Concomitant inhaled corticosteroid resensitises cardiac beta2-adrenoceptors in the presence of long-acting beta2-agonist therapy.
OBJECTIVE
The aim of the present study was to evaluate the effects of concomitant inhaled corticosteroid therapy on the sensitivity of cardiac beta2-adrenoceptors in patients receiving regular long-acting beta2-agonists.


METHODS
Twelve healthy subjects (6 female), mean age 29 years, were randomised in a double-blind cross-over study to receive either inhaled placebo or inhaled budesonide 1.2 mg twice daily, each for 7 days, with a minimum of 7 days washout period between the two treatments. Patients also received concomitant treatment with inhaled eformoterol 24 microg twice daily during each of the 2 treatment periods. The patients attended the laboratory during both treatment periods at 0730 hours, when a dose-response curve for systemic beta2-adrenoceptor responses to inhaled salbutamol (0.8-3.2 mg) was constructed before and after completing 7 days of each treatment. Early morning (0800 hours) plasma cortisol was also evaluated as a marker of systemic glucocorticoid activity.


RESULTS
There was a significant fall in 0800 hours plasma cortisol induced by budesonide comparing pre- and post-values (407 vs 322 nmol.1(-1), but not with placebo. There were no differences in the response to salbutamol prior to treatment when comparing eformoterol with placebo versus eformoterol with budesonide. Comparing before and after within-treatment heart rate response, there was a significant reduction in peak salbutamol response with eformoterol and placebo, which was partially reversed by eformoterol and budesonide. For between-treatment comparisons after eformoterol treatment, the heart rate was significantly higher in the presence of budesonide in comparison with placebo for peak salbutamol response (change from baseline), i.e. 24.2 vs 34.7 beats min(-l). There was, however, no significant difference in the peak delta potassium response to salbutamol after eformoterol treatment when comparing budesonide with placebo (-0.39 vs -0.48 mmol.1(-1)).


CONCLUSIONS
Concomitant therapy with inhaled budesonide resensitised the cardiac beta2-adrenoceptor response to salbutamol in subjects who were receiving regular twice-daily eformoterol. This may be of clinical relevance in terms of the propensity for systemic beta2-mediated adverse effects with repeated puffs of salbutamol, which might conceivably occur in the setting of acute asthma.
Aziz
I
I
Department of Clinical Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Scotland, UK.
McFarlane
L C
LC
Lipworth
B J
BJ
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000328:Adult; D000420:Albuterol / Q000627:therapeutic use*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D019819:Budesonide / Q000008:administration & dosage*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004983:Ethanolamines / Q000627:therapeutic use*; D005260:Female; D000068759:Formoterol Fumarate; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D009206:Myocardium / Q000648:ultrastructure; D010919:Placebos; D011188:Potassium / Q000097:blood; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000502:physiology; D012680:Sensitivity and Specificity
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D010919:Placebos; D018343:Receptors, Adrenergic, beta-2; D019819:Budesonide; D000420:Albuterol; D011188:Potassium; D000068759:Formoterol Fumarate; D006854:Hydrocortisone