A Textbook of Clinical Pharmacology and Therapeutics

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Case history A 24-year-old woman whose secondary generalized tonic–clonic seizures have been well controlled with carbamazepine for the previous four years develops confusion, somnolence, ataxia, vertigo and nausea. Her concurrent medication includes the oral contraceptive, Loestrin 20 (which contains norethisterone 1 mg and ethinylestradiol 20 μg) and erythromycin, which was started one week earlier for sinusitis. She has no history of drug allergy. Question 1 What is the likely cause of her symptoms? Question 2 Is the oral contraceptive preparation appropriate? Answer 1 Erythromycin inhibits the metabolism of carbamazepine, and the symptoms described are attributable to a raised plasma concentration of carbamazepine. Answer 2 This patient is not adequately protected against conception with the low-dose oestrogen pill, since carbamazepine induces the metabolism of oestrogen. FURTHER READING FEBRILE CONVULSIONS 141 Anon. When and how to stop antiepileptic drugs in adults. Drugs and Therapeutics Bulletin 2003; 41: 41–43. Duncan JS, Sander JW, Sisodiya SM, Walker ML. Adult epilepsy. Lancet 2006; 367: 1087–100.
● Pathophysiology 142 ● Drugs used for the acute migraine attack 142 PATHOPHYSIOLOGY Migraine is common and prostrating, yet its pathophysiology remains poorly understood. The aura is associated with intracranial vasoconstriction and localized cerebral ischaemia. Shortly after this, the extracranial vessels dilate and pulsate in association with local tenderness and the classical unilateral headache, although it is unclear whether this or a neuronal abnormality (‘spreading cortical depression’) is the cause of the symptoms. 5-Hydroxytryptamine (5HT, serotonin) is strongly implicated, but this longstanding hypothesis remains unproven. 5HT is a potent vasoconstrictor of extracranial vessels in humans and also has vasodilator actions in some vascular beds. Excretion of 5-HIAA (the main urinary metabolite of 5HT) is increased following a migraine attack, and blood 5HT (reflecting platelet 5HT content) is reduced, suggesting that platelet activation and 5HT release may occur during an attack. This could contribute to vasoconstriction during the aura and either summate with or oppose the effects of kinins, prostaglandins and histamine to cause pain in the affected arteries. The initial stimulus for platelet 5HT release is unknown. Ingestion by a migraine sufferer of vasoactive amines in food may cause inappropriate responses of intra- and extracranial vessels. Several other idiosyncratic precipitating factors are recognized anecdotally, although in some cases (e.g. precipitation by chocolate), they are not easily demonstrated scientifically. These include physical trauma, local pain from sinuses, cervical spondylosis, sleep (too much or too little), ingestion of tyraminecontaining foods such as cheese, alcoholic beverages (especially brandy), allergy (e.g. to wheat, eggs or fish), stress, hormonal changes (e.g. during the menstrual cycle and pregnancy, and at menarche or menopause), fasting and hypoglycaemia. Some of the most effective prophylactic drugs against migraine inhibit 5HT reuptake by platelets and other cells. Several of these have additional antihistamine and anti-5HT activity. Assessment of drug efficacy in migraine is bedevilled by variability in the frequency and severity of attacks both within an individual and between different sufferers. A scheme for the acute treatment and for the prophylaxis of migraine, as well as the types of medication used for each, is shown in Figure 23.1. CHAPTER 23 MIGRAINE ● Drugs used for migraine prophylaxis 143 DRUGS USED FOR THE ACUTE MIGRAINE ATTACK In the majority of patients with migraine, the combination of a mild analgesic with an anti-emetic and, if possible, a period of rest aborts the acute attack. 5HT 1D agonists (see below) can also be used and have largely replaced ergotamine in this context (although ergot-containing preparations are still available), due to better tolerability and side-effect profile. They are very useful in relieving migraine which is resistant to simple therapy. SIMPLE ANALGESICS Aspirin, 900 mg, or paracetamol, 1 g, are useful in the treatment of headache. They are inexpensive and are effective in up to 75% of patients. Other NSAIDs (see Chapter 26) can also be used. During a migraine attack, gastric stasis occurs and this impairs drug absorption. If necessary, analgesics should be used with metoclopramide (as an anti-emetic and to enhance gastric emptying). ANTI-EMETICS FOR MIGRAINE Metoclopramide, a dopamine and weak 5HT 4 antagonist, or domperidone, a dopamine antagonist that does not penetrate the blood–brain barrier, are appropriate choices. Sedative antiemetics (e.g. antihistamines, phenothiazines) should generally be avoided. Metoclopramide should be used with caution in adolescents and women in their twenties because of the risk of spasmodic torticollis and dystonia (see Chapter 21). 5HT 1 AGONISTS The 5HT 1 agonists (otherwise known as ‘triptans’) stimulate 5HT 1B/1D receptors, which are found predominantly in the cranial circulation, thereby causing vasoconstriction predominantly of the carotids; they are very effective in the treatment of an acute migraine attack. Examples are rizatriptan, sumatriptan
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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
Page 102 and 103: ETHICS COMMITTEES Protocols for all
Page 104 and 105: Table 16.1: Recombinant proteins/en
Page 106 and 107: duration and benefit. Adenoviral ve
Page 108 and 109: ● Introduction 97 ● Garlic 97
Page 110 and 111: A case report has suggested a possi
Page 112 and 113: including hypericin and pseudohyper
Page 114 and 115: PART II THE NERVOUS SYSTEM
Page 116 and 117: ● Introduction 105 ● Sleep diff
Page 118 and 119: and daytime sleeping should be disc
Page 120 and 121: Key points • Insomnia and anxiety
Page 122 and 123: Box 19.1: Dopamine theory of schizo
Page 124 and 125: The Boston Collaborative Survey ind
Page 126 and 127: Oral medication, especially in liqu
Page 128 and 129: e.g. interpersonal difficulties or
Page 130 and 131: Partial response to first-line trea
Page 132 and 133: 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 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 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
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Table 28.2: Examples of calcium-cha
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Key points Drugs used in essential
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Case history A 72-year-old woman se
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Assess risk factors Investigations:
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Persistent ST segment elevation Thr
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Mechanism of action GTN works by re
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Because of the risks of haemorrhage
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Intrinsic pathway XIIa XIa the acti
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that the pharmacodynamic response i
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used with apparent benefit in acute
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● Introduction 211 ● Pathophysi
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The drugs that are most effective i
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therapeutic plasma concentration ca
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● Common dysrhythmias 217 ● Gen
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BASIC LIFE SUPPORT CARDIOPULMONARY
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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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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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