Recent Advances in the Pharmacokinetics of Local Anaesthetics

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Abstract
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 pure S-(−)-enantiomer. It is associated with a reduced incidence of both cardiovascular and central nervous system toxicity, a concern with racemic bupivacaine, in preclinical studies. The relevant pharmacokinetic differences include a lower lipid solubility, a slightly higher plasma clearance and shorter elimination half-life (t1/2β) compared with racemic bupivacaine, with a similar degree of plasma protein binding. More recently levobupivacaine, the pure S-(−)-enantiomer of bupivacaine, has been produced. Stereoselective differences have been observed between the 2 enantiomers and the racemic mixture, with levobupivacaine exhibiting a slightly higher degree of plasma protein binding, a lower volume of distribution, a higher plasma clearance, and a shorter t1/2β than the R-(+)-enantiomer. In common with ropivacaine, levobupivacaine has been shown to have a reduced incidence of toxicity in comparison the R-(+)-enantiomer in preclinical 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 the drug administered in this manner has only recently been elucidated and indicates 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 complications related to systemic toxicity are rarely observed with this technique. However, continuous administration of individual enantiomers may potentially serve as a safer option in the future.