Study objective: To compare the maximal extrapulmonary effects of the [beta]-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 [[QS.sub.2]I]--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 [mu]g of each drug was administered every 10 min until [QS.sub.2]I and plasma K+ had reached a plateau ([+ or -]0.1 mmol/L for K+, and [+ or -]10 ms for [QS.sub.2]I). The maximum response (Emax) and the dose of albuterol required to produce 50% of the maximum response to fenoterol [(ED.sub.5.sub.0.sub.F]) were calculated.
Results: The Emax for fenoterol was significantly greater than albuterol for plasma K+ (-1.4 vs -1.03 mmol/L; p[less than]0.002), [QS.sub.2]I (-71.8 vs -57.5 ms; p=0.047), and cAMP (33.8 vs 18.1 nmol/L; p[less than]0.002). The dose required to produce the [ED.sub.5.sub.0.sub.F] was significantly greater for albuterol than for fenoterol with potency ratios of 1.75, 1.61, and 2.26 for plasma K+, [QS.sub.2]I, 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.
Key words: [beta]-agonist; cardiovascular effects; intrinsic activity
Recent reviews published in CHEST have considered the debate concerning the use of regular [beta]-adrenergic agonists in the management of asthma.(1),(2) This debate has arisen in part from a series of case-control and cohort studies from New Zealand,(3) (4) (5) Canada,(6) and Germany(7) that have demonstrated that the use of the [beta]-agonist fenoterol is associated with an increased risk of death in patients with severe asthma or COPD compared with the more commonly used [beta]-agonist, albuterol. These studies, together with other epidemiologic and experimental evidence,(8) (9) (10) (11) have led to the hypothesis that the high-dose preparation of fenoterol was a major cause of the recent asthma mortality epidemic in New Zealand. This followed the identification of the overuse of isoproterenol forte as the most likely cause of the first epidemic of asthma deaths that occurred in a number of countries in the 1960s.(8),(9),(12),(13)
The mechanisms by which fenoterol and isoproterenol may increase the risk of death are unknown. Three main groups of mechanisms have been proposed, relating to greater bronchodilation (leading to delay in seeking medical help), an increased severity of asthma from long-term regular use,(11) and extrapulmonary effects (causing cardiac toxic) reactions resulting from their overuse in the situation of severe asthma. Although experimental and clinical studies have provided some insight into these possible mechanisms, their relative importance has not yet been established....