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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

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FURTHER READING American Diabetes Association. Implications of the diabetes control and complications trial. Diabetes 1993; 42: 1555–8. Bolli GB, Owens DR. Insulin glargine. Lancet 2000; 356: 443–5. deFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. New England Journal of Medicine 1995; 333: 541–9 (see also accompanying editorial on metformin by OB Crofford, pp. 588–9). Dornhorst A. Insulinotropic meglitinide analogues. Lancet 2001; 358: 1709–16. Gale EAM. Lessons from the glitazones: a story of drug development. Lancet 2001; 357: 1870–5. Gerich JE. Oral hypoglycemic agents. New England Journal of Medicine 1989; 321: 1231–45. DRUGS USED TO TREAT DIABETES MELLITUS 291 Hirsch IB. Drug therapy: Insulin analogues. New England Journal of Medicine 2005; 352: 174–83. Owens DR, Zinman B, Bolli GB. Insulins today and beyond. Lancet 2001; 358: 739–46. Perfetti R, D’Amico E. Rational drug design and PPAR agonists. Current Diabetes Report 2005; 5: 340–5. Pickup JC, Williams J (eds). Handbook of diabetes, 3rd edn. Oxford: Blackwell Science, 2004. Skyler JS, Cefalu WT, Kourides IA et al. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomized proof-of-concept study. Lancet 2001; 357: 324–5. Yki-Jarvinen H. Drug therapy: thiazolidinediones. New England Journal of Medicine 2004; 351: 1106–18.

● Introduction 292 ● Pathophysiology and principles of treatment 292 ● Iodine 292 INTRODUCTION The thyroid secretes thyroxine (T 4) and tri-iodothyronine (T 3), as well as calcitonin, which is discussed in Chapter 39. The release of T 3 and T 4 is controlled by the pituitary hormone thyrotrophin (thyroid-stimulating hormone, TSH). This binds to receptors on thyroid follicular cells and activates adenylyl cyclase, which stimulates iodine trapping, iodothyronine synthesis and release of thyroid hormones. TSH is secreted by basophil cells in the adenohypophysis. Secretion of TSH by the anterior pituitary is stimulated by the hypothalamic peptide thyrotrophin-releasing hormone (TRH). Circulating T 4 and T 3 produce negative-feedback inhibition of TSH at the pituitary and hypothalamus. Drug treatment is highly effective in correcting under- or over-activity of the thyroid gland. The diagnosis of abnormal thyroid function and monitoring of therapy have been greatly facilitated by accurate and sensitive assays measuring TSH, because the serum TSH level accurately reflects thyroid state, whereas the interpretation of serum concentrations of T 3 and T 4 is complicated by very extensive and somewhat variable protein binding. Negative feedback of biologically active thyroid hormones ensures that when there is primary failure of the thyroid gland, serum TSH is elevated, whereas when there is overactivity of the gland, serum TSH is depressed. Hypothyroidism caused by hypopituitarism is relatively uncommon and is associated with depressed sex hormone and adrenal cortical function. Hyperthyroidism secondary to excessive TSH is extremely rare. PATHOPHYSIOLOGY AND PRINCIPLES OF TREATMENT Thyroid disease is more common in women than in men, and is manifested either as goitre or as under- or over-activity of the gland. Hypothyroidism is common, especially in the elderly. It is usually caused by autoimmune destruction of the gland and, if untreated, leads to the clinical picture of myxoedema. Treatment is by lifelong replacement with thyroxine. CHAPTER 38 THYROID ● Thyroxine and tri-iodothyronine 293 ● Antithyroid drugs 293 ● Special situations 295 Hyperthyroidism is also common and again autoimmune processes are implicated. Treatment options comprise: • antithyroid drugs; • radioactive iodine; • surgery. Antithyroid drugs enable a euthyroid state to be maintained until the disease remits or definitive treatment with radioiodine or surgery is undertaken. Radioactive iodine is well tolerated and free of surgical complications (e.g. laryngeal nerve damage), whereas surgery is most appropriate when there are local mechanical problems, such as tracheal compression. In older patients, the most common cause of hyperthyroidism is multinodular toxic goitre. In young women it is usually caused by Graves’ disease, in which an immunoglobulin binds to and stimulates the TSH receptor, thereby promoting synthesis and release of T 3 and T 4 independent of TSH. In addition to a smooth vascular goitre, there is often deposition of mucopolysaccharide, most notably in the extrinsic eye muscles which become thickened and cause proptosis. Graves’ disease has a remitting/relapsing course and often finally leads to hypothyroidism. Other aetiologies of hyperthyroidism include acute viral or autoimmune thyroiditis (which usually resolve spontaneously), iatrogenic iodine excess (e.g. thyroid storm following iodine-containing contrast media and hyperthyroidism in patients treated with drugs, such as amiodarone; see below and Chapter 32), and acute postpartum hyperthyroidism. IODINE The thyroid gland concentrates iodine. Dietary iodide normally amounts to 100–200 mg per day and is absorbed from the stomach and small intestine by an active process. Following systemic absorption and uptake into the thyroid gland, iodide is oxidized to iodine, which is the precursor to various iodinated tyrosine compounds including T 3 and T 4. Iodine is used to treat simple non-toxic goitre due to iodine

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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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    ● 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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  • Page 312 and 313: Further reading Block GA, Martin KJ
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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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