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Review / Derleme
Role of leukotriene antagonists and antihistamines in
treatment of allergic rhinitis and asthma comorbidity
Alerjik rinit ve ast›m komorbiditesinin tedavisinde lökotriyen antagonisti ve
antistaminiklerin rolü
Ayfle Baçç›o¤lu1, Arzu Yorganc›o¤lu2, Cemal Cingi3, Ça¤lar Çuhadaro¤lu4
1Department of Immunology and Allergy, Erzurum Region Training and Research Hospital, Erzurum, Turkey 2Department of Chest Diseases, Celal Bayar University Medical Faculty, Manisa, Turkey 3Department of Otorhinolaryngology, Osmangazi University Medical Faculty, Eskiflehir, Turkey 4Department of Chest Diseases, Ac›badem University, ‹stanbul Turkey Abstract
Leukotriene receptor antagonists and antihistamines are efficient in Yaln›z bafllar›na veya kombinasyon fleklinde kullan›ld›klar›nda lökotri- reducing symptoms of allergic rhinitis and asthma when used alone or yen reseptörleri ve antistaminikler alerjik rinit semptomlar›n› azaltma- in combination. In patients with allergic rhinitis, H1-antihistamines da etkilidir. Alerjik rinit hastalar›nda H1 antistaminikleri alerjene yan›- prevent and relieve the sneezing, itching, rhinorrhea, and nasal conges- t›n erken ve geç dönem yan›tlar› olan aks›rma, kafl›nma, burun akmas› tion that characterize the early and the late response to allergen. H1- ve nazal konjestiyonu önlemekte ve geçirmektedir. Ast›m hastalar›nda antihistamines are not medications of choice in asthmatic patients, but H1-antistaminikleri seçilecek ilaçlar olmamalar›na ra¤men rinitin kon- controlling rhinitis will improve asthma concomitantly. Leukotriene trol alt›na al›nmas› ayn› zamanda ast›m› da iyilefltirecektir. Orta-a¤›r de- antagonist such as montelukast may be an alternative treatment for mild recede fliddetli inatç› ast›mda inhale kortikosteroidin ek tedavi olarak persistent asthma as monotherapy where inhaled corticosteroid cannot verilemedi¤i veya uzun etkili beta agonistin alternatif olmad›¤› durum- be administered or alternative to long-acting beta agonist as an add-on larda hafif derecede ve inatç› ast›m›n alternatif tedavisi olarak montelu- therapy to ICS for moderate to severe persistent asthma. Although kast gibi bir lökotriyen antagonistiyle monoterapi uygulanabilir. Alerjik montelukast is an effective drug in allergic rhinitis indicated as rinitte monoterapi olarak montelukast etkili bir ilaç olmas›na ra¤men monotherapy, but widely recommended as adjunct to antihistamine or yayg›n olarak antistamin veya intranazal kortikosteroide ek olarak öne- intranasal corticosteroid. Antileukotriene agents are also widely used in rilmektedir. Antilökotriyen ilaçlar yine pediyatrik ast›m›n tedavisinde the treatment of pediatric asthma. In children, maintenance treatment yayg›n biçimde kullan›lmaktad›r. Çocuklarda kortikosteroitler inhalas- with inhaled corticosteroids in pure episodic (viral) wheeze was ineffec- yonlar›yla idame tedavisi olarak saf epizodik (viral) h›fl›lt›l› solunum tive, but maintenance as well as intermittent montelukast was shown to (wheezing) tedavisinde etkisiz olmalar›na ra¤men hem devaml› hem de have an efficient role in both episodic and multi trigger wheeze.
aral›kl› olarak verilen montelukast›n hem epizodik hem de birden fazla Furthermore, their advantage to inhaled corticosteroids is that tetikleyici faktörü olan wheezingde etkili bir rolü oldu¤u gösterilmifltir.
leukotriene receptor antagonists do not affect short-term lower leg Ayr›ca, lökotriyen reseptör antagonistlerinin prepubertal çocuklarda k›- sa vadede alt ekstremite geliflme h›z›n› olumsuz etkilememesi kortikos-teroit inhalasyon tedavisine göre avantajlar›n› oluflturmaktad›r. Key words: Leukotriene antagonist; antihistamines; allergic rhinitis;
Anahtar sözcükler: Lökotrien antagonisti; antihistaminik: alerjik ri-
Allergy is a reaction with inflammatory cell infiltration in E dependent reaction characterized by an early and late the target organ which allergen has been found to cause phase reaction. Histamine is released after 15 min of expo- the pathology.[1,2] Allergens cause an immunoglobulin (Ig) sure to allergen, whereas leukotriene is increased in the Correspondence: Ayfle Baçç›o¤lu, MD. Department of Immunology and Allergy,
Erzurum Region Training and Research Hospital, Erzurum, Turkey.
Received: fiubat / February 13, 2013; Accepted: Mart / March 12, 2013;
Published online: May›s / May 4, 2013
2013 Sürekli E¤itim ve Bilimsel Araflt›rmalar Derne¤i (SEBAD) Role of leukotriene antagonists and antihistamines in treatment of allergic rhinitis and asthma comorbidity early as well as the late phase of the allergic reaction.
The Role of Antihistamines in Allergic Rhinitis
These and other mediators lead to vasodilatation, and Asthma
increased permeability, and bronchoconstriction, which H1-antihistamines are widely used in the treatment of aller- result to rhinitis, asthma and urticaria.[3] Allergic rhinitis gic and nonallergic disorders.[11] In patients with allergic has a wide range of comorbidities such as asthma, rhinos- rhinitis, second generation H1-antihistamines prevent and inusitis, dermatitis, and conjunctivitis.[4] relieve the sneezing, itching, rhinorrhea, and nasal conges-tion that characterize the early and the late response to The Link Between Allergic Rhinitis and Asthma
allergen.[10] In the treatment of allergic rhinitis, oral H1- About 70-90% of asthmatics have rhinitis, and 10-40% of antihistamines are more efficacious than chromones; but rhinitics are reported to have asthma.[1,2] Allergen-specific less efficacious than nasal glucocorticoids.[11] In a study done challenge of rhinitic patients also causes an increased comparing nasal H1-antihistamine and nasal glucocorticoid response of bronchi with the presence of eosinophilia in in patients with allergic and nonallergic rhinitis, azelastine secretions from the nose and sputum.[5] Non-allergic dis- was as effective as triamcinolone in improving nasal symp- eases of the nose, such as common cold or sinusitis, can toms; sleep symptoms and quality of life.[12] often lead to the development or worsening of asthmasymptoms.[6] In conclusion, there is an increased risk that H1-antihistamines are not medications of choice in asthma will develop in patients with either allergic rhinitis asthmatic patients. However, comorbidity of asthma and or non-allergic persistent rhinitis, thus uncontrolled aller- allergic rhinitis is very high (80%) and they have clinically gic rhinitis can lead to worsening of co-existing asthma.[1,6] relevant antiasthmatic properties by controlling rhinitis.[13] Furthermore, having comorbidity in rhinitis or asthma Confirming this statement, it was shown that antihistamines also impairs quality of life.[7] Therefore a strategy should have reduced asthma symptoms in patients with seasonal combine the treatment of upper and lower airways in allergic rhinitis when given alone or in combination with an terms of efficacy and safety. There are three major classes antileukotriene.[14] The early treatment of atopic child of commonly used allergicrhinitis medications-intranasal (ETAC) study also showed that the onset of asthma was corticosteroids, antihistamines, and antileukotrienes.[1] prevented by continuous antihistamine treatment.[15] Combination of antihistamine and montelukast is a thera- Therefore, H1-antihistamines appear to provide indirect peutic option in allergic rhinitis that would benefit from benefit in patients with concomitant asthma and allergic successful inhibition of persistent inflammation.[8] Antihistamines
Antileukotrienes
Antihistamines downregulate allergic inflammation by Leukotriene modifiers represent the first mediator specific interfering with histamine action at histamine-1 (H1) therapeutic option for rhinitis and asthma.[16] receptors on sensory neurons, and small blood vessels.[9] Antileukotrienes are classified in two groups; cysteinyl H1-antihistamines are functionally classified into 3 leukotriene receptor antagonists (LTRAs) – zafirlukast, groups. First generation antihistamines have poor H1 pranlukast, and montelukast – block the leukotriene recep- receptor selectivity, and cross the blood brain barrier, tor and thus block the end organ response of leukotriene.[16] whereas second and third generation antihistamines are Zafirlukast is a leukotriene (LT) D4 receptor antagonist and highly selective for the H1 receptor, and do not cross the is efficient in LTD4 induced bronchoconstriction, early and blood brain barrier.[10] Third generation antihistamines are late responses, exercise challenge, cold induced asthma, and the active enantiomer (levocetirizine) or metabolite chronic asthma. Leukotriene synthesis inhibitors – zileuton (desloratadine and fexofenadine) derivatives of second – block the biosynthesis of cysteinyl leukotrienes. Zileuton generation drugs (cetirizine, loratadine, terfenadine).
is a 5-lipoxygenase inhibitor and is used in exercise, cold, They intended to have increased efficacy with fewer aspirin induced bronchial hyper-responsiveness. There are adverse drug reactions.Some antihistamines, such as fex-ofenadine, have a strong interaction with grapefruit also FLAP inhibitors, which are not approved by food and juice.[11] The overall safety profiles of antihistamines such drug administration, but they have benefits in early and late as levocetirizine and desloratadine were similar to placebo allergic responses and cold induced asthma.[16] in children and adults, which had been confirmed in ran- Montelukast is the prevalent used antileukotriene, and is the only such agent approved for use in pediatric Cilt / Volume 3 | Say› / Issue 1 | Nisan / April 2013
patients.[17] It does not have any documented interactions sites of inflammation when combined to inhaled corticos- with food, nonetheless, recently an interaction was report- teroid therapy which was shown by a higher reduction in ed that showed an increase of plasma concentration of fractional exhaled nitric oxide levels-a marker of inflam- montelukast after excessive grapefruit juice intake due to mation- in combination therapy than inhaled corticos- cytochrome p450.[18] Patient satisfaction and compliance was better with montelukast than inhaled antiinflammato- Antileukotriene agents are also widely used in the ry agents due to oral, and once a day administration.[19] treatment of pediatric asthma. In children maintenance Furthermore, it provides a safe and effective additional treatment with inhaled corticosteroids in pure episodic antiinflammatory treatment option not only for asthma (viral) wheeze was ineffective, but maintenance as well as and rhinitis but also for chronic obstructive disease.[20] intermittent montelukast was shown to have an efficientrole in both episodic and multi trigger wheeze.[24] The Role of Antileukotrienes in Allergic
Furthermore, their advantage to inhaled corticosteroids is Rhinitis and Asthma
that LTRAs do not affect short-term lower leg growth Presently, the available evidence does not support routine use of oral LTRAs in acute asthma.[21] However, trials of Leukotriene receptor antagonists have particular bene- intravenous treatment of LTRAs in adults and children fit for patients with exercise-induced asthma. They can be demonstrated a reduction in the risk of hospital admission used prior to exercise to prevent exercise-induced bron- which was not quite statistically significant, and a statisti- choconstriction just as short or long acting beta2 ago- cally significant small increase in FEV1 was determined in Leukotriene receptor antagonists have beneficial At present, antileukotrienes serve as alternative effects in aspirin-sensitive rhinitis and asthma besides cor- monotherapy to inhaled corticosteroids in the manage- ticosteroids.[21,27] Aspirin sensitivity is characterized by ment of mild persistent asthma in adults and children.[21] As intense eosinophilic inflammation of nasal and bronchial monotherapy in adults and children with persistent asth- tissues in non-atopic patients with chronic rhino-sinusitis ma and moderate airway obstruction, inhaled corticos- and/or nasal polyps.[21] Montelukast reduces peripheral teroids were superior in most secondary outcomes includ- blood eosinophilia, but do not affect tissue eosinophilia.[27] ing exacerbation requiring hospital admission, FEV1 and Corticosteroids are the mainstay of treatment in aller- other lung function parameters, asthma symptoms, noc- gic rhinitis, however montelukast may be considered as an turnal awakenings, rescue medication use, symptom-free additional agent especially in treatment of patients with days, the quality of life, parents’ and physicians’ satisfac- impaired quality of life and it may be used to reduce nasal tion.[22] Furthermore, antileukotriene therapy was associat- symptom scores and to improve the disease-specific quali- ed with increased risk of withdrawals due to poor asthma ty of life.[2,28,29] Although montelukast is an effective drug in control and exacerbation requiring systemic corticos- allergic rhinitis to decrease nasal inflammation and limit teroids. On the other hand, asthma control may remain nasal congestion, sneezing, and rhinorrhea, indicated as suboptimal when relying on inhaled corticosteroid monotherapy, but widely recommended as adjunct to anti- because of problems with compliance, poor inhaler tech- histamine or intranasal corticosteroid.[11] These agents pri- nique and concerns about the side effects of steroids.[17] In marily help with congestion and are particularly useful in this case, montelukast may be an alternative treatment for asthmatics where they may have the double benefit of mild persistent asthma as monotherapy where inhaled cor- In nasal polyposis, surgery and corticosteroids is the Leukotriene receptor antagonists have indication as mainstay of treatment.[1] However, there exists an add on therapy to inhaled steroids as alternative to long increased leukotriene production in nasal polyps, and acting beta2 agonists in moderate-severe persistent asth- antileukotrienes, especially montelukast, may represent a ma.[21] In comparison of long acting beta2 agonists as an potential effective therapy.[30,31] In a recent study it was add-on therapy to inhaled corticosteroid in patients with shown that montelukast therapy might have a clinical ben- moderate to severe persistent asthma, montelukast was efit as an adjunct to nasal steroids in subjects with nasal found to be less efficacious and less cost-effective.[22] polyposis accompanying bronchial asthma in means of rhi- However, LTRAs might decrease small airway/alveolar Journal of Medical Updates
Role of leukotriene antagonists and antihistamines in treatment of allergic rhinitis and asthma comorbidity Antileukotrienes are also used in allergen specific bining montelukast with either levocetirizine or deslorata- immunotherapy concomitantly to prevent local and sys- dine gave additional benefits in comparison to each agent temic reactions. Studies showed that both antihistamines in patients with persistent allergic rhinitis.[38] Another and montelukast pretreatment have been shown to reduce study showed that, fexofenadine with montelukast combi- anaphylactic side effects when used alone which improved nation therapy was more effective than fexofenadine alone patients' adherence to specific immunotherapy.[33] in means of allergic rhinitis symptoms, and rhinomanom-etry results.[39] Combination of H1-Antihistamine and
Some studies reported no further benefit of combina- Cysteinyl Leukotriene Receptor Antagonist
tion of montelukast and antihistamine than used alone.
Both antihistamines and antileukotrienes have been found Fexofenadine as monotherapy was shown to be equally to be useful when used alone in allergic rhinitis and asth- effective as the combination of montelukast and levoceti- ma. Combination of both drugs showed a synergistic rizine in improving nasal peak flow and controlling symp- effect in treating seasonal allergic rhinitis.[34] The first toms in seasonal allergic rhinitis and asthma.[40] Similarly, a combination treatment studies with montelukast was done study of patients with seasonal allergic rhinitis found that with second generation antihistamines such as loratidine the combination of loratadine and montelukast was no and cetirizine, followed by combinations with third gener- more effective than montelukast alone on day-time or ation antihistamines-fexofenadine, desloratadine, levoceti- night-time symptoms.[41] Furthermore, similar efficiency rizine. Then fixed combinations of montelukast-levoceti- of monotherapy and combined therapy of antihistamine or rizine and montelukast-desloratadine tablets were aiming antileukotriene was only found in patients with mild per- to increase the quality of life of the patients. sistent rhinitis, and further studies are required to evaluateputative additivity of response with combined therapy in The Role of Combination of H1-Antihistamine
and Cysteinyl Leukotriene Receptor
Antagonist in Allergic Rhinitis

The Role of H1-Antihistamine and Cysteinyl
Leukotriene Receptor Antagonist in Asthma

It is reported that antihistamines and antileukotrieneshave been found to be useful when used alone in allergic In asthma, montelukast is given on regular basis to reduce rhinitis and asthma. Combination of antihistamines and eosinophilic airway inflammation. Addition of the antihis- antileukotrienes showed a synergistic effect in treating tamine can amplify the early and late anti-inflammatory seasonal allergic rhinitis. But further studies are needed activities of montelukast.[17] Combination therapy syner- for fized combinations. In a study of patients with season- gistically inhibits the allergen-induced early asthmatic al allergic rhinitis showed that neither loratadine nor response, and montelukast also suppresses the allergen- montelukast, when used on their own, conferred any ben- induced late asthmatic response.[17,37] As a result combina- efit in terms of improving day-time nasal symptoms, while tion of antihistamine and LTRAs has an effect that is day-time nasal symptoms were significantly improved greater than that of either drug given alone.[37] when the two drugs were combined.[35] Similarly, mon- In a randomized study of two combinations of antihis- telukast plus cetirizine treatment started 6 weeks before tamine plus [in patients with seasonal allergic rhinitis and the pollen season was effective in preventing allergic rhini- mild intermittent asthma, after 2 weeks cetirizine might tis symptoms and reduces allergic inflammation in nasal exert more beneficial activity than desloratadine when mucosa during natural allergen exposure.[36] In persistent added to montelukast as shown by the reduced nasal allergic rhinitis, montelukast, levocetirizine, desloratadine, symptoms, inflammatory cells and cytokines in nasal and the montelukast/antihistamine combinations signifi- lavage. In this study antileukotriene-antihistamine combi- cantly improved nasal symptoms during the first 24 hours, nations were only effective in relieving nasal symptoms, but improvement at the end of 6 weeks was significantly but control of rhinitis may have a positive effect on asth- greater than that achieved on the 1st day of therapy in ma later. In a randomized study of patients with mild-to- patients treated with montelukast alone or in combination moderate atopic asthma, after 26 hours of the treatment, therapy with the antihistamine.[37] In a 32-week random- early response to inhaled allergen was unchanged after ized study, placebo, montelukast, desloratadine and levo- desloratadine therapy and partially inhibited with mon- cetirizine significantly improved quality of life, but com- telukast therapy, whereas combination of desloratadine Cilt / Volume 3 | Say› / Issue 1 | Nisan / April 2013
and montelukast provided superior efficacy to either 3. Canonica GW. Introduction to nasal and pulmonary allergy cas- 4. Cingi C, Catli T. Phenotyping of allergic rhinitis. Curr Allergy Antileukotriene-antihistamine combinations when used as either monotherapy or add-on therapy to local 5. Passalacqua G, Ciprandi G, Canonica GW. The nose-lung inter- corticosteroids have been shown to attenuate the response action in allergic rhinitis and asthma: united airways disease. Curr to adenosine monophosphate-a sensitive marker of inflammatory process in airways further reinforcing the 6. Settipane G, Settipane RJ, Hagy GW. Long-term risk factors for concept of the united allergic airway.[43] The putative ben- developing asthma and allergic rhinitis: a 23-year follow-up studyof college students. Allergy Proc 1994;15:21-25.
efits of such combination therapy certainly become evi- 7. Kalpaklio¤lu AF, Baççio¤lu A. Evaluation of quality of life: impact dent when looking at concomitant effects on asthma con- of allergic rhinitis on asthma. J Investig Allergol Clin Immunol trol in patients who have concomitant allergic rhinitis.
In a multicentricrandomised double-blind crossover 8. Canonica GW, Compalati E. Minimal persistent inflammation in study comparing single-dose placebo, 5 mg desloratadine, allergic rhinitis: implications for current treatment strategies. ClinExp Immunol 2009;158:260-71. 10 mg montelukast and the combination administered 2 h 9. O’Mahony L, Akdis M, Akdis CA. Regulation of the immune prior to allergen inhalation challenge showed that single- response and inflammation by histamine and histamine receptors.
dose co-administration of desloratadine and montelukast 2 J Allergy ClinImmunol 2011;128(6):1153-62.
h prior to allergen inhalation clinically abolished the late 10. Criado PR, Criado RF, Maruta CW, et al. Histamine, histamine atopic asthmatic response in means of eosinophil recruit- receptors and antihistamines: new concepts. An Bras Dermatol ment and exhaled NO levels. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed 11. Kalpaklioglu F, Baccioglu A. Efficacy and safety of H1-antihist- at 7 h with desloratadine and combination therapy, and at amines: an update. Antiinflamm Antiallergy Agents Med Chem2012;11:230-7.
24 h with montelukast and combination therapy.[44] 12. Kalpaklioglu AF, Kavut AB. Comparison of azelastine versus tri- In a study with patients of mild-to-moderate persistent amcinolone nasal spray in allergic and nonallergic rhinitis. Am J asthmatics, treatments of montelukast + desloratadine, montelukast alone and placebo were given 10-14 h prior to 13. Yamauchi K, Shikanai T, Nakamura Y, et al. Roles of histamine in challenge with mannitol. Both montelukast/desloratadine the pathogenesis of bronchial asthma and reevaluation of the clini-cal usefulness of antihistamines. Yakugaka Zasshi 2011;131:185-91.
and montelukast compared to placebo, shortened recovery 14. Roquet A, Dahlén B, Kumlin M, et al. Combined antagonism of following both challenges. Montelukast was not significant- leukotrienes and histamine produces predominant inhibition of ly different from placebo montelukast/desloratadine combi- allergen-induced early and late phase airway obstruction in asth- nation on AHR and recovery time, highlights the relative matics. Am J Respir Crit Care Med 1997;155:1856-63.
roles of histamine in initiating the bronchoconstrictor 15. Warner JO; ETAC Study Group. Early Treatment of the Atopic response and cysteinylleukotrienes in sustaining it.[45] Child. A double-blinded, randomized, placebo-controlled trial ofcetirizine in preventing the onset of asthma in children with atopic In conclusion, antihistamines and antileukotrienes as dermatitis: 18 months’ treatment and 18 months’ posttreatment monotherapy significantly improves nasal symptoms, with follow-up. J Allergy Clin Immunol 2001;108:929-37.
the expectation of additional benefit conferred by combi- 16. Bäck M, Dahlén SE, Drazen JM, et al. International Union of Basic and Clinical Pharmacology. LXXXIV: leukotriene receptornomenclature, distribution, and pathophysiological functions.
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Conflict of Interest: No conflicts declared.
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to an antileukotriene in treating seasonal allergic rhinitis: hista- This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported (CC BY-NC-ND3.0) Licence (http://creativecommons.org/licenses/by-nc-nd/3.0/) which permits unrestricted noncommercial use, distribution, and reproduc-tion in any medium, provided the original work is properly cited.
Please cite this article as: Baçç›o¤lu A, Yorganc›o¤lu A, Cingi C, Çuhadaro¤lu Ç. Role of leukotriene antagonists and antihistamines in treatment of aller-gic rhinitis and asthma comorbidity. J Med Updates 2013;3(1):34-39.
Cilt / Volume 3 | Say› / Issue 1 | Nisan / April 2013

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