Rapid onset of tolerance to beta-agonist bronchodilation.
BACKGROUND
Regular use of beta-agonists leads to tolerance to their bronchodilator effects. This is easily demonstrated if dilation is tested following methacholine challenge. It is not known how quickly tolerance develops or how long it lasts after stopping beta-agonist therapy.


METHODS
Ten subjects with stable asthma were studied. Following 2 weeks without beta-agonists, methacholine was inhaled to induce a 20% reduction in FEV1. The response to inhaled salbutamol (100, 100, 200 microg at 5-min intervals) was then measured. This procedure was repeated 24 h after one dose and 24 h after 3, 7 and 14 days of inhaled formoterol 12 microg twice daily, and 3 and 5 days after formoterol was discontinued. Unscheduled use of beta-agonists was not permitted.


RESULTS
Bronchodilator tolerance, assessed by a reduction of the area under the salbutamol dose-response curve, occurred after 1 dose of formoterol (28% reduction, 95% CI 12, 45%), increased up to 1 week and plateaued between 1 and 2 weeks (58% reduction, 95% CI 38, 78%). Three days after stopping formoterol, the response to salbutamol was similar to baseline (12% reduction, 95% CI -9, 33%). The first dose of formoterol provided significant bronchoprotection to methacholine (1.6 doubling doses, P=0.007). This diminished with regular treatment and by 2 weeks the PD20 methacholine was not significantly different to baseline.


CONCLUSIONS
Bronchodilator tolerance occurs after a single dose and reaches a maximum after 1 week of regular formoterol. Sensitivity recovers 3 days after stopping treatment.
Haney
Sarah
S
Department of Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand.
Hancox
Robert J
RJ
D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D000420:Albuterol / Q000627:therapeutic use*; D000704:Analysis of Variance; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004983:Ethanolamines / Q000627:therapeutic use*; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D016210:Methacholine Chloride; D008875:Middle Aged; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D004983:Ethanolamines; D016210:Methacholine Chloride; D000420:Albuterol; D000068759:Formoterol Fumarate