Clinical Pharmacology and Therapeutics

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DRUGS FOR HEART FAILURE 215 therapeutic plasma concentration can be obtained more rapidly by administering a loading dose (Chapter 3). Mechanism of action Digoxin inhibits Na /K adenosine triphosphatase (Na /K ATPase). This causes accumulation of intracellular Na and increased intracellular [Ca 2 ] concentrations via reduced Na /Ca 2 exchange. The rise in availability of intracellular Ca 2 accounts for the positive inotropic effect of digoxin. Excessive inhibition of Na /K ATPase causes numerous non-cardiac as well as cardiac (dysrhythmogenic) toxic effects. Ventricular slowing results from increased vagal activity on the AV node. Slowing of ventricular rate improves cardiac output in patients with atrial fibrillation by improving ventricular filling during diastole. Clinical progress is assessed by measuring heart rate (at the apex): apical rates of 70–80 per minute can be achieved at rest. Unfortunately, since vagal activity is suppressed during exercise (when heart rate is controlled by sympathetic activation), control of rate during exercise is not usually achievable. Pharmacokinetics Approximately 80% is excreted unchanged in the urine in patients with normal renal function with a half-life of 30–48 hours. It is eliminated mainly by glomerular filtration, although small amounts are secreted and reabsorbed. A small amount (5–10%) undergoes metabolism to inactive products or excretion via the bile and elimination in faeces. The proportion eliminated by these non-renal clearance mechanisms increases in patients with renal impairment, being 100% in anephric patients, in whom the half-life is approximately 4.5 days. Blood for digoxin concentration determination should be sampled more than six hours after an oral dose or immediately before the next dose is due (trough level) to allow its tissue distribution to be complete. The usual therapeutic range is 1–2 ng/mL, although toxicity can occur at concentrations of less than 1.5 ng/mL in some individuals. Drug interactions Digoxin has a steep dose–response curve and a narrow therapeutic range, and clinically important interactions are common (see Chapters 13 and 32). Pharmacokinetic interactions with digoxin include combined pharmacokinetic effects involving displacement from tissue-binding sites and reduced renal elimination (e.g. digoxin toxicity due to concurrent treatment with amiodarone or quinidine). Pharmacodynamic interactions are also important. In particular, drugs that cause hypokalaemia (e.g. diuretics, β-agonists, glucocorticoids) predispose to digoxin toxicity by increasing its binding to (and effect on) Na /K ATPase. OTHER POSITIVE INOTROPES Positive inotropes for intravenous infusion (e.g. adrenaline) have a place in treating acute shock, but not for chronic heart failure. Orally active positive inotropes other than digoxin include phosphodiesterase inhibitors, e.g. milrinone. These increase cardiac output and may bring some symptomatic benefit, but they worsen survival. Key points Heart failure: pathophysiology and principles of therapeutics • Heart failure has diverse aetiologies; ischaemic and idiopathic cardiomyopathy are especially important. • Neurohumoral activation (e.g. of sympathetic and renin–angiotensin systems) may have adverse consequences. • Treatment is sometimes specific (e.g. valve replacement), but is also directed generally at: – reducing preload (diuretics, nitrates, ACE inhibitors and sartans); – reducing afterload (ACE inhibitors and hydralazine); – increasing contractility (digoxin); – reducing heart rate (rapid rates do not permit optimal filling; rapid atrial fibrillation is slowed by digoxin). Treatment of chronic heart failure • Dietary salt should be restricted. • Drugs that improve survival usually reduce preload, afterload or heart rate by interrupting counterregulatory hormonal mechanisms. They comprise: – diuretics (e.g. furosemide); – ACEI (e.g. captopril acutely, then ramipril, trolandopril); – sartans (e.g. candesartan); – β-adrenoceptor antagonists (e.g. bisoprolol, carvedilol); – aldosterone antagonists (e.g. spironolactone); – hydralazine plus an organic nitrate in African- American patients. • Digoxin does not influence survival, but can improve symptoms. • Other positive inotropes (e.g. phosphodiesterase inhibitors, milrinone) worsen survival. Case history A 62-year-old physician has developed symptoms of chronic congestive cardiac failure in the setting of treated essential hypertension. He had had an angioplasty to an isolated atheromatous lesion in the left anterior descending coronary artery two years previously, since when he had not had angina. He also has a past history of gout. He is taking bendroflumethiazide for his hypertension and takes meclofenamate regularly to prevent recurrences of his gout. He disregarded his cardiologist’s advice to take aspirin because he was already taking another cyclo-oxygenase inhibitor (in the form of the meclofenamate). On examination, he has a regular pulse of 88 beats/minute, blood pressure of 160/98 mmHg, a 4–5 cm raised jugular venous pressure, mild pretibial oedema and cardiomegaly. Routine biochemistry tests are unremarkable except for a serum urate level of 0.76 mmol/L, a total cholesterol concentration of 6.5 mmol/L, a triglyceride concentration of 5.2 mmol/L and γ-glutamyltranspeptidase twice the upper limit of normal. An echocardiogram shows a diffusely poorly contracting myocardium. Question Decide whether each of the following would be appropriate as immediate measures. (a) Digitalization (b) Intravenous furosemide
216 HEART FAILURE (c) A detailed personal/social history (d) Substitution of allopurinol for the meclofenamate (e) Hold the bendroflumethiazide temporarily and start an ACE inhibitor (f) Start bezafibrate. Answer (a) False (b) False (c) True (d) False (e) True (f) False. Comment The aetiology of the heart failure in this case is uncertain. Although ischaemia and hypertension may be playing a part, the diffusely poorly contracting myocardium suggests the possibility of diffuse cardiomyopathy, and the raised γ-glutamyltranspeptidase and triglyceride levels point to the possibility of alcohol excess. If this is the case, and if it is corrected, this could improve the blood pressure, dyslipidaemia and gout, as well as cardiac function. In the long term, allopurinol should be substituted for the NSAID, but if done immediately this is likely to precipitate an acute attack. Aspirin should be taken (for its antiplatelet effect, which may not be shared by all other NSAIDs). Treatment with a fibrate would be useful for this pattern of dyslipidaemia, but only after establishing that it was not alcoholinduced. FURTHER READING Brater DC. Diuretic therapy. New England Journal of Medicine 1998; 339: 387–95. Cohn JN. The management of chronic heart failure. New England Journal of Medicine 1996; 335: 490–8. Frishman WH. Carvedilol. New England Journal of Medicine 1998; 339: 1759–65. Jessup M, Brozena S. 2003 Medical progress: heart failure. New England Journal of Medicine 2003; 348: 2007–18. McMurray JJV, Pfeffer MA. Heart failure. Lancet 2005; 365: 1877–89. Nabel EG. Cardiovascular disease. New England Journal of Medicine 2003; 349: 60–72. Palmer BF. Managing hyperkalemia caused by inhibitors of the renin–angiotensin–aldosterone system. New England Journal of Medicine 2004; 351: 585–92. Pfeffer MA, Stevenson LW. β-Adrenergic blockers and survival in heart failure. New England Journal of Medicine 1996; 334: 1396–7. Schrier RW, Abraham WT. Mechanisms of disease – hormones and hemodynamics in heart failure. New England Journal of Medicine 1999; 341: 577–85. Weber KT. Mechanisms of disease – aldosterone in congestive heart failure. New England Journal of Medicine 2001; 345: 1689–97.
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A Textbook of Clinical Pharmacology
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A Textbook of Clinical Pharmacology
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This fifth edition is dedicated to
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CONTENTS FOREWORD PREFACE ACKNOWLED
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PREFACE Clinical pharmacology is th
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PART I GENERAL PRINCIPLES
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CHAPTER 1 INTRODUCTION TO THERAPEUT
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SCIENTIFIC BASIS OF USE OF DRUGS IN
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AGONISTS 7 100 100 Effect (%) Effec
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SLOW PROCESSES 9 100 2 Dose ratio -
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CHAPTER 3 PHARMACOKINETICS ● Intr
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REPEATED (MULTIPLE) DOSING 13 In re
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NON-LINEAR (‘DOSE-DEPENDENT’) P
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CHAPTER 4 DRUG ABSORPTION AND ROUTE
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ROUTES OF ADMINISTRATION 19 ROUTES
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ROUTES OF ADMINISTRATION 21 Transde
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ROUTES OF ADMINISTRATION 23 FURTHER
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PHASE II METABOLISM (TRANSFERASE RE
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ENZYME INDUCTION 27 and lorazepam.
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METABOLISM OF DRUGS BY INTESTINAL O
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CHAPTER 6 RENAL EXCRETION OF DRUGS
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ACTIVE TUBULAR REABSORPTION 33 ACTI
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RENAL DISEASE 35 DISTRIBUTION Drug
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LIVER DISEASE 37 Detailed recommend
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THYROID DISEASE 39 DIGOXIN Myxoedem
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CHAPTER 8 THERAPEUTIC DRUG MONITORI
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DRUGS FOR WHICH THERAPEUTIC DRUG MO
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CHAPTER 9 DRUGS IN PREGNANCY ● In
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PHARMACOKINETICS IN PREGNANCY 47 va
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PRESCRIBING IN PREGNANCY 49 an anti
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PRESCRIBING IN PREGRANCY 51 Case hi
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BREAST-FEEDING 53 METABOLISM At bir
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RESEARCH 55 lifelong effects as a r
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PHARMACODYNAMIC CHANGES 57 DISTRIBU
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EFFECT OF DRUGS ON SOME MAJOR ORGAN
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RESEARCH 61 FURTHER READING Dhesi J
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ADVERSE DRUG REACTION MONITORING/SU
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ADVERSE DRUG REACTION MONITORING/SU
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PREVENTION OF ALLERGIC DRUG REACTIO
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EXAMPLES OF ALLERGIC AND OTHER ADVE
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CHAPTER 13 DRUG INTERACTIONS ● In
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HARMFUL INTERACTIONS 73 Response Re
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HARMFUL INTERACTIONS 75 Table 13.1:
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HARMFUL INTERACTIONS 77 Table 13.5:
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CHAPTER 14 PHARMACOGENETICS ● Int
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GENETIC INFLUENCES ON DRUG METABOLI
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INHERITED DISEASES THAT PREDISPOSE
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INHERITED DISEASES THAT PREDISPOSE
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CLINICAL TRIALS 87 • Discovery
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CLINICAL DRUG DEVELOPMENT 89 Too ma
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GLOBALIZATION 91 ETHICS COMMITTEES
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CELL-BASED AND RECOMBINANT DNA THER
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HUMAN STEM CELL THERAPY 95 duration
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CHAPTER 17 ALTERNATIVE MEDICINES: H
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SOY 99 A case report has suggested
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MISCELLANEOUS HERBS 101 including h
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PART II THE NERVOUS SYSTEM
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CHAPTER 18 HYPNOTICS AND ANXIOLYTIC
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ANXIETY 107 and daytime sleeping sh
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ANXIETY 109 Key points • Insomnia
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SCHIZOPHRENIA 111 Box 19.1: Dopamin
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SCHIZOPHRENIA 113 The Boston Collab
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BEHAVIOURAL EMERGENCIES 115 Oral me
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DEPRESSIVE ILLNESSES AND ANTIDEPRES
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DEPRESSIVE ILLNESSES AND ANTIDEPRES
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LITHIUM, TRYPTOPHAN AND ST JOHN’S
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SPECIAL GROUPS 123 Case history A 4
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PARKINSON’S SYNDROME AND ITS TREA
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PARKINSON’S SYNDROME AND ITS TREA
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MYASTHENIA GRAVIS 129 CHOREA The γ
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ALZHEIMER’S DISEASE 131 Cholinerg
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CHAPTER 22 ANTI-EPILEPTICS ● Intr
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GENERAL PRINCIPLES OF TREATMENT OF
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GENERAL PRINCIPLES OF TREATMENT OF
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WITHDRAWAL OF ANTI-EPILEPTIC DRUGS
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FEBRILE CONVULSIONS 141 Case histor
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DRUGS USED FOR MIGRAINE PROPHYLAXIS
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CHAPTER 24 ANAESTHETICS AND MUSCLE
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INHALATIONAL ANAESTHETICS 147 is th
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SUPPLEMENTARY DRUGS 149 • Respira
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MUSCLE RELAXANTS 151 NON-DEPOLARIZI
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LOCAL ANAESTHETICS 153 have also pr
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CHAPTER 25 ANALGESICS AND THE CONTR
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DRUGS USED TO TREAT MILD OR MODERAT
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OPIOIDS 159 Key points Drugs for mi
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OPIOIDS 161 increases, correlating
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MANAGEMENT OF POST-OPERATIVE PAIN 1
Page 176 and 177: PART III THE MUSCULOSKELETAL SYSTEM
Page 178 and 179: CHAPTER 26 ANTI-INFLAMMATORY DRUGS
Page 180 and 181: DISEASE-MODIFYING ANTIRHEUMATIC DRU
Page 182 and 183: HYPERURICAEMIA AND GOUT 171 • Sto
Page 184 and 185: HYPERURICAEMIA AND GOUT 173 Pharmac
Page 186 and 187: PART IV THE CARDIOVASCULAR SYSTEM
Page 188 and 189: CHAPTER 27 PREVENTION OF ATHEROMA:
Page 190 and 191: PREVENTION OF ATHEROMA 179 responsi
Page 192 and 193: DRUGS USED TO TREAT DYSLIPIDAEMIA 1
Page 194 and 195: DRUGS USED TO TREAT DYSLIPIDAEMIA 1
Page 196 and 197: CHAPTER 28 HYPERTENSION ● Introdu
Page 198 and 199: DRUGS USED TO TREAT HYPERTENSION 18
Page 204 and 205: OTHER ANTIHYPERTENSIVE DRUGS 193 Ke
Page 206 and 207: OTHER ANTIHYPERTENSIVE DRUGS 195 Ca
Page 208 and 209: MANAGEMENT OF STABLE ANGINA 197 Ass
Page 210 and 211: MANAGEMENT OF UNSTABLE CORONARY DIS
Page 212 and 213: DRUGS USED IN ISCHAEMIC HEART DISEA
Page 214 and 215: DRUGS USED IN ISCHAEMIC HEART DISEA
Page 216 and 217: ANTICOAGULANTS 205 Intrinsic pathwa
Page 218 and 219: ANTICOAGULANTS 207 that the pharmac
Page 220 and 221: ANTICOAGULANTS IN PREGNANCY AND PUE
Page 222 and 223: CHAPTER 31 HEART FAILURE ● Introd
Page 224 and 225: DRUGS FOR HEART FAILURE 213 The dru
Page 228 and 229: CHAPTER 32 CARDIAC DYSRHYTHMIAS ●
Page 230 and 231: CARDIOPULMONARY RESUSCITATION AND C
Page 232 and 233: TREATMENT OF OTHER SPECIFIC DYSRHYT
Page 234 and 235: SELECTED ANTI-DYSRHYTHMIC DRUGS 223
Page 242 and 243: PART V THE RESPIRATORY SYSTEM
Page 244 and 245: CHAPTER 33 THERAPY OF ASTHMA, CHRON
Page 246 and 247: CHRONIC BRONCHITIS AND EMPHYSEMA 23
Page 248 and 249: DRUGS USED TO TREAT ASTHMA AND CHRO
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Page 252 and 253: RESPIRATORY FAILURE 241 use in asth
Page 254 and 255: DRUG-INDUCED PULMONARY DISEASE 243
Page 256 and 257: PART VI THE ALIMENTARY SYSTEM
Page 258 and 259: CHAPTER 34 ALIMENTARY SYSTEM AND LI
Page 260 and 261: PEPTIC ULCERATION 249 • With rega
Page 262 and 263: PEPTIC ULCERATION 251 Ranitidine ha
Page 264 and 265: ANTI-EMETICS 253 Vestibular stimula
Page 266 and 267: INFLAMMATORY BOWEL DISEASE 255 cort
Page 268 and 269: CONSTIPATION 257 • in hepatocellu
Page 270 and 271: PANCREATIC INSUFFICIENCY 259 Ciprof
Page 272 and 273: LIVER DISEASE 261 withdrawal), smal
Page 274 and 275: DRUGS THAT MODIFY APPETITE 263 Tabl
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CHAPTER 35 VITAMINS AND TRACE ELEME
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VITAMIN C(ASCORBIC ACID) 267 dinucl
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TRACE ELEMENTS 269 Table 35.1: Comm
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PART VII FLUIDS AND ELECTROLYTES
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CHAPTER 36 NEPHROLOGICAL AND RELATE
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DIURETICS 275 Key points Diuretics
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VOLUME DEPLETION 277 is sometimes c
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DRUGS THAT AFFECT THE BLADDER AND G
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DRUGS THAT AFFECT THE BLADDER AND G
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PART VIII THE ENDOCRINE SYSTEM
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CHAPTER 37 DIABETES MELLITUS ● In
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DRUGS USED TO TREAT DIABETES MELLIT
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ANTITHYROID DRUGS 293 deficiency. P
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SPECIAL SITUATIONS 295 fertility. I
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CHAPTER 39 CALCIUM METABOLISM ● I
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BISPHOSPHONATES 299 effective in li
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CINACALCET 301 Further reading Bloc
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ADRENAL CORTEX 303 Table 40.1: Acti
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ADRENAL MEDULLA 305 injection may b
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CHAPTER 41 REPRODUCTIVE ENDOCRINOLO
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FEMALE REPRODUCTIVE ENDOCRINOLOGY 3
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FEMALE REPRODUCTIVE ENDOCRINOLOGY 3
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MALE REPRODUCTIVE ENDOCRINOLOGY 313
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MALE REPRODUCTIVE ENDOCRINOLOGY 315
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ANTERIOR PITUITARY HARMONES AND REL
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POSTERIOR PITUITARY HARMONES 319 FU
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PART IX SELECTIVE TOXICITY
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CHAPTER 43 ANTIBACTERIAL DRUGS ●
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COMMONLY PRESCRIBED ANTIBACTERIAL D
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PRINCIPLES OF MANAGEMENT OF MYCOBAC
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FIRST-LINE DRUGS IN TUBERCULOSIS TH
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MYCOBACTERIUM LEPRAE INFECTION 339
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ANTIFUNGAL DRUG THERAPY 341 POLYENE
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ANTIFUNGAL DRUG THERAPY 343 therapy
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ANTIVIRAL DRUG THERAPY (EXCLUDING A
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ANTIVIRAL DRUG THERAPY (EXCLUDING A
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INTERFERONS AND ANTIVIRAL HEPATITIS
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CHAPTER 46 HIV AND AIDS ● Introdu
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ANTI-HIV DRUGS 353 Table 46.1: Exam
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ANTI-HIV DRUGS 355 NON-NUCLEOSIDE A
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OPPORTUNISTIC INFECTIONS IN HIV-1-S
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ANTI-HERPES VIRUS THERAPY 359 salva
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CHAPTER 47 MALARIA AND OTHER PARASI
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MALARIA 363 Pharmacokinetics Chloro
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HELMINTHIC INFECTION 365 Table 47.2
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CHAPTER 48 CANCER CHEMOTHERAPY ●
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COMMON COMPLICATIONS OF CANCER CHEM
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DRUGS USED IN CANCER CHEMOTHERAPY 3
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PART X HAEMATOLOGY
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CHAPTER 49 ANAEMIA AND OTHER HAEMAT
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HAEMATINICS - IRON, VITAMIN B 12 AN
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HAEMATOPOIETIC GROWTH FACTORS 393 S
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IDIOPATHIC THROMBOCYTOPENIC PURPURA
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PART XI IMMUNOPHARMACOLOGY
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CHAPTER 50 CLINICAL IMMUNOPHARMACOL
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IMMUNOSUPPRESSIVE AGENTS 401 Ag Ant
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IMMUNOSUPPRESSIVE AGENTS 403 Table
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CHEMICAL MEDIATORS OF THE IMMUNE RE
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IMMUNOGLOBULINS AS THERAPY 407 DRUG
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PART XII THE SKIN
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CHAPTER 51 DRUGS AND THE SKIN ● I
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DERMATITIS (ECZEMA) 413 Avoid preci
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PSORIASIS 415 Emollients Improving?
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ADVERSE DRUG REACTIONS INVOLVING TH
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ADVERSE DRUG REACTIONS INVOLVING TH
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PART XIII THE EYE
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CHAPTER 52 DRUGS AND THE EYE ● In
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DRUGS USED TO CONSTRICT THE PUPIL A
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DRUGS USED TO TREAT INFLAMMATORY DI
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CONTACT LENS WEARERS 429 Table 52.6
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PART XIV CLINICAL TOXICOLOGY
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CHAPTER 53 DRUGS AND ALCOHOL ABUSE
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OPIOID/NARCOTIC ANALGESICS 435 Tabl
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DRUGS THAT ALTER PERCEPTION 437 whi
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CENTRAL DEPRESSANTS 439 Peak plasma
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CENTRAL DEPRESSANTS 441 Key points
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MISCELLANEOUS 443 FURTHER READING G
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INTENTIONAL SELF-POISONING 445 Tabl
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INTENTIONAL SELF-POISONING 447 Tabl
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CRIMINAL POISONING 449 Commission o
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INDEX Note: Page numbers in italics
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INDEX 453 atrial fibrillation 217,
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INDEX 455 Cushing’s syndrome 302
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INDEX 457 5-fluorouracil 375-6 fluo
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INDEX 459 children 54 diazepam 108
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INDEX 461 non-steroidal anti-inflam
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INDEX 463 puberty (male), delay 314
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INDEX 465 tolerance 9, 433 benzodia
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