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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

DISTRIBUTION Ageing is

DISTRIBUTION Ageing is associated with loss of lean body mass, and with an increased ratio of fat to muscle and body water. This enlarges the volume of distribution of fat-soluble drugs, such as diazepam and lidocaine, whereas the distribution of polar drugs such as digoxin is reduced compared to younger adults. Changes in plasma proteins also occur with ageing, especially if associated with chronic disease and malnutrition, with a fall in albumin and a rise in gamma-globulin concentrations. HEPATIC METABOLISM There is a decrease in the hepatic clearance of some but not all drugs with advancing age. A prolonged plasma half-life (Figure 11.2), can be the result either of reduced clearance or of increased apparent volume of distribution. Ageing reduces metabolism of some drugs (e.g. benzodiazepines) as evidenced by reduced hepatic clearance. The reduced clearance of benzodiazepines has important clinical consequences, as does the long half-life of several active metabolites (Chapter 18). Slow accumulation may lead to adverse effects whose onset may occur days or weeks after initiating therapy. Consequently, confusion or memory impairment may be falsely attributed to ageing rather than to adverse drug effects. Diazepam t 1/2� (h) 120 100 80 60 40 20 0 10 20 30 40 50 60 70 80 100 Age (years) Figure 11.2: Relationship between diazepam half-life and age in 33 normal individuals. Non-smokers, ; smokers, •. (Redrawn with permission from Klotz U et al. Journal ° of Clinical Investigation 1975; 55: 347.) Table 11.1: Examples of drugs requiring dose adjustment in the elderly Aminoglycosides (e.g. gentamicin) Atenolol Cimetidine Diazepam Digoxin Non-steroidal anti-inflammatory drugs Oral hypoglycaemic agents Warfarin RENAL EXCRETION PHARMACODYNAMIC CHANGES 57 The most important cause of drug accumulation in the elderly is declining renal function. Many healthy elderly individuals have a glomerular filtration rate (GFR) �50 mL/min. Although glomerular filtration rate declines with age, this is not necessarily reflected by serum creatinine, which can remain within the range defined as ‘normal’ for a younger adult population despite a marked decline in renal function. This is related to the lower endogenous production of creatinine in the elderly secondary to their reduced muscle mass. Under-recognition of renal impairment in the elderly is lessened by the routine reporting by many laboratories of an estimated GFR (eGFR) based on age, sex and serum creatinine concentration and reported in units normalized to 1.73 m 2 body surface area (mL/min/1.73 m 2 ). When estimating doses of nephrotoxic drugs, it is important to remember that the drug elimination depends on the absolute GFR (in mL/min) rather than that normalized to an ideal body surface area (in mL/min/1.73 m 2 ), and to estimate this if necessary using a nomogram (see Chapter 7) that incorporates height and weight, as well as age, sex and creatinine. Examples of drugs which may require reduced dosage in the elderly secondary to reduced renal excretion and/or hepatic clearance are listed in Table 11.1. The principal age-related changes in pharmacokinetics are summarized in Figure 11.1.Key points Key points Pharmacokinetic changes in the elderly include: • Absorption of iron, calcium and thiamine is reduced. • There is an increased volume of distribution of fatsoluble drugs (e.g. diazepam). • There is a decreased volume of distribution of polar drugs (e.g. digoxin). • There is reduced hepatic clearance of long half-life benzodiazepines. • Declining renal function is the most important cause of drug accumulation. PHARMACODYNAMIC CHANGES Evidence that the elderly are intrinsically more sensitive to drugs than the young is scarce. However, the sensitivity of the elderly to benzodiazepines as measured by psychometric tests is increased, and their effects last longer than in the young. It is common clinical experience that benzodiazepines given to the elderly at hypnotic doses used for the young can produce prolonged daytime confusion even after single doses. The incidence of confusion associated with cimetidine is increased in the elderly. Other drugs may expose physiological defects that are a normal concomitant of ageing. Postural hypotension can occur in healthy elderly people, and the incidence of postural hypotension from drugs such as phenothiazines, β-adrenoceptor

58 DRUGS IN THE ELDERLY antagonists, tricyclic antidepressants and diuretics is increased in elderly patients. The QT interval is longer in the elderly, which may predispose to drug-induced ventricular tachydysrhythmias. Clotting factor synthesis by the liver is reduced in the elderly, and old people often require lower warfarin doses for effective anticoagulation than younger adults. Key points Pharmacodynamic changes in the elderly include: • increased sensitivity to central nervous system (CNS) effects (e.g. benzodiazepines, cimetidine); • increased incidence of postural hypotension (e.g. phenothiazines, beta-blockers, tricyclic antidepressants, diuretics); • reduced clotting factor synthesis, reduced warfarin for anticoagulation; • increased toxicity from NSAIDs; • increased incidence of allergic reactions to drugs. COMPLIANCE IN THE ELDERLY Incomplete compliance is extremely common in elderly people. This is commonly due to a failure of memory or to not understanding how the drug should be taken. In addition, many patients store previously prescribed drugs in the medicine cupboard which they take from time to time. It is therefore essential that the drug regimen is kept as simple as possible and explained carefully. There is scope for improved methods of packaging to reduce over- or under-dosage. Multiple drug regimens are confusing and increase the risk of adverse interactions (see Chapter 13). EFFECT OF DRUGS ON SOME MAJOR ORGAN SYSTEMS IN THE ELDERLY CENTRAL NERVOUS SYSTEM Cerebral function in old people is easily disturbed, resulting in disorientation and confusion. Drugs are one of the factors that contribute to this state; sedatives and hypnotics can easily precipitate a loss of awareness and clouding of consciousness. NIGHT SEDATION The elderly do not sleep as well as the young. They sleep for a shorter time, their sleep is more likely to be broken and they are more easily aroused. This is quite normal, and old people should not have the expectations of the young as far as sleep is concerned. Before hypnotics are commenced, other possible factors should be considered and treated if possible. These include: 1. pain, which may be due to such causes as arthritis; 2. constipation – the discomfort of a loaded rectum; 3. urinary frequency; 4. depression; 5. anxiety; 6. left ventricular failure; 7. dementia; 8. nocturnal xanthine alkaloids, e.g. caffeine in tea, theophylline. A little more exercise may help, and ‘catnapping’ in the day reduced to a minimum and regularized (as in Mediterranen cultures). The prescription of hypnotics (see Chapter 18) should be minimized and restricted to short-term use. ANTIDEPRESSANTS Although depression is common in old age and may indeed need drug treatment, this is not without risk. Tricyclic antidepressants (see Chapter 20) can cause constipation, urinary retention and glaucoma (due to their muscarinic blocking action which is less marked in the case of lofepramine than other drugs of this class), and also drowsiness, confusion, postural hypotension and cardiac dysrhythmias. Tricyclic antidepressants can produce worthwhile remissions of depression but should be started at very low dosage. Selective 5-hydroxytryptamine reuptake inhibitors (e.g. fluoxetine) are as effective as the tricyclics and have a distinct side-effect profile (see chapter 20). They are generally well tolerated by the elderly, although hyponatraemia has been reported more frequently than with other antidepressants. ANTI-PARKINSONIAN DRUGS The anticholinergic group of anti-parkinsonian drugs (e.g. trihexyphenidyl, orphenadrine) commonly cause side effects in the elderly. Urinary retention is common in men. Glaucoma may be precipitated or aggravated and confusion may occur with quite small doses. Levodopa combined with a peripheral dopa decarboxylase inhibitor such as carbidopa can be effective, but it is particularly important to start with a small dose, which can be increased gradually as needed. In patients with dementia, the use of antimuscarinics, levodopa or amantidine may produce adverse cerebral stimulation and/or hallucinations, leading to decompensation of cerebral functioning, with excitement and inability to cope. CARDIOVASCULAR SYSTEM HYPERTENSION There is excellent evidence that treating hypertension in the elderly reduces both morbidity and mortality. The agents used (starting with a C or D drug) are described in Chapter 28. It is important to start with a low dose and monitor carefully. Some adverse effects (e.g. hyponatraemia from diuretics) are much more common in the elderly, who are also much more likely to suffer severe consequences, such as falls/fractures from common effects like postural hypotension. Alphablockers in particular should be used as little as possible. Methyldopa might be expected to be problematic in this age group but was in fact surprisingly well tolerated when used as add-on therapy in a trial by the European Working Party on Hypertension in the Elderly (EWPHE).

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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

  • 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
  • Page 26 and 27: lood (from which samples are taken
  • 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 66 and 67: lifelong effects as a result of tox
  • 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
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  • 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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    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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    ● Introduction 177 ● Pathophysi

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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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    ● Introduction 185 ● Pathophysi

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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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    ● 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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    ● Introduction 285 ● Pathophysi

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    in prefilled injection devices (‘

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    Metformin should be withdrawn and i

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    FURTHER READING American Diabetes A

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    deficiency. Potassium iodide (3 mg

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    fertility. It is contraindicated du

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    ● Introduction 297 ● Vitamin D

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    effective in life-threatening hyper

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    Further reading Block GA, Martin KJ

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    Table 40.1: Actions of cortisol and

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    injection may be useful, but if don

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    CHAPTER 41 REPRODUCTIVE ENDOCRINOLO

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    elease by the pituitary via negativ

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    Treatment with depot progestogen in

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    infusion using an infusion pump to

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    significant proportion of men who r

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    with symptoms caused by the release

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    FURTHER READING Birnbaumer M. Vasop

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    PART IX SELECTIVE TOXICITY

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    ● Principles of antibacterial che

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    2. transfer of resistance between o

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    Pharmacokinetics Absorption of thes

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    Mechanism of action Macrolides bind

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    asic quinolone structure dramatical

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    Case history A 70-year-old man with

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    PRINCIPLES OF MANAGEMENT OF MYCOBAC

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    Pharmacokinetics Absorption from th

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    MYCOBACTERIUM LEPRAE INFECTION Lepr

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    POLYENES AMPHOTERICIN B Uses Amphot

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    therapy is adequate though more fre

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    NUCLEOSIDE ANALOGUES ACICLOVIR Uses

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    Table 45.3: Summary of available ac

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    Uses Interferon-α when combined wi

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    ● Introduction 351 ● Immunopath

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    Table 46.1: Examples of combination

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    NON-NUCLEOSIDE ANALOGUE REVERSE TRA

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    FUSION INHIBITORS Uses Currently, e

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    salvage therapy include azithromyci

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    ● Malaria 361 ● Trypanosomal in

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    Pharmacokinetics Chloroquine is rap

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    Table 47.2: Drug therapy of non-mal

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    ● Introduction 367 ● Pathophysi

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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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    ● Introduction 433 ● Pathophysi

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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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