Sections

Asthma

Medication

Medication Summary

Asthma medications are generally divided into two categories:

Quick relief (also called reliever medications)
Long-term control (also called controller medications)

Quick relief

Quick relief medications are used to relieve acute asthma exacerbations and to prevent exercise-induced bronchoconstriction (EIB) symptoms. These medications include short-acting beta agonists (SABAs), anticholinergics (used only for severe exacerbations), and systemic corticosteroids, which speed recovery from acute exacerbations.

Long-term control

Long-term control medications include inhaled corticosteroids (ICSs),^{[99, 100]} long-acting beta agonists (LABAs), long-acting anticholinergics, combination inhaled corticosteroids and long-acting beta agonists, methylxanthines, and leukotriene receptor antagonists. Inhaled corticosteroids are considered the primary drug of choice for control of chronic asthma, but unfortunately the response to this treatment is characterized by wide variability among patients. A study by Tantisira et al showed the glucocorticoid-induced transcript 1 gene (GLCCI1) to be the cause of this decrease in response.^[113]

In a study by Peters et al, the use of the anticholinergic agent tiotropium in 210 asthmatic patients resulted in a superior outcome compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow and other secondary outcomes. The addition of tiotropium in this study was also shown to be noninferior to the addition of salmeterol.^[114]

Kerstjens et al evaluated 912 patients already taking an ICS/LABA combination who were randomized to 48 weeks of tiotropium versus placebo in two replicate, randomized, controlled trials. The patients had a mean baseline FEV₁ of 62% of the predicted value. The use of tiotropium compared to placebo increased the time to first exacerbation (282 versus 226 days) and resulted in a higher peak change in FEV₁ from baseline of 86 ± 34 mL (Trial 1) and 154 ± 32 mL (Trial 2) for those patients taking tiotropium.^[115]

In a cross-sectional population-level comparison study of asthmatics from 1997-1998 and 2004-2005, researchers evaluated controller-to-total asthma medication ratio (greater than 0.5) with asthma exacerbation rates (dispensing of systemic corticosteroid or emergency department visit/hospitalization for asthma). They were able to demonstrate an increased use of asthma controllers based on a 16% increase in controller-to-total asthma medication ratio. However, there was no change in annual asthma exacerbation rates (0.27/year to 0.23/year) despite this improvement in controller use.^[116]

Two systematic reviews indicate that the regular use of ICSs for the treatment of pediatric asthma may suppress linear growth in the first year of treatment, but lower ICS doses may minimize such effects.^{[1, 2, 117]}The investigators of both reviews also noted that head-to-head comparison trials are needed to assess the effects of different ICSs, ICS doses, inhalation devices, and patient ages on growth suppression over time.

Class Summary

Beta₂ agonists relieve reversible bronchospasm by relaxing the smooth muscles of the bronchi. These agents act as bronchodilators and are used to treat bronchospasm in acute asthmatic episodes and to prevent bronchospasm associated with exercise-induced asthma or nocturnal asthma.

In December 2018, the US Food and Drug Administration (FDA) approved the ProAir Digihaler (albuterol), the first digital and mobile-connected inhaler. The built-in sensors detect when the device is used and measure the strength of the user’s inhalation. The inhaler sends the user’s data to its mobile app companion and their healthcare provider.

Albuterol sulfate (Proventil HFA, Ventolin HFA, ProAir HFA, ProAir RespiClick, ProAir Digihaler)

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This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for nebulization, metered-dose inhaler, oral solution). This is most commonly used in rescue therapy for acute asthmatic symptoms and is used as needed. Prolonged use may be associated with tachyphylaxis due to beta2-receptor down-regulation and receptor hyposensitivity.

Levalbuterol (Xopenex, Xopenex HFA)

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A nonracemic form of albuterol, levalbuterol (R isomer), is effective in smaller doses and is reported to have fewer adverse effects (eg, tachycardia, hyperglycemia, hypokalemia). The dose may be doubled in acute severe episodes when even a slight increase in the bronchodilator response may make a big difference in the management strategy (eg, in avoiding patient ventilation).

Class Summary

The long-acting anticholinergic agent, tiotropium, may be considered for long-term maintenance therapy, but not for acute treatment of asthma exacerbations.

Tiotropium (Spiriva HandiHaler, Spiriva Respimat)

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Tiotropium is a long-acting antimuscarinic agent, often referred to as an anticholinergic. It inhibits M₃-receptors at smooth muscle, leading to bronchodilation. It is indicated for long-term, once-daily, maintenance treatment of asthma in patients aged 6 years or older.

Ipratropium (Atrovent HFA)

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Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. It is approved for COPD, but off-label use for acute exacerbations of asthma in addition to beta2-agonist therapy has been described in the literature. It is a short-acting anticholinergic agent with an onset of 15 minutes.

Class Summary

Combination agents with ipratropium and albuterol. A test spray of 3 sprays is recommended before using this combination for the first time and when the aerosol has not be used for more than 24 hours. Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Albuterol is beta-agonist for bronchospasm refractory to epinephrine. It relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility.

Ipratropium and albuterol (Combivent Respimat)

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Ipratropium is chemically related to atropine. It has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Albuterol is beta-agonist for bronchospasm refractory to epinephrine. It relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility.

Class Summary

Oral steroids are used for short courses (3-10 d) to gain prompt control of inadequately controlled acute asthmatic episodes. They are also used for long-term prevention of symptoms in severe persistent asthma as well as for suppression, control, and reversal of inflammation. Frequent and repetitive use of beta₂ agonists has been associated with beta₂ -receptor subsensitivity and down-regulation; these processes are reversed with corticosteroids.

Prednisone (Deltasone, Rayos)

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Prednisone is an immunosuppressant for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.

Methylprednisolone (Solu-Medrol, Medrol, Depo-Medrol)

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Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.

Prednisolone (Pediapred, Millipred, Orapred ODT)

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This glucosteroid occurs naturally and synthetically. It is used for both acute and chronic asthma. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity.

Class Summary

Long-acting bronchodilators are not used for the treatment of acute bronchospasm. In combination with corticosteroids, they are used for the preventive treatment of asthma symptoms.

Salmeterol (Serevent Diskus)

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Salmeterol can relieve bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis. The effect also may facilitate expectoration. Adverse effects are more likely when salmeterol is administered at high doses or more frequent doses than recommended. It is to be used with inhaled corticosteroids and not as monotherapy.

Formoterol (Perforomist)

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Formoterol is a long acting beta2 agonist. By relaxing the smooth muscles of bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, formoterol can relieve bronchospasms. The effects may also facilitate expectoration. It has been shown to improve symptoms and morning peak flows. Adverse effects are more likely when formoterol is administered at high doses or more frequent doses than recommended. To be used with inhaled corticosteroids and not as monothrapy.

Class Summary

These combinations may decrease asthma exacerbations when inhaled short-acting beta₂ agonists and corticosteroids have failed.

Budesonide/formoterol (Symbicort)

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Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma. Budesonide is an inhaled corticosteroid that alters the level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators involved in the asthmatic response.

Mometasone and formoterol (Dulera)

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Combination corticosteroid and long-acting selective beta-2 agonist (LABA) metered-dose inhaler. Mometasone elicits local anti-inflammatory effects to respiratory tract with minimal systemic absorption. Formoterol elicits bronchial smooth muscle relaxation. Indicated for prevention and maintenance of asthma symptoms in patients inadequately controlled with other asthma controller medications (eg, low- to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including a LABA. Available in 3 strengths; each actuation delivers mometasone/formoterol 50 mcg/5 mcg, 100 mcg/5 mcg, or 200 mcg/5 mcg.

Salmeterol/fluticasone inhaled (Advair Diskus, Advair HFA, AirDuo RespiClick)

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Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease the number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It also has vasoconstrictive activity. Salmeterol relaxes the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, and can relieve bronchospasms. Its effects may also facilitate expectoration. Adverse effects are more likely to occur when the agent is administered at high or more frequent doses than recommended.

Vilanterol/fluticasone furoate inhaled (Breo Ellipta)

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Indicated for once-daily treatment of asthma for adults not adequately controlled on a long-term asthma control medication (eg, inhaled corticosteroid), or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and a long-acting beta agonist (LABA). Use prescribed strength (25 mcg/100 mcg or 25 mcg/200 mcg per actuation) once daily via oral inhalation. Fluticasone furoate is a corticosteroid with anti-inflammatory activity. Vilanterol is a long-acting beta agonist (LABA) that stimulates intracellular adenyl cyclase (catalyzes the conversion of ATP to cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Albuterol/budesonide inhaled (Airsupra)

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Fixed dose inhaler indicated for as-needed treatment or prevention of bronchoconstriction and for prevention of exacerbations in adults with asthma. It is the first combination of an inhaled corticosteroid (ICS) and a short-acting beta-agonist to be approved in the U.S. Additionally, it is the first product containing an ICS to be approved in the U.S. as a reliever treatment (rather than as a controller) for asthma.

Class Summary

These agents are used for long-term control and prevention of symptoms, especially nocturnal symptoms.

Theophylline (Theo-24, Theochron, Ellixophyllin)

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Theophylline is available in short- and long-acting formulations. Because of the need to monitor the drug levels, this agent is used infrequently. The dose and frequency of administration depend on the particular product selected.

Class Summary

These agents (cromolyn sodium) block early and late asthmatic responses, interfere with chloride channels, stabilize the mast cell membrane, and inhibit the activation and release of mediators from eosinophils and epithelial cells. They inhibit acute responses to cold air, exercise, and sulfur dioxide.

Cromolyn sodium

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Cromolyn sodium (oral inhalation) inhibits the release of histamine, leukotrienes, and other mediators from sensitized mast cells exposed to specific antigens. It has no intrinsic anti-inflammatory, antihistamine, or vasoconstrictive effects.

Class Summary

Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active, poorly absorbed, and least likely to cause adverse effects.

Ciclesonide (Alvesco)

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Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients aged 12 years and older. It is not indicated for relief of acute bronchospasm. Corticosteroids have a wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (eg, histamines, eicosanoids, leukotrienes, cytokines) involved in inflammation.

Beclomethasone (QVAR Redihaler)

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This agent inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation; and may decrease the number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness.

Fluticasone inhaled (Flovent Diskus, Flovent HFA, ArmonAir RespiClick, Arnuity Ellipta)

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Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak HPA-axis inhibitory potency when applied topically. It is available as a metered-dose inhaler aerosolized product (HFA) or DPI (Diskus).

Budesonide inhaled (Pulmicort, Pulmicort Flexhaler)

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Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak HPA-axis inhibitory potency when applied topically.

Mometasone (Asmanex Twisthaler, Asmanex HFA)

Mometasone is a corticosteroid for oral inhalation. It is indicated for asthma as prophylactic therapy.

Class Summary

Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal edema, and inflammatory cell infiltration leads to the concept of modifying their action by using pharmacologic agents.

Zafirlukast (Accolate)

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Zafirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors.

Montelukast (Singulair)

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Montelukast is the last agent introduced in its class. The advantages are that it is chewable, it has a once-a-day dosing, and it has no significant adverse effects.

Class Summary

Monoclonal antibody effects vary depending on their receptor target. Omalizumab binds to IgE on the surface of mast cells and basophils. It reduces the release of these mediators that promote an allergic response. Mepolizumab, reslizumab, and benralizumab inhibit IL-5 binding to eosinophils and result in reduced blood, tissue, and sputum eosinophil levels. Dupilumab inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. Tezepelumab targets TSLP, a key epithelial cytokine.

Omalizumab (Xolair)

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Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE on the surface of mast cells and basophils. It reduces mediator release, which promotes an allergic response. It is indicated for moderate-to-severe persistent asthma in patients aged 6 years or older who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.

Mepolizumab (Nucala)

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Mepolizumab is a humanized IgG1 kappa monoclonal antibody specific for IL-5. Mepolizumab binds to IL-5 and therefore stops IL-5 from binding to its receptor on the surface of eosinophils. It is indicated for add-on maintenance treatment of patients with severe asthma aged 12 years or older and with an eosinophilic phenotype.

Reslizumab (Cinqair)

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Reslizumab is an IL-5 antagonist monoclonal antibody (IgG kappa). It is indicated for add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype.

Benralizumab (Fasenra)

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Benralizumab is a humanized monoclonal antibody (IgG1/kappa-class) selective for the IL-5 alpha subunit of basophils and eosinophils. It is indicated for add-on maintenance treatment of severe asthma in patients aged 12 years or older who have an eosinophilic phenotype.

Dupilumab (Dupixent)

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Dupilumab inhibits IL-4 receptor alpha, and thereby blocks IL-4 and IL-13 signaling. This, in turn, reduces the cytokine-induced inflammatory response. It is indicated as an add-on maintenance treatment for moderate-to-severe asthma in patients aged 12 years or older with eosinophilic phenotype or oral corticosteroid–dependent asthma.

Tezepelumab (Tezspire)

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Human monoclonal antibody immunoglobulin G2-lambda that inhibits thymic stromal lymphopoietin (TSLP), a key epithelial cytokine involved in multiple inflammatory cascades and initiates an over reactive immune response to allergic, eosinophilic, and other types of airway inflammation associated with severe asthma. Tezepelumab is indicated as add-on maintenance treatment for severe asthma in adults and adolescents aged 12 years and older.

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Media Gallery

Pathogenesis of asthma. Antigen presentation by the dendritic cell with the lymphocyte and cytokine response leading to airway inflammation and asthma symptoms.
Asthma symptoms and severity. Recommended guidelines for determination of asthma severity based on clinical symptoms, exacerbations, and measurements of airway function. Adapted from Global Strategy for Asthma Management and Prevention: 2002 Workshop Report.
Stepwise approach to pharmacological management of asthma based on asthma severity. Adapted from Global Strategy for Asthma Management and Prevention: 2002 Workshop Report.
Asthma. High-resolution CT scan of the thorax obtained during inspiration in a patient with recurrent left lower lobe pneumonia shows a bronchial mucoepidermoid carcinoma (arrow).
Asthma. High-resolution CT scan of the thorax obtained during expiration in a patient with recurrent left lower lobe pneumonia shows a bronchial mucoepidermoid carcinoma. Note the normal increase in right lung attenuation during expiration (right arrow). The left lung remains lucent, especially the upper lobe, secondary to bronchial obstruction with airtrapping (left upper arrow). The vasculature on the left is diminutive, secondary to reflex vasoconstriction. Left pleural thickening and abnormal linear opacities are noted in the left lower lobe; these are the result of prior episodes of postobstructive pneumonia (left lower arrow).
High-resolution CT scan of the thorax obtained during inspiration demonstrates airtrapping in a patient with asthma. Inspiratory findings are normal.
High-resolution CT scan of the thorax obtained during expiration demonstrates a mosaic pattern of lung attenuation in a patient with asthma. Lucent areas (arrows) represent areas of airtrapping (same patient as in the previous image).
Posteroanterior chest radiograph demonstrates a pneumomediastinum in bronchial asthma. Mediastinal air is noted adjacent to the anteroposterior window and airtrapping extends to the neck, especially on the right side.
Lateral chest radiograph demonstrates a pneumomediastinum in bronchial asthma. Air is noted anterior to the trachea (same patient as in the previous image).
Asthma. High-resolution CT scan of the thorax obtained during inspiration in a patient with recurrent left lower lobe pneumonia shows a bronchial mucoepidermoid carcinoma (arrow).
Asthma. High-resolution CT scan of the thorax obtained during expiration in a patient with recurrent left lower lobe pneumonia shows a bronchial mucoepidermoid carcinoma (same patient as in the previous image). Note the normal increase in right lung attenuation during expiration (right arrow). The left lung remains lucent, especially the upper lobe, secondary to bronchial obstruction with airtrapping (left upper arrow). The vasculature on the left is diminutive, secondary to reflex vasoconstriction. Left pleural thickening and abnormal linear opacities are noted in the left lower lobe; these are the result of prior episodes of postobstructive pneumonia (left lower arrow).
Asthma. High-resolution CT scan of the thorax demonstrates mild bronchial thickening and dilatation in a patient with bilateral lung transplants and bronchial asthma.
Asthma. High-resolution CT scan of the thorax demonstrates central bronchiectasis, a hallmark of allergic bronchopulmonary aspergillosis (right arrow), and the peripheral tree-in-bud appearance of centrilobular opacities (left arrow), which represent mucoid impaction of the small bronchioles.
Asthma is characterized by chronic inflammation and asthma exacerbations, where an environmental trigger initiates inflammation, which makes it difficult to breathe. This video covers the pathophysiology of asthma, signs and symptoms, types, and treatment.

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Author

Michael J Morris, MD, FACP, FCCP Clinical Faculty, Pulmonary Disease/Critical Care Service, Department of Medicine, Brooke Army Medical Center; Assistant Dean for Research, SAUSHEC, Brooke Army Medical Center; Clinical Professor, niversity of Texas Health Science Center at San Antonio, Joe R and Teresa Lozano Long School of Medicine; Professor, Uniformed Services University of the Health Sciences

Michael J Morris, MD, FACP, FCCP is a member of the following medical societies: American Association for Respiratory Care, American College of Chest Physicians, American College of Physicians, The Society of Federal Health Professionals (AMSUS)

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Janssen Pharmaceuticals.

Coauthor(s)

Daniel J Pearson, MD, FCCP ICU Medical Director, Respiratory Therapy Medical Director, Soin Medical Center

Daniel J Pearson, MD, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Zab Mosenifar, MD, FACP, FCCP is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Thoracic Society

Disclosure: Nothing to disclose.

Acknowledgements

Edward Bessman, MD, MBA Chairman and Clinical Director, Department of Emergency Medicine, John Hopkins Bayview Medical Center; Assistant Professor, Department of Emergency Medicine, Johns Hopkins University School of Medicine

Edward Bessman, MD, MBA is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine