药理学教学课件：Chapter 12 ANTIATHEROSCLEROSIS DRUGS

CHAPTER12ANTIATHEROSCLEROSISDRUGSAtherosclerosis（AS）--isan

arterydisease,whichisthepathologicalbasisofischemiccerebral,myocardialvasculardisease.--isaninflammatorydisease.IntroductionWhydoesitbecalledAS？Lipidaccumulationinendarterium,looklikeyellowporridgeshape.动脉粥样硬化斑块肉眼观察NomallumenConfinedlumenDangerousfactorsendotheliuminjury

MC

becohesivetoVECMCinvadeintosubendothelium

MФfoamcell

SMChyperplasiaformfatstripe

ASplaque

MC:monocyte

MФ:

macrophage

ProcessofASIntimaEndotheliumVesselLumenmuscularlayer

LPLPmonocyteLipoprotein(Mostimportant-oxLDL)IntimaEndotheliumVesselLumenmuscularlayer

macrophageIntimaEndotheliumVesselLumenmuscularlayer

IntimaEndotheliumVesselLumenmuscularlayer

FoamcellIntimaEndotheliumVesselLumenmuscularlayer

LipidcorePlateletIntimaEndotheliumVesselLumenmuscularlayer

thrombus

动脉粥样硬化:进展性系统性疾病CRP=C-reactiveprotein;LDL-C=low-densitylipoproteincholesterol.LibbyP.Circulation.2001;104:365-372;RossR.NEnglJMed.1999;340:115-126.单核细胞LDL-C黏附分子巨噬细胞泡沫细胞氧化的LDL-C斑块破裂平滑肌细胞CRP斑块不稳定和血栓形成氧化炎症内皮功能受损CRP:C-reactiveprotein--Metabolicdisorder

ofplasmalipidMechanismofAS--LipidperoxidationSection1DisorderofplasmalipidandASApolipoprotein(apo)Cholesterol(Ch)

Cholesterolester(CE）triacylglycerol

(TG)

Phosphoruslipid(PL)Plasmalipidlipoprotein--Chylomicron(CM)--Verylowdensitylipoprotein(VLDL)--Lowdensitylipoprotein(LDL)--Intermediatedensitylipoprotein(IDL)--Highdensitylipoprotein(HDL)LipoproteinMetabolismofplasmalipoproteinsApoCⅡ:apolipoproteinCⅡfoundinchylomicronsandVLDLMetabolicdisorder

ofplasmaLipidVLDLLDLIDLHDLnormalnormalCharacteristicofthemajorhyperlipidemias

TypeshyperlipidemiaslipoproteinplasmalipidⅠ高TG血症外源性CMTGⅡa自发性家族性LDL

Ch

高Ch血症Ⅱb自发性家族性LDL、VLDLCh、TG高Ch血症Ⅲ高Ch血症及高TG血症IDLCh、TGⅣ高TG血症内源性VLDLTGⅤ高TG血症（内源CM、VLDLTG和外源）混合型Treatment

DietLifestyleDrugtreatmentLipidemic-modulatingdrugsAntioxidantsn-3PUFAsOthers

Thecommonlyusedlipidemic-modulatingdrugs

1.Statins(他汀类）2.Bileacid-bindingresins3.Fibrates（贝特类）4.Nicoticacid

—InhibitorsofHMG-CoAreductase—TotalCholesterolandLDL-loweringDrugs

Section2Lipidemic-modulatingdrugsStatins(他汀类)HMG-CoA:Hydroxy-methyl-glutarylcoenzymeA,羟甲基戊二酰辅酶ALovastatin洛伐他汀,simvastatin辛伐他汀,pravastatin普伐他汀,fluvastatin氟伐他汀:seldommyalgia肌痛

atorvastatin阿托伐他汀:TGrosuvastatin瑞舒伐他汀

CommonlyuseddrugsPharmacologicaleffects

Regulationofbloodlipids

↓Ch↓LDL-C>TC>TG,↓VLDL↑HDL-COthereffects--Improvethefunctionofvascularendothelium--Stabilizeatheromatousplaque,inhibitthrombus--InhibitproliferationandmigrationofVSMC--Inhibitplateletaggregationandthrombosis---↓CRP,↓inflammatoryresponseMechanism①CompetitiveinhibitHMG-CoAreductase,blocksynthesisofcholesterol.

②ElevatedamountandactivationofhepaticLDL-R③DecreasereleaseofVLDLLovastatinMechanismofaction↓Ch↑LDL-R↓LDLinplasmaInhibitionofHMGCoAreductasebythestatinsdrugsEffectsofstatinsonleveloflipiprotein

Drugdose

changeoflipiprotein（%）（mg/d）TCLDL-CHDL-CTGlovastatin20-22-25+8-10fluvastatin20-15-20+5-10pravastatin20-19-25+6-11simvastatin20-27-34+6-15note：+increase，-decreaseClinicaluses

--Ⅱa、Ⅱb、IIItypehyperlipoproteinemia

additionalstrategies:diet,exercise,oradditionalagents

--renaldiseasesymptoms--AS,anginalpectorisLovastatinAdversereactions1.GI,flushing,headache2.Elevatedhepatictransaminase

injuretoliverfunction,returntonormalonsuspensionofdrug

3.Skeletalmuscletoxicity:myalgia(肌痛),

CPK(creatinephosphokinase)↑,rhabdomyolysis

(横纹肌溶解症).LovastatinRhabdomyolysis--Disintegrationanddissolutionofmuscle--Patientssufferedfromrenalinsufficiencyorweretakingotherdrugs(interaction)--↑PlasmaCPKDrugsinteraction+Cyclosporine环孢素rhabdomyolysis

+

Erythromycin红霉素rhabdomyolysis

+

Warfarin华法林bleed+

Gemfibrozil吉非贝齐rhabdomyolysis

+

Nicotinicacid烟酸rhabdomyolysis

Bileacid-bindingresins(胆汁酸结合树脂)—drugswhichaffectsabsorptionofCholesterin.

Cholestyramine(考来烯胺)

Colestipol

(考来替泊)ABasicanionexchangeresinsMechanismofactionBasicaction:Bindnegativelychargedbileacidsandbilesaltsreabsorption↓Secondaryaction:↑theconversionofcholesteroltobileacid,↓thelevelofcholesterol↑LDL-R:LDL-C↓MechanismofbileacidbindingresinsIIa

andIIb

hyperlipoproteinemia

(TCandLDL-C)ASrelievepruritus瘙痒,causedbyaccumulationofbileacidsinpatientswithbiliaryobstruction(combinationwithStatins,becauseitcanenhanceHMG-CoAreducaseactivity)

Clinicaluses

CholestyramineAdversereactionGastrointestinal

disturbances:nausea,abdominaldistention腹胀,constipationetal.(markedly)

Impairedabsorptions:fat-solublevitamins,A,D,E,K;folicacidcholestyramineCholesterolabsorptioninhibitor

Ezetimibe依折麦布InhibitChexogenousabsorptioninhibitNPC1L1transportproteinforChabsorptionbyactingonintestinalcellbrushborder刷状缘，DecreaseLDL-C、TC、TG，IncreaseHDL-C

NPC1L1:Niemann-pickC1Like1

Fibrates(贝特类)—drugswhichaffectedthemetabolismofChandtriglycerideClofibrate(氯贝丁酯)

Gemfibrazil(吉非贝齐)Fenofibrate(非诺贝特)Benzafibrate(苯扎贝特)CommonlydrugsPharmacologicalactionsandmechanism

1.Lipidemic-modulatingactions：

↓TG、VLDL-C

↑HDL--activeperoxisomeproliferatoractivatedreceptor,PPARα)，inhibitfatdissolution.--stimulatinglipoproteinlipase(LPL)activity(hydrolyzeTGandVLDL)--DecreaseexpressionofapoCⅢ--PromotetheexpressionofapoAIandapoAⅡActivationoflipoproteinlipasebyclofibrateClinicalusesIII,IV,Ⅴtypehyperlipoproteinemia;particularlyfamilialIIIhyperlipidemia.

Benzafibratecanimprovesugarmetabolize，beusedfordiabetesaccompaniedwithhighTG.

AdversereactionClofibrateCommon:gastrointestinaldisturbancesLithiasis(结石病）:increasebiliarycholesterolexcretion,apredispositiontotheformationofgallstoneMalignancy:resultedinmalignancy-relateddeaths

Nicotinicacid

Pharmacologicalactions

—AlsoaffectedthemetabolismofChandtriglyceridebyinhibitinglipase.

--Lipidemic-modulatingactions：

↓VLDL,TG20%～60%

↓

LDL-CandLP(a)10%～25%

↑

HDL15%～30%Mechanismsofaction

--fatdissolution

byGproteincoupledreceptorofHM74A--decreasecAMPinfattissue,inhibitcAMP-dependentlipaseactivity,suppressfatdissolution，decreaseFFAinbloodandTGsynthesisinliver.--enhanceLPLactivity，increaseTGelimination.--DecreaseTXA2synthesis,increasePGI2MechanismofAction:

Nicotinicacid

NiacinNiacininhibitslipolysisinadiposetissueresultingindecreasedhepaticVLDLsynthesisandproductionofLDLintheplasma.

III,IV,VhyperlipidemiaAlsousedincombinationwithotherantihyperlipidemicagents.ThemostpotentantihyperlipidemicagentforraisingplasmaHDLlevels.ClinicalusesNicotinicacid

AdversereactionCommonsideeffects:anintensecutaneousflush(accompaniedbyanuncomfortablefeelingofwarmth)andpruritus瘙痒.Aspirinpriortoniacindecreasesthisflush.(becauseofinhibitionofprostaglandinsynthesis)Nauseaandabdominalpain.Nicotinicacid

Lp(a)-loweringDrugsElevationofbloodLp(a)ariskfactorofrestenosisafterpercutaneoustransluminalcoronaryangioplasty.Lp(a)caninhibitactivationofplasminogencompetitively,advancethrombus;OX-Lp(a)caninduceendotheliumtoexpressmoreP-selectinandstrengththeadhesionofMC.

Acipimox阿西莫司降Lp(a)的药物