Antagonism of detomidine sedation with atipamezole in horses

The reversal of detomidine-induced sedation with iv atipamezole was studied in 6 horses. All horses were injected iv with 10 μg and 20 μg/kg bwt detomidine and 15 min later this was followed by 6-, 8- and 10-fold doses of iv atipamezole. Atipamezole caused a quick arousal in all horses with minor side effects. Bradycardia, rhythm disturbances and head ptosis caused by detomidine were not abolished completely at the end of the 15 min observation period, even with the highest atipamezole doses. All horses remained slightly sedated but without ataxia. There were no significant differences in head height, heart rate and sedation score between the different doses of atipamezole for either dose of detomidine. According to the degree of sedation, doses of 100 μg to 160 μg/kg bwt atipamezole are adequate to antagonise detomidine-induced sedation in the horse.     

Antagonism of detomidine with tolazoline in isoflurane-anaesthetised ponies

The effects of tolazoline (4.0 mg/kg iv) antagonism of detomidine (0.02 mg/kg iv) were evaluated in isoflurane-anaesthetised, ventilated ponies. Each of 6 ponies received both tolazoline and saline treatment during separate anaesthetic episodes only (no surgery was performed). Detomidine administration produced an increase in blood pressure, decrease in heart rate and decrease in P_aO₂ Tolazoline treatment transiently increased heart rate while blood pressure returned to baseline after both treatments. Arterial oxygenation decreased further after tolazoline treatment while oxgenation recovered towards baseline with saline treatment. No other cardiopulmonary effects were detected. Recovery from anaesthesia tended to be more rapid when detomidine was antagonized. The potential benefit of antagonizing detomidine-induced bradycardia with tolazoline, during isoflurane anaesthesia should be weighed against the potential to produce a decrease in arterial oxygenation. The mechanism for this effect is not clear.     

Antagonism of medetomidine sedation by atipamezole in pigs.

The efficacy of atipamezole as a medetomidine antagonist was evaluated in pigs. The atipamezole doses (intramuscularly) were 80, 160, 320 and 480 micrograms/kg of body weight, which were one, two, four and six times higher than the preceding medetomidine dose (80 micrograms/kg, intramuscularly). Atipamezole effectively reversed medetomidine-induced sedation, and the optimal action was seen at doses of 160 and 320 micrograms/kg. Recovery from sedation was quick and smooth, and adverse effects such as hyperactivity or tachycardia were minimal with either dose.     

Effect of sedation with detomidine and butorphanol on pulmonary gas exchange in the horse

Background

Sedation with α₂-agonists in the horse is reported to be accompanied by impairment of arterial oxygenation. The present study was undertaken to investigate pulmonary gas exchange using the Multiple Inert Gas Elimination Technique (MIGET), during sedation with the α₂-agonist detomidine alone and in combination with the opioid butorphanol.

Methods

Seven Standardbred trotter horses aged 3–7 years and weighing 380–520 kg, were studied. The protocol consisted of three consecutive measurements; in the unsedated horse, after intravenous administration of detomidine (0.02 mg/kg) and after subsequent butorphanol administration (0.025 mg/kg). Pulmonary function and haemodynamic effects were investigated. The distribution of ventilation-perfusion ratios (V_A/Q) was estimated with MIGET.

Results

During detomidine sedation, arterial oxygen tension (PaO₂) decreased (12.8 ± 0.7 to 10.8 ± 1.2 kPa) and arterial carbon dioxide tension (PaCO₂) increased (5.9 ± 0.3 to 6.1 ± 0.2 kPa) compared to measurements in the unsedated horse. Mismatch between ventilation and perfusion in the lungs was evident, but no increase in intrapulmonary shunt could be detected. Respiratory rate and minute ventilation did not change. Heart rate and cardiac output decreased, while pulmonary and systemic blood pressure and vascular resistance increased. Addition of butorphanol resulted in a significant decrease in ventilation and increase in PaCO₂. Alveolar-arterial oxygen content difference P(A-a)O₂ remained impaired after butorphanol administration, the V_A/Q distribution improved as the decreased ventilation and persistent low blood flow was well matched. Also after subsequent butorphanol no increase in intrapulmonary shunt was evident.

Conclusion

The results of the present study suggest that both pulmonary and cardiovascular factors contribute to the impaired pulmonary gas exchange during detomidine and butorphanol sedation in the horse.     

The influence of atipamezole on the cardiovascular effects of detomidine in horses

The reversal of the cardiovascular effects of the α₂-adrenoceptor agonist detomidine by the α₂-antagonist atipamezole was studied. Nine horses were given detomidine 20 μg/kg iv. On a separate occasion they were given atipamezole 100 μg/kg iv 15 mins after the detomidine injection. Blood gas tensions were measured and clinical signs of sedation were also observed. Bradycardia and the frequency of heart blocks induced by detomidine were reduced after atipamezole and blood pressure decreased. These reversal effects of atipamezole were of short duration (a few minutes) at the dose level tested. Two of the nine horses exhibited premature depolarisations after administration of detomidine, but not after atipamezole injection. PaO₂ decreased and PaCO₂ increased slightly after detomidine injection, but the arterial pH was within reference values or slightly elevated. Administration of atipamezole did not alter these values. Base excess rose after detomidine, and it decreased more quickly towards the baseline level, when the horses were given detomidine alone. No clinical adverse effects were seen from the administration of atipamezole. Atipamezole may be beneficial, if detomidine-induced bradycardia needs to be reversed in horses.     

Evaluation of combinations of nalbuphine with acepromazine or detomidine for sedation in ponies

The effect of combinations of nalbuphine (0.3 mg/kg) with either detomidine (10 μg/kg) or acepromazine (50 μg/kg) was investigated in ponies. Nalbuphine enhanced the degree of sedation produced by both sedatives; sedation with detomidine and nalbuphine was profound. Cardiovascular and respiratory effects were mild and could usually be attributed to the effect of the sedative itself. Side effects were minimal and gave no cause for concern. It was concluded that nalbuphine, in combination with acepromazine or detomidine, is a safe and effective sedative for use in ponies.     

Single-dose pharmacokinetics of detomidine in the horse and cow

The pharmacokinetics of detomidine, a novel analgesic sedative, was studied in the major target species after high (80 micrograms/kg) i.v. and i.m. doses. In addition, drug residues in some organs were determined. Concentrations were measured using a sensitive, detomidine-specific radio-immunoassay method. Rapid absorption following i.m. dosing occurred. Absorption half-lives were 0.15 h (horse) and 0.08 h (cattle). The mean peak concentration in the horse (51.3 ng/ml) was achieved in 0.5 h and in the cow (65.8 ng/ml) in 0.26 h. The areas under the concentration curve after i.m. dosing were 66% (horse) and 85% (cow) of the corresponding i.v. values. Distribution was rapid with half-lives of 0.15 h (horse, i.v.) and 0.24 h (cow, i.v.). The apparent volume of distribution was higher after the i.m. dosing (horse 1.56 l/kg, cow 1.89 l/kg) than after i.v. dosing (horse 0.74 l/kg, cow 0.73 l/kg). Elimination half-lives were 1.19 h (horse) and 1.32 h (cow) for the i.v. dose and 1.78 h (horse) and 2.56 h (cow) for the i.m. dose. Total clearances ranged from 6.7 (horse, i.v.) to 12.3 (cow, i.m.) ml/min/kg. Renal clearances were less than 1% of the total clearances showing negligible excretion of the drug in urine and suggesting elimination by metabolism. A cross-reacting metabolite in urine corresponded to less than 1.5% of the detomidine dose's immunoreactivity. High-dose detomidine increased urine flow significantly. Excretion of detomidine in milk in cattle was extremely low. No detectable amounts were present 23 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reversal of medetomidine sedation by atipamezole in dogs

Atipamezole reversed the sedative effect of medetomidine in twelve laboratory beagles. The dogs were sedated with medetomidine doses of 20, 40 and 80 micrograms/kg body wt i.m. Atipamezole was injected (i.m.) 20 min later at dose rates two, four, six and ten times higher (in micrograms/kg) than the preceding medetomidine dose. Placebo treatment was included in the study. The deeply sedated dogs showed signs of arousal in 3-7 min and took their first steps 4-12 min after atipamezole injection. The dose-related reversal effect of atipamezole proved to be optimal with doses which were four, six or ten times higher than the preceding medetomidine dose. Drowsiness was found 0.5-1 h after atipamezole injection in 41% of the cases. No adverse effects nor cases of over-alertness or excitement were found.     

Combined use of detomidine with opiates in the horse

The effects of administration of one of four opiates (pethidine 1 mg/kg bodyweight (bwt), morphine 0.1 mg/kg bwt, methadone 0.1 mg/kg bwt, and butorphanol 0.05 mg/kg bwt) given intravenously to horses and ponies already sedated with detomidine (10 micrograms/kg bwt) were investigated. Behavioural, cardiovascular and respiratory effects of the combinations were compared with those occurring with detomidine alone. Addition of the opiate increased the apparent sedation and decreased the response of the animal to external stimuli. At doses used, butorphanol produced the most reliable response. Side effects seen were increased ataxia (greatest following methadone and butorphanol) and excitement (usually muzzle tremors and muscle twitching). Following pethidine, generalised excitement was sometimes seen. Marked cardiovascular changes occurred in the first few minutes after morphine or pethidine injection, but within 5 mins cardiovascular changes were minimal. Following morphine or pethidine there was a significant increase in arterial carbon dioxide tension. Fourteen clinical cases were successfully sedated using detomidine/butorphanol combinations.     

Preliminary study of the effects of xylazine or detomidine with or without butorphanol for standing sedation in dairy cattle

The sedative effect induced by administering xylazine hydrochloride or detomidine hydrochloride with or without butorphanol tartrate to standing dairy cattle was compared in two groups of six adult, healthy Holstein cows. One group received xylazine (0.02 mg/kg i.v.) followed by xylazine (0.02 mg/kg) and butorphanol (0.05 mg/kg i.v.) 1 week later. Cows in Group B received detomidine (0.01 mg/kg i.v.) followed by detomidine (0.01 mg/kg i.v.) and butorphanol (0.05 mg/kg i.v.) 1 week later. Heart rate, respiratory rate, and arterial blood pressure were monitored and recorded before drugs were administered and every 10 minutes for 1 hour after drug administration. The degree of sedation was evaluated and graded. Cows in each treatment group had significant decreases in heart rate and respiratory rate after test drugs were given. Durations of sedation were 49.0 +/- 12.7 minutes (xylazine), 36.0 +/- 14.1 (xylazine with butorphanol), 47.0 +/- 8.1 minutes (detomidine), and 43.0 +/- 14.0 minutes (detomidine with butorphanol). Ptosis and salivation were observed in cows of all groups following drug administration. Slow horizontal nystagmus was observed from three cows following administration of detomidine and butorphanol. All cows remained standing while sedated. The degree of sedation seemed to be most profound in cows receiving detomidine and least profound in cows receiving xylazine.     

Effects of atipamezole on xylazine sedation in ponies.

Atipamezole antagonism of xylazine sedation was evaluated in six ponies. Atipamezole (0.15 mg/kg) or saline was injected intravenously 15 minutes after the ponies had been sedated with xylazine (1.0 mg/kg). Arterial blood pressure and gases, pulse and respiratory rates, the electrocardiogram, nose-to-ground distance and a subjective sedation score were recorded. The pretreatment nose-to-ground distance and PaO2 returned to normal sooner after atipamezole than after saline and the ponies' appetite and normal locomotion also recovered sooner. No significant differences were observed between the effects of saline and atipamezole on the other measurements.     

Antagonism of ketamine-xylazine anesthesia in rats by administration of yohimbine, tolazoline, or 4-aminopyridine

Antagonism of ketamine-xylazine (85 mg of ketamine/kg of body weight and 15 mg of xylazine/kg, IM) anesthesia in rats by yohimbine (YOH; 1, 5, 10, and 20 mg/kg, IP), tolazoline (TOL; 10, 20, or 50 mg/kg, IP), 4-aminopyridine (4-AP; 1 or 5 mg/kg, IP), or a combination of yohimbine and 4-aminopyridine (YOH:4-AP, 1 mg/kg:1 mg/kg or 5 mg/kg:1 mg/kg, IP) was studied. All dosages of YOH, TOL, 4-AP, and YOH:4-AP reduced the time to appearance of corneal and pedal reflexes. Only TOL was effective in reducing time to appearance of the crawl reflex and recovery time. Yohimbine, 4-AP, YOH:4-AP, and TOL were effective in reversing respiratory depression caused by ketamine-xylazine anesthesia, but anesthetic-induced hypothermia was not antagonized. When given to non-anesthetized rats, the antagonists had little influence on respiratory rate, but all antagonists caused significant (P less than 0.05) reduction in core body temperature for at least 90 minutes. When YOH was used as an anesthetic antagonist at dosage of 20 mg/kg, 20% mortality was observed and was attributable to acute respiratory arrest. The use of 4-AP and YOH:4-AP at the dosages studied induced moderate to severe muscular tremors. In conclusion, TOL at dosage of 20 mg/kg given IP, appears to be an appropriate antagonist for ketamine-xylazine anesthesia in rats.     

Antagonistic effects of intravenous or epidural atipamezole on xylazine-induced dorsolumbar epidural analgesia in cattle

This study was performed to clarify the antagonistic actions of intravenous or epidural atipamezole on the sedative and analgesic effects of xylazine administered between the epidural fat and dura mater through the first interlumbar space in cattle.Cattle received 5 mL of a solution containing 0.05 mg x kg(-1) xylazine in 0.9% saline. Thirty minutes later, 5 mL of 0.9% saline was administered through the same needle (treatment 1) (XSE). In treatments 2 (XAE) and 3 (XAV), 5 mL of a solution containing 0.025 mg x kg(-1) atipamezole in 0.9% saline was administered epidurally or intravenously, respectively.Sedation and analgesia were similar in all three treatment groups and could be reversed by atipamezole given by either route. In the XAV treatment, the flank area relapsed into analgesia 25+/-5.8 min following reversal of the analgesic effect, and was maintained for 112.5+/-63.8 min.The present study confirmed that the sedative and analgesic effects of xylazine are completely reversed by atipamezole and can be influenced by the epidural fat in cattle. Furthermore, it seems probable that analgesia following epidural administration of xylazine is mediated by alpha(2)-adrenergic receptors, not by a local anaesthetic effect.     

Investigation of romifidine and detomidine for the clinical sedation of horses

The effects of two intravenous doses of romifidine (80 and 120 microg/kg) and one dose of detomidine (20 microg/kg) were compared in a blinded study in 30 horses requiring to be sedated for routine dental treatment. Several physiological parameters were assessed before and for two hours after the administration of the drugs, and the horses' teeth were rasped 30 minutes after they were administered. Romifidine produced a dose-dependent effect on most parameters. Detomidine at 20 microg/kg was similar to romifidine at 120 microg/kg in the magnitude of its sedative effects, but was similar to romifidine at 80 pg/kg in its duration. There were no significant differences between the three treatments in terms of the clinical procedure score.     

Selectivity of atipamezole, yohimbine and tolazoline for alpha-2 adrenergic receptor subtypes: Implications for clinical reversal of alpha-2 adrenergic receptor mediated sedation in sheep

The α₂-adrenergic receptor antagonists, yohimbine, atipamezole and tolazoline, are used in veterinary medicine as reversal agents for the sedative/hypnotic effects of α₂-agonists. Ruminants have increased sensitivity to the sedative/hypnotic effects of α₂-agonists compared to other species. The receptors mediating the sedative effects of α₂-agonsts are located primarily on locus coeruleus neurons in the pons of the lower brainstem. Four pharmacological subtypes of the α₂-adrenergic receptor (A,B, C and D) have been identified based on differences in ligand affinity. The aim of this study was to: 1) determine the pharmacological profile of atipamezole, yohimbine and tolazoline at the four α₂-adrenergic receptor subtypes and; 2) determine whether these agents differ in their affinities at the α₂-adrenergic receptor present in the sheep brainstem. In inhibition binding studies against the selective α₂-adrenergic receptor ligand [³H]-MK-912, tolazoline showed the lowest affinity for all four α₂-adrenergic receptor subtypes compared to yohimbine and atipamezole. The affinities of yohimbine and atipamezole were similar at the α_2A-, α_2B- and α_2C-adrenergic receptors but differed by approximately 100 fold at the α_2D-adrenergic receptor. Atipamezole had a 100 fold higher affinity at the α_2D-adrenergic receptor when compared to yohimbine. To determine the ligand binding characteristics of these agents at the α₂-adrenergic receptor in sheep brainstem, membranes were labelled with [³H]-MK-912 and inhibition competition curves were performed. Atipamezole showed approximately a 100 fold higher affinity for the sheep brainstem α₂-adrenergic receptor compared to yohimbine which was similar to what was observed for the α_2D-adrenergic receptor in PC12 cells transfected with RG-20. The results from these studies suggest that atipamezole has a high affinity for the α_2D-adrenergic receptor that appears to be the receptor subtype in sheep brainstem.     

The effects of yohimbine on the pharmacokinetic parameters of detomidine in the horse

ObjectiveTo describe the pharmacokinetics of detomidine and yohimbine when administered in combination.Study designRandomized crossover design.AnimalsNine healthy adult horses aged 9 ± 4 years and weighing of 561 ± 56 kg.MethodsThree dose regimens were employed in the current study. 1) 0.03 mg kg^?1 detomidine IV (D), 2) 0.2 mg kg^?1 yohimbine IV (Y) and 3) 0.03 mg kg^?1 detomidine IV followed 15 minutes later by 0.2 mg kg^?1 yohimbine IV (DY). Each horse received all three dose regimens with a minimum of 1 week in between subsequent regimens. Blood samples were obtained and plasma analyzed for detomidine and yohimbine concentrations by liquid chromatography-mass spectrometry. Data were analyzed using both non-compartmental and compartmental analysis.ResultsThe maximum measured detomidine concentrations were 76.0 and 129.9 ng mL^?1 for the D and DY treatments, respectively. Systemic clearance and volume of distribution of detomidine were not significantly different for either treatment. There was a significant increase in the maximum measured yohimbine plasma concentrations from Y (173.9 ng mL^?1) to DY (289.8 ng mL^?1). Both the Cl and V_d for yohimbine were significantly less (6.8 mL minute^?1 kg^?1 (Cl) and 1.7 L kg^?1 (V_d)) for the DY as compared to the Y treatments (13.9 mL minute^?1 kg^?1 (Cl) and 2.7 L kg^?1 (V_d)). Plasma concentrations were below the limit of quantitation (0.05 and 0.5 ng mL^?1) by 18 hours for both detomidine and yohimbine.Conclusion and clinical relevanceThe Cl and V_d of yohimbine were affected by prior administration of detomidine. The elimination half life of yohimbine remained unaffected when administered subsequent to detomidine. However, the increased plasma concentrations in the presence of detomidine has the potential to cause untoward effects and therefore further studies to assess the physiologic effects of this combination of drugs are warranted.     

Medetomidine/ketamine sedation in calves and its reversal with atipamezole

Atipamezole was used to reverse the sedation induced in calves by medetomidine/ketamine. Thirteen claves subjected to umbilical surgery received medetomidine 20 μg/kg bodyweight (bwt) and ketamine 0.5 mg/kg bwt intravenously (iv) from a mixture of the drugs in one syringe. Atipamezole was given at doses of 20 to 60 μg/kg iv and intramuscularly (im) to the calves at the end of the operation. Following the administration of medetomidine and ketamine, PaCO₂ increased whereas pH, PaO₂ and heart rate decreased. Reversing the effects of medetomidine with atipamezole did not cause undesirable effects; recovery was rapid and smooth, most of the animals reached a standing position within 1 to 3 mins after the atipamezole injection.     

Electroretinogram responses of the normal thoroughbred horse sedated with detomidine hydrochloride

Purpose The main objective was to record electroretinogram (ERG) parameters of normal thoroughbred mares using the HMsERG, a mini-Ganzfeld electroretinographic unit, and a contact lens electrode. The second objective was to determine whether IV detomidine hydrochloride at 0.015?mg/kg is consistently an effective choice for sedation of horses undergoing this ERG protocol. Methods The study population consisted of 30 normal thoroughbred mares. ERG data were harvested using a protocol that included three different light intensities (10, 3000, and 10?000?mcd?s/m(2) ) and a 30-Hz flicker at 3000?mcd?s/m(2) . Results Mean, median, standard deviation, and estimated normal ranges using the 5-95% of the data for a- and b-wave implicit times (IT), amplitudes (AMP), and b/a ratios were reported. Scotopic results at low intensity (10?mcd?s/m(2) ) had estimated ranges for b-wave IT of 41.8-72.9?ms and AMP of 19.8-173.3?μV. Middle intensity (3000?mcd?s/m(2) ) a-wave IT was 13.2-14.7?ms with a-wave AMP of 68.4-144?μV; the b-wave IT was 28.7-41.5?ms with b-wave AMP of 105.7-271.5?μV; and the b/a ratio was 0.95-2.71. The high-intensity (10?000?mcd?s/m(2) ) average recordings showed an a-wave IT of 13-14.9?ms, a-wave AMP of 85.7-186.8?μV; b-wave IT of 26.6-45.4?ms, b-wave AMP of 104.7-250.6?μV; and a b/a wave ratio of 0.7-2.0. The 30-Hz cone flicker showed an IT of 22.8-28.9?ms and AMP of 44.1-117.1?μV. Conclusions Results of normal thoroughbred ERG responses are reported. The protocol proved to be simple and safe and provided consistent results.