A Textbook of Clinical Pharmacology and Therapeutics

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educed). The risk of muscle damage is increased if they are taken with a statin, although lipid specialists sometimes employ this combination. They can cause a variety of gastrointestinal side effects, but are usually well tolerated. Contraindications Fibrates should be used with caution, if at all, in patients with renal or hepatic impairment. They should not be used in patients with gall-bladder disease or with hypoalbuminaemia. They are contraindicated in pregnancy and in alcoholics (this is particularly important because alcohol excess causes hypertriglyceridaemia; see Table 27.1). Pharmacokinetics Bezafibrate and gemfibrozil are completely absorbed when given by mouth, highly protein bound, and excreted mainly by the kidneys. OTHER DRUGS Other drugs sometimes used by lipidologists are summarized in Table 27.2. These include nicotinic acid which needs to be administered in much larger doses than needed for its effect as a B vitamin (Chapter 35). Its main effects on lipids are distinctive, namely to increase HDL, reduce TG and reduce Lp(a). Unfortunately, it has troublesome adverse effects including flushing (mediated by release of vasodilator prostaglandin D 2) which is reduced by giving the dose 30 minutes after a dose of aspirin. Key points Treatment of dyslipidaemia • Treatment goals must be individualized according to absolute risk. Patients with established disease need treatment irrespective of LDL. • Dietary measures involve maintaining ideal body weight (by caloric restriction if necessary) and reducing consumption of saturated fat – both animal (e.g. red meat, dairy products) and vegetable (e.g. coconut oil) – as well as cholesterol (e.g. egg yolk). • Drug treatment is usually with a statin (taken once daily at night) which is effective, well tolerated and reduces mortality. Consider the possibility of secondary dyslipidaemia. • Ezetimibe is well tolerated. It is a useful adjunct to a statin in severely dyslipidaemic patients who show an inadequate response to a statin alone, and has almost completely replaced bile acid binding resins for this indication. • Fibrates are useful as a first-line treatment in patients with primary mixed dyslipidaemias with high triglyceride concentrations, as well as high LDL (and often low HDL). Avoid in alcoholics. • Other reversible risk factors for atheroma (e.g. smoking, hypertension) should be sought and treated. • Consideration should be given to adjunctive use of aspirin as an antiplatelet/antithrombotic drug. Case history DRUGS USED TO TREAT DYSLIPIDAEMIA 183 A 36-year-old male primary-school teacher was seen because of hypertension at the request of the surgeons following bilateral femoral artery bypass surgery. His father had died at the age of 32 years of a myocardial infarct, but his other relatives, including his two children, were healthy. He did not smoke or drink alcohol. He had been diagnosed as hypertensive six years previously, since which time he had been treated with slow-release nifedipine, but his serum cholesterol level had never been measured. He had been disabled by claudication for the past few years, relieved temporarily by angioplasty one year previously. There were no stigmata of dyslipidaemia, his blood pressure was 150/100 mmHg and the only abnormal findings were those relating to the peripheral vascular disease and vascular surgery in his legs. Serum total cholesterol was 12.6 mmol/L, triglyceride was 1.5 mmol/L and HDL was 0.9 mmol/L. Serum creatinine and electrolytes were normal. The patient was given dietary advice and seen in clinic four weeks after discharge from hospital. He had been able to run on the games field for the first time in a year, but this had been limited by the new onset of chest pain on exertion. His cholesterol level on the diet had improved to 8.0 mmol/L. He was readmitted. Questions Decide whether each of the following statements is true or false. (a) This patient should receive a statin. (b) Coronary angiography is indicated. (c) Renal artery stenosis should be considered. (d) The target for total cholesterol should be 6.0 mmol/L. (e) Ezetimibe would be contraindicated. (f) An α 1-blocker for his hypertension could coincidentally improve his dyslipidaemia. (g) His children should be screened for dyslipidaemia and cardiovascular disease. Answer (a) True. (b) True. (c) True. (d) False. (e) False. (f) True. (g) True. Comment It was unfortunate that this young man’s dyslipidaemia was not recognized earlier. Coronary angiography revealed severe inoperable triple-vessel disease. The target total cholesterol level should be �5.0 mmol/L and was achieved with a combination of diet, a statin at night and ezetimibe in the morning. Renal artery stenosis is common in the setting of peripheral vascular disease, but renal angiography was negative. This patient’s relatively mild hypertension was treated with doxazosin (a long-acting α 1-blocker, see Chapter 28) which increases HDL, as well as lowering blood pressure. He probably has heterozygous monogenic familial hypercholesterolaemia and his children should be screened. One of his sons is hypercholesterolaemic and is currently being treated with a combination of diet and a statin. FURTHER READING Durrington PN. Dyslipidaemia. Lancet 2003; 362: 717–31. Durrington PN. Hyperlipidaemia: diagnosis and management, 3rd edn. London: Hodder Arnold, 2005.
184 PREVENTION OF ATHEROMA: LOWERING PLASMA CHOLESTEROL AND OTHER APPROACHES Feher MD, Richmond W. Lipids and lipid disorders. London: Gower Medical Publishing, 1991. Hansson GK. Mechanisms of disease: inflammation, atherosclerosis, and coronary artery disease. New England Journal of Medicine 2005; 352: 1685–95. Kosoglou T, Statkevich P, Johnson-Levonas AO et al. Ezetimibe – A review of its metabolism, pharmacokinetics and drug interactions. Clinical Pharmacokinetics 2005; 44: 467–94. Ross R. Atherosclerosis – an inflammatory disease. New England Journal of Medicine 1999; 340: 115–26. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–9. Shepherd J, Cobbe SM, Ford I et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. New England Journal of Medicine 1995; 333: 1301–7.
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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
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 184 and 185: Pharmacokinetics Allopurinol is wel
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 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
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
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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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