Mono- and Combination Therapy of Long-acting Bronchodilators and Inhaled Corticosteroids in Advanced COPD

Jill A. Ohar; James F. Donohue


Semin Respir Crit Care Med. 2010;31(3):321-333. 

In This Article



Theophylline is a nonselective phosphodiesterase inhibitor that acts as both a weak bronchodilator and a respiratory stimulant. It has been shown to improve diaphragmatic contractility and has some antiinflammatory properties.[76] Low-dose theophylline increases activation of the histone deacetylase, which is subsequently recruited by corticosteroids to suppress inflammatory genes.[77] Cigarette smoke reduces histone deacetylase (HDAC) activity. Because of its potential ability to activate the HDAC system, theophylline may have the ability to enhance the effects of inhaled corticosteroids in patients with COPD, especially those who continue to smoke.[78] Effects due to adenosine receptor antagonism and phosphodiesterase inhibition are not clarified. This agent is available worldwide and is inexpensive. However, the frequency of side effects with oral delivery limits its use. In a recent VA hospital study patients treated with ipratropium plus theophylline compared with those treated with ipratropium alone had a 1.11-fold increase in the risk of death (95% CI 1.04 to 1.18);[79] however, the benefits of theophylline in this study on other factors such as symptoms, quality of life, and activities of daily living, were not measured. A new methylxanthine doxofylline may have less affinity for α-1 and α-2 receptors than theophylline, does not antagonize calcium channels, nor does it interfere with the influx of calcium into the cells. It does not affect sleep rhythm, gastric secretions, heart rate and rhythm, and central nervous system (CNS) functioning.[80] Novel approaches, including using the inhalation route to reduce side effects and combining with ICS, are undergoing study.[81] However, because of its potential adverse effects and narrow therapeutic index, it should only be used when symptoms persist despite optimal bronchodilator therapy.

Clinical Benefits

Relative to other available agents such as LABAs and tiotropium, the bronchodilatory effect of theophylline is weak. Several studies have demonstrated the additive effect for theophylline when used in combination with other treatments in patients with COPD.[82,83] Analysis of a large (n = 36,492) health administration database revealed that users of theophylline were less likely than users of LABAs but more likely than users of inhaled glucocorticoids to suffer an exacerbation.[84]

In a 12-week trial, ZuWallack and colleagues, showed that salmeterol plus theophylline caused significantly greater improvements in pulmonary function and symptoms, compared with either single agent.[85]


Theophylline is associated with tremors and nausea and less frequently with cardiac arrhythmias and seizures.[86] The fact that serum toxicity levels overlap therapeutic levels explains the high incidence of toxic side effects. The risk of such adverse events can be reduced by monitoring the drug's plasma levels and reducing the dose accordingly; however, the high frequency of drug interactions and clinical conditions that interfere with hepatic metabolism of theophylline limit its extensive use in clinical practice.[87]

Nonbronchodilator Effects of Methylxanthines

The salutary effects of theophylline may be due as much to its nonbronchodilator as to its bronchodilator activity.[76,88,89,90,91] In addition to its steroid-sparing effects on histone deacetylase, theophylline has both ionotropic and chronotropic cardiac effects. It enhances mucociliary sweep, diaphragmatic contractility, and central respiratory drive.

Novel Methylxanthines

Although theophylline is a weak nonselective phosphodiesterase inhibitor, the phosphodiesterase 4 inhibitor roflumilast can improve lung function and prevent exacerbations in COPD. In two placebo-controlled, double-blind, multicenter trials in the outpatient acute, bronchitic patient with COPD, the prebronchodilator FEV1 increased 48 mL and the exacerbation rate decreased 17% compared with placebo.[92] Roflumilast improved prebronchodilator FEV1 in twp other trials with patients on either tiotropium or salmeterol (80 mL and 49 mL, respectively) and similarly improved postbronchodilator FEV1. Adverse events in these trials were nausea, diarrhea, and weight loss.


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