第四章循环系统药物CirculatorySystemA

Chapter7Antihyperlipoproteinemics降血脂药lipoproteinCholesterolandCholesterolester胆固醇triglycerides,甘油三脂Phospholipids,磷脂Cholesterol:cellmembranes,androgens,estrogensandprogesteronelipoproteinCM(乳麋微粒)：ChylomicronsVLDL(极低密度脂蛋白)：verylow-densitylipoproteinLDL(低密度脂蛋白):low-densitylipoproteinHDL(高密度脂蛋白):high-densitylipoproteinhyperlipidemiaHypercholesterolemia(LDL)240mg/dl,Hypertriglyceridemia(VLDL)140mg/dlStronglyassociatedwithatherosclerotic(动脉粥样硬化)lesionsandcoronary(冠状动脉)heartdisease,---50%CHDrelatedcigarettesmoking,physicalinactivityandobesity.ClassifiedbystructureThetreatmentofHypercholesterolemia1,Bileacidsequestrants（胆汁酸结合树脂）2,HMGCoAreductaseinhibitors（HMGCoA还原酶抑制剂）ThetreatmentofHypertriglyceridemia3,Fibrates（苯氧酸类）4,Niacin（烟酸）586Antihyperlipidemicdrugsinthetop200Rankin2001GenericnameTradenameManufacturer2AstorvastatinLipitorPfizer21SimvastatinZocorMerck47PravastatinPravacolBMS68FluvastatinsodiumLescol115GemfibrozilLopid157CerivastatinBaycol176fenofibrateTricor1,BileAcidSequestrants胆汁酸结合树脂Cholestyramine(考来烯胺),1960sColestipol(考来替泊),1977Bindbileacidandincreasetheirfecal(粪便的)eliminationAnion-exchangeresinBileacidsequestrantsQuaternaryAmmonium1973SecondaryTertiaryAmines1977587考来烯胺考来替泊四亚乙基戊胺PhysicochemicalPropertiesLarge,Water–insolubleresins,MW1,000,000Cholestyramine(考来烯胺),16~24grams/D,apowder(aslurry)Colestipol(考来替泊),530grams/D,granules(粒剂)andtabletTabletshouldnottobechewed,crushed,cutMetabolismNotorallyabsorbedandmetabolizedbygastrointestinalenzymes:onsetofaction1~2days,1month.ExcretedinthefecesasaninsolublecomplexwithbileacidsIndicationsandadverseeffectsHypercholesterolemia:50%reductionofplasmaLDLlevelsOneofthesafestdrugstouseGastrointestinalsymptomsConstipation（便秘）,bloating(腹胀)，abdominaldiscomfort2,HMGCoAreductaseinhibitorsOHCholesterolC27steroidHMGCoAreductaseinhibitors3-hydroxy-3-methylglutarylCoAreductaseHMG-CoAreductase,AprimarycontrolsiteHMG-CoA还原酶抑制剂HMG-CoAReductaseOCOO-CH3OHSCoACOO-CH3OHSCoAOHOCOO-CH3OHHCOO-CH3OHOHHMG-CoA:3-hydroxy-3-methylglutaryCoAHMG-CoAReductaseHMG-CoAReductaseInhibitorMevalonicacid588HistoricalOverview1976，EndoandKuroda,Mevastatin（美伐他丁,Compatin）fromPenicillium,affinityfortheenzyme10,000timesgraterthanthatofHMGCoADiscontinuanceofMevastatinPre-clinicaltrail:Reportsofalteredintestinalmorphology(形态)LovastatinLovastatinisolatedfromMonascusruber（红曲霉菌）andAspergillusterreus(土霉菌)Over2-foldpotentthanMevastatinCH3HH3COOHOOCH3LovastatinCH3HH3COOHOOCH3MerckReceivedFDAapproval1987,markedLovacor2001/6,patentSimvastadin辛伐他丁Merk，88,Zocor97，3billion;2000,5.3billion;2005,12,patentCH3HH3COOHOOCH3H3C589OPravastadin普伐他丁1989,Pravachol(普拉固)BMS97,0.6billions2001，3.4billions;tops,47CH3HHOOHOHOOCH3OHRing-opened6’-hydroxylgroupOPhysicochemicalPropertiesLovastatinWhitecrystalpowderinsolubleinwaterHighestlipidsolubility---chloroform,acetoneCH3HH3COOHOOCH33R5ROPhysicochemicalPropertiesCH3HH3COOHOOCH3H3CCH3HHOOHOHOOCH3OHSimvastadinPravastadinOO3R5R3R5RChemicalstabilityCH3HH3COOHOOCH3OxidationhydrolysisMetabolismCH3HH3COOHOOCH3hydrolysis-OH-OHPro-drugOHOHHRCOOH12345Extensivefirst-passmetabolismLoworalbioavailability592MechanismofactionComparewithhalf-reducedintermediateOCOO-CH3OHSCoACOO-CH3OHSCoAOHOCOO-CH3OHHCOO-CH3OHOHOHOHHRCOOH12345HMGCoAReductaseTherapeuticapplicationsHypercholesterolemiaReduceplasmaLDLlevelsReducethemortality(死亡率)ofcoronaryheartdiseaseandstrokeGastrointestinaldisturbancesRhabdomyolysis横纹肌溶解Structure-ActivityRelationshipCH3HH3COOHOOCH3BicyclicringsLactoneEthylenebridgestrereochemistryAromaticring590SyntheticagentsSimplifythestructureofLovastatinReplacementofthebicyclicringwithvarioussubstituted,aromaticringsystemsCH3HH3COOHOOCH3Fluvastatin94,Novas,Switzerland氟伐他丁Lescol,来适可2001,68NOHOHFOHOAtorvastatin阿托伐他丁,LipitorPfizer19972000，5billiondollars2001,22004,1,morethan6billiondollars589592NONHFOHOHHCOONaCerivastatin拜斯汀,BaycolBayer&SmithklineBeechamNFOH3CCOOCaHOOH589Propertiesofsynthetic“vastatin”NONHFOHOHHCOONaNFOH3CCOOCaHOOHAcidicdrugs;3,5-dihydroxycarboxylatesignificantlyimproveswatersolubilityNOHOHOHOFFluvastatinAtorvastatinCerivastatinPropertiesofsynthetic“vastatin”LogPOralbioavailabilityMetaboloismElimination592AdverseeffectsGastrointestinaldisturbancesCerivastatin,拜斯汀2001,157,31deathsRhabdomyolysis横纹肌溶解Itwasvoluntarilywithdrawin2001NFOH3CCOOCaHOOHStructure-activityRelationshipA—3,5-dihydroxycarboxylate；stereochemistrymustbesameasthelovastatin;C—ethylgroupordoublebond；B—aromaticringRCOOHOHOHACB12345675903,Fibrates苯氧乙酸类1962，arandomscreentestClofibrate,氯贝丁酯1967,approvedfortherapeuticuse1978,WorldHealthOrganizationtrialCIOCH3CH3OOCH2CH3Structuremodifications1981,Gemfibrozil(吉非贝齐)Lopid2001,115OCOOH596GemfibrozilOCOOHAnacidicdrugHighlylipidsolubilityGemfibrozil,吉非贝齐OCOOHCYP3A4-OH,-COOHCYP3A4-OH,-COOHT1/2=1.5hr,2~5daystocauseaninitialdecreaseinplasmatriglyceridelevels,renalelimination596Fenofibrate1998,非诺贝特,lipid-solubleTricor2001,176OOOOIChydrolysisFenofibrateT1/2=20-22hr,6~8weekstodetermineeffi