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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Pharmacokinetics

Pharmacokinetics Chloroquine is rapidly and well absorbed from the intestine. It is approximately 50% bound to plasma proteins. About 70% of a dose is excreted unchanged in the urine, and the main metabolite is desethylchloroquine. The mean t 1/2 is 120 hours. High tissue concentrations (relative to plasma) are found, especially in melanin containing tissues, e.g. the retina. Drug interactions Chloroquine and quinine are antagonistic and should not used in combination. ARYLAMINOALCOHOLS (4-AMINOQUINOLINE DERIVATIVES) This group consists of quinoline methanols (quinine, quinidine and mefloquine) and the phenanthrene methanol halofantrine. QUININE Uses Quinine is the main alkaloid of cinchona bark. The mechanism of its antimalarial activity remains unclear, but may be similar to that of chloroquine. 1. Quinine sulphate (quinidine gluconate in the USA) is the drug of choice in the treatment of an acute attack of falciparum malaria where the parasite is known to be resistant to chloroquine. Initially, these drugs may be given intravenously and then orally when the patient improves. The mean t 1/2 is quite long and in patients with renal or hepatic dysfunction dosing should be reduced to Table 47.1: Uses and properties of other arylaminoalcohols MALARIA 363 once or twice daily. Doxycycline or clindamycin may be used as an adjunct to quinine. 2. Quinine should not be used for nocturnal cramps as its adverse effects outweigh any benefit in this benign condition. Adverse effects These include the following: • large therapeutic doses of quinine cause cinchonism (tinnitus, deafness, headaches, nausea and visual disturbances); • abdominal pain and diarrhoea; • rashes, fever, delirium, stimulation followed by depression of respiration, renal failure, haemolytic anaemia, thrombocytopenic purpura and hypoprothrombinaemia; • intravenous quinine can produce neurotoxicity such as tremor of the lips and limbs, delirium, fits and coma. Pharmacokinetics Quinine is almost completely absorbed in the upper part of the small intestine and peak concentrations occurring 1–3 hours after ingestion are similar following oral or intravenous administration. The mean t1/2 is ten hours, but is longer in severe falciparum malaria. Approximately 95% or more of a single dose is metabolized in the liver, principally to inactive hydroxy derivatives, with less than 5% being excreted unaltered in the urine. The uses and properties of other arylaminoalcohols are listed in Table 47.1. Drug Use and Pharmacokinetics Side effects Precautions/ pharmacodynamics comments Mefloquine Used for prophylaxis and Acute treatment: oral Gastro-intestinal Not used in pregnancy or acute treatment of drug- dosing disturbances are in patients with resistant malaria (especially Hepatic metabolism with common (up to neuropsychiatric disorders P. falciparum) enterohepatic circulation 50% of cases) Do not use in patients Schizonticidal in the blood t1/2 is 14–22 days CNS – hallucinations, with renal or hepatic psychosis, fits dysfunction Potentiates bradycardia of beta-blockers and quinine potentiates its toxicity Halofantrine Used for only uncomplicated Acute treatment: oral Gastro-intestinal Embryotoxic in animals – chloroquine-resistant dosing disturbances; less not used in pregnancy P. falciparum Food improves absorption. common than with Cross-resistance with Schizonticidal in the blood t1/2 is 1–2 days. Hepatic mefloquine mefloquine may occur metabolism to an active Pruritus metabolite Prolongs the QTc Hepatitis. CNS – neuromuscular spasm

364 MALARIA AND OTHER PARASITIC INFECTIONS 8-AMINOQUINOLINES (PRIMAQUINE) Primaquine is used to eradicate the hepatic forms of P. vivax or P. malariae after standard chloroquine therapy, provided that the risk of re-exposure is low. It may also be used prophylactically with chloroquine. It interferes with the organism’s mitochondrial electron transport chain. Gastro-intestinal absorption is good and it is rapidly metabolized, with a mean t 1/2 of six hours. Its major adverse effects are gastro-intestinal upsets, methaemoglobinaemia and haemolytic anaemia in G6PDdeficient individuals. ARTENUSATE AND ARTEMETHER Uses Artemisinin (derived from the weed Quin Hao, Artemesia annua) is a sesquiterpene lactone endoperoxide. It has been used in China for at least 2000 years. Artenusate and artemether are semi-synthetic derivatives of artemisinin and are effective and well-tolerated antimalarials. They should not be used as monotherapy or for prophylaxis because of the risk of resistance developing. In many developed countries, artemisinin derivatives are not yet licensed and can only be used on a namedpatient basis. Currently, there is no clinical evidence of resistance to artemesinin derivatives. Treatment can be started i.v. and switched to oral with adjunctive doxycycline or clindamycin as with quinine. Mechanism of action Artemesinins undergo haem-mediated decomposition of the endoperoxide bridge to yield carbon-centred free radicals. The involvement of haem explains why they are selectively toxic to malaria parasites. The resulting carbon-centred free radicals alkylate haem and proteins, particularly in the membranes of the parasite’s food vacuole and mitochondria, causing rapid death. Adverse effects Side effects are mild and include the following: • nausea, vomiting and anorexia; • dizziness. Preclinical toxicology suggested neuro-, hepato- and bone marrow toxicity. Pharmacokinetics Oral absorption is fair (F � 0.3). Artenusate and artemether reach peak plasma concentration in minutes and two to six hours, respectively. Both are extensively metabolized to dihydroartemesinin (active metabolite) which has a half-life of one to two hours. They autoinduce their CYP450 catalysed metabolism. Drug–drug interactions are still being elucidated. ANTI-FOLATES (DAPSONE PROGUANIL, PYRIMETHAMINE) Combinations of these drugs are taken orally in malaria prophylaxis, but their efficacy in acute malaria treatment is limited due to resistance. These agents inhibit folate biosynthesis at all stages of the malaria parasite’s life cycle, acting as competitive inhibitors of the malarial dihydropteroate synthase (dapsone) or the malarial dihydrofolate reductase (proguanil or pyrimethamine). They exhibit typical anti-folate adverse effect profiles (gastro-intestinal upsets, skin rashes, myelosuppression; see Chapters 43 and 46). TREATMENT OF A MALARIA RELAPSE Plasmodium falciparum does not cause a relapsing illness after treating the acute attack with schizonticides, because there is no persistent liver stage of the parasite. Infections with P. malariae can cause recurrent attacks of fever for up to 30 years, but standard treatment with chloroquine eradicates the parasite. Following treatment of an acute attack of vivax malaria with schizonticides, or a period of protection with prophylactic drugs, febrile illness can recur. Such relapsing illness can be prevented (or treated) by eradicating the parasites in the liver with primaquine, as described above. Proguanil hydrochloride administered continuously for three years, in order to suppress the parasites and allow time for the hepatic stages to die out naturally, is a useful alternative for patients with G6PD deficiency. Key points Treatment of acute malaria • If the infective species is not known or is mixed, initial therapy is with intravenous quinine or mefloquine. • P. falciparum is mainly resistant to chloroquine; treat with quinine, mefloquine or halofantrine. • Benign malaria (caused by P. malariae) is treated with chloroquine alone. • Benign malaria due to P. ovale or P. vivax requires chloroquine therapy plus primaquine to achieve a radical cure and prevent relapse. • Careful attention to hydration and blood glucose is necessary. • Anticipate complications and monitor the patient frequently. TRYPANOSOMAL INFECTION African sleeping sickness is caused by Trypanosoma gambiense and T. rhodesiense. The insect vector is the Glossina (tsetse) fly. Drugs used in antitrypanosomal therapy include: • those active in blood and peripheral tissues: melarsoprol, pentamidine, suramin and trimelarsan; • those active in the central nervous system: tryparsamide and melarsoprol. Table 47.2 summarizes the drugs used to treat trypanosomal and other non-malarial protozoan infections. HELMINTHIC INFECTION Table 47.3 summarizes the primary drugs used to treat common helminthic infections.

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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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  • Page 346 and 347: PRINCIPLES OF MANAGEMENT OF MYCOBAC
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  • Page 398 and 399: PART X HAEMATOLOGY
  • Page 400 and 401: ● Haematinics - iron, vitamin B 1
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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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