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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Table 22.2: Metabolic

Table 22.2: Metabolic interactions of anticonvulsants concentration. The time to approach a plateau plasma concentration is longer than is predicted from the t 1/2 of a single dose of the drug. Phenytoin is extremely insoluble and crystallizes out in intramuscular injection sites, so this route should never be used. Intravenous phenytoin is irritant to veins and tissues because of the high pH. Phenytoin should be given at rates of �50 mg/min, because at higher rates of administration cardiovascular collapse, respiratory arrest and seizures may occur. Electrocardiographic monitoring with measurement of blood pressure every minute during administration is essential. If blood pressure falls, administration is temporarily stopped until the blood pressure has risen to a satisfactory level. Fosphenytoin, a prodrug of phenytoin can be given more rapidly, but still requires careful monitoring. At therapeutic concentrations, 90% of phenytoin is bound to albumin and to two α-globulins which also bind thyroxine. In uraemia, displacement of phenytoin from plasma protein binding results in lower total plasma concentration and a lower therapeutic range (see Chapter 3). Phenytoin elimination is impaired in liver disease. This can lead to increased plasma concentration and toxicity, but is not reliably predicted by liver function tests. Conversely hypoalbuminaemia from whatever cause (e.g. cirrhosis or nephrotic syndrome) can result in low total plasma concentrations, and reductions in both effective and toxic plasma concentration. PHENOBARBITAL Phenobarbital is an effective drug for tonic and partial seizures, but is sedative in adults and causes behavioural disturbances and hyperkinesia in children. It has been used as a second-line drug for atypical absence, atonic and tonic seizures, but is obsolete. Rebound seizures may occur on withdrawal. Monitoring GENERAL PRINCIPLES OF TREATMENT OF EPILEPSY 137 Enzyme-inducing effect of anti-epileptic drugs Drugs that inhibit the metabolism of anticonvulsants Anti-epileptic drug Drugs whose metabolism is enhanced Inhibitor Anticonvulsant Carbamazepine Warfarin Amiodarone Phenytoin Phenobarbitone Oral contraceptives Fluoxetine Phenytoin, carbamazepine Phenytoin Theophylline Diltiazem, nifedipine Phenytoin Primidone Ciclosporin Chloramphenicol Phenytoin Topiramate Some tricyclic antidepressants Disulfiram Phenytoin Doxycycline Corticosteroids Erythromycin and clarithromycin Carbamazepine Anticonvulsants Cimetidine Phenytoin Isoniazid Carbamazepine, ethosuximide, phenytoin Metronidazole Phenytoin Miconazole, fluconazole Phenytoin Valproate Lamotrigine plasma concentrations is less useful than with phenytoin because tolerance occurs, and the relationship between plasma concentration and therapeutic and adverse effects is less predictable than is the case with phenytoin. Other adverse effects include dependency, rashes, anaphylaxis, folate deficiency, aplastic anaemia and congenital abnormalities. BENZODIAZEPINES Use Benzodiazepines (e.g. diazepam, clobazepam and clonazepam) have anticonvulsant properties in addition to their anxiolytic and other actions. Tolerance to their anti-epileptic properties limits chronic use. Clonazepam was introduced specifically as an anticonvulsant. It is used intravenously in status epilepticus. Clonazepam has a wide spectrum of activity, having a place in the management of the motor seizures of childhood, particularly absences and infantile spasms. It is also useful in complex partial seizures and myoclonic epilepsy in patients who are not adequately controlled by phenytoin or carbamazepine. Oral treatment is usually started with a single dose at night. The dose is gradually titrated upwards until control is achieved or adverse effects become unacceptable. Adverse effects Adverse effects are common and about 50% of patients experience lethargy, somnolence and dizziness. This is minimized by starting with a low dose and then gradually increasing it. Sedation often disappears during chronic treatment. More serious effects include muscular incoordination, ataxia, dysphoria, hypotonia and muscle relaxation, increased salivary secretion and hyperactivity with aggressive behaviour.

138 ANTI-EPILEPTICS Pharmacokinetics Oral clonazepam is well absorbed and the t 1/2 is about 30 hours. Neither therapeutic nor adverse effects appear to be closely related to plasma concentrations. Control of most types of epilepsy occurs within the range 30–60 ng/mL. Clonazepam is extensively metabolized to inactive metabolites. VIGABATRIN Use Vigabatrin, a structural analogue of GABA, increases the brain concentration of GABA (an inhibitory neurotransmitter) through irreversible inhibition of GABA transaminase. It is reserved for the treatment of epilepsy that is unsatisfactorily controlled by more established drugs. Lower doses should be used in the elderly and in those with impaired renal function. Vigabatrin should be avoided in those with a psychiatric history. Adverse effects • The most common reported adverse event (up to 30%) is drowsiness. • Fatigue, irritability, dizziness, confusion and weight gain have all been reported. • Behavioural side effects (e.g. ill temper) may occur. • Psychotic reactions, including hallucinations and paranoia, are common. • Nystagmus, ataxia, tremor, paraesthesia, retinal disorders, visual-field defects and photophobia. Regular testing of visual fields is recommended. The patient should be warned to report any visual symptoms and an urgent ophthalmological opinion should be sought if visual-field loss is suspected. Pharmacokinetics Absorption is not influenced by food and peak plasma concentrations occur within two hours of an oral dose. In contrast to most other anticonvulsants, vigabatrin is not metabolized in the liver, but is excreted unchanged by the kidney and has a plasma half-life of about five hours. Its efficacy does not correlate with the plasma concentration and its duration of action is prolonged due to irreversible binding to GABA transaminase. LAMOTRIGINE Lamotrigine prolongs the inactivated state of the sodium channel. It is indicated as monotherapy and adjunctive treatment of partial seizures, generalized tonic–clonic seizures that are not satisfactorily controlled with other drugs, and seizures associated with Lennox–Gastaut syndrome (a severe, rare seizure disorder of young people). It is contraindicated in hepatic and renal impairment. Side effects include rashes (rarely angioedema, Steven–Johnson syndrome and toxic epidermal necrolysis), flu-like symptoms, visual disturbances, dizziness, drowsiness, gastro-intestinal disturbances and aggression. The patient must be counselled to seek urgent medical advice if rash or influenza symptoms associated with hypersensitivity develop. GABAPENTIN Gabapentin is licensed as an ‘add-on’ therapy in the treatment of partial seizures and is also used for neuropathic pain. It is a GABA analogue, but its mechanism of action is thought to be at calcium channels. It is generally well tolerated; somnolence is the most common adverse effect. It is well absorbed after oral administration and is eliminated by renal excretion; the average half-life is five to seven hours. It does not interfere with the metabolism or protein binding of other anticonvulsants. TOPIRAMATE Topiramate blocks sodium channels, attenuates neuronal excitation and enhances GABA-mediated inhibition. It is licensed as monotherapy and as adjunctive therapy of generalized tonic–clonic and partial seizures. Topiramate induces cytochrome P450, and its own metabolism is induced by carbamazepine and phenytoin. Topiramate has been associated with several adverse effects on the eye. Raised intra-ocular pressure necessitates urgent specialist advice. Other adverse effects include poor concentration and memory, impaired speech, mood disorders, ataxia, somnolence, anorexia and weight loss. TIAGABINE Tiagabine inhibits the neuronal and glial uptake of GABA. Tiagabine has recently been licensed as adjunctive therapy in the UK for partial seizures with or without secondary generalization. Reported adverse events include dizziness, asthenia, nervousness, tremor, depression and diarrhoea. It has a t1/2 of approximately seven hours, which may be halved by concurrent administration of carbamazepine and phenytoin. ETHOSUXIMIDE Use Ethosuximide is a drug of choice in absence seizures. It is continued into adolescence and then gradually withdrawn over several months. If a drug for tonic–clonic seizures is being given concurrently, this is continued for a further three years. It may also be used in myoclonic seizures and in atypical absences. Adverse effects Apart from dizziness, nausea and epigastric discomfort, side effects are rare and it appears safe. Tonic–clonic and absence seizures may coexist in the same child. Ethosuximide is not effective against tonic–clonic seizures, in contrast to valproate which is active against both absence and major seizures and is used when these coexist. Pharmacokinetics Ethosuximide is well absorbed following oral administration. Its plasma t1/2 is 70 hours in adults, but only 30 hours in children. Thus, ethosuximide need be given only once daily and steady-state values are reached within seven days. Plasma concentration estimations are not usually required.

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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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  • Page 102 and 103: ETHICS COMMITTEES Protocols for all
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  • Page 110 and 111: A case report has suggested a possi
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  • Page 114 and 115: PART II THE NERVOUS SYSTEM
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  • Page 120 and 121: Key points • Insomnia and anxiety
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  • Page 130 and 131: Partial response to first-line trea
  • Page 132 and 133: Key points Drug treatment of depres
  • 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 140 and 141: CHOREA The γ-aminobutyric acid con
  • Page 142 and 143: Cholinergic crisis Treatment of mya
  • Page 144 and 145: ● Introduction 133 ● Mechanisms
  • Page 146 and 147: absolute arbiter. The availability
  • 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 170 and 171: Key points Drugs for mild pain •
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  • Page 184 and 185: Pharmacokinetics Allopurinol is wel
  • Page 186 and 187: PART IV THE CARDIOVASCULAR SYSTEM
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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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    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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