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. 2000 Aug;55(8):650–656. doi: 10.1136/thorax.55.8.650

Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects

A Guhan 1, S Cooper 1, J Oborne 1, S Lewis 1, J Bennett 1, A Tattersfield 1
PMCID: PMC1745819  PMID: 10899240

Abstract

BACKGROUND—The main adverse effects of inhaled long acting β2 agonists relate to their systemic activity. The systemic effects seen over eight hours after inhalation of three doses of salmeterol and formoterol were therefore compared in normal subjects.
METHODS—A double blind, randomised, crossover study was carried out in 16 healthy subjects who inhaled formoterol 24, 48 and 96 µg (via Turbuhaler®), salmeterol 100, 200 and 400 µg (via Diskhaler®), or placebo on separate days. Heart rate, systolic and diastolic blood pressure, and plasma potassium and glucose concentrations were measured for eight hours following each drug and mean values were used to plot the time course of change after each dose. Mean maximum (or minimum) absolute values were used to construct dose-response curves to calculate the relative dose potency of the two drugs. Lunch was taken after the four hour readings and, since this caused additional changes to the main outcome measures, data from the first four hours are also presented in a post hoc analysis.
RESULTS—Both salmeterol and formoterol caused an early dose dependent increase in heart rate and glucose concentrations and a fall in diastolic blood pressure and plasma potassium concentration; formoterol also caused an early increase in systolic blood pressure. The cardiovascular effects occurred more rapidly than the metabolic effects and the response to formoterol was faster than that of salmeterol, apart from the glycaemic response. The effects of salmeterol were slightly more prolonged than those of formoterol, although some dose related effects were apparent at eight hours with both drugs. The relative dose potency for formoterol compared with salmeterol at four and eight hours for the different end points excluding systolic blood pressure ranged from 1.6 to 7.0after adjusting for baseline values. Relative dose potencies (95% CI) for maximum heart rate and plasma potassium concentrations were 4.1 (3.0 to 5.6) and 5.8 (4.1 to 8.6) over four hours and 2.4 (1.2 to 3.8) and 3.0 (1.2 to 5.7) over eight hours.
CONCLUSIONS—Formoterol and salmeterol cause dose related changes in heart rate, diastolic blood pressure, and plasma glucose and potassium concentrations. Formoterol has a more rapid onset for most end points whereas salmeterol has slightly more prolonged activity. Both drugs have a relatively modest therapeutic window. The relative dose potencies of the two drugs for the main end points were similar to the fourfold difference in recommended doses. Some differences in the pharmacological profile of the two drugs emerged and are as yet unexplained.



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Selected References

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  1. Anderson G. P. Formoterol: pharmacology, molecular basis of agonism, and mechanism of long duration of a highly potent and selective beta 2-adrenoceptor agonist bronchodilator. Life Sci. 1993;52(26):2145–2160. doi: 10.1016/0024-3205(93)90729-m. [DOI] [PubMed] [Google Scholar]
  2. Ball D. I., Brittain R. T., Coleman R. A., Denyer L. H., Jack D., Johnson M., Lunts L. H., Nials A. T., Sheldrick K. E., Skidmore I. F. Salmeterol, a novel, long-acting beta 2-adrenoceptor agonist: characterization of pharmacological activity in vitro and in vivo. Br J Pharmacol. 1991 Nov;104(3):665–671. doi: 10.1111/j.1476-5381.1991.tb12486.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bennett J. A., Harrison T. W., Tattersfield A. E. The contribution of the swallowed fraction of an inhaled dose of salmeterol to it systemic effects. Eur Respir J. 1999 Feb;13(2):445–448. doi: 10.1183/09031936.99.13244599. [DOI] [PubMed] [Google Scholar]
  4. Bennett J. A., Smyth E. T., Pavord I. D., Wilding P. J., Tattersfield A. E. Systemic effects of salbutamol and salmeterol in patients with asthma. Thorax. 1994 Aug;49(8):771–774. doi: 10.1136/thx.49.8.771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bennett J. A., Tattersfield A. E. Time course and relative dose potency of systemic effects from salmeterol and salbutamol in healthy subjects. Thorax. 1997 May;52(5):458–464. doi: 10.1136/thx.52.5.458. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bremner P., Woodman K., Burgess C., Crane J., Purdie G., Pearce N., Beasley R. A comparison of the cardiovascular and metabolic effects of formoterol, salbutamol and fenoterol. Eur Respir J. 1993 Feb;6(2):204–210. [PubMed] [Google Scholar]
  7. Burgess C., Ayson M., Rajasingham S., Crane J., Della Cioppa G., Till M. D. The extrapulmonary effects of increasing doses of formoterol in patients with asthma. Eur J Clin Pharmacol. 1998 Apr;54(2):141–147. doi: 10.1007/s002280050435. [DOI] [PubMed] [Google Scholar]
  8. Decker N., Quennedey M. C., Rouot B., Schwartz J., Velly J. Effects of N-aralkyl substitution of beta-agonists on alpha- and beta-adrenoceptor subtypes: pharmacological studies and binding assays. J Pharm Pharmacol. 1982 Feb;34(2):107–112. doi: 10.1111/j.2042-7158.1982.tb04195.x. [DOI] [PubMed] [Google Scholar]
  9. Kaumann A. J., Molenaar P. Modulation of human cardiac function through 4 beta-adrenoceptor populations. Naunyn Schmiedebergs Arch Pharmacol. 1997 Jun;355(6):667–681. doi: 10.1007/pl00004999. [DOI] [PubMed] [Google Scholar]
  10. Kesten S., Chapman K. R., Broder I., Cartier A., Hyland R. H., Knight A., Malo J. L., Mazza J. A., Moote D. W., Small P. A three-month comparison of twice daily inhaled formoterol versus four times daily inhaled albuterol in the management of stable asthma. Am Rev Respir Dis. 1991 Sep;144(3 Pt 1):622–625. doi: 10.1164/ajrccm/144.3_Pt_1.622. [DOI] [PubMed] [Google Scholar]
  11. Källén A., Larsson P. Dose response studies: how do we make them conclusive? Stat Med. 1999 Mar 30;18(6):629–641. doi: 10.1002/(sici)1097-0258(19990330)18:6<629::aid-sim72>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  12. Lecaillon J. B., Kaiser G., Palmisano M., Morgan J., Della Cioppa G. Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via Aerolizer. Eur J Clin Pharmacol. 1999 Apr;55(2):131–138. doi: 10.1007/s002280050607. [DOI] [PubMed] [Google Scholar]
  13. Löfdahl C. G., Svedmyr N. Formoterol fumarate, a new beta 2-adrenoceptor agonist. Acute studies of selectivity and duration of effect after inhaled and oral administration. Allergy. 1989 May;44(4):264–271. doi: 10.1111/j.1398-9995.1989.tb01068.x. [DOI] [PubMed] [Google Scholar]
  14. Maconochie J. G., Forster J. K. Dose-response study with high-dose inhaled salmeterol in healthy subjects. Br J Clin Pharmacol. 1992 Mar;33(3):342–345. doi: 10.1111/j.1365-2125.1992.tb04049.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Maesen F. P., Costongs R., Smeets J. J., Brombacher P. J., Zweers P. G. The effect of maximal doses of formoterol and salbutamol from a metered dose inhaler on pulse rates, ECG, and serum potassium concentrations. Chest. 1991 Jun;99(6):1367–1373. doi: 10.1378/chest.99.6.1367. [DOI] [PubMed] [Google Scholar]
  16. Palmqvist M., Ibsen T., Mellén A., Lötvall J. Comparison of the relative efficacy of formoterol and salmeterol in asthmatic patients. Am J Respir Crit Care Med. 1999 Jul;160(1):244–249. doi: 10.1164/ajrccm.160.1.9901063. [DOI] [PubMed] [Google Scholar]
  17. Pauwels R. A., Löfdahl C. G., Postma D. S., Tattersfield A. E., O'Byrne P., Barnes P. J., Ullman A. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med. 1997 Nov 13;337(20):1405–1411. doi: 10.1056/NEJM199711133372001. [DOI] [PubMed] [Google Scholar]
  18. Pearlman D. S., Chervinsky P., LaForce C., Seltzer J. M., Southern D. L., Kemp J. P., Dockhorn R. J., Grossman J., Liddle R. F., Yancey S. W. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N Engl J Med. 1992 Nov 12;327(20):1420–1425. doi: 10.1056/NEJM199211123272004. [DOI] [PubMed] [Google Scholar]
  19. Politiek M. J., Boorsma M., Aalbers R. Comparison of formoterol, salbutamol and salmeterol in methacholine-induced severe bronchoconstriction. Eur Respir J. 1999 May;13(5):988–992. doi: 10.1034/j.1399-3003.1999.13e10.x. [DOI] [PubMed] [Google Scholar]
  20. Rabe K. F., Jörres R., Nowak D., Behr N., Magnussen H. Comparison of the effects of salmeterol and formoterol on airway tone and responsiveness over 24 hours in bronchial asthma. Am Rev Respir Dis. 1993 Jun;147(6 Pt 1):1436–1441. doi: 10.1164/ajrccm/147.6_Pt_1.1436. [DOI] [PubMed] [Google Scholar]
  21. Roux F. J., Grandordy B., Douglas J. S. Functional and binding characteristics of long-acting beta 2-agonists in lung and heart. Am J Respir Crit Care Med. 1996 May;153(5):1489–1495. doi: 10.1164/ajrccm.153.5.8630591. [DOI] [PubMed] [Google Scholar]
  22. Smyth E. T., Pavord I. D., Wong C. S., Wisniewski A. F., Williams J., Tattersfield A. E. Interaction and dose equivalence of salbutamol and salmeterol in patients with asthma. BMJ. 1993 Feb 27;306(6877):543–545. doi: 10.1136/bmj.306.6877.543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Strauss M. H., Reeves R. A., Smith D. L., Leenen F. H. The role of cardiac beta-1 receptors in the hemodynamic response to a beta-2 agonist. Clin Pharmacol Ther. 1986 Jul;40(1):108–115. doi: 10.1038/clpt.1986.146. [DOI] [PubMed] [Google Scholar]
  24. Tötterman K. J., Huhti L., Sutinen E., Backman R., Pietinalho A., Falck M., Larsson P., Selroos O. Tolerability to high doses of formoterol and terbutaline via Turbuhaler for 3 days in stable asthmatic patients. Eur Respir J. 1998 Sep;12(3):573–579. doi: 10.1183/09031936.98.12030573. [DOI] [PubMed] [Google Scholar]
  25. Ullman A., Svedmyr N. Salmeterol, a new long acting inhaled beta 2 adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients. Thorax. 1988 Sep;43(9):674–678. doi: 10.1136/thx.43.9.674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wallin A., Melander B., Rosenhall L., Sandström T., Wåhlander L. Formoterol, a new long acting beta 2 agonist for inhalation twice daily, compared with salbutamol in the treatment of asthma. Thorax. 1990 Apr;45(4):259–261. doi: 10.1136/thx.45.4.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wilding P., Clark M., Thompson Coon J., Lewis S., Rushton L., Bennett J., Oborne J., Cooper S., Tattersfield A. E. Effect of long-term treatment with salmeterol on asthma control: a double blind, randomised crossover study. BMJ. 1997 May 17;314(7092):1441–1446. doi: 10.1136/bmj.314.7092.1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. van Noord J. A., Smeets J. J., Raaijmakers J. A., Bommer A. M., Maesen F. P. Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action. Eur Respir J. 1996 Aug;9(8):1684–1688. doi: 10.1183/09031936.96.09081684. [DOI] [PubMed] [Google Scholar]
  29. van der Molen T., Postma D. S., Turner M. O., Jong B. M., Malo J. L., Chapman K., Grossman R., de Graaff C. S., Riemersma R. A., Sears M. R. Effects of the long acting beta agonist formoterol on asthma control in asthmatic patients using inhaled corticosteroids. The Netherlands and Canadian Formoterol Study Investigators. Thorax. 1997 Jun;52(6):535–539. doi: 10.1136/thx.52.6.535. [DOI] [PMC free article] [PubMed] [Google Scholar]

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