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Bronchodilator tolerance: the impact of increasing bronchoconstriction

¹ Depts of Medical and Surgical Sciences and ² Preventive and Social Medicine, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

CORRESPONDENCE: D.R. Taylor, Dunedin School of Medicine, P.O. Box 913, Dunedin, New Zealand. Fax: 64 34747641. E-mail: robin.taylor@stonebow.otago.ac.nz

Keywords: asthma, ß-agonist, tachyphylaxis, tolerance, salbutamol

Received: July 26, 2002
Accepted January 4, 2003

This study was supported by the Asthma and Respiratory Foundation of New Zealand. J.M. Wraight was a GlaxoSmithKline research fellow.

Chronic exposure to ß-agonists causes tolerance to their bronchodilator effects, which is best demonstrated during acute bronchoconstriction. The aim of the present study was to assess whether tolerance becomes more evident with increasing bronchoconstriction, as might occur in acute asthma.

In a randomised, double-blind, placebo-controlled, crossover study comprising 15 patients, the treatments were salbutamol 400 µg q.i.d. or placebo given via Diskhaler® for 28 days with a 2-week washout between treatments. Patients attended on days 14, 21 and 28. Bronchoconstriction was induced on two of these three occasions to achieve a reduction in the forced expiratory volume in one second (FEV₁) of 0 (no methacholine), 15 and 30% (using methacholine) in a randomised order. Immediately after this, salbutamol 100 µg, 100 µg and 200 µg was inhaled at 0, 5, and 10 min. FEV₁ was measured over 40 min. Dose/response curves were plotted and values for the area under the curve (AUC)_0–40 FEV₁ were compared between treatments and by degree of bronchoconstriction.

Regular salbutamol resulted in attenuation of the acute response to ß-agonist, which was increasingly evident with greater bronchoconstriction. With a reduction in FEV₁ of 0, 15 and 30%, the AUC_0–40 FEV₁ with salbutamol were 11.2, –14.6 and –35.7% respectively, compared to placebo. There was a linear relationship between the magnitude of bronchoconstriction and the between-treatment differences in AUC_0–40 FEV₁.

Increasing bronchoconstriction conferred greater susceptibility to the effects of bronchodilator tolerance.

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