, with no persistent neurological deficit; TIAs are most commonly associated with occlusive vascular disease, especially in the distribution of the carotid and vertebral-basilar systems. TRH: (protirelin) thyrotropin-releasing hormone. Trigeminal neuralgia: Paroxysmal pain that extends along the course of one or more nerves. Many varieties of neuralgia are distinguished according to the part affected or to the cause, as trigeminal, brachial, facial, occipital, supraorbital, etc., or postherpatic, anaemic, diabetic, gouty, malarial, syphilitic, etc. (carbamazepine) TSH: (thyrotropin) Thyroid-stimulating hormone. Tuberculosis: any of the infectious diseases of humans or other animals caused by species of Mycobacterium and characterized by the formation of tubercles and caseous necrosis in the tissues. The usual causative species are M. tuberculosis and M. bovis. Type I reaction: that occurring within minutes when a sensitized individual is reexposed to antigen, resulting from interaction of IgE and the antigen; clinical manifestations can range from localized dermatitis, urticaria, or angioedema to allergic rhinitis or asthma to systemic anaphylaxis. The first exposure to the antigen induces the production of IgE antibodies that bind to receptors on mast cells and basophils. Upon subsequent exposure the antigen cross-links receptor-bound IgE molecules, triggering production and release of a diverse array of mediators that act on other cells, producing symptoms such as bronchospasm, edema, mucous secretion, and inflammation. (penicillin) Type II reaction: tissue or cell damage resulting from the interaction of antibodies and antigens on cell surfaces; specific IgG or IgM against cell surface or extracellular matrix antigens or cell surface receptors binds and causes damage at the site of binding by any of several mechanisms involving either complement activation and lysis or opsonization mediated by receptors for Fc or C3b leading to phagocytosis and destruction by macrophages and neutrophils. Examples of

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disorders caused by such tissue damage include myasthenia gravis, hemolytic anemia, Goodpasture's syndrome, and Rh incompatibility and transfusion reactions. Type III reaction: local or general inflammatory response due to formation of circulating antigenantibody complexes and their deposition in tissues; the complexes activate complement and other inflammatory mediators, initiating processes including increased vascular permeability, stimulation of mast cell degranulation and neutrophil chemotaxis and accumulation, and aggregation of platelets, and resulting in tissue damage. Ensuing diseases, called also immune complex diseases, can be roughly classified as being due to persistent infection, to autoimmunity, or to inhalation of antigenic material; examples include serum sickness, Arthus reaction, subacute bacterial endocarditis, systemic lupus erythematosus, and farmer's lung. Type IV reaction: a reaction of cell-mediated immunity, the immune response being initiated by antigen-specific T lymphocytes; in contrast to the reactions of immediate hypersensitivity, reactions take one or more days to develop and can be transferred by lymphocytes but not by serum. Reactions are mediated by T lymphocytes both through release of cytokines and through direct cytolysis. In the former mechanism, release of vasoactive and chemotactic cytokines is triggered by contact between the T cells and specific antigens on antigen-presenting cells; the cytokines attract and activate non antigen-specific monocytes and macrophages, resulting in local erythema and induration, and leading to granuloma formation and necrosis if the eliciting stimulus cannot be eliminated. A common example is the tuberculin reaction elicited in skin testing for tuberculosis. In direct cytolysis, sometimes called cell-mediated cytotoxicity, cytotoxic T lymphocytes interact with foreign antigens presented by class I MHC molecules on cell surfaces, causing lysis of these foreign cells, as in allograft rejection. Type IV reactions can be induced by intracellular parasites, such as certain viruses, mycobacteria, and fungi, foreign tissue, tumour cells, soluble proteins, and haptens. The term is often equated with delayed hypersensitivity reaction, although the latter is sometimes restricted to cytokine-mediated reactions (as contrasted with direct cytolysis). U: unit. Ulcerative colitis: chronic, recurrent ulceration in the colon, chiefly of the mucosa and submucosa, of unknown cause; it is manifested clinically by cramping abdominal pain, rectal bleeding, and loose discharges of blood, pus, and mucus with scanty fecal particles. Complications include hemorrhoids, abscesses, fistulas, perforation of the colon, pseudopolyps, and carcinoma.

Essentials of Medical Pharmacology

Majid A.K. Lafi

Unipolar affective disorder: that unaccompanied by episodes of mania or hypomania, as in major depressive disorder. Ureteral colic: colicky pains due to obstruction of the ureter. Urinary frequency: urination at short intervals without increase in daily volume of urinary output, due to reduced bladder capacity. Urinary retention: accumulation of urine within the bladder because of inability to urinate. Urolithiasis: 1. the formation of urinary calculi (stones). 2. the diseased condition associated with the presence of urinary calculi. Urticaria: a vascular reaction in the upper dermis, usually transient, consisting of localized oedema caused by dilatation and increased capillary permeability, with development of wheals. Uterine fibroids: a benign tumour derived from smooth muscle of the uterus. Uterine rupture: forcible tearing of the uterus. Uveitis: an inflammation of part or all of the uvea, commonly involving the other tunics of the eye (sclera, cornea, and retina). Vagotomy: interruption of the impulses carried by the vagus nerve or nerves. Vertigo: an illusory sense that either the environment or one's own body is revolving; it may result from diseases of the inner ear or may be due to disturbances of the vestibular centers or pathways in the central nervous system. Visual haloes: the seeing of coloured rings around an individual light source; indicative of glaucoma. Vulvovaginitis: inflammation of the vulva and vagina, or of the vulvovaginal glands. Whooping Cough: an acute, highly contagious infection of the respiratory tract, usually affecting young children and caused by Bordetella pertussis; similar illnesses are caused by B. parapertussis and B. bronchiseptica. Wolff-Parkinson-White syndrome: the association of paroxysmal tachycardia (or atrial fibrillation) and preexcitation, in which the electrocardiogram displays a short P R interval and a wide QRS complex which characteristically shows an early QRS vector (delta wave); sometimes used synonymously with preexcitation s. Called also WPW s. Zollinger-Ellison syndrome: a triad comprising (1) intractable, sometimes fulminating, and in many ways atypical peptic ulcers; (2) extreme gastric hyperacidity; and (3) gastrin-secreting, non beta islet cell tumours of the pancreas, which may be single or multiple, small or large, benign or malignant.

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