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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Peak plasma levels after

Peak plasma levels after smoking cigarettes can be matched by nicotine gum or patches but the rate of increase is much slower after chewing gum or applying transdermal patches. Effect of smoking on drug disposition and effects The most common effect of tobacco smoking on drug disposition is an increase in elimination consistent with induction of drug-metabolizing enzymes. Nicotine itself is metabolized more extensively by smokers than by non-smokers. Substrates for cytochrome P450 1A2 (e.g. theophylline, caffeine, imipramine) are metabolized more rapidly in smokers than in non-smokers. Drug treatment for nicotine dependence Nicotine is a potent drug of dependence. Withdrawal can lead to an abstinence syndrome consisting of craving, irritability and sometimes physical features (e.g. alimentary disturbances). Substitution of nicotine via skin patches or nicotine gum as part of a smoking cessation programme significantly increases success rates. The antidepressant bupropion appears to reduce the desire to smoke and is licensed as an adjunct to motivational support in smoking cessation. It is contraindicated in patients with a history of seizures or of eating disorders, or who are experiencing acute alcohol or benzodiazepine withdrawal. Varenicline, a selective nicotinic receptor partial agonist, is an oral adjunct to smoking cessation. It is started 1–2 weeks before stopping smoking. It is contraindicated in pregnancy. Side effects include gastro-intestinal disturbances, headache, dizziness and sleep disorders. XANTHINES This group of compounds includes caffeine (present in tea and colas, as well as coffee), theobromine (present in chocolate) and theophylline (Chapter 33). Caffeine is included in a number of proprietary and prescription medicines, particularly in analgesic combinations. The major effects of these compounds are mediated by inhibition of phosphodiesterase, resulting in a raised intracellular cyclic adenosine monophosphate (AMP) concentration. Adverse effects In large doses, caffeine exerts an excitatory effect on the CNS that is manifested by tremor, anxiety, irritability and restlessness, and interference with sleep. Its use does not lead to improved intellectual performance except perhaps when normal performance has been impaired by fatigue. Circulatory effects include direct myocardial stimulation producing tachycardia, increased cardiac output, ectopic beats and palpitations. Caffeine use should be curtailed in patients who suffer paroxysmal dysrhythmias. Its effect on blood pressure is unpredictable. Cerebral vasoconstriction provides some rationale for use of caffeine in migraine. Bronchial smooth muscle relaxes and respiration is stimulated centrally. Mild diuresis occurs due to an increased glomerular filtration rate subsequent to dilatation of the afferent arterioles. Caffeine increases gastric acid secretion via its action on cyclic AMP. Pharmacokinetics Caffeine is rapidly and completely absorbed after oral administration and undergoes hepatic metabolism. The plasma t1/2 of caffeine is 2.5–12 hours. Caffeine dependence Tolerance is low grade and dependence is not clinically important. CENTRAL DEPRESSANTS CENTRAL DEPRESSANTS 439 ALCOHOL Ethyl alcohol (alcohol) has few clinical uses when given systemically, but is of great medical importance because of its pathological and psychological effects when used as a beverage. Alcohol is the most important drug of dependence, and in Western Europe and North America the incidence of alcoholism is about 5% among the adult population. Pharmacokinetics Ethyl alcohol is absorbed from the buccal, oesophageal, gastric and intestinal mucosae – approximately 80% is absorbed from the small intestine. Alcohol delays gastric emptying and in high doses delays its own absorption. Following oral administration, alcohol can usually be detected in the blood within five minutes. Peak concentrations occur between 30 minutes and two hours. Fats and carbohydrates delay absorption. Alcohol is distributed throughout the body water. About 95% is metabolized (mainly in the liver) and the remainder is excreted unchanged in the breath, urine and sweat. Hepatic oxidation to acetaldehyde is catalysed by three parallel processes. The major pathway (Figure 53.1) is rate limited by cytoplasmic alcohol dehydrogenase using nicotinamide adenine dinucleotide (NAD) as coenzyme. Alcohol elimination follows Michaelis–Menten kinetics, with saturation occurring in the concentration range encountered during social drinking. A small additional ‘dose’ can thus have a disproportionate effect on the concentration of alcohol in the plasma. Effects of alcohol Nervous system: Alcohol decreases concentration, judgement, discrimination, and reasoning and increases self-confidence. Progressively increasing plasma concentrations are associated with sensations of relaxation followed by mild euphoria, incoordination, ataxia and loss of consciousness. At high blood concentrations, the gag reflex is impaired, vomiting may occur and death may result from aspiration of gastric contents. The importance of alcohol as a factor in road traffic accidents is well known (see Figure 53.2). The central depressant actions of alcohol greatly enhance the effects of other central depressant drugs. In patients with organic brain damage, alcohol may induce unusual aggression and destructiveness, known as pathological intoxication. Death may also result from direct

440 DRUGS AND ALCOHOL ABUSE Catalase (H 2 O 2 ) Ethanol Acetaldehyde Acetate Cytoplasmic alcohol dehydrogenase (NAD � ) Aldehyde dehydrogenase (NAD � ) Acetyl coenzyme A CO 2 � H 2 O Krebs tricarboxylic acid cycle Microsomal oxidase (NADPH) Figure 53.1: Pathways of ethanol oxidation. :, major pathway. – – – , minor pathways; NAD, nicotinamide adenine dinucleotide; NADP, nicotinamide adenine dinucleotide phosphate. Relative probability 50 45 40 35 30 25 20 15 10 5 0 20 40 60 80 100 120 140 160 180 Blood alcohol concentration (mg/100 mL) Figure 53.2: Relative probability of causing a road accident at various blood alcohol concentrations. (Redrawn with permission from Harvard JDJ. Hospital Update 1975; 1: 253). respiratory depression. Chronic neurological accompaniments of persistent alcohol abuse include various forms of central and peripheral neurodegeneration, most commonly involving the vermis of the cerebellum, and a peripheral neuropathy. Nutritional deficiencies may contribute to the pathogensesis of neurodegeneration. Wernicke’s encephalopathy (difficulty in concentrating, confusion, coma, nystagmus and ophthalmoplegia) and Korsakov’s psychosis (gross memory defects with confabulation and disorientation in space and time) are mainly due to the nutritional deficiency of thiamine associated with alcoholism. Any evidence of Wernicke’s encephalopathy should be immediately treated with intravenous thiamine followed by oral thiamine for several months. Psychiatric disorder is common and devastating, with social and family breakdown. Circulatory: Cutaneous vasodilatation causes the familiar drunkard’s flush. Atrial fibrillation (� embolization) is important. Chronic abuse is an important cause of cardiomyopathy. Withdrawal (see below) causes acute hypertension and heavy intermittent alcohol consumption can cause variable hypertension by this mechanism which can exacerbate or be mistaken for essential hypertension (Chapter 28). Gastrointestinal: Gastritis, peptic ulceration, haematemesis (including the Mallory–Weiss syndrome, which is haematemesis due to oesophageal tearing during forceful vomiting, as well as from peptic ulcer or varices). Liver pathology includes fatty infiltration, alcoholic hepatitis and cirrhosis. Alcohol can cause pancreatitis (acute, subacute and chronic). Metabolic: Alcohol suppresses ADH secretion and this is one of the reasons why polyuria occurs following its ingestion. Reduced gluconeogenesis leading to hypoglycaemia may cause fits. The accumulation of lactate and/or keto acids produces metabolic acidosis. Hyperuricaemia occurs (particularly, it is said, in beer drinkers) and can cause acute gout. Haematological effects: Bone marrow suppression occurs. Folate deficiency with macrocytosis is common and chronic GI blood loss causes iron deficiency. Sideroblastic anaemia is less common but can occur. Mild thrombocytopenia is common and can exacerbate haemorrhage. Neutrophil dysfunction is common even when the neutrophil count is normal, predisposing to bacterial infections (e.g. pneumococcal pneumonia), which are more frequent and serious in alcoholics. In pregnancy: Infants of alcoholic mothers may exhibit features of intra-uterine growth retardation and mental deficiency, sometimes associated with motor deficits and failure to thrive. There are characteristic facial features which include microcephaly, micrognathia and a short upturned nose. This so-called fetal alcohol syndrome is unlike that reported in severely undernourished women. Some obstetricians now recommend total abstinence during pregnancy.

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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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    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

  • Page 400 and 401: ● Haematinics - iron, vitamin B 1
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  • Page 424 and 425: DERMATITIS (ECZEMA) PRINCIPLES OF T
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  • Page 428 and 429: TREATMENT OF OTHER SKIN INFECTIONS
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  • Page 434 and 435: ● Introduction: ocular anatomy, p
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  • Page 444 and 445: ● Introduction 433 ● Pathophysi
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  • Page 454 and 455: FURTHER READING Goldman D, Oroszi G
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  • Page 462 and 463: Note: Page numbers in italics refer
  • Page 464 and 465: atrial fibrillation 217, 221 digoxi
  • Page 466 and 467: Cushing’s syndrome 302 cyclic ade
  • Page 468 and 469: 5-fluorouracil 375-6 fluoxetine, mo
  • Page 470 and 471: children 54 diazepam 108 iron prepa
  • Page 472 and 473: non-steroidal anti-inflammatory dru
  • Page 474 and 475: puberty (male), delay 314 puerperiu
  • Page 476: tolerance 9, 433 benzodiazepines 10
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