Environmental and host influences

body weight- or surface area-related daily doses are the same for all ages.

Dosage in the young. No single rule or formula suffices for all cases. The dose may be established by scaling for body weight but this approach may overdose an obese child, for whom the ideal weight should calculated from age and height. Doses based on body surface area are generally more accurate, and preferably should take into account both body weight and height.33 The fact that the surface area of a 70 kg adult human is 1.8m2 (see p. 118) may then be used for adjustment, as follows:

Approximate dose = surface area of child (m2) / 1.8 x adult dose

Information is increased by making pharmacokinetic and pharmacodynamic measurements when opportunities present. General guidance is available from formularies, e.g. the British National Formulary, and specialist publications.34

The elderly

The incidence of adverse drug reactions rises with age in the adult, especially after 65 years because of:

• The increasing number of drugs that they need to take because they tend to have multiple diseases

• Poor compliance with dosing regimens

• Bodily changes of aging that require modification of dosage regimens.

Absorption of drugs may be slightly slower because gastrointestinal blood flow and motility are reduced but the effect is rarely important.

Distribution is influenced by the following changes:

• There is a significant decrease in lean body mass so that standard adult doses provide a greater amount of drug per kg.

• Total body water is less and in general the distribution volume of water-soluble drugs is

33 For example: Insley J 1996 A Paediatric Vade-Mecum, 13th Edition, London, Arnold.

34 Royal College of Paediatrics and Child Health, Neonatal and Paediatric Pharmacists Group. Pocket Medicines for Children. 2001, London.

reduced. Hence standard doses of drugs, especially the priming doses of those that are water-soluble, may exceed the requirement.

• Plasma albumin concentration tends to be well maintained in the healthy elderly but may be reduced by chronic disease, giving scope for a greater proportion of unbound (free) drug; this may be important when priming doses are given.

Metabolism is reduced because liver mass and liver blood flow are decreased. Consequently:

• Metabolic inactivation of drugs is slower.

• Drugs that are normally extensively eliminated in first-pass through the liver appear in higher concentration in the systemic circulation and persist in it for longer. There is thus particular cause initially to use lower doses of most neuroleptics, tricyclic antidepressants and cardiac antiarrhythmic agents.

• Capacity for hepatic enzyme induction appears to be lessened.

Elimination. Renal blood flow, glomerular filtration and tubular secretion decrease with age above 55 years, a decline that is not signalled by raised serum creatinine concentration because production of this metabolite is diminished by the age-associated diminution of muscle mass. Indeed, in the elderly, serum creatinine may be within the concentration range for normal young adults even when the creatinine clearance is 50 ml/min (compared to 127 ml/min in adult male). Particular risk of adverse effects arises with drugs that are eliminated mainly by the kidney and that have a small therapeutic ratio, e.g. aminoglycosides, chlorpropamide, digoxin, lithium.

Pharmacodynamic response may alter with age, to produce either a greater or lesser effect than is anticipated in younger adults, for example:

• Drugs that act on the central nervous system appear to produce an exaggerated response in relation to that expected from the plasma concentration, and sedatives and hypnotics may have a pronounced hangover effect. These drugs are also more likely to depress respiration because vital capacity and maximum breathing capacity are lessened in the elderly.

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