Pharmacokinetics of detomidine and its metabolites following intravenous and intramuscular administration in horses

Reasons for performing study: Detomidine is commonly used i.v. for sedation and analgesia in horses, but the pharmacokinetics and metabolism of this drug have not been well described. Objectives: To describe the pharmacokinetics of detomidine and its metabolites, 3‐hydroxy‐detomidine (OH‐detomidine) and detomidine 3‐carboxylic acid (COOH‐detomidine), after i.v. and i.m. administration of a single dose to horses. Methods: Eight horses were used in a balanced crossover design study. In Phase 1, 4 horses received a single dose of i.v. detomidine, administered 30 μg/kg bwt and 4 a single dose i.m. 30 üg/kg bwt. In Phase 2, treatments were reversed. Plasma detomidine, OH‐detomidine and COOH‐detomidine were measured at predetermined time points using liquid chromatography‐mass spectrometry. Results: Following i.v. administration, detomidine was distributed rapidly and eliminated with a half‐life (t_1/2(el)) of approximately 30 min. Following i.m. administration, detomidine was distributed and eliminated with t_1/2(el) of approximately one hour. Following, i.v. administration, detomidine clearance had a mean, median and range of 12.41, 11.66 and 10.10–18.37 ml/min/kg bwt, respectively. Detomidine had a volume of distribution with the mean, median and range for i.v. administration of 470, 478 and 215–687 ml/kg bwt, respectively. OH‐detomidine was detected sooner than COOH‐detomidine; however, COOH‐detomidine had a much greater area under the curve. Conclusions and potential relevance: These pharmacokinetic parameters provide information necessary for determination of peak plasma concentrations and clearance of detomidine in mature horses. The results suggest that, when a longer duration of plasma concentration is warranted, the i.m. route should be considered.     

Serum concentrations and effects of detomidine delivered orally to horses in three different mediums

Objective To compare the effect of orally delivered detomidine on head posture when administered alone or in combination with two different food items, and to determine the serum concentrations of detomidine after oral delivery. Study Design Prospective randomized experimental study. Animals Fifteen adult grade mares weighing 328–537 kg. Methods The horses were randomly assigned to one of the three treatment groups (five horses each). The groups were given detomidine (0.06 mg kg^?1): alone; mixed with 3 mL of an apple sauce and gum mixture; or mixed with 3 mL molasses. Head droop, measured before treatment and at 15, 30, 45, 60, 75, 90, and 105 minutes after treatment, was used to evaluate sedation. Yohimbine (0.1 mg kg^?1 IV) was administered after the 90‐minute evaluation. Blood samples were collected from the detomidine‐alone group before treatment and at 15, 30, 45, 60, 75, and 90 minutes after treatment. Sera were analyzed for detomidine equivalent concentrations by an ELISA. Head droop percentages were compared using a repeated measures analysis of variance. Results Significant mean head droop developed in each treatment group by 30 minutes and persisted until reversal with yohimbine. After yohimbine administration, head positions returned to 87–91% of pre‐treatment levels. There were no significant differences among the oral treatment groups at any time. Mean serum detomidine equivalents increased slowly until 45‐minute post‐administration, but never exceeded 30 ng mL^?1. Conclusions Orally administered detomidine results in measurable serum drug concentrations using any of the delivery mediums investigated, and can be expected to produce profound head droop in horses approximately 45 minutes after administration.     

Pharmacokinetics of detomidine administered to horses at rest and after maximal exercise

Reason for performing study: Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses. Objectives: To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest. Methods: Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatographymass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis. Results: Median back‐extrapolated time zero plasma concentration was significantly lower and median plasma half‐life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations. Conclusions and potential relevance: Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect.     

The intravenous pharmacokinetics of butorphanol and detomidine dosed in combination compared with individual dose administrations to exercised horses

In equine and racing practice, detomidine and butorphanol are commonly used in combination for their sedative properties. The aim of the study was to produce detection times to better inform European veterinary surgeons, so that both drugs can be used appropriately under regulatory rules. Three independent groups of 7, 8 and 6 horses, respectively, were given either a single intravenous administration of butorphanol (100 µg/kg), a single intravenous administration of detomidine (10 µg/kg) or a combination of both at 25 (butorphanol) and 10 (detomidine) µg/kg. Plasma and urine concentrations of butorphanol, detomidine and 3-hydroxydetomidine at predetermined time points were measured by liquid chromatography–tandem mass spectrometry (LC-MS/MS). The intravenous pharmacokinetics of butorphanol dosed individually compared with co-administration with detomidine had approximately a twofold larger clearance (646 ± 137 vs. 380 ± 86 ml hr⁻¹ kg⁻¹) but similar terminal half-life (5.21 ± 1.56 vs. 5.43 ± 0.44 hr). Pseudo-steady-state urine to plasma butorphanol concentration ratios were 730 and 560, respectively. The intravenous pharmacokinetics of detomidine dosed as a single administration compared with co-administration with butorphanol had similar clearance (3,278 ± 1,412 vs. 2,519 ± 630 ml hr⁻¹ kg⁻¹) but a slightly shorter terminal half-life (0.57 ± 0.06 vs. 0.70 ± 0.11 hr). Pseudo-steady-state urine to plasma detomidine concentration ratios are 4 and 8, respectively. The 3-hydroxy metabolite of detomidine was detected for at least 35 hr in urine from both the single and co-administrations. Detection times of 72 and 48 hr are recommended for the control of butorphanol and detomidine, respectively, in horseracing and equestrian competitions.     

Hormonal, metabolic and physiological effects of laparoscopic surgery using a detomidine-buprenorphine combination in standing horses

Objective To assess the hormonal, metabolic and physiological effects of laparascopic surgery performed under a sedative analgesic combination of detomidine and buprenorphine in standing horses. Study design Prospective study. Animals Eight healthy adult Dutch Warmblood horses and five healthy adult ponies undergoing laparoscopy were studied. Five healthy adult horses not undergoing laparoscopy were used as a control group. Methods The sedative effect of an initial detomidine and buprenorphine injection was maintained using a continuous infusion of detomidine alone. The heart and respiratory rate, arterial blood pH and arterial oxygen and carbon dioxide tensions were monitored, while blood samples were taken for the measurement of glucose, lactate, cortisol, insulin and nonesterified fatty acids (NEFA). The same variables were monitored in a control group of horses which were sedated, but which did not undergo surgery. At the end of the sedation period the effects of detomidine were antagonized using atipamezole. Results The protocol provided suitable conditions for standing laparoscopy in horses. Laparoscopy induced obvious metabolic and endocrine responses which, with the exception of NEFA values, were not significantly different from changes found in the control group. While atipamezole did not produce detectable adverse effects, it is possible that anatagonism may not be essential. Conclusions The technique described reliably produces adequate sedation and analgesia for laparoscopic procedures. The level of sedation/analgesia was controlled by decreasing or increasing the infusion rate. Antagonism of the effects of detomidine may not be necessary in all cases.     

Retrospective analysis of detomidine infusion for standing chemical restraint in 51 horses

Objective To assess the effectiveness of a detomidine infusion technique to provide standing chemical restraint in the horse. Design Retrospective study. Animals Fifty‐one adult horses aged 9.5 ± 6.9 years (range 1–23 years) and weighing 575 ± 290.3 kg. Methods Records of horses presented to our clinic over a 3‐year period in which a detomidine infusion was used to provide standing chemical restraint were reviewed. Information relating to the types of procedure performed, duration of infusion, drug dosages and adjunct drugs administered was retrieved. Results Detomidine was administered as an initial bolus loading dose (mean ± SD) of 7.5 ± 1.87 µg kg^?1. The initial infusion rate was 0.6 µg kg^?1 minute^?1, and this was halved every 15 minutes. The duration of the infusion ranged from 20 to 135 minutes. Twenty horses received additional detomidine or butorphanol during the procedure. All horses undergoing surgery received local anesthesia or epidural analgesia in addition to the detomidine infusion. A wide variety of procedures were performed in these horses. Conclusions Detomidine administered by infusion provides prolonged periods of chemical restraint in standing horses. Supplemental sedatives or analgesics may be needed in horses undergoing surgery. Clinical relevance An effective method that provides prolonged periods of chemical restraint in standing horses is described. The infusion alone did not provide sufficient analgesia for surgery and a significant proportion of animals required supplemental sedatives and analgesics.     

Effects of detomidine or romifidine during maintenance and recovery from isoflurane anaesthesia in horses

ObjectiveTo evaluate the effects of detomidine or romifidine on cardiovascular function, isoflurane requirements and recovery quality in horses undergoing isoflurane anaesthesia.Study designProspective, randomized, blinded, clinical study.AnimalsA total of 63 healthy horses undergoing elective surgery during general anaesthesia.MethodsHorses were randomly allocated to three groups of 21 animals each. In group R, horses were given romifidine intravenously (IV) for premedication (80 μg kg^–1), maintenance (40 μg kg^–1 hour^–1) and before recovery (20 μg kg^–1). In group D2.5, horses were given detomidine IV for premedication (15 μg kg^–1), maintenance (5 μg kg^–1 hour^–1) and before recovery (2.5 μg kg^–1). In group D5, horses were given the same doses of detomidine IV for premedication and maintenance but 5 μg kg^–1 prior to recovery. Premedication was combined with morphine IV (0.1 mg kg^–1) in all groups. Cardiovascular and blood gas variables, expired fraction of isoflurane (Fe′Iso), dobutamine or ketamine requirements, recovery times, recovery events scores (from sternal to standing position) and visual analogue scale (VAS) were compared between groups using either anova followed by Tukey, Kruskal-Wallis followed by Bonferroni or chi-square tests, as appropriate (p < 0.05).ResultsNo significant differences were observed between groups for Fe′Iso, dobutamine or ketamine requirements and recovery times. Cardiovascular and blood gas measurements remained within physiological ranges for all groups. Group D5 horses had significantly worse scores for balance and coordination (p = 0.002), overall impression (p = 0.021) and final score (p = 0.008) than group R horses and significantly worse mean scores for VAS than the other groups (p = 0.002).Conclusions and clinical relevanceDetomidine or romifidine constant rate infusion provided similar conditions for maintenance of anaesthesia. Higher doses of detomidine at the end of anaesthesia might decrease the recovery quality.     

Comparative study between atropine and hyoscine-N-butylbromide for reversal of detomidine induced bradycardia in horses

Reasons for performing study: Bradycardia may be implicated as a cause of cardiovascular instability during anaesthesia. Hypothesis: Hyoscine would induce positive chronotropism of shorter duration than atropine, without adversely impairing intestinal motility in detomidine sedated horses. Methods: Ten minutes after detomidine (0.02 mg/kg bwt, i.v.), physiological saline (control), atropine (0.02 mg/kg bwt) or hyoscine (0.2 mg/kg bwt) were randomly administered i.v. to 6 horses, allowing one week intervals between treatments. Investigators blinded to the treatments monitored cardiopulmonary data and intestinal auscultation for 90 min and 24 h after detomidine, respectively. Gastrointestinal transit was assessed for 96 h via chromium detection in dry faeces. Results: Detomidine significantly decreased heart rate (HR) and cardiac index (CI) from baseline for 30 and 60 min, respectively (control). Mean ± s.d. HR increased significantly 5 min after atropine (79 ± 5 beats/min) and hyoscine (75 ± 8 beats/min). After this time, HR was significantly higher after atropine in comparison to other treatments, while hyoscine resulted in intermediate values (lower than atropine but higher than controls). Hyoscine and atropine resulted in significantly higher CI than controls for 5 and 20 min, respectively; but this effect coincided with significant hypertension (mean arterial pressures >180 mmHg). Auscultation scores decreased from baseline in all treatments. Time to return to auscultation scores ≥12 (medians) did not differ between hyoscine (4 h) and controls (4 h) but atropine resulted in significantly longer time (10 h). Atropine induced colic in one horse. Gastrointestinal transit times did not differ between treatments. Conclusion: Hyoscine is a shorter acting positive chronotropic agent than atropine, but does not potentiate the impairment in intestinal motility induced by detomidine. Because of severe hypertension, routine use of anticholinergics combined with detomidine is not recommended. Potencial relevance: Hyoscine may represent an alternative to atropine for treating bradycardia.     

Plasma drug concentrations and clinical effects of a peripheral alpha‐2‐adrenoceptor antagonist,MK‐467, in horses sedated with detomidine

ObjectiveTo investigate plasma drug concentrations and the effect of MK-467 (L-659′066) on sedation, heart rate and gut motility in horses sedated with intravenous (IV) detomidine.Study designExperimental randomized blinded crossover study.AnimalsSix healthy horses.MethodsDetomidine (10 μg kg^?1 IV) was administered alone (DET) and in combination with MK-467 (250 μg kg^?1 IV; DET + MK). The level of sedation and intestinal sounds were scored. Heart rate (HR) and central venous pressure (CVP) were measured. Blood was collected to determine plasma drug concentrations. Repeated measures anova was used for HR, CVP and intestinal sounds, and the Student's t-test for pairwise comparisons between treatments for the area under the time-sedation curve (AUC_sed) and pharmacokinetic parameters. Significance was set at p < 0.05.ResultsA significant reduction in HR was detected after DET, and HR was significantly higher after DET + MK than DET alone. No heart blocks were detected in any DET + MK treated horses. DET + MK attenuated the early increase in CVP detected after DET, but later the CVP decreased with both treatments. Detomidine-induced intestinal hypomotility was prevented by MK-467. AUC_sed was significantly higher with DET than DET + MK, but maximal sedations scores did not differ significantly between treatments. MK-467 lowered the AUC of the plasma concentration of detomidine, and increased its volume of distribution and clearance.Conclusions and clinical relevanceMK-467 prevented detomidine induced bradycardia and intestinal hypomotility. MK-467 did not affect the clinical quality of detomidine-induced sedation, but the duration of the effect was reduced, which may have been caused by the effects of MK-467 on the plasma concentration of detomidine. MK-467 may be useful clinically in the prevention of certain peripheral side effects of detomidine in horses.     

Effect of detomidine or romifidine constant rate infusion on plasma lactate concentration and inhalant requirements during isoflurane anaesthesia in horses

Objective

Influence of detomidine or romifidine constant rate infusion (CRI) on plasma lactate concentration and isoflurane requirements in horses undergoing elective surgery.

Evaluation of the sedative,analgesic, clinicophysiological and haematological effects of intravenous detomidine,detomidine‐butorphanol,romifidine and romifidine‐butorphanol in standing donkeys

The aim of this investigation was to determine and evaluate the sedative, analgesic, clinicophysiological and haematological effects of intravenous (i.v.) injection of detomidine, detomidine‐butorphanol, romifidine and romifidine‐butorphanol. Six standing donkeys were used. Each donkey received 4 i.v. treatments and the order of treatment was randomised with a one‐week interval between each treatment. We found that i.v. injection of a combination of detomidine‐butorphanol or romifidine‐butorphanol produced potent neuroleptanalgesic effects thus providing better, safe and effective sedation with complete analgesia in standing donkeys compared with injection of detomidine or romifidine alone. The changes and reduction in pulse rate were within acceptable limits. The changes in clinicophysiological, haematological and biochemical values were mild and transient in these clinically healthy donkeys.     

Evaluation of intramuscular anesthetic protocols in healthy domestic horses

ObjectiveTo assess anesthetic induction, recovery quality and cardiopulmonary variables after intramuscular (IM) injection of three drug combinations for immobilization of horses.Study designRandomized, blinded, three-way crossover prospective design.AnimalsA total of eight healthy adult horses weighing 470–575 kg.MethodsHorses were administered three treatments IM separated by ≥1 week. Combinations were tiletamine–zolazepam (1.2 mg kg⁻¹), ketamine (1 mg kg⁻¹) and detomidine (0.04 mg kg⁻¹) (treatment TKD); ketamine (3 mg kg⁻¹) and detomidine (0.04 mg kg⁻¹) (treatment KD); and tiletamine–zolazepam (2.4 mg kg⁻¹) and detomidine (0.04 mg kg⁻¹) (treatment TD). Parametric data were analyzed using mixed model linear regression. Nonparametric data were compared using Skillings–Mack test. A p value <0.05 was considered statistically significant.ResultsAll horses in treatment TD became recumbent. In treatments KD and TKD, one horse remained standing. PaO₂ 15 minutes after recumbency was significantly lower in treatments TD (p < 0.0005) and TKD (p = 0.001) than in treatment KD. Times to first movement (25 ± 15 minutes) and sternal recumbency (55 ± 11 minutes) in treatment KD were faster than in treatments TD (57 ± 17 and 76 ± 19 minutes; p < 0.0005, p = 0.001) and TKD (45 ± 18 and 73 ± 31 minutes; p = 0.005, p = 0.021). There were no differences in induction quality, muscle relaxation score, number of attempts to stand or recovery quality.Conclusions and clinical relevanceIn domestic horses, IM injections of tiletamine–zolazepam–detomidine resulted in more reliable recumbency with a longer duration when compared with ketamine–detomidine and tiletamine–zolazepam–ketamine–detomidine. Recoveries were comparable among protocols.     

The effects of detomidine, romifidine or acepromazine on echocardiographic measurements and cardiac function in normal horses

OBJECTIVE: To evaluate by echo- and electrocardiography the cardiac effects of sedation with detomidine hydrochloride, romifidine hydrochloride or acepromazine maleate in horses. STUDY DESIGN: An experimental study using a cross-over design without randomization. ANIMALS: Eight clinically normal Standardbred trotters. MATERIALS AND METHODS: Echocardiographic examinations (two-dimensional, guided M-mode and colour Doppler) were recorded on five different days. Heart rate (HR) and standard limb lead electrocardiograms were also obtained. Subsequently, horses were sedated with detomidine (0.01 mg kg(-1)), romifidine (0.04 mg kg(-1)) or acepromazine (0.1 mg kg(-1)) administered intravenously and all examinations repeated. RESULTS: Heart rate before treatment with the three drugs did not differ significantly (p = 0.98). Both detomidine and romifidine induced a significant decrease (p < 0.001) in HR during the first 25 minutes after sedation; while acepromazine had a varying effect on HR. For detomidine, there was a significant increase in LVIDd (left ventricular internal diameter in diastole; p = 0.034) and LVIDs (left ventricular internal diameter in systole; p < 0.001). In addition, a significant decrease was found in IVSs (the interventricular septum in systole; p < 0.001), LVFWs (the left ventricular free wall in systole; p = 0.002) and FS% (fractional shortening; p < 0.001). The frequency of pulmonary regurgitation was increased significantly (p < 0.001). Romifidine induced a significant increase in LVIDs (p < 0.001) and a significant decrease in IVSs (p < 0.001) and FS% (p = 0.002). Acepromazine had no significant effect upon any of the measured values. CONCLUSIONS: and clinical relevance The results indicate that sedation of horses with detomidine and to a lesser extent romifidine at the doses given in this study has a significant effect on heart function, echocardiographic measurements of heart dimensions and the occurrence of valvular regurgitation. Although the clinical significance of these results may be minimal, the potential effects of sedative drugs should be taken into account when echocardiographic variables are interpreted in clinical cases.     

Atipamezole in the management of detomidine overdose in a pony

OBSERVATIONS: A pony undergoing elective castration accidentally received an overdose of IV detomidine (200 microg kg(-1)) before anaesthesia was induced with ketamine and midazolam. A further 100 microg kg(-1) IV dose of detomidine was administered during anaesthesia. The mistake was recognized only when the animal failed to recover from anaesthesia in the expected time. The overdose (300 microg kg(-1) in total) was treated successfully with atipamezole, initially given IV and subsequently IM and titrated to effect to a total dose of 1100 microg kg(-1). The pony regained the standing position. A further injection of atipamezole (76 microg kg(-1) IM) was given 5 hours later to counteract slight signs of re-sedation. CONCLUSIONS: Atipamezole proved an effective antagonist for detomidine in a pony at an initial dose 3.65 x and a final total dose 3.9 x greater than the alpha2 agonist.     

Sedative and antinociceptive effects of different combinations of detomidine and methadone in standing horses

Objective

To evaluate intravenous (IV) detomidine with methadone in horses to identify a combination which provides sedation and antinociception without adverse effects.

Pharmacokinetics and pharmacodynamics of hydromorphone after intravenous and intramuscular administration in horses

ObjectiveTo compare the pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) and intramuscular (IM) administration.Study designRandomized, masked, crossover design.AnimalsA total of six adult horses weighing [mean ± standard deviation (SD))] 447 ± 61 kg.MethodsHorses were administered three treatments with a 7 day washout. Treatments were hydromorphone 0.04 mg kg^⁻1 IV with saline administered IM (H-IV), hydromorphone 0.04 mg kg^⁻1 IM with saline IV (H-IM), or saline IV and IM (P). Blood was collected for hydromorphone plasma concentration at multiple time points for 24 hours after treatments. Pharmacodynamic data were collected for 24 hours after treatments. Variables included thermal nociceptive threshold, heart rate (HR), respiratory frequency (f_R), rectal temperature, and fecal weight. Data were analyzed using mixed-effects linear models. A p value of less than 0.05 was considered statistically significant.ResultsThe mean ± SD hydromorphone terminal half-life (t_1/2), clearance and volume of distribution of H-IV were 19 ± 8 minutes, 79 ± 12.9 mL minute^⁻1 kg^⁻1 and 1125 ± 309 mL kg^⁻1. The t_1/2 was 26.7 ± 9.25 minutes for H-IM. Area under the curve was 518 ± 87.5 and 1128 ± 810 minute ng mL^⁻1 for H-IV and H-IM, respectively. The IM bioavailability was 217%. The overall thermal thresholds for both H-IV and H-IM were significantly greater than P (p < 0.0001 for both) and baseline (p = 0.006). There was no difference in thermal threshold between H-IV and H-IM. No difference was found in physical examination variables among groups or in comparison to baseline. Fecal weight was significantly less than P for H-IV and H-IM (p = 0.02).Conclusions and clinical relevanceIM hydromorphone has high bioavailability and provides a similar degree of antinociception to IV administration.IM hydromorphone in horses provides a similar degree and duration of antinociception to IV administration.