Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta(2) agonists

Background - In vitro the long acting beta (2) agonist salmeterol can, in c ontrast to formoterol, behave as a partial agonist and become a partial ant agonist to other beta (2) agonists. To study this in vive, the broncfiodila ting effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting beta (2) agonists. Methods - A randomised double blind crossover study was performed in 19 ast hmatic patients with mean forced expiratory volume in one second (FEV1) of 88.4% predicted and median concentration of methacholine provoking a fall i n FEV1 of 20% or more (PC20) of 0.62 mglml at entry. One hour after the las t dose of 2 weeks of treatment with formoterol (24 mug twice daily by Turbu haler), salmeterol (100 mug twice daily by Diskhaler), or placebo a methach oline provocation test was performed and continued until there was at least a 30% decrease in FEV1. Salbutamol (50 mug) was administered immediately t hereafter, followed by ipratropium bromide (40 mug) after a further 30 minu tes. Lung function was monitored for i hour after provocation. Results - There was a significant bronchodilating and bronchoprotective eff ect after 2 weeks of active treatment. The dose of methacholine needed to p rovoke a fall in FEV1 of greater than or equal to 30% was higher after pret reatment with formoterol (2.48 mg) than with salneterol (1.58mg) or placebo (0.74mg). The difference between formoterol and salmeterol was statistical ly significant: 0.7 doubling dose steps (95% CI 0.1 to 1.2, p=0.016). The i mmediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs (p <0.0003 for b oth). Three minutes after inhaling salbutamol the increase in FEV1 relative to the pre-methacholine baseline was 15.8%, 7.3%, and 5.5% for placebo, fo rmoterol and salmeterol, respectively (equivalent to increases of 26%, 14%, and 12%, respectively, from the lowest FEV, after methacholine). At 30 min utes significant differences remained, but 1 hour after completing the meth acholine challenge FEV1 had returned to baseline values in all three treatm ent groups. Conclusion - Formoterol has a greater intrinsic activity than salmeterol as a bronchoprotective agent, indicating that salmeterol is a partial agonist compared with formoterol in contracted human airways in vive. Irrespective of this, prior long term treatment with both long acting beta (2) agonists reduced the bronchodilating effect of an additional single dose of salbuta mol equally, indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmet erol. Patients on regular treatment with long acting beta (2) agonists shou ld be made aware that an additional single dose of a short acting beta (2) agonist may become less effective.