Pharmacodynamic interactions of hypnotic and opioid agents : analysis by response-surface methodology and influence of age and gender.

This research project introduces a new method for quantification of pharmacodynamic interactions between hypnotic and opioid agants. With the concept of concentration-effect-surfaces, the interaction between two drugs is determined for the whole domain of pharmacodynamic effect using a sigmoid Emax model. The drugs are administered with computer-driven infusion pumps to maintain constant concentrations of each drug in the biophase. The biophase concentrations used to model the concentration-response surfaces are derived from the measured plasma concentrations of the drugs using the NONMEM pharmacokinetic analysis technique. As a measure of clinical effect we will use the EEG with bispectral analysis which gives a higher resolution for the measurement of the cerebral effects of the drugs. The modelling of the concentration-effect surfaces will permit characterising interactions of two drugs at 90 and 95% probability level of drug effect. Moreover, we will correlate the relation between EEG effects and analgesic and hypnotic end-points. This project will also analyse the effect of age as contributing to the variability of pharmacodynamic interactions of drugs affecting the central nervous system.