Partial vs full beta-receptor agonism. A clinical study of inhaled albuterol and fenoterol.
OBJECTIVE
To compare the maximal extrapulmonary effects of the beta-agonists albuterol and fenoterol in eight healthy volunteers.


METHODS
In this double-blind study, we have examined the maximum cardiac effects (electromechanical systole [QS2I]--a measure of inotropy, heart rate, BP) and metabolic effects (plasma K+ and cyclic adenosine monophosphate [cAMP]) of repeated inhalation of albuternol and fenoterol. In eight healthy volunteers, 400 microg of each drug was administered every 10 min until QS2I and plasma K+ had reached a plateau (+/- 0.1 mmo l/L for K+, and +/- 10 ms for QS2I). The maximum response (Emax) and the dose of albuterol required to produce 50% of the maximum response to fenoterol (ED50F) were calculated.


RESULTS
The Emax for fenoterol was significantly greater than albuterol for plasma K+ (-1.4 vs -1.03 mmol/L; p<0.002), QS2I (-71.8 vs 57.5 ms; p=0.047), and cAMP (33.8 vs 18.1 nmol/L; p<0.002). The dose required to produce the ED50f was significantly greater for albuterol than for fenoterol with potency ratios of 1.75, 1.61, and 2.26 for plasma K+, QS2I, and cAMP, respectively. There were no significant differences between fenoterol and albuterol with respect to heart rate (Emax, 44.9 vs 32.5 beats/min; p=0.19; potency ratio, 1.98; p=0.052).


CONCLUSIONS
These findings suggest that albuterol behaves as a partial agonist at beta-receptors when compared with fenoterol, and that when inhaled in doses currently recommended for severe asthma, albuterol will result in lesser maximum cardiac and metabolic effects than fenoterol. These findings are consistent with the hypothesis that the property of full receptor agonism may contribute to the increased risk of death associated with fenoterol.
Bremner
P
P
Department of Medicine, Wellington, School of Medicine, New Zealand.
Siebers
R
R
Crane
J
J
Beasley
R
R
Burgess
C
C
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy; D001794:Blood Pressure / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D000242:Cyclic AMP / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005280:Fenoterol / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D011188:Potassium / Q000097:blood; D012307:Risk Factors; D013599:Systole / Q000187:drug effects; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D005280:Fenoterol; D000242:Cyclic AMP; D000420:Albuterol; D011188:Potassium