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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

● Introduction 11 ●

● Introduction 11 ● Constant-rate infusion 11 ● Single-bolus dose 12 ● Repeated (multiple) dosing 13 INTRODUCTION CHAPTER 3 PHARMACOKINETICS Pharmacokinetics is the study of drug absorption, distribution, metabolism and excretion (ADME) – ‘what the body does to the drug’. Understanding pharmacokinetic principles, combined with specific information regarding an individual drug and patient, underlies the individualized optimal use of the drug (e.g. choice of drug, route of administration, dose and dosing interval). Pharmacokinetic modelling is based on drastically simplifying assumptions; but even so, it can be mathematically cumbersome, sadly rendering this important area unintelligible to many clinicians. In this chapter, we introduce the basic concepts by considering three clinical dosing situations: • constant-rate intravenous infusion; • bolus-dose injection; • repeated dosing. Bulk flow in the bloodstream is rapid, as is diffusion over short distances after drugs have penetrated phospholipid membranes, so the rate-limiting step in drug distribution is usually penetration of these membrane barriers. Permeability is determined mainly by the lipid solubility of the drug, polar watersoluble drugs being transferred slowly, whereas lipid-soluble, non-polar drugs diffuse rapidly across lipid-rich membranes. In addition, some drugs are actively transported by specific carriers. The simplest pharmacokinetic model treats the body as a well-stirred single compartment in which an administered drug distributes instantaneously, and from which it is eliminated. Many drugs are eliminated at a rate proportional to their concentration – ‘first-order’ elimination. A single (one)compartment model with first-order elimination often approximates the clinical situation surprisingly well once absorption and distribution have occurred. We start by considering this, and then describe some important deviations from it. CONSTANT-RATE INFUSION If a drug is administered intravenously via a constant-rate pump, and blood sampled from a distant vein for measurement of drug concentration, a plot of plasma concentration versus time can be constructed (Figure 3.1). The concentration rises from zero, rapidly at first and then more slowly until a plateau (representing steady state) is approached. At steady state, the rate of input of drug to the body equals the rate of elimination. The concentration at plateau is the steady-state concentration (C SS). This depends on the rate of drug infusion and on its ‘clearance’. The clearance is defined as the volume of fluid (usually plasma) from which the drug is totally eliminated (i.e. ‘cleared’) per unit time. At steady state, so ● Deviations from the one-compartment model with first-order elimination 14 ● Non-linear (‘dose-dependent’) pharmacokinetics 15 administration rate � elimination rate elimination rate � C SS � clearance clearance � administration rate/C SS [Drug] in plasma Constant infusion of drug Time → Figure 3.1: Plasma concentration of a drug during and after a constant intravenous infusion as indicated by the bar.

12 PHARMACOKINETICS Clearance is the best measure of the efficiency with which a drug is eliminated from the body, whether by renal excretion, metabolism or a combination of both. The concept will be familiar from physiology, where clearances of substances with particular properties are used as measures of physiologically important processes, including glomerular filtration rate and renal or hepatic plasma flow. For therapeutic drugs, knowing the clearance in an individual patient enables the physician to adjust the maintenance dose to achieve a desired target steady-state concentration, since required administration rate � desired C SS � clearance This is useful in drug development. It is also useful in clinical practice when therapy is guided by plasma drug concentrations. However, such situations are limited (Chapter 8). Furthermore, some chemical pathology laboratories report plasma concentrations of drugs in molar terms, whereas drug doses are usually expressed in units of mass. Consequently, one needs to know the molecular weight of the drug to calculate the rate of administration required to achieve a desired plasma concentration. When drug infusion is stopped, the plasma concentration declines towards zero. The time taken for plasma concentration to halve is the half-life (t 1/2). A one-compartment model with first-order elimination predicts an exponential decline in concentration when the infusion is discontinued, as shown in Figure 3.1. After a second half-life has elapsed, the concentration will have halved again (i.e. a 75% drop in concentration to 25% of the original concentration), and so on. The increase in drug concentration when the infusion is started is also exponential, being the inverse of the decay curve. This has a very important clinical implication, namely that t 1/2 not only determines the time-course of disappearance when administration is stopped, but also predicts the time-course of its accumulation to steady state when administration is started. Half-life is a very useful concept, as explained below. However, it is not a direct measure of drug elimination, since Key points • Pharmacokinetics deals with how drugs are handled by the body, and includes drug absorption, distribution, metabolism and excretion. • Clearance (Cl) is the volume of fluid (usually plasma) from which a drug is totally removed (by metabolism � excretion) per unit time. • During constant i.v. infusion, the plasma drug concentration rises to a steady state (C SS) determined by the administration rate (A) and clearance (C SS � A/Cl). • The rate at which C SS is approached, as well as the rate of decline in plasma concentration when infusion is stopped are determined by the half-life (t 1/2). • The volume of distribution (V d) is an apparent volume that relates dose (D) to plasma concentration (C ): it is ‘as if’ dose D mg was dissolved in V d L to give a concentration of C mg/L. • The loading dose is C p � V d where C p is the desired plasma concentration. • The maintenance dose � C SS � Cl, where C SS is the steady-state concentration. differences in t 1/2 can be caused either by differences in the efficiency of elimination (i.e. the clearance) or differences in another important parameter, the apparent volume of distribution (V d). Clearance and not t 1/2 must therefore be used when a measure of the efficiency with which a drug is eliminated is required. SINGLE-BOLUS DOSE The apparent volume of distribution (V d) defines the relationship between the mass of a bolus dose of a drug and the plasma concentration that results. V d is a multiplying factor relating the amount of drug in the body to the plasma concentration, C p (i.e. the amount of drug in the body � C p � V d). Consider a very simple physical analogy. By definition, concentration (c) is equal to mass (m) divided by volume (v): c m � v Thus if a known mass (say 300 mg) of a substance is dissolved in a beaker containing an unknown volume (v) of water, v can be estimated by measuring the concentration of substance in a sample of solution. For instance, if the concentration is 0.1 mg/mL, we would calculate that v � 3000 mL (v � m/c). This is valid unless a fraction of the substance has become adsorbed onto the surface of the beaker, in which case the solution will be less concentrated than if all of the substance had been present dissolved in the water. If 90% of the substance is adsorbed in this way, then the concentration in solution will be 0.01 mg/mL, and the volume will be correspondingly overestimated, as 30 000 mL in this example. Based on the mass of substance dissolved and the measured concentration, we might say that it is ‘as if’ the substance were dissolved in 30 L of water, whereas the real volume of water in the beaker is only 3 L. Now consider the parallel situation in which a known mass of a drug (say 300 mg) is injected intravenously into a human. Suppose that distribution within the body occurs instantaneously before any drug is eliminated, and that blood is sampled and the concentration of drug measured in the plasma is 0.1 mg/mL. We could infer that it is as if the drug has distributed in 3 L, and we would say that this is the apparent volume of distribution. If the measured plasma concentration was 0.01 mg/mL, we would say that the apparent volume of distribution was 30 L, and if the measured concentration was 0.001 mg/mL, the apparent volume of distribution would be 300 L. What does V d mean? From these examples it is obvious that it is not necessarily the real volume of a body compartment, since it may be greater than the volume of the whole body. At the lower end, V d is limited by the plasma volume (approximately 3 L in an adult). This is the smallest volume in which a drug could distribute following intravenous injection, but there is no theoretical upper limit on V d, with very large values occurring when very little of the injected dose remains in the plasma, most being taken up into fat or bound to tissues.

  • 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 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 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
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    FURTHER READING Dhesi JK, Allain TJ

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    Factors involved in the aetiology o

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    analgesic. Following its release, t

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    antibiotics, such as penicillin or

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    predisposes to non-immune haemolysi

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    ● Introduction 71 ● Useful inte

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    Response Therapeutic range Toxic ra

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    Table 13.1: Interactions outside th

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    Table 13.5: Competitive interaction

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    ● Introduction: ‘personalized m

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    Table 14.2: Variations in drug resp

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    lipoprotein (LDL) is impaired. LDL

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    Key points • Genetic differences

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    • Discovery • • Screening Pre

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    Too many statistical comparisons pe

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    ETHICS COMMITTEES Protocols for all

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    Table 16.1: Recombinant proteins/en

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    duration and benefit. Adenoviral ve

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    ● Introduction 97 ● Garlic 97

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    A case report has suggested a possi

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    including hypericin and pseudohyper

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    PART II THE NERVOUS SYSTEM

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    ● Introduction 105 ● Sleep diff

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    and daytime sleeping should be disc

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    Key points • Insomnia and anxiety

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    Box 19.1: Dopamine theory of schizo

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    The Boston Collaborative Survey ind

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    Oral medication, especially in liqu

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    e.g. interpersonal difficulties or

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    Partial response to first-line trea

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    Key points Drug treatment of depres

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    Case history A 45-year-old man with

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    Levodopa PRINCIPLES OF TREATMENT IN

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    • pulmonary, retroperitoneal and

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    CHOREA The γ-aminobutyric acid con

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    Cholinergic crisis Treatment of mya

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    ● Introduction 133 ● Mechanisms

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    absolute arbiter. The availability

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    Table 22.2: Metabolic interactions

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    FURTHER ANTI-EPILEPTICS Other drugs

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    Case history A 24-year-old woman wh

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    Assessment of migraine severity and

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    ● General anaesthetics 145 ● In

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    is the theoretical concern of a ‘

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    • Respiratory system - apnoea fol

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    Competitive antagonists (vecuronium

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    have also proved useful in combinat

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    ● Introduction 155 ● Pathophysi

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    ASPIRIN (ACETYLSALICYLATE) Use Anti

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    Key points Drugs for mild pain •

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    increases, correlating with the hig

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    • If possible, use oral medicatio

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    PART III THE MUSCULOSKELETAL SYSTEM

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    ● Introduction: inflammation 167

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    Chapter 33). All NSAIDs cause wheez

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    • Stomatitis suggests the possibi

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    Pharmacokinetics Allopurinol is wel

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    PART IV THE CARDIOVASCULAR SYSTEM

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    ● Introduction 177 ● Pathophysi

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    esponsible for the strong predilect

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    Ezetimibe Fat Muscle Dietary fat In

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    educed). The risk of muscle damage

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    ● Introduction 185 ● Pathophysi

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    Each of these classes of drug reduc

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    AT 1 receptor) produce good 24-hour

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    Table 28.2: Examples of calcium-cha

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    Key points Drugs used in essential

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    Case history A 72-year-old woman se

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    Assess risk factors Investigations:

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    Persistent ST segment elevation Thr

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    Mechanism of action GTN works by re

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    Because of the risks of haemorrhage

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    Intrinsic pathway XIIa XIa the acti

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    that the pharmacodynamic response i

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    used with apparent benefit in acute

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    ● Introduction 211 ● Pathophysi

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    The drugs that are most effective i

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    therapeutic plasma concentration ca

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    ● Common dysrhythmias 217 ● Gen

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    BASIC LIFE SUPPORT CARDIOPULMONARY

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    arrest. The electrocardiogram is li

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    should be given to insertion of an

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    Drug interactions Amiodarone potent

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    effect when treating sinus bradycar

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    Case history A 24-year-old medical

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    PART V THE RESPIRATORY SYSTEM

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    CHAPTER 33 THERAPY OF ASTHMA, CHRON

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    STEP 5: CONTINUOUS OR FREQUENT USE

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    Adenylyl cyclase Table 33.1: Compar

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    Drug interactions Although synergis

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    use in asthma has declined consider

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    α 1-antitrypsin deficiency, neutro

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    PART VI THE ALIMENTARY SYSTEM

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    ● Peptic ulceration 247 ● Oesop

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    PEPTIC ULCERATION 249 • With rega

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    Ranitidine has a similar profile of

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    Vestibular stimulation ? via cerebe

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    cortical centres affecting vomiting

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    • in hepatocellular failure to re

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    Ciprofloxacin is occasionally used

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    withdrawal), small doses of benzodi

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    Table 34.7: Dose-independent hepato

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    ● Introduction 265 ● General ph

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    dinucleotide (NAD) and nicotinamide

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    Table 35.1: Common trace element de

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    PART VII FLUIDS AND ELECTROLYTES

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    ● Introduction 273 ● Volume ove

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    Key points Diuretics Diuretics are

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    is sometimes caused by drugs, notab

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    or with potassium-sparing diuretics

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    Greger R, Lang F, Sebekova, Heidlan

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    PART VIII THE ENDOCRINE SYSTEM

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    ● Introduction 285 ● Pathophysi

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    in prefilled injection devices (‘

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    Metformin should be withdrawn and i

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    FURTHER READING American Diabetes A

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    deficiency. Potassium iodide (3 mg

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    fertility. It is contraindicated du

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    ● Introduction 297 ● Vitamin D

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    effective in life-threatening hyper

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    Further reading Block GA, Martin KJ

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    Table 40.1: Actions of cortisol and

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    injection may be useful, but if don

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    CHAPTER 41 REPRODUCTIVE ENDOCRINOLO

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    elease by the pituitary via negativ

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    Treatment with depot progestogen in

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    infusion using an infusion pump to

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    significant proportion of men who r

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    with symptoms caused by the release

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    FURTHER READING Birnbaumer M. Vasop

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    PART IX SELECTIVE TOXICITY

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    ● Principles of antibacterial che

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    2. transfer of resistance between o

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    Pharmacokinetics Absorption of thes

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    Mechanism of action Macrolides bind

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    asic quinolone structure dramatical

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    Case history A 70-year-old man with

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    PRINCIPLES OF MANAGEMENT OF MYCOBAC

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    Pharmacokinetics Absorption from th

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    MYCOBACTERIUM LEPRAE INFECTION Lepr

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    POLYENES AMPHOTERICIN B Uses Amphot

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    therapy is adequate though more fre

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    NUCLEOSIDE ANALOGUES ACICLOVIR Uses

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    Table 45.3: Summary of available ac

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    Uses Interferon-α when combined wi

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    ● Introduction 351 ● Immunopath

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    Table 46.1: Examples of combination

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    NON-NUCLEOSIDE ANALOGUE REVERSE TRA

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    FUSION INHIBITORS Uses Currently, e

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    salvage therapy include azithromyci

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    ● Malaria 361 ● Trypanosomal in

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    Pharmacokinetics Chloroquine is rap

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    Table 47.2: Drug therapy of non-mal

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    ● Introduction 367 ● Pathophysi

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    Table 48.1: Classification of commo

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

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    doses are used to prepare patients

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    Adverse effects Methotrexate Inhibi

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    Table 48.7: Summary of clinical pha

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    Table 48.9: Summary of the clinical

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    Plasma membrane Signal transduction

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    Table 48.10: Monoclonal antibodies

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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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