New millennium bronchodilators for asthma: single-isomer beta agonists

Racemic beta2 agonists are composed of a 50:50 mixture of R and S isomers. The R isomer exhibits virtually all the bronchodilation, whereas the S isomers are generally considered inert. However, (S)-albuterol was shown to enhance bronchial reactivity to methacholine, eosinophil activation, and histamine-induced influx of fluid, proteins, and neutrophils into the airspaces. Actions such as these may compress the potency and foreshorten the duration of (R)-albuterol. Accordingly, pure (R)-albuterol provides bronchodilation at lower doses than racemate, allowing for fewer beta-adrenergic-mediated side effects. In addition, differential metabolism may allow for the progressive accumulation of (S)-albuterol. This logic is applicable to long-acting beta2 agonists: the therapeutically active (R,R)-formoterol is currently being developed in the United States, and preliminary results suggest rapid improvements in FEV1 with up to 24-hour duration of action. These combined observations with the R isomers of beta2 agonists suggest that potential improvements in therapeutic indices can be achieved with isomerically pure versions of existing racemic drugs.