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The pharmacologic effects induced by any one of the α₂ agonists can be antagonized effectively with an α₂ antagonist, such as yohimbine, tolazoline, or atipamezole. These antagonists can be used to shorten the time of recovery to standing, to treat severe α₂ agonist‐induced bradycardia, and to minimize adverse effects associated with accidental overdose. The α₂ agonists are known to cause bloating and ruminal tympany by decreasing gastrointestinal (GI) motility. Administration of any of the α₂ antagonists effectively reversed the decrease in GI motility [88, 111]. However, administration of these antagonists is not without risk. Sudden awareness of pain, significant peripheral vasodilation, and CNS excitement have occurred following rapid IV administration of an antagonist. The death of a sheep after administration of a large dose of yohimbine (0.8 mg/kg IV) has been reported [75]. Rapid IV injection of tolazoline has also been reported to cause significant cardiac stimulation, tachycardia, increased cardiac output, vasodilation, and GI distress [112]. Ruminants and camelids are more sensitive to tolazoline than other species, and death has been reported after its use [113, 114]. When administered alone at 1.5 mg/kg IV to Holstein calves, tolazoline caused coughing, an increased frequency of defecation, and a mild increase in breathing effort. At higher doses (2–10 mg/kg IV), adverse effects including bright red conjunctival mucous membranes, coughing, nasal discharge, salivation, labored breathing, CNS depression, signs of abdominal pain, straining, head pressing, restlessness, and severe diarrhea were observed. All calves in the study recovered uneventfully [114]. Currently, lower doses of tolazoline (0.5–1.5 mg/kg IV) are recommended for use in all ruminants including camelids. Others have suggested that, except in emergency situations, IV administration of tolazoline should be avoided to prevent adverse effects such as cardiac asystole [115]. When atipamezole (0.1 mg/kg IV) was administered to six goats to antagonize medetomidine (0.02 mg/kg IV)‐induced sedation and recumbency, all goats stood within 2 minutes. Four goats developed piloerection and all appeared to be agitated and vocalized [116]. When given to reverse IM xylazine‐ or medetomidine‐induced sedation in free‐ranging cattle, atipamezole (0.04–0.09 mg/kg) induced a brief period of excitement following IV administration. Relapse into medetomidine (0.04 mg/kg IV)‐induced sedation 1–2 hours after the administration of atipamezole (0.2 mg/kg IV) as a result of the shorter half‐life (t½) of the drug has been observed in dairy calves. In free‐ranging cattle, atipamezole (0.057 ± 0.017 mg/kg IV) has been administered to reverse xylazine‐induced immobilization. Eight cows receiving xylazine in this report were in the last 2 months of pregnancy and all cows calved normally and no premature parturition occurred [70]. Administration of a reversal agent (atipamezole) may have shortened the duration of xylazine‐induced increases in uterine contraction, thus preventing the adverse effect of xylazine on pregnant cows. Slow injection is recommended when administering an antagonist to avoid sudden awareness of pain and excitement. The undesirable effects of α₂ antagonists are extremely rare in healthy animals when the drugs are administered at appropriate dosages and by slow IV injection.

Vatinoxan, also known as MK‐467, is a peripherally acting α₂ antagonist. The drug is incapable of entering the CNS to act on the central α₂ receptors due to its low lipophilicity and inability to penetrate the blood–brain barrier [117]. Studies in dogs [118–121], cats [122], horses [123, 124], and sheep [125] have shown that concurrent administration with an α₂ agonist, vatinoxan, was able to attenuated the adverse cardiovascular effects that are often associated with the α₂ agonists. Studies in dogs and horses also showed that vatinoxan enhanced the absorption and volume of distribution of an α₂ agonist following IV or IM administration [123, 124, 126, 127]. In sheep, concurrent IM administration of vatinoxan (0.15, 0.3, or 0.6 mg/kg) with medetomidine (0.03 mg/kg IM) and ketamine (1 mg/kg IM) showed that the drug did not completely prevent early vasoconstriction‐related cardiopulmonary effects of medetomidine, but it accelerated, in a dose‐dependent manner, the return of certain physiologic variables to baseline values [128]. It appeared that the absorption of IM vatinoxan was slower than that of the IM medetomidine and hence the presence of the initial cardiopulmonary effects of medetomidine. When vatinoxan (0.25 mg/kg) was administered prior to medetomidine, it was able to attenuate medetomidine‐induced reduction in heart rate and changes in mean arterial blood pressure in sheep [125]. α₂ agonist‐induced hypoxemia was believed to be the result of activation of peripheral α₂ adrenoceptors in sheep [82] and the administration of vatinoxan was able to increase PaO₂ and SpO₂ and minimize the detrimental effect of hypoxemia by blocking the effects of the α₂ agonist on the peripheral α₂ receptors [128].