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Leukotriene Antagonists Offer a New Mechanism for Asthma Control.

Asthma, a chronic inflammatory syndrome of the lower airways, affects 1 in 20 persons. Over the last 10 years, the prevalence of asthma has been increasing. Asthma hospitalizations, emergency department visits for asthma, and deaths attributable to asthma have been increasing worldwide, particularly in urban areas (Lang & Polansky, 1994; Weiss & Wagener, 1990). The exact reasons for this upswing in number of asthma cases remains unclear. Many attribute the increasing number of diagnoses to an exponential rise in the allergen density of our environment. Others disagree, theorizing that the causes of asthma are very complex. Regardless of etiology, it has become a very complex disease for patients to understand and self-manage. Therefore, prevalence is mainly increasing in the less-educated, lower-socioeconomic sector of the population who have suboptimal access to health care.

Despite the disagreements, investigators agree that there has been one aspect of this disease that has greatly contributed to increasing prevalence: inadequate treatment. Asthma severity has been classically underestimated and undertreated by substantial numbers of primary care physicians (Buist & Vollmer, 1994). Improving primary care prevention of asthma has become the major focus in managing the disease.

In the past, asthma has been treated as an episodic disease with exacerbations requiring large doses of dampening therapy as needed.

According to the 1997 guidelines of the National Heart, Lung and Blood Institute (NHLBI) this view of asthma needs to change. Asthma should be viewed as a chronic inflammatory condition which can be controlled to avoid symptoms. The patient's asthma symptoms should be regarded as evidence of-inadequate therapy. Exacerbations of asthma are preventable if the disease is understood and managed correctly.

Asthma: A Chronic Inflammatory

Since 1991, the NHLBI has focused on the inflammation cascade as the major pathophysiologic process occurring in asthma. A new understanding of the inflammation process confirms that in asthma the bronchioles sustain acute and long-term pathologic changes. In susceptible persons, the inflammation cascade can be triggered by a variety of stimuli which include viruses, cold or dry air, exercise, allergens, and aspirin. Triggers vary from person to person and can change over time in susceptible persons. Acute inflammatory changes include bronchial edema, mucus hypersecretion, and bronchoconstriction which result in shortness of breath, cough, or wheezing. These acute dramatic symptoms are reversible with rapid-acting medications such as beta 2 adrenergic agonist inhalers, commonly called bronchodilators.

It is these acute, "breakthrough" episodes that define asthma for the layperson.

However, the inflammation process in asthma is not only episodic and sporadic. The inflammation cascade can cause long-term, irreversible changes in the airways also. Inflammatory changes in the bronchioles do not disappear after acute exacerbations. Airway epithelial injury occurs which requires healing and remodeling, resulting in decreased bronchial tube caliber. Also, the inflammation leaves bronchioles even more hypersensitive to a widening array of stimuli (Rachelefsky, 1998). Such lasting effects caused by the inflammatory process have confirmed the need for the emphasis on anti-inflammatory drug use in asthma. Preventing airway inflammation before it starts has become a mandate for primary care providers. Proactive prevention through the use of anti-inflammatory drugs has become the cornerstone of therapy in asthma (Busse, 1998; NHLBI, 1997).

Airway inflammation is a reaction mediated by many cell types and chemical mediators. Some of these mediators have been fully elucidated through scientific investigations, others are still a mystery. Histamine has long been known as a major activator of airway constriction and inflammation in allergic reactions and asthma. However, inhibiting histamine alone has never been sufficient to control the inflammation of asthma. A new class of substances called leukotrienes has been identified as integral participants in airway inflammation. The increasing understanding of leukotriene involvement in inflammation has resulted in the design of new types of anti-inflammatory medications for asthma: leukotriene antagonists.

What Are Leukotrienes?

Leukotrienes are potent inflammatory mediators which are released from lung tissue and cells; mainly macrophages, eosinophils, and mast cells. These are powerful inflammatory mediators which exert their biologic activity by binding to and activating specific receptors in the bronchioles. In persons with asthma, leukotrienes cause tissue edema, smooth muscle constriction, migration of eosinophils, and mucus secretion in the bronchioles (Drazen, Israel, & O'Byrne, 1999). Leukotrienes are both inflammation stimulators and bronchoconstrictors. Compared to histamine, leukotrienes are 1,000 times more potent as constrictors of human bronchial smooth muscle (Dahlen, Hedquist, Hammarstrom, & Samuelsson, 1980).

Leukotrienes are derived from a parent molecule called arachidonic acid, a fatty acid which resides inside cells. In response to an inflammatory stimulus, arachidonic acid is biochemically changed into leukotrienes via an enzyme called 5-lipoxygenase. Arachidonic acid is also the parent molecule of other familiar mediators of inflammation: prostaglandins. Prostaglandins are generated from arachidonic acid via the cycloxygenase (cox) pathway. These pathways of inflammation have recently been under intense investigation. Leukotriene antagonists as well as cycloxygenase inhibitors (cox 2 inhibitors) are two classes of drugs recently synthesized from years of analyzing the exact participants in the inflammation cascade (see Figure 1).

[Figure 1 Illustration Omitted]

Oral and Inhaled Corticosteroid Control of Inflammation

Controlling inflammation has been the mainstay of asthma therapy for many years. Anti-inflammatory agents in the form of inhaled and oral corticosteroids have been the most effective treatment for asthma. Inhaled corticosteroids have consistently been effective for long-term control of asthma. Oral corticosteroids have been indicated for acute exacerbations only for short-term use since the systemic side effects from long-term use are considerable. Prolonged use of oral corticosteroids are known to cause adrenal suppression, osteoporosis, gastroduodenal ulceration, growth suppression, cataract formation, glaucoma, and infections.

Because of the known systemic side effects of oral corticosteroids, the safety of prolonged use of inhaled corticosteroids has been a topic of investigation. Many investigators are studying the long-term effects of prolonged use of inhaled corticosteroids. Most studies have not tracked the use of inhaled corticosteroids for more than 5 years. Many researchers report that inhaled corticosteroids used in recommended doses are relatively safe even with prolonged use (Kavuru, Subramony, & Vann, 1998; Lucas & Craig, 1998; Pedersen, 1998). However, some investigators remain skeptical and continue to cautiously analyze the long-term effects on patients, particularly children. Lipworth (1999a) found an increased risk of osteoporosis, cataract formation, glaucoma, adrenal suppression, and skin bruising in asthma patients who have used the high-dose inhaled corticosteroid flucatisone for prolonged periods. Although these side effects were less severe than those experienced with prolonged use of oral corticosteroids, prudent dosing of inhaled corticosteroid is warranted. In light of this controversy, health care providers are advised to use the lowest possible dosages of inhaled corticocosteroids to achieve asthma control. However, during times of heightened symptoms, prescription of high dosages of inhaled corticosteroid is standard practice (Rennard, 1998). With the issue of systemic side effects unresolved, the safety of prolonged use of high-dose inhaled corticosteroid will continue to be investigated.

Problems With Inhaled Corticosteroids

Although very effective when used properly, patient compliance with inhaled corticosteroids has been problematic (Fish, Kaiser, & Tinkelman, 1997; O'Hollaren, 1999). Many patients do not adhere to the required schedule of inhaler use. Long-term inhaled corticosteroids must be used prophylactically on a regular schedule for optimal effect. Many patients find using these corticosteroid inhalers along with beta 2 agonist inhalers confusing and inconvenient. Children and adolescents particularly have trouble adhering to the required preventive inhaler schedule. Studies have confirmed that asthma patients are less likely to adhere to inhaled drug regimens compared to oral medication schedules (Keenan, 1998). Children, in particular, are erratic with compliance to inhaled drug schedules. School-age children are often required to use an inhaler prior to exercise. During school hours children frequently neglect to prophylactically inhale a dose of medication due to forgetfulness or peer pressure. This neglect of appropriate preventive treatment increases the likelihood of acute asthma exacerbations.

Patient understanding of correct inhaler technique has been another obstacle in the use of inhaled corticosteroid therapy (LoGalbo, 1999; O'Hollaren, 1999). A great many patients do not use proper technique with inhalers resulting in an inadequate therapeutic response. To obtain maximal medication via inhalation a specific breathing technique must be mastered. Many persons who use inhalers deposit the medication in the oral cavity rather than the airways due to poor technique. Aerosolized corticosteroid medication deposited on the tongue or oropharynx is somewhat absorbed but has an insufficient anti-inflammatory effect on the airways. Nurses can be particularly instrumental in educating patients regarding proper inhaler technique.

There are well-known local side effects of inhaled corticosteroids which may inhibit patient use. Oral candidiasis, dysphonia or hoarseness, and reflex cough are among the most common side effects.

Lastly, there are some patients with chronic persistent asthma who remain symptomatic despite use of high-dose inhaled corticosteroids. Patients with this type of chronic asthma have symptoms of bronchoconstriction often, especially at night. Symptoms which affect activity may occur daily or several times a week. Persons with persistent asthma usually need a daily inhaled corticosteroid plus long-acting beta 2 agonist (bronchodilator) as prophylaxis and a short-acting inhaled beta 2 agonist (bronchodilator) for exacerbations (Lockey, 1998).

Although inhaled corticosteroid therapy has the greatest anti-inflammatory effects in asthma, some patients will not achieve optimal results. The oral nonsteroidal, anti-inflammatory agents leukotriene antagonists, available in chewable tablets for children, are the newest addition to the armamentarium against asthma. Although these agents are not meant to replace inhaled corticosteroids, they offer an additional and new mechanism of asthma control.

Indications for Leukotriene Antagonists

In 1997, the NHLBI reclassified asthma according to severity of disease. There are four categories of asthma: mild intermittent, mild persistent, moderate persistent, and severe persistent. Asthma is a highly variable disorder but basically it is either intermittent or chronically persistent. The categories are characterized by symptom frequency, nocturnal occurrences, and lung function in terms of forced expiratory volume (FEV1) and peak expiratory flow (PEF) (Karpel & Wait, 1999). The leukotriene antagonists (zafirlukast, montelukast, and zileuton) are particularly suited for patients with chronic persistent asthma (Drazen et al., 1999). Persons with chronic persistent asthma need emphasis on long-term, preventive control with daily medication. These asthma patients endure symptoms frequently which limit their activity. They have nocturnal symptoms and evidence of diminished lung function. In addition to their daily preventive control, they often require "rescue" or "stepped up" care for acute asthma exacerbations. "Stepped-up" care frequently involves short courses of oral corticosteroid therapy (Lockey, 1998).

Administration of any of the leukotriene antagonists to patients with chronic persistent asthma can improve airway function and decrease the frequency of exacerbations of asthma. Over periods of long-term treatment with leukotriene antagonists, patients can decrease the amount of inhaled corticosteroid required to maintain control of asthma. These agents have also reduced the patient's asthma exacerbations, in turn reducing the need for oral corticosteroids. Thus, leukotriene antagonists have a "corticosteroid-sparing effect" on persons affected with persistent asthma (Drazen et al., 1999; Spector, 1998).

Leukotriene antagonists are not for acute exacerbations of asthma. These agents improve airway function within 1 to 3 hours; however, most of the improvement in airway function usually occurs within 2 to 4 weeks after initiating treatment. Since leukotrienes are instrumental in causing inflammation as well as bronchoconstriction, leukotriene antagonists exert anti-inflammatory and bronchodilator effects. Leukotriene antagonists do not interfere with the bronchial smooth muscle response to beta 2 agonists (Lipworth, 1999b). The bronchodilator effects of leukotriene antagonists and beta 2 agonists are additive. These additive effects are congruent with the theory that the two types of drugs have different mechanisms of bronchial relaxation. Since there is a synergism between the two agents, both serve as valuable treatment for patients with refractory asthmatic bronchoconstriction.

Studies show that the effect of leukotriene antagonists are greatest in those who have severe bronchoconstriction. FEV1 values showed greatest improvement in those who are severely affected (Drazen et al., 1999). Persons on leukotriene antagonists benefit by having less nighttime episodes. Also patient compliance with the oral leukotriene antagonists is better than with inhalers. The data available indicate that the magnitude of the improvement in FEV1 in response to inhaled glucocorticoid therapy exceeds that in response to leukotriene antagonists. However, the better compliance with leukotriene antagonists offsets the therapeutic advantage of inhaled corticosteroids, giving these new oral agents an edge (Drazen et al., 1999).

There are two conditions in which leukotriene antagonists have particular advantages over other drugs: aspirin-induced and exercise-induced asthma. It has been suggested that leukotriene antagonists may be advantageous over other drugs particularly in children with persistent asthma who require inhaled beta agonists before exercise. Children with persistent asthma can maintain their long-acting beta agonist but may be able to refrain from the intermediate-acting beta agonist inhaler when taking leukotriene antagonists (Drazen et al., 1999).

In summary, leukotriene antagonists are not recommended as first line therapy in all patients with asthma. According to Drazen and colleagues (1999), persons with mild persistent asthma can now choose between inhaled corticosteroid and oral leukotriene antagonists as first-line therapy. In patients with moderate to severe chronic persistent asthma, leukotriene antagonists can be combined with inhaled corticosteroids to maintain control of asthma with lower doses of inhaled corticosteroids.

Nursing Implications of Leukotriene Antagonists

Zafirlukast. (Accolate[R]). Zafirlukast is a potent, highly selective leukotriene receptor blocker which exerts its activity in the bronchioles. The recommended dose is 20 mg taken orally twice daily in adults and children 12 years and older. Food substantially reduces the bioavailability of zafirlukast requiring it to be taken on an empty stomach. Zafirlukast is metabolized by the liver and at high doses may cause an elevation in liver enzymes. This agent can interact with a number of other drugs, specifically theophylline, warfarin, terfenadine, aspirin, and erythromycin. When zafirlukast is administered to patients taking warfarin, prothrombin times must be carefully monitored. Antico-agulation enhancement occurs when these two medications are used together. Co-adminstration of zafirlukast with aspirin can enhance the effect of zafirlukast. When erythromycin, terfenadine, or theophylline are administered with zafirlukast, plasma levels and action of zafirlukast are diminished (Medical Economics, 1999).

The most common adverse reaction reported by users of zafirlukast is headache. A rare side effect known as Churg-Strauss syndrome has been reported in several patients. This syndrome consists of fever, muscle pain, high white cell count with an increased eosinophil fraction, pulmonary infiltrates, and cardiomyopathy. Persons who have had oral corticosteroids discontinued after initiating zafirlukast seem susceptible. The withdrawal of zafirlukast and reinstitution of corticosteroids helps resolve this syndrome (Weiland, 1998).

Montelukast (Singulair[R]). This is also a potent, highly selective leukotriene receptor blocker which exerts activity in the bronchiole. This oral agent is administered in 10 mg tablets for adults and children 6 years of age and older. The agent is available in 5 mg chewable tablets which are convenient for children. It is not affected by food ingestion, another advantage for use in children (Medical Economics, 1999). There are no extensive drug interactions reported for montelukast. Side effects are significantly less common with montelukast than other leukotriene antagonists.

Zileuton (Zyflo[R]). This leukotriene antagonist works by inhibiting the enzyme, 5-lipoxygenase, in the biochemical pathway of inflammation (see Figure 1). This agent inhibits the synthesis of leukotrienes. It is available as oral 600 mg tablets recommended 4 times a day in adults and children 12 years of age and older. This drug requires more frequent dosage and can be taken with food. Nurses can recommend patients take this medication at meals and at bedtime. The drug is metabolized by the liver and can cause elevation of liver enzymes. The patient should be advised about the need for frequent monitoring of liver enzymes.

There are significant drug interactions with zileuton. Zileuton can potentiate the anticoagulant effect of warfarin, making cautious monitoring of prothrombin time necessary. Zileuton can also potentiate effects of propranolol, thereby enhancing beta adrenergic blockade causing a drop in heart rate. Theophylline levels are enhanced by zileuton, thus making it necessary to decrease the dosage of theophylline in patients. Terfenadine clearance is reduced when zileuton is adminstered concurrently. Co-administration of terfenadine and zileuton are not recommended (Medical Economics, 1999). The most common side effects when taking zileuton are nausea and indigestion.

Conclusion

Leukotriene antagonists are a new class of oral, nonsteroidal, antiinflammatory agents with bronchodilating effects well suited for persons with chronic persistent asthma. These agents are not meant to replace corticosteroids, which play a critical role in treating asthma. Leukotriene antagonists are complementary agents which have synergism with beta 2 agonists and may have a "corticosteroid-sparing" effect. By inhibiting inflammatory mediators, leukotriene antagonists provide another mechanism for control of asthma different from corticosteroids. These are prophylactic medications which are designed to prevent "asthma attacks" before they start. All the agents are oral medications with superior compliance over inhaler-delivered drugs.

Patients started on leuk-otriene antagonists must understand that these medications only work if used daily, regardless of symptoms. These are not drugs that can quickly relieve an acute "asthma attack." Most experts do not recommend the use of leukotriene antagonists as monotherapy. For the majority of patients, leukotriene antagonists work in conjunction with their usual asthma medications, not in place of them. The chewable form, montelukast, is a particularly advantageous asthma control medication for children.

References

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Teri Caprlotti, MSN, CRNP, DO, is Clinical Assistant Professor, Villanova University, Villanova, PA
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Publication:MedSurg Nursing
Date:Oct 1, 1999
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