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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

withdrawal), small doses

withdrawal), small doses of benzodiazepines that are metabolized to inactive glucuronide conjugates, e.g. oxazepam are preferred to those with longer-lived metabolites. The hazards of narcotic analgesics to the patient with acute or chronic liver disease cannot be overemphasized; • prophylactic broad-spectrum intravenous antibiotics, especially if there is evidence of infection (e.g. spontaneous peritonitis); • intravenous acetylcysteine (the precise value of this has not yet been fully confirmed). Key points Treatment of hepatic encephalopathy • Supportive. • Measures to reduce absorption of ammonia from the gut (e.g. low-protein diet, lactulose � neomycin). • Prophylactic broad spectrum antibiotics, prompt treatment of infection. • Prophylactic vitamin K. • Fresh frozen plasma/platelets as indicated. • H 2 antagonist (e.g. ranitidine) or proton-pump inhibitor (e.g. omeprazole) to prevent gastric erosions and bleeding. • i.v. acetylcysteine (unproven). • Avoidance of sedatives, potassium-losing diuretics, opioids, drugs that cause constipation and hepatotoxic drugs whenever possible. DRUG THERAPY OF PORTAL HYPERTENSION AND OESOPHAGEAL VARICES Oesophageal varices form a collateral circulation in response to raised blood pressure in the portal system and are of clinical importance because of their tendency to bleed. Two-thirds of patients with varices die as a result and of these, one-third die of the first bleed, one-third rebleed within six weeks and only one-third survive for one year. Sclerotherapy and surgical shunt procedures are the mainstay of treatment, and drug therapy must be judged against these gloomy survival figures. In addition to resuscitation, volume replacement and, when necessary, balloon tamponade using a Sengstaken–Blakemore tube, the emergency treatment of bleeding varices may include vasoconstrictor drugs, e.g vasopressin analogues. These reduce portal blood flow through splanchnic arterial constriction. Drugs currently used for the management of acute variceal haemorrhage include octreotide (the long-acting analogue of somatostatin), vasopressin and terlipressin (a derivative of vasopressin). Terlipressin and octreotide are used to reduce portal pressure urgently, to control bleeding before more definitive treatment, such as sclerotherapy or variceal banding. Betablockers and vasodilators, such as nitrates, are used for long-term therapy to reduce portal pressure. Somatostatin and its long-acting analogue octreotide reduce blood flow and cause LIVER DISEASE 261 a significant reduction in variceal pressure without effects on the systemic vasculature. To date, a clear-cut response in variceal bleeding has not been demonstrated. Side effects include vomiting, anorexia, abdominal pain, diarrhoea, headache and dizziness. Newer vasoactive drugs, such as terlipressin, appear to have a better therapeutic index and fewer side effects, although terlipressin has a short half-life and needs to be administered frequently or as an infusion. A number of trials have demonstrated efficacy of noncardioselective beta-adrenergic antagonists (propranolol, nadolol) in reducing the incidence of gastro-intestinal bleeding in patients with portal hypertension, especially in combination with endoscopic sclerotherapy. MANAGEMENT OF CHRONIC VIRAL HEPATITIS Chronic viral hepatitis is associated with chronic liver disease, cirrhosis and hepatocellular carcinoma. The carrier rate for hepatitis B in the UK is 0.1–1% (it is particularly prevalent in socially deprived areas of inner cities) and the seroprevalence for hepatitis C is 0.1–0.7%. Chronic viral hepatitis is diagnosed when there is evidence of continuing hepatic damage and infection for at least six months after initial viral infection. In hepatitis C, the liver function may remain normal for months to years, while the patient’s blood remains infectious (confirmed by hepatitis C virus RNA detection). The course of the liver damage often fluctuates. While up to 90% of patients with acute hepatitis B clear the virus spontaneously, up to 60% of those with hepatitis C virus do not do so. About 20% of those with chronic active hepatitis progress insidiously to cirrhosis, and about 2–3% go on to develop hepatocellular carcinoma. Hepatitis B virus is a DNA virus that is not directly cytopathic and hepatic damage occurs as a result of the host immune response. Hepatocytes infected with hepatitis B virus produce a variety of viral proteins, of which the ‘e’ antigen (HBeAg) is clinically the most important. HBeAg is a marker for continued viral replication and therefore for infectivity. Hepatitis C virus is a single-stranded RNA virus. Controlled trials have shown that interferon-alfa, lamivudine (a nucleoside analogue inhibitor of viral DNA polymerase) and adefovir dipivoxil (a phosphorylated nucleotide analogue inhibitor of viral DNA polymerases) are beneficial in reducing the viral load in patients with chronic hepatitis B virus infection. Pegylated interferon alfa-2a (peginterferon alfa-2a) may be preferred to interferon alfa. Pegylation (polyethylene glycolconjugation) prolongs the interferon half-life in the blood, allowing subcutaneous once weekly dosing. The National Institute of Health and Clinical Excellence (NICE) has recommended adefovir as an option in chronic hepatitis B if interferon is unsuccessful, if relapse occurs following successful initial interferon treatment, or if interferon is poorly tolerated or contraindicated (see Chapters 45 and 46). In chronic hepatitis C, the combination of peginterferon alfa and ribavarin (see Chapter 45) is recommended. Details on the regimens can be found at www.nice.org.uk/TA075.

262 ALIMENTARY SYSTEM AND LIVER Table 34.6: Dose-dependent hepatotoxicity Drug Mechanism Comment/predisposing factors Paracetamol Hepatitis See Chapter 54 Salicylates Focal hepatocellular necrosis Autoimmune disease (especially systemic lupus erythematosus) Reye’s sydrome In children with viral infection (contraindicated in children �16 years) Tetracycline Central and mid-zonal necrosis with fat droplets – Azathioprine Cholestasis and hepatitis Underlying liver disease Methotrexate Hepatic fibrosis – Fusidic acid Cholestasis, conjugated hyperbilirubinaemia Rare Rifampicin Cholestasis, conjugated and unconjugated hyperbilirubinaemia Transient Synthetic oestrogens Cholestasis, may precipitate gallstone disease Underlying liver disease, rare now that low-dose oestrogens are generally given HMG CoA reductase inhibitors Unknown Usually mild and asymptomatic (statins) DRUG-INDUCED LIVER DISEASE After oral administration, the entire absorbed dose of a drug is exposed to the liver during the first pass through the body. The drug itself or its metabolites may affect liver function. Metabolic pathways may become saturated at high concentrations and drug or metabolites may accumulate, leading to toxicity. The drugs shown in Table 34.6 predictably cause hepatotoxicity at excessive doses. Although hepatotoxicity is traditionally divided into dose-dependent and dose-independent hepatotoxicity, the relationship is not always clear-cut. For example, even with predictable hepatotoxins, there is considerable interindividual variation in susceptibility to hepatic damage. This can sometimes be attributed to genetic polymorphism or to environmental stimuli affecting hepatic microsomal enzymes, or to previous liver disease. Although dose-independent hepatotoxicity is used to classify those reactions that are ‘idiosyncratic’ and usually unpredictable (Table 34.7), the severity of the resulting liver disease may be related to dose or to duration of therapy. Particular drugs tend to produce distinctive patterns of liver injury, but this is not invariable (see also Chapter 12). INVESTIGATION AND MANAGEMENT OF HEPATIC DRUG REACTIONS Depending on the clinical presentation the most important differential diagnoses are hepatic dysfunction due to viral infection (which may be asymptomatic), malignant disease, alcohol and congestive cardiac failure. The aetiology of a minor elevation of transaminases is often undetermined. If the patient is being treated for a disease associated with hepatic dysfunction, particularly with multiple drugs, identification of the responsible agent is particularly difficult. Minor elevations of transaminase activity are often picked up on routine biochemical profiles. If they are considered to be drug related, but further treatment is indicated, it is reasonable to continue the drug with regular monitoring of liver enzymes if a better alternative therapy is not available. If the transaminases reach more than twice, and/or the bilirubin rises to �1.5 � the upper limit of the normal range, it is prudent to stop the drug if the clinical situation permits. DRUGS THAT MODIFY APPETITE APPETITE-SUPPRESSING (ANORECTIC) DRUGS The most common form of malnutrition in the UK is obesity. Obesity is a major risk factor for cardiovascular disease, stroke and type 2 diabetes mellitus. It is preventable, since obese patients are fat because they eat too many calories for their energy needs. Naturally, a calorie-controlled diet and adequate but sensible amounts of exercise are the essentials of treatment. Unfortunately, the results of treating patients at weight-reduction clinics are disappointing and only a few individuals achieve permanent weight loss. There has accordingly been a great deal of interest in the possibility of altering appetite pharmacologically in order to help the patient to reduce his or her calorie intake. Unfortunately, the causes of obesity are only currently being more comprehensively studied. In 1994, the gene for obesity (OB) in the mouse was identified. The OB gene encodes the protein leptin, which is produced only in fat cells and is secreted into the blood. The human homologue of the OB gene has now been identified. Leptin is thought to be a blood-borne signal from the adipose tissue that informs the brain about the size of an individual’s fat mass. Much more research is required to determine its exact role in neuroendocrine, reproductive, haematopoietic

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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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    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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