Synergistic interaction between alpha 2-adrenergic agonists and benzodiazepines in rats.
Both alpha 2-adrenergic agonists and benzodiazepines exert anxiolytic and sedative effects when administered as preoperative medications. Clinical effects achieved with a combination of drugs, representative of these classes of compounds, is greater than that which could be expected from a simple additive response. Therefore, we investigated the nature of the interaction between dexmedetomidine, the highly-selective alpha 2-adrenergic agonist, and midazolam in a series of in vivo and in vitro studies in rats. Rats were administered midazolam, dexmedetomidine, or a combination of midazolam and dexmedetomidine intravenously to derive three dose-response curves for loss of righting reflex (LRR). LRR was determined in rats in a rotating cage (4 rotations/min) by observing whether the rat failed to maintain its upright posture for greater than or equal to 15 s exactly 2.5 min after drug administration. The effect of either flumazenil (benzodiazepine receptor antagonist) or atipamezole (the alpha 2-adrenergic antagonist) on the LRR was also determined. A probit analysis was performed and an isobologram for the ED50 was derived to assess the nature of the interaction. Rat brain membranes were prepared for receptor binding assays using [3H]-flumazenil and [3H]-rauwolscine to characterize the benzodiazepine and alpha 2-adrenergic receptors, respectively. The ability of either midazolam or dexmedetomidine to displace the radiolabeled ligand from the alternative receptor was assessed. To detect a possible kinetic interaction between the two drugs, separate cohorts of rats were administered the two drugs individually or in combination at the combination ED50 doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Salonen
M
M
Department of Anesthesia, Stanford University, Palo Alto, California.
Reid
K
K
Maze
M
M
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage*; D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007093:Imidazoles / Q000008:administration & dosage; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D020926:Medetomidine; D008874:Midazolam / Q000008:administration & dosage; D011187:Posture / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012018:Reflex / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D001569:Benzodiazepines; D020926:Medetomidine; D008874:Midazolam