Medication use for asthma

Miles Weinberger, MD
Professor of Pediatrics
Allergy, Immunology, and Pulmonary 

Medication for asthma should be viewed in two broad functional categories:

• Intervention measures - those medications used to stop acute symptoms of asthma
• Maintenance measures - those medications used to prevent symptoms from occurring. However, maintenance medications do not prevent urgent medical care or hospitalizations from acute exacerbations of asthma and are therefore of no routine value for those patients whose asthma is limited to intermittent viral respiratory infection induced exacerbations, as is most common among preschool age children. Early use of intervention measures is essential for those acute exacerbations.

All patients with asthma require the availability of intervention measures. Only patients with chronic asthma or extended periods of persistent symptoms or airway obstruction require maintenance medication. However, no safe maintenance medication is reliably effective in preventing all acute exacerbations, especially those triggered by viral respiratory infections. Patients who have only intermittent asthma triggered by viral respiratory infections are not likely to benefit from maintenance medication at those times.

Which are the most effective intervention measures?

There are two categories of medication that, when used appropriately, provide highly effective intervention:

• Inhaled bronchodilators - these rapidly relax the spasm of bronchial smooth muscle that narrows the airway and creates obstruction to air flow.
• Anti-inflammatory corticosteroid medications taken by mouth or, if necessary, by injection - these decrease the mucosal edema and stop the mucous secretions that obstruct airways.

The most effective initial intervention measures are inhaled bronchodilators of the drug class known as beta-2 agonists. The most common of these is albuterol (known as salbutamol outside the United States). It can be delivered by various nebulizer devices and metered dose inhalers. Pirbuterol is closely related to albuterol and is therapeutically equivalent; it is available as a metered dose device that delivers the medication automatically upon inhalation (the brand name is Maxair Autohaler). There are several others available in this family but are less commonly used and have no advantage over albuterol and pirbuterol. As effective as these agents are for relief of acute symptoms, they provide no value as routinely scheduled medication.

Albuterol and other beta-2 agonists are also available in tablets and syrups for oral administration. However, they are much less effective by that route and have more side effects. Another inhaled bronchodilator unrelated to the beta-2 agonists is ipratropium (Atrovent). It is available as a nebulizer solution or metered dose inhaler. It has no routine role in the outpatient management of asthma but may be of value by aerosal in the emergency care setting when there is severe airway obstruction that responds inadequately to albuterol aerosol.

WARNING: The greatest danger from overuse of inhaled bronchodilators for intervention results from their prompt but often transient effectiveness. This can result in delayed recognition and progression of the inflammatory component of airway obstruction from asthma. The inhaled bronchodilators relieve only the airway narrowing from spasm of the bronchial smooth muscle. A short course of oral corticosteroids may be needed for patients who have progressive or prolonged periods of asthmatic symptoms as a result of airway inflammation. However, corticosteroids are slow to work, so it is important to recognize as early as possible when this inhaler is incompletely effective, suggesting that inflammation in addition to bronchospasm is present and that oral corticosteroids may be needed to prevent emergency care or hospitalization. While repeating the inhaler is appropriate if an initial use is incompletely effective, the need for a third use in a 4 hour period for recurrent symptoms or repeated use with decreasing periods of effectiveness requires a prompt call to your doctor for further advice.

When response to inhaled beta-2 agonist bronchodilators is incomplete, airway inflammation is generally a major contributor to the airway obstruction, and an anti-inflammatory corticosteroid medication is needed. The oral route is most effective for reversing the acute inflammatory process causing bronchodilator sub-responsiveness. The most common medications in this class used are prednisone, prednisolone, methylprednisolone, and dexamethasone. High doses for short periods of time (5-10 days) are safe and highly effective at reversing airway obstruction. If used early enough at adequate doses, this strategy prevents progression of asthmatic symptoms and avoids the need for urgent medical care or hospitalization. While high doses are generally well tolerated for this period of time, some people (about 10%) experience irritability and other minor side effects after the first day or two. Decreasing the dose at that time to once daily in the morning generally eliminates those side effects. Methylprednisolone appears to be less likely to cause such side effects. Prednisolone is available as liquid formulations. Orapred and a generic preparation from Morton Grove Pharmaceuticals at 3 mg/ml are the best tasting and most convenient of these liquid medications, which are always more expensive than their comparable solid dosage forms and certainly messier. Children can often be taught to swallow solid dosage forms without chewing (you don't want to chew a prednisone or methylprednisolone tablet- they are very bitter). After all, they have all swallowed chewing gum or food particles larger than a tablet by that time. One successful technique is to use a non-threatening product like M&Ms or jelly beans and tell them that for each one they swallow whole, they get to chew the next two. Most catch on quite quickly. To assure a young child doesn't get the taste of prednisone while swallowing the tablet (which will be a potential turnoff to future attempts), clear gelatin capsules can be obtained from a pharmacist and the tablet placed in that (breaking the tablet in half if necessary so it will fit). The traditional practice of many physicians of using tapering doses is irrational and inconsistent with controlled clinical trials in the medical literature. The best practice is to continue a high dose till symptoms are gone and then discontinue. If improvement has not unequivocally occurred by 5 days, or if there is not complete absence of symptoms by 7-10 days, further medical evaluation is needed.

While anti-inflammatory corticosteroid medications are available for inhaled and oral administration, the inhaled route is not optimally effective for treating acute symptoms. The oral or injectable route is therefore preferred for intervention when acute exacerbations of asthmatic symptoms occur. The inhaled route is best reserved for maintenance medication of chronic asthma with persistent symptoms. Injections of corticosteroids are no more effective than oral administration unless oral medication cannot be given or is not retained.

What are the choices for maintenance medication to prevent symptoms in patients identified as having a chronic or extended seasonal pattern of symptoms?

Maintenance medication is indicated as a preventative measure for patients who have continuous or frequently recurring symptoms of asthma. These patients have asthmatic symptoms that promptly return even after being completely cleared with vigorous intervention measures. Since maintenance medication may be needed on a long-term basis, safety and convenience are prime considerations. In general, there are enough alternatives to avoid side effects from the medication, and any suspected side effects should be discussed with your physician. Each alternative has its own advantages and disadvantages. Maintenance medication needs to be systematically determined for each patient. No more should be used than is necessary to control the asthma. A single maintenance medication is often sufficient. Two medications should be used only if the two provide an advantage over one. More than two maintenance medications for asthma are occasionally justified for patients with severe asthma. Intervention measures must still be available for breakthrough symptoms. No maintenance medications reliably prevent all acute exacerbations, especially those triggered by viral respiratory infections.
For patients requiring long-term maintenance medications, careful consideration should be given to treatment measures that do not involve medication. Some patients have their asthmatic symptoms reduced with environmental measures. While some environmental exposures such as cigarette smoke and wood burning stoves are common irritants that can worsen asthma in many patients, others involve allergic reactions to substances that are otherwise harmless to nonallergic people. Identification of allergy as a cause of asthma requires evaluation by a physician knowledgeable about environmental allergens who will review the medical history of symptoms and perform tests to identify allergic antibody to environmental allergens. In some cases, the use of allergy shots may be considered as an effort to decrease sensitivity to inhalant allergens judged important in triggering asthma.
Once maintenance measures that control the asthma are determined, repeated re-evaluation at regular intervals helps assure continued safety and effectiveness of treatment in addition to assessing the continued adequacy and/or need for medication.

Inhaled corticosteroids

Inhaled corticosteroids that have a high degree of topical potency at low delivered doses have been available in the U.S. since 1977 with experience elsewhere for several years prior to that. They are the most effective single medications for asthma. These include beclomethasone dipropionate fluticasone (Flovent 44, 110 & 220), and budesonide (Pulmicort Turbuhaler and Respules). The inhaled corticosteroids have acquired a sufficient safety record that their use as an initial maintenance medication for chrinic asthma is justified. However, there are some potential side effects that appear to be dose related. Small decreases in growth have been shown, predominantly at higher doses (but uncontrolled asthma also has the potential to suppress growth). A very small increased risk of cataracts has been seen in adults; that risk appears to be related to the dose and duration of administration. Potential effects on bone metabolism have been suggested from sensitive biochemical studies, but development of osteoporosis seen with long-term daily oral corticosteroids has not been seen. However, since the potential for side effects, even if very low risk, justifies determining the lowest dose that provides good control of asthma, other medications can be added. These include salmeterol (Serevent) and slow-release theophylline, which when added to inhaled corticosteroids provide greater benefit than increasing the dose of inhaled corticosteroids.A combination product containing an inhaled corticosteroid (fluticasone) and salmeterol is marketed with three alternative concentrations of fluticasone, each with the standard dose of salmeterol (Advair 100, 250, and 500). Montelukast (Singulair) also provides some degree of added benefit when added to an inhaled corticosteroid.

Oral corticosteroids

Alternate-morning oral corticosteroids have been used for over 30 years as maintenance medications for asthma and other corticosteroid responsive diseases. The purpose of the alternate-morning schedule was a strategy to use the effectiveness of oral corticosteroids to suppress the disease while avoiding the well-recognized and potentially serious side effects of long-term daily oral corticosteroids. While most patients do not experience recognizable side effects from alternate morning oral corticosteroids, they have generally been used for asthma in combination with theophylline to obtain maximal clinical effect at doses of 20 to 40 mg every other morning. They are easier to use and less expensive than inhaled corticosteroids, but some patients gain weight with their usage because of appetite stimulation. The inhaled corticosteroids are generally more effective than alternate morning oral steroids and rarely cause weight gain. However, they do require more frequent administration, cost more, sometimes cause hoarseness and thrush, a minor fungal infection in the mouth, and are more frequently not taken as regularly as prescribed.

Theophylline

Theophylline is administered as an oral slow release capsule or tablet which require only twice daily administration. This medication had been the most commonly used maintenance medication for asthma in the U.S. for many years prior to extensive use of the inhaled corticosteroids in recent years, and it still has a high degree of efficacy as an initial agent or when added to inhaled or alternate-morning oral corticosteroids. The combination of theophylline and low dose inhaled corticosteroid is more effective than a higher dose of inhaled corticosteroid alone. The generic capsule from Inwood Laboratories can be opened, and the contents can be sprinkled on a spoonful of food for young children. Many patients appear to take an oral medication like theophylline more regularly than an inhaled maintenance medication. Only a morning and evening dose are needed. However, dosage needs to be individually adjusted based on a blood test to assure effectiveness and safety.

Long acting inhaled beta-2 agonist bronchodilators

Long acting inhaled beta-2 agonist bronchodilators such as salmeterol (Serevent) and formoterol are chemically related to intervention bronchodilators such as albuterol and pirbuterol but can last 12 hours. They are not a substitute for albuterol or pirbuterol for acute symptoms but are intended as daily maintenance treatment rather than as intervention for acute symptoms. Not generally recommended as initial therapy, their primary role is as additive therapy to inhaled corticosteroids. Combination products, Advair and Symbicort, provide a convenient means of providing the two medications in a single inhaler. Adding a long acting inhaled beta-2 agonist bronchodilator or theophylline to low doses of inhaled corticosteroid is generally more effective than higher doses of inhaled corticosteriod alone. However, there are occasional patients for whom these medications can make asthma more difficult to control with decreased response to their intervention inhaler used for acute symptoms. Worsening asthma with use of salmeterol or formoterol should promptly be discussed with the prescribing physician.

Leukotriene

Leukotriene modifiers include a medication, zileutin (Zyflo) that decreases the production of a leukotriene, a substance that is one of the mediators of inflammation in asthma, and two medications that antagonize the activity of that leukotriene, zafirlukast (Accolate) and montelukast (Singulair). Zileutin requires 4 times daily administration and has been associated with liver abnormalities; it therefore has little general appeal. Zafirlukast is a twice daily medication that is generally quite free of side effects but does have some potential for certain drug interactions and has been associated with a rare but serious disorder called the Churg Strauss syndrome, but the medication has not been established as the cause. The most common theory about the appearance of Churg Strauss Syndrome in patients taking leukotriene antagonists is that this is simply being unmasked as patients are withdrawn from their previous dose of oral corticosteroids used for what was believed to be asthma but was in fact suppressing the symptoms and signs of Churg Strauss syndrome. Montelukast (Singulair) is currently the most commonly used medication in this class. It is a modestly effective medication that may be adequate for some patients with relatively mild asthma.

Cromolyn (Intal)

Cromolyn and a related medication with similar effect, nedocromil (Tilade) are inhaled medications that are relatively weakly potent, require multiple daily administration, and have little or no additive effect with other medications. They act by preventing the release of some mediators of the asthmatic response. Their primary merit is an almost complete lack of any serious side effects, even with overdose. Unlike the inhaled bronchodilators, cromolyn and nedocromil have no immediate effect and do not relieve acute symptoms. Although potentially effective for many patients with mild chronic asthma, they appear to be no more effective than montelukast, a once daily oral medication, and less effective than theophylline or inhaled corticosteroids.

Ketotifen

Ketotifen is an oral medication with antihistaminic effects that also is reported to have some of the effects of cromolyn or nedocromil. While popular elsewhere, studies regarding its efficacy for asthma have been unimpressive, and it has not become available in the U.S.

Omalizumab (Xolair)

Omalizumab is a humanized monoclonal antibody against immunoglobulin E (IgE), the allergic antibody that can cause allergen-induced asthma from airborne substances such as pollen, molds, dust mite, and animal dander. Given as an injection every 2-4 weeks (depending on the dose determined by body weight and the total IgE level measured in a blood test), this very expensive medication has the potential to almost completely eliminate the allergic antibody and thereby prevent that allergic antibody from causing asthma. The degree of benefit from Xolair is likely to relate to the extent to which allergy contributes to the individual's asthma. Since asthma is a multifactorial disease, the extent to which allergy contributes to asthma ranges from none in some to a major component of the disease in others.