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 "Treatment 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 stable 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 .
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- 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
- SUMMARY AND RECOMMENDATIONS