Clinical Pharmacology and Therapeutics

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DRUGS USED TO TREAT DIABETES MELLITUS 291 FURTHER READING American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes 1993; 42: 1555–8. Bolli GB, Owens DR. Insulin glargine. Lancet 2000; 356: 443–5. deFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. New England Journal of Medicine 1995; 333: 541–9 (see also accompanying editorial on metformin by OB Crofford, pp. 588–9). Dornhorst A. Insulinotropic meglitinide analogues. Lancet 2001; 358: 1709–16. Gale EAM. Lessons from the glitazones: a story of drug development. Lancet 2001; 357: 1870–5. Gerich JE. Oral hypoglycemic agents. New England Journal of Medicine 1989; 321: 1231–45. Hirsch IB. Drug therapy: Insulin analogues. New England Journal of Medicine 2005; 352: 174–83. Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet 2001; 358: 739–46. Perfetti R, D’Amico E. Rational drug design and PPAR agonists. Current Diabetes Report 2005; 5: 340–5. Pickup JC, Williams J (eds). Handbook of diabetes, 3rd edn. Oxford: Blackwell Science, 2004. Skyler JS, Cefalu WT, Kourides IA et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomized proof-of-concept study. Lancet 2001; 357: 324–5. Yki-Jarvinen H. Drug therapy: thiazolidinediones. New England Journal of Medicine 2004; 351: 1106–18.
CHAPTER 38 THYROID ● Introduction 292 ● Pathophysiology and principles of treatment 292 ● Iodine 292 ● Thyroxine and tri-iodothyronine 293 ● Antithyroid drugs 293 ● Special situations 295 INTRODUCTION The thyroid secretes thyroxine (T 4 ) and tri-iodothyronine (T 3 ), as well as calcitonin, which is discussed in Chapter 39. The release of T 3 and T 4 is controlled by the pituitary hormone thyrotrophin (thyroid-stimulating hormone, TSH). This binds to receptors on thyroid follicular cells and activates adenylyl cyclase, which stimulates iodine trapping, iodothyronine synthesis and release of thyroid hormones. TSH is secreted by basophil cells in the adenohypophysis. Secretion of TSH by the anterior pituitary is stimulated by the hypothalamic peptide thyrotrophin-releasing hormone (TRH). Circulating T 4 and T 3 produce negative-feedback inhibition of TSH at the pituitary and hypothalamus. Drug treatment is highly effective in correcting under- or over-activity of the thyroid gland. The diagnosis of abnormal thyroid function and monitoring of therapy have been greatly facilitated by accurate and sensitive assays measuring TSH, because the serum TSH level accurately reflects thyroid state, whereas the interpretation of serum concentrations of T 3 and T 4 is complicated by very extensive and somewhat variable protein binding. Negative feedback of biologically active thyroid hormones ensures that when there is primary failure of the thyroid gland, serum TSH is elevated, whereas when there is overactivity of the gland, serum TSH is depressed. Hypothyroidism caused by hypopituitarism is relatively uncommon and is associated with depressed sex hormone and adrenal cortical function. Hyperthyroidism secondary to excessive TSH is extremely rare. Hyperthyroidism is also common and again autoimmune processes are implicated. Treatment options comprise: • antithyroid drugs; • radioactive iodine; • surgery. Antithyroid drugs enable a euthyroid state to be maintained until the disease remits or definitive treatment with radioiodine or surgery is undertaken. Radioactive iodine is well tolerated and free of surgical complications (e.g. laryngeal nerve damage), whereas surgery is most appropriate when there are local mechanical problems, such as tracheal compression. In older patients, the most common cause of hyperthyroidism is multinodular toxic goitre. In young women it is usually caused by Graves’ disease, in which an immunoglobulin binds to and stimulates the TSH receptor, thereby promoting synthesis and release of T 3 and T 4 independent of TSH. In addition to a smooth vascular goitre, there is often deposition of mucopolysaccharide, most notably in the extrinsic eye muscles which become thickened and cause proptosis. Graves’ disease has a remitting/relapsing course and often finally leads to hypothyroidism. Other aetiologies of hyperthyroidism include acute viral or autoimmune thyroiditis (which usually resolve spontaneously), iatrogenic iodine excess (e.g. thyroid storm following iodine-containing contrast media and hyperthyroidism in patients treated with drugs, such as amiodarone; see below and Chapter 32), and acute postpartum hyperthyroidism. PATHOPHYSIOLOGY AND PRINCIPLES OF TREATMENT Thyroid disease is more common in women than in men, and is manifested either as goitre or as under- or over-activity of the gland. Hypothyroidism is common, especially in the elderly. It is usually caused by autoimmune destruction of the gland and, if untreated, leads to the clinical picture of myxoedema. Treatment is by lifelong replacement with thyroxine. IODINE The thyroid gland concentrates iodine. Dietary iodide normally amounts to 100–200 mg per day and is absorbed from the stomach and small intestine by an active process. Following systemic absorption and uptake into the thyroid gland, iodide is oxidized to iodine, which is the precursor to various iodinated tyrosine compounds including T 3 and T 4 . Iodine is used to treat simple non-toxic goitre due to iodine
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A Textbook of Clinical Pharmacology
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A Textbook of Clinical Pharmacology
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This fifth edition is dedicated to
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CONTENTS FOREWORD PREFACE ACKNOWLED
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PREFACE Clinical pharmacology is th
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PART I GENERAL PRINCIPLES
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CHAPTER 1 INTRODUCTION TO THERAPEUT
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SCIENTIFIC BASIS OF USE OF DRUGS IN
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AGONISTS 7 100 100 Effect (%) Effec
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SLOW PROCESSES 9 100 2 Dose ratio -
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CHAPTER 3 PHARMACOKINETICS ● Intr
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REPEATED (MULTIPLE) DOSING 13 In re
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NON-LINEAR (‘DOSE-DEPENDENT’) P
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CHAPTER 4 DRUG ABSORPTION AND ROUTE
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ROUTES OF ADMINISTRATION 19 ROUTES
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ROUTES OF ADMINISTRATION 21 Transde
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ROUTES OF ADMINISTRATION 23 FURTHER
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PHASE II METABOLISM (TRANSFERASE RE
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ENZYME INDUCTION 27 and lorazepam.
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METABOLISM OF DRUGS BY INTESTINAL O
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CHAPTER 6 RENAL EXCRETION OF DRUGS
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ACTIVE TUBULAR REABSORPTION 33 ACTI
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RENAL DISEASE 35 DISTRIBUTION Drug
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LIVER DISEASE 37 Detailed recommend
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THYROID DISEASE 39 DIGOXIN Myxoedem
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CHAPTER 8 THERAPEUTIC DRUG MONITORI
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DRUGS FOR WHICH THERAPEUTIC DRUG MO
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CHAPTER 9 DRUGS IN PREGNANCY ● In
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PHARMACOKINETICS IN PREGNANCY 47 va
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PRESCRIBING IN PREGNANCY 49 an anti
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PRESCRIBING IN PREGRANCY 51 Case hi
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BREAST-FEEDING 53 METABOLISM At bir
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RESEARCH 55 lifelong effects as a r
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PHARMACODYNAMIC CHANGES 57 DISTRIBU
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EFFECT OF DRUGS ON SOME MAJOR ORGAN
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RESEARCH 61 FURTHER READING Dhesi J
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ADVERSE DRUG REACTION MONITORING/SU
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ADVERSE DRUG REACTION MONITORING/SU
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PREVENTION OF ALLERGIC DRUG REACTIO
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EXAMPLES OF ALLERGIC AND OTHER ADVE
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CHAPTER 13 DRUG INTERACTIONS ● In
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HARMFUL INTERACTIONS 73 Response Re
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HARMFUL INTERACTIONS 75 Table 13.1:
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HARMFUL INTERACTIONS 77 Table 13.5:
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CHAPTER 14 PHARMACOGENETICS ● Int
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GENETIC INFLUENCES ON DRUG METABOLI
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INHERITED DISEASES THAT PREDISPOSE
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INHERITED DISEASES THAT PREDISPOSE
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CLINICAL TRIALS 87 • Discovery
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CLINICAL DRUG DEVELOPMENT 89 Too ma
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GLOBALIZATION 91 ETHICS COMMITTEES
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CELL-BASED AND RECOMBINANT DNA THER
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HUMAN STEM CELL THERAPY 95 duration
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CHAPTER 17 ALTERNATIVE MEDICINES: H
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SOY 99 A case report has suggested
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MISCELLANEOUS HERBS 101 including h
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PART II THE NERVOUS SYSTEM
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CHAPTER 18 HYPNOTICS AND ANXIOLYTIC
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ANXIETY 107 and daytime sleeping sh
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ANXIETY 109 Key points • Insomnia
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SCHIZOPHRENIA 111 Box 19.1: Dopamin
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SCHIZOPHRENIA 113 The Boston Collab
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BEHAVIOURAL EMERGENCIES 115 Oral me
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DEPRESSIVE ILLNESSES AND ANTIDEPRES
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DEPRESSIVE ILLNESSES AND ANTIDEPRES
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LITHIUM, TRYPTOPHAN AND ST JOHN’S
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SPECIAL GROUPS 123 Case history A 4
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PARKINSON’S SYNDROME AND ITS TREA
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PARKINSON’S SYNDROME AND ITS TREA
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MYASTHENIA GRAVIS 129 CHOREA The γ
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ALZHEIMER’S DISEASE 131 Cholinerg
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CHAPTER 22 ANTI-EPILEPTICS ● Intr
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GENERAL PRINCIPLES OF TREATMENT OF
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GENERAL PRINCIPLES OF TREATMENT OF
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WITHDRAWAL OF ANTI-EPILEPTIC DRUGS
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FEBRILE CONVULSIONS 141 Case histor
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DRUGS USED FOR MIGRAINE PROPHYLAXIS
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CHAPTER 24 ANAESTHETICS AND MUSCLE
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INHALATIONAL ANAESTHETICS 147 is th
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SUPPLEMENTARY DRUGS 149 • Respira
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MUSCLE RELAXANTS 151 NON-DEPOLARIZI
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LOCAL ANAESTHETICS 153 have also pr
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CHAPTER 25 ANALGESICS AND THE CONTR
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DRUGS USED TO TREAT MILD OR MODERAT
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OPIOIDS 159 Key points Drugs for mi
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OPIOIDS 161 increases, correlating
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MANAGEMENT OF POST-OPERATIVE PAIN 1
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PART III THE MUSCULOSKELETAL SYSTEM
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CHAPTER 26 ANTI-INFLAMMATORY DRUGS
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DISEASE-MODIFYING ANTIRHEUMATIC DRU
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HYPERURICAEMIA AND GOUT 171 • Sto
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HYPERURICAEMIA AND GOUT 173 Pharmac
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PART IV THE CARDIOVASCULAR SYSTEM
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CHAPTER 27 PREVENTION OF ATHEROMA:
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PREVENTION OF ATHEROMA 179 responsi
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DRUGS USED TO TREAT DYSLIPIDAEMIA 1
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DRUGS USED TO TREAT DYSLIPIDAEMIA 1
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CHAPTER 28 HYPERTENSION ● Introdu
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DRUGS USED TO TREAT HYPERTENSION 18
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OTHER ANTIHYPERTENSIVE DRUGS 193 Ke
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OTHER ANTIHYPERTENSIVE DRUGS 195 Ca
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MANAGEMENT OF STABLE ANGINA 197 Ass
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MANAGEMENT OF UNSTABLE CORONARY DIS
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DRUGS USED IN ISCHAEMIC HEART DISEA
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DRUGS USED IN ISCHAEMIC HEART DISEA
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ANTICOAGULANTS 205 Intrinsic pathwa
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ANTICOAGULANTS 207 that the pharmac
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ANTICOAGULANTS IN PREGNANCY AND PUE
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CHAPTER 31 HEART FAILURE ● Introd
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DRUGS FOR HEART FAILURE 213 The dru
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DRUGS FOR HEART FAILURE 215 therape
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CHAPTER 32 CARDIAC DYSRHYTHMIAS ●
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CARDIOPULMONARY RESUSCITATION AND C
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TREATMENT OF OTHER SPECIFIC DYSRHYT
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SELECTED ANTI-DYSRHYTHMIC DRUGS 223
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PART V THE RESPIRATORY SYSTEM
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CHAPTER 33 THERAPY OF ASTHMA, CHRON
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CHRONIC BRONCHITIS AND EMPHYSEMA 23
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DRUGS USED TO TREAT ASTHMA AND CHRO
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DRUGS USED TO TREAT ASTHMA AND CHRO
Page 252 and 253: RESPIRATORY FAILURE 241 use in asth
Page 254 and 255: DRUG-INDUCED PULMONARY DISEASE 243
Page 256 and 257: PART VI THE ALIMENTARY SYSTEM
Page 258 and 259: CHAPTER 34 ALIMENTARY SYSTEM AND LI
Page 260 and 261: PEPTIC ULCERATION 249 • With rega
Page 262 and 263: PEPTIC ULCERATION 251 Ranitidine ha
Page 264 and 265: ANTI-EMETICS 253 Vestibular stimula
Page 266 and 267: INFLAMMATORY BOWEL DISEASE 255 cort
Page 268 and 269: CONSTIPATION 257 • in hepatocellu
Page 270 and 271: PANCREATIC INSUFFICIENCY 259 Ciprof
Page 272 and 273: LIVER DISEASE 261 withdrawal), smal
Page 274 and 275: DRUGS THAT MODIFY APPETITE 263 Tabl
Page 276 and 277: CHAPTER 35 VITAMINS AND TRACE ELEME
Page 278 and 279: VITAMIN C(ASCORBIC ACID) 267 dinucl
Page 280 and 281: TRACE ELEMENTS 269 Table 35.1: Comm
Page 282 and 283: PART VII FLUIDS AND ELECTROLYTES
Page 284 and 285: CHAPTER 36 NEPHROLOGICAL AND RELATE
Page 286 and 287: DIURETICS 275 Key points Diuretics
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Page 290 and 291: DRUGS THAT AFFECT THE BLADDER AND G
Page 292 and 293: DRUGS THAT AFFECT THE BLADDER AND G
Page 294 and 295: PART VIII THE ENDOCRINE SYSTEM
Page 296 and 297: CHAPTER 37 DIABETES MELLITUS ● In
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Page 304 and 305: ANTITHYROID DRUGS 293 deficiency. P
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Page 308 and 309: CHAPTER 39 CALCIUM METABOLISM ● I
Page 310 and 311: BISPHOSPHONATES 299 effective in li
Page 312 and 313: CINACALCET 301 Further reading Bloc
Page 314 and 315: ADRENAL CORTEX 303 Table 40.1: Acti
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Page 318 and 319: CHAPTER 41 REPRODUCTIVE ENDOCRINOLO
Page 320 and 321: FEMALE REPRODUCTIVE ENDOCRINOLOGY 3
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Page 324 and 325: MALE REPRODUCTIVE ENDOCRINOLOGY 313
Page 326 and 327: MALE REPRODUCTIVE ENDOCRINOLOGY 315
Page 328 and 329: ANTERIOR PITUITARY HARMONES AND REL
Page 330 and 331: POSTERIOR PITUITARY HARMONES 319 FU
Page 332 and 333: PART IX SELECTIVE TOXICITY
Page 334 and 335: CHAPTER 43 ANTIBACTERIAL DRUGS ●
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Page 346 and 347: PRINCIPLES OF MANAGEMENT OF MYCOBAC
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ANTIFUNGAL DRUG THERAPY 341 POLYENE
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ANTIFUNGAL DRUG THERAPY 343 therapy
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ANTIVIRAL DRUG THERAPY (EXCLUDING A
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ANTIVIRAL DRUG THERAPY (EXCLUDING A
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INTERFERONS AND ANTIVIRAL HEPATITIS
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CHAPTER 46 HIV AND AIDS ● Introdu
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ANTI-HIV DRUGS 353 Table 46.1: Exam
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ANTI-HIV DRUGS 355 NON-NUCLEOSIDE A
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OPPORTUNISTIC INFECTIONS IN HIV-1-S
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ANTI-HERPES VIRUS THERAPY 359 salva
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CHAPTER 47 MALARIA AND OTHER PARASI
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MALARIA 363 Pharmacokinetics Chloro
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HELMINTHIC INFECTION 365 Table 47.2
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CHAPTER 48 CANCER CHEMOTHERAPY ●
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COMMON COMPLICATIONS OF CANCER CHEM
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DRUGS USED IN CANCER CHEMOTHERAPY 3
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PART X HAEMATOLOGY
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CHAPTER 49 ANAEMIA AND OTHER HAEMAT
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HAEMATINICS - IRON, VITAMIN B 12 AN
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HAEMATOPOIETIC GROWTH FACTORS 393 S
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IDIOPATHIC THROMBOCYTOPENIC PURPURA
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PART XI IMMUNOPHARMACOLOGY
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CHAPTER 50 CLINICAL IMMUNOPHARMACOL
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IMMUNOSUPPRESSIVE AGENTS 401 Ag Ant
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IMMUNOSUPPRESSIVE AGENTS 403 Table
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CHEMICAL MEDIATORS OF THE IMMUNE RE
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IMMUNOGLOBULINS AS THERAPY 407 DRUG
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PART XII THE SKIN
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CHAPTER 51 DRUGS AND THE SKIN ● I
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DERMATITIS (ECZEMA) 413 Avoid preci
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PSORIASIS 415 Emollients Improving?
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ADVERSE DRUG REACTIONS INVOLVING TH
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ADVERSE DRUG REACTIONS INVOLVING TH
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PART XIII THE EYE
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CHAPTER 52 DRUGS AND THE EYE ● In
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DRUGS USED TO CONSTRICT THE PUPIL A
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DRUGS USED TO TREAT INFLAMMATORY DI
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CONTACT LENS WEARERS 429 Table 52.6
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PART XIV CLINICAL TOXICOLOGY
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CHAPTER 53 DRUGS AND ALCOHOL ABUSE
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OPIOID/NARCOTIC ANALGESICS 435 Tabl
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DRUGS THAT ALTER PERCEPTION 437 whi
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CENTRAL DEPRESSANTS 439 Peak plasma
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CENTRAL DEPRESSANTS 441 Key points
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MISCELLANEOUS 443 FURTHER READING G
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INTENTIONAL SELF-POISONING 445 Tabl
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INTENTIONAL SELF-POISONING 447 Tabl
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CRIMINAL POISONING 449 Commission o
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INDEX Note: Page numbers in italics
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INDEX 453 atrial fibrillation 217,
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INDEX 455 Cushing’s syndrome 302
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INDEX 457 5-fluorouracil 375-6 fluo
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INDEX 459 children 54 diazepam 108
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INDEX 461 non-steroidal anti-inflam
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INDEX 463 puberty (male), delay 314
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INDEX 465 tolerance 9, 433 benzodia
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