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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

with symptoms caused by

with symptoms caused by the release of pharmacologically active substances from gastro-enteropancreatic tumours, including patients with carcinoid syndrome, insulinoma, VIPoma or glucagonoma. It reduces symptoms of flushing, diarrhoea or skin rash, but does not reduce the size of the tumour. It is more effective than bromocriptine (now mainly used in Parkinson’s disease, see Chapter 21) in lowering somatotropin levels in patients with acromegaly, but it is not generally an acceptable alternative to surgery, and must be administered parenterally (usually subcutaneously three times daily). It is also effective in patients with TSH-secreting basophil tumours of the adenohypophysis causing thyrotoxicosis (an extremely rare cause of hyperthyroidism). It reduces portal pressure in portal hypertension, and is effective in the acute therapy of bleeding oesophageal varices. It is also used to reduce ileostomy diarrhoea and the diarrhoea associated with cryptosporidiosis in AIDS patients. Gastro-intestinal side effects are minimized if octreotide is given between meals. A long-acting microsphere octreotide formulation in poly (alkyl cyanoacrylate) nanocapsules is administered intramuscularly once a month. Adverse effects These include: • gastro-intestinal upset, including anorexia, nausea, vomiting, abdominal pain, diarrhoea and steatorrhoea; • impaired glucose tolerance, by reducing insulin secretion; • increased incidence of gallstones and/or biliary sludge after only a few months of treatment, especially at higher doses. Ultrasound evaluation of the gall bladder is recommended before starting therapy and if biliary symptoms occur during therapy. Key points Growth hormone (GH, somatropin) • Somatropin (recombinant GH) is used to treat short stature due to: – GH deficiency; – Turner’s syndrome; – Prader–Willi syndrome; – chronic renal impairment; – children who were born small for gestational age. • Somatropin is also used for adults with severe symptomatic GH deficiency. • GH secretion is controlled physiologically by: – somatorelin (stimulates GH secretion); – somatostatin (inhibits GH secretion). • Somatostatin is secreted by D cells in the islets of Langerhans, as well as centrally, and inhibits the secretion of many gut hormones in addition to GH. • Octreotide is a somatostatin analogue used: – in acromegalics with persistent raised GH despite surgery/radiotherapy; – in functional neuroendocrine tumours (e.g. carcinoid, VIPomas, glucagonomas); – to reduce portal pressure in variceal bleeding (unlicensed indication). • Pegvisomant is a specific GH receptor antagonist: it is used for acromegaly when conventional treatment has failed. ANTERIOR PITUITARY HARMONES AND RELATED DRUGS 317 GONADOTROPHINS The human pituitary gland secretes follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH is a glycoprotein which in females controls development of the primary ovarian follicle, stimulates granulosa cell proliferation and increases oestrogen production, while in males it increases spermatogenesis. LH is also a glycoprotein. It induces ovulation, stimulates thecal oestrogen production and initiates and maintains the corpus luteum in females. In males, LH stimulates androgen synthesis by Leydig cells, and thus has a role in the maturation of spermatocytes and the development of secondary sex characteristics. Human menopausal urinary gonadotrophin (HMG), human chorionic gonadotrophin (HCG) and synthetic LH and recombinant FSH (follitropin alfa and beta) are all commercially available. They are used to induce ovulation in anovulatory women with secondary ovarian failure in whom treatment with clomifene (see Chapter 41) has failed. Treatment must be supervised by specialists experienced in the use of gonadotrophins and be carefully monitored with repeated pelvic ultrasound scans to avoid ovarian hyperstimulation and multiple pregnancies. Gonadotrophins are also effective in the treatment of oligospermia due to secondary testicular failure. They are, of course, ineffective in primary gonadal failure. GONADORELIN ANALOGUES Gonadorelin (gonadotrophin-releasing hormone, GnRH) is the FSH/LH-releasing factor produced in the hypothalamus. It may be used in a single intravenous dose to assess anterior pituitary reserve. Analogues of GnRH (Table 42.1) such as goserelin, buserelin and leuprorelin are also used to treat endometriosis, female infertility (see Chapter 41), prostate cancer and advanced breast cancer (see Chapter 48). Buserelin is given intranasally, and goserelin is usually given by subcutaneous injection/implant into the anterior abdominal. In benign conditions use should be limited to a maximum of six months because reduced oestrogen levels lead to reduced bone density, in addition to menopausal-type symptoms (see below). For indications such as endometriosis, it is possible to combine a GnRH analogue with low-dose oestrogen replacement to avoid this. Mechanism of action GnRH analogues initially stimulate the release of FSH/LH, but then downregulate this response (usually after two weeks) Table 42.1: GnRH analogues Drug Use and additional comments Goserelin Used to treat endometriosis, prostate cancer and advanced breast cancer Leuprorelin Used to treat endometriosis and prostate cancer Buserelin Used to treat endometriosis. Prostate cancer. Induction of ovulation prior to IVF

318 THE PITUITARY HORMONES AND RELATED DRUGS and thereby reduce pituitary stimulation of male or female gonads, effectively leading to medical orchidectomy/ovariectomy (a state of hypopituitary hypogonadism). Adverse effects Menopausal symptoms are common in addition to decreased trabecular bone density, and local symptoms caused by irritation of the nasal mucosa with buserelin. Pharmacokinetics Gonadorelin analogues are peptides and are given parenterally. Goserelin may be given as intravenous pulses to mimic the physiological release of GnRH. Depot preparations are available to suppress FSH/LH release (see above). GnRH analogues are cleared by a combination of hepatic metabolism and renal excretion. Key points Gonadotrophins and GnRH analogues • FSH and LH are secreted in pulses and stimulate gonadal steroid synthesis. • GnRH analogues initially stimulate, but then downregulate the release of FSH and LH. • GnRH analogues (e.g. goserelin, buserelin) are used in the treatment of : – endometriosis; – female infertility; – prostate cancer; – advanced breast cancer. • Side-effects of GnRH analogues include: – menopausal symptoms; – reduced bone density (by reducing oestrogen secretion). ADRENOCORTICOTROPHIC HORMONE Adrenocorticotrophic hormone (ACTH, corticotropin) is no longer commercially available in the UK. A synthetic analogue of ACTH, containing only the first 24 amino acids, is available as tetracosactide. This possesses full biological activity, the remaining 15 amino acids of ACTH being species specific and associated with antigenic activity. The t1/2 of tetracosactide (15 minutes) is slightly longer than that of ACTH, but otherwise its properties are identical. Tetracosactide is used as a diagnostic test in the evaluation of patients in whom Addison’s disease (adrenal insufficiency) is suspected. A single intravenous or intramuscular dose is administered, followed by venous blood sampling for plasma cortisol determination. There is a small risk of anaphylaxis. POSTERIOR PITUITARY HORMONES Vasopressin (antidiuretic hormone, ADH) and oxytocin are related octapeptide hormones synthesized in the supra-optic and paraventricular hypothalamic nuclei and transported along nerve fibres to the posterior lobe of the pituitary gland for storage and subsequent release (neurosecretion). Vasopressin and desmopressin (DDAVP) are discussed in Chapter 36, in relation to the treatment of diabetes insipidus. Demeclocycline is an antagonist of ADH and has been used in patients with hyponatraemia caused by the syndrome of inappropriate ADH secretion (SIADH). More specific antagonists of ADH are in development. The use of oxytocin for induction of labour is described in Chapter 41. Key points Physiology of the pituitary Anterior pituitary secretes: • growth hormone (GH); • follicle-stimulating hormone (FSH); • luteinizing hormone (LH); • adrenocorticotrophic hormone (ACTH); • prolactin; • thyroid-stimulating hormone (TSH). is controlled by: • hypothalamic hormones (stimulatory/inhibitory); • feedback inhibition. Posterior pituitary Related octapeptides, synthesized in the hypothalamus and released by neurosecretion: 1. Vasopressin (ADH): – increases blood pressure; – causes renal water retention. 2. Oxytocin: – stimulates uterine contractions; – used in obstretrics (for induction of labour). Case history A 64-year-old man was investigated for worsening chronic back pain and was found to have osteosclerotic bony metastases from prostate carcinoma. Analgesia with adequate doses of NSAIDs successfully controlled his bone pain, and he was started on GnRH analogue therapy with goserelin given subcutaneously, 3.6 mg per month. After one week his pain was worse, especially at night, without evidence of spinal compression. Question What is the likely cause of the deterioration in his symptoms and how would you treat him? Answer The most likely cause of his symptoms worsening in the first week of GnRH analogue therapy is the ‘tumour flare reaction’. GnRH analogues increase secretion of FSH/LH for one to two weeks, causing an initial increase in testosterone. They subsequently produce downregulation, leading to decreased secretion of FSH/LH and hence decreased testosterone levels. In patients with metastatic prostate cancer it is essential to initiate GnRH analogue therapy only after several weeks of treatment with an androgen receptor antagonist such as cyproterone acetate, flutamide or bicalutamide. The use of anti-androgens prevents the ‘tumour flare’. Thus this patient should be given adequate analgesia and an androgen receptor antagonist (e.g. oral flutamide) started at once. Goserelin can then be restarted in several weeks time.

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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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    ● Introduction 265 ● General ph

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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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