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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Table 46.1: Examples

Table 46.1: Examples of combinations to be used as initial anti-HIV drug therapy a Two nucleoside analogues � e.g. ZDV � 3-TC or HIV protease inhibitor FTC � Lop/rit Two nucleoside analogues � e.g. ZDV or TDF � 3-TC or non-nucleoside reverse transcriptase inhibitor FTC � Efav or Nvp Three nucleoside reverse e.g. ABC � ZDV � 3-TC transcriptase inhibitors ABC, abacavir; ZDV, zidovudine; FTC, emtracitabine; 3-TC, 3-thiacytidine (lamivudine); d4T, didehydrothymidine (stavudine); Lop, lopinavir; rit, ritonovir; Efav, efavirenz; Nvp, nevirapine; TDF, tenofovir. a Combinations usually include ZDV or d4T because they have better CSF penetration than other nucleoside analogues and combinations attempt to avoid overlapping toxicities, and to avoid using agents that are phosphorylated by the same enzymes (combinations of ZDV� d4T and 3-TC � ddC are avoided. ddC � 2 � 3-dideoxycytidine, also known as zalcitabine). specialist care. Current principles emphasize combination therapy, regime convenience, tolerability and lifelong therapy. Anti- HIV therapy is a complex therapeutic arena, necessitating specialist supervision. Key points General guidelines for anti-HIV-1 therapy • Treat before significant immunosuppression develops. • BHIVA treatment criteria are CD4 count (if �350/�L) or symptoms or in USA HIV RNA �100,000 copies/mL plus CD4 �350/�L. • Standard therapy is highly active antiretroviral therapy (HAART) combination therapy. • HAART is two nucleoside analogue inhibitors plus one protease inhibitor, e.g. ZDV � 3-TC � amprenavir (or lopinavir/ritonavir). • If there is drug treatment failure or resistance, change at least two and preferably all three drugs being used. • The revised regimen may be guided by genotyping of the HIV genome for mutations associated with drug resistance. ANTI-HIV DRUGS NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs) Of these agents, only zidovudine (ZDV) has been proved to reduce mortality in late-stage AIDS. It reduces the incidence of opportunistic infections and possibly also the rate of progression of HIV-1 infection to AIDS. Other members of the class include lamivudine (3-TC), stavudine (d4T), didanosine (ddI), emtricitabine (FTC) and abacavir (ABC). These drugs are used in combinations and are available as combined products, e.g. 3-TC/ZDV, ABC/3-TC, ZDV/tenofovir. They ANTI-HIV DRUGS 353 reduce HIV-1 viral replication as indicated by plasma HIV RNA load. ZIDOVUDINE (AZIDOTHYMIDINE) This was originally synthesized in 1964 in the hope that it would be useful in treating malignancies. These hopes were not fulfilled, but it was the first nucleoside analogue effective in treating HIV-1 infection. Use Zidovudine (ZDV) is given orally to patients with HIV infection. Mechanism of action The parent drug, ZDV, enters virally infected cells by diffusion and undergoes phosphorylation first to its monophosphate (ZDV-MP) then to the diphosphate (ZDV-DP), the rate-limiting step, and finally to the triphosphate (ZDV-TP). The intracellular t1/2 of ZDV-TP is two to three hours. ZDV-TP is a competitive inhibitor of the HIV-1 reverse transcriptase and when incorporated into nascent viral DNA causes chain termination. Human cells lack reverse transcriptase and human nuclear DNA polymerases are much less sensitive (by at least 100-fold) to inhibition by ZDV-TP, thus producing a selective effect on viral replication. This mechanism of action is common to all anti-HIV nucleoside analogues. Adverse effects These include the following: • dose-dependent bone marrow suppression causing anaemia with reticulocytopenia and granulocytopenia. This occurred in 15% of patients in the original studies with high-dose ZDV. At currently recommended doses, it occurs in only 1–2% of patients; • nausea and vomiting; • fatigue and headache; • melanonychia (blue-grey nail discoloration); • lipodystrophy; • mitochondrial myopathy (uncommon); • hepatic steatosis with lactic acidosis (rarely); • it is mutagenic and carcinogenic in animals. However, ZDV is used in HIV-positive pregnant women as it reduces HIV maternal–fetal transmission and thus fetal/neonatal HIV-1 infection and has not been shown to be teratogenic if given to women after the first trimester. Pharmacokinetics Zidovudine is almost totally absorbed (�90%) from the gastro-intestinal tract, it achieves cerebrospinal fluid (CSF) concentrations that are 50% of those in plasma. The ZDV plasma elimination t1/2 is one to two hours. About 25–40% of a dose undergoes presystemic metabolism in the liver. The major metabolite (80%) is the glucuronide and approximately 20% of a dose appears unchanged in the urine.

354 HIV AND AIDS Drug interactions These are numerous and clinically important; the following list is not comprehensive: 1. probenecid inhibits the glucuronidation and renal excretion of ZDV; 2. ZDV glucuronidation is reduced by atovaquone; 3. rifamycins increase ZDV metabolism; 4. ZDV and antituberculous chemotherapy cause a high incidence of anaemia; 5. ganciclovir and ZDV combined therapy produces profound bone marrow suppression; 6. ZDV/ddI or ZDV/3-TC combinations (but not ZDV/D4T) are synergistic. Table 46.2 shows the properties of other NRTIs used in HIV therapy. NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITOR Tenofovir is the first nucleotide (as distinct from nucleoside) reverse transcriptase inhibitor (NERTI) and is used in combination with NRTIs. It is a derivative of adenosine monophosphate, but lacks the ribose ring. It is phosphorylated sequentially to the diphosphate and then the triphosphate which is a competitive inhibitor of HIV reverse transcriptase. It is adequately absorbed orally and administered once a day (half life 14–17 hours). It is Table 46.2: Properties of other anti-HIV NRTIs renally eliminated. Tenofovir is well tolerated with few adverse effects (mainly flatulence). Occasional cases of renal failure and Fanconi syndrome have been reported, so it should be used with caution in patients with pre-existing renal dysfunction. Although it is not a CYP450 inhibitor or inducer, it increases the AUC of didanosine and reduces the AUC of atazanavir. Ritonavir and atazanavir increase the AUC of tenofovir. Tenofovir is also active against hepatitis B virus (HBV). Key points Anti-HIV drugs – nucleoside analogue reverse transcriptase inhibitors – ZDV • Used in combinations to increase anti-HIV efficacy and reduce resistance. • Zidovudine is phosphorylated intracellularly to ZDV-TP, which inhibits viral reverse transcriptase. • Good oral absorption, penetration of CSF, hepatic metabolism and short half-life. • Adverse effects include bone marrow suppression and myopathy in the long term. • Used in HIV-positive pregnant women, in whom it reduces transmission to the fetus/neonate by approximately 60%. • Combination NRTI therapy, e.g. ZDV/3-TC form the ‘backbone components’ of HAART. • Resistance develops slowly to NRTIs. • Genotyping of the HIV mutations for drug resistance may guide drug choice. Anti-HIV nucleoside analogue Side effects Pharmacokinetics Additional comments Emtricitabine (FTC) – a One of the least toxic NRTIs. Well absorbed. Food – no FTC-TP long intracellular cytosine analogue, Skin pigmentation, hepatitis, effect on AUC, t1/2 is 8–10 h. half-life chemically related to lamivudine pancreatitis Renal excretion Didanosine (ddI; Peripheral neuropathy, Acid-labile absorption Intracellular triphosphate dideoxyinosine) pancreatitis, bone-marrow affected by pH – given anabolite ddA-TP has a t1/2 of toxicity is rare. as a buffered capsule. 24–40 h. Didanosine decreases Gastro-intestinal upsets Plasma t1/2 is 0.5–1.5 h. absorption of drugs requiring and hyperuricaemia Renal excretion (50%) and acid pH (e.g. keto- or hepatic metabolism itraconazole) Stavudine (d4T; Peripheral neuropathy Well absorbed (86% Intracellular triphosphate has didehydro-thymidine) bioavailability). Tmax is 2 h; t1/2 of 3–4 h. In vitro data show plasma t1/2 is 1 h, rapidly antagonism with ZDV cleared by renal (50%) and non-renal routes against HIV Lamivudine (3-TC; 2-deoxy- Well tolerated. Uncommon Well absorbed; t1/2 of Intracellular triphosphate has 3-thiacytidine) gastro-intestinal upsets, 3–6 h. Renal excretion t1/2 of 12 h. Synergy in vitro with hair loss, myelosuppression, (unchanged), requires dose ZDV against HIV. Coneuropathy reduction in renal impairment trimoxazole reduces clearance by 40%

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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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  • Page 346 and 347: PRINCIPLES OF MANAGEMENT OF MYCOBAC
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  • Page 370 and 371: salvage therapy include azithromyci
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  • Page 398 and 399: PART X HAEMATOLOGY
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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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