Effects of medetomidine on intestinal and colonic motility in the dog

The motor responses of the jejunum and colon to stimulation of α₂-adrenoceptors by medetomidine and clonidine were investigated in four dogs. In fasting dogs, medetomidine, at a dose rate of 30 μg/kg i.v., disrupted the migrating myoelectric complex (MMC) pattern of the small intestine for about 2 h. Similar, but shorter-lasting effects were also induced by clonidine (30 μg/kg i.v.) on the jejunum. The administration of α₂-agonists inhibited colonic motility in fasting dogs, although medetomidine-induced inhibition was preceded by a short period of increased muscle tone. All these effects were reversed by the α₂-antagonists atipamezole (0.15 mg/kg i.v.) and yohimbine (0.20 mg/kg i.v.). In fed dogs, medetomidine (30 μg/kg i.v.) induced a strong increase of the tone on the proximal colon, while the activity of the medium and distal colon was completely suppressed. Yohimbine (0.50 mg/kg i.v.) immediately restored the activity of the colon and induced a propagated giant contraction and defaecation by the animal. These data confirm the importance of a₂-adrenergic receptors in the control of intestinal and colonic motility in the dog.     

Radioreceptor assay for determination of xylazine and medetomidine in sheep plasma

A radioreceptor assay technique is described for the measurement of xylazine and medetomidine in sheep plasma. The assay was based on the displacement of tritiated clonidine from a 2-adrenoceptors in a rat brain homogenate by xylazine or medetomidine extracted from plasma. Plasma samples from sheep which had been given xylazine and medetomidine were treated with alumina to remove endogenous catecholamines which would otherwise have bound to α₂-_- adrenoceptors and interfered with the assay. The drugs were then extracted using chloroform, reconstituted in buffer and used to displace [³H]clonidine. The concentration of α₂-agonist was calculated by reference to standard curves. The method had a detection limit of 2.5 ng/mL for xylazine and 0.24 ng/mL for medetomidine. The assay could also be used to detect metabolites capable of binding to α₂-receptors.     

Affinity of detomidine, medetomidine and xylazine for alpha-2 adrenergic receptor subtypes

α₂-Adrenergic receptor agonists are widely used in veterinary medicine as sedative/hypnotic agents. Four pharmacological subtypes of the α₂-adrenergic receptor (A, B, C and D) have been identified based primarily on differences in affinity for several drugs. The purpose of this study was to examine the affinities of the sedative agents, xylazine, detomidine and medetomidine at the four α₂-adrenergic receptor subtypes. Saturation and inhibition binding curves were performed in membranes of tissues containing only one subtype of a₂-adrenergic receptor. The K_D for the α₂-adrenergic receptor radioligand, [³H]-MK-912, in HT29 cells (α_2A-), neonatal rat lung (α_2B-), OK cells (α_2C-) and PC12 cells transfected with RG20 (α_2D-) were 0.38 ± 0.08 n m , 0.70 ± 0.5 n m , 0.07 ± 0.02 n m and 0.87 ± 0.03 n m , respectively. Detomidine and medetomidine had approximately a 100 fold higher affinity for all the α₂-adrenergic receptors compared to xylazine but neither agonist displayed selectivity for the α₂-adrenergic receptor subtypes. These data suggest that available sedative/hypnotic α₂-adrenergic receptor agonists can not discriminate between the four known α₂-adrenergic receptor subtypes.     

The actions of medetomidine may not be mediated exclusively by α2-adrenoceptors in the equine saphenous vein

Spirals of endothelially denuded equine saphenous vein were used to study the pre- and post-junctional effects of medetomidine in vitro . The pD₂ values were calculated for noradrenaline (6.7 /pm 0.1), phenylephrine (5.6 /pm 0.1), BHT 920 (6.2 /pm 0.2) and UK 14304 (5.7 /pm 0.2). Medetomidine produced a biphasic response, with a pD₂1 of 8.2 /pm 0.1 and a pD₂2 of 5.7 /pm 0.1 in the equine saphenous vein ( n = 6 ). Prazosin (10⁻⁷ m) significantly shifted the second phase of the medetomidine concentration-response curve to the right (pD₂1 was 8.1 /pm 0.2 and pD₂2 was 5.0 /pm 0.2, P < 0.05). Rings of equine saphenous vein were electrically stimulated to investigate the pre-junctional effects of medetomidine. Increasing concentrations of the α₂-adrenoceptor agonist BHT 920 reduced the response to electrical stimulation in a concentration dependent manner to a maximum of 40 /pm 5%. whereas medetomidine (0.1-100 nm) caused a concentration dependent enhancement to a maximum of 490 /pm 150%. These results suggest α₁- and α₂-adrenoceptors are functional in the equine saphenous vein, but that medetomidine is not acting exclusively as an α₂-adrenoceptor agonist.     

Single dose pharmacokinetics of medetomidine in sheep

The pharmacokinetics of medetomidine hydrochloride (Domitor) administered at a single dose of 15 μg/kg IV in sheep are described. Plasma medetomidine concentrations were determined using a sensitive radioreceptor assay technique, capable of also measuring metabolites which would bind to α₂ adrenergic receptors. Medetomidine was rapidly distributed, with a half-life of distribution of 4.65/pm0.65 min. The apparent volume of distribution was 2.69/pm0.62 L/kg, while elimination half-life was 37.85/pm2.84 min. Total body clearance varied between 16.29 and 151.81 mL/min.kg. Pharmacological effects of medetomidine paralleled its plasma concentration.     

Atipamezole increases medetomidine clearance in the dog: an agonist—antagonist interaction

Medetomidine, an α₂-adrenoceptor agonist, is a potent sedative and analgesic agent in the dog. When necessary, its action can be effectively antagonized by atipamezole. The present work was designed to study the effects of these drugs on each others' pharmacokinetics when a single intramuscular dose of medetomidine (50 μg kg^-1) was followed by a dose of atipamezole (250 μg kg^-1). Three different treatments were used: medetomidine alone, atipamezole alone, and atipamezole after medetomidine. Drug concentrations in plasma were measured by GC-MS. Statistical analysis of the results (anova) revealed significant differences between treatments in the kinetic parameters of medetomidine. Atipamezole decreased the AUC of medetomidine from 41.3 to 28.6 ng h ml"¹(P = 0.005), t_1/4 from 1.44 to 0.87 h ( P = 0.015), and increased Cl from 21 to 31 ml min^-1kg^-1(P = 0.017). Differences in V₂ did not reach statistical significance. The only statistically significant effects of medetomidine on the pharmacokinetics of atipamezole in this study were the slight decrease of Cl and C _max as well as the increase of AUC . It is suggested that the large dose of medetomidine used caused haemodynamic changes, resulting in decreased hepatic circulation and slower drug metabolism. Antagonism by atipamezole restored the hepatic blood flow and, consequently, increased the elimination of medetomidine by biotransformation.     

Seizures during medetomindine sedation and local anaesthesia in two dogs undergoing skin biopsy

Each of two dogs presented for multiple skin biopsies were sedated with intravenous medetomidine and lignocaine was injected subcutaneously to provide local anaesthesia for skin biopsy. One dog had a seizure during skin biopsy and again immediately following reversal of medetomidine with atipamezole. The other dog developed seizures 2 h following skin biopsy at which time the medetomidine was reversed with atipamezole. Both dogs were neurologically normal with no history of seizures prior to the procedure and remained neurologically normal for 14 weeks and 9 months, respectively, following the procedure. A drug interaction between the α₂-adrenergic agonist medetomidine and lignocaine is suspected and highlights the potential for seizures following the subcutaneous administration of relatively large doses of lignocaine under medetomidine sedation.     

The effect of xylazine on plasma thromboxane B2 concentration in sheep

α₂-adrenoceptor agonist drugs can cause respiratory changes leading to a short period of hypoxaemia in sheep. It has been suggested that this is due to transient platelet aggregation and pulmonary microembolism. If platelet aggregation were to follow platelet activation in response to the administration of α₂ agonists, plasma thromboxane levels would be expected to rise. This study was carried out to measure plasma thromboxane B₂ concentrations before and after the intravenous administration of the α₂-agonist drug xylazine at a dose of 0.1 mg/kg. It was found that the plasma thromboxane concentration rose by 320% and, furthermore, the rise was prevented by the prior administration of atipamezole hydrochloride (0.125 mg/kg), an α₂-adrenoceptor antagonist.     

The effect of medetomidine premedication upon propofol induction and infusion anaesthesia in the dog

The effect of premedication with four different intramuscular doses of medetomidine (5.0,10.0, 20.0 and 40.0 μg.kg-¹) and a saline placebo were compared in a group of six adult beagle dogs anaesthetised with propofol on five separate occasions. Anaesthesia was induced 30 minutes after premedication and maintained by intravenous injection and continuous infusion of propofol. The effects of medetomidine were reversed with atipamezole 30 minutes after anaesthetic induction. The marked synergistic effects of medetomidine with propofol were demonstrated by a dose related reduction in the induction and infusion requirements for a similar degree of anaesthesia. The effect appeared exponential in nature; lower medetomidine doses produced a disproportionately greater effect.
The maintenance of anaesthesia with propofol following a saline placebo or low doses of medetomidine proved to be difficult. Higher doses of medetomidine required less propofol for induction and infusion and allowed a more stable anaesthesia to be maintained. Propofol produced no statistically significant change in heart rate during infusion. Changes in respiratory rate were markedly group specific. A significant reduction in respiratory rate was seen in dogs given either 5 μg.kg- or 10 μ-g.kg-¹ medetomidine. No change was recorded in dogs given 20 /μg.kg-¹ medetomidine and a significant increase was seen in dogs given 40 μg.kg-¹ medetomidine. Recovery was monitored following the termination of propofol infusion after the reversal of medetomidine using atipamezole at five times the medetomidine dose. Recovery was slower for dogs given lower doses of medetomidine and consequently higher doses of propofol.     

Reversal of medetomidine-induced sedation in reindeer (Rangifer tarandus tarandus) with atipamezole increases the medetomidine concentration in plasma

The pharmacokinetics of two potent α₂-adrenoceptor agents that can be used for immobilization (medetomidine) and reversal (atipamezole) of the sedation in mammals, were studied in three reindeer ( Rangifer tarandus tarandus) in winter and again in summer. Medetomidine (60 μg/kg) was injected intravenously (i.v.), followed by atipamezole (300 μg/kg) intravenously 60 min later. Drug concentrations in plasma were measured by HPLC. The administration of atipamezole resulted in an immediate 2.5–3.5 fold increase in the medetomidine concentration in plasma. Clearance for medetomidine (median 19.3 mL/min·kg) was lower than clearance for atipamezole (median 31.0 mL/min·kg). The median elimination half-lives of medetomidine and atipamezole in plasma were 76.1 and 59.9 min, respectively. The animals became resedated 0.5–1 h after the reversal with atipamezole. Resedation may be explained by the longer elimination half-life of medetomidine compared to atipamezole.     

The effect of xylazine on the isolated sheep trachea

The effect of xylazine on the isolated sheep trachea and its possible interactions with the α₂-adrenergic antagonist, atipamezole, and the anticholinergic agent, atropine, was studied. The mechanical responses of the tracheal preparations were recorded after exposing each one to cumulatively increasing concentrations of xylazine alone or in the presence of atipamezole or atropine.
Xylazine exerted a concentration-dependent contractile effect, with a threshold concentration of 10^--⁷M while the maximum activity was produced at a concentration of 10^--⁵M (EC₅₀= 2.3 × 10^--⁷). This xylazine-induced contractile effect was inhibited by atipamezole, but not significantly modified by atropine. Thus, it is concluded that α₂-adrenoceptors exist in the sheep trachea and it is suggested that α₂-adrenoceptor agonists may act on airways in sheep directly through stimulation of peripheral α₂-adrenergic receptors and indirectly via central α₂-adrenergic receptor activation of parasympathetic tone.     

Gastro-intestinal motor disturbances induced by lysine-acetylsalicylate treatment in sheep

The effects of intravenous (i.v.), intramuscular (i.m.) and oral administration of lysine-acetylsalicylate (Lys-ASA) on gastro-intestinal motility were investigated in sheep using electromyography. A dose of 20 mg/kg Lys-ASA intravenously reduced the frequency of reticular contractions for 86 ± 18 min, produced abomasal hypomotility and caused a disruption of the cyclical pattern of intestinal motility for at least 120 min. The frequency of reticular contractions measured from 20 to 30 min after Lys-ASA administration was negatively correlated (ß= 0.97; PΔ0.01) to the log of the dose used for doses varying from 10 to 40 mg/kg. Similar effects were observed with intramuscular and oral dose rates of 40 and 80 mg/kg, respectively. Previous i.v. administration of phentolamine (0.1 mg/kg) or tolazoline (2 mg/kg) abolished the effects of Lys-ASA (20 mg/kg) administered intravenously on both reticular contractions and abomaso-intestinal motility.
It was concluded that Lys-ASA administered at therapeutic doses in sheep produced gastro-intestinal motor disturbances and that α-and α₂-adrenergic antagonists are able to block them.     

The effects of medetomidine hydrochloride on the electroretinogram of normal dogs

Purpose  To determine the effects of a standardized intravenous dose of an α-2 agonist (Domitor^®, Orion Pharma, distributed by Pfizer Animal Health, Exton, PA) on the electroretinogram (ERG) response in normal dogs.
Methods  Twenty-five normal dogs were used to collect ERG responses including a- and b-wave implicit times (IT) and amplitudes (AMP) before and after administration of medetomidine. Dogs were dark adapted for 20 min and ERGs were obtained using the HMsERG (RetVetCorp Inc., Columbia, MO). The QuickRetCheck protocol (Narfström) was employed to provide the following flash intensities: 10 mcd s/m², 3 cd s/m², and 10 cd s/m². ERGs were repeated after 375 µg/m² of medetomidine intravenously. Statistical analysis of the difference between the responses before and after medetomidine at all flash intensities was performed using a mixed effects model for anova .
Results  The P value for the effect of medetomidine on each of the ERG responses was < 0.01. The estimates of the effect of medetomidine were (+)1.35 ms, (–)23 µV, (+)3.16 ms, and (–)47 µV for the a-wave IT, a-wave AMP, b-wave IT, and the b-wave AMP, respectively.
Conclusions  Medetomidine significantly prolongs the implicit time and lowers the amplitude response of both the a- and b-waves in normal dogs at all flash intensities examined. Clinically, however, medetomidine only minimally affects the retinal responses and is a viable choice for use in dog ERGs.     

Neurohormonal and metabolic effects of medetomidine compared with xylazine in beagle dogs

This study was aimed to investigate and compare the effects of medetomidine and xylazine on the blood level of some stress-related neurohormonal and metabolic variables in clinically normal dogs, especially focusing on time and dose relations of the effects. A total of 9 beagle dogs were used for 9 groups, which were treated with physiological saline solution (control), 10, 20, 40, and 80 μg/kg medetomidine, and 1, 2, 4, and 8 mg/kg xylazine, intramuscularly. Blood samples were taken at 10 times during 24 h from a central venous catheter. Plasma norepinephrine, epinephrine, cortisol, glucose, insulin, glucagon, and non-esterified fatty acid concentrations were determined. Both medetomidine and xylazine similarly and dose-dependently inhibited norepinephrine release and lipolysis. Medetomidine suppressed epinephrine release dose-dependently with greater potency than xylazine. Xylazine also tended to decrease epinephrine levels dose-dependently. The cortisol and glucagon levels did not change significantly in any treatment group. Both drugs suppressed insulin secretion with similar potency. Both medetomidine and xylazine increased glucose levels. The hyperglycemic effect of medetomidine, in contrast with xylazine, was not dose-dependent at the tested dosages. The results suggested that the effect of medetomidine on glucose metabolism may not be due only to α₂-adrenoceptor-mediated actions.     

Pharmacokinetics and tissue residues of norfloxacin and its N-desethyl- and oxo-metabolites in healthy pigs

The pharmacokinetic properties of norfloxacin were determined in healthy pigs after single intramuscular (i.m.) and intravenous (i.v.) dosage of 8 mg/kg body weight After i.m. and i.v. administration, the plasma concentration-time graph was characteristic of a two-compartment open model. After single i.m. administration, norfloxacin was absorbed rapidly, with a t _max of 1.46 ± 0.06 h. The elimination half-life ( t _1/2β) and the mean residence time of norfloxacin in plasma were 4.99 ± 0.28 and 6.05 ± 0.22 h, respectively, after i.m. administration and 3.65 ± 0.16 and 3.34 ± 0.16 h, respectively, after i.v. administration. Intramuscular bioavailability was found to be 53.7 ± 4.4%. Plasma concentrations greater than 0.2 μg/mL were achieved at 20 min and persisted up to 8 h post-administration. Maximal plasma concentration was 1.11 ± 0.03 μg/mL. Statistically significant differences between the two routes of administration were found for the half-lives of both distribution and elimination phases ( t _1/2α, t _1/2β) and apparent volume of distribution (V_d(area)). In pigs, norfloxacin was mainly converted to desethylenenorfloxacln and oxonorfloxacin. Considerable tissue concentrations of norfloxacin, desethylenenorfloxacin, and oxonorfloxacin were found when norfloxacin was administered intramuscularly (8 mg/kg on 4 consecutive days). The concentration of the parent fluoroquinolone in liver and kidney ranged between 0.015 and 0.017 μg/g on day 12 after the end of dosing.     

Cardiopulmonary effects of clonidine, diazepam and the peripheral α2 adrenoceptor agonist ST-91 in conscious sheep

The cardiopulmonary effects of the intravenous administration of clonidine (15 μg/kg), ST-91 (30 μg/kg) and diazepam (0.4 mg/kg) were compared in five healthy sheep using a randomized cross-over design, to determine whether the hypoxaemic effects of α₂ adrenoceptor agonists are due to sedation, or to peripheral α₂ adrenoceptor stimulation. All three drugs significantly lowered arterial oxygen tension (PaO₂) levels within 2 min of their administration; however, clonidine and ST-91 produced long lasting and severe hypoxaemia with mean PaO₂ levels of ≈40 mm Hg and 50 mm Hg (5.3 kPa and 6.6 kPa), respectively. The fall in PaO₂ was considerably less with diazepam (63 mm Hg or 8.4 kPa at 2 min) and by 15 min the values did not differ from placebo treated animals. None of the drugs increased arterial carbon dioxide tension (PaCO₂) levels when compared to saline treatment and the acid base variables did not show any significant change. A significant increase was recorded in the packed cell volume of the ST-91 treated group throughout the study. Within 2 min of their administration, all drugs caused a significant increase in mean arterial pressure (MAP) as compared to the placebo treated group. The MAP remained significantly increased for 5 and 60 min after clonidine and ST-91 treatment, respectively. The study shows that ST-91 and clonidine produce a greater degree of hypoxaemia than occurs with diazepam sedation, and that the hypoxaemic effect of α₂ adrenoceptor agonists in sheep are mainly mediated by peripheral α₂ adrenoceptors.     

Plasma and urine disposition and dose proportionality of ceftiofur and metabolites in dogs after subcutaneous administration of ceftiofur sodium

Nine male dogs (10.3–13.5 kg body weight) were randomly assigned to three groups of three dogs each and administered ceftiofur sodium subcutaneously as a single dose of 0.22, 2.2, or 4.4 mg ceftiofur free acid equivalents/kg body weight. Plasma and urine samples were collected serially for 72 h and assayed for ceftiofur and metabolites (derivatized to desfuroylceftiofur acetamide) using high-performance liquid chromatography. Urine concentrations remained above the MIC ₉₀ for Escherichia coll (4.0 μg/mL) and Proteus mirabilis (1.0 μg/mL) for over 24 h after doses of 2.2 mg/kg (8.1 μg/mL) and 4.4 mg/kg (29.6 μg/mL), the interval between treatments for ceftiofur sodium in dogs, whereas urine concentrations 24 h after dosing at 0.22 mg/kg (0.1 mg/Ib) were below the MIC ₉₀ for E.coli and P. mirabills (0.6 μg/mL). Plasma concentrations were dose-proportional, with peak concentrations of 1.66 ± 0.0990 μg/mL, 8.91 ± 6.42 μg/mL, and 26.7 ± 1.07 μg/mL after doses of 0.22, 2.2, and 4.4 mg/kg, respectively. The area under the plasma concentration versus time curve, when normalized to dose, was similar across all dosage groups.     

Metoclopramide Reversal of Decreased Gastrointestinal Myoelectric and Contractile Activity in a Model of Canine Postoperative Ileus

Postoperative ileus is characterized by decreased gastrointestinal myoelectric activity and motility. Metoclopramide was used to treat experimentally induced postoperative ileus in six dogs. Contractile activity was monitored by extraluminal strain gages on the pyloric antrum and proximal segment of the duodenum, and myoelectric activity was measured by recording bipolar electromyograms (EMGs) at the pyloric antrum, pyloric canal, proximal segment of the duodenum, proximal and distal parts of the jejunum, and ileum. Measurements were obtained from animals without ileus (baseline) and those with ileus that were either untreated or treated with metoclopramide. Adynamic ileus was induced by rubbing a 50 cm segment of jejunum with a dry sponge for 5 minutes and exposing the bowel to the air for 30 minutes. Treated dogs received metoclopramide (0.4 mg/kg 4 times daily [QID] intravenously [IV]), whereas untreated dogs received a saline placebo, starting 1 hour after celiotomy closure. Recordings were made for 26 hours after induction of ileus. The phases of the migrating myoelectric complex (MMC) were identified and motility index values were determined. During ileus, the MMC phase II duration was increased at the duodenum and phase III duration was decreased at the antrum, pylorus, duodenum, and proximal segment of the jejunum (p less than 0.05). Motility index values were decreased at the antrum and duodenum during ileus (p less than 0.05). Treatment with metoclopramide reversed the MMC phase III inhibition at the antrum and pylorus, and partially reversed the inhibition at the duodenum and jejunum (p less than 0.05). Motility index values were restored to preoperative baseline values with metoclopramide treatment (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The α2-adrenoceptor agonists xylazine and guanfacine exert different central nervous system, but comparable peripheral effects in calves

Acute pharmacodynamic effects of the α₂-adrenoceptor agonists, xylazine and guanfacine, were investigated in nine healthy calves in an open crossover trial. Xylazine (100 μg/kg body weight intravenously (i.v.)) and guanfacine (20 μg/kg body weight i.v.) were equi-effective in lowering heart rate by 25–30% at 5 min. Under these conditions, xylazine induced strong sedation and increased plasma growth hormone levels, indicating central nervous system mediated actions, whereas guanfacine was not sedative and did not induce release of growth hormone. Oxygen consumption was decreased by both drugs, but respiratory exchange ratio decreased only in response to xylazine. However, in response to both drugs, plasma levels of noradrenaline, adrenaline, insulin and non esterified fatty acids decreased similarly and glucose increased comparably. These results demonstrate marked differences in the central nervous system-mediated effects of the two α₂-adrenoceptor agonists, whereas peripheral actions are similar.     

Xylazine-induced mydriasis: possible involvement of a central postsynaptic regulation of parasympathetic tone

Intravenous injection of xylazine (0.01 – 1 mg/kg) produced a dose-dependent mydriasis associated with a depression of tonic ciliary nerve activity in anesthetized cats. Xylazine-induced mydriasis was apparent in the sympathectomized iris but was absent in the parasympathectomized, physostigmine-treated iris. Epinephrine (30 μg/kg, i.v.) produced a slighdy greater mydriasis in the sympathectomized iris than in the parasympathectomized, physostigmine-treated iris. The α₂-adrenergic blocking agent, yohimbine (0.5 mg/kg, i.v.) antagonized the pupillary dilation and reversed the depression of ciliary nerve activity induced by xylazine administration.
In rats pretreated with reserpine (7.5 mg/kg, s.c., 20 h) and α-methyl-p-tyrosine (250 mg/kg, i.p., 5 h), intravenous injection of xylazine (0.01 – 1 mg/kg) resulted in mydriasis of similar magnitude as control animals. However, xylazine induced bradycardia in the control group but not in die pretreated animals.
The results suggest that pupillary dilation produced by i.v. xylazine is primarily die result of a central inhibition of parasympathetic tone to the iris. It also appears that xylazine produces this effect via postsynaptic α₂-adrenergic mechanisms, while it produces bradycardia through a presynaptic α₂-adrenergic mechanism.