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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

ROUTES OF ADMINISTRATION

ROUTES OF ADMINISTRATION ORAL ROUTE FOR LOCAL EFFECT Oral drug administration may be used to produce local effects within the gastro-intestinal tract. Examples include antacids, and sulphasalazine, which delivers 5-amino salicylic acid (5-ASA) to the colon, thereby prolonging remission in patients with ulcerative colitis (Chapter 34). Mesalazine has a pHdependent acrylic coat that degrades at alkaline pH as in the PRODRUG Various enzymes in body DRUG Relatively wellabsorbed and/or good tissue penetration INACTIVE Figure 4.3: Clinical use of prodrugs. Table 4.1: Prodrugs Passive diffusion of a water-soluble drug through an aquas channel or pore Drug D D D D D D Relatively poorly absorbed and/or poor tissue penetration D D ACTIVE Prodrug Product Enalapril Enalaprilat Benorylate Aspirin and paracetamol Levodopa Dopamine Minoxidil Minoxidil sulphate Carbimazole Methimazole Vanciclovir Aciclovir ATP Carrier-mediated active transport of drug Passive diffusion of a lipid-soluble drug D D ROUTES OF ADMINISTRATION 19 colon and distal part of the ileum. Olsalazine is a prodrug consisting of a dimer of two 5-ASA moieties joined by a bond that is cleaved by colonic bacteria. FOR SYSTEMIC EFFECT Oral administration of drugs is safer and more convenient for the patient than injection. There are two main mechanisms of drug absorption by the gut (Figure 4.4). Passive diffusion This is the most important mechanism. Non-polar lipid-soluble agents are well absorbed from the gut, mainly from the small intestine, because of the enormous absorptive surface area provided by villi and microvilli. Active transport This requires a specific carrier. Naturally occurring polar substances, including sugars, amino acids and vitamins, are absorbed by active or facilitated transport mechanisms. Drugs that are analogues of such molecules compete with them for transport via the carrier. Examples include L-dopa, methotrexate, 5-fluorouracil and lithium (which competes with sodium ions for absorption). Other factors that influence absorption include: 1. surgical interference with gastric function – gastrectomy reduces absorption of several drugs; 2. disease of the gastro-intestinal tract (e.g. coeliac disease, cystic fibrosis) – the effects of such disease are unpredictable, but often surprisingly minor (see Chapter 7); 3. the presence of food – the timing of drug administration in relation to meal times can be important. Food and drink dilute the drug and can bind it, alter gastric emptying and increase mesenteric and portal blood flow; D D D D Lumen Epithelial cell membrane Figure 4.4: Modes of absorption of drugs from the gut.

20 DRUG ABSORPTION AND ROUTES OF ADMINISTRATION 4. drug metabolism by intestinal flora – this may affect drug absorption. Alteration of bowel flora (e.g. by concomitant use of antibiotics) can interrupt enterohepatic recycling and cause loss of efficacy of oral contraceptives (Chapter 13); 5. drug metabolism by enzymes (e.g. cytochrome P450 family 3A (CYP3A)) in the gastro-intestinal epithelium (Chapter 5); 6. drug efflux back into the gut lumen by drug transport proteins (e.g. P-glycoprotein (P-gp), ABCB1). Prolonged action and sustained-release preparations Some drugs with short elimination half-lives need to be administered frequently, at inconveniently short intervals, making adherence to the prescribed regimen difficult for the patient. A drug with similar actions, but a longer half-life, may need to be substituted. Alternatively, there are various pharmaceutical means of slowing absorption of a rapidly eliminated drug. The aim of such sustained-release preparations is to release a steady ‘infusion’ of drug into the gut lumen for absorption during transit through the small intestine. Reduced dosing frequency may improve compliance and, in the case of some drugs (e.g. carbamazepine), reduce adverse effects linked to high peak plasma concentrations. Absorption of such preparations is often incomplete, so it is especially important that bioavailability is established and substitution of one preparation for another may lead to clinical problems. Other limitations of slow-release preparations are: 1. Transit time through the small intestine is about six hours, so once daily dosing may lead to unacceptably low trough concentrations. 2. If the gut lumen is narrowed or intestinal transit is slow, as in the elderly, or due to other drugs (tricyclic antidepressants, opiates), there is a danger of high local drug concentrations causing mucosal damage. Osmosin, an osmotically released formulation of indometacin, had to be withdrawn because it caused bleeding and ulceration of the small intestine. 3. Overdose with sustained-release preparations is difficult to treat because of delayed drug absorption. 4. Sustained-release tablets should not be divided. 5. Expense. BUCCAL AND SUBLINGUAL ROUTE Drugs are administered to be retained in the mouth for local disorders of the pharynx or buccal mucosa, such as aphthous ulcers (hydrocortisone lozenges or carbenoxolone granules). Sublingual administration has distinct advantages over oral administration (i.e. the drug to be swallowed) for drugs with pronounced presystemic metabolism, providing direct and rapid access to the systemic circulation, bypassing the intestine and liver. Glyceryl trinitrate, buprenorphine and fentanyl are given sublingually for this reason. Glyceryl trinitrate is taken either as a sublingual tablet or as a spray. Sublingual administration provides short-term effects which can be terminated by swallowing the tablet. Tablets for buccal absorption provide more sustained plasma concentrations, and are held in one spot between the lip and the gum until they have dissolved. RECTAL ROUTE Drugs may be given rectally for local effects (e.g. to treat proctitis). The following advantages have been claimed for the rectal route of administration of systemically active drugs: 1. Exposure to the acidity of the gastric juice and to digestive enzymes is avoided. 2. The portal circulation is partly bypassed, reducing presystemic (first pass) metabolism. 3. For patients who are unable to swallow or who are vomiting. Rectal diazepam is useful for controlling status epilepticus in children. Metronidazole is well absorbed when administered rectally, and is less expensive than intravenous preparations. However, there are usually more reliable alternatives, and drugs that are given rectally can cause severe local irritation. SKIN Drugs are applied topically to treat skin disease (Chapter 51). Systemic absorption via the skin can cause undesirable effects, for example in the case of potent glucocorticoids, but the application of drugs to skin can also be used to achieve a systemic therapeutic effect (e.g. fentanyl patches for analgesia). The skin has evolved as an impermeable integument, so the problems of getting drugs through it are completely different from transport through an absorptive surface such as the gut. Factors affecting percutaneous drug absorption include: 1. skin condition – injury and disease; 2. age – infant skin is more permeable than adult skin; 3. region –plantar � forearm � scalp � scrotum � posterior auricular skin; 4. hydration of the stratum corneum – this is very important. Increased hydration increases permeability. Plastic-film occlusion (sometimes employed by dermatologists) increases hydration. Penetration of glucocorticosteroids is increased up to 100-fold, and systemic side effects are more common; 5. vehicle – little is known about the importance of the various substances which over the years have been empirically included in skin creams and ointments. The physical chemistry of these mixtures may be very complex and change during an application; 6. physical properties of the drug – penetration increases with increasing lipid solubility. Reduction of particle size enhances absorption, and solutions penetrate best of all; 7. surface area to which the drug is applied – this is especially important when treating infants who have a relatively large surface area to volume ratio.

  • Page 2 and 3: A Textbook of Clinical Pharmacology
  • Page 4 and 5: A Textbook of Clinical Pharmacology
  • Page 6 and 7: This fifth edition is dedicated to
  • Page 8 and 9: FOREWORD viii PREFACE ix ACKNOWLEDG
  • Page 10 and 11: PREFACE Clinical pharmacology is th
  • Page 12 and 13: PART I GENERAL PRINCIPLES
  • Page 14 and 15: ● Use of drugs 3 ● Adverse effe
  • Page 16 and 17: and acquired factors, notably disea
  • Page 18 and 19: 100 Effect (%) 0 0 5 10 1 10 100 (a
  • Page 20 and 21: Dose ratio -1 100 50 The relationsh
  • Page 22 and 23: ● Introduction 11 ● Constant-ra
  • Page 24 and 25: In reality, processes of eliminatio
  • Page 26 and 27: lood (from which samples are taken
  • Page 28 and 29: ● Introduction 17 ● Bioavailabi
  • 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
  • Page 52 and 53: ● Introduction 41 ● Role of dru
  • 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 78 and 79: 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

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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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