α2-Agonists*

C H A P T E R 10

a2-Agonists* Bruno H. Pypendop

he a2-agonists are a group of sedative-analgesic drugs (Box 10-1) that exert their clinical effects by interacting with a2-adrenergic receptors in the central nervous system (CNS). They also decrease anesthetic requirements and produce muscle relaxation. Although not considered first-line analgesics like opioids or nonsteroidal anti-inflammatory drugs, a2-agonists are increasingly used as analgesic adjuvants. In contrast to other classes of drugs used to manage pain, a2-agonists are distinguished by their significant cardiovascular adverse effects.

T

HISTORICAL BACKGROUND • 1962: Xylazine was synthesized in Germany for use as an antihypertensive agent in human beings; its sedative properties in animals were recognized soon afterward. • Early 1970s: Xylazine and xylazine-ketamine combinations became popular for inducing sedation and general anesthesia in large animals; use in small animals soon followed. • 1981: The sedative, analgesic, and muscle relaxant properties of xylazine were linked to stimulation of central a2-adrenoceptors.1 • Late 1980s: New, more specific a2-agonists (medetomidine, detomidine, and romifidine) were introduced; drug distribution and labeling varied widely from country to country. • 1996: Medetomidine and the a2-antagonist atipamezole became available in the United States (labeled for use in dogs only); veterinarians began using a2-agonists in lower doses, often in combination with opioids, as anesthetic and analgesic adjuvants. • 2006: Dexmedetomidine was approved in the United States for use in dogs and cats. • Currently, dexmedetomidine is the most commonly used a2-agonist for analgesia in small animal practice in the United States; medetomidine is not available, and romifidine and xylazine are rarely used as analgesic adjuvants. *The author would like to acknowledge Leigh Lamont for her work on the previous edition.

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BOX 10-1 a2-Agonists • • • • • •

Clonidine Detomidine Dexmedetomidine Medetomidine Romifidine Xylazine

MOLECULAR PHARMACOLOGY OF a2-ADRENOCEPTORS a2-Adrenoceptor Structure • All a2-adrenoceptor proteins contain approximately 450 amino acids.2 • Each protein contains seven transmembrane domains with segments of lipophilic amino acids separated by segments of hydrophilic amino acids; these form an extracellular amino terminus and an intracellular carboxyl terminus with three small extracellular loops and three intracellular loops. a2-Adrenoceptor Subtypes • Three distinct a2-adrenoceptor subtypes have been recognized: a2A, a2B, and a2C.3 • A fourth subtype (a2D) has been identified and represents the rodent homologue of the human a2A-adrenoceptor.4 • The genes for the three human subtypes have been cloned and are designated a2-C10, a2-C2, and a2-C4 for the a2A, a2B, and a2C subtypes, respectively.3 • Related subtypes have been cloned in other species including rat, mouse, pig, opossum, and fish; partial complementary DNA sequences from bovine and avian a2A-receptors have also been identified. • All three a2 subtype genes share a common evolutionary origin; several key structural and functional domains are well conserved despite only 50% protein homology at the amino acid level. • The a2-agonists currently available do not exhibit selectivity for receptor subtypes. a2-Adrenoceptor Expression • Expression is somewhat species specific, resulting in varied physiologic effects and pharmacologic activity profiles and making extrapolation of data among species difficult.5 • Distribution of a2-adrenoceptor subtypes in several species is given in Table 10-1.

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Expression and Distribution of a2-Adrenoceptor Subtypes in Different Species

Rodents6 Humans6 Dogs7,24,83

BRAINSTEM

SPINAL CORD

a2A a2A a2A

a2A, a2C a2A, a2B a2A, a2C

a2-Adrenoceptor Subtype Functional Significance • The sedative-hypnotic and anesthetic-sparing responses appear to be mediated by the a2A subtype.6–8 • The analgesic responses are mediated by the a2A and possibly the a2C subtypes. • Hypotensive and bradycardic actions are also mediated by the a2A subtype.9 • Initial increase in systemic vascular resistance appears to be mediated by the a2B subtype, with lesser contribution of the a2A subtype in certain vascular compartments.10 • Hypothermic effects and modulation of dopaminergic activity are mediated by the a2C subtype.6 Imidazoline Receptors • All a2-agonists commonly used in veterinary medicine, with the exception of xylazine, and atipamezole contain an imidazole moiety that binds to a second class of non-noradrenergic receptors called imidazoline receptors.11 • Imidazoline receptors are involved in central control of vasomotor tone and are located in the nucleus reticularis lateralis of the ventrolateral region of the medulla.11 • Central hypotensive effects observed after administration of imidazole a2-agonists appear to result from activation of imidazoline receptors, a2A-adrenoceptors, or both.12–14 Signal Transduction Mechanisms of a2-Adrenoceptors • The process by which any transmembrane receptor notifies the cell of receptor occupancy by a ligand is called signal transduction. • a2-Adrenoceptors are part of a larger receptor superfamily including dopaminergic, cholinergic, and serotonergic receptor systems that are coupled to guanine nucleotide binding proteins (G proteins) that function in signal transduction. • G proteins link cell membrane receptors to intracellular effector mechanisms, amplify the signal, and transduce external chemical stimuli into cellular responses.

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• Binding of a specific ligand (neurotransmitter, endogenous hormone, or exogenous drug) induces a conformational change in the a2-adrenoceptor, which leads to activation of specific G proteins.3 • Activated G proteins then modulate the synthesis or availability of intracellular second messenger molecules or directly alter the activity of transmembrane ion channels.3 • Relevant a2-adrenoceptor effector mechanisms include the following: 1. Increased potassium conductance leading to hyperpolarization of membrane ion channels and a decreased firing rate of excitable cells in the CNS.3 2. Inhibition of calcium influx through N-type voltage-gated calcium channels resulting in reduced fusion of synaptic vesicles with postsynaptic membranes and reduced neurotransmitter release.15 3. Inhibition of the enzyme adenylate cyclase, resulting in decreased intracellular cyclic adenosine monophosphate accumulation and decreased phosphorylation of target regulatory proteins.16 MECHANISM OF ANALGESIC ACTION • a2-Adrenoceptors within the CNS are found on noradrenergic and nonnoradrenergic neurons. • Noradrenergic a2-adrenoceptors are called autoreceptors and are located at supraspinal sites. • Non-noradrenergic a2-adrenoceptors are called heteroreceptors and are located in the dorsal horn of the spinal cord.17,18 • Both populations of receptors appear to be involved in a2-agonist analgesia. Analgesia Mediated at the Level of the Dorsal Horn • a2-Heteroreceptors are located presynaptically and postsynaptically on nociceptive neurons in the dorsal horn. • Activation by norepinephrine or an exogenous a2-agonist produces analgesia by one of two potential mechanisms: 19 1. Presynaptic a2-heteroreceptors found on primary afferent C fibers bind the agonist. This causes a G protein–mediated decrease in calcium influx (see previous section), which results in decreased release of neurotransmitters and neuropeptides such as glutamate, vasoactive intestinal peptide, calcitonin gene–related peptide, substance P, and neurotensin. 2. Postsynaptic a2-heteroreceptors found on wide dynamic range projection neurons also bind the agonist. This produces neuronal hyperpolarization via G protein–coupled potassium channels (see previous section) and inhibits ascending nociceptive transmission.

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Analgesia Mediated at the Level of the Brainstem • Traditionally, it has been accepted that a2-agonist–induced analgesia results from activation of dorsal horn a2-heteroreceptors, whereas sedative-hypnotic effects are mediated by activation of supraspinal (brainstem) a2-autoreceptors. • It now appears that brainstem a2-autoreceptors also contribute indirectly to analgesia. • a2-Autoreceptors are concentrated in three catecholaminergic nuclei in the pons: A5, A6 (also called the locus ceruleus [LC]), and A7.20,21 • The locus ceruleus (LC) is the most important of these, extending noradrenergic neurons to all segments of the spinal cord and modulating noradrenergic input from higher structures such as the periaqueductal gray matter (PAG) of the midbrain. • Activation of a2-autoreceptors in the LC by norepinephrine or an exogenous a2-agonist results in neuronal inhibition and a decreased release of norepinephrine. • Dampening of LC activity disinhibits activity in the adjacent cell bodies of A5 and A7 nuclei, resulting in increased release of norepinephrine from their terminals in the dorsal horn, which in turn activates spinal presynaptic and postsynaptic a2-heteroreceptors to produce analgesia.20 • Higher supraspinal structures may also play a role. The PAG of the midbrain extends noradrenergic innervation to the LC and may lead to a2mediated decreases in LC norepinephrine release, which indirectly feeds back on spinal a2-adrenoceptors to produce analgesia.17

CLINICAL PHARMACOLOGY OF a2-AGONISTS Xylazine • Xylazine is the least selective a2-agonist used clinically, with an a2:a1 binding ratio of only 160:1.22 • A variety of a2-antagonists have been used to reverse the effects of xylazine, including yohimbine, tolazoline, idazoxan, and, more recently, atipamezole. • Although still used extensively in large animal practice as a sedativeanalgesic agent, xylazine is rarely used as an analgesic adjuvant in dogs and cats. Clonidine • An a2-agonist approved in the United States in 1997 for use in humans as an antihypertensive agent. • Possesses some a1 effects, with an a2:a1 binding ratio of 220:1.22

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• Has gained popularity as an analgesic adjuvant for certain types of pain syndromes in humans. • Not currently used clinically in dogs and cats. Dexmedetomidine • Dexmedetomidine is the pure S-enantiomer of the racemic a2-agonist medetomidine; it is considered to be twice as potent as medetomidine.23 • Dexmedetomidine was approved in the United States in 1999 for use in human beings as a continuous infusion to provide sedation in intensive care unit (ICU) settings; since that time its use has expanded into anesthesia and pain management practice. • Dexmedetomidine was approved in the United States in 2006 for use in dogs and cats. Evidence suggests that equipotent doses of dexmedetomidine and medetomidine induce similar sedative, analgesic, and cardiovascular effects in these species.23,24 Medetomidine • Medetomidine is an equal mixture of two optical enantiomers: dexmedetomidine (see previous discussion) and levomedetomidine. • Dexmedetomidine is the active component, whereas levomedetomidine is considered pharmacologically inactive (although it may play a role in drug interactions).23 • Racemic medetomidine is lipophilic, facilitating rapid absorption after intramuscular administration; peak plasma concentrations are reached in approximately ½ hour.25 • Medetomidine and dexmedetomidine are the most specific a2-agonists available clinically, with an a2:a1 binding ratio of 1620:1.22 • A specific a2-antagonist, atipamezole, was marketed alongside medetomidine and rapidly reverses all sedative, analgesic, and cardiovascular effects associated with medetomidine, dexmedetomidine, and other a2-agonists, if desired. • Dexmedetomidine and medetomidine are presently the only a2-agonists used routinely as analgesic adjuvants in dogs and cats, so further clinical discussions will focus on these agents. Romifidine • Romifidine is an imino-imidazolidine derivative of clonidine. • Romifidine is a potent and reasonably selective a2-agonist, producing sedative and analgesic effects comparable to those achieved with medetomidine.26,27 • Romifidine has a a2:a1 binding ratio of 340:1. • Romifidine is not currently approved for use in dogs or cats in the United States and is not used commonly as an analgesic adjuvant at this time.

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BOX 10-2 Pharmacokinetic Properties of a2-Agonists • • •

Rapid absorption (intramuscular, subcutaneous, oral) Rapid hepatic metabolism and renal excretion Active metabolites possible

Detomidine • A weakly basic, lipophilic imidazole derivative. • Also possesses greater a1 binding than medetomidine, with an a2:a1 binding ratio of 260:1.22 • Not commonly used as an analgesic adjuvant in dogs and cats (Box 10-2). CONSIDERATIONS FOR VETERINARY PATIENT SELECTION • a2-Agonists may induce significant alterations in cardiopulmonary function (see the discussion of cardiovascular effects); these alterations, although somewhat dose dependent, are seen even after administration of a low dose. • In most cases, use of a2-agonists should be reserved for young to middleaged animals without significant systemic disease. • As a rule, a2-agonists should be avoided in the following: 1. Animals adversely affected by an increase in cardiac afterload or a decrease in cardiac output (e.g., mitral or tricuspid regurgitation or dilated cardiomyopathy) 2. Animals with cardiac arrhythmias or conduction disturbances (e.g., premature ventricular contractions, atrioventricular block, or other bradyarrhythmias) 3. Animals with preexisting hypertension 4. Animals with an increased potential for arterial hemorrhage (e.g., traumatic arterial laceration) 5. Animals for whom vomiting could have serious detrimental effects (e.g., upper gastrointestinal obstruction or corneal descemetocele) CLINICAL USE AS ANALGESIC ADJUVANTS See Box 10-3. Sedation and Analgesia for Short, Noninvasive Procedures • Medetomidine and dexmedetomidine are used extensively for short, noninvasive procedures in dogs and cats, whereas romifidine is used less frequently; dosage guidelines are presented in Table 10-2.

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BOX 10-3 Clinical Use of a2-Agonists 1. Sedative-analgesic agent for short, noninvasive procedures 2. Adjunct to general anesthesia a. Component of total injectable anesthesia protocols b. Preanesthetic sedative-analgesic agent c. Supplemental continuous infusion during inhalant anesthesia 3. Sedative-analgesic agent in postoperative or intensive care unit settings 4. Epidural or intrathecal administration 5. Intra-articular administration 6. Perineural administration

TABLE 10-2

Recommended Dosages of Selected a2-Agonists for Routine Sedation and Analgesia

DRUG

DOSAGE

Dexmedetomidine*{

Dog: 0.005-0.01 mg/kg IM 0.0025-0.005 mg/kg IV Cat: 0.008-0.015 mg/kg IM 0.005-0.008 mg/kg IV

Medetomidine*{

Dog: 0.01-0.02 mg/kg IM 0.005-0.01 mg/kg IV Cat: 0.015-0.03 mg/kg IM 0.01-0.015 mg/kg IV

Romifidine*{

Dog: 0.02-0.04 mg/kg IM 0.01-0.02 mg/kg IV Cat: 0.03-0.06 mg/kg IM 0.015-0.03 mg/kg IV

*Often combined with an opioid to enhance sedation and analgesia. { May be reversed with atipamezole at end of procedure.

• Medetomidine and dexmedetomidine can be used alone but are often combined with an opioid (e.g., hydromorphone, morphine, buprenorphine, or butorphanol) to enhance sedation and provide more intense analgesia. • Examples of short, noninvasive procedures include radiographs, ultrasound examinations, minor laceration repair, wound debridement, bandage placement, ear canal examination and cleaning, skin biopsy, and oral examination. • Despite the fact that many animals appear profoundly sedated with (dex) medetomidine-opioid combinations, it is crucial to recognize that they are not anesthetized and may be acutely aroused by any type of stimulation. • If general anesthesia is required, an anesthetic agent must be titrated to effect (see next section). • For intramuscular administration, medetomidine or dexmedetomidine is injected 20 minutes before initiation of the procedure.

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• For intravenous administration, lower doses of medetomidine or dexmedetomidine are used; onset time is within minutes of injection. • Duration of effect is relatively short, ranging from 30 to 180 minutes, depending in part on the dose administered. The addition of an opioid may prolong analgesia depending on the opioid chosen, the dose, and the route of administration. • Some evidence suggests that high doses are required for the production of analgesia. • Concurrent use of anticholinergics is not recommended when medetomidine or dexmedetomidine is administered. • Basic hemodynamic parameters should be monitored closely when medetomidine or dexmedetomidine is used (see discussion of cardiovascular effects). • Reversal of all a2-mediated effects can be accomplished by intramuscular atipamezole administration if desired. Adjunct to General Anesthesia Component of Total Injectable Anesthesia Protocols

• Medetomidine and dexmedetomidine are often used in combination with injectable anesthetic agents such as ketamine, tiletamine-zolazepam, and propofol to produce short-term general anesthesia; opioids and benzodiazepines are also commonly included in such protocols. • The addition of medetomidine or dexmedetomidine means that lower doses of anesthetic agents are required, analgesia is supplemented, and muscle relaxation is optimized. • Numerous intramuscular and intravenous drug combinations involving medetomidine (or dexmedetomidine) have been used clinically in dogs and cats, and the reader is referred elsewhere for a review of these techniques.28 Preanesthetic Sedative-Analgesic Agent

• Medetomidine-opioid or dexmedetomidine-opioid combinations are commonly administered in the preanesthetic period before induction of anesthesia; dosage guidelines are given in Table 10-3. • Addition of medetomidine or dexmedetomidine in the preanesthetic period greatly reduces the required dose of induction and maintenance agent (injectable or inhalant).29–33 • (Dex)medetomidine-opioid combinations can be administered intramuscularly (IM) or intravenously (IV). • Concurrent administration of an anticholinergic is appropriate only in cases in which both severe bradycardia and hypotension are observed. It should be noted that in most cases, because of the vasoconstriction

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Recommended Dosages of Selected a2-Agonists as Adjuncts to General Anesthesia PREANESTHETIC AGENT*

Dexmedetomidine

Dog: 0.0025-0.005 mg/kg IM 0.0015-0.0025 mg/kg IV Cat: 0.005-0.01 mg/kg IM 0.0025-0.005 mg/kg IV

Medetomidine

Dog: 0.005-0.01 mg/kg IM 0.003-0.005 mg/kg IV Cat: 0.01-0.02 mg/kg IM 0.005-0.01 mg/kg IV

Romifidine

Dog: 0.01-0.02 mg/kg IM 0.005-0.01 mg/kg IV Cat: 0.02-0.03 mg/kg IM 0.01-0.02 mg/kg IV

SUPPLEMENTAL CRI DURING INHALANT ANESTHESIA Dog: 0.0005 mg/kg/hr IV25

Key: CRI, Constant rate infusion. *Often combined with an opioid to enhance sedation and analgesia.

induced by a2-agonists, blood pressure is normal or elevated. In addition, the accuracy of noninvasive blood pressure measurements may be compromised. • As with any general anesthesia protocol, hemodynamic monitoring (including heart rate, rhythm, and blood pressure) is essential (see discussion of cardiovascular effects). • Reversal with atipamezole should be considered when excessive sedation and/or cardiovascular effects persist in the recovery period. Supplemental Continuous Infusion During Inhalant Anesthesia

• The use of medetomidine or dexmedetomidine in continuous infusions as part of balanced anesthesia, typically in combination with inhalants, has been described. • It has been proposed that the use of very low doses administered via continuous infusion concurrently with an inhalant anesthetic may attenuate the adverse cardiovascular effects seen when larger doses are administered as boluses. • The cardiovascular effects of medetomidine in dogs anesthetized with sevoflurane have been evaluated. Medetomidine at 1, 2, and 3 mg/kg/ hr produced significant cardiovascular depression. It was concluded that low-dose medetomidine constant rate infusion should be used with caution in dogs.34 • The effects of dexmedetomidine on inhalant requirements and on cardiorespiratory function have been evaluated in dogs and cats. In dogs, dexmedetomidine 0.5 and 3 mg/kg followed by 0.5 and 3 mg/kg/hr respectively

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reduced the minimum alveolar concentration (MAC) of isoflurane by 18% and 59%.35 The low dose resulted in a decrease in heart rate, whereas the higher dose produced more profound cardiovascular alterations.35 In cats, dexmedetomidine decreased the MAC of isoflurane in a plasma concentration–dependent manner, by up to 86%.33 However, it appeared that at plasma concentrations reducing MAC in a clinically relevant manner, the isoflurane-dexmedetomidine combination resulted in greater cardiovascular depression (decrease in cardiac output, increase in systemic vascular resistance) than an equipotent, higher concentration of isoflurane alone.36 • Additional studies are warranted to explore the potential use of medetomidine and dexmedetomidine as intravenous infusions in inhalantanesthetized animals, alone or in combination with other adjunctive agents such as opioids, ketamine, and lidocaine. Sedative-Analgesic Agent in Postoperative or Intensive Care Unit Settings Based on experience with dexmedetomidine in human ICU patients, there is increasing interest in the use of low doses of medetomidine and dexmedetomidine administered as intravenous infusions in dogs and cats to provide extended periods of sedation and analgesia. • Studies with dexmedetomidine infusions in humans show significant reductions in benzodiazepine and opioid requirements in intubated, mechanically ventilated patients without induction of serious impairment of cardiopulmonary function.37,38 • Also, a significantly improved cumulative nitrogen balance has been documented in patients receiving a2-agonist infusions after surgery, probably as a result of stimulation of growth hormone release.39 • Evidence in cats suggests that low doses of dexmedetomidine administered intramuscularly may be ineffective at providing analgesia; it is, however, possible that low doses potentiate the analgesia induced by opioids.40,41 Dexmedetomidine administered intravenously in cats, at doses ranging from 5 to 50 mg/kg produced antinociception. The duration of the effect appeared somewhat dose-dependent, and the effect was closely associated with the sedative effect. 42 • Medetomidine (2 mg/kg followed by 1 mg/kg/hr or 4 mg/kg followed by 2 mg/kg/hr IV) caused typical cardiovascular alterations in dogs, with the higher dose producing more pronounced effects.43 A study on dexmedetomidine in dogs suggested that analgesia was produced during administration of 3 and 5 mg/kg/hr IV; the cardiovascular effects were not characterized.44 • Additional studies are needed to characterize further the cardiovascular and sedative-analgesic effects of medetomidine and dexmedetomidine infusions before their routine use can be recommended for animals in the ICU.

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Epidural and Intrathecal Administration • The spinal site of action appears to be important in mediating a2agonist–induced analgesia. • Stimulation of spinal cord cholinergic interneurons also may contribute to analgesia after neuraxial a2-agonist administration.45–47 • Although intrathecal drug administration is not routinely used in veterinary medicine, epidural administration is common. • Incorporation of a low dose of medetomidine combined with morphine for epidural administration prolonged the analgesia compared with use of morphine alone.48 Other studies have found minimal or no benefits of adding (dex)medetomidine to epidural opioids or local anesthetics.49–51 • Medetomidine or dexmedetomidine may be combined with standard epidural doses of morphine, oxymorphone, buprenorphine, fentanyl, lidocaine, or bupivacaine and injected into the epidural space at the lumbosacral junction. • The lipophilicity of medetomidine and dexmedetomidine means that it is rapidly cleared from the cerebrospinal fluid (CSF) in the vicinity of the spinal injection site; this anatomically restricts the action of the drug, and results in significant systemic absorption. • The cardiovascular effects observed after epidural administration are comparable to those seen with systemic administration.52 • Clinical use of epidural medetomidine or dexmedetomidine in dogs and cats remains less common than that of morphine or local anesthetics. Additional studies are warranted to better characterize both benefits and adverse effects. Intra-articular Administration • a2-Adrenoceptors are located in the peripheral nervous system on terminals of primary afferent nociceptive fibers; they appear to contribute to analgesia by inhibition of norepinephrine release at nerve terminals.45 • Studies in human beings have demonstrated a peripheral analgesic effect after intra-articular administration of a2-agonists to patients undergoing arthroscopic knee surgery that is unrelated to vascular uptake of the drug and redistribution to central sites.53 • Addition of clonidine to bupivacaine or bupivacaine-morphine provided analgesic benefits after intra-articular administration in humans undergoing arthroscopic knee surgery.54 • Similarly, addition of dexmedetomidine to intra-articular ropivacaine improved quality and duration of analgesia in humans after arthroscopic knee surgery.55 • There is currently no study evaluating the intra-articular use of medetomidine or dexmedetomidine in dogs and cats.

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Perineural Administration • In human patients, clinical evidence suggests that a2-agonists enhance peripheral nerve block intensity and duration when added to local anesthetics administered perineurally. • Enhanced perineural blockade with a2-agonists may be a result of the following: 1. Hyperpolarization of C fibers through blockade of a specific type of potassium channel.45 2. Local vasoconstriction that decreases vascular removal of local anesthetic surrounding neural structures and prolongs duration of action. • A recent meta-analysis of the perineural use of dexmedetomidine in humans concluded that it may exhibit a facilitatory effect, but that insufficient safety data were available to support its use in the clinical setting.56 • One study reported that perineural administration of medetomidine prolonged the duration of mepivacaine-induced radial nerve block in dogs. Systemic administration of the same dose had a similar effect.57 Similarly, dexmedetomidine prolonged the duration of vasodilation produced by sympathetic block with mepivacaine in dogs.58 CLINICAL ADVERSE EFFECTS OF a2-AGONISTS Comprehensive reviews of the physiologic adverse effects of a2-agonists used in veterinary medicine are available elsewhere;28,59 the following is a brief summary of relevant points. Cardiovascular Effects See Box 10-4. • Immediately after administration, a2-agonists bind vascular postsynaptic a2-adrenoceptors, resulting in vasoconstriction.60

BOX 10-4 Cardiovascular Effects of a2-Agonists Immediate (Peripheral) Effects " Systemic vascular resistance " Arterial blood pressure # Heart rate (baroreceptor reflex) # Cardiac output Delayed (Central) Effects # Sympathetic activity # Arterial blood pressure # Cardiac output

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• The increase in systemic vascular resistance produces a short-lived hypertensive phase accompanied by a compensatory baroreceptor-mediated reflex bradycardia.60 • The initial hypertension may be decreased or even absent after intramuscular administration, likely because of reduced peak plasma levels of the drug. • Bradyarrhythmias as a result of increased vagal tone are not uncommon, with heart rates decreasing by as much as 70%.60 • Sinus arrhythmia, sinoatrial block, and first-degree and second-degree atrioventricular block are frequently seen; third-degree atrioventricular block and sinoatrial arrest occur rarely. • Cardiac output decreases, typically in proportion to the decrease in heart rate.60 • Over time, heart rate and systemic vascular resistance return toward baseline; the duration of the effects is largely dose dependent.60 Respiratory Effects See Box 10-5. • Although respiratory rate, minute ventilation, and central respiratory drive decrease with administration of a2-agonists, arterial pH, PaO2, and PaCO2 typically remain within a clinically acceptable range.61,62 • At high doses, especially in combination with other CNS depressants, decreases in mixed-venous PO2 and oxygen content have been noted; venous desaturation is presumably related to increased tissue oxygen extraction associated with decreased cardiac output. Gastrointestinal Effects See Box 10-6. • Up to 20% of dogs and up to 90% of cats vomit after medetomidine.63 Dexmedetomidine likely has similar effects. BOX 10-5 Respiratory Effects of a2-Agonists Low Doses (for Adjunctive Analgesia) # Respiratory rate # Normal minute ventilation Normal PaCO2, PO2, and pH High Doses (in Combination) # Respiratory rate # Tidal volume # Minute ventilation " CO2, # pH, # P⊽O2,* possible # PaO2 *Partial oxygen pressure in mixed venous blood.

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BOX 10-6 Gastrointestinal Effects of a2-Agonists # Salivation # Gastric secretions # Gastrointestinal motility " Vomiting # Swallowing reflex Predisposition to gastric dilation (large-breed dogs)?

• Emesis is seen most often after subcutaneous and, less frequently, intramuscular administration. • Medetomidine and dexmedetomidine also inhibit small intestinal and colonic motility in dogs.64 They may decrease the lower esophageal sphincter tone and increase the likelihood of gastroesophageal reflux. Renal Effects See Box 10-7. • Significant increases in urine output are seen transiently after administration of a2-agonists to dogs and cats.65,66 • Increased urinary output may be the result of one or more of the following: 1. Increased renal blood flow and glomerular filtration rate.65,66 Such increases were observed following IV administration, while IM administration resulted in decreased renal blood flow and glomerular filtration rate.65 2. Suppression of antidiuretic hormone (ADH) release centrally.65 3. Antagonism of ADH at the level of the renal tubule.67 Endocrine Effects • a2-agonists cause hyperglycemia because of suppression of insulin secretion.68 • Cortisol and glucagon levels do not appear to change significantly,68 but medetomidine has been shown to attenuate the stress response induced by other anesthetic agents (opioids and ketamine).69 Dexmedetomidine likely produces similar effects. • Medetomidine may blunt the perioperative stress response in dogs.70,71 BOX 10-7 Renal and Endocrine Effects of a2-Agonists Diuresis and natriuresis (" water and sodium excretion) • Inhibition of ADH release • Inhibition of rennin release • Increase atrial natriuretic peptide # Insulin release (hyperglycemia, glucosuria)

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• Other hormonal changes include transient alterations in growth hormone, testosterone, prolactin, ADH, and follicle-stimulating hormone levels. Miscellaneous Effects • Increased myometrial tone and intrauterine pressure have been noted in several species after xylazine administration;72–74 medetomidine, dexmedetomidine, and detomidine appear less likely to have this effect. • Mydriasis has been reported after administration of xylazine and (dex) medetomidine because of central inhibition of parasympathetic innervation to the iris or direct sympathetic stimulation of a2-receptors located in the iris and CNS.75–78 • Variable changes in intraocular pressure have been reported in some species after systemic administration of a2-agonists.79–83 REFERENCES 1. Hsu WH: Xylazine-induced depression and its antagonism by alpha adrenergic blocking agents. J Pharmacol Exp Ther. 218:188–192, 1981. 2. MacDonald E, Kobilka BK, Scheinin M: Gene targeting—homing in on alpha 2-adrenoceptor-subtype function. Trends Pharmacol Sci. 18:211–219, 1997. 3. Aantaa R, Marjamaki A, Scheinin M: Molecular pharmacology of alpha 2-adrenoceptor subtypes. Ann Med. 27:439–449, 1995. 4. Blaxall HS, Heck DA, Bylund DB: Molecular determinants of the alpha-2D adrenergic receptor subtype. Life Sci. 53:PL255–259, 1993. 5. Ongioco RR, Richardson CD, Rudner XL, et al.: Alpha2-adrenergic receptors in human dorsal root ganglia: Predominance of alpha2b and alpha2c subtype mRNAs. Anesthesiology. 92:968–976, 2000. 6. Maze M, Fujinaga M: Alpha2 adrenoceptors in pain modulation: Which subtype should be targeted to produce analgesia? Anesthesiology. 92:934–936, 2000. 7. Schwartz DD, Jones WG, Hedden KP, et al.: Molecular and pharmacological characterization of the canine brainstem alpha-2A adrenergic receptor. J Vet Pharmacol Ther. 22:380–386, 1999. 8. Lakhlani PP, MacMillan LB, Guo TZ, et al.: Substitution of a mutant alpha2a-adrenergic receptor via “hit and run” gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo. Proc Natl Acad Sci U S A. 94:9950–9955, 1997. 9. MacMillan LB, Lakhlani PP, Hein L, et al.: In vivo mutation of the alpha 2A-adrenergic receptor by homologous recombination reveals the role of this receptor subtype in multiple physiological processes. Adv Pharmacol. 42:493–496, 1998. 10. MacMillan LB, Hein L, Smith MS, et al.: Central hypotensive effects of the alpha2aadrenergic receptor subtype. Science. 273:801–803, 1996. 11. Bousquet P: Imidazoline receptors: From basic concepts to recent developments. J Cardiovasc Pharmacol. 26 Suppl 2:S1–S6, 1995. 12. Bousquet P, Bruban V, Schann S, et al.: Participation of imidazoline receptors and alpha(2-)-adrenoceptors in the central hypotensive effects of imidazoline-like drugs. Ann N Y Acad Sci. 881:272–278, 1999. 13. Head GA: Central imidazoline- and alpha 2-receptors involved in the cardiovascular actions of centrally acting antihypertensive agents. Ann N Y Acad Sci. 881:279–286, 1999.

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14. Zhu QM, Lesnick JD, Jasper JR, et al.: alpha 2A-adrenoceptors, not I1-imidazoline receptors, mediate the hypotensive effects of rilmenidine and moxonidine in conscious mice. in vivo and in vitro studies. Ann N Y Acad Sci. 881(287-289), 1999. 15. Limbird LE: Receptors linked to inhibition of adenylate cyclase: Additional signaling mechanisms. FASEB J. 2:2686–2695, 1988. 16. Schwinn DA: Adrenoceptors as models for G protein-coupled receptors: Structure, function and regulation. Br J Anaesth. 71:77–85, 1993. 17. Budai D, Harasawa I, Fields HL: Midbrain periaqueductal gray (PAG) inhibits nociceptive inputs to sacral dorsal horn nociceptive neurons through alpha2-adrenergic receptors. J Neurophysiol. 80:2244–2254, 1998. 18. Millan MJ, Bervoets K, Rivet JM, et al.: Multiple alpha-2 adrenergic receptor subtypes. II. Evidence for a role of rat R alpha-2A adrenergic receptors in the control of nociception, motor behavior and hippocampal synthesis of noradrenaline. J Pharmacol Exp Ther. 270:958-972, 1994. 19. Buerkle H, Yaksh TL: Pharmacological evidence for different alpha 2-adrenergic receptor sites mediating analgesia and sedation in the rat. Br J Anaesth. 81:208–215, 1998. 20. Guo TZ, Jiang JY, Buttermann AE, et al.: Dexmedetomidine injection into the locus ceruleus produces antinociception. Anesthesiology. 84:873–881, 1996. 21. Peng YB, Lin Q, Willis WD: Involvement of alpha-2 adrenoceptors in the periaqueductal gray-induced inhibition of dorsal horn cell activity in rats. J Pharmacol Exp Ther. 278:125–135, 1996. 22. Virtanen R: Pharmacological profiles of medetomidine and its antagonist, atipamezole. Acta Vet Scand Suppl. 85:29–37, 1989. 23. Kuusela E, Raekallio M, Anttila M, et al.: Clinical effects and pharmacokinetics of medetomidine and its enantiomers in dogs. J Vet Pharmacol Ther. 23:15–20, 2000. 24. Savola JM, Virtanen R: Central alpha 2-adrenoceptors are highly stereoselective for dexmedetomidine, the dextro enantiomer of medetomidine. Eur J Pharmacol. 195:193–199, 1991. 25. Salonen JS: Pharmacokinetics of medetomidine. Acta Vet Scand Suppl. 85:49–54, 1989. 26. England GC, Flack TE, Hollingworth E, et al.: Sedative effects of romifidine in the dog. J Small Anim Pract. 37:19–25, 1996. 27. Lemke KA: Sedative effects of intramuscular administration of a low dose of romifidine in dogs. Am J Vet Res. 60:162–168, 1999. 28. Sinclair MD: A review of the physiological effects of alpha2-agonists related to the clinical use of medetomidine in small animal practice. Can Vet J. 44:885–897, 2003. 29. McSweeney PM, Martin DD, Ramsey DS, et al.: Clinical efficacy and safety of dexmedetomidine used as a preanesthetic prior to general anesthesia in cats. J Am Vet Med Assoc. 240:404–412, 2012. 30. Mendes GM, Selmi AL, Barbudo-Selmi GR, et al.: Clinical use of dexmedetomidine as premedicant in cats undergoing propofol-sevoflurane anaesthesia. J Feline Med Surg. 5:265–270, 2003. 31. Kojima K, Nishimura R, Mutoh T, et al.: Effects of medetomidine-midazolam, acepromazine-butorphanol, and midazolam-butorphanol on induction dose of thiopental and propofol and on cardiopulmonary changes in dogs. Am J Vet Res. 63:1671–1679, 2002. 32. Pascoe PJ, Raekallio M, Kuusela E, et al.: Changes in the minimum alveolar concentration of isoflurane and some cardiopulmonary measurements during three continuous infusion rates of dexmedetomidine in dogs. Vet Anaesth Analg. 33:97–103, 2006. 33. Escobar A, Pypendop BH, Siao KT, et al.: Effect of dexmedetomidine on the minimum alveolar concentration of isoflurane in cats. J Vet Pharmacol Ther. 35:163–168, 2012.

CHAPTER 10 a2-Agonists

213

34. Carter JE, Campbell NB, Posner LP, et al.: The hemodynamic effects of medetomidine continuous rate infusions in the dog. Vet Anaesth Analg. 37:197–206, 2010. 35. Lin GY, Robben JH, Murrell JC, Aspegrén J, McKusick BC, Hellebrekers LJ. Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs. Vet Anaesth Analg. 35(2):141–153, 2008. 36. Pypendop BH, Barter LS, Stanley SD, et al.: Hemodynamic effects of dexmedetomidine in isoflurane-anesthetized cats. Vet Anaesth Analg. 38:555–567, 2011. 37. Venn RM, Bradshaw CJ, Spencer R, et al.: Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia. 54:1136–1142, 1999. 38. Hall JE, Uhrich TD, Barney JA, et al.: Sedative, amnestic, and analgesic properties of smalldose dexmedetomidine infusions. Anesth Analg. 90:699–705, 2000. 39. Mertes N, Goeters C, Kuhmann M, et al.: Postoperative alpha 2-adrenergic stimulation attenuates protein catabolism. Anesth Analg. 82:258–263, 1996. 40. Slingsby LS, Taylor PM: Thermal antinociception after dexmedetomidine administration in cats: A dose-finding study. J Vet Pharmacol Ther. 31:135–142, 2008. 41. Slingsby LS, Murrell JC, Taylor PM: Combination of dexmedetomidine with buprenorphine enhances the antinociceptive effect to a thermal stimulus in the cat compared with either agent alone. Vet Anaesth Analg. 37:162–170, 2010. 42. Pypendop BH, Ilkiw JE: Relationship between plasma dexmedetomidine concentration and sedation score and thermal threshold in cats. Am J Vet Res. In Press, 2014. 43. Lamont LA, Burton SA, Caines D, et al.: Effects of 2 different infusion rates of medetomidine on sedation score, cardiopulmonary parameters, and serum levels of medetomidine in healthy dogs. Can J Vet Res. 76:308–316, 2012. 44. van Oostrom H, Doornenbal A, Schot A, et al.: Neurophysiological assessment of the sedative and analgesic effects of a constant rate infusion of dexmedetomidine in the dog. Vet J. 190:338–344, 2011. 45. Eisenach JC, De Kock M, Klimscha W: alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984–1995). Anesthesiology. 85:655–674, 1996. 46. De Kock M, Eisenach J, Tong C, et al.: Analgesic doses of intrathecal but not intravenous clonidine increase acetylcholine in cerebrospinal fluid in humans. Anesth Analg. 84:800–803, 1997. 47. Eisenach JC, Hood DD, Curry R: Intrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers. Anesth Analg. 87:591–596, 1998. 48. Branson KR, Ko JC, Tranquilli WJ, et al.: Duration of analgesia induced by epidurally administered morphine and medetomidine in dogs. J Vet Pharmacol Ther. 16:369–372, 1993. 49. Pacharinsak C, Greene SA, Keegan RD, et al.: Postoperative analgesia in dogs receiving epidural morphine plus medetomidine. J Vet Pharmacol Ther. 26:71–77, 2003. 50. Steagall PV, Millette V, Mantovani FB, et al.: Antinociceptive effects of epidural buprenorphine or medetomidine, or the combination, in conscious cats. J Vet Pharmacol Ther. 32:477–484, 2009. 51. Smith LJ: A comparison of epidural analgesia provided by bupivacaine alone, bupivacaine + morphine, or bupivacaine + dexmedetomidine for pelvic orthopedic surgery in dogs. Vet Anaesth Analg. 40(5):527–536, 2013. 52. Duke T, Cox AM, Remedios AM, et al.: The cardiopulmonary effects of placing fentanyl or medetomidine in the lumbosacral epidural space of isoflurane-anesthetized cats. Vet Surg. 23:149–155, 1994. 53. Gentili M, Juhel A, Bonnet F: Peripheral analgesic effect of intra-articular clonidine. Pain. 64:593–596, 1996. 54. Joshi W, Reuben SS, Kilaru PR, et al.: Postoperative analgesia for outpatient arthroscopic knee surgery with intraarticular clonidine and/or morphine. Anesth Analg. 90:1102–1106, 2000.

214

PART TWO

Pain Therapy

55. Paul S, Bhattacharjee DP, Ghosh S, et al.: Efficacy of intra-articular dexmedetomidine for postoperative analgesia in arthroscopic knee surgery. Ceylon Med J. 55:111–115, 2010. 56. Abdallah FW, Brull R: Facilitatory effects of perineural dexmedetomidine on neuraxial and peripheral nerve block: A systematic review and meta-analysis. Br J Anaesth. 110:915–925, 2013. 57. Lamont LA, Lemke KA: The effects of medetomidine on radial nerve blockade with mepivacaine in dogs. Vet Anaesth Analg. 35:62–68, 2008. 58. Tezuka M, Kitajima T, Yamaguchi S, et al.: Addition of dexmedetomidine prolongs duration of vasodilation induced by sympathetic block with mepivacaine in dogs. Reg Anesth Pain Med. 29:323–327, 2004. 59. Murrell JC, Hellebrekers LJ: Medetomidine and dexmedetomidine: A review of cardiovascular effects and antinociceptive properties in the dog. Vet Anaesth Analg. 32:117–127, 2005. 60. Pypendop BH, Verstegen JP: Hemodynamic effects of medetomidine in the dog: A dose titration study. Vet Surg. 27:612–622, 1998. 61. Lerche P, Muir WW: Effect of medetomidine on breathing and inspiratory neuromuscular drive in conscious dogs. Am J Vet Res. 65:720–724, 2004. 62. Pypendop B, Verstegen J: Cardiorespiratory effects of a combination of medetomidine, midazolam, and butorphanol in dogs. Am J Vet Res. 60:1148–1154, 1999. 63. Vainio O: Introduction to the clinical pharmacology of medetomidine. Acta Vet Scand Suppl. 85:85–88, 1989. 64. Maugeri S, Ferre JP, Intorre L, et al.: Effects of medetomidine on intestinal and colonic motility in the dog. J Vet Pharmacol Ther. 17:148–154, 1994. 65. Saleh N, Aoki M, Shimada T, et al.: Renal effects of medetomidine in isofluraneanesthetized dogs with special reference to its diuretic action. J Vet Med Sci. 67:461–465, 2005. 66. Grimm JB, Grimm KA, Kneller SK, et al.: The effect of a combination of medetomidinebutorphanol and medetomidine, butorphanol, atropine on glomerular filtration rate in dogs. Vet Radiol Ultrasound. 42:458–462, 2001. 67. Gellai M, Edwards RM: Mechanism of alpha 2-adrenoceptor agonist-induced diuresis. Am J Physiol. 255:F317–323, 1988. 68. Ambrisko TD, Hikasa Y: Neurohormonal and metabolic effects of medetomidine compared with xylazine in beagle dogs. Can J Vet Res. 66:42–49, 2002. 69. Ambrisko TD, Hikasa Y, Sato K: Influence of medetomidine on stress-related neurohormonal and metabolic effects caused by butorphanol, fentanyl, and ketamine administration in dogs. Am J Vet Res. 66:406–412, 2005. 70. Benson GJ, Grubb TL, Neff-Davis C, et al.: Perioperative stress response in the dog: Effect of pre-emptive administration of medetomidine. Vet Surg. 29:85–91, 2000. 71. 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. 63:969–975, 2002. 72. Wheaton LG, Benson GJ, Tranquilli WJ, et al.: The oxytocic effect of xylazine on the canine uterus. Theriogenology. 31:911–915, 1989. 73. Hodgson DS, Dunlop CI, Chapman PL, et al.: Cardiopulmonary effects of xylazine and acepromazine in pregnant cows in late gestation. Am J Vet Res. 63:1695–1699, 2002. 74. Schatzmann U, Jossfck H, Stauffer JL, et al.: Effects of alpha 2-agonists on intrauterine pressure and sedation in horses: Comparison between detomidine, romifidine and xylazine. Zentralbl Veterinarmed A. 41:523–529, 1994. 75. Hsu WH, Lee P, Betts DM: Xylazine-induced mydriasis in rats and its antagonism by alpha-adrenergic blocking agents. J Vet Pharmacol Ther. 4:97–101, 1981.

CHAPTER 10 a2-Agonists

215

76. Hsu WH, Betts DM, Lee P: Xylazine-induced mydriasis: Possible involvement of a central postsynaptic regulation of parasympathetic tone. J Vet Pharmacol Ther. 4:209–214, 1981. 77. Jin Y, Wilson S, Elko EE, et al.: Ocular hypotensive effects of medetomidine and its analogs. J Ocul Pharmacol. 7:285–296, 1991. 78. Horvath G, Kovacs M, Szikszay M, et al.: Mydriatic and antinociceptive effects of intrathecal dexmedetomidine in conscious rats. Eur J Pharmacol. 253:61–66, 1994. 79. Rauser P, Pfeifr J, Proks P, et al.: Effect of medetomidine-butorphanol and dexmedetomidine-butorphanol combinations on intraocular pressure in healthy dogs. Vet Anaesth Analg. 39:301–305, 2012. 80. Artigas C, Redondo JI, Lopez-Murcia MM: Effects of intravenous administration of dexmedetomidine on intraocular pressure and pupil size in clinically normal dogs. Vet Ophthalmol. 15 Suppl 1:79–82, 2012. 81. Wallin-Hakanson N, Wallin-Hakanson B: The effects of topical tropicamide and systemic medetomidine, followed by atipamezole reversal, on pupil size and intraocular pressure in normal dogs. Vet Ophthalmol. 4:3–6, 2001. 82. Verbruggen AM, Akkerdaas LC, Hellebrekers LJ, et al.: The effect of intravenous medetomidine on pupil size and intraocular pressure in normotensive dogs. Vet Q. 22:179–180, 2000. 83. Potter DE, Ogidigben MJ: Medetomidine-induced alterations of intraocular pressure and contraction of the nictitating membrane. Invest Ophthalmol Vis Sci. 32:2799–2805, 1991.