General Pharmacology

Anticholinergics competitively antagonize acetylcholine at postganglionic terminations of cholinergic fibers in the autonomic nervous system. They are used as preanesthetic medications to decrease salivary secretions, decrease gastric fluid acidity, and inhibit the bradycardic effects of vagal stimulation. Other effects include mydriasis, decreased tear formation, decreased intestinal motility, and bronchodilation. Atropine and glycopyrrolate are the two anticholinergic drugs used in dogs and cats.

Atropine Sulfate

Atropine sulfate (0.02 to 0.04 mg/kg) can be administered intramuscularly, subcutaneously, or intravenously. The duration of action is 60 to 90 minutes. Atropine may stimulate vagal nuclei in the medulla and cause an initial bradycardia before the desired effect is seen, particularly when the drug is administered intravenously. Other central effects of atropine include depression, restlessness, and delirium. Atropine administration may cause cardiac arrhythmias and sinus tachycardia. Atropine does cross the placental barrier and may lead to central and peripheral anticholinergic effects in the fetus when administered to the dam. Arrhythmias are more common after intravenous administration and include second-degree atrioventricular block, unifocal ventricular premature contractions, and ventricular bigeminy.¹ Atropine is contraindicated in animals with preexisting tachycardia.

Glycopyrrolate

Glycopyrrolate is a synthetic quaternary ammonium anticholinergic. Glycopyrrolate may be given intramuscularly, subcutaneously, or intravenously at a dose of 0.011 mg/kg. The duration of action of vagal inhibition is 2 to 4 hours, significantly longer than with atropine. The antisialagogue effect may persist for up to 7 hours. The cardiovascular effects of glycopyrrolate are similar to those of atropine. Because of its large structure, glycopyrrolate does not cross the blood–brain or placental barrier readily and therefore has minimal central or fetal effects.²

Acepromazine

Acepromazine (0.05 to 0.1 mg/kg intravenously, intramuscularly, or subcutaneously, not to exceed a total dose of 3 mg; oral dose is 1 to 2 mg/kg), a phenothiazine tranquilizer, is used commonly as a premedication before general anesthesia in dogs and cats to relieve anxiety. Through depression of the reticular activating system and antidopaminergic actions in the central nervous system (CNS), acepromazine produces mental calming, decreased motor activity, and increased threshold for responding to external stimuli. Acepromazine does not produce analgesia but may act synergistically when administered concurrently with other drugs with analgesic activity. Administration of acepromazine will decrease the dose of subsequent anesthetic agents. Other effects include antiemetic activity and antihistaminergic properties. Hypotension and hypothermia can result from depression of vasomotor reflexes. Acepromazine is metabolized by the liver and should not be used in patients with liver disease. Because of the potential for hypotension, acepromazine should be used cautiously in compromised patients, particularly those with significant cardiovascular disease. Acepromazine may inhibit platelet function and should be avoided in patients with coagulopathies.²

In many veterinary textbooks, authors cautioned against the use of acepromazine in animals at risk for seizures. Recently, this caution is being questioned on account of a lack of references. In two retrospective studies, no evidence was found that acepromazine lowered the seizure threshold in dogs with a history of seizure disorders.^3,4 It was further concluded that a controlled prospective study is necessary for a more thorough evaluation of the use of acepromazine both in this patient population and in the general canine population.

Diazepam

Diazepam (0.1 to 0.2 mg/kg intravenously) is a benzodiazepine tranquilizer that possesses muscle relaxant and anticonvulsant properties. Benzodiazepines exert their effect by enhancing the CNS inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine and by combining with CNS benzodiazepine receptors.¹ Diazepam may produce a mild calming effect in some patients, but agitation and excitement can also occur. Diazepam is solubilized by mixing with propylene glycol. Diazepam has minimal cardiovascular effects; bradycardia and hypotension may be seen after rapid intravenous administration. Propylene glycol is associated with pain on injection and incompatibility when mixed in the same syringe with other drugs. Clinical uses of diazepam in small animal anesthesia include providing muscle relaxation when given concurrently with dissociative anesthetics and as a co-induction agent with injectable anesthetics (thiopental, propofol, etomidate) to decrease their doses or side effects (or both). The effects of diazepam can be reversed with the benzodiazepine antagonist flumazenil.

Midazolam

Midazolam (0.1 to 0.2 mg/kg intravenously and intramuscularly) is a benzodiazepine tranquilizer with behavioral effects and clinical uses similar to those of diazepam. Midazolam is more potent and has a shorter duration of action than diazepam. Midazolam is water soluble at a pH of 3.5. At a pH above 4, the chemical structure changes to become lipid soluble.⁵ Unlike diazepam, midazolam can be mixed with other anesthetic agents and can be administered intramuscularly without causing irritation. Flumazenil can be used to antagonize the effects of midazolam.

Midazolam is often used as a component of a total intravenous anesthetic technique (TIVA). The advantage of TIVA is that general anesthesia can be maintained without the use of inhalant agents, which can cause significant cardiovascular depression in certain high-risk patients. Midazolam, 8 μg/kg/min, combined with fentanyl, 0.8 μg/kg/min, are delivered as a constant-rate infusion (CRI) after induction of anesthesia. The dose can be adjusted as needed to produce a desirable level of anesthesia. Typically, the dose is lowered periodically during the anesthetic period, based on the judgment of the level of anesthesia. This technique makes recovery less prolonged. In certain patients a low concentration of inhalant (e.g., sevoflurane) may be added if the TIVA is inadequate to maintain a desirable level of anesthesia. This is particularly true in animals that are alert and active preoperatively. These patients have significant cardiovascular disease precluding a primary inhalant regimen but are asymptomatic or well-compensated. Examples include young dogs with valvular stenosis or patent ductus arteriosis without evidence of heart failure.

Xylazine

Xylazine (0.2 to 1 mg/kg intravenously and intramuscularly) can be given as a premedication agent alone or in combination with opioids to facilitate intravenous catheter placement and decrease dose requirements of subsequent injectable and inhalant anesthetic agents. It is also used commonly as an adjuvant with dissociative anesthetic agents to improve muscle relaxation and provide visceral analgesia for short surgical procedures.