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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

that the pharmacodynamic

that the pharmacodynamic response is closely related to plasma concentration and its pharmacokinetics are more predictable than those of heparin. Other hirudin analogues have also been synthesized. The place of hirudin and its analogues in therapeutics is currently being established in clinical trials. ORAL ANTICOAGULANTS Warfarin, a racemic mixture of R and S stereoisomers, is the main oral anticoagulant. Phenindione is an alternative, but has a number of severe and distinct adverse effects (see below), so it is seldom used except in rare cases of idiosyncratic sensitivity to warfarin. Use The main indications for oral anticoagulation are: • deep vein thrombosis and pulmonary embolism; • atrial fibrillation (see Chapter 32); • mitral stenosis; • prosthetic valve replacements. Treatment of deep-vein thrombosis and pulmonary embolus is started with a heparin to obtain an immediate effect. This is usually continued for up to seven days to allow stabilization of the warfarin dose. The effect of warfarin is monitored by measuring the international normalized ratio (INR). (The INR is the prothrombin time corrected for an international standard for thromboplastin reagents. Prothrombin time varies from laboratory to laboratory, but the INR in Oxford should be the same as that in, say, Boston, facilitating dose adjustment in these days of international travel.) Before starting treatment, a baseline value of INR is determined. Provided that the baseline INR is normal, anticoagulation is started by administering two consecutive doses 24 hours apart at the same time of day (most conveniently in the evening). If the baseline INR is prolonged or the patient has risk factors for bleeding (e.g. old age or debility, liver disease, heart failure, or recent major surgery), treatment is started with a lower dose. The INR is measured daily, and on the morning of day 3 about 50% of patients will be within the therapeutic range and the heparin can be discontinued. Once the situation is stable, the INR is checked weekly for the first six weeks and then monthly or two-monthly if control is good. The patient is warned to report immediately if there is evidence of bleeding, to avoid contact sports or other situations that put them at increased risk of trauma, to avoid alcohol (or at least to restrict intake to a moderate and unvarying amount), to avoid over-the-counter drugs (other than paracetamol) and to check that any prescription drug is not expected to alter their anticoagulant requirement. Women of childbearing age should be warned of the risk of teratogenesis and given advice on contraception. Appropriate target ranges for different indications reflect the relative risks of thrombosis/haemorrhage in various clinical situations. Table 30.1 lists the suggested ranges of INR that are acceptable for various indications. ANTICOAGULANTS 207 Table 30.1: Suggested acceptable INR ranges for various indications Clinical state Target INR range Prophylaxis of DVT, including surgery on 2.0–2.5 high-risk patients Treatment of DVT/PE/systemic embolism/ 2.0–3.0 mitral stenosis with embolism Recurrent DVT/PE while on warfarin; 3.0–4.5 mechanical prosthetic heart valve Mechanism of action Oral anticoagulants interfere with hepatic synthesis of the vitamin K-dependent coagulation factors II, VII, IX and X. Preformed factors are present in blood so, unlike heparin, oral anticoagulants are not effective in vitro and are only active when given in vivo. Functional forms of factors II, VII, IX and X contain residues of γ-carboxyglutamic acid. This is formed by carboxylation of a glutamate residue in the peptide chain of the precursor. This is accomplished by cycling of vitamin K between epoxide, quinone and hydroquinone forms. This cycle is interrupted by warfarin, which is structurally closely related to vitamin K, and inhibits vitamin K epoxide reductase. Adverse effects 1. Haemorrhage If severe, vitamin K is administered intravenously, but its effect is delayed and it renders the patient resistant to re-warfarinization. Life-threatening bleeding requires administration of fresh frozen plasma, or specific coagulation factor concentrates, with advice from a haematologist. 2. Other adverse actions of warfarin include: • teratogenesis; • rashes; • thrombosis is a rare but severe paradoxical effect of warfarin and can result in extensive tissue necrosis. Vitamin K is involved in the biosynthesis of anticoagulant proteins C and S. Protein C has a short elimination half-life, and when warfarin treatment is started, its plasma concentration declines more rapidly than that of the vitamin K-dependent coagulation factors, so the resulting imbalance can temporarily favour thrombosis. 3. Adverse effects of phenindione: • interference with iodine uptake by the thyroid; • renal tubular damage; • hepatitis; • agranulocytosis; • dermatitis; • secretion into breast milk. Pharmacokinetics Following oral administration, absorption is almost complete and maximum plasma concentrations are reached within two to eight hours. Approximately 97% is bound to plasma albumin. Warfarin does gain access to the fetus, but does not

208 ANTICOAGULANTS AND ANTIPLATELET DRUGS appear in breast milk in clinically relevant amounts. There is substantial variation between individuals in warfarin t 1/2. The R and S enantiomers are metabolized differently in the liver. The (active) S enantiomer is metabolized to 7-hydroxywarfarin by a cytochrome P450-dependent mixed function oxidase, while the less active R enantiomer is metabolized by soluble enzymes to warfarin alcohols. Hepatic metabolism is followed by conjugation and excretion into the gut in the bile. Deconjugation and reabsorption then occur, completing the enterohepatic cycle. Knowledge of the plasma concentration of warfarin is not useful in routine clinical practice because the pharmacodynamic response (INR) can be measured accurately, but it is valuable in the investigation of patients with unusual resistance to warfarin, in whom it helps to distinguish poor compliance, abnormal pharmacokinetics and abnormal sensitivity. Since warfarin acts by inhibiting synthesis of active vitamin K-dependent clotting factors, the onset of anticoagulation following dosing depends on the catabolism of preformed factors. Consequently, the delay between dosing and effect cannot be shortened by giving a loading dose. Drug interactions Potentially important pharmacodynamic interactions with warfarin include those with antiplatelet drugs. Aspirin not only influences haemostasis by its effect on platelet function, but also increases the likelihood of peptic ulceration, displaces warfarin from plasma albumin, and in high doses decreases prothrombin synthesis. Despite these potential problems, recent clinical experience suggests that with close monitoring the increased risk of bleeding when low doses of aspirin are taken regularly with warfarin may be more than offset by clinical benefits to patients at high risk of thromboembolism following cardiac valve replacement. Broad-spectrum antibiotics potentiate warfarin by suppressing the synthesis of vitamin K1 by gut flora. Several pharmacokinetic interactions with warfarin are of clinical importance. Several non-steroidal anti-inflammatory drugs (NSAIDs) and dextropropoxyphene inhibit warfarin metabolism. The gastrotoxic and platelet-inhibitory actions of the NSAIDs further increase the risk of serious haemorrhage. Cimetidine (but not ranitidine) and amiodarone also potently inhibit warfarin metabolism and potentiate its effect, as do other inhibitors of hepatic cytochrome P450, such as erythromycin, ciprofloxacin and omeprazole (Chapter 5). Drugs that induce hepatic microsomal enzymes, including rifampicin, carbamazepine and phenobarbital, increase warfarin metabolism and increase the dose required to produce a therapeutic effect; furthermore, if the dose is not reduced when such concurrent therapy is discontinued, catastrophic over-anticoagulation and haemorrhage may ensue. ANTIPLATELET DRUGS ASPIRIN Aspirin is the main antiplatelet drug in clinical use. It works by inhibiting the synthesis of thromboxane A2 (TXA2), and its use Prostacyclin synthase Prostacyclin Arachidonic acid Prostaglandin endoperoxides (PGH 2) Vasodilatation Inhibition of platelet aggregation Cyclo-oxygenase Thromboxane A 2 synthase Thromboxane A 2 Vasoconstriction Platelet aggregation Figure 30.3: Formation of prostacyclin and thromboxane A 2 in vivo. These two products of arachidonic acid metabolism exert competing and opposite physiological effects. in the treatment and prevention of ischaemic heart disease is described in Chapter 29. Numerous clinical trials have demonstrated its efficacy. Efficacy is not directly related to dose and low doses cause less adverse effects. TXA 2 is synthesized by activated platelets and acts on receptors on platelets (causing further platelet activation) and on vascular smooth muscle (causing vasoconstriction). Figure 30.3 shows the pathway of its biosynthesis from arachidonic acid. Aspirin inhibits thromboxane synthesis – it acetylates a serine residue in the active site of constitutive (type I) cyclo-oxygenase (COX-1) in platelets, irreversibly blocking this enzyme. The most common side effect is gastric intolerance and the most common severe adverse reaction is upper gastro-intestinal bleeding. Both effects stem from inhibition of COX-1 in the stomach, resulting in decreased production of the gastroprotective PGE 2. EPOPROSTENOL (PROSTACYCLIN) Epoprostenol is the approved drug name for synthetic prostacyclin, the principal endogenous prostaglandin of large artery endothelium. It acts on specific receptors on the plasma membranes of platelets and vascular smooth muscle. These are coupled by G-proteins to adenylyl cyclase. Activation of this enzyme increases the biosynthesis of cyclic adenosine monophosphate (cAMP), which inhibits platelet aggregation and relaxes vascular smooth muscle. Epoprostenol relaxes pulmonary as well as systemic vasculature, and this underpins its use in patients with primary pulmonary hypertension. It (or a related synthetic prostanoid, iloprost) is administered chronically to such patients while awaiting heart–lung transplantation. Epoprostenol inhibits platelet activation during haemodialysis. It can be used with heparin, but is also effective as the sole anticoagulant in this setting, and is used for haemodialysis in patients in whom heparin is contraindicated. It has also been used in other types of extracorporeal circuit (e.g. during cardiopulmonary bypass). Epoprostenol has been

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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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  • Page 170 and 171: Key points Drugs for mild pain •
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  • Page 178 and 179: ● Introduction: inflammation 167
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  • Page 204 and 205: Key points Drugs used in essential
  • Page 206 and 207: Case history A 72-year-old woman se
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  • Page 210 and 211: Persistent ST segment elevation Thr
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  • Page 216 and 217: Intrinsic pathway XIIa XIa the acti
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  • Page 224 and 225: The drugs that are most effective i
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  • Page 232 and 233: arrest. The electrocardiogram is li
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  • Page 236 and 237: Drug interactions Amiodarone potent
  • Page 238 and 239: effect when treating sinus bradycar
  • Page 240 and 241: Case history A 24-year-old medical
  • Page 242 and 243: PART V THE RESPIRATORY SYSTEM
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  • Page 246 and 247: STEP 5: CONTINUOUS OR FREQUENT USE
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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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