Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine.
The pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine--a novel alpha 2-adrenergic receptor agonist under development for preanesthetic use--were studied in healthy male volunteers. Single intramuscular doses of dexmedetomidine (0.5, 1.0, and 1.5 microgram/kg) and placebo were administered to six subjects in a single-blind, multiple crossover study. Dexmedetomidine induced dose-related impairment of vigilance assessed both objectively and subjectively. The drug also caused moderate decreases in blood pressure and heart rate. Plasma norepinephrine was dose-dependently (maximum 89%) decreased. The intramuscular doses resulted in linearly dose-related plasma concentrations of dexmedetomidine. Pharmacokinetic calculations revealed a time to maximum concentration from 1.6 to 1.7 hours, an elimination half-life of 1.6 to 2.4 hours, an apparent total plasma clearance of 0.7 to 0.9 L/hr/kg, and apparent volume of distribution of 2.1 to 2.6 L/kg. The sedative effect of dexmedetomidine dissipated during the 6-hour observation time, but all other effects were still evident 6 hours after administration of the higher doses, paralleling the plasma concentration curves. The relationship of plasma concentrations of dexmedetomidine to pharmacodynamic variables was consistent with a linear pharmacodynamic model. The pharmacodynamic-pharmacokinetic profile of intramuscular dexmedetomidine may be suited to the proposed preanesthetic clinical use of this alpha 2-agonist.
Department of Pharmacology, University of Turku, Finland.
H
H
Scheinin
S
S
Karhuvaara
K T
KT
Olkkola
A
A
Kallio
M
M
Anttila
L
L
Vuorilehto
M
M
Scheinin
D000316:Adrenergic alpha-Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000704:Analysis of Variance; D001143:Arousal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D007273:Injections, Intramuscular; D008297:Male; D020926:Medetomidine; D012016:Reference Values; D016037:Single-Blind Method
D000316:Adrenergic alpha-Agonists; D002395:Catecholamines; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D020926:Medetomidine