Asthmatic Conditions and Treatment: Gasping for Air

Pharmacists should reinforce adherence and education for all asthma patients.

When we think about asthma, we think of a complex syndrome and turn to the experts. The National Institutes of Health’s 2007 National Asthma Education and Prevention Program Expert Panel simplified asthma’s definition to “A common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation. The interaction of these features of asthma determines the clinical manifestations and severity of asthma and the response to treatment.”¹ This definition underscores asthma’s 2 defining features:

1. Asthma involves only the bronchial tubes, usually leaving the air sacs and lung tissue untouched.

2. Asthma’s variable, recurring course is defined by the triad of inflammation, leading to bronchospasm, and hyperreactivity.²

Asthma affects 1 of every 15 children— numbering some 6 million—making it the most common pediatric chronic illness. Altogether, asthma affects a total of 22 million people.³ Its breathlessness leaves sufferers gasping for air. If uncontrolled or undercontrolled, asthma’s impact on patients and families includes missed school or work, emergency department visits, and frequent hospitalizations.

Experts base their first management decisions on asthma severity (see Table), employing objective measures of lung function. Later, the deciding factor stems from their assessment of how well behavioral and pharmaceutical interventions achieved asthma control.¹

Every asthma patient’s symptom constellation (shortness of breath, wheezing, cough, sputum production, exercise intolerance, and chest tightness) and precipitants (allergens or irritants) are unique, but wheezing and nocturnal cough are usually presenting complaints. Patients need to know—and avoid—their precipitants, which is why patient education is so important. The pharmacist is a key figure in this education process.

About 90% of patients have extrinsic (allergic) asthma, usually developing before age 6 years and associated with exposure to allergens such as dust mites, tobacco smoke, and viral respiratory infections. A family history of allergies, current active allergies, or allergic conditions, such as sinusitis, atopic dermatitis, or eczema, are commonly found.

Remission in early adulthood is common, but in 75% of all cases, the asthma recurs later in life. The remaining 10% of patients have intrinsic asthma, which typically develops after age 30 years and is independent of allergies. This refractory, often chronic condition is more common in women and often follows a respiratory tract infection.¹ Exercise-induced asthma is an asthma variant; heightened airway reactivity results in acute bronchospasm pursuant to vigorous exercise. Although usually confined to people with asthma, it also occurs in healthy people.^4,5

Treatment

Two categories of medications are the cornerstone of asthma prevention and treatment: quick-relief agents (also called “reliever medications”) and long-term control agents (also called “controller medications”). Bronchodilators ameliorate bronchospasm, and corticosteroids reduce inflammation. Inhaled medications are generally preferred over systemic oral medications because they act directly on the airway surface and airway muscles, and systemic absorption and subsequent adverse effects are minimal.

The beta₂ agonists bronchodilate like the prototypical asthma drug, adrenaline, but with fewer side effects. Pharmacists need to separate the short-acting (SABA) and the long-acting (LABA) beta2 agonists in their minds, because they are 2 different categories. The SABAs are quick relief and the LABAs are controller medications. The SABAs’ agonists’ action begins within minutes after inhalation, lasts an average of 4 hours, and is used for intermittent asthma. Inhaled corticosteroids (ICSs) are added if symptoms are uncontrolled. Side effects may include anxiety, tremor, palpitations or tachycardia, and hypokalemia.¹

The next step in patients who are not controlled is to add a LABA or increase the dose of ICSs.¹ LABAs’ duration is up to 12 hours. The SMART trial, which included 26,000 patients, found increased risk when LABAs were used alone in asthma patients. Asthma exacerbations, hospitalizations, and death increased.⁶ The FDA plans to change change the LABAs’ labeling, making use of these products alone in asthma patients a contraindication—they must be used with ICSs or other asthma controller medications.

Related to atropine, which was used to treat asthma for the first time in 1831, the anticholinergic agents decrease airway vagal tone by antagonizing muscarinic receptors and inhibiting vagally mediated reflexes. ⁷ When used with the beta2 agonists in acute asthma attacks (not chronic), ipratropium can enhance bronchodilation. Ipratropium’s effect begins in 2 hours and diminishes at 6 hours. Anticholinergics are more effective in patients with chronic obstructive pulmonary disease.⁸

Clinicians often add ICSs to the patient’s regimen if beta2 agonists are insufficient for control. Corticosteroids gradually improve lung function and reduce airway obstruction. Patients may report hoarseness, loss of voice, and oral yeast infections. Early use of ICSs may prevent irreversible damage to the airways. Oral corticosteroids are used for asthma unresponsive to other medications. Osteoporosis, bone fractures, diabetes mellitus, high blood pressure, thinning of the skin, bruising, insomnia, emotional changes, and weight gain are side effects of chronic treatment.¹ A recent study indicates that supplemental vitamin D may improve lung function and corticosteroid response in patients with refractory asthma.⁹

The mast cell stabilizer cromolyn sodium prevents histamine release, and its exact mechanism of action is unknown. Its use is primarily preventive for acute exacerbations of asthma triggered by exercise, cold air, and allergens.¹

Methylxanthines still play an important role in treatment-resistant asthma; they relax muscles surrounding the air passages and prevent mast cells from releasing chemicals, such as histamine. These drugs have narrow therapeutic windows, and can cause nausea, vomiting, arrhythmias, and seizures. They are also subject to drug interactions with cimetidine, calcium channel blockers, quinolones, and allopurinol.¹⁰

Leukotrienes induce several biological effects; they augment eosinophil and neutrophil migration, monocyte and neutrophil aggregation, leukocyte adhesion, increased capillary permeability, and smooth muscle contraction. The result is increased airway bronchoconstriction, edema, inflammation, and mucus secretion in asthmatic patients. The leukotriene antagonists are direct antagonists of airway inflammation mediators in asthma, and reduce the risk of airway narrowing. They are used for prophylaxis of exerciseinduced bronchospasm and long-term treatment of asthma as an alternative to low doses of ICSs.¹¹ Zileuton, a specific inhibitor of 5-lipoxygenase, inhibits leukotriene formation.¹²

Omalizumab (Xolair), a recombinant DNA-derived humanized immunoglobulin G monoclonal antibody, binds selectively to human immunoglobulin E on mast cell and basophil surfaces. It reduces mediator release and allergic response. It is indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens, in whom symptoms are uncontrolled by ICSs. It must be administered by injection in a clinic or physician’s office, and it carries a black box warning for anaphylaxis.¹³

Table 2. Asthma Medications

Type of Medication

Action or Purpose

Examples

Quick-relief medications

Relieve acute exacerbations and prevent exercise-induced asthma or bronchospasm

Short-acting beta-agonists (SABAs)^a; albuterol (Ventolin HFA, Proventil HFA), levalbuterol (Xopenex), metaproterenol (Alupent), pirbuterol acetate (Maxair), and terbutaline sulfate (Brethaire)

Anticholinergics (only for severe exacerbations); ipratropium bromide (Atrovent)

Systemic corticosteroids, to accelerate recovery from acute exacerbations^b:methylxanthine (aminophylline)

Long-term control medications

Used in a stepwise approach to control chronic asthma

Inhaled corticosteroids (ICSs)^a; beclomethasone dipropionate (Beclovent, Qvar, and Vanceril), triamcinolone acetonide (Azmacort), budesonide (Pulmocort), and flunisolide (Aerobid)

Cromolyn sodium^a; Intal

Long-acting beta-agonists (LABAs)^a; Salmeterol xinafoate (Serevent) and formoterol (Foradil)

Combination inhaled corticosteroids and long-acting beta-agonists^a; fluticasone and salmeterol (Advair) and budesonide and formoteral (Symbicort)

Methylxanthine^b; theophylline (Theodur, Theoair, Slo-bid, Uniphyl, Theo-24)

Leukotriene antagonists^b; montelukast (Singulair), zafirlukast (Accolate)

5-Lipoxygenase inhibitors; zileuton (Zyflo)

a = inhaled; b = oral

Counseling

Pharmacists need to reinforce learning for all asthmatic patients, focusing on inhaler technique and compliance. Aspirin or other nonsteroidal anti-inflammatory drugs and beta-blockers can precipitate or aggravate asthma in some patients, especially those who have severe, persistent asthma. Comorbidities such as esophageal reflux, obesity, obstructive sleep apnea, and stress or depression can complicate asthma as well. Treating these can improve outcomes for asthma patients.

Ms. Wick is a senior clinical research pharmacist at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. The views expressed are those of the author and not of any government agency.

References

1. National Institutes of Health. Guidelines for the diagnosis and management of asthma. July 2007 Available at: www.nhlbi.nih.gov/guidelines/asthma/asthsumm.pdf.

2. Busse WW, Calhoun WF, Sedgwick JD. Mechanism of airway inflammation in asthma. Am Rev Respir Dis. 1993;147(6 part 2):S20-24.

3. Centers for Disease Control and Prevention. Asthma--United States, 1982-1992. MMWR Morb Mortal Wkly Rep. 1995;43:952-955.

4. McFadden ER Jr. Exercise-induced airway obstruction. Clin Chest Med. 1995;16:671-82.

5. Randolph C. Exercise-induced asthma: update on pathophysiology, clinical diagnosis, and treatment. Curr Probl Pediatr. 1997;27:53-77.

6. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. The Salmeterol Multicenter Asthma Research Trial: a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129:15-26.

7. Courty MA. Treatment of asthma. Edin Med J. 1859;5:665.

8. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax. 2005;60:740-6.

9. Sutherland ER, Goleva E, Jackson LP, Stevens AD, Leung DY. Vitamin D levels, lung function and steroid response in adult asthma. Am J Respir Crit Care Med. 2010 Jan 14. [Epub ahead of print]

10. Makino S, Adachi M, Ohta K, et al; Safety of Sustained-Release Theophylline and Injectable Methylxanthines Committee; Asthma Prevention and Management Guidelines Committee. A prospective survey on safety of sustained-release theophylline in treatment of asthma and COPD. Allergol Int. 2006;55:395-402.

11. Ulrik CS, Diamant Z. Add-on montelukast to inhaled corticosteroids protects against excessive airway narrowing. Clin Exp Allergy. 2010 Feb 1. [Epub ahead of print]

12. Zyflo CR [package insert]. Lexington, MA: Cornerstone Therapeutics; July 2009.

13. Long AA. Monoclonal antibodies and other biologic agents in the treatment of asthma. MAbs. 2009;1:237-246.