Skip to main content
SpringerLink
Log in

Combination Bronchodilator Therapy

  • Review Articles
  • Published:
Drugs Aims and scope Submit manuscript

Summary

Bronchodilators may be classified into 3 groups: anticholinergics, β-adrenoceptor agonists and methylxanthines. These drugs act through related biochemical pathways and there are theoretical reasons for expecting beneficial additive or synergistic interactions between them. While there is in vitro evidence of synergistic interactions producing bronchodilatation, in vivo studies indicate that the interactions are additive rather than synergistic but still of therapeutic value.

There have been no clinical studies on methylxanthines combined with anticholinergic drugs, but there is an extensive and growing literature on the other combinations. The majority show clear evidence of an additive bronchodilator effect when anticholinergics are combined with β2-adrenoceptor agonists, although atropine sulphate is less effective in this regard than atropine methylnitrate or ipratropium bromide. This type of combination has only been tested by inhalation and, because of the slower onset of action of the anticholinergic group, it is preferable that the β2-adrenoceptor agonist be inhaled first. There is no evidence for an additive interaction of the side effects of these drugs. In general, bronchitics respond better than asthmatics to anticholinergic drugs.

Studies on methylxanthines (usually theophylline) and adrenoceptor agonists may be divided into 2 groups: those using ephedrine and those using more selective β-adrenoceptor agonists. Ephedrine is a relatively ineffective bronchodilator and often fails to add any useful bronchodilatation to theophylline. Also, there does seem to be a synergistic increase in side effects of the two drugs and this combination is therefore undesirable. Ephedrine has now been superseded by the more selective β2- adrenoceptor agonist drugs all of which, whether given orally, intravenously or by inhalation, appear to have an additive effect with the methylxanthines.

It is often possible to achieve the same theapeutic effect with half doses of drugs from 2 different groups as with a full dose of 1 drug. This may sometimes, but not always, reduce side effects. There is evidence that giving 2 drugs by different routes is a useful therapeutic procedure: for example, the addition of an inhaled β2-adrenoceptor agonist may improve upon the maximal bronchodilatation achieved with intravenous theophylline. When theophylline is administered plasma levels of the drug should be monitored and it is possible that, when used in combination with a β2-adrenoceptor agonist, a therapeutic range lower than that normally recommended may apply.

There is no longer any place for fixed combination bronchodilators and, in spite of recent suggestions, there is no evidence that bronchodilator combinations are responsible for an increase in asthma mortality.

Further studies to clarify some aspects of bronchodilator combinations are needed. The therapeutic use of various combinations is briefly discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adams, F.: Commentary on the seven books of Paulus Aeginata (Trans.) pp.475–479 (Sydenham Society, London 1844).

    Google Scholar 

  • Ahlquist, R.P.: A study of the adrenotropic receptors. American Journal of Physiology 153: 586–598 (1948).

    PubMed  CAS  Google Scholar 

  • Akenside, M.: Of the use of ipecacuanha in asthmas. Medical Transactions of the Royal College of Physicians 1: 93–98 (1785).

    Google Scholar 

  • Allen, C.J. and Campbell, A.H.: Comparison of inhaled atropine sulphate and atropine methonitrate. Thorax 35: 932–935 (1980).

    PubMed  CAS  Google Scholar 

  • Alliott, R.J.; Land, D.B.; Rawson, D.R.W. and Leckie, W.J.H.: Effects of salbutamol and isoprenaline/phenylephrine in reversible airways obstruction. British Medical Journal 1: 539–542 (1972).

    PubMed  CAS  Google Scholar 

  • Altounyan, R.E.C.: Variation of drug action on airway obstruction in man. Thorax 19: 406–415 (1964).

    PubMed  CAS  Google Scholar 

  • Anderson, J.K.: On the treatment of spasmodic asthma by the subcutaneous injection of morphia. Practitioner 15: 321–325 (1875).

    Google Scholar 

  • Anderson, S.D.; Seale, J.P.; Rosea, P.; Bandler, L; Thobald, G. and Lindsay, D.A.: Inhaled and oral salbutamol in exercise-induced asthma. American Review of Respiratory Disease 114: 493–500 (1976).

    PubMed  CAS  Google Scholar 

  • Anderson, S.D.; Seale, J.P.; Ferris, L.; Schoeffel, R. and Lindsay, D.A.: An evaluation of pharmacotherapy for exercise-induced asthma. Journal of Allergy and Clinical Immunology 64: 612–624 (1979).

    PubMed  CAS  Google Scholar 

  • Andersson, R.; Bergh, N.P. and Svedmyr, N.: Metabolic actions in human bronchial muscle associated with ACTH induced relaxation. Scandinavian Journal of Respiratory Diseases 53: 125–128 (1972).

    PubMed  CAS  Google Scholar 

  • Andersson, R.G.G. and Nilsson, K.B.: Role of cyclic nucleotides metabolism and mechanical activity in smooth muscle; in Stephens (Ed.) Biochemistry of Smooth Muscle, pp.263–292 (University Park Press, Baltimore 1977).

    Google Scholar 

  • Barclay, J.; Whiting, B.; Meredith, P.A. and Addis, G.J.: Theophylline-salbutamol interaction: bronchodilator response to salbutamol at maximally effective plasma theophylline concentrations. British Journal of Clinical Pharmacology 11: 203–208 (1981).

    PubMed  CAS  Google Scholar 

  • Barnett, D.B. and Gold, W.M.: The regulation of cyclic nucleotides and the response to histamine in canine lung in vivo; in Lichtenstein and Austen (Eds) Asthma: Physiology, Immunopharmacology and Treatment, 2nd International Symposium, New York, pp. 181–195 (Academic Press, New York 1973).

    Google Scholar 

  • Beaglehole, R.; Harris, E.A. and Rea, H.N.: Has the change to beta-agonists combined with oral theophylline increased cases of fatal asthma? Lancet 2: 38 (1981).

    Google Scholar 

  • Beardsall, J.L.: Instances of successful treatment of asthma by chloroform. Lancet 1: 336–339 (1849).

    Google Scholar 

  • Berkhardt, J.B.: On bronchial asthma — its pathology and treatment, 2nd ed. (J. & A. Churchill, London 1889).

    Google Scholar 

  • Bierman, C.W.; Pierson, W.E. and Shapiro, G.G.: Pharmacological assessment of single drugs and drug combinations. Journal of the American Medical Association 234: 295–298 (1975).

    PubMed  CAS  Google Scholar 

  • Binz, C.: Lectures on pharmacology for practitioners and students. (The New Sydenham Society, London 1895).

    Google Scholar 

  • Blumenthal, I.: A comparative trial of slow-release aminophylline, salbutamol and a half dose combination in the prevention of childhood asthma. Journal of International Medical Research 8: 400–403 (1980).

    PubMed  CAS  Google Scholar 

  • Brady, R.E. and Easton, J.G.: The value of atropine in the documentation of reversible airways obstruction. Annals of Allergy 42: 211–217 (1979).

    PubMed  CAS  Google Scholar 

  • Brooks, S.N.; Werk, E.E.; Ackerman, S.J.; Sullivan, I. and Thrasher, K.: Adverse effects of phenobarbital on corticosteroid metabolism in patients with bronchial asthma. New England Journal of Medicine 286: 1125–1128 (1972).

    PubMed  CAS  Google Scholar 

  • Brown, E.A.: New type of medication (ephedrine, phenobarbital and theophyllin) to be used in bronchial asthma. New England Journal of Medicine 223: 843–845 (1940).

    Google Scholar 

  • Butcher, R.W. and Sutherland, E.W.: Adenosine-3′–5′-phosphate in biological materials. 1. Purification and properties of cyclic 3′–5′-nucleotide phosphodiesterase and use of this enzyme to characterise adenosine-3′–5′phosphate in human urine. Journal Biological Chemistry 237: 1244–1250 (1962).

    CAS  Google Scholar 

  • Campbell, I.A.; Middleton, W.G.; McHardy, G.J.R.; Shooter, M.V.; McKenzie, R. and Kay, A.B.: Interaction between isoprenaline and aminophylline in asthma. Thorax 32: 424–428 (1977).

    PubMed  CAS  Google Scholar 

  • Caplin, I. and Haynes, J.T.: A re-evaluation of ephedrine/theophylline combinations in the treatment of asthma. Journal of Indiana State Medical Association 71: 492–495 (1978).

    CAS  Google Scholar 

  • Cavanaugh, M.J. and Cooper, D.M.: Inhaled atropine sulphate: dose response characteristics. American Review of Respiratory Disease 114: 517–524 (1976).

    PubMed  CAS  Google Scholar 

  • Chamberlain, D.A.; Muir, D.C. and Kennedy, K.P.: Atropine methonitrate and isoprenaline in bronchial asthma. Lancet 2: 1019–1021 (1962).

    PubMed  CAS  Google Scholar 

  • Chen, K.K. and Schmidt, C.F.: The action and clinical use of ephedrine. Journal of the American Medical Association 87: 836–838 (1926).

    Google Scholar 

  • Chodosh, S. and Baigelman, W.: Bronchodilator effects of metaproterenol and oxtriphylline in asthma. Chest 73 (Suppl.): 1014–1015 (June 1978).

    PubMed  CAS  Google Scholar 

  • Chodosh, S. and Doraiswami, S.: An evaluation of theophylline/ ephedrine with and without hydroxyzine in asthma. Current Therapeutic Research 18: 773–784 (1975).

    PubMed  CAS  Google Scholar 

  • Collins, J.V.; Clark, T.J.H.; Brown, D. and Townsend, J.: The use of corticosteroids in the treatment of acute asthma. Quarterly Journal of Medicine 44: 259–273 (1975).

    PubMed  CAS  Google Scholar 

  • Committee on the Review of Medicines: Recommendations on barbiturate preparations. British Medical Journal 2: 719–720 (1979).

    Google Scholar 

  • Crofton, D.: On the therapeutic effect of inhalation of fumes of burning nitrate paper in asthma. Medical Press and Circular 27: 283–286 (1879).

    Google Scholar 

  • Crompton, G.K.: Comparison of responses to bronchodilator drugs in chronic bronchitis and chronic asthma. Thorax 23: 45–55 (1968).

    Google Scholar 

  • Davies, D.S.: Pharmacokinetics of inhaled substances. Postgraduate Medical Journal 51(Suppl. 17): 69–75 (1975).

    PubMed  CAS  Google Scholar 

  • Deutsch, R.I.; Tashkin, D.P.; Simmons, M.; Calvarese, B.; Wanger, J. and Lee, Y.E.: Bronchodilator effects of low doses of oral theophylline and terbutaline in asthmatic subjects. Annals of Allergy 45: 137–143 (1980).

    PubMed  CAS  Google Scholar 

  • Dorow, P.: Long-term study on a new beta 2-sympathomimetic agent and a combination of an oral theophylline-ethylenediamine with retard effect and hexoprenaline. Arzneimittel-Forschung 29: 145–147 (1979).

    PubMed  CAS  Google Scholar 

  • Douglas, N.J.; Davidson, I.; Sudlow, M.F. and Flenley, D.C.: Bronchodilatation and the site of airway resistance in severe chronic bronchitis. Thorax 34: 51–56 (1979).

    PubMed  CAS  Google Scholar 

  • Drug and Therapeutics Bulletin: Theophylline in asthma. Drug and Therapeutics Bulletin 17: 91–92 (1979).

    Google Scholar 

  • Dyson, A.J. and Campbell, I.A.: Interaction between choline theophyllinate and salmefamol in patients with reversible airways obstruction. British Journal of Clinical Pharmacology 4: 677–682 (1977).

    Google Scholar 

  • Editorial: The proper use of current bronchodilators. Lancet 1: 23–24 (1981).

  • Eggleston, P.A.; Beasley, P.P. and Kindley, R.T.: The effects of oral doses of theophylline and fenoterol in exercise-induced asthma. Chest 79: 399–405 (1981).

    PubMed  CAS  Google Scholar 

  • Engelhardt, A. and Klupp, H.: The pharmacology and toxicology of a new tropane alkaloid derivative. Postgraduate Medical Journal 51(Suppl. 7): 82–84 (1975).

    PubMed  CAS  Google Scholar 

  • Evrard, P.: Observation d’un cas d’asthma guéri par la pulvérisation liquide de l’iodure de potassium. Revue Médicale Française et Etrangère 58: 321–334 (1878).

    Google Scholar 

  • Falliers, C.J.; Cato, A.E. and Harris, J.R.: Controlled assessment of oral bronchodilators for asthmatic children. Journal of International Medical Research 6: 326–336 (1978).

    PubMed  CAS  Google Scholar 

  • Falliers, C.J. and Redding, M.A.: Combined vs single-entity pharmacologic inhibition of induced asthma. Annals of Allergy 44: 335–340 (1980).

    PubMed  CAS  Google Scholar 

  • Freedman, B.J.: Report on clinical trial comparing terbutaline and salbutamol when taken by inhalation. Proceedings of the United Kingdom and Scandinavian Conference on Bronchodilatation (Astra, Watford, London 1972).

  • Gal, P.; Jusko, W.J.; Yurchak, A.M. and Franklin, B.A.: Theophylline disposition in obesity. Clinical Pharmacology and Therapeutics 23: 438–444 (1978).

    PubMed  CAS  Google Scholar 

  • Gandevia, B.: Pressurised sympathomimetic aerosols and their lack of relationship to asthma mortality in Australia. Medical Journal of Australia 1: 272–277 (1973).

    Google Scholar 

  • Gandevia, B.; Hume, K.M. and Prime, F.J.: Outpatient bronchodilator therapy. Lancet 1: 956–960 (1957).

    Google Scholar 

  • General Practitioners Research Group, Report No. 36: A compound ephedrine preparation for asthma. Practitioner 190: 253–257 (1963).

    Google Scholar 

  • Grant, I.W.B.: Has the change to beta-agonists combined with oral theophylline increased cases of fatal asthma? Lancet 2: 36–37 (1981).

    Google Scholar 

  • Green, C.: A simple standardised approach to childhood asthma. Practitioner 223: 690–695 (1979).

    PubMed  CAS  Google Scholar 

  • Groggins, R.C.; Lenney, W.; Milner, A.D. and Stokes, G.M.: Efficacy of orally administered salbutamol and theophylline in pre-schoolchildren with asthma. Archives of Diseases in Childhood 55: 204–206 (1980).

    CAS  Google Scholar 

  • Hambleton, G.; Weinberger, M.; Taylor, J.; Cavanaugh, M.; Ginchansky, E.; Godfrey, S.; Tooley, M.; Bell, T. and Greenwood, S.: Comparison of cromoglycate (cromolyn) and theophylline in controlling systems of chronic asthma. A collaborative study. Lancet 1: 381–385 (1977).

    PubMed  CAS  Google Scholar 

  • Hendeles, L.; Weinberger, M. and Johnson, G.: Monitoring serum theophylline levels. Clinical Pharmacokinetics 3: 294–312 (1978).

    PubMed  CAS  Google Scholar 

  • Henry, P.J.; Lulich, K.M. and Paterson, J.W.: The effect of theophylline on the relaxant action of isoprenaline in isolated rat tracheal smooth muscle. Clinical and Experimental Pharmacology and Physiology (In press, 1982).

    Google Scholar 

  • Hermann, G. and Aynesworth, M.B.: Successful treatment of persistent extreme dyspnea “status asthmaticus”. Use of theophylline-ethylene diamine (aminophylline, U.S.P.) intravenously. Journal of Laboratory and Clinical Medicine 23: 135–140 (1937).

    Google Scholar 

  • Hume, K.M. and Rhys-Jones, E.: The response to bronchodilators in intrinsic asthma. Quarterly Journal of Medicine 30: 189–196 (1961).

    PubMed  CAS  Google Scholar 

  • Ingram, R.H.; Wellman, J.J.; McFadden, Jr, E.R. and Mead, J.: Relative contributions of large and small airways to flow limitation in normal subjects before and after atropine and isoproterenol. Journal of Clinical Investigation 59: 696–703 (1977).

    PubMed  CAS  Google Scholar 

  • Jenne, J.W.; Wyse, E.; Rood, B.S. and MacDonald, F.M.: The pharmacokinetics of theophylline. Application to adjustment of the clinical dose of aminophylline. Clinical Pharmacology and Therapeutics 13: 349–360 (1972).

    PubMed  CAS  Google Scholar 

  • Josephson, G.W.; Mackenzie, E.J.; Lietman, P.S. and Gibson, G.: Emergency treatment of asthma. A comparison of two treatment regimens. Journal of the American Medical Association 242: 639–643 (1979).

    PubMed  CAS  Google Scholar 

  • Julius, F.G.: Arsenic smoking in asthma. Lancet 2: 138–141 (1861).

    Google Scholar 

  • Jusko, W.J.: Role of tobacco smoking in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics 6: 7–39 (1978).

    PubMed  CAS  Google Scholar 

  • Kennedy, M.C.S. and Thursby-Pelham, D.C.: Some adrenergic drugs and atropine methonitrate given by inhalation for asthma: a comparative study. British Medical Journal 1: 1018–1021 (1964).

    PubMed  CAS  Google Scholar 

  • Koch-Weser, J.; Webb-Johnson, D.C. and Andrews, J.L.: Drug therapy: bronchodilator therapy. New England Journal of Medicine 297: 758–764 (1977).

    CAS  Google Scholar 

  • Kok-Jensen, A.: Combined inhalation of salbutamol and ipratropin in chronic bronchial obstruction. Ugeskrift for Laeger (Copenhagen) 141: 2039–2041 (1979).

    CAS  Google Scholar 

  • Konzett, H.: Neues zur asthmatherapie. Klinische Wochenschrift 19: 1303–1307 (1940).

    Google Scholar 

  • Kuo, J.F. and Kuo, W.N.: Regulation by beta-adrenergic receptor and muscarinic cholinergic receptor activation of intracellular cyclic AMP and cyclic GMP levels in rat lung slices. Biochemical and Biophysical Research Communications 55: 660–665 (1973).

    PubMed  CAS  Google Scholar 

  • Lal, S.; Bhalla, K.K. and Davey, A.J.: Slow release salbutamol and Tedral in the treatment of reversible airways obstruction. Postgraduate Medical Journal 47 (Suppl.): 89–92 (March 1971).

    PubMed  Google Scholar 

  • Lands, A.M.; Arnold, A.; McAulif, J.P.; Luduena, F.P. and Brown, T.G.: Differential of receptor systems activated by sympathomimetic amines. Nature 214: 597–599 (1967).

    PubMed  CAS  Google Scholar 

  • Larsson, S. and Svedmyr, N.: Bronchodilating effect and side effects of β 2-adrenoceptor stimulants by different modes of administration (tablets, metered aerosol and combinations thereof). A study with salbutamol in asthmatics. American Review of Respiratory Disease 116: 861–869 (1977).

    PubMed  CAS  Google Scholar 

  • Lees, A.W.; Allan, G.W. and Smith, J.: Nebulised ipratropium bromide and salbutamol in chronic bronchitis. British Journal of Clinical Practice 34: 340–342 (1980).

    PubMed  CAS  Google Scholar 

  • Lefcoe, N.M.; Toogood, J.H. and Jones, T.R.: In-vitro pharmacologic studies of bronchodilator compounds: interactions and mechanisms. Journal of Allergy and Clinical Immunology 55: 94 (1975).

    Google Scholar 

  • Leopold, D. and Handslip, P.: Additive interaction of aminophylline and salbutamol in asthma: an in vivo study using dose-response curves. Journal of International Medical Research 7 (Suppl.): 52–55 (1979).

    PubMed  Google Scholar 

  • Lichtenstein, L.M. and Margolis, S.: Histamine release in-vitro: inhibition by catecholamines and methylxanthines. Science 161: 902–903 (1968).

    PubMed  CAS  Google Scholar 

  • Lightbody, L.M.; Ingram, C.G.; Legge, J.S. and Johnston, R.N.: Ipratropium bromide, salbutamol and prednisolone in bronchial asthma and chronic bronchitis. British Journal of Diseases of the Chest 72: 181–186 (1978).

    PubMed  CAS  Google Scholar 

  • Lönnerholm, G.; Foucard, T. and Lindström, B.: Treatment of chronic asthma in children with a sustained-release preparation of theophylline in addition to beta 2-stimulating agents. European Journal of Respiratory Disease 109 (Suppl.): 95–97 (1980).

    Google Scholar 

  • Lönnerholm, G.; Foucard, T. and Lindström, B.: Combined treatment with sustained-release theophylline and beta 2-adrenoceptor-stimulating agents in chronic childhood asthma. British Medical Journal 282: 1029–1032 (1981).

    PubMed  Google Scholar 

  • Lowry, R.: Oral theophylline and fatal asthma. Lancet 2: 200 (1981).

    Google Scholar 

  • MacDonald, J.B.; Macdonald, E.T.; Seaton, A. and Williams, D.A.: Asthma deaths in Cardiff 1963–1974; 53 deaths in hospital. British Medical Journal 2: 721–723 (1976a).

    PubMed  CAS  Google Scholar 

  • MacDonald, J.B.; Seaton, A. and Williams, D.A.: Asthma deaths in Cardiff 1963–1974; 90 deaths outside hospital. British Medical Journal 1: 1493–1495 (1976b).

    PubMed  CAS  Google Scholar 

  • Maddock, A.B.: Practical observations on the efficiency of medicated inhalations in the treatment of pulmonary consumption, asthma, bronchitis and other diseases of the respiratory organs (Simpkin, Marshall, London 1845).

    Google Scholar 

  • Marlin, G.E.; Berend, N. and Harrison, A.C.: Combined cholinergic antagonist and beta 2-adrenoceptor agonist bronchodilator therapy by inhalation. Australian and New Zealand Journal of Medicine 9: 511–514 (1979).

    PubMed  CAS  Google Scholar 

  • Marlin, G.E.; Hartnett, B.J.S.; Berend, N. and Hacker, N.B.: Assessment of combined and theophylline inhaled β-adrenoceptor agonist bronchodilator therapy. British Journal of Clinical Pharmacology 5: 45–50 (1978).

    PubMed  CAS  Google Scholar 

  • Murad, F. and Kimura, H.: Cyclic nucleotide levels in incubations of guinea-pig trachea. Biochimica et Biophysica Acta 343: 275–286 (1974).

    PubMed  CAS  Google Scholar 

  • Nadel, J.A.: Neurophysiologic aspects of asthma; in Austen et al. (Eds) Asthma Physiology, Immunopharmacology and Treatment, 2nd International Symposium, pp.29–38 (Academic Press, New York 1973).

    Google Scholar 

  • Nadel, J.A.: Autonomic control of airway smooth muscle and airway secretions. American Review of Respiratory Disease 115: 117–126 (1977).

    PubMed  CAS  Google Scholar 

  • O’Donnell, T.V.; Butler, G.M. and Tocker, M.D.: A comparison of orciprenaline and salbutamol administered orally in 12 adult asthmatic patients. Postgraduate Medical Journal 47 (Suppl.): 115–118 (1971).

    PubMed  Google Scholar 

  • Offermeier, J.: Synergistic effects of SCH 1000 and beta-adrenergics on isolated organs. Postgraduate Medical Journal 51 (Suppl.): 117–118 (1975).

    Google Scholar 

  • Ogilvie, R.I.: Clinical pharmacokinetics of theophylline. Clinical Pharmacokinetics 3: 267–293 (1978).

    PubMed  CAS  Google Scholar 

  • Ormerod, L.P. and Stableforth, D.E.: Asthma mortality in Birmingham 1975–7: 53 deaths. British Medical Journal 1: 687–690 (1980).

    Google Scholar 

  • Parker, C.W. and Smith, J.W.: Alterations of cyclic adenosine monophosphate metabolism in human bronchial asthma. 1. Leukocyte responsiveness to β-adrenergic agents. Journal of Clinical Investigation 52: 48–59 (1973).

    PubMed  CAS  Google Scholar 

  • Paterson, J.W. and Shenfield, G.M.: Bronchodilators, Parts I and II. British Thoracic and Tuberculosis Association Review 4: 25–40 and 61-74 (1974).

    CAS  Google Scholar 

  • Paterson, J.W. and Shenfield, G.M.: Bronchodilators in Scientific Foundations of Respiratory Medicine; Scadding et al. (Eds) [William Heinemann Medical Books, London 1981].

  • Paterson, J.W. and Tarala, R.A.: Asthma: Common pitfalls in management. Current Therapeutics 22(No 8): 33–44 (August 1981).

    Google Scholar 

  • Paterson, J.W.; Woolcock, A.J. and Shenfield, G.M.: State of the art: bronchodilator drugs. American Review of Respiratory Disease 120: 1149–1188 (1979).

    PubMed  CAS  Google Scholar 

  • Paterson, J.W. and Yellin, R.H.: Combined bronchodilators in severe outpatient asthma. Current Therapeutics 19(No 10): 14–16 (October 1978).

    Google Scholar 

  • Paterson, J.W.; Yellin, R.H.; Ilett, K.F. and Madson, B.W.: Plasma theophylline assay service for outpatients. Therapeutic Drug Monitoring 3: 51–56 (1981).

    PubMed  CAS  Google Scholar 

  • Petrie, G.R. and Palmer, K.N.: Comparison of aerosol ipratropium bromide and salbutamol in chronic bronchitis and asthma. British Medical Journal 1: 430–432 (1975).

    PubMed  CAS  Google Scholar 

  • Piafsky, K.M.; Sitar, D.S.; Rangno, R.E. and Ogilvie, R.I.: Theophylline disposition in patients with hepatic cirrhosis. New England Journal of Medicine 296: 1495–1497 (1977).

    PubMed  CAS  Google Scholar 

  • Pierce, R.J.; Allen, C.J. and Campbell, A.H.: A comparative study of atropine methonitrate, salbutamol and their combination in airways obstruction. Thorax 34: 45–50 (1979).

    PubMed  CAS  Google Scholar 

  • Rachelefsky, G.S.; Tashkin, D.P.; Katz, R.M.; Kershnar, H. and Siegel, S.C.: Comparison of aerosolised atropine, isoproterenol, atropine plus isoproterenol, disodium cromoglycate and placebo in the prevention of exercise-induced asthma. Chest 73 (Suppl.): 1017–1019 (1978).

    PubMed  CAS  Google Scholar 

  • Rall, T.W.: Central nervous system stimulants. The xanthines; in Gilman et al. (Eds) The Pharmacological Basis of Therapeutics, 6th ed, pp.592–607 (Macmillan, New York 1980).

    Google Scholar 

  • Read, J.: The reported increase in mortality from asthma: a clinico-functional analysis. Medical Journal of Australia 1: 879–884 (1968).

    PubMed  CAS  Google Scholar 

  • Rebuck, A.S. and Read, J.: Assessment and management of severe asthma. American Journal of Medicine 51: 788–798 (1971).

    PubMed  CAS  Google Scholar 

  • Richardson, J. and Beland, J.: Noradrenergic inhibitory nervous system in human airways. Journal of Applied Physiology 41: 764–771 (1976).

    PubMed  CAS  Google Scholar 

  • Rossing, T.H.; Fanta, C.H. and McFadden, E.R., Jr A controlled trial of the use of single versus combined-drug therapy in the treatment of acute episodes of asthma 1–3. American Review of Respiratory Diseases 123: 190–194 (1981).

    CAS  Google Scholar 

  • Ruffin, R.E.; Fitzgerald, J.D. and Rebuck, A.S.: A comparison of the bronchodilator activity of Seh 1000 and salbutamol. Journal of Allergy and Clinical Immunology 59: 136–141 (1977).

    PubMed  CAS  Google Scholar 

  • Salter, H.H.: On asthma its pathology and treatment, 2nd ed, p.24 (John Churchill and Sons, London 1868).

  • Schultz, G.: Possible interactions between calcium and cyclic nucleotides in smooth muscle; in Lichtenstein, L.M. and Austen, K.F. (Eds) Asthma, Physiology, Immunopharmacology and Treatment, 2nd International Symposium, New York, pp. 77–91 (Academic Press, New York 1977).

    Google Scholar 

  • Schultz, G.; Hardman, J.G.; Schultz, F.; Baird, C.E. and Sutherland, E.W.: The importance of calcium ions for the regulation of guanosine 3′5′-cyclic monophosphate levels. Proceedings of the National Academy of Science 70: 3889–3893 (1973).

    CAS  Google Scholar 

  • Schwartz, A.L.; Lipton, J.M.; Warburton, D.; Johnson, L.B. and Tuarog, F.J.: Management of acute asthma in childhood. A randomised evaluation of beta-adrenergic agents. American Journal of Diseases of Children 134: 474–478 (1980).

    PubMed  CAS  Google Scholar 

  • Sears, M.R.: Sudden death in asthmatics. Current Therapeutics 22(No 5): 13–17 (1981).

    Google Scholar 

  • Shapiro, G.G.; McPhillips, J.J; Smith, K.; Furukawa, C.T.; Pierson, W.F. and Bierman, C.W.: Effectiveness of terbutaline and theophylline alone and in combination in exercise-induced bronchospasm. Pediatrics 67: 508–513 (1981).

    PubMed  CAS  Google Scholar 

  • Sheldrake, R.: A new science of life. New Scientist 90: 766–768 (1981).

    Google Scholar 

  • Shenfield, G.M.: Fixed combination drug therapy. Drugs 23: 462–480 (1982).

    PubMed  CAS  Google Scholar 

  • Shenfield, G.M.; Evans, M.E. and Paterson, J.W.: The effect of different nebulisers with or without positive pressure breathing on the absorption and metabolism of salbutamol. British Journal of Clinical Pharmacology 1: 295–301 (1974).

    PubMed  CAS  Google Scholar 

  • Shenfield, G.M.; Evans, M.E.; Walker, S.R. and Paterson, J.W.: The fate of nebulised salbutamol (albuterol) administered by intermittent positive pressure respiration to asthmatic patients. American Review of Respiratory Disease 108: 501–505 (1973).

    PubMed  CAS  Google Scholar 

  • Shenfield, G.M.; Hodson, M.E.; Clarke, S.W. and Paterson, J.W.: Interaction of corticosteroids and catecholamines in the treatment of asthma. Thorax 30: 430–435 (1975).

    PubMed  CAS  Google Scholar 

  • Shenfield, G.M. and Paterson, J.W.: Clinical assessment of bronchodilator drugs delivered by aerosol. Thorax 28: 124–128 (1973).

    PubMed  CAS  Google Scholar 

  • Simonson, B.G.; Jacobs, F.M. and Nadel, J.A.: Role of autonomic nervous system and the cough reflex in the increased responsiveness of airways in patients with obstructive airways disease. Journal of Clinical Investigation 46: 1812–1827 (1967).

    Google Scholar 

  • Smith, J.A.; Weber, R.W. and Nelson, H.S.: Theophylline and aerosolised terbutaline in the treatment of bronchial asthma. Double-blind comparison of optimal doses. Chest 78: 816–818 (1980).

    PubMed  CAS  Google Scholar 

  • Smith, R.; Kuo, J. and Steen, S.N.: Metaproterenol with and without theophylline in bronchospasmodic disease. IRCS Medical Science 4: 562 (1976).

    CAS  Google Scholar 

  • Snider, G.L.: The treatment of asthma (editorial). New England Journal of Medicine 298: 397–399 (1978).

    PubMed  CAS  Google Scholar 

  • Solis-Cohen, S.: The use of adrenal substance in the treatment of asthma. Journal of the American Medical Association 34: 1164–1166 (1900).

    Google Scholar 

  • Speizer, F.E.; Doll, R.; Heaf, P. and Strang, L.B.: Investigation into drugs preceding death from asthma. British Medical Journal 1: 335–339 (1968).

    PubMed  CAS  Google Scholar 

  • Svedmyr, N.: Theophyllines today. Scandinavian Journal of Respiratory Disorders 101 (Suppl.): 125–138 (1977).

    CAS  Google Scholar 

  • Svedmyr, N: Terbutaline and terbutaline combined with theophylline in asthmatics. Acta Pharmacologica et Toxicologica (Copenhagen) 44 (Suppl.): 47–53 (1979).

    CAS  Google Scholar 

  • Svedmyr, N. and Simonsson, B.G.: Drugs in the treatment of asthma. Pharmacology and Therapeutics 3: 397–440 (1978).

    CAS  Google Scholar 

  • Svedmyr, N. and Svedmyr, K.: In-vitro and in-vivo effects of theophylline and beta 2-adrenostimulants in combination. European Journal of Respiratory Diseases 61 (Suppl.): 83–91 (1980).

    Google Scholar 

  • Tarala, R.A.; Madsen, B.W. and Paterson, J.W.: Comparative efficacy of salbutamol by pressurised aerosol and wet nebuliser in acute asthma. British Journal of Clinical Pharmacology 10: 393–398 (1980).

    PubMed  CAS  Google Scholar 

  • Tashkin, D.P.; Katz, R.M.; Kerschnar, H; Rachelefsky, G.S. and Siegel, S.C.: Comparison of aerosolised atropine, isoproterenol, atropine plus isoproterenol, disodium cromoglycate and placebo in the prevention of exercise-induced asthma. Annals of Allergy 39: 311–318 (1977).

    PubMed  CAS  Google Scholar 

  • Tinkelman, G.D. and Avner, S.E.: Ephedrine therapy in asthmatic children. Clinical tolerance and absence of side effects. Journal of the American Medical Association 237: 553–557 (1977).

    PubMed  CAS  Google Scholar 

  • Toennesen, I.: Oral theophylline and fatal asthma. Lancet 2: 200 (1981).

    Google Scholar 

  • Trembath, P.W. and Shaw, J.: Potentiation of isoprenaline-induced plasma cyclic AMP response by aminophylline in normal and asthmatic subjects. British Journal of Clinical Pharmacology 6: 499–503 (1978).

    PubMed  CAS  Google Scholar 

  • Van Asperen, P.P.; Mellis, C.M.; South, R.T. and Simpson, S.J.: Value of combining β 2-sympathomimetic metered aerosol and oral theophylline in children with asthma. Medical Journal of Australia 1: 643–645 (1981).

    PubMed  Google Scholar 

  • Verstraeten, J.M.: Can the association of atropinic (SCH 1000) and a sympathicomimetic improve the bronchodilatation obtained by a sympathicomimetic alone? Acta Tuberculosea et Pneumologica Belgica 65: 395–408 (1974).

    PubMed  CAS  Google Scholar 

  • Vincent, N.J.; Knudson, R. and Leith, D.E.: Factors influencing pulmonary resistance. Journal of Applied Physiology 29: 236–243 (1970).

    PubMed  CAS  Google Scholar 

  • Ward, M.J.; Fentem, P.H.; Roderick-Smith, W.H. and Davies, D.: Ipratropium bromide in acute asthma. British Medical Journal 282: 598–600 (1981).

    PubMed  CAS  Google Scholar 

  • Weinberger, M.M.: Use of ephedrine in bronchodilator therapy. Pediatric Clinics of North America 22: 121–127 (1975).

    PubMed  CAS  Google Scholar 

  • Weinberger, M.M. and Bronsky, E.A.: Evaluation of oral bronchodilator therapy in asthmatic children. Journal of Pediatrics 84: 421–427 (1974).

    PubMed  CAS  Google Scholar 

  • Whittington, J.R.: Has the change to beta-agonists combined with oral theophylline increased cases of fatal asthma? Lancet 2: 37–38 (1981).

    Google Scholar 

  • Widdicombe, J.G.; Kent, D.C and Nadel, J.A.: Mechanism of bronchoconstriction during inhalation of dust. Journal of Applied Physiology 17: 613–622 (1962).

    PubMed  CAS  Google Scholar 

  • Wilson, J.D.; Sutherland, D.C and Thomas, A.C.: Has the change to beta-agonists combined with oral theophylline increased cases of fatal asthma? Lancet 1: 1235–1237 (1981).

    PubMed  CAS  Google Scholar 

  • Wolfe, J.D.; Tashkin, D.P.; Calvarese, B. and Simmons, M.: Bronchodilator effects of terbutaline and aminophylline alone and in combination with asthmatic patients. New England Journal of Medicine 298: 363–367 (1978).

    PubMed  CAS  Google Scholar 

  • Woolcock, A.J.: Sympathomimetic and anticholinergic bronchodilators. Current Therapeutics 22 (No. 12): 65–78 (December 1981).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Royal North Shore Hospital, St Leonards, Sydney, NSW, 2065, Australia

    Gillian M. Shenfield

Authors
  1. Gillian M. Shenfield
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shenfield, G.M. Combination Bronchodilator Therapy. Drugs 24, 414–439 (1982). https://doi.org/10.2165/00003495-198224050-00004

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-198224050-00004

Keywords

Search

Navigation