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Can Vet J. Nov 2003; 44(11): 885–897.
PMCID: PMC385445

A review of the physiological effects of α2-agonists related to the clinical use of medetomidine in small animal practice

Abstract

Medetomidine is a relatively new sedative analgesic drug that is approved for use in dogs in Canada. It is the most potent α2-adrenoreceptor available for clinical use in veterinary medicine and stimulates receptors centrally to produce dose-dependent sedation and analgesia. Significant dose sparing properties occur when medetomidine is combined with other anesthetic agents correlating with the high affinity of this drug to the α2-adrenoreceptor. Hypoventilation occurs with medetomidine sedation in dogs; however, respiratory depression becomes most significant when given in combination with other sedative or injectable agents. The typical negative cardiovascular effects produced with other α2-agonists (bradycardia, bradyarrhythmias, a reduction in cardiac output, hypertension ± hypotension) are also produced with medetomidine, warranting precautions when it is used and necessitating appropriate patient selection (young, middle-aged healthy animals). While hypotension may occur, sedative doses of medetomidine typically raise the blood pressure, due to the effect on peripheral α2-adrenoreceptors. Anticholinergic premedication has been recommended with α2-agonists to prevent bradyarrhythmias and, potentially, the reduction in cardiac output produced by these agents; however, current research does not demonstrate a clear improvement in cardio vascular function. Negatively, the anticholinergic induced increase in heart rate potentiates the α2-agonist mediated hypertension and may increase myocardial oxygen tension, demand, and workload. Overall, reversal with the specific antagonist atipamezole is recommended when significant cardiorespiratory complications occur. Other physiological effects of medetomidine sedation include; vomiting, increased urine volumes, changes to endocrine function and uterine activity, decreased intestinal motility, decreased intraocular pressure and potentially hypothermia, muscle twitching, and cyanosis. Decreased doses of medetomidine, compared with the recommended label dose, should be considered in combination with other sedatives to enhance sedation and analgesia and lower the duration and potential severity of the negative cardiovascular side effects. The literature was searched in Pubmed, Medline, Agricola, CAB direct, and Biological Sciences.

Introduction

Medetomidine is a potent and highly specific α2-adrenoreceptor agonist that has been used extensively in Europe and is registered in 34 countries world-wide. It is licensed for IM and IV use only in dogs in Canada and the United States, but in other countries, such as the United Kingdom and Finland, it is approved for use in both dogs and cats. Medetomidine is a lipophillic compound that is rapidly and completely absorbed after IM injection. The absorption half-life is approximately 7 min with peak serum levels at 30 min in the dog (1). The drug is not licensed for SC use, due to potentially less reliable and incomplete sedation compared with IM administration (2). It is supplied as a 0.1% or 1 mg/mL (1000 μg/mL) solution and is marketed as a racemic mixture of 2 stereoisomers, dextro-medetomidine and levo-medetomidine. The dextro-isomer, dexmedetomidine, is the active isomer of the medetomidine formulation and when administered at half the dose induces similar effects to medetomidine (3,4). Dexmedetomidine is currently not marketed for veterinary medicine; however, research using this isomer has been performed in dogs and cats and this information is included in this review. The levo-isomer, levomedetomdine, lacks pharmacological activity and only shows mild sedative and analgesic properties at high doses (3).

The beneficial effects of medetomidine are the same as those of other α22-agonists and include reliable sedation, analgesia, muscle relaxation, and anxiolysis, as well as a decrease in the anesthetic requirements of injectable and inhalant agents (anesthetic sparing). It is not a controlled substance and, therefore, does not require extensive record keeping. These qualities make medetomidine a viable option in small animal anesthesia. Unfortunately, the negative cardiovascular effects of earlier α2-agonists (xylazine), including bradycardia and associated arrhythmias, hypertension or hypotension, and reduced cardiac output, are still observed with medetomidine and cause concern among clinicians with respect to their use as premedication or sedative agents.

When xylazine was introduced on the veterinary market, its potency was not always respected and it was used indiscriminately on all types of patients at high doses, without consideration always being given to the dose sparing benefits of these agents. This was compounded by the fact that there were no commercially available reversal agents at this time. It is likely that the manner in which xylazine was used in combination with the negative cardiovascular effects resulted in the increase in mortality rate in healthy dogs demonstrated with xylazine premedication compared with other preanesthetic regimes in the mortality studies to date (5,6). Comparable clinical data are not yet available for medetomidine.

With this history in mind, practitioners need to 1) review the general physiologic effects of α2-agonists; 2) recognize the significant dose sparing effect and added respiratory depression that occurs when these drugs are used in combination with other sedatives, injectable anesthetics, inhalant anesthetics, or both; and 3) consider using clinically lowered doses of these agents. The purpose of this article is to provide the reader with an overview of the main physiologic effects of α2-agonists and to provide a summary of the current scientific and clinical data on the use of medetomidine in small animals. The literature cited was highlighted from searches of Pubmed, Medline, Agricola, CAB-direct, and Biological Sciences encompassing the relevant physiologic effects of α2-agonists, specifically medetomidine, in dogs and cats.

Alpha2 adrenoreceptors

The α2-adrenoreceptor is a distinct subclassification of α-adrenergic receptors, which are located in the central nervous system (CNS) and virtually every peripheral tissue (7). Alpha2-adrenoreceptors are comprised of numerous subtypes, α2A, α2B, α2C, and α2D, based on classical pharmacologic and molecular biologic studies (7,8,9), and these subtypes are distributed throughout the CNS (9,10). The diversity in α2-adrenoreceptor subtype, density, and location in animals and humans has led to considerable differences in drug doses and overall effects of α2-agonists in the various species. The receptor subtypes of general clinical importance include the α2A subtype, which regulates the stage of awareness, arousal, and vigilance in the brainstem, and the α2B subtype, which regulates the peripheral vasoconstrictive effects (7). Species differences exist, based on the proportion of these subtypes centrally at the level of the brainstem. For example, α2A subtypes predominate in canine and rat brainstems (11), while the α2D subtype appears to predominate in the sheep brainstem (12). It is interesting to speculate that ruminants as a group may primarily harbor the α2D adrenergic receptor homologue of the α2A adrenergic receptor within the brainstem, since compared with other species, they have greater sensitivity to the sedative effects of α2-agonists.

Clinically, the degree of sedation and analgesia produced by an α2-agonist is related not only to the density, location, and type of α2-adrenoreceptors within the animal, but also to the individual selectivity and affinity of the drug molecule between the α1 and α2 receptor binding sites. Most currently available α2-agonists can activate the α1-adrenoreceptors; therefore, these receptors play some part in the effect of these agents, especially nonspecific agents such as xylazine. Activation of α1-adrenoreceptors induces arousal, restlessness, increased locomotor activity, and increased vigilance (13). These effects may be noted when high doses (4 and 8 mg/kg BW) of xylazine are used (14). Studies have demonstrated that central α1-adrenoreceptor stimulation antagonizes the hypnotic response to even potent α2-agonists, such as dexmedetomidine (15), and that the α1-adrenoreceptor effects will predominate with increased or toxic doses of α2-agonists (16,17).

At clinical doses, the more selective a drug is to the α2-adrenoreceptor, the more potent it is, so that a lowered dose, and hence a smaller injection volume, is required to achieve a similar degree of sedation. The following order of α21 selectivity has been reported: medetomidine (1620:1), detomidine (260:1), clonidine (220:1), and xylazine (160:1) (18,19). The selectivity of romifidine has not been documented, although, clinically, it appears to be between xylazine and detomidine.

Physiological effects of a2-agonists

Sedative effects

The interest in the use of α2-agonists in veterinary anesthesia is related to the ability of these drugs to produce reliable sedation and anxiolysis. These effects are mediated by receptors located primarily in locus coeruleus neurons on the pons and lower brainstem (20,21,22,23). Alpha2-agonists bind with and intrinsically change the membranes of the α2-adrenoreceptors, preventing further release of the neurotransmitter norepinephrine. Centrally, norepinephrine is necessary for arousal. If the release of norepinephrine is blocked, the net result is sedation.

Failure to achieve optimum sedation with α2-agonists may be due to preexisting stress, fear, excitement, or pain, as all of these conditions can increase endogenous catecholamine levels that interfere with α2-agonist-induced reductions in excitatory neurotransmitter release. Extremely apprehensive patients may prove refractory to the sedative actions of α2-agonists. Sedation is consistently achieved when α2-agonists are given to patients in calm and quiet surroundings with minimal environmental stimuli. Dogs or cats that appear sedated may suddenly become aroused and aggressive, if disturbed, and many demonstrate an increased sensitivity to sound and initial tactile stimulation (24).

Cardiovascular effects

Alpha2-adrenoreceptor agonists, through stimulation of central and peripheral adrenoreceptors, significantly affect cardiovascular function, which becomes most significant in sick, unstable, or cardiovascular compromised patients (25,26). The main negative cardiovascular effects of all α2-agonists include bradycardia and associated bradyarrhythmias (1st and 2nd degree atrioventricular heart block), a dramatic reduction in cardiac output (CO) by up to 50% (L blood/min), and an increase in systemic vascular resistance (SVR) (27,28,29).

It is important to realize that there are actually 2 main causes of the α2-agonist-induced bradycardia: diminished sympathetic tone and increased SVR. Alpha2-agonists reduce norepinephrine outflow within the CNS, thus dampening central sympathetic tone and beneficially resulting in sedation, but the reduced sympathetic tone also promotes a reduction in heart rate (HR). The action of the α2-agonist at the peripheral α2-adrenoreceptors accounts for the dramatic increase in SVR, which will be recognized clinically as an increase in arterial blood pressure. When medetomidine is administered alone at a dose of 40 μg/kg BW, IV to healthy beagle dogs, there is a dramatic increase in mean arterial blood pressure (MAP) (average of 175 mmHg within 3 min) (29). This hypertension induces a reflex baroreceptor-mediated physiologic bradycardia, associated bradyarrhythmias, and dramatic reduction in CO, which is perpetuated by the central effects of sedation and reduced sympathetic tone. Various research articles have demonstrated that the drop in CO is not due to a direct negative action of the α2-agonist on myocardial contractility, but is secondary to the increased SVR and reduced HR (30,31,32).

Over time, the peripheral effects of the α2-agonist will subside, and the blood pressure will decrease towards normal (33). The extent and duration at which an α2-agonist will increase SVR depends on several factors: 1) Selectivity of the drug at the α2-adrenoreceptor; 2) dose (high or low), and 3) route of drug administration, IV or IM.

Xylazine has been noted to increase systemic blood pressure, but this effect is generally not as profound or as long standing as that of medetomidine (34). In fact, an early report on the effects of xylazine warns of a potential hypotension (35). In small animals sedated with medetomidine alone, clinically significant hypotension (MAP < 60–80 mmHg) is unlikely to result due to the increased selectivity of this drug at the α2-adrenoreceptor. Hypotension is more likely to result when α2-agonists are administered with other sedatives or anesthetics. Blood pressure in dogs (29,36,37) and cats (38) sedated with medetomidine alone is elevated in a dose dependent manner initially, but it will decrease over time to more normal levels. Analysis of the results of various studies on the use of medetomidine in dogs did not reveal clinically significant hypotension during the study periods, but a general trend of decreasing blood pressure toward baseline or normal levels (29,33,34,36,37,39,40). For example, in dogs sedated with medetomidine (10 μg/kg BW, IV), initial values of MAP were on average 140 to 160 mmHg, which decreased to an average of 90 to 110 mmHg within 1 h (29).

Cats do not appear to have the same degree of hypertension associated with the sole administration of dexmedetomidine (41) or medetomidine (42). Lamont et al (42) concluded that the cats in their study were potentially stressed during baseline measurements, which caused increased concentrations of circulating catecholamines and a relatively high baseline MAP (139 mmHg) and prevented substantial increases in pressure values from being detected when the cats were sedated with medetomidine (42). Stress and heightened circulating catecholamine levels could also be a contributing factor in the effects of dexmedetomidine reported by Selmi et al (41); however, these authors suggested that the different pressor response might be associated with a predominance of central α2-adrenergic effects over peripheral vascular effects in the cat. When cats were anesthetized prior to medetomidine administration, an increase in systemic blood pressure occurred, as in other species (38,43). For example, in cats anesthetized with isoflurane, the MAP increased from a baseline of 77 mmHg to 132 mmHg with medetomidine (10 μg/kg BW, IM), which suggests that a pressor response occurs in cats as well (38).

Increases in arterial blood pressure are typically dose related with the administration of medetomidine, the higher the dose the more profound the increase. Lower doses of α2-agonists may be associated with more predominant CNS effects, whereas higher doses probably cause a more pronounced stimulation of peripheral adrenoreceptors and vasoconstriction (29). Not only is the dose important, the route of administration also plays a role on the extent of increased systemic vascular resistance. The initial hypertension is greater when the α2-agonist is administered, IV, than when it is administered, IM (34). Vainio and Palmu (34) demonstrated a 26% increase in MAP after medetomidine or xylazine was administered, IV, compared with an 18% increase when the same doses were administered, IM. The differences in the initial blood pressure response with different routes of drug administration are likely related to variations in the speed of uptake and absorption of the drug on the overall effect at the peripheral adrenoreceptors (34). Based on these findings, it is typically recommended that lowered doses of α2-agonists be administered, IM, to avoid extremes of blood pressure.

Respiratory effects

Sedation with α2-agonists results in a reduction in respiratory rate for varying periods. Respiratory depression occurs secondary to the CNS depression produced by α2-adrenoreceptor stimulation; however, the degree of depression with α2-agonists alone is less than that with other sedatives, even at sublethal doses (27). In dogs at doses between 20 and 60 μg/kg BW, medetomidine significantly depressed respiratory rate (2,34,44). In those studies in which arterial blood gas tensions were measured, an increased arterial carbon dioxide tension was observed; however, the reductions in arterial oxygen tensions were not significant when medetomidine was administered alone (36,39,45,46). These results are consistent with those in studies of romifidine administered at 40 and 120 μg/kg BW in dogs, when a decrease in respiratory rate without significant alterations in arterial blood gases was noted (47). In cats, dexmedetomidine alone did not reduce respiratory rate (41) and medetomidine alone did not alter arterial blood gas values significantly (42).

It is important to realize that the degree and significance of respiratory depression produced with any α2-agonist will be increased when the agonist is given with other sedatives. Decreased respiratory rate, increased arterial carbon dioxide tension (48,49), hypoxemia and cyanosis (49,50,51,52) have been reported in dogs premedicated with medetomidine and induced with propofol. The respiratory rate was significantly decreased in dogs sedated with medetomidine (30 μg/kg BW, IM) and butorphanol (0.2 mg/kg BW, IM), compared with that in dogs sedated with medetomidine (30 μg/kg BW, IM) alone or medetomidine with ketamine (3 mg/kg BW, IM) (39). In this latter study, a respiratory acidosis and a significantly lowered arterial oxygen tension in the medetomidine/butorphanol group (as low 64 mmHg, 20 min after administration) and the medetomidine/ketamine group (as low as 61 mmHg, 5 min after administration) were observed with all drug combinations. Other studies with medetomidine and opioids in dogs also concluded that there is greater respiratory depression, acidosis, and potential hypoxemia when these drugs are administered together (45,53,54). Respiratory depression has also been reported in cats when dexmedetomidine-butorphanol or dexmedetomidine-ketamine (41) combinations and medetomidine-ketamine combinations were administered (55,56,57). Based on these reports, oxygen should be administered by face-mask or endotracheal intubation when α2-agonists are used in combination with other sedatives or injectable anesthetics, respectively.

Cyanosis has been reported in up to 33% of dogs that have been sedated with medetomidine (2,24,54,58). Cyanosis is obvious when the unoxygenated hemoglobin concentration is > 50 g/L of blood and can develop from 3 mechanisms (59). Clinically, cyanosis is generally considered to develop either when blood is insufficiently oxygenated in the lungs or when hemoglobin is unable to carry oxygen. The 3rd mechanism of cyanosis development involves the stagnation of blood within peripheral capillary beds, which results in increased oxygen extraction. In the above reports of cyanosis in association with the administration of medetomidine, the animals had no significant reductions in arterial oxygen content and arterial oxygen saturation remained above 95%; how ever, venous oxygen tensions and filling were low. Thus, the cyanosis observed with the administration of medetomidine is likely due to low blood flow through peripheral capillary beds and an actual venous desaturation; however, this theory has yet to be proven in the trials to date. Although cyanosis may be observed in small animals, more commonly, the mucous membranes are pale secondary to the peripheral α2-mediated vasoconstriction.

Muscle relaxation

It has long been recognized that α2-agonists provide muscle relaxation and analgesia (26). The muscle relaxant effect that accompanies sedation is due to inhibition at α2-adrenoreceptors at the interneuron level of the spinal cord and is a beneficial property of the α2-agonists in veterinary medicine (25). Interestingly, tizanide, a new α2-agonist used in human medicine, has been found to be effective in relieving muscle spasticity resulting from stroke, cerebral trauma, and multiple sclerosis, because of its profound muscle relaxant properties (60,61,62).

Analgesia

Alpha2-agonists produce analgesia by stimulating receptors at various sites in the pain pathway within the brain and spinal cord (63). Radioligand studies have demonstrated high concentrations of α2-adrenoreceptor binding sites in the dorsal horn of the spinal cord where nociceptive fibers synapse (64) and in the brainstem where modulation of nociceptive signals are likely to be started (65). Electrophysiological studies have indicated that pre- and postsynaptic inhibitory mechanisms are responsible for the antinociceptive action of α2-adrenoreceptor agonists (66).

In the modulation of pain, there are interactions between opiate receptors and α2-adrenoreceptors in the brain (33) and spinal cord (67,68). Alpha2 and opioid receptors are found in similar regions of the brain and even on some of the same neurons. These receptors share common molecular machinery beyond that of the receptor. Binding of either α2-agonists or μ-opioid agonists to their receptors results in activation of the same signal transduction systems (membrane associated G proteins), which induces a chain of events that open potassium channels in the neuronal membrane. Activation of potassium channels in the postsynaptic neuron leads to hyperpolarization of the cell, which ultimately makes the cell unresponsive to excitatory input and effectively severs the pain pathway. Consequently, the α2-agonists and μ-opioid agonists produce analgesia by similar mechanisms.

Experimental and clinical evidence indicates that analgesia is not present throughout the entire period of sedation with α2-agonists and that these agents alone are not suitable for painful or major surgical procedures. The analgesic effects of these agents typically only last for half the duration of the sedation. For example, medetomidine administered at 20 to 40 μg/kg BW will induce sedation for 60 to 90 min, while its analgesic effects may last for only 30 to 45 min (25), and if painful manipulations are continued, the period of sedation will be shortened and recovery will be hastened. In general, α2-agonists should be combined with local anesthetics or other anesthetic agents for surgical procedures. Current research on the use microdoses of α2-agonists for acute and chronic pain have demonstrated their usefulness both systemically and epidurally (69,70,71,72); however, the sedative and cardiovascular effects that accompany analgesia with α2-agonists may be undesirable.

Other effects

Hypothermia

Temperatures may decrease in animals sedated with α2-agonists. In general, the reduction in temperature with α2-agonists can be attributed to CNS depression, in combination with a reduction in muscular activity (73,74). However, in dogs, only slight reductions in rectal temperature were observed with medetomidine (29,46,74,75) or romifidine (76), while no reductions were noted with romifidine sedation (47,77,78,79,80). Alpha2-agonists may allow for better maintenance of body temperature due to the peripheral vasoconstriction and central redistribution of blood, with a consequent reduction in cutaneous heat losses, in contrast to the consistent reductions in body temperature reported with the use of other anesthetic agents that induce vasodilation. However, body temperature should still be monitored in small animals and appropriate attempts should be made to conserve body heat and prevent dramatic reductions in temperature.

Muscle twitching

Muscle twitching following sedation with medetomidine has been described in some dogs (2,24,54,58,81,82,83) and cats (55,57,58). Similar twitching has also been observed in dogs sedated with xylazine (84) and romifidine (78,85). It has been speculated that because the muscle twitching occurs more frequently in animals in a noisy environment, hypersensitivity to noise may be a possible explanation for it (2). However, muscle twitching was not noted in studies in which the α2-agonist was administered, IM (76), compared with other studies in which it was administered, IV (85). Therefore, the occurrence of twitching may depend not only on the environment but also on the drug, the route of administration, and the absorption rate.

Endocrine

Various studies have shown that α2-agonists reduce the perioperative levels of stress-related hormones and thus attenuate the stress response of surgery in dogs (14,86,87,88). In human anesthesia and surgery, the stress response is an important factor contributing to patient morbidity; therefore, preanesthetics include an α2-agonist to minimize this response (89). The importance of the stress response that is associated with surgery in veterinary medicine is still unknown; however, there is increasing interest in using medetomidine as a preanaesthetic to promote balanced anesthesia and minimize the overall stress response (86,88).

Alpha2-agonists, typically xylazine, have been reported to induce an increase in serum glucose by suppressing insulin release, stimulating glucagon release, or both, in β and α cells of the pancreas, respectively (90,91). However, medetomidine given at doses of 10 and 20 μg/kg BW, IV, decreased insulin values significantly but was not found to alter plasma glucose concentrations in normal beagles (92). Differences in plasma glucose concentrations are likely associated with the greater specificity of medetomidine, compared with that of xylazine, at the α2-adrenoreceptors. The hyperglycemia associated with xylazine has been attributed to the actions at both the α2- and α1-adrenoreceptors. In cattle, the xylazine induced hyperglycemia is reversed with the α1-adrenoreceptor antagonist prazosin (93). Despite this, the use of medetomidine in animals with diabetes mellitus cannot be recommended until more information is available.

It is well recognized that animals recovering from α2-agonist sedation typically have large volumes of urine with low specific gravity (2,24,94). Administration of medetomidine at dosages of 10 and 20 μg/kg BW, IV, induced a diuretic effect that lasted for up to 4 h (95). Xylazine administration has also been associated with increased urine production in several species (96,97,98). This diuretic effect negates the use of these agents in animals with a urinary tract obstruction.

Reasons for the diuresis involve the actions of α2-agonists on antidiuretic hormone (ADH) and the renin-angiotensin system. Central stimulation of α2-adrenoreceptors in the hypothalamus by α2-agonists was reported to decrease the secretion, production, or both, of ADH from the pituitary gland in dogs and rats (99,100); however, other authors have postulated that ADH is indirectly decreased due to the circulatory changes induced with α2-agonist sedation (101). Alpha2-agonists have also been shown to have a peripheral renal effect due to their antagonism of the renal tubular effects of ADH (102,103) and their potentiation of urinary sodium output (104,105).

Sedation with α2-agonists can also impact the renin-angiotensin system directly or indirectly. Experiments in vitro have demonstrated a clear decrease in renin production directly via specific renal α2-adrenoreceptors (106); however, the renin-angiotensin system may also be affected indirectly by α2-agonist-induced hypertension (107). Alpha2-agonists also potentiate the release of growth hormone (108), although it is unlikely that the clinical implications of this are serious.

Arrhythmogenecity

The administration of medetomidine to dogs frequently causes a reduction in heart rate by as much as 30% to 50% (25). Vagal-induced bradyarrhythmias, 1st and 2nd degree atrioventricular heart block, are also commonly reported in the dog (109). Typically, these arrhythmias are not life threatening and are attributed to a baroreceptor mediated reflex to the peripheral vasoconstriction and a diminished sympathetic outflow, as described above. Rarely, and more consequentially, 3rd degree atrioventricular heart block and sinus arrest may occur with α2-agonist sedation (110). In cats, bradycardia is also typically associated with medetomidine sedation, with reductions in heart rate from 30% to 40% (16,42,111,112). However, only sinus bradycardia was reported when rhythm was recorded electrocardiographically (111).

Despite its association with these common bradyarrhythmias, medetomidine is not, by definition, arrhythmogenic. Arrhythmogenecity of anesthetics refers to the ability of the drug to induce myocardial sensitivity to epinephrine and promote ventricular arrhythmias. Scientifically, this is defined as the arrhythmogenic dose of epinephrine (ADE). A lowering of the ADE, or dose of epinephrine required to produce an arrhythmia with an anesthetic agent, increases the arrhythmogenecity of the agent. Various studies have looked at alterations in the arrhythmogenicity in α2-agonist sedated animals and have found that the occurence of arrhythmogenecity is dependent on the selectivity of the α2-agonist, its dose, and the route of administration (113). Typically the less selective α2-agonists are more arrhythmogenic and the more selective α2-agonists actually prevent epinephrine induced arrhythmias. It is likely that arrhythmogenecity is mediated by α1-adrenoreceptors and that stimulation of central α2-adrenoreceptors by the more selective α2-agonists reduces arrhythmogenicity by decreasing sympathetic tone and enhancing parasympathetic tone. For example, administration of xylazine decreases the ADE required to induce ventricular arrhythmias in halothane- (114,115) and isoflurane- (116) anesthetized dogs; however, the more selective α2-agonists, detomidine, medetomidine, and dexmedetomidine, do not decrease the ADE: Intramuscular administration of medetomidine does not alter the ADE in dogs anesthetized with halothane (117) or isoflurane (118), and dexmedetomidine may even increase the ADE dose dependently in halothane-anesthetized dogs (119).

Uterine activity

Drugs stimulating α-adrenoreceptors increase the contractility of the pregnant (120) and nonpregnant (120,121) uterus. Xylazine, like oxytocin, causes contraction of the bovine uterus (122); therefore, anesthesia textbooks caution the use of xylazine in heavily pregnant cows due to anecdotal reports of premature labor and abortions (84,123). However, the administration of small doses of detomidine in pregnant cows (124) and clinical doses of medetomidine in pregnant dogs (120) leads to a decrease in myometrial contractility. No abortions were observed in either study, but in the canine study, an increase in the activity of the myometrium was noted in all cases during the postparturient period. The effect of drugs that stimulate the α-adrenoreceptors depends to a high degree on the level of steroid hormones: An increased level of estrogen increases the sensitivity of the α-adrenoreceptors, while a high level of progesterone during pregnancy stimulates the sensitivity of β-adrenoreceptors and actually decreases the contractility of the uterus (120). No literature was found that related the effects of α2-agonists on the feline uterus. Overall, based on the literature reviewed, the use of medetomidine does not appear to promote abortions in pregnant dogs; however, the drug company does not recommend medetomidine for use in breeding or pregnant dogs.

Vomiting

In small animals, α2-agonists typically induce vomiting by stimulating the chemoreceptor trigger zone, which is in close proximity to the locus coeruleus in the brain (125). Xylazine induces vomiting during early sedation in as many as 50% of dogs and 90% of cats (84). With medetomidine sedation, vomiting was observed in 8% to 20% of dogs (2,24,46,58,81,82,83,126) and up to 90% of cats (58,83).

Gastrointestinal motility

The adrenergic regulation of gastrointestinal secretions and motility seems to be mainly dependent on the activation or inhibition of α2-adrenoreceptors located both presynaptically and postsynaptically. In general, α2-agonists decrease gastric acid secretion (127,128), prolong intestinal transit time (129,130), and inhibit reticuloruminal contractions and colonic motility in sheep and cattle (131) and in horses (132). The gastrointestinal suppression is affected by dose and specificity of the α2-agonist. Medetomidine was demonstrated to inhibit the electrical activity of the small intestine and dramatically inhibit the motility of the colon in dogs (133). These effects were completely antagonized by the α2-adrenergic antagonist atipamezole, confirming that the effect on gastrointestinal motility is mediated through α2-adrenoreceptors.

Intraocular pressure

Mydriasis is reported to occur after α2-agonist administration in animals. This effect is postulated to occur from central inhibition of parasympathetic tone to the iris, a direct sympathetic stimulation of the α2-adrenoreceptors located in the iris, CNS, or both (134,135). Topical administration of medetomidine in the eye of rabbits and cats readily induces mydriasis and decreases intraocular pressure by suppressing sympathetic neuronal function and decreasing aqueous flow (135). However, the IV administration of medetomidine to dogs induced miosis and did not lower intraocular pressure (136). Despite these conflicting results, the detrimental effects of vomiting and lowered head posture on the intraocular pressure induced with medetomidine sedation would contraindicate the use of α2-agonists in small animal patients with ocular problems in which an increase in intraocular pressure would be detrimental.

Intracranial pressure

A primary consideration in the anesthetic management of animals with intracranial lesions is the prevention of increased intracranial pressures (ICP). Studies have indicated that α2-agonists lower cerebral blood flow via α2-adrenoreceptor-mediated vasoconstriction, and hence ICP, in mechanically ventilated dogs anesthetized with isoflurane (137,138). The α2-agonists may possess a role in anesthetic supplementation in cases with increased ICP; however, consideration must be given to the detrimental effects of vomiting and hyperglycemia induced by them.

Anesthetic sparing properties

One of the primary reasons for using α2-agonists in veterinary medicine is their potent anesthetic sparing effect of injectable and inhalant anesthetics. The anesthetic sparing effect roughly correlates with the affinity of the drugs for the α2-adrenoreceptors (7). That is, the more specific the α2-agonist, the greater the anesthetic sparing effect. For example, in dogs, premedication with either romifidine or medetomidine, followed by induction with propofol, leads to marked synergism between the drugs (44,48,80). Romifidine at 20 μg/kg BW reduced the induction dose of propofol by 60% (80). Medetomidine has been found to decrease the dose requirements of propofol for induction and maintenance up to 75%, depending on the dose administered for pre-medication (44,48,49,50,51,52). Dose reductions of propofol to 1 mg/kg BW are recommended with medetomidine at premedication doses of 20 to 40 μg/kg, BW (139). Similarly, both medetomidine (81) and romifidine (77) markedly reduced the thiopentone induction dose in dogs by up to 75%.

Alpha2-agonists also dramatically reduce the mean alveolar concentration (MAC) of the inhalant anesthetics. In dogs, clonidine (20 μg/kg BW, IV) reduced the MAC of halothane by 48% (140). Similarly, xylazine (1.1 mg/kg BW, IV) reduced the MAC of halothane in dogs by 39% (141), while medetomidine (30 μg/kg BW, IV) reduced the MAC of isoflurane by 47.2% (142). Dexmedetomidine, the active isomer of medetomidine, at 10 μg/kg BW, IV produced a 90% reduction in the MAC of halothane in dogs (143). The mechanisms by which the α2-agonists potentiate the anesthetic effects of inhalant anesthetics have not been fully clarified. Alpha2-agonist drugs do not share a common receptor mechanism with inhalant anesthetics, as demonstrated by the inability of α2-antagonists to reverse halothane anesthesia; however, a synergism likely exists with these agents as both increase potassium conductance and induce neuronal hyperpolarization in the brain (18).

Antagonism

An added benefit of the α2-agonists in clinical practice is the reversibility of their effects with the α2-antagonists. There are at least 4 α2-antagonists available in veterinary practice: yohimbine, tolazoline, atipamezole, and idazoxan. These α2-antagonists exhibit individual selectivity and affinity for the α2 and α1 receptors, similar to the α2-agonists. The α21 reversal specificity of the antagonist drugs is as follows: atipamezole > idazoxan > yohimbine > tolazoline (7). If both the α2-agonists and α2-antagonist have a high receptor specificity and selectivity, reversal results in an animal not being different from untreated state. This competitive antagonism is especially important in reversing potentially threatening cardiovascular complications with routine doses, or in situations of inadvertent overdose.

Atipamezole, with the highest α2-receptor selectivity (8500:1 in comparison with idazoxan) (18), is the preferred antagonist for reversal of medetomidine and may also be used to antagonize other α2-agonists, such as xylazine or detomidine (144). Atipamezole (Antisedan, 5 mg/mL; Novartis Animal Health Canada, Mississauga, Ontario) is marketed with medetomidine. Other advantages of atipamezole compared with the less selective antagonists are the lack of activity at beta, histaminergic, serotonergic, dopaminergic, GABA-ergic, opioid, or benzodiazepine receptor sites (145). At a dose 4 to 6 times the dose of medetomidine, atipamezole administered, IM, will efficiently antagonize the sedative and behavioral effects of medetomidine within 3 to 7 min (24). The half-life of atipamezole is twice that of medetomidine; therefore, resedation is uncommon, although, occasional resedation has been reported in dogs and cats (81).

The use of these antagonists may also have adverse effects, like hypotension, tachycardia, excitement, and the removal of the α2-agonist induced analgesia (146,147,148). Death has also been reported following rapid IV administration of yohimbine and tolazoline to xylazine-sedated sheep (148). Abrupt changes in cardiovascular function occur after IV administration; therefore, IM administration of atimpamezole is recommended to allow for a gradual awakening and to minimize the changes in blood pressure, HR, and CO (144). A transient hypotension may still occur even with IM administration of atimpamezole in medetomidine-sedated dogs (149). This may not be clinically significant in healthy stable animals; however, clinicians should be aware of this side effect. In unsedated animals, inadvertent administration of atipamezole may cause minor excitatory effects and an increase in circulating plasma levels of norepinephrine (27). Atipamezole is not licensed for IV use, due to these potential complications; however, in emergency situations, IV administration is appropriate.

The use of anticholinergics with a2-agonists

It is likely that all small animal patients will become bradycardic after sedation with an α2-agonist, secondary to the baroreceptor reflex to hypertension and reduction in sympathetic tone. Anticholinergic premedication with α2-agonists has been recommended to prevent bradyarrhythmias and, potentially, a reduction in cardiac output (150), and this recommendation has been widely adopted within most veterinary practices. However, conflicting opinions exist in various articles with respect to treating α2-agonist mediated bradycardia and decreases in cardiac output with anticholinergics (25,26,29,34,144,151,152,153,154). Some authors have recommended reversal of the α2-agonist as the safest remedy for bradycardia due to the potential detrimental cardiovascular effects of using anticholinergics with α2-agonists (29,47,108).

Few authors have actually addressed the direct cardiovascular effects of using an anticholinergic with an α2-agonist alone or in combination with opioids, or injectable or inhalant anesthetics. In the research involving anticholinergics and sedative doses of α2-agonists, a clear improvement in cardiovascular function was not noted in either dogs (47,154) or cats (152). Overall, the anticholinergic-induced increase in HR potentiated the α2-agonist mediated hypertension (34,37,47,151,152,155,156,157,158), and it was speculated that it increased myocardial tension, oxygen demand, and workload (47,152,154,159).

Typically, preemptive administration of an anticholinergic prevents the reduction in HR and associated bradyarrhythmias associated with an α2-agonist (37,47,155), but it may cause an initial tachycardia (47) and may even induce certain dysrhythmias (37,109). Dysrhythmias characterized by heart block, premature ventricular contraction, and tachycardia have been noted with anticholinergic and α2-agonist combinations, especially if the anticholinergic is administered concurrently rather than prior to the α2-agonist (47,109,151). Sustained increases in heart rate decrease myocardial oxygen supply and increase myocardial oxygen demand (160). Atropine or glycopyrrolate given before, simultaneously, or after medetomidine (30 to 60 μg/kg BW) resulted in heart block, premature ventricular contractions, and tachycardia (108). Preemptive administration of atropine in medetomidine-sedated dogs induced hypertension and pulsus alternans, an alternating strong and weak pulse, which suggests cardiovascular compromise in human medicine (37). Glycopyrrolate was more effective and produced fewer undesirable side effects when given prior to romifidine in dogs; when the anticholinergic was administered concurrently with romifidine, a rapid decrease in HR with variable atrioventricular (AV) conduction, followed by a period of tachycardia, was noted (47). Therefore, concurrent administration of the anticholinergic with the α2-agonist is not recommended (47,109).

The significance of this anticholinergic-induced increased HR in the face of the α2-agonist-induced hypertension in domesticated animal species cannot be quantified or ruled out, especially in those patients with cardiovascular disease, due to the potential for an increase in myocardial workload and oxygen demand. However, the above disadvantages of anticholinergic use must be weighed against its potential advantages; namely, an improvement in cardiac output (although not normalized), a reduction in the frequency of bradyarrhythmias, a decrease in central venous pressure (CVP), and potentially improved tissue oxygen delivery (47). These advantages appear greatest when the anticholinergic is administered with a lowered dose of the α2-agonist.

When making clinical decisions, it is important to consider the use of anticholinergics with α2-agonists in 2 situations; when the α2-agonist is used alone as a sedative, and when the α2-agonist is used as a premedicant prior to induction and maintenance with propofol or an inhalation anesthetic that promotes vasodilation. The reduction in HR that occurs when an α2-agonist is used alone is a normal response, and in this situation, high HR working against the high systemic vascular resistance may increase myocardial workload. This is most likely to become clinically significant in cardio vascular compromised patients, when high doses of α2-agonists are used, or when both situations are present. The peripheral vasodilation that occurs with certain injectable or inhalation anesthetics will offset the α2-agonist-induced increase in blood pressure from vasoconstriction, and it does make physiologic sense to treat bradycardia in this situation with an anticholinergic. In this situation, the combination of medetomidine with other sedative drugs, such as opioids, may promote a more profound vagally mediated bradycardia in which anticholinergic treatment would be indicated.

Further research is required in these areas to fully clarify the effects of the use of α2-agonists and anticholinergics with various anesthetic regimes that promote vasodilation or significantly increase vagal tone. At this time, routine use of anticholinergics with sedative doses of α2-agonists does not appear to be beneficial and may even be detrimental. Concurrent administration of anticholinergics and α2-agonists is not recommended. Overall, in any emergency situation with the use of medetomidine alone or as a premedicant to general anesthesia, reversal with atipamezole is the most appropriate treatment.

Clinical use of medetomidine

Medetomidine is the most potent α2-agonist available for use in veterinary anesthesia, since it induces a longer duration of sedation and analgesia compared with xylazine. These characteristics likely make medetomidine the overall best choice for small animal clinical use. Medetomidine is marketed only as a sedative-analgesic agent to facilitate clinical examinations; clinical procedures; minor surgical procedures, with the exception of those requiring muscle relaxation; and minor dental procedures, where intubation is not required in healthy exercise tolerant dogs. It is contraindicated in dogs that are debilitated; in shock; or stressed due to extreme heat, cold, or fatigue; as well as in dogs with cardiovascular, respiratory, liver, or renal dysfunction.

The recommended label dose of medetomidine as a sedative-analgesic in dogs is 750 μg/m2 IV, or 1000 μg/m2, IM, which is equivalent to approximate doses of 20 μg/kg BW, IV, and 40 μg/kg BW, IM, respectively. Typical label sedative doses are as follows: dogs 10 to 20 μg/kg BW, IV; 20 to 40 μg/kg BW, IM; cats 10 to 40 μg/kg BW, IV; 40 to 80 μg/kg BW, IM. Sedation develops within 1 min after IV administration and within 5 min after IM administration. The lower dose is preferred for IV use. Within this range, medetomidine induces the desired sedation, analgesia, and muscle relaxation, but endotracheal intubation is typically not tolerated. At 30 μg/kg BW, IM, medetomidine induces sedation that lasts approximately 70 to 90 min (82). Clinically, it is also important to realize that high doses of medetomidine (> 80 μg/kg BW) will not result in a greater degree of sedation, but they will prolong the duration of sedation and adverse cardiovascular effects (82). In addition, lower doses of medetomidine (< 10 μg/kg BW, IM) alone do not always result in the desired degree of sedation or a reduction in the frequency and severity of adverse effects (29,36).

Currently, the cardiovascular alterations induced by medetomidine are the most problematic effects produced, and they usually preclude its use in critical and cardiovascular compromised patients in veterinary medicine. Despite the obvious negative cardiovascular effects, α2-agonists are increasingly being utilized in human anesthesia to improve hemodynamic stability, alleviate stress, prevent tachyarrhythmias, and reduce shivering (7,161,162). There are obvious discrepancies in the negative and positive cardiovascular effects of α2-agonists in veterinary and human patients, in addition to the differences in species, economics, and sophistication of anesthesia.

A primary difference between how α2-agonists are used in animals and humans is simply an issue of dose. The doses used in humans are much lower than label dose ranges in animals. While there may be obvious species differences, lower doses of α2-agonists are usually adequate in veterinary species when they are used in combination with other sedatives, and they are already being used with considerable success in many practices as sedatives or preanesthetics. Decreased doses of medetomidine ranging from 2 to 10 μg/kg BW have been combined with various preanesthetics (butorphanol, oxymorphone, hydromorphone, buprenorphine, meperidine, midazolam) to enhance sedation and analgesia, while potentially reducing the duration of the adverse cardiovascular effects associated with its use. Although lowered doses of medetomidine will not prevent cardiovascular and respiratory depression (29), it will promote greater patient safety when used alone or in combination with injectable and inhalant agents.

Summary

Medetomidine is the newest and most specific α2-agonist licensed for use in dogs to achieve sedation, analgesia, and muscle relaxation. In addition to these desirable effects, a variety of other pharmacologic responses can occur due to α2-receptor activation in a variety of nontargeted tissues. The cardiovascular alterations induced by medetomidine are the most problematic side effects and usually preclude its use in critical and cardiovascular compromised patients. Additive cardiopulmonary dysfunction may occur when medetomidine is used in combination with other CNS depressants.

Anticholinergic premedication will not fully reverse all of the negative cardiovascular effects associated with medetomidine or other α2-agonists, and it may promote tachycardia, hypertension, and an increase in myocardial workload in dogs and cats. Although not ideal, healthy animals will likely tolerate the cardiovascular changes associated with anticholinergics and medetomidine. Concurrent administration of anticholinergics and α2-agonists is not recommended due to the increased frequency of dysrhythmias.

Appropriate case selection is important at any dose of medetomidine in dogs or cats. The use of lower doses of medetomidine, alone or with other anesthetic agents, in combination with oxygen administration, appropriate monitoring, and reversal with atipamezole, where indicated, will promote greater patient safety. Overall, the future successful use of medetomidine in clinical practice for sedation, analgesia, and preanesthetic medication will continue to involve lowered doses and combinations with other sedatives to promote a balanced anesthetic technique.CVJ

Footnotes

Address all correspondence and reprint requests to Dr. Sinclair; e-mail: ac.hpleugou.cvo@ialcnism

References

1. Salonen JS. Pharmacokinetics of medetomidine. Acta Vet Scand 1989;85:49–54. [PubMed]
2. England GCW, Clarke KW. The effect of route of administration upon the efficacy of medetomidine. J Assoc Vet Anaes 1989;16:32–34.
3. Kuusela E, Raekallio M, Anttila M, Falck I, Molsa S, Vainio O. Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs. J Vet Pharmacol Therap 2000;23:15–20. [PubMed]
4. Savola JM, Virtanen R. Central α2-adrenoceptors are highly stereoselective for dexmedetomidine, the dextro enantiomer of medetomidine. Eur J Pharmacol 1991;195:193–199. [PubMed]
5. Clarke KW, Hall LW. A survey of anaesthesia in small animal practice: AVA/BSAVA report. J Assoc Vet Anaesth 1990;17:4–10.
6. Dyson DH, Maxie MG, Schnurr D. Morbidity and mortality associated with anesthetic management in small animal veterinary practice in Ontario. J Am Anim Hosp Assoc 1998;34:325–335. [PubMed]
7. Vainio O. α2-Adrenergic agonists and antagonists. 6th Proc Int Cong Vet Anaes 1997:75–77.
8. Ruffolo Jr RR, Stadel JM, Hieble JP. α-Adrenoceptors: recent developments. Med Res Rev 1994;14:229–270. [PubMed]
9. Scheinin M, Lomasney JW, Hayden-Hixson DM. Distribution of α2-adrenergic receptor subtype gene expression in rat brain. Mol Brain Res 1994;21:133–149. [PubMed]
10. MacDonald E, Scheinin M. Distribution and pharmacology of α2-adrenoceptors in the central nervous system. J Physiol Pharmacol 1995;46:241–258. [PubMed]
11. Schwartz DD, Jones WG, Hedden KP, Clark TP. Molecular and pharmacological characterization of the canine brainstem alpha-2A adrenergic receptor. J Vet Pharmacol Therap 1999;22:380–386. [PubMed]
12. Schwartz DD, Clark TP. Selectivity of atipamezole, yohimbine and tolazoline for alpha-2 adrenergic receptor subtypes: implications for clinical reversal of alpha-2 adrenergic mediated sedation in sheep. J Vet Pharmacol Therap 1998;21:342–347. [PubMed]
13. Puumala T, Riekkinen P, Sirvo J. Modulation of vigilance and behavioural activation by alpha-1 adrenoreceptors in rat. Pharmacol Biochem Behav 1997;56:705–712. [PubMed]
14. Ambrisko TD, Hikashi Y. Neurohormonal and metabolic effects of medetomidine compared with xylazine in beagle dogs. Can J Vet Res 2002;66:42–49. [PMC free article] [PubMed]
15. Guo TZ, Tinklenberg J, Oliker R, Maze M. Central alpha-1 adrenoreceptor stimulation functionally antagonizes the hypnotic response to dexmedetomidine, and alpha-2 adrenoreceptor agonist. Anesthesiology 1991;71:75–79. [PubMed]
16. Anash OB, Raekallio M, Vainio O. Correlation between serum concentrations following continuous intravenous infusion of dexmedetomidine or medetomidine in cats and their sedative and analgesic effects. J Vet Pharmacol Therap 2000;23:1–8. [PubMed]
17. Doze V, Chen BX, Maze M. Pharmacologic characterization of the receptor mediating the hypnotic action of dexmedetomidine. Acta Vet Scand 1989;85:61–64. [PubMed]
18. Scheinin H, Virtanen A, MacDonald E, Lammintausta A, Schenin M. Medetomidine — a novel α2-adrenoceptor agonist: a review of its pharmacodynamic effects. Prog Neuropsychopharmacol Biol Psychiatry 1989;13:635–651. [PubMed]
19. Virtanen R. Pharmacology of detomidine and other α2- adrenoreceptor agonists in the brain. Acta Vet Scand 1986;82:35–46. [PubMed]
20. Correa-Sales C, Rabin BC, Maze M. A Hypnotic response to dexmedetomidine, an α2 agonist, is mediated in the locus coeruleus in rats. Anesthesiology 1992;76:948–952. [PubMed]
21. Scheinin H, Karhuvaara S, Olkkola KT, et al. Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine. Clin Pharmacol Ther 1992;52:537–546. [PubMed]
22. Doze VA, Chen BX, Maze M. Dexmedetomidine produces hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors. Anesthesiology 1989;71:75–79. [PubMed]
23. De Sarro GB, Ascioti C, Froio F, Libri V, Nistico G. Evidence that locus coeruleus is the site where clonidine and drugs acting at α1- and α2-adrenoceptors affect sleep and arousal mechanisms. Br J Pharmacol 1987;90:675–685. [PMC free article] [PubMed]
24. Clarke KW, England GCW. Medetomidine, a new sedative- analgesia for use in the dog and its reversal with atipamezole. J Small Anim Pract 1989;30:343–348.
25. Cullen LK. Medetomidine sedation in dogs and cats: a review of its pharmacology, antagonism and dose. Br Vet J 1996;152:519–535. [PubMed]
26. Paddleford RR, Harvey RC. Alpha2 agonists and antagonists. Vet Clin North Am Small Anim Pract 1999;29:737–745. [PubMed]
27. Lammintausta R. The alpha-2 adrenergic drugs in veterinary anaesthesia. 4th Proc Int Cong Vet Anaes 1991:3–8.
28. Haskins SC, Patz JD, Farver TB. Xylazine and xylazine ketamine in dogs. Am J Vet Res 1986;47:636–641. [PubMed]
29. Pypendop B, Verstegen JP. Hemodynamic effects of medetomidine in the dog: a dose titration study. Vet Surg 1998;27:612–622. [PubMed]
30. Autran de Morais HS, Muir WW. The effects of medetomidine on cardiac contractility in autonomically blocked dogs. Vet Surg 1995;24:356–364. [PubMed]
31. Schmeling WT, Kampine JP, Roerig DL, Warltier DC. The effects of stereoisomers of the α2-adrenergic agonist medetomidine on systemic and coronary hemodynamics in conscious dogs. Anesthesiology 1991;75: 499–511. [PubMed]
32. Muir WW, Piper FS. The effect of xylazine on indices of myocardial contractility in the dog. Am J Vet Res 1977;38:931–935. [PubMed]
33. Savalo JM. Cardiovascular actions of medetomidine and their reversal by atipamezole. Acta Vet Scand Suppl 1989;85:39–47. [PubMed]
34. Vainio O, Palmu L. Cardiovascular and respiratory effects of medetomidine in dogs and influence of anticholinergics. Acta Vet Scand 1989;30:401–408. [PubMed]
35. Klide AM, Calderwood HW, Soma LR. Cardiopulmonary effects of xylazine in dogs. Am J Vet Res 1975;40:931–935. [PubMed]
36. Ko JCH, Bailey JE, Pablo LS, Heaton-Jones TG. Comparison of sedative and cardiorespiratory effects of medetomidine and medetomidine-butorphanol combination in dogs. Am J Vet Res 1996;57:535–540. [PubMed]
37. Ko JCH, Fox SM, Mandsager RE. Effects of preemptive atropine administration on incidence of medetomidine-induced bradycardia in dogs. J Am Vet Med Assoc 2001;218:52–58. [PubMed]
38. Golden AL, Bright JM, Daniel GB, Fefee D, Schmidt D, Harvey RC. Cardiovascular effects of the α2-adrenergic receptor agonist medetomidine in clinically normal cats anesthetized with isoflurane. Am J Vet Res 1998;59:509–513. [PubMed]
39. Ko JCH, Fox SM, Mandsager RE. Sedative and cardiorespiratory effects of medetomidine, medetomidine-butorpanol, and medetomidine-ketamine in dogs. J Am Vet Med Assoc 2000; 216:1578–1583. [PubMed]
40. Pypendop B, Serteyn D, Verstegen J. Hemodynamic effects of medetomidine-midazolam-butorphanol and medetomidine-midazolam-buprenorphine combinations and reversibility by atipamezole in dogs. Am J Vet Res 1996; 57:724–730. [PubMed]
41. Selmi AL, Mendes GM, Lins BT, Figueiredo JP, Barbudo-Selmi GR. Evaluation of the sedative and cardiorespiratory effects of dexmedetomidine, dexmedetomidine-butorphanol, and dexmedetomidine-ketamine in cats. J Am Vet Med Assoc 2003;222:37–42. [PubMed]
42. Lamont LA, Bulmer BJ, Grimm KA, Tranquilli WJ, Sisson DD. Cardiopulmonary evaluation of the use of medetomidine hydrochloride in cats. Am J Vet Res 2001;62:1745–1749. [PubMed]
43. Muir WW, Gadawski JE. Cardiovascular effects of a high dose of romifidine in propofol-anesthetized cats. Am J Vet Res 2002;63:1241–1246. [PubMed]
44. Hammond RA, England GCW. The effect of medetomidine premedication upon propofol induction and infusion anaesthesia in the dog. J Assoc Vet Anaes 1994;21:24–28.
45. Pypendop B, Verstegen J. Cardiorespiratory effects of a combination of medetomidine, midazolam, and butorphanol in dogs. Am J Vet Res 1999;60:1148–1154. [PubMed]
46. Pettifer GR, Dyson DH. Comparison of medetomidine and fentanyl-droperidol in dogs: sedation, analgesia, arterial blood gases and lactate levels. Can J Vet Res 1993;57:99–105. [PMC free article] [PubMed]
47. Sinclair MD, McDonell WN, O'Grady M, Pettifer G. The cardiopulmonary effect of romifidine in dogs with or without prior or concurrent administration of glycopyrrolate. Vet Anaesth Analg 2002;29:1–13.
48. Thurmon JC, Ko JCH, Benson GJ, Tranquilli WJ, Olson WA. Hemodynamic and analgesic effects of propofol infusion in medetomidine-premedicated dogs. Am J Vet Res 1994;55: 363–367. [PubMed]
49. Cullen LK, Reynoldson JA. Xylazine or medetomidine premedication before propofol anaesthesia. Vet Rec 1993;132:378–383. [PubMed]
50. Lagerweij E, Hall LW, Nolan AM. Effects of medetomidine premedication on propofol anesthesia in dogs. J Assoc Vet Anaes 1993;20:78–83.
51. Sap R, Hellebrekers LJ. Medetomidine/propofol anesthesia for gastroduodenal endoscopy in dogs. J Assoc Vet Anaes 1993;20:100–102.
52. Vainio O. Propofol infusion anesthesia in dogs pre-medicated with medetomidine. J Assoc Vet Anaes 1991;18:35–37.
53. Ko JCH, Nicklin CF, Melendaz M, Hamilton P, Kounen CD. Effects of a microdose of medetomidine on diazepam-ketamine induced anesthesia in dogs. J Am Vet Med Assoc 1998;213:215–219. [PubMed]
54. Vaha-Vahe AT. Clinical efficacy of medetomidine. Acta Vet Scand 1989;85:151–153. [PubMed]
55. Dobromylskyj P. Cardiovascular changes associated with anaesthesia induced by medetomidine combined with ketamine in cats. J Small Anim Pract 1996;37:169–172. [PubMed]
56. Verstegen J, Fargotton X, Donnay L, Ectors F. An evaluation of medetomidine/ketamine and other drug combinations for anaesthesia in cats. Vet Rec 1991;128:32–35. [PubMed]
57. Verstegen J, Fargotton X, Ectors F. Medetomidine/ketamine anaesthesia in cats. Acta Vet Scand 1989;85:117–123. [PubMed]
58. Vaha-Vahe AT. Clinical evaluation of medetomidine, a novel sedative and analgesic drug for dogs and cats. Acta Vet Scand 1989;30:267–273. [PubMed]
59. Laguchik MS. Respiratory Distress. In: Wingfield WE, ed. Veterinary Emergency Medicine Secrets, 2nd Edition. Philadelphia: Hanley and Belfus, 2001:16–17.
60. Kita M, Goodkin DE. Drugs used to treat spasticity. Drugs 2000;59:487–495. [PubMed]
61. Groves L, Shellenberger MK, Davis CS. Tizanide treatment of spasticity: a meta-analysis of controlled, double-blind, comparative studies with baclofen and diazepam. Adv Ther 1998;15:241–251. [PubMed]
62. Nance PW, Bugaresti J, Shellenberger K, Sheremata W, Martinez-Arizala A. Efficacy and safety of tizanide in the treatment of spasticity in patients with spinal cord injury. Neurology 1994;44:44–51. [PubMed]
63. Stenberg D. Physiological role of alpha2-adrenoreceptors in the regulation of vigilance and pain. Acta Vet Scand 1989;85: 21–28. [PubMed]
64. Unnerstall JR, Kopajtic TA, Kuhar MJ. Distribution of α2-agonist binding sites in the rat and human CNS: Analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agonists. Brain Res Rev 1984;7:69–101. [PubMed]
65. Giron CT, McCann SA, Crist-Orland SG. Pharmacologic characterization and regional distribution of α-nonadrenergic binding sites in the rate spinal cord. Eur J Pharmacol 1985;115: 285–290. [PubMed]
66. Yaksh TL. Pharmacology of spinal adrenergic systems which modulate spinal nociceptive processing. Pharmacol Biochem Behav 1985;22:845–858. [PubMed]
67. Osmote K, Kitahata LM, Collins JG, Nakatani K, Nakagawa I. Interactions between opiate subtype and alpha2 adrenergic agonists in suppression of noxiously evoked activity of WDR neurons in the spinal dorsal horn. Anesthesiology 1991;74: 737–743. [PubMed]
68. Ossipov MH, Suarez LJ, Spalding TC. Antinociceptive interactions between alpha2 adrenergic and opiate agonists at the spinal level in rats. Anesth Analg 1989;68:194–200. [PubMed]
69. Weinbroum AA, Ben-Abraham R. Dextromethorphan and dexmedetomidine: new agents for the control of perioperative pain. Eur J Surg 2001;167:563–569. [PubMed]
70. Ripamonti C, Dickerson ED, Kitahata LM. Strategies for the treatment of cancer in the new millennium. Drugs 2001;61: 955–977. [PubMed]
71. Dahl V, Raeder JC. Non-opioid postoperative analgesia. Acta Anaesthesiol Scand 2000;44:1191–1203. [PubMed]
72. Eisenach JC, Dewan DM, Rose JC, Angelo JM. Epidural clonidine produces antinociception but not hypotension, in sheep. Anesthesiology 1987;66:496–501. [PubMed]
73. Virtanen R. Pharmacological profiles of medetomidine and its antagonist, atipamezole. Acta Vet Scand 1989;85:29–37. [PubMed]
74. MacDonald E, Scheinin H, Scheinin M. Behavioural and neurochemical effects of medetomidine, a novel veterinary sedative. Eur J Pharmacol 1988;158:119–127. [PubMed]
75. Verstegen J, Petcho A. Medetomidine-butorphanol-midazolam for anaesthesia in dogs and its reversal by atipamezole. Vet Rec 1993;132:353–357. [PubMed]
76. Lemke KA. Sedative effects of intramuscular administration of low dose romifidine in dogs. Am J Vet Res 1999;60:162–168. [PubMed]
77. England GCW, Hammond R. Dose-sparing effects of romifidine premedication for thiopentone and halothane anaesthesia in the dog. J Small Anim Pract 1997;38:141–146. [PubMed]
78. England GCW, Thompson S. The influence of route of administration upon the sedative effect of romifidine in dogs. J Assoc Vet Anaes 1997;24:21–23.
79. England GCW, Watts N. Effect of romifidine and romifidine- butorphanol for sedation in dogs. J Small Anim Pract 1997;14:561–564. [PubMed]
80. England GCW, Andrews F, Hammond RA. Romifidine as a premedicant to propofol induction and infusion anaesthesia in the dog. J Small Anim Pract 1996;37:79–83. [PubMed]
81. Young LE, Brearly JC, Richards DL, Bartram DH, Jones RS. Medetomidine as a premedicant in dogs and its reversal by atipamezole. J Small Anim Pract 1990;31:554–559.
82. Vainio O, Vaha-Vahe T, Palmu L. Sedative and analgesic effects of medetomidine in dogs. J Vet Pharmacol Therap 1989;12: 225–231. [PubMed]
83. Vainio O, Palmu L, Virtanen R, Wecksell J. Medetomidine, a new sedative and analgesic drug for dogs and cats. J Assoc Vet Anaes 1986;14:53–55.
84. Lumb WV, Jones EW. Preanesthetics and Anesthetic Adjuncts. In: Thurmon JC, Tranquilli WJ, Benson GJ, eds. Veterinary Anesthesia. 3rd Edition. Philadelphia: Williams and Wilkins, 1996:183–209.
85. England GCW, Flacke TE, Hollingworth E, Hammond R. Sedative effects of romifidine in the dog. J Small Anim Pract 1996;37:19–25. [PubMed]
86. Ambrisko TD, Hikashi Y. The antagonistic effects of atipamezole and yohimbine on stress-related neurohormonal and metabolic responses induced by medetomidine in dogs. Can J Vet Res 2002;67:64–67. [PMC free article] [PubMed]
87. Vaisanen M, Raekallio M, Kuusela E, et al. Evaluation of the perioperative stress response in dogs administered medetomidine or acepromazine as part of the preanesthetic medication. Am J Vet Res 2002;63:969–975. [PubMed]
88. Benson GJ, Grubb TL, Neff-Davis C, et al. Perioperative stress response in the dog: Effect of pre-emptive administration of medetomidine. Vet Surg 2000;29:85–91. [PubMed]
89. Desborough JP. The stress response to trauma and surgery. Br J Anaesth 2000;85:109–117. [PubMed]
90. Angel I, Langer SZ. Adrenergic induced hyperglycaemia in anaesthetised rats: involvement of peripheral α2-adrenoceptors. Eur J Pharmacol 1988;154:191–196. [PubMed]
91. Brockman RP. Effect of xylazine on plasma glucose, glucagons and insulin concentrations in sheep. Res Vet Science 1981;30:383–384. [PubMed]
92. Burton S, Lemke KA, Ihle SL, Mackenzie AL. Effects of medetomidine on serum insulin and plasma glucose concentrations in clinically normal dogs. Am J Vet Res 1997;58:1440–1442. [PubMed]
93. Hsu WH, Hummel SK. Xylazine induced hyperglycemia in cattle: a possible involvement of α-adrenergic receptors regulating insulin release. Endocrinology 1980;109:825–829. [PubMed]
94. Crighton M. Diuresis following medetomidine. Vet Rec 1990;126:201. [PubMed]
95. Burton S, Lemke KA, Ihle SL, Mackenzie AL. Effects of medetomidine on serum osmolality; urine volume, osmolality and pH; free water clearance; and fractional clearance of sodium, chloride, potassium, and glucose in dogs. Am J Vet Res 1998;59: 756–761. [PubMed]
96. Trim CM, Hanson RR. Effects of xylazine on renal function and plasma glucose in ponies. Vet Rec 1986;118:65–67. [PubMed]
97. Thurmon JC, Steffey EP, Zinkl JG, Woliner M, Howland D. Xylazine causes transient dose related hyperglycemia and increased urine volumes in mares. Am J Vet Res 1984;45: 224–227. [PubMed]
98. Thurmon JC, Nelson DR, Hartsfield SM, Rumore CA. Effects of xylazine hydrochloride on urine in cattle. Aust Vet J 1978;54:178–184. [PubMed]
99. Reid LA, Nolan PL, Wolf JA, Keil LC. Suppression of vasopression secretion by clonidine: effect of α-adrenoceptor antagonists. Endocrinology 1979;104:1403–1406. [PubMed]
100. Roman RJ, Cowley AW, Lechene C. Water diuretic and natriuretic effect of clonidine in the rat. J Pharmacol Exp Ther 1979;211:385–393. [PubMed]
101. Humphreys MH, Reid LA, Chou LYN. Supression of antidiuretic hormone secretion by clonidine in the anesthetized dog. Kidney Int 1975;7:405–412. [PubMed]
102. Gellai M, Edwards RM. Mechanism of α2-adrenoceptor agonist-induced diuresis. Am J Physiol 1988;255:317–323. [PubMed]
103. Smyth DD, Unemura S, Pettinger WA. Alpha2-adrenoceptor antagonism of vasopression-induced changes in sodium excretion. Am J Physiol 1985;248:767–772. [PubMed]
104. Strandhoy JW, Morris M, Buckalew VW. Renal effects of the antihypertensive, guanabenz, in the dog. J Pharmacol Exp Ther 1982;221:347–352. [PubMed]
105. Barr JG, Kauker ML. Renal tubular site and mechanism of clonidine-induced diuresis in rats: clearance and micropuncture studies. J Pharmacol Exp Ther 1979;209:389–395. [PubMed]
106. Smyth DD, Unemura S, Yang E, Pettinger WA. Inhibition of renin release by α-adrenoceptor stimulation in the isolated perfused rat kidney. Eur J Pharmacol 1987;140:33–38. [PubMed]
107. Short CE, Stauffer JL, Goldberg G, Vainio O. The use of atropine to control heart rate responses during detomidine sedation in horses. Acta Vet Scand 1986;27:548–559. [PubMed]
108. Hayashi Y, Maze M. Alpha2 adrenoceptor agonists and anaesthesia. Br J Anaesth 1993;71:108–118. [PubMed]
109. Short CE. Effects of anticholinergic treatment on the cardiac and respiratory systems of dogs sedated with medetomidine. Vet Rec 1991;129:310–313. [PubMed]
110. Muir WW, Mason D. Cardiovascular System. In: Thurmon JC, Tranquilli WJ, Benson GJ, eds. Veterinary Anesthesia. 3rd ed. Philadelphia: Williams and Wilkins, 1996:62–114.
111. Lamont LA, Bulmer BJ, Sisson DD, Grimm KA, Tranquilli WJ. Doppler echocardiographic effects of medeomidine on dynamic left ventricular outflow tract obstruction in cats. J Am Vet Med Assoc 2002;221:1276–1281. [PubMed]
112. Anash OB, Raekallio M, Vainio O. Comparison of three doses of dexmedetomidine with medetomidine in cats following intramuscular administration. J Vet Pharmacol Ther 1998;21: 380–387. [PubMed]
113. Lemke KA, Tranquilli WJ, Thurmon JC, Benson GJ, Olson WA. Influence of cholinergic blockade on the development of epinephrine-induced ventricular arrhythmias in halothane- and isoflurane-anesthetized dogs. Vet Surg 1994;23:61–66. [PubMed]
114. Tranquilli WJ, Thurmon JC, Benson GJ, Davis LE. Alterations in the arrhythmogenic dose of epinephrine (ADE) following xylazine administration to halothane-anesthetized dogs. J Vet Pharmacol Ther 1986;9:198–203. [PubMed]
115. Muir WW, Werner LL, Hamlin RL. Effect of xylazine and acetylpromazine upon induced ventricular fibrillation in dogs anesthetized with thiamylal and halothane. Am J Vet Res 1975;36: 1299–1303. [PubMed]
116. Tranquilli WJ, Thurmon JC, Benson GJ. Alterations in epinephrine-induced arrhythmogenesis after xylazine and subsequent yohimbine administration in isoflurane-anesthetized dogs. Am J Vet Res 1988;49:1072–1075. [PubMed]
117. Lemke KA, Tranquilli WJ, Thurmon JC, Benson GJ, Olson WA. Alterations in the arrhythmogenic dose of epinephrine after xylazine or medetomidine administration in halothane anesthetized dogs. Am J Vet Res 1993;54:2132–2136. [PubMed]
118. Lemke KA, Tranquilli WJ, Thurmon JC, Benson GJ, Olson WA. Alterations in the arrhythmogenic dose of epinephrine after xylazine or medetomidine administration in isoflurane anesthetized dogs. Am J Vet Res 1993;54:2139–2144. [PubMed]
119. Hayashi Y, Sumikawa K, Maze M, et al. Dexmedetomidine prevents epinephrine-induced arrhythmias through stimulation of central α2-adrenoceptors in halothane-anesthetized dogs. Anesthesiology 1991;75:113–117. [PubMed]
120. Jedruch J, Gajewski Z, Ratajska-Michalczak K. Uterine motor responses to an α2-adrenergic agonist medetomidine hydrochloride in the bitches during the end of gestation and the post-partum period. Acta Vet Scand 1989;85:129–134. [PubMed]
121. Rexroad CE, Barb CR. Contractile response of the uterus of the estrous ewe to adrenergic stimulation. Biol Reprod 1978;19:297–305. [PubMed]
122. LeBlanc MM, Hubbell JAE, Smith HC. The effect of xylazine hydrochloride on intrauterine pressure in the cow. Theriogenology 1984;21:681–690. [PubMed]
123. Hall LW, Clarke KW, Trim CM. Veterinary Anaesthesia, 10th Edition. London: WB Saunders, 2001:317.
124. Jedruch J, Gajewski Z. The effect of detomidine hydrochloride (Domosedan) on the electrical activity of the uterus in cows. Acta Vet Scand 1986;82:189–192. [PubMed]
125. Colby ED, McCarthy LE, Borison HL. Emetic action of xylazine on the chemoreceptor trigger zone for vomiting in cats. J Vet Pharmacol Therap 1981;4:93–96. [PubMed]
126. Nilsfors L, Garmer L, Adolfsson A. Sedative and analgesic effects of medetomidine in dogs — an open clinical study. Acta Vet Scand 1989;85:155–159. [PubMed]
127. Soldani G, Del Tacca M, Bernardini C, Martinottie E, Impicciatore M. Evidence for two opposite effects of clonidine on gastric acid secretion in the dog. Naunyn Schmiedeberg's Arch Pharmacol 1984;327:139–142. [PubMed]
128. Del Tacca M, Soldani G, Bernardini C, Martinotti E, Impicciatore M. Pharmacological studies on the mechanisms underlying the inhibitory and excitatory effects of clondine on gastric acid secretion. Eur J Pharmacol 1982;81: 255–261. [PubMed]
129. McNeel SV, Hsu WH. Xylazine-induced prolongation of gastrointestinal transit in dogs: reversal by yohimbine and potentiation by doxapram. J Am Vet Med Assoc 1984;185: 878–881. [PubMed]
130. Ruwart MJ, Klepper MS, Rush BD. Clonidine delays small intestinal transit in the rat. J Pharmacol Exp Ther 1980;212:487–490. [PubMed]
131. Ruckerbusch Y, Allal G. Depression of the reticulo-ruminal motor functions through stimulation of α2-adrenoceptors. J Vet Pharmacol Ther 1987;10:1–10. [PubMed]
132. Roger T, Ruckebusch Y. Colonic α2-adrenoceptor-mediated responses in the body. J Vet Pharmacol Ther 1987;10:310–318. [PubMed]
133. Maugeri S, Ferre JP, Intorre L, Soldani G. Effects of medetomidine on intestinal and colonic motility in the dog. J Vet Pharmacol Ther 1994;17:148–154. [PubMed]
134. Jin Y, Wilson S, Elko EE, Yorio T. Ocular hypotensive effects of medetomidine and its analogs. J Ocul Pharmacol 1991;7: 285–296. [PubMed]
135. Potter D, Ogidigben MJ. Medetomidine-induced alteration of intraocular pressure and contraction of the nictitating membrane. Invest Ophthalmol Vis Sci 1991;32:2799–2805. [PubMed]
136. Verbruggen AMJ, Akkerdaas LC, Hellebrekers LJ, Stades FC. The effect of intravenous medetomidine on pupil size and intraocular pressure in normotensive dogs. Vet Q 2000;22:179–180. [PubMed]
137. Keegan RD, Greene SA, Bagley RS, Moore MP, Weil AB, Short CE. Effects of medetomidine administration on intracranial pressure and cardiovascular variables of isoflurane-anesthetized dogs. Am J Vet Res 1995;56:193–198. [PubMed]
138. Zornow MH, Fleischer JE, Scheller MS, et al. Dexmedetomidine, and α2-adrenergic agonist, decreases cerebral blood flow in the isoflurane-anesthetized dog. Anesth Analg 1990;70:624–630. [PubMed]
139. Manners M. Anaesthesia following medetomidine. Vet Rec 1990;126:174. [PubMed]
140. Bloor BC, Flacke WE. Reduction in halothane anesthetic requirement by clonidine, an α-adrenergic agonist. Anesth Analg 1982;62:741–745. [PubMed]
141. Tranquilli WJ, Thurmon JC, Corbin JE, Davis LE. Halothane sparing effect of xylazine in dogs and subsequent reversal with tolazoline. J Vet Pharmacol Ther 1984;7:23–28. [PubMed]
142. Ewing KK, Mohammed HO, Scarlett JM, Short CE. Reduction of isoflurane anesthetic requirement by medetomidine and its restoration by atipamezole in dogs. Am J Vet Res 1993;54: 294–299. [PubMed]
143. Vickery RG, Sheridan BC, Segal IS, Maze M. Anesthetic and hemodynamic effects of the stereoisomers of medetomidine, an α2-adrenergic agonist, in halothane-anesthetized dogs. Anesth Analg 1988;67:611–615. [PubMed]
144. Greene SA. Pros and cons of using α2 agonists in small animal anesthesia practice. Clin Tech Small Anim Pract 1999;14: 10–14. [PubMed]
145. Virtanen R, Savola JM, Saano V. Highly selective and specific antagonism of central and peripheral alpha-2 adrenoreceptors by atipamezole. Arch Int Pharmacodyn Ther 1989;297:190–204. [PubMed]
146. Maze M, Tranquilli W. Alpha-2 adrenoreceptor agonists: defining the role in clinical anesthesia. Anesthesiology 1991;74: 581–605. [PubMed]
147. Vaha-Vahe AT. The clinical effectiveness of atipamezole as a medetomidine antagonist in the dog. J Vet Pharmacol Ther 1990;13:198–205. [PubMed]
148. Hsu WH, Schaffer DD, Hanson CE. Effects of tolazoline and yohimbine on xylazine induced central nervous system depression, bradycardia, and tachypnea in sheep. J Am Vet Med Assoc 1987;190:423–426. [PubMed]
149. Vainio O. Reversal of medetomidine-induced cardiovascular and respiratory changes with atipamezole in dogs. Vet Rec 1990;127:447–450. [PubMed]
150. Mirakhur RK. Anticholinergic drugs and anesthesia. Can J Anaes 1988;35;443–447. [PubMed]
151. Alibhai HIK, Clarke KW, Lee YH, Thompson J. Cardiopulmonary effects of combinations of medetomidine hydrochloride and atropine sulphate in dogs. Vet Rec 1996;138:11–13. [PubMed]
152. Dunkle N, Sydney-Moise N, Scarlett-Kranz J, Short CE. Cardiac performance in cats after administration of xylazine or xylazine glycopyrrolate: Echocardiographic evaluations. Am J Vet Res 1986;47:2212–2216. [PubMed]
153. Hall LW, Clarke KW. Veterinary Anesthesia. 9th Edition. London, England: Bailliere Tindall, 1991:52–64.
154. Sinclair MD, O'Grady M, Kerr C, McDonell WN. The echocardiographic effect of romifidine in dogs with or without prior or concurrent administration of glycopyrrolate. Vet Anaesth Analg 2003 (In press). [PubMed]
155. Lemke KA. Electrocardiographic and cardiopulmonary effects of intramuscular administration of glycopyrrolate and romifidine in conscious beagle dogs. Vet Anaesth Analg 2001;28:75–86.
156. Hsu WH, Lu ZX, Hembrough FB. Effect of xylazine on heart rate and arterial blood pressure in conscious dogs as influenced by atropine, 4-aminopyridine, doxapram, and yohimbine. J Am Vet Med Assoc 1985;186:153–156. [PubMed]
157. Bergstrom K. Cardiovascular and pulmonary effects of a new sedative/analgesic (medetomidine) as a preanaesthetic drug in the dog. Acta Vet Scand 1988;29:109–116. [PubMed]
158. Jacobson JD, McGrath CJ, Ko JCH, Smith EP. Cardiorespiratory effects of glycopyrrolate-butorphanol-xylazine combination, with and without nasal administration of oxygen in dogs. Am J Vet Res 1994;55:835–841. [PubMed]
159. Muir WW. Effects of atropine on cardiac rhythm and rate in dogs. J Am Vet Med Assoc 1978;172:917–921. [PubMed]
160. Lemke KA, Tranquilli WJ, Thurmon JC, Benson GJ, Olson WA. Hemodynamic effects of atropine and glycopyrrolate in isoflurane-xylazine-anesthetized dogs. Vet Surg 1993;22: 163–169. [PubMed]
161. Maze M. Clinical uses of α2 agonists. In: Barash PG, ed. The American Society of Anesthesiologists Refresher Course Lectures. Philadelphia: JB Lippincott, 1992:133–142.
162. Flacke WE, Flacke JW, McIntee DF, Blow K, Bloor BC. Dexmedetomidine: effects of the alpha2 agonist on the isolated mammalian heart. Anesthesiology 1989;71:A543.

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