Paradoxical asthma hazard of short‐acting β2‐agonists

Abstract

Paradoxical asthma hazard of short-acting b2-agonists Bonniaud et al. (1) report a case of bronchoconstriction in a patient caused by inhalation of short-acting b2-agonists. In an occupational setting, exposures to such agents can be even greater than those encountered therapeutically and there have been at least two reported cases of occupational asthma attributed to salbutamol exposure in pharmaceutical process workers (2). However, in the above-mentioned report the authors postulated that the mechanism might be tachyphylactic rather than IgE-mediated. Thus, salbutamol was one of the 78 low molecular weight (LMW) organic chemicals known to cause occupational asthma from which a quantitative structure-activity relationship (QSAR) model was developed (3). This asthma hazard prediction program is freely available through the internet (4), and we have previously illustrated how a positive Ôasthma hazard indexÕ can help corroborate evidence of potential asthmagenicity of LMW organic chemicals (3,5).Although designed for the purpose of predicting the asthma hazard of industrial chemicals, this QSAR model has been used by others, in clinical pharmacology. Thus an independent user of the model found that a chemical ingredient of salmeterol inhalers, xinafoate, had an asthma hazard index of 0.73. This index is expressed on a scale of 0-1 with a value of 0.5 or higher indicating asthmagenic potential. Based on a validation set containing 21 asthmagens this cutpoint results in a sensitivity of 86% and specificity 99%. It was postulated that xinafoate might be the cause of severe asthma exacerbations observed in some patients using this long-acting b2-agonist (6).In the case reported by Bonniaud et al.(1) the b-agonist drugs themselves were clearly demonstrated to cause bronchoconstriction, perhaps through an IgE-mediated mechanism. Salbutamol has an asthma hazard index of 0.84. Interestingly, terbutaline, and pirbuterol, which were not in the QSAR model development set, have hazard indices of 0.79 and 0.97, respectively. Common structural features might explain why these three chemicals are capable of sharing reactive features potentially leading to asthmagenicity (Fig. 1), such as by reacting with native proteins resulting in IgE neoepitopes. Proof (or otherwise) that the mechanism is IgE-mediated would however require in vivo and in vitro studies to search for specific IgE antibodies.

Tremor and Paradoxical bronchospasm caused by Terbutaline

“…All short-acting β2 -adrenoceptor agonists approved by the FDA have warnings about causing paradoxical bronchospasm [4], and the instructions for terbutaline sulfate also suggest that the drug may cause bronchospasm, but the incidence rate the mechanisms are tillunknown. Some studies suggest that bronchospasm caused by β2 -adrenoceptor agonists may be mediated by IgE, and that salbutamol, terbutaline, and pibuterol share common structural features: a tert-butyl group attached to a nitrogen atom may explain that they can all bind to proteins to produce IgE and cause bronchospasm [11][12] . Other studies have suggested that β2 -adrenoceptor agonists induced bronchospasm may be related to inhalant excipients (propellants and surfactants), preservatives (benzalkonium bromide), osmotic pressure, and/or pH [1,8] .…”

Transient paradoxical bronchospasm associated with inhalation of the LAMA AZD9164: analysis of two Phase I, randomised, double-blind, placebo-controlled studies

“…A review of adverse reaction reports for inhaled β 2 -selective, adrenergic-agonist bronchodilators between 1974 and 1988 revealed 126 reports consistent with a diagnosis of paradoxical bronchospasm associated with use of these drugs by metered-dose inhaler, and a further 58 such reports between 1983 and 1988 for these drugs delivered by nebulisation [13]. Salbutamol has been shown to cause occupational asthma in pharmaceutical workers and has an asthma hazard index of 0.84 on a scale of 0–1, with a value of 0.5 or higher indicating asthmagenic potential [14]. …”