Factors Affecting Drug Action

The same dose of the same drug can produce very different plasma concentrations and clinical effects in different patients. This review explains why, using a pharmacokinetic and pharmacodynamic framework in which four patient factors (age, sex, genetics and disease) modify absorption, distribution, metabolism, excretion and the response of the target tissue. Four quantities underlie almost every dosing adjustment: bioavailability, volume of distribution, clearance and half-life. Age changes drug handling at both ends of life: neonates have immature clearance and a large water volume, children often clear drugs faster per kilogram, and older adults have reduced renal and hepatic clearance, more body fat and greater central nervous system sensitivity. Sex-related differences arise mainly from body size and composition, renal clearance, QTc interval and pregnancy. Genetic variation in metabolising enzymes, transporters and HLA genes explains severe, avoidable reactions and failures of prodrug activation. Disease of the kidney, liver, heart, gut and thyroid, as well as inflammation, alters clearance and protein binding, often within days. The review closes with a practical approach to dose individualisation, three worked cases and a discussion of the limits of the evidence.