Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: Dose response☆☆☆★★★

Abstract 

BACKGROUND: Two adverse effects of inhaled β₂-agonists are increased airway responsiveness to allergen and tolerance to the bronchoprotective effect of β_{2-agonists versus bronchoconstrictors (e.g., methacholine).} OBJECTIVE: We studied three doses of inhaled salbutamol, 200, 400, and 800 μg/day, to determine dose-response curves for these two adverse effects. METHODS: Ten atopic patients with mild, stable asthma free of all asthma medications, allergen exposure, and respiratory tract infection for at least 4 weeks participated in a double-blind, random-order, crossover study. There were four 1-week treatment periods with a 1-week washout period: placebo, salbutamol 200 μg, 400 μg and 800 μg per day. After each treatment, we assessed FEV ₁, bronchodilation 10 minutes after administration of 200 μg of salbutamol, methacholine PC ₂₀, methacholine dose-shift after administration of 200 μg of salbutamol, and allergen PC ₂₀. RESULTS: There was no significant difference in baseline FEV₁, bronchodilation, or methacholine PC ₂₀. The methacholine dose shift was maximum after the placebo (3.4 ± 0.22 doubling doses) and was significantly greater (p < 0.01) than all salbutamol regimens (2.2 to 2.6), which were not significantly different from each other (p > 0.05). Allergen PC ₂₀ was significantly lower (p < 0.02) after salbutamol 800 μ g/day (geometric mean = 288 protein nitrogen units [PNU]/ml) than each of the other treatments (447 to 550 PNU/ml), which were not significantly different from each other (p >0.05). CONCLUSION: Significant increase in airway responsiveness to allergen occurred only with the largest dose of inhaled salbutamol (800 μg/d); however, tolerance to the acute bronchoprotective effect of salbutamol was observed with all the three salbutamol regimens, even 200 μ g/day. This suggests different mechanisms may be operative in producing these two effects. (J ALLERGY CLIN IMMUNOL 1996;97:47-52.)

Keywords:  β₂-agonist tolerance, allergen inhalation test, methacholine inhalation test

Abbreviations:  AMP: , Adenosine monophosphate, EAR: , Early asthmatic response, LAR: , Late asthmatic response, PNU: , Protein nitrogen units