PHARMACODYNAMICS AND DRUG ACTION The pulmonary and extrapulmonary effects of inhaled P-agonists in patients with asthma The cardiovascular, respiratory, and hypokalemic effects of repeated inhalation of fenoterol, albuterol, and isoproterenol were compared in 12 subjects with stable asthma according to a double-blind, crossover design. Ipratropium bromide served as a control providing bronchodilatation without extrapuhnonary effects. Subjecs inhaled the f3-agonists on an equal-weight basis (400 lig) at 0, 30, 40, and 45 minutes. Measurements of heart rate, blood pressure, total electromechanical systole (measure of inotropic activity), preejection period, QTc interval, plasma potassium levels, and forced expiratory volume in 1 second were made 5 minutes after each dose and again at 60 and 75 minutes. There were no differences in the bronchodilating effect between the 8-agonists. However, both fenoterol and isoproterenol resulted in greater positive inotropic stimulation than did albuterol, and fenoterol caused a greater fall in plasma potassium levels than did the other 0-agonists. (CLIN PHARMACOL THER 1990;48:296-301.) Hugh H. Windom, MD, Carl D. Burgess, MD, MRCP, Robert W. L. Siebers, MIBiol, FNZIMLT, Gordon Purdie, BSc, Neil Pearce, PhD, Julian Crane, FRACP, and Richard Beasley, FRACP Wellington, New Zealand The risk of dying of asthma among patients with severe asthma in New Zealand has been shown to be increased at least tenfold in patients prescribed the p- adrenergic agonist fenotero1.1'2 This followed previous analyses of the multinational asthma death epidemic of the late 1960s that implicated inhaled high-dose iso- proterenol in the rise in mortality rates.3'4 Before these large-scale epidemiologic studies validated the associ- ation between certain B-agonists and death as a result of asthma, others had expressed concerns about the potential for deleterious effects of aerosolized bron- chodilators in the treatment of asthma.' Complementing the epidemiologic studies, labora- tory investigations have demonstrated considerably greater cardiovascular, electrophysiologic, and meta- From the Department of Medicine, Department of Community Health, Wellington School of Medicine. Supported by the Medical Research Council of New Zealand and the Asthma Foundation of New Zealand. Received for publication Dec. 4, 1989; accepted June 14, 1990. Reprint requests: Carl D. Burgess, MD, Department of Medicine, Wellington School of Medicine, P.O. Box 7343, Wellington S., Wellington, New Zealand. 13/1/23253 296 bolic effects with inhaled fenoterol and isoproterenol compared with alternative 13-agonists such as albuterol and terbutaline.9-14 These distinct characteristics reflect the wide range of 13-2-receptor selectivity and potency within the overall class of 13-agonists. We confirmed these earlier findings in a study in healthy subjects in which repeated inhalation of fenoterol demonstrated inotropic effects similar to those of isoproterenol and greater chronotropic, electrocardiographic (ECG), and hypokalemic effects than both isoproterenol and albu- tero1.15 Simply extrapolating these findings from healthy vol- unteers to a population with asthma would ignore the influence of 13-receptor tachyphylaxis caused by chronic 13-agonist use16-2° and intrinsic differences in 13-receptor function in patients with asthma.21'22 We have thus at- tempted to extend our previous investigation by ex- amining the cardiovascular, respiratory, and hypoka- lemic effects of inhaled fenoterol, albuterol, and isoproterenol in a group of patients with asthma. Ipratropium bromide was included as a hemodynamic and metabolic placebo," providing active respiratory effects ethically necessary for patients who were told to withhold 13-agonists for at least 6 hours before the study.