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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

significant proportion

significant proportion of men who receive placebo discontinue their participation because of the occurrence of impotence which they attribute to therapy. Drugs that affect the autonomic supply to the sex organs are not alone in interfering with sexual function. Indeed, bendroflumethiazide, a thiazide diuretic, caused significantly more impotence in the Medical Research Council (MRC) trial of mild hypertension than did propranolol, a β-adrenoceptor antagonist. Drugs that do interfere with autonomic function and can also cause erectile dysfunction include phenothiazines, butyrophenones and tricyclic antidepressants. Pelvic non-adrenergic, non-cholinergic nerves are involved in erectile function and utilize nitric oxide as their neurotransmitter. Nitric oxide release from endothelium in the corpus cavernosum is abnormal in some cases of organic impotence, e.g. in diabetes mellitus. Phosphodiesterase type 5 inhibitors licensed for the treatment of erectile dysfunction include sildenafil, tadalafil and vardenafil. They have revolutionized the treatment of erectile dysfunction. Caution is needed in patients with cardiovascular disease, anatomical deformation of the penis, e.g. Peyronie’s disease, and in those with a predisposition to prolonged erection, e.g. in sickle-cell disease. They are contraindicated in patients who are on nitrates and in patients with a previous history of non-arteritic anterior ischaemic optic neuropathy. The side effects include dyspepsia, vomiting, headache, flushing, dizziness, myalgia, visual disturbances, raised intraocular pressure and nasal congestion. Other therapeutic options for erectile dysfunction include intracavernosal injection or urethral application of alprostadil (prostaglandin E 1). Priapism and hypotension are side effects. Any treatment for erectile dysfunction should only be initiated after treatable medical causes have been excluded. A few cases of reduced libido and impotence in males and females are associated with idiopathic hyperprolactinaemia, and in such cases bromocriptine may restore potency. Androgens play a role in both male and female arousal, but their use is not appropriate except in patients with reduced circulating concentrations of testosterone. Case history A 26-year-old woman consults you in your GP surgery regarding advice about starting the combined oral contraceptive pill. Question Outline your management of this patient. Answer It is very important to take a careful history in order to exclude any risk factors which would contraindicate the combined oral contraceptive, such as a past history of thrombo-embolic disease or risk factors for thrombo-embolic disease. In addition, it is important to ascertain whether the patient is a smoker and when she last had a cervical smear. It is important to exclude a history of migraine and to check her blood pressure. The combined oral contraceptive is probably an appropriate form of contraception in a woman of this age, who would possibly be highly fertile, as it is the most reliable form of contraception available, provided that there are no risk factors to contraindicate the combined oral contraceptive. There are many COCs on the market and selection for this individual would be dependent on a balance of achieving good cycle FURTHER READING MALE REPRODUCTIVE ENDOCRINOLOGY 315 control and weighing the beneficial effects on plasma lipids offered by the newer progestogens, such as desogestrel, gestadine and norgestimate, against the recently reported two-fold increased risk of venous thrombo-embolism noted with desogestrel and gestadine. In a woman of this age, the beneficial effects on plasma lipids are probably of minor importance and in view of the increased risk of venous thrombo-embolism it would probably be appropriate to choose a pill containing norethisterone, levonorgestrel or norgestimate. The majority of women achieve good cycle control with combined oral contraceptives containing oestrogen at a dose of about 30–35 μg; pills containing the higher dose of oestrogen would only be required if the individual was on long-term enzyme-inducing therapy (e.g. rifampicin) or anticonvulsant medication. Case history A 50-year-old woman consults you about her symptoms of flushing and vaginal discomfort. She is thin and is a smoker. Question Outline the therapy most likely to be of benefit, including the reasons for this. Answer This woman is probably menopausal and is suffering the consequences of the vasomotor effects of the menopause, as well as vaginal dryness. The vaginal dryness could be treated locally with short periods of treatment with topical oestrogens. However, in view of her other symptoms, a better option would be to start her on hormone replacement therapy. If she still has an intact uterus then it is important to give both oestrogen and cyclical progestogen to protect the endometrium from hyperplasia. Depending on preference, life-style and the likelihood of compliance, either oral therapy or patches may be appropriate. In this woman, who has risk factors for osteoporosis, such as smoking and thinness, it may be of benefit to continue the hormone replacement therapy for a period of at least five years and possibly longer, although it is important to exercise caution with regard to her risk for breast cancer and cardiovascular disease. Baird DT, Glasier AF. Science, medicine, and the future: Contraception. British Medical Journal 1999; 319: 969–72. Nelson HD. Assessing benefits and harms of hormone replacement therapy: clinical applications. Journal of the American Medical Association 2002; 288: 882–4. Nelson HD, Humphrey LL, Nygren P et al. Postmenopausal hormone replacement therapy: scientific review. Journal of the American Medical Association 2002; 288: 872–81. US Preventive Services Task Force. Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the US Preventive Services Task Force. Annals of Internal Medicine 2005; 142: 855–60. Wathen CN, Feig DS, Feightner JW et al. and The Canadian Task Force on Preventive Health Care. Hormone replacement therapy for the primary prevention of chronic diseases: recommendation statement from the Canadian Task Force on Preventive Health Care. Canadian Medical Association Journal 2004; 170: 1535–7.

CHAPTER 42 THE PITUITARY HORMONES AND RELATED DRUGS ● Anterior pituitary hormones and related drugs 316 ● Posterior pituitary hormones 318 ANTERIOR PITUITARY HORMONES AND RELATED DRUGS GROWTH HORMONE: PHYSIOLOGY AND PATHOPHYSIOLOGY Growth hormone (GH) is a 191-amino-acid protein secreted by the acidophil cells in the anterior pituitary. Secretion occurs in brief pulses, with a slower underlying diurnal variability, and is greatest during sleep. Secretion is much greater during growth than in older individuals. Secretion is stimulated by hypoglycaemia, fasting and stress, and by agonists at dopamine, serotonin and at α- and β-adrenoceptors. The serotoninergic pathway is involved in the stimulation of somatotropin release during slowwave sleep. Secretion is inhibited by eating, by glucocorticosteroids and by oestrogens. The hypothalamus controls GH secretion from the pituitary by secreting a GH-releasing hormone (GHRH), somatorelin and a GH-release-inhibiting hormone, somatostatin, which is also synthesized in D cells of the islets of Langerhans in the pancreas. GH-secreting pituitary adenomas cause acromegaly in adults (gigantism in children), whereas GH deficiency in children causes growth retardation and short stature. GROWTH HORMONE (SOMATROPIN): THERAPEUTIC USE Somatropin is the synthetic recombinant form of human growth hormone used therapeutically. It promotes protein synthesis and is synergistic with insulin. Its effect on skeletal growth is mediated by somatomedin (a small peptide synthesized in the liver, secretion of which depends on somatotropin). Somatropin is used to treat children with dwarfism due to isolated growth hormone deficiency or deficiency due to hypothalamic or pituitary disease. This is often difficult to diagnose, and requires accurate sequential measurements of height together with biochemical measurements of endogenous GH during pharmacological (e.g. insulin, clonidine, glucagon, arginine or L-dopa) or physiological (e.g. sleep, exercise) stimulation. Somatropin treatment also increases height in children with Turner’s syndrome. Injections should start well before puberty in order to optimize linear growth, and should continue until growth ceases. Replacement therapy with gonadotrophin or sex hormones is delayed until max-imum growth has been achieved. Other indications are to increase growth in children with chronic renal failure, with Prader–Willi syndrome and in short children born short for gestational age. It is used in adults with severe GH deficiency accompanying deficiency of another pituitary hormone and associated with impaired quality of life. In this setting it should be discontinued if the quality of life does not improve after nine months of treatment. In adults aged less than 25 years in whom growth is complete, severe GH deficiency (e.g. following neurosurgery) should be treated with somatropin until adult peak bone mass has been achieved. GROWTH HORMONE EXCESS Over-secretion of GH is usually associated with a functional adenoma of the acidophil cells of the adenohypophysis, and treatment is by neurosurgery and radiotherapy. The place of medical treatment is as an adjunct to this when surgery has not effected a cure, and while awaiting the effect of radiotherapy, which can be delayed by up to ten years. The visual fields and size of the pituitary fossa must be assessed repeatedly in order to detect further growth of the tumour during such treatment. Somatostatin lowers GH levels in acromegalics, but has to be given by continuous intravenous infusion and also inhibits many gastro-intestinal hormones. Octreotide and lanreotide are long-acting analogues of somatostatin which lower somatotropin levels. They are given by intermittent injection. Pegvisomant is a selective antagonist of the GH receptor. It is a genetically modified GH analogue and is injected subcutaneously once daily. It is used for acromegaly with an inadequate response to surgery, radiotherapy and somatostatin analogues. It has a range of gastro-intestinal, metabolic, neurological and other adverse effects and should be used only by physicians experienced in treating acromegaly. OCTREOTIDE Uses Octreotide is a synthetic octapeptide analogue of somatostatin which inhibits peptide release from endocrine-secreting tumours of the pituitary or gastro-intestinal tract. It is used to treat patients

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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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    use in asthma has declined consider

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    α 1-antitrypsin deficiency, neutro

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    PART VI THE ALIMENTARY SYSTEM

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    ● Peptic ulceration 247 ● Oesop

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    PEPTIC ULCERATION 249 • With rega

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    Ranitidine has a similar profile of

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    Vestibular stimulation ? via cerebe

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    cortical centres affecting vomiting

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    • in hepatocellular failure to re

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    Ciprofloxacin is occasionally used

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    withdrawal), small doses of benzodi

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    Table 34.7: Dose-independent hepato

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    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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