BACKGROUNDIn vitro the long acting ₂ agonist salmeterol can, in contrast to formoterol, behave as a partial agonist and become a partial antagonist to other ₂ agonists. To study this in vivo, the bronchodilating effect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting ₂ agonists.
METHODSA randomised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second (FEV₁) of 88.4% predicted and median concentration of methacholine provoking a fall in FEV₁ of 20% or more (PC₂₀) of 0.62 mg/ml at entry. One hour after the last dose of 2 weeks of treatment with formoterol (24 µg twice daily by Turbuhaler), salmeterol (100 µg twice daily by Diskhaler), or placebo a methacholine provocation test was performed and continued until there was at least a 30% decrease in FEV₁. Salbutamol (50 µg) was administered immediately thereafter, followed by ipratropium bromide (40 µg) after a further 30 minutes. Lung function was monitored for 1 hour after provocation.
RESULTSThere was a significant bronchodilating and bronchoprotective effect after 2 weeks of active treatment. The dose of methacholine needed to provoke a fall in FEV₁ of 30% was higher after pretreatment with formoterol (2.48 mg) than with salmeterol (1.58 mg) or placebo (0.74 mg). The difference between formoterol and salmeterol was statistically significant: 0.7 doubling dose steps (95% CI 0.1 to 1.2, p=0.016). The immediate bronchodilating effect of subsequently administered salbutamol was significantly impaired after pretreatment with both drugs (p<0.0003 for both). 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, formoterol and salmeterol, respectively (equivalent to increases of 26%, 14%, and 12%, respectively, from the lowest FEV₁ after methacholine). At 30 minutes significant differences remained, but 1 hour after completing the methacholine challenge FEV₁ had returned to baseline values in all three treatment groups.
CONCLUSIONFormoterol 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 vivo. Irrespective of this, prior long term treatment with both long acting ₂ agonists reduced the bronchodilating effect of an additional single dose of salbutamol equally, indicating that the development of tolerance or high receptor occupancy overshadowed any possible partial antagonistic activity of salmeterol. Patients on regular treatment with long acting ₂ agonists should be made aware that an additional single dose of a short acting ₂ agonist may become less effective.


Keywords: formoterol; salmeterol; salbutamol; asthma; tolerance