Perioperative use of selective alpha-2 agonists and antagonists in small animals

Abstract

Alpha-2 agonists are the only single class of anesthetic drugs that induce reliable, dose-dependent sedation, analgesia, and muscle relaxation in dogs and cats. Used at low doses, as adjuncts to injectable and inhalational anesthetics, selective alpha-2 agonists dramatically reduce the amount of anesthetic drug required to induce and maintain anesthesia. This reduction in anesthetic requirements is achieved without significant depression of pulmonary function and with limited effects on cardiovascular function. Selective alpha-2 agonists can also be used postoperatively to potentiate the analgesic effects of opioids and other drugs. Given the nearly ideal pharmacodynamic profile and reversibility of alpha-2 agonists, these drugs will play a central role in balanced approaches to anesthesia and the management of perioperative pain in healthy dogs and cats.

Introduction

Alpha-2 adrenergic receptor agonists induce reliable, dose-dependent sedation, analgesia, and muscle relaxation in dogs and cats that can be readily reversed by administration of selective antagonists. Two alpha-2 agonists (xylazine, medetomidine) and 2 antagonists (yohimbine, atipamezole) are approved for use in small animals in Canada. Another alpha-2 agonist, romifidine, is approved for use in horses, but not in dogs and cats. Xylazine has been used as a sedative in small animals for over 2 decades, and medetomidine has been used for over a decade in Europe and has recently been approved for use in North America (1,2). Traditionally, these drugs have been used at relatively high doses to induce not only sedation and analgesia, but immobilization. Currently, xylazine and medetomidine are used at relatively low doses, alone or in combination with other drugs (benzodiazepines, opioids), to induce sedation for minor diagnostic and surgical procedures, and as adjuncts to injectable (ketamine, thiopental, propofol) and inhalational (halothane, isoflurane) anesthetics (3). The purpose of this article is to review relevant adrenergic physiology and pharmacology, and to discuss the advantages and disadvantages of perioperative use of selective alpha-2 agonists (medetomidine, romifidine) and antagonists (atipamezole). A search of the PubMed database was conducted using the terms medetomidine, romifidine, atipamezole, dogs, and cats. Papers concerned with the perioperative use of xylazine are included for comparison and to illustrate specific points.

Perioperative use of alpha-2 agonists in small animals has been controversial (4,5). Certainly, the initial vasoconstriction and reflex bradycardia induced by the administration of alpha-2 agonists are problematic. However, at the low doses used perioperatively, these cardiovascular effects are not as pronounced and are well tolerated by healthy dogs and cats. Alpha-2 agonists also produce a dramatic reduction in the amount of thiopental or propofol required to induce anesthesia, and the amount of isoflurane required to maintain anesthesia (6–8). Given that all 3 of these general anesthetics have dramatic effects on myocardial function and a very narrow therapeutic range, the dose reduction achieved by administering alpha-2 agonists preoperatively reduces the adverse cardiovascular effects associated with administration of most general anesthetics. Isoflurane also produces marked vasodilation and significant reductions in arterial blood pressure at concentrations normally required to induce and maintain anesthesia (9). In dogs, concurrent administration of alpha-2 agonists increases vascular tone and attenuates the vasodilation and reduction in arterial blood pressure induced by isoflurane (10,11). Therefore, preoperative administration of alpha-2 agonists counteracts the cardiovascular effects of isoflurane, first, by reducing the amount of isoflurane required to maintain anesthesia and, then, by restoring vascular tone. In sharp contrast, preoperative or concurrent administration of acepromazine — a drug that also reduces vascular tone — intensifies the vasodilation and reduction in arterial blood pressure induced by isoflurane (12). In fact, when blood pressure is monitored routinely, hypotension is by far the most common complication that occurs in anesthetized dogs and cats (13,14).

Concerns have also been raised about the potential for alpha-2 agonists to sensitize the myocardium to epinephrine-induced arrhythmias (15). Initial studies suggested that high doses of xylazine may facilitate the development of reentrant ventricular arrhythmias (premature depolarizations, tachycardia) in dogs anesthetized with thiopental and halothane — 2 drugs that dramatically sensitize the myocardium to epinephrine (16,17). Subsequent studies in dogs anesthetized with halothane or isoflurane and given lower doses of xylazine or medetomidine showed that alpha-2 agonists do not facilitate the development of reentrant ventricular arrhythmias (18,19). Results of the latter studies were confirmed by additional studies at the University of Guelph (20,21). Further, the decrease in sympathetic tone and increase in parasympathetic tone induced by the administration of selective alpha-2 agonists appears to attenuate the development of epinephrine-induced arrhythmias in dogs (22).

An increase in the occurrence of anesthetic complications has been reported following administration of xylazine to small animals by veterinarians in Ontario in 1993 (23). Failure to appreciate the dramatic reduction in anesthetic requirements produced by preoperative administration of high doses of xylazine and subsequent administration of a relative overdose of injectable or inhalational anesthetic may have contributed to the increased risk reported in this study. Further, patient monitoring standards were extremely lax a decade ago, and failure to recognize and treat significant bradyarrhythmias could have been a factor as well.

Physiology

Norepinephrine is the endogenous ligand for alpha-2 adrenergic receptors, and these receptors are located in tissues throughout the body. Alpha-2 receptors exist presynaptically and postsynaptically in neuronal and nonneuronal tissues, and extrasynaptically in the vasculature. Within the central nervous system, alpha-2 receptors located on noradrenergic neurons are called “autoreceptors” and those on nonnoradrenergic neurons are called “heteroceptors.” In general, the sedative and anxiolytic effects of alpha-2 agonists are mediated by activation of supraspinal autoreceptors located in the pons (locus ceruleus), and the analgesic effects are mediated by activation of heteroceptors located in the dorsal horn of the spinal cord. However, the supraspinal autoreceptors located in the pons also play a prominent role in descending modulation of nociceptive input (24). Three distinct alpha-2 receptor subtypes (A, B, and C) have also been identified (25,26). Alpha-2 A receptors mediate sedation, analgesia, hypotension, and bradycardia, while alpha-2 B receptors mediate the initial surge in vascular resistance and reflex bradycardia. Alpha-2 C receptors mediate the hypothermia that accompanies administration of alpha-2 agonists. Subtype selective agonists are not currently available, but alpha-2 A selective agonists with fewer vascular side effects could potentially be developed in the near future.

As with other adrenergic drugs, selective alpha-2 receptor agonists induce dose-dependent changes in cardiovascular function (27–29). Cardiovascular effects are best described in 2 phases: an initial peripheral phase characterized by vasoconstriction, increased blood pressure, and reflex bradycardia; and a subsequent central phase characterized by decreased sympathetic tone, heart rate, and blood pressure. Atrioventricular blockade can also occur secondary to the initial increase in blood pressure and reflex increase in vagal tone. The peripheral cardiovascular effects are most pronounced when alpha-2 receptor agonists are given, IV, at high doses, and these effects can be reduced by giving these drugs, IM, at low doses (30). Although cardiac output decreases after administration of alpha-2 receptor agonists, blood flow to the heart, brain, and kidneys is maintained by redistribution of flow from less vital organs (31).

Unlike opioids, alpha-2 receptor agonists have little effect on pulmonary function. Respiratory rate and minute ventilation decrease after administration of xylazine or medetomidine, but blood gas values do not change appreciably. Even at relatively high doses, xylazine does not alter pH, PaCO₂, and PaO₂ in dogs and cats (30,32). Similarly, medetomidine and romifidine have little effect on blood gas values in dogs (33–35). Hypoxemia is a common response to administration of alpha-2 receptor agonists in most ruminants. This response appears to be an inflammatory reaction, and is confined to ruminant species that have a unique population of pulmonary intravascular macrophages (36).

Alpha-2 agonists have significant effects on gastrointestinal function. Vomiting occurs in approximately 20% of dogs and in most cats that are given xylazine or medetomidine. Normally, this is not a problem and may be advantageous if owners or hospital staff fail to withhold food from patients before anesthesia and surgery. However, the potential for development of an aspiration pneumonia exists if a properly inflated cuffed endotracheal tube is not in place. Administration of anticholinergics 10 to 20 min before administration of alpha-2 agonists appears to reduce the occurrence of vomiting in dogs (35). Vomiting also produces dramatic increases in intraocular pressure, which is a potential problem for some patients with ocular injury or disease. Administration of alpha-2 agonists increases gastrointestinal sphincter tone and decreases gastrointestinal motility. These effects are mediated by activation of visceral alpha-2 receptors and inhibition of acetycholine release.

Alpha-2 agonists also have significant effects on renal and endocrine function in small animals. Administration of xylazine or medetomidine activates alpha-2 receptors on pancreatic beta cells and inhibits release of insulin for approximately 2 h (37,38). While both drugs produce a comparable inhibition of insulin release, medetomidine produces a less dramatic change in plasma glucose concentrations (38). This difference may be due to a difference in selectivity for the alpha-2 versus the alpha-1 receptor. Xylazine, a less selective agonist, appears to increase plasma glucose concentrations directly by activating alpha-1 receptors and stimulating hepatic glucose production. Administration of medetomidine also decreases urine specific gravity and increases urine production for approximately 4 h (39). Apparently, alpha-2 agonists interfere with the action of antidiuretic hormone on the renal tubules and collecting ducts, which increases the production of dilute urine (40,41).

Clinical pharmacology

Two selective alpha-2 agonists, medetomidine and romifidine, and a selective anatgonist, atipamezole, are currently licensed for use in animals in Canada. Medetomidine is approved for use in dogs as a sedative-analgesic, and studies on the sedative, analgesic, and cardiopulmonary effects of medetomidine in cats have been completed (42–44). Romifidine is not approved for use in small animals, but studies on the sedative and cardiopulmonary effects of romifidine in dogs and cats have been completed (28,45–47). Atipamezole is approved for use in dogs for the reversal of the sedative and analgesic effects of medetomidine. These selective alpha-2 agonists and antagonists have a high affinity for the alpha-2 receptor and are administered on a mcg/kg basis, rather than a mg/kg basis.

Medetomidine is a highly selective alpha-2 agonist that is supplied as a racemic mixture of 2 optical enantiomers. Dexmedetomidine is the active enantiomer and levomedetomidine has no apparent pharmacological activity. Shortly after medetomidine was approved for use in dogs as a sedative-analgesic in North America, dexmedetomidine was approved for use in humans as a postoperative sedative in the United States. Medetomidine is approximately 10 times more selective for the alpha-2 receptor than is xylazine (48). The drug has a rapid onset of action and can be given IV or IM. After IM injection, the drug is rapidly absorbed and peak plasma concentrations are reached within 30 min. The elimination half-life after either IV or IM administration is approximately 1 h (49). Administration of medetomidine at a dose of 20 mcg/kg BW induces sedation comparable with that of xylazine at a dose of 1 mg/kg BW (50,51). When medetomidine is given IM, the onset of sedation is rapid (<10 min), regardless of dose (52). In healthy dogs, the label dose of medetomidine ranges from 30 to 60 mcg/kg BW, but IM doses of 5 to 10 mcg/kg BW are more appropriate for perioperative use when given with an opioid (53). In healthy cats, the use of medetomidine is “off-label” and IM doses of 10 to 20 mcg/kg BW appear to be appropriate for perioperative use when given with an opioid (54).

Romifidine is a selective alpha-2 agonist derived from clonidine, and is not labeled for use in small animals in Canada. The drug is more selective than xylazine but much less selective than medetomidine for the alpha-2 receptor. Romifidine has a slower onset of action and a much longer duration of action than either xylazine or medetomidine. Intramuscular administration of romifidine at a dose of 40 mcg/kg BW induces sedation comparable with that of xylazine at a dose of 1 mg/kg BW (28,51). At doses that produce equivalent degrees of sedation, romifidine induces changes in cardiovascular function that are comparable with those of xylazine and medetomidine. In healthy dogs, IM administration of romifidine at doses of 10 to 20 mcg/kg BW induces mild to moderate sedation with limited effects on cardiovascular function (28). In healthy cats, IM administration of romifidine at a dose of 40 mcg/kg BW induces moderate sedation (47). Because romifidine has not been approved for use in small animals and because clinical research experience with this drug is limited, romifidine should not be used in small animals at this time.

Atipamezole is a highly selective alpha-2 antagonist that is labeled for the reversal of the sedative and analgesic effects of medetomidine in dogs. The drug is 200 to 300 times more selective for the alpha-2 receptor than is yohimbine (48). After IM administration of atipamezole, peak plasma concentrations are reached within 10 min and the elimination half-life is approximately 2 to 3 h (atipamezole package insert). Atipamezole reverses not only the neurological effects of medetomidine, but also the cardiovascular side-effects. Therefore, atipamezole can be used to reverse the bradycardia that accompanies medetomidine administration. Atipamezole is usually given to reverse the effects of medetomidine after nonpainful diagnostic or therapeutic procedures, and it is not usually given perioperatively. Calculation of the dose of alpha-2 receptor antagonist required should always be based on the amount of agonist given and the time since administration. Generally, it is better to “underdose” than to “overdose” the antagonist. If a “relative overdose” of atipamezole is given, neurological (excitement and muscle tremors), cardiovascular (hypotension and tachycardia), and gastrointestinal (salivation and diarrhea) side effects can occur. Complete reversal of the sedative and analgesic effects of medetomidine is achieved when atipamezole is given IM to dogs and cats at 4 to 6 times and 2 to 3 times the dose of medetomidine, respectively (55,56). Atipamezole and anticholinergics can both cause dramatic increases in heart rate, and concurrent use of these drugs should be avoided.

Perioperative use

As adjuncts to general anesthetics, alpha-2 receptor agonists have a nearly ideal pharmacodynamic profile in dogs and cats. In addition to providing sedation, analgesia, and muscle relaxation, preoperative administration of xylazine or medetomidine produces substantial reductions in the amount of injectable and inhalational anesthetic required to induce and maintain anesthesia. Alpha-2 receptor agonists also attenuate the stress response to surgical trauma by reducing catecholamine and cortisol levels postoperatively (57–59). The initial increase in vascular resistance and blood pressure, and subsequent bradycardia, are potential problems, but these side effects are well tolerated by healthy dogs and cats. Vomiting is also a potential problem for some patients. As a general rule, alpha-2 agonists should not be given to pediatric or geriatric animals, or to animals with significant neurological, cardiovascular, respiratory, hepatic, or renal disease. In other words, proper patient evaluation and selection is critically important. Once preanesthetic and anesthetic drugs are given, patients should be monitored carefully throughout the perioperative period, paying special attention to heart rate and rhythm.

Alpha-2 agonists and acepromazine are the only reliable sedatives currently available for use in dogs and cats. Acepromazine is used preoperatively on a routine basis to provide sedation for catheter placement and induction of anesthesia; it is often given in combination with opioids to provide both sedation and analgesia. However, acepromazine is not suitable for every patient (brachycephalics, epileptics, boxers) and can cause significant hypotension in animals anesthetized with isoflurane (12). Medetomidine can be given preoperatively at low doses to healthy dogs and cats, alone or in combination with opioids (Table 1). Compared with acepromazine, medetomidine produces better analgesia for catheter placement and greater reductions in anesthetic requirements, and it is less likely to cause hypotension in animals anesthetized with isoflurane (59). Bradycardia and atrioventricular block can occur after administration of low doses of medetomidine, but these can be prevented by concurrent administration of atropine.

Table 1.

Preoperative sedation and analgesia for healthy dogs and cats

Drugs	Doses for healthy dogsa	Doses for healthy catsb
Atropine	0.05 mg/kg, IM	0.05 mg/kg, IM
Medetomidine	10–20 mcg/kg, IM	20–40 mcg/kg, IM
Atropine	0.05 mg/kg, IM	0.05 mg/kg, IM
Medetomidine	5–10 mcg/kg, IM	10–20 mcg/kg, IM
Butorphanol	0.2–0.4 mg/kg, IM	0.2–0.4 mg/kg, IM
Atropine	0.05 mg/kg, IM	0.05 mg/kg, IM
Medetomidine	5–10 mcg/kg, IM	10–20 mcg/kg, IM
Morphine	0.2–0.4 mg/kg, IM	0.2–0.4 mg/kg, IM
Atropine	0.05 mg/kg, IM	0.05 mg/kg, IM
Medetomidine	5–10 mcg/kg, IM	10–20 mcg/kg, IM
Hydromorphone	0.04–0.08 mg/kg, IM	0.04–0.08 mg/kg, IM
Atropine	0.05 mg/kg, IM	0.05 mg/kg, IM
Medetomidine	5–10 mcg/kg, IM	10–20 mcg/kg, IM
Oxymorphone	0.04–0.08 mg/kg, IM	0.04–0.08 mg/kg, IM

^a Medetomidine should not be given to pediatric or geriatric dogs, or to dogs with significant neurological, cardiac, respiratory, hepatic, or renal disease

^b Medetomidine should not be given to pediatric or geriatric cats, or to cats with significant neurological, cardiac, respiratory, hepatic, or renal disease. Medetomidine is not approved for use in cats in Canada

The use of anticholinergics to prevent the bradycardia and atrioventricular blockade induced by preoperative administration of selective alpha-2 agonists is controversial (33,35,60–62). Although concurrent anticholinergic administration is not mandatory, it is recommended for the following reasons: First, even at low preanesthetic doses, significant bradycardia can occur if an anticholinergic is not given concurrently with medetomidine. Second, the potential for severe vagotonic responses and profound bradycardia, secondary to surgical manipulation and administration of other anesthetic drugs, is higher during the perioperative period. And third, while concurrent administration of anticholinergics with high doses of medetomidine causes dramatic increases in vascular resistance and myocardial work, these increases are less pronounced with low doses of medetomidine.

Bradycardia is prevented more consistently when anticholinergics are given 10 to 20 min before administration of medetomidine (33,53,63), but this is not always practical. Atropine has a more rapid onset of action than does glycopyrrolate and can be given at the same time as low doses of medetomidine. It is also important to remember that anticholinergic administration enhances vagal tone initially and can increase the severity of alpha-2 agonistinduced bradycardia and atrioventricular block transiently, if atropine or glycopyrrolate is given after administration of alpha-2 agonists (35). Concurrent administration of anticholinergics with alpha-2 agonist-ketamine combinations should be avoided, because prolonged increases in heart rate can occur (64). Further, the use of anticholinergic-ketamine combinations has been associated with myocardial infarcts and perioperative mortality in cats (65).

Ultra low doses of medetomidine can be given postoperatively to dogs and cats, alone or in combination with opioids (Table 2). Administration of selective alpha-2 agonists at these doses enhances and prolongs the analgesic effects of opioids with limited effects on cardiovascular function. Lower doses of opioids can also be used, which may reduce the frequency of postoperative respiratory depression. Selective alpha-2 agonists can also be used to manage anxiety and dysphoria postoperatively. Further, the duration of action of medetomidine is significantly less than that of acepromazine, and the degree of sedation can be more readily controlled and, if necessary, reversed.

Table 2.

Postoperative sedation and analgesia for healthy dogs and cats

Drugs	Doses for healthy dogsa	Doses for healthy catsb
Medetomidine	2–4 mcg/kg, IM	4–8 mcg/kg, IM
Medetomidine	1–2 mcg/kg, IM	2–4 mcg/kg, IM
Butorphanol	0.1–0.2 mg/kg, IM	0.1–0.2 mg/kg, IM
Medetomidine	1–2 mcg/kg, IM	2–4 mcg/kg, IM
Morphine	0.1–0.2 mg/kg, IM	0.1–0.2 mg/kg, IM
Medetomidine	1–2 mcg/kg, IM	2–4 mcg/kg, IM
Hydromorphone	0.02–0.04 mg/kg, IM	0.02–0.04 mg/kg, IM
Medetomidine	1–2 mcg/kg, IM	2–4 mcg/kg, IM
Oxymorphone	0.02–0.04 mg/kg, IM	0.02–0.04 mg/kg, IM

^a Medetomidine should not be given to pediatric or geriatric dogs, or to dogs with significant neurological, cardiac, respiratory, hepatic, or renal disease

^b Medetomidine should not be given to pediatric or geriatric cats, or to cats with significant neurological, cardiac, respiratory, hepatic, or renal disease. Medetomidine is not approved for use in cats in Canada