药理学教学课件：Chapter 17 Drugs for the Treatment of Degenerative Disease

Chapter17

DrugsfortheTreatmentofDegenerativeDiseaseinCentralNervousSystem

Agroupofchronicdevelopingdeseasesofnervoussystemduetoretrogradedegenerationandapoptosisofcentralneurons.

Include：

Parkinson’sdisease，PDAlzheimer’sdisease，ADHuntingtondisease，HDAmyotrophiclateralsclerosis，ALSParkinson’sdisease，PDAlzheimer’sdisease，ADdegenerativediseaseincentralnervoussystem

ThereisnocureforPDandAD.DengXiaoPingFormerpresidentofUSAPathogenesyexcitotoxicity:glutamicintracellularcalciumoverload

apoptosis:deficiencyofgrowthfactor

oxidativestress:lipidperoxidation

ofcellularmembrane

nervecelldeath

Anti-Parkinson’sdiseaseAgentsParkinson’sdisease(

PD),Alsocalled

paralysisagitants,isakindofdegenerationdeseases

ofextrapyramidalsysteminCNS.Thetypicalsymptomsofthedeseaseisresttremor、muscularrigidityandbradykinesia.

Primary（Parkinson’sDisease

）

Secondary（Parkinson’sSyndrome）

纹状体（壳核、尾核）DA(-)

脊髓前角运动NputamencaudatenucleusstriatumnMechanism:

Substantianigra(SN)——striatumpathway

regulateextrapyramidaltractfunctionNormalState:DopaminergicNerveinbalancewithCholinergicNerveInhibitoryeffectsexcitingeffectsPDPatientsDopamine（DA）↓Acetylcholine（Ach）↑

TherapyMethodofPD:

EnhancingDopaminergicNerveFunctionBlockingAcetylcholinergicNerveFunction

Ordinary:Anti-cholinergicAgentsand

InhititingdrugsofMAO-B

Severe:L-dopa，AgonistsofDA-RifineffectiveClassificationPrecursorofdopamine（L-dopa）EnzymeinhibitorsAminoaciddecarboxylaseinhibitors（carbidopa）MAOinhibitors（selegiline）COMTinhibitors（tocapone）DAreceptoragonistsSelectiveD2receptor（bromocriptine）Nonselective（pergolide）DrugsthatpromoteDAreleasing（amantadine）Anticholinergicdrugs（benzhexol）

PrecursorofDopamine

LevodopaorL-dopa

【TheInVivoProcess】Absorption:Smallintestine,QuicklyP.O.MostaredecarboxylatedbyAADCandproduceDA，1%±enterbrain↗re-uptakebyPresynapticmembraneProducedDA↘metablizedbyMAOorCOMT【PharmacologicalAction】

Afterenterbrain,levodopaisdecarboxylatedandtransferredasDA.

SupplyDAinSN-striatumpathway【ClinicalUses】

TreatmentofPD

Early：80%ofpatientsshowbetter

20%amongthemrecoverd

Later：Theeffects↓，3-5yineffective

Characteristics

A.Sloweffects，2-3wbetter，1-6Mmaxmumeffects

Asthetimeextending,theeffectsisreduced

B.BettereffectsinlightsymptomandyoungpatientsButworseinseveresymptomandadults.

C.Bettereffectsforthesymptomsofstiffandmovementdifficulty，butworseforthemusculartremor

D.IneffectivetoPDinducedbyphenothiazine

E.Combinedmedication：Carbidopa

+

L-dopa1:10/4Sinemet

Benserazide+

L-dopa

1:4Madopa

ImprovingtheeffectsandreducingthedosageofL-dopaWhywereusedcombinationwithL-dopaandcarbidopa?Treatmentofhepaticcoma

LevodopatransferredintoNAinbrain,andthelattercanimproveandrecovernormalnerveactivities,andthenthepatientwakeup.

Butthedrugcannotimproveliverfunctionandthediseaseisnotcured.Synthesisofnorepinephrin(NA/NE)DAisprecursorofNATH:tyrosinehydroxylaseAAD:aminoaciddecarboxylaseDBHdopa-βhydroxylaseMAOmono-amineoxidaseCOMT:catechol-o-methyltransferase【AdverseReaction】

MostisduetotheproductionofDAfromlevodopainvivo.

EarlyReaction

A.GastrointestinalReaction

80%ofthesuffershavethesymptomsofanorexia、nausea、vomitingandabdominaldiscomfort.

B.CardiovascularResponse30%ofthesuffershavethesymptomsof

orthostatichypotensionandfewofthempresentarrhythmia

Theincidenceisabout90%aftermedicationfor2years.

Long-termReaction

A.HyperkinesiaTheincidence

isabout90%aftermedicationfor2years.

B.On-offresponse

Theincidence

isabout40～80%aftermedicationfor3—5years.

C.

Psychiatricsymptoms

Theincidence

isabout10～15%

Anxiety、Illusion、ManicorDepressionetc.InteractionofDrugs：

VitaminB6isaco-enzymeofAADC,soitcanweakentheeffectsoflevodopa.

Enzymeinhibitors

InhibitingdrugsofAADC

CarbidopaA.CannotpassBBB，inhibitingAADC→

L-DOPAdecarboxylatedinperipheral↓→Enterbrain↑Reduce75%dosageofmedication，thesidereactionisdownobviously.B.Carbidopa

+

L-dopa1:10/4Sinemet

——TreatmentofPD

1%70%29%more10%40%50%lessCNSGastrointestinalmetabolism

Peripheraltissue

AdversereactionLevodopaCarbidopaBenserazideA.SimilartoCarbidopaB.Benserazide+

L-dopa

1:4Madopa——TreatmentofPD

InhibitingdrugsofMAO-B

MAO-B：Distributedmainlyinsubstantianigra(SN)——striatum,tometablizeDA

Selegiline

Characteristic：

A.QuicklyenterSubstantianigra(SN)—striatumofCNS

，selectivelyinhibitingMAO-BinalowdoseandreducingthemetablismofDA.NoinfluencetoMAO-Ainintestine

B.GiventogetherwithL-DOPA，ReducingthedoseofL-DOPAandtheperipheralside-reaction.Benificialtorelievethe“on-offresponse”.

C.Neuroprotectiveagents，inhibitingtheproductionofhydroxylfreeradicalinSN—striatumanddelayingthedegenerationanddevelopingofPD.InhibitingDrugsofCOMT：

AADCCOMT

L-DOPA————DA————3-OMD

3-OMDcancompetetransporterofL-DOPA——promotingtheentranceofL-DOPAtobraintissue

NitecaponeCannotpassBBB，inhibitingCOMT

in

peripheralandenhancetheentranceof

L-DOPAtoCNS.

Tocapone

TheonlydrugcannotonlyinhibitCOMTinperipheralbutalsoinCNS.

HighBioavailability,longt1∕2and

Stongereffects.

EntacaponeInhibitCOMTinperipheral

Application：EspeciallyforpatientswithsymptomFluctuation.Adversereaction：Liverdysfuntion；Diarrhea

DAReceptorAgonists

Bromocriptine

StonglystimulateD2—likeReceptorinSN—striatum

，bettereffectsgiventogetherwithL-DOPA.ClinicalApplication:1．TreatmentofPD：Largerdose,theeffectsislikeL-DOPA

usedtogethermayreduce“on-offresponse”。

2．StimulateD2

Rofhypothalamus—pituitary

A.releaseofPRL↓——treatlactationalamenorrheasyndrome。

B.releaseofGH↓——treatingpituitarytumoretc.

LisurideD2agonist（＋）D2

likereceptor＝1000timesofbromocriptineTreatmentofPD：

reduce“on-offresponse”andabnormalmovementdisorders（Chorea）

PergolideD1

、D2likereceptoragonist，

（＋）D2likereceptor

>Lisuride

Effectivetimeislong，suitbleforthepatientsthattheeffectsofL-DOPAgodownRopinirole、PramipexoleASelectivelystimulatingD2likeR（D2、D3、D4）BThepatientsaretolerant，canreacheffectivetherapeuticconcerntrationinaweek.CUsedinthetreatmentofearlyperiodofPDDMinorgastrointestinalreaction.ApomorphineAStimulatingDAR

——Usedinthetreatmentof

PD，

improving“on-offresponse”.BUsedforalongtime——causekidneydysfunction.Drugsthatpromotingdopamine

release

AmantadineMechanism

A.PromotingL-DOPAtoenterbrainandproductionofDA.AlsopromotingthereleaseofDAandreducingthere-uptakeofDA；

B.StimulatingDARdirectly；

C.Blockingexcitingamino-acidR.TreatingPD：

Fasteffects，shortmaintaintime，Theeffects>Anticholinergicdrugs，<L-DOPA，

andhassynergisticeffectswithL-DOPA。

AnticholinergicDrugs

BenzhexolAStrongerblockingcholinergicreceptoreffectsinCNSandweakereffectsinperipheral.

Characteristics：Betterresultsinanti-tremor

andanti-salivation，butworsetostiffandslowmovement。BUsedinordinaryPDpatientsorcannotundergoLevodopa.Alsousedinpatientswhichlevodopaisnotpermitted.CUsedintreatingPDinducedbychlorpromazine,has

synergisticeffectswithL-DOPAin50％ofsuffers.DNotpermittedinglaucomaandhypertrophyoftheprostate.GenerallySpeaking——D1likeR(D1、D5R):ShowexcitingeffectsD2likeR(D2、D3、D4R):

SN-StriatumRegionShowinhibitoryeffects

(MRshowexcitingeffects)

MidbrainLimbicsystemShowexcitingeffects(hippocampus)MidbraincortexsystemShowexcitingeffectsDrugsfortreatingAD

SenileDementia：Includeprimary（AlsocalledAlzheimer’sdisease,AD）andvasculardementia（VD）.SenileDementiaisakindofdisturbanceofintelligenceinducedbyorganicbraindamage.Themainrepresentationsofthedeseasearethelossofabilityaboutmemory、judgmentandabstractthinking.Incidence：

ADaccountfor70%ofseniledementia.Thereareabout5%patientsamang65yadults，but＞90%amang95yadults.ThecourseofADdisease

lastwhin3-20years.Patientscansurvivefor10yearsinavarageafterabsolutelydiagnosis.Thespiritdiefirstandthentheflesh.PathologicalChange：

A.Amyloidprotein(AP)depositionoutofthecells

RelatedtothevariationofAPPrecursor

B.FiberTangleinneuron

C.SenileSpot

AnatomicalFeatures：

Cerebralshrinkage（hippocampusandtheforebrain）

FunctionalFeatures：

Transmissionimpairmentofcholinergicnerveexcitation;degenerationofAchRinCNSandreductionoftheneuronnumber.TreatingMethods

islieonimprovingthesymptomsmainly.

InhibitingdrugsofAch-E;StimulantofCerebralmetabolism;Drugsforimprovingcerebralmicro-circle;Calciumantagonists老年斑（SP）

Alzheimer’sdiseaseisaprogressivebraindisorderthatgraduallydestroysaperson’smemoryandabilitytolearn,reason,makejudgments,communicateandcarryoutdailyactivities.AsAlzheimer’sprogresses,individualsmayalsoexperiencechangesinpersonalityandbehavior,suchasanxiety,suspiciousness,aswellashallucinationsordelusions.

AlthoughthereiscurrentlynocureforAlzheimer’s,effectivecareandsupportcanimprovequalityoflifeforindividuals.IInhibitingDrugsofAch-E

Tacrine

Productoffirstgeneration.Maydelaythecourseofdiseasefor1－12month.【TheInVivoProcess】

AMedicationbyP.O.orinjection.BAbsorptionisinfluencedbyfood.EasytopassBBBanddistributedalloverthebody.【PharmacologicalEffects】

Improvingthereductionoflearningandmemoryduetomedication、hypoxiaandageing.

Mechanism:A.InhibitingAch-EReversibily，AChinCNS↑;B.StimulatingM、NR，andpromotingthereleasingofAch、NMDAand5－HT;C.ImprovingtheuseofCNStoglucose【ClinicalApplications】

TreatingADwithlecithin，improvingtheabilityofcognitionandselfmanagement.

MosteffectivedrugfortreatingADatpresent.【AdverseReaction】Livertoxicity（25%,mayrecoverwhenstopmedication）；Gastrointestinalreaction（1/3ofthesuffers）

【InteractionofDrugs】A.CimetidinemayimprovetheplasmaconcerntrationoftacrineB.ThecurativeeffectsoftacrinetoADmaybeenhancedbythecombinedapplicationwithlecithin.

DonepezilAProductofsecondgeneration.Bioavailabilitybyp.o.is100%，andabsorptionisnotinfluencedbyfood.BInhibitingAChEinCNSselectively,theadversereactioninperipheralisweakandless.CUsedinthetreatmentofmildandmoderateAD.Improvingthe

cognitionability.

GalanthamineAProductofsecondgeneration.HashighlyselectivitytoAChEinneurons.BUsedinthetreatmentofmildandmoderateAD.Theeffectiverateis60%，andissimilartotacrine.

Beginningtorepresentingeffectsaftermedicationfor6-8w.Thedrughasnolivertoxicityandisbecomingthedrugofchoice.CMainadversereaction：Gastrointestinalreactionintheearlyperiodoftreatment.

Rivastigmine

AChEinhibitorofsecondgeneration.ReducingtheformationofAPP.Improvingtheabilityofcognition,memory，attention

andsenseofdirectionforADsuffers.

Thedrughastheadvantagesofsafety.Especiallysuitbleforthepatientswithheartdeseases、liverdeseasesandkidneydeseases.Themainadversereactionincludenausea、vomitting、sleepiness、abdominalpainanddiarrheaetc.

StimulantsofCerebralMetabolism