Effect of cessation of short-term therapy with ipratropium bromide on lung function and airway responsiveness

Regular exposure to antimuscarinic drugs would be expected to upregulate airway muscarinic receptors and could cause a transient increase in airways obstruction if treatment was stopped or omitted. We have examined peak expiratory flow rate (PEFR) during treatment and forced expiratory flow in one second (FEV1) and airway responsiveness to three constrictor agonists (as the provocative dose of agonist causing a 20% fall in FEV1, (PD20)) following cessation of regular inhaled ipratropium bromide, in 13 subjects with mild stable asthma. Subjects inhaled placebo and ipratropium bromide, 80 microg q.i.d. for 14 days in a cross-over fashion with a 1 week run-in/wash-out period before and after each treatment period. Subjects recorded symptom scores and PEFR throughout the study, and FEV1 and PD20 to histamine, methacholine and metabisulphite were measured before and after cessation of treatment. When compared to baseline, FEV1 was lower after cessation of ipratropium than after placebo, with a significant difference 30 h after the last dose (difference 190 mL; 95% confidence interval (95% CI) 310-70 mL; p<0.02). FEV1 measured 6-10 days later, did not differ significantly. PEFR was significantly lower after cessation of ipratropium than after placebo on Day 15 (19-37 h after the last dose) (mean difference 4.6%; 95% CI 1.6-7.5%; p<0.01) but not on Day 16. There were no significant changes in PD20 histamine, methacholine and metabisulphite, symptom scores or rescue bronchodilator use after cessation of treatment. Thus, transient bronchoconstriction was found around 30 h after cessation of regular therapy with inhaled ipratropium for 2 weeks. The mechanism is unclear, as no evidence of muscarinic receptor upregulation was found. Although the changes were small and unlikely to be important for most patients, the results of this study indicate that the timing of lung function measurements relative to the last dose of ipratropium is important when interpreting the course of lung function in long-term studies.