Effects of three antagonists on selected pharmacodynamic effects of sublingually administered detomidine in the horse

ObjectiveTo describe the effects of alpha₂-adrenergic receptor antagonists on the pharmacodynamics of sublingual (SL) detomidine in the horse.Study designRandomized crossover design.AnimalsNine healthy adult horses with an average age of 7.6 ± 6.5 years.MethodsFour treatment groups were studied: 1) 0.04 mg kg^?1 detomidine SL; 2) 0.04 mg kg^?1 detomidine SL followed 1 hour later by 0.075 mg kg^?1 yohimbine intravenously (IV); 3) 0.04 mg kg^?1 detomidine SL followed 1 hour later by 4 mg kg^?1 tolazoline IV; and 4) 0.04 mg kg^?1 detomidine SL followed 1 hour later by 0.12 mg kg^?1 atipamezole IV. Each horse received all treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for yohimbine, atipamezole and tolazoline concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume (PCV) and plasma proteins were monitored.ResultsChin-to-ground distance increased following administration of the antagonists, however, this effect was transient, with a return to pre-reversal values as early as 1 hour. Detomidine induced bradycardia and increased incidence of atrioventricular blocks were either transiently or incompletely antagonized by all antagonists. PCV and glucose concentrations increased with tolazoline administration, and atipamezole subjectively increased urination frequency but not volume.Conclusions and clinical relevanceAt the doses administered in this study, the alpha₂-adrenergic antagonistic effects of tolazoline, yohimbine and atipamezole on cardiac and behavioral effects elicited by SL administration of detomidine are transient and incomplete.     

Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine,medetomidine, and dexmedetomidine in the horse: a population analysis

The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α₂‐adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half‐maximal effect (IC₅₀) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data.     

Cardiovascular effects of halothane in the horse

Cardiovascular effects of venous alveolar concentrations of halothane in oxygen were studied in 8 young, healthy horses under conditions of constant arterial carbon dioxide tension. The alveolar concentration of halothane was expressed as a multiple of the minimal alveolar concentration (MAC) which was known for each animal. Increasing alveolar halothane concentrations to MAC 2.0 resulted in a progressive and significant (P less than 0.05) decline in systemic arterial pressure and left ventricular work. Cardiac output decreased between MAC 1.0 and MAC 2.0 as a result of a significant (P less than 0.05) decrease in stroke volume. Heart rate, total peripheral resistance, pulmonary artery pressure, hematocrit, plasma protein concentration, arterial oxygen tension, and arterial pH remained constant over the same range of anesthetic dosages. Continuation of anesthesia, spontaneous ventilation, and the accompanying rise in arterial carbon dioxide tension and electrical stimulation of the horse's oral mucous membranes produced varying degrees of stimulation of cardiovascular function at MAC 1.5.     

Cardiopulmonary effects of clenbuterol in the horse

Clenbuterol, a bronchospasmolytic agent (β₂ agonist) was studied in terms of its hemodynamic and airflow response in eight, healthy horses. Four animals were instrumented to record intrapleural pressure and air flow, these were used to compute pulmonary resistance, peak flow rates, and tidal volumes. Four animals were instrumented to record pulmonary arterial pressure, carotid arterial pressure, cardiac output, and arterial gas tensions. After control values were recorded, clenbuterol (0.8 μg/kg) was intravenously administered to each horse in each experiment group.
Following clenbuterol administration, non-elastic resistance of the lung or pulmonary resistance significantly decreased, 33.6% reduction at 10 min post-clenbuterol. Pulmonary resistance remained lowered during the entire procedure and showed no tendency of returning toward control values by 3 h post-clenbuterol. Within 30 sec following clenbuterol injection carotid arterial pressure decreased (mean pressure decrease 28.2%). Accompanying the change in arterial pressure, the heart rate drastically increased, 99.0%. Both changes were transient and returned to control ranges within 2 min.
Clenbuterol appears to be effective in reducing non-elastic resistance of the lung, however intravenous administration to an animal with pre-existing cardiovascular or cardiopulmonary disease should be avoided.     

Doxapram: cardiopulmonary effects in the horse

The cardiopulmonary effects of 3 dosages of doxapram hydrochloride (0.275 mg/kg, 0.55 mg/kg, and 1.1 mg/kg, IV) were studied in 6 adult horses. Doxapram given IV significantly (P less than 0.05) decreased PaCO2 and increased respiratory rate, cardiac output arterial blood pressures (systolic, mean, and diastolic) arterial pH, and PaO2 at 1 minute after each dose was administered. Heart rate and mean and diastolic pulmonary arterial blood pressure were significantly (P less than 0.05) increased 1 minute after the 2 larger dosages of doxapram were given (0.55 mg/kg and 1.1 mg/kg, IV), but not after the smallest dosage was given. All measurements, except heart rate and cardiac output, had returned to base line by 5 minutes after each dosing. Heart rate remained significantly (P less than 0.05) increased 10 minutes after the 0.55 mg/kg dosage was given and 30 minutes after the 1.1 mg/kg dosage. Cardiac output remained significantly (P less than 0.05) increased at 10 minutes, 5 minutes, and 30 minutes after the 0.275, 0.55, and 1.1 mg/kg dosages, respectively, were given.     

Cardiovascular effects of romifidine in the standing horse

The cardiovascular effects of romifidine, an alpha-2 adrenoreceptor agonist, were investigated in six horses using two doses (80 and 120 microg kg(-1)) in a cross-over study design. Cardiac index and mixed venous oxygenation were significantly decreased at 15 and 30 minutes after both doses of romifidine. Systemic vascular resistance was significantly increased with romifidine (120 microg kg(-1)). Arterial blood pressure increased initially and then gradually decreased; the doses of decrease was significant at 90 and 120 minutes with romifidine 80 and 120 microg kg(-1). There were minimal differences between the two doses of romifidine, and both should be used with care especially in horses with cardiovascular compromise, or when used in combination with other cardiovascular depressant drugs.     

Some unusual cases of abnormal respiratory noises in the horse

Extract

Any condition which leads to a diminution in the size or alteration of the shape of the lumen of the respiratory tract in the horse may result in the production of abnormal respiratory noises at exercise.     

Cardiopulmonary effects of epidurally administered xylazine in the horse

This study was designed to determine whether the epidural administration of an alpha2 agonist, xylazine, would produce measurable changes in arterial blood pressure, electrocardiographic (ECG) activity and arterial blood gas values in horses. Six horses were given each of four treatments: epidural xylazine, intravenous xylazine, epidural lidocaine and epidural saline. A carotid artery catheter was used to measure arterial blood pressure and to collect samples for blood gas analysis before treatment and at intervals post treatment. Heart rate, arterial pressures, ECG activity and respiratory rate were recorded at the same intervals. No significant changes were recorded between time intervals or between individual treatments. It was concluded that this method of xylazine administration to horses produced potent caudal analgesia without measurable cardiopulmonary effects.     

Cardiovascular and pharmacokinetic effects of isoxsuprine in the horse

Isoxsuprine (0.6 mg/kg) administered IV to 6 standing horses produced substantial, transient decreases in systemic blood pressure, systemic vascular resistance, and stroke volume. It also produced substantial, transient increases in heart rate, cardiac output, and purposeful movement. Plasma concentrations of isoxsuprine peaked soon after the drug was administered IV and then decreased over a 12-hour period in a biexponential manner, with distribution and elimination half-lives of 14 minutes and 2.67 hours, respectively. Total body clearance and steady-state volume of distribution were calculated to be 53.8 ml/min/kg and 10.5 L/kg, respectively. When a recommended therapeutic dosage regimen (0.6 mg/kg 2 times a day, per os) was used in 4 of these horses, changes were not detected. Isoxsuprine was not detected in plasma after the drug was given orally. We conclude that 0.6 mg of isoxsuprine/kg given orally every 12 hours is not likely to produce cardiovascular changes in the resting horse and that this is probably because plasma concentrations are not high enough to do so.     

Oral and intravenous administration of nimesulide in the horse: rational dosage regimen from pharmacokinetic and pharmacodynamic data

REASONS FOR PERFORMING STUDY: The selective COX-2-inhibitor nimesulide is used extra-label in equine veterinary practice as an anti-inflammatory agent. However, there are no data on which to base the rational use of the drug in this species. OBJECTIVES: To determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule. METHODS: The pharmacokinetics of nimesulide in the horse after oral administration (1 mg/kg bwt), and oral and i.v. administration (1.5 mg/kg bwt) were investigated, effects of feeding status on bioavailability determined, and plasma protein binding of the drug and its principal metabolites measured. Compartmental and noncompartmental pharmacokinetic analyses were performed. The plasma concentration-time profile was used, together with in vitro literature data on nimesulide inhibition of COX isoforms, to determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule. RESULTS AND CONCLUSIONS: The findings suggest that 1.5 mg/kg bwt may produce adequate clinical effects, and the dosing interval should be 12-24 h depending on condition severity. However, at that dose, the concentration in the animal exceeds the in vitro IC50 for both isoforms, so that COX-1/COX-2 selectivity is lost and side-effects due to COX-1 inhibition are a possibility. Nimesulide should therefore be used with caution in equine clinical practice.