The Role of Inhaled Long-Acting Beta-2 Agonists in the Management of Asthma

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The role of inhaled beta-2 agonists in the management of asthma has changed significantly over the last several years. This review outlines the most recent understanding of the pathophysiology of asthma and the studies that define the roles lhat both short- and long-acting beta-2 agonists play in therapy for this disease. A concentration on the clinical pharmacology and genetic implications for clinical use of this class of drugs in accordance with the national and international guidelines are described.

INTRODUCTION
In recent years, our understanding of the role of inhaled beta-2 agonists in the management of asthma has changed significantly. This has resulted partly from the findings of cellular, animal and clinical research on the pathophysiology of asthma—and partly from the findings of large clinical trials exploring the outcomes from various drug therapies. Both national and international guidelines for the diagnosis and management of asthma affirm that asthma is primarily an inflammatory lung disease that is effectively treated with antiinflammatory drugs—preferably the inhaled corticosteroids. Recent evidence suggests that the combination of an inhaled long-acting beta-2 agonist (LABA) and an inhaled corticosteroid is the most effective long-term control therapy for moderate or severe persistent asthma.

The National Asthma Education and Prevention Program defines asthma as: “a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role—in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells.” In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment. The inflammation also causes an associated increase in the existing bronchial hyperresponsive-ness to a variety of stimuli”.

Acute inflammatory responses may be provoked by inhalation of a sensitizing allergen and by viral or, possibly, airway infection (e.g., chlamydia or mycoplasma). The nature of the provoked inflammation is not necessarily identical. Allergic inflammation is characterized by activation of IgE- and T-helper type-2 (Th2) lymphocyte-dependent pathways, resulting in the activation of mast cells and macrophages, and the attraction and activation of inflammatory cells from the circulation—most notably, eosinophils but also neutrophils, basophils and mononuclear cells. Repeated low-level exposure to sensitizing allergens is thought to result in the chronic increases in lymphocyte and eosinophil numbers in the bronchial mucosa of patients with even mild asthma. Infections appear to provoke a predominantly neutrophilic inflammatory response, initiated by activation of epithelial cells and Thl lymphocytes. How chronic allergic inflammation or recurrent infectious inflammation contributes to “airway remodeling” is unknown, but structural abnormalities of the airways are common in patients with asthma, especially in those with chronic asthma of many years. These abnormalities, collectively referred to as “remodeling” include hyperplasia of all tissue elements (secretory cells and glands, vessels, smooth muscle), increased deposition of collagen beneath the subepithelial basement membrane (lamina reticularis) and increased extracellular matrix. The development and progression of remodeling is thought to account for the more rapid decline in lung function and development of irreversible airflow obstruction in some adults with persistent asthma. cheap viagra online

The most important clinical expression of acute inflammation in remodeled or chronically inflamed airways is the development of an asthma exacerbation, characterized by bronchial smooth-muscle contraction, mucus hypersecretion and mucosal edema, resulting in marked narrowing of airway lumens. These acute exacerbations are most commonly triggered by infection with a respiratory virus, especially a rhinovirus.

Perhaps the most dramatic clinical expression of chronic allergic inflammation is heightened bronchial responsiveness; enhancing the acute bron-chospasm provoked by exercise; hyperventilation of cold, dry air; and inhalation of noxious stimuli, such as sulfur dioxide, smoke or other pollutants. This bronchial hyperresponsiveness is associated with exaggeration of diurnal variability in airway caliber, often resulting in nocturnal bronchospasm severe enough to wake patients from sleep. Mounting evidence suggests that this bronchial hyperresponsiveness reflects an increase in smooth-muscle mass in asthmatic airways, which may be as much as 3-4-fold greater than in healthy, nonasthmatic subjects. One result of this increase in mass is that the smooth muscle in asthmatic airways needs to shorten by only 40% to completely occlude the airway, whereas even maximal shortening of smooth muscle in healthy, nonasthmatic airways narrows the lumen to a “plateau” without causing complete occlusion. The magnitude of the increase in bronchial responsiveness is predictive of subsequent asthma exacerbations as is the magnitude of the decrease in forced expiratory volume in one second (FEVj).
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Exacerbations of asthma are not only an important clinical marker of inadequately controlled or worsening asthma but also the most important outcome from the humanistic and health economics viewpoint as well. Approximately 14-15 million people in the United States now have asthma (about 5% of the population), reflecting an increase in prevalence of 75% from 1980 to 1994. Severe asthma exacerbations lead to >5,000 deaths and 470,000 hospitalizations per year. Total costs to society for asthma in the United States exceed $12 billion, with >50% attributable to direct medical costs. Thirty-seven percent, or $2.7 billion, is attributable to med¬ical care of severe acute exacerbations. It is unknown how many of the some 13.7 million ambu¬latory care visits for asthma per year are secondary to asthma exacerbations. But it is known that asthma results in an estimated 100 million restricted work days annually and that the indirect costs to society, a little over $5.3 billion for time lost from work or school, are primarily driven by exacerbations.