Renewed perspective on efficacy and safety of inhaled muscarinic antagonists as asthma management therapies
Background: Although muscarinic antagonists are currently used to treat asthma, there remain various characteristics that have yet to be fully elucidated. The other major class of bronchodilators, beta 2-agonists, have been extensively studied and through these investigations, it was found that significant tolerance to the bronchoprotective effects of beta 2-agonists occurs along with increased allergen responsiveness. These findings have informed clinical use of beta 2-agonists to ensure patient safety. For this reason, formulations of long-acting beta 2-agonists are combined with inhaled corticosteroids and a recommended upper limit for dosing short-acting beta 2-agonists use has been established. By contrast, the regular use effects of muscarinic antagonists on methacholine and allergen responsiveness are not well established. These characteristics can be determined through methacholine challenge testing and allergen inhalation challenges, respectively. Methods: Two double blind, placebo-controlled, randomized crossover clinical trials were performed. The first trial examined the regular use effect of the inhaled short-acting muscarinic antagonist (SAMA), ipratropium bromide (Atrovent®), on methacholine-responsiveness in twelve well-controlled mild asthmatics. This investigation employed methacholine challenge testing at various timepoints to determine if tolerance developed following 40mcg of ipratropium thrice daily for 1-week. The second trial examined the regular use effect of the inhaled long-acting muscarinic antagonist (LAMA), tiotropium bromide (Spiriva® Respimat®), on the allergen-induced early asthmatic response in thirteen well-controlled mild allergic asthmatics. This investigation used an allergen-inhalation challenge and the indirect measures of inflammation: fractional exhaled nitric oxide (FeNO) and sputum differential cell counts (sDCC). Tiotropium was administered 5mcg once daily for 1-week. Results: The first trial found that tolerance to the bronchoprotective effect of ipratropium did not occur after 1-week of regular use. The second trial found that regular tiotropium slightly increased the early asthmatic response to allergen and did not inhibit eosinophil recruitment after allergen. Conclusion: The absence of tolerance to ipratropium bromide suggest muscarinic antagonists may be safer alternatives for regular use compared to beta 2-agonists. This finding is contradicted by the observed increase in allergen responsiveness following regular use of tiotropium. Muscarinic antagonists need to be further evaluated to determine their safety and efficacy as asthma management therapies.
asthma, muscarinic antagonist, tiotropium, ipratropium, allergic asthma
Master of Science (M.Sc.)