Leukotrienes: A new attack on asthma

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Over the past 20 years, it has been documented that asthma mortality has been rising despite our improved knowledge of the causes of asthma. But it has only been in the last 10 years that the understanding that asthma is primarily an inflammatory condition has surfaced. Recently, this has led to the development of new classes of medications targeted towards counteracting the inflammatory process. Two of the newer medications, Accolate (zafirlukast) and zileuton, target the leukotriene pathway and have proven very effective in the maintenance treatment of asthma.

What are leukotrienes?

When people with asthma are exposed to asthma triggers, a series of chemical reactions take place in the lungs. These reactions produce a number of chemical substances called mediators that can cause asthma symptoms. One series of reactions, the arachidonic acid cascade produces mediators called leukotrienes. Leukotrienes are potent inflammatory mediators that contribute to airway obstruction by causing smooth muscles to constrict, mucus to accumulate and swelling in surrounding tissue. This airway obstruction results in asthma symptoms such as wheezing, coughing, and shortness of breath.

Why are leukotrienes important?

Leukotrienes are important mediators in the inflammatory condition. Asthma is an inflammatory condition. Leukotrienes are important in the recruitment of inflammatory cells to the target site. The have a myriad of activities that include, but are not limited to constriction of bronchial smooth muscle, increasing mucous production in the airways, increasing vascular permeability and the stimulation of the production of other important mediators of inflammation such as platelet activating factor and some of the prostaglandins. In fact, leukotrienes have been shown to be important mediators in many forms of asthma, including exercise induced asthma, cold induced asthma, aspirin induced asthma and allergen related asthma.

Leukotrienes and the treatment of asthma

Having shown without a doubt the significance of the leukotrienes to the asthmatic condition, it would make sense to develop a treatment of asthma which would target either the production of leukotrienes or the activity of leukotrienes. Both of these strategies have been utilized in the development of two recent additions to our pharmacopoeia. The two classes of drugs are the leukotriene pathway inhibitors and the leukotriene pathway antagonists. An inhibitor of the leukotriene pathway would be a substance which slows or prevents the formation of leukotriene molecules from their precursor, arachadonic acid. One medication that does this is Zileuton which is a fairly fast acting drug with a short half life so it must be taken four times a day. The dose is 600 mg four times daily. It has also been shown to be particularly effective in preventing exercise induced asthma.

The other strategy involves the blocking of the receptor site for the action of the leukotrienes. A compound which acts in this manner would be structural similar to the leukotriene yet inactive, so that it would compete with the leukotrienes for their receptor binding sites. They can thus, either partially or completely block the activity of leukotrienes. Accolate is the first medication to employ this strategy. The dose is 20 mg twice a day. It has been found to be less potent than zileuton with fewer side effects. ent that zileuton, but has not been associated with any liver toxicity. Zafirlukast has been found to increase peak expiratory flow rates in moderately severe asthmatics. These patients were also noted to require less frequent use of inhaled
b-agonists. Zafirlukast has also been shown to be effective in aspirin induced asthma. Both zileuton and zafirlukast have been indicated for patients 12 years and older. Neither should be used to treat acute episodes of asthma.

A new leukotriene receptor antagonist, montelukast, has recently been introduced that has FDA approval for pediatric use for patients 6 years and older. In addition, this new medication is dosed once daily, which, as in the case with the twice-daily dosed Accolate, would potentially
lead to better patient compliance.

In summary, the leukotriene pathway inhibitors and antagonists have been valuable adjuncts to the treatment of asthma. Accolate has the advantage of twice daily dosing. These agents are generally safe, though certain concerns have arisen, as outlined above. There is great promise for the development of similar medications that may utilize other target points on the leukotriene pathway. This is an area of great promise in the treatment of asthma, which could potentially lead to decreased mortality rates and less steroid use and complications.

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