results from blood and urine samples in horses suggested a 48‐hour and 3‐day withdrawal time of detomidine should be sufficient [63, 65]. In calves undergoing disbudding, the efficacy of sublingual administration of detomidine (0.08 mg/kg) was compared to IV detomidine (0.03 mg/kg). The bioavailability of detomidine was 34% with time to maximum plasma concentration at 66.0 ± 36.9 minutes. Maximal sedation occurred at 40 minutes following sublingual application as compared to 10 minutes following IV administration. Heart rate decreased in both groups. All calves were adequately sedated and offered little resistance for injection of local anesthetic prior to disbudding [66].
When administered at 0.08 mg/kg IV or IM to six cows, the concentration of detomidine measured in milk was below 0.4 ng/g at 11 hours, and no detectable concentration was measured at 23 hours post administration. Drug residue was detected in the liver of three cows (0.3–3.9 μg/kg tissue weight) and in the lung (2.3 μg/kg), kidney (0.3 μg/kg), and muscle of the injection site (0.5 μg/kg) of one cow, respectively. Only minute concentrations of 0.4 and 2.5 ng/g in the lungs and 0.7 and 0.8 ng/g in the muscle sample from the injection site were detected in two cows at 48 hours post administration [67]. These residual concentrations of detomidine in different tissues would affect the withdrawal time in food‐producing animals.
2.3.1.3 Medetomidine
IV administration of medetomidine (0.005 mg/kg) to domestic ruminants produced a short duration of standing sedation with minimal analgesia [54]. However, IM administration of 0.03 mg/kg in domestic calves resulted in lateral recumbency with analgesia lasting for 60–75 minutes [68]. Higher doses of medetomidine (0.04 mg/kg in heifers, 0.08 mg/kg in cows) delivered by tranquilizer gun have been used successfully to produce immobilization for the capture of free‐ranging cattle. In both studies, atipamezole was used effectively to reverse medetomidine's effect [69, 70]. In one study, two cows were in the last month of pregnancy and both calved normally at full term [70]. Caudal epidural injection of medetomidine (0.015 mg/kg) has been reported to induce rapid onset of perineal analgesia, similar to that of lidocaine, but with a significantly longer duration (4–9.5 hours). Moderate sedation and ataxia were observed in these cows. Two cows became recumbent at 20 and 40 minutes following drug administration, but both were easily coaxed to stand. It was believed that the recumbency in these two cows was caused by the nature of the ruminants during deep sedation and was not the result of motor nerve function disruption due to caudal epidural medetomidine [71].
2.3.1.4 Romifidine
When administered at 0.02 mg/kg IM to cattle, romifidine produced deep sedation with recumbency at 14.8 ± 3.4 minutes after injection. The duration of immobilization was 45.2 ± 3.4 minutes, and standing recovery occurred at 78.7 ± 17.7 minutes. The degree of analgesia produced by romifidine at this dose was similar to that produced by 0.2 mg/kg of IM xylazine. Similar to other α2 agonists, romifidine caused bradycardia, and the heart rate was significantly lower with romifidine. Other side effects of romifidine observed included bradypnea, decreased hematocrit, and ruminal tympany [72]. Romifidine (0.05 mg/kg) and morphine (0.1 mg/kg) have been combined and diluted in saline to a total volume of 30 ml and administered through a caudal epidural to Holstein–Friesian cows. Significant perineal analgesia with moderate sedation lasted 6 hours, but on occasion analgesia lasted up to 12 hours. Cows in this study tended to sit down and assume a recumbent position. The authors were not clear whether the recumbency was due to the deep sedation and ataxia from systemic absorption of romifidine and morphine into the blood circulation or the natural instinct of the cattle to sit down during sedation. One cow developed hind limb paresis and became recumbent 24 hours after drug administration. The cow showed no improvement 72 hours later and was humanely euthanized. Postmortem examination did not reveal any pathological changes like necrosis, inflammation, or degenerative lesions in the spinal cord to explain the hind limb paresis. However, the cow did have severe muscle necrosis of the adductor muscles, mild hepatic lipidosis, and moderate acute abomasal ulceration [73].
2.3.2 Small Ruminants and Camelids
2.3.2.1 Xylazine
Similar to cattle, small ruminants (e.g. sheep and goats) are very sensitive to xylazine, and goats are more sensitive than sheep [6]. Camelids (e.g. alpacas, llamas), though more sensitive to xylazine than horses, are not as sensitive as cattle and small ruminants. Therefore, the dose of xylazine required to produce a similar degree of sedation in goats is equal to or slightly less than that of cattle, whereas a slightly higher dose is required in camelids than in cattle and small ruminants. Compared to llamas, alpacas require dosages 10–15% higher than the recommended dose for llamas. Xylazine alone produces dose‐dependent CNS depression ranging from standing sedation to recumbency and immobilization in small ruminants and camelids. Extreme caution should be practiced when xylazine is used in animals with preexisting cardiopulmonary disease and urinary tract obstruction or in late pregnancy [33, 40, 74]. Severe hypoxemia and pulmonary edema have been implicated as the cause of death in sheep under xylazine sedation/anesthesia [75–78]. Lateral recumbency in conscious sheep has been reported to induce a significant decrease in PaO2 [79]. Xylazine has been reported to cause hypoxemia in xylazine‐sedated standing sheep [80, 81]. Apparently, all α2 agonists cause similar and significant decrease in PaO2 in sheep without affecting the PaCO2 [82]. Nolan et al. (1986) [83] demonstrated that xylazine‐induced increased airway pressure (from 13.7 to 35 mmHg) in sheep was a result of dose‐dependent stimulation of peripheral (postsynaptic) α2 adrenoceptors located in the airway smooth muscles (0.002–0.02 mg/kg). The effect of xylazine on the airway smooth muscles occurred within 5 minutes following IV administration and lasted longer than 60 minutes, long after the measured cardiovascular variables had returned to baseline values [83]. Furthermore, severe pulmonary parenchymal damage was seen with substantial morphological changes, such as extensive damages to capillary endothelium and alveolar type I cells, intra‐alveolar hemorrhage, and interstitial and alveolar edema. Such changes occurred almost immediately following IV administration of 0.15 mg/kg of xylazine [84]. Bronchospasm and venospasm due to direct action of α2 adrenoceptors on the vascular and bronchial smooth muscles, transient α2‐induced platelet aggregation with pulmonary microembolism, and release of cytokines and other inflammatory mediators subsequent to α2‐induced pulmonary intravascular macrophage activation have been suggested as the contributing factors for the development of hypoxemia in sheep [85].
Caudal epidural administration of xylazine (0.07–0.1 mg/kg), with or without lidocaine, induced long‐lasting somatic analgesia for open castration in rams (8 hours, without lidocaine) and correction of vaginal prolapse in ewes (24 hours, with 0.5 mg/kg of lidocaine) [86, 87]. However, visceral analgesia induced by epidural xylazine alone may not be sufficient for ligation of the spermatic cord [86].
2.3.2.2 Detomidine
At 0.02 mg/kg IV, detomidine produced sedation which is comparable to that of 0.04 mg/kg of xylazine [88]. Increasing the dose to 0.03 mg/kg, detomidine induced recumbency in sheep with sedation that was equivalent to 0.15 mg/kg of xylazine and 0.01 mg/kg of medetomidine [89]. Effective sedation and significant but transient hypotension and bradycardia followed by tachycardia and hypoxemia were reported during sedation with 0.091 ± 0.004 mg/kg of IV detomidine. Cardiac arrhythmias (e.g. atrioventricular block, ST elevation, and premature ventricular contraction) were also observed in this study [90]. Deep sedation with hypotension of 108 ± 9.1 minutes occurred when detomidine (0.092 ± 0.006 mg/kg IV) was combined with diazepam (0.7 ± 0.2 mg/kg IV). Cardiac arrhythmias, but not hypoxemia or hypercapnia, were observed when diazepam was administered with detomidine [91]. Obviously, hypoxemia and pulmonary edema can occur with any of the α2 agonists, but the severity of hypoxemia was reported to be less with detomidine [85]. IV administration of α2 agonists normally induces a characteristic biphasic blood pressure response characterized by transient hypertension followed by longer‐lasting hypotension. The initial hypertension is the result of vasoconstriction from stimulation of peripheral (postsynaptic) α2 adrenoceptors, and the subsequent hypotension is due to activation of central (presynaptic) α2 adrenoceptors resulting in decreased sympathetic