【医学课件大全】antiathrosclerotic drugs (68p)

Introduction Atherosclerosis（AS） Ross R: Atherosclerosis is an inflammatory disease 动脉粥样硬化斑块肉眼观察 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 主要 次要新近提出 年龄龄 体力活动动减少氧化低密度脂蛋白 性别别 （脑脑力活动紧动紧 张张） （高血压压促进进之） 高脂血症 肥胖和超重血管内膜损伤损伤 高血压压A型性格饮饮食中缺少抗氧化剂剂 吸烟遗传遗传胰岛岛素抵抗 糖尿病 微量元素铁贮铁贮 存增多 缺氧血管紧张紧张 素转换转换 酶基因的多态态性和过过度表 达 抗原抗体作用左心室肥厚 维维生素纤维纤维 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、细细菌） 冠心病（动脉粥样硬化）的危险因素 危险因素 损伤血管内皮 MC向 VEC粘附 MC进入内皮下 M 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 AS形成过程： IntimaIntima EndotheliumEndothelium Vessel LumenVessel Lumen muscular layermuscular layer LP LP monocyte Lipoprotein (Most important- oxLDL) IntimaIntima EndotheliumEndothelium Vessel LumenVessel Lumen muscular layermuscular layer macrophage IntimaIntima EndotheliumEndothelium Vessel LumenVessel Lumen muscular layermuscular layer IntimaIntima EndotheliumEndothelium Vessel LumenVessel Lumen muscular layermuscular layer Foam cell IntimaIntima EndotheliumEndothelium Vessel LumenVessel Lumen muscular layermuscular layer Lipid core Platelet IntimaIntima EndotheliumEndothelium Vessel LumenVessel Lumen muscular layermuscular layer thrombus Treatment Diet Lifestyle Drug treatment Lipidemic-modulating drugs Antioxidants n-3 PUFAs Section 1 Lipidemic-modulating drugs 1. The composition of blood lipid 我国人群血脂的年龄龄和性别别分布 男性 女性 TC HDL-C TG 2. The Composition and Function of Lipoprotein 0.950.95 1.0061.006 1.021.02 1.101.10 1.151.15 1.201.20 2020404060608080500500 diameterdiameter (nm) (nm) 5 5 1010 VLDLVLDL HDL2HDL2 乳糜 微粒 LDLLDL HDL3HDL3 CMCM IDLIDL Lp(a)Lp(a) CMCM残粒残粒 density density (g/ml)(g/ml) 【The size of lipoproteinThe size of lipoprotein】 【physiological function of lipoproteinphysiological function of lipoprotein】 LDLLDL 转运胆固醇转运胆固醇 到肝外组织到肝外组织 细胞细胞 HDLHDL 将胆固醇从将胆固醇从 周围组织转周围组织转 运到肝脏运到肝脏 CMCM 将食物中的将食物中的 TGTG从小肠从小肠 转运转运到肝脏到肝脏 VLDLVLDL 转运内源性转运内源性 TGTG到脂肪到脂肪 及肌肉组织及肌肉组织 LDLLDLCMCMVLDLVLDLHDLHDL 【clinical meaning of lipoprotein clinical meaning of lipoprotein 】 3. 3. Metabolic abnormality of lipid Hyperlipoproteinemia Hypercholesterolemia Hypertriglyceridemia Low high-density lipoproteinemia Hyperlipoprotein (a) The aims level of modulating lipids 血脂指标合适水平 增高水平 降低水平 ( mg/dl) (mg/dl) (mg/dl) TC 200 220 LDL-C120 140 HDL-C40 35 TG 150 150 【Type of HyperlipoproteinemiaType of Hyperlipoproteinemia 】 表型表型 血浆血浆4 4 过夜外观过夜外观 TCTCTGTGCMCMVLDLVLDLLDLLDL备注备注 I I 奶油上层奶油上层 下层清下层清 易发胰腺炎易发胰腺炎 IIaIIa透明透明易发冠心病易发冠心病 IIbIIb透明透明 易发冠心病易发冠心病 IIIIII 奶油上层奶油上层 下层混浊下层混浊 易发冠心病易发冠心病 IVIV混浊混浊 易发冠心病易发冠心病 V V 奶油上层奶油上层 下层混浊下层混浊 易发胰腺炎易发胰腺炎 Type of Hyperlipoproteinemia(1970),WHOType of Hyperlipoproteinemia(1970),WHO The commonly used drugs 1.Statins (他汀类） 2.Bile acid-binding resins 3.Fibrates（贝特类） 4.Nicotic acid 1. Statins (他汀类） (Inhibitors of HMG-CoA reductase ) ) Pharmacological effects Pharmacokinetics Clinical uses Adverse reactions Drug interaction History 1976 Endo penicillium citricum compactin 1979 Endo monascus ruber monacolin k 1980 Alberts aspergillus terreus movinolin lovastatinlovastatin ( (洛伐他汀洛伐他汀) ) pravastatinpravastatin ( (普伐他汀普伐他汀) ) simvastatinsimvastatin ( (辛伐他汀辛伐他汀) ) fluvastatinfluvastatin ( (氟伐他汀氟伐他汀) ) atorvastatinatorvastatin ( (阿伐他汀阿伐他汀) ) Pharmacological effects a. a.LipidemicLipidemic-modulating action-modulating action b. LDL-c TC TG , HDL-c b. b. Non Non lipidemiclipidemic-modulating action-modulating action Mechanism Competitive inhibit HMG-CoA reductase, block synthesis of cholesterol. Elevate amount and activation of hepatic LDL-R 乙酰乙酰CoACoA 乙酰乙酰乙酰乙酰CoACoA HMG-CoAHMG-CoA MVAMVA 鲨烯鲨烯 HMG-CoAHMG-CoA还原酶还原酶 胆固醇胆固醇 【 Synthesis of cholesterol 】 乙酰乙酰CoACoA 乙酰乙酰乙酰乙酰CoACoA HMG-CoAHMG-CoA MVAMVA 鲨烯鲨烯 HMG-CoAHMG-CoA还原酶还原酶 胆固醇胆固醇 STATINS 【 Statins 】 Improve the function of vascular endothelium proliferation and transfer of VSMCs formation of foam cells CRP,inflammation response Platelet aggregation and thrombosis Stabilize atheromatous plaque Non lipidemic-modulating action Pharmacokinetics Clinical uses 1. a、b、III type hyperlipoproteinemia 2. Restenosis after percutaneous transluminal coronary angioplasty 3. Prevention of acute cardiocerebrovascular attack WOSCOPS (West of Scotland Coronary Prevention Study )： Pravastatin(普伐他汀) 40mg/d,TC20%，LDL- C26%，TG12%，HDL-C5%，CHD事件的相 对危险性31%，心血管病总死亡率32%。 4S： Simvastatin(辛伐他汀) 2040mg/d，TC、 LDL-C、TG分别25%、35%和10%, HDL-C 8%， 心血管疾病总死亡的相对危险性30%, 冠心 病死亡相对危险性42%。 Clinical experiment Adverse reactions 1. Flushing, headache 2. Elevated hepatic enzymes 3. Skeletal muscle toxicity: myalgia, CPK (肌酸磷酸激酶）, rhabdomyolysis (横纹肌溶解症) 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,lipobay），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 Rhabdomyolysis 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（黑色或红色），并伴有全身不适、发 热、恶心、呕吐等 。 Drug interaction + 环孢环孢 菌素类类 肌病和横纹纹肌溶解 + 大环环内酯酯抗菌素 （红红霉素、克拉霉素） 肌病和横纹纹肌溶解 + 华华法令低凝血酶原血症或出血 + 贝贝特类类 肌病危险险 + 烟酸类类 肌病危险险 2. Bile acid-binding resins (胆汁酸结合树脂) n n cholestyramine cholestyramine ( (考来烯胺考来烯胺, ,消胆胺消胆胺) ) n n colestipolcolestipol ( (考来替泊，降胆宁考来替泊，降胆宁) ) Pharmacological effects: Combine with bile acid in the intestines, prevent reabsorption of bile acid Enhance the conversion of Ch to bile acids in liver Decrease the absorption of Ch in intestine Up-regulate LDL-R in liver : LDL-c Clinical usesClinical uses II II a a and II and II b b hyperlipoproteinemia hyperlipoproteinemia High dosage: 2030g/d High dosage: 2030g/d 3. 3. NiacinsNiacins Nicotinic acid (烟酸) Acipimox (阿西莫司) Pharmacological actionsPharmacological actions Lipidemic-modulating actions VLDL, TG 20%60% VLDL, TG 20%60% LDL-C 10% LDL-C 10%25%25% HDL 15% HDL 15%30%30%； Lp(aLp(a) ) Mechanism of Action 1.inhibit TG hydrolysis from fatty tissue 2.decrease TG production 3.increase LPL activity 4. increase HDL and apoA- Clinical uses II, III, IV, V hyperlipidemia Gemfibrazil (吉非贝齐, 诺衡) Fenofibrate (非诺贝特, 力平脂) Benzafibrate (苯扎贝特, 必降脂) 4.Fibrates4.Fibrates（贝特类）（贝特类） Pharmacological Actions 1. Lipidemic-modulating actions ： TG 20%60%、VLDL-C 63% TC 6%25%、LDL-C 26% HDL-C 10%30% Mechanism: Activate PPAR (peroxisome proliferator activated receptor). Increase synthesis of LPL Decrease transcription of apoC Promote the expression of apo AI and apoA 2.Anticoagulation and Antithrombosis 3. Antiinflammation Clinical uses IIb, III, IV type hyperlipoproteinemia; particularly familial III hyperlipidemia . 5. Lp(a)-lowering Drugs Elevation of blood Lp(a) is a independent risk factor，and a risk factor of restenosis after percutaneous transluminal coronary angioplasty Lp(a) can inhibit activation of plasminogen competitively, advance thrombus ; OX-Lp（a）can induce endothelium to express more P-selectin and strength the adhesion of MC 降Lp(a)的药物 Section 2 Antioxidants 1OX-LDL促进AS病变发生和发展 损伤血管内皮, 促MC向内皮粘附和转移。 阻止M返回血流。 M大量摄取OX-LDL泡沫细胞。 促EC释放PDGF。 促血小板聚集和血栓形成。 2. Lp(a)和VLDL被氧化可增强其致AS作用 3. HDL被氧化可转化为致AS作用 Probucol（普罗布考） Pharmacological action 1. Protect LDL be free of peroxidation 2. Decrease blood lipi