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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

dinucleotide (NAD)

dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Niacin can be generated in the body in small amounts from tryptophan. Deficiency of niacin causes pellagra, that can manifest clinically as a syndrome complex which includes dementia, dermatitis and diarrhoea. Uses 1. Niacin is used to treat and prevent pellagra. If oral treatment is not possible, intravenous injections are available. 2. Nicotinic acid (or nicotinic acid analogues, e.g. acipomox) may be used to treat dyslipidaemia (Chapter 27), but hypolipidaemic dosing is limited by vasodilatation/flushing. Adverse effects In replacement therapy for pellagra, adverse effects are uncommon. High doses (as used for hyperlipidaemia) cause the following: 1. vasodilatation due to prostaglandin D 2 – this can be reduced by premedication with aspirin; 2. nausea, vomiting and itching; 3. hyperglycaemia; 4. exacerbation of hyperuricaemia. Pharmacokinetics Both niacin and nicotinamide are well absorbed via the intestine and are widely distributed to tissues. When the usual dietary amounts are administered, a high proportion is excreted as N-methyl nicotinamide and other metabolites. When increased doses are administered, a higher proportion is excreted unchanged in the urine. VITAMIN B 6 (PYRIDOXINE) Physiology Vitamin B6 occurs naturally in three forms, namely pyridoxine, pyridoxal and pyridoxamine. All three forms are converted in the body into pyridoxal phosphate, which is an essential cofactor in several metabolic reactions, including decarboxylation, transamination and other steps in amino acid metabolism. Pyridoxine is present in wheatgerm, yeast, bran, rice and liver. Deficiency causes glossitis, seborrhoea, fits, peripheral neuropathy and sideroblastic anaemia. Isoniazid prevents the activation of pyridoxal to pyridoxal phosphate by inhibiting the enzyme pyridoxal kinase, and slow acetylators of isoniazid are at increased risk of developing peripheral neuropathy for this reason (Chapters 14 and 44). Use Pyridoxine hydrochloride is given to patients at risk (e.g. alcoholics) during long-term therapy with isoniazid to prevent peripheral neuropathy, and in deficiency states. Large doses are used in sideroblastic anaemia. Pyridoxine is also used to treat certain uncommon inborn errors of metabolism, including primary hyperoxaluria. Large doses are sometimes used to treat premenstrual syndrome, and there is a lobby of enthusiasts for this, despite a paucity of evidence. Adverse effects There have been reports of ataxia and sensory neuropathy following administration of large doses (2 g/day) of pyridoxine for more than two months. VITAMIN C (ASCORBIC ACID) VITAMIN C(ASCORBIC ACID) 267 Physiology Ascorbic acid is present in large quantities in citrus fruits, tomatoes and green vegetables. Vitamin C is essential to humans, monkeys and guinea pigs which, unlike other mammals, cannot synthesize it from glucose. Dietary lack of vitamin C causes scurvy, which is characterized by bleeding gums and perifollicular purpura. Ascorbic acid is involved in several metabolic processes (Figure 35.2). It is a potent watersoluble anti-oxidant. The nutritional status of vitamin C can be assessed by measuring the intracellular leukocyte concentration, but this is not routinely performed or available. Uses 1. Ascorbic acid is used in the prophylaxis and treatment of scurvy. (Perhaps the first recorded clinical trial involved the distribution of citrus fruit to some, but not all, British naval vessels and observation of the incidence of scurvy. The Admiralty were (after some prevarication) convinced and British sailors were subsequently provided with limes – whence the term ‘limeys’.) 2. Ascorbic acid increases the absorption of orally administered iron. 3. The reducing properties of ascorbate may be used in the treatment of methaemoglobinaemia. 4. In scorbutic patients, wound healing is delayed and this is restored to normal by administration of ascorbic acid. Adverse effects Ascorbic acid is non-toxic in low doses. However, administration of �4 g daily raises the urinary excretion of oxalate. Large Anti-oxidant CYP450 drug-metabolizing enzyme function Collagen biosynthesis VITAMIN C Folic acid activation Figure 35.2: Functions of vitamin C. Steroid metabolism Mitochondrial electron transport chain function

268 VITAMINS AND TRACE ELEMENTS doses of vitamin C taken chronically have resulted in calcium oxalate urolithiasis. There is theoretical concern that high doses of vitamin C (in common with other anti-oxidants) can have pro-oxidant actions. Pharmacokinetics Ascorbic acid is well absorbed following oral administration and its sodium salt may be given by intramuscular or intravenous injection. Ascorbic acid is mainly metabolized by oxidation to oxalic acid. Normally about 40% of urinary oxalate is derived from ascorbic acid. When the body stores of ascorbic acid are saturated, some ingested ascorbic acid is excreted in the urine unchanged. VITAMIN E (TOCOPHEROL) Vitamin E is found in many foods, including nuts, wheatgerm and bananas. Deficiency in animals causes abortion and degeneration of the germinal epithelium of the testes. No defined deficiency syndrome exists in humans, but low vitamin E intake is associated with anaemia in premature and malnourished infants. Vitamin E protects erythrocytes against haemolysis, and is a fat-soluble anti-oxidant and detoxifies free radicals. Free radicals cause membrane and epithelial injury and have been implicated in the pathophysiology of numerous diseases, including cancer and atheroma. Epidemiological studies suggested that reduced vitamin E intake is associated with increased atherogenesis (Chapter 27). Large studies of vitamin E supplementation for a number of cardiovascular disorders and cancers have not shown clear benefit, and there is a theoretical risk that prolonged ingestion of high doses could be harmful. Key points Vitamin deficiency and disease • In general, vitamin deficiencies are due to inadequate dietary intake or malabsorption. • Vitamin B deficiencies do not often occur in isolation. • Vitamin A deficiency causes night blindness. • Vitamin B 1 (thiamine) deficiency causes beriberi (neuropathy, paralysis, muscle wasting and cardiac failure). • Vitamin B 3 (nicotinic acid) deficiency causes pellagra (photosensitive dermatitis, diarrhoea, dementia and death (the 4 Ds)). • Vitamin B 12 deficiency causes megaloblastic anaemia, dementia and neuropathy. • Vitamin C deficiency causes scurvy (perifollicular petechiae, gingivitis and swollen joints). • Vitamin D deficiency causes rickets (in young) and osteomalacia (adults). • Folate deficiency causes megaloblastic anaemia and neural tube defects (in the developing fetus). Key points Population groups at high risk for vitamin deficiency • Infants • Pregnant women • Elderly people, especially the elderly with chronic disease • Alcoholics and drug abusers • Vegans and undernourished populations • Patients taking long-term anticonvulsants • Patients with malabsorption syndromes. Key points Vitamin toxicities • Vitamin A – gastro-intestinal upsets, headache (raised intracranial pressure), desquamation, hepatotoxicity and teratogenicity. • Nicotinic acid – flushing, vasodilatation and hepatotoxicity. • Vitamin C – hyperoxaluria and oxalate stones. • Vitamin D – hypercalcaemia. ESSENTIAL FATTY ACIDS Several naturally occurring unsaturated fatty acids are essential dietary components. Linoleic and linolenic acids occur in vegetable oils and nuts, arachidonic acid occurs in meat, and longer-chain fatty acids (eicosapentanoic acid and docosahexanoic acid) are found in cold-water oily fish. Humans synthesize arachidonic acid (C20:4) from shorter-chain (C18:2) essential fatty acids by chain elongation and desaturation. Arachidonic acid is present in the lipid component of cell membranes throughout the body. It is esterified on the 2�-position of glycerol in membrane phospholipids and is liberated by phospholipases when cells are injured or stimulated. Free arachidonic acid is the precursor of the 2-series of prostaglandins, thromboxanes, the 4-series of leukotrienes and epoxyeicosatetraenoic acids which are important in many physiologic and pathologic states, including control of inflammation, haemostasis and vascular tone. Deficiency states have been described in patients receiving long-term parenteral nutrition and are prevented by the use of lipid emulsions. TRACE ELEMENTS A total of 13 nutritionally essential trace elements are recognized, namely fluorine, silicon, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, selenium, tin and iodine. These are required in the human body at �0.01% of body weight. Most of them are highly reactive chemically and one or more of these elements is present at the active site of many enzymes. They are present in small but adequate amounts in a normal diet, but evidence is accumulating that in addition to iron, cobalt (Chapter 49) and iodine (Chapter 38), zinc,

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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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    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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    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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