Medication Summary
Pharmacologic management includes the use of control agents such as inhaled corticosteroids, inhaled cromolyn or nedocromil, long-acting bronchodilators, theophylline, leukotriene modifiers, and more recent strategies such as the use of anti-immunoglobulin E (IgE) antibodies (omalizumab). Relief medications include short-acting bronchodilators, systemic corticosteroids, and ipratropium
Bronchodilators, Beta2-Agonists
Class Summary
These agents are used to treat bronchospasm in acute asthmatic episodes, and used to prevent bronchospasm associated with exercise-induced asthma or nocturnal asthma. Several studies have suggested that short-acting beta2-agonists such as albuterol may produce adverse outcomes (eg, decreased peak flow or increased risk of exacerbations) in patients homozygous for arginine (Arg/Arg) at the 16th amino acid position of beta-adrenergic receptor gene compared with patients homozygous for glycine (Gly-Gly). Similar findings are reported for long-acting beta2-agonists, such as salmeterol.
Albuterol sulfate (Proventil HFA, Ventolin HFA, ProAir HFA)
This beta2-agonist is the most commonly used bronchodilator that is available in multiple forms (eg, solution for nebulization, MDI, PO solution). This is most commonly used in rescue therapy for acute asthmatic symptoms. Used as needed. Prolonged use may be associated with tachyphylaxis due to beta2-receptor downregulation and receptor hyposensitivity.
Pirbuterol (Maxair Autohaler)
Pirbuterol is available as a breath-actuated or ordinary inhaler. The ease of administration with the breath-actuated device makes it an attractive choice in the treatment of acute symptoms in younger children who otherwise cannot use an MDI. The Autohaler delivers 200 mcg per actuation.
Nonracemic Form of the Beta2-Agonist Albuterol
Class Summary
This nonracemic form of albuterol offers a significant reduction in the adverse effects associated with racemic albuterol (eg, muscle tremors, tachycardia, hyperglycemia, hypokalemia).
Levalbuterol (Xopenex)
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). It is available as an MDI (45 mcg per actuation) or solution for nebulized inhalation.
Long-Acting Beta2-Agonists
Class Summary
Long-acting bronchodilators (LABA) are not used for the treatment of acute bronchospasm. They are used for the preventive treatment of nocturnal asthma or exercise-induced asthmatic symptoms, for example.
Currently, 2 LABA are available in the United States: salmeterol (Serevent) and formoterol (Foradil). Salmeterol and formoterol are available as combination products with inhaled corticosteroids in the United States (Advair, Symbicort, Dulera).
LABA may increase the chance of severe asthma episodes and death when those episodes occur. Most cases have occurred in patients with severe and/or acutely deteriorating asthma; they have also occurred in a few patients with less severe asthma.
LABAs are not considered first-line medications to treat asthma. LABAs should not be used as isolated medications and should be added to the asthma treatment plan only if other medicines do not control asthma, including the use of low- or medium-dose corticosteroids. If used as isolated medication, LABAs should be prescribed by a subspecialist (ie, pulmonologist, allergist).
Salmeterol (Serevent Diskus)
This long-acting preparation of a beta2-agonist is used primarily to treat nocturnal or exercise-induced symptoms. It has no anti-inflammatory action and is not indicated in the treatment of acute bronchospastic episodes. It may be used as an adjunct to inhaled corticosteroids to reduce the potential adverse effects of the steroids. The medication is delivered via a Diskus DPI.
Formoterol (Foradil Aerolizer)
Formoterol relieves bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma.
Methylxanthines
Class Summary
These agents are used for long-term control and prevention of symptoms, especially nocturnal symptoms.
Theophylline (Theo-24, Theochron, Uniphyl)
Theophylline is available in short-acting and long-acting formulations. Because of the need to monitor serum concentrations, this agent is used infrequently. The dose and frequency depend on the particular product selected.
Inhaled Corticosteroids
Class Summary
Steroids are the most potent anti-inflammatory agents. Inhaled forms are topically active, poorly absorbed, and least likely to cause adverse effects. They are used for long-term control of symptoms and for the suppression, control, and reversal of inflammation. Inhaled forms reduce the need for systemic corticosteroids.
Inhaled steroids block late asthmatic response to allergens; reduce airway hyperresponsiveness; inhibit cytokine production, adhesion protein activation, and inflammatory cell migration and activation; and reverse beta2-receptor downregulation and subsensitivity (in acute asthmatic episodes with LABA use).
Ciclesonide (Alvesco)
Ciclesonide is an aerosol inhaled corticosteroid indicated for maintenance treatment of asthma as prophylactic therapy in adult and adolescent patients aged 12 y and older. Not indicated for relief of acute bronchospasm.
Corticosteroids have 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.
Individual patients experience variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 4 wk or longer after initiation of therapy.
After asthma stability is achieved, it is best to titrate to lowest effective dosage to reduce the possibility of adverse effects. For patients who do not adequately respond to the starting dose after 4 wk of therapy, higher doses may provide additional asthma control.
Beclomethasone (QVAR)
Beclomethasone inhibits bronchoconstriction mechanisms; causes direct smooth muscle relaxation; and may decrease the number and activity of inflammatory cells, which, in turn, decreases airway hyperresponsiveness. It is available as 40 mcg/actuation or 80 mcg/actuation.
Fluticasone (Flovent Diskus, Flovent HFA)
Fluticasone has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as an MDI aerosolized product (HFA) or DPI (Diskus).
Budesonide inhaled (Pulmicort Flexhaler or Respules)
Budesonide has extremely potent vasoconstrictive and anti-inflammatory activity. It has a weak hypothalamic-pituitary adrenocortical axis inhibitory potency when applied topically. It is available as a DPI in 90 mcg/actuation (delivers about 80 mcg/actuation) or 180 mcg/actuation (delivers about 160 mcg/actuation). A nebulized susp (ie, Respules) is also available for young children.
Mometasone furoate inhalation powder (Asmanex Twisthaler)
Mometasone is a corticosteroid for inhalation. It is indicated for asthma as prophylactic therapy.
Systemic Corticosteroids
Class Summary
These agents 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 downregulation; these processes are reversed with corticosteroids.
Higher-dose corticosteroids have no advantage in severe asthma exacerbations, and intravenous administration has no advantage over oral therapy, provided that GI transit time or absorption is not impaired. The usual regimen is to continue frequent multiple daily dosing until the FEV1 or peak expiratory flow (PEF) is 50% of the predicted or personal best values; then, the dose is changed to twice daily. This usually occurs within 48 hours.
Prednisone (Deltasone, Orasone) and prednisolone (Pediapred, Prelone, Orapred)
An immunosuppressant for the treatment of autoimmune disorders, prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity.
Methylprednisolone (Solu-Medrol)
Methylprednisolone may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Leukotriene Modifiers
Class Summary
Knowledge that leukotrienes cause bronchospasm, increased vascular permeability, mucosal edema, and inflammatory cell infiltration has led to the concept of modifying their action by using pharmacologic agents. These are either 5-lipoxygenase inhibitors or leukotriene-receptor antagonists.
Zafirlukast (Accolate)
Zafirlukast is a selective competitive inhibitor of LTD4 and LTE4 receptors.
Montelukast (Singulair)
The last agent introduced in its class, montelukast has the advantages that it is chewable, it has a once-a-day dosing, and it has no significant adverse effects.
Monoclonal Antibodies
Class Summary
These agents bind selectively to human IgE on the surface of mast cells and basophils.
Omalizumab (Xolair)
Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE on surface of mast cells and basophils. It reduces mediator release, which promotes allergic response. It is indicated for moderate-to-severe persistent asthma in patients who react to perennial allergens in whom symptoms are not controlled by inhaled corticosteroids.
Combination Inhaled Steroids/Long-Acting Beta2-Agonists
Class Summary
These combinations may decrease asthma exacerbations when inhaled short-acting beta2-agonists and corticosteroids have failed. Refer to previous discussion in the LABAs section regarding increased risk of severe asthma episodes and death with LABAs. In a recent study, use of combination therapy using fluticasone propionate and salmeterol prolonged time to first severe asthma exacerbation.[46]
Budesonide is an inhaled corticosteroid that alters level of inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing production of cytokines and other mediators involved in the asthmatic response. Available as MDI in 2 strengths; each actuation delivers formoterol 4.5 mcg with either 80 mcg or 160 mcg.
Budesonide/formoterol (Symbicort)
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 production of cytokines and other mediators involved in the asthmatic response. This combination is available as an MDI in 2 strengths; each actuation delivers formoterol 4.5-mcg with either 80-mcg or 160-mcg of budesonide.
Mometasone and formoterol (Dulera)
This is a combination corticosteroid and LABA metered-dose inhaler. Mometasone elicits local anti-inflammatory effects in the respiratory tract with minimal systemic absorption. Formoterol elicits bronchial smooth muscle relaxation.
This combination is indicated for prevention and maintenance of asthma symptoms in patients inadequately controlled with other asthma controller medications (eg, low-dose to medium-dose inhaled corticosteroids) or whose disease severity clearly warrants initiation of treatment with 2 maintenance therapies, including a LABA. Available in 2 strengths; each actuation delivers mometasone/formoterol 100 mcg/5 mcg or 200 mcg/5 mcg.
Fluticasone and salmeterol (Advair)
This is a combination corticosteroid and LABA metered-dose inhaler. Fluticasone inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, in turn decreasing airway hyper-responsiveness. 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 effect may also facilitate expectoration. Adverse effects are more likely to occur when administered at high or more frequent doses than recommended. Two delivery mechanisms are available (ie, powder for inhalation [Diskus], metered-dose inhaler [MDI]). Diskus is available as a combination of salmeterol 50 mcg with fluticasone 100 mcg, 250 mcg, or 500 mcg. The MDI is available as 21 mcg salmeterol with fluticasone 45 mcg, 115 mcg, or 230 mcg.
Anticholinergic Agents
Class Summary
These agents may be added to beta2-agonist therapy for treatment of acute exacerbations.
Ipratropium (Atrovent)
Chemically related to atropine, protropium has antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. The MDI delivers 17 mcg/actuation. Solution for inhalation contains 500 mcg/2.5 mL (ie, 0.02% solution for nebulization).
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| Intermittent Asthma | Persistent Asthma: Daily Medication | |||||
| Age | Step 1 | Step 2 | Step 3 | Step 4 | Step 5 | Step 6 |
| < 5 y | Rapid-acting beta2-agonist prn | Low-dose inhaled corticosteroid (ICS) | Medium-dose ICS | Medium-dose ICS plus either long-acting beta2-agonist (LABA) or montelukast | High-dose ICS plus either LABA or montelukast | High-dose ICS plus either LABA or montelukast; Oral systemic corticosteroid |
| Alternate regimen: cromolyn or montelukast | ||||||
| 5-11 y | Rapid-acting beta2-agonist prn | Low-dose ICS | Either low-dose ICS plus either LABA, LTRA, or theophylline OR Medium-dose | Medium-dose ICS plus LABA | High-dose ICS plus LABA | High-dose ICS plus LABA plus oral systemic corticosteroid |
| Alternate regimen: cromolyn, leukotriene receptor antagonist (LTRA), or theophylline | Alternate regimen: medium-dose ICS plus either LTRA or theophylline | Alternate regimen: high-dose ICS plus either LABA or theophylline | Alternate regimen: high-dose ICS plus LRTA or theophylline plus systemic corticosteroid | |||
| 12 y or older | Rapid-acting beta2-agonist as needed | Low-dose ICS | Low-dose ICS plus LABA OR Medium-dose ICS | Medium-dose ICS plus LABA | High-dose ICS plus LABA (and consider omalizumab for patients with allergies) | High-dose ICS plus either LABA plus oral corticosteroid (and consider omalizumab for patients with allergies) |
| Alternate regimen: cromolyn, LTRA, or theophylline | Alternate regimen: low-dose ICS plus either LTRA, theophylline, or zileuton | Alternate regimen: medium-dose ICS plus either LTRA, theophylline, or zileuton | ||||
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