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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Pharmacokinetics

Pharmacokinetics Absorption of these drugs from the gut is inadequate in the life-threatening infections for which they are mainly indicated. They are given intravenously every 4–6 hours. Their half-lives range from 1 to 1.5 hours and they are renally excreted. CEPHALOSPORINS FIRST-GENERATION CEPHALOSPORINS So-called first-generation cephalosporins (e.g. cephalexin, cefaclor, cefadroxil) are effective against Streptococcus pyogenes and Streptococcus pneumoniae, E. coli and some staphylococci. They have few absolute (i.e. uniquely advantageous) indications. Their pharmacology is similar to that of the penicillins and they are principally renally eliminated. SECOND- AND THIRD-GENERATION CEPHALOSPORINS Second- and third-generation cephalosporins are active against H. influenzae and in some instances Pseudomonas and anaerobes, at the expense of reduced efficacy against Grampositive organisms. β-Lactamase stability has been increased. Arguably the most generally useful member of the group is cefuroxime, which combines lactamase stability with activity against streptococci, staphylococci, H. influenzae and E. coli. It is given by injection eight-hourly (an oral preparation is also available, as cefuroxime axetil). It is expensive, although when used against Gram-negative organisms that would otherwise necessitate use of an aminoglycoside, this cost is partly offset by savings from the lack of need for plasma concentration determinations. Of the third-generation cephalosporins, ceftazidime, ceftriaxone and cefotaxime are useful in severe sepsis, especially because (unlike earlier cephalosporins) they penetrate the blood–brain barrier well and are effective in meningitis. Adverse effects About 10% of patients who are allergic to penicillins are also allergic to cephalosporins. Some first-generation cephalosporins are nephrotoxic, particularly if used with furosemide, aminoglycosides or other nephrotoxic agents. Some of the thirdgeneration drugs are associated with bleeding due to increased prothrombin times, which is reversible with vitamin K. MONOBACTAMS Monobactams (e.g. aztreonam) contain a 5-monobactam ring and are resistant to β-lactamase degradation. AZTREONAM Uses Aztreonam is primarily active against aerobic Gram-negative organisms and is an alternative to an aminoglycoside. It is used COMMONLY PRESCRIBED ANTIBACTERIAL DRUGS 327 in severe sepsis, often hospital acquired, especially infections of the respiratory, urinary, biliary, gastro-intestinal and female genital tracts. It has a narrow spectrum of activity and cannot be used alone unless the organism’s sensitivity to aztreonam is known. Mechanism of action The 5-monobactam ring binds to bacterial wall transpeptidases and inhibits bacterial cell wall synthesis in a similar way to the penicillins. Adverse effects Rashes occur, but there appears to be no cross-allergenicity with penicillins. Pharmacokinetics Aztreonam is poorly absorbed after oral administration, so it is given parenterally. It is widely distributed to all body compartments, including the cerebrospinal fluid. Excretion is renal and the usual half-life (one to two hours) is increased in renal failure. IMIPENEM–CILASTATIN AND MEROPENEM Uses Imipenem, a carbapenem, is combined with cilastatin, which is an inhibitor of the enzyme dehydropeptidase I found in the brush border of the proximal renal tubule. This enzyme breaks down imipenem in the kidney. Imipenem has a very broad spectrum of activity against Gram-positive, Gram-negative and anaerobic organisms. It is β-lactamase stable and is used for treating severe infections of the lung and abdomen, and in patients with septicaemia, where the source of the organism is unknown. Meropenem is similar to imipenem, but is stable to renal dehydropeptidase I and therefore can be given without cilastatin. Adverse effects Imipenem is generally well tolerated, but seizures, myoclonus, confusion, nausea and vomiting, hypersensitivity, positive Coombs’ test, taste disturbances and thrombophlebitis have all been reported. Meropenem has less seizure-inducing potential and can be used to treat central nervous system infection. Pharmacokinetics Imipenem is filtered and metabolized in the kidney by dehydropeptidase I. This is inhibited by cilastatin in the combination. Imipenem is given intravenously as an infusion in three or four divided daily doses. AMINOGLYCOSIDES Uses Aminoglycosides are highly polar, sugar-containing derivatives. They are powerful bactericidal agents that are active against many Gram-negative organisms and some Grampositive organisms, with activity against staphylococci and

328 ANTIBACTERIAL DRUGS Enterococcus faecalis, but not (when used alone) against other streptococci. They synergize with penicillins in killing Streptococcus faecalis in endocarditis. Aminoglycosides are used in serious infections including septicaemia, sometimes alone but usually in combination with other antibiotics (penicillins or cephalosporins). Gentamicin is widely used and has a broad spectrum, but is ineffective against anaerobes, many streptococci and pneumococci. Tobramycin is probably somewhat less nephrotoxic than gentamicin. Amikacin is more effective than gentamicin for pseudomonal infections and is occasionally effective against organisms resistant to gentamicin. It is principally indicated in serious infections caused by Gram-negative bacilli that are resistant to gentamicin. Topical gentamicin or tobramycin eye drops are used to treat eye infections. Mechanism of action These drugs are transported into cells and block bacterial protein synthesis by binding to the 30S ribosome. Adverse effects These are important and are related to duration of therapy and trough plasma concentrations. They are more frequent in the elderly and in renal impairment. Therapeutic monitoring is performed by measuring plasma concentrations before dosing (trough) and at ‘peak’ levels (usually at an arbitrary one hour after dosing). Eighth nerve damage is potentially catastrophic and is often irreversible. Acute tubular necrosis and renal failure are usually reversible if diagnosed promptly and the drug stopped or the dose reduced. Hypersensitivity rashes are uncommon. Bone marrow suppression is rare. Exacerbation of myasthenia gravis is predictable in patients with this disease. Pharmacokinetics Aminoglycosides are poorly absorbed from the gut and are given by intramuscular or intravenous injection. They are poorly protein bound (30%) and are excreted renally. The halflife is short, usually two hours, but once daily administration is usually adequate. This presumably reflects a post-antibiotic effect whereby bacterial growth is inhibited following clearance of the drug. In patients with renal dysfunction, dose reduction and/or an increased dose interval is required. Cerebrospinal fluid (CSF) penetration is poor. Drug interactions Aminoglycosides enhance neuromuscular blockade of nondepolarizing neuromuscular antagonists. Loop diuretics potentiate their nephrotoxicity and ototoxicity. CHLORAMPHENICOL Uses Chloramphenicol has a broad spectrum of activity and penetrates tissues exceptionally well. It is bacteriostatic, but is extremely effective against streptococci, staphylococci, H. influenzae, salmonellae and others. Uncommonly it causes aplastic anaemia, so its use is largely confined to life-threatening disease (e.g. H. influenzae epiglottitis, meningitis, typhoid fever) and to topical use as eyedrops. Mechanism of action Chloramphenicol inhibits bacterial ribosome function by inhibiting the 50S ribosomal peptidyl transferase, thereby preventing peptide elongation. Adverse effects These include: 1. haematological effects – dose-related erythroid suppression is common and predictable, but in addition aplastic anaemia occurs unpredictably with an incidence of approximately 1:40 000. This is irreversible in 50% of cases. It is rarely, if ever, related to the use of eyedrops. 2. grey baby syndrome – the grey colour is due to shock (hypotension and tissue hypoperfusion). Chloramphenicol accumulates in neonates (especially if premature) due to reduced glucuronidation in the immature liver (see Chapter 10). 3. other – sore mouth, diarrhoea, encephalopathy and optic neuritis. Pharmacokinetics Chloramphenicol is well absorbed following oral administration and can also be given by the intramuscular and intravenous routes. It is widely distributed and CSF penetration is excellent. It mainly undergoes hepatic glucuronidation, but in neonates this is impaired. Drug interactions Chloramphenicol inhibits the metabolism of warfarin, phenytoin and theophylline. MACROLIDES Macrolide antibiotics (e.g. erythromycin, clarithromycin, azithromycin) have an antibacterial spectrum similar, but not identical to that of penicillin. Distinctively, they are effective against several unusual organisms, including Chlamydia, Legionella and Mycoplasma. ERYTHROMYCIN Uses Uses include respiratory infections (including Mycoplasma pneumoniae, psittacosis and Legionnaires’ disease), whooping cough, Campylobacter enteritis and non-specific urethritis. Erythromycin is a useful alternative to penicillin in penicillinallergic patients (except meningitis: it does not penetrate the CSF adequately). It is useful for skin infections, such as lowgrade cellulitis and infected acne, and is acceptable for patients with an infective exacerbation of chronic bronchitis. It is most commonly administered by mouth four times daily, although when necessary it may be given by intravenous infusion.

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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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  • Page 302 and 303: FURTHER READING American Diabetes A
  • Page 304 and 305: deficiency. Potassium iodide (3 mg
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  • Page 310 and 311: effective in life-threatening hyper
  • Page 312 and 313: Further reading Block GA, Martin KJ
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  • Page 332 and 333: PART IX SELECTIVE TOXICITY
  • Page 334 and 335: ● Principles of antibacterial che
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  • Page 340 and 341: Mechanism of action Macrolides bind
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  • Page 344 and 345: Case history A 70-year-old man with
  • Page 346 and 347: PRINCIPLES OF MANAGEMENT OF MYCOBAC
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  • Page 352 and 353: POLYENES AMPHOTERICIN B Uses Amphot
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  • Page 368 and 369: FUSION INHIBITORS Uses Currently, e
  • Page 370 and 371: salvage therapy include azithromyci
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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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