Leukotriene Receptor Antagonists For Asthma

What is asthma?

Asthma is a chronic inflammatory disease of the lungs. It is clinically characterised by airway obstruction and hyperresponsiveness. When the patient is exposed to triggers such as allergens, infections and irritants, the airway is mainly affected and causes acute exacerbation (increase in cough, secretions and difficulty in breathing).¹

Management of asthma

It is important to manage asthma to prevent unwanted serious illnesses. There are different medications to reduce the symptoms of asthma. They are used based on the severity of the disease. Asthma medications include:²

• Short-acting beta₂ agonists (SABAs)
• Long-acting beta₂ agonists (LABAs)
• Short-acting muscarinic antagonist (SAMA)
• Long-acting muscarinic antagonists (LAMAs)
• Corticosteroids
• Leukotriene modulators/modifiers
• Methylxanthines

Leukotrienes and asthma

It is important to fully understand the role of leukotrienes in asthma to know the inflammatory mediators released by the body. Eosinophils are essential inflammatory cells. They contribute significantly to mucus formation, airway remodelling, and hyperresponsiveness in allergic asthma. Other key players in the pathophysiology of asthma include immune cells such as neutrophils, macrophages, mast cells, dendritic cells (DCs), and Th2 lymphocytes. 

Inflammatory reactions mediated by these cells are usually the cause of allergic asthma. Dendritic cells absorb allergens upon exposure and entrance into the airways, causing the growth of Th2 cells. Consequently, Th2 cells release important cytokines, which increase B cell activation, bronchial hyper-reactivity, goblet cell metaplasia, mucus secretion, and fibrosis.

One of these cytokines, IL-5, also enhances the survival and maturation of eosinophils. Leukotrienes (LTs), chemokines, cytokines, and histamine are released due to these reactions. After that, inflammatory mediators generated by mast cells activate more inflammatory cells. In addition, other cells, such as smooth muscle, endothelial, and epithelial cells in the structure, are also activated. This leads to the invasion of inflammatory cells and changes in lung function.

Leukotrienes (LTs) are one of the intermediate compounds. Lipid mediators, or LTs, have a role in the cause of numerous inflammatory illnesses, including asthma. TMast cells and eosinophil mediators produce arachidonic acid, converted into leukotrienes.

These leukotrienes bind to the leukotriene receptor and cause airway oedema, smooth muscle contraction, and increased mucus secretion in the lungs. Hence, leukotriene receptor antagonists are medications that prevent the binding of certain leukotrienes called leukotriene D₄. By doing so, the symptoms of asthma can be reduced.¹

Leukotriene modulators

Leukotriene modulators can be classified into two types:

• Leukotriene synthesis inhibitors
• Leukotriene receptor antagonists (LTRA)

Leukotriene synthesis inhibitors

These drugs inhibit the synthesis of leukotrienes, hence preventing their action. It works by blocking an enzyme called 5-lipoxygenase (5-LO). This inhibits the production of leukotrienes and products associated with bronchoconstriction. An example of a leukotriene synthesis inhibitor is zileuton.

Leukotriene receptor antagonists (LTRA)

LT receptor antagonists act by binding to the leukotriene receptors. This prevents the leukotriene D₄ from binding, thereby inhibiting its action. This reduces bronchospasm and airway hyperresponsiveness. Examples for LTRA are montelukast, pranlukast, and zafirlukast.²

Indications of leukotriene receptor antagonists

Indications for leukotriene receptor antagonists are:

• Allergies (allergic rhinitis)
• Allergic asthma
• Exercise-induced asthma 

Take these medications as prescribed by your physician at the required dose. Do not self-medicate yourself too much, as it may cause unwanted effects.

Side effects of leukotriene receptor antagonists

Possible side effects:

• Cough, runny nose, sore throat
• Diarrhea
• Ear infection
• Fatigue (tiredness)
• Flu-like symptoms, such as fever
• Headache
• Heartburn
• Itchy skin or rash
• Lack of appetite

Studies show that montelukast and zafirlukast have few negative adverse effects. Hepatitis has been linked to only the prolonged use of zafirlukast. Such prolonged use can result in hepatic failure, liver transplantation, and death. Chronic usage of zileuton can cause increased liver enzymes in approximately 5% of asthma patients.

Drug-drug interactions of leukotriene receptor antagonists

Before taking a new medication, it is crucial to know about possible drug interactions. This is because many individuals have comorbidities and take other drugs as well. The reported drugs which interact with leukotriene receptor antagonists include:^2,3

• Alpelisib, dabrafenib or enzalutamide 
• Erythromycin and rifapentine 
• Loxapine 
• Lumacaftor 
• Terfenadine
• Warfarin

Are leukotriene receptor antagonists a potent drug for asthma of the elderly?

People who are above 60 may have comorbidities, and patients with asthma will have further complications. Hence, it is important to have potent inhibitors so that the potential health problems can be reduced. 

A 12-week randomised, open-label, parallel-design clinical trial found that montelukast is effective for asthmatic patients over 60. The trial volunteers had mild asthma. They were randomly assigned to take either an inhaled corticosteroid (800 mg of budesonide, 800BUD) or an inhaled corticosteroid (400 mg of budesonide plus 10 mg of montelukast (MON-400 BUD)). Each group took their medication(s) daily for 12 weeks. Adding montelukast to a low-dose inhaled corticosteroid (ICS) was as effective as a medium-dose ICS.

Furthermore, the MON-400BUD group experienced fewer asthma exacerbations and side effects. The incidence of a sore throat was reduced in particular. This study demonstrates that adding an LTRA to a low-dose ICS may be more effective than doubling the ICS dose for patients with moderate elderly asthma (EA) who do not respond well to a low-dose ICS alone. 

A different study examined the effectiveness of adding montelukast to anti-asthmatic medication. This clinical trial included 512 individuals over 60 with severe asthma. The study ran for 24 months. After 12 months of combining an ICS and a Long-acting beta₂ agonist (LABA), two-thirds of the study individuals were randomly assigned to receive montelukast (active group).

In contrast, the rest of the study participants were assigned to the ICS/LABA treatment (control group). After 24 months, the active group outperformed the control group; the active group did better regarding asthma symptom-free days, beta-agonist use, asthma control test scores, and asthma control status, as defined by the GINA guideline.⁴ This shows that LTRA can be added as a potent adjuvant to elderly patients to improve their well-being.

Summary

Leukotriene receptor antagonists are a class of medications used to treat allergic rhinitis and asthma. They are especially used to prevent asthma so that the symptoms can be reduced. These drugs either prevent leukotriene synthesis, an important inflammatory mediator or block its binding to the leukotriene receptor.

They are usually well tolerated. But if any adverse effects arise, consult your healthcare provider immediately. Before taking these medications, it is also important to look for any drug-drug interactions. Therefore, consult your physician about the medications you are already taking.