An introduction to enantiomers in psychopharmacology

Abstract

There is growing scientific, clinical, commercial and regulatory recognition that enantiomers offer benefits over racemates in the management of psychiatric diseases as well as in clinical medicine generally. However, relatively few studies consider enantiomers' individual characteristics. This review considers some of the clinical benefits associated with using stereochemically pure drugs in psychiatric conditions other than depression.A review of the evidence shows that enantiomers offer four main benefits. Firstly, using a single enantiomer may allow a reduction in total dose, while maintaining or improving outcomes. For example, (+)-nefopam's antinociceptive activity is greater than that produced by both the racemate and (-)-nefopam, but with the same level of acute toxicity. Thus, a single enantiomer may offer greater efficacy, dose for dose, than the racemate. Secondly, assessing dose-response relationships is simpler. There is no reason to suppose that a racemate will necessarily contain the isomers' optimum therapeutic ratio, that one of the isomers will be inactive or that the enantiomers' dose-response curves will coincide. For example, the dose-response relationship for the induction of catalepsy in the rat by thioridazine suggested that the racemate was around 12 times more potent than (+)-thioridazine and three times more potent than (-)-thioridazine, when considering the actual concentrations in the striatum. Thirdly, using a single enantiomer may reduce pharmacokinetic and pharmacodynamic variability between patients. For example, the coefficients of variation for some of methadone's pharmacokinetic parameters may reach 70%, which might have clinical consequences. Finally, using a single enantiomer may reduce toxicity arising from the therapeutically inactive stereoisomer. For example, the single enantiomers of bupivacaine and ropivacaine are significantly less cardiotoxic than their respective racemates.This review illustrates why stereochemistry should be considered when assessing the toxicology, pharmacokinetics, metabolism and efficacy of a racemate. Indeed, the differences may be so marked that achiral analyses may be misleading, and clinicians should consider prescribing an enantiomer whenever possible. In many cases, prescribing a single enantiomer improves the benefit:risk ratio. Finally, there is no reason to suppose that a racemate's characteristics will apply to the constituent enantiomers. Copyright 2001 John Wiley & Sons, Ltd.