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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

● Introduction 155 ●

● Introduction 155 ● Pathophysiology and mechanism of pain 155 ● Sites of action of analgesics 156 ● Drugs used to treat mild or moderate pain 156 CHAPTER 25 ANALGESICS AND THE CONTROL OF PAIN INTRODUCTION Pain is a common symptom and is important because it both signals ‘disease’ (in the broadest sense) and aids diagnosis. Irrespective of the cause, its relief is one of the most important duties of a doctor. Fortunately, pain relief was one of the earliest triumphs of pharmacology, although clinicians have only recently started to use the therapeutic armamentarium that is now available adequately and rationally. PATHOPHYSIOLOGY AND MECHANISM OF PAIN Pain is usually initiated by a harmful (tissue-damaging, noxious) stimulus. The perception of such stimuli is termed ‘nociception’ and is not quite the same as the subjective experience of pain, which contains a strong central and emotional component. Consequently, the intensity of pain is often poorly correlated with the intensity of the nociceptive stimulus, and many clinical states associated with pain are due to a derangement of the central processing such that a stimulus that is innocuous is perceived as painful. Trigeminal neuralgia is an example where a minimal mechanical stimulus triggers excruciating pain. The main pathways are summarized in Figure 25.1. The afferent nerve fibres involved in nociception consist of slowly conducting non-myelinated C-fibres that are activated by stimuli of various kinds (mechanical, thermal and chemical) and fine myelinated (Aδ) fibres that conduct more rapidly but respond to similar stimuli. These afferents synapse in the dorsal horn of grey matter in the spinal cord in laminae I, V and II (the substantia gelatinosa). The cells in laminae I and V cross over and project to the contralateral thalamus, whereas cells in the substantia gelatinosa have short projections to laminae I and V and function as a ‘gate’, inhibiting transmission of impulses from the primary afferent fibres. The gate provided by the substantia gelatinosa can also be activated centrally by descending pathways. There is a similar gate mechanism in the thalamus. Descending inhibitory controls are very important, a key ● Opioids 159 ● Opioid antagonists 162 ● Analgesics in terminal disease 162 ● Management of post-operative pain 163 Cortex Thalamus Spinal cord Pain signals Periaqueductal grey matter Descending inhibition Dorsal root ganglion Peripheral sensory nerve Figure 25.1: Neural pain pathways. Pain signals component being the small region of grey matter in the midbrain known as the periaqueductal grey (PAG) matter. Electrical stimulation of the PAG causes profound analgesia. The main pathway from this area runs to the nucleus raphe magnus in the medulla and thence back to the dorsal horn of the cord connecting with the interneurones involved in nociception. Key mediators of nociception are summarized in Figure 25.2. Stimulation of nociceptive endings in the periphery is predominantly chemically mediated. Bradykinin, prostaglandins and various neurotransmitters (e.g. 5-hydroxytryptamine, 5HT) and metabolites (e.g. lactate) or ions (e.g. K � ) released from damaged tissue are implicated. Capsaicin, the active principle of red peppers, potently stimulates and then desensitizes nociceptors. The neurotransmitters of the primary nociceptor fibres include fast neurotransmitters – including glutamate and probably adenosine triphosphate (ATP) – and various neuropeptides, including substance P and calcitonin gene-related peptide (CGRP). Neurotransmitters involved in modulating the pathway include opioid peptides (e.g. endorphins), endocannabinoids (e.g. anandamide), 5HT and noradrenaline.

156 ANALGESICS AND THE CONTROL OF PAIN Cell body SITES OF ACTION OF ANALGESICS Drugs can prevent pain: Spinal ganglion (DRG) Cytokines Na + TTX resistant TTX sensitive K + • at the site of injury (e.g. NSAIDs); • by blocking peripheral nerves (local anaesthetics); • by closing the ‘gates’ in the dorsal horn and thalamus (one action of opioids and of tricyclic antidepressants that inhibit axonal re-uptake of 5HT and noradrenaline); • by altering the central appreciation of pain (another effect of opioids). Prostaglandins Bradykinin Neurotrophins Histamine Serotonin GP130 trk VDCCs Ca 2+ 5-HT EP B Nociceptor H ATP Adrenaline ACh P2X Adren. H + Ca 2+ Na + Ca 2+ K + Mechanical stimuli TRPV1 Capsaicin, Heat, Protons Resiniferatoxin aggregation. It has no irritant effect on the gastric mucosa and can be used safely and effectively in most individuals who are intolerant of aspirin. It is the standard analgesic/antipyretic in paediatrics since, unlike aspirin, it has not been associated with Reye’s syndrome and can be formulated as a stable suspension. The usual adult dose is 0.5–1 g repeated at intervals of four to six hours if needed. Mechanism of action Paracetamol inhibits prostaglandin biosynthesis under some circumstances (e.g. fever), but not others. The difference from other NSAIDs is still under investigation. Adverse effects The most important toxic effect is hepatic necrosis leading to liver failure after overdose, but renal failure in the absence of liver failure has also been reported after overdose. There is no convincing evidence that paracetamol causes chronic liver disease when used regularly in therapeutic doses (�4 g/24 hours). Paracetamol is structurally closely related to phenacetin (now withdrawn because of its association with analgesic nephropathy) raising the question of whether long-term abuse of paracetamol also causes analgesic nephropathy, an issue which is as yet unresolved. Pharmacokinetics, metabolism and interactions Absorption of paracetamol following oral administration is increased by metoclopramide, and there is a significant relationship between gastric emptying and absorption. Paracetamol is rapidly metabolized in the liver. The major sulphate and glucuronide conjugates (which account for approximately 95% of a paracetamol dose) are excreted in the urine. When paracetamol is taken in overdose (Chapter 54), the capacity of the conjugating mechanisms is exceeded and a toxic metabolite, N-acetyl benzoquinone imine (NABQI), is formed via metabolism through the CYP450 enzymes. M Neuropeptides NK1 CGRP SST,etc. Proteinases Figure 25.2: Influence of inflammatory mediators on activity of a C-fibre nociceptor. DRG, dorsal root ganglion, TTX, tetrodotoxin; GP130, glycoprotein 130; trk, tyrosine kinase; 5-HT, 5-hydroxytryptamine (serotonin) receptor; EP, prostaglandin EP receptor; B, bradykinin receptor; H, histamine receptor; P2X, purinergic P2X receptor; Adren, adrenoceptor; M, muscarinic receptor; NKT, neokyotorphine; CGRP, calcitonin gene-related peptide; SST, somatostatin; PARs protease activated receptors; TRPV1, transient receptor potential vanilloid 1 receptor; VDCCs, voltage-dependent calcium channels. Key points Mechanisms of pain and actions of analgesic drugs • Nociception and pain involve peripheral and central mechanisms; ‘gating’ mechanisms in the spinal cord and thalamus are key features. • Pain differs from nociception because of central mechanisms, including an emotional component. • Many mediators are implicated, including prostaglandins, various peptides that act on μ-receptors (including endorphins), 5HT, noradrenaline and anandamide. • Analgesics inhibit, mimic or potentiate natural mediators (e.g. aspirin inhibits prostaglandin biosynthesis, morphine acts on μ-receptors, and tricyclic drugs block neuronal amine uptake). DRUGS USED TO TREAT MILD OR MODERATE PAIN PARACETAMOL Uses Paracetamol is an antipyretic and mild analgesic with few, if any, anti-inflammatory properties and no effect on platelet PARs

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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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    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

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    INTERFERON-ALFA 2B Interferon-alfa

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    PART X HAEMATOLOGY

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    ● Haematinics - iron, vitamin B 1

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    one marrow to produce red cells. Th

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    EPO Erythroid precursors Erythrocyt

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    Therapeutic principles The extent o

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    PART XI IMMUNOPHARMACOLOGY

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    ● Introduction 399 ● Immunity a

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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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