Chronic obstructive pulmonary disease (COPD) is defined by the American Thoracic Society and European Respiratory Society as a lung disease characterized by airflow limitation that is usually progressive and is associated with an abnormal inflammatory response by the lungs to noxious inhalants.¹

Bronchodilator medications are essential to the symptomatic management of COPD and are the primary pharmacologic intervention. Beta₂-adrenergic receptor agonists, anticholinergics, and methylxanthines are the three classes of bronchodilators available for COPD. In the early stages of COPD, short-acting b₂-agonists (SABA) like albuterol or anticholinergic (SAAC) bronchodilators such as ipratropium bromide are given on an as-needed basis for prompt symptomatic control. As disease severity worsens, long-acting b-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are given as the treatment of choice for maintenance therapy. Salmeterol and formoterol are the two LABAs used for COPD. Tiotropium bromide is a LAMA and is a fairly recent addition to COPD medications. Theophylline is the only approved methylxanthine for patients with COPD and is a weak bronchodilator. Bronchodilators induce relaxation on airway smooth muscle cells. Thus, improvements in FEV₁ are observed on pulmonary function tests with their use, and, as the degree of air trapping lessens, patients have less lung hyperinflation with exertion.

When single-agent therapy does not control symptoms, combination treatment should be initiated. Combination therapies with LABAs and LAMAs have been shown to provide better control than single-agent treatment. Anti-inflammatory medications such as inhaled corticosteroids (ICS), when combined with a LABA, improve FEV₁, reduce exacerbations, and reduce hyperinflation. Common strategies for COPD management are outlined in Table 1.

BRONCHODILATORS

B₂-ADRENERGIC AGONISTS

Beta₂-adrenergic receptor agonists are commonly used bronchodilators for COPD. They act by binding to the b₂-adrenergic receptor (b₂AR). Binding to the b₂AR leads to increased production of cellular cyclic AMP and subsequent activation of protein kinase A (PKA), which phosphorylates and inactivates myosin light chain kinase. The exact PKA phosphorylation targets are not known, but cellular pathways ultimately lead to relaxation of airway smooth muscles.⁵ Beta₂ARs are located in high density on airway smooth muscle cells, but they are also found in cholinergic ganglia, submucosal glands, vascular endothelium, ciliated epithelium, circulating inflammatory cells, Clara cells, mast cells, and type-II pneumocytes. Beta agonists likely have effects at each of these sites and, therefore, have multiple mechanisms by which they cause bronchodilation and airway protection. Patients with COPD may benefit from the nonbronchodilator effects of b₂-agonists. Beta₂-adrenergic receptor agonists have numerous effects on airway epithelial cells, including increased ciliary beating, hydration of the airway, and increased mucociliary clearance (MCC).⁶ Airway cytoprotective effects of beta agonists are current topics of research. Studies have shown that MCC is reduced in smokers as well as in patients with chronic bronchitis. Beta agonists may improve symptoms and lessen exacerbation by increasing ciliary beat frequency and improving mucus clearance. Most studies of bronchodilators and MCC are one-dose studies, however, and more investigation is needed to determine the clinical significance of beta agonist effects on MCC and airway protection.

SHORT-ACTING B₂-AGONISTS

Short-acting b₂-adrenergic receptor agonists have a rapid onset of action and are the primary drug for rescue of worsening symptoms in COPD. The commonly used SABAs are albuterol, pirbuterol, and terbutaline. They are all available by pressurized metered dose inhaler. Albuterol is also available in a nebulized solution. Albuterol and terbutaline are available in parenteral formulation but are not used in older patients because of the side effects. SABAs act within a few minutes and have lasting effects for about 4 to 6 hours. The quick onset of action makes them ideal for rescue of symptoms. Some COPD patients may have little change in spirometry results when using bronchodilators; but, if SABAs are used on a regular basis, patients may have a modest increase in lung function and less dyspnea. If SABAs are given, for instance, shortly prior to 6-minute walk testing, patients have an increase in exercise tolerance.⁷ Short-acting b-agonists are frequently combined with anticholinergics. This is a useful combination and works on both the central and peripheral airways. In COPD patients, the combination of albuterol and ipratropium had a superior bronchodilator response than either agent alone.⁸ Unfortunately, there are an insufficient number of clinical studies to accurately estimate the impact of regular versus intermittent use of SABAs on outcomes in COPD.

LONG-ACTING BETA AGONISTS

Salmeterol and formoterol are LABAs and are intended to provide sustained improvements in lung function. In contrast to short-acting agents, salmeterol and formoterol are given every 12 hours and may be more convenient in stable COPD patients. They can be delivered via dry powder inhalation or pMDI. Both formoterol and salmeterol provide improvements in pulmonary function. As airflow improves, patients may have less lung hyperinflation. Reductions in hyperinflation may result in less dyspnea. Studies confirm that in symptomatic patients with COPD, salmeterol has been shown to improve lung function and reduce dyspnea.⁹ Formoterol, unlike salmeterol, has a dose response, is rapid in onset, and is a potent complete b-agonist.

The quick onset and dose response of formoterol are appealing because it can serve as a rescue and maintenance therapy.¹⁰ LABAs can be used in combination therapy with anticholinergic agents as well as with inhaled cortico-steroids. Mahler et al¹¹ compared the efficacy of salmeterol to ipratropium bromide. Patients had much more improvement in lung function when given salmeterol. Another study,¹² however, shows that salmeterol used along with ipratropium bromide provides greater improvements in airway obstruction versus ipratropium alone. In patients with mild-to-moderate COPD, salmeterol use resulted in a greater increase in FEV₁ and better quality of life when compared to theophylline.¹³ Both formoterol and ipratropium bromide have been shown to improve lung function, although lung function improvement with formoterol when compared to ipratropium bromide was associated with a reduction in daily symptoms and less use of rescue bronchodilators.¹⁴ When compared to tiotropium, formoterol showed a superior effect on FEV₁ in the first 2 hours after administration. Combination therapy with formoterol and tiotropium exhibited greater improvements in FEV₁ and FVC measurements when compared to monotherapy with those individual agents.¹⁵ ICS can be combined with LABAs to improve lung function. Improvements in airflow likely reduce the degree of lung hyperinflation and may lead to less dyspnea. There is some controversy as to the potency of their anti-inflammatory effects when used in COPD patients, although GOLD guidelines recommend inhaled corticosteroids as add-on therapy in patients with stage III or IV disease. Inhaled cortico-steroids do improve lung function, but their effect on frequency of COPD exacerbation has been the topic of more recent investigations. Kardos and colleagues¹⁶ have shown that when treated with ICS in combination with LABAs, COPD patients have fewer exacerbations. Studies are ongoing in regard to the effect of ICS on health status and mortality in patients with COPD.

SAFETY OF BETA ADRENERGIC AGENTS

SABAs and LABAs are relatively safe in patients with COPD. SABAs have pharmacological predictable dose-related and potency-related adverse effects. The side effects of SABAs include tremor, tachycardia, hypokalemia, and elevated plasma glucose. Tolerance to all of these adverse effects develops with continued exposure. Patients with comorbid heart disease are prone to arrhythmias, and those with long QTc-intervals on ECG are at risk for cardiac events, but the use of high-dose nebulized albuterol in the elderly COPD population does not seem to be harmful. The cause of variability of response and degree of side effects in patients is not completely clear. Genetic variations in the b₂AR might account for the increased side-effect susceptibility to SABAs observed in some populations. This is a focus of ongoing research. The use of LABAs in COPD has a good safety record, and tolerance to these agents is not usually seen in patients with COPD. The Salmeterol Multicenter Research Trial (SMART) study of asthmatic patients was terminated early due to a slight increase in deaths among African Americans on salmeterol. Because of the SMART study, the FDA has a black-box label on all LABAs. In the TOwards a Revolution in COPD Health (TORCH) study, however, salmeterol arms showed a trend toward a survival advantage over placebo and ICS arms.¹⁷

Anticholinergics

Anticholinergic bronchodilators are also used in the treatment of COPD. They are analogs of atropine and act at the muscarinic receptors on airway smooth muscle cells. Cholinergic fibers arise from the dorsal motor nucleus of the vagus nerve. Impulses from the vagus nerve extend down to parasympathetic ganglia. When the post-ganglionic fibers innervating the airway smooth muscle cells, submucosal glands, and the lung are activated, acetylcholine is released and causes bronchoconstriction. It is through the muscarinic receptors that vagal stimulation is mediated in the lung. Receptors M1, M2, and M3 are the subtypes on airway smooth muscle cells. Increased cholinergic tone contributes to increased bronchial smooth muscle tone and mucus hypersecretion. Anticholinergics improve expiratory flow limitations, hyperinflation, and exercise capacity by alleviating bronchoconstriction. Similar to b-adrenergic agents, anticholinergic agents may have a role in airway protection. Muscarinic antagonism may result in reduced airway inflammation in patients with COPD.¹⁸ Anticholinergics are relatively safe medications when used in the proper doses. Class effects include dry mouth, increased risk of glaucoma, and urinary retention, and can be observed even with recommended doses. These drugs should be used cautiously in patients with bladder neck issues or severe glaucoma.

Craig Rosebrock, MD, is a clinical fellow and James Donohue, MD, is professor of medicine, School of Medicine, University of North Carolina, Chapel Hill. For further information, contact .