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

Abstract and Introduction


Beta-2 adrenergic agonists are sympathomimetic agents that stimulate bronchodilation by activation of adenyl cyclase to produce cyclic 3'5' adenosine monophosphate (AMP). Short-acting β-agonists (SABAs) have a 3- to 6-hour duration of action, and the duration of action of long-acting β-agonists (LABAs) exceeds 12 hours. Because of their rapid onset of action, SABAs are effective for rescue from symptoms of chronic obstructive pulmonary disease (COPD). LABAs—salmeterol and formoterol—have been shown to significantly improve lung function, health status, and symptom reduction, compared with ipratropium. Despite safety concerns over the use of LABAs as monotherapy in asthma the use of these medications in COPD has generally been described as safe. Novel bronchodilators for COPD in late-stage development include the β-agonists indacterol and carmoterol.
Parasympathetic activity in the large and medium-size airways is mediated through the muscarinic receptors and results in airway smooth-muscle contraction, mucus secretion, and possibly increased ciliary activity. Although short-acting ipratropium has been used as monotherapy or in combination with albuterol the use of long-acting antimuscarinics is superior in improving health outcomes. The use of tiotropium results in improved health status, dyspnea, and exercise capacity, and reduced hyperinflation and COPD exacerbation rate in patients with moderate to severe COPD. Analysis of prospective clinical trial data shows a mortality reduction in subjects treated with tiotropium, despite retrospective review of insurance claims that show an enhanced mortality.
Theophylline is a nonselective phosphodiesterase inhibitor that acts as both a weak bronchodilator and a respiratory stimulant. Novel approaches include using the inhalation route to reduce side effects and combination with inhaled corticosteroids (ICS). However, because of its potential adverse effects and narrow therapeutic index, it should only be used when symptoms persist despite optimal bronchodilator therapy.
Current guidelines highlight that for COPD patients uncontrolled by bronchodilator monotherapy, combination therapy is recommended. These include LABA/ICS and LAMA/LABA combinations. Bronchodilators and their combination with ICS are central to the management of COPD. The choice of agents is based primarily on disease stage, individual response, cost, side effect profile, and availability.


Both short-acting and long-acting bronchodilators have been used for many years for the treatment of chronic obstructive pulmonary disease (COPD). Patient response to these agents is characterized by a large degree of heterogeneity due in part to genetic and phenotypic variability and differences in disease severity. Furthermore, initiation of guideline-based treatment is often poorly applied in developed countries due to lack of awareness and in developing countries due to cost or cultural preferences. Guidelines[1,2] recommend initiating scheduled long-acting bronchodilators for moderate COPD—GOLD stage 2 and above [i.e., forced expiratory volume in 1 second (FEV1) >50% but <80% predicted]. However, most trials that demonstrate efficacy and safety of bronchodilators have excluded subjects with COPD and an FEV1 ≥60 to 65% predicted.[3] This review focuses on the use of bronchodilators and inhaled glucocorticoids in advanced COPD (FEV1 ≤50% predicted), and, whereas the results of clinical trials have been, by inference, expanded for use in moderate COPD, their results are directly applicable to advanced COPD. Three classes of bronchodilators—β2-adrenoceptoragonists, anticholinergics, and methylxanthines—are currently available and can be used individually or in combination with each other or inhaled glucocorticoids ( Table 1 and Table 2 ). Several novel bronchodilators are under development.[4,5]


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