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Partial vs Full β-Receptor Agonism

1996; Elsevier BV; Volume: 109; Issue: 4 Linguagem: Inglês

10.1378/chest.109.4.957

1931-3543

Peter Bremner, Robert Siebers, Julian Crane, Richard Beasley, Carl Burgess,

Inhalation and Respiratory Drug Delivery

Study objective To compare the maximal extrapulmonary effects of the β-agonists albuterol and fenoterol in eight healthy volunteers. Subjects and 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 albuterol and fenoterol. In eight healthy volunteers, 400 µg of each drug was administered every 10 min until QS2I and plasma K+ had reached a plateau (±0.1 mmol/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 β-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. To compare the maximal extrapulmonary effects of the β-agonists albuterol and fenoterol in eight healthy volunteers. 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 albuterol and fenoterol. In eight healthy volunteers, 400 µg of each drug was administered every 10 min until QS2I and plasma K+ had reached a plateau (±0.1 mmol/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. 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). These findings suggest that albuterol behaves as a partial agonist at β-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.