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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...

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  2. '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 do 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 do 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 do not want two diseases — one nature-made, one doctor- made.' 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 do no harm.' 'It is a good remedy sometimes to use nothing.' Hippocrates 460-355 B.C.
  3. 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
  4. CHURCHILL LIVINGSTONE Commissioning Editor: Timothy Home An imprint of Elsevier Science Limited Project Development Manager: Colin Arthur Copy Editor: Leslie Smillie © D. R. Laurence 1960,1962,1966,1973 Project Controller: Nancy Arnott © D. R. Laurence and P. N. Bennett 1980,1987,1992 Designer: Erik Bigland © D. R. Laurence, P. N. Bennett, M. J. Brown 1997 © P. N. Bennett, M. J. Brown 2003 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: You may also complete your request on-line via the Elsevier Science homepage (, by selecting 'Customer Support' and then 'Obtaining Permissions'. First edition 1960 Previous editions translated into Second edition 1962 Italian, Chinese, Spanish, Third edition 1966 Serbo-Croat, Russian Fourth edition 1973 Fifth edition 1980 Sixth edition 1987 Seventh edition 1992 Eighth edition 1997 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
  5. Preface For your own satisfaction and for mine, please does not always demand wearying solemnity. An read this preface!1 author, poet and critic said that he judged fiction thus: 'Could I read it? If I could read it, did I believe Professor D. R. Laurence was either author or co- it? If I believed it, did I care about it, what was the author of this textbook from its 1st edition in 1960 to quality of my caring, and did it last?'2 It would be its 8th in 1997. This is a long life for any textbook. Its presumptuous for us to aspire to satisfy the criteria achievement bears testimony to a style of pre- for fiction but we have been mindful of them in sentation that strives to be clear and readable, and producing this book. to retain the reader's interest whilst imparting All who prescribe drugs would be wise to keep information about a subject that can be at times in mind that the expectations of patients and of both complex and confusing. As he withdraws from society in general are becoming ever more exacting active involvement in the book it is opportune to and that doctors who prescribe casually or ignorantly pay tribute in this 9th edition to an achievement in now face not only increasing criticism but also civil authorship sustained over four decades, during (or even criminal) legal charges. The ability to handle which 'Laurence's pharmacology' became the aid, new developments depends, now more than ever, advisor and companion to generations of students on comprehension of the principles of pharma- and doctors seeking guidance in the vital field of cology. These principles are not difficult to grasp medicinal therapeutics. and are not so many as to defeat even the busiest doctors who take on themselves the responsibility This book is about the scientific basis and practice of drug of introducing manufactured medicines into the therapy. It is particularly intended for medical students and bodies of their patients. doctors, and indeed for anyone concerned with evidence-based The principles of pharmacology and drug drug therapy and prescribing. therapy will be found in chapters 1-8 and they are applied in the subsequent specialist chapters which The scope and rate of drug innovation increases. are offered as a reasonably brief solution to the Doctors are now faced with a professional lifetime problem of combining practical clinical utility with handling drugs that are new to themselves — drugs some account of the principles on which clinical that do new things as well as drugs that do old practice rests. things better; drugs that become familiar during How much practical technical detail to include is training will be superseded. difficult to decide. In general, where therapeutic We do not write only for readers who, like us, practices that are complex, potentially dangerous have a special interest in pharmacology. We try to and commonly up-dated, e.g. anaphylactic shock, make pharmacology understandable for those whose we provide more detail together with web-sites that primary interests lie elsewhere but who recognise list the latest advice; less, or even no detail is given that they need some knowledge of pharmacology if on therapy that is generally conducted only by they are to meet their moral and legal 'duty of care' specialists, e.g. anticancer drugs and i.v. oxytocin. to their patients. We try to tell them what they need But always, especially with modern drugs with which to know without burdening them with irrelevant the prescriber may not be familiar, formularies, information and we try to make the subject approved guidelines, or the manufacturer's current interesting. We are very serious, but seriousness literature should be consulted. 1 St Francis of Sales: Preface to Introduction to the devout life 2 (1609) Philip Larkin: 1922-85 v
  6. PREFACE Use of the book. Students are, or should be, in particular situations. Similarly, it is assumed that concerned to understand and to develop a rational, the reader possesses a formulary, local or national, critical attitude to drug therapy and they should which will provide guidance on the availability, therefore chiefly concern themselves with how drugs including doses, of a broad range of drugs. But the act and interact in disease and with how evidence practice of therapeutics by properly educated and of therapeutic effect is obtained and evaluated. conscientious doctors working in settings com- To this end they should read selectively and should plicated by intercurrent disease, metabolic differences not impede themselves by attempts to memorise or personality, involves challenges beyond the rigid lists of alternative drugs and doses and minor adherence to published recommendations. The role differences between them, which should never of a textbook is to provide the satisfaction of be required of them in examinations. Thus the text understanding the basis for a recommended course has not been encumbered with exhaustive lists of action so that an optimal result may be achieved of preparations which properly belong in a by informed selection and use of drugs. formulary, although it is hoped that enough have The guide to further reading at the end of each been mentioned to cover much routine prescribing, chapter generally comprises a few references to and many drugs have been included solely for original papers, to referenced editorials and review identification. articles from a small range of English language The role and status of a textbook. If a book is to journals that are likely to be available in most hospital be a useful guide to drug use it must offer clear libraries in order to enable anyone, anywhere, to gain conclusions and advice. If it is to be of reasonable access to the original literature and to informed size, alternative acceptable courses of action will opinion, and also to provide interest and sometimes often have to be omitted. What is recommended amusement. We urge readers to select a title that should be based on sound evidence where this looks interesting and to read the article. We do not exists, and on an assessment of the opinions of the attempt to document all the statements we make, experienced where it does not. which would be impossible in a book of this size. Increasingly, the selection of drugs is influenced by guidelines produced by specialist societies and national bodies. We have provided or made reference Bath, Cambridge P.N.B., to these as representing a consensus of best practice 2003 M.J.B. vi
  7. Farewell This book originated in 1957 when I, then senior I have seen too many elderly academics become lecturer in the Department of Pharmacology and in unable, or unwilling, to recognise that they are no the Department of Medicine at University College longer quite the people that they once were and that and Medical School London, told the Professor of they have become an embarrassment to their Medicine that there was no book on Clinical younger colleagues, who are often too kind to Pharmacology that I could recommend to our enlighten them; though they may murmur behind medical students. He replied that if that was so then their senior's back. I long ago decided that I must I should get down to it and write such a book. I not join that group, and I hope I may just have doubted that I could accomplish the task. He escaped doing so. marched me off to a nearby medical publisher and a Perhaps my greatest reward has been the contract was soon signed. Without this pressure kindness of people from all over the world who and the long-sustained support of Max Rosenheim have taken the trouble to communicate to me that (later Lord Rosenheim of Camden and President of they have not only profited from, but have actually the Royal College of Physicians of London) this enjoyed, reading Clinical Pharmacology. book would not have materialised in its first edition The world of clinical pharmacology has greatly in 1960. Since that date, both in collaboration and changed since 1957 when I took up my pen, and I alone, there have been eight editions. I am deeply wish my successors well. grateful to my collaborators. Now, after above 40 years with the book, and in D R Laurence, Professor Emeritus of Pharmacology my eightieth year, the time has come to stand aside. and Therapeutics, University College London vii
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  9. Contributors It is not possible for two individuals to cover the Christopher R Lovell MD FRCP whole field of drug therapy from their own Consultant Dermatologist, Royal United Hospital, knowledge and experience. For the first time in this Bath, UK 9th edition, we invited selected experts to review Chapter 16. Drugs and the skin chapters in their specialty. They were given free rein to add, delete or amend existing text as they deemed G R Park MD, DMedSci appropriate. As a result, some chapters exhibit Director of Intensive Care Research, Addenbrooke's substantial changes from the 8th edition, and all Hospital, Cambridge, UK have benefited greatly from the knowledge and experience of these individuals. We are deeply J Grewal MBBS indebted for their contributions. They are: SHO, The John Farman Intensive Care Unit, Addenbrooke's Hospital, Cambridge, UK Nigel S Baber BSc, FRCP, FRCPEd, FFPM, Dip Clin Chapter 17. Pain and analgesics Pharmacol Head of Renewals, Reclassification and Patient Jerry Nolan FRCA Safety, Medicines Control Agency, London, UK and Consultant in Anaesthesia and Intensive Care, Visiting Professor, Queen Mary and Westfield Royal United Hospital, Bath, UK College, University of London, London, UK Chapter 18. Anaesthesia and neuromuscular block Chapter 3. Discovery and development of drugs Chapter 4. Evaluation of drugs in man Simon J C Davies MA (Oxon), MBBS (Lond), Chapter 5. Official regulation of medicines MRCPsych Chapter 6. Classification and naming of drugs Clinical Research Fellow, University of Bristol, Bristol, UK Mark Farrington MA, MB, BChir, FRCPath Consultant Microbiologist, Addenbrooke's Sue Wilson PhD Hospital, Cambridge, UK Research Fellow, University of Bristol, Bristol, UK Chapter 11. Chemotherapy of infections David J Nutt MB BChir, MA, DM, FRCP, Chapter 12. Antibacterial drugs FRC Psych, FMedSci Chapter 13. Chemotherapy of bacterial infections Professor of Psychopharmacology, Head of the Chapter 14. Viral, fungal, protozoal and helminthic Department of Clinical Medicine, infections Dean of Clinical Medicine and Dentistry, Nicola J Minaur BSc, MB ChB, PhD University of Bristol, Bristol, UK Specialist Registrar in Rheumatology, Royal National Chapter 19. Psychotropic drugs Hospital for Rheumatic Diseases, Bath, UK D Bateman MD FRCP Neil John McHugh MB, ChB, FRACP, MD, FRCP Consultant Neurologist, Royal United Hospital Consultant Rheumatologist, Royal National NHS Trust, Bath, UK Hospital for Rheumatic Diseases, Bath, UK Chapter 20. Epilepsy, parkinsonism and allied Chapter 15. Inflammation, arthritis and nonsteroidal conditions anti-inflammatory drugs ix
  10. CONTRIBUTORS Kevin M O'Shaughnessy MA, BM, BCh, DPhil, Charles R J Singer BSc, MB, ChB, FRCP, FRCPath FRCP Consultant Haematologist, Royal United Hospital, University Lecturer in Clinical Pharmacology and Bath, UK Honorary Consultant Physician, Addenbrooke's Chapter 30. Neoplastic disease and immunosuppression Hospital, Cambridge, UK Chapter 21. Cholinergic and antimuscarinic Michael Davis MD FRCP, Consultant (anticholinergic) mechanisms and drugs Gastroenterologist, Royal United Hospital, Bath, Chapter 22. Adrenergic mechanisms and drugs UK Chapter 23. Arterial hypertension, angina pectoris, Chapter 31. Stomach, oesophagus and duodenum myocardial infarction Chapter 32. Intestines Chapter 24. Cardiac arrhythmia and cardiac failure Chapter 33. Liver, biliary tract, pancreas Chapter 25. Hyperlipidaemias Chapter 26. Kidney and urinary tract D C Brown MD, MSc, FRCP Chapter 27. Respiratory system Consultant Endocrinologist, Cromwell Hospital, London, UK Andrew Grace PhD, FRCP, FACC Chapter 34. Adrenal corticosteroids, antagonists, Consultant Cardiologist, Papworth Hospital, corticotrophin Cambridge, UK Chapter 35. Diabetes mellitus, insulin, oral Chapter 24. Cardiac arrhythmia and cardiac failure antidiabetes agents, obesity Chapter 36. Thyroid hormones, antithyroid drugs Charles R J Singer BSc, MB, ChB, FRCP, FRCPath Chapter 37. Hypothalamic, pituitary and sex hormones Consultant Haematologist, Royal United Hospital, Chapter 38. Vitamins, calcium, bone Bath, UK Chapter 28. Drugs and haemostasis Chapter 29. Cellular disorders and anaemias Pippa G Corrie PhD, FRCP Consultant and Associate Lecturer in Medical Oncology, Addenbrooke's Hospital and University of Cambridge, Cambridge, UK X
  11. Acknowledgements Aditionally, we express our gratitude to others who others too numerous to mention who have put their have, with such good grace, given us their time and knowledge and practical experience of the use of energy to supply valuable facts and opinions for drugs at our disposal. We hope that this collective this and previous editions; they principally include: acknowledgement will be acceptable. Errors are our Dr E S K Assem, Dr Stella Barnass, Dr N B Bennett, own. Dr Noeleen Foley, Dr Sheila Gore, Professor J In addition, permission to quote directly from Guillebaud, Professor D H Jenkinson, Dr H Ludlam, the writings of some authorities has been generously Professor P J Maddison, Dr P T Macgee, the late granted and we thank the authors and their Professor Sir William Paton, Professor B N C Prichard, publishers who have given it. If we have omitted Dr J P D Reckless, Dr Catriona Reid, Dr Andrew any acknowledgement that ought to have been Souter, Professor P L Weissberg. made we will make such amends as we can as soon Other acknowledgements are made in the as we can. appropriate places. Much of any merit this book may have is due to P.N.B. the generosity of those named above as well as M.J.B. Note from the authors and publisher Medical knowledge is constantly changing. Standard dose, the method and duration of administration, safety precautions must be followed, but as new and contraindications. It is the responsibility of the research and clinical experience broaden our practitioner, relying on experience and knowledge knowledge, changes in treatment and drug therapy of the patient, to determine dosages and the best may become necessary or appropriate. Readers are treatment for each individual patient. Neither the advised to check the most current product Publisher nor the authors assumes any liability for information provided by the manufacturer of each any injury and/or damage to persons or property drug to be administered to verify the recommended arising from this publication. xi
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  13. Contents Preface v Section 4 NERVOUS SYSTEM Farewell vii 17. Pain and analgesics 319 Contributors ix 18. Anaesthesia and neuromuscular block 345 Acknowledgements xi 19. Psychotropic drugs 367 Note from the authors and publishers xi 20. Epilepsy, parkinsonism and allied conditions Section 1 413 GENERAL Section 5 1. Topics in drug therapy 3 CARDIORESPIRATORY AND RENAL 2. Clinical pharmacology 37 SYSTEMS 3. Discovery and development of drugs 41 21. Cholinergic and antimuscarinic (anticholinergic) mechanisms and drugs 432 4. Evaluation of drugs in man 51 22. Adrenergic mechanisms and drugs 447 5. Official regulation of medicines 73 23. Arterial hypertension, angina pectoris, 6. Classification and naming of drugs 83 myocardial infarction 461 Section 2 24. Cardiac arrhythmia and cardiac failure 497 FROM PHARMACOLOGY TO TOXICOLOGY 25. Hyperlipidaemias 521 7. General pharmacology 89 26. Kidney and Genitourinary tract 529 8. Unwanted effects and adverse drug 27. Respiratory system 549 reactions 135 9. Poisoning, overdose, antidotes 151 Section 6 BLOOD AND NEOPLASTIC DISEASE 10. Nonmedical use of drugs 165 28. Drugs and haemostasis 567 Section 3 29. Cellular disorders and anaemias 587 INFECTION AND INFLAMMATION 30. Neoplastic disease and immunosuppression 11. Chemotherapy of infections 201 603 12. Antibacterial drugs 215 Section 7 13. Chemotherapy of bacterial infections 237 GASTROINTESTINAL SYSTEM 14. Viral, fungal, protozoal and helminthic 31. Stomach, oesophagus and duodenum 625 infections 257 32. Intestines 639 15. Inflammation, arthritis and nonsteroidal anti- inflammatory drugs 279 33. Liver, biliary tract, pancreas 651 16. Drugs and the skin 299 xiii
  14. CONTENTS Section 8 36. Thyroid hormones, antithyroid drugs 699 ENDOCRINE SYSTEM, METABOLIC 37. Hypothalamic, pituitary and sex hormones CONDITIONS 709 34. Adrenal corticosteroids, antagonists, 38. Vitamins, calcium, bone 735 corticotrophin 663 35. Diabetes mellitus, insulin, oral antidiabetes agents, obesity 679 Index 745 xiv
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  17. 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 Poisons in small doses are the best medicines; and useful relating to prescribers themselves and to medicines in too large doses are poisonous (William patients. Withering,'discoverer' of digitalis, 1789). • The therapeutic situation — latrogenic disease The use of drugs1 to increase human happiness by — Benefits and risks elimination or suppression of diseases and symptoms — Public view of drugs and prescribers and to improve the quality of life in other ways is a — Criticisms of modern drugs serious matter and involves not only technical, but — Drug-induced injury also psychosocial considerations. — Complementary medicine Overall, the major benefits of modern drugs are on • Prescribing, drug consumption and quality of life (measured with difficulty), and exceed economics those on quantity of life (measured with ease).2 — Reasons for taking a drug history We therefore begin this book with a series of — Cost-containment essays on what we think are important topics. — Repeat prescriptions — Warnings and consent 1 — Legal hazards for prescribers A World Health Organization Scientific Group has defined — Formularies and 'essential' drugs a drug as 'any substance or product that is used or intended • Compliance — patient and doctor to be used to modify or explore physiological systems or pathological states for the benefit of the recipient'. WHO • Placebo medicines 1966 Technical Report Series no. 341: 7. A less restrictive • Pharmacoeconomics definition is 'a substance that changes 'a biological system by • Self-medication interacting with it'. A drug is a single chemical substance that forms the active Appendix I: WHO list of essential drugs ingredient of a medicine (a substance or mixture of substances Appendix 2: The prescription 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. 3
  18. I TOPICS IN DRUG T H E R A P Y Medicines are part of our way of life from birth, 8. Whether the likelihood of benefit, and its when we enter the world with the aid of drugs, to importance, outweighs the likelihood of death where drugs assist (most of) us to depart with damage, and its importance, i.e. to consider minimal distress and perhaps even with a remnant benefit versus risk, or efficacy in relation to of dignity. In between these events we regulate our safety. fertility, often, with drugs. We tend to take such usages for granted. But during the intervals remaining, an average Drug therapy involves a great deal more than matching family experiences illness on one day in four and the name of the drug to the name of a disease; it requires between the ages of 20 and 45 years a lower- knowledge, judgement, skill and wisdom, but above all a sense of responsibility. middle-class man experiences approximately one life-endangering illness, 20 disabling (temporarily) illnesses, 200 non-disabling illnesses and 1000 A book can provide knowledge and can symptomatic episodes: the average person in the contribute to the formation of judgement, but it can USA can expect to have about 12 years of bad health do little to impart skill and wisdom, which are the in an average lifespan.3 And medicines play a major products of example of teachers and colleagues, of role in these. 'At any time, 40-50% of adults [UK] experience and of innate and acquired capacities. are taking a prescribed medicine.'4 'It is evident that patients are not treated in a Before treating any patient with drugs, doctors should vacuum and that they respond to a variety of subtle have made up their minds on eight points: forces around them in addition to the specific 1. Whether they should interfere with the patient therapeutic agent.'5 When a patient is given a drug the at all and if so — responses are the resultant of numerous factors: 2. What alteration in the patient's condition they • The pharmacodynamic effect of the drug and hope to achieve. interactions with any other drugs the patient 3. That the drug they intend to use is best capable may be taking of bringing this about. • The pharmacokinetics of the drug and its 4. How they will know when it has been brought modification in the individual due to genetic about. influences, disease, other drugs 5. That they can administer the drug in such a way • The physiological state of the end-organ — that the right concentration will be attained in whether, for instance, it is over- or underactive the right place at the right time and for the right • The act of medication, including the route of duration. administration and the presence or absence of 6. What other effects the drug may have and the doctor whether these may be harmful. • The doctor's mood, personality, attitudes and 7. How they will decide to stop the drug. beliefs • The patient's mood, personality, attitudes and beliefs 2 Consider, for example, the worldwide total of suffering • What the doctor has told the patient relieved and prevented each day by anaesthetics (local and • The patient's past experience of doctors general) and by analgesics, not forgetting dentistry which, • The patient's estimate of what has been received because of these drugs, no longer strikes terror into even the most stoical as it has done for centuries. and of what ought to happen as a result 3 Quoted in: Anderson J A D (ed) 1979 Self medication. MTP • The social environment, e.g. whether supportive Press, Lancaster; USA Public Health Service 1995. or dispiriting. 4 George C F 1994 Prescribers' Journal 34: 7. A moment's reflection will bring home to us that this is an astounding The relative importance of these factors varies statistic which goes a long way to account for the aggressive according to circumstances. An unconscious patient promotional activities of the highly competitive international pharmaceutical industry; the markets for medicines are 5 colossal. Sherman L J 1959 American Journal of Psychiatry 116: 208. 4
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