Traditionally, asthma has been treated with oral and inhaled bronchodilators, which help control the symptoms of asthma but do nothing for the inflammation. Now, the focus is on prevention, which involves treating the underlying inflammation as well as the bronchoconstriction, and constantly monitoring breathing efficacy.
It is essential that asthmatic patients understand how to manage drug therapy and side effects, monitor breathing efficiency, and deal with environmental factors that contribute to bronchoconstriction (irritants, allergens, exercise, cold air inhalation, and infection). Unfortunately, despite the fact that much is known about asthma and its cause and care, the disease is seriously undertreated. One study of 94 adult asthmatics found that nearly 75% were not receiving the appropriate therapy, or were not using medications properly. The newly issued Guidelines of the National Asthma Education and Prevention Program advocate a stepwise approach to asthma therapy, starting with short-acting inhaled beta2-agonists as needed for mild intermittent asthma; these are followed, depending on disease severity, by the addition of an inhaled corticosteroid and/or cromolyn or nedocromil sodium, a long-acting inhaled beta2-agonist, an oral beta-agonist or theophylline, or a leukotriene inhibitor. For very severe disease, an oral corticosteroid may be added (see Table).
Table 2. Drugs Used for Asthma
|Generic Name||Trade Name(s)|
|Proventil, VentolinBrethaire, Brethine, Bricanyl
|Mast Cell Inhibitors|
|cromolyn sodiumnedocromil sodium||IntalTilade|
|Corticosteroids: Metered-Dose Inhaler|
Beclovent, Vanceril, Vanceril DS
|Leukotriene Inhibitors or Antagonists|
Bronchodilators: Beta2-Agonists, Theophylline
The introduction three decades ago of bronchodilating beta2-agonists – adrenergic agonists selective for the beta2 receptor – revolutionized the treatment of asthma. These agents proved to be more potent and longer acting (4-6 hours) than the nonselective adrenergic receptor agonists such as isoproterenol, which stimulate both alpha- and beta-adrenergic receptors. Beta2-agonists give rapid symptomatic relief and also protect against acute bronchoconstriction caused by stimuli such as exercise or the inhalation of frigid air. Frequency of use can also serve as an indicator of asthma control. Recently, an extra long- acting beta2-agonist-salmeterol (duration up to 12 hours)-was introduced in the United States. Salmeterol is so potent that it may mask inflammatory signs; therefore, it should be used with an anti-inflammatory.
Theophylline is a relatively weak bronchodilator with a narrow therapeutic margin (blood level monitoring is recommended to avoid toxicity) and a propensity for drug interactions (competition for hepatic cytochrome P450 drug-metabolizing enzymes alters plasma levels of several important drugs metabolized by that same system). On the plus side, theophylline has some anti-inflammatory activity, can be taken orally, and is available in long-acting formulations; patient compliance is good with once- or twice-daily oral formulations.
About 60% to 70% of asthmatics have mild disease that can be managed with inhaled beta2-agonists alone, when pretreatment is provided before allergen exposure or exercise (cromolyn or nedocromil sodium can be substituted). Asthmatics with more severe disease are generally treated with inhaled beta2-agonists as needed, along with other antiasthma medications, in particular, inhaled corticosteroids (regular use of inhaled corticosteroids, but not beta-agonists, has been shown to reduce the number of exacerbations of asthma, even in patients with mild disease). Theophylline is generally reserved for use in conjunction with other antiasthma agents for patients with moderate to severe disease.
Before 1990, beta2-agonists were often administered on a regular schedule, which was thought to provide better asthma control. However, recent studies have shown that scheduled use is associated with poorer control and possibly with increasing asthma mortality worldwide. This association was first noted in the late 1960s with the use of a potent formulation of the nonselective isoproterenol. A second dramatic increase in asthma mortality was associated with the introduction in the late 1970s of a high-dose formulation of fenoterol. Later, frequent use of fenoterol or albuterol (primarily via nebulizer, and not metered-dose inhaler) was found to increase the risk of death in patients with severe asthma.
It is possible that the overuse of inhaled beta2-agonists is simply a marker for severe uncontrolled asthma, and may not be the cause of death. However, it is also possible that the transient deterioration of airway responsiveness observed when the medication is stopped contributes to the risk. Also, beta-agonists have been associated with a rebound increase in bronchoconstrictor response to allergens, and with a partial loss of protection against exercise-induced bronchoconstriction. Several studies have shown that as-needed administration is at least as effective as regularly scheduled administration; therefore, using beta2-agonists on demand is preferred. One recent trial involved 255 patients with mild asthma who received albuterol inhalation therapy either on a regular schedule (126 patients) or as needed (129 patients). The follow-up period lasted 18 weeks, and outcomes measured included peak expiratory flow, forced expiratory volume in one second, asthma symptoms, asthma exacerbations, quality of life, need for additional albuterol, and airway responsiveness to methacholine.
The average total use of albuterol in the scheduled group was 9.3 puffs per day, and in the as-needed group, 1.6 puffs per day. Basically, there were no clinically important differences between the two groups, although bronchodilator response to albuterol was increased in the scheduled-treatment group at the end of the trial. The investigators concluded, “In patients with mild asthma, neither deleterious nor beneficial effects derived from the regular use of inhaled albuterol beyond those derived from use of the drug as needed. Inhaled albuterol should be prescribed for patients with mild asthma on an as- needed basis.”
Anti-inflammatory Agents: Corticosteroids, Mast Cell Inhibitors, Antileukotrienes
Moderate asthma is treated with a daily inhaled anti-inflammatory-corticosteroid or mast cell inhibitor (cromolyn or nedocromil sodium)-plus an inhaled beta2-agonist as needed (3 – 4 times per day) to relieve breakthrough symptoms or allergen- or exercise-induced asthma. Cromolyn and nedocromil sodium block bronchospasm and inflammation, but are usually effective only for asthma that is associated with allergens or exercise. Inhaled corticosteroids improve inflammation, airways hyperreactivity, and obstruction, and reduce the number of acute exacerbations. They may entirely eliminate symptoms, although noncompliance is often a problem because relief is not immediate (it takes a month before effects are apparent and up to a year for marked improvement to occur). The most frequent side effects are hoarseness and oral candidiasis. More serious side effects have been reported – partial adrenal suppression, growth inhibition, and reduced bone formation – but only with the use of higher doses. Beclomethasone, triamcinolone, and flunisolide probably have a similar mg-for-mg potency; the newer approvals budesonide and fluticasone are more potent and reportedly have fewer systemic side effects. This is caused, in part, by negligible oral bioavailability (a small portion of each dose is swallowed). Spacer devices are recommended for all inhaled corticosteroids; they reduce systemic effects by increasing drug delivery to the lungs and reducing residue on the pharynx and tongue.
For severe asthma, the dosage of the inhaled corticosteroid can be increased or a long- acting bronchodilator (including an oral beta2-agonist or theophylline) added, especially for nocturnal symptoms. Oral corticosteroids are used for severe flare-ups and should be administered early (when bronchodilators fail to reverse an episode) because they take 12 to 24 hours to act. When long-term oral corticosteroids are needed, alternate-day therapy with the lowest effective dose should be used to help prevent long-term side effects (cataracts, osteoporosis, weight gain, skin fragility, fluid retention, growth suppression, exacerbation of diabetes, and hypothalamic-pituitary-adrenal suppression).
Despite optimal use of bronchodilators and anti-inflammatory agents, many patients continue to suffer from uncontrolled asthma. These patients may benefit from therapy with one of the new antileukotrienes. These drugs are members of a heterogeneous class of antiasthma agents with the potential to interfere with the initial steps in the inflammatory cascade. Leukotrienes are inflammatory substances related to prostaglandins; both are generated from arachidonic acid in cell membranes. When arachidonic acid in mast cells, macrophages, monocytes, eosinophils, and basophils is released from membrane phospholipids by phospholipase A2, it is metabolized via two major pathways: the cyclooxygenase pathway (which produces prostaglandins and thromboxanes) and the 5- lipoxygenase pathway (which produces leukotrienes). Leukotrienes play an important role in bronchial inflammation. They induce migration, aggregation, and adhesion of various white blood cells (neutrophils, eosinophils, monocytes), increase capillary permeability, and cause bronchial smooth muscle contraction. The results include edema, leukocyte chemotaxis, enhanced production of mucus, reduced mucociliary transport, and bronchospasm. Certain classes of leukotrienes – for example, the cysteinyl leukotrienes – are particularly potent bronchoconstrictors, being approximately 100 to 1,000 times more active than histamine.
In recent months, the FDA has approved two antileukotrienes: zafirlukast and zileuton. Zafirlukast blocks receptors for cysteinyl leukotrienes C4, D4, and E4, and zileuton specifically inhibits 5-lipoxygenase, thus preventing the synthesis of leukotrienes B4, C4, D4, and E4. With long-term use, these new drugs significantly relieve the wheezing, coughing, and dyspneic symptoms of asthma. They are not bronchodilators and should not be used to reverse bronchospasm, although therapy can be continued during acute attacks.