A Textbook of Clinical Pharmacology and Therapeutics

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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 DRUGS FOR HEART FAILURE 215 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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FOREWORD viii PREFACE ix ACKNOWLEDG
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PREFACE Clinical pharmacology is th
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PART I GENERAL PRINCIPLES
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● Use of drugs 3 ● Adverse effe
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and acquired factors, notably disea
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100 Effect (%) 0 0 5 10 1 10 100 (a
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Dose ratio -1 100 50 The relationsh
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● Introduction 11 ● Constant-ra
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In reality, processes of eliminatio
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lood (from which samples are taken
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● Introduction 17 ● Bioavailabi
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ROUTES OF ADMINISTRATION ORAL ROUTE
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Transdermal absorption is sufficien
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FURTHER READING Fix JA. Strategies
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and thromboxanes are CYP450 enzymes
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and lorazepam. Some patients inheri
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Orally administered drug Parenteral
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● Introduction 31 ● Glomerular
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ACTIVE TUBULAR REABSORPTION This is
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DISTRIBUTION Drug distribution is a
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Detailed recommendations on dosage
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DIGOXIN Myxoedematous patients are
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● Introduction 41 ● Role of dru
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25 20 10 Life-threatening toxicity
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● Introduction 45 ● Harmful eff
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vagina in girls in their late teens
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an anti-analgesic effect when combi
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Case history A 20-year-old female m
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METABOLISM At birth, the hepatic mi
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lifelong effects as a result of tox
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DISTRIBUTION Ageing is associated w
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DIGOXIN Digoxin toxicity is common
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FURTHER READING Dhesi JK, Allain TJ
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Factors involved in the aetiology o
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analgesic. Following its release, t
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antibiotics, such as penicillin or
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predisposes to non-immune haemolysi
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● Introduction 71 ● Useful inte
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Response Therapeutic range Toxic ra
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Table 13.1: Interactions outside th
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Table 13.5: Competitive interaction
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● Introduction: ‘personalized m
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Table 14.2: Variations in drug resp
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lipoprotein (LDL) is impaired. LDL
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Key points • Genetic differences
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• Discovery • • Screening Pre
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Too many statistical comparisons pe
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ETHICS COMMITTEES Protocols for all
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Table 16.1: Recombinant proteins/en
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duration and benefit. Adenoviral ve
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● Introduction 97 ● Garlic 97
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A case report has suggested a possi
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including hypericin and pseudohyper
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PART II THE NERVOUS SYSTEM
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● Introduction 105 ● Sleep diff
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and daytime sleeping should be disc
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Key points • Insomnia and anxiety
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Box 19.1: Dopamine theory of schizo
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The Boston Collaborative Survey ind
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Oral medication, especially in liqu
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e.g. interpersonal difficulties or
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Partial response to first-line trea
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Key points Drug treatment of depres
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Case history A 45-year-old man with
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Levodopa PRINCIPLES OF TREATMENT IN
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• pulmonary, retroperitoneal and
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CHOREA The γ-aminobutyric acid con
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Cholinergic crisis Treatment of mya
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● Introduction 133 ● Mechanisms
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absolute arbiter. The availability
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Table 22.2: Metabolic interactions
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FURTHER ANTI-EPILEPTICS Other drugs
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Case history A 24-year-old woman wh
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Assessment of migraine severity and
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● General anaesthetics 145 ● In
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is the theoretical concern of a ‘
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• Respiratory system - apnoea fol
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Competitive antagonists (vecuronium
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have also proved useful in combinat
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● Introduction 155 ● Pathophysi
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ASPIRIN (ACETYLSALICYLATE) Use Anti
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Key points Drugs for mild pain •
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increases, correlating with the hig
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• If possible, use oral medicatio
Page 176 and 177: PART III THE MUSCULOSKELETAL SYSTEM
Page 178 and 179: ● Introduction: inflammation 167
Page 180 and 181: Chapter 33). All NSAIDs cause wheez
Page 182 and 183: • Stomatitis suggests the possibi
Page 184 and 185: Pharmacokinetics Allopurinol is wel
Page 186 and 187: PART IV THE CARDIOVASCULAR SYSTEM
Page 188 and 189: ● Introduction 177 ● Pathophysi
Page 190 and 191: esponsible for the strong predilect
Page 192 and 193: Ezetimibe Fat Muscle Dietary fat In
Page 194 and 195: educed). The risk of muscle damage
Page 198 and 199: Each of these classes of drug reduc
Page 200 and 201: AT 1 receptor) produce good 24-hour
Page 202 and 203: Table 28.2: Examples of calcium-cha
Page 204 and 205: Key points Drugs used in essential
Page 206 and 207: Case history A 72-year-old woman se
Page 208 and 209: Assess risk factors Investigations:
Page 210 and 211: Persistent ST segment elevation Thr
Page 212 and 213: Mechanism of action GTN works by re
Page 214 and 215: Because of the risks of haemorrhage
Page 216 and 217: Intrinsic pathway XIIa XIa the acti
Page 218 and 219: that the pharmacodynamic response i
Page 220 and 221: used with apparent benefit in acute
Page 224 and 225: The drugs that are most effective i
Page 228 and 229: ● Common dysrhythmias 217 ● Gen
Page 230 and 231: BASIC LIFE SUPPORT CARDIOPULMONARY
Page 232 and 233: arrest. The electrocardiogram is li
Page 234 and 235: should be given to insertion of an
Page 236 and 237: Drug interactions Amiodarone potent
Page 238 and 239: effect when treating sinus bradycar
Page 240 and 241: Case history A 24-year-old medical
Page 242 and 243: PART V THE RESPIRATORY SYSTEM
Page 244 and 245: CHAPTER 33 THERAPY OF ASTHMA, CHRON
Page 246 and 247: STEP 5: CONTINUOUS OR FREQUENT USE
Page 248 and 249: Adenylyl cyclase Table 33.1: Compar
Page 250 and 251: Drug interactions Although synergis
Page 252 and 253: use in asthma has declined consider
Page 254 and 255: α 1-antitrypsin deficiency, neutro
Page 256 and 257: PART VI THE ALIMENTARY SYSTEM
Page 258 and 259: ● Peptic ulceration 247 ● Oesop
Page 260 and 261: PEPTIC ULCERATION 249 • With rega
Page 262 and 263: Ranitidine has a similar profile of
Page 264 and 265: Vestibular stimulation ? via cerebe
Page 266 and 267: cortical centres affecting vomiting
Page 268 and 269: • in hepatocellular failure to re
Page 270 and 271: Ciprofloxacin is occasionally used
Page 272 and 273: withdrawal), small doses of benzodi
Page 274 and 275: Table 34.7: Dose-independent hepato
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● Introduction 265 ● General ph
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dinucleotide (NAD) and nicotinamide
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Table 35.1: Common trace element de
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PART VII FLUIDS AND ELECTROLYTES
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● Introduction 273 ● Volume ove
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Key points Diuretics Diuretics are
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is sometimes caused by drugs, notab
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or with potassium-sparing diuretics
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Greger R, Lang F, Sebekova, Heidlan
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PART VIII THE ENDOCRINE SYSTEM
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in prefilled injection devices (‘
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Metformin should be withdrawn and i
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FURTHER READING American Diabetes A
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deficiency. Potassium iodide (3 mg
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fertility. It is contraindicated du
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● Introduction 297 ● Vitamin D
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effective in life-threatening hyper
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Further reading Block GA, Martin KJ
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Table 40.1: Actions of cortisol and
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injection may be useful, but if don
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CHAPTER 41 REPRODUCTIVE ENDOCRINOLO
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elease by the pituitary via negativ
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Treatment with depot progestogen in
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infusion using an infusion pump to
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significant proportion of men who r
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with symptoms caused by the release
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FURTHER READING Birnbaumer M. Vasop
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PART IX SELECTIVE TOXICITY
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● Principles of antibacterial che
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2. transfer of resistance between o
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Pharmacokinetics Absorption of thes
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Mechanism of action Macrolides bind
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asic quinolone structure dramatical
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Case history A 70-year-old man with
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PRINCIPLES OF MANAGEMENT OF MYCOBAC
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Pharmacokinetics Absorption from th
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MYCOBACTERIUM LEPRAE INFECTION Lepr
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POLYENES AMPHOTERICIN B Uses Amphot
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therapy is adequate though more fre
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NUCLEOSIDE ANALOGUES ACICLOVIR Uses
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Table 45.3: Summary of available ac
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Uses Interferon-α when combined wi
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● Introduction 351 ● Immunopath
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Table 46.1: Examples of combination
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NON-NUCLEOSIDE ANALOGUE REVERSE TRA
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FUSION INHIBITORS Uses Currently, e
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salvage therapy include azithromyci
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● Malaria 361 ● Trypanosomal in
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Pharmacokinetics Chloroquine is rap
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Table 47.2: Drug therapy of non-mal
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Table 48.1: Classification of commo
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Polymorph count/mm 3 (a) (b) 10 000
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doses are used to prepare patients
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Adverse effects Methotrexate Inhibi
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Table 48.7: Summary of clinical pha
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Table 48.9: Summary of the clinical
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Plasma membrane Signal transduction
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Table 48.10: Monoclonal antibodies
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INTERFERON-ALFA 2B Interferon-alfa
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PART X HAEMATOLOGY
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● Haematinics - iron, vitamin B 1
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one marrow to produce red cells. Th
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EPO Erythroid precursors Erythrocyt
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Therapeutic principles The extent o
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PART XI IMMUNOPHARMACOLOGY
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● Introduction 399 ● Immunity a
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Key points Antigen recognition Expr
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Table 50.1: Novel anti-proliferativ
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Key points Treatment of anaphylacti
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DRUGS THAT ENHANCE IMMUNE SYSTEM FU
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PART XII THE SKIN
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● Introduction 411 ● Acne 411
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DERMATITIS (ECZEMA) PRINCIPLES OF T
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SPECIALISTS ONLY SPECIALISTS ONLY E
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TREATMENT OF OTHER SKIN INFECTIONS
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effect of too high a dose of UVB in
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PART XIII THE EYE
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● Introduction: ocular anatomy, p
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to cause pupillary dilatation, name
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Table 52.3: Antibacterial agents us
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Table 52.6: Common drug-induced pro
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PART XIV CLINICAL TOXICOLOGY
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Table 53.2: Central nervous system
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which provide anonymized data to th
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Peak plasma levels after smoking ci
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Key points Acute effects of alcohol
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FURTHER READING Goldman D, Oroszi G
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Table 54.2: Common indications for
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Table 54.5: Antidotes and other spe
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Commission on Human Medicines (CHM)
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Note: Page numbers in italics refer
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atrial fibrillation 217, 221 digoxi
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Cushing’s syndrome 302 cyclic ade
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5-fluorouracil 375-6 fluoxetine, mo
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children 54 diazepam 108 iron prepa
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non-steroidal anti-inflammatory dru
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puberty (male), delay 314 puerperiu
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tolerance 9, 433 benzodiazepines 10
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