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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

NON-NUCLEOSIDE ANALOGUE

NON-NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS The non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) are used as part of triple-therapy schedules in combination with nucleoside analogue RT inhibitors (e.g. ZDV/ 3-TC). Agents in this group include efavirenz, nevirapine and delavirdine. Efavirenz is administered orally and causes a marked (�50%) reduction in viral load during eight weeks of therapy. They are synergistic with NRTIs. NNRTIs should only be used in combination therapy due to the rapid development of viral resistance. Mechanism of action Non-nucleoside agents inhibit HIV reverse transcriptase by binding to an allosteric site and causing non-competitive enzyme inhibition, reducing viral DNA production. Adverse effects These include the following: • abdominal pain and nausea/vomiting/diarrhoea; • lipodystrophy; • arthralgia, myalgia; • drug–drug interactions: complex effects on other CYP450 metabolized drugs (see below); • neural tube defects in the fetus. Pharmacokinetics Efavirenz is well absorbed. It has a plasma t1/2 of 40–60 hours, is highly protein bound and metabolized by hepatic CYP2B6 � CYP3A) to its hydroxylated metabolite, which is glucuronidated and excreted in the urine. Drug interactions Efavirenz inhibits CYP3A4, CYP2C9 and CYP2C19 and may reduce the clearance of co-administered drugs metabolized by these isoenzyme systems. Efavirenz autoinduces its own metabolism. In contrast, nevirapine induces CYP3A and thus increases the clearance of drugs metabolized by this isoenzyme. Key points Anti-HIV drugs – Non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs) • Used in combination, because of synergy with NRTIs, e.g. ZDV. • Efavirenx, nevirapine and delavirdine are allosteric (noncompetitive) inhibitors of the HIV reverse transcriptase. • Oral absorption is good, hepatic metabolism by CYP3A or 2B6, short–intermediate half-lives. • Adverse effects include gastro-intestinal disturbances, rashes and drug interactions. • Resistance develops quickly; not to be used as monotherapy. HIV PROTEASE INHIBITORS Uses Compounds in this class include amprenavir, ritonavir, indinavir, lopinavir, nelfinavir, saquinavir, atazanavir and tipranavir (Table 46.3). They cause a rapid and marked reduction of HIV-1 replication as measured by a fall of 100- to 1000fold over 4–12 weeks in the number of HIV RNA copies per mL of plasma. Reductions in viral load are paralleled by increases in CD4 count of approximately 100–150 cells/μL. Resistance is a problem and leads to cross-resistance between protease inhibitors (PIs), so they are used in combination therapy (see Table 46.1). Mechanism of action These agents prevent HIV protease from cleaving the gag and gag–pol protein precursors encoded by the HIV genome, arresting maturation and blocking the infectivity of nascent virions. The HIV protease enzyme is a dimer and has aspartylprotease activity. Anti-HIV protease drugs contain a synthetic analogue structure of the phenylalanine–proline sequence of positions 167–168 of the gag–pol polyprotein. Thus they act as competitive inhibitors of the viral protease and inhibit maturation of viral particles to form an infectious virion. Adverse effects These include the following: ANTI-HIV DRUGS 355 • nausea, vomiting and abdominal pain; • fatigue; • glucose intolerance (insulin resistance or frank diabetes mellitus) and hypertriglyceridaemia; • fat redistribution – buffalo hump, increased abdominal girth; • drug–drug interactions – complex effects on many other drugs that are hepatically metabolized (see Chapter 13). Key points Anti-HIV protease inhibitors • Used in combination, because of synergy with anti-HIV RT inhibitors and reduced resistance. • They competitively inhibit the HIV protease enzyme, and are the most potent and rapid blockers of HIV replication available. • Oral absorption is variable, hepatic metabolism is mainly by CYP3A. • Boosted PI therapy involves combinations such as lopinavir/ritonavir where low-dose ritonavir potentiates the bioavailability of lopinavir by inhibiting gastrointestinal CYP3A and P-glycoprotein (MDR1). • Side-effects: include gastrointestinal upsets, hyperglycaemia, fat redistribution and drug–drug interactions. • HIV resistance to one agent usually means crossresitance to others in this class.

356 HIV AND AIDS Table 46.3: Properties of commonly available HIV-1 protease inhibitors Protease inhibitors Side effects Pharmacokinetics Additional comments Amprenavir Gastro-intestinal upsets, skin Well absorbed Tmax 1–2 h, t1/2 Inhibits CYP3A (fosamprenavir) rashes, fat redistribution 7–10 h. Hepatic metabolism CYP3A Atazanavir Hyperbilirubinaemia, gastro- Well absorbed with food. Does not induce CYP450, but intestinal upsets Tmax 2 h, t1/2 is 6–8 h, 80–90% does inhibit CYP3A drug hyperglycaemia, fat protein bound. Hepatic interactions redistribution metabolism. No autoinduction of metabolism Indinavir Renal stones (5–15%), gastro- Well absorbed (65% Does not induce CYP450, but intestinal upsets fewer than bioavailable). Tmax is 0.8–1.5 h, does inhibit it, especially CYP3A with other PIs, hepatic t1/2 is 2 h. 60–65% protein dysfunction, hyperglycaemia, fat redistribution bound. Hepatic metabolism Saquinavir Gastro-intestinal upsets, Poorly absorbed (13% Does not induce CYP450, but (soft gel) hepatitis hyperglycaemia, fat bioavailable). Hepatic inhibits it, at the concentrations redistribution metabolism achieved clinically (CYP3A) Nelfinavir Gastro-intestinal upsets 20%, Well absorbed (20–80% Does induce CYP450 and hyperglycaemia, fat bioavailable). Tmax is inhibits it, especially CYP3A redistribution, transaminitis 2–4 h, t1/2 is 3.5–5 h, 98% protein bound. Hepatic metabolism Tipranavir Gastro-intestinal disturbances, Well absorbed (40–60% Induces CYP450, especially hyperglycaemia, hepatitistransaminitis cerebral haemorrhage bioavailable). t1/2 is 5–6 h CYP3A Pharmacokinetics Lopinavir is well absorbed with food and 98–99% protein bound (albumin and alpha-1-acid glycoprotein). It undergoes oxidative metabolism by the CYP3A isozyme, with a half-life of five to six hours. The majority of lopinavir is excreted as metabolites in the faeces, with only about 4% appearing in urine. Ritonavir is also well absorbed (bioavailability �60%). It is 60% plasma protein bound and metabolized by CYP3A � CYP2D6. It has a half life of between three and five hours. Ritonavir inhibits the metabolism of certain CYP3A substrates (and certain drugs metabolized by CYP2D6) and induces its own metabolism. Therefore drug–drug interactions are complex. Drug interactions These are numerous and clinically important; the following list is not comprehensive: 1. Most protease inhibitors are inhibitors of hepatic CYP3A. This leads to reduced clearance and increased toxicity of a number of drugs often causing severe adverse effects (e.g. increased sedation with midazolam, triazolam and excessive hypotension with calcium channel blockers). Protease inhibitors inhibit the metabolism of rifabutin increasing the risk of rifabutin toxicity. 2. Enzyme inducers (e.g. rifamycins – rifampicin/rifabutin or nevirapine) enhance the metabolism of protease inhibitors, making them less effective, producing subtherapeutic plasma concentrations and increasing the likelihood of HIV resistance. 3. Several protease inhibitors reduce gastro-intestinal metabolism (by CYP3A) and luminal transport (via P-gp/MDR1) of co-administered protease inhibitors, thereby increasing plasma concentrations. Combining two agents from this group is called ‘boosted protease inhibitor’ therapy, e.g. lopinavir is available combined with low-dose ritonavir; ritonavir inhibits CYP3A and P-glycoprotein (MDR1) increasing the bioavailability of lopinavir. The same principle applies if saquinavir/ low-dose ritonavir or amprenavir/low-dose ritonavir are combined.

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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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  • Page 330 and 331: FURTHER READING Birnbaumer M. Vasop
  • Page 332 and 333: PART IX SELECTIVE TOXICITY
  • Page 334 and 335: ● Principles of antibacterial che
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  • Page 338 and 339: Pharmacokinetics Absorption of thes
  • Page 340 and 341: Mechanism of action Macrolides bind
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  • Page 346 and 347: PRINCIPLES OF MANAGEMENT OF MYCOBAC
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  • Page 356 and 357: NUCLEOSIDE ANALOGUES ACICLOVIR Uses
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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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  • Page 374 and 375: Pharmacokinetics Chloroquine is rap
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  • Page 392 and 393: Plasma membrane Signal transduction
  • Page 394 and 395: Table 48.10: Monoclonal antibodies
  • Page 396 and 397: INTERFERON-ALFA 2B Interferon-alfa
  • Page 398 and 399: PART X HAEMATOLOGY
  • Page 400 and 401: ● Haematinics - iron, vitamin B 1
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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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