Acepromazine is the prototype tranquilizer and is the only drug in that category commonly used in clinical practice (Box 7.3). Acepromazine is a phenothiazine compound. It antagonizes the actions of dopamine as a central neurotransmitter. It also blocks the effects of dopamine at peripheral D₁ and D₂ receptors. Its onset of action is long (15 minutes after IV administration, 30 to 45 minutes after IM administration), and it has a long (3 to 6 hours) duration of action. Acepromazine is sometimes administered PO, but its bioavailability appears poor,⁷ although data in cats are not available. High doses should therefore be used.

Acepromazine produces sedation. Typically, patients are rousable by stimuli of sufficient intensity. The sedative effect is variable among individuals but may be improved by combining acepromazine and opioids (neuroleptanalgesia). Chlorpromazine, another phenothiazine, was shown to decrease morphine-induced excitement in cats,8 and acepromazine is expected to have similar effects. Phenothiazines appear to suppress aggressive behaviors related to dominance rather than fear. Acepromazine is usually not thought to produce analgesia. However, in one study in cats, acepromazine produced mechanical antinociception and potentiated the effect of tramadol.⁹ Acepromazine has been reported to decrease anesthetic requirements, both for injectable and inhaled anesthetics.^10,11 In a study in cats, however, acepromazine did not reduce the induction dose of propofol.¹² Phenothiazines may decrease the seizure threshold,^13,14 and acepromazine should be used with caution in patients with a history of seizures or during procedures or with drugs that may cause seizures.

Acepromazine produces minimal effects on the respiratory system. Respiratory rate may decrease, but blood gases remain normal, probably because of an increase in tidal volume. Acepromazine produces vasodilation and hypotension.¹⁵ The effect is mainly due to alpha-adrenergic blockade; central sympatholysis, direct vasodilation, and/or stimulation of beta₂ adrenergic receptors may contribute. If a vasoconstrictor is used to treat hypotension in cats receiving acepromazine, an alpha₁ agonist devoid of beta₂ effect such as phenylephrine or norepinephrine should be used. Heart rate may decrease, but the effect is usually mild. Phenothiazines protect against epinephrine-induced arrhythmias.¹⁶ They cause splenic sequestration of red blood cells and markedly reduce the hematocrit level.

Acepromazine interferes with temperature regulation. Hypothermia or hyperthermia may result, depending on ambient temperature, although hypothermia is more common. Acepromazine produces antiemetic effects because of its interaction with central dopaminergic receptors at the level of the chemoreceptor trigger zone. Acepromazine reduces gastroesophageal sphincter pressure, possibly increasing the incidence of esophageal reflux and regurgitation.¹⁷ Acepromazine blocks histamine H₁ receptors and may affect the results of intradermal skin testing.¹⁸ Acepromazine applied topically does not affect intraocular pressure in normal eyes but may reduce it when elevated.¹⁹ Acepromazine reduces tear production in normal cats.²⁰

According to the authors’ clinical experience, cats treated with acepromazine appear sedated in the absence of stimulation, but the effects seem to disappear with handling. Acepromazine worsens the hypotensive effect of inhalant anesthetics in cats, and the authors do not commonly use this drug in feline patients.

Three drugs in the benzodiazepine class are used in clinical practice as part of anesthetic management: diazepam, midazolam, and zolazepam. Zolazepam is available only in combination with tiletamine (Telazol) and will not be discussed here (Box 7.4).

Clinical effects relevant to anesthesia include sedation or dysphoria, decreased anxiety, inhibition of aggressive behavior, amnesia, muscle relaxation, anticonvulsant effects, and reduced anesthetic requirements. Benzodiazepines do not appear to produce analgesia after systemic administration. In cats, 1 mg/kg of diazepam administered IM caused apparent sedation; however, when cats were restrained for handling, they vigorously objected.21 A study examined the effects of midazolam, administered IV or IM, at various doses ranging from 0.05 to 5 mg/kg.²² Restlessness was observed initially, followed by sedation, with most cats receiving the higher doses IV assuming lateral recumbency. When cats were restrained, an approximately equal proportion responded more and less than normal, independent of dose and time. It therefore appears that benzodiazepines do not consistently produce sedation in cats, at least when administered alone. Combinations with opioids may improve the consistency of the sedative effect.

Benzodiazepines are commonly used with induction agents to improve muscle relaxation and/or reduce the anesthetic dose. Diazepam and midazolam have been reported to decrease the anesthetic dose of both inhaled and injectable anesthetics.^23–31 They are very effective at preventing and treating convulsions. In humans, midazolam is useful in the treatment of status epilepticus refractory to phenobarbital, phenytoin, and diazepam.³²

Benzodiazepines produce minimal cardiovascular and respiratory effects. Diazepam may decrease ventricular arrhythmias resulting from myocardial ischemia.³³ In hypovolemic patients, high doses of midazolam may produce hypotension.³⁴ Hypotension, arrhythmias, and asystole have been reported after IV administration of diazepam; this is thought to be due to propylene glycol, which is used as a solvent in commercially available solutions.³⁵

The main difference between diazepam and midazolam is related to their physicochemical characteristics and pharmacokinetics. Diazepam is highly hydrophobic, and studies in humans suggest that absorption may be poor after administration in some muscle groups. Midazolam is hydrophilic at low pH and lipophilic at higher pH; it may be better suited to IM administration than diazepam. Its bioavailability after IM administration is higher than 90% in humans and dogs. Onset of effect is short for both drugs. Diazepam undergoes oxidation to nordiazepam, an active metabolite, which is eliminated about six times more slowly than diazepam. The clearance of diazepam itself in cats is low. Diazepam is therefore expected to have long-lasting effects.³⁶ There are no published data on the pharmacokinetics of midazolam in cats. However, midazolam is rapidly eliminated in dogs, in contrast to diazepam.^37,38 In the species in which it has been examined, the metabolism of midazolam results in the production of hydroxymidazolams, which have pharmacologic activity but are usually rapidly eliminated. Clinically, the duration of effect of midazolam appears much shorter than that of diazepam.

Acute fulminant hepatic necrosis has been reported in cats following diazepam administration.³⁹ However, it followed repeated oral administration; similar toxicity has not been reported after occasional parenteral administration of the drug.

Clinically, benzodiazepines are sometimes used for premedication before general anesthesia, in combination with opioids, in an attempt to improve the sedation produced by the opioid.

Agonists of the alpha₂-adrenergic receptors (alpha₂ agonists) act mainly by modulating noradrenergic transmission in the central nervous system. They also have direct effects on various organs. Drugs in this class commonly used in cats include xylazine, medetomidine, and dexmedetomidine (Box 7.5).

Alpha₂ agonists produce sedation; the effect is dose dependent.40 At high doses, sedation is profound, and patients are unresponsive to most stimuli, although arousal and aggressive behavior is always possible. Alpha₂ agonists also produce analgesia.⁴¹ The duration of the analgesic effect of both xylazine and dexmedetomidine appears short.^42,43 Alpha₂ agonists reduce anesthetic requirements in a dose-dependent manner. They induce hypothermia through an effect on the hypothalamic thermoregulatory center.

Respiratory effects produced by alpha₂ agonists are considered minimal in cats. Respiratory rate tends to decrease, but blood gases are usually unaffected.^44,45

The typical cardiovascular response to the administration of alpha₂ agonists is biphasic. Initially, blood pressure and systemic vascular resistance increase, whereas heart rate and cardiac output decrease.^42,45,46 The increase in blood pressure may not be seen after IM administration. These effects are followed by a decrease in arterial pressure; heart rate and cardiac output remain lower than normal. Systemic vascular resistance either returns progressively toward normal or remains elevated, depending on the drug and the dose considered. The bradycardia may be accompanied by other arrhythmias. The cardiovascular effects of alpha₂ agonists are usually considered to be dose dependent. The increase in systemic vascular resistance is due to stimulation of alpha₂ receptors on the vascular smooth muscle, resulting in vasoconstriction. The decrease in cardiac output is due both to a decrease in heart rate and stroke volume. Myocardial contractility appears unaffected; the decrease in stroke volume is likely a result of vasoconstriction producing an increase in afterload.

Because the decrease in cardiac output appears to be at least in part related to the bradycardia, combining these drugs with anticholinergics has been advocated. However, the concomitant use of anticholinergics with alpha₂ agonists is controversial. The effectiveness in increasing heart rate could depend on the timing of administration of the drugs. When given before the alpha₂ agonist, anticholinergics tend to increase heart rate, which decreases after the alpha₂ agonist is administered. When given simultaneously, there is an initial bradycardia followed by a return of heart rate toward baseline values. In both cases, severe hypertension is produced, and cardiac performance further decreases.^47–49 More recently, the use of vatinoxan has been proposed to minimize the cardiovascular effects of medetomidine and dexmedetomidine.^50,51 Vatinoxan is an alpha₂ antagonist that does not cross the blood-brain barrier. When coadministered with dexmedetomidine, it blunts the vasoconstrictive effect (which is produced in the vascular smooth muscle), and thereby the decrease in cardiac output, with minimal effect on sedation (which is produced within the central nervous system). A medetomidine-vatinoxan combination (Zenalpha) is commercially available and approved for use in dogs. It should be noted that the formulation is based on the optimal vatinoxan dose relative to that of medetomidine in dogs. The optimal vatinoxan dose relative to that of medetomidine is lower in cats than in dogs. Therefore, this formulation should not be used in cats as it would likely result is moderate to severe hypotension.

Alpha₂ agonists inhibit insulin release and cause an increase in glycemia. They also inhibit the release of antidiuretic hormone and its effect on renal tubules, resulting in water diuresis. Alpha₂ agonists cause vomiting in cats and have been used for that purpose. The incidence of vomiting is higher after xylazine than after dexmedetomidine administration.

Xylazine is shorter acting, less potent, and less selective for the alpha₂ receptors than dexmedetomidine. Some of the effects following xylazine administration may be related to its action on alpha₁ receptors.

Clinically, xylazine and dexmedetomidine are used mainly for their sedative effect. They are sometimes used to improve analgesia. Combinations with opioids may reduce the dose required to produce sedation.⁵² Because of their cardiovascular effects, they should be used with caution in geriatric patients or patients with significant organ dysfunction. The use of medetomidine in cats with hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction has been suggested to decrease the obstruction; dexmedetomidine is expected to produce similar effects.⁵³

Ketamine and Telazol (Zoetis) are sometimes used as premedication before general anesthesia. Their pharmacology is reviewed in the section on induction agents. Dissociative anesthetics produce dose-dependent effects ranging from mild or moderate sedation to anesthesia. They may be useful in the intractable cat if an injection can be administered. Ketamine should not be used alone because of an increase in muscle tone and the risk for convulsions; it should be combined with acepromazine, a benzodiazepine, or an alpha₂ agonist (Box 7.6).