Drug Safety

, Volume 7, Issue 1, pp 54–70

Risks Versus Benefits of Inhaled β2-Agonists in the Management of Asthma

  • Brian J. Lipworth
Drug Experience

Summary

The therapeutic goal for the treatment of asthma should be to suppress bronchial mucosal inflammation with preventive drugs such as inhaled corticosteroids, and to relieve symptoms of wheezing and breathlessness with bronchodilator drugs. The lower recommended doses of inhaled β2-agonists produce rapid effective bronchodilatation without systemic adverse effects; higher doses may produce substantial improvements in airway response which may help patients with more severe airflow obstruction. Higher doses of inhaled β2-agonists also cause dose-related systemic adverse β2 effects including tremor, tachycardia, hypokalaemia and associated electrocar-diographic sequelae. In this respect, although fenoterol appears to cause greater extrapulmonary β2-mediated adverse effects at higher doses, there is no evidence to suggest that it is any less β2 selective. There is also some evidence to suggest that use of regular inhaled β2-agonists may cause increased bronchial hyperreactivity and possibly deterioration in disease control. Patients who require such regular use should therefore be given additional anti-inflammatory therapy with inhaled corticosteroids. The recent availability of novel, longer-acting inhaled β2-agonists such as salmeterol and formoterol will also make necessary a careful reappraisal of their long term use in patients with asthma.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ariens EJ, Simonis AM. Physiological and pharmacological aspects of adrenergic receptor classification. Biochemical Pharmacology 32: 1539–1545, 1983PubMedGoogle Scholar
  2. Arnold JMO, McDevitt DG. Reflex vagal withdrawal and the haemodynamic response to intravenous isoproterenol in the presence of beta-antagonists. Clinical Pharmacology and Therapeutics 40: 199–208, 1986PubMedGoogle Scholar
  3. Arnold JMO, O’Connor PC, Riddell JG, Harron DWG, Shanks RG, et al. Effects of the beta-2 adrenoceptor antagonist ICI 1118,551 on exercise tachycardia and isoprenaline-induced beta-adrenoceptor responses in man. British Journal of Clinical Pharmacology 19: 619–630, 1985PubMedGoogle Scholar
  4. Arvidsson P, Larsson S, Lofdahl CG, Melander B, Wahlander L, et al. Formoterol, a new long-acting bronchodilator for inhalation. European Respiratory Journal 2: 325–330, 1989PubMedGoogle Scholar
  5. Ask JA, Stene-Larsen G, Helle KB, Resch F. Functional β1 and β2-adrenoceptors in the human myocardium. Acta Physiologica Scandinavica 123: 81–88, 1985PubMedGoogle Scholar
  6. Baker AJ, Fuller RW. Anti-inflammatory effect of salmeterol on human alveolar macrophages. American Review of Respiratory Disease 141: A394, 1990Google Scholar
  7. Blackwell EW, Briant RH, Conolly ME, Davies DS, Dollery CT. Metabolism of isoprenaline after aerosol and direct intrabronchial administration in man and dog. British Journal of Pharmacology 50: 587–591, 1974PubMedGoogle Scholar
  8. Bradshaw J, Brittain RT, Coleman RA, Jack D, Kennedy I, et al. The design of salmeterol, a long-acting selective -adrenoceptor agonist. British Journal of Pharmacology 92: 590P, 1987Google Scholar
  9. Bristow MR, Ginsburg R. Beta-2 receptors on myocardial cells in human ventricular myocardium. American Journal of Cardiology 57: 3F-6F, 1986Google Scholar
  10. Bristow MR, Ginsburg R, Umans V, et al. β 1- and β2-adrenergic receptor subpopulations in non-failing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective β≃receptor down regulation in heart failure. Circulation Research 59: 297–309, 1986PubMedGoogle Scholar
  11. Britton J, Hanley SP, Garnett HV, Hadfield JW, Tattersfield AE. Dose related effects of salbutamol and ipratropium bromide on airway calibre and reactivity in subjects with asthma. Thorax 43: 300–305, 1988PubMedGoogle Scholar
  12. Britton J, Pavord I, Wong C, Tattersfield AE. β2-Agonists in asthma. Lancet 336: 300–301, 1991Google Scholar
  13. Britton M. Salmeterol: three month comparison with salbutamol in asthmatic patients. European Respiratory Journal 3: 786, 1990Google Scholar
  14. Brodde OE, Brinkmann M, Schemoth R, O’Hara N, Daul A. Terbutaline induced desensitization of human lymphocyte beta-2 adrenoceptors: accelerated restoration of beta-adrenoceptor responses by prednisolone and ketotifen. Journal of Clinical Investigation 76: 1096–1101, 1985PubMedGoogle Scholar
  15. Brodde OE, Howe U, Egerszegi S, Konietzko N, Michel MC. Effect of prednisolone and ketotifen on β2-adrenoceptors in asthmatic patients receiving β2-bronchodilators. European Journal of Clinical Pharmacology 34: 145–150, 1988PubMedGoogle Scholar
  16. Brodde OE, Karad K, Zerkowski HR, Rohm N, Reidmesiter JC. Coexistence of beta-1 and beta-2 adrenoceptors in human right atrium: direct identification by (−)−[125I]-iodocyanopindolol binding. Circulation Research 53: 752–758, 1983PubMedGoogle Scholar
  17. Brodde OE, O’Hara N, Zerkowski HR, Rohn N. Human cardiac β-adrenoceptor: both β 1- and fo-adrenoceptors are functionally coupled to the adenylate-cyclose in the right atrium. Journal of Cardiovascular Pharmacology 6: 1184–1191, 1984PubMedGoogle Scholar
  18. Brown MJ, Brown DG, Murphy MB. Hypokalaemia from beta-2 receptor stimulation by circulating epinephrine. New England Journal of Medicine 309: 1414–1419, 1983PubMedGoogle Scholar
  19. Butchers PR, Cousins SA, Vardey CJ. Salmeterol: a potent and long acting inhibitor of the release of inflammatory and spasmogenic medications from human lung. British Journal of Pharmacology 92 (Suppl.): 745P, 1987Google Scholar
  20. Clauzel AM, Rifai N, Godard P, Bony C, Vergnand A, et al. Efficacy and tolerance of formoterol long term treatment (12 months) in severe asthmatic patients. American Review of Respiratory Disease 141 (Suppl.): A206, 1990Google Scholar
  21. Cockroft DW, Murdock KY. Comparative effects of inhaled salbutamol, soldium cromoglycate and beclomethasone dipro-pionate on allergen-induced early asthmatic responses, late asthmatic responses and increased bronchial responsiveness to histamine. Journal of Allergy and Clinical Immunology 79: 734–740, 1987Google Scholar
  22. Collier JG, Dobbs RJ, Williams I. Salbutamol causes a tachycardia due to the inhaled rather than the swallowed fraction. British Journal of Clinical Parmacology 9: 273–274, 1980Google Scholar
  23. Crane J, Burgess C, Beasley R. Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline. Thorax 44: 136–140, 1989bPubMedGoogle Scholar
  24. Crane J, Pearce N, Flatt A, Burgess C, Jackson R, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981–1983: case-control study. Lancet I: 917–922, 1989aGoogle Scholar
  25. Dahl R. (1989). Salmeterol one month studies in asthmatic patients. European Respiratory Journal 2(Suppl. 8): 677s, 1989Google Scholar
  26. Dangman KJ, Danilo Jr P, Hordof AJ, Mary-Rabine L, Reder RF, et al. Electrophysiologic characteristics of human ventricular and Purkinje fibres. Circulation 65: 362–368, 1982PubMedGoogle Scholar
  27. Deenstra M, Haalboom JRE, Struyvenberg A. Decrease of plasma potassium due to inhalation of beta-2 agonists: absence of an additional effect of intravenous theophylline. European Journal of Clinical Investigation 18: 162–165, 1988PubMedGoogle Scholar
  28. Ellul-Micalef R, Fenech FF. Effect of intravenous prednisolone in asthmatics with diminished adrenergic responsiveness. Lancet 2: 1269–1271, 1975Google Scholar
  29. Gille E, Lemoine H, Ehle B, Kaumann AJ. The affects of (−)- propranolol for β1- and β2-adrenoceptors of human heart: differential antagonism of the positive inotropic effects and adenylate cyclase stimulation by (-)-noradrenaline and (−)adrenaline. Naunyn-Schmiedeberg’s Archives of Pharmacology 331: 60–70, 1985PubMedGoogle Scholar
  30. Grainger J, Woodman K, Pearce N, Crane J, Burgess C, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981–7: a further case-control study. Thorax 46: 105–111, 1991PubMedGoogle Scholar
  31. Gray BJ, Frame MH, Costello JF. A comparative double-blind study of the bronchodilator effects and side-effects of inhaled fenoteral and terbutaline administered in equipotent doses. British Journal of Diseases of the Chest 76: 341–350, 1982PubMedGoogle Scholar
  32. Hall JA, Petch MC, Brown MJ. Intracoronary injections of salbutamol demonstrate the presence of functional beta-2 adrenoceptors in the human heart. Circulation Research 65: 546–553, 1989PubMedGoogle Scholar
  33. Harvey JE, Tattersfield AE. Airway response to salbutamol: effect of regular salbutamol inhalation in normal, atopic and asthmatic subjects. Thorax 37: 280–287, 1982PubMedGoogle Scholar
  34. Hauck RW, Böhm M, Gengenbach S, Sunder-Plassmann L, Fruhmann G, et al. β2-adrenoceptors in human lung and peripheral mononuclear leukocytes of untreated and terbutaline treated patients. Chest 98: 376–381, 1990PubMedGoogle Scholar
  35. Heitz A, Schwartz J, Velly J. Beta-adrenoceptors of the human myocardium: determination of beta-1 and beta-2 subtypes by radioligand binding. British Journal of Pharmacology 80: 711–717, 1983PubMedGoogle Scholar
  36. Higgins RM, Cookson WOCM, Lane DG, John SM, McCarthy GL. Cardiac arrhythmias caused by nebulised beta-agonist therapy. Lancet 2: 863–864, 1987PubMedGoogle Scholar
  37. Howarth PH, Durham SR, Lee TH, Kay AB, Church MK, et al. Influence of albuterol, cromalyn sodium and ipratropium bromide on airway and circulating mediator responses to allergic bronchial provocation in asthma. American Review of Respiratory Disease 132: 986–992, 1985PubMedGoogle Scholar
  38. Inman WHN, Adelstein AM. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet 2: 279–283, 1969PubMedGoogle Scholar
  39. Jack D. A way of looking at agonism and antagonism: lessons from salbutamol, salmeterol and other β-adrenoceptor agonists. British Journal of Clinical Pharmacology 31: 501–514, 1991PubMedGoogle Scholar
  40. Jackson RT, Beaglehole R, Rea HH, Sutherland DC. Mortality from asthma: a new epidemic in New Zealand. British Medical Journal 285: 771–774, 1982PubMedGoogle Scholar
  41. Jeppsson AB, Lofdahl CG, Waldeck B, Widmark E. On the predictive value of experiments in vitro in the evaluation of the effect duration of bronchodilator drugs for local administration. Pulmonary Pharmacology 2: 81–85, 1989PubMedGoogle Scholar
  42. Kerrebijn KF, van Essen-Zandvliet EEM, Neijens HJ. Effects of long-term treatment with inhaled corticosteroids and beta-agonists on the bronchial responsiveness in children with asthma. Journal of Allergy and Clinical Immunology 79: 653–659, 1987PubMedGoogle Scholar
  43. Kraan J, Koeter GH, van der Mark TW, Sluiter HJ, de Vries K. Changes in bronchial hyperreactivity induced by 4 weeks treatment with anti-asthma drugs in patients with allergic asthma: a comparison of budesonide and terbutalene. Journal of Allergy and Clinical Immunology 76: 628–636, 1985PubMedGoogle Scholar
  44. Kung M, Croley SW, Phillips BA. Systemic cardiovascular and metabolic effects associated with the inhalation of an increased dose of albuterol; influence of mouth rinsing and gargling. Chest 91: 382–387, 1987PubMedGoogle Scholar
  45. Lai CKW, Twentyman OP, Holgate ST. The effect of an increase in inhaled antigen dose after inhaled rimeterol hydrobromide on the occurrence and magnitude of the late asthmatic response and the associated changes of non-specific bronchial responsiveness. American Review of Respiratory Disease 140: 917–923, 1989PubMedGoogle Scholar
  46. Lands AM, Arnold A, McAuliff JP, Ludvena FP, Brown Jr PE. Differentiation of receptor systems activated by sympathomimetic amines. Nature 214: 597–598, 1967PubMedGoogle Scholar
  47. Larsson S, Svedmyr N. Bronchodilatory effect and side effects of beta-2 adrenoceptor stimulants by different modes of administration (tablets, metered aerosol and combinations thereof). American Review of Respiratory Disease 116: 861–868, 1977PubMedGoogle Scholar
  48. Lipworth BJ, Brown RA, McDevitt DG. Assessment of airways, tremor and chronotropic responses to inhaled salbutamol in the quantification of beta-2 adrenoceptor blockade. British Journal of Clinical Pharmacology 28: 95–102, 1989aPubMedGoogle Scholar
  49. Lipworth BJ, Clark RA, Dhillon DP, Brown RA, McDevitt DG. Beta-adrenoceptor responses to high doses of inhaled salbutamol in patients with bronchial asthma. British Journal of Clinical Pharmacology 26: 527–533, 1988PubMedGoogle Scholar
  50. Lipworth BJ, Clark RA, Dhillon DP, McDevitt DG. Comparison of the effects of prolonged treatment with low and high doses of inhaled terbutaline on β-adrenoceptor responsiveness in patients with chronic obstructive pulmonary disease. American Review of Respiratory Disease 142: 338–342, 1990aPubMedGoogle Scholar
  51. Lipworth BJ, Clark RA, Dhillon DP, McDevitt DG. Subsensitivity of β-adrenoceptor responses in asthmatic patients taking regular low-dose inhaled salbutamol. European Journal of Clinical Pharmacology 38: 203–205, 1990bPubMedGoogle Scholar
  52. Lipworth BJ, Clark RA, Dhillon DP, Moreland TA, Struthers AD, et al. Pharmacokinetics, efficacy and adverse effects of sublingual salbutamol in patients with asthma. European Journal of Clinical Pharmacology 37: 567–571, 1989bPubMedGoogle Scholar
  53. Lipworth BJ, Irvine NA, McDevitt DG. A dose-ranging study to evaluate the β1-adrenoceptor selectivity of bisoprolol. European Journal of Clinical Pharmacology 40: 135–139, 1991bPubMedGoogle Scholar
  54. Lipworth BJ, McDevitt DG. Beta-adrenoceptor responses to inhaled salbutamol in normal subjects. European Journal of Clinical Pharmacology 36: 239–245, 1989cPubMedGoogle Scholar
  55. Lipworth BJ, McDevitt DG, Struthers AD. Systemic beta-adrenoceptor responses to salbutamol given by metered-dose inhaler alone and with pear-shaped spacer attachment: comparison of electrocardiographic, hypokalaemic and haemodynamic effects. British Journal of Clinical Pharmacology 27: 837–842, 1989dPubMedGoogle Scholar
  56. Lipworth BJ, McDevitt DG, Struthers AD. Prior treatment with diuretic augments the hypokalaemic and electrocardiographic effects of inhaled albuterol. American Journal of Medicine 86: 653–657, 1989fPubMedGoogle Scholar
  57. Lipworth BJ, McFarlane LC, Coutie WJ, McDevitt DG. Evaluation of the metabolic responses to inhaled salbutamol in the measurement of beta-2 adrenoceptor blockade. European Journal of Clinical Pharmacology 37: 297–300, 1989ePubMedGoogle Scholar
  58. Lipworth BJ, Struthers AD, McDevitt DG. Tachyphylaxis to systemic but not to airways responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. American Review of Respiratory Disease 140: 586–592, 1989gPubMedGoogle Scholar
  59. Lipworth BJ, Tregaskis BF, McDevitt DG. Comparison of hypokalaemic, elctrocardiographic and haemodynamic responses to inhaled isoprenaline and salbutamol in young and elderly subjects. European Journal of Clinical Pharmacology 40: 255–260, 1991aPubMedGoogle Scholar
  60. Lofdahl CG, Svedmyr N. Formoterol fumarate, a new β2-adrenoceptor agonist. Allergy 44: 264–271, 1989PubMedGoogle Scholar
  61. McAlpine LG, Thomson NC. Prophylaxis of exercise-induced asthma with inhaled formoterol, a long-acting β2-adrenergic agonist. Respiratory Medicine 84: 293–295, 1990PubMedGoogle Scholar
  62. McDevitt DG, Shanks RG, Swanton RG. Further observations on the cardiotoxicity of isoprenaline during hypoxià. British Journal of Pharmacology 50: 335–344, 1974PubMedGoogle Scholar
  63. Maesen FPV, Smeets JJ, Gubbelmans HLL, Zweers PGM. Bronchodilator effect of inhaled formoterol vs salbutamol over 12 hours. Chest 97: 590–594, 1990aPubMedGoogle Scholar
  64. Maesen FPV, Smeets JJ, Gubbelmans JLL, Zweers PGM. Formoterol in the treatment of nocturnal asthma. Chest 98: 866–876, 1990bPubMedGoogle Scholar
  65. Molema J, Lammers JWJ, van Herwaarden CLA, Folgering HTM. Effects of inhaled beclomethasone dipropionate on beta-2 receptor function in the airways and adrenal responsiveness in bronchial asthma. European Journal of Clinical Pharmacology 34: 577–583, 1988PubMedGoogle Scholar
  66. Newnham D, Ingram C, Earnshaw J, Palmer JBD, Dhillon DP. Duration of action of inhaled salmeterol against exercise induced asthma. American Review of Respiratory Disease 143: A29, 1991Google Scholar
  67. Newnham DM, Wheeldon NM, McDevitt DG, Lipworth BJ. Comparison of the β2-adrenoceptor selectivity of fenoterol and salbutamol. Proceedings of the American Thoracic Society. Abstract. American Review of Respiratory Disease, in press, 1992Google Scholar
  68. Nordrehaug JE, Johannessen KE, Von Der Lippe G. Serum potassium concentration as a risk factor of ventricular arrhythmias early in acute myocardial infarction. Circulation 71: 645–649, 1985PubMedGoogle Scholar
  69. O’Donnell SR. An examination of some β-adrenoceptor stimulants for selectivity using the isolated trachea and atria of the guinea pig. European Journal of Pharmacology 19: 371–379, 1972PubMedGoogle Scholar
  70. O’Donnell SR, Wanstall JC. Potency and selectivity in vitro of compounds related to isoprenaline and orciprenaline on β- adrenoceptors in the guinea pig. British Journal of Pharmacology 52: 401–417, 1974Google Scholar
  71. O’Donnell SR, Wanstall JC. Evidence that the efficacy (intrinsic activity) of fenoterol is higher than that of salbutamol on β- adrenoceptors in guinea-pig trachea. European Journal of Pharmacology 47: 333–340, 1978PubMedGoogle Scholar
  72. O’Shaughnessy K, Taylor IK, Fuller RW. β2-Agonists in asthma. Lancet 337: 45–46, 1991Google Scholar
  73. Page CP. One explanation of the asthma paradox: inhibition of natural anti-inflammatory mechanism by fo-agonists. Lancet 337: 717–720, 1991PubMedGoogle Scholar
  74. Paterson JW, Conolly ME, Davies DS, Dollery CT. Isoprenaline resistance and the use of pressurised aerosols in asthma. Lancet 2: 426–429, 1968PubMedGoogle Scholar
  75. Pearce N, Grainger J, Atkinson M, Crane J, Burgess C, et al. Case control study of prescribed fenoterol and death from asthma in New Zealand 1977–1981. Thorax 45: 170–175, 1990PubMedGoogle Scholar
  76. Reisman RE. Asthma induced by adrenergic aerosols. Journal of Allergy 46: 162–170, 1970PubMedGoogle Scholar
  77. Repsher LH, Anderson JA, Bush RK, et al. Assessment of tachyphylaxis following prolonged therapy of asthma with albuterol aerosol. Chest 85: 34–38, 1984PubMedGoogle Scholar
  78. Roden DM, Iansmith DHS. Effects of low potassium or magnesium concentrations on isolated cardiac muscle. American Journal of Medicine 82 (Suppl. 3A): 18–23, 1987PubMedGoogle Scholar
  79. Rogers T, Higgins K, Morice A. β2-Agonists in asthma. Lancet 336: 46, 1991Google Scholar
  80. Rosenhall L, Sandstrom T, Wallin A. Formoterol, a long acting inhaled β2-agonist, twice-daily for 1 year in asthmatic patients. American Review of Respiratory Diseases 141 (Suppl.): A210, 1990Google Scholar
  81. Scheinin M, Koulu M, Laurikainen E, Allonen H. Hopokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled dose-response study in healthy volunteers. British Journal of Clinical Pharmacology 24: 645–653, 1987PubMedGoogle Scholar
  82. Sears MR, Rea HH, Fenwick J, et al. 75 deaths in asthmatics prescribed home nebulisers. British Medical Journal 294: 477–480, 1987PubMedGoogle Scholar
  83. Sears MR, Taylor RD, Print CG, Lake DC, Quingquing L, et al. Regular inhaled β-agonist treatment in bronchial asthma. Lancet 336: 1391–1396, 1990PubMedGoogle Scholar
  84. Shamroth L. The Q-T interval. In An introduction to electrocar-diography, pp. 141–144, Blackwell Scientific Publications, Oxford 1982Google Scholar
  85. Speizer FE, Doll R, Heaf P, Strang LB. Investigation into use of drugs preceeding death from asthma. British Medical Journal 1: 339–343, 1968PubMedGoogle Scholar
  86. Stewart DE, Ikram H, Espiner E, Nichols GM. Arrhythmogenic potential of diuretic induced hypokalaemia in patients with mild hypertension and ischaemic heart disease. British Heart Journal 54: 290–297, 1985PubMedGoogle Scholar
  87. Strauss MH, Reeves RA, Smith DL, Leenen FHH. The role of cardiac beta-1 receptors in the haemodynamic response to a beta-2 agonist. Clinical Pharmacology Therapeutics 40: 108–115, 1986Google Scholar
  88. Surawicz B. Relation between electrocardiogram and electrolytes. American Heart Journal 13: 814–834, 1967Google Scholar
  89. Surawicz B, Knoebel S. Long QT: good, bad or indifferent? Journal of the American College of Cardiology 4: 494–516, 1985Google Scholar
  90. Surawicz, Lepeschkin E, Herrlich HC, Hoffman BF. Effect of potassium and calcium deficiency on the monophasic action potential, electrocardiogram and contractility of isolated rabbit hearts. American Journal of Physiology 196: 1302–1307, 1959Google Scholar
  91. Tandon MK. Cardiopulmonary effects of fenoterol and salbutamol aerosols. Chest 77: 429–431, 1980PubMedGoogle Scholar
  92. Tinkelman DG, Avner SE, Cooper DM. Assessing bronchodilator responsiveness. Journal of Allergy and Clinical Immunology 59: 109–114, 1977PubMedGoogle Scholar
  93. Twentyman O, Finnerty JP, Harris A, Palmer J, Holgate ST. Protection against allergen-induced asthma by salmeterol. Lancet 336: 1338–1342, 1990PubMedGoogle Scholar
  94. Ullman A, Hedner J, Svedmyr N. Inhaled salmeterol and salbutamol in asthmatic patients: an evaluation of asthma symptoms and the possible development of tachyphylaxis. American Review of Respiratory Diseases 142: 571–575, 1990Google Scholar
  95. Ullman A, Svedmyr N. Salmeterol, a new long-acting inhaled β2- adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients. Thorax 43: 674–678, 1988PubMedGoogle Scholar
  96. Van Schayck CP, Visch MB, van Herwaarden CLA, Dorpeling H, van Wed C. Increased bronchial hyperresponsiveness after inhaling salbutamol during one year is not caused by desensitisation to salbutamol. Journal of Allergy and Clinical Immunology 86: 793–800, 1990PubMedGoogle Scholar
  97. Vathenen AS, Knox AJ, Higgins BG, Britton JR, Tattersfield AE. Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1: 554–558, 1988PubMedGoogle Scholar
  98. Viskum K. Inhaled salmeterol improves control in moderate to severe asthmatics: a 3 month study. European Respiratory Journal 3: 839, 1990Google Scholar
  99. Wagner J, Reinhardt D, Schumann HJ. Comparison of the bronchodilator and cardiovascular actions of isoprenaline, Th 1165a, terbutaline and salbutamol in cats and isolated organ preparations. Research and Experimental Medicine 162: 49–62, 1973Google Scholar
  100. Wallin A, Melander B, Rosenhai L, Sandstrom T, Wahlander L. Formoterol, a new long acting β2-agonist for inhalation twice daily, compared with salbutamol in the treatment of asthma. Thorax 45: 259–261, 1990PubMedGoogle Scholar
  101. Weaver WF, Burchell H. Serum potassium and the electrocardiograph and hypokalaemia. Circulation 21: 505–521, 1960PubMedGoogle Scholar
  102. Weir DC, Sherwood-Burge P. Measures of reversibility in response to bronchodilators in chronic airflow obstruction: relation to airway calibre. Thorax 46: 43–45, 1991PubMedGoogle Scholar
  103. Whicker SD, Armour CL, Black JL. Responsiveness of bronchial smooth muscle from asthmatic patients to relaxant and contractile agents. Pulmonary Pharmacology 1: 25–31, 1988PubMedGoogle Scholar
  104. Whyte KF, Reid C, Addis GJ, Whitesmith R, Reid JL. Salbutamol induced hypokalaemia: the effect of theophylline alone and in combination with adrenaline. British Journal of Clinical Pharmacology 25: 571–578, 1988PubMedGoogle Scholar
  105. Windom H, Burgess CD, Siebers RWL, Purdie G, Pearce N, et al. The pulmonary and extrapulmonary effects of inhaled β- agonists in patients with asthma. Clinical Pharmacology and Therapeutics 48: 296–301, 1990PubMedGoogle Scholar
  106. Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield AE. Bronchodilator, cardiovascular, and hypokalaemic effects of enoterol, salbutamol and terbutaline in asthma. Lancet 336: 1396–1399, 1990PubMedGoogle Scholar

Copyright information

© Adis International Limited 1992

Authors and Affiliations

  • Brian J. Lipworth
    • 1
  1. 1.Department of Clinical PharmacologyNinewells Hospital and Medical SchoolDundeeScotland

Personalised recommendations