Pharmacologic Treatment of Asthma

Beta agonists

Beta2-adrenergic receptor agonists and non-selective beta-agonists (eg, epinephrine, norepinephrine) 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 Beta2-adrenergic receptor agonists and non-selective beta-agonists (eg, epinephrine, norepinephrine) 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 tablesPharmacologic Treatment of Asthma and Pharmacologic Treatment of Asthma Exacerbations).

Short-acting beta-2 agonists (eg, albuterol) 2 puffs every 4 hours inhaled may be used for relieving acute bronchoconstriction, and 2 puffs 15 to 30 minutes before exercise is used for preventing exercise-induced bronchoconstriction. There is a strong recommendation against the use of short-acting beta-2-agonist monotherapy for all patients with asthma (beta-2 agonists (eg, albuterol) 2 puffs every 4 hours inhaled may be used for relieving acute bronchoconstriction, and 2 puffs 15 to 30 minutes before exercise is used for preventing exercise-induced bronchoconstriction. There is a strong recommendation against the use of short-acting beta-2-agonist monotherapy for all patients with asthma (1), because monotherapy without the addition of an inhaled glucocorticoid has led to significantly more exacerbations, asthma-related emergency department visits, and worse lung function outcomes. Short-acting beta-2 agonists take effect within minutes and are active for up to 6 to 8 hours, depending on the medication. Tachycardia and tremor are the most common acute adverse effects of inhaled beta agonists and are dose-related. Mild hypokalemia occurs uncommonly. Use of levalbuterol (a solution containing the occurs uncommonly. Use of levalbuterol (a solution containing theR-isomer of albuterol) theoretically minimizes adverse effects, but its long-term efficacy and safety are unproved. Oral beta agonists have more systemic effects and generally should be avoided.

Long-acting beta agonists (eg, salmeterol) are active for up to 12 hours. They are used in addition to inhaled glucocorticoids for moderate and severe asthma, and should never be used as monotherapy. Furthermore, they should not be used for acute symptom relief in an exacerbation. The dose is 1 to 2 puffs every 12 hours (except for formoterol, which in combination with an inhaled glucocorticoid may be dosed every 3 to 4 hours according to some protocols). For the prevention (and not the treatment) of exercise-induced bronchoconstriction, they may be administered along with glucocorticoids and taken 30 to 60 minutes before exercise. Long-acting beta agonists interact synergistically with inhaled glucocorticoids and permit lower dosing of glucocorticoids. beta agonists (eg, salmeterol) are active for up to 12 hours. They are used in addition to inhaled glucocorticoids for moderate and severe asthma, and should never be used as monotherapy. Furthermore, they should not be used for acute symptom relief in an exacerbation. The dose is 1 to 2 puffs every 12 hours (except for formoterol, which in combination with an inhaled glucocorticoid may be dosed every 3 to 4 hours according to some protocols). For the prevention (and not the treatment) of exercise-induced bronchoconstriction, they may be administered along with glucocorticoids and taken 30 to 60 minutes before exercise. Long-acting beta agonists interact synergistically with inhaled glucocorticoids and permit lower dosing of glucocorticoids.

Ultra-long-acting beta agonists (eg, olodaterol, indacaterol) are active for up to 24 hours and, as with long-acting beta agonists, are used for moderate to severe asthma. Ultra-long-acting beta agonists should never be used as a monotherapy. They interact synergistically with inhaled glucocorticoids and permit lower dosing of glucocorticoids. beta agonists (eg, olodaterol, indacaterol) are active for up to 24 hours and, as with long-acting beta agonists, are used for moderate to severe asthma. Ultra-long-acting beta agonists should never be used as a monotherapy. They interact synergistically with inhaled glucocorticoids and permit lower dosing of glucocorticoids.

The safety of regular long-term use of beta agonists has been confirmed by multiple randomized trials and meta-analyses (3). Because the safety and efficacy of long-acting beta agonists have been demonstrated only when used in combination with an inhaled glucocorticoid, all long-acting and ultra-long beta agonists should be used only in combination with an inhaled glucocorticoid for patients whose condition is not adequately controlled with other asthma controllers (eg, low- to medium-dose inhaled glucocorticoids) or whose disease severity clearly warrants additional maintenance therapies. Daily use or diminishing effects of short-acting beta agonists or the use of ≥ 1 canister per month suggests inadequate control and the need to begin or intensify other therapies.

Anticholinergics (antimuscarinics)

Anticholinergics relax bronchial smooth muscle through competitive inhibition of muscarinic (M3) cholinergic receptors. Ipratropium and tiotropium are examples of anticholinergics. They may have an additive effect when combined with short-acting beta-2 agonists. The dose of Anticholinergics relax bronchial smooth muscle through competitive inhibition of muscarinic (M3) cholinergic receptors. Ipratropium and tiotropium are examples of anticholinergics. They may have an additive effect when combined with short-acting beta-2 agonists. The dose ofipratropium is 2 puffs every 6 hours as needed (maximum 12 puffs/day). Adverse effects include pupillary dilation, blurred vision, and dry mouth. Tiotropium soft mist inhaler is a 24-hour inhaled anticholinergic that can be used for patients with asthma. The dose is 2 puffs once a day (maximum 2 puffs/day). In patients with asthma, clinical trials of tiotropium added to either inhaled glucocorticoids or to a combination of an inhaled long-acting beta-2 agonist plus an inhaled glucocorticoid showed improved pulmonary function and decreased asthma exacerbations compared to placebo (4).

Inhaled combination therapy with glucocorticoids, long-acting beta-2 agonists, and long-acting muscarinic antagonists are recommended for the maintenance treatment of asthma for severe persistent asthma (step 5) in adults (1). Glucocorticoids provide anti-inflammatory effects, muscarinic antagonists provide bronchodilation via muscarinic receptor antagonism, and beta-2 agonists provide smooth muscle relaxation through beta-2 agonism. Fluticasone furoate/umeclidinium/vilanterol is used in the United States. Similar agents are used elsewhere; 2 combination inhalers, one containing mometasone furoate, indacaterol acetate, and glycopyrronium bromide and the other containing beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide are available in the European Union. With the exception of the compound containing beclomethasone, which is administered twice daily, these agents are administered as one single inhalation daily.). Glucocorticoids provide anti-inflammatory effects, muscarinic antagonists provide bronchodilation via muscarinic receptor antagonism, and beta-2 agonists provide smooth muscle relaxation through beta-2 agonism. Fluticasone furoate/umeclidinium/vilanterol is used in the United States. Similar agents are used elsewhere; 2 combination inhalers, one containing mometasone furoate, indacaterol acetate, and glycopyrronium bromide and the other containing beclomethasone dipropionate, formoterol fumarate, and glycopyrronium bromide are available in the European Union. With the exception of the compound containing beclomethasone, which is administered twice daily, these agents are administered as one single inhalation daily.

Glucocorticoids

Glucocorticoids 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 glucocorticoids often aborts the exacerbation, decreases the need for hospitalization, prevents relapse, and speeds recovery. Oral and IV routes are equally effective.

Inhaled glucocorticoids, also referred to as inhaled corticosteroids (ICS), are generally indicated for long-term suppression, control, and reversal of inflammation and symptoms. There is substantial evidence that the preferred reliever across all steps is a low-dose ICS–beta-agonist combination, used as needed for mild asthma and as both maintenance and reliever therapy for moderate-to-severe persistent asthma (5, 6). Specifically, clinical trials comparing inhaled glucocorticoid–beta-agonists to beta-agonist monotherapy demonstrated a substantial reduction in severe exacerbations compared to beta-agonist-only regimens, with similar or improved symptom control and lung function outcomes. Initiating as-needed inhaled glucocorticoid–beta-agonist therapy in patients with mild asthma effectively provides symptom relief and reduces the risk of severe asthma exacerbations, eliminating the necessity for daily maintenance treatment (7). Patients who adhere to inhaled glucocorticoid regimens also substantially reduce their need for maintenance oral glucocorticoid therapy.

Adverse local effects of inhaled glucocorticoids include dysphonia and oral candidiasis, which can be prevented or minimized by having the patient use a spacer, gargle with water after glucocorticoid inhalation, or both. Systemic effects are all dose related, can occur with oral or inhaled forms, and when due to inhaled forms, occur mainly with doses > 800 mcg/day. They include suppression of the adrenal-pituitary axis, osteoporosis, cataracts, skin atrophy, hyperphagia, and easy bruisability. Whether inhaled glucocorticoids suppress growth in children is unclear. Most children treated with inhaled glucocorticoids eventually reach their predicted adult height. Latent tuberculosis may be reactivated by systemic glucocorticoid 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 bronchoconstriction or allergen-induced asthma. They are ineffective once symptoms have occurred. They are the safest of all antiasthmatic medications but the least effective. They are not recommended for maintenance therapy of asthma in the United States.

Leukotriene modifiers

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 primarily with zileuton). Although rare, patients have developed a clinical syndrome resembling 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 primarily with zileuton). Although rare, patients have developed a clinical syndrome resemblingeosinophilic granulomatosis with polyangiitis.

The potential for severe neuropsychiatric reactions with montelukast has led to restrictions on its use and a boxed label warning in the United States in 2020 (The potential for severe neuropsychiatric reactions with montelukast has led to restrictions on its use and a boxed label warning in the United States in 2020 (8). These reports have led to concerns that the benefits of montelukast may not outweigh the risks in some patients, especially when symptoms are mild and can be adequately managed with other conventional therapies. Large-scale observational studies published after 2020 have provided mixed results on this potential association. For example, one nationwide cohort study from Sweden of children aged 6 to 17 years who used montelukast between 2007 and 2021 did not detect an association between neuropsychiatric adverse events and montelukast use (9). However, in a large systematic review of children and adults with asthma, montelukast use was not associated with depressive of suicidal symptoms, but older adults were found to be particularly susceptible to developing anxiety and sleep disorders (10). Additional longitudinal post-marketing surveillance studies are needed to make more definitive conclusions. Thus, in the context of asthma maintenance therapy, montelukast should only be prescribed after careful consideration of the potential risk of neuropsychiatric adverse drug events and a thorough discussion with the patient.

Methylxanthines

Methylxanthines (eg, theophylline) relax bronchial smooth muscle (probably by inhibiting phosphodiesterase) and may improve myocardial and diaphragmatic contractility; it is hypothesized that these effects may be related to their action on Methylxanthines (eg, theophylline) relax bronchial smooth muscle (probably by inhibiting phosphodiesterase) and may improve myocardial and diaphragmatic contractility; it is hypothesized that these effects may be related to their action onadenosine receptors and the inhibition of release of intracellular calcium. They also decrease microvascular leakage into the airway mucosa and inhibit the late response to allergens. They decrease the infiltration of eosinophils into the bronchial mucosa and T cells into respiratory epithelium.

Theophylline is used for long-term control as an adjunct to beta-2 agonists. Sustained-release oral Theophylline is used for long-term control as an adjunct to beta-2 agonists. Sustained-release oraltheophylline helps manage nocturnal asthma. Theophylline has fallen into disfavor because of its many adverse effects and interactions compared with other medications. Adverse effects include headache, vomiting, cardiac arrhythmias, seizures, and aggravation of gastroesophageal reflux (by reducing lower esophageal sphincter pressure).

Methylxanthines have a narrow therapeutic index; multiple medications (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).Methylxanthines have a narrow therapeutic index; multiple medications (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).

Biologic medications

Biologic medications used in the treatment of asthma include agents that are anti-IgE antibodies (eg, omalizumab), antibodies to interleukin (IL)-5 (eg, benralizumab, mepolizumab, reslizumab), a monoclonal antibody that blocks IL-4 receptor-alpha to inhibit IL-4 and IL-13 signaling (dupilumab), and one that blocks thymic stromal lymphopoietin (TSLP) (tezepelumab). Biologics are used for the management of severe asthma refractory to a combination of step-up asthma therapies, usually high-dose inhaled glucocorticoids with a long-acting beta2-adrenergic receptor agonist, and primarily characterized by elevated allergic inflammation biomarkers (serum IgE, blood eosinophil count). Medication selection should be individualized for each patient's clinical scenario based on route, frequency, cost, and comorbid atopic disease. For example, in a patient with atopic dermatitis and asthma, dupilumab could be considered because it is also used in patients with atopic dermatitis.Biologic medications used in the treatment of asthma include agents that are anti-IgE antibodies (eg, omalizumab), antibodies to interleukin (IL)-5 (eg, benralizumab, mepolizumab, reslizumab), a monoclonal antibody that blocks IL-4 receptor-alpha to inhibit IL-4 and IL-13 signaling (dupilumab), and one that blocks thymic stromal lymphopoietin (TSLP) (tezepelumab). Biologics are used for the management of severe asthma refractory to a combination of step-up asthma therapies, usually high-dose inhaled glucocorticoids with a long-acting beta2-adrenergic receptor agonist, and primarily characterized by elevated allergic inflammation biomarkers (serum IgE, blood eosinophil count). Medication selection should be individualized for each patient's clinical scenario based on route, frequency, cost, and comorbid atopic disease. For example, in a patient with atopic dermatitis and asthma, dupilumab could be considered because it is also used in patients with atopic dermatitis.

Omalizumab or omalizumab-igec is indicated for patients with severe, allergic asthma who have elevated IgE levels. These medications may decrease asthma exacerbations, glucocorticoid requirements, and symptoms. Dosing is determined by a dosing chart based on the patient’s weight and IgE levels. The medication is administered subcutaneously every 2 to 4 weeks. Omalizumab or omalizumab-igec is indicated for patients with severe, allergic asthma who have elevated IgE levels. These medications may decrease asthma exacerbations, glucocorticoid requirements, and symptoms. Dosing is determined by a dosing chart based on the patient’s weight and IgE levels. The medication is administered subcutaneously every 2 to 4 weeks.

Mepolizumab, reslizumab, and benralizumab were developed for use in patients with eosinophilic (T2-high) asthma and are monoclonal antibodies that block IL-5 or its receptor, IL-5R. IL-5 is a cytokine that promotes eosinophilic inflammation in the airways. An ultra-long-acting anti-IL-5 monoclonal antibody depot preparation, depemokimab, intended to be administered subcutaneously every 6 months as maintenance therapy in severe eosinophilic asthma, has reduced asthma exacerbations and hospitalization rates in clinical trials (Mepolizumab, reslizumab, and benralizumab were developed for use in patients with eosinophilic (T2-high) asthma and are monoclonal antibodies that block IL-5 or its receptor, IL-5R. IL-5 is a cytokine that promotes eosinophilic inflammation in the airways. An ultra-long-acting anti-IL-5 monoclonal antibody depot preparation, depemokimab, intended to be administered subcutaneously every 6 months as maintenance therapy in severe eosinophilic asthma, has reduced asthma exacerbations and hospitalization rates in clinical trials (11).

Mepolizumab reduces exacerbation frequency, decreases asthma symptoms, and reduces the need for systemic glucocorticoid therapy in patients with asthma who depend on chronic systemic glucocorticoid therapy. Based on data from clinical trials, efficacy occurs with blood absolute eosinophil counts > 150/microL (0.15 × 10Mepolizumab reduces exacerbation frequency, decreases asthma symptoms, and reduces the need for systemic glucocorticoid therapy in patients with asthma who depend on chronic systemic glucocorticoid therapy. Based on data from clinical trials, efficacy occurs with blood absolute eosinophil counts > 150/microL (0.15 × 10⁹/L) (12). In patients requiring chronic systemic glucocorticoid therapy, the threshold for efficacy is unclear due to the suppressive effects of glucocorticoids on blood eosinophil counts yet mepolizumab has been shown to reduce or eliminate the need for systemic glucocorticoid therapy. Mepolizumab is administered subcutaneously every 4 weeks.

Reslizumab, a monoclonal antibody that binds to IL-5 receptors, also appears to reduce frequency of exacerbations and decrease asthma symptoms; however, it is administered intravenously every 4 weeks and therefore is used less often. Reslizumab, a monoclonal antibody that binds to IL-5 receptors, also appears to reduce frequency of exacerbations and decrease asthma symptoms; however, it is administered intravenously every 4 weeks and therefore is used less often.

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 6 years or older with an eosinophilic phenotype. It has been shown to decrease exacerbation frequency and reduce and/or eliminate oral glucocorticoid use. It is administered as a subcutaneous loading dose followed by maintenance doses once every 8 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 6 years or older with an eosinophilic phenotype. It has been shown to decrease exacerbation frequency and reduce and/or eliminate oral glucocorticoid use. It is administered as a subcutaneous loading dose followed by maintenance doses once every 8 weeks.

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 6 years or older with an eosinophilic phenotype or with oral glucocorticoid–dependent asthma. It is administered as a subcutaneous loading dose followed by maintenance dosing. The higher dosage is recommended for patients requiring concomitant oral glucocorticoids for whom dose reductions and cessation of systemic glucocorticoids is a goal. 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 6 years or older with an eosinophilic phenotype or with oral glucocorticoid–dependent asthma. It is administered as a subcutaneous loading dose followed by maintenance dosing. The higher dosage is recommended for patients requiring concomitant oral glucocorticoids for whom dose reductions and cessation of systemic glucocorticoids is a goal.

Tezepelumab is a monoclonal antibody that binds specifically to TSLP and prevents its interaction with the TSLP receptor. It is prescribed as an add-on maintenance treatment for patients aged 12 years or older with severe asthma. Tezepelumab is a monoclonal antibody that binds specifically to TSLP and prevents its interaction with the TSLP receptor. It is prescribed as an add-on maintenance treatment for patients aged 12 years or older with severe asthma.Tezepelumab has been shown to significantly reduce asthma exacerbations compared with placebo (13). It is administered subcutaneously once every 4 weeks.

Clinicians who give any of these biologic medications should be prepared to identify and treat anaphylaxis or allergic hypersensitivity reactions. Anaphylaxis may occur after any dose of dupilumab, benralizumab, omalizumab, tezepelumab, or reslizumab even if previous doses have been well tolerated. Allergic hypersensitivity reactions have been reported with mepolizumab. . Anaphylaxis may occur after any dose of dupilumab, benralizumab, omalizumab, tezepelumab, 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; therefore, zoster vaccination is recommend prior to initiation of therapy unless contraindicated. Pharyngitis and arthralgias have been reported with tezepelumab.

Other therapeutic approaches

Other medications are used in asthma treatment uncommonly and in specific circumstances. Magnesium is often used in the emergency department for the treatment of acute exacerbations, but it is not recommended in the management of chronic asthma.

Allergen immunotherapy may be indicated when symptoms are triggered by allergy, as suggested by history and confirmed by allergy testing. Immunotherapy refers to the controlled, repeated administration of specific allergens to induce immunologic tolerance, primarily through the modulation of IgE-mediated immune responses. It consists of a build-up (where doses are systematically increased as tolerated based on established protocols) and maintenance phase (where the highest tolerated dose is administered). If symptoms are not significantly relieved after 3 to 5 years of maintenance therapy, then therapy is stopped. The optimum duration of maintenance therapy is unknown.