Background: Two adverse effects of inhaled beta 2-agonists are increased airway responsiveness to allergen and tolerance to the bronchoprotective effect of beta 2-agonists versus bronchoconstrictors (e.g., methacholine).
Objective: We studied three doses of inhaled salbutamol, 200, 400, and 800 micrograms/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 micrograms, 400 micrograms and 800 micrograms per day. After each treatment, we assessed FEV1, bronchodilation 10 minutes after administration of 200 micrograms of salbutamol, methacholine PC20, methacholine dose-shift after administration of 200 micrograms of salbutamol, and allergen PC20.
Results: There was no significant difference in baseline FEV1, bronchodilation, or methacholine PC20. 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 PC20 was significantly lower (p < 0.02) after salbutamol 800 micrograms/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 micrograms/d); however, tolerance to the acute bronchoprotective effect of salbutamol was observed with all the three salbutamol regimens, even 200 micrograms/day. This suggests different mechanisms may be operative in producing these two effects.