CLINICAL PHARMACOLOGY 'Nature is not only odder than we think, but it is odder than we can think.' J B S Haldane 1893-1964 'Patients may recover in spite of drugs or because of them.' J H Gaddum 1959 'But know also, man has an inborn craving for medicine the desire to take medicine is one feature which distinguishes man the animal, from his fellow creatures It is really one of the most serious difficulties with which we have to contend the doctor's visit is not thought to be complete without a prescription.' William Osier 1894 'Morals not forbid making experiments on one's neighbour or on one's self among the experiments that may be tried on man, those that can only harm are forbidden, those that are innocent are permissible, and those that may good are obligatory.' 'Men who have excessive faith in their theories or ideas are not only ill prepared for making discoveries; they make very poor observations they can see in [their] results only a confirmation of their theory This is what made us say that we must never make experiments to confirm our ideas, but simply to control them.' 'Empiricism is not the negation of science, as certain physicians seem to think; it is only its first stage.' 'Medicine is destined to get away from empiricism little by little; like all other sciences, it will get away by the scientific method.' 'Considered in itself, the experimental method is nothing but reasoning by whose help we methodically submit our ideas to experience — the experience of facts.' Claude Bernard 1865 'I not want two diseases — one nature-made, one doctormade.' Napoleon Bonaparte 1820 'The ingenuity of man has ever been fond of exerting itself to varied forms and combinations of medicines.' William Withering 1785 'All things are poisons and there is nothing that is harmless, the dose alone decides that something is no poison.' Paracelsus 1493-1541 'First no harm.' 'It is a good remedy sometimes to use nothing.' Hippocrates 460-355 B.C CLINICAL PHARMACOLOGY P N Bennett MD FRCP Reader in Clinical Pharmacology, University of Bath, and Consultant Physician, Royal United Hospital, Bath, UK M J Brown MA MSC MD FRCP Professor of Clinical Pharmacology, University of Cambridge; Consultant Physician, Addenbrooke's Hospital, Cambridge and Director of Clinical Studies Gonville and Caius College, Cambridge, UK NINTH EDITION CHURCHILL LIVINGSTONE EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2003 CHURCHILL LIVINGSTONE An imprint of Elsevier Science Limited © D R Laurence 1960,1962,1966,1973 © D R Laurence and P N Bennett 1980,1987,1992 © D R Laurence, P N Bennett, M J Brown 1997 © P N Bennett, M J Brown 2003 Commissioning Editor: Timothy Home Project Development Manager: Colin Arthur Copy Editor: Leslie Smillie Project Controller: Nancy Arnott Designer: Erik Bigland The right of P N Bennett and M J Brown to be identified as the authors of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988 No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without either the prior permission of the publishers or a licence permitting restricted copying in the United Kingdom issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London WIT 4LP Permissions may be sought directly from Elsevier's Health Sciences Rights Department in Philadelphia, USA: phone: (+1) 215 238 7869, fax: (+1) 215 238 2239, e-mail: healthpermissions@elsevier.com You may also complete your request on-line via the Elsevier Science homepage (http://www.elsevier.com), by selecting 'Customer Support' and then 'Obtaining Permissions' First edition 1960 Second edition 1962 Third edition 1966 Fourth edition 1973 Fifth edition 1980 Sixth edition 1987 Seventh edition 1992 Eighth edition 1997 Previous editions translated into Italian, Chinese, Spanish, Serbo-Croat, Russian Standard edition ISBN 0443064806 International Student Edition ISBN 0443064814 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress The publisher's policy is to use paper manufactured from sustainable forest! Printed in Spain Preface For your own satisfaction and for mine, please read this preface!1 Professor D R Laurence was either author or coauthor of this textbook from its 1st edition in 1960 to its 8th in 1997 This is a long life for any textbook Its achievement bears testimony to a style of presentation that strives to be clear and readable, and to retain the reader's interest whilst imparting information about a subject that can be at times both complex and confusing As he withdraws from active involvement in the book it is opportune to pay tribute in this 9th edition to an achievement in authorship sustained over four decades, during which 'Laurence's pharmacology' became the aid, advisor and companion to generations of students and doctors seeking guidance in the vital field of medicinal therapeutics This book is about the scientific basis and practice of drug therapy It is particularly intended for medical students and doctors, and indeed for anyone concerned with evidence-based drug therapy and prescribing The scope and rate of drug innovation increases Doctors are now faced with a professional lifetime handling drugs that are new to themselves — drugs that new things as well as drugs that old things better; drugs that become familiar during training will be superseded We not write only for readers who, like us, have a special interest in pharmacology We try to make pharmacology understandable for those whose primary interests lie elsewhere but who recognise that they need some knowledge of pharmacology if they are to meet their moral and legal 'duty of care' to their patients We try to tell them what they need to know without burdening them with irrelevant information and we try to make the subject interesting We are very serious, but seriousness does not always demand wearying solemnity An author, poet and critic said that he judged fiction thus: 'Could I read it? If I could read it, did I believe it? If I believed it, did I care about it, what was the quality of my caring, and did it last?'2 It would be presumptuous for us to aspire to satisfy the criteria for fiction but we have been mindful of them in producing this book All who prescribe drugs would be wise to keep in mind that the expectations of patients and of society in general are becoming ever more exacting and that doctors who prescribe casually or ignorantly now face not only increasing criticism but also civil (or even criminal) legal charges The ability to handle new developments depends, now more than ever, on comprehension of the principles of pharmacology These principles are not difficult to grasp and are not so many as to defeat even the busiest doctors who take on themselves the responsibility of introducing manufactured medicines into the bodies of their patients The principles of pharmacology and drug therapy will be found in chapters 1-8 and they are applied in the subsequent specialist chapters which are offered as a reasonably brief solution to the problem of combining practical clinical utility with some account of the principles on which clinical practice rests How much practical technical detail to include is difficult to decide In general, where therapeutic practices that are complex, potentially dangerous and commonly up-dated, e.g anaphylactic shock, we provide more detail together with web-sites that list the latest advice; less, or even no detail is given on therapy that is generally conducted only by specialists, e.g anticancer drugs and i.v oxytocin But always, especially with modern drugs with which the prescriber may not be familiar, formularies, approved guidelines, or the manufacturer's current literature should be consulted St Francis of Sales: Preface to Introduction to the devout life (1609) Philip Larkin: 1922-85 v PREFACE Use of the book Students are, or should be, concerned to understand and to develop a rational, critical attitude to drug therapy and they should therefore chiefly concern themselves with how drugs act and interact in disease and with how evidence of therapeutic effect is obtained and evaluated To this end they should read selectively and should not impede themselves by attempts to memorise lists of alternative drugs and doses and minor differences between them, which should never be required of them in examinations Thus the text has not been encumbered with exhaustive lists of preparations which properly belong in a formulary, although it is hoped that enough have been mentioned to cover much routine prescribing, and many drugs have been included solely for identification The role and status of a textbook If a book is to be a useful guide to drug use it must offer clear conclusions and advice If it is to be of reasonable size, alternative acceptable courses of action will often have to be omitted What is recommended should be based on sound evidence where this exists, and on an assessment of the opinions of the experienced where it does not Increasingly, the selection of drugs is influenced by guidelines produced by specialist societies and national bodies We have provided or made reference to these as representing a consensus of best practice vi in particular situations Similarly, it is assumed that the reader possesses a formulary, local or national, which will provide guidance on the availability, including doses, of a broad range of drugs But the practice of therapeutics by properly educated and conscientious doctors working in settings complicated by intercurrent disease, metabolic differences or personality, involves challenges beyond the rigid adherence to published recommendations The role of a textbook is to provide the satisfaction of understanding the basis for a recommended course of action so that an optimal result may be achieved by informed selection and use of drugs The guide to further reading at the end of each chapter generally comprises a few references to original papers, to referenced editorials and review articles from a small range of English language journals that are likely to be available in most hospital libraries in order to enable anyone, anywhere, to gain access to the original literature and to informed opinion, and also to provide interest and sometimes amusement We urge readers to select a title that looks interesting and to read the article We not attempt to document all the statements we make, which would be impossible in a book of this size Bath, Cambridge 2003 P.N.B., M.J.B Farewell This book originated in 1957 when I, then senior lecturer in the Department of Pharmacology and in the Department of Medicine at University College and Medical School London, told the Professor of Medicine that there was no book on Clinical Pharmacology that I could recommend to our medical students He replied that if that was so then I should get down to it and write such a book I doubted that I could accomplish the task He marched me off to a nearby medical publisher and a contract was soon signed Without this pressure and the long-sustained support of Max Rosenheim (later Lord Rosenheim of Camden and President of the Royal College of Physicians of London) this book would not have materialised in its first edition in 1960 Since that date, both in collaboration and alone, there have been eight editions I am deeply grateful to my collaborators Now, after above 40 years with the book, and in my eightieth year, the time has come to stand aside I have seen too many elderly academics become unable, or unwilling, to recognise that they are no longer quite the people that they once were and that they have become an embarrassment to their younger colleagues, who are often too kind to enlighten them; though they may murmur behind their senior's back I long ago decided that I must not join that group, and I hope I may just have escaped doing so Perhaps my greatest reward has been the kindness of people from all over the world who have taken the trouble to communicate to me that they have not only profited from, but have actually enjoyed, reading Clinical Pharmacology The world of clinical pharmacology has greatly changed since 1957 when I took up my pen, and I wish my successors well D R Laurence, Professor Emeritus of Pharmacology and Therapeutics, University College London vii This page intentionally left blank CONTENTS Section ENDOCRINE SYSTEM, METABOLIC CONDITIONS 34 Adrenal corticosteroids, antagonists, corticotrophin 663 35 Diabetes mellitus, insulin, oral antidiabetes agents, obesity 679 xiv 36 Thyroid hormones, antithyroid drugs 699 37 Hypothalamic, pituitary and sex hormones 709 38 Vitamins, calcium, bone 735 Index 745 SECTION | GENERAL This page intentionally left blank I Topics in drug therapy SYNOPSIS The therapeutic situation Drug therapy involves considerations beyond the strictly scientific pharmacological aspects of medicines.These include numerous issues relating to prescribers themselves and to patients • The therapeutic situation — latrogenic disease — Benefits and risks — Public view of drugs and prescribers — Criticisms of modern drugs — Drug-induced injury — Complementary medicine • Prescribing, drug consumption and economics — Reasons for taking a drug history — Cost-containment — Repeat prescriptions — Warnings and consent — Legal hazards for prescribers — Formularies and 'essential' drugs • Compliance — patient and doctor • Placebo medicines • Pharmacoeconomics • Self-medication Appendix I: WHO list of essential drugs Appendix 2: The prescription Poisons in small doses are the best medicines; and useful medicines in too large doses are poisonous (William Withering,'discoverer' of digitalis, 1789) The use of drugs1 to increase human happiness by elimination or suppression of diseases and symptoms and to improve the quality of life in other ways is a serious matter and involves not only technical, but also psychosocial considerations Overall, the major benefits of modern drugs are on quality of life (measured with difficulty), and exceed those on quantity of life (measured with ease).2 We therefore begin this book with a series of essays on what we think are important topics A World Health Organization Scientific Group has defined a drug as 'any substance or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient' WHO 1966 Technical Report Series no 341: A less restrictive definition is 'a substance that changes 'a biological system by interacting with it' A drug is a single chemical substance that forms the active ingredient of a medicine (a substance or mixture of substances used in restoring or preserving health) A medicine may contain many other substances to deliver the drug in a stable form, acceptable and convenient to the patient The terms will be used more or less interchangeably in this book To use the word 'drug' intending only a harmful, dangerous or addictive substance is to abuse a respectable and useful word I TOPICS IN DRUG T H E R A P Y Medicines are part of our way of life from birth, when we enter the world with the aid of drugs, to death where drugs assist (most of) us to depart with minimal distress and perhaps even with a remnant of dignity In between these events we regulate our fertility, often, with drugs We tend to take such usages for granted But during the intervals remaining, an average family experiences illness on one day in four and between the ages of 20 and 45 years a lowermiddle-class man experiences approximately one life-endangering illness, 20 disabling (temporarily) illnesses, 200 non-disabling illnesses and 1000 symptomatic episodes: the average person in the USA can expect to have about 12 years of bad health in an average lifespan.3 And medicines play a major role in these 'At any time, 40-50% of adults [UK] are taking a prescribed medicine.'4 Before treating any patient with drugs, doctors should have made up their minds on eight points: Whether they should interfere with the patient at all and if so — What alteration in the patient's condition they hope to achieve That the drug they intend to use is best capable of bringing this about How they will know when it has been brought about That they can administer the drug in such a way that the right concentration will be attained in the right place at the right time and for the right duration What other effects the drug may have and whether these may be harmful How they will decide to stop the drug Consider, for example, the worldwide total of suffering relieved and prevented each day by anaesthetics (local and general) and by analgesics, not forgetting dentistry which, because of these drugs, no longer strikes terror into even the most stoical as it has done for centuries Quoted in: Anderson J A D (ed) 1979 Self medication MTP Press, Lancaster; USA Public Health Service 1995 George C F 1994 Prescribers' Journal 34: A moment's reflection will bring home to us that this is an astounding statistic which goes a long way to account for the aggressive promotional activities of the highly competitive international pharmaceutical industry; the markets for medicines are colossal Whether the likelihood of benefit, and its importance, outweighs the likelihood of damage, and its importance, i.e to consider benefit versus risk, or efficacy in relation to safety Drug therapy involves a great deal more than matching the name of the drug to the name of a disease; it requires knowledge, judgement, skill and wisdom, but above all a sense of responsibility A book can provide knowledge and can contribute to the formation of judgement, but it can little to impart skill and wisdom, which are the products of example of teachers and colleagues, of experience and of innate and acquired capacities 'It is evident that patients are not treated in a vacuum and that they respond to a variety of subtle forces around them in addition to the specific therapeutic agent.'5 When a patient is given a drug the responses are the resultant of numerous factors: • The pharmacodynamic effect of the drug and interactions with any other drugs the patient may be taking • The pharmacokinetics of the drug and its modification in the individual due to genetic influences, disease, other drugs • The physiological state of the end-organ — whether, for instance, it is over- or underactive • The act of medication, including the route of administration and the presence or absence of the doctor • The doctor's mood, personality, attitudes and beliefs • The patient's mood, personality, attitudes and beliefs • What the doctor has told the patient • The patient's past experience of doctors • The patient's estimate of what has been received and of what ought to happen as a result • The social environment, e.g whether supportive or dispiriting The relative importance of these factors varies according to circumstances An unconscious patient Sherman L J 1959 American Journal of Psychiatry 116: 208 ... reading Clinical Pharmacology The world of clinical pharmacology has greatly changed since 1957 when I took up my pen, and I wish my successors well D R Laurence, Professor Emeritus of Pharmacology. .. a good remedy sometimes to use nothing.'' Hippocrates 460-355 B.C CLINICAL PHARMACOLOGY P N Bennett MD FRCP Reader in Clinical Pharmacology, University of Bath, and Consultant Physician, Royal... special interest in pharmacology We try to make pharmacology understandable for those whose primary interests lie elsewhere but who recognise that they need some knowledge of pharmacology if they