NDLI: Decreased bronchodilating effect of salbutamol in relievingmethacholine induced moderate to severe bronchoconstriction during highdose treatment with long acting β2 agonists

Content Provider	PubMed Central
Author	Woude, H. J. Van Der Winter, T. Aalbers, R.
Abstract	BACKGROUND—In vitrothe long acting β2 agonist salmeterol can, in contrast toformoterol, behave as a partial agonist and become a partial antagonistto other β2 agonists. To study this in vivo, thebronchodilating effect of salbutamol was measured during methacholineinduced moderate to severe bronchoconstriction in patients receivingmaintenance treatment with high dose long acting β2 agonists. METHODS—A randomiseddouble blind crossover study was performed in 19 asthmatic patientswith mean forced expiratory volume in one second (FEV1) of88.4% predicted and median concentration of methacholine provoking afall in FEV1 of 20% or more (PC20) of0.62 mg/ml at entry. One hour after the last dose of 2 weeks oftreatment with formoterol (24 µg twice daily by Turbuhaler),salmeterol (100 µg twice daily by Diskhaler), or placebo amethacholine provocation test was performed and continued until therewas at least a 30% decrease in FEV1. Salbutamol (50 µg)was administered immediately thereafter, followed by ipratropiumbromide (40 µg) after a further 30 minutes. Lung function wasmonitored for 1 hour after provocation. RESULTS—There was asignificant bronchodilating and bronchoprotective effect after 2 weeksof active treatment. The dose of methacholine needed to provoke a fallin FEV1 of ⩾30% was higher after pretreatment withformoterol (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 0.1to 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 thepre-methacholine baseline was 15.8%, 7.3%, and 5.5% for placebo,formoterol and salmeterol, respectively (equivalent to increases of26%, 14%, and 12%, respectively, from the lowest FEV1after methacholine). At 30 minutes significant differences remained,but 1 hour after completing the methacholine challenge FEV1had returned to baseline values in all three treatment groups. CONCLUSION—Formoterolhas a greater intrinsic activity than salmeterol as a bronchoprotectiveagent, indicating that salmeterol is a partial agonist compared withformoterol in contracted human airways in vivo. Irrespective of this,prior long term treatment with both long acting β2agonists reduced the bronchodilating effect of an additional singledose of salbutamol equally, indicating that the development oftolerance or high receptor occupancy overshadowed any possible partialantagonistic activity of salmeterol. Patients on regular treatment withlong acting β2 agonists should be made aware that anadditional single dose of a short acting β2 agonist maybecome less effective.
Related Links	http://dx.doi.org/10.1136/thorax.56.7.529
Starting Page	529
File Format	PDF
ISSN	14683296
e-ISSN	14683296
Journal	Thorax
Issue Number	7
Volume Number	56
Language	English
Publisher	BMJ Group
Publisher Date	2001-07-01
Access Restriction	Open
Rights Holder	BMJ Group
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Pulmonary and Respiratory Medicine

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