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

Abstract

β 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 β 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 β agonists, essentially all congeners of (R)-adrenaline, exhibit the observed bronchodilation and clinical benefit of the racemate. The S isomers of the racemic β 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 β 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 β agonist, retains the clinical benefit of racemic albuterol without the proinflammatory and potentially detrimental effects of (S)-albuterol. (J Allergy Clin Immunol 1999;104:S69-76.)