to being handled and restrained, particularly free‐ranging animals. In addition to relocation to unfamiliar surroundings for the intended procedure, special equipment like a head catch or restraining chute that may be used for proper restraint of an intractable animal can add another level of stress to the patient. In large aggressive animals, the use of a tranquilizer/sedative will minimize the stress from forceful restraint, ease the anesthetic induction process, and decrease the dose of general anesthetic required, thus preventing the possibility of disastrous hypotension due to the use of large doses of an anesthetic. Camelids and swine are less tolerant of physical restraint; consequently, deep sedation or general anesthesia is often needed to perform even minor surgical procedures. Oral administration of a tranquilizer/sedative may be used to reduce stress associated with physical restraint in free‐ranging animals under field conditions or for animals intolerant of physical restraint. Drugs used for tranquilization and sedation are also used to produce chemical restraint. In ruminants and camelids, oral medication has to pass through the rumen or rumen‐like C1 compartment, respectively. Thus, the absorption and distribution of the drug will be affected by forestomach motility and the pH of the contained fluid [1]. Reticuloruminal motility is controlled by the medullary gastric center of the brain. Physical conditions affecting the patient, such as depression, pain, fear, excitement, and extreme distension of the ruminal wall (e.g. bloating), or administration of analgesics like opioids, α2 agonists, or anesthetics (e.g. thiopental and propofol) have been reported to decrease gastric motility resulting in prolonged gastric emptying time and increased absorption of a drug [1].
The difference in pH between saliva (8.2), plasma (7.4), and ruminal content (5.5–6.5) also affects the absorption and distribution of the drug by its effect on the degree of ionization of the drug. Nonionized drugs have higher lipid solubility and easily diffuse across cell membranes, whereas ionized drugs have lower lipid solubility and are therefore less capable of diffusion across cell membranes. Weak acidic drugs ionize and accumulate in the alkalinized saliva and thus allow the delivery of large quantities of the drug into the rumen with the flow of saliva. Once in the more acidic environment of the rumen, ionized drugs become nonionized and diffuse across the rumen membrane into the local blood circulation. On the contrary, drugs that are weak bases become ionized and accumulate in the rumen. The degree of ionization and the diffusion of the drug between saliva, ruminal content, and plasma is constantly changing, which increases the difficulty in predicting the bioavailability, distribution, and calming effect of an orally administered tranquilizer/sedative [1]. Drugs administered intramuscularly or intravenously usually produce more predictable and reliable calming effects in ruminants and camelids, and are the preferred routes for administering a tranquilizer/sedative when possible. For monogastric animals like pigs, the pH in the stomach is acidic (1.5–2.5) [2], therefore orally administered acidic drugs will present with a greater percentage in nonionized form and thus better and faster absorption from the stomach and greater bioavailability of the drug. Basic drugs tend to have lower bioavailability due to a higher degree of ionization of the drugs in the stomach.
2.1 Acepromazine (Phenothiazine Derivatives)
2.1.1 Cattle
Acepromazine produces mild tranquilization without analgesia in animal species. It produces a calming effect by blocking dopaminergic receptors at the basal ganglia in the brain [3]. The drug has minimal effects on heart rate and respiratory function. Direct depression on myocardial contractility and a decrease in cardiac output with subsequent hypotension often observed with the administration of acepromazine are the result of its effect on blocking α1 adrenoceptors located at the myocardium [4, 5]. In addition to a calming effect, acepromazine produces beneficial effects such as antiarrhythmic and antiemetic effects. Acepromazine may cause relaxation of the esophagus and cardia, which increases the risk of regurgitation in ruminants [6, 7]. Thus, special measures to protect the airway should be taken if the animal is to be placed in lateral or dorsal recumbency during the procedure. Use of the coccygeal vein for intravenous (IV) injection should be avoided when administering acepromazine because of its close proximity to the coccygeal artery [3]. Prolapse of the penis with potential subsequent trauma following the administration of acepromazine as reported in horses may occur in ruminants as well. The IV and intramuscular (IM) doses of acepromazine recommended for ruminants are 0.01–0.02 and 0.03–0.1 mg/kg, respectively [8]. The duration of tranquilization of acepromazine is usually 2–4 hours when administered at recommended dosages, but effects of 4–8 hours have been reported [9]. The use of acepromazine is contraindicated in debilitated or hypovolemic animals due to its hypotensive effect [3]. In addition, acepromazine depresses the thermoregulatory center, resulting in significant hypothermia and prolonged recovery in anesthetized newborns and neonatal animals. Acepromazine (0.03 mg/kg IM) has been administered occasionally to calm fractious bulls prior to induction of anesthesia with IV xylazine and ketamine.
2.1.2 Small Ruminants and Camelids
Acepromazine, though rarely used in small ruminants, can be administered at 0.05–0.1 mg/kg to produce mild tranquilization [10]. The drug has been used as an alternative for xylazine in goats with urethral obstruction where increased urine output associated with α2 agonists is contraindicated. Doses from 0.05 to 0.2 mg/kg can be administered IM or IV to produce tranquilization in sheep and goats [11]. In camelids, 0.033 mg/kg has been used to produce some calming effect in a female guanaco for eye examination [12]. However, a dose of up to 0.15 mg/kg was needed to quiet an aggressive male llama prior to induction of anesthesia with halothane [13].
2.1.3 Swine
Acepromazine is not an effective tranquilizer in pigs, for though tranquilized, they can still resist and fight the imposing restraint viciously. The doses of acepromazine recommended for pigs are 0.11–0.44 mg/kg IV or IM with a maximum total dose of 15 mg [8]. Large doses of acepromazine have been administered in addition to local anesthesia to sows undergoing cesarean section surgery, resulting in severe hypotensive shock. Several sows did not recover following the surgery [14]. IM doses of 0.05–0.5 mg/kg have been given to Vietnamese potbellied pigs with an unreliable calming effect even with high doses [15]. Acepromazine is frequently used in combination with ketamine or Telazol (tiletamine/zolazepam) to produce excellent sedation and muscle relaxation [16]. In pigs susceptible to malignant hyperthermia, acepromazine at 1.1 and 1.65 mg/kg IM has been reported to reduce the incidence of malignant hyperthermia by 40% and 73%, respectively. A lower dose of 0.55 mg/kg IM only delayed but did not prevent the onset of the episode [17].
2.2 Droperidol and Azaperone (Butyrophenone Derivatives)
Butyrophenone derivatives like droperidol and azaperone have pharmacological effects very similar to acepromazine (phenothiazine derivatives). Droperidol alone has been administered to pigs at 0.3 mg/kg IM to produce sedation for 2 hours [18]. However, droperidol is seldom administered alone to animals; it is manufactured as a proprietary combination of droperidol (20 mg/ml) and fentanyl (0.4 mg/ml) and marketed as Innovar‐Vet for veterinary use. Innovar‐Vet is a neuroleptanalgesic combination which consists of a tranquilizer (droperidol) and an analgesic (fentanyl). The combination of two drugs not only potentiates the central nervous system (CNS)‐depressing effect and the analgesic effect of each drug but also reduces the dose requirement for each drug, which decreases the side effects of each drug. Innovar‐Vet is often used to calm intractable or vicious animals but is rarely used in ruminants. When given at 0.19, 0.25, or 0.3 ml/kg to sheep, Innovar‐Vet was reported to produce adequate analgesia and smooth induction and recovery [19]. Innovar‐Vet had been shown to produce satisfactory calming effect in pigs (1 ml/12–25 kg [26.4–55 lb] IM). However, pigs often sneezed and became more excited if stimulated while under the influence of Innovar‐Vet [20]. Variable responses ranging from light sedation to pronounced relaxation and analgesia have been reported when 1 ml/10 kg (22 lb) of Innovar‐Vet was administered to young pigs [21]. Better and more reliable sedation was observed when xylazine was administered with Innovar‐Vet [14]. When
