Antagonism of xylazine sedation in dogs by 4-aminopyridine and yohimbine

Abstract

SUMMARY Groups of fasted, atropinized crossbred dogs of both sexes were given a standard dosage (2.2 mg/kg of body weight) of xylazine, im . When fully sedated, the dogs were given iv 4-aminopyridine (4- ap ; 0.3 mg/kg), yohimbine (0.125 mg/kg), or a combination of 4- ap +yohimbine in weekly trials. Control groups were given saline solution. Two additional groups were given a 5× overdose of xylazine (11 mg/kg), im . When fully sedated, 1 of these groups was given 4- ap +yohimbine, iv ; the other group was given saline solution. In dogs given the standard dosage of xylazine, 4- ap decreased mean walk time ( wt ; time to cognition and ability to walk on a leash) to 6 minutes (saline-treated groups = 14.1 and 17.8 minutes). Mean total recovery time ( trt ) was not shortened. Yohimbine decreased wt to 2.2 minutes and decreased trt to 0.4 hours ( trt in saline-treated groups = 0.8 and 2.7 hours). In 1 group of control dogs, weekly injections of xylazine caused decreases in normal wt and trt , indicating development of tolerance to xylazine. The combination of 4- ap +yohimbine decreased wt to 1.4 and 1.9 minutes in 2 groups of dogs. The trt in these 2 groups was decreased to 0.5 hours. In previously untreated dogs given the 5× overdose of xylazine, 4- ap +yohimbine decreased wt to 3.3 minutes (saline-treated group = 73 minutes) and slightly decreased trt to 5.1 hours (saline-treated group = 6.1 hours). Additional doses of 4- ap +yohimbine were not given. Relapses to unconsciousness did not occur in any of the dogs; recovery was characterized by somnolence and easy elicitation of walking. In 3 dogs anesthetized with xylazine and pentobarbital, the combination of 4- ap +yohimbine iv caused (in order): transient femoral arterial hypotension with tachycardia and increases in respiratory rate, depth, and minute volume; parietal monopolar eeg activation; biceps femoris bipolar electromyogram activation; and behavioral arousal in less than 2 minutes. Increases in heart rate and in respiratory rate and depth (“respiratory lift”) were also observed clinically in intact dogs. The combination of 4- ap +yohimbine seems to be a safe, highly effective, specific antagonist of xylazine in dogs. The combination may be useful for reversal of the effects of standard dosages and overdoses of xylazine or for arousal of animals anesthetized or overanesthetized by combinations of xylazine with other drugs.