Electroencephalographic effects of thiopentone and its enantiomers in the rat

Abstract

Electrophysiological studies with some chiral barbiturates have shown that one enantiomer can be excitant while the other is depressant. Thiopentone, a chiral barbiturate, has both differences in potency between enantiomers and biphasic effects on the electroencephalogram (EEG). This study investigated whether a differential EEG activity between the enantiomers of thiopentone could account for the biphasic effects. Rats were administered me-, R- or S-thiopentone to determine the nature and time course of quantitative EEG effects. Two studies using computer-controlled i.v. Infusions of the three drugs were performed in groups of animals previously prepared with EEG electrodes and/or arterial blood sampling cannulae. Study 1 used several stepwise increments in plasma drug concentration over 35 min, followed by washout. Study 2 used a 4 min period of constant plasma drug concentration, followed by washout. In both studies, both enantiomers and racemate caused an initial EEG activation followed by deactivation. Quantitative enantioselectivity was found for depression. The extent of depression was significantly less for R-thiopentone (P = 0.008) and racthiopentone (P = 0.038) than for S-thiopentone; recovery from depression appeared to be faster for R-thiopentone than either rac- or S-thiopentone. Fatality was only found with S-thiopentone ( 3 7 animals in Study 2). R-thiopentone plasma concentrations were ~8% less than those of S-thiopentone in rats treated with rac-thiopentone. Although small differences in clearance between enantiomers were found that may influence recovery, they were not large enough to account for the reported differences in potency between the two enantiomers.