US Pharm. 2007:32(7):38-47.

One in 15 Americans suffers from asthma, and every day in the United States 40,000 people miss work or school and 11 people die from the disease.1 Although there is no cure, asthma can be managed with appropriate treatment and these daily occurrences can be avoided. With hundreds of prescriptions filled at a given pharmacy each day, the pharmacist is in a unique position to improve the quality of life (QOL) in those with asthma. This article will describe the pathophysiology of asthma and why it plays an important role in medication selection; provide educational tips that will improve the care of asthmatic patients; and detail medications and their evidence.

Understanding of the underlying pathophysiology of asthma will allow the pharmacist to better evaluate drug therapy for appropriateness. Current drug therapies target the two basic components of asthma: airway inflammation and bronchoconstriction. Chronic inflammation plays a key role in the changes that occur in patients. 2

Airway inflammation can be classified as either acute or chronic.2,3 Acute inflammation can be further characterized as either early-phase or late-phase reactions. In the early-phase reaction, immunoglobulin (Ig) E antigens initiate the activation of mast cells and macrophages.2-4 Activated mast cells release prostaglandins, leukotrienes, and other proinflammatory mediators. These mediators cause airway smooth muscle constriction and mucous secretion, ultimately decreasing the airway lumen. In the late-phase reaction, T lymphocytes, eosinophils, basophils, neutrophils, and macrophages are activated.3 Eosinophils enhance the inflammatory process further by releasing proteins, leukotrienes, and cytokines, which damage airway epithelial cells and lead to hyperreactivity and bronchospasm.5 The proinflammatory cells and mediators involved in acute inflammation also contribute to chronic inflammation. Over time, activation of the airway immune system, epithelial cell destruction, and thickening of the basement membrane cause airway remodeling, resulting in an increase in airflow resistance.3 Mucous secretion and subsequent formation of mucous plugs further complicate airflow-resistance problems. Inflammation also causes an increase in the sensitivity of the bronchioles to stimuli, or triggers, causing bronchoconstriction.

Patient Education
Patient education is essential in the long-term success of asthma management. Education provided by pharmacists, nurses, and physicians has proved effective. The patient plays a vital role in this process and should be considered a partner. Pharmacists should offer counseling on the following to all patients with asthma:

Basic facts about asthma: The difference between normal lung function and that of a patient with asthma, especially during an attack.

Trigger management: Identification and management of triggers of asthma attacks.

Skills: Appropriate inhaler technique and use of a spacer device with metered-dose inhalers (MDIs). Peak flow monitors are an easy way to monitor long-term control and detect early deterioration. Written asthma action plans can supplement peak flow use.

Role of controller medications: Controller medications target the underlying cause of asthma and prevent attacks from occurring. Compliance with these medications should be emphasized, even if the patient has not had an attack in some time.

Role of rescue medications: Rescue medications relax muscles around the airway, helping reverse an acute attack. They should not be used on a scheduled basis, and frequent use may be a sign of worsening.

In combination with medications, limiting exposure to triggers plays a vital role in controlling asthma symptoms and decreasing the number of attacks.2 Triggers include allergens, irritants, infections, and medications.6-8 The pharmacist can play a role in asthma control by providing patients with tips and techniques for minimizing contact with triggers.

Strategies for reducing exposure to animal dander involve either the removal of the pet from the house or minimizing contact by not allowing the pet in the patient's bedroom. Weekly washings can also help to decrease the accumulation of dander. Dust mites are found in bedding, upholstered furniture, carpets, clothes, and soft toys. Encasing bedding in allergen-impermeable covers, along with regular washing in hot water (>130F), will help to control mites.2,9 Soft toys should be washed regularly in hot water, and there should be a limited number of toys available to the child to sleep with. Dust mites are also prevalent in areas of high humidity, and reducing the indoor humidity with a dehumidifier to below 50% can reduce a patient's exposure.2 Simple household hygiene may also reduce asthma attacks. However, there is little evidence to suggest extensive measures, such as high-efficiency particulate air filters, are of any benefit.2 Steps to minimize exposure to outdoor allergens include keeping windows closed, using air conditioners, and staying indoors during the afternoon when the pollen and spore levels peak. 2

Exposure to irritants should be assessed. Examples of common irritants can include tobacco smoke, chemical gases or sprays, fumes, and any chemical with a strong odor.7 Patients and parents of children with asthma who smoke should be encouraged to stop. Pharmacists who notice increased use of rescue medications can offer counseling on these adjunctive measures to aid in improving control of asthma symptoms and decreasing attacks.

Allergic rhinitis is a common trigger, and the use of intranasal corticosteroids or antihistamine/decongestant combination medications is recommended to relieve symptoms. Asthma attacks can be induced by respiratory viral infections. Annual influenza vaccinations should therefore be offered to all patients.

Pharmacists should review all medications to avoid drug-induced asthma attacks. Severe and even fatal attacks have been associated with the use of aspirin or nonsteroidal anti-inflammatory drugs.8 All patients with asthma should be counseled on the potential risk of attacks with these medications and instructed to ask their pharmacist or physician before starting any OTC products that contain these agents. Safer alternatives such as acetaminophen or salsalate may be recommended. Nonselective beta-blockers (propranolol, nadolol, and timolol) are not recommended for asthma patients. Cardioselective beta-blockers (atenolol, bisoprolol, and metoprolol) can be used if patients require this medication class to control other conditions.

Peak Flow Monitoring and Asthma Action Plans
A peak flow meter is a simple and inexpensive device that can aid in assessing a patient's current asthma control.2 A peak flow meter measures the peak expiratory flow (PEF) rate. Peak flow monitoring is recommended for patients with moderate to severe persistent asthma. Daily peak flow measurements can serve as a tool for the physician and the patient to judge responses to controller medications and aid in early recognition of worsening asthma. Pharmacists can provide peak flow education to patients with asthma.10 While relatively simple to use, patients will require training on the appropriate technique and how to monitor and record their peak flow readings. Education and evaluation of patient technique should be offered during each pharmacy consultation. Peak flow meters are often used in conjunction with action plans.

Self-management through the use of written action plans has been found to decrease emergency department visits and hospitalization.2,11 Action plans are based on personal best peak flow (PBPF) measurements and divided into green (>80% PBPF), yellow (50%-80% PBPF), and red (<50% PBPF) zones. Instructions are based on which zone the patient is currently in. Patients in the green zone will continue their controller medications, and those in the yellow zone are instructed to make adjustments to their regimen with the goal to return to their green zone. Patients falling in the red zone may require immediate attention by medical professionals. Counseling on how to use written action plans provides pharmacists with another opportunity to impact patient care.

Symptoms and Classification
Patients may experience long periods of time with little or no symptoms, followed by episodes of acute attacks. Common symptoms include shortness of breath, chest tightness, wheezing, or coughing, particularly at night. Severe asthma episodes may involve audible wheezing, rapid respirations or heart rate, and difficulty speaking. Acute episodes may last from several minutes to hours or even days and resolve spontaneously or with treatment.

Early and accurate classification of asthma severity ensures appropriate use of medications because drug therapy recommendations are based upon severity. The National Asthma Education and Prevention Program (NAEPP) classifies patients as having either mild, intermittent, or persistent asthma (TABLE 1).12 †Persistent asthma is further classified as mild, moderate, or severe. Exercise-induced asthma is a form of intermittent asthma, and patients can be managed by using a rescue medication such as albuterol 15 minutes before physical activity. Patients with persistent asthma are classified by frequency of their day and nighttime symptoms, PEF rates, forced expiratory volume in one second (FEV1), and daily PEF variability. Over time, patients can move up or down in severity level based on control.

Therapy Review
The NAEPP recommends using a stepwise approach for the management of asthma. Based on the classification, a treatment regimen is recommended (TABLE 2).12 Gaining control quickly is important in order to treat the patient effectively. Once sustained control is achieved, a gradual, or step-down, reduction in therapy is recommended. The step-up approach is required when a patient is experiencing worsening symptoms requiring more medication. Patients should be evaluated every one to six months to determine if therapy needs to be stepped up or down. In some cases, clinical judgment is used to meet individual needs.

Short-acting beta2 -agonists (SABAs), or rescue inhalers, provide quick relief for acute attacks and are recommended in all patients despite severity classification. Long-term controllers are dosed daily in those patients with persistent asthma to prevent attacks. Counseling patients on compliance with long-term controllers will allow them to receive the maximum benefit from their medications.

Mild Intermittent Asthma: Patients do not require daily medications.12 A rescue inhaler is recommended for symptom control. If the patient is experiencing an increase in frequency and/or severity of symptoms, controller medications may be necessary. Monitoring rescue inhaler use is an effective technique to determine control. A patient's use of two or more doses per week or more than one canister per month is a sign of worsening asthma. Severe exacerbations can be treated with a short burst of systemic corticosteroids.

Mild Persistent Asthma: The preferred treatment for mild persistent asthma is a low-dose inhaled cortico-steroid (ICS).12 Most patients can be controlled using an ICS alone. Other treatment options for this classification included leukotriene modifiers, mast cell stabilizers, or sustained-release theophylline. Inhaled corticosteroids have been proven to be superior to the leukotriene modifiers.13 Alternative therapies are reserved for those who cannot use or tolerate inhaled corticosteroids. Inhaled corticosteroid dosing ranges are presented in TABLE 3.

Moderate Persistent Asthma: Low- to medium-dose ICS plus a long-acting beta2-agonist (LABA) is the preferred treatment. Alternative options include a medium-dose ICS or the use of a low- to medium-dose ICS plus a leukotriene modifier. In patients with recurring severe exacerbations, it is recommended to use a medium-dose ICS in combination with a LABA, leukotriene modifier, or theophylline. Several ICS/LABA combination products are available (TABLE 4).14-16 Inhaled corticosteroids used in combination with LABAs are superior to monotherapy with either agent, higher doses of an ICS alone, or the addition of a leukotriene modifier to an ICS.17-19

Severe Persistent Asthma: A high-dose inhaled cortico-steroid along with a LABA is the preferred treatment regimen.12 Systemic corticosteroids may also be used for long-term control. Patients should receive the lowest strength possible to maintain control, and every effort should be made to decrease the corticosteroid to reduce the risk of side effects seen with chronic use.

Short-Acting Beta2 -Agonists: Short-acting beta2-agonists are the most effective medications for the treatment of acute symptoms and exercise-induced asthma. They provide rapid bronchodilation via relaxation of the bronchial smooth muscle, which occurs within minutes of inhalation. Albuterol is the most commonly prescribed SABA and is available in nebulized and MDI formulations. Other SABAs include terbutaline, pirbuterol, and levalbuterol. Common side effects include tachycardia, palpitations, and nervousness.20 SABAs are not adequate for long-term control and are only indicated for short-term relief. OTC epinephrine inhalers (Bronkaid and Primatene Mist) should be avoided. Chlorofluorocarbon (CFC)-containing albuterol MDIs will not be available after 2008. Chlorofluorocarbons are used as a propellant for MDIs and have also been shown to deplete the ozone. Therefore, the U.S. Food and Drug Administration has mandated that production of CFC-containing products stop after 2008. Metered-dose inhalers have been reformulated using hydrofluoroalkane (HFA) as a propellant that will not cause deleterious effects to the environment. Proventil HFA, Ventolin HFA, and ProAir HFA are CFC-free albuterol products.

Inhaled Corticosteroids: Inhaled corticosteroids are the treatment of choice for persistent asthma.12 When compared to all other classes of medications, ICSs were proven to be more effective for improving symptoms and lung function. 21-24 The mechanism by which ICSs control asthma symptoms is the production of a direct local anti-inflammatory effect on the lung mucosa. These agents should not be used for acute exacerbations. Local side effects include thrush and throat irritation, which is usually seen with high-dose ICSs. Advising the patient to rinse the mouth with water after each dose will reduce the incidence of thrush. Systemic adverse effects can be seen with high doses of ICSs.25

Long-Acting Bronchodilators: NAEPP guidelines recommend adding a LABA to an ICS for the treatment of moderate-to-severe asthma. The addition of a LABA to ICS reduces symptoms and attacks when compared to similar ICS doses alone, but did not reduce the risk of attacks when compared to a high-dose ICS alone.26,27 Clinical study results linking LABA use to an increase in severe and life-threatening attacks, as well as asthma-related deaths (one death per 1,000 patients using LABAs for one year), prompted the FDA to issue a black box warning.28-30 Simply stated, LABAs should not be used as the first medication to treat asthma and should never be used alone or for quick relief. Patients should not stop their LABA without consulting their physician. Based on this, it may be appropriate to maximize ICS doses and only add LABAs when symptoms remain.

Leukotriene Modifiers: Montelukast (Singulair) and zafirlukast (Accolate) inhibit leukotriene receptors, resulting in the reduction of leukotriene-induced bronchoconstriction.31 They are considered an alternative to ICSs for mild persistent asthma.12 Further evidence has proven that switching from an ICS to a leukotriene modifier was associated with an increase in exacerbations and asthma-related hospitalizations.32 The leukotriene modifiers are also beneficial in patients with concomitant allergic rhinitis. Common side effects include dizziness, fatigue, stomach upset, elevated liver enzymes, cough, and nasal congestion.31 Zileuton (Zyflo), a 5-lipoxygenase inhibitor, is not routinely prescribed due to a cumbersome dosing schedule of four times a day and the potential for liver function test elevations.

Mast Cell Stabilizers: Cromolyn sodium and nedocromil sodium inhibit bronchoconstriction in response to an allergen challenge. Both medications are considered to be nontoxic and are used in childhood asthma, and there is no apparent difference in efficacy between the two drugs. These agents are not used as monotherapy and should be reserved as an adjunct to other controller medications.

Methyxanthines: Theophylline use has declined since the introduction of newer, more effective agents. The risks of severe toxicity, numerous drug interactions, and questionable efficacy when compared to ICSs have limited their utilization. Theophylline produces bronchodilation through phosphodiesterase inhibition. Sustained-release theophylline is considered an adjuvant therapy to ICS for nocturnal symptoms. Theophylline is not recommended for long-term use because it has a narrow therapeutic index and serum levels need to be monitored frequently. Symptoms of toxicity include nausea, vomiting, tachycardia, jitteriness, insomnia, arrhythmias, and seizures.33

Monoclonal Antibodies: Omalizumab (Xolair) is the first human recombinant anti-IgE antibody approved for the treatment of allergic asthma with elevated IgE levels that are not well controlled with high doses of ICSs. The dose is determined by the patient's baseline serum IgE level and total body weight. It is administered subcutaneously every two to four weeks in conjunction with ICS therapy.34 This therapeutic option is very costly.

Oral Corticosteroids: Systemic corticosteroids may be used for quick relief of a severe attack or daily for those with severe, difficult-to-control asthma.12 Daily use for long periods of time is not recommended due to the potential for adrenal suppression. Low doses for three to 10 days are recommended for severe exacerbations. Doses of prednisone 60 mg used for up to 10 days do not require tapering.12,35 Side effects from oral corticosteroid use include insomnia, nervousness, increased appetite, indigestion, arthralgia, and hyperglycemia.36

Conclusions/Pharmacist's Role
There are more than 4,000 asthma-related deaths per year, many of which are preventable.1 As one of the most conspicuous health care system practitioners, pharmacists are in the opportune position to impact QOL in their patients with asthma. Reviewing the underlying causes of asthma will help us to teach controller and rescue medications better. Several opportunities exist for the pharmacist to participate in the care of the asthmatic patient,37 including certification as an asthma educator.

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