Extrapulmonary Effects of Fenoterol and Salbutamol in Normal Subjects

Letters to the editor 191

subjects there was an increase in bronchial Extrapulmonary effects the relative potency of fenoterol and salbuta- hyperresponsiveness only during the first mol, which requires dose-response curves in two weeks of the study, but by the end of of fenoterol and asthmatic subjects to ascertain relative bron- four weeks this increase had disappeared. In salbutamol in normal chodilator and systemic P2 receptor activity. Thorax: first published as 10.1136/thx.49.2.191-a on 1 February 1994. Downloaded from the study of Vathenen et al (ref 7) with eight subjects The 25 mg dose of atenolol in our study was asthmatic subjects it was observed that a chosen on the basis of it producing relatively (rebound) increase in hyperresponsiveness selective ,1 blockade. It is, however, well occurred, not whilst using the 13 agonist Newnham et al have attempted the difficult documented that atenolol displays dose but afterwards. In our own study (ref 14) task of trying to dissect relative and 12 related 02 blockade,'2 and so it is not, per- an increase in hyperresponsiveness was mediated cardiovascular responses to large haps, surprising that even a 25 mg dose pro- observed when using a.0 agonist in a selected doses of salbutamol and fenoterol in normal duced a degree of 02 antagonism. The im- group of 15 patients. These 15 patients were subjects with a low dose of atenolol (June portant point is that a comparable degree of selected on the condition that they had not 1993;48:656-8). There are two issues: firstly, attenuation occurred with heart rate and used any 1 agonists or 1 blockers for one year the comparative responses to similar doses of potassium responses, both of which have before the start of the study. They were part these agents by inhalation and, secondly, been shown to be 12 mediated.'-3 Indeed, this of a much larger group of 144 patients who, their selectivity at the receptor. occurred to the same extent with both feno- on average, did not show an increase in Newnham et al showed that salbutamol terol and salbutamol. bronchial hyperresponsiveness during the and fenoterol in doses of 1 mg and 3 mg from If fenoterol had stimulated cardiac ,1 use of the 13 agonist (ref 1, not presented in metered dose inhalers led to similar increases receptors to a greater degree than salbuta- in heart rate, distance, and tremor, the table). Looking at the presented table, it stroke mol, one would have predicted atenolol to seems that the more patients involved in with fenoterol causing a slightly greater fall have antagonised the chronotropic response these studies the less clear is the adverse in serum potassium concentration and a to fenoterol more than salbutamol. This was prognosis of bronchial hyperresponsiveness greater rise in systolic blood pressure than clearly not the case, with the percentage during the continuous use of a bronchodila- salbutamol. Their findings suggest smaller attenuation by atenolol at the 4 mg dose tor. This underlines our conclusion that only differences between higher doses of salbuta- being 14% for fenoterol and 16% for salbu- in subgroups of patients might the continu- mol and fenoterol on extrapulmonary effects tamol. The percentage attenuation of than other the ous use of a 12 adrenergic drug have an studies, whether the comparisons systolic blood pressure was also comparable adverse effect on bronchial hyperresponsive- have been Inade in vitro, in vivo, or in for both fenoterol (10%) and different fenoterol has salbutamol ness. The only exception seems to be the species.'2 Invariably (8%). Thus, whilst fenoterol may exhibit study of Sears and Taylor themselves (ref 3) been found to be more potent in large doses than salbutamol. intravenous greater P2 potency, there is no evidence for it with a relatively large number of 64 patients. Studies using being less selective in terms of relative car- preparations have found a 2-4 times greater However, this is the only study in which diac 11/12 receptor stimulation. It is also effect on heart rate with and this patients were allowed to use anti-inflamma- fenoterol, worth pointing out that in a study from has led to a tenfold difference in the concen- tory drugs as well as their bronchodilator Windom et a14 in asthmatic subjects there drugs. tration of intravenous solutions used rout- inely (500 salbutamol was no difference in either chronotropic or As Sears and Taylor have already acknow- pg/ml compared with systolic blood pressure responses to fenoterol ledged, the observed changes in hyper- 50 jg/ml fenoterol). The reasons for the dif- and salbutamol, in contrast with isoprenaline ferent of et are responsiveness are small. They are all findings Newnham al unclear. which produced greater effects, presumably The attempts to between 0-5 and 1-5 doubling doses of the by the authors dissect 13 adrenoceptor mediated.5 challenge test, which is virtually similar to relative and 12 effects have failed as they Our in vivo data are indeed supported by the repeatability of the challenge test' and is have shown that atenolol significantly at- in vitro data in human right atria,6 showing tenuates the 12 mediated effect on heart rate,

therefore of doubtful clinical significance. that the relative pA2 values for practolol (1, http://thorax.bmj.com/ The purpose of writing our editorial was tremor, and serum potassium concentration. antagonist) and ICI 18 551 (12 antagonist) Other based on not to present a neutral position in this designs studies by Wellstein were 5-47 and 8-24 respectively, for antagon- important issue but to show that the general et aP' or Hall et al4 may enable such relative ism of the inotropic response to fenoterol. fear that exists among doctors and patients receptor specificity to be shown. Taken together we believe that the body of about the chronic use of bronchodilators evidence the J CRANE supports hypothesis that the does not seem to be justified by the data C BURGESS effects of fenoterol on the human heart are available at this moment. We did not, and do R BEASLEY predominantly caused by stimulation of car- not, doubt that bronchodilators probably Department of Medicine, Wellington School of Medicine, diac P2 receptors. have a (small) negative influence on the long Wellington, term prognosis of bronchial hyperrespons- New Zealand B J LIPWORTH on October 2, 2021 by guest. Protected copyright. iveness in certain groups of asthmatic D M NEWNHAM patients. Subgroup analyses of our own data C WONG D G McDEVITT Department of Medicine, Department of Clinical Pharmacology, have shown that especially allergic hyper- University of Otago, Ninewells Hospital and Medical School, responsive asthmatic patients seem to have Dunedin, Dundee DDI 9SY an increased progression of asthma with con- New Zealand tinuous use of a 1 agonist.2 Another important issue which still has to be settled is what 1 Wong C, Pavord I, Williams J, Briton J, Tatters- 1 Lipworth BJ, Brown RA, McDevitt DG. Assess- field A. Bronchodilator, cardiovascular and ment of airways, tremor and chronotropic additional bronchodilator drug should be hypokalaemic effects of fenoterol, salbutamol responses to inhaled salbutamol in the quanti- used (and in what dose) when the patient and terbutaline in asthma. Lancet 1990; fication of 12 adrenoceptor blockade. BrJI Clin receives a combination of an anti-inflamma- 336:1396-9. Pharmacol 1989;28:95-102. tory drug and a bronchodilator. 2 Burgess C. An overview of experimental 2 Lipworth BJ, McFarlane LC, Coutie WJ, methods. In: Beasley C, Pearce N, eds. The McDevitt DG. Evaluation of metabolic re- role of beta receptor agonist therapy in asthma sponses to inhaled salbutamol in the measure- C P VAN SCHAYCK mortality. Boca Raton: CRC Press, 1993:127- ment of f adrenoceptor blockade. Eur J Clin C L A VAN HERWAARDEN 48. Pharmacol 1989;37:297-300. Departments of General Practice and Pulmonary 3 Wellstein A, Belz G, Palm D. Beta adrenoceptor 3 Hall JA, Petch MC, Brown MJ. Intracoronary Diseases, subtype binding activity in plasma and beta injections of salbutamol demonstrate the pres- Nijmegen University, blockade by propanolol and beta-I selective ence of functional 02 adrenoceptors in the PO Box 9101, bisoprolol in humans. Evaluation with Schild human heart. Circ Res 1989;65:546-53. 6500 HB Nijmegen, plots.JPharmacolExp Ther 1988;246:328-37. 4 Windom HH, Burgess CD, Siebers RWL, The Netherlands 4 Hall J, Petch M, Brown M. Intracoronary injec- Purdie GP, Pearce N, Crane J, et al. The pul- tions of salbutamol demonstrate the presence monary and extrapulmonary effects of inhaled of functional f2 adrenoceptors in the human ,B-agonists in patients with asthma. Clin 1 Cockcroft DW, Killian DN, Mellon JJA, Har- heart. Circ Res 1989;65:546-53. Pharmacol Ther 1990;48:296-301. greave FE. Bronchial rectivity to inhaled his- 5 Lipworth BJ, Tregaskis BF, McDevitt DG. tamine: a method and clinical survey. Clin Comparison of hypokalaemic, electrocardio- Allergy 1977;7:235-9. graphic and haemodynamic responses to 2 Schayck CP van, Kraak A, Dompeling E, Folger- AUTHORS' REPLY In reply to the letter of inhaled isoprenaline and salbutamol in young ing H, Weel C van. Dose-response relation- Crane et al there are some fundamental and elderly subjects. Eur J Clin Pharmacol ship between the decline in lung function and issues which, although discussed in the 1991;40:255-60. the daily dose of salbutamol and ipratropium 6 Wilson C, Lincoln C. 13-adrenoceptor subtypes paper, further bromide. Am Rev Respir Dis 1992;145(Sup- require clarification. in human, rat, guinea-pig and rabbit atria. J pl 2):A61. The purpose of our study was not to assess Cardiovasc Pharmacol 1984;6:1216-21.