Pharmacokinetics and pharmacodynamics of three intravenous doses of yohimbine in the horse

Yohimbine is an alpha 2 adrenergic receptor antagonist, which has been shown to counteract the CNS depressant effects of alpha 2 receptor agonists in a number of species. Recently, our laboratory identified yohimbine in the absence of detectable concentrations of an alpha 2 agonist in a regulatory sample collected from a horse racing in California. This coupled with anecdotal reports of CNS stimulation and documented reports of cardiovascular changes when administered in conjunction with an agonist led us to investigate the pharmacokinetics and pharmacodynamics of yohimbine when administered alone. Nine healthy adult horses received a single intravenous dose of 0.1, 0.2, and 0.4 mg/kg yohimbine. Blood samples were collected at time 0 (prior to drug administration) and at various times up to 24 h postdrug administration. Plasma samples were analyzed using liquid chromatography-mass spectrometry (LC-MS), and resulting data analyzed using both noncompartmental and compartmental analysis. Peak plasma concentrations were 106.0 ± 28.9, 156.7 ± 34.3, and 223.0 ± 44.5 ng/mL for doses of 0.1, 0.2, and 0.4 mg/kg, respectively. Immediately following administration, two horses showed signs of sedation, one horse appeared excited, while the other six appeared behaviorally unaffected. Episodes of tachycardia were noted within minutes of administration for all horses at all doses; however, there was no correlation between behavioral responses and episodes of increased heart rate. Sixty-three percent of the horses (8, 6, and 4 of the 9 horses in the 0.1, 0.2, and 0.4 mg/kg dose groups, respectively) exhibited second-degree atrial-ventricular conduction blocks and bradycardia prior to drug administration that transiently improved or disappeared upon administration of yohimbine. Gastrointestinal sounds were transiently increased following all doses.