Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: dose response.

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.