Asthma Treatment: Guidelines and Medications

Asthma, a chronic lung condition, affects millions of Americans. In 2001, more than 20 million Americans reported having asthma, including over 6 million children.¹ In children, asthma is more common in boys than in girls. In adults, the reverse holds true. The cost of treating asthma creates a huge financial burden on the health care system. In 1996, the direct health care costs associated with asthma were estimated to be nearly $6 billion.² In 2002, asthma-related costs were estimated to be $14 billion.³ Asthma-related symptoms cause nearly 14 million outpatient visits, 2 million Emergency Department visits, and more than 400,000 hospitalizations annually. Although only 3% of persons with asthma were hospitalized in 1997, inpatient costs accounted for 30% of asthma-related health care costs.⁴ Along with direct health care costs, asthma also accounts for $4.6 billion in lost productivity due to 3 million lost workdays and 10 million lost school days annually.^5,6,7

Because of the prevalence of asthma and the need for appropriate care, the National Heart, Lung and Blood Institute formed the National Asthma Education Program (NAEP) Expert Panel. This panel consists of physicians, scientists, pharmacists, and nurses who are experts in asthma care. This panel and the subsequent National Asthma Education Prevention Program (NAEPP) published recommendations for the management and treatment of asthma. These recommendations remain the standard guidelines for the care of patients with asthma.

NAEPP II Guidelines

According to the NAEPP II guidelines,⁸ asthma is 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 hyperresponsiveness to a variety of stimuli."

The first concept provided by this definition is that chronic inflammation causes asthmatic symptoms. Now research and treatment are aimed at controlling the mediators of inflammation and preventing permanent lung damage. The second concept is the reversibility of airflow obstruction, as compared with irreversible disorders, such as chronic obstructive pulmonary disease.

Because symptoms are reversible, rescue agents aim to provide immediate relief, whereas anti-inflammatory agents control chronic inflammation. The final concept is the hyperresponsiveness of the bronchioles. This hyperresponsiveness is caused by patient-specific triggers. Recognition of each patient's triggers, whether allergens or exercise, can guide treatment options.

Along with defining asthma, the NAEPP II established categories to classify the severity of asthma. These classifications provide a means to guide therapy and assess progression of symptoms. The 4 categories, as defined in the guidelines, are severe persistent, moderate persistent, mild persistent, and mild intermittent. The categories are determined by the frequency of symptoms, severity of exacerbations, effect on activity, and predictability of peak flow rates (Table 1).

Treatment

The asthma treatment market is changing rapidly. New medications and delivery systems are available continuously. Delivery systems currently available include metered-dose inhalers (MDIs), breath-actuated inhalers, nebulizers, and dry-powder inhalers.

MDIs consist of a pressurized canister with a valve that dispenses a measured amount of medication when pressed. Although MDIs remain popular due to ease of use, efficacy, and portability, the availability of this formulation is decreasing. In the past, all MDIs contained chlorofluorocarbon (CFC) as the propellant. Because of its detrimental effects on the ozone layer, the use of CFC is being phased out. Some manufacturers have opted to reformulate their MDI to contain hydrofluoroalkane as the propellant. Other manufacturers are discontinuing production of MDIs and utilizing dry-powder formulations instead.

Breath-actuated inhalers provide medication only under the pressure of inspiration, rather than through compression of the valve. This option is helpful for patients who are unable to coordinate inspiration with actuation of a conventional MDI. Unfortunately, the breath-actuated system, unlike the MDI, does not allow for the use of a spacer.

Nebulizers, jet nebulizer and ultrasonic types, aerosolize a liquid solution for inhalation. Jet nebulizers use oxygen or pressurized air to draw the aerosolized solution through a tube to which a mouthpiece or mask is attached. Ultrasonic nebulizers aerosolize the solution through vibration. Although very effective at delivering adequate doses, the nebulizer is bulky and requires electrical power.

The availability of dry, micronized powder formulations continues to increase. Some products are self-contained with medication, whereas others require the patient to add the medication to the delivery device prior to administration. These formulations require a high inspiratory flow rate in order to inhale the powder directly into the lungs. The advantages of dry powder are that it is breath-actuated and requires minimal coordination.

Medications

The medications available to treat asthma can be classified as rescue agents or agents for long-term control. The severity of the patient's asthma determines the need for one or both classes of medications (Table 2).

Regardless of severity classification, all asthma patients should receive a rescue agent for symptomatic relief. The drug of choice for rescue therapy is the short-acting bronchodilator. Albuterol remains the most widely used bronchodilator. Levalbuterol, the R-enantiomer of albuterol, also is available. Because levalbuterol costs many times more than albuterol, its primary role is for use by patients who cannot tolerate the increased heart rate that occurs with albuterol. The 0.63-mg dose of levalbuterol is equipotent to 2.5 mg of racemic albuterol.

The NAEPP II guidelines recommend the addition of longterm control agents for all patients except those with mild intermittent asthma. These agents?including long-acting beta-agonists, leukotriene inhibitors, corticosteroids, and theophylline?are necessary to control symptoms along with modifying the inflammatory process.

Inhaled corticosteroids are the mainstay of therapy because they prevent the irreversible loss of lung function. Corticosteroids decrease the production of proinflammatory cytokines. The NAEPP II guidelines do not recommend a specific corticosteroid; rather they recommend a dose range, depending on the severity classification (Table 3). Common side effects include respiratory infection, rhinitis, cough, otitis media, diarrhea, rash, and moniliasis.

Two long-acting beta-agonists are currently available for twice-daily administration. Due to a delayed onset of action, it is not appropriate to substitute them for short-acting beta-agonists as rescue therapy. The first long-acting beta-agonist, salmeterol, was originally available as an MDI formulation but has been reformulated to a dry-powder form. The second agent, formoterol, is also a dry powder for oral inhalation. It has a shorter onset of action than salmeterol. In response to the Serevent Multi-center Asthma Research Trial, the FDA recently issued a black-box warning for products containing salmeterol due to an increased risk of life-threatening asthma episodes or death. In this study, comparing salmeterol to placebo, there were 13 deaths and 36 life-threatening episodes in the salmeterol arm, versus 4 deaths and 23 life-threatening episodes in the placebo arm.⁹

Due to recent discoveries that eosinophil infiltration into the airway plays an important role in chronic inflammation, leukotriene-receptor antagonists (montelukast and zafirlukast), along with a leukotriene-synthesis inhibitor (zileuton), have been developed. They offer the advantage of oral administration. Although inhaled-corticosteroid monotherapy is superior to leukotriene-modifier therapy, the addition of a leukotriene modifier improves lung function and symptom control in patients uncontrolled on inhaled corticosteroids. Side effects include fatigue, dyspepsia, headache, cough, rash, increased liver enzymes, nausea, and sinusitis.

Research into the inflammatory process is advancing the treatment of asthma into the high-technology arena. The first high-tech product is omalizumab, a monoclonal antibody. It is administered subcutaneously, and peak concentration is achieved within 3 to 14 days. The dose is determined by the patient's baseline serum immunoglobulin E level and body weight. Adverse events associated with omalizumab include fatigue, musculoskeletal effects, gastrointestinal effects, and urticaria.

Patient Education

Patient education can prevent asthma exacerbations. Pharmacists are the experts on medications. Therefore, they should always remind patients of the role for each medication (rescue versus prevention), the administration techniques, care for inhalers, and when to seek medical attention.

Patients should understand the basic mechanisms of asthma, including inflammation and bronchoconstriction. They should understand what causes their symptoms, what their personal triggers are, and what their symptoms are. A lack of understanding often creates misconceptions and leads to noncompliance.

Pharmacists can motivate patients to comply with prescribed therapy and monitoring measures. Involving the family in this education will increase the patient's support system and encourage participation in the patient's care.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. D. Ryan, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: dryan@mwc.com.