Possible advantages of the single stereoisomer over the racemic mixture
1. Reduction in the therapeutic dose.
2. Reduction in the interpatient variability in metabolism and in response to treatment.
3. Simplification of the relationship between the dose and the response to treatment.
4. Reduction in the toxicity and side effects due to the greater specificity of action of the isomer with the relevant biological processes.
In addition to the possible advantages of the single enantiomer, the pharmacologically inactive enantiomer may reduce the efficacy of the active isomer by reducing its activity at its site of action or by interfering with its metabolism. Thus separating a racemic mixture into its enantiomers, and assessing the individual properties of the isomers would seem to be a reasonable approach to improving the clinical profile of many wellestablished psychotropic drugs. The process whereby a racemic mixture is reintroduced as a single enantiomer is termed ‘‘chiral switching’’. While there appears to be a compelling argument for using single enantiomers whenever possible in order to improve the efficacy and safety of a racemic drug, there is no certainty that chiral switching will always be beneficial. For example, in 1979 seven cases of inadvertent injection of the local anaesthetic racemic bupivacaine resulted in cardiovascular collapse in a few patients. The toxicity appeared to reside entirely in the R-isomer so th at, by chiral switching, a safer and less toxic local anaesthetic was produced. Other examples have not been so successful however. For example, the chiral switching of racemic fenfluramine to its R-enantiomer, dexfenfluramine (the nomenclature has changed recently so that Denantiomers, Dex enantiomers, are now termed R-enantiomers while the L-enantiomers, levoenantiomers, become S-enantiomers) was at first heralded as a successful new appetite suppressant. However, it was soon shown that, despite its improved efficacy, the R-enantiomer was more likely to cause pulmonary hypertension. This has resulted in the withdrawal of the drug.
1. Reduction in the therapeutic dose.
2. Reduction in the interpatient variability in metabolism and in response to treatment.
3. Simplification of the relationship between the dose and the response to treatment.
4. Reduction in the toxicity and side effects due to the greater specificity of action of the isomer with the relevant biological processes.
In addition to the possible advantages of the single enantiomer, the pharmacologically inactive enantiomer may reduce the efficacy of the active isomer by reducing its activity at its site of action or by interfering with its metabolism. Thus separating a racemic mixture into its enantiomers, and assessing the individual properties of the isomers would seem to be a reasonable approach to improving the clinical profile of many wellestablished psychotropic drugs. The process whereby a racemic mixture is reintroduced as a single enantiomer is termed ‘‘chiral switching’’. While there appears to be a compelling argument for using single enantiomers whenever possible in order to improve the efficacy and safety of a racemic drug, there is no certainty that chiral switching will always be beneficial. For example, in 1979 seven cases of inadvertent injection of the local anaesthetic racemic bupivacaine resulted in cardiovascular collapse in a few patients. The toxicity appeared to reside entirely in the R-isomer so th at, by chiral switching, a safer and less toxic local anaesthetic was produced. Other examples have not been so successful however. For example, the chiral switching of racemic fenfluramine to its R-enantiomer, dexfenfluramine (the nomenclature has changed recently so that Denantiomers, Dex enantiomers, are now termed R-enantiomers while the L-enantiomers, levoenantiomers, become S-enantiomers) was at first heralded as a successful new appetite suppressant. However, it was soon shown that, despite its improved efficacy, the R-enantiomer was more likely to cause pulmonary hypertension. This has resulted in the withdrawal of the drug.
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