Effects of obesity on pharmacokinetics - Implications for drug therapy

Obesity is a worldwide problem, with major health, social and economic impl ications, The adaptation of drug dosages to obese patients is a subject of concern, particularly for drugs with a narrow therapeutic index. The main f actors that affect the tissue distribution of drugs an body composition, re gional blood flow and the affinity of the drug for plasma proteins and/or t issue components. Obese people have larger absolute lean body masses as well as fat masses th an non-obese individuals of the same age, gender and height. However, the p ercentage of fat per kg of total bodyweight (TBW) is markedly increased, wh ereas that of lean tissue is reduced. Cardiac performance and adipose tissu e blood flow may be altered in obesity, There is uncertainty about the bind ing of drugs to plasma proteins in obese patients. Some data suggest that t he activities of hepatic cytochrome P450 isoforms are altered, but no clear overview of drug hepatic metabolism in obesity is currently available. Pha rmacokinetic studies provide differing data on renal function in obese pati ents. This review analyses recent publications on several classes of drugs: antib acterials. anticancer drugs, psychotropic drugs, anticonvulsants, general a naesthetics, opioid analgesics, neuromuscular blockers, beta-blockers and d rugs commonly used in the management of obesity. Pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate Lipophi licity (e.g. lithium and vecuronium) is generally rather predictable, as th ese drugs are distributed mainly in lean tissues. The dosage of these drugs should be based on the ideal bodyweight (IBW). However, some of these drug s (e.g. antibacterials and some anticancer drugs) are partly distributed in adipose tissues, and their dosage is based on IBW plus a percentage of the patient's excess bodyweight. There is no systematic relationship between the degree of lipophilicity of markedly lipophilic drugs (e.g. remifentanil and some beta-blockers) and th eir distribution in obese individuals. The distribution of a drug between f at and lean tissues may influence its pharmacokinetics in obese patients. T hus, the loading dose should be adjusted to the TBW or IBW, according to da ta from studies carried out in obese individuals. Adjustment of the mainten ance dosage depends on the observed modifications in clearance. Our present knowledge of the influence of obesity on drug pharmacokinetics is limited. Drugs with a small therapeutic index should be used prudently a nd the dosage adjusted with the help of drug plasma concentrations.