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Long-Acting β2-Agonists in Asthma: Enantioselective Safety Studies are Needed

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Abstract

Long-acting β2-agonists (LABAs) such as formoterol and salmeterol are used for prolonged bronchodilatation in asthma, usually in combination with inhaled corticosteroids (ICSs). Unexplained paradoxical asthma exacerbations and deaths have been associated with LABAs, particularly when used without ICS. LABAs clearly demonstrate effective bronchodilatation and steroid-sparing activity, but long-term treatment can lead to tolerance of their bronchodilator effects. There are also concerns with regard to the effects of LABAs on bronchial hyperresponsiveness (BHR), where long-term use is associated with increased BHR and loss of bronchoprotection. A complicating factor is that formoterol and salmeterol are both chiral compounds, usually administered as 50:50 racemic (rac-) mixtures of two enantiomers. The chiral nature of these compounds has been largely forgotten in the debate regarding LABA safety and effects on BHR, particularly that (S)-enantiomers of β2-agonists may be deleterious to asthma control. LABAs display enantioselective pharmacokinetics and pharmacodynamics. Biological plausibility of the deleterious effects of β2-agonists (S)-enantiomers is provided by in vitro and in vivo studies from the short-acting β2-agonist (SABA) salbutamol. Supportive clinical findings include the fact that patients in emergency departments who demonstrate a blunted response to salbutamol are more likely to benefit from (R)-salbutamol than rac-salbutamol, and resistance to salbutamol appears to be a contributory mechanism in rapid asthma deaths. More effort should therefore be applied to investigating potential enantiospecific effects of LABAs on safety, specifically bronchoprotection. Safety studies directly assessing the effects of LABA (S)-enantiomers on BHR are long overdue.

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Authors and Affiliations

  1. School of Medicine, University of Tasmania, Private Bag 26, Hobart, TAS, 7001, Australia

    Glenn A. Jacobson, Richard Wood-Baker & E. Haydn Walters

  2. School of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, NSW, Australia

    Sharanne Raidal

  3. Department of Respiratory Medicine, Bispebjerg University Hospital, Copenhagen, Denmark

    Morten Hostrup

  4. Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark

    Morten Hostrup

  5. Department of Systems Medicine, University of Rome “Tor Vergata”, Rome, Italy

    Luigino Calzetta

  6. Indiana University School of Medicine, Indianapolis, IN, USA

    Mark O. Farber

  7. Sackler Institute of Pulmonary Pharmacology, Kings College London, London, UK

    Clive P. Page

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Correspondence to Glenn A. Jacobson.

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For the conception and writing of this manuscript, Glenn Jacobson was funded by an ongoing academic appointment at the University of Tasmania.

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Glenn Jacobson and Morten Hostrup have received funding from the World Anti-Doping Agency (WADA), including investigations into the enantioselective detection and performance-enhancing effects of β2-agonists. Sharanne Raidal, Luigino Calzetta, Richard Wood-Baker, Mark O. Farber, and Clive P. Page have not received funding related to this work and have no conflicts of interest to declare. E. Haydn Walters is in receipt of investigator-initiated funding from Boehringer-Ingelheim for a study of airway infection mechanisms in COPD and has received honoraria funding from GlaxoSmithKline for speaking on asthma and COPD therapy to medical practitioners.

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Jacobson, G.A., Raidal, S., Hostrup, M. et al. Long-Acting β2-Agonists in Asthma: Enantioselective Safety Studies are Needed. Drug Saf 41, 441–449 (2018). https://doi.org/10.1007/s40264-017-0631-1

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