Recent advances in the pharmacokinetics of local anaesthetics - Long-acting amide enantiomers and continuous infusions

The most widely used long-acting amide local anaesthetic is bupivacaine, a racemic mixture of 2 stereoisomers. However, there is evidence that the use of single enantiomer compounds offers advantages over racemic agents. Ropivacaine, the recently introduced propyl homologue of bupivacaine, is a purl S-(-)-enantiomer, It is associated with a reduced incidence of both ca rdiovascular and central nervous system toxicity, a concern with racemic bu pivacaine, in preclinical studies. The relevant pharmacokinetic differences include a lower lipid solubility, a slightly higher plasma clearance and s horter elimination half-life (t1/2 beta) compared with racemic bupivacaine, with a similar degree of plasma protein binding. More recently levobupivacaine, the pure S-(-)-enantiomer of bupivacaine, ha s been produced. Stereoselective differences have been observed between the 2 enantiomers and the racemic mixture, with levobupivacaine exhibiting a s lightly higher degree of plasma protein binding, a lower volume of distribu tion, a higher plasma clearance, and a shorter t1/2 beta than the R-(+)-ena ntiomer. In common with ropivacaine, levobupivacaine has been shown to have a reduced incidence of toxicity in comparison the R-(+)-enantiomer in prec linical studies, explained in part by a reduced affinity to both brain and myocardial tissue. Racemic bupivacaine is increasingly administered by continuous infusion to provide prolonged postoperative analgesia. The pharmacokinetic profile of t he drug administered in this manner has only recently been elucidated and i ndicates a slow rise in total plasma concentration with increasing duration of infusion, mitigated by changes in plasma protein concentrations during the postoperative period. This appears to be the predominant reason why com plications related to systemic toxicity are rarely observed with this techn ique. However, continuous administration of individual enantiomers may pote ntially serve as a safer option in the future.