Medetomidine, an investigational drug indicated for clinical use as a short-term chemical restraint in dogs, was evaluated for its cardiopulmonary effects, in 10 naturally heartworm-infected (HW+) and 10 noninfected (HW-) Beagles. The drug was randomly administered IV (30 microgram/kg of body weight) and IM (40 microgram/kg) in single injections to all dogs. Heart rate, respiratory rate, ECG, blood gas tensions, blood pH, central venous and arterial pressures were measured at 0, 15, 30, 60, 90, 120, and 180 minutes. Medetomidine induced an immediate significant (P less than or equal to 0.001) increase in mean arterial blood pressure followed by decreased blood pressure that remained below normal throughout the study in both groups, irrespective of route of administration. Medetomidine increased central venous pressure, over time, for both groups and both routes of administration. Heart and respiratory rates were significantly (P less than or equal 0.001) decreased after medetomidine administration and remained reduced for the duration of the study in all dogs. The ECG variables were not significantly different between groups or between routes of administration. The HW+ dogs tended to have higher mean PaO2 than did HW- dogs at several postinjection determination times, particularly when the drug was administered IM. The PaO2 decreased during the first 30 minutes in both groups and tended to increase gradually thereafter. The pH decreased over time for both groups and both routes. A significant (P less than or equal to 0.05) decrease in pH was seen in the HW- dogs, compared with HW+ dogs at each measuring time for both routes. The PaCO2 did not significantly change for groups or routes. In general, bradycardia was the predominant cardiovascular effect seen after medetomidine administration in all dogs, irrespective of route. Lowering of blood pressure and heart rate (after a transient blood pressure increase) was synchronized with sedation in these dogs. The overall clinical response with regard to cardiopulmonary effects in HW+ dogs was similar to that in HW- dogs.

Pharmacokinetic variables of propofol were investigated in 6 mixed-breed dogs, and the effect of medetomidine (10 microgram/kg of body weight) on these kinetics was investigated using a two-way crossover design. On 2 occasions, dogs received either a bolus dose of propofol sufficient to allow endotracheal intubation, followed by an infusion of propofol (0.4 mg/kg/min) for 120 minutes, or medetomidine (10 microgram/kg, IM), 15 minutes prior to induction of anesthesia as described, followed by infusion of propofol (0.2 mg/kg/min). Dogs given medetomidine received atipamezole (50 microgram/kg, IM) at the end of the 120-minute propofol infusion. Blood propofol concentration was measured, using high- performance liquid chromatography with fluorescence detection. Mean elimination half-life, blood clearance, mean residence time, and mean volume of distribution at steady state, were 486.2 minutes, 34.4 ml/kg/min, 301.8 minutes, and 6.04 L/kg, respectively, in the absence of medetomidine, and 136.9 minutes, 36.2 ml/kg/min, 215.1 minutes, and 3.38 L/kg, respectively, in the presence of medetomidine. Mean time to walking without ataxia was 174 minutes in the nonpremedicated dogs (with a median blood propofol concentration of 2.2 microgram/ml) and was 160 minutes in the premedicated dogs in which median blood propofol concentration was 1.03 microgram/ml.

Pharmacokinetic variables of etomidate were determined after IV administration of etomidate (3.0 mg/kg of body weight). Blood samples were collected for 6 hours. Disposition of this carboxylated imidazole best conformed to a 2- (n = 2) and a 3- compartment (n = 4) open pharmacokinetic model. The pharmacokinetic values were calculated for the overall best-fitted model, characterized as a mixed 2- and 3-compartmental model. The first and most rapid distribution half-life was 0.05 hour and a second distribution half-life was 0.35 hour. Elimination half-life was 2.89 hours, apparent volume of distribution was 11.87 +/- 4.64 L/kg, apparent volume of distribution at steady state was 4.88 +/- 2.25 L/kg, apparent volume of the central compartment was 1.17 +/- 0.70 L/kg, and total clearance was 2.47 +/- 0.78 L/kg/h.

We compared the ability of 2 alpha2-adrenergic receptor antagonists, atipamezole and yohimbine, to reverse medetomidine-induced CNS depression and cardiorespiratory changes in lambs. Twenty lambs (7.8 +/- 2.6 kg) were randomly allotted to 4 treatment groups (n = 5). Each lamb was given medetomidine (30 micrograms/kg of body weight, IV), followed in 15 minutes by IV administration of atipamezole (30 or 60 micrograms/kg), yohimbine (1 mg/kg), or 0.9% NaCl (saline) solution. Medetomidine caused lateral recumbency in 1 to 2 minutes in all treated lambs. Medetomidine significantly (P < 0.05) decreased heart rate at 5 and 10 minutes after its administration. Heart rate remained above 120 beats/min, and severe bradycardia (< 70 beats/min) and other arrhythmias did not occur throughout the study. Medetomidine also induced tachypnea in all treated lambs. The tachypnea was abolished by atipamezole and yohimbine, but not by saline solution administration. The medetomidine-induced tachypnea did not significantly affect arterial pH and PaCO2. Arterial oxygen tension was within acceptable range (PaO2 = 71 to 62 mm of Hg), but was lower than expected. Administration of atipamezole, yohimbine, or saline solution did not change PaO2 significantly. Lambs treated with 30 or 60 micrograms of atipamezole/kg were able to walk unassisted in 2.4 +/- 0.4 and 2.3 +/- 0.7 minutes, respectively, whereas yohimbine- and saline-treated lambs did not walk unassisted until 15.6 +/- 2.7 and 73.0 +/- 6.8 minutes later, respectively. Results of this study indicated that medetomidine is a potent CNS depressant in lambs. Atipamezole at dosage of 30 or 60 micrograms/kg was equally effective, and was more effective in antagonizing medetomidine-induced CNS depression than was yohimbine.

Effects of alpha 2-adrenergic receptor stimulation on the cholinergic contractile response of bovine tracheal smooth muscle were studied. To determine the presence and function of alpha 2-adrenergic receptors on cholinergic nerves innervating bovine tracheal muscle, effects of 2 alpha 2-adrenoceptor agonists and an antagonist were determined. Muscular contractions were elicited by either electrical field stimulation (EFS) or exogenous acetylcholine (ACH). The contractile response to EFS and exogenous ACH was examined for each tissue. Electrical field stimulation of bovine tracheal smooth muscle caused contractions that were completely abolished by atropine, indicating the predominant excitatory innervation of bovine trachea is cholinergic. The alpha 2-adrenoceptor agonists clonidine and medetomidine (10(-6)M to 10(-4)M) concentration-dependently inhibited the contractile response to EFS but not the response to exogenous ACH. Contractions induced by EFS were significantly (P < 0.05) inhibited in clonidine (10(-4) M)-treated tissues at low frequencies (0.1 to 10 Hz), whereas medetomidine (10(-5)M, 10(-4)M) inhibited contractions at all frequencies (0.1 to 30 Hz). Inhibitory effects of the alpha 2-adrenoceptor agonists clonidine and medetomidine were attenuated by the alpha 2-adrenoceptor antagonist tolazoline. The alpha 2-agonists used in this study appear to cause prejunctional inhibition of cholinergic nerves, because the smooth muscle contractions elicited by EFS, but not exogenous ACH, were inhibited, compared with controls.

Seven adult mares were used to determine the analgesic, CNS, and cardiopulmonary effects of detomidine hydrochloride solution after epidural or subarachnoid administration, using both regimens in random sequence. At least 1 week elapsed between experiments. A 17-gauge Huber point (Tuohy) directional needle was used to place a catheter with stylet into either the epidural space at the first coccygeal interspace or the subarachnoid space at the lumbosacral intervertebral junction. Catheters were advanced so that the tips lay at the caudal sacral (S5 to S4) epidural space or at the midsacral (S3 to S2) subarachnoid space. Position of the catheter was confirmed radiographically. A 1% solution of detomidine HCl was injected into the epidural catheter at a dosage of 60 micrograms/kg of body weight, and was expanded to a 10-ml volume with sterile water to induce selective caudal epidural analgesia (CEA). A dose of 30 micrograms of detomidine HCl/kg expanded to a 3-ml volume with spinal fluid was injected into the subarachnoid catheter to induce caudal subarachnoid analgesia (CSA). Analgesia was determined by lack of sensory perception to electrical stimulation (avoidance threshold > 40 V, 0.5-ms duration) at the perineal dermatomes and no response to superficial and deep muscular pinprick stimulation at the pelvic limb and lumbar and thoracic dermatomes. Maximal CEA and CSA extended from the coccyx to spinal cord segments T15 and T14 at 10 to 25 minutes after epidural and subarachnoid drug administrations in 2 mares. Analgesia at the perineal area lasted longer after epidural than after subarachnoid administration (142.8 +/- 28.8 minutes vs 127.1 +/- 27.7 minutes). All mares remained standing. Both CEA and CSA induced marked sedation, moderate ataxia, minimal cardiopulmonary depression, increased frequency of second-degree atrioventricular heart block, and renal diuresis. All treatments resulted in significantly (P < 0.05) decreased heart rate, respiratory rate, systemic arterial blood pressure, PCV, and plasma total solids concentration. To the contrary, arterial carbon dioxide tension, plasma bicarbonate, and standard base excess concentrations were significantly (P < 0.05) increased. Arterial oxygen tension, pH, and rectal temperature did not change significantly from baseline values. Results indicate that use of detomidine for CEA and CSA in mares probably induces local spinal and CNS effects, marked sedation, moderate ataxia, mild cardiopulmonary depression, and renal diuresis.

Dexmedetomidine (Dex), an alpha 2-receptor agonist, is the pharmacologically active d-isomer of medetomidine, a compound used as a sedative in veterinary medicine. Isoflurane anesthetic requirement (minimum alveolar concentration; MAC), rectal temperature, and cardiorespiratory variables were studied in chronically instrumented Yucatan miniature swine during DEX (20 micrograms/kg of body weight)-induced changes in body temperature. All studies were performed at room temperature of 22 C. The DEX was given as a 2-minute infusion into the left atrium. Each pig was studied twice. For protocol 1, the core temperature of the pigs was maintained at (mean +/- SD) 38.2 +/- 0.5 C by use of a thermostatically controlled water blanket and a heating lamp. For protocol 2, the core temperature was not externally manipulated and it decreased from 38.2 +/- 0.4 C to 32.2 +/- 1.2 C during the more than 3 hours of the protocol. Control isoflurane MAC was 1.66 +/- 0.2% and was 1.74 +/- 0.3% for protocols 1 and 2, respectively; DEX decreased MAC by 34 and 44%, respectively. For protocol 1, reduction in MAC after DEX administration returned by 50 and 80% at 84 and 138 minutes, respectively. If rectal temperature was not maintained (eg, allowed to decrease), MAC was reduced by 57% at the same time as the return to 80% in the swine with maintained body temperature. Respiratory rate and minute ventilation were significantly higher in swine with maintained temperature. The PaCO2 was lower and, accordingly, pH was higher in these swine. Blood pressure and heart rate were not affected by temperature changes.

Hemodynamic and analgesic effects of medetomidine (15 microgram/kg of body weight, IM) and etomidate (0.5 mg/kg, IV, loading dose; 50 micrograms/kg/min, constant infusion) were evaluated in 6 healthy adult Beagles. Instrumentation was performed during isoflurane/ oxygen-maintained anesthesia. Before initiation of the study, isoflurane was allowed to reach end-tidal concentration less than or equal to 0.5%, when baseline measurements were recorded. Medetomidine and atropine (0.044 mg/kg) were given IM after recording of baseline values. Ten minutes later, the loading dose of etomidate was given IM, and constant infusion was begun and continued for 60 minutes. Oxygen was administered via endotracheal tube throughout the study. Analgesia was evaluated by use of the standard tail clamp technique and a direct-current nerve stimulator. Sinoatrial and atrial-ventricular blocks occurred in 4 of 6 dogs within 2 minutes after administration of a medetomidine-atropine combination, but disappeared within 8 minutes. Apnea did not occur after administration of the etomidate loading dose. Analgesia was complete and consistent throughout 60 minutes of etomidate infusion. Medetomidine significantly (P < 0.05) increased systemic vascular resistance and decreased cardiac output. Etomidate infusion caused a decrease in respiratory function, but minimal changes in hemodynamic values. Time from termination of etomidate infusion to extubation, sternal recumbency, standing normally, and walking normally were 17.3 +/- 9.4, 43.8 +/- 14.2, 53.7 +/- 11.9, and 61.0 +/- 10.9 minutes, respectively. All recoveries were smooth and unremarkable. We concluded that this anesthetic drug combination, at the dosages used, is a safe technique in healthy Beagles.

Cardiopulmonary and behavioral responses to detomidine, a potent alpha 2-adrenergic agonist, were determined at 4 plasma concentrations in standing horses. After instrumentation and baseline measurements in 7 horses (mean +/- SD for age and body weight, 6 +/- 2 years, and 531 +/- 48.5 kg, respectively), detomidine was infused to maintain 4 plasma concentrations: 2.1 +/- 0.5 (infusion 1), 7.2 +/- 3.5 (infusion 2), 19.1 +/- 5.1 (infusion 3), and 42.9 +/- 10 (infusion 4) ng/ml, by use of a computer-controlled infusion system. Detomidine caused concentration-dependent sedation and somnolence. These effects were profound during infusions 3 and 4, in which marked head ptosis developed and all horses leaned heavily on the bars of the restraining stocks. Heart rate and cardiac index decreased from baseline measurements (42 +/- 7 beats/min, 65 +/- 11 ml.kg of body weight-1.min-1) in linear relationship with the logarithm of plasma detomidine concentration (ie, heart rate = -4.7 [log(e) detomidine concentration] + 44.3, P < 0.01; cardiac index = -10.5 [log(e) detomidine concentration] + 73.6, P < 0.01). Second-degree atrioventricular block developed in 5 of 7 horses during infusion 3, and in 6 of 7 horses during infusion 4. Mean arterial blood pressure increased significantly from 118 +/- 11 mm of Hg at baseline to 146 +/- 27 mm of Hg at infusion 4. Similar responses were observed for mean pulmonary artery and right atrial pressures. Systemic vascular resistance (baseline, 182 +/- 28 mm of Hg.ml-1.min-1.kg-1) increased significantly during infusions 3 and 4 (to 294 +/- 79 and 380 +/- 58, respectively). Plasma atrial natriuretic peptide concentration was significantly increased with increasing detomidine concentration (20.4 +/- 3.8 pg/ml at baseline to 33.5 +/- 9.1 at infusion 4). There were few significant changes in respiration rate and arterial blood gas and pH values. We conclude that maintenance of steady-state detomidine plasma concentrations resulted in cardiopulmonary changes that were quantitatively similar to those induced by detomidine bolus administration in horses.

Complete atrioventricular block was induced in 26 pentobarbital-anesthetized dogs to determine the effects of the alpha 2-adrenergic receptor agonists, xylazine and medetomidine, on supraventricular and ventricular automaticity. Prazosin and atipamezole, alpha-adrenoceptor antagonists, were administered to isolate alpha 1- or alpha 2-adrenoceptor effects. Six dogs served as controls and were given glycopyrrolate (0.1 mg/kg of body weight, IV) and esmolol (50 to 75 microgram/kg/min, IV) to induce parasympathetic and beta 1-adrenergic blockade, respectively. Eight dogs were given sequentially increasing doses of xylazine (n = 5), 0.000257 mg (10(-9)M) to 25.7 mg (10(-4)M) and medetomidine (n = 3), 0.000237 mg (10(-9)M) to 2.37 mg (10(-5) < M) after parasympathetic and beta 1-adrenergic blockade. Twelve dogs were given xylazine (n = 6, 1.1 mg/kg, IV) or medetomidine (n = 6, 0.05 mg/kg, IV) after parasympathetic and beta 1-adrenergic blockade. Three dogs given xylazine and 3 dogs given medetomidine were administered prazosin (0.1 mg/kg, IV) followed by atipamezole (0.3 mg/kg, IV). The order of prazosin and atipamezole was reversed in the remaining 3 dogs given either xylazine or medetomidine. Complete atrioventricular block and administration of glycopyrrolate and esmolol resulted in stable supraventricular and ventricular rates over a 4-hour period. Increasing concentration of xylazine or medetomidine did not cause significant changes in supraventricular or ventricular rate. Xylazine and medetomidine, in the presence of the alpha-adrenoceptor antagonists, prazosin (alpha(1)) and atipamezole (alpha(2)), did not cause significant changes in supraventricular or ventricular rate. alpha 2-Adrenoceptor agonists do not induce direct alpha 1- or alpha 2-adrenoceptor-mediated depression of supraventricular or ventricular rate in dogs with complete atrioventricular block.