Basic Pharmacology PDF
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Basic Pharmacology Third edition Editor R W Foster, BSc, PhD, MB, BS Reader in Pharmacology AAuutthhoorrss TThhee pphhaarrmmaaccoollooggiissttss ooff tthhee DDeeppaarrttmn ent of Physiological Sciences UUnniivveerrssiittyy ooff MMaanncchheesstteerr,, UUKK,, aanndd tt heir teaching collaborators: A J M Boulton, MD, BS, MRCP I D Morris, BPharm, PhD J R Carpenter, BSc, PhD Barbara J Pleuvry, BPharm, M J Dascombe, BPharm, PhD MSc, PhD, MRPharmS J F W Deakin, PhD, MRCPsych J L Shaffer, MB, BS, MRCP A J Duxbury, MSc, PhD, DDS, FDS, R C Small, BSc, MSc, PhD, RCPSGlas MRPharmS D J S Fernando, MD, BS, MRCP D G Thompson, MD, FRCP R W Foster, BSc, PhD, MB, BS R D G Tunbridge, MD, FRCP C C Hardy, MD, MRCP M Janet Vale, MSc, MRPharmS Ariane L Herrick, MD, MRCP A J Watt, BSc, PhD M Hollingsworth, BSc, PhD A H Weston, MSc, PhD G E Mawer, MB, ChB, BSc, PhD, P M Wilkinson, MB, ChB, FRCPEd FRCP Butterworth-Heinemann Ltd Linacre House, Jordan Hill, Oxford OX2 8DP £& IS PART OF REED INTERNATIONAL BOOKS OXFORD LONDON BOSTON MUNICH NEW DELHI SINGAPORE SYDNEY TOKYO TORONTO WELLINGTON First published 1980 Reprinted 1983,1985 Second edition 1986 Reprinted 1990 Third edition 1991 © Butterworth-Heinemann Ltd 1991 All rights reserved. No part of this publication may be reproduced in any material form (including photocopying or storing in any medium by electronic means and whether or not transiently or incidentally to some other use of this publication) without the written permission of the copyright holder except in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London, England W1P 9HE. Applications for the copyright holder's written permission to reproduce any part of this publication should be addressed to the publishers. British Library Cataloguing in Publication Data Basic pharmacology. - 3rd ed. I. Foster, R. W. 615 ISBN 0 7506 1414 5 Library of Congress Cataloguing in Publication Data Basic pharmacology / editor, R. W. Foster: authors, A. J. M. Boulton ... [et al.] - 3rd ed. p. cm. Includes bibliographical references and index. ISBN 0 7506 1414 5 1. Pharmacology. I. Foster, R. W. II. Boulton, A. J. M. (Andrew James Michael) [DNLM: 1. Drug Therapy. 2. Pharmacology. QV 4 B3109] RM300.B287 1991 615M—dc20 DNLM/DLC 91-26593 for Library of Congress CIP Printed in England by Clays Ltd, St Ives pic Preface This third edition of Basic Pharmacology retains the overall objectives of the first. It aims to present accounts of drug actions and their mechanisms in a compact, inexpensive and up-to-date form. The book is therefore designed to help students of subjects allied to medicine to appreciate the rationale underlying the uses of drugs in therapeutics. The authors of this book, the pharmacologists of the Department of Physiological Sciences at Manchester University and their teaching col leagues, have been able to draw on experience developed during many years of teaching pharmacology to students of several different disciplines. Such experience is tempered by other aspects of their work with drugs (prescrib ing, dispensing, laboratory-based and clinical research). The book is divided into sections. Each section follows a particular theme and is introduced by the relevant pharmacological general principles. Prompts to revise the relevant anatomical, biochemical or physiological concepts and data are also given. In each section the major groups of drugs relevant to the theme are discussed with detailed expositions of the import ant 'type' substances. Drugs of lesser importance are placed in proper context. As outlined in the introduction, this book is addressed to a wide spectrum of readers. We hope that no reader who intends to exploit the properties of drugs will fail to appreciate two key notions. (1) Selectivity (that is the ability to influence chemically one kind of biologi cal activity without modifying another) is the central theme of pharmacology. (2) Such selectivity is relative, rather than absolute. This places the onus of responsibility for safe usage firmly on the intending exploiter of the properties of drugs. The principal changes that this third edition of Basic Pharmacology shows from the second are: (1) updating (as of 1990) of the accounts of mechanisms of drug action; (2) updating (after British National Formulary [BNF] 1990, Number 20) of the selection of drugs for discussion; this encompasses not only the x Preface inclusion of new drugs and new mechanisms of drug action but also the deletion of drugs that have become obsolete; on this occasion the deletions outnumber the additions of new drug names; (3) movement of the section entitled General pharmacology from last to first position; (4) expansion of the chapters on adverse drug interactions, cardiac antidys- rhythmic drugs, calcium channel blockers, local hormones, chemother apy of bacterial infections; (5) substitution of fully rewritten chapters on adverse effects of drugs, drugs in diabetes mellitus, inflammatory bowel disease, congestive heart fail ure, asthma, drugs and mental disorders, epilepsy; (6) provision of new chapters on allergically determined hypersensitivity to drugs; (7) the provision of additional figures. Introduction This book is intended for all who are embarking on the study of pharmacol ogy. Most of its readers will be students of medicine, or of subjects allied to medicine (pharmacy, dentistry, nursing). These students will be studying pharmacology as a subsidiary subject and will require emphasis on the therapeutic exploitation of the properties of drugs. However, other students will regard pharmacology as their main or second subject in biological science. We teach all such students ourselves and have attempted to satisfy their needs in a single text. The text is broadly introductory, covering the first and second years of study by any of the above student groups. Our various readers will have two things in common: an interest in the uses to which drugs are put, and the fact that they are embarking on the study of pharmacology. Thus, we have provided a textbook that begins at the beginning, assuming only a modicum of chemistry, biology and physi ology as prerequisites. The book proceeds in the direction of paramedical or therapeutic, rather than chemical, pharmacology and it is assumed that the student will still be developing his knowledge of biology or physiology. The principal aim is to explain the basis of the current therapeutic exploi tation of drugs. Though some large reference texts already achieve this aim at an advanced level (the most eminent and highly recommended bears the title that most succinctly expresses this aim - The Pharmacological Basis of Therapeutics - see Suggested further reading) this book is offered to fill the need for a comprehensive yet simple and concise student text. Drug names A major problem encountered in the learning of pharmacology is the large and ever-increasing number of drug names. Certainly new students often complain of this. The complaint is not simply about weight of numbers but also about the apparent similarity in the names of drugs from different pharmacological groups. For the inexperienced (for whom drug names are invested with no 'personality') this can lead to misunderstanding and con fusion. Therefore, in this book we have defined a rigorous policy on drug names {see below). We have limited the number of drugs included, and have attempted an approach to the teaching of pharmacology that places a xii Introduction premium on understanding, clothing drug names with personality and re ducing rote memorization to the essential minimum. Policy on drug names We have used the nonproprietary names approved by the British Pharmaco- poeial Commission and have largely excluded trade names. For readers who are more familiar with North American terminology the US Pharmaco- poeial name has been included in square brackets in the text after the first occurrence of the name. However, only significant Anglo-American differ ences have been declared; we have not bothered to draw special attention to systematic differences arising from different spelling conventions (-ph- [-f-], -oe- [-e-]). Neither did -trophin [-tropin] nor -barbitone [-barbital] seem likely to mystify our readers. We were pleasantly surprised by the currently small number of significant differences, for there was formerly an era of fundamental differences, witness paracetamol [acetaminophen] and pethidine [meperidine]. Modern drugs are deliberately being assigned the same name on both sides of the Atlantic. Policy on which drugs to include We have actively sought to limit the number of different drugs described because our primary objective has been to teach the principles of the pharmacological basis of therapeutics rather than familiarity with all drugs. We have therefore a narrower scope than the BNF, MIMS or the Data Sheet Compendium, which seek full coverage of available drugs - we describe a limited selection of the most useful drugs. We have followed the advice offered in the Notes for prescribers sections of the BNF on the selection of drugs with maximum available therapeutic efficacy and minimal contam inating toxicity. An acknowledged reference drug - described first and placed out of alphabetical order - is an obvious choice for one of our 'type substances' (see below). This policy is very similar to that adopted by the WHO Expert Committee reporting on The Selection of Essential Drugs. Drugs have been categorized according to two criteria: (1) Drugs listed in BNF (1990) and printed in bold type in one of the Notes for prescribers sections are italicized (for example, nonproprietary name). (2) From each pharmacological group of drugs we have, if possible, chosen one that typifies the group. If its actions are understood the rest of the group, too, has been comprehended. We show these substances in bold type (for example, nonproprietary name). The plan of the book Each of the eight sections of the book is a reasonably self-contained unit that expounds a particular pharmacological theme. We have tried to limit the presentation of material to a single occasion, in its most appropriate lo cation. Cross-references are provided, in preference to succumbing to the temptation to repeat material, when it is relevant to more than one theme. Introduction xiii Book use that follows the order of the sections will therefore result in minimal following of cross-references leading to new material but the reader intent on acquiring all the contained information on one drug will have to use the index. The book opens with a section, the theme of which is those general principles that need no specific drug group, physiological system or disease state for their discussion but that can be exemplified from any or all of the other sections. The drugs that act on peripheral excitable tissues by modulating signalling and transduction mechanisms directly related to receptors for the neu- rotransmitters acetylcholine and noradrenaline impinge on so many physio logical systems that they are most efficiently dealt with as a theme, and comprise our second section. This is a theme presented early in the book because it is in this area that mechanisms of drug action are probably best understood. Also, the system can be used as a model to predict or infer the mechanism of action of drugs in other less well understood areas (for example, central nervous system, CNS). The third section collects together groups of drugs also acting on periph eral tissues but by modulating signalling and transduction mechanisms other than those directly related to receptors for neurotransmitters and hormones. The fourth and fifth sections - Endocrine pharmacology and Drug action on the central nervous system - correspond with the system-based subdivision of the subject common in therapeutic texts, though the former section includes Local hormones. Our understanding of drug action in the CNS leans heavily on the concepts of specific interaction with physiological chemical mediators developed in the preceding sections. A second important principle - that of nonspecific depressant action on biological function - also emerges. So far the section themes have been drug interactions with endogenous systems but in the sixth section consideration is given to the mechanism of drug action on parasites, be they metazoa, microorganisms or neoplastic cells. The emphasis is now on mechanisms by which parasitic cell growth or survival is selectively inhibited. By now the student has been provided with sufficient information in pharmacology for drugs to be no longer simply names. The theme of the seventh section therefore changes from drug action to drug disposition and metabolism - from what drugs do to the body to what the body does to drugs - so that an appreciation of how these factors influence drug action can be gained. Our eighth section - Clinical pharmacology - illustrates, at least for certain carefully selected disease states, how the principles and concepts of mechanistic pharmacology are exploited in the setting of practical therapeutics. Policy on unfamiliar words Words that are unfamiliar to the reader may be part of the technical language of medicine or pharmacology and all such we have defined or explained on their first occurrence. A second category exists in the ordinary stock of the English language - definitions are not provided in the text and the reader is advised to consult a dictionary. xiv Introduction Text revision Pharmacology, like most other scientific disciplines, develops rapidly and the perennial problem of any text is that of keeping up-to-date. We intend to make regular revisions of this book. The text has had the benefit of passing through several stages of evolution and refinement. In the form of comprehensive lecture note handouts it was used by Manchester students in its prepublication years and we thank all our previous students who have consciously or unconsciously suggested im provements. We should be happy to receive suggestions for further im provement from users of the book. Acknowledgements We thank John Carpenter for preparing the new and altered diagrams, Kay Bond for typing the new sections of manuscript, staff at Butterworth- Heinemann for their care and attention in guiding this book through to publication, John Carpenter for preparing the index and all our colleagues for the time invested in evolving common policies and in proof reading. Aims and objectives The aim of this book is to provide the sound pharmacological basis on which could be built a rational approach to therapeutics. By the end of the book the reader should: • recognize a selection of the British Pharmacopoeia Commission Ap proved names of drugs appearing in bold type in the Notes for prescribers sections of the BNF (latest edition) and be able to group together those drugs that share common pharmacological properties; • know the pharmacological properties of each drug group that are relevant to its therapeutic uses and adverse effects, with special emphasis on those that can be deduced from a knowledge of the site and mechanism of action; • know the general principles of the subject and thus be able to assess the described properties and therapeutic claims made for any new drug or group of drugs. List of abbreviations These abbreviations are used in multiple locations in the book; there are others, just used in a single chapter, that are defined where first used. ACE angiotensin converting enzyme ACh acetylcholine AChE acetylcholinesterase ACTH adrenocorticotrophic hormone, corticotrophin ADH antidiuretic hormone ATP adenosine triphosphate AV atrioventricular BMR basal metabolic rate BNF British National Formulary BP blood pressure C. Corynebacterium cAMP cyclic 3'5'adenosine monophosphate cf- (lit. confer) compare cGMP cyclic 3'5'guanosine monophosphate ChE cholinesterase Cl. Clostridium CL clearance CNS central nervous system CoA coenzyme A COMT catechol-O-methyl transferase CSF cerebrospinal fluid CTZ chemosensitive trigger zone d- deci (10-!) Da Dalton DHF dihydrofolate DNA deoxyribonucleic acid dopa dihydroxyphenylalanine E. Escherichia EC50 concentration of drug evoking a half maximal effect ECF extracellular fluid xvi List of abbreviations eg- (lit. exampli gratia) for example epp end plate potential epsp excitatory postsynaptic potential FEV! forced expiratory volume in one second FSH follicle stimulating hormone g gram GABA gamma-aminobutyric acid GFR glomerular filtration rate GH growth hormone GMP guanosine monophosphate GTP guanosine triphosphate H. Haemophilus h hour HCG human chorionic gonadotrophin HMG human menopausal gonadotrophin 5-HT 5-hydroxytryptamine Hz Hertz (1 Hertz is 1 cycle per second) Ig- immunoglobulin- im intramuscular, intramuscularly ip inositol 1,4,5-trisphosphate 3 iv intravenous, intravenously k- kilo- (103) Kl. Klebsiella 1 litre LH luteinizing hormone lit. literally log logarithm LT leukotriene ^ micro- (10~6) M. Mycobacterium m metre m- milli- (10-3) MAC minimum alveolar concentration for anaesthesia MAO monoamine oxidase MFO mixed function oxidase mic minimum inhibitory concentration min minute mol mole (gram molecular weight) mRNA messenger ribonucleic acid MW molecular weight N. Neisseria n- nano- (10~9) NA noradrenaline NADPH nicotinamide adenine nucleotide phosphate (reduced) NSAID nonsteroidal anti-inflammatory drug P. Plasmodium P- partial pressure Pa- arterial blood partial pressure PG prostaglandin Ps. Pseudomonas
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