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抗动脉粥样硬化药课件_2

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抗动脉粥样硬化药课件 抗动脉粥样硬化药 抗动脉粥样硬化药物PPT 抗动脉粥样硬化药ppt 抗动脉粥样硬化药抗动脉粥样硬化药 动脉粥样硬化 抗动脉粥样硬化药 ppt
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With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 抗动脉粥样硬化药抗动脉粥样硬化药 (antiatherosclerotic drugs)(antiatherosclerotic drugs) With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 概述 nAtherosclerosis(AS)是心脑血管病的主 要病理学基础。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 主要次要新近提出 年龄体力活动减少氧化低密度脂蛋白 性别肥胖和超重血管内膜损伤 高脂血症高脂血症A型性格饮食中缺少抗氧化剂 高血压遗传胰岛素抵抗 吸烟微量元素铁贮存增多 糖尿病缺氧血管紧张素转换酶基因的多态性和过度表达 抗原-抗体作用左心室肥厚 维生素纤维蛋白原增多 某些酶活性降低同型半胱氨酸增高 ……感染(病毒、衣原体、细菌) 动脉粥样硬化的危险因素 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society Atherogenesis MONOCYTEMONOCYTE PLASMA LDLPLASMA LDL MM LDLMM LDL OX.LDLOX.LDL AdhesionAdhesion Endothelial cellsEndothelial cells PG/LDLPG/LDL SmoothSmooth muscle cellmuscle cell CellCell deathdeath FOAM CELLFOAM CELL MACROPHAGEMACROPHAGE MigrationMigration Oxidized LDLOxidized LDL uptakeuptake LIPIDLIPID CORECORE CollagenCollagen productionproduction With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 动脉粥样硬化斑块肉眼观察 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 动脉粥样硬化显微镜观察 正常管腔正常管腔变窄的管腔变窄的管腔 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society AS形成过程: 危险因素 损伤血管内皮 MC向VEC 粘附 MC进入内皮下 MФ 泡沫细胞 脂肪条纹 AS斑块 凡能抑制AS病变发生和发展的药物都 可能是抗AS药 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 第一节 调血脂性抗AS药 血脂与AS的关系: 1.血脂的组成与含量 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 我国人群血脂的年龄龄和性别别分布 男性 女性 TC HDL-C TG With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 2. 脂蛋白的种类、组成及功能 脂蛋白 CM VLDL LDL HDL 密度(g/ml) <0.95 0.951~1.006 1.006~1.063 1.063~1.210 电泳 原点 前β β α 组成(%) 蛋白质 0.5~2 5~10 20~25 50 脂类 98~99 90~95 75~80 50 三酰甘油 80~95 50~70 10 5 磷脂 5~7 15 20 25 总胆固醇 1~4 15 45~50 20 游离胆固醇 1~2 5~7 8 5 胆固醇脂 3 10~12 40~42 15~17 apo组成(%)AⅠ 7 <1 - 65~70 AⅡ 5 ― ― 20~25 B100 - 20~60 95 - B48 9 - - - CⅠ 11 3 ― 6 CⅡ 15 6 微量 1 CⅢ 41 40 ― 4 E 微量 7~15 <5 2 合成部位 小肠粘膜细胞 肝细胞 血浆 肝、肠 功能 转运外源TG及Ch 转运内源TG及Ch 转运内源Ch 逆向转运Ch With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 脂蛋白的大小 0.95 1.006 1.02 1.10 1.10 1.20 204060801000 密度 (g/ml) 直径 (nm) VLDL 510 IDL VLDL 乳糜 残粒 HDL3 HDL2 乳糜 微粒 LDL With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society LDLLDLCMCMVLDLVLDLHDLHDL 3.3. 脂蛋白的意义脂蛋白的意义 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 4. 高脂蛋白血症分型 名 称 过多的脂蛋白 血脂的相对含量 TC TG TC/TG ⅠⅠ 高乳糜微粒血症 CM + +++ 1.5 ⅡⅡb b 高胆固醇和 高甘油三酯血症 LDL+VLDL ++ ++ 可变 ⅢⅢ 阔β脂蛋白血症 CM残骸+IDL +~+++ +~+++ 1.0 ⅣⅣ 高甘油三酯血症 VLDL 正常~+ +~+++ 可变 ⅤⅤ 高甘油三酯和 高乳糜微粒血症 CM+VLDL + +++ 0.15~0.6 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 临床实用的高脂血症分型 n高胆固醇血症(高低密度脂蛋白胆固醇) n高甘油三酯血症(高极低密度脂蛋白) n混合性高脂血症(上述两者都高) n低高密度脂蛋白血症 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 血脂指标合适范围边缘升高增高降低 TC<200200~239≥240 LDL-C<130130~159≥160 HDL-C≥40≥60<40 TG<150150-199≥200 5.调脂的目标水平 我国人群血脂水平分类(mg/dl) With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 高脂血症患者开始治疗标准值及治疗目标值 危险等级危险等级 TLCTLC开始开始 (mg)(mg) 药物治疗开始药物治疗开始 (mg)(mg) 治疗目标值治疗目标值 (mg)(mg) 低危低危: :((1010年危险性年危险性 95 95-98 98 98 50 消除半衰期(h) 3 2 1.2 1.8 14 活性代谢产物 有 有 无 无 有 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 临床应用 n1.高脂蛋白血症:Ⅱa型、Ⅱb和Ⅲ型; 2型糖尿病和肾病综合征致高Ch血症。 n2.预防心脑血管急性事件:用于冠心病 一级和二级预防,明显减少发病率和 死亡率;脑血管病二级预防可显著减 少脑血管事件。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society WOSCOPS: 普伐他汀40mg/d,TC↓20%,LDL-C↓26%, TG↓12%,HDL-C↑5%,CHD事件的相对危险性 ↓31%,心血管病总死亡率↓32%。 4S: 辛伐他汀20~40mg/d,TC、LDL-C、TG分别 ↓25%、35%和10%,HDL-C↑8%,冠心病死亡的 相对危险性↓42%,脑卒中发生率↓28%。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society JUPITER(2008): 瑞舒伐他汀降低LDL至1.4mmol/L,hsCRP 降至2.2mg/L,主要心血管终点事件的相对危 险性↓44%,心梗相对危险性↓54%,脑卒中 发生率↓48%,血运重建或不稳定心绞痛相 对危险性↓47% ,总死亡相对危险↓20%。 即使仅hsCRP升高而无除年龄以外的其 他危险因素,亦能使患者的相对危险性↓37%. 但糖尿病发生增加。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society LDL-C降低幅度与心脏事件减少(%) 58项他汀类临床试验(治疗者76359;安慰者71962) Law MR. BMJ, 2003;326:1423 LDL-CLDL-C降低降低 ( (mmol/L)mmol/L) 试验时间试验时间0.2-0.70.2-0.70.8-1.40.8-1.4≥1.5≥1.5P P值值 第第1-21-2年年 6 6 191933330.0150.015 第第3-53-5年年1919313150500.0010.001 第第6 6年后年后2121303052520.0260.026 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 不良反应 n发生率2%~9%, 多见GI、皮肤潮红、 头痛。 n约1%致GPT↑, 与剂量有关, 停药2~ 3月可恢复。 n<0.1%发生肌病综合征,肌痛、 CK↑, 严重者可因横纹肌溶解而急性肾衰。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 拜斯亭事件 2001年8月8日,德国拜尔公司宣布停止销售拜 斯亭(西立伐他汀钠),原因是美国有31例,其他 国家有21例因服用该药导致横纹肌溶解症而死亡。 横纹肌溶解症是指肌细胞受损伤分解,将内容物 释放入血浆,而导致肾脏损害(肾衰)的一种疾病, 临床表现为肌肉痉挛性疼痛、压痛、关节疼痛和疲 劳、肌无力等。病人尿色异常(黑色、红色),全 身不适、发热、恶心、呕吐等 。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society PRIMO研究(2008) 氟伐他汀肌病发生风险最低 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 挽救生命:挽救生命: 50~60/100050~60/1000例例/ /年年 肌病:肌病:1/10001/1000例例 横纹肌溶解症:横纹肌溶解症:1~2/1000001~2/100000例例 他汀类治疗的益处和安全性他汀类治疗的益处和安全性 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 药物相互作用 n他汀类+胆汁酸结合树脂:降TC、LDL-C 效应↑ 。 n他汀类+贝特类:↑调脂作用,但可使肌病 发生率↑2%~5%。 n他汀类+环孢菌素或红霉素:肌病发生率 ↑. n他汀类+香豆素类:凝血酶原时间↑。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 血脂康 n由特制红曲精制,含洛伐他汀20mg/g 以上,还含其他monacolins、不饱和 脂肪酸、甾醇、氨基酸及少量黄酮类。 n1.2g/d的调血脂效应≈辛 10mg/d;洛 20mg/d n疗效稳定,耐受较好。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society (二)胆固醇吸收抑制剂 依折麦布(Ezetimibe) n作用:降LDL-C达20.4%、降TC为15.1% n机制:与小肠壁上特异的转运蛋白NPC1L1 结合,选择性地强效抑制小肠吸收胆 固醇和植物甾醇。 n特点:不通过细胞色素P450同工酶代谢,与 他汀类、吉非贝齐、非诺贝特等在药代动 力学上无显著的相互作用。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 食物胆固醇 胆系排泄 INTESTINE 排泄 VLDLLDL LDL-R 胆固醇吸收抑制 剂—依折麦布 Synthesis IDL 吸收 依折麦布 对胆固醇代谢的影响 19% 50% 50% 31% 50% With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 复方制剂 nVytorin/Inegy :辛伐他汀 + Ezetimibe 2004年上市。 n作用:双重抑制HMG-CoA还原酶和胆固醇 重吸收,降TG和LDL作用增强。 n用于严重高LDL症和他汀类无效的混合型血 脂异常症。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 他汀类与依折麦布合用的互补作用 食物胆固醇 胆系排泄 INTESTINE 排 泄 VLDLLDL 吸收 synthesis IDL 他汀类 胆固醇吸收抑制 剂——依折麦布 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society (三)胆汁酸隔置剂(Bile-acid sequestrants) 考来烯胺(消胆胺,cholesteramine) 降胆宁(colestipol) 降胆葡胺(polidexide) 地维烯胺(divistyramine) 维康(welchol) With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 作用 ↓TC20%~25%,↓LDL-C25%~45%, apoB↓。 机制: 在肠道中与胆汁酸牢固结合 n⑴ ↓食物中脂类吸收 n⑵ 阻滞胆汁酸在肠道重吸收和利用 n⑶ 促肝中Ch转化为胆汁酸 n⑷ ↑肝细胞表面LDL受体密度和活性 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 副作用: 潮红、高血糖、高尿酸血症、胃肠道 不适、肝脏毒性 禁忌症: 肝脏疾病、严重痛风、消化道溃疡 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society (四)酰基辅酶A胆固醇酰基转移酶抑制药 ACAT 脂肪酸酰基辅酶A +Ch CE ACAT的生理功能: 促进食物中ch吸收 参与脂蛋白合成 维持细胞内ch平衡 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 甲亚油酰胺(melinamide) 作用: n阻止细胞内Ch向CE转化。 ⑴↓外源性 ch 吸收。 ⑵↓肝脏VLDL形成。 ⑶↓CE蓄积,↓泡沫细胞形成。 ⑷↑Ch逆向转运,↓血浆及组织Ch。 n用于Ⅱ型高脂蛋白血症。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 二、主要降低TG及VLDL的药物 (一) 贝特类 n吉非贝齐(gemfibrazil) n非诺贝特(fenofibrate) n苯扎贝特(benzafibrate) With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 药理作用 n1.调血脂:↓TG 20%~60% ↓VLDL-C 63% ↓TC 6%~25% ↓ LDL-C 26% ↑HDL-C 10%~30% n2. 抗炎、抗凝血、抗血栓 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 作用机制 激活核受体PPARα (peroxisome proliferator activated receptorα) 1.↓apoCⅢ转录,↑LPL生成和活性, 加速CM及VLDL分解代谢。 ↑apoAI、apoAII分泌,↑HDL合成。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 2. ↓NF-κB的信息转导途径, 加速 NF -κB在细胞核的灭活, ↓NF-κB驱动的炎 性因子基因的转录活性,↓炎症反应的持 续时间。 3. ↓某些凝血因子活性,↓纤溶酶原 激活物抑制物(PAI-1)产生。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 临床应用 n原发性高TG血症、Ⅲ型和混合型高脂 蛋白血症。 n非诺贝特可用于伴高尿酸血症患者。 n苯扎贝特能改善糖代谢,可用于糖尿病 伴高TG者。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 不良反应 发生率5%~10%。 GI、 乏力、头痛、失眠、皮疹多见 。偶有肌痛、尿素氮↑、转氨酶↑。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 药物相互作用 n与口服抗凝药合用,抗凝活性↑。 n与他汀类合用,可↑肌病发生。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society (二)烟酸类 烟酸 (nicotinic acid) 作用 大剂量↓TG、VLDL达20%~60%, 生效快(1~4h);↓LDL-C慢(5~7d) 而弱, 10%~25%;↑HDL 15%~30%; ↓Lp(a)。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 机 制 1.↓脂肪组织中激素敏感脂酶活性, ↓FFA,致合成TG原料不足,并↓TG 酯化,致VLDL合成释放↓,继而LDL 来源↓。 2.↑LPL活性,促CM及VLDL-TG消除。 3.↓apoAI的清除,↑Ch的逆向转运。 4.↓TXA2生成,↑PGI2生成而↓Pt聚 集,扩血管。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 烟酸的作用机制 肝脏肝脏循环循环 HDLHDL 血清血清VLDLVLDL分解为分解为 LDLLDL减少减少 血清血清 LDL-CLDL-C VLDL 肝脏产生肝脏产生VLDL VLDL 和和apo Bapo B减少减少 VLDL VLDL 分泌分泌 Apo BApo B 肝细胞肝细胞全身循环全身循环 动员动员 FFAFFA TG TG 合成合成 VLDL LDL With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 应 用 广谱,对Ⅱb、Ⅳ型高脂血症最好。 适用于混合型、高TG、低HDL及高Lp(a )血症。 With the improving quality of life as well as the ever-accelerating pace of life, the quality of people's food needs and rate also changing.In order to meet the needs of society 阿西莫司(acipimox) 化
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