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

OBJECTIVE: To describe the effects of alpha2 -adrenergic receptor antagonists on the pharmacodynamics of sublingual (SL) detomidine in the horse. STUDY DESIGN: Randomized crossover design. ANIMALS: Nine healthy adult horses with an average age of 7.6 ± 6.5 years. METHODS: Four 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. RESULTS: Chin-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 RELEVANCE: At 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.

Pharmacokinetics and pharmacodynamic effects of tolazoline following intravenous administration to horses.

Tolazoline is an α2-adrenergic receptor antagonist, used in veterinary medicine to antagonize the central nervous system depressant and cardiovascular effects of α2 receptor agonists. The pharmacokinetics and pharmacodynamic effects of tolazoline when administered subsequent to detomidine in the horse were recently reported, although the reversal of the sedative and cardiovascular effects following detomidine may not be complete. The current study therefore investigated the pharmacokinetics and pharmacodynamic effects of tolazoline when administered as a sole agent. Nine healthy adult horses were administered tolazoline (4mg/kgIV) and blood samples were collected at time 0 (prior to drug administration) and at various times up to 72h post drug administration. Plasma samples were analyzed using liquid chromatography-mass spectrometry and resulting data analyzed using compartmental analysis. Systemic clearance, steady state volume of distribution and terminal elimination half-life were 0.820±0.182L/h/kg, 1.68±0.379L/kg and 2.69±0.212h, respectively. Tolazoline administration had no effect on chin to ground distance, but the heart rate decreased (relative to baseline) and the percentage of atrial-ventricular block increased in all horses within 2min of administration. Packed cell volume and glucose concentrations were also increased throughout the sampling period. While not commonly used as a sole agent, caution is indicated whenever tolazoline is administered since the effects may be unpredictable.

Pharmacokinetics of xylazine, 2,6-dimethylaniline, and tolazoline in tissues from yearling cattle and milk from mature dairy cows after sedation with xylazine hydrochloride and reversal with tolazoline hydrochloride.

Xylazine hydrochloride was administered i.m. at 0.35 mg/kg to 13 steers and 10 lactating dairy cows at Time 0. Ten minutes later, tolazoline hydrochloride was given i.v. at 4 mg/kg. Tissue and milk samples were analyzed using gas chromatography with nitrogen and phosphorous detection to determine concentrations of xylazine, 2,6-dimethylaniline (a toxic metabolite of xylazine), and tolazoline (at various intervals). Concentrations of xylazine and 2,6- dimethylaniline were below the limit of quantitation (10 microg/kg) by 72 hours in tissues and 12 hours in milk. The concentration of tolazoline was below 10 microg/kg by 96 hours in tissues and 48 hours in milk. Based on the results of these residue studies submitted by the sponsoring agency to the Ministry of Agriculture and Forestry in New Zealand, withholding periods for both xylazine hydrochloride and tolazoline hydrochloride injection were established.

Endotracheal tolazoline: pharmacokinetics and pharmacodynamics in dogs.

Tolazoline is a potent vasodilator of both arteries and veins and has a powerful effect on the pulmonary vasculature, reducing hypoxic pulmonary vasoconstriction and lowering pulmonary artery pressure. Intravenous tolazoline lowers the mean pulmonary arterial pressure and resistance and increases the cardiac index when given to infants with persistent pulmonary hypertension of the newborn (PPHN). Endotracheally administered tolazoline decreases mean pulmonary arterial pressure and pulmonary vascular resistance, and improves oxygenation without the harmful decline in systemic arterial pressure. The purpose of our study was to examine the pharmacokinetic and pharmacodynamic characteristics of endotracheal tolazoline in order to determine the relationship between endotracheal tolazoline administration, plasma concentration and its effects on the cardiovascular and respiratory systems. Tolazoline was administered endotracheally to 7 newborn dogs, and its serum concentration and the haemodynamic parameters were monitored for 270 min post-delivery. Results are expressed as median and quartiles. It was found that 15 s after dosing, tolazoline plasma concentrations started to increase significantly above baseline levels, reaching a maximum of 2.64 (1.36; 13.16) microg/ml. The extent of tolazoline absorption was 305 (148;453) microg/ min/ml. The volume of distribution was 3.4 (1.6;7.4) 1/kg. The total body clearance was 12.1 (10.9;23.9) ml/min/kg and the elimination half-life was 225 (171;303) min. Endotracheal tolazoline produced an initial short-lived decrease in mean blood pressure in all the dogs, but thereafter the blood pressure increased gradually above baseline levels. Immediately following endotracheal tolazoline significant tachycardia developed, peaking at 90 min. Subsequently, the heart rate gradually decreased and stabilized at values above baseline for 200 min. A single endotracheal dose of tolazoline is effectively absorbed and produces measurable pharmacological effects. Determining the optimal endotracheal dose of tolazoline in the clinical setting requires additional evaluation.

Isotachophoretic determination of bisoprolol, clonidine, disopyramide and tolazoline in human fluids.

Separation and determination of bisoprolol, clonidine, disopyramide and tolazoline in control serum and in human urine was investigated by capillary isotachophoresis. The drugs were separated by using the cationic electrolyte system. viz., sodium acetate buffer (pH 4.64) (c1 = 10 mM)-beta-alanine. The compounds were almost totally isolated from serum by solid-phase extraction using a Sep-Pak C18 cartridge. The recovery of compounds varied from 87 to 99%. The linear calibration range was studied to apply the method to real human fluids. The limit of determination of the drugs was 40.0 micrograms/ml serum. The limit of determination by direct sampling for bisoprolol is 3 micrograms/ml urine.

Treatment of persistent fetal circulation syndrome of the newborn. Comparison of different doses of tolazoline.

The effects of two doses of tolazoline have been compared in 2 groups of newborns suffering from the persistent fetal circulation syndrome. The effects on PaO2 and AaDO2 were similar in the 2 groups who received either a bolus of 1 or 0.5 mg X kg-1 tolazoline, followed by a continuous infusion of 1 or 0.5 mg X kg-1 X h-1. The observed changes did not differ significantly from those previously observed in babies treated with 2 mg X kg-1. A rise in PaO2 and a reduction in AaDO2 were usually observed shortly after the bolus injection and at plasma levels between 1.5 and 4 micrograms X ml X -1. A progressive rise in plasma level over time occurred after 1 mg X kg-1 (and in the previous study of 2 mg) but not with 0.5 g/kg tolazoline. The elimination half-life of tolazoline in 6 patients was 5 to 13 h. The data suggest that continuous infusion of tolazoline is not necessarily required and that the dose of 0.5 mg/kg is more appropriate and safer than the higher doses usually proposed.

Quantitative determination of tolazoline in human serum by high performance liquid chromatography.

A micro high performance liquid chromatography assay is reported for the measurement of tolazoline in newborn infants. Pharmacokinetic data are presented for a single infant receiving tolazoline therapy. Tolazoline and the internal standard, clonidine, are extracted from alkaline serum into butylchloride/isopropanol (95/5). The organic layer is then back extracted with 50 mM phosphoric acid. A portion of the phosphoric acid layer is injected onto a 15-cm CN-bonded phase column. A mobile phase consisting of acetonitrile and phosphate buffer (pH 3) is used to elute tolazoline and the internal standard in less than 5 min. The effluent is monitored with a fixed wavelength detector at 214 nm. Using 50 microliters of serum, concentrations as low as 0.25 mg/L can be routinely determined with a coefficient of variation (CV) of 7.2%. However, when a 100-microliters sample is used, and the injection volume increased, a concentration of 0.05 mg/L can be routinely monitored with a CV of 1.2%. Interference from other drugs that are often used concurrently with tolazoline therapy was not observed.

Oliguria and tolazoline pharmacokinetics in the newborn.

Tolazoline treatment of neonates has been reported since 1965. Dosages increased from pulse doses of 1 to 2 mg/kg to continuous infusions of 10 mg/kg X h before neonatal plasma tolazoline concentrations were measured. We developed a microassay for tolazoline and determined neonatal distribution volume, 1.61 +/- 0.21 L/kg, and disposition rate constant (beta), 0.0027 +/- 0.005 min-1 (mean +/- SEM). Half-life (gamma) ranged from 1.47 to 41.25 (median = 4.43) hours and correlated inversely with urine output (x); y (h) = -0.46 + 7.63/x (mL/kg X h), r = .61, P less than .05. The highest plasma tolazoline concentration in a neonate was 20.3 mg/L. Lethal tolazoline concentrations in lambs ranged from 21.8 to 56.8 mg/L. Initial tolazoline concentrations during infusions and after 1- to 2-mg/kg pulse doses ranged from 0.35 to 2.3 mg/L and PaO2 increased greater than or equal to 15 mm Hg in 64% of 14 treatments. The average neonatal pharmacokinetics predict that each 1 mg of tolazoline HCl per kilogram pulse dose will increase the plasma concentration of tolazoline base by 0.5 mg/L. The plasma concentration should remain constant with infusion dose increments of 0.16 mg of tolazoline HCl per kilogram per hour for every 1.0-mg/kg loading dose. Tolazoline dose requirements for specific patients will vary, especially with renal dysfunction. Reduced tolazoline doses were used to treat two patients, concentrations remained constant, and PaO2 was maintained. Tolazoline doses derived from neonatal kinetics are less than current infusion doses and may avoid high concentrations.

Quantitative determination of tolazoline in serum and urine.

A high-performance liquid chromatographic procedure is described for the analysis of tolazoline in serum and urine. This assay procedure is suitable for the analysis of micro-samples (50 or 100 microliters serum and 100 microliters urine). Samples are extracted in a single step and injected into a reversed-phase high-performance liquid chromatography system for detection at 210 nm. The clinical applicability of this assay is demonstrated by the determination of tolazoline serum and urine concentrations in neonates. In addition, the presence of urine conjugates and the extent of serum protein binding were investigated. This assay procedure has the required sensitivity (0.1 microgram/ml), accuracy and precision for both routine monitoring and pharmacokinetic characterization of tolazoline in neonates and adults.

Tolazoline pharmacokinetics in lambs.

Tolazoline has often been administered experimentally to lambs without consideration of its pharmacokinetics. We have used a chemically specific assay to determine tolazoline pharmacokinetic parameters in lambs after pulse and infusion doses: alpha = 0.184 +/- 0.046 (min-1), beta = 0.010 (pulse) and 0.0098 (infusion) +/- 0.0010 (min-1), Vdarea = 2534 +/- 688 ml/kg (pulse), and Vdss = 2890 +/- 342 ml/kg (infusion). The following doses can be used to reach steady-state plasma tolazoline concentrations: loading dose (microgram/kg) = 2890 X desired concentration (microgram/ml); infusion rate (microgram/kg X min) = 2890 (.010) X desired concentration (microgram/ml). These doses were used to produce 68 steady-state concentrations from 0.25 to 10.0 micrograms/ml. Clearances at steady state averaged 166 ml/min or 27.1 ml/min X kg at 2-17 days but increased markedly by 4 weeks of age. Using these doses, tolazoline-receptor interactions can be studied at constant plasma concentrations that approximate constant receptor concentrations.