detomidine does not produce an oxytocin‐like effect on the uterus in gravid cattle at IV doses less than 0.04 mg/kg. However, doses greater than 0.04 mg/kg were observed to cause increased electrical activity of the uterine muscle without inducing synchronizing burst potentials characteristics of parturition [56, 57]. This indicates that detomidine is less likely to induce premature parturition in pregnant ruminants at recommended doses and this may make it safer for use in pregnant ruminants. Slight sedation without analgesic effect was observed when 0.01 mg/kg of IM detomidine was given to Lanka buffaloes. Moderate sedation with analgesia was observed at 0.02 mg/kg, while deep sedation with excellent analgesia occurred with 0.04 mg/kg. However, 50% of the animals receiving 0.04 mg/kg became recumbent. When increasing the dose to 0.08 mg/kg, detomidine induced recumbency and complete immobilization in these buffaloes. The author of the study concluded that 0.02 and 0.04 mg/kg of detomidine induced adequate sedation and analgesia that suffices most clinical and practical purposes [58]. At higher doses (0.08–0.1 mg/kg IM), detomidine induced complete immobilization and excellent muscle relaxation, but regurgitation and subsequent aspiration pneumonia could be a risk if the animal's airway is not protected [58, 59]. In dairy cattle, IV detomidine alone (0.1 mg/kg) induced moderate sedation with significant decreased heart rate and respiratory rate for 39–55 minutes. Similar to xylazine and butorphanol administered to Holstein cows as mentioned previously, CNS excitation produced by butorphanol (0.05 mg/kg IV) seemed to offset the sedative effect of detomidine (0.1 mg/kg IV) when the two drugs were administered concurrently [45].
Caudal epidural administration of detomidine (0.04 mg/kg) induced perineal analgesia within 5 minutes following administration and lasted for 175 minutes [60]. In horses, caudal epidural detomidine has a slightly faster onset and shorter duration of perineal analgesia than xylazine, 12.5 ± 2.7 and 160 ± 8 minutes versus 13.1 ± 3.7 and greater than 165–180 minutes, respectively [61].
Recently, sublingual detomidine gel with a concentration of 7.6 mg/ml in a 3‐ml syringe is available for horses to be used in the field or on the farm. When administered sublingually to horses, the oral bioavailability was 22% and the peak plasma concentration was approximately 40% that of the plasma concentration following IM administration. A mild to moderate degree of sedation occurred within 30–40 minutes and lasted 90–180 minutes [62, 63]. Minor procedures like grooming or examination can be accomplished with this application [64]. The pharmacokinetic 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
