Leukotriene Receptor Antagonist

Normal Physiology, Mechanism of Action, and Adverse Effects

Leukotrienes (LTs) are inflammatory intermediates that operate in the natural defense of the host and are involved in inflammatory conditions. It is a derivative of arachidonic acid that is catalyzed by 5-lipoxygenase in two steps. LTs are involved in many provocative disorders, including asthma, AR, interstitial lung disease, chronic obstructive pulmonary disease (COPD), and obstructive bronchiolitis after lung transplantation. In addition, it is categorized into two classes: Cysteinyl ​​LTs (CysLTs) and chemical adsorbent LTB4, which carry amino acids and fractions. BLT1 receptor and The LTB4 receptor are binds, which is one of the strongest chemicals for many immune cells. Investigations stated that BLT1 expression through non-myeloid cells e.g. skeletal muscle cells, nerve stem cells, endothelial cells, and vascular smooth muscle cells. Additional studies also documented that the LTB4-BLT1 axis is involved in a diversity of diseases other than allergic disorders, e.g. age-related macular degeneration, arthritis, cardiovascular disease, metabolic diseases, COPD, and cancer. While the BLT2 receptor is in the vicinity of BLT1 in humans and mice (Jo-Watanabe i., 2019).

Concerning CysLTs, investigations have indicated that they improve vascular permeability, guiding to nasal congestion, improved mucus production and secretion, rhinorrhea, and the uptake of inflammatory cells into tissues. Additional investigations also recommended the association of CysLTs in AR pathophysiology. Significantly, an enhance in the number of investigations has revealed that patients with AR respond favorably to develop CysLTs receptor antagonists of AR, e.g montelukast (MNT), zafirlukast, and pranlukast, which stop the impacts of CysLTs and advance the chronic respiratory diseases symptoms, especially AR and bronchial asthma (Jo-Watanabe et al., 2019). 

Leukotriene antagonists operate by stopping the activity of leukotriene via two main mechanisms: 1) blockade of CysLT-1 receptors on target cells (such as Montelukast, Pranlocast, and Saffronlocast) or 2) inhibiting leukotriene synthesis by stopping the 5-lipoxygenase pathway (e.g., zileuton). While LTRAs are now known to play a role in the treatment of asthma, there is a growing interest in their results on AR. MNT is documented in the U.S only for seasonal allergic rhinitis treatment. to our knowledge, other LTRAs are not presently confirmed for allergic rhinitis but they have been investigated clinically and non-clinically for their effect on AR (Van Hoecke et al., 2007).

In addition, LTRAs are excreted through the biliary system, rapidly absorbed through the mouth, bind to approximately plasma proteins, and hepatic biotransformation. In general, LTRAs are well tolerated with few reported negative results, e.g. sneezing/fatigue, headache (5%), angioedema, pulmonary eosinophilia, rashes, dry mouth, upper respiratory tract infection, abdominal pain, dizziness, pruritus, sinusitis, arthralgia, and nasopharyngitis (Nayak & Langdon, 2007; Van Hoecke et al., 2007). Nevertheless, MNT has been stated to cause painless multiple ecchymotic lesions of 3-5 cm in the lower extremities of a 31-year-old woman known to have moderate persistent asthma, and AR (Aypak et al., 2013). Also, early concerns were attributed to the development of LTRAs-induced Strauss-Cherg syndrome in patients with asthma.

Nevertheless, the development of this syndrome was found to be attributed to corticosteroids withdrawal, indicating that LTRAs unmasked a pre-existing Churg-Strauss syndrome (Van Hoecke et al., 2007). MNT, the commonly used and only approved LTRAs, have been thoroughly studied and prescribed in asthma since the late 1990s following multiple large, randomized, controlled clinical trials (Nayak & Langdon, 2007). It has a half-life of five hours and is administered once daily. Further, the recommended dose in adults is 10mg, 5mg in children from 6-14 years, and 4mg between 2 to 5 years of age (Van Hoecke et al., 2007).

Evidence-Based Medicine

Chen et al. had conducted an RCT on 46 participants, assessing the efficacy of MNT in addition to nasal budesonide (CD) compared to BD alone. Both regimens significantly improved the five main AR symptoms; however, the combination therapy provides superior efficacy than BD alone in nasal blockage, itching, and subclinical lower airway inflammation (Chen et al., 2021). Moreover, a single-center, randomized, open-label study comparing the efficacy of MNT and half-dose nasal BD combination to MNT or BD alone was conducted for 100 AR patients. The study resulted in significantly greater nasal congestion improvements than BD or MNT alone (Chen et al., 2018). Another RCT by Yamamoto et al. had examined the prophylactic efficacy of adding loratadine (antihistamine) to MNT compared to MNT alone. Similarly, the combination therapy provided a significant reduction in total scores of nasal symptoms (P<0.05), sneezing (P<0.05), and rhinorrhea (P<0.05) when compared to placebo addition to MNT (Yamamoto et al., 2012). Also, Hung et al. had measured the exhaled nitric oxide (eNO) in children with perennial AR in response to four regimens; loratadine, loratadine with nasal cromoglycate, loratadine with oral MNT, and loratadine with nasal BD. The eNO, a simple and non-invasive method for assessing inflammatory airway disease, was successfully reduced in the nasal BD and MNT groups. Notably, children with perennial AR with high eNO levels might require oral MNT or nasal BD to prevent airway hyperresponsiveness (Hung et al., 2007).

In addition, a systematic review of seven investigations, such as 6,231 grown-ups with AR, evaluated the effectiveness of oral MNT monotherapy compared to MNT compounds. As a result, oral MNT extremely decreased, nocturnal nasal symptoms, quality of life compared with placebo, ocular symptoms, and daytime nasal symptoms. However, there was no considerable dissimilarity in oral antihistamine compared with oral MNT on nasal symptoms, eyesight, and life quality. In addition, MNT was lower in reducing nasal symptoms day and night compared to nasal BD. The mixture of antihistamines and MNT also provided more relief from ocular symptoms than antihistamines alone. Finally, nasal BD particularly reduced nasal congestion compared to the combination of MNT and antihistamines (Rodrigo & Yañez, 2006). According to the Rhinitis Severity Score (RSS), MNT, azelastine, and BD were compared in AR patients using RSS. Compared to placebo all three drugs were effective, but MNT was the most influential of the three drugs in relieving palate itching, throat, and ocular itching (Sardana et al., 2010). Further, a systematic review and meta-analyses were conducted by Wilson et al., evaluating the efficacy of oral MNT compared with antihistamine and nasal BD. 11 studies were selected and showed that MNT is effectively better than placebo, a similar effect to antihistamines, but less effective than nasal BD in improving nasal, rhinoconjunctivitis and quality of life for AR patients (Wilson et al., 2004).

Liu et al. had conducted a meta-analysis comparing oral LTRA alone with combined LRTA with an antihistamine. Likewise, the combination therapy increased the therapeutic efficacy against daytime and composite nasal symptoms, including rhinorrhea, sneezing, and itching; nonetheless, it does not affect nighttime nasal symptoms and eye symptoms (Liu et al., 2018). Feng et al. conducted another meta-analysis and assessed the efficacy of oral LTRA compared with an oral antihistamine. While the 2 treatments are secure and influential in enhancing the AR patient's life quality, LTRA is better influential in enhancing nocturnal symptoms but less sufficient in enhancing during the day symptoms compare to antihistamines (Feng et al., 2021). Likewise, among nine studies with 5781 AR participants, Xu et al. had conducted a meta-analysis evaluating the safety and efficacy of selective antihistamine vs. LTRA. The meta-analysis showed that LTRA provides a greater effect for nighttime symptoms (difficulty going to sleep, nighttime awakening, and nasal congestion on awakening), the selective antihistamine is more effective for daytime nasal symptoms (congestion, rhinorrhea, pruritis, and sneezing) (Liu et al., 2016).

In addition, recent instruction suggests the use of LTRA in patients with AR and asthma, as it enhances both illnesses, however, this first-line treatment is not for independent AR. The FDA authorized LTRA (montelukast) for the treatment of seasonal AR in grown-ups and patients with children over two years of age and permanent AR in grown-ups and children over six months of age (Seidman et al., 2015). Based on the 2017 Joint Task Force on Practice Parameters, Intranasal corticosteroids for primary treatment of seasonal AR in patients over 15 years of age are superior to LTRA. (Wallace et al., 2017).

Conclusion

Allergic rhinitis is one of the commonest disorders worldwide, with a significant burden on healthcare costs, the productivity of patients, and life quality. Leukotriene receptor antagonists are an effective agent in an asthmatic patient. However, current guidelines recommend its use when allergic rhinitis coexists with asthma due to its beneficial effect in both conditions. LTRA, when combined with an antihistamine or nasal corticosteroids, provides a more significant effect than LTRA monotherapy. Additionally, nasal corticosteroids appear to provide a greater beneficial effect in comparison to LTRAs. Hence, the beneficial use of LTRA in allergic rhinitis must outweigh the risks, including side effects and costs.

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