stimulation rather than sedation [22]. Contrary to the previous report, Piermattei and Swan [23] showed that 1 ml/14 kg (30.8 lb) of Innovar‐Vet IM produced good sedation prior to halothane anesthesia.
Azaperone, another butyrophenone derivative, has pharmacologic effects similar to acepromazine and droperidol. Hughes et al. [24] compared the effects of azaperone and acepromazine in free‐ranging sheep. At 1 mg/kg, azaperone produced a calming effect and reduced the stress response as evidenced by calmer behavior and a greater comfort level of the animals studied. In this study, azaperone appeared to be more effective in reducing the stress response than acepromazine [24]. Madsen et al. [25] observed greater disorientation for a longer duration with azaperone. Interestingly, sheep tended to disperse with acepromazine but they tended to congregate with azaperone.
In pigs, azaperone has been shown to be the most effective tranquilizer. Azaperone has been used for the prevention of aggressiveness and savaging of newborn pigs by sows, for the treatment of stress, and for the completion of minor surgical procedures. At 2.2 mg/kg IM, azaperone was effective in reducing fighting following intermingling [26]. Approximately 20 minutes of deep sedation sufficient for minor surgeries was produced by 4–8 mg/kg of azaperone IM. Excessive salivation during deep sedation has been observed [26–31]. Practitioners should keep in mind that tranquilizers like acepromazine, droperidol, azaperone, diazepam, and midazolam do not possess analgesic effect. Therefore, a tranquilizer may render the animal unresponsive to painful manipulations, but the physiological stress response resulting from painful stimulations still exists. Similar to acepromazine, azaperone is effective in preventing malignant hyperthermia episodes due to halothane in susceptible pigs. Doses of 0.5–2.0 mg/kg IM azaperone offered 100% protection against malignant hyperthermia in susceptible Pietrain pigs [32].
2.3 Detomidine, Dexmedetomidine, Medetomidine, Romifidine, and Xylazine (α2 Agonists)
The α2 agonists (e.g. xylazine, detomidine, medetomidine, dexmedetomidine, and romifidine) are classified as sedatives/analgesics. In addition to effective sedation, these drugs produce profound analgesia and good central muscle relaxation. The α2 agonists produce their pharmacologic effects by their actions on both the central and peripheral α2 adrenoceptors. Stimulation of central (presynaptic) α2 adrenoceptors inhibits the release of catecholamines, thus reducing the response to excitatory input, and as a result sedation occurs. Peripheral (postsynaptic) α2 receptors are found in the vasculature, pancreatic islet cells, and uterine muscles. As a result, transient hypertension, hypoinsulinemia, hyperglycemia, and oxytocin‐like effect are often associated with the administration of an α2 agonist [33]. Other side effects associated with the administration of α2 agonists include direct myocardial depression and augmentation of parasympathetic stimulation resulting in a decrease in cardiac output, bradycardia, and hypotension. Up to a sixfold increase in urine output subsequent to a decrease in secretion of antidiuretic hormone is a common side effect of α2 agonists. The central muscle‐relaxing effect produced by α2 agonists is believed to be mediated through the inhibition of nerve impulse transmission at the internuncial neurons of the spinal cord, brain stem, and subcortical level of the brain [34]. Because of this, α2 agonists are often given in combination with anesthetics that do not provide adequate muscle relaxation for surgical procedures. For example, when ketamine is administered alone, it is often associated with muscle tremors, jerking activity, and rigidity; xylazine is administered concurrently to improve the muscle relaxation during ketamine anesthesia. All α2 agonists, though considered as pure α2 agonists, also have affinity for α1 receptors. The α2 : α1 selectivity ratios for xylazine, detomidine, romifidine, and medetomidine/dexmedetomidine are 160 : 1, 260 : 1, 340 : 1, and 1620 : 1, respectively [35, 36].
2.3.1 Cattle
2.3.1.1 Xylazine
Xylazine is the most popular sedative in large animal practice today. Cattle are much more sensitive to xylazine than horses and require only one‐tenth of the dose needed for horses to produce the same degree of sedation [33]. The degree of sensitivity to xylazine varies within breeds, and Brahmans appear to be the most sensitive, Herefords intermediate, and Holsteins are the least sensitive [37]. Xylazine produces potent sedation, profound analgesia, and good muscle relaxation. It is frequently used for chemical restraint or anesthetic adjunct in ruminants. Xylazine alone produces dose‐dependent CNS depression from standing sedation (0.015–0.025 mg/kg IV or IM) [21, 38] to recumbency and immobilization (0.1 mg/kg IV or 0.2 mg/kg IM) [39]. Administration of xylazine to ruminants in the final trimester of pregnancy may cause premature parturition and retention of fetal membranes [40, 41]. In pregnant dairy cows during late gestation, administration of xylazine (0.04 mg/kg IV) resulted in a significant increase in uterine vascular resistance (118–156%) and a decrease in uterine blood flow (25–59%) accompanied by a drastic decrease in fetal O2 delivery (59%) [42]. Due to these detrimental effects on the fetus, the use of xylazine during late gestation in pregnant cows is not recommended. Fayed et al. [43] observed pronounced and prolonged drug effects when xylazine was administered to cattle under high ambient temperature. Xylazine should be used with extreme caution in animals with preexisting cardiopulmonary disease or urinary tract obstruction due to its adverse effects on the myocardium and urine output [33]. Higher dose of xylazine (single average dose, 0.55 ± 0.18 mg/kg) delivered by tranquilizer gun has been used to produce complete immobilization to capture free‐ranging cattle [44]. Xylazine is often used with butorphanol to produce neuroleptanalgesia. Enhanced sedation and analgesia develop when these two drugs are administered concurrently. Administration of high doses of butorphanol alone to nonpainful cattle may induce slight CNS stimulation and behavioral changes. Thus, when used in combination with xylazine, it is recommended the dose of butorphanol be maintained below 0.05 mg/kg to avoid butorphanol‐induced CNS excitation offsetting the sedative effect of xylazine [45]. Detailed discussion of chemical restraint techniques using xylazine combinations is described in Chapter 3.
Epidural administration of xylazine to standing cattle produced effective perineal analgesia for 2.5–4 hours. Compared to epidural lidocaine, xylazine produced less disruption of hind limb motor function and provides a longer duration of perineal analgesia [46, 47]. Systemic effects like mild to moderate sedation and slight ataxia sometimes occur following caudal epidural administration of xylazine, which is a result of absorption of the drug into blood circulation from the injection site and/or diffusion of the drug into cerebrospinal fluid (CSF) with subsequent cranial migration of the drug into the CNS. Similarly, studies in humans [48] and dogs [49] showed that diffusion of epidurally administered morphine into the CSF and the subsequent migration of the drug up the spinal cord, rather than the total injected drug volume, were the primary factors responsible for the widespread analgesia of epidural morphine. IV administration of an α2 antagonist such as tolazoline reversed the systemic effects (sedation and ataxia) but did not affect the caudal epidural analgesia of xylazine [50]. It is believed that the epidural analgesia of xylazine is the result of the binding of xylazine to the α2 adrenoceptors located in the dorsal horn of the spinal cord, not the effect of xylazine on the central α2 adrenoceptors in the CNS [51, 52]. Therefore, IV or IM administration of an α2 antagonist does not affect the binding of an α2 agonist to the receptors in the epidural space due to low concentration of the α2 antagonist in the epidural space.
2.3.1.2 Detomidine
Detomidine has pharmacologic effects that are very similar to those of xylazine. Interestingly, ruminants appear to be less sensitive to detomidine than they are to xylazine. The dose of detomidine required to produce standing sedation is similar to the dose required for horses. When administered at 0.05 mg/kg IV or IM to adult cattle, detomidine produced effective sedation, though the analgesic effect appeared to be more intense when the drug was administered intravenously [53]. Standing sedation of 30–60 minutes was evident with 0.025–0.01
