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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Key points Drugs for

Key points Drugs for mild pain • The main drugs for mild pain are paracetamol, aspirin and ibuprofen. • These work by inhibiting prostaglandin synthesis, and are available over the counter. • Paracetamol: – is analgesic; – is antipyretic but not anti-inflammatory; – lacks gastric toxicity, and can be used safely in children; – does not cause bleeding; – is dangerous in overdose because of production of a toxic metabolite (N-acetyl-p-benzoquinone imine, NABQI). • Aspirin: – is anti-inflammatory, analgesic and antipyretic; – is uniquely useful for its antiplatelet effect (see Chapters 29 and 30); – is a common cause of indigestion and severe gastrointestinal bleeding – especially in the elderly; – is associated with Reye’s syndrome in children and should not be prescribed for children �12 years of age; – is dangerous in overdose (salicylate toxicity). • Ibuprofen: – is similar as an analgesic to aspirin, but is preferred by some patients (e.g. for dysmenorrhoea); – is not proven to have a clinically useful antiplatelet effect. • Topical NSAIDs (e.g. piroxicam gel): – have modest efficacy (at best); – have low toxicity. OPIOIDS Opium is derived from the dried milky juice exuded by incised seed capsules of a species of poppy, Papaver somniferum, that is grown in Turkey, India and South-East Asia. Homer refers to it in the Odyssey as ‘nepenthes’, a drug given to Odysseus and his followers ‘to banish grief or trouble of the mind’. Osler referred to it as ‘God’s own medicine’. A number of notably discreditable events, including the Opium Wars, ensued from the commercial, social, moral and political interests involved in its world-wide trade and use. Opium is a complex mixture of alkaloids, the principal components being morphine, codeine and papaverine. The main analgesic action of opium is due to morphine. Papaverine is a vasodilator without analgesic actions. Until 1868, opium could be purchased without prescription from grocers’ shops in the UK. Much work has gone into synthesizing morphine analogues in the hope of producing a drug with the therapeutic actions of morphine, but without its disadvantages. Morphine was introduced as a ‘non-addictive’ alternative to opium and this in turn was superseded by diamorphine, which was also believed to be non-addicting! Synthetic drugs such as pethidine, dextropropoxyphene and pentazocine were originally incorrectly thought to lack potential for abuse. OPIOIDS 159 Morphine is active when given by mouth and a more rapid effect can be obtained if it is administered intravenously, but the potential for abuse is also greatly increased. Some anaesthetists give synthetic high potency opioids, such as fentanyl, either intravenously or epidurally, for obstetric surgery (e.g. Caesarean section).+ OPIOID RECEPTORS Stereospecific receptors with a high affinity for opioid analgesics are present in neuronal membranes. They are found in high concentrations in the PAG, the limbic system, the thalamus, the hypothalamus, medulla oblongata and the substantia gelatinosa of the spinal cord. Several endogenous peptides with analgesic properties are widely distributed throughout the nervous system. They can be divided into the following three groups: 1. encephalins (leu-encephalin and met-encephalin) are pentapeptides; 2. dynorphins are extended forms of encephalins; 3. endorphins (e.g. β-endorphin). These peptides are derived from larger precursors (proopiomelanocortin, pro-encephalin and pro-dynorphin) and act as neurotransmitters or neuromodulators (neurotransmitters convey information from an axon terminal to a related nerve cell, whereas neuromodulators influence the responsiveness of one or more neurons to other mediators, see Figure 25.6). There are three types of opioid receptor, named μ, δ and κ. All belong to the G-protein coupled receptor family, and μ is the most important. A fourth category, σ, is now not classified as an opioid receptor because they bind non-opioid psychotomimetic drugs of abuse, such as phencyclidine and the only opioids that bind appreciably to them are drugs like pentazocine that have psychotomimetic adverse effects. Blocking opioid receptors with naloxone (see below) has little effect in normal individuals, but in patients suffering from chronic pain it produces hyperalgesia. Electrical stimulation of areas of the brain that are rich in encephalins and opioid receptors elicits analgesia which is abolished by naloxone, implying Neuromodulator NT release NT responsiveness NT Molecule NT Receptor Figure 25.6: Role of neurotransmitter and neuromodulator at synapse. --->, Stimulatory or inhibitory action; NT, neurotransmitter.

160 ANALGESICS AND THE CONTROL OF PAIN that it is caused by liberation of endogenous opioids. Pain relief by acupuncture may also be mediated by encephalin release, because it is antagonized by naloxone. Narcotic analgesics exert their effects by binding to opioid receptors. The resulting pattern of pharmacological activity depends on their affinity for the various receptors and whether they are full or partial agonists. The affinity of narcotic analgesics for μ-receptors parallels their analgesic potency. In addition to their involvement in brain function, the opioid peptides play a neuroendocrine role. Administration in humans suppresses the pituitary–gonadal and pituitary–adrenal axis and stimulates the release of prolactin, thyroid-stimulating hormone (TSH) and growth hormone. High concentrations of opioid peptides are also present in sympathetic ganglia and the adrenal medulla. Their function at these sites has not been elucidated, but they may play an inhibitory role in the sympathetic system. Following repeated administration of an exogenous opioid, the sensitivity of the receptors decreases, necessitating an increased dose to produce the same effect (‘tolerance’). On withdrawal of the drug, endogenous opioids are not sufficient to stimulate the insensitive receptors, resulting in a withdrawal state characterized by autonomic disturbances, e.g. pallor, sweating and piloerection (‘cold turkey’) and abdominal pain. MORPHINE Use • The most important use of morphine is for pain relief. The effective dose is highly variable. Previous analgesic requirements (if known) should be taken into account when selecting a dose. • Morphine may be given as an intravenous bolus if rapid relief is required (e.g. during myocardial infarction). • Alternatively, morphine can be given continuously by an infusion pump (e.g. post-operatively), either intravenously or subcutaneously. • Morphine is effective orally, although larger doses are needed due to presystemic metabolism. Morphine is given by mouth initially every four hours, giving additional doses as needed between the regular doses as a ‘top-up’, the daily dose being reviewed and titrated. Once the dose requirement is established, sustained-release morphine (12-hourly) is substituted, which should still be supplemented by immediate release morphine, for breakthrough pain. • Spinal (epidural or intrathecal) administration of morphine is effective at much lower doses than when given by other routes and causes fewer systemic side effects. It is useful in those few patients with opioidresponsive pain who experience intolerable side effects when morphine is administered by other routes. • Continuous subcutaneous infusions by pump are useful in the terminally ill. There is an advantage in using diamorphine rather than morphine for this purpose, since its greater solubility permits smaller volumes of more concentrated solution to be used. • Morphine is effective in the relief of acute left ventricular failure, via dilatation of the pulmonary vasculature and the great veins. • Morphine inhibits cough, but codeine is preferred for this indication. • Morphine relieves diarrhoea, but codeine is preferred for this indication. Mechanism of action Morphine relieves both the perception of pain and the emotional response to it. Adverse effects Certain patients are particularly sensitive to the pharmacological actions of morphine. These include the very young, the elderly and those with chronic lung disease, untreated hypothyroidism, chronic liver disease and chronic renal failure. Overdose leads to coma. Morphine depresses the sensitivity of the respiratory centre to carbon dioxide, thus causing a progressively decreased respiratory rate. Patients with decreased respiratory reserve due to asthma, bronchitis, emphysema or hypoxaemia of any cause are more sensitive to the respiratory depressant effect of opioids. Bronchoconstriction occurs via histamine release, but is usually mild and clinically important only in asthmatics, in whom morphine should be used with care and only for severe pain. Morphine causes vomiting in 20–30% of patients by stimulation of the chemoreceptor trigger zone. Dopamine receptors are important and opioidinduced emesis is responsive to dopamine-receptor antagonists (e.g. prochlorperazine). Morphine increases smooth muscle tone throughout the gastro-intestinal tract, which is combined with decreased peristalsis. The result is constipation with hard dry stool. The increase in muscle tone also involves the sphincter of Oddi and morphine increases intrabiliary pressure. Dependence (both physical and psychological) is particularly likely to occur if morphine is used for the pleasurable feeling it produces, rather than in a therapeutic context. In common with most other opioids it causes pupillary constriction. This provides a useful diagnostic sign in narcotic overdosage or chronic abuse. Patients with prostatic hypertrophy may suffer acute retention of urine, as morphine increases the tone in the sphincter of the bladder neck. Pharmacokinetics Morphine can be given orally or by subcutaneous, intramuscular or intravenous injection. Morphine is metabolized by combination with glucuronic acid and also by N-dealkylation and oxidation, about 10% being excreted in the urine as morphine and 60–70% as a mixture of glucuronides. Metabolism occurs in the liver and gut wall, with extensive presystemic metabolism. The dose–plasma concentration relationships for morphine and its main metabolite are linear over a wide range of oral dosage. Morphine-6-glucuronide has analgesic properties and contributes substantially to the analgesic action of morphine. Only low concentrations of this active metabolite appear in the blood after a single oral dose. With repeated dosing the concentration of morphine-6-glucuronide

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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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  • Page 134 and 135: Case history A 45-year-old man with
  • Page 136 and 137: Levodopa PRINCIPLES OF TREATMENT IN
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  • Page 144 and 145: ● Introduction 133 ● Mechanisms
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  • Page 148 and 149: Table 22.2: Metabolic interactions
  • Page 150 and 151: FURTHER ANTI-EPILEPTICS Other drugs
  • Page 152 and 153: Case history A 24-year-old woman wh
  • Page 154 and 155: Assessment of migraine severity and
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  • Page 160 and 161: • Respiratory system - apnoea fol
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  • Page 176 and 177: PART III THE MUSCULOSKELETAL SYSTEM
  • Page 178 and 179: ● Introduction: inflammation 167
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  • Page 182 and 183: • Stomatitis suggests the possibi
  • Page 184 and 185: Pharmacokinetics Allopurinol is wel
  • Page 186 and 187: PART IV THE CARDIOVASCULAR SYSTEM
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  • Page 198 and 199: Each of these classes of drug reduc
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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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    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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    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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