Reza Seddighi
␣-2 adrenoceptor agonists, also referred to as␣-2 agonists, pro-vide dose-dependent sedation, analgesia, and muscle relaxation.
These effects are primarily caused by stimulation of presynaptic
␣-2 adrenergic receptors resulting in a decrease in norepinephrine release, centrally and peripherally, and a subsequent reduction in central nervous system sympathetic outflow and circulating cate-cholamine concentrations (Berthelsen & Pettinger, 1977; Bylund &
U’Prichard, 1983). Activation of␣-2 adrenoreceptors in supraspinal and spinal sites produces antihyperalgesia, analgesia, and sedation (Yaksh & Reddy, 1981; Pertovaara et al., 1991; Molina & Herrero, 2006).
␣-2 agonists are frequently used in veterinary patients for seda-tion prior to general anesthesia, and to reduce the dose of inducseda-tion and maintenance agents (Gomez-Villamandos et al., 2006; Oku et al., 2011).␣-2 agonists are often used in combination with other analgesics and anesthetics (e.g., opioids, ketamine), to attenuate the stress response associated with surgery or diagnostic procedures (Ethier et al., 2008; Jeong et al., 2009). The analgesic efficacy of
␣-2 agonists is enhanced by the concomitant use of opioids (Kuo
& Keegan, 2004), and small doses of␣-2 agonists provide seda-tion and analgesia postoperatively and facilitate a smooth recovery (Larenza et al., 2008; Valtolina et al., 2009; Valverde et al., 2010).
PHARMACOLOGY OF␣-2 ADRENOCEPTOR AGONISTS
Adrenergic Receptors
Adrenergic receptors (or adrenoceptors) are targets for cat-echolamines, particularly norepinephrine (noradrenaline) and epinephrine (adrenaline), and are present in a variety of tissues.
Adrenergic receptors are closely associated, structurally and func-tionally, with membrane-associated G proteins, which are respon-sible for initiating intracellular signaling cascades and, as such, are classified as G-protein-coupled receptors (GPCRs) (Hayashi &
Maze, 1993; Westfall & Westfall, 2011).
Classification of Adrenergic Receptors
Early descriptions classified adrenergic receptors into two groups, those with activity that results in excitation, and those with activity that results in inhibition of the effector cells (Dale, 1906; Cannon,
1933). However, further experiments indicated that this classifi-cation scheme is overly simple, and each type may have either excitatory or inhibitory action (Ahlquist, 1948). Ahlquist proposed that catecholamines could be excitatory or inhibitory, and the vari-ation in the adrenoceptors’ physiological effects could be due to differences in the receptors involved and quantitative differences in potency. Thus, he tentatively classified adrenergic receptors into␣- and-adrenotropic receptors. With further studies on the function and anatomical location of adrenergic receptors, hetero-geneity among␣- and-adrenergic receptors was recognized, and receptor subtypes were identified (Westfall, 1977). In an effort to refine the classification of␣-adrenoceptors, a classification based on the synaptic location of these receptors (i.e., presynaptic␣-2 and postsynaptic␣-1) was proposed (Langer, 1974; Berthelsen &
Pettinger, 1977). However, as postsynaptic and extrasynaptic (i.e., located in vascular endothelium and platelets)␣-2 receptors were also found, a classification strictly based on anatomical location has proven to be untenable (Drew & Whiting, 1979; Stoelting &
Hillier, 2006). Ultimately, with the development of more selective
␣-adrenoceptor antagonists, and investigations of their interaction with each adrenoceptor, the pharmacological basis for classification of␣-adrenergic receptors was developed (Bylund & U’Prichard, 1983). For instance, based on pharmacological effects,␣-1 recep-tors are those that are more sensitive to prazosin (a selective␣-1 receptor antagonist), whereas yohimbine (an␣-2 receptor antag-onist) is more potent than prazosin at␣-2 receptors (Hayashi &
Maze, 1993).
␣-2 Adrenoceptor Subtypes
Receptor cloning has revealed additional heterogeneity of ␣-2 adrenergic receptors, and resulted in the classification of three dis-tinct␣-2 receptor subtypes (A, B, and C) (Bylund 1992)
␣-2A subtype: Although the cellular distribution of the three sub-types is incompletely understood, it appears that subtype A is the predominant subtype in the central nervous system. In situ hybridization of receptor mRNA and receptor subtype-specific antibodies indicates that ␣-2A receptors in the brain may be either presynaptic or postsynaptic.␣-2A receptors in the canine brain seem to mediate sedation, supraspinal antinociception, and hypothermia (Fagerholm et al., 2008). They provide centrally
Pain Management in Veterinary Practice, First Edition. Edited by Christine M. Egger, Lydia Love and Tom Doherty.
C2014 John Wiley & Sons, Inc. Published 2014 by John Wiley & Sons, Inc.
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94 Section 2 / Pharmacology of Analgesic Drugs mediated sympatholysis by inhibition of norepinephrine release
from sympathetic nerve endings, and this results in bradycar-dia and hypotension (Philipp et al., 2002; Ma et al., 2004;
Fagerholm et al., 2008; Westfall & Westfall, 2011). The␣-2A adrenergic receptor is the primary mediator of spinal analgesia from endogenous norepinephrine as well as exogenous adren-ergic agonists (Stone et al., 1997). This subtype, also located postsynaptically on pancreaticcells, is responsible for hyper-glycemia secondary to inhibition of insulin release (Angel et al., 1988, 1990).
␣-2B subtype: The␣-2B subtype is mainly found in the periph-eral vasculature and it mediates the initial increase in systemic vascular resistance (vasoconstriction) that results in reflex brady-cardia. It has also been reported that the␣-2B receptor subtype is involved in spinal analgesia (Philipp et al., 2002). The anti-shivering properties of ␣-2 agonists in people are thought to be mediated via the␣-2B receptor subtype (Stoelting & Hillier, 2006).
␣-2C subtype: The␣-2C subtype is located in the ventral and dor-sal striatum and hippocampus, and inhibits the release of cate-cholamines from the adrenal medulla, modulates dopamine neu-rotransmission in the brain, and has a role in various behavioral responses (Hunter et al., 1997; Westfall & Westfall, 2011).
Molecular Basis of Adrenergic Receptor Function
Adrenergic receptors are GPCRs that convert a transmembrane signal to an effector mechanism that may include a transmembrane ion channel or generation of an intracellular second messenger cascade. There are more than 20 species of G proteins that are characterized by differences in the amino acid sequence of one of three subunits, the ␣ subunit. Each major type of adrenergic receptor is associated with a particular class of G proteins (i.e.,␣-1 with Gq,␣-2 with Gi, andwith Gs) (Westfall & Westfall, 2011), and these discrete differences in the␣subunit provide the unique response mediated by each of the adrenergic receptors (Hayashi &
Maze, 1993; Westfall & Westfall, 2011).
Inhibition of adenyl cyclase activity is the main pathway by which␣-2 adrenergic receptors exert their effect. This inhibition results in a decrease in the accumulation of cAMP, and dimin-ishes the stimulation of cAMP-dependent protein kinase and sub-sequent phosphorylation of target regulatory proteins. Efflux of K+ via activation of G-protein-gated K+ channels results in hyper-polarization of excitable membranes, and provides an effective means of suppressing neuronal firing.␣-2 adrenoceptor stimula-tion also suppresses Ca2+entry into the nerve terminals via inhi-bition of voltage-gated Ca2+channels, which may be responsible for its inhibitory effect on the secretion of neurotransmitters. Other second-messenger systems linked to␣-2 receptor activation include acceleration of Na+/H+exchange, arachidonic acid mobilization, and increased phosphoinositide hydrolysis (Hayashi & Maze, 1993;
Stoelting & Hillier, 2006; Westfall & Westfall, 2011).
Binding to spinal presynaptic␣-2 receptors blocks the release of neurotransmitters and neuropeptides from C fibers terminating in the superficial laminae of the dorsal horn of the spinal cord (Buerkle
& Yaksh, 1998). This occurs via activation of G0proteins, which results in a decrease in calcium flux and glutamate, substance P, neu-rotensin, calcitonin gene-related peptide, and vasoactive intestinal peptide release. Stimulation of spinal␣-2 receptors located
post-synaptically on wide-dynamic-range projection neurons results in hyperpolarization via Gi-protein-coupled potassium channels.
MECHANISMS OF ACTION OF␣-2 ADRENOCEPTOR AGONISTS
The sedative and anxiolytic effects of ␣-2 agonists are medi-ated by decreased activity of ascending neural projections to the cerebral cortex and limbic systems via activation of supraspinal presynaptic or postsynaptic receptors located in the pontine locus coeruleus, an important modulator of vigilance (Stoelting & Hillier, 2006; Hellyer et al., 2007). Conversely, although the mechanism of
␣-2 agonist-mediated antinociception is not entirely understood, it appears that it is primarily the result of spinal␣-2 receptor stimula-tion.␣-2 adrenergic receptors are present in high density in the sub-stantia gelatinosa and intermediolateral cell columns of the spinal cord and on primary afferent terminals, indicating a direct involve-ment of spinal␣-2 receptors in antinociception (Yaksh, 1985; Yaksh et al., 1995). Stimulation of␣-2 adrenergic receptors could suppress nociceptive signals at various points in the pain pathway via inhi-bition of neurotransmitter release from the primary afferent fibers in the dorsal horn. This affects pre- and postsynaptic modulation of nociceptive signals, influences descending modulatory systems from the brainstem, inhibits the release of substance P, and alters ascending modulation of nociceptive signals in the diencephalon and limbic areas (Kuraishi et al., 1985; Murrell & Hellebrekers, 2005).
Activation of supraspinal␣-2 receptors within the pons plays an important role in the descending noradrenergic-serotonergic mod-ulation of nociceptive input, resulting in analgesic and antihyper-algesic effects (Guo et al., 1996; Hellyer et al., 2007). It has been proposed that␣-2 agonists not only mediate their analgesic action via stimulation of the spinal␣-2 receptors but also directly suppress the locus coeruleus, which, in turn, increases spinal cord nore-pinephrine concentrations. This increase in spinal norenore-pinephrine concentration activates spinal␣-2 receptors and results in antinoci-ception (Guo et al., 1996).
␣-2 agonists may also attenuate or reverse allodynia in states of chronic pain via a spinally mediated antinociceptive effect. In a nerve ligation model in rats, lumbar intrathecal administration of
␣-2 agonists significantly reduced allodynia via activation of spinal␣-2 receptors and decreased presynaptic sympathetic out-flow (Yaksh et al., 1995).
The analgesic and antihyperalgesic effects of ␣-2 agonists are more pronounced during inflammation, although the effects depend on the stage of the inflammatory process. In a rat model, the antiallo-dynic and antihyperalgesic activities of medetomidine were greater in the middle phase of the inflammatory process than in the early or late phases (Molina & Herrero, 2006).
Clinically, the degree of sedation and analgesia produced by an
␣-2 agonist is related not only to the density, location, and type of
␣-2 adrenoceptors but also to the individual selectivity and affinity of the specific drug molecule for the␣-1 and␣-2 receptor binding sites (Sinclair, 2003). At least in the case of dexmedetomidine, it is known that the␣-2 adrenoceptor selectivity is dose dependent.
During administration of small to medium doses or slow infusion rates, a high degree of␣-2 adrenoceptor selectivity is observed, and large doses or rapid infusion rates are associated with both␣-1 and
␣-2 activation (Virtanen et al., 1988).
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7 /␣-2 Adrenoceptor Agonists 95 PHYSIOLOGICAL EFFECTS OF␣-2 ADRENOCEPTOR
AGONISTS
␣-2 receptors are located in the peripheral and central nervous systems and in other tissues such as the liver, kidney, pancreas, eye, vascular smooth muscle, and platelets (Maze & Tranquilli, 1991). Thus, the physiological responses mediated by ␣-2 ago-nists depend on the location of the affected receptors, accounting for the diversity of their effects. Some drugs in this group (e.g., clonidine, medetomidine, and dexmedetomidine) also activate the nonadrenergic imidazoline receptors, and this may be responsible for the centrally mediated hypotensive and antiarrhythmic effects of these drugs (Tibirica et al., 1991; Noyer et al., 1994; Hieble &
Ruffolo, 1995). Additionally, the net effect of␣-2 agonists may be influenced by factors such as the receptor selectivity of the drug, the dosage used, concurrently administered drugs, species, health status, and environmental factors. The main effects of␣-2 agonists on the function of different organ systems are described below.
Effects on the Cardiovascular System
The effects of ␣-2 adrenergic agents on the cardiovascular sys-tem can be significant, and include bradycardia, first- or second-degree atrioventricular (AV) blockade, decreased cardiac output, and an initial increase in peripheral vascular resistance followed by hypotension. The initial vasoconstriction results in an early hyper-tensive effect due to stimulation of postsynaptic␣-2B receptors in arterial and venous vasculature (Ruffolo, 1985; Stoelting & Hillier, 2006). Currently, there is no strong evidence to support the exis-tence of postsynaptic␣-2 receptors in the myocardium; therefore, a direct effect of␣-2 agonists on the myocardium is doubtful (Hous-mans, 1990; Hayashi & Maze, 1993). The decrease in heart rate is mainly due to the central sympatholytic effect of␣-2 agonists and a reflex response to the increased peripheral vascular resistance. Anti-cholinergic agents (e.g., atropine) resolve the␣-2 agonist-induced bradycardia; however, as the bradycardia is a physiological reflex and a protective response to the␣-2 agonist-induced increase in peripheral vascular resistance, coadministration of an anticholin-ergic drug may further increase mean arterial blood pressure and heart rate, resulting in myocardial hypoxia and deleterious cardiac arrhythmias (Alibhai et al., 1996; Congdon et al., 2011).
The initial increase in peripheral vascular resistance and hyper-tension is followed by peripheral vasodilation and a decrease in arterial blood pressure. The latter changes primarily result from stimulation of inhibitory ␣-2 adrenergic receptors (principally
␣-2A) in the medullary vasomotor center, and result in decreased sympathetic nervous system outflow (Stoelting & Hillier, 2006).
The decrease in systolic left ventricular pressure and plasma catecholamines in dogs after dexmedetomidine administration is attributed to this decrease in sympathetic outflow (Flacke et al., 1993).␣-2 agonists may also potentiate parasympathetic activity via the nucleus tractus solitarius, which has an important role in modulation of autonomic control, especially vagal activity (Kubo
& Misu, 1981). Although these cardiovascular effects appear to be dose dependent (Pypendop & Verstegen, 1998), infusion of dexmedetomidine, at rates as low as 1g/kg/h, decreased cardiac output in dogs (Carter et al., 2010).
The receptor selectivity of the particular␣-2 agonist is another determinant of the magnitude of the cardiovascular effects of these drugs. The ␣-2 to ␣-1 adrenoceptor selectivity ratios reported
for medetomidine and dexmedetomidine are much greater than those reported for detomidine, clonidine, and levomedetomidine (Virtanen et al., 1988; Scheinin et al., 1989). It is generally accepted that less selective␣-2 adrenoceptor agonists (e.g., xylazine) cause more significant cardiovascular effects as, in addition to antag-onizing the hypnotic responses (Guo et al., 1991), ␣-1 adreno-ceptors may participate in the centrally mediated bradycardia and peripheral vasoconstriction (Xu et al., 1998). Medetomidine and dexmedetomidine are examples of␣-2 agonists that have a very low affinity for ␣-1 adrenoceptors and which interact with cen-tral imidazoline receptors and, thus, are expected to have a better cardiovascular profile than less selective drugs such as xylazine (Murrell & Hellebrekers, 2005). However, in horses, the effects of medetomidine were similar to an equipotent dose of xylazine (Yamashita et al., 2002). In another study in horses, medetomidine induced dose-dependent cardiovascular effects similar to detomi-dine (AV blockade, decrease in cardiac index and stroke volume, and an initial hypertension); however, the cardiovascular effects of medetomidine and xylazine were not as prolonged as that of detomidine (Yamashita et al., 2000).
Although␣-2 agonists may cause bradyarrhythmias, particularly first- and second-degree AV block, there is evidence that they may also have antiarrhythmogenic properties. For instance, dexmedeto-midine increased the arrhythmogenic threshold of epinephrine nec-essary to induce ventricular fibrillation in a dose-dependent man-ner in dogs anesthetized with halothane (Hayashi et al., 1991). The antiarrhythmogenic effect of ␣-2 agonists is primarily due to an increase in parasympathetic tone and a decrease in sympathetic tone via stimulation of central␣-2 (primarily␣-2A) adrenergic recep-tors. In addition, imidazoline receptor activation, which results in reduction of sympathetic tone and the concentration of circulating catecholamines, may be involved in the antiarrhythmogenic effect of those␣-2 agonists (e.g., dexmedetomidine) that have an affin-ity for imidazoline receptors (Kagawa et al., 2005; Chrysostomou et al., 2008).
In summary, although␣-2 agonists may cause significant brady-cardia and an increase in afterload resulting in reduced brady-cardiac output, these effects are usually well tolerated in healthy animals (Lemke, 2007; Martinez, 2012). Lower doses of␣-2 agonists (e.g., medetomidine at 2–10g/kg IM) were demonstrated to be safe in middle-aged and older dogs, provided cardiopulmonary function is closely monitored and supported during and after drug administra-tion (Muir et al., 1999).
Effects on the Respiratory System
The main adverse effect of␣-2 agonists on the respiratory system is hypoxemia, due to ventilation–perfusion mismatch and a decrease in the respiratory rate. Alveolar ventilation is usually not affected in healthy animals given clinical doses of␣-2 agonists, and there is no significant increase in PaCO2 (Bloor et al., 1989; Nguyen et al., 1992; Lamont et al., 2001). Nevertheless, with large doses, dark or cyanotic mucous membranes may be evident in dogs, in spite of a normal or near normal PaO2. The peripheral cyanosis is believed to be the result of an increase in the concentration of desat-urated hemoglobin in the mucous membranes, due to decreased perfusion of the peripheral tissues and increased oxygen extrac-tion during capillary transit (Vaha-Vahe, 1989b; Sinclair, 2003).
Although blood flow to the vital organs may not decrease to the same extent as it does in peripheral tissues, and the degree of mucous
96 Section 2 / Pharmacology of Analgesic Drugs membrane cyanosis may not necessarily correlate with hypoxia of
the vital organs, oxygen supplementation is recommended when-ever␣-2 agonists are used in animals already at risk for hypoxemia or when other respiratory depressant drugs (e.g., sedatives, opioids, anesthetics) are administered concurrently (Sinclair, 2003). Con-current administration of L-methadone (Raekallio et al., 2009), butorphanol, or ketamine (Ko et al., 2000) significantly decreased the PaO2and increased the PaCO2when compared with medeto-midine alone.
In horses, commonly used doses of xylazine and detomidine cause laryngeal relaxation and alteration of lung dynamic compli-ance and pulmonary vascular resistcompli-ance (Reitemeyer et al., 1986;
Lavoie et al., 1992b; McDonell & Kerr, 2007). The position of the head and neck is largely responsible for changes in respi-ratory mechanics in horses sedated with xylazine (Lavoie et al., 1992a). A decrease in PaO2 of 10–20 mm Hg is commonly observed after administration of ␣-2 agonists to horses (Reite-meyer et al., 1986; Wagner et al., 1991; Lavoie et al., 1992a);
however, an increase in PaCO2is uncommon (Wagner et al., 1991;
Bettschart-Wolfensberger et al., 2005). Nevertheless, detomidine significantly increased PaCO2and decreased PaO2in horses sec-ondary to ventilation–perfusion mismatch, and concurrent admin-istration of butorphanol further increased PaCO2 (Nyman et al., 2009).
Hypoxemia (PaO2≤50 mm Hg) is a prominent finding in sheep given clinically relevant sedative doses of␣-2 agonists (Celly et al., 1997a, 1997b). The hypoxemia in sheep is mainly due to ␣-2 agonist activation of pulmonary intravascular macrophages, which results in bronchoconstriction and intra-alveolar edema and hem-orrhage (Celly et al., 1999). Interestingly, there was no difference in the magnitude of the hypoxemia in sheep after administration of equipotent doses of xylazine, romifidine, detomidine, or medeto-midine (Celly et al., 1997b).
Effects on the Renal System
␣-2 agonists induce diuresis and changes in urine specific grav-ity and pH, plasma creatinine concentration and osmolalgrav-ity, and the concentrations of sodium, potassium, and chloride in urine and plasma (Burton et al., 1998; Saleh et al., 2005). Several mecha-nisms have been proposed for the diuretic effect of␣-2 agonists.
The increase in plasma glucose concentration and glucose excre-tion rate caused by␣-2 agonist administration is not of sufficient magnitude to account for the diuresis observed (Miller et al., 2001).
The primary mechanism responsible for diuresis relates to antidi-uretic hormone (arginine vasopressin (AVP)).␣-2 agonists inhibit secretion of AVP, and inhibit AVP-induced cAMP formation in the distal nephrons (Pettinger et al., 1987). ␣-2 agonists also cause an increase in the plasma concentration of atrial natriuretic pep-tide (ANP). In dogs, the increase in the plasma concentration of ANP was greater with medetomidine than with xylazine, and the diuretic effect of medetomidine was less dose dependent than that of xylazine (Talukder & Hikasa, 2009). Activation of imidazoline receptors also causes diuresis via an increase in ANP concentration (Mukaddam-Daher & Gutkowska, 2000; Greven & von Bronewski-Schwarzer, 2001), and the differences between the diuretic effect of xylazine and medetomidine could be due to differences in the action at imidazoline receptors, as only medetomidine activates imidazoline receptors (Talukder & Hikasa, 2009).
In addition to changes in plasma concentrations of AVP and ANP, other mechanisms may be involved in the diuretic response to
␣-2 agonists (Ruskoaho and Leppaluoto, 1989; Talukder & Hikasa, 2009). These may include increased glomerular filtration rate or decreased sodium reabsorption due to sympatholysis, and decreased renal sympathetic nerve influence on tubular sodium reabsorption (Kline & Mercer, 1990, Rouch et al., 1997; Leino et al., 2011).
Although␣-2 agonists have a strong diuretic effect, and should be used cautiously in animals with urethral obstruction, they may pro-tect the kidneys by inhibiting renin release, increasing glomerular filtration, and increasing secretion of sodium and water (Gellai &
Ruffolo, 1987; de Leeuw & Birkenhager, 1988). In animals with urinary blockage, the author reserves␣-2 agonist administration for those with no significant electrolyte imbalance and that will soon have the obstruction relieved.
Effects on the Gastrointestinal System
␣-2 adrenoceptors constitute the main receptor types on autonomic nerve terminals and cholinergic neurons of the myenteric plexus (DiJoseph et al., 1984). Prolongation of gastrointestinal transit time occurs after administration of␣-2 agonists, and this is mediated via activation of␣-2 adrenoceptors in the myenteric plexus, resulting in decreased gastrointestinal muscle contractions due to inhibition of acetylcholine release (Roger & Ruckebusch, 1987; Ross et al., 1990). In horses, clinically relevant doses of xylazine or detomidine significantly decreased duodenal motility (Merritt et al., 1998), and xylazine significantly increased gastric emptying time in ponies (Doherty et al., 1999). In dogs, decreased gastroesophageal sphinc-ter pressure was associated with the administration of xylazine, which may result in reflux of gastric contents (Strombeck & Har-rold, 1985).␣-2 agonists may modulate the release of gastric acid (Berthelsen & Pettinger, 1977), yet no significant change in gastric pH was observed after administration of these drugs to humans (Orko et al., 1987).␣-2 agonists decrease intestinal ion and water secretion in the large bowel, when administered orally, and are considered an effective treatment for watery diarrhea in humans (McArthur et al., 1982).
Nausea and vomiting are frequently observed after administra-tion of␣-2 agonists to dogs and cats (Vaha-Vahe, 1989a; Granholm et al., 2006); therefore, these drugs should be administered cau-tiously in animals prone to aspiration (e.g., brachycephalic animals) or those that may suffer from significant gastrointestinal distur-bances. Although the involvement of␣-1 adrenoceptors cannot be ruled out,␣-adrenoceptor-mediated emesis appears to be mediated mainly by␣-2 receptors in the dog (Hikasa et al., 1992).
Effects on the Hepatobiliary System
The cardiovascular effects induced by␣-2 agonist administration may affect hepatic blood flow, and this suggests that these drugs should be used cautiously in animals with moderate to severe liver disease (Greene & Marks, 2007). In addition, as the elimination of␣-2 agonists occurs mainly by biotransformation in the liver (Salonen, 1989), their clearance may be altered in animals with severe liver disease. However, in a study of human patients in early septic shock, a 24-hour continuous rate infusion of dexmedetomidine (0.2–2.5g/kg/h) did not affect hepatic blood flow (Memis et al., 2009). Moreover, the anti-inflammatory proper-ties of dexmedetomidine had protective effects on the liver in a rat model of endotoxemia (Sezer et al., 2010). Thus, the consideration
7 /␣-2 Adrenoceptor Agonists 97 of␣-2 agonists for sedation and analgesia in animals with liver
disease should be based on the individual animal’s health status, though lower doses are recommended.
Effects on the Ocular System
In dogs, xylazine alone did not decrease tear production, but it potentiated the effect of butorphanol in decreasing tear production (Dodam et al., 1998). An overall decrease in intraocular pressure (IOP) can be expected when an␣-2 adrenergic agent is adminis-tered as a sole agent, as these agents commonly cause bradycardia and hypotension, a decrease in sympathetic activity, and possibly a decrease in aqueous production. A study of rabbit and cat nictitat-ing membrane preparations showed that medetomidine decreases IOP, in part, by interacting with␣-2 adrenoceptors located on sym-pathetic nerve endings. The effect of medetomidine on imidazo-line receptors may also have some role in decreasing IOP (Potter
& Ogidigben, 1991). However, because␣-2 agonists may induce vomiting, these drugs should be used with caution in animals in which an increase in IOP would be deleterious to ocular health.
Pupil size may also be affected by ␣-2 agonists. Intravenous administration of medetomidine produced mydriasis in anes-thetized rats (Potter et al., 1990); however, the clinical importance of this is unclear.
Metabolic Effects
␣-2 agonists induce hyperglycemia through inhibition of insulin release secondary to stimulation of ␣-2 adrenoceptors on the  cells of the pancreas (Yamazaki et al., 1982; Hillaire-Buys et al., 1985). Conversely, imidazoline receptors may have the opposite role in increasing insulin release fromcells (Hirose et al., 1997).
Thus,␣-2 agonists with an affinity for imidazoline receptors (e.g., medetomidine and dexmedetomidine) (Hikasa et al., 1992; Kanda
& Hikasa, 2008) may induce a different insulin response than␣-2 agonists that lack imidazoline affinity, such as xylazine. Medetomi-dine and xylazine induced hyperglycemia and hypoinsulinemia and inhibited catecholamine release and lipolysis in dogs, but the hyper-glycemic effect of medetomidine, in contrast to that of xylazine, was not dose dependent (Ambrisko & Hikasa, 2002). Medetomidine and xylazine induced a similar degree of hyperglycemia, suppression of epinephrine, norepinephrine, and insulin release, and inhibition of lipolysis in cats (Kanda & Hikasa, 2008). Interestingly, in the latter study, although the decrease in the plasma insulin concentration in cats was similar to that reported in dogs, the increase in plasma glucose concentration was considerably greater. The authors con-cluded that factors in addition to the effect of␣-2 agonists on the plasma insulin concentration may be responsible for the observed difference in the hyperglycemic response between dogs and cats.
Similar neurohormonal alterations after administration of␣-2 ago-nists are reported in other species, including cattle and sheep (Gore-wit, 1980; Ranheim et al., 2000). However, a study in neonatal foals demonstrated that, unlike in adult horses, intravenous xylazine (1.1 mg/kg) does not produce hypoinsulinemia and hyperglycemia, and that the process leading to inhibition of insulin release by xylazine is immature or absent in foals under 1 month of age (Robertson et al., 1990).
Effects on Other Body Systems
␣-2 agonists affect thermoregulation. Administration of an␣-2 ago-nist (mivazerol) selectively antagonized the early thermoregulatory
responses to bacterial infection in rats (Tolchard et al., 2009). The authors of that study suggested that patients receiving ␣-2 ago-nists may not be capable of mounting a normal thermal response to infecting organisms, and monitoring the core temperature may not be as helpful in detection of infection in these patients. Rectal tem-perature decreased significantly by 30 minutes after administration of xylazine and was still decreased after 120 minutes in 10- and 28-day-old foals (Robertson et al., 1990). In rabbits, medetomidine markedly decreased body temperature and exhibited antipyretic and hypothermic effects (Szreder, 1993). The authors of the latter study claimed that these effects were associated with inhibition of the metabolic rate and/or redistribution of body heat to peripheral tissues and increased heat loss to the environment. A decrease in prostaglandin E2in the hypothalamus after administration of cloni-dine to Guinea pigs has also been reported (Feleder et al., 2004), and a similar mechanism may also be responsible for the antipyretic effect in febrile horses (Kendall et al., 2010).
ROUTES OF ADMINISTRATION OF␣-2 AGONISTS Systemic Administration
␣-2 adrenoceptor agonists are administered systemically for seda-tion, as part of a premedication protocol (Maddern et al., 2010), or in the form of a constant rate infusion (CRI) during the maintenance of anesthesia in many species, including dogs (Ethier et al., 2008;
Gomez-Villamandos et al., 2008) and horses (Solano et al., 2009;
Valverde et al., 2010). Single dose and CRI administration of these drugs have also been successfully used during the recovery period to provide analgesia (Valtolina et al., 2009; van Oostrom et al., 2011).␣-2 agonists interact synergistically with opioids to provide analgesia (Ambrisko et al., 2005).
Epidural Administration
Epidural administration of␣-2 agonists blocks nociceptive path-ways at the level of the spinal cord via activation of␣-2 receptors (primarily␣-2A). Epidurally administered␣-2 agonists and opi-oids have synergistic analgesic effects because they act via similar mechanisms (Branson et al., 1993), and also because opioids induce changes in the ␣-2 adrenergic receptor density. Systemic daily administration of morphine in a rat model enhanced the analgesic effect of intrathecally administered dexmedetomidine via upregu-lation of the␣-2A,␣-2B, and␣-2C receptor subtypes in the lumbar dorsal root ganglion and dorsal horn (Tamagaki et al., 2010).
In addition to spinally mediated analgesia, supraspinal analgesia, secondary to systemic absorption and cranial migration of drug, may contribute to the analgesic effects of epidurally or spinally administered ␣-2 agonists (Stone et al., 1997; Fairbanks et al., 2002; Virgin et al., 2010; Valverde et al., 2010).
Dose-dependent adverse cardiovascular and respiratory effects can be expected due to systemic absorption of epidurally and spinally administered␣-2 agonists (Vesal et al., 1996; Seddighi, 2003). The onset and the extent of these effects are primar-ily affected by the lipid solubility of the drug. For instance, as dexmedetomidine is more rapidly absorbed than medetomi-dine, systemic effects can be expected sooner after epidural or spinal administration of dexmedetomidine (Kallio et al., 1989;
Scheinin et al., 1989). In dogs, however, epidural administration of dexmedetomidine caused adequate neuroaxial analgesia with
98 Section 2 / Pharmacology of Analgesic Drugs minimal cardiovascular and respiratory adverse effects, and
sys-temic administration caused a hypnotic state with significant car-diorespiratory depression (Sabbe et al., 1994).
In horses, ␣-2 agonists are commonly injected at the caudal epidural space (S-C1or C1-2). However, because the equine spinal cord terminates in the lumbosacral area, agents administered at more caudal spaces have to diffuse further cranially to reach the target receptors (Skarda & Tranquilli, 2007), and the resultant analgesic effect depends on the extent of cranial migration of the drug. Regardless, epidural xylazine in horses was shown to produce potent perineal analgesia without measurable cardiopul-monary effects (Leblanc & Eberhart, 1990). Ataxia and sedation due to the systemic absorption of epidurally administered␣-2 ago-nists may limit their clinical application, especially when higher doses are used (Doria et al., 2008).
Intra-articular Administration
Although in humans the intra-articular administration of␣-2 ago-nists, such as dexmedetomidine (Paul et al., 2010) and clonidine (Joshi et al., 2000; Tran et al., 2005), has significant synergistic effects with opioids and local anesthetics for pain control in knee surgery, currently, there are no reports of similar application of these drugs in animals.
␣-2 Adrenoceptor Agonists and Local Nerve Blockade
␣-2 adrenoceptor agonists have occasionally been used in humans, alone or in combination with local anesthetics, to improve analgesia and/or extend the duration of peripheral nerve conduction blockade in brachial plexus blocks (Singelyn et al., 1996), peribulbar blocks (Madan et al., 2001), intravenous regional blocks (Memis et al., 2004), spinal blocks with local anesthetics (Calasans-Maia et al., 2005; Kanazi et al., 2006), and intercostal nerve blocks (Tschernko et al., 1998). Although the exact mechanism of action of these drugs in enhancement of the local nerve blockade is not clear, sev-eral mechanisms have been proposed. One possible mechanism is that local vasoconstriction induced by these drugs leads to a delay in the absorption of the local anesthetic. Studies in laboratory ani-mals have indicated other mechanisms of action for␣-2 agonists in local nerve blockade. In a study of frog sciatic nerve blockade, dexmedetomidine produced nerve blockade that was resistant to␣-2 antagonists (Kosugi et al., 2010). It was concluded that␣-2 agonist inhibitory effects on nerve conduction are unlikely to be related to G-protein-coupled membrane receptors, such as ␣-2 adreno-ceptors, or to imidazoline receptors. Other receptors that may be involved in nerve blockade by␣-2 agonists are tetrodotoxin (TTX)-sensitive voltage-gated Na+channels and/or tetraethylammonium (TEA)-sensitive (delayed-rectifier) K+ channels. Dexmedetomi-dine is more effective than cloniDexmedetomi-dine, lidocaine, and cocaine and is similar to ropivacaine in its nerve conduction blocking effects (Kosugi et al., 2010). An inhibitory effect of dexmedetomidine on voltage-gated Na+channels in rat dorsal root ganglia has also been demonstrated (Oda et al., 2007), and this effect was not reversed with yohimbine administration. In laboratory animal models of nerve blockade, enhancement of the hyperpolarization-activated cation current, which prevents the nerve from returning from a hyperpolarized state to the resting membrane potential for subse-quent firing, has also been shown to be responsible for the periph-eral analgesic effects of dexmedetomidine and clonidine. This
mechanism is independent of the action of these drugs on ␣-2 receptors (Dale, 1906; Kroin et al., 2004; Brummett et al., 2011)
In summary, although incorporation of␣-2 agonists into local nerve blocks appears to be promising based on preliminary data from laboratory animal studies, it has not been fully investigated in veterinary practice. The author occasionally includes an ␣-2 adrenoceptor agonist (e.g., dexmedetomidine, 1–2 g/kg) in brachial plexus, sciatic, and femoral nerve blocks. However, objec-tive evaluation of the benefits and any potential adverse effects from systemic absorption of these drugs in the clinical setting has yet to be determined.
SUMMARY
␣-2 adrenoceptor agonists are sedative-analgesics commonly used in veterinary medicine. These drugs are administered systemically or in locoregional techniques to achieve sedation, analgesia, and muscle relaxation. Administration may cause adverse systemic effects, primarily cardiovascular in nature, in patients with cardio-vascular instability or when used at higher doses. Careful patient selection is important, but many patients will benefit from the desir-able clinical effects of these drugs.
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