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# A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

## In reality, processes

In reality, processes of elimination begin as soon as the bolus dose (d) of drug is administered, the drug being cleared at a rate Cl s (total systemic clearance). In practice, blood is sampled at intervals starting shortly after administration of the dose. Cl s is determined from a plot of plasma concentration vs. time by measuring the area under the plasma concentration vs. time curve (AUC). (This is estimated mathematically using a method called the trapezoidal rule – important in drug development, but not in clinical practice.) Cl If the one-compartment, first-order elimination model holds, there is an exponential decline in plasma drug concentration, just as at the end of the constant rate infusion (Figure 3.2a). If the data are plotted on semi-logarithmic graph paper, with time on the abscissa, this yields a straight line with a negative slope (Figure 3.2b). Extrapolation back to zero time gives the concentration (c 0) that would have occurred at time zero, and this is used to calculate V d: V Half-life can be read off the graph as the time between any point (c 1) and the point at which the concentration c 2 has decreased by 50%, i.e. c 1/c 2 � 2. The slope of the line is the elimination rate constant, k el: k t 1/2 and k el are related as follows: t [Drug] in plasma (a) Time (b) Time Figure 3.2: One-compartment model. Plasma concentration–time curve following a bolus dose of drug plotted (a) arithmetically and (b) semi-logarithmically. This drug fits a one-compartment model, i.e. its concentration falls exponentially with time. d � el s 1/ 2 d � AUC d c 0 Cl � V s d ln 2 0 693 � � k k . el el V d is related partly to characteristics of the drug (e.g. lipid solubility) and partly to patient characteristics (e.g. body size, Log [Drug] in plasma plasma protein concentration, body water and fat content). In general, highly lipid-soluble compounds that are able to penetrate cells and fatty tissues have a larger V d than more polar water-soluble compounds. V d determines the peak plasma concentration after a bolus dose, so factors that influence V d, such as body mass, need to be taken into account when deciding on dose (e.g. by expressing dose per kg body weight). Body composition varies from the usual adult values in infants or the elderly, and this also needs to be taken into account in dosing such patients (see Chapters 10 and 11). V d identifies the peak plasma concentration expected following a bolus dose. It is also useful to know V d when considering dialysis as a means of accelerating drug elimination in poisoned patients (Chapter 54). Drugs with a large V d (e.g. many tricyclic antidepressants) are not removed efficiently by haemodialysis because only a small fraction of the total drug in the body is present in plasma, which is the fluid compartment accessible to the artificial kidney. If both V d and t 1/2 are known, they can be used to estimate the systemic clearance of the drug using the expression: Cl s V �0693 . � t d 1/ 2 REPEATED (MULTIPLE) DOSING 13 Note that clearance has units of volume/unit time (e.g. mL/min), V d has units of volume (e.g. mL or L ), t 1/2 has units of time (e.g. minutes) and 0.693 is a constant arising because ln �(0.5) � ln 2 � 0.693. This expression relates clearance to V d and t 1/2, but unlike the steady-state situation referred to above during constant-rate infusion, or using the AUC method following a bolus, it applies only when a single-compartment model with first-order elimination kinetics is applicable. Key points • The ‘one-compartment’ model treats the body as a single, well-stirred compartment. Immediately following a bolus dose D, the plasma concentration rises to a peak (C 0) theoretically equal to D/V d and then declines exponentially. • The rate constant of this process (k el) is given by Cl/V d. k el is inversely related to t 1/2, which is given by 0.693/k el. Thus, Cl � 0.693 � V d/t 1/2. • Repeated bolus dosing gives rise to accumulation similar to that observed with constant-rate infusion, but with oscillations in plasma concentration rather than a smooth rise. The size of the oscillations is determined by the dose interval and by t 1/2. The steady state concentration is approached (87.5%) after three half-lives have elapsed. REPEATED (MULTIPLE) DOSING If repeated doses are administered at dosing intervals much greater than the drug’s elimination half-life, little if any accumulation occurs (Figure 3.3a). Drugs are occasionally used in

14 PHARMACOKINETICS this way (e.g. penicillin to treat a mild infection), but a steady state concentration greater than some threshold value is often needed to produce a consistent effect throughout the dose interval. Figure 3.3b shows the plasma concentration–time curve when a bolus is administered repeatedly at an interval less than t 1/2. The mean concentration rises toward a plateau, as if the drug were being administered by constant-rate infusion. That is, after one half-life the mean concentration is 50% of the plateau (steady-state) concentration, after two half-lives it is 75%, after three half-lives it is 87.5%, and after four half-lives it is 93.75%. However, unlike the constant-rate infusion situation, the actual plasma concentration at any time swings above or below the mean level. Increasing the dosing frequency smoothes out the peaks and troughs between doses, while decreasing the frequency has the opposite effect. If the peaks are too high, toxicity may result, while if the troughs are too low there may be a loss of efficacy. If a drug is administered once every half-life, the peak plasma concentration (C max) will be double the trough concentration (C min). In practice, this amount of variation is tolerable in many therapeutic situations, so a dosing interval approximately equal to the half-life is often acceptable. Knowing the half-life alerts the prescriber to the likely time-course over which a drug will accumulate to steady state. Drug clearance, especially renal clearance, declines with age (see Chapter 11). A further pitfall is that several drugs have active metabolites that are eliminated more slowly than [Drug] in plasma (a) [Drug] in plasma (b) Time Figure 3.3: Repeated bolus dose injections (at arrows) at (a) intervals much greater than t 1/2 and (b) intervals less than t 1/2. the parent drug. This is the case with several of the benzodiazepines (Chapter 18), which have active metabolites with half-lives of many days. Consequently, adverse effects (e.g. confusion) may appear only when the steady state is approached after several weeks of treatment. Such delayed effects may incorrectly be ascribed to cognitive decline associated with ageing, but resolve when the drug is stopped. Knowing the half-life helps a prescriber to decide whether or not to initiate treatment with a loading dose. Consider digoxin (half-life approximately 40 hours). This is usually prescribed once daily, resulting in a less than two-fold variation in maximum and minimum plasma concentrations, and reaching �90% of the mean steady-state concentration in approximately one week (i.e. four half-lives). In many clinical situations, such a time-course is acceptable. In more urgent situations a more rapid response can be achieved by using a loading dose. The loading dose (LD) can be estimated by multiplying the desired concentration by the volume of distribution (LD � C p � V d). DEVIATIONS FROM THE ONE-COMPARTMENT MODEL WITH FIRST-ORDER ELIMINATION TWO-COMPARTMENT MODEL Following an intravenous bolus a biphasic decline in plasma concentration is often observed (Figure 3.4), rather than a simple exponential decline. The two-compartment model (Figure 3.5) is appropriate in this situation. This treats the body as a smaller central plus a larger peripheral compartment. Again, these compartments have no precise anatomical meaning, although the central compartment is assumed to consist of Plasma concentration (log scale) 60 50 40 30 20 Mainly distribution � some elimination Mainly elimination � some distribution (kinetic homogeneity attained) 10 0 1 2 3 4 5 Time, t 6 7 8 9 10 Figure 3.4: Two-compartment model. Plasma concentration–time curve (semi-logarithmic) following a bolus dose of a drug that fits a two-compartment model.

• 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 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
• Page 72 and 73: 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

• Page 308 and 309:

● Introduction 297 ● Vitamin D

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effective in life-threatening hyper

• Page 312 and 313:

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

• Page 474 and 475:

puberty (male), delay 314 puerperiu

• Page 476:

tolerance 9, 433 benzodiazepines 10

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