Phenothiazines in general have a large volume of distribution (Vd) and are highly protein bound. In the horse, acepromazine Vd = 6.6 l/kg and is >99% protein bound (Ballard et al., 1982). Time to clinical effect is generally ∼10–15 minutes after IV administration and ∼30 minutes after IM administration. Acepromazine is long acting in most species; elimination half-life is 3.1 hours in the horse and 7.1 hours in the dog (Ballard et al., 1982; Hashem et al., 1992). Acepromazine undergoes extensive hepatic metabolism and metabolites are excreted in the urine (Dewey et al., 1981). The metabolites of acepromazine have not been evaluated extensively in most species, but horses and humans have differing metabolites and in differing concentrations (Dewey et al., 1981; Elliott and Hale, 1999). Bioavailability in dogs after oral administration is ∼20% (Hashem et al., 1992), which must be accounted for if tablets are administered instead of injection. There is no available antagonist to reverse the effects of phenothiazines.

Acepromazine is the most commonly used phenothiazine in veterinary medicine. It is routinely used for sedation of many veterinary species, although it only approved for use in dogs, cats, and horses. It is approved for administration IV, IM, or SQ.

Promazine is phenothiazine similar to acepromazine. It is rarely used in the parenteral form, but is more popular as a granular oral medication that is mixed with feed for use in horses.

Chlorpromazine is primarily used as an antiemetic in dogs and cats, and less commonly used as a preanesthetic sedative. It is generally contraindicated for use with horses, due to a high incidence of ataxia and altered mentation.

Acepromazine is approved by the FDA for use in dogs, cats and horses.

• Acepromazine Maleate Injection 10 mg/ml (Boehringer Ingelheim Vetmedica, Inc.).
  
• Acepromazine Maleate 10 or 25-mg Tablets (Boehringer Ingelheim Vetmedica, Inc.).

Promazine is approved by the FDA for use in dogs, cats, and horses.

• Promazine HCl Injectable 50 mg/ml (Zoetis)
  
• Promazine HCl Granules 10.25 oz containers, 27.5 mg/gram (Zoetis).

There are no veterinary approved products. It is supplied as 25 mg/ml injection for human use (Thorazine, and generic brands), and is used off label in veterinary patients. It is also supplied in 10, 25, 50, 100, and 200-mg tablets for people.

There is limited information regarding the pharmacokinetics of the butyrophenones in veterinary species. The onset time after intramuscular injection is less than 10 minutes in most species with a peak effect seen approximately 30 minutes after administration (Serrano and Lees, 1976). The duration of action is 2–4 hours in pigs, longer in older pigs. Azaperone in pigs is biotransformed in the liver with 13% excreted in the feces. In rats, 25% of the drug in removed via the kidney and 10% is excreted unchanged (Fish et al., 2011). Metabolite residues are highest in the kidneys and are present in the urine for at least 3 days after administration; however, most of the drug is eliminated from the body with 16 hours (Arneth, 1985).

See Box 14.2.

Butyrophenones potentiates the effects of other anesthetic agents (CNS depressants), which will necessitate a reduction in the dose of induction and inhalational agents (Geel, 1991; Bustamante and Valverde, 1999; Nunes et al., 2001; Yamashita et al., 2003). Butyrophenones inhibit the effect of dopamine on renal blood flow (Bradshaw et al., 1980). The use of butyrophenones in patients receiving selegiline may precipitate extrapyramidal movement signs.

There are no known antagonists for butyrophenone drugs and treatment for overdoses should focus on supportive care. Patients should be monitored for hypotension and respiratory depression and treated accordingly.

• Azaperone: Stresnil, Azaperone 40 mg/ml (Elanco, Eli Lilly).

The first benzodiazepine, chlordiazepoxide, was discovered accidently in 1954 by Dr Leo Sternbach. Diazepam (Valium^®) is a simplified version of chlordiazepoxide and was marketed in 1963 for anxiety. Although many benzodiazepines (>50) are used in people and animals for behavioral modification, only diazepam, midazolam, lorazepam, and zolazepam will be discussed as sedatives and adjuncts to veterinary anesthesia. The use of benzodiazepines for managing behavior problems in animals is discussed in Chapter 18.

Benzodiazepines are sedative-hypnotics due of their propensity to cause anxiolysis, sedation, and an ability to cause sleep. They are classified as minor tranquilizers.

Benzodiazepines bind to the benzodiazepine receptor binding site on the gamma subunit of the gamma-aminobutyric acid receptor subtype A (GABA_A). Gamma-aminobutyric acid (GABA) is the primary inhibitor neurotransmitter in the CNS. Activation of the benzodiazepine receptor enhances the effects of GABA on the GABA_A receptor. GABA_A is a large macromolecule, which also contains a number of binding sites for other sedative drug classes such as barbiturates and alcohols. This explains the synergistic effect of these drugs on GABA_A-mediated inhibition of the CNS. Activation of the benzodiazepine binding site on GABA_A receptors increase the frequency of the opening of the chloride ion channel, leading to hyperpolarization of the postsynaptic neuron (Yeh et al., 1988), producing decreased neuronal transmission. The heterogeneity of the GABA_A subunits is in part responsible for the differing clinical actions of the various benzodiazepines (Upton et al., 2001). The highest concentration of GABA_A receptors is found in the cerebral cortex, with very few receptor sites found outside the CNS, hence the minimal cardiopulmonary effects of benzodiazepine drugs (Cornick-Seahorn and Seahorn, 1998).

Benzodiazepines are used in veterinary medicine as: anticonvulsants (Chapter 17); adjuncts to anesthetic induction agents; skeletal muscle relaxants; and for behavioral modification (anxiolysis and sedation) (Chapter 18). In the healthy patient, behavioral effects are mild, and may be paradoxical as the reduction in inhibitions can result in vocalization, excitement, and dysphoria. Sedation is more reliable in neonates, geriatrics, or ill patients, or as the author would say “very young, very old, or very sick.” In small ruminants benzodiazepines are generally effective at causing sternal recumbency and sedation.

It is not uncommon to see a transient period of agitation, vocalization, or excitement following parenteral benzodiazepine administration in a number of species. This unwanted effect is seen more commonly in healthy animals, and less commonly in very young, very old, or ill patients. Since, benzodiazepine drugs when used alone can produce unpredictable behavioral effects, they are often administered in conjunction with other CNS depressants to minimize the risk of paradoxical excitation.

As an anxiolytic, benzodiazepines can decrease inhibitions. Therefore caution should be used when sedating animals exhibiting fear-induced aggression, as the disinhibition caused by the benzodiazepines may provoke aggressive behavior.

See Section Diazepam Hydrochloride.

Patients discontinuing a benzodiazepine require their dose to be tapered off to avoid abstinence syndrome from sudden cessation. Long-term use of benzodiazepines does cause physical dependence in the dog (McNicholas et al., 1983) and the use of flumazenil may precipitate abstinence syndrome (tremors, hot foot walking twitches, tonic clonic seizures, and occasional death) (Oliver et al., 2000; Klotz, 1988).

Flumazenil was introduced in 1987 by Hoffmann-La Roche under the trade name Anexate™. It is the only benzodiazepine antagonist available in the USA. It has also been marketed under the trade name Romazicon, but is currently used as a generic.

Flumazenil is a specific and exclusive benzodiazepine competitive antagonist with a high affinity for the benzodiazepine receptor site of the GABA_A receptor. Flumazenil has virtually no agonist activity at the benzodiazepine receptor site.

Alpha-2-adrenergic receptors produce profound, reliable sedation in most veterinary species (see Section Mechanism of Action). However, there are differences in response based on species, drug, and dose. The pharmacodynamic differences between species are likely caused by differences in the α₂-adrenergic receptor subtypes in the CNS between species, most notably the presence of α_2D-adrenergic receptors in ruminants (Schwartz and Clark, 1998). Ruminants in particular are very sensitive to the sedative effects of certain α₂-adrenergic agonists (e.g., xylazine) in the locus coeruleus nucleus (Scheinin and Schwinn, 1992). Therefore, it is likely that the population of α_2D-receptor subtypes in the ruminant CNS is different than other animals.

The duration and depth of the sedation are dose dependent. Lower doses generally produce mild to moderate sedation, where high doses can produce unconsciousness in some species, such as dogs (Kuusela et al., 2001a, 2003). There does appear to be a ceiling effect for sedation in some species, such as horses, where increased doses generally do not result in recumbency, but rather increases the duration of effect.

Alpha-2-adrenergic agonists produce a biphasic cardiovascular response. In the “first” phase, activation of presynaptic central α₂-adrenergic receptors reduce the sympathetic outflow (decreased norepinephrine) and thereby increases the parasympathetic tone, which will result in negative inotropic, chronotropic, and dromotropic effects on the heart as well as peripheral vasodilation. High vagal tone and decreased dromotropy often causes first and second-degree atrioventricular heart block. Peripherally, postsynaptic α₂ and α₁-adrenergic receptors are activated in the vascular endothelium causing profound vasoconstriction (which overshadows the vasodilation from the lack of norepinephrine). The increase in arterial blood pressure results in a baroreceptor-mediated reflex bradycardia. Most patients in this first phase are hypertensive and bradycardic. During the “second” phase there is a decrease in systemic vascular resistance (less activation of peripheral vascular adrenergic receptors); however, the heart rate remains low (likely due to decreased norepinephrine). Patients during the second phase may be hypotensive and bradycardic.

At therapeutic doses, α₂-agonists decrease cardiac output in most species by more than 50% (Pypendop and Verstegen, 1998; Lamont et al., 2001; Bueno et al., 1999). Reduction in cardiac output is not only due to the baroreceptor reflex but concomitant reduction in stroke volume, increase afterload, and low catecholamine levels. There appears to be a ceiling effect with the cardiovascular responses to α₂-adrenergic agonists (Kuusela et al., 2000; Pypendop and Verstegen, 1998, 1999). Higher doses produce more sedation, analgesia, and longer duration of action, but do not necessarily worsen the cardiovascular response.

The use of anticholinergics prior to or at the same time as an α₂-adrenergic agonist is controversial. During the first phase, bradycardia is a protective baroreceptor reflex and generally should not be treated. Treatment with anticholinergics only partially prevent the decrease in cardiac output and increase the risk of dysthymia (Sinclair, 2003; Short, 1991) and hypertension (Singh et al., 1997). Hypertension is more likely when the anticholinergic is administered during the initial vasoconstrictive phase than in the secondary hypotensive phase (Pimenta et al., 2011). Arrhythmias are more likely to occur when the anticholinergic is given after the cardiovascular effects (i.e., hypertension and bradycardia) are seen compared with prior to or concurrently with an α₂-agonist (Short, 1991). Arrhythmias associated with α₂-agonists and anticholinergics are likely due to increases in myocardial workload (increased heart rate and increased afterload) and oxygen consumption. α₁-adrenergic receptors have also been implicated in the formation of arrhythmias mediated via α₂-adrenergic agonists, especially with xylazine due to its relatively low α₂ : α₁-adrenergic receptor affinity (Bozdogan and Dogan, 1999).

Alpha-2-adrenergic agonists will redistribute blood flow from nonessential regions such as the skin and viscera to the central organs like the brain, heart, and kidneys (Pypendop and Verstegen, 1998; Lawrence et al., 1996). Furthermore, they do not decrease coronary artery perfusion or myocardial oxygenation (Snapir et al., 2006). This may explain why a class of drugs with so many cardiac effects has been shown to improve survivability in human patients undergoing cardiovascular surgery (Wijeysundera et al., 2003).

Alpha-2-adrenergic agonists tend to cause a centrally mediated reduction in respiratory rate and minute ventilation, with no or with mild increases in PaCO₂ and mild reductions in PaO₂ (Kolliasbaker et al., 1993; Pypendop and Verstegen, 1999; Sinclair, 2003; Lerche and Muir, 2004). The respiratory depression is not as great compared to other anesthetic drugs such as opioids (Sinclair, 2003) or inhalational anesthetics (Bloor et al., 1989). Respiratory depression is exaggerated with the addition of other respiratory depressants or CNS depressants, which can result in hypercapnia, hypoxemia, and cyanosis (Pypendop and Verstegen, 1999). It is speculated that cyanosis of mouth and gums may also be due to slower blood flow through the peripheral capillary beds and an increased oxygen extraction (Sinclair, 2003). It is therefore recommended to monitor patients for hypoventilation and hypoxemia and administer supplemental oxygen as needed, especially in those receiving a combination of respiratory depressants.

Serious, species-specific, respiratory side effects caused by α₂-adrenergic agonists can occur (Bloor et al., 1989; Celly et al., 1997). The most noted complication occurs in sheep. Within minutes of α₂-adrenergic agonist administration in sheep there can be activation of pulmonary intravascular macrophages (PIM) that produce extensive damage to the capillary endothelium and alveolar type I cells, intraalveolar hemorrhage, and interstitial and alveolar edema (Celly et al., 1997). Pulmonary edema causes decreased alveolar gas exchange, an increase in respiratory rate and airway pressures, and a decrease in pulmonary compliance. Hypoxemia is frequently observed and some sheep will die (Celly et al., 1997). While many animal species (e.g., horses) have PIMs, the activation of these by α₂-agonists in sheep is more commonly seen clinically. Dexmedetomidine causes similar pulmonary changes in the sheep and goat (Kutter et al., 2006). Treatment with an α₂-adrenergic antagonists appears to prevent further activation of PIMs, reverses sedation, and many animals improve clinically. However, the pulmonary effects are not completely eliminated with reversal.

Alpha-2-adrenergic agonists produce reliable muscle relaxation, which is mediated via their interaction with the interneurons in the spinal cord (Sinclair, 2003). They are frequently administered for this effect and to balance drugs that do not provide good muscle relaxation (e.g., ketamine). Muscle twitching has been noted in the dog (Sinclair, 2003) and head bobbing and facial twitching has also been observed in the horse (Lloyd Industries, 2014).

Alpha-2-agonist drugs can effect muscle tone and contraction of smooth muscle such as the uterus and GI tract (see Sections Gastrointestinal Effects and Reproductive Effects).

Alpha-2-adrenergic agonists cause diuresis by multiple mechanisms. They reduce the production or release of antidiuretic hormone (ADH, arginine vasopressin) from the pituitary (Humphreys et al., 1975; Reid et al., 1979); inhibit the actions of ADH on the collecting tubules; and enhance the excretion of sodium (Gellai and Edwards, 1988; Smyth et al., 1985). Renin levels are decreased by the direct activation of renal α₂-adrenergic receptors and indirectly by the initial hypertension produced by the α₂-adrenergic agonists (Smyth et al., 1987) further contributing to diuresis.

Alpha-2-adrenergic agonists also affect micturition by decreasing micturition pressure, bladder capacity, micturition volume, and residual volume via both spinal and peripherally mediated mechanism (Ishizuka et al., 1996). This, combined with diuresis, will cause animals treated with α₂-agonists to produce large amounts of dilute urine that is frequently voided.

Predicting the effects of α₂-adrenergic agonists on catecholamines and cortisol levels is difficult. In general, α₂-adrenergic agonists will decrease catecholamine due to their presynaptic effects on the release of norepinephrine. However, the effects on basal or induced cortisol varies based on drug, dose, and species. In the horse, detomidine will suppress catecholamine activity without suppressing cortisol activity (Raekallio, 1991) whereas in cattle, medetomidine will suppress catecholamine activity without suppressing cortisol activity (Ranheim, 2000). Interestingly, in the dog, high doses (80 μg/kg) of dexmedetomidine suppressed cortisol levels as well as prevented stimulation with ACTH (Maze et al., 1991). However, at clinical doses, dexmedetomidine did not change cortisol level in dogs (Restitutti et al., 2012).

The effect of α₂-adrenergic agonists on glucose homeostasis is complex and dependent upon the drug, the dose, and the species. Hyperglycemia reported after the use of α₂-adrenergic agonists is likely due to a decrease in insulin release from the β-cells in the pancreas and/or increase glucagon release from the α-cells (increased gluconeogenesis) (Angel et al., 1990; Niddam et al., 1990). The α₂-adrenergic agonist, xylazine, causes a mild transient hyperglycemia in cows and horses (Thurmon et al., 1984; Hsu and Hummel, 1981). Medetomidine causes a decrease in insulin without the resultant increase in glucose in dogs (Ambrisko and Hikasa, 2003). Clinical hyperglycemia secondary to α₂-adrenergic agonist administration is generally not high enough to pass the renal threshold for glucose (∼180 mg/dl) and therefore should not produce glucosuria.

Alpha-2-agonist drugs can effect myometrial tone as well as myometrial contraction; however, these effects are related to species, dose, time of reproductive cycle, and species. Furthermore, the clinical effect of α₂-adrenergic agonists on uterine contractility and blood flow is influenced by the level of estrogen and progesterone. Estrogen leads to an up-regulation in α-adrenergic receptors while progesterone will cause a down-regulation due to changes in the transmembrane signal pathways that cause the differences in myometrial contractility (Re et al., 2002).

Myometrial contractions in the nongravid uterus were observed at any equipotent dose of α₂-adrenergic agonists (Schatzmann et al., 1994; Jedruch et al., 1989) and there is a case report of cows having premature labor after the administration of xylazine (Vanmetre, 1992). Lower doses of detomidine (<60 μg/kg IM) in the cow and horse, and medetomidine (<20 μg/kg IV) in the dog, decreased myometrial contractions (Jedruch and Gajewski, 1986; Jedruch et al., 1988, 1989). Higher doses of medetomidine in the dog did cause an increase in myometrial contraction (Jedruch et al., 1989). This biphasic response in the gravid uterus to α₂-adrenergic agonists may possibly be mediated by their effect on the α₁-adrenergic receptor (Ford, 1995; Gaspar et al., 2001; Jedruch et al., 1989).

The effects of medetomidine (40 μg/kg IM) and xylazine (200 μg/kg IM) on intrauterine pressure and uterine blood flow have been studied in the goat (Sakamoto et al., 1996, 1997). Both agents crossed the placenta, reduced uterine blood flow for 120 minutes, and increased intrauterine pressure. These observations would suggest α₂-adrenergic agents should be used with caution in near-term pregnant animals, especially if there are historical or physical evidence to suggest fetal distress is already present.

Alpha-2-agonists produce profound analgesia and can be administered parenterally and neuraxially (e.g., epidurally). The first report of α₂-adrenergic agonist-induced analgesia was in 1974 evaluating clonidine as an analgesic in rats (Paalzow, 1974). Analgesia is produced by activation of α₂-receptors in the CNS in the locus coeruleus (Guo et al., 1996; Schwartz and Clark, 1998) and in the substantia gelatinosa of the dorsal horn of the spinal cord (Savola and Savola, 1996). The effects in the brain are primarily by decreased neural conduction, whereas the effects in the spinal cord are primarily through decreasing release of norepinephrine and substance P (see Section Mechanism of Action). Some of the analgesia may be mediated via I₂-imidazoline receptors (Diaz et al., 1997; Regunathan, 2006) as imidazoline receptor agonist and antagonists can modulate the analgesia produced by morphine (Gentili et al., 2006).

The analgesia produced by α₂-agonists is synergistic with opioids, lidocaine, and N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., ketamine) (Glynn and O’Sullivan, 1996; Lee and Yaksh, 1995; Regunathan, 2006). Therefore these drugs are often used in conjunction with other analgesics.

In people with tolerance to opioids or chronic pain syndromes, α₂-adrenergic agonists are routinely used for rescue analgesia. A major limiting factor to use of this class for analgesia is the concurrent sedation and ataxia. Interestingly, higher plasma levels are needed to produce analgesia than sedation, with horses needing 10 times the plasma level to produce visceral nociception compared with plasma levels needed to produce sedation (Elfenbein et al., 2009).

Epidural administration can produce potent analgesia with minimal sedative or cardiovascular effects compared with intravenous administration (Aminkov and Pascalev, 1998; Greene et al., 1995). The primary receptor subtypes found in the spinal cord are α_2A and α_2C, but α_2A-receptors appears to most active in the nociceptive pathway (Stone et al., 1998). Due to the high lipophilicity of these drugs, there is some systemic absorption and systemic effect (e.g., sedation) after neuraxial administration. The use of α₂-adrenergic antagonists following neuraxially administered α₂-agonists can reduce the side effects whilst maintaining a good level of analgesia (Skarda, 1991).

Clinicians should also note that when α₂-agonist reversal agents are administered (α₂-antagonists; see Section Alpha-2-Adrenergic Antagonists), to reverse sedation, the analgesic effects will be reversed also.

Equipotent intravenous doses for sedation in the horse are considered to be the following: xylazine (1 mg/kg), medetomidine (5–10 μg/kg), romifidine (40–80 μg/kg), and detomidine (20–40 μg/kg) (England et al., 1992; Yamashita et al., 2002). The order in which they are listed also demonstrates the duration of sedation from the shortest to longest in duration (Freeman and England, 2000; Hamm et al., 1995; Yamashita et al., 2002). Detomidine tends to cause the longest duration of ataxia (Hamm et al., 1995; England et al., 1992). There appears to be less ataxia and lowering of the head with romifidine as compared to the other α₂-adrenergic agonists; however, the level of analgesia achieve may be comparable to (England et al., 1992; Spadavecchia et al., 2005) or lower than (Moens et al., 2003; Hamm et al., 1995) other α₂-adrenergic agonists, depending upon the stimulus used. The apparent order of ataxia in horses produced by these agents from least to most appears to be: romifidine < xylazine < medetomidine and detomidine.