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Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta2 agonists.
Thorax. 2001 Jul; 56(7):529-35.T

Abstract

BACKGROUND

In vitro the long acting beta2 agonist salmeterol can, in contrast to formoterol, behave as a partial agonist and become a partial antagonist to other beta2 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 beta2 agonists.

METHODS

A 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 (PC(20)) of 0.62 mg/ml at entry. One hour after the last dose of 2 weeks of treatment with formoterol (24 microg twice daily by Turbuhaler), salmeterol (100 microg 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 microg) was administered immediately thereafter, followed by ipratropium bromide (40 microg) after a further 30 minutes. Lung function was monitored for 1 hour after provocation.

RESULTS

There 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 > or = 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.

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 beta2 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 beta2 agonists should be made aware that an additional single dose of a short acting beta2 agonist may become less effective.

Authors+Show Affiliations

Department of Pulmonology, Martini Hospital, 9700 RM Groningen, The Netherlands.No affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11413351

Citation

van der Woude, H J., et al. "Decreased Bronchodilating Effect of Salbutamol in Relieving Methacholine Induced Moderate to Severe Bronchoconstriction During High Dose Treatment With Long Acting Beta2 Agonists." Thorax, vol. 56, no. 7, 2001, pp. 529-35.
van der Woude HJ, Winter TH, Aalbers R. Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta2 agonists. Thorax. 2001;56(7):529-35.
van der Woude, H. J., Winter, T. H., & Aalbers, R. (2001). Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta2 agonists. Thorax, 56(7), 529-35.
van der Woude HJ, Winter TH, Aalbers R. Decreased Bronchodilating Effect of Salbutamol in Relieving Methacholine Induced Moderate to Severe Bronchoconstriction During High Dose Treatment With Long Acting Beta2 Agonists. Thorax. 2001;56(7):529-35. PubMed PMID: 11413351.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Decreased bronchodilating effect of salbutamol in relieving methacholine induced moderate to severe bronchoconstriction during high dose treatment with long acting beta2 agonists. AU - van der Woude,H J, AU - Winter,T H, AU - Aalbers,R, PY - 2001/6/20/pubmed PY - 2001/7/28/medline PY - 2001/6/20/entrez SP - 529 EP - 35 JF - Thorax JO - Thorax VL - 56 IS - 7 N2 - BACKGROUND: In vitro the long acting beta2 agonist salmeterol can, in contrast to formoterol, behave as a partial agonist and become a partial antagonist to other beta2 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 beta2 agonists. METHODS: A 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 (PC(20)) of 0.62 mg/ml at entry. One hour after the last dose of 2 weeks of treatment with formoterol (24 microg twice daily by Turbuhaler), salmeterol (100 microg 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 microg) was administered immediately thereafter, followed by ipratropium bromide (40 microg) after a further 30 minutes. Lung function was monitored for 1 hour after provocation. RESULTS: There 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 > or = 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. 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 beta2 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 beta2 agonists should be made aware that an additional single dose of a short acting beta2 agonist may become less effective. SN - 0040-6376 UR - https://www.unboundmedicine.com/medline/citation/11413351/Decreased_bronchodilating_effect_of_salbutamol_in_relieving_methacholine_induced_moderate_to_severe_bronchoconstriction_during_high_dose_treatment_with_long_acting_beta2_agonists_ L2 - http://thorax.bmj.com/cgi/pmidlookup?view=long&amp;pmid=11413351 DB - PRIME DP - Unbound Medicine ER -