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Beta2-adrenergic receptor agonists and beta 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 and Drug Treatment of Asthma Exacerbations).

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 agonists and are dose-related. Mild hypokalemia 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 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 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 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 agonists has been confirmed by multiple randomized, controlled trials and meta-analyses, including a large international safety study that was followed by removal of a black box warning by the Food and Drug Administration (1). Because the safety and efficacy of long-acting beta agonists have been demonstrated only when used in combination with an inhaled corticosteroid, all long-acting and ultra-long beta agonists 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 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 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 corticosteroids suppress growth in children is unclear. Most children treated with inhaled corticosteroids eventually reach their predicted adult height. Latent tuberculosis may be reactivated by systemic corticosteroid use.

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.

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 (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 blocks IL-4 receptor-alpha to inhibit IL-4 and IL-13 signaling (dupilumab). Immunomodulators are used for the management of severe asthma refractory to a combination of step-up asthma therapies, usually high-dose inhaled corticosteroids with a long-acting beta2-adrenergic receptor agonist, and primarily characterized by elevated allergic inflammation biomarkers (serum IgE, blood eosinophil count). Drug selection should be individualized for each patient's clinical scenario based on route, frequency, cost, and collateral atopic disease. For example, a patient with atopic dermatitis and asthma could consider dupilumab because it is also used in patients with atopic dermatitis.

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 or its receptor, IL-5R. 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 depend on chronic systemic corticosteroid therapy. Based on data from clinical trials, efficacy occurs with blood absolute eosinophil counts > 150/microL (0.15 × 10⁹/L). In patients requiring chronic systemic corticosteroid therapy, the threshold for efficacy is unclear due to the suppressive effects of corticosteroids on blood eosinphil counts , yet mepolizumab has been shown to reduce or eliminate the need for systemic corticosteroid therapy. 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.

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 for whom dose reductions and cessation of systemic corticosteroids is a goal.

Clinicians who give any of these immunomodulators should be prepared to identify and treat anaphylaxis or allergic hypersensitivity reactions. 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; therefore, zoster vaccination is recommend prior to initiation of therapy unless contraindicated.

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. 1. US Food and Drug Administration: FDA Drug Safety Communication: FDA review finds no significant increase in risk of serious asthma outcomes with long-acting beta agonists (LABAs) used in combination with inhaled corticosteroids (ICS).April 15, 2011. Updated December 20, 2017. Accessed January 21, 2022.