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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Table 53.2: Central

Table 53.2: Central nervous system effects of opioids Analgesia Euphoria Drowsiness : sleep : coma Decrease in sensitivity of respiratory centre to CO2 Depression of cough centre Stimulation of chemoreceptor trigger zone (vomiting in 15% of cases) Release of antidiuretic hormone Table 53.3: Medical complications of opioid addiction Infection Endocarditis – bacterial, often tricuspid valve, staphyloccocal, fungal (e.g. Candida) HIV/hepatitis B virus (HBV)/hepatitis C virus (HCV) Abscesses Tetanus Septicaemia Hepatitis Pulmonary Pneumonia – bacterial, fungal, aspiration Pulmonary oedema – ‘heroin lung’ Embolism Atelectasis Fibrosis/granulomas Skin Injection scars Abscesses Cellulitis Lymphangitis Phlebitis Gangrene Neurological Cerebral oedema Transverse myelitis Horner’s syndrome Polyneuritis Crush injury Myopathy Hepatic Cirrhosis Renal Nephrotic syndrome with proliferative glomerulonephritis Musculoskeletal Osteomyelitis (usually lumbar vertebrae, Pseudomonas, Staphylococcus, Candida), crush injury, myoglobinuria, rhabdomyolysis as a way of minimizing medical complications of opioid dependence. INTOXICATION AND OVERDOSE For several seconds following intravenous injection, heroin produces an intense euphoria (rush) which may be accompanied by nausea and vomiting, but is nevertheless pleasurable. Over the next few hours the user may describe a warm sensation in the abdomen and chest. However, chronic users often state that the only effect they obtain is remission from abstinence symptoms. On examination, the patient may appear to be alternately dozing and waking. The patient may be hypotensive with a slow respiratory rate, pin-point pupils and infrequent and slurred speech. These signs can be reversed with naloxone. Opioids predispose to hypothermia. Overdose is commonly accidental due to unexpectedly potent heroin or waning tolerance (e.g. after release from prison). Severe overdose may cause immediate apnoea, circulatory collapse, convulsions and cardiopulmonary arrest. Alternatively, death may occur over a longer period of time, usually due to hypoxia from direct respiratory centre depression with mechanical asphyxia (tongue and/or vomit blocking the airway). A common complication of opioid poisoning is noncardiogenic pulmonary oedema. This is usually rapid in onset, but may be delayed. Therefore, any patient who is admitted following heroin overdose should usually be hospitalized for approximately 24 hours. Naloxone reverses opioid poisoning with a rapid increase in pupil diameter, respiratory rate and depth of respiration. It may precipitate an acute abstinence syndrome in addicts and (very rarely) convulsions. This does not contraindicate its use in opioid overdoses in addicts. Severe hypoxia causes mydriasis and some opioids (notably pethidine) have an anti-muscarinic atropine-like mydriatic effect, so absence of small pupils should not preclude a trial of naloxone when the clinical situation suggests the possibility of opioid overdose. Naloxone is eliminated more rapidly than morphine and may need to be administered repeatedly (Chapter 25). TOLERANCE AND WITHDRAWAL OPIOID/NARCOTIC ANALGESICS 435 Increasing doses of opioid must be administered in order to obtain the effect of the original dose. Such tolerance affects the euphoric and analgesic effects, so the addict requires more and more opioid for his or her ‘buzz’. Changes in tolerance are much less apparent in the therapeutic use of opioids for the treatment of pain. Withdrawal symptoms usually start at the time when the next dose would normally be given, and their intensity is related to the usual dose. For heroin, symptoms usually reach a maximum at 36–72 hours and gradually subside over the next five to ten days. Table 53.4 lists features of the opioid abstinence syndrome.

436 DRUGS AND ALCOHOL ABUSE Table 53.4: Symptoms of the opioid abstinence syndrome Early Intermediate Late Yawning Mydriasis Involuntary muscle spasm Lacrimation Piloerection Fever Rhinorrhoea Flushing Nausea and vomiting Perspiration Tachycardia Abdominal cramps Twitching Tremor Restlessness Diarrhoea Withdrawal symptoms can be treated acutely by substitution with a longer-acting opioid agonist (e.g. methadone by mouth) or a partial agonist (e.g. buprenorphine, administered sublingually). The dose can be tapered over one to two weeks. Alternatively, withdrawal symptoms are alleviated by lofexidine (an α 2-antagonist with less marked hypotensive effects than clonidine) and an antidiarrhoeal agent, such as loperamide, administered over 48–72 hours. MANAGEMENT OF OPIOID ADDICTS Opioid addicts should be managed by specialized addiction clinics when possible. A highly simplified outline of management is summarized in the Key points below. Morbidity of opioid dependence is related more to the use of infected needles, injection of unsterile material, adulterants and cost (e.g. theft, prostitution) than to the acute toxicity of opioids per se. Key points Management of opioid addicts in hospital • Attempt to confirm addiction by telephoning prescriber. Confirm dosing regimen. • Obtain urine screen for a full drug misuse screen. • Look for evidence of needle marks. • Look for signs of opioid withdrawal. • Contact psychiatric liaison team. • In the Accident and Emergency Department, it is rarely appropriate to prescribe methadone. If clear withdrawal signs are evident, treat symptomatcially (e.g. with antidiarrhoeal agent); discuss with psychiatric liaison team regarding dose titration. • For in-patients, methadone may be appropriate – consult with psychiatric liaison regarding dose titration. • Analgesia – address needs as for other patients, but note the effects of tolerance. • On discharge, contact the patient’s usual prescriber, or if this is a new presentation make arrangements through psychiatric team. An orally available long-acting opioid antagonist, such as naltrexone, is sometimes used as an adjunct to maintain abstinence once opioid-free. (If given prematurely naltrexone precipitates withdrawal.) Few opioid addicts choose to remain on longterm antagonist therapy, in contrast to long-term methadone. Opioid addicts rarely present to hospital asking for treatment of their addiction, but more commonly present to physicians during routine medical or surgical treatment for a condition which may or may not be related to their addiction. Some patients will deny drug abuse and clinical examination should always include a search for signs of needle-tracking and withdrawal. Acute abstinence in a casualty/general hospital setting is uncomfortable for the patient, but most unlikely to be dangerous. Physicians are not allowed to prescribe diamorphine or cocaine to addicts for treatment of their addiction or abstinence unless they hold a special licence. It is reasonable to treat a genuine opioid withdrawal syndrome with a low dose of opioid (e.g. sublingual buprenorphine). If a patient says that they are being treated for addiction it is always wise to confirm this by telephoning their usual prescriber and/or the supplying pharmacist. If the patient is admitted to hospital, expert advice must be obtained. Knowledge of local policies towards drug addicts is essential for anyone working in the Accident and Emergency Department or who comes into contact with drug addicts. Newborn children of addicted mothers may be born with an abstinence syndrome or, less commonly, with features of drug overdose. Assisted ventilation is preferred to naloxone if apnoeic at birth in this situation. Key points Management of opioid dependence • Refer to specialized addiction clinic. • Conduct assessment (to include two urine samples positive for opioids). • Give maintenance treatment (e.g. full agonists such as methadone, or partial agonists such as buprenorphine). • Give antagonist treatment (e.g. naltrexone). • Provide detoxification regimens (e.g. lofexidine plus loperamide). • Give counselling/social support. • Repeat urine testing to confirm use of methadone and not other drugs. • Contract system. • Avoid prescriptions of other opioids/sedatives. • Special ‘drug-free’ centres – concentrate on psychological and social support through the acute and chronic abstinence phases, and are successful in some patients. There are legal requirements for the prescription of controlled drugs (Misuse of Drugs Regulations, 1985) distinguished in the British National Formulary by the symbol CD (e.g. diamorphine, morphine, injectable dihydrocodeine, dipipanone, fentanyl, buprenorphine, dexamfetamine, methylphenidate, Ritalin ® , barbiturates, temazepam). Among the requirements are that the prescription must be written by hand by the prescriber, in ink, with the dose and quantity of dose units stated in both figures and words (see British National Formulary). Diamorphine, dipipanone and cocaine may only be prescribed to an addict for their addiction by doctors with a special licence. Doctors are expected to continue to report the treatment demands of all drug misusers by returning the local drug misuse database reporting forms,

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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

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    Pharmacokinetics Absorption of thes

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    Mechanism of action Macrolides bind

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    asic quinolone structure dramatical

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    Case history A 70-year-old man with

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    PRINCIPLES OF MANAGEMENT OF MYCOBAC

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    Pharmacokinetics Absorption from th

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    MYCOBACTERIUM LEPRAE INFECTION Lepr

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    POLYENES AMPHOTERICIN B Uses Amphot

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    therapy is adequate though more fre

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    NUCLEOSIDE ANALOGUES ACICLOVIR Uses

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    Table 45.3: Summary of available ac

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    Uses Interferon-α when combined wi

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    ● Introduction 351 ● Immunopath

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    Table 46.1: Examples of combination

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    NON-NUCLEOSIDE ANALOGUE REVERSE TRA

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    FUSION INHIBITORS Uses Currently, e

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    salvage therapy include azithromyci

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    ● Malaria 361 ● Trypanosomal in

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    Pharmacokinetics Chloroquine is rap

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    Table 47.2: Drug therapy of non-mal

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    ● Introduction 367 ● Pathophysi

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    Table 48.1: Classification of commo

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    Polymorph count/mm 3 (a) (b) 10 000

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    doses are used to prepare patients

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    Adverse effects Methotrexate Inhibi

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    Table 48.7: Summary of clinical pha

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    Table 48.9: Summary of the clinical

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    Plasma membrane Signal transduction

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    Table 48.10: Monoclonal antibodies

  • Page 396 and 397: INTERFERON-ALFA 2B Interferon-alfa
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  • Page 472 and 473: non-steroidal anti-inflammatory dru
  • Page 474 and 475: puberty (male), delay 314 puerperiu
  • Page 476: tolerance 9, 433 benzodiazepines 10
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