Pharmacokinetic-pharmacodynamic relationships for benzodiazepines.

This article reviews the literature on the plasma concentration-effect relationships for benzodiazepines, in humans and in experimental animals. Only literature that explicitly links pharmacokinetics to pharmacodynamics is included. The following questions are evaluated. Can concentration-effect relationships be demonstrated? If so, are these relations stable? Are the influences of specific factors such as age and disease on these relationships established? It is clear that, when studies are conducted and interpreted appropriately, relations can be found for a wide range of benzodiazepine effects. These include objective measures such as electroencephalography, semisubjective measures such as psychomotor performance, and subjective measures such as mood/sedation scales. A generally applicable model of the relationship which will allow prediction of effect is, however, not yet established. The relationship appears to be dependent on route and rate of administration, because of factors such as distributional delay, formation of active metabolites and, probably, acute tolerance. Furthermore, intra- and interindividual variability is considerable, probably due to varying experimental conditions and intrinsic interindividual differences. The limited data available on factors influencing the plasma concentration-effect relationships for benzodiazepines demonstrate clear changes in the pharmacodynamics after multiple doses, suggesting the development of tolerance, and a subsensitivity in patients with panic disorder. The influence of factors such as age, disease and drug interactions on the pharmacokinetic-pharmacodynamic relationship remains less clear.