2.3.3.3 Medetomidine
In pigs, medetomidine at IM doses of 0.03–0.08 mg/kg induced dose‐dependent sedation and muscle relaxation. Increasing the dose to greater than 0.1 mg/kg did not increase the degree of sedation or muscle relaxation but did prolong the duration of activity. Compared to 2 mg/kg of xylazine, enhanced sedation, better muscle relaxation, and greater analgesia were observed with 0.03 mg/kg of medetomidine [109]. Medetomidine has been used in combination with butorphanol (0.2 mg/kg IM) and ketamine (10 mg/kg IM) (MBK) to produce anesthesia for 98.8 ± 22.5 minutes, which is significantly longer than for a xylazine (2 mg/kg IM)–butorphanol (0.2 mg/kg IM)–ketamine (10 mg/kg IM) combination (47.5 ± 16.5 minutes). The muscle relaxation was adequate for tracheal intubation, but moderate cardiovascular depression was observed during MBK anesthesia [110]. Atipamezole effectively reversed the effects produced by 0.16–0.32 mg/kg IM of medetomidine [103].
2.4 Atipamezole, Tolazoline, Yohimbine, and Vatinoxan (α2 Antagonists)
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].
2.5 Diazepam and Midazolam (Benzodiazepine Derivatives)
Benzodiazepine derivatives like diazepam and midazolam are classified as minor tranquilizers. These drugs are used for their anxiolytic, anticonvulsant, and central muscle‐relaxing effects. Benzodiazepines produce little or no analgesic effect, but they can reduce the dose requirement of the concurrently administered general anesthetics [22]. Benzodiazepines produce minimal cardiovascular depression. For this reason these drugs are favorable for use in animals with increased anesthetic risk. Benzodiazepines can be used as alternatives to α2 agonists to produce tranquilization when adverse effects associated with α2 agonists (e.g. hypoxemia, pulmonary edema, or increased airway pressure) become undesirable. Diazepam and midazolam are the two most commonly used benzodiazepines in clinical veterinary practice. Diazepam is insoluble in water; its injectable solution contains 40% propylene glycol as solvent. IV propylene glycol administered rapidly sometimes results in hypotension and vascular irritation. Dilution, mixture of the injectable solution of diazepam with water, or a water‐soluble drug solution may cause cloudiness of the mixture which does not affect the potency of the drug. Midazolam is two to three times more potent than diazepam. Its injectable solution is water soluble. Thus, IM administration of midazolam will not cause tissue irritation [129]. In contrast to the general perception that benzodiazepines like diazepam and midazolam do not produce an analgesic effect, Kyle et al. [130] and Lizarraga and Chambers [131] reported that midazolam appeared to provide mediation of antinociception at the level of the spinal cord in sheep. Midazolam was rapidly absorbed with an elimination t½ of midazolam of 0.79 and 0.94 hours following IV and IM administration, respectively. A transient decrease in respiratory rate has been observed during midazolam‐induced tranquilization [132]. Diazepam and midazolam can be used as a preanesthetic for their anxiolytic and muscle‐relaxing effect, or they can be used with ketamine to improve muscle relaxation during anesthesia [133]. Other benzodiazepines, including flurazepam (2 mg/kg IV) [134], lorazepam (0.1 mg/kg IV) [135], and brotizolam (1–10 mg/kg PO) [136], have been used in pigs.
2.5.1 Cattle, Small Ruminants, and Camelids
Diazepam can be administered alone to produce dose‐dependent CNS depression from mild sedation to recumbency for 15–30 minutes. The tranquilizing effects of diazepam in healthy animals tend to be variable and somewhat unreliable [10]. Doses from 0.55 to 1.1 mg/kg IM have been recommended for use in ruminants and swine [137]. Diazepam at 0.2 mg/kg IV has been used to produce mild tranquilization