Asthma Treatment Guidelines and Use of Inhalers

Learning Objectives

After completing this continuing education article, the health care provider should be able to:

• Discuss the epidemiology and pathophysiology of asthma.

Explain current guidelines for long-term management of asthma in ambulatory patients.

• Develop a treatment plan and establish goals for asthma control.

Teach patients the correct use of inhaler devices.

• Educate patients on the law and issues regarding the transition of chlorofluorocarbon products to hydrofluoroalkane products.

Asthma is a chronic inflammatory disease of the airways that causes widespread narrowing of the airways. Accumulation of activated eosinophils, mast cells, and lymphocytes in the alveolar capillaries, interstitium, and alveoli are the cellular processes that cause inflammation. Epithelial shedding, bronchial smooth muscle enlargement, hyaline thickening of the basement membrane, and mucus secretion result from these cellular processes.¹ Inflammation, bronchial hyperresponsiveness, and bronchospasm are all components of asthma. These components contribute to narrowing of the airways, which causes episodes of dyspnea, cough, and wheezing–the common symptoms of asthma.² Unlike other respiratory diseases, such as chronic obstructive airway disease, the bronchospasm and bronchial hyperresponsiveness can be reversed with medications and long-term treatment. Asthma symptoms can be worsened by triggers that include tobacco smoke, animal dander, pollen, molds, aerosol chemicals, domestic dust mites, exercise, viral respiratory infections, and gastroesophageal reflux disease.³ Medications, such as aspirin, nonsteroidal anti-inflammatory drugs, and nonselective beta blockers, can also trigger an asthma attack. Cyclooxygenase-2 inhibitors do not seem to have an effect on asthma, even in patients with aspirin-induced asthma.⁴

Asthma Overview

In 2004, 21.3 million adults had a diagnosis of asthma, and 3780 deaths were attributed to asthma.⁵ Asthma was listed as the primary reason for 13.6 million physician office appointments and 1.8 million emergency department visits that same year.⁵ Direct costs of asthma reached $7.5 billion in 1998, which included $3.6 billion for hospital care–the largest component of direct cost.⁶ Estimated 1994 cost of prescription asthma medications, excluding allergy shots, was $2.45 billion.⁷

Asthma management has 2 components: acute exacerbation and long-term management. Acute exacerbation can range from mild to severe. Acute exacerbation signs and symptoms include not being able to lay supine and using accessory muscles during inspiration. Severe acute exacerbations can lead to the need for hospital treatment that includes inhaled beta₂ adrenergic agonists, oxygen, intravenous fluids, and systemic corticosteroids.⁸ Since 1997, experts have recommended against including antibiotics in the treatment of acute asthma exacerbations, except as needed when other conditions, such as pneumonia, are present.⁹

Chronic asthma management requires quick relief and long-term control medications. The 1997 National Asthma Education and Prevention Program Expert Panel Report 2 (NAEPP-EPR 2) and Guidelines for the Diagnosis and Management of Asthma-Update on Selected Topics 2002 provide clinicians with guidelines for long-term asthma management.¹⁰

Using the guidelines, long-term medication treatment is determined by the severity of the disease. There are 4 classifications: mild intermittent, mild persistent, moderate persistent, and severe persistent. Each classification's treatment builds on the medications already recommended in the lower classification. Written patient information and action plans also play a role in the success of pharmacotherapy and asthma control. Individualized instructions provide patients with directions on how to react to signs, symptoms, and changes in objective measures. Studies have shown no benefit to written action plans, but the guidelines suggest that the studies had enough limitations that written action plans are still warranted, especially in moderate and severe persistent asthma. This concept applies to action plans based on symptoms with subjective measures and peak-flow monitoring with objective measures.

Pharmacotherapy

In deciding on an approach to pharmacotherapy for a patient, it is important to determine the severity of the patient's asthma and the goals of treatment (Table 1). Mild intermittent disease is defined as symptoms occurring less than 2 days or nights per week, whereas severe persistent disease symptoms take place continually during the day or frequently at night.

Chronic asthma control goals include objective measures like forced expiratory volume in 1 second (FEV₁) and subjective measures, such as patient satisfaction and expectations. NAEPP goals for chronic asthma management include:

• Maintain (near) normal pulmonary function
• Prevent recurrent exacerbations of asthma and minimize the need for emergency department visits or hospitalizations
• Meet patients' and families' expectations of and satisfaction with asthma care

A stepwise approach to pharmacologic therapy is recommended.¹⁰ The amount and frequency of medication is dictated by asthma severity and directed toward suppression of increasing airway inflammation. Therapy should be initiated at a higher level at the onset to establish prompt control and then downregulated. Continual monitoring is essential to ensure that asthma control is maintained. Downregulation is necessary to identify the minimum medication necessary to maintain control.

Rescue Medications

The 2002 update recommends a short-acting bronchodilator as needed for symptoms for all patients.¹⁰ Albuterol (Ventolin) is the most common rescue medication used for acute asthma attacks and prevention of exercise-induced asthma. Improvement can be seen in 15 minutes.¹¹ Albuterol is a short-acting beta₂ agonist that causes bronchodilation. It is available via metereddose inhaler (MDI) and nebulizer solution formulations. It can be administered via MDI every 30 minutes for up to 4 hours or continuously via nebulization. For patients who only experience wheezing and chest tightness during exercise, albuterol should be administered before these activities take place to prevent these symptoms.

Albuterol can have systemic adverse effects, such as tachycardia, cardiac dysrhythmias, hypokalemia, and hyperglycemia. Some of these adverse effects can be potentiated with other medications. Monoamine oxidase inhibitors or tricyclic antidepressants can enhance the effect of albuterol on the vascular system, such as increase blood pressure and heart rate. This effect can still be seen up to 2 weeks after discontinuation of the antidepressants.¹¹ A patient who is receiving beta adrenergic receptor blocking agents, also known as beta blockers, may not see the full effect of albuterol, because these agents can cause bronchospasm in asthma patients and also block albuterol from achieving bronchodilation. Selective beta adrenergic receptor blockers may not cause these problems to the same extent and are generally considered safe to use with monitored asthma patients.

Paradoxical bronchospasm can occur with short-acting inhaled beta₂ agonists. If this occurs, the beta₂ agonists should be discontinued immediately. Paradoxical bronchospasm can mimic an asthma attack that is not responding to treatment with a beta² agonist. According to the Ventolin package insert, paradoxical bronchospasm occurs most commonly with the first use of a new canister or vial.

Structurally similar to albuterol, pirbuterol (Maxair) is also a beta₂ agonist. With pirbuterol, improvement in breathing can be seen within 5 minutes of administration.¹² Pirbuterol and albuterol have similar adverse effects, drug-interaction profiles, beta selectivity, and duration of bronchodilation, but pirbuterol is available in an Autohaler delivery device. Unlike the Ventolin inhaler, Maxair Autohaler needs to be primed if not used within the past 48 hours instead of 2 weeks. The Autohaler releases an inhalation when the patient inhales from the device, decreasing the need for breathing-hand coordination.

Levalbuterol (Xopenox) is the R enantiomer of albuterol. It is thought to be the active enantiomer and to have more affinity for the receptors in the lungs and less effect on cardiac tissue.¹³ Levalbuterol is available in hydrofluoroalkane (HFA) inhaler and nebulizer solution formulations. Although levalbuterol is the R enantiomer of albuterol, it has a similar adverse effect and drug-interaction profiles as albuterol. Studies in children and adults have not shown that levalbuterol is superior to albuterol.¹⁴ In one large, multicenter, randomized, double-blind clinical trial, time to discharge and hospitalization rates did not differ between adults treated with levalbuterol and albuterol in the emergency department.¹⁵ A subgroup analysis of the study, however, showed that hospitalizations were significantly reduced for levalbuterol-treated patients who had not received recent corticosteroid therapy. In addition, a 2000 literature analysis concluded that, although more expensive, levalbuterol nebulizer treatments offer no advantages over albuterol.¹⁶

Patients that use their short-acting beta₂ agonist more than 2 times per week or approximately 1 canister per month may indicate the need to start or increase long-term control therapy.¹⁰ Overuse can signify the need for education. Patients may incorrectly believe short-acting beta₂ agonists are not working until they feel some of the side effects, such as quickening heart rate, tremor, or bitter taste.¹⁷

Controller Medications

Mild-intermittent disease does not require daily medications according to the guidelines. As the disease progresses, daily medications are recommended, starting with low-dose inhaled corticosteroids. Inhaled corticosteroids available include fluticasone (Flovent), beclomethasone (QVAR), budesonide (Pulmicort), flunisolide (Aerobid), and triamcinolone acetonide (Azmacort). Table 2 defines low, medium, and high doses of the inhaled agents. In a study of 30 569 patients, consistent use of low-dose inhaled corticosteroids was linked with a decreased risk of death from asthma.¹⁸

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Inhaled corticosteroids have anti-inflammatory effects in the lungs while minimizing systemic effects. Beneficial effects are not seen immediately. Improvement may happen as early as 1 week, but maximum improvement should occur in 2 weeks. Inhaled corticosteroids have benefits as well as adverse effects. infections of the mouth and pharynx can occur and lead to white plaques inside the mouth, cottony feeling in the mouth, loss of taste, and pain when eating or swallowing.¹⁹ These infections can spontaneously resolve or require treatment. This is why it is important to counsel patients to rinse and spit after each dose of inhaled corticosteroids. When using nebulizer systems, patients need to rinse their mouths and clean the skin around the mouth to avoid fungal infections. Potential adverse effects of inhaled corticosteroids include increased risk of osteoporosis. In a 2003 meta-analysis, the authors concluded that patients taking high doses of inhaled corticosteroids who have other risk factors for osteoporosis should have their bone mass density closely monitored.²⁰

Preferred treatment for moderatepersistent disease is to increase to medium-dose inhaled corticosteroids and add long-acting inhaled beta₂ agonists. Long-acting inhaled beta₂ agonists include salmeterol (Serevent) and formoterol (Foradil). These agents relax bronchial smooth muscle by selective action on beta₂ receptors with little effect on heart rate. Improvements in FEV₁ are seen within 180 minutes and last for about 12 hours.²¹ Adding this medication to corticosteroids decreases exacerbations, improves asthma symptoms, and decreases short-acting beta₂ agonist use. These effects are not seen when used for prevention of exercise-induced asthma.²¹

Long-acting beta₂ agonists have a similar side-effect profile and drug interactions as short-acting beta₂ agonists. The combination of long-acting beta₂ agonists and methylxanthines has not been clinically evaluated. Products such as fluticasone and salmeterol (Advair) or budesonide and formoterol (Symbicort) are available as combinations of inhaled long-acting beta₂ agonists and corticosteroids. Symbicort received US Food and Drug Administration (FDA) approval in July 2006 but may not be available commercially until mid-2007.²²

The safety of inhaled long-acting beta₂ agonists is of some concern. On November 18, 2005, the FDA alerted health care professionals and patients that these agents had been associated with possible increased risk of asthma-related deaths in a study. In March and June of 2006, new labels for salmeterol (Serevent) and formoterol (Foradil) were approved by the FDA that included a warning that long-acting beta₂ agonists should only be used in patients who are uncontrolled on inhaled corticosteroids.²³ In the Salmeterol Multicenter Asthma Research Trial (SMART),²⁴ which was the study that caused the FDA to issue the alert and require the label changes, small but statistically significant increases in respiratory-related and asthma-related deaths and combined asthma-related deaths or life-threatening experiences occurred in the salmeterol treatment group. Further analysis revealed the risk may be greater in blacks than whites. The authors were unable to identify the exact mechanism causing the increased risk discovered by the study.

Alternative treatment options include the leukotriene-receptor antagonists montelukast sodium (Singulair) and zafirlukast (Accolate); sustained-release theophylline (Theo-24); cromolyn (Intal); and nedocromil (Tilade). Alternative treatment options are not recommended in any preference according to the guidelines. In studies, inhaled corticosteroids were superior to montelukast sodium or nedocromil.²⁵

Leukotriene-receptor antagonists, such as montelukast sodium and zafirlukast, are oral tablets that can be used for asthma and allergies. Leukotriene-receptor antagonists block leukotriene-mediated effects, such as airway edema, smooth muscle contraction, and inflammatory processes, and decrease daytime and nighttime symptoms.²² Unlike montelukast sodium, zafirlukast has some drug-drug interactions. Zafirlukast can have an effect on warfarin, increasing prothrombin time. This interaction is thought to be attributed to zafirlukast's effect on the CYP450 2C9 isoenzyme. Most other interactions result in the decrease of zafirlukast concentrations. Zafirlukast has also been associated with hepatic toxicity, generally occurring when the product is taken at doses higher than recommended.

Sustained-release theophylline is another option listed in the guidelines, but has fallen out of favor due to the side-effect profile. Theophylline causes bronchodilation by blocking phosphodiesterases. Theophylline has a small therapeutic index and wide interpatient variability. Serum concentration levels are used to evaluate safety and efficacy. Theophylline requires loading and maintenance dosing based on ideal body weight and indication. Among the many drug-drug interactions, CYP450 1A2 and 3A4 inducers, such as phenytoin or phenobarbital, decrease theophylline levels. Patients should take this medication on an empty stomach and avoid dietary stimulants, such as caffeine, tea, or chocolate, because they may increase adverse effects. Adverse effects of theophylline include gastrointestinal upset, diarrhea, tachycardia, seizures, and arrhythmias, most of which are serum-concentration dependent. Seizures and arrhythmias can occur at any serum concentration. Persistent, repetitive vomiting is a sign of theophylline toxicity. Patients need to be educated that diet can affect concentrations. Charbroiled food and extreme intake of protein and carbohydrates can affect the pharmacokinetics of theophylline.

Cromolyn sodium and nedocromil are anti-inflammatory agents that prevent mast cell degranulation and are used for asthma attack prevention. Both agents are dosed multiple times per day based on symptom improvement and clinical judgment. If patients are going to respond to the agents, a decrease in symptoms should be seen within 2 to 4 weeks of continuous treatment. Common adverse effects include throat irritation or dryness, bad taste, cough, wheezing, and nausea. Drug-drug interactions do not seem to be significant with either agent.^26,27

In severe-persistent asthma, oral corticosteroids may be added to the preferred treatment of inhaled corticosteroids and long-acting beta₂ agonists. According to the guidelines, this option should be avoided if possible.¹⁰

Omalizumab (Xolair), a recombinant humanized monoclonal anti-immunoglobin E (IgE) antibody, received FDA approval in June 2003 and hence is not mentioned in the 2002 guidelines. Xolair is produced by a Chinese hamster ovary cell suspension culture in a nutrient medium containing the antibiotic gentamicin, which is not detectable in the final product. Omalizumab inhibits the binding of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils leading to the reduction in the degree of release of mediators of allergic response. Omalizumab is indicated in patients 12 years of age and older who have a positive skin test to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Common adverse reactions include injection site reaction, viral infections, upper respiratory tract infection, sinusitis, headache, and pharyngitis.²⁸ These reactions are to be expected with an injectable immune system-modifying agent. Dosing is weight-based, and it is administered subcutaneously every 2 or 4 weeks. This product has been shown to reduce exacerbations and other medication requirements, and to improve quality of life in patients with severe-persistent asthma.²⁹ The current annual cost of omalizumab treatment ranges from $7500 to $40 000 per patient depending on the dosage. Even though this treatment option is very expensive, it may be cost-effective for patients with severe-persistent asthma who require many hospitalizations and emergency department visits despite treatment.²⁵

Inhalers

Many delivery systems are available for medications approved for asthma treatment: oral tablets, nebulizers, MDIs, and dry powder inhalers (DPIs). Inhalers are the most common delivery system for asthma medications. They provide the advantage of being portable, but can be difficult to use. MDIs require coordination of breathing and initiation of dose from the MDI canister. If hand coordination is a problem, inhalers can spray the product in the eyes and face. Inhalers require priming, 2 to 4 sprays in the air, before use if the product is new or unused for a certain amount of time (Table 3). If the patient does not prime the device, less than the desired dose of active ingredient may be received. The patient also needs to shake the inhaler and wait approximately 1 minute between inhalations. If a bronchodilator and maintenance medications are prescribed, the patient needs to use the bronchodilator first, wait 5 minutes, and then use the maintenance inhaler. Inhalers may also lead to oropharyngeal deposition, which can cause hoarseness and thrush from inhaled corticosteroids. Cleaning inhalers is not necessary. Wiping the mouthpiece with a damp rag should be all that is necessary.

Spacer devices are available to decrease oropharyngeal deposition and enhance product delivery. The propellant in MDIs can sometimes cause the product to hit the back of the patient's throat instead of being inhaled into the lungs, which can reduce the dose that is inhaled into the lungs. Spacer designs range from an open-ended tube to holding chambers. Spacers eliminate the need for coordination of breathing and initiation of dose. Holding-chamber spacers allow the patient to inhale the medication at their own pace. This can be convenient for children and older adults. Spacers require cleaning at least weekly to prevent static buildup inside of the chamber, which causes medication particles to stick to the tubing, thus preventing the full dose from reaching the patient.

Most patients do not use their MDIs optimally,³⁰ so when patients state their inhaler does not work very well, it is important to ask questions rather than assume the product needs to be replaced. As a first step, review the patient's technique to determine if the inhaler is dysfunctional or if the patient's technique is contributing to lack of efficacy. By adding a spacer or improving technique with repeated demonstration and education, patients can get the most from their delivery device. Another factor contributing to the patient's belief that the inhaler is not working can be the language that health care professionals use.¹⁷ The term controller or long-term controller to a patient can mean medication that controls symptoms such as cough, wheezing, and shortness of breath.Thus, they will use this medication when they experience symptoms that need to be controlled. Rescue medication can also lose meaning from provider to patients, who may perceive that these medications are only to be used when they experience life-threatening symptoms, only for it to be too late. Incorrect administration of rescue medication is also a problem. Health care providers say that rescue medications open airways. This can be taken to mean the force of the product leaving the inhaler actually inflates the lungs.¹⁷ Educational sessions that include asking the patient to describe under what circumstances he or she uses each medication can correct or prevent miscommunication.

For the past 10 years, DPIs have made an impact on the field of asthma medication delivery systems. Like other systems, they have advantages and disadvantages. Dry inhalers may be more patient-friendly because they require less coordination and no priming. Although they are breath actuated, the inhaler must be held parallel to the ground once activated to prevent powder from moving from the inside loading area. A disadvantage to dry inhalers is their sensitivity to moisture. Humidity can cause the powder to clump together. If the patient exhales into the device prior to inhalation, this can moisten the powder or cause that dose to exit the device. With any delivery device, it is important to educate the patient both verbally and with a demonstration.

CFC versus HFA

A new generation of MDIs is now available. These products have the same active ingredients, but the delivery systems have been modified to help protect the environment. HFA propellant inhalers are replacing inhalers that contained ozone-depleting chlorofluorocarbon (CFC) propellant delivery systems. CFCs are nontoxic, nonflammable chemicals that are used in aerosol sprays, solvents, and refrigerants, but they contribute to global warming by reducing the ozone layer of the earth's atmosphere.

Since March 17, 1978, the FDA and Environmental Protection Act have banned the use of CFCs as propellants in aerosol containers. This ruling allowed metered-dose adrenergic bronchodilator human drugs for oral inhalation to remain commercially available, however. Under an international agreement established through the Montreal Protocol on Substances that Deplete the Ozone Layer³¹ and the US Clean Air Act, CFC-containing products would be phased-out starting in 1996. Like the 1978 ruling, essential medical products, such as albuterol MDIs, were exempt. In March 2005, however, the FDA announced that albuterol CFC propellant delivery systems could no longer be produced, marketed, or sold in the United States after December 31, 2008.³² This legislation only affects single-ingredient albuterol CFC inhalers. Other CFC-based medications for asthma are still considered essential medical devices, including albuterol combination products.

The FDA determined the loss of CFC-based albuterol inhalers' exempt status on the following facts³²:

• Supplies and production capacity for the non-ozone-depleting substance products will exist at levels sufficient to meet patient need
• Patients who medically require the ozone-depleting substance product will be adequately served by the non-ozone-depleting substance products containing that active moiety and other available products

The first HFA albuterol medication, Proventil HFA, received FDA approval in 1996,³³ but as late as 2004, generic CFC albuterol inhalers still accounted for 96% of the retail market for albuterol inhalers.³⁴ When the phase out reaches full effect in 2008, the cost of asthma medications is expected to rise, because lower-cost generic CFC-based albuterol products will be replaced with HFA-based brand name albuterol products.

http://www.fda.gov/cder/ob

It is important to note that CFC-based albuterol inhalers cannot be substituted with HFA-based albuterol inhalers without a new prescription. Individual states' Boards of Pharmacy regulate substitution laws, and, in most states, pharmacists can only substitute products that have an Orange Book rating of AB. Health care professionals can consult the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book, online at to determine what products are considered pharmaceutical equivalents. The AB rating indicates that products are equivalent and can be substituted. According to the Orange Book, CFC and HFA albuterol products have a BX rating and thus are not considered to be pharmaceutical equivalents and cannot be substituted for each other. It is important to educate patients about the laws and circumstances surrounding the availability of generic CFC albuterol products and the transition to HFA products.

Summary

Asthma is a disease with varying levels of severity that affects many people and costs billions of dollars in direct and indirect costs. Combined with clinical judgment, treatment guidelines are available to provide patients with the best approaches to treatment.

Pharmacotherapy is important, but patient education is also necessary to ensure optimal use of pharmacotherapy and effective control of the disease. Patient education can come in the form of written action plans based on subjective or objective measures; reinforcing correct delivery device administration with verbal instructions and demonstrations is also helpful. Reminding patients of the importance of priming and how the different types of medications (ie, long-term controller and rescue medications) are intended to be used can improve patient outcomes as well. Asthma is now complicated by legislation regarding a cornerstone of treatment medication. Understanding and educating patients and other care providers regarding this new legislation can help smooth the transition of CFC-based albuterol products to HFA products.

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CME INSTRUCTIONS

TESTING AND GRADING PROCEDURES

1. Each participant achieving a passing grade of 70% or higher on any examination will receive an official computer form stating the number of CME credits earned. This form should be safeguarded and may be used as documentation of credits earned.

2. Participants receiving a failing grade on any exam will be notified and permitted to take one reexamination at no cost.

3. All answers should be recorded on the answer form. Please print clearly to ensure receipt of CME credit.

4. Detach and mail or fax your completed exam form to: University of Cincinnati, Office of CME, P.O. Box 670556, Cincinnati, OH 45267-0556; phone: 513-558-7277; fax: 513-558-1708.

AMA PRA Category 1 CME Creditsâ„¢

The University of Cincinnati College of Medicine designates this educational activity for a maximum of 2.0 . Physicians should only claim credit commensurate with the extent of their participation in this activity.

The American Academy of Physician Assistants accepts AMA Category 1 CME credit for the PRA from organizations accredited by ACCME.

The University of Cincinnati College of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor medical education for physicians.

Release Date: November 2006 ^-Expiration Date: November 30, 2007

Dawn S. Knudsen, PharmD

University College of Pharmacy—Glendale, Glendale, Ariz

Quinn Wells, MD, PharmD

Boston, Mass

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