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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

● Introduction 17 ●

● Introduction 17 ● Bioavailability, bioequivalence and generic vs. proprietary prescribing 17 CHAPTER 4 DRUG ABSORPTION AND ROUTES OF ADMINISTRATION INTRODUCTION Drug absorption, and hence the routes by which a particular drug may usefully be administered, is determined by the rate and extent of penetration of biological phospholipid membranes. These are permeable to lipid-soluble drugs, whilst presenting a barrier to more water-soluble drugs. The most convenient route of drug administration is usually by mouth, and absorption processes in the gastro-intestinal tract are among the best understood. BIOAVAILABILITY, BIOEQUIVALENCE AND GENERIC VS. PROPRIETARY PRESCRIBING Drugs must enter the circulation if they are to exert a systemic effect. Unless administered intravenously, most drugs are absorbed incompletely (Figure 4.1). There are three reasons for this: 1. the drug is inactivated within the gut lumen by gastric acid, digestive enzymes or bacteria; 2. absorption is incomplete; and 3. presystemic (‘first-pass’) metabolism occurs in the gut wall and liver. Together, these processes explain why the bioavailability of an orally administered drug is typically less than 100%. Bioavailability of a drug formulation can be measured experimentally (Figure 4.2) by measuring concentration vs. time curves following administration of the preparation via its intended route (e.g. orally) and of the same dose given intravenously (i.v.). Bioavailability � AUCoral/AUCi.v. � 100% Many factors in the manufacture of the drug formulation influence its disintegration, dispersion and dissolution in the gastrointestinal tract. Pharmaceutical factors are therefore important in determining bioavailability. It is important to distinguish ● Prodrugs 18 ● Routes of administration 19 Inactivation in liver Systemic circulation Portal blood Inactivation in gut wall Oral administration Inactivation in stomach Inactivation in gut lumen Incomplete absorption Figure 4.1: Drug bioavailability following oral administration may be incomplete for several reasons. statistically significant from clinically important differences in this regard. The former are common, whereas the latter are not. However, differences in bioavailability did account for an epidemic of phenytoin intoxication in Australia in 1968–69. Affected patients were found to be taking one brand of phenytoin: the excipient had been changed from calcium sulphate to lactose, increasing phenytoin bioavailability and thereby precipitating toxicity. An apparently minor change in the manufacturing process of digoxin in the UK resulted in reduced potency due to poor bioavailability. Restoring the original manufacturing conditions restored potency but led to some confusion, with both toxicity and underdosing. These examples raise the question of whether prescribing should be by generic name or by proprietary (brand) name. When a new preparation is marketed, it has a proprietary name

18 DRUG ABSORPTION AND ROUTES OF ADMINISTRATION 10 [Drug] in plasma 100 i.v.dosing Oral dosing 1 Time→ Figure 4.2: Oral vs. intravenous dosing: plasma concentration–time curves following administration of a drug i.v. or by mouth (oral). supplied by the pharmaceutical company, and a non-proprietary (generic) name. It is usually available only from the company that introduced it until the patent expires. After this, other companies can manufacture and market the product, sometimes under its generic name. At this time, pharmacists usually shop around for the best buy. If a hospital doctor prescribes by proprietary name, the same drug produced by another company may be substituted. This saves considerable amounts of money. The attractions of generic prescribing in terms of minimizing costs are therefore obvious, but there are counterarguments, the strongest of which relates to the bioequivalence or otherwise of the proprietary product with its generic competitors. The formulation of a drug (i.e. excipients, etc.) differs between different manufacturers’ products of the same drug, sometimes affecting bioavailability. This is a particular concern with slow-release or sustained-release preparations, or preparations to be administered by different routes. Drug regulatory bodies have strict criteria to assess whether such products can be licensed without the full dataset that would be required for a completely new product (i.e. one based on a new chemical entity). It should be noted that the absolute bioavailability of two preparations may be the same (i.e. the same AUC), but that the kinetics may be very different (e.g. one may have a much higher peak plasma concentration than the other, but a shorter duration). The rate at which a drug enters the body determines the onset of its pharmacological action, and also influences the intensity and sometimes the duration of its action, and is important in addition to the completeness of absorption. Prescribers need to be confident that different preparations (brand named or generic) are sufficiently similar for their substitution to be unlikely to lead to clinically important alterations in therapeutic outcome. Regulatory authorities have responded to this need by requiring companies who are seeking to introduce generic equivalents to present evidence that their product behaves similarly to the innovator product that is already marketed. If evidence is presented that a new generic product can be treated as therapeutically equivalent to the current ‘market leader’, this is accepted as ‘bioequivalence’. This does not imply that all possible pharmacokinetic parameters are identical between the two products, but that any such differences are unlikely to be clinically important. It is impossible to give a universal answer to the generic vs. proprietary issue. However, substitution of generic for brandname products seldom causes obvious problems, and exceptions (e.g. different formulations of the calcium antagonist diltiazem, see Chapter 29) are easily flagged up in formularies. Key points • Drugs must cross phospholipid membranes to reach the systemic circulation, unless they are administered intravenously. This is determined by the lipid solubility of the drug and the area of membrane available for absorption, which is very large in the case of the ileum, because of the villi and microvilli. Sometimes polar drugs can be absorbed via specific transport processes (carriers). • Even if absorption is complete, not all of the dose may reach the systemic circulation if the drug is metabolized by the epithelium of the intestine, or transported back into lumen of the intestine or metabolized in the liver, which can extract drug from the portal blood before it reaches the systemic circulation via the hepatic vein. This is called presystemic (or ‘first-pass’) metabolism. • ‘Bioavailability’ describes the completeness of absorption into the systemic circulation. The amount of drug absorbed is determined by measuring the plasma concentration at intervals after dosing and integrating by estimating the area under the plasma concentration/time curve (AUC). This AUC is expressed as a percentage of the AUC when the drug is administered intravenously (100% absorption). Zero per cent bioavailability implies that no drug enters the systemic circulation, whereas 100% bioavailability means that all of the dose is absorbed into the systemic circulation. Bioavailability may vary not only between different drugs and different pharmaceutical formulations of the same drug, but also from one individual to another, depending on factors such as dose, whether the dose is taken on an empty stomach, and the presence of gastro-intestinal disease, or other drugs. • The rate of absorption is also important (as well as the completeness), and is expressed as the time to peak plasma concentration (T max). Sometimes it is desirable to formulate drugs in slow-release preparations to permit once daily dosing and/or to avoid transient adverse effects corresponding to peak plasma concentrations. Substitution of one such preparation for another may give rise to clinical problems unless the preparations are ‘bioequivalent’. Regulatory authorities therefore require evidence of bioequivalence before licensing generic versions of existing products. • Prodrugs are metabolized to pharmacologically active products. They provide an approach to improving absorption and distribution. PRODRUGS One approach to improving absorption or distribution to a relatively inaccessible tissue (e.g. brain) is to modify the drug molecule chemically to form a compound that is better absorbed and from which active drug is liberated after absorption. Such modified drugs are termed prodrugs (Figure 4.3). Examples are shown in Table 4.1.

  • 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 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
  • 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
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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

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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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