Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2-adrenoceptor antagonist atipamezole: a pharmacodynamic and kinetic study in healthy volunteers.
BACKGROUND
Specific and selective alpha2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because alpha2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with atipamezole, an alpha2-antagonist, in healthy persons.


METHODS
The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of atipamezole to reverse the sedative effects of 2.5 microg/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of atipamezole (15, 50, and 150 microg/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h.


RESULTS
The mean +/- SD atipamezole dose needed in part 1 was 104+/-44 microg/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 microg/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 microg/kg dose of atipamezole. The pharmacokinetics of atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine.


CONCLUSIONS
The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous atipamezole. The applied infusion rate (75 microg x kg(-1) x min(-1)) for the highest atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Similar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.
Scheinin
H
H
Department of Anesthesiology, Turku University Hospital, Finland. harry.scheinin@utu.fi
Aantaa
R
R
Anttila
M
M
Hakola
P
P
Helminen
A
A
Karhuvaara
S
S
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006993:Hypnotics and Sedatives / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020926:Medetomidine; D009638:Norepinephrine / Q000097:blood; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*; D013565:Sympatholytics / Q000037:antagonists & inhibitors*
D000317:Adrenergic alpha-Antagonists; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; D013565:Sympatholytics; C050701:atipamezole; D020926:Medetomidine; D009638:Norepinephrine