Over the past three decades the pharmacotherapy of asthma has been based on glucocorticoids, ß2 agonists and theophyllines. Research conducted over the past 10 years has led to greater understanding of the cellular and molecular basis of asthma, particularly the role of the underlying inflammatory process.peer-reviewe

Cordina, Maria

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No3 Summer 1999 thechronic✱ill         7Over the past three decades thepharmacotherapy of asthma hasbeen based on glucocorticoids, ß2agonists and theophyllines.Research conducted over the past10 years has led to greaterunderstanding of the cellular andmolecular basis of asthma,particularly the role of theunderlying inflammatory process.Both national and internationalguidelines stress the importance ofswitching off the inflammatory cascade(Figure 1).  Glucocorticoids are themost effective anti-inflammatoryagents available and in many countries,including Malta, they are used as firstline treatment.  However, despite theirproven safety and efficacy, there arestill a number of patients whose asthmais not adequately controlled and as aconsequence have a poor quality of life.The search for alternativeThe Treatmentof Asthma withLeukotrieneReceptorAntagonistsMaria Cordina B.Pharm.(Hons.), Ph.D. (QUB)pharmacological agents that targetairway inflammation and ease theproblem of compliance has led to anovel class of non-steroidal anti-asthmadrugs which are effective over a widerange of asthma severity, have a hightherapeutic index, are orally active andhave a once daily or twice dailyregimen.  Leukotriene receptorantagonists are a hybrid between apreventer of inflammation (antagonismof inflammatory activities ofleukotrienes) and bronchodilatingreliever (antagonism of leukotrieneinduced smooth musclebronchoconstriction).  Currentlyavailable on the local market iszafirlukast (Accolate®, Zeneca) which isa cysteinyl leukotriene antagonist.Another drug within this class, howevernot as yet available locally, ismontelukast (Singulair®, Merck).What are leukotrienes?Leukotrienes are a group ofarachidonic acid derivatives that areproduced during asthmatic reactions bycells involved in the pathogenesis ofasthma and other inflammatorydiseases.  The cysteinyl leukotrienes C4(LTC4), D4 (LTD4) and E4 (LTE4) areimportant mediators of inflammation.They are formed in many cells includingmast cells and eosinophils and arepotent inducers of bronchoconstriction,plasma exudation and mucusproduction.How do the new anti-leukotriene drugs work?There are currently four classes ofanti-asthma and anti-inflammatorydrugs which interfere with leukotrienesynthesis or activity which are underdevelopment as seen in Figure 2.  Theseare 5-lipoxygenase inhibitors and 5-lipoxygenase activating protein (FLAP)inhibitors which block the synthesis ofcysteinyl leukotrienes and theCompletion of Assessment Questions following this articleentitles members to one credit towards C.E. requirement.Genetic influenceFigure 1   The inflammatory cascade in asthmaAirway inflammationTriggering factorsRelease of MediatorsTwichy smooth muscle+ • Avoidance• Inhaledglucocorticoids•  Leukotrieneantagonists• ß2 agonists8 thechronic✱ill No3 Summer 1999leukotriene B4 (LTB4).  The third classare competitive antagonists of LTB4.The drugs which are currently availablein Malta and the UK are those of the4th class and act by competitivelyblocking the activity of cysteinylleukotrienes at the LTD4 receptor.  Theyare termed cysteinyl leukotrienereceptor antagonists.When should leukotrienereceptor antagonists be used?The local guidelines on themanagement of asthma issued by theMalta Lung Study Group do not mentionthe use of leukotriene receptorantagonists.  However, these guidelinesare in the process of being revised.  Theposition of these drugs in theinternational guidelines is still uncleardue to the lack of published data at thetime of drawing up these guidelines.  Itis debatable whether these drugsshould be used as first-line preventivemonotherapy instead of low doseinhaled corticosteroids in patients withmild persistent asthma or as analternative to long-actingbronchodilators, i.e. second-linetherapy, in addition to inhaledcorticosteroids in patients withmoderate to severe persistent asthma.It is important to note thatleukotriene receptor antagonists shouldbe taken on a regular basis to achievebenefit, even during symptom freeperiods and should normally becontinued during acute exacerbationsof asthma.  However, they are notindicted to relieve an attack of acutesevere asthma.In the UK, zafirlukast is licensed foruse in patients aged 12 years and over.It may be used as first line therapyinstead of inhaled corticosteroids inmild persistent asthma.  Montelukast islicensed in patients aged 6 and over assecond line asthma treatment incombination with inhaledcorticosteroids and as monotherapy inexercise induced asthma.Clinical considerationsZafirlukast and montelukast bothachieve peak plasma concentrationsapproximately 3 hours after oraladministration.  There is a 40%decrease in the bioavailability ofzafirlukast when taken with food; it istherefore recommended that the tabletsshould not be taken with food as thiscould lead to a decreasedpharmacological response.  Co-adminstration of zafirlukast witherythromycin, theophylline orterfenadine results in a decrease in theplasma concentration of zafirlukast,while an increase results when it is co-administered with aspirin.  In smokersthe clearance of zafirlukast may beincreased by about 20%.  Prescribinginformation regarding the use ofzafirlukast states that the safety of thisdrug in pregnancy has not beenestablished and since it is excreted inbreast milk it should not beadministered to lactating mothers.Official montelukast prescribinginformation advises that the use ofmontelukast is avoided in pregnancyand lactation unless essential.ConclusionLeukotriene receptor antagonistsrepresent an important advance inasthma therapy.  They are active over awide range of asthma severity and haveboth an anti-inflammatory and abronchodilator property.  They areactive orally, therefore overcoming thepotential problems with compliancewhen using inhalers.They also act within the first 24hours while inhaled corticosteroids takea much longer time to achieve maximalThe literature suggests that leukotrienereceptor antagonists may be of particular use in:• exercise induced asthma• asthmatics who are intolerant to aspirin and other non-steroidalanti- inflammatory drugs• nocturnal asthma• asthmatics who concomitantly present with allergic rhinitis.Figure 2 The four groups of anti-asthma and anti-inflammatory drugsdirected against LT synthesis and activity5-LO inhibitorse.g. zileutonLTB4 antagonistse.g. U-75,302FLAP inhibitorse.g. MK-886Cysteinyl-LT antagonistse.g. zafirlukast, pranlukast,montelukastArachidonic Acid5-Lipoxygenase FLAPLTB4LTC4  LTD4  LTE4LTA4ChemotaxisImmunomodulationBronchoconstrictionMucus secretionOedemaHyperrespnsivenessEosinophiliaTable 1 Leukotriene Receptor AntagonistsGeneric Propriety Oral dose Other informationZafirlucast Accolate 20 mg bd Take 1hr before or 2hr(Zeneca) after eating.Montelukast Singulair Adults: Paediatric dose(Merck) 10 mg at night available aschewablePaed: (6-12yr): tablets.5 mg at nightNo3 Summer 1999 thechronic✱ill         9response.  However, when compared to inhaledbeclomethosone 400 micrograms daily both the abovementioned drugs appear to be less effective in mild tomoderate asthmatics.  They are comparable in cost to longacting ß2 agonists but more expensive than low dose inhaledsteroids.While further long term studies are required to determinethe position of these drugs in asthma treatment guidelines,they provide oral, safe and effective therapy. ✱1. The inflammatory processin asthma is:a. of secondary importanceb the main pathologicalprocess in asthmac the target of all anti-asthma drugsd all of the above.BibliographyDahlen, S-E, Bjork, J., Hedqvist, P.,et al.  (1981)  Leukotrienespromote plasma leakage andleukocyte adhesion in post-capillary venules: in vivo effectswith relevance to the acuteinflammatory response.Proceedings of The NationalAcademy of Sciences USA, 78:3887-3891.-Dahlen, S-E, Hedqvist, P.,Hammarstrom, S. andSamuelsson, B.  (1980)Leukotrienes are potentconstrictors of human bronchi.Nature, 288: 484-486.Drazen, J.M., Israel, E. and O’Byrne,P.M.  (1999)  Treatment ofasthma with drugs modifyingthe Leukotriene pathway.  NewEngland Journal of Medicine,340: 197-206.Geddes, D.  (1992)  Inhaledcorticosteroids: benefits andrisks.  Thorax, 47:404-407.Holgate, S.T., Bradding, B.M. andSampson, A.P.  (1996)Leukotriene antagonists andsynthises inhibitors: newdirections in asthma therapy.Journal of Allergy and ClinicalImmunology, 98:1-13.Lipworth, B.J.  (1999)Leoukotriene-receptorantagonists.  Lancet, 353:57-62.Lipworth, B.J.  (1999)  Moderntreatment of modern asthma.British Medical Journal, 318:380-384.Malta Lung Study Group.  (1998)Asthma: Guidelines forManagement.  Department ofHealth, Malta.Marom, Z., Shelhamer, J.H., Bach,M.K., Morton, D.K. and Kaliner,M.  (1982)  Slow-reactingsubstances, leukotrienes C4, D4and E4.  Proceedings of TheNational Academy of SciencesUSA.  American Review ofRespiratory Disease, 126: 449-451.National Asthma Education andPrevention Programme.  (1997)Expert panel report II:.Guidelines for the diagnosis andmanagement of asthma.Bethesda: National Institutes ofHealth Publication, 97-4051.Taylor, I.K.  (1995)  CysteinylLeukotrienes in asthma: currentstate of therapeutic evaluation.Thorax, 50:1005-1010.The Treatmentof Asthma withLeukotrieneReceptorAntagonistsAssessmentQuestions:2. Which of the followingstatements is true?a. Leukotrienes arearachidonic acidderivativesb. Leukotrienes are onlyinvolved in thepathogenesis of asthmac. Leukotrienes are onlyproduced in mast cellsd. Leukotrienes are notinvolved in mucusproduction.Select only ONE option in each questionby ticking the respective boxon the Response Sheet (page 39).10 thechronic✱ill No3 Summer 19993. Leukotriene receptorantagonists area. non-steroidal drugsb. enhance theinflammatory processc. steroidal drugsd a combination of answersa and b.4. Leukotriene receptorantagonistsa. have anti-inflammatoryactivitiesb. act in the same way as ß2agonistsc. have bronchodilatingeffectsd. a combination of answersa and c.5. Leukotriene receptorantagonists currentlyavailable on the localmarket area. pranlukastb. montelukastc. zafirlukastd. salbutamol6. The cysteinyl leukotrienereceptor antagonists actbya reducing arachidonicproductionb. reducing FLAP synthisesc. competing with the LTB4receptord. blocking the LTD4receptor.7. Which of the followingstatements is truea. an example of a 5-lipoxygenase inhibitor ismontelukastb. LTD4 is a not cysteinylleukotrienec. zafirlukast is a cysteinylleukotriene receptorantagonistd. cysteinyl leukotrienereceptor antagonists areineffective if taken withinhaled corticosteroids.12. Which of the followingstatements is true?a. zafirlukast is licensedonly for use in patientsover 12 years of age.b. zafirlukast is alsolicensed for use inchildren over 6 years ofagec. montelukast is of no usein exercise inducedasthmad. montelukast has a lowtherapeutic index.13. Zafirlukast andmontelukast achieve peakplasma concentrationshow long afteradministration?a. after 30 minutesb. after 1 hour when takenwith foodc. after 3 hoursd. none of the above14. Zafirlukast is available asa. an inhalerb. nebuliser solutionc a tabletd. a combination of answersa and b.15. Montelukast is availableasa. chewable tablets forchildrenb. suspensionc. tablets for adultsd. a combination of answersa and c.16. The dosage regimen forzafirlukast isa. 20 mg bd. with foodb. 20 mg bd. 2 hours afterfoodc. 20 mg bd. 1 hour beforefoodd. a combination of answersb and c17.The use of cysteinylleukotriene receptorantagonists in pregnancyand lactationa. is absolutely safe.b. is recommended after the2nd trimesterc. is not recommendedd. none of the above.18.One of the majoradvantages of cysteinylleukotriene receptorantagonists isa. their low costb. that they over come theproblem of compliancewith inhalersc. that they can safely beused in children of allagesd. that they have no sideeffects.19.When used in mild tomoderate asthmaleukotriene receptorantagonistsa. are the most effectiveanti-inflammatory agentsb. are less effective thaninhaled beclomethosone400(g dailyc. are just as effective asany anti-asthma drugd. are of no use.20.Which of the followingstatements is true?a. cysteinyl leukotrienereceptor antagonistsshould be taken on a prnbasisb. cysteinyl leukotrienereceptor antagonistsshould be taken on aregular basisc. cysteinyl leukotrienereceptor antagonistsshould only be taken inconjunction withsalmeterold. cysteinyl leukotrienereceptor antagonistsshould not be taken ifcough is present.8. The recommended use ofcysteinyl leukotrienereceptor antagonistsa. as reliever therapy i.e.instead of short acting (2agonistsb. instead of oralprednisolonec. instead of inhaledsteroids in mildpersistent asthmad. instead of nebulisedtherapy.9. Zafrilukast is alsolicensed for use ina. COPDb. bronchitisc. emphysemad. none of the above.10.Leukotriene receptorantagonists are ofparticular use ina. aspirin sensitiveasthmaticsb. asthmatics allergic tosalbutamolc. persons presenting withoccupational asthmad. none of the above.11.Which of the followingstatements is false?a. cortocosteriods are themost effective anti-inflammatory agentsavailableb. zafirlukast is the onlycysteinyl leukotrienereceptor antagonistavailable locallyc. montelukast is licensedfor use in the UKd. leukotriene receptorantagonists only have abronchodilating effect.”To loose one’s health renders science null, art inglorious,strenght effortless, wealth useless and eloquence powerless.”Adversus Ethicus

The treatment of asthma with leukotriene receptor antagonists

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The treatment of asthma with leukotriene receptor antagonists

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