DRUGS FOR HEART DISEASE

Transcription

1 DRUGS FOR HEART DISEASE

2 DRUGS FOR HEART DISEASE SECOND EDITION Edited by John Hamer MD. Ph.D F.R.C.P. Formerly Consultant Cardiologist St Bartholomew's Hospital London SPRINGER-SCIENCE+BUSINESS MEDIA. B.V.

3 1987 Springer Science+Business Media Dordrecht Originally published by Chapman and Hall Ltd in 1987 Softcover reprint of the hardcover 2nd edition 1987 ISBN All rights reserved. No part of this book may be reprinted, or reproduced or utilized in any form or by any electronic, mechanical or other means, now known or hereafter invented, including photocopying and recording, or in any information storage and retrieval system, without permission in writing from the publisher. British Library Cataloguing in Publication Data Drugs for heart disease.-2nd ed. 1. Cardiovascular system-diseases- Chemotherapy I. Hamer, John, '061 RC669 ISBN ISBN (ebook) DOI /

4 Contents Preface to the second edition Preface to the first edition Contributors xi xiii xv 1 Antiarrhythmic drugs 1 JOHN HAMER 1.1 Introduction - pharmacokinetics Need for treatment Alternative treatment Electrophysiological testing Class I drugs: membrane-stabilizing agents Class II - sympathetic antagonism Class III Class IV Class V 20 References 20 2 Beta-adrenergic blocking drugs 29 CYRUS R. KUMANA 2.1 In trod uction Membrane stabilizing activity (MSA)llocal anaesthetic activity Selectivity (cardioselectivity, beta I-selectivity) Partial agonist activity Lipid solubility Coexistent alpha-receptor blocking activity Sustained hypertension The influence of beta adrenoceptor blockade on surges of blood pressure due to sympathetic stimulation 48 v

5 Contents 2.9 Coronary artery disease Pharmacokinetics, dosing frequency and dosage, compliance Adverse reactions/drug and non-drug interactions Blood glucose and beta-adrenoceptor blockade Beta-blockers in the management of thyrotoxicosis and anxiety 67 References 70 3 Calcium antagonists 77 JOHN HAMER 3.1 Introduction Clinical pharmacology Myocardial protection Ventricular arrhythmias Verapamil Nifedipine Newer dihydropyridines Diltiazem The less used calcium antagonists A V nodal block Angina Hypertension Myocardial disease 93 References 96 4 Antianginal vasodilators 103 L.H. OPIE and U. THADANI 4.1 Production of angina pectoris Calcium and regulation of vascular smooth muscle tone Pharmacological vasodilators - possible sites of action Nitrates: mechanisms of action Nitrates: clinical implications Problems in the use of nitrates Calcium antagonists for angina pectoris Verapamil Nifedipine 128 vi

6 Contents 4.10 Diltiazem Newer calcium antagonists Other potential antianginal agents Which agent for which type of angina? Summary 136 References Digitalis: the present position 145 ROGER HAYWARD 5.1 Introduction Digitalis actions at a cellular level Digitalis actions on cardiovascular haemodynamics with particular reference to heart failure Electrophysiological effects of digitalis Clinical pharmacology of digitalis 178 References Positive inotropic drugs for treating heart failure 195 LEON RESNEKOV 6.1 Introduction Positive inotropic drugs Discussion 203 References Diuretics 207 ARIEL LANT 7.1 Introduction Classification of diuretics Localization of diuretic action in the nephron Molecular mechanisms of diuretic action Extrarenal vascular effects of diuretics 'High-ceiling'diuretics Medium efficacy diuretics Adjunct diuretics Polyvalent compounds Therapeutic choice of diuretic Diuretic resistance Adverse effects 226 References 230 vii

7 Contents 8 Antihypertensive drugs 237 ANN ERRICHETTI and BRIAN F. JOHNSON 8.1 Introduction Diuretics Peripheral adrenergic neurone blockade Alpha-adrenergic blockers Beta-adrenergic blocking drugs Central andrenergic inhibitors Renin-angiotensin blockers Direct vasodilators Calcium channel blockers The selection of a drug regimen 261 References Vasodilator therapy in congestive heart failure 275 JOHN HAMER 9.1 Preload effects Afterload effects Vasodilator drugs Problems of vasodilator therapy 287 References Prostaglandins and cardiovascular medicine 299 J. O'GRADY and S.G. MOODY 10.1 Introduction Clinical pharmacology Metabolism Therapeutic role Other prostaglandins Prostaglandin inhibition and the patent ductus arteriosus Summary 311 References Antithrombotic agents 317 J.R.A. MITCHELL 11.1 Introduction 317 viii

8 Contents 11.2 The theoretical basis for contemporary antithrombotic regimes Anticoagulants Platelet modifying agents Fibrinolytic agents Do they work? Thebestbuy 345 References The management of the hyperlipidaemias 349 N.r. JOWETT and D.J. GALTON 12.1 Introduction Lipids, lipoproteins and the hyperlipidaemias Classification of the hyperlipidaemias Management of the hyperlipidaemias Drug therapy for hyperlipidaemia Non-drug therapy Other drugs which affect lipoprotein levels Conclusions 360 References Techniques for the blood level measurement of cardiac drugs and their application 365 A. JOHNSTON 13.1 Introduction Measurement of cardiac drugs Physical methods Immunoassays 373 References 377 Index 379 ix

9 Preface to the second edition This book is the outcome of a cardiologist switching to clinical pharmacology in mid-career and may be seen as representing the interface between the two disciplines. In this second edition I have not tried to be encyclopaedic, but have asked the contributors to give a brief account of current practice, so that it represents the present state of cardiac therapeutics. Although some contributors are from Bart's, I have tried to spread my net widely and produce a general view from the English speaking world. I hope this will be enough to draw the teeth of my colleagues who will react at once to say that 'this is not what we do at Bart's.' Some chapters, mostly the early ones, are drug orientated and describe the use and properties of individual groups of drugs. Other later chapters are disease orientated and describe the use of various groups of drugs in different conditions, such as angina or hypertension. This necessarily leads to some overlap, but I have not tried to produce a uniformity of view, but have been content with Chairman Mao 'to let a hundred flowers bloom'. I am grateful to my cardiological colleague, Professor A. John Camm for his help and advice on current cardiological practice. To improve the flow of the text I have limited the references to key publications, rather than trying to quote all the papers published on each topic. Obsessional collectors of bibliography will find their needs met by collecting the references in the references. Surrey 1986 John Hamer xi

10 Preface to the first edition This book reviews the clinical pharmacology of cardiovascular drugs. I have started from the premise that 'clinical pharmacology' is the scientific study of the use of drugs in man. It is inevitably necessary to refer to much basic work in animals as it is not technically feasible to investigate drug actions on the myocardium at a cellular level in man, or ethically acceptable to use invasive methods to study drug action in patients unless opportunities arise during diagnostic investigation. I have sought to avoid the detailed consideration of mechanisms derived from animal pharmacology, but to draw on animal work for features helpful in the understanding of the response of human disease to treatment. The apparent remoteness of animal pharmacology from clinical practice is in part responsible for the emergence of Clinical Pharmacology as a new independent discipline with immediate relevance to the treatment of patients, and it is this aspect of pharmacology I am seeking to emphasize in relation to my experience as a clinical cardiologist. In numerical terms, cardiovascular disease forms half of medicine and it is hoped that the book will be of interest to general physicians as well as to specialist cardiologists and trainees. The early activity of clinical pharmacology has been connected with the development of techniques to measure drug concentrations in blood and other biological fluids. This development has led to a close concern with 'pharmacokinetics', i.e. the way drugs are handled in the body, and is dealt with in the final chapter (13) which outlines the advantages of measuring drug blood levels and the techniques in current use; it is hoped that this section will be helpful to physicians planning to set up such a service. Blood level measurements lend themselves to the study of pharmacokinetics, including the comparison of different formulations of a drug (bioavailability), and to the study of drug interactions. Although a knowledge of how drugs are handled in the body is fundamental to their sensible use in treatment, I hope to avoid the impression that blood level measurement is the essential basis of the discipline. Clinical pharmacology is primarily concerned with the selection of appropriate therapy, and adjustment of dose and administration of drugs to the needs of the patient. I have attempted to consider the mechanisms xiii

11 Preface to the first edition of drug action, the absorption, metabolism excretion of drugs (pharmacokinetics); the effects of the drugs in man (pharmacodynamics), and the rational use of the drugs in disease, including interactions with other drugs and toxic effects. I have attempted to marshall and synthesize the often contradictory reports from the continuously growing medical literature to give a picture of the current state of therapeutics in the light of my experience as a clinical cardiologist in academic, hospital and private practice, and as an undergraduate and postgraduate teacher both in England and in the United States. My early experience as a registrar to both William Evans and Clifford Hoyle, who showed the way with a sound study of drugs for angina, gave me a healthy scepticism about the effects of drugs in heart disease, which susbequent contact with the pharmaceutical industry has failed to eradicate, although it has helped me to appreciate the problems of the development of new drugs and their introduction into therapeutics. I was personally fortunate to be early in the field when betablockers appeared and comparative studies have led to a continued interest in antiarrhythmic drugs. This is something of a Bart's book and I am particularly grateful for outside help with the prostaglandin chapter from my friends of the Wellcome Foundation. I seek understanding from authors who will feel that insufficient prominence is given to their research and from pharmaceutical companies who may consider the advantages of their drugs inadequately described. If many doctors handle drugs badly the fault must lie in part with their training. It is my aim to correct such faults in my own field and to expiate my previous sins in this respect! London November, 1977 John Hamer xiv

12 Contributors Ann Errichetti, MD Fellow in Clinical Pharmacology University of Massachusetts Medical School Department of Medicine Worcester Massachusetts USA Dr D.J. Galton, MSc, MD, FRCP Consultant Physician St Bartholomew's Hospital London EC1A 7BE Dr John Hamer, MD, PhD, FRCP Consultant Cardiologist, now retired Department of Clinical Pharmacology St Bartholomew's Hospital London EC1A 7BE Dr Roger Hayward, MD, MRCP Senior Registrar Department of Cardiology Middlesex Hospital Mortimer Street London WIN 8AA Professor Brian F. Johnson, MB, FRCP Professor of Medicine and Pharmacology University of Massachusetts Medical School Department of Medicine Worcester Massachusetts USA xv

13 Contribu tors Mr Atholl Johnston Head of Analytical Unit Department of Clinical Pharmacology St Bartholomew's Hospital London EClA 7BE Dr N.!. Jowett Honorary Senior Registrar Department of Diabetes and Lipids St Bartholomew's Hospital London EClA 7BE Dr Cyrus R. Kumana, B.Sc, MB, FRCP (London & Canada) Reader in Clinical Pharmacology University of Hong Kong Department of Medicine Queen Mary Hospital Hong Kong Professor Ariel Lant Department of Therapeutics Charing Cross and Westminster Medical School Page St Wing Westminster Hospital London SWlP 2AP Professor J.R.A. Mitchell, BSc, MD, DPhil, MA, FRCP Foundation Professor of Medicine Department of Medicine University Hospital Queen's Medical Centre Nottingham NG7 2UH Mr S.G. Moody Department of Clinical Therapeutics Wellcome Research Laboratories Langley Court Beckenham Kent BR3 3BS xvi

14 Dr J. O'Grady, MD, MRCP Clinical Research Manager May & Baker Limited Rainham Road South Dagenham Essex RMlO 7XS Contributors Professor Lionel H. Opie, MD, PhD, FRCP Professor of Medicine University of Cape Town Department of Medicine Medical School Observatory 7925 Cape Town South Africa Professor Leon Resnekov, MD, FRCP Frederick H. Rawson Professor of Medicine University of Chicago Department of Medicine/Cardiology 950 East 59th Street Chicago Illinois 60637, USA Professor U. Thadani, MBBS, MRCP, FRCP (c) Professor of Medicine and Director of Clinical Cardiology Department of Medicine University of Oklahoma Oklahoma City Oklahoma USA xvii