Asthma medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Philip Marcus, M.D., M.P.H. [2]; Associate Editor(s)-in-Chief:

Overview

Specific therapies available for the management of asthma are broadly classified into three groups: relievers, preventers and emergency treatment. The Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2) of the U.S. National Asthma Education and Prevention Program, and the British Guideline on the Management of Asthma are the two current guidelines that followed in the management of asthma. Bronchodilators are recommended for short-term relief in all patients. For those who experience occasional attacks, no other medication is needed. For those with mild persistent disease (more than two attacks a week), low-dose inhaled glucocorticoids or alternatively, an oral leukotriene modifier, a mast-cell stabilizer, or theophylline may be administered. For those who suffer daily attacks, a higher dose of glucocorticoid in conjunction with a long-acting inhaled β-2 agonist may be prescribed; alternatively, a leukotriene modifier or theophylline may substitute for the β-2 agonist. In severe asthmatics, oral glucocorticoids may be added to these treatments during severe attacks. For those in whom exercise can trigger an asthma attack (exercise-induced asthma), higher levels of ventilation and cold, dry air tend to exacerbate attacks.

Medical Therapy

Quick Relief Medication

There is no cure for asthma; however, medications could help to prevent future attacks and relieve associated symptoms such as, tightness of the chest and troubled breathing. The specific medical treatment recommended depends on the severity and the frequency of exacerbations.

• Symptomatic control of episodes of wheezing and shortness of breath is generally achieved with fast-acting bronchodilators (LABA).
• There is no clear evidence, however, that they are more effective than inhalers used with a spacer.

  

  A typical inhaler, of Serevent (salmeterol), a long-acting bronchodilator.

• LABA are typically provided in pocket-sized, metered-dose inhalers (MDIs).
• In young sufferers, who may have difficulty with the coordination necessary to use inhalers, or those with a poor ability to hold their breath for 10 seconds after inhaler use (generally the elderly), an asthma spacer is used. The spacer is a plastic cylinder that mixes the medication with air in a simple tube, making it easier for patients to receive a full dose of the drug and allows for the active agent to be dispersed into smaller, more fully inhaled bits.
• A nebulizer which provides a larger, continuous dose can also be used. Nebulizers work by vaporizing a dose of medication in a saline solution into a steady stream of foggy vapor, which the patient inhales continuously until the full dosage is administered. Nebulizers may be helpful to some patients experiencing a severe attack. Such patients may not be able to inhale deeply, so regular inhalers may not deliver medication deeply into the lungs, even on repeated attempts. Since a nebulizer delivers the medication continuously, it is thought that the first few inhalations may relax the airways enough to allow the following inhalations to draw in more medication.

Relievers:

• Short-acting selective beta₂-adrenoceptor agonists, such as salbutamol (albuterol USAN), levalbuterol, terbutaline and bitolterol. Tremors, the major side effect, have been greatly reduced by inhaled delivery, which allows the drug to target the lungs specifically; oral and injected medications are delivered throughout the body. There may also be cardiac side effects at higher doses (due to Beta-1 agonist activity), such as elevated heart rate or blood pressure; with the advent of selective agents, these side effects have become less common. Patients must be cautioned against using these medicines too frequently, as with such use their efficacy may decline, producing desensitization resulting in an exacerbation of symptoms which may lead to refractory asthma and death.
• Older, less selective adrenergic agonists, such as inhaled epinephrine and ephedrine tablets, have also been used. Cardiac side effects occur with these agents at either similar or lesser rates to albuterol. When used solely as a relief medication, inhaled epinephrine has been shown to be an effective agent to terminate an acute asthmatic exacerbation. In emergencies, these drugs were sometimes administered by injection. Their use via injection has declined due to related adverse effects.

• Anticholinergic medications, such as ipratropium bromide may be used instead. They have no cardiac side effects and thus can be used in patients with heart disease; however, they take up to an hour to achieve their full effect and are not as powerful as the β₂-adrenoreceptor agonists.

• Inhaled glucocorticoids are usually considered preventive medications; however, a randomized controlled trial has demonstrated the benefit of 250 microg beclomethasone when taken as an as-needed combination inhaler with 100 microg of albuterol.

Long-term Control Medications

Long-acting bronchodilators (LABA) are similar in structure to short-acting selective beta₂-adrenoceptor agonists, but have much longer side chains resulting in a 12-hour effect, and are used to give a smoothed symptomatic relief (used morning and night). While patients report improved symptom control, these drugs do not replace the need for routine preventers, and their slow onset means the short-acting dilators may still be required.

• Currently available long-acting beta₂-adrenoceptor agonists include salmeterol, formoterol, bambuterol, and sustained-release oral albuterol. Combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread; the most common combination currently in use is fluticasone/ salmeterol (Advair in the United States, and Seretide in the United Kingdom). Another combination is budesonide/formoterol which is commercially known as symbicort.

• In November of 2005, the American FDA released a health advisory alerting the public to findings that show the use of long-acting β₂-agonists could lead to a worsening of symptoms, and in some cases death.

• A recent meta-analysis of the roles of long-acting beta- agonists may indicate a danger to asthmatics. "These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms," said Shelley Salpeter in a Cornell study. The study goes on to say that "Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five US asthma-related deaths per year and should be taken off the market". This assertion has drawn criticism from many asthma specialists for being inaccurate. As Dr. Hal Nelson points out in a recent letter to the Annals of Internal Medicine, Salpeter and colleagues also assert that salmeterol may be responsible for 4000 of the 5000 asthma-related deaths that occur in the United States annually. However, when salmeterol was introduced in 1994, more than 5000 asthma-related deaths occurred per year. Since the peak of asthma deaths in 1996, salmeterol sales have increased about 5-fold, while overall asthma mortality rates have decreased by about 25%, despite a continued increase in asthma diagnoses. In fact, according to the most recent data from the National Center for Health Statistics, U.S. asthma mortality rates peaked in 1996 (with 5667 deaths) and have decreased steadily since. The last available data, from 2004, indicate that 3780 deaths occurred. Thus, the suggestion that a vast majority of asthma deaths could be attributable to LABA use is inconsistent with the facts. Dr. Salpeter has since tempered her comments regarding LABAs.

Glucocorticoids, either inhaled or oral, may help with does up to fluticaonse equivalent of 1600 to 2000 mcg per day.

Macolide antibiotics such as azithromycin and clarithromycin may reduce exacerbations.

Biologic therapy

Many monoclonal antibodies have been investigated and reviewed.

Anti-IgE therapy such as omalizumab may help.

Monoclonal antibodies against type 2 helper T (Th2) cytokines (interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13)) or their receptors may help eosinophilic asthma:

• IL-5 or its receptor blockers include mepolizumab, reslizumab, or benralizumab. These drugs may reduce exacerbations of asthma by half in patients with eosinophilic asthma.
  • The large ZONDA trial of benralizumab reported benefit
  • A more recent trial of benralizumab was terminated early
• Dupilumab is active against IL-4 and IL-13
• Tralokinumab is active against IL-13 but may not be effective at reducing exacerbations of asthma.

Monoclonal antibodies against thymic stromal lymphopoietin (TSLP) may be effective:

• Tezepelumab

Therapeutic Regimens

Mild Intermittent Asthma

Step 1 Therapy:

• Preferred treatment:
  • Short-acting inhaled β2-agonist PRN

Mild Persistent Asthma

Step 2 Therapy:

• Preferred treatment:
  • Low-dose inhaled corticosteroid combined with a short-acting inhaled β2-agonist PRN
• Alternative therapies include:
  • Either cromolyn or nedocromil, or Theophylline, or montelukast, or zafirlukast combined with a short-acting inhaled β2-agonist PRN

Moderate Persistent Asthma

Step 3 Therapy:

• Preferred treatment:

• Medium-dose inhaled corticosteroid combined with a short-acting inhaled β2-agonists PRN, OR
• Low-dose inhaled corticosteroid along with either inhaled long-acting β2-agonists or sustained-release theophylline for nocturnal symptoms combined with a short-acting inhaled β2-agonists PRN

• Alternative therapies include:
  • Low-dose of inhaled steroid combined with long-acting bronchodilators (either inhaled long-acting β2-agonists or sustained-release theophylline) combined with a short-acting inhaled β2-agonists PRN

Severe Persistent Asthma

Step 4 Therapy:

• Preferred treatment:
  • Medium-dose inhaled corticosteroid combined with inhaled long-acting β2-agonists
• Alternative therapies include:
  • Medium-dose inhaled corticosteroid combined with long-acting bronchodilators (such as inhaled β2-agonists or sustained-release theophylline used alone or in combination) combined with a short-acting inhaled β2-agonists PRN

Step 5 Therapy:

• Preferred treatment:
  • High-dose inhaled corticosteroid combined with inhaled long-acting β2-agonists and omalizumab in patients who have allergies

Step 6 Therapy:

• Preferred treatment:
  • High-dose inhaled corticosteroid combined with oral corticosteroids, inhaled long-acting β2-agonists, and omalizumab in patients who have allergies

Guidelines for Diagnosis and Management of Asthma Based On The National Heart, Blood, and Lung Institute Expert Panel Report 3 (EPR3)

Severity Components	Intermittent	Persistent Asthma
		Mild	Moderate	Severe
Symptoms	Less than 1 day/week	More than 2 days/week Not daily	Daily	Daily Throughout the day
Nocturnal Symptoms	Less than 2 times/month	3 to 4 times/month	More than 1 time/week Not every night	Every night
Interference w/ Activity	Minimal to none	Minor limitation of activity	Some limitation of activity	Severe limitation of activity
Short-Acting Beta-Agonist Use	Less than 2 days/week	More than 2 days/week but not daily Not more than once/day	Daily	Several times/day
Pulmonary Function Test	Normal FEV1 between exacerbations FEV1 > 80% predicted FEV1/FVC normal	FEV1 > 80% predicted FEV1/FVC normal	FEV1 > 60% but < 80% predicted FEV1/FVC reduced by 5%	FEV1 < 60% predicted FEV1/FVC reduced by > 5%
Recommended Treatment Strategy	STEP 1 Preferred: Short-acting beta-agonist PRN	STEP 2 Preferred: Low-dose inhaled corticosteroids Alternative: Cromolyn, Leukotriene receptor antagonist, Nedocromil, or Theophylline	STEP 3 Preferred: Either low-dose inhaled corticosteroids + long-acting beta-agonist OR Medium-dose inhaled corticosteroid Alternative: Low-dose inhaled corticosteroid + either Leukotriene receptor antagonist, Theophylline, or Zileuton	STEP 4 Preferred: Medium-dose inhaled corticosteroid + long-acting beta-agonist Alternative: Medium-dose inhaled corticosteroids + either Leukotriene receptor antagonist, Theophylline, or Zileuton STEP 5 Preferred: High-dose inhaled corticosteroids + long-acting beta-agonist Consider adding Omalizumab for patients with allergies STEP 6 Preferred: High-dose inhaled corticosteroids + long-acting beta-agonist + oral corticosteroids Consider adding Omalizumab for patients with allergies
Step down if possible and asthma is controlled for at least 3 months Step-up if needed, but first check adherence, environmental control, and comorbidities
In each step, patient education, environmental control, and management of comorbidities are important. In STEP 2 - 4, consider subcutaneous allergen immunotherapy for patients with allergic asthma
Short-acting beta-agonist as needed for symptoms. Up to 3 treatments at 20 minute intervals as needed. A short course of oral systemic corticosteroids may be needed. Use of a short-acting beta agonist for >2 days a week for symptom control indicates inadequate control and the need to step up therapy.

Monitoring response to treatment

Methods of monitoring response to treatment include:

• Sputum eosinophils percentage can guide corticosteroid therapy. One approach is:
  • If the sputum eosinophil count is less than 1%, reduce anti-inflammatory treatment irrespective of asthma control.
  • If the eosinophil count is 1–3%, make no changes to anti-inflammatory treatment
  • If the eosinophil count is greater than 3%, increase anti-inflammatory treatment
• If measuring of sputum eosinophils is not available, a blood eosinophil count of 260 cells per μL or more or a eosinophil percentage of white blood cells of 2.7% or more can indicate eosinophilic inflammation. Alternative cut-offs of 200 cells per μL and 2% and 300 cells per μL in the AZISAST trial and 3% in the AMAZES trial have been used.

The role of monitoring peak expiratory flow rates is limited by variability of measurement.

The role of monitoring exhaled nitric oxide levels is not established although an early trial showed benefit.