A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

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ROUTES OF ADMINISTRATION 23 FURTHER READING Fix JA. Strategies for delivery of peptides utilizing absorptionenhancing agents. Journal of Pharmaceutical Sciences 1996; 85: 1282–5. Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules. Nature Reviews Drug Discovery 2003; 2: 289–95. Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral delivery of peptide and protein drugs. Critical Reviews in Therapeutic Drug Carrier Systems 2003; 20: 153–2. Mathiovitz E, Jacobs JS, Jong NS et al. Biologically erodable microspheres as potential oral drug delivery systems. Nature 1997; 386: 410–14. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications, 3rd edn. Baltimore, MD: Williams and Wilkins, 1995: 11–50. Skyler JS, Cefalu WT, Kourides I A et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomized proof-of-concept study. Lancet 2001; 357: 324–5. Varde NK, Pack DW. Microspheres for controlled release drug delivery. Expert Opinion on Biological Therapy 2004; 4: 35–51.
CHAPTER 5 DRUG METABOLISM ● Introduction 24 ● Phase I metabolism 24 ● Phase II metabolism (transferase reactions) 25 ● Enzyme induction 27 ● Enzyme inhibition 28 ● Presystemic metabolism (‘first-pass’ effect) 28 ● Metabolism of drugs by intestinal organisms 29 INTRODUCTION Drug metabolism is central to biochemical pharmacology. Knowledge of human drug metabolism has been advanced by the wide availability of human hepatic tissue, complemented by analytical studies of parent drugs and metabolites in plasma and urine. The pharmacological activity of many drugs is reduced or abolished by enzymatic processes, and drug metabolism is one of the primary mechanisms by which drugs are inactivated. Examples include oxidation of phenytoin and of ethanol. However, not all metabolic processes result in inactivation, and drug activity is sometimes increased by metabolism, as in activation of prodrugs (e.g. hydrolysis of enalapril, Chapter 28, to its active metabolite enalaprilat). The formation of polar metabolites from a non-polar drug permits efficient urinary excretion (Chapter 6). However, some enzymatic conversions yield active compounds with a longer half-life than the parent drug, causing delayed effects of the long-lasting metabolite as it accumulates more slowly to its steady state (e.g. diazepam has a half-life of 20–50 hours, whereas its pharmacologically active metabolite desmethyldiazepam has a plasma half-life of approximately 100 hours, Chapter 18). It is convenient to divide drug metabolism into two phases (phases I and II: Figure 5.1), which often, but not always, occur sequentially. Phase I reactions involve a metabolic modification of the drug (commonly oxidation, reduction or hydrolysis). Products of phase I reactions may be either pharmacologically active or inactive. Phase II reactions are synthetic conjugation reactions. Phase II metabolites have increased polarity compared to the parent drugs and are more readily excreted in the urine (or, less often, in the bile), and they are usually – but not always – pharmacologically inactive. Molecules or groups involved in phase II reactions include acetate, glucuronic acid, glutamine, glycine and sulphate, which may combine with reactive groups introduced during phase I metabolism (‘functionalization’). For example, phenytoin is initially oxidized to 4-hydroxyphenytoin which is then glucuronidated to 4-hydroxyphenytoin-glucuronide, which is readily excreted via the kidney. PHASE I METABOLISM The liver is the most important site of drug metabolism. Hepatocyte endoplasmic reticulum is particularly important, but the cytosol and mitochondria are also involved. ENDOPLASMIC RETICULUM Hepatic smooth endoplasmic reticulum contains the cytochrome P450 (CYP450) enzyme superfamily (more than 50 different CYPs have been found in humans) that metabolize foreign substances – ‘xenobiotics’, i.e. drugs as well as pesticides, fertilizers and other chemicals ingested by humans. These metabolic reactions include oxidation, reduction and hydrolysis. OXIDATION Microsomal oxidation causes aromatic or aliphatic hydroxylation, deamination, dealkylation or S-oxidation. These reactions all involve reduced nicotinamide adenine dinucleotide phosphate (NADP), molecular oxygen, and one or more of a group of CYP450 haemoproteins which act as a terminal oxidase in the oxidation reaction (or can involve other mixed function oxidases, e.g. flavin-containing monooxygenases or epoxide hydrolases). CYP450s exist in several distinct isoenzyme families and subfamilies with different levels of amino acid homology. Each CYP subfamily has a different, albeit often overlapping, pattern of substrate specificities. The major drug metabolizing CYPs with important substrates, inhibitors and inducers are shown in Table 5.1. CYP450 enzymes are also involved in the oxidative biosynthesis of mediators or other biochemically important intermediates. For example, synthase enzymes involved in the oxidation of arachidonic acid (Chapter 26) to prostaglandins
Page 2 and 3: A Textbook of Clinical Pharmacology
Page 4 and 5: A Textbook of Clinical Pharmacology
Page 6 and 7: This fifth edition is dedicated to
Page 8 and 9: CONTENTS FOREWORD PREFACE ACKNOWLED
Page 10 and 11: PREFACE Clinical pharmacology is th
Page 12 and 13: PART I GENERAL PRINCIPLES
Page 14 and 15: CHAPTER 1 INTRODUCTION TO THERAPEUT
Page 16 and 17: SCIENTIFIC BASIS OF USE OF DRUGS IN
Page 18 and 19: AGONISTS 7 100 100 Effect (%) Effec
Page 20 and 21: SLOW PROCESSES 9 100 2 Dose ratio -
Page 22 and 23: CHAPTER 3 PHARMACOKINETICS ● Intr
Page 24 and 25: REPEATED (MULTIPLE) DOSING 13 In re
Page 26 and 27: NON-LINEAR (‘DOSE-DEPENDENT’) P
Page 28 and 29: CHAPTER 4 DRUG ABSORPTION AND ROUTE
Page 30 and 31: ROUTES OF ADMINISTRATION 19 ROUTES
Page 32 and 33: ROUTES OF ADMINISTRATION 21 Transde
Page 36 and 37: PHASE II METABOLISM (TRANSFERASE RE
Page 38 and 39: ENZYME INDUCTION 27 and lorazepam.
Page 40 and 41: METABOLISM OF DRUGS BY INTESTINAL O
Page 42 and 43: CHAPTER 6 RENAL EXCRETION OF DRUGS
Page 44 and 45: ACTIVE TUBULAR REABSORPTION 33 ACTI
Page 46 and 47: RENAL DISEASE 35 DISTRIBUTION Drug
Page 48 and 49: LIVER DISEASE 37 Detailed recommend
Page 50 and 51: THYROID DISEASE 39 DIGOXIN Myxoedem
Page 52 and 53: CHAPTER 8 THERAPEUTIC DRUG MONITORI
Page 54 and 55: DRUGS FOR WHICH THERAPEUTIC DRUG MO
Page 56 and 57: CHAPTER 9 DRUGS IN PREGNANCY ● In
Page 58 and 59: PHARMACOKINETICS IN PREGNANCY 47 va
Page 60 and 61: PRESCRIBING IN PREGNANCY 49 an anti
Page 62 and 63: PRESCRIBING IN PREGRANCY 51 Case hi
Page 64 and 65: BREAST-FEEDING 53 METABOLISM At bir
Page 66 and 67: RESEARCH 55 lifelong effects as a r
Page 68 and 69: PHARMACODYNAMIC CHANGES 57 DISTRIBU
Page 70 and 71: EFFECT OF DRUGS ON SOME MAJOR ORGAN
Page 72 and 73: RESEARCH 61 FURTHER READING Dhesi J
Page 74 and 75: ADVERSE DRUG REACTION MONITORING/SU
Page 76 and 77: ADVERSE DRUG REACTION MONITORING/SU
Page 78 and 79: PREVENTION OF ALLERGIC DRUG REACTIO
Page 80 and 81: EXAMPLES OF ALLERGIC AND OTHER ADVE
Page 82 and 83: 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
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RESPIRATORY FAILURE 241 use in asth
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DRUG-INDUCED PULMONARY DISEASE 243
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PART VI THE ALIMENTARY SYSTEM
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CHAPTER 34 ALIMENTARY SYSTEM AND LI
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PEPTIC ULCERATION 249 • With rega
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PEPTIC ULCERATION 251 Ranitidine ha
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ANTI-EMETICS 253 Vestibular stimula
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INFLAMMATORY BOWEL DISEASE 255 cort
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CONSTIPATION 257 • in hepatocellu
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PANCREATIC INSUFFICIENCY 259 Ciprof
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LIVER DISEASE 261 withdrawal), smal
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DRUGS THAT MODIFY APPETITE 263 Tabl
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CHAPTER 35 VITAMINS AND TRACE ELEME
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VITAMIN C(ASCORBIC ACID) 267 dinucl
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TRACE ELEMENTS 269 Table 35.1: Comm
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PART VII FLUIDS AND ELECTROLYTES
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CHAPTER 36 NEPHROLOGICAL AND RELATE
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DIURETICS 275 Key points Diuretics
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VOLUME DEPLETION 277 is sometimes c
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DRUGS THAT AFFECT THE BLADDER AND G
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DRUGS THAT AFFECT THE BLADDER AND G
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PART VIII THE ENDOCRINE SYSTEM
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CHAPTER 37 DIABETES MELLITUS ● In
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DRUGS USED TO TREAT DIABETES MELLIT
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ANTITHYROID DRUGS 293 deficiency. P
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SPECIAL SITUATIONS 295 fertility. I
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CHAPTER 39 CALCIUM METABOLISM ● I
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BISPHOSPHONATES 299 effective in li
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CINACALCET 301 Further reading Bloc
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ADRENAL CORTEX 303 Table 40.1: Acti
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ADRENAL MEDULLA 305 injection may b
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CHAPTER 41 REPRODUCTIVE ENDOCRINOLO
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FEMALE REPRODUCTIVE ENDOCRINOLOGY 3
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FEMALE REPRODUCTIVE ENDOCRINOLOGY 3
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MALE REPRODUCTIVE ENDOCRINOLOGY 313
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MALE REPRODUCTIVE ENDOCRINOLOGY 315
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ANTERIOR PITUITARY HARMONES AND REL
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POSTERIOR PITUITARY HARMONES 319 FU
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PART IX SELECTIVE TOXICITY
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CHAPTER 43 ANTIBACTERIAL DRUGS ●
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COMMONLY PRESCRIBED ANTIBACTERIAL D
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PRINCIPLES OF MANAGEMENT OF MYCOBAC
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FIRST-LINE DRUGS IN TUBERCULOSIS TH
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MYCOBACTERIUM LEPRAE INFECTION 339
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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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