title: Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2-adrenoceptor antagonist atipamezole: a pharmacodynamic and kinetic study in healthy volunteers.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Turku University Hospital, Finland. harry.scheinin@utu.fi
authors.forename: H
authors.initials: H
authors.lastname: Scheinin
authors.forename: R
authors.initials: R
authors.lastname: Aantaa
authors.forename: M
authors.initials: M
authors.lastname: Anttila
authors.forename: P
authors.initials: P
authors.lastname: Hakola
authors.forename: A
authors.initials: A
authors.lastname: Helminen
authors.forename: S
authors.initials: S
authors.lastname: Karhuvaara
mesh_terms: 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*
chemical_list: D000317:Adrenergic alpha-Antagonists; D006993:Hypnotics and Sedatives; D007093:Imidazoles; D018341:Receptors, Adrenergic, alpha-2; D013565:Sympatholytics; C050701:atipamezole; D020926:Medetomidine; D009638:Norepinephrine