disease帕金森病（ppt39）课件

Parkinson sDisease Parkinson sDisease Thebasalganglia throughtheactionofdopamine areresponsibleforplanningandcontrollingautomaticmovementsofthebody suchaspointingwithafinger pullingonasock writingorwalking Ifthebasalgangliaarenotworkingproperly asinParkinson sdiseasepatients allaspectsofmovementareimpaired resultinginthecharacteristicfeaturesofthedisease slownessofmovement stiffnessandeffortrequiredtomovealimband often tremor Dopaminelevelsinthebrain ssubstantianigradonormallyfallwithageing However theyhavetofalltoone fifthofnormalvaluesforthesymptomsandsignsofparkinsonismtoemerge Parkinson sDisease History JamesParkinson 1755 1824 whilebestrememberedforthediseasestatenamedafterhimbyCharcot wasamanofmanytalentsandinterests Publishingonchemistry paleontologyandotherdiversetopics hewas earlyinhiscareer asocialactivistchampioningtherightsofthedisenfranchisedandpoor HiseffortsinthisareawereenoughtoresultinhisarrestandappearancebeforeThePrivyCouncilinLondononatleastoneoccasion Incollaborationwithhisson whowasasurgeon healsoofferedthefirstdescription intheEnglishlanguage ofarupturedappendix HistoryofParkinson sDisease Hissmallbutfamouspublication EssayontheShakingPalsy appearedin1817 7yearsbeforehisdeathin1824 Theclinicaldescriptionof6patientswasaremarkablemasterpiecetestifyingtohisprodigiouspowersofobservationformostofthe6wereneveractuallyexaminedbyParkinsonhimself rather theyweresimplyobservedwalkingonthestreetsofLondon TreatmentofParkinson sDisease SincePDisrelatedtoadeficiencyofdopamine itwouldbeappropriatetoadministerdopamineProblem DopaminedoesnotcrossBBB sinceitistoopolar HistoryofTreatmentofPD ArvidCarlsson b January25 1923 isaSwedishscientistwhoisbestknownforhisworkwiththeneurotransmitterdopamineanditseffectsinParkinson sdisease CarlssonwontheNobelPrizeinPhysiologyorMedicinein2000alongwithco recipientsEricKandelandPaulGreengard Inthe1950s Carlssondemonstratedthatdopaminewasaneurotransmitterinthebrainandnotjustaprecursorfornorepinephrine ashadbeenpreviouslybelieved Hedevelopedamethodformeasuringtheamountofdopamineinbraintissuesandfoundthatdopaminelevelsinthebasalganglia abrainareaimportantformovement wereparticularlyhigh HistoryofTreatmentofPD Carlssonthenshowedthatgivinganimalsthedrugreserpinecausedadecreaseindopaminelevelsandalossofmovementcontrol TheseeffectsweresimilartothesymptomsofParkinson sdisease ByadministeringtotheseanimalsL Dopa aprecursortodopamine hecouldalleviatethesymptoms ThesefindingsledotherdoctorstryL DopawithhumanParkinson spatientsandfoundittoalleviatesomeofthesymptomsintheearlystagesofParkinson s L DopaisstilltodaythecornerstoneofParkinsontherapy BiosynthesisofEpinephrine Waitaminute IfdopamineistoopolartocrosstheBBB howcanL DOPAcrossit L DOPAistransportedacrosstheBBBbyanaminoacidtransportsystem sameoneusedfortyrosineandphenylalanine Onceacross L DOPAisdecarboxylatedtodopaminebyDopaDecarboxylase DDC Thisisanexampleofa prodrug thatis amoleculethatisaprecursortothedrugandisconvertedtotheactualdrugatanappropriateplaceinthebody Inactualpractice L DOPAisalmostalwayscoadminsteredtogetherwithaninhibitorofaromaticL aminoaciddecarboxylase soitdoesn tgetconvertedtodopaminebeforeitcrossestheBBB Theinhibitorcommonlyusediscarbidopa whichdoesnotcrosstheBBBitself TheinhibitoralsopreventsundesirablesideeffectsofdopaminereleaseintothePNS includingnausea SINEMET CARBIDOPA LEVODOPA DESCRIPTIONSINEMET Carbidopa Levodopa isacombinationofcarbidopaandlevodopaforthetreatmentofParkinson sdiseaseandsyndrome http www learningcommons umn edu neuro mod6 carb html TreatmentofParkinson sDisease MonoamineOxidaseInhibitors MAOI s Asshownabove monoamineoxidaseisanenzymethatcatalyzesthedestructionofprimaryamines suchasdopamine norepinephrine seritonin andsecondaryamines ThetypeBisoformofMAO MAO B isprimarilyresponsibleformetabolismofdopamine MetabolismofDopamineviaMonoamineOxidase MAO InhibitorofMAO B Selegiline l deprenyl Eldepryl orAnipryl veterinary isadrugusedforthetreatmentofearly stageParkinson sdiseaseandseniledementia InnormalclinicaldosesitisaselectiveirreversibleMAO Binhibitor InlatestageParkinson sDisease Selegilineisusuallyaddedtolevodopatoprolongandenhanceitseffect MetabolismofDopamineviaCatachol O MethylTransferase COMT InhibitorsofCOMT Entacapone Tolcapone InhibitorsofCOMT EntacaponeismarketedbyNovartisasComtanintheUSStalevoisacombinationofLevodopa Carbidopa andEntacapone SummaryoftheTreatmentofParkinson sDisease Endorphin Endorphins ormorecorrectlyEndomorphines areendogenousopioidbiochemicalcompounds Theyarepeptidesproducedbythepituitaryglandandthehypothalamusinvertebrates andtheyresembletheopiatesintheirabilitiestoproduceanalgesiaandasenseofwell being Inotherwords theymightworkas naturalpainkillers Usingdrugsmayincreasetheeffectsoftheendorphins Serotonin AlthoughtheCNScontainslessthan2 ofthetotalserotonininthebody serotoninplaysaveryimportantroleinarangeofbrainfunctions Itissynthesizedfromtheaminoacidtryptophan Withinthebrain serotoninislocalisedmainlyinnervepathwaysemergingfromtheraphenuclei agroupofnucleiatthecentreofthereticularformationintheMidbrain ponsandmedulla Theseserotonergicpathwaysspreadextensivelythroughoutthebrainstem thecerebralcortexandthespinalcord Inadditiontomoodcontrol serotoninhasbeenlinkedwithawidevarietyoffunctions includingtheregulationofsleep painperception bodytemperature bloodpressureandhormonalactivity Outsidethebrain serotoninexertsanumberofimportanteffects particularlyinvolvingthegastrointestinalandcardiovascularsystems Serotonin Inthecentralnervoussystem serotoninisbelievedtoplayanimportantroleintheregulationofbodytemperature mood sleep vomiting sexuality andappetite Lowlevelsofserotoninhavebeenassociatedwithseveraldisorders namelyclinicaldepression obsessive compulsivedisorder OCD migraine irritablebowelsyndrome tinnitus fibromyalgia bipolardisorder andanxietydisorders Ifneuronsofthebrainstemthatmakeserotonin serotonergicneurons areabnormal thereisariskofsuddeninfantdeathsyndrome SIDS inaninfant Serotonin UnderstandingSerotonin Thepharmacologyof5 HTisextremelycomplex withitsactionsbeingmediatedbyalargeanddiverserangeof5 HTreceptors Atleastsevendifferentreceptor families areknowntoexist eachlocatedindifferentpartsofthebodyandtriggeringdifferent