Drugs for Asthma

No truly new drugs have been approved for treatment of asthma since omalizumab (Xolair) in 2003, but some randomized controlled trials of older drugs have been published, and new guidelines have become available.1
INHALATION DEVICES
Inhalation is the preferred route of delivery for most asthma drugs. Chlorofluorocarbons (CFCs), which have ozone-depleting properties, are being phased out as propellants in metered-dose inhalers; albuterol inhalers with CFCs will not be available in the US after December 31, 2008. Non-chlorinated hydrofluoroalkane (HFA) propellants, which do not deplete the ozone layer, will replace them.2
Metered-dose inhalers (MDIs) require coordination of inhalation with hand-actuation of the device. Valved holding chambers (VHCs) or spacers can help young children or elderly patients use MDIs effectively. VHCs have one-way valves that prevent the patient from exhaling into the device, eliminating the need for coordinated actuation and inhalation. Spacers are open tubes placed on the mouthpiece of an MDI. Both VHCs and spacers retain the large particles emitted from the MDI, preventing their deposition in the oropharynx and leading to a higher proportion of small respirable particles being inhaled.
Dry powder inhalers (DPIs), which are breath-actuated, can be used in patients who are capable of performing a rapid deep inhalation.
Delivery of inhaled asthma medications through a nebulizer with a face mask or mouthpiece is less dependent on the patient’s coordination and cooperation, but more time-consuming than delivery through an MDI or DPI.3
INHALED CORTICOSTEROIDS
For mild, moderate or severe persistent asthma, inhaled corticosteroids are the most effective long-term treatment for control of symptoms in all age groups. In randomized, controlled trials, they have been significantly more effective than leukotriene modifiers, long-acting beta-2 agonists, cromolyn or theophylline in improving pulmonary function, preventing symptoms and exacerbations, reducing the need for emergency department treatment, and decreasing deaths due to asthma. The majority of the benefit is achieved at relatively low doses. The optimal dose for a given patient may increase or decrease over time, but should always be the lowest that maintains asthma control. Doses vary depending on the inhaled corticosteroid and the delivery device; these medications are not precisely interchangeable on a per mcg or per puff basis.
Adverse Effects – Local adverse effects of inhaled corticosteroids may include oral candidiasis (thrush), dysphonia (hoarseness), and reflex cough and bronchospasm. Use of a VHC or a spacer and rinsing the mouth after use may reduce the incidence of these effects. No clinically relevant changes occur in hypothalamic- pituitary-adrenal axis function with low- or medium-dose inhaled corticosteroids, but children’s growth should be monitored. Patients who require high-dose inhaled corticosteroid treatment should be monitored for osteoporosis and development of cataracts.
SHORT-ACTING BETA-2 AGONISTS
Inhaled short-acting selective beta-2 agonists (albuterol, levalbuterol, pirbuterol) increase airflow within 3-5 minutes; they are the medications of first choice for treating acute wheeze, chest tightness, cough and shortness of breath as needed, and for preventing exercise-induced bronchospasm. Regularly scheduled daily use is not recommended. Use of these agents for symptom relief on more than 2 days per week suggests inadequate control of asthma, and the need for starting or possibly increasing the dose of an inhaled corticosteroid. Over-reliance of asthma patients on a short-acting beta-2 agonist has been associated with an increased risk of death.4 Levalbuterol and racemic albuterol (which is 50% levalbuterol, the pharmacologically active isomer of the racemate) in recommended doses produce comparable bronchodilation and have comparable adverse effects.5,6
Adverse Effects – Systemic toxicity from short-acting beta-2 agonists is uncommon, but may occur with high doses or use in elderly patients. Adverse effects can include paradoxical bronchospasm, tachycardia and other cardiovascular symptoms, skeletal muscle tremor, headache, hypokalemia and hyperglycemia.
LONG-ACTING BETA-2 AGONISTS
Long-acting beta-2 agonists should be used in combination with an inhaled corticosteroid; they should not be used to relieve acute asthma symptoms and are not recommended for use as monotherapy in the treatment of asthma. Addition of salmeterol (Serevent) or formoterol (Foradil) to the treatment of patients with persistent asthma not well controlled on low-dose inhaled corticosteroids improves lung function, decreases symptoms, and reduces exacerbations and rescue use of short-acting beta-2 agonists.7,8,9 Long-acting beta-2 agonists are best administered in a fixeddose combination in the same inhaler with an inhaled corticosteroid. How the fixed-dose combinations of fluticasone/salmeterol and budesonide/formoterol compare with each other remains to be determined.10
Adverse Effects – Addition of a long-acting beta-2 agonist to inhaled corticosteroid therapy has been reported in a few patients to cause down-regulation of the beta-2 receptor with loss of the bronchoprotective effect from rescue therapy with a short-acting beta-2 agonist.11 In one large trial in patients with asthma in which salmeterol or placebo was added to usual asthma treatment, 13 of 13,176 salmeterol-treated patients died of asthma, compared to only 3 of 13,179 placebo-treated patients12; therefore, a black box warning about a higher risk of asthmarelated death was added to the package inserts of all preparations containing a long-acting beta-2 agonist. However, a matched case-control study found that long-acting beta-2 agonist use during the prior 3 months was not associated with increased risk of death from asthma.13 In doses higher than recommended, long-acting beta-2 agonists can produce clinically relevant tremor, cardiovascular effects including tachycardia and QTc interval prolongation, hypokalemia and hyperglycemia.
LEUKOTRIENE MODIFIERS
Leukotriene modifiers are used as an alternative to inhaled corticosteroids for persistent asthma, but they are less effective. They can be used as an additional treatment for patients with mild or moderate persistent asthma not well controlled on inhaled corticosteroids, but addition of a long-acting beta-2 agonist (in the same inhaler) is preferred. Leukotriene modifiers are not recommended for treatment of acute asthma symptoms, and their dose-response curve is flat. Most published efficacy data relate to montelukast, and it is the only one of these drugs approved by the FDA for use in preventing exercise-induced asthma.
Adverse Effects – Churg-Strauss vasculitis has been reported with montelukast and zafirlukast, but in most cases it could have been a consequence of corticosteroid withdrawal rather than a direct effect of the leukotriene modifier. Montelukast is less likely than zafirlukast or zileuton to cause drug-drug interactions or hepatitis, and is generally considered safe for long-term use, but the FDA has received post-marketing reports of psychiatric symptoms including suicidality. Zafirlukast is a moderate inhibitor of CYP2C9 that increases the serum concentrations of concomitantly administered medications such as warfarin (Coumadin, and others). Zileuton is a moderate inhibitor of CYP1A2 that inhibits the metabolism of theophylline and many other drugs.14 Both zafirlukast and zileuton have been reported to cause life-threatening hepatic injury; alanine aminotransferase should be monitored, and patients should be warned to discontinue the medication immediately if abdominal pain, nausea, jaundice, itching or lethargy occur.
CROMOLYN SODIUM
Cromolyn is now infrequently used for treatment of mild persistent asthma. Although relatively ineffective compared to inhaled corticosteroids (it may take weeks to detect any benefit), it has an excellent safety profile, except for occasional complaints of cough and irritation. Nedocromil, which was similar to cromolyn, is no longer available.
THEOPHYLLINE
Sustained-release theophylline is now infrequently used for persistent asthma, taken either alone or concurrently with an inhaled corticosteroid. Monitoring of serum theophylline concentrations and keeping them between 5 and 15 mcg/mL is recommended. Many other drugs used concomitantly can interact with theophylline, either by increasing its metabolism and decreasing its serum concentrations and efficacy, or by decreasing its metabolism, leading to higher concentrations and toxicity.14
Adverse effects include nausea, vomiting, nervousness, headache and insomnia. At high serum concentrations, hypokalemia, hyperglycemia, tachycardia, cardiac arrhythmias, tremor, neuromuscular irritability, seizures and death can occur.
ANTICHOLINERGICS
Ipratropium bromide (Atrovent, and others), an inhaled short-acting anticholinergic bronchodilator used to treat chronic obstructive pulmonary disease (COPD), has also been used as an alternative to short-acting beta-2 agonists in patients with asthma who cannot tolerate them; it should not be used in the treatment of persistent asthma and has not been approved for any use in asthma by the FDA. Tiotropium bromide (Spiriva), an inhaled long-acting anticholinergic agent, is also used to treat COPD, but it has not been studied in persistent asthma, and is not FDA-approved for use in asthma.
Adverse effects from these agents include dry mouth, pharyngeal irritation, urinary retention, and increased intraocular pressure; they should be used with caution in patients with glaucoma, prostatic hypertrophy or bladder neck obstruction.
ANTI-IgE ANTIBODY
Omalizumab (Xolair) is a recombinant humanized monoclonal antibody that prevents IgE from binding to mast cells and basophils, thereby preventing release of inflammatory mediators after allergen exposure. It is approved by the FDA for adjunctive use in patients at least 12 years old with well-documented specific allergies and moderate to severe persistent asthma that is not well controlled on an inhaled corticosteroid with or without a long-acting beta-2 agonist. Subcutaneous injection of omalizumab every 2-4 weeks has been reported to lead to fewer asthma exacerbations, with a modest (inhaled) corticosteroid-sparing effect.15,16 It is expensive.17
Adverse Effects – Adverse effects of omalizumab include injection site pain and bruising in up to 20% of patients. Anaphylaxis, usually occurring within 2 hours after injection but sometimes up to 4 days later, has been reported in 0.2% of patients, resulting in an FDA black box warning.18 An asthma task force has advised keeping patients under observation for 2 hours after the first three omalizumab injections, and for 30 minutes after subsequent injections, and educating patients about recognition of anaphylaxis and the need for prompt treatment with self-injected epinephrine.19 Serum sickness and Churg-Strauss vasculitis have occurred rarely after omalizumab injection. Malignant neoplasms have been reported in 0.5% of patients receiving omalizumab, compared to 0.2% of those receiving placebo; cause and effect have not been established.
EXERCISE-INDUCED BRONCHOSPASM
Exercise-induced bronchospasm may be the only manifestation of asthma in patients with mild disease. Short-acting inhaled beta-2 agonists used just before exercise will prevent it in more than 80% of patients; they have a duration of action of 2-3 hours. Long-acting beta-2 agonists can prevent exercise-induced bronchospasm for up to 12 hours, but if they are administered on a regular basis, the protection may wane and not last throughout the day. Montelukast decreases exercise-induced bronchospasm in up to 50% of patients; its onset of action has been reported to begin as soon as 2 hours after administration and persist for up to 24 hours,20 with no loss of protection over time. In patients whose exercise-induced bronchospasm occurs because of poorly controlled persistent asthma, daily long-term anti-inflammatory medication should be started or its dosage increased.21
ASTHMA DURING PREGNANCY
Maternal asthma increases the risk of pre-eclampsia, perinatal mortality, pre-term birth and low birth weight. It is safer for pregnant women who have asthma to be treated with asthma medications than to have poorly controlled asthma symptoms. Albuterol is the preferred short-acting beta-2 agonist for use in pregnancy because of its excellent safety profile. Inhaled corticosteroids are the preferred long-term controller medication. More data are available on the safety of budesonide during pregnancy than on that of other inhaled corticosteroids. Long-acting beta-2 agonists, used in combination with an inhaled corticosteroid, also appear to be safe in pregnancy. Limited data suggest that montelukast appears to be safe.22 Animal studies have found teratogenicity with zileuton.23
Table 1 - Revised 11/13/08: The last sentence of footnote 7 was incomplete; "within one hour after morning and evening meals" was added.


ASTHMA IN INFANTS AND CHILDREN
For infants and children with mild intermittent asthma, a short-acting beta-2 agonist should be used as needed. One report suggested that a short course of montelukast started at the first sign of an asthma episode may be beneficial.24 For mild, moderate or severe persistent asthma, inhaled corticosteroids are the preferred long-term treatment for control of symptoms25,26; however, they do not affect the underlying severity or progression of the disease.27,28
Inhaled corticosteroids can be delivered through a metered-dose inhaler (MDI) with a valved holding chamber (VHC) and face mask or mouthpiece, or through a nebulizer or dry powder inhaler (DPI). Inhaled corticosteroids given in low doses even for extended periods of time are generally safe for use in infants and children, but linear growth should be monitored. Low- to medium-dose inhaled corticosteroids may reduce growth velocity slightly during the first year of treatment, but usually not after that, and final height appears not to be affected.29
Dry powder inhalers (DPIs) are not suitable for use in infants or young children. Fluticasone and mometasone dry powder inhalers are approved for children as young as four years of age, but children that young may have difficulty inhaling rapidly or deeply enough to use the device effectively. Budesonide nebulizer suspension is approved for children as young as one year of age. Montelukast is also approved for use in children as young as one year.
IMMUNOTHERAPY
In selected patients with allergic asthma, specific immunotherapy (“allergy shots”) may provide long-lasting benefits in reducing asthma symptoms and the need for medications.30
FAILURE OF PHARMACOLOGIC TREATMENT
Lack of adherence to the prescribed medication regimen is the most common cause of pharmacologic failure in asthma. Co-morbid conditions that may make asthma management more difficult include chronic rhinitis/sinusitis,31 gastroesophageal reflux disease (GERD),32 obesity,33,34 and depression and psychosocial factors. Some patients with asthma may concurrently be taking aspirin or other NSAIDs that can cause asthma symptoms. Oral or topical nonselective betaadrenergic blockers such as propranolol (Inderal, and others) or timolol (Blocadren, and others) can precipitate bronchospasm in patients with asthma and decrease the bronchodilating effect of beta-2 agonists.
Patients with asthma who continue to smoke do not respond optimally to inhaled corticosteroids8; they may respond better to montelukast.35 Asthmatics should also avoid exposure to second-hand smoke, airborne pollutants, and allergens.36 Patients with asthma may also benefit from meeting with trained asthma educators.37
MANAGING EXACERBATIONS OF ASTHMA
Patient education, including a written Asthma Action Plan, should guide the initial self-management of exacerbations at home.37 Such a plan involves recognition of early signs of worsening asthma, appropriate intensification of treatment by increasing the dose of inhaled short-acting beta-2 agonists, and in some patients, initiating a short course of an oral corticosteroid; patients should also communicate with their clinician about symptoms and responsiveness to intervention. Doubling the dose of inhaled corticosteroids is not effective.38
Oral Corticosteroids – Oral systemic corticosteroids are the most effective drugs available for exacerbations of asthma incompletely responsive to bronchodilators. Even when an acute exacerbation responds to bronchodilators, addition of a short course of an oral corticosteroid can decrease symptoms and may prevent a relapse. For asthma exacerbations, daily systemic corticosteroids are generally required for only 3-10 days, after which no tapering is needed.39
Oral corticosteroids should only rarely be used as long-term control medications and then only in that small minority of patients with uncontrolled severe persistent asthma. In this situation, an oral corticosteroid should be given at the lowest effective dose, preferably on alternate mornings, in order to produce the least toxicity.39 Steroid resistance has been recognized in some patients with asthma.40
Potential adverse effects of long-term oral corticosteroids include endocrinologic effects such as adrenal suppression, weight gain, Cushingoid stigmata and diabetes mellitus; musculoskeletal effects such as osteoporosis, aseptic necrosis and myopathy; ophthalmologic effects such as cataracts and glaucoma; dermatologic effects such as dermal thinning, striae, acne, hirsutism and delayed wound healing; psychologic effects such as mood swings, depression and psychosis; metabolic effects such as hypokalemia, hyperglyclemia, and hyperlipidemia; and cardiovascular effects such as hypertension. Immune function is potentially impaired, and re-activation of latent tuberculosis, herpes, varicella, and Strongyloides infections may occur. Short-term use of oral corticosteroids may cause increased appetite, weight gain, changes in mood and hypertension.
In the urgent care or emergency department setting, treatment of asthma exacerbations includes: oxygen to relieve hypoxemia; a short-acting beta-2 agonist, sometimes in combination with ipratropium, to relieve airflow obstruction; and a systemic corticosteroid to decrease airway inflammation. Ipratropium is a useful bronchodilator for patients with acute asthma symptoms who do not respond adequately to or cannot tolerate a short-acting beta-2 agonist, or who are taking nonselective beta-blockers. Severe asthma exacerbations unresponsive to the above treatments may respond to intravenous magnesium sulfate or inhalation of heliox, a mixture of helium and oxygen; helium decreases airway resistance.41
SUMMARY
For monotherapy of persistent asthma, inhaled corticosteroids are more effective than long-acting beta-2 agonists, leukotriene modifiers, theophylline or cromolyn. If regular use of an inhaled corticosteroid in a low dose does not prevent symptoms, the dose can be increased or regular daily treatment with an inhaled long-acting beta-2 agonist in the same inhaler can be started. In patients with allergic asthma, immunotherapy may provide long-lasting benefits. If severe persistent allergic asthma remains uncontrolled, omalizumab can be added in patients ≥12 years. Failure of pharmacologic treatment in asthma may occur due to lack of adherence to prescribed medication, co-morbid conditions, or ongoing exposure to tobacco smoke, airborne pollutants or allergens.