title: Infusion strategies to investigate the pharmacokinetics and pharmacodynamics of hypnotic drugs: etomidate as an example.
abstract: Etomidate was administered to six healthy volunteers by microprocessor controlled infusions, to generate three cycles of linearly increasing plasma levels, with an anticipated slope of 0.05 microgram ml-1 min-1. The infusions were stopped when a deep hypnotic state was obtained, as indicated by burst suppressions in the EEG. The infusions were restarted when the volunteers were fully orientated to person, place and time. The mean (+/-SD) doses of etomidate delivered by the first, second and third infusion were 165 +/- 30, 137 +/- 25 and 157 +/- 26 mg, respectively. Certain clinical signs were observed and related to the plasma concentrations of etomidate. Pharmacokinetic analysis was undertaken using an open two-compartment model. The therapeutic window was in a range of plasma concentrations between 0.3 and 1.0 microgram ml-1 of etomidate. Pharmacokinetic analysis gave a volume for the central compartment of 50 +/- 11 litre, an apparent volume of distribution of 252 +/- 51 litre and a total clearance of 1693 +/- 504 ml min-1. Microprocessor controlled infusions can serve as a powerful tool for research in clinical pharmacology. The achievement of linearly increasing plasma levels of etomidate allowed further pharmacokinetic and pharmacodynamic modelling concepts to be realized.
mesh_terms: D000328:Adult; D000758:Anesthesia; D003315:Cornea / Q000187:drug effects; D005045:Etomidate / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007263:Infusions, Parenteral; D007700:Kinetics; D008297:Male; D011485:Protein Binding; D012018:Reflex / Q000187:drug effects; D012119:Respiration / Q000187:drug effects; D012890:Sleep / Q000187:drug effects; D013060:Speech / Q000187:drug effects
chemical_list: D006993:Hypnotics and Sedatives; D007093:Imidazoles; D005045:Etomidate