Contrasting properties of albuterol stereoisomers

Racemic albuterol is composed of an equimolar mixture of stereoisomers. For asthma therapy, (R)-albuterol is the eutomer and (S)-albuterol is the distomer. By interacting with beta(2 )-adrenoceptors, (R)-albuterol has bronchodilator, bronchoprotective, anti-edematous properties and inhibits activation of mast cells and eosinophils. (S)-albuterol does not activate beta(2 )-adrenoceptors and does not modify activation of beta(2 )-adrenoceptors by (R)-albuterol so that for many years it was presumed to be biologically inert. Recently, it has been established that regular and excessive use of racemic albuterol induces paradoxical reactions in some subjects with asthma. Because such effects cannot be accounted for by activation of beta(2 )-adrenoceptors, the pharmacologic profile of (S)-albuterol has been more carefully defined. (S)-albuterol has distinctive pharmacologic properties that are unrelated to activation of beta(2 )-adrenoceptors. Thus, (S)-albuterol intensifies bronchoconstrictor responses of sensitized guinea pigs and induces hypersensitivity of asthmatic airways; it also promotes the activation of human eosinophils in vitro. These actions of (S)-albuterol may explain why racemic albuterol can intensify allergic bronchospasm and promote eosinophil activation in asthmatic airways. The capacity of (S)-albuterol to elevate intracellular Ca(2+) would account for the paradox because this action will oppose, or even nullify, the consequences of adenylyl cyclase activation by (R)-albuterol. Because (S)-albuterol is metabolized more slowly than (R)-albuterol and is retained preferentially within the airways, paradoxical effects become more prominent during regular and excessive use of racemic albuterol. Because (S)-albuterol has detrimental effects in asthmatic airways, levalbuterol [homochiral (R)-albuterol] should have advantages over racemic albuterol in therapy for asthma.