The relationship between the myocardial kinetics of meperidine and its effect on myocardial contractility: Model independent analysis and optimal regional model

The myocardial kinetics of meperidine and the relationship between these ki netics and the effect of meperidine on myocardial contractility (maximum po sitive rate of change of left ventricular pressure) were examined by analys is of previously published data collected in sheep after the i.v. injection of 100 mg of meperidine over 1 s. There was significant hysteresis between reductions In myocardial contractility and the arterial concentrations of meperidine, but not the coronary sinus blood (effluent from the heart) or c alculated myocardial concentrations. The peak reduction in contractility oc curred after the peak arterial concentration, at the time of the peak myoca rdial concentration, but before the peak coronary sinus concentration, sugg esting that the site of drug action in the heart was not in equilibrium wit h either arterial blood or effluent blood from the heart. The most appropri ate form of a dynamic model (a linear model with a threshold) was determine d, without the need to assume a kinetic model, by directly fitting the obse rved reductions in myocardial contractility to the calculated myocardial co ncentrations. To determine the optimal kinetic and combined kinetic-dynamic models, a variety of one-, two-, and three-compartment models of the myoca rdium were fitted to the coronary sinus concentrations by using hybrid mode ling. These included "tank in series" models that accounted well for drug d ispersion and "peripheral compartment" models that accounted well for deep distribution. The most appropriate model was a "compilation" model, which i ncorporated features of both these; extremes and was a better fit to the ob served data than either a traditional single flow-limited compartment or a traditional membrane-limited model.