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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

antibiotics, such as

antibiotics, such as penicillin or neomycin). The mechanism here is that the drug applied to the skin forms an antigenic conjugate with dermal proteins, stimulating formation of sensitized T-lymphocytes in the regional lymph nodes, with a resultant rash if the drug is applied again. Drug photosensitivity is due to a photochemical combination between the drug (e.g. amiodarone, chlorpromazine, ciprofloxacin, tetracyclines) and dermal protein. Delayed sensitivity can also result from the systemic administration of drugs. Key points Drug or its metabolites Drug or its metabolites Drug (large molecule) Figure 12.1: The immune response to drugs. Cell membrane How to attempt to define the drug causing the adverse drug reaction: • Attempt to define the likely causality of the effect to the drug, thinking through the following: Did the reaction and its time-course fit with the duration of suspected drug treatment and known adverse drug effects? Did the adverse effect disappear on drug withdrawal and, if rechallenged with the drug, reappear? Were other possible causes excluded? • Provocation testing with skin testing – intradermal tests are neither very sensitive nor specific. • Test the patient’s serum for anti-drug antibodies, or test the reaction of the patient’s lymphocytes in vitro to the drug and/or drug metabolite if appropriate. • Consider stopping all drugs and reintroducing essential ones sequentially. • Carefully document and highlight the adverse drug reaction and the most likely culprit in the case notes. PREVENTION OF ALLERGIC DRUG REACTIONS Protein Antigen Although it is probably not possible to avoid all allergic drug reactions, the following measures can decrease their incidence: 1. Taking a detailed drug history (prescription and over-the-counter drugs, drugs of abuse, nutritional and PREVENTION OF ALLERGIC DRUG REACTIONS 67 Central immune apparatus vitamin supplements and alternative remedies) is essential. A history of atopy, although not excluding the use of drugs, should make one wary. 2. Drugs given orally are less likely to cause severe allergic reactions than those given by injection. 3. Desensitization (hyposensitization) should only be used when continued use of the drug is essential. It involves giving a very small dose of the drug and increasing the dose at regular intervals, sometimes under cover of a glucocorticosteroid and β 2-adrenoceptor agonist. An antihistamine may be added if a drug reaction occurs, and equipment for resuscitation and therapy of anaphylactic shock must be close at hand. It is often successful, although the mechanism by which it is achieved is not fully understood. 4. Prophylactic skin testing is not usually practicable, and a negative test does not exclude the possibility of an allergic reaction. Key points T Lymphocytes Macrophages B Lymphocytes Type IV response Sensitized lymphocytes Type I, II and III responses Humoral antibodies Classification of immune-mediated adverse drug reactions: • Type I – urticaria or anaphylaxis due to the production of IgE against drug bound to mast cells, leading to massive release of mast cell mediators locally or systemically (e.g. ampicillin skin allergy or anaphylaxis). • Type II – IgG and IgM antibodies to drug which, on contact with antibodies on the cell surface, cause cell lysis by complement fixation (e.g. penicillin, haemolytic anaemia; quinidine, thrombocytopenia). • Type III – circulating immune complexes produced by drug and antibody to drug deposit in organs, causing drug fever, urticaria, rash, lymphadenopathy, glomerulonephritis, often with eosinophilia (e.g. co-trimoxazole, β-lactams). • Type IV – delayed-type hypersensitivity due to drug forming an antigenic conjugate with dermal proteins and sensitized T cells reacting to drug, causing a rash (e.g. topical antibiotics).

68 ADVERSE DRUG REACTIONS EXAMPLES OF ALLERGIC AND OTHER ADVERSE DRUG REACTIONS Adverse drug reactions can be manifested in any one or multiple organ systems, and in extraordinarily diverse forms. Specific instances are dealt with throughout this book. Some examples to illustrate the diversity of adverse drug reactions are given here. RASHES These are one of the most common manifestations of drug reactions. A number of immune and non-immune mechanisms may be involved which produce many different types of rash ranging from a mild maculopapular rash to a severe erythema multiforme major (Stevens Johnson syndrome; Figures 12.2 and 12.3). Commonly implicated drugs/drug classes include beta-lactams, sulphonamides and other antimicrobial agents; anti-seizure medications (e.g. phenytoin, carbamazepine); NSAIDs. Some drugs may give rise to direct tissue toxicity (e.g. DMPS, used as chelating therapy in patients with heavy metal poisoning; Figure 12.4, see Chapter 54). LYMPHADENOPATHY Lymph-node enlargement can result from taking drugs (e.g. phenytoin). The mechanism is unknown, but allergic factors Figure 12.2: Mouth ulcer as part of Stevens Johnson syndrome as a reaction to phenytoin therapy (see Chapter 22). may be involved. The reaction may be confused with a lymphoma, and the drug history is important in patients with lymphadenopathy of unknown cause. BLOOD DYSCRASIAS Thrombocytopenia, anaemia (aplastic, iron deficiency, macrocytic, haemolytic) and agranulocytosis can all be caused by drugs. Thrombocytopenia can occur with many drugs, and in many but not all instances the mechanism is direct suppression of the megakaryocytes rather than immune processes. Drugs that cause thrombocytopenia include: • heparin; • gold salts; • cytotoxic agents (e.g. azathioprine/6-mercaptopurine); • quinidine; • sulphonamides; • thiazides. Haemolytic anaemia can be caused by a number of drugs, and sometimes immune mechanisms are responsible. Glucose-6-phosphate dehydrogenase deficiency (Chapter 14) Figure 12.3: Stevens Johnson syndrome following commencement of penicillin therapy (see Chapter 43). Figure 12.4: Mouth ulcer following DMPS treatment (see Chapter 54).

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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

  • Page 28 and 29: ● Introduction 17 ● Bioavailabi
  • Page 30 and 31: ROUTES OF ADMINISTRATION ORAL ROUTE
  • Page 32 and 33: Transdermal absorption is sufficien
  • Page 34 and 35: FURTHER READING Fix JA. Strategies
  • Page 36 and 37: and thromboxanes are CYP450 enzymes
  • Page 38 and 39: and lorazepam. Some patients inheri
  • Page 40 and 41: Orally administered drug Parenteral
  • Page 42 and 43: ● Introduction 31 ● Glomerular
  • Page 44 and 45: ACTIVE TUBULAR REABSORPTION This is
  • Page 46 and 47: DISTRIBUTION Drug distribution is a
  • Page 48 and 49: Detailed recommendations on dosage
  • Page 50 and 51: DIGOXIN Myxoedematous patients are
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  • Page 54 and 55: 25 20 10 Life-threatening toxicity
  • Page 56 and 57: ● Introduction 45 ● Harmful eff
  • Page 58 and 59: vagina in girls in their late teens
  • Page 60 and 61: an anti-analgesic effect when combi
  • Page 62 and 63: Case history A 20-year-old female m
  • Page 64 and 65: METABOLISM At birth, the hepatic mi
  • Page 66 and 67: lifelong effects as a result of tox
  • Page 68 and 69: DISTRIBUTION Ageing is associated w
  • Page 70 and 71: DIGOXIN Digoxin toxicity is common
  • Page 72 and 73: FURTHER READING Dhesi JK, Allain TJ
  • Page 74 and 75: Factors involved in the aetiology o
  • Page 76 and 77: analgesic. Following its release, t
  • Page 80 and 81: predisposes to non-immune haemolysi
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  • Page 84 and 85: Response Therapeutic range Toxic ra
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  • Page 88 and 89: Table 13.5: Competitive interaction
  • Page 90 and 91: ● Introduction: ‘personalized m
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  • Page 96 and 97: Key points • Genetic differences
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  • Page 102 and 103: ETHICS COMMITTEES Protocols for all
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  • Page 108 and 109: ● Introduction 97 ● Garlic 97
  • Page 110 and 111: A case report has suggested a possi
  • Page 112 and 113: including hypericin and pseudohyper
  • Page 114 and 115: PART II THE NERVOUS SYSTEM
  • Page 116 and 117: ● Introduction 105 ● Sleep diff
  • Page 118 and 119: and daytime sleeping should be disc
  • Page 120 and 121: Key points • Insomnia and anxiety
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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

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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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