A Textbook of Clinical Pharmacology and Therapeutics

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lifelong effects as a result of toxicity occurring at a sensitive point in development (a ‘critical window’) during fetal or neonatal life (‘programming’) as with thalidomide/ phocomelia or hypothyroid drugs/congenital hypothyroidism RESEARCH Research in paediatric clinical pharmacology is limited. Not only is there concern about the potential for adverse effects of new drugs on those who are growing and developing mentally, but there are also considerable ethical problems encountered in research involving individuals who are too young to give informed consent. New drugs are often given to children for the first time only when no alternative is available or when unacceptable side effects have been encountered in a particular individual with established drugs. Pharmaceutical companies seldom seek to license their products for use in children. When drugs are prescribed to children that are not licensed for use in this age group, it is important to make careful records of both efficacy and possible adverse effects. Prescribers take sole responsibility for prescribing unlicensed preparations (e.g. formulated to appeal to children) or for prescribing licensed preparations outside the licensed age range. Parents should be informed and their consent obtained. Case history FURTHER READING RESEARCH 55 A 14-year-old boy with a history of exercise-induced asthma, for which he uses salbutamol as necessary (on average two puffs twice daily and before exercise) is seen by his GP because of malaise and nocturnal cough. On examination, he has a mild fever (38°C), bilateral swollen cervical lymph nodes and bilateral wheeze. Ampicillin is prescribed for a respiratory tract infection. The next day the boy develops a widespread maculopapular rash. Question 1 What is the cause of the rash? Question 2 What is the likely cause of the nocturnal cough and how may this be treated? Answer 1 Ampicillin rash in infectious mononucleosis (glandular fever). Answer 2 Poorly controlled asthma. Regular inhaled glucocorticosteroid or cromoglicate. Baber N, Pritchard D. Dose estimation in children. British Journal of Clinical Pharmacology 2003; 56: 489–93. British National Formulary for Children 2007. www.bnfc.org Kearns GL, Abdel-Rahmen SM. Developmental pharmacology – drug disposition, action and therapy in infants and children. New England Journal of Medicine 2003; 349: 1157–67. Paediatric Special Issue. British Journal of Clinical Pharmacology 2005; 59 (6). Paediatric formulary, 7th edn. London: Guy’s, St Thomas’, King’s College and Lewisham Hospitals, revised 2005.
● Introduction 56 ● Pharmacokinetic changes 56 ● Pharmacodynamic changes 57 ● Compliance in the elderly 58 INTRODUCTION CHAPTER 11 DRUGS IN THE ELDERLY The proportion of elderly people in the population is increasing steadily in economically developed countries. The elderly are subject to a variety of complaints, many of which are chronic and incapacitating, and so they receive a great deal of drug treatment. There is a growing evidence base for the use of drugs in elderly patients, with important implications for prescribing of many important classes of drugs, including statins, β-adrenoceptor antagonists, thrombolytics, ACE inhibitors, angiotensin receptor blockers, vitamin D and bisphosphonates (see reviews by Mangoni and Jackson, 2006). Adverse drug reactions and drug interactions become more common with increasing age. In one study, 11.8% of patients aged 41–50 years experienced adverse reactions to drugs, but this increased to 25% in patients over 80 years of age. There are several reasons for this. 1. Elderly people take more drugs. In one survey in general practice, 87% of patients over 75 years of age were on regular drug therapy, with 34% taking three to four different drugs daily. The most commonly prescribed drugs were diuretics (34% of patients), analgesics (27%), tranquillizers and antidepressants (24%), hypnotics (22%) and digoxin (20%). All of these are associated with a high incidence of important adverse effects. 2. Drug elimination becomes less efficient with increasing age, leading to drug accumulation during chronic dosing. 3. Homeostatic mechanisms become less effective with advancing age, so individuals are less able to compensate for adverse effects, such as unsteadiness or postural hypotension. 4. The central nervous system becomes more sensitive to the actions of sedative drugs. 5. Increasing age produces changes in the immune response that can cause an increased liability to allergic reactions. 6. Impaired cognition combined with relatively complex dose regimens may lead to inadvertent overdose. ● Effect of drugs on some major organ systems in the elderly 58 ● Practical aspects of prescribing for the elderly 60 ● Research 60 PHARMACOKINETIC CHANGES ABSORPTION Absorption of carbohydrates and of several nutrients, including iron, calcium and thiamine, is reduced in elderly people. Lipid-soluble drugs are absorbed by simple diffusion down the concentration gradient (Chapter 3), and this is not impaired by age. Intestinal blood flow is reduced by up to 50% in the elderly. However, age per se does not affect drug absorption to a large extent (Figure 11.1). ↑Gastric motility ↓Intestinal blood flow ↓Hepatic blood flow ↓Renal blood flow ↓GFR Metabolism↓ Drug Figure 11.1: Pharmacokinetic changes with age. Absorption↔ ↓Weight ↓Lean body mass ↑Fat ↓Concentration of fat-soluble drugs ↑Concentration of water-soluble drugs Excretion↓
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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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Page 18 and 19: 100 Effect (%) 0 0 5 10 1 10 100 (a
Page 20 and 21: Dose ratio -1 100 50 The relationsh
Page 22 and 23: ● Introduction 11 ● Constant-ra
Page 24 and 25: In reality, processes of eliminatio
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Page 28 and 29: ● Introduction 17 ● Bioavailabi
Page 30 and 31: ROUTES OF ADMINISTRATION ORAL ROUTE
Page 32 and 33: Transdermal absorption is sufficien
Page 34 and 35: FURTHER READING Fix JA. Strategies
Page 36 and 37: and thromboxanes are CYP450 enzymes
Page 38 and 39: and lorazepam. Some patients inheri
Page 40 and 41: Orally administered drug Parenteral
Page 42 and 43: ● Introduction 31 ● Glomerular
Page 44 and 45: ACTIVE TUBULAR REABSORPTION This is
Page 46 and 47: DISTRIBUTION Drug distribution is a
Page 48 and 49: Detailed recommendations on dosage
Page 50 and 51: DIGOXIN Myxoedematous patients are
Page 52 and 53: ● Introduction 41 ● Role of dru
Page 54 and 55: 25 20 10 Life-threatening toxicity
Page 56 and 57: ● Introduction 45 ● Harmful eff
Page 58 and 59: vagina in girls in their late teens
Page 60 and 61: an anti-analgesic effect when combi
Page 62 and 63: Case history A 20-year-old female m
Page 64 and 65: METABOLISM At birth, the hepatic mi
Page 68 and 69: DISTRIBUTION Ageing is associated w
Page 70 and 71: DIGOXIN Digoxin toxicity is common
Page 72 and 73: FURTHER READING Dhesi JK, Allain TJ
Page 74 and 75: Factors involved in the aetiology o
Page 76 and 77: analgesic. Following its release, t
Page 78 and 79: antibiotics, such as penicillin or
Page 80 and 81: predisposes to non-immune haemolysi
Page 82 and 83: ● Introduction 71 ● Useful inte
Page 84 and 85: Response Therapeutic range Toxic ra
Page 86 and 87: Table 13.1: Interactions outside th
Page 88 and 89: Table 13.5: Competitive interaction
Page 90 and 91: ● Introduction: ‘personalized m
Page 92 and 93: Table 14.2: Variations in drug resp
Page 94 and 95: lipoprotein (LDL) is impaired. LDL
Page 96 and 97: Key points • Genetic differences
Page 98 and 99: • Discovery • • Screening Pre
Page 100 and 101: 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
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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
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● Introduction 133 ● Mechanisms
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absolute arbiter. The availability
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Table 22.2: Metabolic interactions
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FURTHER ANTI-EPILEPTICS Other drugs
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Case history A 24-year-old woman wh
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Assessment of migraine severity and
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● General anaesthetics 145 ● In
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is the theoretical concern of a ‘
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• Respiratory system - apnoea fol
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Competitive antagonists (vecuronium
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have also proved useful in combinat
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● Introduction 155 ● Pathophysi
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ASPIRIN (ACETYLSALICYLATE) Use Anti
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Key points Drugs for mild pain •
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increases, correlating with the hig
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• If possible, use oral medicatio
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PART III THE MUSCULOSKELETAL SYSTEM
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● Introduction: inflammation 167
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Chapter 33). All NSAIDs cause wheez
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• Stomatitis suggests the possibi
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Pharmacokinetics Allopurinol is wel
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PART IV THE CARDIOVASCULAR SYSTEM
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esponsible for the strong predilect
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Ezetimibe Fat Muscle Dietary fat In
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educed). The risk of muscle damage
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Each of these classes of drug reduc
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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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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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