Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta2 agonists

Abstract

Background-In 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 eVect of salbutamol was measured during methacholine induced moderate to severe bronchoconstriction in patients receiving maintenance treatment with high dose long acting 2 agonists. Methods-A randomised double blind crossover study was performed in 19 asthmatic patients with mean forced expiratory volume in one second (FEV 1 ) of 88.4% predicted and median concentration of methacholine provoking a fall in FEV 1 of 20% or more (PC 20 ) 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 FEV 1 . 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. Results-There was a significant bronchodilating and bronchoprotective eVect after 2 weeks of active treatment. The dose of methacholine needed to provoke a fall in FEV 1 of >30% was higher after pretreatment with formoterol (2.48 mg) than with salmeterol (1.58 mg) or placebo (0.74 mg). The diVerence 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 eVect 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 FEV 1 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 FEV 1 after methacholine). At 30 minutes significant diVerences remained, but 1 hour after completing the methacholine challenge FEV 1 had returned to baseline values in all three treatment 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 vivo. Irrespective of this, prior long term treatment with both long acting 2 agonists reduced the bronchodilating eVect 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 eVective. (Thorax 2001;56:529-535)

Bronchodilator tolerance: the impact of increasing bronchoconstriction

“…Compared to pre-treatment with placebo, there was a highly significant near-linear reduction in AUC0-40 FEV1 with b-agonist as bronchoconstriction increased (pv0.0001). Thus, the present study goes further than earlier investigations [12][13][14] by demonstrating that, in the same patient, the effects of pharmacological tolerance become increasingly apparent with increasing degrees of bronchoconstriction.…”

“…In both of these studies, measuring the response to b-agonist in the presence of methacholineinduced bronchoconstriction permitted the demonstration of tolerance which would not otherwise have been detected. These findings raise the possibility that the effects of tolerance to inhaled b-agonists may be further accentuated by bronchoconstriction beyond the 20% fall in FEV1 that was induced in these investigations [12][13][14]. In acute severe asthma, patients will usually have a reduction in their FEV1 that greatly exceeds 20%.…”

“…In that study, a 36% reduction in the area under the curve (AUC) for forced expiratory volume (FEV1) was observed in patients who had been using regular inhaled b-agonist compared to placebo. Subsequently, other authors have used the same methodology to show similar effects in patients using long-acting b-agonists [13,14]. In both of these studies, measuring the response to b-agonist in the presence of methacholineinduced bronchoconstriction permitted the demonstration of tolerance which would not otherwise have been detected.…”

Serum total IgE levels and total eosinophil counts: relationship with treatment response in patients with acute asthma

“…In the current study, the effect of the treatment was evaluated two weeks after its conclusion, because another group of authors reported that there is a significant bronchodilating and bronchoprotective effect after two weeks of active treatment. (19) Patients with COPD and elevated IgE levels, atopy or sputum eosinophilia form a subgroup of patients with a better prognosis and a greater likelihood of corticosteroid responsiveness. (20) In our patients, we found no statistically significant difference between those with high serum total IgE and those with low serum total IgE in terms of the response to treatment.…”

Heterogeneity of transcription factor expression and regulation in human airway epithelial and smooth muscle cells

“…The impact of these changes is yet to be explored, but it is likely that there are those that are detrimental in terms of the cellular or organ physiology in these two syndromes. Indeed, ␤-agonist use continues to be controversial in asthma, with multiple reports of increased mortality or other indices of poor asthma control during continuous (chronic) therapy (4,17,22,25). Given the efficacy of ␤-agonists for relieving bronchospasm, one strategy for new, combined, pharmacological therapy may involve an additional agent that inhibits dysregulation of certain transcription factors by ␤-agonists.…”