Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific α2-adrenoceptor antagonist atipamezole. A pharmacodynamic and kinetic study in healthy volunteers
Background: Specific and selective α2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because α2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with atipamezole, an α2-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 μg/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 μg/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 μg/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by atipamezole (P &lt; 0.001). Complete resolution of sedation was evident after the highest (150 μg/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P &lt; 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 μg/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 μg·kg-1·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.