Influence of Hypovolemia on the Pharmacokinetics and the Electroencephalographic Effect of Etomidate in the Rat

• Published in: The Journal of pharmacology and experimental therapeutics 1999-09, Vol.290 (3), p.1048-1053
• Main Authors: De Paepe, P, Belpaire, F M, Van Hoey, G, Boon, P A, Buylaert, W A
• Format: Article
• Language: English
• Subjects: Anesthetics, Intravenous - pharmacokinetics; Anesthetics, Intravenous - pharmacology; Animals; Blood Pressure - drug effects; Blood Volume - physiology; Body Temperature - physiology; Disease Models, Animal; Dose-Response Relationship, Drug; Electroencephalography - drug effects; Etomidate - pharmacokinetics; Etomidate - pharmacology; Heart Rate - drug effects; Hypnotics and Sedatives - pharmacokinetics; Hypnotics and Sedatives - pharmacology; Male; Random Allocation; Rats; Rats, Wistar; Shock - physiopathology
• ISSN: 0022-3565; 1521-0103

The influence of hypovolemia (removal of 30% of the blood volume) on the pharmacokinetics and pharmacodynamics of etomidate was investigated in the rat. Chronically instrumented animals were randomly allocated to either a control ( n = 9) or a hypovolemia ( n = 9) group, and etomidate was infused (50 mg/kg/h) until isoelectric periods of 5 s or longer were observed in the electroencephalogram. The changes observed in the electroencephalogram were quantified using aperiodic analysis in the 2.5- to 7.5-Hz frequency band and used as a surrogate measure of hypnosis. The righting reflex was used as a clinical measure of hypnosis. The etomidate dose that had to be infused to reach the electroencephalographic endpoint was almost 40% lower ( p < .01) in the hypovolemic animals than in the control animals. This difference could be attributed to a decrease in clearance (−20%; p = .06) and distribution volume (−30%; p < .01) of etomidate. Protein binding was similar in both groups. To investigate changes in end organ sensitivity during hypovolemia, the electroencephalographic effect-versus-effect-site concentration relationship was studied. The effect-plasma concentration relationship was biphasic, exhibiting profound hysteresis in both hypovolemic and control animals. Semiparametric minimization of this hysteresis revealed similar equilibrium half-lives in both groups, and the biphasic effect-concentration relationship was characterized nonparametrically by descriptors. With these descriptors, a slightly increased potency of etomidate during hemorrhage was observed. The concentration at the return of righting reflex was 16% ( p < .05) lower in the hypovolemic animals. In conclusion, an increased hypnotic effect of etomidate was observed during hypovolemia that is mainly attributed to pharmacokinetic changes. Our data also suggest a small increase in central nervous system sensitivity for etomidate in hypovolemic animals.