Leukotriene Inhibitors

Definition

Leukotriene inhibitors are prescription medications that treat asthma and some allergies by blocking the formation or activity of leukotrienes—small mediator chemicals produced by cells in the body.

Purpose

More than 50 million Americans suffer from asthma and allergies. Asthma is one of the most prevalent chronic diseases in the United States, affecting 9 million (12.7%) of children. Seasonal allergies affect 20-40 million (20%) of Americans, about 40% of them children. It is estimated that 60-70% of those with asthma also suffer from allergic rhinitis, allergies affecting the mucous membranes of the nose.

Asthma, an inflammation of the bronchial airways, and seasonal allergies and allergic rhinitis involve several chemical mediators including histamine and leukotrienes. Leukotrienes are a class of unsaturated fatty-acid chains containing 20 carbon atoms.

During an asthma attack or within minutes of exposure to an allergen such as dust or pollen, leukotrienes are released by a type of blood cell in the lungs, causing the following responses:

• contraction of the bronchial airway muscles
• inflammation of the airway linings
• swelling and narrowing of the airways
• production of mucus and fluid
• wheezing and shortness of breath
• nasal congestion

Leukotriene inhibitors may decrease the symptoms of mild to moderate allergen-induced asthma, improve nighttime symptoms, and reduce the number of acute asthma attacks. Taken daily on a long-term basis they may help to prevent or control the symptoms of persistent asthma—asthma with symptoms that last at least two days per week or two nights per month. They also are prescribed for children with frequent or more severe asthma attacks and for those who dislike or have difficulty using asthma inhalers. Although leukotriene inhibitors may decrease the need for inhaled beta-agonists or corticosteroids, they are not used to treat asthma attacks. Leukotriene inhibitors also may be used to treat symptoms of allergic rhinitis or short-term seasonal allergies, including sneezing, runny nose, itching, and wheezing.

Description

Leukotriene inhibitors are often called leukotriene:

• blockers
• modifiers
• antagonists
• pathway modifiers

When they were first introduced in 1996, leukotriene inhibitors represented the first new class of asthma medication in two decades. Classified as anti-inflammatories, they were originally developed to improve lung function in asthmatics by relaxing the smooth muscles around the bronchial airways and by reducing lung inflammation.

Types of leukotriene inhibitors

The available leukotriene inhibitors are: montelukast (Singulair), zafirlukast (Accolate), and zileuton (Zyflo).

Montelukast and zafirlukast are leukotriene-receptor antagonists that prevent leukotriene from binding to cell receptors and initiating the chain of events leading to symptoms of allergy and asthma. Montelukast works rapidly. It is the only leukotriene inhibitor that has been approved by the U.S. Food and Drug Administration (FDA) for use in children as young as two, as well as for the treatment of seasonal allergies.

Zafirlukast is a synthetic peptide that inhibits the receptor binding of three leukotreines (LTC4, LTD4, and LTE4) that cause smooth muscle constriction. It is used for mild to moderate persistent asthma, exercise-induced asthma, and the management of allergic rhinitis in those aged seven and older.

Zileuton is a 5-lipooxygenase pathway inhibitor that interferes with the synthesis of LTA4, LTC4, LTD4, and LTE4. It is used to treat chronic asthma in adolescents and adults.

Effectiveness

Leukotriene inhibitors may be prescribed along with inhaled corticosteroids for control of mild to moderate, persistent asthma. Used alone they are less effective than low-dose inhaled corticosteroids. However, they enable some people to reduce their doses of inhaled corticosteroids. Leukotriene inhibitors may be an option for people with mild asthma who want to avoid corticosteroids, which can cause serious side effects with long-term use. When used in conjunction with beta-agonists, leukotriene inhibitors reduce symptoms and may lower the beta-agonist usage.

Leukotriene inhibitors appear to decrease the symptoms of seasonal allergic rhinitis. Although they may relieve nasal congestion better than antihistamines, they are less effective than corticosteroid nasal sprays. A leukotriene inhibitor combined with an anti-histamine may be more effective than either drug alone.

Leukotriene inhibitors have helped some children who suffer from nocturnal asthma, exercise- and aspirin-induced asthma, allergic rhinitis, and seasonal allergies.

Clinical studies

Montelukast appears to be an effective asthma controller in about one-third of patients. Another one-third receives no benefit. However, most long-term studies have found that standard inhaled corticosteroids are more effective for controlling asthma than either beta-agonists or leukotriene inhibitors.

A 2003 analysis of 13 clinical studies found that Singulair and Accolate resulted in 60% more asthma flare-ups and other symptoms as compared with traditional asthma treatments. Patients using inhaled corticosteroids had fewer daytime symptoms and night awakenings than those taking Singulair or Accolate. The researchers advised against switching to a leukotriene inhibiter unless the dosage of inhaled medication is less than 400 micrograms per day.

A 2005 study sponsored by Merck, the maker of Singulair, found that a one-year course of Singulair was useful for treating two-to five-year-olds with occasional asthma attacks that were triggered by respiratory infections. Singulair reduced this type of asthma flare-up by 32% as compared with a control group receiving a placebo. Singulair also delayed the onset of the first asthma flare-up and reduced the need for inhaled medication. However, it did not reduce the length or severity of the flare-up once it had begun. The researchers suggested that children with infection-triggered asthma should begin taking a leukotriene inhibitor before the start of the flu season or at the onset of an upper-respiratory-tract infection.

Another 2005 study found that children whose asthma improved with montelukast alone were younger and had had asthma for a shorter period of time as compared with children whose asthma improved only with inhaled corticosteroids. Among the children whose lung function improved by at least 7.5%, 5% took montelukast alone, 23% were on inhaled corticosteroids only, and 17% were on both medications.

Other uses

Leukotriene inhibitors have been used successfully to treat inflammations of the esophagus (esophagitis) or stomach and intestines (gastroenteritis ) that are caused by white blood cells called eosinophils that are involved in allergic reactions. Montelukast has been used to successfully treat symptoms of interstitial cystitis, a chronic inflammation of the bladder.

Recommended dosage

Montelukast is taken once per day in the evening so as to relieve morning allergy symptoms. Although dosing may vary, average daily doses of montelukast for asthma and seasonal allergies are: children aged 1-5: one 4-mg chewable tablet or 4-mg oral granules (one packet), swallowed whole or mixed in a spoonful of soft food; children aged 6-14: one 5-mg chewable tablet; children over 14 and adults: one 10-mg tablet.

The average doses of zafirlukast for children aged 7-11 are 10-mg tablets twice a day. Children aged 12 and older and adults usually take 20-mg tablets twice a day. Zafirlukast is taken one hour before or two hours after a meal, since food reduces its bioavailability by about 49%.

The average dose of zileuton is a 600-mg tablet four times per day for children aged 12 and older and adults.

Leukotriene inhibitors are expensive. Missed doses should be taken as soon as possible unless it is almost time for the next dose, in which case the dose should be skipped.

Precautions

Although leukotriene inhibitors are considered safe, they can raise the levels of liver enzymes. The FDA recommends liver function tests monthly for the first three months on medication, followed by quarterly monitoring for the next year, and continued interim testing. Zileuton is contraindicated for those with elevated liver enzymes, active alcoholism, or liver disease. Increased levels of liver enzymes may be detectable in the blood within two months of starting zileuton. Zileuton can affect liver function and, one rare occasions, can damage the liver.

It is unclear whether leukotriene inhibitors should be taken during pregnancy. Zafirlukast and zileuton should not be used by a woman who is breastfeeding. Both medications have been found to increase the risk of mild to moderate respiratory tract infections in patients aged 55 and older.

Medical conditions that may interfere with the use of montelukast include: allergies to aspirin or nonsteroidal anti-inflammatories (NSAIDs); liver disease, which can increase the blood levels of the drug; and phenylketonuria because chewable tablets may contain aspartame.

A healthcare provider should be contacted if an increased number of short-acting bronchodilator inhalations are needed to relieve an acute asthma attack or if more than the maximum number of daily inhalations are required while using zileuton.

To be effective montelukast and zafirlukast must be taken at the same time every day. Zileuton must be taken at regularly spaced intervals every day, even if asthma symptoms appear to improve. Montelukast should be continued through an acute asthma attack in addition to rescue medication.

Side effects

Although leukotriene inhibitors generally have few side effects and those may subside as the body adjusts to the drug, headaches are common with these medications. Headaches occur in 18-19% of those taking montelukast and in 25% of those taking zileutin. Among 7 to 11 year olds on zanfirlukast, 4.5% suffer from headaches, as do 12.9% of those aged 12 and over.

Other less common side effects of leukotriene inhibitors include:

• rash
• fatigue
• dizziness
• abdominal pain
• nausea and vomiting
• diarrhea

Montelukast appears to cause fewer side effects than other leukotriene inhibitors and is less likely to affect the liver. Side effects occurring in less than 4.2% of patients include:

• heartburn
• weakness
• fever
• nasal congestion
• cough
• dental pain
• rarely, pus in the urine

Rare side effects of zileuton include:

• itching
• flu-like symptoms
• upper right abdominal pain
• yellow eyes or skin (jaundice)

Interactions

Drugs that may interact with montelukast include:

• aspirin
• NSAIDs
• phenobarbital
• rifampin

Zafirlukast and zileuton can raise the blood levels of the asthma medication theophylline (Theo Dur and others) and the blood thinner warfarin (Coumarin). Theophylline levels and blood-clotting times should be monitored frequently.

Medications that may interact with zafirlukast include:

• aspirin
• blood pressure medications
• some seizure medications

Medications that may interact with zileuton include:

• the beta-blocker propanolol
• beta-agonists
• terfenadine (Seldane and others)

Resources

BOOKS

Haughney, John. Leukotriene Receptor Antagonists: Evidence and Experience Examined. London: Royal Society of Medicine Press, 2001.

Sampson, A. P., and S. T. Holgate. Leukotriene Modifiers in Asthma Treatment. London: Martin Dunitz, 1999.

PERIODICALS

"Asthma: Corticosteroids Are More Effective than Beta-Agonists or Leukotriene Antagonists." Health & Medicine Week (December 20, 2004): 77.

"Asthma: Journal Publishes Research on Tailoring Asthma Treatment in Children." Health & Medicine Week (February 28, 2005): 75.

Banasiak, Nancy Cantey, and Mikki Meadows-Oliver. "Leukotrienes: Their Role in the Treatment of Asthma and Seasonal Allergic Rhinitis." Pediatric Nursing 31, no. 1 (January/February 2005): 35-8.

Ducharme, F. M. "Inhaled Glucocorticoids Versus Leukotriene Receptor Antagonists as Single Agent Asthma Treatment: Systematic Review of Current Evidence." British Medical Journal 236, no. 7390 (March 22, 2003): 621-6.

ORGANIZATIONS

American Academy of Allergy, Asthma and Immunology. 555 East Wells Street, Suite 1100, Milwaukee, WI 53202-3823. (800)822-2762. 〈http://www.aaaai.org〉.

Childhood Asthma Research and Education (CARE) Network. National Heart, Lung, and Blood Institute. 6701 Rockledge Drive, MSC 7952, Bethesda, MD 20892-7952. (301) 435-0202. 〈http://www.asthmacarenet.org〉.

OTHER

Lehnert, Paul. "Leukotriene Modifiers for Allergic Rhinitis." Health Guide A-Z. WebMD. October 8, 2003 [cited March 14, 2005]. 〈http://my.webmed.com/hw/allergies/ug2390.asp〉.

――――――. "Leukotriene Pathway Modifiers for Asthma." Health Guide A-Z. WebMD. March 5, 2004 [cited March 14, 2005]. 〈http://my.webmed.com/hw/asthma/hw163553.asp〉.

Mayo Clinic Staff. "Medications and Immunotherapy for Asthma." Asthma Center. MayoClinic.com. August 13, 2004 [cited March 14, 2005]. 〈http://www.mayoclinic.com/invoke.cfm?objectid=58BCFCCC-BB00-4E67-A29876A9D30B65ED〉.

KEY TERMS

Allergic rhinitis— Nasal symptoms caused by an allergic reaction.

Asthma— A disease that causes the bronchial airways to narrow, swell, and produce mucus, making breathing difficult.

Beta-agonist— Beta2-agonist; beta-adrenergic agonist; a bronchodilator medication—inhaled or oral—that relaxes the muscles surrounding the airways to relieve asthma symptoms.

Corticosteroids— Inhaled medications for long-term control of asthma.

Leukotrienes— A class of small molecules produced by cells in response to allergen exposure; they contribute to allergy and asthma symptoms.

Montelukast (Singulair)— An inhibitor that prevents leukotrienes from binding to cell receptors; taken over time, montelukast can reduce or prevent symptoms of asthma and allergies.

Zafirlukast (Accolate)— An inhibitor that prevents leukotrienes from binding to cell receptors; taken over time, zafirlukast can help reduce or prevent asthma symptoms.

Zileuton (Zyflo)— A medication that interferes with the biosynthetic pathway that produces leukotrienes; used to help prevent asthma attacks.