A Textbook of Clinical Pharmacology and Therapeutics

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Pharmacokinetics Allopurinol is well absorbed. Hepatic metabolism yields oxypurinol, itself a weak xanthine oxidase inhibitor. Drug interactions • Allopurinol decreases the breakdown of 6-mercaptopurine (the active metabolite of azathioprine) with a potential for severe toxicity (haematopoietic and mucosal). • Metabolism of warfarin is inhibited. URICOSURIC DRUGS Use These drugs (e.g. sulfinpyrazone, probenecid) have been largely superseded by allopurinol, but are useful for patients who require prophylactic therapy and who have severe adverse reactions to allopurinol. Uricosuric drugs inhibit active transport of organic acids by renal tubules (Chapter 6). Their main effect on the handling of uric acid by the kidney is to prevent the reabsorption of filtered uric acid by the proximal tubule, thus greatly increasing excretion. Probenecid can precipitate an acute attack of gout. Sulfinpyrazone is a weak NSAID in its own right, and a flare of gout is less likely to occur when using it. Unlike other NSAIDs, there is also evidence that it has a clinically useful antiplatelet action. The patient should drink enough water to have a urine output of 2 L/day during the first month of treatment and a sodium bicarbonate or potassium citrate mixture should be given to keep the urinary pH above 7.0 to avoid precipitation of uric acid stones. Other adverse effects include rashes and gastro-intestinal upsets. RASBURICASE Rasburicase, a recently introduced preparation of recombinant xanthine oxidase, is used to prevent complications of acute hyperuricaemia in leukaemia therapy, especially in children. Key points Gout • Gout is caused by an inflammatory reaction to precipitated crystals of uric acid. • Always consider possible contributing factors, including drugs (especially diuretics) and ethanol. • Treatment of the acute attack: – NSAIDs (e.g. ibuprofen); – colchicine (useful in cases where NSAIDs are contraindicated). • prophylaxis (for recurrent disease or tophaceous gout): – allopurinol (xanthine oxidase inhibitor) is only started well after the acute attack has resolved and with NSAID cover to prevent a flare; – uricosuric drugs (e.g. sulfinpyrazone, which has additional NSAID and antiplatelet actions) are less effective than allopurinol. They are a useful alternative when allopurinol causes severe adverse effects (e.g. rashes). A high output of alkaline urine should be maintained to prevent stone formation. Case history FURTHER READING HYPERURICAEMIA AND GOUT 173 A 45-year-old publican presents to a locum GP with symptoms of a painful, swollen and red big toe. There is a history of essential hypertension, and he has had a similar but less severe attack three months previously which settled spontaneously. Following this, serum urate concentrations were determined and found to be within the normal range. His toe is now inflamed and exquisitely tender. His blood pressure is 180/106 mmHg, but the examination is otherwise unremarkable. The locum is concerned that treatment with an NSAID might increase the patient’s blood pressure, and that, since his uric acid was recently found to be normal, he might not have gout. He therefore prescribes cocodamol for the pain and repeated the serum urate measurement. The patient returns the following day unimproved, having spent a sleepless night, and you see him yourself for the first time. The examination is as described by your locum, and serum urate remains normal. What would you do? Comment Normal serum urate does not exclude gout. The patient requires treatment with an NSAID, such as ibuprofen. Review his medication (is he on a diuretic for his hypertension?) and enquire about his alcohol consumption. Blood pressure is commonly increased by acute pain. Despite his occupation, the patient does not drink alcohol and he was receiving bendroflumethiazide for hypertension. This was discontinued, amlodipine was substituted and his blood pressure fell to 162/100 mmHg during treatment with ibuprofen. A short period of poor antihypertensive control in this setting is not of great importance. After the pain has settled and ibuprofen stopped, the patient’s blood pressure decreases further to 140/84 mmHg on amlodipine. He did not have any recurrence of gout. (Only if recurrent gout was a problem would prophylactic treatment with allopurinol be worth considering.) Boers M. NSAIDs and selective COX-2 inhibitors: competition between gastroprotection and cardioprotection. Lancet 2001; 357: 1222–3. De Broe ME, Elseviers MM. Analgesic nephropathy. New England Journal of Medicine 1998; 338: 446–42. Emmerson BT. The management of gout. New England Journal of Medicine 1996; 334: 445–51. Feldmann M. Development of anti-TNF therapy for rheumatoid arthritis. Nature Reviews. Immunology 2002; 2: 364–71. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. New England Journal of Medicine 2001; 345: 433–42. Graham DJ, Campen D, Hui R et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case control study. Lancet 2005; 365: 475–81. Klippel JHK. Biologic therapy for rheumatoid arthritis. New England Journal of Medicine 2000; 343: 1640–1. Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Annual Review of Medicine 2000; 51: 207–29. O’Dell JR, Haire CE, Erikson N et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine or a combination of all three medications. New England Journal of Medicine 1996; 334: 1287–91. Rongean JC, Kelly JP, Naldi L. Medication use and the risk of Stevens- Johnson syndrome or toxic epidermal necrolysis. New England Journal of Medicine 1995; 333: 1600–7. Vane JR, Bakhle YS, Botting RM. Cyclo-oxygenases 1 and 2. Annual Review of Pharmacology and Toxicology 1998; 38: 97–120.
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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
Page 134 and 135: Case history A 45-year-old man with
Page 136 and 137: Levodopa PRINCIPLES OF TREATMENT IN
Page 138 and 139: • pulmonary, retroperitoneal and
Page 140 and 141: CHOREA The γ-aminobutyric acid con
Page 142 and 143: Cholinergic crisis Treatment of mya
Page 144 and 145: ● Introduction 133 ● Mechanisms
Page 146 and 147: absolute arbiter. The availability
Page 148 and 149: Table 22.2: Metabolic interactions
Page 150 and 151: FURTHER ANTI-EPILEPTICS Other drugs
Page 152 and 153: Case history A 24-year-old woman wh
Page 154 and 155: Assessment of migraine severity and
Page 156 and 157: ● General anaesthetics 145 ● In
Page 158 and 159: is the theoretical concern of a ‘
Page 160 and 161: • Respiratory system - apnoea fol
Page 162 and 163: Competitive antagonists (vecuronium
Page 164 and 165: have also proved useful in combinat
Page 166 and 167: ● Introduction 155 ● Pathophysi
Page 168 and 169: ASPIRIN (ACETYLSALICYLATE) Use Anti
Page 170 and 171: Key points Drugs for mild pain •
Page 172 and 173: increases, correlating with the hig
Page 174 and 175: • 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 186 and 187: PART IV THE CARDIOVASCULAR SYSTEM
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 226 and 227: therapeutic plasma concentration ca
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
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should be given to insertion of an
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Drug interactions Amiodarone potent
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effect when treating sinus bradycar
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Case history A 24-year-old medical
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PART V THE RESPIRATORY SYSTEM
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CHAPTER 33 THERAPY OF ASTHMA, CHRON
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STEP 5: CONTINUOUS OR FREQUENT USE
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Adenylyl cyclase Table 33.1: Compar
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Drug interactions Although synergis
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use in asthma has declined consider
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α 1-antitrypsin deficiency, neutro
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PART VI THE ALIMENTARY SYSTEM
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● Peptic ulceration 247 ● Oesop
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PEPTIC ULCERATION 249 • With rega
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Ranitidine has a similar profile of
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Vestibular stimulation ? via cerebe
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cortical centres affecting vomiting
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• in hepatocellular failure to re
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Ciprofloxacin is occasionally used
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withdrawal), small doses of benzodi
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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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● Introduction 285 ● Pathophysi
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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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