Myocardial Pharmacokinetics of Thiopental in Sheep after Short-Term Administration: Relationship to Thiopental-Induced Reductions in Myocardial Contractility

Abstract

The myocardial kinetics and dynamics of thiopental (750mg over 2 min) were examined in chronically instrumented sheep (five studies in four sheep). The myocardial kinetics were studied by simultaneous rapid sampling of arterial and coronary sinus blood for 30min. The myocardial kinetics for four of the five studies were best described by a single flow-limited compartment with apparent volumes of between 42 and 113mL. These volumes equated to half-lives of equilibration between blood and myocardium of between 0.49 and 1.00min when baseline blood flow was taken into account. The remaining study was better described by a model with a slight membrane limitation (permeability/flow ratio of approximately 2). Myocardial contractility was studied as a measure of myocardial pharmacodynamics and was reduced to 53% of baseline at approximately 2.5min after the start of the dose. Effect compartment analysis showed that there was hysteresis between the time course of these contractility changes and the time course of the arterial concentrations, with effect compartment half-lives between 0.08 and 0.87min. There was significantly less hysteresis for the coronary sinus concentrations. It is concluded that thiopental equilibrated rapidly with a component of the myocardium, and that consequently its effects on myocardial contractility also rapidly equilibrated with both afferent and effluent myocardial blood.