The pursuit of precision pharmaceuticals: divergent effects of β2 agonist isomers

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Abstract
2 agonists are the most commonly used treatment for acute bronchoconstriction. However, during regular use there is a progressive decline of protective efficacy of bronchodilators. Airway hyperresponsiveness is itself a feature of asthma, however, there may be an increase in airway hyperresponsiveness following regular use of 2 agonists. This progressive decline has long been considered anomalous because with short-acting 2 agonists, there is no corresponding change in bronchodilator efficacy. It was recognised that airway hyperresponsiveness could diminish the capacity of 2 agonists to protect from or result in paradoxical bronchospasm. There have been reports of increased morbidity and mortality associated with excessive use of 2 agonists. As all 2 agonists used clinically are racemates composed of 1:1 mixtures of R and S isomers, studies were conducted on the possible involvement of the isomers in hyperresponsiveness and adverse effects were initiated. Hyperresponsiveness cannot be attributed to the R isomer, whose capacity to activate β adrenoceptors will nullify this effect. In contrast, extensive evidence indicated that the S isomer might cause hyperresponsiveness and potential airway inflammation. Further, the S isomer shows a propensity to activate human eosinophils and alter muscarinic M2 receptor functions. The S isomer, which makes no contribution to therapeutic efficacy and may exacerbate asthma, might therefore be excluded from asthma therapy [1].