Clinical application of nonsteroidal agents.

Inflammation of the airway may be the most important variable in treating asthma. Nonsteroidal agents can be used as a substitute for corticosteroids or synergistically to reduce the need for higher doses of corticosteroids. This issue will discuss the clinical application of nonsteroidal agents, as well as present common side effects.

Cromolyn sodium

Cromolyn sodium is considered an anti-asthmatic, an antiallergic and a mast cell stabilizer. Pretreatment with inhaled cromolyn sodium results in inhibition of mast cell degranulation, thereby blocking release of the chemical mediators of inflammation.

Cromolyn prevents the extrusion of granules containing the mediators of inflammation. The exact mechanism by which this inhibition is accomplished is not completely understood, but the following details of cromolyn activity and mast cell function are known:

* The mode of action of cromolyn sodium is prophylactic. Pretreatment is necessary for inhibition of mast cell degranulation.

* Cromolyn sodium does not have an antagonist effect on any of the chemical mediators themselves.

* Cromolyn sodium does not operate through the cyclic adenosine 3',5'-monophosphate (cAMP) system and does not affect alpha or beta receptors.

* Antibody formation, attachment of antibody (IgE) to the mast cell, and antigen-antibody union are not prevented by cromolyn. Cromolyn does prevent release of mediators.

As with other inhaled aerosols, cromolyn sodium is distributed to the airway and to the stomach via a swallowed portion. Distribution to the stomach (swallowed portion) can be modified by use of reservoir devices with the MDI formulation. The dose reaching the airway is absorbed from the lung and quickly excreted unchanged in the bile and urine. The lung portion does not appear to be metabolized in the airway. The swallowed portion is largely unabsorbed from the gastrointestinal tract (less than 1 percent) and excreted in the feces.

Cromolyn sodium is a safe drug. It has effectiveness similar to theophylline in controlling asthma with a better therapeutic margin than theophylline. In studies comparing the two agents, subjects using theophylline reported more side effects, including nervousness, nausea, school behavioral problems and more office visits. The overall incidence of adverse effects with cromolyn has been reported at 2 percent. Nasal congestion may be seen after beginning cromolyn sodium use.

Three points should be emphasized concerning the clinical application of cromolyn sodium with asthma and hyperreactive airway states:

* First, the drug is only prophylactic and should not be used during acute bronchospasm. This is based on its mode of action because the drug must already be present to prevent mast cell degranulation. It has no bronchodilating action and, in fact, may cause further bronchial irritation as an aerosol.

* Second, abrupt withdrawal of oral corticosteroids and substitution of cromolyn sodium in asthmatic patients can result in inadequate adrenal function. Cromolyn has no effect on the adrenal system, and tapered withdrawal of corticosteroids is necessary while beginning cromolyn use with patients.

* Third, it may take from two to four weeks for improvement in the patient's symptoms, enabling a decrease in concomitant therapy such as bronchodilator or steroid use.

Guidelines for the management of asthma indicate that cromolyn sodium is used in subjects requiring regular use of beta agonists for control of symptoms. It is considered an alternative to the use of inhaled corticosteroids, especially in children.

Nedocromil sodium

Nedocromil sodium exerts its anti-inflammatory and antiasthmatic effect by inhibiting the activation and activity of multiple inflammatory cells, including mast cells, eosinophils, airway epithelial cells and sensory neurons. Unlike corticosteroids, which downregulate cytokine production to reverse inflammation in the airway, nedocromil sodium blocks further inflammation by blocking the activation of inflammatory cells. Nedocromil is well-tolerated in both healthy volunteers and asthmatic subjects.

In adults, a dose of two MDI actuations two or four times daily has been shown to provide equal or better control of mild to moderate asthma compared with theophylline. This is based on daytime and nighttime asthma symptoms, need for inhaled bronchodilator, cough and morning tightness.

Nedocromil sodium has also been shown to be of potential use in reducing high-dose inhaled steroid use. Patients taking 2,000 mcg of inhaled steroid were able to reduce their daily use by 31 percent after taking 4 mg (approximately two MDI actuations) of nedocromil sodium four times daily. In a large metaanalysis of double-blind, placebo-controlled clinical trials of nedocromil sodium, the drug demonstrated a significant effect compared with placebo on outcome variables of daytime and nighttime asthma symptoms, cough, peak expiratory flow rate, FEV1, inhaled bronchodilator use, and patient report of control. Clinical improvement was greatest in mild to moderate asthma and with continued bronchodilator treatment.

When nedocromil sodium in a four-times-daily dose was added to current therapy in stable, mild asthmatic children in placebo comparisons, there was significant improvement in daily peak expiratory flow and a reduction in daily bronchodilator use. Nedocromil sodium, 4 mg given twice daily, has also been found to be equally effective compared with cromolyn sodium, 5 mg four times daily, in controlling asthma in children, offering a compliance advantage in the reduced dosing frequency.

Zileuton 

Taken orally, zileuton inhibits the 5-LO enzyme, which would otherwise catalyze the formation of leukotrienes from arachidonic acid. By interrupting the synthesis of these biologically active leukotrienes, their contribution to the inflammatory responses in asthma is effectively blocked.

Zafirlukast 

Zafirlukast is a leukotriene receptor antagonist. Specifically, zafirlukast binds to the CysLT1 receptors with no agonist effect. This causes competitive inhibition of leukotrienes which subsequently blocks the inflammatory effects of leukotrienes.

Montelukast 

Like zafirlukast, montelukast is a competitive antagonist for the cysteinyl leukotrienes. It binds with high affinity and selectivity to the CysLTl receptor subtype. Blockade of the CysLTl receptor prevents leukotriene stimulation of the receptor on target cells such as airway smooth muscle and secretory glands. Montelukast has been shown to inhibit both early and late-phase bronchocon-striction caused by antigen challenge.

Antileukotriene Drugs in Asthma Management

Antileukotriene agents are recommended in the NAEPP guidelines for the treatment of mild to moderate asthma. Antileukotrienes are particularly useful in controlling asthma resulting from certain triggers, including exercise-induced asthma, aspirin-induced asthma and, to a lesser extent, allergen-induced asthma.

Evidence to date supports the use of antileukotriene agents in the management of chronic asthma, including mild, moderate or severe. In mild to moderate asthma, antileukotrienes improve lung function, reduce the need for rescue beta-agonist use and decrease asthma symptoms, including nocturnal symptoms. In moderate to severe asthma, the additive effect between antileukotrienes and inhaled corticosteroids is the basis for asthma control with lower steroid doses or without an increase in steroid dosing.

Asthma guidelines agree that corticosteroids are the most effective anti-inflammatory drugs for use in asthma, and they have broader antiinflammatory activity than the more limited effect of the antileukotrienes. Leukotriene modifiers affect only one biochemical pathway--the lipoxygenase path and resulting leukotriene effects. Two aspects of antileukotriene therapy should be considered in relation to the use of corticosteroids in asthma.

Antileukotriene drug therapy is effective in approximately 50 percent of patients (although this proportion is higher for aspirin-sensitive individuals), but there is no method to predict which patients will be responders.

Omalizumab

Omalizumab is a recombinant DNA-derived humanized monoclonal antibody that selectively binds to human IgE. The drug blocks the binding of IgE to the IgE receptor on the surface of mast cells and basophils. This allows the reduction of mediators that can be released in an allergic response.

Omalizumab's use is supported in uncontrolled moderate to severe asthma. It has been found that omalizumab reduced asthma exacerbations, and it decreased corticosteroid and rescue medication use. Another study found similar results in that asthma exacerbations per patient were reduced and use of corticosteroids had dropped. Seventy-nine percent of patients taking omalizumab were able to drop their steroid dose by 50 percent or more, compared with only 55 percent in the placebo group.

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By Douglas S. Gardenhire MS, RRT-NPS

Douglas S. Gardenhire is a veteran therapist, author, educator and lecturer and the Director of Clinical Education in the Respiratory Care Program at Georgia State University.