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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Drug interactions

Drug interactions Although synergism between β 2-adrenergic agonists and theophylline has been demonstrated in vitro, clinically the effect of this combination is at best additive. Many drugs inhibit CYP1A2mediated theophylline metabolism, e.g. erythromycin (and other macrolides), fluoroquinolones (e.g. ciprofloxacin), interferon and cimetidine, thus precipitating theophylline toxicity. Theophylline metabolism is induced in the presence of hepatic CYP450-inducing agents, such as rifampicin. GLUCOCORTICOSTEROIDS Glucocorticosteroids are used in the treatment of asthma and in severe exacerbations of COPD because of their potent anti-inflammatory effect. This involves interaction with an intracellular glucocorticosteroid receptor that in turn interacts with nuclear DNA, altering the transcription of many genes and thus the synthesis of pro-inflammatory cytokines, β 2-adrenoceptors, tachykinin-degrading enzymes and lipocortin (an inhibitor of phospholipase A 2, reducing free arachidonic acid and thus leukotriene synthesis). They are used both in maintenance therapy (prophylaxis) and in the treatment of the acute severe attack. SYSTEMIC GLUCOCORTICOSTEROIDS For more information on the use of systemic glucocorticosteroids, see Chapter 40. Hydrocortisone is given intravenously in urgent situations. Improvement (a rise in FEV1 and forced vital capacity, FVC) does not begin until after six hours, and is usually maximal 10–12 hours following the start of treatment. This delay is due to the action of glucocorticosteroids via altered gene transcription and subsequent modified protein synthesis. Oral glucocorticosteroids (e.g. prednisolone) are usually started within 12–24 hours. INHALED GLUCOCORTICOSTEROIDS (E.G. BECLOMETASONE, BUDESONIDE, FLUTICASONE, MOMETASONE) Use Modern inhalational devices deliver up to 20% of the administered dose to the lungs. Glucocorticosteroids can be administered via nebulizers, ‘spacer’ devices, metered-dose inhalers or as dry powders. The fluorinated derivatives are extremely potent and mainly exert a local action because they are highly polar and hence only a small fraction of the dose is systemically absorbed. Approximately 15–20% enters the lungs, the rest being swallowed and then rapidly converted to inactive metabolites by intestinal and hepatic CYP3A enzymes. The comparative pharmacology of the commonly used inhaled glucocorticosteroids is summarized in Table 33.2. Adverse effects of inhaled steroids • At the lowest recommended daily dose for adults, there is no prolonged suppression of the hypothalamic–pituitary– adrenal (HPA) axis. Higher doses can produce clinically important depression of adrenal function. DRUGS USED TO TREAT ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE 239 • Candidiasis of the pharynx or larynx occurs in 10–15% of patients. Using the minimum effective dose, or a ‘spacer device’, or gargling/using mouthwashes after dosing, minimizes this problem. • A hoarse voice may develop due to a laryngeal myopathy at high doses. This is reversible and its occurrence is minimized by the use of a ‘spacer’. • Bruising and skin atrophy occur at high doses. • Inhibition of long bone growth during prolonged highdose treatment in children. • Posterior subcapsular cataracts may develop following prolonged use. CROMOGLICATE AND NEDOCROMIL Use Sodium cromoglicate may be used to prevent exercise-induced asthma and as prophylaxis for allergic asthma in children. Its use as a prophylactic in children has been largely superseded by inhaled glucocorticosteroids which are more effective. It is used as a nasal spray for perennial and allergic rhin-itis, and as eyedrops in allergic conjunctivitis. Cromoglicate produces no benefit during an acute asthmatic attack. Nedocromil sodium is an alternative to cromoglicate. Mechanism of action Cromoglicate and nedocromil inhibit mediator release from sensitized mast cells in vitro, and also reduce firing of sensory Key points Anti-inflammatory agents – cromoglicate and glucocorticosteroids Sodium cromoglicate • Its mechanism of action is unclear. It has an antiinflammatory effect. • Largely superseded in chronic prophylactic therapy of ‘allergic asthma’ by glucocorticosteroids. • Prevents exercise-induced asthma. • Inhaled therapy is administered via metered-dose inhaler or dry powder. • Side-effects are minimal (headache, cough). • Its use is very safe in children. Glucocorticosteroids • Mechanism is anti-inflammatory. • They are administered systemically (i.v./p.o.) in severe acute and chronic asthma. • They are inhaled topically or nebulized in chronic asthma. • Glucocorticosteroids are well absorbed from the gastrointestinal tract–hepatic (CYP3A) metabolism. • Dosing is once daily for oral glucocorticosteroids and twice daily for inhaled agents. • Side effects are minimal with topical therapy (oral thrush, hoarse voice, HPA suppression only at high dose). • Side effects with systemic therapy are the features of Cushing’s syndrome.

240 THERAPY OF ASTHMA, COPD AND OTHER RESPIRATORY DISORDERS Table 33.2: Comparative pharmacology of some inhaled glucocorticosteroids Drug Relative binding affinity Relative blanching Comments to receptors a potency a Beclometasone 0.4 600 Equi-effective compared to dipropionate budesonide. May be used in children Budesonide 9.4 980 Nebulized formulation (0.5–1mg/2 mL) Fluticasone 18 1200 available. May be used in children to avoid systemic steroids May cause fewer systemic side effects than others a Relative to dexamethasone binding to glucocorticosteroid receptors in vitro and blanching of human skin in vitro. C-fibres in response to tachykinins (e.g. bradykinin). However, the complete mechanism underlying their therapeutic efficacy is uncertain. Adverse effects • Sodium cromoglicate is virtually non-toxic. The powder can (very rarely) produce bronchospasm or hoarseness. • Nausea and headache are rare adverse effects. • Nedocromil has a bitter taste. Pharmacokinetics Sodium cromoglicate, an inhaled powder, undergoes little systemic absorption. Most of the powder is swallowed, about 10% reaching the alveoli. Nedocromil sodium has similarly low systemic bioavailability. LEUKOTRIENE MODULATORS These fall into two classes, namely leukotriene receptor antagonists and 5�-lipoxygenase inhibitors. Leukotrienes (LT) are fatty acid-derived mediators containing a conjugated triene structure. They are formed when arachidonic acid (Chapter 26) is liberated from the cell membrane of cells, as a result of cell activation by allergic or other noxious stimuli. 5�-Lipoxygenase is the enzyme required for the synthesis of LTA 4, which is an unstable epoxide precursor of the two subgroups of biologically important leukotrienes. LTB 4 is a dihydroxy 20-carbon-atom fatty acid which is a potent pro-inflammatory chemo-attractant. The other group is the cysteinyl leukotrienes (LTC 4, LTD 4 and LTE 4). LTC 4 is a conjugate of LTA 4 plus glutathione, a tripeptide which combines with LTA 4 via its cysteine residue. LTC 4 is converted to an active metabolite (LTD 4) by the removal of the terminal amino acid in the peptide side-chain. Removal of a second amino acid results in a less active metabolite (LTE 4). LTC 4, LTD 4 and LTE 4, the ‘sulphidopeptide leukotrienes’ or ‘cysteinyl leukotrienes’, collectively account for the activity that used to be referred to as ‘slow-reacting substance of anaphylaxis’ (SRS-A). They all (but especially LTD 4) bind to the Cys-LT 1 receptor to cause bronchoconstriction, attraction of eosinophils and production of oedema. LEUKOTRIENE C4 AND D4 ANTAGONISTS Use Leukotriene receptor antagonists are used to treat asthma and are given orally, usually in the evening. Montelukast was the first of these drugs to become available clinically. It reduced the requirement for glucocorticosteroid and improved symptoms in chronic asthma. It is also useful in the prophylaxis of exercise- or antigen-induced asthma. Montelukast is effective in aspirinsensitive asthma, which is associated with diversion of arachidonic acid from the cyclo-oxygenase pathway (blocked by aspirin) to the formation of leukotrienes via 5�-lipoxygenase. Mechanism of action Montelukast is a competitive inhibitor of LTD4 and LTC4 at the Cys-LT1 receptor. Adverse effects Montelukast is generally well tolerated, but side effects include: • gastro-intestinal upsets; • asthenia and drowsiness; • rash, fever, arthralgias; • elevation of serum transaminases. Pharmacokinetics This drug is rapidly absorbed from the gastro-intestinal tract. The mean plasma t1/2 is 2.7–5.5 hours. It undergoes hepatic metabolism by CYP 3A and 2C9, and is mainly excreted in the bile. Drug interactions No clinically important drug–drug interactions are currently recognized. 5�-LIPOXYGENASE INHIBITORS Zileuton (available in the USA) is a competitive inhibitor of the 5�-lipoxygenase enzyme. It is used in asthma therapy and administered orally and undergoes hepatic metabolism. Its

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    A Textbook of Clinical Pharmacology

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    A Textbook of Clinical Pharmacology

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    This fifth edition is dedicated to

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    FOREWORD viii PREFACE ix ACKNOWLEDG

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    PREFACE Clinical pharmacology is th

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    PART I GENERAL PRINCIPLES

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    ● Use of drugs 3 ● Adverse effe

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    and acquired factors, notably disea

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    100 Effect (%) 0 0 5 10 1 10 100 (a

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    Dose ratio -1 100 50 The relationsh

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    ● Introduction 11 ● Constant-ra

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    In reality, processes of eliminatio

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    lood (from which samples are taken

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    ● Introduction 17 ● Bioavailabi

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    ROUTES OF ADMINISTRATION ORAL ROUTE

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    Transdermal absorption is sufficien

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    FURTHER READING Fix JA. Strategies

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    and thromboxanes are CYP450 enzymes

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    and lorazepam. Some patients inheri

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    Orally administered drug Parenteral

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    ● Introduction 31 ● Glomerular

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    ACTIVE TUBULAR REABSORPTION This is

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    DISTRIBUTION Drug distribution is a

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    Detailed recommendations on dosage

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    DIGOXIN Myxoedematous patients are

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    ● Introduction 41 ● Role of dru

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    25 20 10 Life-threatening toxicity

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    ● Introduction 45 ● Harmful eff

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    vagina in girls in their late teens

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    an anti-analgesic effect when combi

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    Case history A 20-year-old female m

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    METABOLISM At birth, the hepatic mi

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    lifelong effects as a result of tox

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    DISTRIBUTION Ageing is associated w

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    DIGOXIN Digoxin toxicity is common

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    FURTHER READING Dhesi JK, Allain TJ

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    Factors involved in the aetiology o

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    analgesic. Following its release, t

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    antibiotics, such as penicillin or

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    predisposes to non-immune haemolysi

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    ● Introduction 71 ● Useful inte

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    Response Therapeutic range Toxic ra

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    Table 13.1: Interactions outside th

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    Table 13.5: Competitive interaction

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    ● Introduction: ‘personalized m

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    Table 14.2: Variations in drug resp

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    lipoprotein (LDL) is impaired. LDL

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    Key points • Genetic differences

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    • Discovery • • Screening Pre

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    Too many statistical comparisons pe

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    ETHICS COMMITTEES Protocols for all

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    Table 16.1: Recombinant proteins/en

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    duration and benefit. Adenoviral ve

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    ● Introduction 97 ● Garlic 97

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    A case report has suggested a possi

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    including hypericin and pseudohyper

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    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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    ● 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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    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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