Theophylline use in asthma
- Leslie Hendeles, PharmD
Leslie Hendeles, PharmD
- Professor Emeritus
- University of Florida
- Miles Weinberger, MD
Miles Weinberger, MD
- Professor Emeritus
- University of Iowa
- Section Editors
- Bruce S Bochner, MD
Bruce S Bochner, MD
- Editor-in-Chief — Allergy and Immunology
- Section Editor — Adult Allergy; Asthma
- Samuel M Feinberg Professor of Medicine
- Northwestern University Feinberg School of Medicine
- Robert A Wood, MD
Robert A Wood, MD
- Editor-in-Chief — Allergy and Immunology
- Section Editor — Pediatric Allergy
- Professor of Pediatrics
- Johns Hopkins University School of Medicine
The use of theophylline to treat asthma has undergone several cycles of enthusiasm and unpopularity over the past 50 years. The dissemination of clinical practice guidelines that list theophylline as a "not preferred" alternative, the availability of newer agents, and concerns regarding the risk-benefit ratio of the drug have resulted in infrequent prescribing of theophylline. Nevertheless, its low cost offers an advantage over other long-term maintenance medications that are added to inhaled glucocorticoids, such as montelukast and long-acting beta agonists.
The indications for theophylline in the treatment of asthma and recommendations for its safe use will be discussed here. Overviews of the treatment of acute and chronic asthma are provided elsewhere. (See "Management of acute exacerbations of asthma in adults" and "An overview of asthma management".)
Therapeutic actions — Though traditionally classified as a bronchodilator, the ability of theophylline to control chronic asthma appears disproportionately greater than is explainable by its modest degree of bronchodilator activity alone [1-7]. Theophylline has anti-inflammatory, immunomodulatory, and bronchoprotective effects that potentially contribute to its efficacy as a prophylactic anti-asthma drug [7-14] and for chronic obstructive pulmonary disease (COPD). (See "Management of refractory chronic obstructive pulmonary disease", section on 'Theophylline'.)
The molecular mechanism of bronchodilatation by theophylline is inhibition of phosphodiesterase (PDE)3, but the anti-inflammatory effect may be due to inhibition of PDE4 and activation of histone deacetylases, which are reduced in severe asthma and COPD . Activation of histone deacetylase-2 leads to switching off of activated inflammatory genes, which in turn may contribute to reversal of glucocorticoid resistance by theophylline.
Theophylline down-regulates inflammatory and immune cell function in vitro and in vivo in animals with airway inflammation [16,17]. In patients with allergic asthma, it attenuates the late phase increase in airway obstruction and airway responsiveness to histamine, decreases allergen-induced migration of activated eosinophils into the bronchial mucosa, and decreases the sputum eosinophil count [8,9,18]. Moreover, withdrawal of theophylline from patients with severe chronic asthma receiving high-doses of inhaled glucocorticoid therapy results in increased symptoms of asthma accompanied by an increase in the number of activated cytotoxic T-lymphocytes in the bronchial mucosa and an increase in helper T-lymphocytes in the airway epithelium . The reduction in nocturnal worsening of lung function when theophylline is used is associated with both a decrease in the percentage of neutrophils and a decrease in stimulated leukotriene B4 from macrophages in early morning bronchoalveolar lavage fluid . An in depth review of in vitro and in vivo studies demonstrating the immunomodulatory, anti-inflammatory, and glucocorticoid-sparing effects of theophylline has been published .
- Hambleton G, Weinberger M, Taylor J, et al. Comparison of cromoglycate (cromolyn) and theophylline in controlling symptoms of chronic asthma. A collaborative study. Lancet 1977; 1:381.
- Nassif EG, Weinberger M, Thompson R, Huntley W. The value of maintenance theophylline in steroid-dependent asthma. N Engl J Med 1981; 304:71.
- Dusdieker L, Green M, Smith GD, et al. Comparison of orally administered metaproterenol and theophylline in the control of chronic asthma. J Pediatr 1982; 101:281.
- Joad JP, Ahrens RC, Lindgren SD, Weinberger MM. Relative efficacy of maintenance therapy with theophylline, inhaled albuterol, and the combination for chronic asthma. J Allergy Clin Immunol 1987; 79:78.
- Brenner M, Berkowitz R, Marshall N, Strunk RC. Need for theophylline in severe steroid-requiring asthmatics. Clin Allergy 1988; 18:143.
- Rivington RN, Boulet LP, Côté J, et al. Efficacy of Uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med 1995; 151:325.
- Kidney J, Dominguez M, Taylor PM, et al. Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med 1995; 151:1907.
- Hendeles L, Harman E, Huang D, et al. Theophylline attenuation of airway responses to allergen: comparison with cromolyn metered-dose inhaler. J Allergy Clin Immunol 1995; 95:505.
- Sullivan P, Bekir S, Jaffar Z, et al. Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 1994; 343:1006.
- Magnussen H, Reuss G, Jörres R. Theophylline has a dose-related effect on the airway response to inhaled histamine and methacholine in asthmatics. Am Rev Respir Dis 1987; 136:1163.
- Koenig JQ, Dumler K, Rebolledo V, et al. Theophylline mitigates the bronchoconstrictor effects of sulfur dioxide in subjects with asthma. J Allergy Clin Immunol 1992; 89:789.
- Fabbri LM, Alessandri MV, De Marzo N, et al. Long-lasting protective effect of slow-release theophylline on asthma induced by ultrasonically nebulized distilled water. Ann Allergy 1986; 56:171.
- Pollock J, Kiechel F, Cooper D, Weinberger M. Relationship of serum theophylline concentration to inhibition of exercise-induced bronchospasm and comparison with cromolyn. Pediatrics 1977; 60:840.
- Chorostowska-Wynimko J, Kus J, Skopińska-Rózewska E. Theophylline inhibits free oxygen radicals production by human monocytes via phosphodiesterase inhibition. J Physiol Pharmacol 2007; 58 Suppl 5:95.
- Barnes PJ. Theophylline. Am J Respir Crit Care Med 2013; 188:901.
- Scordamaglia A, Ciprandi G, Ruffoni S, et al. Theophylline and the immune response: in vitro and in vivo effects. Clin Immunol Immunopathol 1988; 48:238.
- Lagente V, Pruniaux MP, Junien JL, Moodley I. Modulation of cytokine-induced eosinophil infiltration by phosphodiesterase inhibitors. Am J Respir Crit Care Med 1995; 151:1720.
- Horiguchi T, Tachikawa S, Kasahara J, et al. Suppression of airway inflammation by theophylline in adult bronchial asthma. Respiration 1999; 66:124.
- Kraft M, Torvik JA, Trudeau JB, et al. Theophylline: potential antiinflammatory effects in nocturnal asthma. J Allergy Clin Immunol 1996; 97:1242.
- Markham A, Faulds D. Theophylline. A review of its potential steroid sparing effects in asthma. Drugs 1998; 56:1081.
- Rabe KF, Magnussen H, Dent G. Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir J 1995; 8:637.
- Lipworth BJ. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 2005; 365:167.
- Torphy TJ. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med 1998; 157:351.
- Barnes PJ. Histone deacetylase-2 and airway disease. Ther Adv Respir Dis 2009; 3:235.
- Barnes PJ. Theophylline and phosphodiesterase inhibitors. In: Middleton's Allergy: Principles and Practice, 6th Ed, Adkinson NF, Yunginger JW, Busse WW, et al (Eds), Mosby, St Louis, MO 2003. p.823.
- Weinberger M, Abu-Hasan M. Life-threatening asthma during treatment with salmeterol. N Engl J Med 2006; 355:852.
- Greening AP, Ind PW, Northfield M, Shaw G. Added salmeterol versus higher-dose corticosteroid in asthma patients with symptoms on existing inhaled corticosteroid. Allen & Hanburys Limited UK Study Group. Lancet 1994; 344:219.
- Woolcock A, Lundback B, Ringdal N, Jacques LA. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996; 153:1481.
- Evans DJ, Taylor DA, Zetterstrom O, et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997; 337:1412.
- Spears M, Donnelly I, Jolly L, et al. Effect of low-dose theophylline plus beclometasone on lung function in smokers with asthma: a pilot study. Eur Respir J 2009; 33:1010.
- Derom E, Van Schoor J, Verhaeghe W, et al. Systemic effects of inhaled fluticasone propionate and budesonide in adult patients with asthma. Am J Respir Crit Care Med 1999; 160:157.
- Vassallo R, Lipsky JJ. Theophylline: recent advances in the understanding of its mode of action and uses in clinical practice. Mayo Clin Proc 1998; 73:346.
- Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients' compliance with prescribed oral and inhaled asthma medications. Arch Intern Med 1994; 154:1349.
- Davies B, Brooks G, Devoy M. The efficacy and safety of salmeterol compared to theophylline: meta-analysis of nine controlled studies. Respir Med 1998; 92:256.
- Paggiaro PL, Giannini D, Di Franco A, Testi R. Comparison of inhaled salmeterol and individually dose-titrated slow-release theophylline in patients with reversible airway obstruction. European Study Group. Eur Respir J 1996; 9:1689.
- Shah AR, Sharples LD, Solanki RN, Shah KV. Double-blind, randomised, controlled trial assessing controller medications in asthma. Respiration 2006; 73:449.
- Phipatanakul W, Greene C, Downes SJ, et al. Montelukast improves asthma control in asthmatic children maintained on inhaled corticosteroids. Ann Allergy Asthma Immunol 2003; 91:49.
- American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007; 175:235.
- Toogood JH, Jennings B, Lefcoe NM. A clinical trial of combined cromolyn/beclomethasone treatment for chronic asthma. J Allergy Clin Immunol 1981; 67:317.
- Hiller EJ, Milner AD. Betamethasone 17 valerate aerosol and disodium chromoglycate in severe childhood asthma. Br J Dis Chest 1975; 69:103.
- Dawood AG, Hendry AT, Walker SR. The combined use of betamethasone valerate and sodium cromoglycate in the treatment of asthma. Clin Allergy 1977; 7:161.
- Svendsen UG, Jørgensen H. Inhaled nedocromil sodium as additional treatment to high dose inhaled corticosteroids in the management of bronchial asthma. Eur Respir J 1991; 4:992.
- O'Hickey SP, Rees PJ. High-dose nedocromil sodium as an addition to inhaled corticosteroids in the treatment of asthma. Respir Med 1994; 88:499.
- Wong CS, Cooper S, Britton JR, Tattersfield AE. Steroid sparing effect of nedocromil sodium in asthmatic patients on high doses of inhaled steroids. Clin Exp Allergy 1993; 23:370.
- Sherman J, Hutson A, Baumstein S, Hendeles L. Telephoning the patient's pharmacy to assess adherence with asthma medications by measuring refill rate for prescriptions. J Pediatr 2000; 136:532.
- Kelloway JS, Wyatt R, DeMarco J, Adlis S. Effect of salmeterol on patients' adherence to their prescribed refills for inhaled corticosteroids. Ann Allergy Asthma Immunol 2000; 84:324.
- National Asthma Education and Prevention Program: Expert Panel Report III: Guidelines for the diagnosis and management of asthma. Bethesda, MD. National Heart, Lung, and Blood Institute, 2007. (NIH publication no. 08-4051) www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm (Accessed on March 17, 2016).
- Baker JW, Mellon M, Wald J, et al. A multiple-dosing, placebo-controlled study of budesonide inhalation suspension given once or twice daily for treatment of persistent asthma in young children and infants. Pediatrics 1999; 103:414.
- Sallent J, Hill M, Stecenko A, et al. Bioavailability of a slow-release theophylline capsule given twice daily to preschool children with chronic asthma: comparison with liquid theophylline. Pediatrics 1988; 81:116.
- Newth CJ, Newth CV, Turner JA. Comparison of nebulised sodium cromoglycate and oral theophylline in controlling symptoms of chronic asthma in pre-school children: a double blind study. Aust N Z J Med 1982; 12:232.
- Furukawa CT, Shapiro GG, Bierman CW, et al. A double-blind study comparing the effectiveness of cromolyn sodium and sustained-release theophylline in childhood asthma. Pediatrics 1984; 74:453.
- Hendeles L, Weinberger M, Bighley L. Disposition of theophylline after a single intravenous infusion of aminophylline. Am Rev Respir Dis 1978; 118:97.
- Milavetz G, Vaughan LM, Weinberger MM, Hendeles L. Evaluation of a scheme for establishing and maintaining dosage of theophylline in ambulatory patients with chronic asthma. J Pediatr 1986; 109:351.
- Derby LE, Jick SS, Langlois JC, et al. Hospital admission for xanthine toxicity. Pharmacotherapy 1990; 10:112.
- Weinberger MM, Bronsky EA. Evaluation of oral bronchodilator therapy in asthmatic children. Bronchodilators in asthmatic children. J Pediatr 1974; 84:421.
- Neijens HJ, Duiverman EJ, Graatsma BH, Kerrebijn KF. Clinical and bronchodilating efficacy of controlled-release theophylline as a function of its serum concentrations in preschool children. J Pediatr 1985; 107:811.
- Jenne JW. Reassessing the therapeutic range for theophylline on laboratory report forms: another viewpoint. Pharmacotherapy 1993; 13:595.
- Weinberger MM. Theophylline QID, TID, BID and now QD? A report on 24-hour dosing with slow-release theophylline formulations with emphasis on analyses of data used to obtain Food and Drug Administration approval for Theo-24. Pharmacotherapy 1984; 4:181.
- Hendeles L, Jenkins J, Temple R. Revised FDA labeling guideline for theophylline oral dosage forms. Pharmacotherapy 1995; 15:409.
- Frederiksen MC, Ruo TI, Chow MJ, Atkinson AJ Jr. Theophylline pharmacokinetics in pregnancy. Clin Pharmacol Ther 1986; 40:321.
- Gardner MJ, Schatz M, Cousins L, et al. Longitudinal effects of pregnancy on the pharmacokinetics of theophylline. Eur J Clin Pharmacol 1987; 32:289.
- Connelly TJ, Ruo TI, Frederiksen MC, Atkinson AJ Jr. Characterization of theophylline binding to serum proteins in pregnant and nonpregnant women. Clin Pharmacol Ther 1990; 47:68.
- Carter BL, Driscoll CE, Smith GD. Theophylline clearance during pregnancy. Obstet Gynecol 1986; 68:555.
- Hendeles L, Weinberger M, Milavetz G, et al. Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity. Chest 1985; 87:758.
- Milavetz G, Vaughan LM, Weinberger MM, et al. Relationship between rate and extent of absorption of oral theophylline from Uniphyl brand of slow-release theophylline and resulting serum concentrations during multiple dosing. J Allergy Clin Immunol 1987; 80:723.
- Weinberger M, Hendeles L, Wong L. Relationship of formulation and dosing interval to fluctuation of serum theophylline concentration in children with chronic asthma. J Pediatr 1981; 99:145.
- Therapeutic actions
- Additive maintenance therapy
- - Compared to other additive therapies
- Primary maintenance therapy when oral agents are preferred
- Additive acute therapy for hospitalized patients
- - Dosing of IV theophylline
- SAFE USE OF THEOPHYLLINE
- Target serum concentration
- Initiating and titrating oral therapy
- Factors affecting metabolism
- Selection of product and dosing interval
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- SUMMARY AND RECOMMENDATIONS