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Current issues with β2-adrenoceptor agonists

Historical background

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Abstract

The discovery that dessicated adrenal glands had beneficial effects in asthma arose in 1900 following a vogue for studying organotherapy at the end of the 19th century. The adrenal hormone adrenaline was found to have sympathomimetic properties and was isolated and synthesized in 1901. The first nonselective β-agonist, isoproterenol, was isolated in 1940, followed by the development of selective β2-agonists in the 1960s and the introduction of the long-acting β2-agonists in the 1990s. The introduction of β2-selectivity reduced adverse effects, as did developments in inhaler technology that allowed subjects to inhale much smaller doses of drug selectively to the airways. The β2-agonists are some of the more important drugs to have been developed in the 20th century. Excessive doses can cause problems, and attempts to maximize the benefit from β2-agonists and to reduce adverse effects has led to considerable epidemiological, clinical, and mechanistic research over the last 50 yr.

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References

  1. Solis-Cohen, S. (1900), The use of adrenal substance in the treatment of asthma. JAMA 34, 1164–1166.

    Google Scholar 

  2. Sneader, W. (1985), Drugs affecting nervous transmission, in Drug Discovery: The Evolution of Modern Medicine. John Wiley, New York, pp. 96–126.

    Google Scholar 

  3. Oliver, G. and Shafer, E. A. (1894), On the physiological action of extracts of the suprarenal capsule. J. Physiol. 16, 1–4.

    Google Scholar 

  4. Persson, C. G. A. (1997), On the history of sympathomimetics in asthma, in β 2-Agonists in Asthma Treatment: Lung Biology in Health and Disease, vol. 106. Pauwels, R., O'Byrne, P., eds., Marcel Dekker, New York, pp. 1–18.

    Google Scholar 

  5. Takamine, J. (1901), Adrenalin the active principle of the suprarenal gland and its mode of preparation. Am. J. Pharm. 73, 523–531.

    CAS  Google Scholar 

  6. Henderson, J. (2005), Ernest Starling and ‘Hormones’: a historical commentary. J. Endocrinol. 184, 5–10.

    Article  PubMed  CAS  Google Scholar 

  7. Konzett, H. (1940), Neue broncholytisch hoch-wirksames Korper der Adrenaline. Naunyn. Schmiederbergs. Arch. Exp. 197, 27–40.

    Article  CAS  Google Scholar 

  8. Gay, L. N. and Long, J. W. (1949), Clinical evaluation of isopropyl-epinephrine in management of bronchial asthma. JAMA 12, 452–458.

    Google Scholar 

  9. Newman S. P. and Clark, S. W. (1992) Inhalation devices and techniques, in Asthma 3rd ed. Clark, T. J. H., Godfrey, S. and Lee, T. H., eds., Chapman and Hall Medical, London, pp. P469-P505.

    Google Scholar 

  10. Ahlquist, R. B. (1948), A study of adrenotropic receptors. Am. J. Physiol. 153, 586–600.

    CAS  PubMed  Google Scholar 

  11. Lands, A. M., Arnold, A., McAuliff, J. P., Luduena, F. P., and Brown, T. G. (1967), Differentiation of receptor-systems activated by sympathomimetic amines. Nature 214, 597–598.

    Article  PubMed  CAS  Google Scholar 

  12. Paterson, J., Woolcock, A. J., and Shenfield, G. M. (1979), Bronchodilator drugs. Am. Rev. Resp. Dis. 120, 1149–1188.

    PubMed  CAS  Google Scholar 

  13. Brittain, R. T., Dean, C. M. and Jack, D. (1981), Sympathomimetic bronchodilator drugs, in Respiratory Pharmacology. Widdicombe, J. G., ed. Oxford Pergamon, pp. 613–653.

    Google Scholar 

  14. Tattersfield, A. E. and McNicol, M. W. (1969), Salbutamol and isoprenaline: a double blind trial to compare bronchodilator and cardiovascular activity. N. Engl. J. Med. 281, 1323–1326.

    Article  PubMed  CAS  Google Scholar 

  15. Warrell, D. A., Robertson, D. G., Newton Howes, J., et al. (1970), Comparison of cardiorespiratory effects of isoprenaline and salbutamol in patients with bronchial asthma. Br. Med. J., I, 65–70.

    Google Scholar 

  16. Paterson, J. W., Courtney-Evans, R. J. and Prime, F. J. (1971), Selectivity of bronchodilator action of salbutamol in asthmatic patients. Brit. J. Dis. Chest. 65, 21–38.

    PubMed  CAS  Google Scholar 

  17. Larsson, S. and Svedmyr, N. (1977), Bronchodilating effect and side-effects of beta2 adrenoceptor stimulants by different modes of administration (tablets, metered aerosol and combination thereof). Am. Rev. Resp. Dis. 116, 861–869.

    PubMed  CAS  Google Scholar 

  18. Johansson, L.-H., Persson, H., and Rosengren, E. (1986), An analysis of the β2-adrenoceptor selectivity in four series of β2-adrenoceptor agonists. Eur. J. Pharmacol. 130, 97–103.

    Article  PubMed  CAS  Google Scholar 

  19. Wong, C. S., Pavord, I. D., Williams, J., Britton, J. R., and Tattersfield, A. E. (1990), Bronchodilator, car diovascular, and hypokalaemic effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 336, 1396–1399.

    Article  PubMed  CAS  Google Scholar 

  20. Tattersfield, A. E. (2000) β2-agonists: mode of action and place in management, in Asthma, 4th ed. Clark, T. J. H., Godfrey, S., Lee, T. H., and Thompson, N. C., eds. New York: Arnold, London and Oxford University Press, pp. 253–282.

    Google Scholar 

  21. Anderson, S. D., Seale, J. P., Rozea P., Bandler, L., Theobald, G., and Lindsay, D. A. (1976), Inhaled and oral salbutamol in exercise-induced asthma. Am. Rev. Respir. Dis. 114, 493–500.

    PubMed  CAS  Google Scholar 

  22. Jack, D. (1991), A way of looking at agonism and antagonism: Lessons from salbutamol, salmeterol and other b2‑adrenoceptor agonists. Br. J. Clin. Pharmacol. 31, 501–514.

    PubMed  CAS  Google Scholar 

  23. Larsson, S., Svedmyr, N., and Thiringer, G. (1977), Lack of bronchial beta-adrenoceptor resistance in asthmatics during long-term treatment with terbutaline. J. Allergy Immunol. 59, 93–100.

    Article  CAS  Google Scholar 

  24. Holgate, S. T., Baldwin, C. J., and Tattersfield, A. E. (1977) b-adrenergic agonist resistance in normal human airways. Lancet 2, 375–377.

    Article  PubMed  CAS  Google Scholar 

  25. Harvey, J. E. and Tattersfield, A. E. (1982) Airway response to salbutamol: effect of regular salbutamol inhalations in normal, atopic and asthmatic subjects. Thorax 37, 280–287.

    PubMed  CAS  Google Scholar 

  26. Kraan J., Koeter, G. H., van der Mark, T. W., Sluiter, H., and de Vries, K. (1985) Changes in bronchial hyperreactivity induced by 4 weeks of treatment with antiasthmatic drugs in patients with allergic asthma: a comparison between budesonide and terbutaline. J. Allergy Clin, Immunol. 76, 628–636.

    Article  CAS  Google Scholar 

  27. Vathenen A. S., Knox A. J., Higgins, B. G., Britton, J. R., and Tattersfield, A. E. (1988), Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet. I, 554–558.

    Article  Google Scholar 

  28. Wahedna, I., Wong, C. S., Wisniewski, A. F. Z., Pavord, I. D., and Tattersfield, A. E. (1993), Asthma control during and after cessation of regular β2-agonists treatment. Am. Rev. Respir Dis. 148, 707–712.

    PubMed  CAS  Google Scholar 

  29. Cockcroft, D. W., McParland, C. P., Britton, S. A., Swystun, V. A., and Rutherford, B. C. (1993), Reuular inhaled salbutamol and airway responsiveness to allergen. Lancet 342, 833–837.

    Article  PubMed  CAS  Google Scholar 

  30. Szentivanyi, A. (1968) The beta-adrenergic theory of the atopic abnormality in bronchial asthma. J. Allergy 42, 203–232.

    Article  Google Scholar 

  31. Assem, E. S. K. and Schild, H. O. (1969), Inhibition by sympathomimetic amines of histamine release induced by antigen in passively sensitized human lung. Nature 224, 1028–1029.

    Article  PubMed  CAS  Google Scholar 

  32. Howarth, P. H., Durham, S. R., Lee, T. H., Kay, A. B., Church, M. K., and Holgate, S. T. (1985), Influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma. Am. Rev. Respir. Dis. 132, 986–992.

    PubMed  CAS  Google Scholar 

  33. Barnes, P. J. (1995), Beta-adrenergic receptors and their regulation. Am. J. Respir. Crit. Care Med. 152, 838–860.

    PubMed  CAS  Google Scholar 

  34. Sutherland, E. W. and Rall, T. W. (1960), The relation of adenosine-3,5-phosphate to the action of catecholamines and other hormones. Pharmac. Rev. 12, 265–299.

    CAS  Google Scholar 

  35. Robison, G. A., Butcher, R. W., and Sutherland, E. W. (1967) Adenyl cyclase as an adrenergic receptor. Ann. NY Acad. Sci. 139, 703–723.

    Article  PubMed  CAS  Google Scholar 

  36. Dixon, R. A. F., Kobilka, B. K., Strader, D., and Benovic, J. L. (1986), Cloning of the gene and cDNA for mammalian β2-adrenergic receptor and homology with rhodopsin. Nature 321, 75–79.

    Article  PubMed  CAS  Google Scholar 

  37. Heaf, P. J. D. (1970), Deaths in asthma: a therapeutic misadventure. Br. Med. Bull. 26, 245–247.

    PubMed  CAS  Google Scholar 

  38. Morrison Smith J. (1966), Death from asthma. Lancet 1, 1042 (letter).

    Article  Google Scholar 

  39. Greenberg, M. and Pines, A. (1968), Pressurised aerosols in asthma. Br. Med. J. 1, 563 (letter).

    Google Scholar 

  40. Inman, W. H. W. and Adelstein, A. M. (1969) Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet ii, 279–285.

    Article  Google Scholar 

  41. Stolley, P. D. (1972), Asthma mortality: why the United States was spared an epidemic of deaths due to asthma. Am. REv. Respir. Dis. 105, 883–890.

    PubMed  CAS  Google Scholar 

  42. Campbell, A. H. (1976), Mortality from asthma and bronchodilator aerosols. Med. J. Australia 1, 386–391.

    PubMed  CAS  Google Scholar 

  43. Blauw, G. J. and Westendorp, R. G. J. (1995), Asthma deaths in New Zealand: whodunit? Lancet 345, 2–3.

    Article  PubMed  CAS  Google Scholar 

  44. Jackson, R. J., Beaglehole, R., Rea, H. H., and Sutherland, D. C. (1982), Mortality from asthma: a new epidemic in New Zealand. Br. Med. J. 285, 771–774.

    CAS  Google Scholar 

  45. Crane, J., Pearce, N., Flatt, A., et al. (1989), Prescribed fenoterol and death from asthma in New Zealand, 1981–83: case-control study: Lancet, I, 917–922.

    Article  Google Scholar 

  46. Grainger, J., Woodman, K., Pearce, N., et al. (1991), Prescribed fenoterol and death from asthma in New Zealand, 1981–87: a further case-control study. Thorax 46, 105–111.

    PubMed  CAS  Google Scholar 

  47. Crane, J, Burgess, C., and Beasley, R. (1989), Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol and isoprenaline. Thorax 44, 136–140.

    PubMed  CAS  Google Scholar 

  48. Rona, G., Chappel, C. I., Balazs, T., and Gaudry, R., (1959), An infract-like myocardial lesion and other toxic manifestations produced by isoproterenol in the rat. Arch. Pathol 67, 443–445.

    CAS  Google Scholar 

  49. Bremner, P., Burgess, C. D., Crane, J., et al. (1992) Cardiovascular effects of fenoterol under conditions of hypoxaemia. Thorax 47, 814–817.

    Article  PubMed  CAS  Google Scholar 

  50. Kiely, D. G., Cargill, R. I., and Lipworth, B. J. (1995), Cardiopulmonary interactions of salbutamol and hypoxaemia in healthy young volunteers. Br. J. Clin. Pharmacol. 40, 313–318.

    PubMed  CAS  Google Scholar 

  51. Van Metre, T. E. (1969), Adverse effects of inhalation of excessive amounts of nebulised isoproterenol in status asthmaticus. J. Allergy 43, 101–113.

    Article  PubMed  Google Scholar 

  52. Reisman, R. E. (1970), Asthma induced by adrenergic aerosols. J. Allergy 46, 162–177.

    Article  PubMed  CAS  Google Scholar 

  53. Cockcroft D. W. and Swysstun, V. A. (1997), Effect of S-Salbutamol, R-Salbutamol racemic Salbutamol and placebo on the airway response to methacholine. Thorax 52, 845–848.

    PubMed  CAS  Google Scholar 

  54. Lipworth, B. J., Clark, D. J., Koch, P., and Arbeeny, C. (1997), Pharmacokinetics and extrapulmonary b2 adrenoceptor activity of nebulised racemic salbutamol and its R and S isomers in healthy volunteers. Thorax 52, 849–852.

    PubMed  CAS  Google Scholar 

  55. Paterson, I. W., Sudlow, M. F., and Walker, S. R. (1971), Blood levels of fluorinated hydrocarbons in asthmatic patients after inhalation of pressurised aerosols. Lancet 2, 565–568.

    Article  PubMed  CAS  Google Scholar 

  56. Dollery, C. T., Draffen, G. H., Davies, D. S., Williams, F. M., and Conolly, M. E. (1970). Blood concentrations in man of fluorinated hydrocabons after inhalation of pressurised aerosols. Lancet 2, 1164–1166.

    Article  PubMed  CAS  Google Scholar 

  57. Sears, M. R., Taylor, D. R., Print, C. G., et al. (1990), Regular inhaled b-agonist treatment in bronchial asthma. Lancet 336, 1391–1396.

    Article  PubMed  CAS  Google Scholar 

  58. Harrison, T. W., Oborne, J., Wilding, P. J., and Tattersfield, A. E. (1999), Randomised placebo controlled trial of β-agonist dose reduction in asthma. Thorax 54, 98–102.

    Article  PubMed  CAS  Google Scholar 

  59. Taylor, D. R., Drazen, J. M., Herbison, G. P., Yandava, C. N., Hancox, R. J., and Town, G. I. (2000), Asthma exacerbations during long term β2-agonist use: influence of b2 adrenoceptor polymorphism. Thorax 55, 762–767.

    Article  PubMed  CAS  Google Scholar 

  60. Hancox, R. J., Sears, M. R., and Taylor, D. R. (1998), Polymorphism of the β2-adrenoceptor and the response to long-term β2-agonist therapy in asthma. Eur. Respir. J. 11, 589–593.

    PubMed  CAS  Google Scholar 

  61. Israel, E., Drazen, J. M., Liggett S. B., et al. (2000), The effect of polymorphisms of the β2-adrenergic receptor on the response to regular use of albuterol in asthma. Am. J. Respir. Crit. Care. Med. 162, 75–80.

    PubMed  CAS  Google Scholar 

  62. Israel, E., Chinchilli, V. M., Ford, J. G., et al. (2004), Use of regulary scheduled albuterol treatment in asthma: genotype-stratified, randomised, placebo-controlled cross-over trial. Lancet 364, 1505–1512.

    Article  PubMed  CAS  Google Scholar 

  63. Anderson G. P. (1993), Long acting inhaled β-adrenoceptor agonist. The comparative pharmacology of formoterol and salmeterol, in New Drugs in Allergy and Asthma. Barnes, P. J., ed., Birkhauser, Basel.

    Google Scholar 

  64. Sovani, M. P., Whale, C. I., and Tattersfield, A. E. (2004), A risk-benefit assessment of inhaled long acting β2-agonists in the management of obstructive pulmonary disease. Drug Safety 27, 689–715.

    Article  PubMed  CAS  Google Scholar 

  65. Pauwels, R. A., Löfdahl, C.-G., Postma, D. S., et al., for the Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. (1997), Effect of inhaled formoterol and budesonide on exacerbations of asthma. N. Engl. J. Med. 337, 1405–1411.

    Article  PubMed  CAS  Google Scholar 

  66. Pearlman, D. S., Chervinski, P., LaForce, C. et al. (1992), A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N. Engl. J. Med. 327, 1420–1425.

    Article  PubMed  CAS  Google Scholar 

  67. Greening, A. P., Ind, P. W., Northfield, M., and Shaw G. (1994), Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Lancet 344, 219–224.

    Article  PubMed  CAS  Google Scholar 

  68. Nelson, H. S., Weiss, S. T., Bielker, E. R., Yancy, S. W., Dorinsky, P. M., and the SMART study group. (2006) The salmeterol multicenter asthma research trial. Chest 129, 15–26.

    Article  PubMed  CAS  Google Scholar 

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Tattersfield, A.E. Current issues with β2-adrenoceptor agonists. Clinic Rev Allerg Immunol 31, 107–117 (2006). https://doi.org/10.1385/CRIAI:31:2:107

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