Yi Fei Huang

Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep.

Commercially available bupivacaine is an equimolar mixture of R(+)-and S(-)-bupivacaine. S(-)-bupivacaine (i.e., levobupivacaine) is currently undergoing preclinical evaluation. Cross-over studies with IV levobupivacaine and bupivacaine were conducted in two groups of seven conscious sheep. Doses we

Systemic and regional pharmacokinetics of levobupivacaine and bupivacaine enantiomers in sheep

Commercially available bupivacaine is an equimolar mixture of R(+)-and S(-)-bupivacaine. S(-)-bupivacaine (levobupivacaine) is the subject of current clinical evaluation. We conducted partial cross-over systemic and regional pharmacokinetic studies of IV bupivacaine (12.5-200 mg) and levobupivacaine (6.25-200 mg) in ewes. Enantiospecific analysis of blood drug concentration-time data and of regional myocardial and brain drug mass balance data indicated that (a) there was a higher mean total body clearance of R(+)-bupivacaine than of S(-)-bupivacaine (as previously reported); (b) there were no differences in the systemic pharmacokinetics of S(-)-bupivacaine whether administered alone or as a component of bupivacaine; (c) there was no evidence of dose-dependent pharmacokinetics with either enantiomer; (d) for both enantiomers, mean calculated myocardial tissue concentrations of 1%-4% dose occurred between 3 and 5 min. Mean brain concentrations of 0.2%-1% dose occurred between 2 and 4 min after the administration of bupivacaine but between 4 and 5 min after the administration of levobupivacaine. There was no evidence that systemic toxicity induced by these local anesthetics significantly modified their pharmacokinetics, and there was no evidence of an enantiomer-enantiomer pharmacokinetic interaction for bupivacaine. Implications: Levobupivacaine comprises 50% of commercially available bupivacaine and is being considered for use in its own right. As a part of its preclinical evaluation, this study considered whether levobupivacaine behaved kinetically in the body in the same way as when administered as a component of bupivacaine. (Anesth Analg 1998;86:805-11)

The Hemodynamic Effects of Intravenous Bolus Doses of Meperidine in Conscious Sheep

The hemodynamic effects of 100, 200, and 300 mg of meperidine injected intravenously were studied in five chronically instrumented adult ewes. The maximum rate of increase of left ventricular pressure was decreased, respectively, by 27.4% +/- 3.9%, 37.5% +/- 5.6%, and 31.9% +/- 13.0%, and recovery occurred by 5, 8, and 0.5 min, respectively. Mild central nervous system stimulatory effects (agitation) were observed in three of five sheep at 200 mg and moderate effects (rigor and jumping movements) were observed in four of five sheep at 300 mg. These doses also produced increases in heart rate (43%-64%) and mean arterial blood pressure (17%-27%). At these doses, cardiac output was increased for 0.5 min by approximately 25% without changes in stroke volume and left ventricular stroke work. Coronary blood flow was increased by 44%-81% for 0.5 min. We conclude that, in unpremedicated sheep, meperidine has a brief direct negative inotropic effect on the myocardium, but that at larger doses this is overridden by stimulatory central nervous system (CNS) and indirect hemodynamic effects.

THE PHARMACOKINETICS OF MEPERIDINE IN THE MYOCARDIUM OF CONSCIOUS SHEEP

The pharmacokinetics of meperidine in blood and myocardium were studied in five conscious sheep. After an intravenous (IV) bolus of 100, 200, or 300 mg meperidine HCl, the maximum arterial blood concentrations (mean±SD) were 27.8±4.6, 66.8±13.3, and 114.5±23.1μg/mL, respectively, and coronary sinus blood concentrations were 2.7±1.0, 7±1.5, and 13.7±2.5μg/mL, respectively. These were linearly related to dose. Net uptake of meperidine into the myocardium occurred during the first minute and the maximum rates of uptake (influxes) were 5.1±2.6, 15.1±4.6, and 27.5±8.7 mg/min. Myocardial meperidine concentrations, calculated using mass balance principles for the 100-, 200-, and 300-mg doses, respectively, were 9.0±1.8, 20.5±8.6, and 34.1±7.4μg/g at peak and had decreased to 57%±11% of peak 5 min after injection. No pseudoequilibrium between blood and myocardial meperidine concentrations had been reached within the 15-min study period. Myocardial perfusion and blood-myocardial concentration gradients were both important determinants of meperidine myocardial pharmacokinetics. The fast uptake and brief sojourn of meperidine in the myocardium agreed with its rapid but transient negative inotropic effect reported previously.

Adverse haemodynamic effects of the rapid intravenous injection of hypotonic solutions in sheep

The rapid intravenous administration of 10 ml of sterile water or hypotonic saline to five conscious sheep induced substantial adverse haemodynamic effects lasting 10 to 20 seconds. They included reductions in cardiac output (to 44 per cent of the baseline value measured in the 30 seconds before the injection), arterial blood pressure (67 per cent of baseline), left ventricular systolic pressure (60 per cent of baseline), myocardial contractility (60 per cent of baseline), and left coronary arterial blood flow (39 per cent of baseline), and increases in heart rate to 137 per cent of the baseline. The intensities of these effects were related directly to the rates of injection and inversely to the osmolalities of the solutions injected. Intravascular haemolysis was associated with the effects. These data are of potential importance to anyone administering drugs intravenously to sheep.