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,estrogensandprogesterone,lipoprotein,CM(乳麋微粒)：ChylomicronsVLDL(极低密度脂蛋白)：verylow-densitylipoproteinLDL(低密度脂蛋白):low-densitylipoproteinHDL(高密度脂蛋白):high-densitylipoprotein,hyperlipidemia,Hypercholesterolemia(LDL)240mg/dl,Hypertriglyceridemia(VLDL)140mg/dlStronglyassociatedwithatherosclerotic(动脉粥样硬化)lesionsandcoronary(冠状动脉)heartdisease,-50%CHDrelatedcigarettesmoking,physicalinactivityandobesity.,Classifiedbystructure,ThetreatmentofHypercholesterolemia1,Bileacidsequestrants（胆汁酸结合树脂）2,HMGCoAreductaseinhibitors（HMGCoA还原酶抑制剂）ThetreatmentofHypertriglyceridemia3,Fibrates（苯氧酸类）4,Niacin（烟酸）,586,Antihyperlipidemicdrugsinthetop200,1,BileAcidSequestrants胆汁酸结合树脂,Cholestyramine(考来烯胺),1960sColestipol(考来替泊),1977Bindbileacidandincreasetheirfecal(粪便的)eliminationAnion-exchangeresin,Bileacidsequestrants,QuaternaryAmmonium1973SecondaryTertiaryAmines1977587,考来烯胺,考来替泊,四亚乙基戊胺,PhysicochemicalProperties,Large,Waterinsolubleresins,MW1,000,000Cholestyramine(考来烯胺),1624grams/D,apowder(aslurry)Colestipol(考来替泊),530grams/D,granules(粒剂)andtabletTabletshouldnottobechewed,crushed,cut,Metabolism,Notorallyabsorbedandmetabolizedbygastrointestinalenzymes:onsetofaction12days,1month.Excretedinthefecesasaninsolublecomplexwithbileacids,Indicationsandadverseeffects,Hypercholesterolemia:50%reductionofplasmaLDLlevelsOneofthesafestdrugstouseGastrointestinalsymptomsConstipation（便秘）,bloating(腹胀)，abdominaldiscomfort,2,HMGCoAreductaseinhibitors,CholesterolC27steroid,HMGCoAreductaseinhibitors,3-hydroxy-3-methylglutarylCoAreductaseHMG-CoAreductase,AprimarycontrolsiteHMG-CoA还原酶抑制剂,HMG-CoAReductase,HMG-CoA:3-hydroxy-3-methylglutaryCoAHMG-CoAReductaseHMG-CoAReductaseInhibitor,Mevalonicacid,588,HistoricalOverview,1976，EndoandKuroda,Mevastatin（美伐他丁,Compatin）fromPenicillium,affinityfortheenzyme10,000timesgraterthanthatofHMGCoA,DiscontinuanceofMevastatin,Pre-clinicaltrail:Reportsofalteredintestinalmorphology(形态),Lovastatin,LovastatinisolatedfromMonascusruber（红曲霉菌）andAspergillusterreus(土霉菌)Over2-foldpotentthanMevastatin,Lovastatin,MerckReceivedFDAapproval1987,markedLovacor2001/6,patent,Simvastadin,辛伐他丁Merk，88,Zocor97，3billion;2000,5.3billion;2005,12,patent,589,O,Pravastadin,普伐他丁1989,Pravachol(普拉固)BMS97,0.6billions2001，3.4billions;tops,47,Ring-opened,6-hydroxylgroup,O,PhysicochemicalProperties,LovastatinWhitecrystalpowderinsolubleinwaterHighestlipidsolubility-chloroform,acetone,3R,5R,O,PhysicochemicalProperties,Simvastadin,Pravastadin,O,O,3R,5R,3R,5R,Chemicalstability,Oxidation,hydrolysis,Metabolism,hydrolysis,-OH,-OH,Pro-drug,Extensivefirst-passmetabolismLoworalbioavailability592,Mechanismofaction,Comparewithhalf-reducedintermediate,HMGCoAReductase,Therapeuticapplications,HypercholesterolemiaReduceplasmaLDLlevelsReducethemortality(死亡率)ofcoronaryheartdiseaseandstrokeGastrointestinaldisturbancesRhabdomyolysis横纹肌溶解,Structure-ActivityRelationship,Bicyclicrings,Lactone,Ethylenebridge,strereochemistry,Aromaticring,590,Syntheticagents,SimplifythestructureofLovastatinReplacementofthebicyclicringwithvarioussubstituted,aromaticringsystems,Fluvastatin,94,Novas,Switzerland氟伐他丁Lescol,来适可2001,68,Atorvastatin,阿托伐他丁,LipitorPfizer19972000，5billiondollars2001,22004,1,morethan6billiondollars,589592,Cerivastatin,拜斯汀,BaycolBayer3,5-dihydroxycarboxylatesignificantlyimproveswatersolubility,Fluvastatin,Atorvastatin,Cerivastatin,Propertiesofsynthetic“vastatin”,LogPOralbioavailabilityMetaboloismElimination,592,Adverseeffects,GastrointestinaldisturbancesCerivastatin,拜斯汀2001,157,31deathsRhabdomyolysis横纹肌溶解Itwasvoluntarilywithdrawin2001,Structure-activityRelationship,A3,5-dihydroxycarboxylate；stereochemistrymustbesameasthelovastatin;Cethylgroupordoublebond；Baromaticring,A,C,B,1,2,3,4,5,6,7,590,3,Fibrates苯氧乙酸类,1962，arandomscreentestClofibrate,氯贝丁酯1967,approvedfortherapeuticuse1978,WorldHealthOrganizationtrial,Structuremodifications,1981,Gemfibrozil(吉非贝齐)Lopid2001,115,596,Gemfibrozil,AnacidicdrugHighlylipidsolubility,Gemfibrozil,吉非贝齐,CYP3A4-OH,-COOH,CYP3A4-OH,-COOH,T1/2=1.5hr,25daystocauseaninitialdecreaseinplasmatriglyceridelevels,renalelimination,596,Fenofibrate,1998,非诺贝特,lipid-solubleTricor2001,176,hydrolysis,Fenofibrate,T1/2=20-22hr,68weekstodetermineefficacy,renalelimination67mgdoseofmicronizedFenofibrate=100mgdoseofnomicronizedFenofibrate,TherapeuticApplication,totreathypertriglyceridemiaGastrointestinalcomplainsCaution:combinedwithHMGRIs;anincreaseinoverallmortality,Structure-ActivityRelationship,acidgroup,AromaticringCI,Longerhalf-lives,SpacergroupPropylspacer,P595,Pheoxyisobutyricacid,4,NicotinicAcid烟酸类,Nicotine,NicotinicAcid,1867,NicotinicAcid,Topreventpellagra(糙皮病)1955,Altschul,highdose,NicotinicAcid,White,crystallinepowder，mp.236.6C；Freelysolubleinalkalinesolution,NicotinicAcid,Hypercholesterolemia,Hypertriglyceridemia,familialcombinedhyperlipidemiavasodilation(皮肤血管扩张，flushingandpruritus(瘙痒症)；gastrointestinalintolerance（20-50%）.,Objects,TolearnhowmanyclassesareAntihyperli