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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

● Introduction 351 ●

● Introduction 351 ● Immunopathogenesis of HIV-1 infection 351 ● General principles for treating HIV-seropositive individuals 352 ● Anti-HIV drugs 353 INTRODUCTION In June 2006, a cumulative total of approximately 80 000 cases of HIV infection had been reported in the UK and 21 000 of these individuals had acquired immunodeficiency syndrome (AIDS), of whom 80% had died. Approximately 7500 new cases of HIV were reported in the UK in 2005. The most recent World Health Organization (WHO) report estimated that 38.6 million adults and 2.3 million children world-wide were living with HIV at the end of 2005. Globally, heterosexual transmission accounts for 85% of HIV infections. During 2005, an estimated 4.1 million became newly infected with HIV and an estimated 3 million people died from AIDS. World-wide, the Key points HIV-1 epidemiology, life-cycle and dynamics • By the end of 2005, the number of individuals infected with HIV world-wide was approximately 40 million. • HIV exposed individuals have CD4/CCR5-expressing cells (mainly lymphoid tissues) invaded; HIV produces its own DNA (from RNA) which is then incorporated into the host DNA, and this is then replicated. • The production rate of HIV virions is 1–3 � 10 9 virions per day. • HIV genome has 10 4 nucleotides, and all single base DNA mutations are generated daily, three-base mutations are unlikely to be produced before treatment. • Plasma virions have a half-life of six hours. • Infected CD4 cells have a half-life of 1.1 days. • The mean time period needed for HIV generation (time from release of virion into plasma until it infects another cell and causes release of a new generation of viruses) is 2.6 days. • HIV viral load should be assessed by measurement of the number of copies of HIV RNA/mL of plasma. • The HIV RNA copy number/mL of plasma is inversely correlated with CD4 count and survival. CHAPTER 46 HIV AND AIDS ● Opportunistic infections in HIV-1-seropositive patients 357 ● Mycobacterium avium-intracellulare complex therapy 359 ● Antifungal therapy 359 ● Anti-herpes virus therapy 359 HIV incidence rate is believed to have peaked in the late 1990s and to have stabilized subsequently, notwithstanding an increasing incidence in South-East Asia and China. IMMUNOPATHOGENESIS OF HIV-1 INFECTION Following innoculation of a naive host with biological fluid (e.g. blood, blood products or sexual secretions) containing HIV-1, the virus adheres to cells, e.g. lymphocytes, macrophages and dendritic cells in the blood, lymphoid organs or central nervous system, expressing the CD4 receptor and chemokine coreceptors (e.g the CXC chemokine receptor 4 (CXCR4) and the chemokine receptor 5 (CCR5)). During entry, gp120 attaches to the cell membrane by binding to the CD4 receptor. Subsequent interactions between virus and chemokine co-receptors (e.g. CXCR4 and CCR5) trigger irreversible conformational changes. The fusion event takes place within minutes by pore formation and releases the viral core into the cell cytoplasm. The virus then disassembles and the viral reverse transcriptase produces complementary DNA (cDNA) coded by viral RNA. This viral DNA is then integrated into the host genome by the HIV-1 integrase enzyme. Viral cDNA is then transcribed by the host, producing messenger RNA (mRNA) which is translated into viral peptides. These peptides are then cleaved by HIV protease to form the structural viral proteins that, together with viral RNA, assemble to form new infectious HIV virions. These exit the cell by endosomal budding. Figure 46.1 illustrates the HIV-1 life cycle, together with current and potential therapeutic targets. Newly formed HIV-1 virions infect previously uninfected CD4/CCR5-positive cells and subsequently impair the host immune response by killing or inhibiting CD4/CCR5-positive cells, thus rendering the host immunosuppressed and consequently at high risk of infections by commensal and opportunistic organisms. The diagnosis of HIV-1 infection is based on a combination of the enzyme-linked immunosorbent assay

352 HIV AND AIDS Fusion inhibitors block interaction of viral gp41 and cell membrane CD4 receptor CCR5/CXCR4 co-receptor CCR5 receptor blocker (e.g. Maraviroc) Reverse transcriptase RNA Host lymphocyte/macrophage Integrase Host DNA + vDNA Protease vDNA gp 120 p41 p18 p24 Reverse transcriptase RNA Figure 46.2: HIV structure consisting of membrane glycoprotein gp120 and peptide protein p41 plus an outer membrane of p18 and a nuclear membrane of p24 protein containing viral RNA and the HIV-1 reverse transcriptase and integrase. (ELISA) techniques that identify HIV-1 antibodies and Western blotting is then used to confirm the presence of HIV-1 structural proteins in blood (see Figure 46.2). Massive viral replication (3 � 10 9 virions per day) occurs in the four to eight weeks immediately post HIV-1 infection. Viral replication falls in 8–12 weeks, and stabilizes within 6–12 months, initiating a latent period of good health which may last 5–12 years. During this latent period, the viral load falls from an initial peak and remains stable at a plateau of 10 2 –10 6 HIV RNA copy number/mL of plasma. The HIV RNA copy number then rises before the development of AIDS. During the latent phase, there is a dynamic equilibrium of HIV replication, T-cell infection and destruction and new T-cell generation with a slow and inexorable decline in CD4 � cell numbers. Only after the CD4 lymphocyte cell count has fallen to �200–500/�L is the Reverse transcriptase inhibitors prevent transcription of viral RNA to viral DNA (vDNA) Integrase inhibitors prevent vDNA being inserted into host DNA (e.g. Raltegravir) Protease inhibitors prevent viral maturation (immature viral particles cannot cause infection) Figure 46.1: Sites of action of anti-HIV drugs. individual predisposed to opportunistic infections (e.g. pneumocystis, tuberculosis) or malignancies (e.g. Kaposi’s sarcoma, lymphoma). It is these infections and malignancies that define the later stages of HIV-1 infection, known as AIDS. GENERAL PRINCIPLES FOR TREATING HIV-SEROPOSITIVE INDIVIDUALS The accepted standard for HIV treatment is that combination highly active antiretroviral therapy (HAART) should be administered before substantial immunodeficiency intervenes. The primary aim of treating patients with HIV infection is maximal suppression of HIV replication for as long as possible. This improves survival. HAART comprises two nucleoside analogues plus either a boosted protease inhibitor or a non-nucleoside reverse transcriptase inhibitor and reduces viral load to �500 copies of HIV RNA/mL in 80% of patients after 12 months treatment. Not all patients tolerate triple therapy due to toxicity, and alternate double therapy may be used. Current British HIV Association (BHIVA) recommendations for initiating anti-HIV therapy are as follows. All HIV seropositive patients with symptoms (or AIDS-defining disease) should receive HAART. If the CD4 count is �350 cells per �L or if there is a rapid decline in CD4 count of �300 cells per �L over 12 months, such patients should be treated. Treatment may be deferred and the patient monitored if asymptomatic and CD4 counts are stable in the range 350–500 cells per �L. The recommended regimens for initial therapy are shown in Table 46.1 and are expected to reduce the HIV RNA copy number per mL of plasma by �0.5 log by week 8 of therapy, and ultimately to undetectable levels, and to maintain this state. The plasma HIV RNA copy number is the accepted gold standard for monitoring therapy and is inversely correlated with CD4 count and survival. HIV therapy guidelines are evolving rapidly, requiring

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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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  • 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
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  • Page 346 and 347: PRINCIPLES OF MANAGEMENT OF MYCOBAC
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  • Page 350 and 351: MYCOBACTERIUM LEPRAE INFECTION Lepr
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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
  • Page 400 and 401: ● Haematinics - iron, vitamin B 1
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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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