Am. J. Respir. Crit. Care Med., Volume 156, Number 1, July 1997, 28-35

Systemic Corticosteriod Rapidly Reverses Bronchodilator Subsensitivity Induced by Formoterol in Asthmatic Patients

KIA SOONG TAN, ALISON GROVE, ALEC MCLEAN, YVONNE GNOSSPELIUS, IAN P. HALL, and BRIAN J. LIPWORTH

Department of Clinical Pharmacology, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland; Astra Draco, Lund, Sweden; and Department of Medicine, University Hospital of Nottingham, Nottingham, United Kingdom

There is evidence that downregulation and desensitization of airway ₂-adrenoceptors (₂-AR) develops after continuous exposure to long-acting ₂-agonists such as formoterol and salmeterol. To investigate the facilitatory effects of acute administration of systemic corticosteroid on bronchodilator subsensitivity, as might occur in the setting of acute asthma, 12 subjects with moderately severe asthma, with a mean FEV₁ of 66% predicted, of whom were all receiving inhaled corticosteriod, were randomized to receive either inhaled placebo (PL) or inhaled formoterol (FM) 24 µg twice daily for 4 wk in a double-blind crossover study. Subjects were also genotyped in terms of ₂-AR polymorphism at loci 16 and 27. A dose-response curve (DRC) and duration-time profile for FM (12 to 108 µg) was produced 1 h after administration of placebo tablets and after injection at 3 wk, and 1 h after administration of oral prednisolone, 50 mg, and intravenous hydrocortisone, 200 mg, at 4 wk. Comparisons between treatments were made with area-under-curve (AUC) measurements as the change from baseline. There was a significant rightward shift in the DRC after FM as opposed to placebo for FEV₁ (as AUC, L · h): 2.51 versus 4.22 (95% CI: 0.54 to 2.89; p = 0.01) and FEF_25-75 (as AUC, L × 10³): 11.30 versus 19.94 (95% CI: 2.12 to 15.12; p = 0.01). This was significantly reversed by steroid (S) for FEV₁ (FM versus FM + S): 2.51 versus 3.57 (95% CI: 0.11 to 2.27; p = 0.03) and for FEF_25-75: 11.30 versus 18.47 (95% CI: 2.52 to 11.70; p = 0.005). Lymphocyte ₂-AR density (log B_max; fmol/10⁶ cells) showed significant upregulation 3 h after steroid (FM + S versus FM): 0.34 versus 0.24 (95% CI: 0.02 to 0.18; p = 0.01). For heart-rate response (as AUC, beats), there was subsensitivity with FM versus PL: 2,700 versus 5,200 (95% CI: 40 to 5,000; p < 0.001), and this was reversed by steroid (FM + S versus FM): 9,600 versus 2,700 (95% CI: 4,900 to 8,800; p < 0.001). This reversal by systemic corticosteroid appears to be generally independent of ₂-AR polymorphism at loci 16 and 27. In conclusion, we have demonstrated that bronchodilator subsensitivity occurs after regular inhaled FM in asthmatic patients, and is rapidly reversed by systemic corticosteroid. Thus, in acute asthma, systemic corticosteroid should be administered a soon as possible, in order to restore normal airway ₂-AR sensitivity, particularly in patients who are receiving regular long-acting ₂-agonists.

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