Antagonism of ketamine anesthesia in cats by 4-aminopyridine and yohimbine
Authors: Hatch Roger C. , Booth Nicholas H. , Kitzman Joseph V. , Wallner Barbara M. , Clark J. Derrell 
Published: February 2025

Two groups of fasted cats (8 cats/group) were injected im with atropine (0.05 mg/kg of body weight) plus an anesthetic dosage of ketamine (20 mg/kg) in weekly experiments. On loss of righting reflex, group 1 (control) cats were given an iv injection of saline solution. Group 2 cats were given an iv injection of a mixture of 4-aminopyridine (4-ap; 0.6 mg/kg) plus yohimbine (0.25 mg/kg, week 1), 4-ap alone (0.6 mg/kg; week 2), or yohimbine alone (0.25 mg/kg; week 3). When the control cats regained the ability to walk, they were given an iv injection of the same test antagonist(s) as the principals were given, so that all cats had the same total drug experience each week.

In cats given 4-ap + yohimbine (week 1), mean arousal time (mat) was shortened to 4.1 minutes (control mat = 16.3 minutes), mean walk time (mwt) to 29.5 minutes (control mwt = 45.6 minutes), and mean total down time (mtdt) to 33.6 minutes (control mtdt = 61.9 minutes). In cats given 4-ap alone (week 2), mat was shortened to 11 minutes (control mat = 27.2 minutes), but mwt was lengthened to 56 minutes (control mwt = 29.9 minutes). The mtdt was not altered significantly (P > 0.05). With yohimbine alone (week 3), mat was shortened to 4.1 minutes (control mat = 40.8 minutes), mwt was lengthened to 48.1 minutes (control mwt = 34.9 minutes), and mtdt was not altered significantly (P > 0.05). Relapses to unconsciousness did not occur. Progressive weekly increases in control group mat may indicate decreases in cns tolerance to ketamine, number of ketamine receptors, or metabolism of ketamine.

In week 4, an overdose of ketamine (100 mg/kg) was given. In the principals, the combination of 4-ap + yohimbine (same dosages as before) markedly decreased depth of anesthesia. Some cats became aroused 2 to 15 minutes after the antagonist was administered, but this initial arousal was not sustained. The mat was shortened to 81.5 minutes (control mat = 385 minutes). Relapse to unconsciousness occurred in 3 to 4 hours. A 2nd dose of 4-ap + yohimbine was then given (same dosages as before). Immediate arousal and limb movements occurred.The mwt was lengthened to 525.8 minutes (control mwt = 289.3 minutes). The mtdt (607.3 minutes) was not altered significantly (P > 0.05), compared with the mtdt in the control group (674.3 minutes).

Four atropinized cats anesthetized with ketamine (50 mg/kg) + local anesthetic had surgically placed cannulas and electrodes. The combination of 4-ap + yohimbine (same iv dosages as before) caused (in order): (i) A brief decrease, then a sustained increase in arterial blood pressure, with increase in pulse pressure; increases in respiratory rate, depth, and minute volume; increase in electromyogram activity (which became progressively larger in amplitude thereafter); and appearance of bursts of low-voltage fast activity in the eeg tracings; (ii) gross muscle movements beginning in the head and neck; (iii) little change or a slight increase in heart rate (without arrhythmias), and minor changes in ecg waveforms; (iv) appearance of predominantly low-voltage fast activity in the eeg tracings (eeg activation); and (v) behavioral arousal within 1.7 to 8.6 minutes.

The combination of 4-ap + yohimbine appeared to be a safe and effective partial antagonist of ketamine anesthesia in cats, although ketamine catalepsy was not antagonized. The antagonist combination may prove useful for producing rapid arousal in cats given anesthetic dosages or overdoses of ketamine, or for arousal of animals anesthetized with ketamine in combination with other drugs.