Pharmacokinetics and pharmacodynamics of a high concentration of buprenorphine (Simbadol) in conscious horses after subcutaneous administration.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of high-concentration formulation of buprenorphine (1.8 mg mL-1; Simbadol) following subcutaneous (SC) administration in horses. STUDY DESIGN: Prospective, randomized, crossover trial. ANIMALS: A group of six healthy adult horses weighing 521-602 kg. METHODS: On three occasions, Simbadol (0.005 mg kg-1; treatment S5), (0.0025 mg kg-1; treatment S2.5) or saline (treatment SAL) were administered SC at least 7 days apart in random order. Electrical nociceptive threshold (ENT) measured on the neck region, physiologic variables, locomotor activity, degree of restlessness and presence of excitatory signs were measured at baseline and for up to 48 hours after injection. Blood was collected for pharmacokinetic analysis at the same time intervals and plasma buprenorphine concentration (Cp) measured using liquid chromatography-tandem mass spectrometry. RESULTS: Buprenorphine was quantifiable in all horses from 15 minutes after administration up to 8-12 hours. ENT was significantly increased in treatment S2.5 compared with treatment SAL at 0.75-6 hours after treatment. Increase in locomotor activity and compulsive behavior were recorded in all horses after Simbadol, and degree of restlessness was significantly higher in treatment S5 than SAL for a sustained time. Gastrointestinal motility significantly decreased in all horses after Simbadol and returned to baseline by 16 hours after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In horses, SC Simbadol was rapidly absorbed and Cp decreased rapidly. Side effects commonly seen in horses after opioids were observed in both Simbadol treatments, but degree of opioid-induced excitement lasted significantly longer in treatment S5. Simbadol (0.0025 mg kg-1) SC has the potential to be used clinically to treat pain in horses. However, at this dose, duration of antinociceptive effects was not longer than that reported for conventional buprenorphine, and side effects, including reduction in gastrointestinal motility and increased locomotor activity, were documented.

Effect of yohimbine on detomidine induced changes in behavior, cardiac and blood parameters in the horse.

OBJECTIVE: To describe selected pharmacodynamic effects of detomidine and yohimbine when administered alone and in sequence. STUDY DESIGN: Randomized crossover design. ANIMALS: Nine healthy adult horses aged 9 ± 4 years and weighing 561 ± 56 kg. METHODS: Three dose regimens were employed in the current study. 1) 0.03 mg kg(-1) detomidine IV, 2) 0.2 mg kg(-1) yohimbine IV and 3) 0.03 mg kg(-1) detomidine IV followed 15 minutes later by 0.2 mg kg(-1) yohimbine IV. Each horse received all three treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for detomidine and yohimbine concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume and plasma proteins were monitored. RESULTS: Yohimbine rapidly reversed the sedative effects of detomidine in the horse. Additionally, yohimbine effectively returned heart rate and the percent of atrio-ventricular conduction disturbances to pre-detomidine values when administered 15 minutes post-detomidine administration. Plasma glucose was significantly increased following detomidine administration. The detomidine induced hyperglycemia was effectively reduced by yohimbine administration. Effects on packed cell volume and plasma proteins were variable. CONCLUSIONS AND CLINICAL RELEVANCE: Intravenous administration of yohimbine effectively reversed detomidine induced sedation, bradycardia, atrio-ventricular heart block and hyperglycemia.

Pharmacokinetics of fentanyl after intravenous administration in isoflurane-anesthetized red-tailed hawks (Buteo jamaicensis) and Hispaniolan Amazon parrots (Amazona ventralis).

OBJECTIVE To compare the disposition of fentanyl citrate after a single IV injection in isoflurane-anesthetized red-tailed hawks (Buteo jamaicensis) and Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS 6 adult red-tailed hawks and 6 adult Hispaniolan Amazon parrots. PROCEDURES Anesthesia was induced and maintained with isoflurane; intermittent positive-pressure ventilation was provided. The minimum alveolar concentration of isoflurane was determined for each bird by use of the bracketing method and a supramaximal electrical stimulus. Fentanyl (20 µg/kg) was administered IV. Arterial (red-tailed hawks) or jugular venous (Hispaniolan Amazon parrots) blood samples were obtained immediately before and 1, 2, 4, 8, 15, 30, 60, 120, 180, 240, and 480 minutes (red-tailed hawks) and 1, 5, 10, 15, 30, 60, 120, and 180 minutes (Hispaniolan Amazon parrots) after fentanyl administration. RESULTS A 3-compartment and a 2-compartment model best described fentanyl pharmacokinetics in red-tailed hawks and Hispaniolan Amazon parrots, respectively. Median apparent volume of the central compartment and volume of distribution at steady state were 222 mL/kg and 987 mL/kg, respectively, for the red-tailed hawks and 5,108 mL/kg and 13,079 mL/kg, respectively, for the Hispaniolan Amazon parrots. Median clearance and elimination half-life were 8.9 mL/min/kg and 90.22 minutes, respectively, for the red-tailed hawks and 198.8 mL/min/kg and 51.18 minutes, respectively, for the Hispaniolan Amazon parrots. CONCLUSIONS AND CLINICAL RELEVANCE Pharmacokinetic results for fentanyl in isoflurane-anesthetized red-tailed hawks and Hispaniolan Amazon parrots indicated large differences and should strongly discourage extrapolation of doses between these 2 species.

Effects of three fentanyl plasma concentrations on the minimum alveolar concentration of isoflurane in Hispaniolan Amazon parrots (Amazona ventralis).

OBJECTIVE To determine effects of 3 plasma concentrations of fentanyl on the minimum alveolar concentration of isoflurane (MACiso) and cardiovascular variables in Hispaniolan Amazon parrots (Amazona ventralis). ANIMALS 6 adult parrots. PROCEDURES In phase 1, anesthesia was induced and maintained with isoflurane; intermittent positive-pressure ventilation was provided. The MACiso was determined for each bird by use of a bracketing method and supramaximal electrical stimulus. Fentanyl (20 µg/kg) was administered IV, and blood samples were collected over time to measure plasma fentanyl concentrations for pharmacokinetic calculations. In phase 2, pharmacokinetic values for individual birds were used for administration of fentanyl to achieve target plasma concentrations of 8, 16, and 32 ng/mL. At each concentration, MACiso and cardiovascular variables were determined. Data were analyzed with mixed-effects multilevel linear regression analysis. RESULTS Mean ± SD fentanyl plasma concentrations were 0 ng/mL, 5.01 ± 1.53 ng/mL, 12.12 ± 3.58 ng/mL, and 24.93 ± 4.13 ng/mL, and MACiso values were 2.09 ± 0.17%, 1.45 ± 0.32%, 1.34 ± 0.31%, and 0.95 ± 0.14% for fentanyl target concentrations of 0, 8, 16, and 32 ng/mL, respectively. Fentanyl significantly decreased MACiso in a dose-dependent manner. Heart rate and blood pressure significantly decreased at all fentanyl doses, compared with values for MACiso at 0 ng of fentanyl/mL. CONCLUSIONS AND CLINICAL RELEVANCE Fentanyl significantly decreased the MACiso in healthy Hispaniolan Amazon parrots, but this was accompanied by a depressive effect on heart rate and blood pressure that would need to be considered for application of this technique in clinical settings.

Pharmacokinetics and pharmacodynamics of detomidine following sublingual administration to horses.

OBJECTIVE: To characterize pharmacokinetics and pharmacodynamics of detomidine gel administered sublingually in accordance with label instructions to establish appropriate withdrawal guidelines for horses before competition. ANIMALS: 12 adult racehorses. PROCEDURES: Horses received a single sublingual administration of 0.04 mg of detomidine/kg. Blood samples were collected before and up to 72 hours after drug administration. Urine samples were collected for 5 days after detomidine administration. Plasma and urine samples were analyzed via liquid chromatography-mass spectrometry, and resulting data were analyzed by use of noncompartmental analysis. Chin-to-ground distance, heart rate and rhythm, glucose concentration, PCV, and plasma protein concentration were also assessed following detomidine administration. RESULTS: Mean ± SD terminal elimination half-life of detomidine was 1.5 ± 1 hours. Metabolite concentrations were below the limit of detection (0.02, 0.1, and 0.5 ng/mL for detomidine, carboxydetomidine, and hydroxydetomidine, respectively) in plasma by 24 hours. Concentrations of detomidine and its metabolites were below the limit of detection (0.05 ng/mL for detomidine and 0.10 ng/mL for carboxydetomidine and hydroxydetomidine) in urine by 3 days. All horses had various degrees of sedation after detomidine administration. Time of onset was ≤ 40 minutes, and duration of sedation was approximately 2 hours. Significant decreases, relative to values at time 0, were detected for chin-to-ground distance and heart rate. There was an increased incidence and exacerbation of preexisting atrioventricular blocks after detomidine administration. CONCLUSIONS AND CLINICAL RELEVANCE: A 48-hour and 3-day withdrawal period for detection in plasma and urine samples, respectively, should be adopted for sublingual administration of detomidine gel.