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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Table 48.7: Summary

Table 48.7: Summary of clinical pharmacology properties of common antimetabolites patients who are concurrently taking allopurinol. This is important because allopurinol pretreatment is used to reduce the risk of acute uric acid nephropathy due to rapid tumour lysis syndrome in patients with leukaemia. ANTIBIOTICS Several antibiotics (e.g. anthracyclines, anthracenediones – mitoxantrone) are clinically useful antineoplastic agents (see Table 48.8). ANTHRACYCLINES Doxorubicin and daunorubicin are the most widely used drugs in this group, but newer analogues (e.g. epirubicin, idarubicin) have reduced hepatic and cardiac toxicity, and idarubicin may be administered orally. DOXORUBICIN Uses Doxorubicin is a red antibiotic produced by Streptomyces peucetius. It is the most widely used drug of the anthracycline group, with proven activity in acute leukaemia, lymphomas, sarcomas and a wide range of carcinomas. Liposomal formulations of doxorubicin are available. DRUGS USED IN CANCER CHEMOTHERAPY 377 Drug Use Mechanism Side effects Additional comments Cytosine arabinoside Acute leukaemia (AML) Inhibits pyrimidine Nausea and vomiting, Short half-life, (cytarabine) synthesis and in its bone marrow suppression, continuous infusions or triphosphate form mucositis, cerebellar daily doses intravenously inhibits DNA syndrome or subcutaneously, dose polymerase reduced in renal dysfunction Fludarabine Chronic lymphocytic Inhibits purine Myelosuppression, pulmonary Daily i.v. dosing, reduce leukaemia (CLL) synthesis toxicity, CNS toxicity dose in renal failure 2-Chlorodeoxy CLL and acute Converted to Severe neutropenia i.v. infusion 2-chlorodeoxy leukaemia (ANLL) triphosphate and adenosine inhibits purine (cladribine) synthesis Gemcitabine Pancreatic and lung cancer Cytidine analogue – Haematopoietic suppression, i.v. infusion, inactivated triphosphate form mucositis, rashes by cytidine deaminase, incorporated into DNA, active throughout the blocks DNA synthesis cell cycle, dose reduced in renal dysfunction Hydroxyurea CML and myelo- Inhibits ribonucleotide Neutropenia, nausea, Oral dosing, short proliferative disorders reductase, affecting skin reactions half-life, rapidly DNA and RNA synthesis reversible toxicity Mechanism of action Cytotoxic actions of anthracyclines lead to apoptosis, and include: • intercalation between adjacent base pairs in DNA, leading to fragmentation of DNA and inhibition of DNA repair, enhanced by DNA topoisomerase II inhibition; • membrane binding alters membrane function and contributes to cardiotoxicity; • free-radical formation also causes cardiotoxicity. Adverse effects These include the following: • cardiotoxicity – acute and chronic (see below); • bone marrow suppression with neutropenia and thrombocytopenia; • alopecia – may be mitigated by scalp cooling; • nausea and vomiting; • ‘radiation recall’ – anthracyclines exacerbate or reactivate radiation dermatitis or pneumonitis; • extravasation causes severe tissue necrosis. Anthracycline cardiotoxicity • Acute: this occurs shortly after administration, with the development of various dysrhythmias that are occasionally life-threatening (e.g. ventricular tachycardia, heart block). These acute effects do not predict chronic toxicity.

378 CANCER CHEMOTHERAPY Table 48.8: Clinical pharmacology of antitumour antibiotics Drug Indications and route of administration Side effects Pharmacokinetics Additional comments Mitoxantrone Advanced breast cancer; Nausea and vomiting, Hepatic metabolism, Intercalates into DNA leukaemia and lymphoma, stomatitis, low incidence extensively bound to and inhibits DNA i.v. dosing of cardiotoxicity (�3%) tissues, t1/2 � 20–40 h topoisomerase II Mitomycin C Gastro-intestinal tumours, Vesicant cumulative Pharmacokinetics not It is a prodrug – advanced breast cancer, toxicity, myelosuppression, affected by renal or transformed to an head and neck tumours. interstitial alveolitis, hepatic function alkylating Intravenous infusions haemolytic-uraemic intermediate; alkylates syndrome guanine residues (10% of its adducts form inter-strand breaks); synergistic with 5-FU and radiotherapy Bleomycin Lymphomas, testicular Fever, shivering, mouth 50–70% of a dose is It causes single- and carcinoma and ulcers, skin erythema – excreted in the urine, double-strand breaks squamous cell pigmentation, interstitial t1/2 � 9 h; prolonged in DNA. Arrests in renal dysfunction cells in G2/M phase tumours, i.v. dosing lung disease if dose Also metabolized by >300 units peptidases; skin and lung have high drug concentrations as they lack peptidases • Chronic: cardiomyopathy, leading to death in up to 60% of those who develop signs of congestive cardiac failure. It is determined by the cumulative dose. Risk factors for cardiomyopathy include prior mediastinal irradiation, age over 70 years and pre-existing cardiovascular disease. Agents to protect against anthracycline cardiomyopathy and allow dose intensification are under investigation. Pharmacokinetics Doxorubicin is given intravenously. The plasma concentration–time profile shows a triphasic decline. Doxorubicin does not enter the central nervous system (CNS). Hepatic extraction is high, with 40% appearing in the bile (as unchanged drug and metabolites, e.g doxorubicinol, which has antitumour activity). Renal excretion accounts for less than 15% of a dose. Dose reduction is recommended in patients with liver disease, particularly if accompanied by hyperbilirubinaemia. TOPOISOMERASE INHIBITORS DNA TOPOISOMERASE I INHIBITORS CAMPTOTHECINS Camptothecins are alkaloids derived from a Chinese tree Camptotheca acuminata. Irinotecan (CPT-11) and topotecan are available for clinical use. Uses The camptothecins are active against a broad range of tumours, including carcinomas of the colon, lung and cervix. They are given intravenously. Mechanism of action Camptothecins act during the S-phase of the cell cycle. DNA topoisomerase I is necessary for unwinding DNA for replication and RNA transcription. Camptothecins stabilize the DNA topoisomerase I–DNA complex. Cell killing is most likely via induction of apoptosis (programmed cell death). Pharmacokinetics Irinotecan is converted to a more potent cytotoxic metabolite SN38, which is inactivated by hepatic glucuronidation (via UGT1A1, see Chapters 5 and 14). Topotecan is hydrolysed by the blood carboxylesterase and is excreted in the urine, requiring dose reduction in renal impairment. Adverse effects The principal adverse effects are myelosuppression, acute and delayed diarrhoea (particularly irinotecan), which can be dose limiting and require prophylactic therapy with anticholinergics (for acute diarrhoea) and loperamide, or treatment with octreotide. Other less severe side effects include alopecia and fatigue.

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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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    injection may be useful, but if don

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    CHAPTER 41 REPRODUCTIVE ENDOCRINOLO

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    elease by the pituitary via negativ

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    Treatment with depot progestogen in

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    infusion using an infusion pump to

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    significant proportion of men who r

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    with symptoms caused by the release

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    FURTHER READING Birnbaumer M. Vasop

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    PART IX SELECTIVE TOXICITY

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    ● Principles of antibacterial che

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    2. transfer of resistance between o

  • 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
  • Page 348 and 349: Pharmacokinetics Absorption from th
  • Page 350 and 351: MYCOBACTERIUM LEPRAE INFECTION Lepr
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  • Page 356 and 357: NUCLEOSIDE ANALOGUES ACICLOVIR Uses
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  • Page 360 and 361: Uses Interferon-α when combined wi
  • Page 362 and 363: ● Introduction 351 ● Immunopath
  • Page 364 and 365: Table 46.1: Examples of combination
  • Page 366 and 367: NON-NUCLEOSIDE ANALOGUE REVERSE TRA
  • Page 368 and 369: FUSION INHIBITORS Uses Currently, e
  • Page 370 and 371: salvage therapy include azithromyci
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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
  • Page 402 and 403: one marrow to produce red cells. Th
  • Page 404 and 405: EPO Erythroid precursors Erythrocyt
  • Page 406 and 407: Therapeutic principles The extent o
  • Page 408 and 409: PART XI IMMUNOPHARMACOLOGY
  • Page 410 and 411: ● Introduction 399 ● Immunity a
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  • Page 418 and 419: DRUGS THAT ENHANCE IMMUNE SYSTEM FU
  • Page 420 and 421: PART XII THE SKIN
  • Page 422 and 423: ● Introduction 411 ● Acne 411
  • Page 424 and 425: DERMATITIS (ECZEMA) PRINCIPLES OF T
  • Page 426 and 427: SPECIALISTS ONLY SPECIALISTS ONLY E
  • Page 428 and 429: TREATMENT OF OTHER SKIN INFECTIONS
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  • Page 434 and 435: ● Introduction: ocular anatomy, p
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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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