The asthma-like pharmacology and toxicology of (S)-isomers of beta agonists.

Beta(2 ) agonists were designed to emulate the bronchodilation and mast cell suppression effects of human adrenaline, an endogenous neuromediator. Endogenous adrenaline is produced exclusively as the single enantiomer or isomer, (R)-adrenaline, although all selective beta(2 ) agonists are marketed as racemic drugs, composed of a precise 50:50 mixture of R and S isomers. Isomers are compounds that are nonsuperimposable mirror images. The R isomers of beta agonists, essentially all congeners of (R)-adrenaline, exhibit the observed bronchodilation and clinical benefit of the racemate. The S isomers of the racemic beta agonists are devoid of clinical benefit, are assumed to be benign, and have not been studied until recently. In contradistinction to their assumed benign status, extensive studies with (S)-albuterol have shown that it opposes the bronchodilation effects of (R)-albuterol (levalbuterol), may be proinflammatory, and exhibits the potential to exacerbate airway reactivity to a variety of spasmogens by enhancing contractile responses. Clinically, (S)-albuterol can increase airway reactivity and, because of its slow metabolism, exists in higher and prolonged plasma concentrations than levalbuterol. The sustained presence of (S)-albuterol may help to explain why racemic beta agonists have not demonstrated a significant clinical anti-inflammatory potential. Furthermore, the adverse effects (S)-albuterol may contribute to paradoxic bronchospasm and the occurrence of severe reagenic-like reactions seen with racemic albuterol. These adverse effects of (S)-albuterol are completely avoided with single isomer version of (R)-albuterol (levalbuterol). The removal of (S)-albuterol increased the clinical potency of levalbuterol, such that bronchodilator efficacy is achieved at one-fourth the dose of racemic albuterol, but with marked reduction in side effects. Levalbuterol, a third generation beta agonist, retains the clinical benefit of racemic albuterol without the proinflammatory and potentially detrimental effects of (S)-albuterol.