title: Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 1: Pharmacodynamic and pharmacokinetic interactions.
abstract: Dexmedetomidine is a highly selective alpha 2-adrenoceptor agonist with anaesthetic-sparing effects. We have determined the pharmacodynamic and pharmacokinetic interactions between dexmedetomidine and isoflurane in volunteers. Nine male subjects were allocated randomly to receive isoflurane anaesthesia preceded by infusion of dexmedetomidine on three separate occasions, 2 weeks apart. Dexmedetomidine target plasma concentrations were 0.0 (placebo), 0.3 ng ml-1 (low-dex) and 0.6 ng ml-1 (high-dex). End-tidal isoflurane concentrations at which gross purposeful movement and response to verbal commands occurred were identified. In the recovery period, sedation scores and digit symbol substitution tests were recorded. Venous blood samples were obtained before, during and after anaesthesia at predetermined intervals for measurement of plasma concentrations of dexmedetomidine and calculation of standard pharmacokinetic indices (AUC, Cl, Vss, T1/2 alpha, T1/2 beta). The end-tidal isoflurane concentration at which 50% of subjects first responded to the tetanic stimulus was 1.05% in the placebo group, 0.72% in the low-dex group and 0.52% in the high-dex group. We conclude that dexmedetomidine decreased isoflurane requirements in a dose-dependent manner and reduced heart rate, systolic and diastolic arterial pressures. Sedation and slight impairment of cognitive function persisted for several hours after anaesthesia and the end of infusion of dexmedetomidine. Isoflurane did not appear to influence the pharmacokinetics of dexmedetomidine.
authors.affiliation: Guy's Drug Research Unit, London, UK.
authors.forename: Z P
authors.initials: ZP
authors.lastname: Khan
authors.forename: I T
authors.initials: IT
authors.lastname: Munday
authors.forename: R M
authors.initials: RM
authors.lastname: Jones
authors.forename: C
authors.initials: C
authors.lastname: Thornton
authors.forename: T G
authors.initials: TG
authors.lastname: Mant
authors.forename: D
authors.initials: D
authors.lastname: Amin
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000097:blood / Q000494:pharmacology*; D000328:Adult; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D018592:Cross-Over Studies; D020927:Dexmedetomidine / Q000097:blood / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004347:Drug Interactions; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male
chemical_list: D000316:Adrenergic alpha-Agonists; D018685:Anesthetics, Inhalation; D020927:Dexmedetomidine; D007530:Isoflurane