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A. Pharmacologic Agents
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Asthma medications can be divided into three categories: (1) long-term controller medications (Table 9–2) used long-term to reduce airway inflammation, symptoms and risk of future exacerbations, (2) reliever medications (Table 9–3) used on an as-needed basis to relieve breakthrough symptoms, and (3) add-on therapies for severe asthma. Figure 9–1 shows a personalized management plan for asthma to control symptoms and minimize future risk.
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Most asthma medications are administered by inhalation or by oral dosing. Inhalation of an appropriate agent results in a more rapid onset of pulmonary effects as well as fewer systemic effects compared with the oral dose required to achieve the same effect on the airways. Proper inhaler technique and the use of an inhalation chamber (a “spacer”) with metered-dose inhalers (MDIs) improve drug delivery to the lung and decrease oropharyngeal drug deposition. Nebulizer therapy is reserved for patients who are acutely ill and those who cannot use inhalers because of difficulties with coordination, understanding, or cooperation.
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1. Inhaled corticosteroids
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Inhaled corticosteroids are essential controller medications (Tables 9–3 and 9–4). Once the diagnosis of asthma is made, early initiation of inhaled corticosteroid therapy leads to a greater improvement in lung function than delayed therapy. Prescribing intermittent or daily controller inhaled corticosteroids at the start of asthma therapy conveys a message to patients that both symptom control and risk reduction are the mainstays of asthma treatment. The most important determinants of medication choice, device and dose are a patient’s symptoms and risk factors, along with practical issues (such as cost and delivery mechanism). Inhaled corticosteroid dosages are classified as low-, medium- and high-dose strengths in various published sources including GINA, but low-dose inhaled corticosteroid provides clinical benefit and is sufficient for most patients with asthma. Dosages for inhaled corticosteroids vary depending on the specific agent and delivery device (Table 9–4). For patients who require high-dose inhaled corticosteroids to achieve adequate symptom control, after 3 months of good control the dose of inhaled corticosteroid should be decreased to the lowest dose that preserves symptom control and minimizes exacerbation risk.
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Concomitant use of a MDI and an inhalation chamber coupled with mouth washing after inhaled corticosteroid use decreases systemic absorption and local side effects (cough, dysphonia, oropharyngeal candidiasis). Dry powder inhalers (DPIs) are not used with an inhalation chamber. Systemic effects (adrenal suppression, osteoporosis, skin thinning, easy bruising, and cataracts) may occur with high-dose inhaled corticosteroid therapy. Combination inhalers with an inhaled corticosteroid and a long-acting beta-2-agonist (LABA) offer convenient treatment of asthma. The GINA report recommends low-dose inhaled corticosteroid/formoterol as its preferred agent due to clinical evidence but notes that its cost and availability in different countries must be taken into consideration. Budesonide/formoterol is listed as a World Health Organization essential medication.
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2. Beta-adrenergic agonists
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Beta-agonists are divided into SABAs and LABAs. SABAs, including albuterol, levalbuterol, bitolterol, pirbuterol, and terbutaline (Table 9–3), are mainstays of reliever or rescue therapy for asthma patients. There is no convincing evidence to support the use of one agent over another. All asthmatics should have immediate access to a SABA because they are the most effective bronchodilators during exacerbations and provide immediate relief of symptoms. Administration before exercise effectively prevents exercise-induced bronchoconstriction.
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Inhaled SABA therapy is as effective as oral or parenteral beta-agonist therapy in relaxing airway smooth muscle and improving acute asthma and offers the advantages of rapid onset of action (less than 5 minutes) with fewer systemic side effects. Beta-2-selective agents may produce less cardiac stimulation than those with mixed beta-1 and beta-2 activities, although clinical trials have not consistently demonstrated this finding. Repetitive administration produces incremental bronchodilation. One or two inhalations of a SABA from an MDI are usually sufficient for mild to moderate symptoms. Severe exacerbations frequently require higher doses: 6–12 puffs every 30–60 minutes of albuterol by MDI with an inhalation chamber or 2.5 mg by nebulizer provide equivalent bronchodilation. Administration by nebulization does not offer more effective delivery than MDIs used correctly but does provide higher doses. With most SABAs, the recommended dose by nebulizer for acute asthma (albuterol, 2.5 mg) is 25–30 times that delivered by a single activation of the MDI (albuterol, 0.09 mg). This difference suggests that standard dosing of inhalations from an MDI may be insufficient in the setting of an acute exacerbation. Independent of dose, nebulizer therapy may be more effective in patients who are unable to coordinate inhalation of medication from an MDI because of age, agitation, or severity of the exacerbation.
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GINA does not recommend SABA-only treatment of asthma in adults or adolescents and does not recommend scheduled daily use of SABAs. Although SABA is effective as a quick relief medication, patients who are treated with SABA alone are at increased risk for asthma-related death and urgent healthcare even if their symptoms are controlled. Increased use (more than one canister a month) or lack of expected effect indicates diminished asthma control and the need for additional long-term controller therapy.
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LABAs provide bronchodilation for up to 12 hours after a single dose. Salmeterol, formoterol, and olodaterol are LABAs available for asthma in the United States. In combination with an inhaled corticosteroid they are indicated for long-term prevention of asthma symptoms (including nocturnal symptoms) and for prevention of exercise-induced bronchospasm. LABAs should not be used as monotherapy because they have no anti-inflammatory effect and because monotherapy has been associated with a small but statistically significant increased risk of severe or fatal asthma attacks in two large studies. Combination inhalers containing formoterol and low-dose budesonide are the preferred option because of a large study in mild asthma that showed a 64% reduction in severe exacerbations compared with SABA-only treatment, and two large studies in mild asthma that showed noninferiority for severe exacerbations compared to low-dose inhaled corticosteroid alone.
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3. Systemic corticosteroids
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Systemic corticosteroids (oral prednisone or prednisolone or parenteral methylprednisolone) are most effective in achieving prompt control of asthma during acute exacerbations. Systemic corticosteroids are effective as primary treatments for patients with moderate to severe asthma exacerbations and for patients with exacerbations that do not respond promptly and completely to inhaled SABA therapy. These medications speed the resolution of airflow obstruction and reduce the rate of relapse. Delays in administering corticosteroids may result in progressive impairment. Therefore, patients with moderate to severe asthma should be prescribed oral corticosteroids so they are available for early, at-home administration. The minimal effective dose of systemic corticosteroids for asthma patients has not been identified. Outpatient prednisone “burst” therapy is 0.5–1 mg/kg/day (typically 40–60 mg) in 1–2 doses for 3–10 days. Severe exacerbations requiring hospitalization typically require 1 mg/kg of prednisone or methylprednisolone every 6–12 hours for 48 hours or until the FEV1 (or PEF rate) returns to 50% of predicted (or 50% of baseline). The dose is then decreased to 0.5 mg/kg/day until the PEF reaches 70% of predicted or personal best. No clear advantage has been found for higher doses of corticosteroids. It may be prudent to administer corticosteroids intravenously to critically ill patients to avoid concerns about altered gastrointestinal absorption.
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In patients with refractory, poorly controlled asthma, systemic corticosteroids may be required for the long-term suppression of symptoms. Repeated efforts should be made to reduce the dose to the minimum needed to control symptoms. Alternate-day treatment is preferred to daily treatment. Concurrent treatment with calcium supplements and vitamin D should be initiated to prevent corticosteroid-induced bone mineral loss with long-term administration. Bone mineral density testing after 3 or more months of cumulative systemic corticosteroid exposure can guide the use of bisphosphonates for treatment of steroid-induced osteoporosis. Rapid discontinuation of systemic corticosteroids after long-term use may precipitate adrenal insufficiency.
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Anticholinergic agents reverse vagally mediated bronchospasm but not allergen- or exercise-induced bronchospasm. They may decrease mucous gland hypersecretion. Both short-acting muscarinic agents (SAMAs) and long-acting muscarinic agents (LAMAs) are available. Ipratropium bromide, a SAMA, is less effective than SABA for relief of acute bronchospasm, but it is the inhaled drug of choice for patients with intolerance to SABA or with bronchospasm due to beta-blocker medications. Ipratropium bromide reduces the rate of hospital admissions when added to inhaled SABAs in patients with moderate to severe asthma exacerbations. Although LAMAs have long been the cornerstone of therapy for COPD, their role in asthma continues to evolve. Studies have shown that the addition of tiotropium to medium-dose inhaled corticosteroid and salmeterol improves lung function and reduces the frequency of asthma exacerbations.
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5. Leukotriene modifiers
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Leukotrienes are potent mediators that contribute to airway obstruction and asthma symptoms by contracting airway smooth muscle, increasing vascular permeability and mucous secretion, and attracting and activating airway inflammatory cells. Zileuton is a 5-lipoxygenase inhibitor that decreases leukotriene production, and zafirlukast and montelukast are cysteinyl leukotriene receptor antagonists. In randomized controlled trials (RCTs), these agents caused modest improvements in lung function and reductions in asthma symptoms and lessened the need for SABA rescue therapy. These agents are less effective than inhaled corticosteroid for exacerbation reduction but may be considered as alternatives in patients with asthma who are unable to take inhaled corticosteroid or have undesirable side effects.
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6. Phosphodiesterase inhibitor
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Theophylline provides mild bronchodilation in asthmatic patients. It also has anti-inflammatory and immunomodulatory properties, enhances mucociliary clearance, and strengthens diaphragmatic contractility. Sustained-release theophylline preparations are effective in controlling nocturnal symptoms and as added therapy in patients with moderate or severe persistent asthma whose symptoms are inadequately controlled by inhaled corticosteroids. Low-dose sustained-release theophylline is included as a less effective option in Step 3 treatment. Neither theophylline nor aminophylline is recommended for therapy of acute asthma exacerbations.
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Theophylline has a notably narrow therapeutic-toxic range. At therapeutic doses, potential adverse effects include insomnia, aggravation of dyspepsia and gastroesophageal reflux, and urination difficulties in men with prostatic hyperplasia. Dose-related toxicities include nausea, vomiting, tachyarrhythmias, headache, seizures, hyperglycemia, and hypokalemia. Theophylline serum levels are highly variable due to many factors that alter drug absorption, significant individual differences in metabolism, and multiple drug-drug interactions. Therefore, serum concentrations need to be monitored closely.
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Theophylline and its intravenous formulation, aminophylline, are not recommended for therapy of asthma exacerbations. Aminophylline has clearly been shown to be less effective than SABAs when used as single-drug therapy for acute asthma; it adds little except toxicity to the acute bronchodilator effects achieved by nebulized metaproterenol alone. Patients with exacerbations who are currently taking theophylline should have its serum concentration measured to exclude theophylline toxicity.
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7. Mediator inhibitors
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Cromolyn sodium and nedocromil are long-term control medications that prevent asthma symptoms and improve airway function in patients with mild persistent or exercise-induced asthma. These agents modulate mast cell mediator release and eosinophil recruitment and inhibit both early and late asthmatic responses to allergen challenge and exercise-induced bronchospasm. The clinical response to these agents is less predictable than to inhaled corticosteroids. Both agents have excellent safety profiles.
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8. Monoclonal antibody agents
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Asthmatic patients who require monoclonal antibody therapies should be evaluated by either a pulmonologist or allergist experienced in their use. Omalizumab is a recombinant antibody that binds IgE without activating mast cells. In clinical trials in patients with moderate to severe asthma and elevated serum IgE levels, omalizumab reduced the need for corticosteroids. Reslizumab, mepolizumab, and benralizumab are interleukin-5 antagonist monoclonal antibodies (anti IL-5/5R) approved for the treatment of severe asthma with peripheral blood eosinophilia that has not responded to standard treatments. Dupilumab is a self-administered monoclonal antibody (anti-IL-4R) that inhibits overactive signalling of interleukin-4 and interleukin-13.
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Immunotherapy for specific allergens may be considered in selected asthma patients who have exacerbations when exposed to allergens to which they are sensitive and when unresponsive to environmental control measures or other therapies. Studies show a reduction in asthma symptoms in patients treated with single-allergen immunotherapy. Because of the risk of immunotherapy-induced bronchoconstriction, it should be administered only in a setting where such complications can be immediately treated.
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Adult patients aged 19–64 with asthma should receive the 23-valent pneumococcal polysaccharide vaccine (Pneumovax 23) and annual influenza vaccinations. Inactive vaccines (Pneumovax) are associated with few side effects. However, the use of the intranasal live attenuated influenza vaccine may be associated with asthma exacerbations in young children.