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畔利麴
5 years ago
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1 Antiatherosclerosis drugs

2 atherogenesis Endothelial damage Hypercholesterolaemia Lipid peroxidation Ox-LDL taken up by macrophages Macrophages migrate subendothelially Subendothelial collections of foam-cells P/M/E release cytokines and growth factors Proliferation of VSM and deposition of connective tissue components Plaque formation

3 二 AS 形成过程危险因素损伤血管内皮炎症反应 MФ 清道夫 R + MC 进入内皮下 Ox-LDL MФ 泡沫 cell PL 内皮 cell MФ MC 向 VEC 粘附沉积于内膜下间隙 AS 血管平滑肌 cell Cytokine 促生长因子胶原合成酶脂肪条纹以 Ch 为核心的脂纹

5 ( 一 ) 原发性高脂蛋白血症 ( 二 ) 继发性高脂血症饮食, 酒精肥胖糖尿病肾病胆道阻塞甲状腺功能低下

6 高血脂症分型分型脂蛋白变化血脂变化 Ⅰ CM TG TC Ⅱa LDL TC Ⅱb VLDL 及 LDL TG TC Ⅲ IDL TG TC Ⅳ VLDL TG Ⅴ CM 及 VLDL TG TC

7 Lipid-regulating drugs Antioxidant Endothelium protective drugs Polyunsaturated fatty acids

8 Lipid-regulating drugs Hyperlipoprotein: VLDL IDL LDL apob HDL apoa

9 HMG-CoA reductase inhibitors( statins) Drugs: mevastatin, lovastatin and their derivatives Pharmacological effects: Apparently decrease plasma TC and LDL-Cholesterol Mechanism: reductase HMG-CoA mevalonic acid(mva) hepatic Ch synthesis LDL-R clearance of LDL IDL hepatic apo B-100 synthesis VLDL synthesis

10 治疗 AS 的机制调节血脂 ( 见图 ) 和非调脂机制竞争性 (-) HMG-CoA 还原酶 Ch 合成促进 LDL 受体的转录肝 cell 表面 LDL-R LDL 向肝内转移 LDL Ch (-) 他汀类 VLDL 代谢加速 VLDL 肝内 ApoB-100 合成 VLDL 合成 TG IDL LDL 扩血管减轻或逆转增厚的血管壁减轻 AS 过程的炎性反应稳定或缩小 AS 斑块抑制 PL 聚集和提高纤溶活性

11 Clinic use: first choice for essential hypercholesterolemia, heterozygous familial hypercholesterolemia Ⅲ-type hyperlipidemia, diabetic and renal hyperlipidemia. Adverse reaction: nearly 10% patients suffer from mild gastrointestional disturdance, insomnia headache and rash. More serious adverse effects are rare but include increased aminotransferase, alkaline phosphatase activity and myositis(rhabdomyolysis), creatine kinase activity.

12 Bile acid binding resins Drugs :cholestyramine, colestipol Pharmacological effects: TC/LDL-C HDL Mechanism: when taken by mouth, they sequester bile acids in the intestine and prevent their reabsorption and enterohepatic recirculation. The result is decreased absorption of exogenous cholestereol and increased metabolism of endogenous cholesterol into bile acids in the liver. This leads to increased expression of LDL receptors on liver cells, and hence to increased removal of LDL from the blood and a reduced concentration of LDL-cholesterol in plasma.

13 Ac-CoA HMG-CoA HMG-CoA 还原酶 MVA 胆固醇分解 7α 羟化酶活性经胆道胆汁酸门静脉树脂类 + 胆汁酸螯合剂

14 Clinic use: Ⅱa-type hyperlipoproteinaemias take effect in 4~7 days, reach maximum effect within 2 weeks Adverse reaction: nausea, abdominal bloating, constipation, malabsorption of fat-soluble vitamins

15 Nicotinic acid Pharmacological effects: to decrease VLDL and TG levels in the plasma of patients with a variety of hyperlipidemias. to inhibit the aggregation of platelet vasodilation Mechanism of action: to inhibit the lipolysis of fat to inhibit the esterification of TG

16 小肠脂肪 CM 食物脂肪 CM FAA 脂肪细胞合成脂肪 VLDL 肝糖脂肪 VLDL 产生和分泌 IDL LDL 合成储存动员脂肪心肌肾 (-) 脂肪酶烟酸

17 HDL 加快清除烟酸 (+) 抑制 LDL 变异 Lp(a)

18 (-) 脂肪酶 FAA VLDL 产生分泌 IDL LDL (+) LPL VLDL 清除 TG HDL ApoAⅠ 烟酸降低血浆 Lp(a) (+) 纤溶酶原活化 AS 血栓不影响胆汁酸的产生 Ch TXA 2 PGI 2 抑制 PL 聚集扩血管

19 Nicotinic acid Clinic uses: Ⅱ Ⅲ Ⅳ and Ⅴ-type hyperlipidemias. Adverse reactions: Pruritus, rashes, flush acanthosis Nausea and abdominal discomfort Hepatic dysfunction hyperuricaemia

20 Fibric acid derivatives: ---brate Drugs: Clofibrate gemfibrozil bezafibrate fenofibrate ciprofibrate Pharmacological effects and mechanisms: to decrease TG VLDL Due to its increase of VLDL-TG hydrolyzation and VLDL lipolysis via increase the lipoprotein lipase activity To increase HDL VLDL-TG exchange HDL-CE exchange VLDL HDL

21 机制调脂机制和非调脂机制 ⒈ 调脂机制 ( 见示意图 ) 调节 LPL ApoCⅢ ApoAⅠ ⑴ 增强 LPL 活性加速基因表达 CM VLDL ApoCⅢ 的分解 ⑵ 增加 HDL 的合成, 促进 LPL 和 Ch ApoAⅠ 转运的生成 ⑶ 促进 LDL 颗粒的清除 ⑷ 抑制 Ac-CoA 羧化酶 FAA 从脂肪组织进入肝合成 TG VLDL ⑸ 改变 Ch 转换蛋白活性 LDL-C 和 TG 含量改变 LDL-R 的亲和力也随之改变 LDL 降低 ⑹Ch 合成 LDL R 表达增强 R 对血浆内 LDL 的胞吞作用增强

22 贝特类 (+) LPL VLDL TG 水解 VLDL TG HDL 合成 + HDL 消除 HDL Ch 激活 LCAT 识别 HDL-R 调节 ApoC-Ⅲ 基因表达降低 ApoC-Ⅲ 转录 (-) LPL apoaⅠ Ac-CoA 羧化酶 FAA 肝 VLDL TG 合成 Ch 合成 LDLR 表达 R 对 LDL 胞吞作用 Ch Ch-Pr 活性改变 Ch,TG 含量改变 LDLR 亲和力改变 LDL

23 Clinic use to decrease TG VLDL and IDL for Ⅱb Ⅲ Ⅳ- hyperlipidemia, especially for familial Ⅲ-hyperlipidemia. mild hypercholesterolemia with reduced HDL-cholesterol ADR: gastrointestinal symptoms, skin rashes, decrease in white blood count, hepatic dysfunction

24 Antioxidant ---probucol Pharmacological effects: to lower TC, LDL-C and HDL MECHANISM: to inhibit the oxidative modification of LDL via the combination with lipoprotein for its hyper-lipophilic property

25 四促进 LDL 清除的药物 ( 抗氧化剂 ) LP(a) VLDL HDL 氧化 OFR PL 聚集和血栓形成氧化 LDL 产生 ox-ldl 损伤血管内皮 AS VSMCs 增殖迁移泡沫细胞促进内皮 cell 释放 PL 衍化生长因子 (PDGF) 促进 MC 向内皮粘附移向内皮下 ( 形成 Mφ)

26 Endothelium protective drugs Drugs: polysaccharide sulfate Mechanisms of action: to prevent the conglutination of white cell and platelet to inhibit the proliferation of vascular smooth muscle

27 Polyunsaturated fatty acids---fish oil EPA and DHA to decrease TG, VLDL,LDL-C to increase HDL-C Potentially important effects: Inhibition of platelet function Prolongation of bleeding time Decrease of blood mucosity Prevention of atherosclerosis

28 HDL 代谢加速 ApoB-100

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