B.T. Veering

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

The effect of age on the systemic absorption, disposition and pharmacodynamics of bupivacaine after epidural administration.

SummaryThe influence of age on the systemic absorption and disposition of bupivacaine following epidural administration in 20 male patients (22 to 81 years) was examined using a stable isotope method to determine whether pharmacokinetics play a role in age-related pharmacodynamic changes seen with the drug. After epidural bupivacaine administration a deuterium-labelled analogue was administered intravenously. Bi- and triexponential functions were fitted to plasma concentration-time data of deuterium-labelled bupivacaine. The systemic absorption was described by 2 parallel first-order absorption processes. The upper level of analgesia and the duration of analgesia at dermatome T-12 increased with age (r = 0.68, p < 0.001; r = 0.56, p < 0.01, respectively). The time to maximal caudad spread of analgesia and the time to onset of motor block decreased with age (r = −0.76, p < 0.0001; r = −0.72, p < 0.001, respectively). Age did not influence systemic absorption or disposition of bupivacaine. We conclude that the changes in the clinical profile of bupivacaine with age are not due to altered pharmacokinetics, but may be related to changes in the pharmacodynamics of the drug.

THE EFFECT OF AGE ON SYSTEMIC ABSORPTION AND SYSTEMIC DISPOSITION OF BUPIVACAINE AFTER SUBARACHNOID ADMINISTRATION

In order to evaluate the role of the pharmacokinetics of the age-related changes in the clinical profile of spinal anesthesia with bupivacaine, we studied the influence of age on the systemic absorption and systemic disposition of bupivacaine after subarachnoid administration in 20 male patients (22-81 yr), ASA Physical Status 1 or 2, by a stable isotope method. After subarachnoid administration of 3 ml 0.5% bupivacaine in 8% glucose, a deuterium-labeled analog (13.4 mg) was administered intravenously. Blood samples were collected for 24 h. Plasma concentrations of unlabeled and deuterium-labeled bupivacaine were determined with a combination of gas chromatography and mass fragmentography. Biexponential functions were fitted to the plasma concentration-time data of the deuterium-labeled bupivacaine. The systemic absorption was evaluated by means of deconvolution. Mono- and biexponential functions were fitted to the data of fraction absorbed versus time. The maximal height of analgesia and the duration of analgesia at T12 increased with age (r = 0.715, P less than 0.001; r = 0.640, P less than 0.01, respectively). In 18 patients the systemic absorption of bupivacaine was best described by a biexponential equation. The half-life of the slow systemic absorption process (r = -0.478; P less than 0.05) and the mean absorption time (r = -0.551; P less than 0.02) decreased with age. The total plasma clearance decreased with age (r = -0.650, P less than 0.002), whereas the mean residence time and terminal half-life increased with age (r = 0.597, P less than 0.01; r = 0.503, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Spinal Anesthesia with Glucose-free Bupivacaine: Effects of Age on Neural Blockade and Pharmacokinetics

Effects of age on spinal anesthesia using glucose-free 0.5% bupivacaine without epinephrine were studied in two groups of patients, one between 20 and 55 yr old, the other older than 55 yr. All patients received 15 mg bupivacaine. The time to onset of analgesia in caudad segments and the time to maximal motor blockade decreased with age. The upper level of analgesia did not change significantly with increasing age. The times to recovery from analgesia at T12 and for the total disappearance of analgesia were longer in the older patient group. Effects of age on duration of motor blockade could not be demonstrated. Peak plasma concentrations of bupivacaine were significantly greater and the total plasma clearance significantly decreased in older patients. Age had no effect on time to peak concentration or the terminal half-life.

Pharmacokinetics and pharmacodynamics of medullar agents

Summary In considering the pharmacokinetics of local anaesthetics, both the systemic absorption and systemic disposition are of importance. Systemic absorption of local anaesthetics limits the duration of nerve block and is of concern in view of systemic toxicity. Initial absorption rates are higher after epidural than after subarachnoid injection, whereas the slower, secondary absorption rates are similar. Amide-type local anaesthetics undergo extensive tissue distribution. Volumes of distribution vary from approximately 60 to nearly 200 litres. Elimination occurs almost exclusively by biotransformation. Amide-type agents are predominantly metabolized in the liver. Total body clearances vary from 0.6 to 2.4 litres/min. Ester-type agents are hydrolysed in the liver and in blood, ensuring very fast elimination. Blood or plasma concentrations after single epidural injections vary with the local anaesthetic and the dose. Addition of adrenaline to local anaesthetic solutions reduces the peak plasma concentrations. Long-term continuous epidural infusions for postoperative pain relief may result in significant accumulation, reflecting increases in plasma protein binding. Plasma concentrations after subarachnoid administration are very low, so the risk of systemic toxicity is very small. The main factors determining the onset, quality and duration of epidural neural blockade are the local anaesthetic employed and its physicochemical properties. Onset in the caudad segments is usually faster, and spread of analgesia is higher in older patients. Addition of adrenaline prolongs the duration. Ongoing clinical studies show that ropivacaine is an effective long-acting local anaesthetic when given epidurally. Bupivacaine has frequently been used, either as a glucose-free or hyperbaric solution, for spinal anaesthesia. Glucose-free bupivacaine solutions provide long-lasting motor blockade, but appear to provide an unpredictable spread of analgesia. Advancing age has been shown to be associated with a prolonged duration of analgesia with glucose-free bupivacaine solutions and a greater spread of analgesia with hyperbaric bupivacaine solutions.