Major drug classes commonly used in the treatment of asthma Asthma Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more and asthma exacerbations Treatment of Acute Asthma Exacerbations The goal of asthma exacerbation treatment is to relieve symptoms and return patients to their best lung function. Treatment includes Inhaled bronchodilators (beta-2 agonists and anticholinergics)... read more include
Bronchodilators (beta-2 agonists, anticholinergics)
Mast cell stabilizers
Drugs in these classes (see table Drug Treatment of Chronic Asthma Drug Treatment of Asthma* Major drug classes commonly used in the treatment of asthma and asthma exacerbations include Bronchodilators (beta-2 agonists, anticholinergics) Corticosteroids Leukotriene modifiers Mast cell... read more ) are inhaled, taken orally, or injected subcutaneously or intravenously; inhaled drugs come in aerosolized and powdered forms. Use of aerosolized forms with a spacer or holding chamber facilitates deposition of the drug in the airways rather than the pharynx; patients are advised to wash and dry their spacers after each use to prevent bacterial contamination. In addition, use of aerosolized forms requires coordination between actuation of the inhaler (drug delivery) and inhalation; powdered forms reduce the need for coordination, because drug is delivered only when the patient fully inhales with a good effort.
(See also Asthma Asthma Asthma is a disease of diffuse airway inflammation caused by a variety of triggering stimuli resulting in partially or completely reversible bronchoconstriction. Symptoms and signs include dyspnea... read more and Treatment of Acute Asthma Exacerbations Treatment of Acute Asthma Exacerbations The goal of asthma exacerbation treatment is to relieve symptoms and return patients to their best lung function. Treatment includes Inhaled bronchodilators (beta-2 agonists and anticholinergics)... read more .)
Beta-2 agonists relax bronchial smooth muscle, decrease mast cell degranulation and histamine release, inhibit microvascular leakage into the airways, and increase mucociliary clearance. Beta-2 agonist preparations may be short-acting, long-acting, or ultra–long-acting (see tables Drug Treatment of Chronic Asthma Drug Treatment of Asthma* Major drug classes commonly used in the treatment of asthma and asthma exacerbations include Bronchodilators (beta-2 agonists, anticholinergics) Corticosteroids Leukotriene modifiers Mast cell... read more and Drug Treatment of Asthma Exacerbations Drug Treatment of Asthma Exacerbations*, † The goal of asthma exacerbation treatment is to relieve symptoms and return patients to their best lung function. Treatment includes Inhaled bronchodilators (beta-2 agonists and anticholinergics)... read more ).
Short-acting beta-2 agonists (eg, albuterol) 2 puffs every 4 hours inhaled as needed are the drug of choice for relieving acute bronchoconstriction and preventing exercise-induced asthma. They should not be used alone for long-term maintenance of chronic asthma. They take effect within minutes and are active for up to 6 to 8 hours, depending on the drug. Tachycardia and tremor are the most common acute adverse effects of inhaled beta-2 agonists and are dose-related. Mild hypokalemia Hypokalemia Hypokalemia is serum potassium concentration 3.5 mEq/L ( 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common cause is... read more occurs uncommonly. Use of levalbuterol (a solution containing the R-isomer of albuterol) theoretically minimizes adverse effects, but its long-term efficacy and safety are unproved. Oral beta-2 agonists have more systemic effects and generally should be avoided.
Long-acting beta-2 agonists (eg, salmeterol) are active for up to 12 hours. They are used for moderate and severe asthma but should never be used as monotherapy. They interact synergistically with inhaled corticosteroids and permit lower dosing of corticosteroids.
Ultra-long-acting beta-2 agonists (eg, indacaterol) are active for up to 24 hours and as with long-acting beta agonists are used for moderate to severe asthma, and should never be used as a monotherapy. They interact synergistically with inhaled corticosteroids and permit lower dosing of corticosteroids.
The safety of regular long-term use of beta-2 agonists remains unclear. Long-acting beta-2 agonists may increase the risk of asthma-related death when used as monotherapy. Therefore, when treating patients with asthma, these drugs (salmeterol, formoterol, vilanterol) should be used only in combination with an inhaled corticosteroid for patients whose condition is not adequately controlled with other asthma controllers (eg, low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants additional maintenance therapies. Daily use or diminishing effects of short-acting beta-2 agonists or use of ≥ 1 canister per month suggests inadequate control and the need to begin or intensify other therapies.
Anticholinergics relax bronchial smooth muscle through competitive inhibition of muscarinic (M3) cholinergic receptors. Ipratropium may have an additive effect when combined with short-acting beta-2 agonists. Adverse effects include pupillary dilation, blurred vision, and dry mouth. Tiotropium soft mist inhaler (1.25 mcg/puff) is a 24-hour inhaled anticholinergic that can be used for patients with asthma. In patients with asthma, clinical trials of tiotropium added to either inhaled corticosteroids or to a combination of an inhaled long-acting beta-2 agonist plus a corticosteroid have shown improved pulmonary function and decreased asthma exacerbations.
Corticosteroids inhibit airway inflammation, reverse beta-receptor down-regulation, and inhibit cytokine production and adhesion protein activation. They block the late response (but not the early response) to inhaled allergens. Routes of administration include oral, IV, and inhaled. In acute asthma exacerbations, early use of systemic corticosteroids often aborts the exacerbation, decreases the need for hospitalization, prevents relapse, and speeds recovery. Oral and IV routes are equally effective.
Inhaled corticosteroids have no role in acute exacerbations but are indicated for long-term suppression, control, and reversal of inflammation and symptoms. They substantially reduce the need for maintenance oral corticosteroid therapy. Adverse local effects of inhaled corticosteroids include dysphonia and oral candidiasis, which can be prevented or minimized by having the patient use a spacer, gargle with water after corticosteroid inhalation, or both. Systemic effects are all dose related, can occur with oral or inhaled forms, and occur mainly with inhaled doses > 800 mcg/day. They include suppression of the adrenal-pituitary axis, osteoporosis Osteoporosis Osteoporosis is a progressive metabolic bone disease that decreases bone mineral density (bone mass per unit volume), with deterioration of bone structure. Skeletal weakness leads to fractures... read more , cataracts Cataract A cataract is a congenital or degenerative opacity of the lens. The main symptom is gradual, painless vision blurring. Diagnosis is by ophthalmoscopy and slit-lamp examination. Treatment is... read more , skin atrophy, hyperphagia, and easy bruisability. Whether inhaled corticosteroids suppress growth in children is unclear. Most children treated with inhaled corticosteroids eventually reach their predicted adult height. Latent tuberculosis Tuberculosis (TB) Tuberculosis (TB) is a chronic, progressive mycobacterial infection, often with a period of latency following initial infection. TB most commonly affects the lungs. Symptoms include productive... read more may be reactivated by systemic corticosteroid use.
Mast cell stabilizers
Mast cell stabilizers inhibit histamine release from mast cells, reduce airway hyperresponsiveness, and block the early and late responses to allergens. They are given by inhalation prophylactically to patients with exercise-induced or allergen-induced asthma. They are ineffective once symptoms have occurred. They are the safest of all antiasthmatic drugs but the least effective.
Leukotriene modifiers are taken orally and can be used for long-term control and prevention of symptoms in patients with mild persistent to severe persistent asthma. The main adverse effect is liver enzyme elevation (which occurs with zileuton). Although rare, patients have developed a clinical syndrome resembling eosinophilic granulomatosis with polyangiitis Eosinophilic Granulomatosis with Polyangiitis (EGPA) Eosinophilic granulomatosis with polyangiitis is a systemic small- and medium-vessel necrotizing vasculitis, characterized by extravascular granulomas, eosinophilia, and tissue infiltration... read more .
Methylxanthines relax bronchial smooth muscle (probably by inhibiting phosphodiesterase) and may improve myocardial and diaphragmatic contractility through unknown mechanisms. Methylxanthines appear to inhibit intracellular release of calcium, decrease microvascular leakage into the airway mucosa, and inhibit the late response to allergens. They decrease the infiltration of eosinophils into bronchial mucosa and of T cells into epithelium.
The methylxanthine theophylline is used for long-term control as an adjunct to beta-2 agonists. Extended-release theophylline helps manage nocturnal asthma. Theophylline has fallen into disuse because of its many adverse effects and interactions compared with other drugs. Adverse effects include headache, vomiting, cardiac arrhythmias, seizures, and aggravation of gastroesophageal reflux Gastroesophageal Reflux Disease (GERD) Incompetence of the lower esophageal sphincter allows reflux of gastric contents into the esophagus, causing burning pain. Prolonged reflux may lead to esophagitis, stricture, and rarely metaplasia... read more (by reducing lower esophageal sphincter pressure).
Methylxanthines have a narrow therapeutic index; multiple drugs (any metabolized by the cytochrome P-450 pathway, eg, macrolide antibiotics) and conditions (eg, fever, liver disease, heart failure) alter methylxanthine metabolism and elimination. Serum theophylline levels should be monitored periodically and maintained between 5 and 15 mcg/mL (28 and 83 micromole/L).
Immunomodulators include omalizumab, an anti-IgE antibody, 3 antibodies to IL-5 (benralizumab, mepolizumab, reslizumab), and a monoclonal antibody that inhibits IL-4 and IL-13 signaling (dupilumab), which are used for the management of severe allergic asthma.
Omalizumab is indicated for patients with severe, allergic asthma who have elevated IgE levels. Omalizumab may decrease asthma exacerbations, corticosteroid requirements, and symptoms. Dosing is determined by a dosing chart based on the patient’s weight and IgE levels. The drug is administered subcutaneously every 2 to 4 weeks.
Mepolizumab, reslizumab, and benralizumab were developed for use in patients with eosinophilic asthma and are monoclonal antibodies that block IL-5. IL-5 is a cytokine that promotes eosinophilic inflammation in the airways.
Mepolizumab reduces exacerbation frequency, decreases asthma symptoms, and reduces the need for systemic corticosteroid therapy in patients with asthma who are dependent on chronic systemic corticosteroid therapy. Based on data from clinical trials, efficacy occurs with blood absolute eosinophil counts > 150/microL (0.15 × 109/L); however, for patients on chronic systemic corticosteroid therapy, the threshold for efficacy is unclear. Mepolizumab is administered subcutaneously 100 mg every 4 weeks.
Reslizumab also appears to reduce frequency of exacerbations and decrease asthma symptoms. In clinical trials, patients had blood absolute eosinophil counts of about 400/microL (0.4 × 109/L). In patients treated with chronic systemic corticosteroids, the eosinophil count threshold for efficacy is unclear. Reslizumab is administered 3 mg/kg IV over 20 to 50 minutes every 4 weeks.
Benralizumab is a monoclonal antibody that binds to IL-5 receptors. It is indicated for the add-on maintenance treatment of severe asthma in patients aged 12 years or older with an eosinophilic phenotype. It has been shown to decrease exacerbation frequency and reduce and/or eliminate oral corticosteroid use. The recommended dose is 30 mg subcutaneously once every 4 weeks for 3 doses, followed by 30 mg once every 8 weeks. The treatment regimens of participants in clinical trials (1, 2 References Major drug classes commonly used in the treatment of asthma and asthma exacerbations include Bronchodilators (beta-2 agonists, anticholinergics) Corticosteroids Leukotriene modifiers Mast cell... read more references) included high-dose inhaled corticosteroids plus long-acting beta-2 agonists with or without other controllers. Blood eosinophil counts were typically > 300/microL (>0.3 × 109/L).
Dupilumab is a monoclonal antibody that blocks the IL-4R-alpha subunit, thereby simultaneously inhibiting IL-4 and IL-13 signaling. It is indicated for add-on maintenance treatment of patients with moderate-to-severe asthma aged 12 years or older with an eosinophilic phenotype or with oral corticosteroid–dependent asthma. The recommended dose is an initial dose of 400 mg subcutaneously followed by 200 mg every other week, or an initial dose of 600 mg subcutaneously followed by 300 mg every other week. The higher dosage is recommended for patients requiring concomitant oral corticosteroids or with co-morbid moderate-to-severe atopic dermatitis Atopic Dermatitis (Eczema) Atopic dermatitis is a chronic relapsing inflammatory skin disorder with a complex pathogenesis involving genetic susceptibility, immunologic and epidermal barrier dysfunction, and environmental... read more .
Clinicians who give any of these immunomodulators should be prepared to identify and treat anaphylaxis Anaphylaxis Anaphylaxis is an acute, potentially life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing antigen. Symptoms... read more or allergic hypersensitivity reactions Overview of Allergic and Atopic Disorders Allergic (including atopic) and other hypersensitivity disorders are inappropriate or exaggerated immune reactions to foreign antigens. Inappropriate immune reactions include those that are... read more . Anaphylaxis may occur after any dose of dupilumab, benralizumab, omalizumab, or reslizumab even if previous doses have been well tolerated. Allergic hypersensitivity reactions have been reported with mepolizumab. Mepolizumab use has been associated with herpes zoster infection Herpes Zoster Herpes zoster is infection that results when varicella-zoster virus reactivates from its latent state in a posterior dorsal root ganglion. Symptoms usually begin with pain along the affected... read more ; therefore, zoster vaccination Herpes Zoster Vaccine Chickenpox (varicella) and shingles (herpes zoster) are caused by the varicella-zoster virus; chickenpox is the acute invasive phase of the virus, and shingles represents reactivation of the... read more is recommend prior to initiation of therapy unless contraindicated.
Pearls & Pitfalls
Other drugs are used in asthma treatment uncommonly and in specific circumstances. Magnesium is often used in the emergency department, but it is not recommended in the management of chronic asthma.
Immunotherapy may be indicated when symptoms are triggered by allergy, as suggested by history and confirmed by allergy testing. Immunotherapy is generally more effective in children than adults. If symptoms are not significantly relieved after 24 months, then therapy is stopped. If symptoms are relieved, therapy should continue for ≥ 3 years, although the optimum duration is unknown.
Other drugs that suppress the immune system are occasionally given to reduce dependence on high-dose oral corticosteroids, but these drugs have a significant risk of toxicity. Low-dose methotrexate (5 to 15 mg orally or IM once a week) can lead to modest improvements in FEV1 and modest decreases in daily oral corticosteroid use. Gold and cyclosporine are also modestly effective, but toxicity and need for monitoring limit their use.
Other therapies for management of chronic asthma include nebulized lidocaine, nebulized heparin, colchicine, and high-dose IV immune globulin. Limited evidence supports the use of any of these therapies, and their benefits are unproved, so none are currently recommended for routine clinical use.
1. Bleecker ER, FitzGerald AM, Chanez P, et al: Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet388(10056):2115–2127, 2016. doi: 10.1016/S0140-6736(16)31324-1
2. FitzGerald AM, Bleecker ER, Nair P, et al: Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 388(10056):2128–2141, 2016. doi: 10.1016/S0140-6736(16)31322-8