The impact of obesity on the pharmacology of medications used for cardiovascular risk factor control.

Most drugs are currently dosed empirically (fixed-dose) or based on total body weight. In obese patients, these dosing strategies might, in theory, lead to inadequate clinical effect (empiric dosing) or toxicity (weight-based dosing). Our objective was to first review body size descriptors used for drug dosing and then to examine the effect of obesity on the pharmacokinetics and pharmacodynamics of drugs used for cardiovascular risk reduction (antihypertensive agents, statins, aspirin, antidiabetic agents). We found a limited number of published studies for most drug classes. For β-blockers, volume of distribution was increased in the obese and this appears to be primarily due to greater distribution into lean tissue. In contrast, clearance was decreased, unchanged or increased, depending on the agent. This suggests that loading doses should be based on lean body weight and maintenance doses adjusted in a drug-specific fashion according to clearance alterations. For antidiabetic agents, glucose-lowering effects were slightly diminished in most studies in obese patients. Outside of these findings, in the studies reported to date, obesity did not exert a consistent, clinically important effect on drug pharmacology. Because obesity can cause drug-specific pharmacological changes for some drug classes (e.g., β-blockers), there is a need to conduct further studies. To avoid detecting pharmacokinetic changes that are ultimately deemed clinically inconsequential, we suggest a "top down" approach in which clinically important outcomes are compared between obese and nonobese subjects. If important differences are found, further studies should be then performed to delineate underlying pharmacological mechanisms and inform the need for dose adjustment.