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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

therapy is adequate

therapy is adequate though more frequent dosing is required for voriconazole. Adverse effects include gastro-intestinal upsets, rashes and hepatitis with rare case of hepatic failure. Voriconazole causes visual disturbances. CYP450 (especially CYP3A but CYP2C9 � CYP3A in the case of voriconazole) inhibition related drug–drug interactions are problematic for both agents. Drugs which decrease gastric acid (e.g. protonpump inhibitors) reduce the bioavailablity of both agents and drugs that induce hepatic CYP3A decrease systemic drug concentrations. Neither drug should be used in pregnancy and i.v. formulations of both should be avoided in patients with significant renal dysfunction (GFR � 30 mL/min) because of accumulation of the drug diluent (sulphobutylether beta cyclodextrin sodium) which has nephro- and hepatoxic effects in animals. Posaconazole is a novel agent with considerable potential due to its extended antifungal spectrum. Key points Azole antifungal drugs • Relatively wide spectrum of antifungal activity, fungistatic, but fungicidal with higher concentrations. • Impair ergosterol biosynthesis by inhibiting lanosterol 14-alpha-demethylase (fungal cytochrome enzyme). • Available as intravenous, oral and topical formulations. • Can be used as therapy for superficial (e.g. Candida) and serious deep-seated (e.g. Cryptococcus) fungal infections. • Fluconazole, itraconazole and voriconazole are currently much more widely used than ketoconazole. • Azole-related common toxicities are gastro-intestinal upsets, rashes, hepatitis and CYP3A inhibition-related drug–drug interactions. ALLYLAMINES TERBINAFINE Terbinafine is an allylamine and is fungicidal. It may be administered orally to treat ringworm (Tinea pedis, T. cruris or T. corporis) or dermatophyte infections of the nails. It is given once daily for two to six weeks (longer in infections of the nailbed, as an alternative to griseofulvin, see below). It acts by inhibiting the enzyme squalene epoxidase, which is involved in fungal ergosterol biosynthesis. It interferes with human CYP450, but only to a limited extent (e.g. 10–15% increase in ciclosporin concentrations). It is well absorbed, strongly bound to plasma proteins and concentrated in the stratum corneum. It is eliminated by hepatic metabolism with a mean elimination t1/2 of 17 hours. Its major side effects are nausea, abdominal discomfort, anorexia, diarrhoea and rashes (including urticaria). Dose reduction is needed in hepatic failure or if co-prescribed with drugs which are potent CYP3A inhibitors (e.g. HIV protease inhibitors). Rifampicin increases terbinafine metabolism, ANTIFUNGAL DRUG THERAPY 343 requiring a dose increase. Naftifine, another allylamine, is available for topical administration. ECHINOCANDINS Caspofungin and micafungin are novel echinocandins that are fungicidal to susceptible species. Echinocandins are semisynthetic lipopeptides. Use Echinocandins are active against Candida and Aspergillus species. They are used primarily for fungal infections that are resistant to azoles or where patients are intolerant of azoles and are administered by intravenous infusion, usually once daily. Mechanism of action Echinocandins are non-competitive inhibitors of 1,3-β-D glucan synthase, an enzyme necessary for synthesis of a glucose polymer crucial to the structure and integrity of the cell walls of some fungi. Fungal cells unable to synthesize this polysaccharide cannot maintain their shape and lack adequate rigidity to resist osmotic pressure, which results in fungal cell lysis. Glucan also appears essential for fungal cell growth and division. The mechanism of action of echinocandins is unique and drugs of this class are potentially additive or synergistic with polyenes and azoles. Adverse effects Adverse effects (usually mild and seldom problematic) include: • infusion phlebitis and fever, histamine-like infusion reactions, if infused rapidly; • infrequently nausea, diarrhoea, hyperbilirubinaemia; • rarely hepatitis, leukopenia. Pharmacokinetics Caspofungin and micafungin are not absorbed from the gastro-intestinal tract and are administered intravenously. Both agents are eliminated by hydrolysis and N-acetylation to inactive metabolites. The mean elimination t1/2 for caspofungin is 9–11 hours and for micafungin is 11–17 hours. Urine excretion of parent drug is insignificant and dose reduction is not indicated in renal failure. The dose of caspofungin should, however, be reduced in significant hepatic dysfunction. Drug interactions These are minimal compared to the azoles. Ciclosporin increases caspofungin AUC by 35% and micafungin increases the bioavailability of sirolimus and nifedipine. Other agents in this expanding class include anidulafungin.

344 FUNGAL AND NON-HIV VIRAL INFECTIONS Key points Echinocandin antifungal drugs • Fungicidal activity against candida and aspergillus. • They are administered by intravenous infusion. • They inhibit 1,3-beta D glucan synthase involved in the formation of glucan polysaccharide in certain fungal cell walls. • They are generally well tolerated, but cause infusion phlebitis, fever and histamine release effects with rapid infusions, gastro-intestinal upsets, hepatitis and leukopenia. • Few drug interactions: ciclosporin increases caspofungin AUC and micafungin increases the AUC of sirolimus and nifedipine. OTHER ANTIFUNGAL AGENTS GRISEOFULVIN Uses Griseofulvin is orally active, but its spectrum is limited to dermatophytes. It is concentrated in keratinized cells. It is given orally with meals and treatment is recommended for six weeks for skin infections and up to 12 months for nail infections. Mechanism of action Griseofulvin is concentrated in fungi and binds to tubulin, blocking polymerization of the microtubule, disrupting the mitotic spindle. Adverse effects These include: • headaches and mental dullness or inattention; • diarrhoea or nausea; • rashes and photosensitivity; Pharmacokinetics Griseofulvin is metabolized by the liver to inactive 6demethylgriseofulvin, which is excreted in the urine. Less than 1% of the parent drug is excreted in the urine. Griseofulvin induces hepatic CYP450s and consequently can interact with many drugs. FLUCYTOSINE (5-FLUOROCYTOSINE) Flucytosine is used to treat systemic candidiasis and cryptococcosis, provided that the strain is sensitive. Its spectrum is relatively restricted and acquired resistance is a major problem. Consequently, it is only used in combination therapy (e.g. with amphotericin B). It is deaminated to 5-fluorouracil in the fungus and converted to an antimetabolite 5-FdUMP. This inhibits thymidylate synthetase, impairing fungal DNA synthesis. Adverse effects include gastro-intestinal upset, leukopenia and hepatitis. Flucytosine is well absorbed after oral administration and penetrates the CSF well (thus it is usefully combined with amphotericin B to treat cryptococcal meningitis). It is excreted unchanged by glomerular filtration (�10% of a dose is metabolized). The normal t 1/2 is six hours and this is prolonged in renal failure. ANTIVIRAL DRUG THERAPY (EXCLUDING ANTI-HIV DRUGS) INTRODUCTION Many viral illnesses are mild and/or self-limiting, but some are deadly (e.g. the now extinct smallpox, some strains of influenza, the global HIV-1 epidemic and various exotic diseases, including Marburg disease, and various encephalitides). Some produce chronic disease (e.g. hepatitis B and C). Even the mild common cold is economically significant, as is its deadly relative SARS (severe acute respiratory syndrome). Patients who are immunocompromised, especially by HIV-1 infection, are at risk of serious illness from viruses that are seldom serious in healthy individuals. Antiviral drug therapy is therefore increasingly important. Antiviral therapy is more difficult than antibacterial therapy because viruses are intimately incorporated in host cells and the therapeutic targets are often similar to the equivalent enzymes/structures in human cells. To summarize these problems: • Viral replication is intracellular, so drugs must penetrate cells in order to be effective. • Viral replication usurps the metabolic processes of host cells. • Although viral replication begins almost immediately after the host cell has been penetrated, the clinical signs and symptoms of infection often appear after peak viral replication is over. Several events in the viral life cycle may prove susceptible as drug targets: • when the virus is outside cells it is susceptible to antibody attack; however, finding drugs that are non-toxic but which can destroy viruses in this situation remains a challenge; • viral coat attachment to the cell surface probably involves interaction between the virus coat and the cell membrane surface; • penetration of the cell membrane can be prevented (e.g. for influenza A by amantadine or neuraminidase inhibitors); • uncoating of the virus with release of viral nucleic acid intracellularly; • viral nucleic acid acts as a template for new strands of nucleic acid that in turn direct the production of new viral components utilizing the host cell’s synthetic mechanisms. Most non-HIV antiviral drugs act at this stage of viral replication; • extracellular release of new viral particles. Figure 45.2 summarizes the sites of action of antiviral drugs.

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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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  • Page 334 and 335: ● Principles of antibacterial che
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  • Page 346 and 347: PRINCIPLES OF MANAGEMENT OF MYCOBAC
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  • Page 392 and 393: Plasma membrane Signal transduction
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  • Page 396 and 397: INTERFERON-ALFA 2B Interferon-alfa
  • Page 398 and 399: PART X HAEMATOLOGY
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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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