title: Overcoming beta-agonist tolerance: high dose salbutamol and ipratropium bromide. Two randomised controlled trials.
abstract: BACKGROUND
  Asthmatics treated with long-acting beta-agonists have a reduced bronchodilator response to moderate doses of inhaled short acting beta-agonists during acute bronchoconstriction. It is not known if the response to higher doses of nebulised beta-agonists or other bronchodilators is impaired. We assessed the effect of long-acting beta-agonist treatment on the response to 5 mg nebulised salbutamol and to ipratropium bromide.
  
  
  METHODS
  Two double-blind, placebo-controlled, crossover studies of inhaled formoterol 12 mug twice daily in patients with asthma.High-dose salbutamol: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled methacholine to produce a 20% fall in FEV1. Salbutamol 5 mg was then administered via nebuliser and the FEV1 was monitored for 20 minutes. Ipratropium: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled 4.5% saline to produce a 20% fall in FEV1. Salbutamol 200 mug or ipratropium bromide 40 mug was then inhaled and the FEV1 was monitored for 30 minutes. Four study arms compared the response to each bronchodilator after formoterol and placebo. Analyses compared the area under the bronchodilator response curves, adjusting for changes in pre-challenge FEV1, dose of provocational agent and FEV1 fall during the challenge procedure.
  
  
  RESULTS
  The response to nebulised salbutamol was 15% lower after formoterol therapy compared to placebo (95% confidence 5 to 25%, p = 0.008). The response to ipratropium was unchanged.
  
  
  CONCLUSIONS
  Long-acting beta-agonist treatment induces tolerance to the bronchodilator effect of beta-agonists, which is not overcome by higher dose nebulised salbutamol. However, the bronchodilator response to ipratropium bromide is unaffected.
authors.affiliation: Department Respiratory Medicine, Waikato Hospital, Hamilton, New Zealand. sas_haney@yahoo.co.uk
authors.forename: Sarah
authors.initials: S
authors.lastname: Haney
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hancox
mesh_terms: D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage*; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy*; D018680:Cholinergic Antagonists / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D004357:Drug Synergism; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D009241:Ipratropium / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D015990:Placebo Effect; D016896:Treatment Outcome
chemical_list: D000318:Adrenergic beta-Agonists; D018680:Cholinergic Antagonists; D004338:Drug Combinations; D009241:Ipratropium; D000420:Albuterol