Management of Stable Chronic Obstructive Pulmonary Disease

The backbone of the pharmacologic regimen for COPD includes short- and long-acting bronchodilators. They are usually given in an inhaled form to maximize local effects on the lungs and minimize systemic side effects. There are 2 main classes of bronchodilators, beta agonists and muscarinic antagonists, and each targets specific receptors on the surface of airway smooth muscle cells. Beta agonists work by stimulating beta-2 receptors, resulting in bronchodilation, while muscarinic antagonists work by blocking the bronchoconstrictor action of M3 muscarinic receptors. Inhaled corticosteroids can be added to long-acting bronchodilator therapy but cannot be used as stand-alone therapy. Theophylline is an oral bronchodilator that is used infrequently due to its narrow therapeutic index, toxicity, and multiple drug interactions.

• Who should be on short-acting bronchodilators? What is the best agent? Should it be scheduled or used as needed?

All patients with COPD should be an on inhaled short-acting bronchodilator as needed for relief of symptoms [7]. Both short-acting beta agonists (albuterol and levalbuterol) and short-acting muscarinic antagonists (ipratropium) have been shown in clinical trials and meta-analyses to improve symptoms and lung function in patients with stable COPD [9,10] and seem to have comparative efficacy when compared head-to-head in trials [11]. However, the airway bronchodilator effect achieved by both classes seems to be additive when used in combination and is also associated with less exacerbations compared to albuterol alone [12]. On the other hand, adding albuterol to ipratropium increased the bronchodilator response but did not reduce the exacerbation rate [11–13]. Inhaled short-acting beta agonists when used as needed rather than scheduled are associated with less medication use without any significant difference in symptoms or lung function [14].

The side effects related to using recommended doses of a short-acting bronchodilator are minimal. In retrospective studies, short-acting beta agonists increased the risk of severe cardiac arrhythmias [15]. Levalbuterol, the active enantiomer of albuterol (R-albuterol) developed for the theoretical benefits of reduced tachycardia, increased tolerability, and better or equal efficacy compared to racemic albuterol, failed to show a clinically significant difference in inducing tachycardia [16]. Beta agonist overuse is associated with tremor and in severe cases hypokalemia, which happens mainly when patients try to achieve maximal bronchodilation; the clinically used doses of beta agonists are associated with fewer side affects but achieve less than maximal bronchodilation [17]. Ipratropium can produce systemic anticholinergic side effects, urinary retention being the most clinically significant especially when combined with long-acting anticholinergic agents [18].

In light of the above discussion, a combination of short-acting beta agonist and muscarinic antagonist is recommended in all patients with COPD unless the patient is on a long-acting muscarinic antagonist [7,18]. In the latter case, a short-acting beta agonist used as a rescue inhaler is the best option. In our patient, albuterol was the choice for his short-acting bronchodilator as he was using the long-acting muscarinic antagonist tiotropium.

• Are short-acting bronchodilators enough? What do we use for maintenance therapy?

All patients with COPD who are category B or higher according to the modified GOLD staging system should be on a long-acting bronchodilator [7,19]: either a long-acting beta agonist (LABA) or long-acting muscarinic antagonist (LAMA). Long-acting bronchodilators work on the same receptors as their short-acting counterparts but have structural differences. Salmeterol is the prototype for long-acting selective beta-2 agonist. It is structurally similar to albuterol but has an elongated side chain that allows it to bind firmly to the area of beta receptors and stimulate them repetitively, resulting in an extendedduration of action [20]. Tiotropium on the other hand is a quaternary ammonium of ipratropium that is a nonselective muscarinic antagonist [21]. Compared to ipratropium, tiotropium dissociates more quickly from M2 receptors, which is responsible for the undesired anticholinergic effects, while at the same time it binds M1 and M3 receptors for a prolonged time, resulting in extended duration of action [21].