Leukotriene receptor antagonist therapy

Leukotriene receptor antagonists (LTRA) are a new class of drugs for asthma treatment, available in tablet form. Their unique mechanism of action results in a ... Skiptomaincontent YouarehereHome Archive Volume76, Issue902 Leukotrienereceptorantagonisttherapy Emailalerts ArticleText Articlemenu ArticleText Articleinfo CitationTools Share RapidResponses Articlemetrics Alerts PDF Review LeukotrienereceptorantagonisttherapyFree OJDempseyAsthmaandAllergyResearchGroup,DepartmentofClinicalPharmacologyandTherapeutics,NinewellsHospitalandMedicalSchool,UniversityofDundee,DundeeDD19SY,UKDrDempseydempseyowen{at}hotmail.com AbstractLeukotrienereceptorantagonists(LTRA)areanewclassofdrugsforasthmatreatment,availableintabletform.Theiruniquemechanismofactionresultsinacombinationofbothbronchodilatorandanti-inflammatoryeffects.Whiletheiroptimalplaceinasthmamanagementisstillunderreview,LTRArepresentanimportantadvanceinasthmapharmacotherapy.leukotrienereceptorantagonistasthmamontelukastzafirlukast http://dx.doi.org/10.1136/pgmj.76.902.767 StatisticsfromAltmetric.com RequestPermissions IfyouwishtoreuseanyorallofthisarticlepleaseusethelinkbelowwhichwilltakeyoutotheCopyrightClearanceCenter’sRightsLinkservice.Youwillbeabletogetaquickpriceandinstantpermissiontoreusethecontentinmanydifferentways. leukotrienereceptorantagonistasthmamontelukastzafirlukastLeukotrienereceptorantagonists(LTRA)areanewclassofdrugsforasthmatreatment,availableintabletform.1 ,2Theiruniquemechanismofactionresultsinacombinationofbothbronchodilatorandanti-inflammatoryeffects.Whiletheiroptimalplaceinasthmamanagementisstillunderreview,LTRArepresentanimportantadvanceinasthmapharmacotherapy.InthisarticleIprovideabriefoverviewofevidencesupportingtheiruseinpatientswithchronicasthma,focusingontwoleukotrienereceptorantagonists,montelukastandzafirlukast,currentlylicensedforuseintheUnitedKingdom.MethodsFullypublishedpapersandreviewarticlesbetween1966andJanuary2000weresoughtusingappropriateindextermsandtheNationalLibraryofMedicine'scomputerisedsearchservice(providingaccesstoMedline,Pre-Medline,andotherrelateddatabases).Studiespublishedonlyinabstractform(andthussubjecttolessrigorouspeerreview)arenotdiscussed.BackgroundTheterm“slowreactingsubstanceofanaphylaxis”(SRS-A),coinedbyBrocklehurstin1960,isstillfamiliartomanyphysicians.3ThechemicalstructureofSRS-A,however,wasnotidentifieduntil1979bySamuelssonandcolleagues,whodiscoveredthatitconsistedofafamilyofbiologicallyactivefattyacidsderivedfromarachidonicacidmetabolisminmanycells,includingeosinophils,mastcells,andlymphocytes(fig1).4 ,5Theterm“leukotriene”isapt,giventheirsynthesisinleucocytesandtheirchemicalstructure(containingthreeconjugateddoublebonds,thatis,atriene).OfparticularimportanceinthepatientwithasthmaareleukotrienesC4,D4,andE4.Asthesecontaintheaminoacidresiduecysteine,theyaresometimesreferredtocollectivelyasthecysteinylleukotrienes.Downloadfigure Openinnewtab Downloadpowerpoint Figure1Arachidonicacidmetabolism.Cysteinylleukotrienes(LTC4,LTD4,LTE4)interactwithaspecificreceptor,whichisblockedbyantagonistssuchasmontelukastorzafirlukast.FLAP,5-lipoxygenaseactivatingprotein;HPETE,5-hydroxyperoxyeicosatetraenoicacid.Cysteinylleukotrienesareimportantbiologicalmediatorsinasthma,interactingwithatleastonespecificreceptorinthelungs,whichhasnowbeenfullyidentified,6 ,7leadingtovariousimportantbiologicaleffects(box1).Ofthese,potentbronchoconstrictioniswellrecognised,buttheyalsohaveavarietyofeffectsthatareproinflammatory.8Thusleukotrienesarecapableofinducingseveralkeyfeaturesofasthma.Furthermore,studieshaveshownthatleukotrienesareproducedinexcessivequantitiesinpatientswithasthma,reinforcingtheviewthattheyareimportantbiologicalmediators.9 Box1:BiologicaleffectsofcysteinylleukotrienesBronchoconstriction(100–10000timesmorepotentthanhistamine).Bronchialsmoothmusclehyperresponsiveness,forexampletoallergen.Inflammatorycellrecruitment,forexampleeosinophils.Vascularpermeability(leadingtotissueoedemaandairflowobstruction).Mucusformation(leadingtofurtherairflowobstruction). Interestingly,inhaledororalcorticosteroidshavenotbeenshowntoattenuateleukotrieneproductionsignificantlyinvivo.Thisledtointerestinthedevelopmentofspecificleukotrienemodifyingasthmadrugs,whichmightconferadditionalbenefitseveninpatientsalreadyreceivinganoptimaldoseofinhaledcorticosteroid.10Severaldrugclassesweredeveloped,affectingvarioussitesintheleukotrienebiosyntheticcascade,ofwhichthemostsuccessfulhavebeenreceptorantagonists.LeukotrienereceptorantagonistsSTRUCTUREMontelukastandzafirlukastaretwoofthemostcommonlyprescribedLTRAavailableworldwide.Theirstructuresareshowninfig2.Downloadfigure Openinnewtab Downloadpowerpoint Figure2Structureofzafirlukast(top)andmontelukast(bottom).PRESCRIBINGINFORMATIONPrescribinginformationisgivenintable1.11 ,12Montelukastandzafirlukastsharesomepharmacokineticpropertiesincludingrapidoralabsorption(threehourstopeakplasmaconcentrations),nearmaximal(99%)plasmaproteinbinding,and,afterextensivehepaticbiotransformation,excretionprincipallyinthebile.Theterminalhalflivesofthetwodrugsarefiveand10hours,respectively.Viewthistable:Viewinline Viewpopup Table1PrescribinginformationZafirlukastcaninhibitthehepaticmicrosomalcytochromeP450isoenzymesCYP2C9andCYP3Aattherapeuticconcentrations,whichclinicallymayresultindruginteractionswithotherdrugsusingtheseenzymes.Similarly,asmontelukastismetabolisedbyCYP3A4,cautionshouldbeexercised,particularlyinchildrenwhenmontelukastisco-administeredwithinducersofthisenzyme,aslistedintable1.Anotherclinicallyrelevantpointisthatco-administrationoffoodwithzafirlukastcanreduceoralbioavailabilitybyapproximately40%,whichmeansthatpatientsshouldavoidtakingthispreparationsoonbeforeorafterfood(seetable1).Thismayhaveimplicationsforpatientcompliance.CLINICALEFFICACYINASTHMATheoptimalplaceofLTRAinasthmamanagementisstillunderreview.Thisreflectstheirrecentintroductionandtherelativepaucityoffullypublishedcomparativestudies,particularlycomparedwithexistingasthmatreatments.Forsimplicity,inthisarticleIwilldescribeasfirstlinetreatmenttheiruseinstudiesinconjunctionwith“asrequired”shortactingβ2agonists.Theiruseinpatientsalreadyreceivinginhaledcorticosteroidsand“asrequired”shortactingβ2agonistswillbedescribedassecondlinetreatment.Firstlinetreatmentstudies—chronicasthmaLTRAvPLACEBOThesestudiesaresummarisedintable2.13-22Mostofthepatientsinthesestudiesweresteroidnaive,andhencethedescription“firstlinetreatmentstudies”;however,somedidincludeaminorityofpatientsreceivinglowdoseinhaledcorticosteroidsororaltheophyllines,orboth.13-16 ,20Viewthistable:Viewinline Viewpopup Table2Firstlinetreatment—leukotrienereceptorantagonistsvplacebo:randomised,placebocontrolled,parallelgroupstudiesTheprimaryendpointinmostofthestudieswaspulmonaryfunction,usuallyforcedexpiratoryvolumeinonesecond(FEV1).ImprovementsinmeanFEV1weretypicallymodest,forexample10%,withmuchinterindividualvariation.Commonlyusedsecondaryendpointsincludedsymptomsandqualityoflifescores,othermeasuresofpulmonaryfunctionsuchaspeakexpiratoryflowrates,theneedforotherdrugs(shortactingβ2agonistorinhaled/oralcorticosteroiduse),andeffectsondailyliving(daysoffschoolorwork).Improvementinthesesecondaryoutcomeswastypicallymoreimpressive,forexample25%.ThemajorityofthesestudiesconcludedthattheuseofanLTRAinpatientswithmildasthmawassuperiortoplacebo,usingthesesubjectiveandobjectivemeasures.OnlyoneofthesestudiesexamineduseofLTRAinpatientswithmoresevereairflowobstruction.18Inthisretrospectivepooledsubgroupanalysis,datawerereviewedfromfourclinicaltrialsinwhichzafirlukast20mgtwicedailyorplacebowasgivenovera13weekperiodto261steroidnaivepatientsidentifiedashavingseverepersistentasthma.Comparedwithplacebo,patientsreceivingzafirlukasthadsignificantly(p  1.5×109/l)andsignsofasystemicvasculitissuchasnon-blanchingrash,cardiaccomplications,andperipheralneuropathy.52 Box2:SafetyofleukotrienereceptorantagonistsGenerallywelltolerated,sideeffectprofilesimilartoplacebo.Commonsideeffectsreportedincludegastrointestinaldisturbance,rashes,fatigue.ReportanysideeffectstoCommitteeofSafetyofMedicinesusingyellowcardscheme.RarecasesofChurg–Strausssyndrome(seetext)—cautionifreducingmaintenanceinhaledororalcorticosteroid. ClinicalefficacyinconditionsotherthanasthmaLeukotrienereceptorantagonistshavebeenusedsuccessfullyinavarietyofotherconditions,notablyrhinitis,whichoftencoexistsinasthmapatients.53-55Otherconditionshaveincludedatopicdermatitis56andeosinophilicgastroenteritis.57Thereisnoevidencethatthecurrentcysteinylleukotrienereceptorantagonistswillbeusefulinpatientswithchronicobstructivepulmonarydisease.PredictorsofresponsetoLTRACurrently,itisnotpossibletopredictwhowillrespondwelltoanLTRAand,asdescribedearlier,thisresponseisnormallydistributed,sosomepatients(perhapsasmanyas50%)mayhaveadisappointingresponse.ThusmanycliniciansoptforafourtoeightweektherapeutictrialofanLTRA,althoughlongertrialsmaybenecessarytodetectbeneficialeffectsintermsofattenuatingairwayinflammation.Recently,geneticpolymorphismsoftheenzymescontrollingbiosynthesisofleukotrieneshavebeendescribedandmaybeimportantpredictorsofresponse.44 ,45 ,58 ,59 PlaceofLTRAinasthmamanagementguidelinesThecurrentBritishThoracicSocietyasthmamanagementguidelines,publishedin1997,areinneedofupdating,asleukotrienereceptorantagonistsonlybecameavailableforprescriptionafterthatdate.ThecurrentAmericanguidelines,similarlypublishedin1997,domentiontheLTRAzafirlukastandsuggestthatitmaybeanoptionasmonotherapyinpatientsaged⩾ 12yearsorolderwithmildpersistentasthma.Bothguidelinesacknowledgethatthepositionofleukotrienereceptorantagonistsincurrentpractice“isnotfullyestablished.”ItseemslikelythatforthcomingUnitedKingdomguidelineswillcontinuetoadviseearlyuseofanti-inflammatorytreatmentintheformoflowdoseinhaledcorticosteroid(⩽ 800μg/dayofbeclomethasoneorequivalent),withLTRAreservedforsecondlineuseinthosepatientswhoarestillsuboptimallycontrolled.Newguidelinesmayalsosuggestthat,inselectedpatients,monotherapywithanLTRAisstillappropriate,particularlyinpatientswithextremelymilddiseasereluctanttotakeinhaledcorticosteroids,orinpatientswithaspirininducedorexerciseinducedsymptoms.AcuteasthmamanagementguidelinesareunlikelytoadvisetheuseofanLTRA,asthereisnoevidencetosupporttheiruseinthesepatients.Box3:Leukotrienereceptorantagonists:summaryNovelclassofchronicasthmatreatment,availableintabletform.InUK,montelukastandzafirlukastareavailableforprescription.Combinationofbronchodilatorandanti-inflammatoryproperties.Rapideffects(days)andeaseofadministrationmayaidcompliance.Usefulinexerciseinducedandaspirin/NSAIDinducedasthmainparticular.Maybeusefulinotherconditions,egallergicrhinitis,atopicdermatitis. 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