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Norepinephrine

Systematic(IUPAC)name

4[(1R)2amino1hydroxyethyl]benzene1,2diol

Clinicaldata

Tradenames Levarterenol,Levophed,Norepin

AHFS/Drugs.com monograph

Licencedata USFDA:link

Pregnancycategory

AU:B3US:C

Legalstatus AU:PrescriptionOnly(S4)CA:onlyUK:POMUS:only

Routes Intravenous

Pharmacokineticdata

Metabolism Hepatic

Excretion Urine(8496%)

Identifiers

CASnumber 51412

ATCcode C01CA03

PubChem CID439260

DrugBank DB00368

ChemSpider 388394

UNII X4W3ENH1CV

KEGG D00076

ChEBI CHEBI:18357

ChEMBL CHEMBL1437

Synonyms Noradrenaline(R)()Norepinephrinel1(3,4Dihydroxyphenyl)2aminoethanol

NorepinephrineFromWikipedia,thefreeencyclopedia

Norepinephrine(INN)(abbreviatednorepiorNE),alsocallednoradrenaline(BAN)(abbreviatedNA,NAd,ornorad),or4,5trihydroxyphenethylamineisacatecholaminewithmultiplerolesincludingthoseasahormoneandaneurotransmitter.[1]Itisthehormoneandneurotransmittermostresponsibleforvigilantconcentrationincontrasttoitsmostchemicallysimilarhormone,dopamine,whichismostresponsibleforcognitivealertness.[2]

Medicallyitisusedinthosewithseverehypotension.Itdoesthisbyincreasingvasculartone(tensionofvascularsmoothmuscle)throughadrenergicreceptoractivation.

Areasofthebodythatproduceorareaffectedbynorepinephrinearedescribedasnoradrenergic.Thetermsnoradrenaline(fromtheLatin)andnorepinephrine(fromtheGreek)areinterchangeable,withnoradrenalinebeingthecommonnameinmostpartsoftheworld.HowevertheU.S.NationalLibraryofMedicine[3]haspromotednorepinephrineasthefavoredname.ItwasdiscoveredbyUlfvonEulerin1946.[4]

Oneofthemostimportantfunctionsofnorepinephrineisitsroleastheneurotransmitterreleasedfromthesympatheticneuronstoaffecttheheart.Anincreaseinnorepinephrinefromthesympatheticnervoussystemincreasestherateofcontractionsintheheart.[5]Asastresshormone,norepinephrineaffectspartsofthebrain,suchastheamygdala,whereattentionandresponsesarecontrolled.[6]Norepinephrinealsounderliesthefightorflightresponse,alongwithepinephrine,directlyincreasingheartrate,triggeringthereleaseofglucosefromenergystores,andincreasingbloodflowtoskeletalmuscle.Itincreasesthebrain'soxygensupply.[7]

Norepinephrineissynthesizedfromdopaminebydopaminehydroxylaseinthesecretorygranulesofthemedullarychromaffincells.[8]Itisreleasedfromtheadrenalmedullaintothebloodasahormone,andisalsoaneurotransmitterinthecentralnervoussystemandsympatheticnervoussystem,whereitisreleasedfromnoradrenergicneuronsinthelocuscoeruleus.Theactionsofnorepinephrinearecarriedoutviathebindingtoadrenergicreceptors.

Contents

1Medicaluses2Physiologicaleffects

2.1Norepinephrinesystem2.2Roleincognition2.3Fasting2.4Macronutrientintake

3Druginteractions3.1Synthesismodulators3.2Releasemodulators3.3Receptorbindingmodulators3.4Terminationmodulators3.5AlzheimersDisease

4Chemistry5Mechanism

5.1Biosynthesis5.2Vesiculartransport5.3Release5.4Receptorbinding5.5Termination

6Nutritionalsources7Seealso



Chemicaldata

Formula C8H11NO3

Molecularmass 169.18g/mol

Physicaldata

Density 1.3970.06g/cm3

Meltingpoint 217C(423F)(decomposes)

Boilingpoint 442.6C(828.7F)40.0C

(whatisthis?)(verify)

8References9Externallinks

Medicaluses

Norepinephrineisusedasavasopressormedicationforpatientswithcriticalhypotension.Itisgivenintravenouslyandactsonboth1and2adrenergicreceptorstocausevasoconstriction.Itseffectsareoftenlimitedtotheincreasingofbloodpressurethroughagonistactivityon1and2receptors,andcausingaresultantincreaseinperipheralvascularresistance.Athighdoses,andespeciallywhenitiscombinedwithothervasopressors,itcanleadtolimbischemiaandlimbdeath.Norepinephrineisusedmainlytotreatpatientsinvasodilatoryshockstatessuchassepticshockandneurogenicshock,whileshowingfeweradversesideeffectscomparedtodopaminetreatment.[9]

Physiologicaleffects

Norepinephrineisreleasedwhenahostofphysiologicalchangesareactivatedbyastressfulevent.

Inthebrain,thisiscausedinpartbyactivationofanareaofthebrainstemcalledthelocuscoeruleus(LC).Thisnucleusistheoriginofmostnorepinephrinepathwaysinthebrain.Noradrenergicneuronsprojectbilaterally(sendsignalstobothsidesofthebrain)fromthelocuscoeruleusalongdistinctpathwaystomanylocations,includingthecerebralcortex,limbicsystem,andthespinalcord,forminganeurotransmittersystem.

Norepinephrineisalsoreleasedfrompostganglionicneuronsofthesympatheticnervoussystem,totransmitthefightorflightresponseineachtissue,respectively.Theadrenalmedullacanalsocontributetosuchpostganglionicnervecells,althoughtheyreleasenorepinephrineintotheblood.

Norepinephrinesystem

Thenoradrenergicneuronsinthebrainformaneurotransmittersystem,that,whenactivated,exertseffectsonlargeareasofthebrain.Theeffectsaremanifestedinalertness,arousal,andinfluencesontherewardsystem.

Thenoradrenergicneuronsoriginatebothinthelocuscoeruleusandthelateraltegmentalfield.Theaxonsoftheneuronsinthelocuscoeruleusactonadrenergicreceptorsin:

AmygdalaCingulategyrusCingulumHippocampusHypothalamusNeocortexSpinalcordStriatumThalamusSomeBrainstemnucleiCerebellum

Ontheotherhand,axonsofneuronsofthelateraltegmentalfieldactonadrenergicreceptorsinhypothalamus,forexample.

Thisstructureexplainssomeoftheclinicalusesofnorepinephrine,sinceamodificationofthissystemaffectslargeareasofthebrain.

Roleincognition

Corticalnorepinephrine(NE)releaseduringattentionparadigms(patterns)canincreasethealterationdetectionrate(frequencyatwhichanalterationwasselected)inmultiplecueprobabilitylearningduringtasksinvolvinggivingpredictivecues(suchasauditoryorvisual),andtherebyenhancesubsequentlearning.[10]A.J.Yuetal.developedaBayesianframeworktoexamineNEreleaseininstancesof"unexpecteduncertainty",whereinadrasticalterationinsensoryinformationproducesalargedisparitybetweentopdownexpectationsandwhatactuallyoccurs.[11]ThemodelpredictsthatNElevelsspikewhenthepredictivecontextisswitched,thensubside.Ithasalsobeenshownthatlesionsofthelocuscoeruleusimpairthisattentionalshift.[11]

SMILES

InChI



Similarly,severalstudieshaveimplicatedtheLCNEsysteminelicitingtheP300,acorticaleventrelatedpotentialthatrespondstoenvironmentalstimuliwithbehaviorallyrelevant,motivational,orattentiongrabbingproperties.[12][13][14][15][16]TheP300mayreflectupdatingofpriorknowledgeregardingstimulirelevantforaccurateandefficientdecisionmaking.SeveralstudieshavesearchedforaP300generatorwithinthebrainandhaveultimatelyconcludedthatthepotentialmusthaveasourcethatisdistributed,synchronousandlocalizedincortex.[17]ThisdefinitionisideallysatisfiedbothfunctionallyandanatomicallybytheLCneuromodulatorysystem.GivenitsbroadprojectionpatternandthecorrelationbetweenNEreleaseandincreasedsensorysignaltransmission,[18]itseemslikelythatnoradrenergiccorticalreleaseistheneuronalmechanismoftheP300.

ExaminationoftheLCstonicfiringpatternhasledtospeculationthatitisimportantfortheexploratorybehavioressentialforlearningrelationsbetweensensoryinput,decisionprocessing,motoroutput,andbehavioralfeedback.[19]Tonicactivationwithintherangeof05Hzhasbeenshowntocorrelatewithlevelsofdrowsiness,accuratetaskperformance,and,whenslightlymoreelevated,distractibilityanderratictaskperformance.Furthermore,phasicactivationoftheLCisobservedinresponsetobothhighlysalient,unconditionedandtaskrelevantstimuli.Thephasicresponseoccursafterstimulationandprecedesabehavioralresponseinatimelockedfashion.[20]Assuch,phasicactivationoftheLCNEsystemisproposedtoenhancesignalprocessingandbehavioralresponsesspecificallytotaskrelevantstimuli.GiventhecontrastingfunctionalrolesofLCtonicandphasicactivity,itisplausiblethatprojectionsfromthisbrainregionareimportantformaintainingabalancebetweenexploratoryandgoaldirectedbehaviorsthatregulateprobabilistic,environmentallearningandcorrespondingdecisionmaking.

TheLCNEsystemreceivesconvergentinputfromtheorbitofrontal(OFC)andanteriorcingulatecortices(ACC).TheOFChasbeenassociatedwithevaluationofreward.Forexample,Tremblayetal.foundthattheresponsemagnitudeofsingleunitsinthisregionisvariedwiththehedonicvalueofastimulus.[21]Additionally,neuronsinthisregionareactivatedbyrewardingstimuli,butnotbyidentificationofthestimulusnorcorrespondingresponsepreparation.ActivationoftheACCappearstoreflectsomeevaluationofcostbenefit.SeveralstudiesshowACCactivationinresponsetoperformanceerror,negativefeedback,ormonetaryloss.[22][23][24]Additionally,ACCrespondstotaskdifficulty.[25]Therefore,ACCactivationmayservetointegrateevaluationsoftaskdifficultywithcorrespondingoutcomeinformationtogaugethebenefitsoftakinganactioninregardstoaparticularenvironmentalstimulus.Conceivably,thefunctionsoftheACCandOFCaredirectlyrelatedtodecisionmaking,andtheirprojectionstoLCmaymodulatethephasicreleaseofNEinordertogainmodulatecorticalresponsestodecisionoutcomes.

LCNEmayplayasignificantroleinsynchronizingcorticalactivityinresponsetoadecisionprocess.Incomputationalmodelingofdecision,themostaccurateandefficientdecisionmechanismsaremathematicallydefinedrandomwalkordriftdiffusionprocessesthatutilizesinglelayerneuralnetworkstocalculatethedisparityinevidencebetweentwooptions.[26]NEreleasegatedbytheLCNEsystemiselicitedafterneuronsprocessingsensoryinformationhavepresumablyreachedadecisionthreshold.[27]Thus,thephasicburstcanalteractivationinallcorticalprocessinglayersinatemporallydependentmanner,essentiallycollapsingthevastinformationprocessingcircuittotheoutcomeofasingledecisionlayer.Brownetal.foundthattheadditionofaphasicLCmechanismwassufficienttoyieldoptimalperformancefromasinglelayerdecisionnetwork.[28]

Fasting

Astudyhasshownthatfastingleadstoincreasedlevelsofnorepinephrine(NE)inthebloodforupto4daysoffasting.[29]

Macronutrientintake

GlucoseintakewasfoundtosignificantlyincreaseplasmaNElevels.Incontrast,proteinandfatintakewasfoundtohavenoeffect.[30]

Druginteractions

Differentmedicationsaffectingnorepinephrinefunctionhavetheirtargetsatdifferentpointsinthemechanism,fromsynthesistosignaltermination.

Synthesismodulators

Methyltyrosineisasubstancethatintervenesinnorepinephrinesynthesisbysubstitutingtyrosinefortyrosinehydroxylase,andblockingthisenzyme.

Vesiculartransportmodulators

Thistransportationcanbeinhibitedbyreserpineandtetrabenazine.[31]

Releasemodulators



InhibitorsofnorepinephrinereleaseSubstance[32] Receptor[32]

acetylcholine muscarinicreceptornorepinephrine(itself)/epinephrine 2receptor5HT 5HTreceptoradenosine P1receptorPGE EPreceptorhistamine H2receptorenkephalin receptordopamine D2receptorATP P2receptor

Stimulatorsofnorepinephrinerelease

Substance[32] Receptor[32]

epinephrine 2receptorangiotensinII AT1receptor

Receptorbindingmodulators

Examplesincludealphablockersforthereceptors,andbetablockersforthereceptors.

Terminationmodulators

Uptakemodulators

Inhibitors[31]ofuptake1include:

cocainetricyclicantidepressants

desipramineserotoninnorepinephrinereuptakeinhibitorsphenoxybenzamineamphetaminereboxetine

Inhibitors[31]ofuptake2include:

normetanephrinesteroidhormonesphenoxybenzamine

AlzheimersDisease

Thenorepinephrinefromlocusceruleuscellsinadditiontoitsneurotransmitterrolelocallydiffusesfrom"varicosities".Assuch,itprovidesanendogenousantiinflammatoryagentinthemicroenvironmentaroundtheneurons,glialcells,andbloodvesselsintheneocortexandhippocampus.[33]Upto70%ofnorepinephrineprojectingcellsarelostinAlzheimersDisease.IthasbeenshownthatnorepinephrinestimulatesmousemicrogliatosuppressAinducedproductionofcytokinesandtheirphagocytosisofA,suggestingthislossmighthavearoleincausingthisdisease.[33]

Chemistry

Norepinephrineisacatecholamineandaphenethylamine.ThenaturalstereoisomerisL()(R)norepinephrine.Theprefixnorindicatesthatnorepinephrineisthenextlowerhomologofepinephrine.Thetwostructuresdifferonlyinthatepinephrinehasamethylgroupattachedtoitsnitrogen,whereasthemethylgroupisreplacedbyahydrogenatominnorepinephrine.Theprefixnorisderivedasanabbreviationoftheword"normal",usedtoindicateademethylatedcompound.[34][35][36]



Biosynthesisofnorepinephrine

Mechanism

Norepinephrineissynthesizedfromtyrosineasaprecursor,andpackedintosynapticvesicles.Itperformsitsactionbybeingreleasedintothesynapticcleft,whereitactsonadrenergicreceptors,followedbythesignaltermination,eitherbydegradationofnorepinephrineorbyuptakebysurroundingcells.

Biosynthesis

Norepinephrineissynthesizedbyaseriesofenzymaticstepsintheadrenalmedullaandpostganglionicneuronsofthesympatheticnervoussystemfromtheaminoacidtyrosine.WhiletheconversionstepsofLtyrosinetodopamineoccurspredominantlyinthecytoplasm,theconversionofdopaminetonorepinephrinebydopaminehydroxylaseoccurspredominantlyintheneurotransmittervesicle.

Vesiculartransport

Betweenthedecarboxylationandthefinaloxidation,norepinephrineistransportedintosynapticvesicles.Thisisaccomplishedbyvesicularmonoaminetransporter(VMAT)inthelipidbilayer.Thistransporterhasequalaffinityfornorepinephrine,epinephrineandisoprenaline.[31]

Release

Toperformitsfunctions,norepinephrinemustbereleasedfromsynapticvesicles.Manysubstancesmodulatethisrelease,someinhibitingitandsomestimulatingit.Anactionpotentialreachesthepresynapticmembrane,whichchangesthemembranepolarisation.Calciumionsthusenter,resultinginvesicularfusion,releasingnorepinephrine.

Forinstance,thereareinhibitory2adrenergicreceptorspresynapticallythatgivenegativefeedbackonreleasebyhomotropicmodulation.

Receptorbinding

Norepinephrineperformsitsactionsonthetargetcellbybindingtoandactivatingadrenergicreceptors.Thetargetcellexpressionofdifferenttypesofreceptorsdeterminestheultimatecellulareffect,andthusnorepinephrinehasdifferentactionsondifferentcelltypes.

Termination

Signalterminationisaresultofreuptakeanddegradation.

Uptake

Extracellularuptakeofnorepinephrineintothecytosolisdoneeitherpresynaptically(uptake1)orbynonneuronalcellsinthevicinity(uptake2).Furthermore,thereisavesicularuptakemechanismfromthecytosolintosynapticvesicles.



Norepinephrinedegradation.Enzymesareshowninboxes.[40]

Comparisonofnorepinephrineuptake

Uptake TransporterVmax(n

mol/g/min)[37]KM[37] Specificity[38] Location Othersubstrates[38] Inhibitors[39]

Uptake1 Norepinephrinetransporter[39]

1.2 0.3norepinephrine>epinephrine>isoprenaline

presynaptic

methylnoradrenaline(nasaldecongestant)tyramineguanethidine

CocaineTricyclicantidepressants(e.g.desipramine)PhenoxybenzamineAmphetamineReboxetine

Uptake2 100 250epinephrine>norepinephrine>isoprenaline

cellmembraneofnonneuronalcells[31]

dopamine5HThistamine

normetanephrinesteroidhormones(e.g.,corticosterone)phenoxybenzamine

Vesicular VMAT[39] [39] ~0.2[39]norepinephrine>epinephrine>isoprenaline[39]

Synapticvesiclemembrane[39]

dopamine[39]

5HT[39]

guanethidine[39]

MPP+[39]

Reserpine[39]

Tetrabenazine

Degradation

Inmammals,norepinephrineisrapidlydegradedtovariousmetabolites.Theprincipalmetabolitesare:

Normetanephrine(viatheenzymecatecholOmethyltransferase,COMT)3,4Dihydroxymandelicacid(viamonoamineoxidase,MAO)Vanillylmandelicacid(3Methoxy4hydroxymandelicacid),alsoreferredtoasvanilmandelateorVMA(viaMAO)3Methoxy4hydroxyphenylethyleneglycol,"MHPG"or"MOPEG"(viaMAO)

Epinephrine(viaPNMT)[41]

Intheperiphery,VMAisthemajormetaboliteofcatecholamines,andisexcretedunconjugatedintheurine.Aminormetabolite(althoughthemajoroneinthecentralnervoussystem)isMHPG,whichispartlyconjugatedtosulfateorglucuronidederivativesandexcretedintheurine.[42]

Nutritionalsources

Thesynthesisofnorepinephrinedependsonthepresenceoftyrosine,anaminoacidfoundinproteinssuchasmeat,nuts,andeggs.Dairyproductssuchascheesealsocontainhighamountsoftyrosine(theaminoacidisnamedfor"tyros",theGreekwordforcheese).However,adulthumansreadilysynthesizetyrosinefromphenylalanine,anessentialaminoacid.Tyrosineistheprecursortodopamine,whichinturnisaprecursortoepinephrineandnorepinephrine.

Seealso

CatecholaminergicpolymorphicventriculartachycardiaHistoryofcatecholamineresearch



ShownhereisthechemicalstructureofLtyrosine.ThebiosynthesisofnorepinephrinedependsuponthepresenceofLtyrosine,anaminoacidbuildingblockofmanyproteinsinmeat,nuts,andeggs,forexample.

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Externallinks

MentalHealth:Areportofsurgeongeneral.EtiologyofAnxietyDisorders(http://www.surgeongeneral.gov/library/mentalhealth/chapter4/sec2_1.html)http://www.biopsychiatry.com/nordop.htm

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Categories: Cardiacstimulants Catecholamines Hormonesofthesuprarenalmedulla Neurotransmitters NorepinephrinereleasingagentsTAAR1agonists

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