药理学-调血脂药和抗动脉粥样硬化药课件

调血脂药和抗动脉粥样硬化药Lipid-modulatingdrugsandAntiatheroscleroticdrugsPathophysiology损伤血脂异常高血压吸烟，等单核细胞巨噬细胞泡沫细胞血管平滑肌细胞脂质Scavengerreceptor脂质AtherosclerosisVascularendotheliummodification

in

atherosclerosisPlaqueformation:ThefattystreakPathophysiologyAtherosclerosis泡沫细胞脂质条纹斑块前期粥样斑块纤维粥样斑块复合病变十年三十年四十年内皮功能障碍Fromplaquetothrombosis,keyevent:plaquerupture第一节调血脂药

胆固醇（Ch)三酰甘油（TG）磷脂（PL）游离脂肪酸（FFA）血脂脂蛋白

1.201.101.061.021.0060.95510204060801000ChylomicronRemnantsVLDLIDLLDLHDL2HDL3Diameter(nm)Density(g/ml)Chylo-micronsLipoprotein(Sub)ClassesLp(a)高脂血症的分型━━━━━━━━━━━━━━━━━━━━━━━━━━━━

表型血浆4℃TCTGCMVLDLLDL备注过夜外观━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

I奶油上层,下层清↑→↑↑↑↑↑↑↓→易发胰腺炎IIa透明↑↑→→→↑↑易发冠心病IIb透明

↑↑↑↑→↑↑易发冠心病III奶油上层↑↑↑↑↑↑↓易发冠心病

下层混浊IV混浊↑→↑↑→↑↑→易发冠心病V奶油上层↑↑↑↑↑↑↓→易发胰腺炎下层混浊━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━注:↑示浓度升高;→示浓度正常;↓示浓度降低一.降低TC和LDL的药物二.降低TG及VLDL的药物三.降低Lp(a)的药物（一）HMG-CoA还原酶抑制药洛伐他汀；辛伐他汀普伐他汀；氟伐他汀（二）胆汁酸结合树脂考来烯胺，考来替泊（三）ACAT抑制药甲亚油酰胺（一）贝特类

吉非贝齐；非诺贝特

（二）烟酸

烟酸；阿莫替司

TreatmentofHyperlipidemiaExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497.HighLDL-CTherapeuticLifestyleChangeDrugTherapyTherapyofChoice:StatinAlternative:ResinorniacinStatins:MechanismofActionLDLreceptor–mediatedhepaticuptakeofLDLandVLDLremnantsSerumVLDLremnantsSerumLDL-CCholesterolsynthesisLDLreceptor(B–Ereceptor)synthesisIntracellularCholesterolApoBApoEApoBSystemicCirculationHepatocyteReducehepaticcholesterolsynthesis,loweringintracellularcholesterol,whichstimulatesupregulationofLDLreceptorandincreasestheuptakeofnon-HDLparticlesfromthesystemiccirculation.LDLSerumIDLVLDLRVLDLPotentialTimeCourseofStatinEffects*TimecourseestablishedDaysYearsLDL-Clowered*Inflammation

reducedVulnerable

plaques

stabilizedEndothelial

function

restoredIschemic

episodes

reducedCardiac

events

reduced*调血脂改善血管内皮细胞功能减轻炎性反应减少缺血发作稳定斑块减少心血管事件调血脂作用非调脂作用

改善血管内皮；促进血管平滑肌细胞凋亡；稳定斑块；减轻血管炎性反应；抑制血小板聚集等他汀类药理作用他汀类临床应用调血脂肾病综合征血管形成术后再狭窄预防心脑血管急性事件器官移植术后的排斥反应和骨质疏松症LawMRetal.BMJ.2003;326:1423-1427.Absolutereductions*(mg/dL)and(percentagereductions†)Statin10mg/d20mg/d40mg/d80mg/dAtorvastatin阿伐他汀69(37)80(43)91(49)102(55)Fluvastatin氟伐他汀29(15)39(21)50(27)61(33)Lovastatin‡洛伐他汀39(21)54(29)68(37)83(45)Pravastatin普伐他汀37(20)45(24)53(29)62(33)Simvastatin辛伐他汀51(27)60(32)69(37)78(42)*StandardizedtoLDL-C186mg/dL(meanconcentrationintrials)beforetreatment.

†IndependentofpretreatmentLDL-C.

‡Maximumdoseof80mg/dadministeredastwo40-mgtablets.§NotFDAapprovedat80mg/d.LDL-CLoweringAccordingtoStatinandDose:AMeta-analysisof164TrialsStatinAdverseEventsCommonsideeffectsHeadache头痛–Myalgia肌痛–Fatigue疲劳GIintolerance–Flu-likesymptoms流感样症状Increaseinliverenzymes（CPK）肌酸磷酸激酶Occursin0.5to2.5%ofcasesindose-dependentmannerSeriousliverproblemsareexceedinglyrareManagebyreducingstatindoseordiscontinueuntillevelsreturntonormalMyopathy肌病Occursin0.2to0.4%ofpatientsRarecasesofrhabdomyolysis横纹肌溶解ReducebyCautiouslyusingstatinsinpatientswithimpairedrenalfunctionUsingthelowesteffectivedoseCautiouslycombiningstatinswithfibratesAvoidingdruginteractionsCarefulmonitoringofsymptomsPresenceofmuscletoxicityrequiresthediscontinuationofthestatinBileacidbinding-resins

胆汁酸结合树脂胆固醇结合剂+胆汁酸↓←HMG-CoA还原酶胆固醇↓←7α羟化酶胆汁酸↓LDL→受体1.减少食物脂类吸收2.阻滞胆汁酸重吸收3.肝内Ch转化为胆汁酸4.LDL受体↑5.血浆LDL进入肝细胞6.HMG-CoA还原酶继发活性增加①②③④⑤⑥肠腔STATIN临床应用

Ⅱa及Ⅱb型高脂蛋白血症,家族性杂合子高脂蛋白血症不良反应特殊臭味,刺激性;胃肠道反应药物相互作用避免和某些药物同时服用,影响其吸收HMG-CoA还原酶抑制药;叶酸;铁剂等

考来烯胺考来替泊二.降低TG和VLDL的药物(一)贝特类吉非贝齐(gimfibrazil)非诺贝特(fenofibrate)

降低LDL-C和TG;升高HDL-C对冠心病防治的价值-----尚无定论(二)烟酸类烟酸(nicotinicacid);阿昔莫司(acimox)降低cAMP水平——脂肪酶活性降低——

TG合成不足——VLDL减少——LDL减少——HDL分解代谢减少——HDL增高抑制血小板聚集和扩张血管NicotinicAcid:MechanismofActionLiverCirculationHDLSerumVLDLresultsinreducedlipolysistoLDLSerumLDLVLDLDecreaseshepaticproductionofVLDLandofapoBVLDLsecretionApoBHepatocyteSystemicCirculationMobilizationofFFATGsynthesisVLDLLDL烟酸niacin临床应用：广谱调血脂药Ⅱb和Ⅳ型高脂蛋白血症最好混合型高脂蛋白血症、高TG血症、低HDL血症、高Lp（a）血症ClinicalFeaturesofNicotinicAcidBestagenttoraiseHDL-CReducescoronaryevents(CoronaryDrugProject)AdverseeffectsFlushing,itching,headache(immediate-release,Niaspan®)Hepatotoxicity,GI(sustained-release)ActivationofpepticulcerHyperglycemiaandreducedinsulinsensitivityContraindicationsActiveliverdiseaseorunexplainedLFTelevationsPepticulcerdiseaseTreatmentofMixedHyperlipidemiaExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497.HighLDL-CandTGsTherapeuticLifestyleChangeDrugTherapyAchievetheLDL-Cgoal1STEPAchievethenon-HDL-Cgoal

IncreaseLDL-Cloweringor