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1、调血脂药和抗动脉粥样硬化药,Lipid-modulating drugs and Antiatherosclerotic drugs,Pathophysiology,损伤,血脂异常高血压吸烟，等,单核细胞,巨噬细胞,泡沫细胞,血管平滑肌细胞,脂质,Scavenger receptor,脂质,Atherosclerosis,Vascular endothelium modification in atherosclerosis,Plaque formation:The fatty streak,Pathophysiology,Atherosclerosis,泡沫细胞,脂质条纹,斑块前期,粥样斑块
2、,纤维粥样斑块,复合病变,十年,三十年,四十年,内皮功能障碍,From plaque to thrombosis,key event:plaque rupture,第一节 调血脂药,胆固醇（Ch)三酰甘油（TG）磷脂（PL）游离脂肪酸（FFA）,血脂,脂蛋白,1.20,1.10,1.06,1.02,1.006,0.95,5,10,20,40,60,80,1000,Diameter(nm),Density(g/ml),Lipoprotein(Sub)Classes,高脂血症的分型,表型 血浆4 TC TG CM VLDL LDL 备注 过夜外观 I 奶油上层,下层清 易发胰腺炎IIa 透明 易发
3、冠心病IIb 透明 易发冠心病III 奶油上层 易发冠心病 下层混浊 IV 混浊 易发冠心病V 奶油上层 易发胰腺炎 下层混浊 注:示浓度升高;示浓度正常;示浓度降低,一.降低TC和LDL的药物二.降低TG及VLDL的药物三.降低Lp(a)的药物,（一）HMG-CoA还原酶抑制药 洛伐他汀；辛伐他汀 普伐他汀；氟伐他汀（二）胆汁酸结合树脂 考来烯胺，考来替泊（三）ACAT抑制药 甲亚油酰胺,（一）贝特类 吉非贝齐；非诺贝特（二）烟酸 烟酸；阿莫替司,Treatment of Hyperlipidemia,Expert Panel on Detection,Evaluation,and Trea
4、tment of High Blood Cholesterol in Adults.JAMA 2001;285:2486-2497.,High LDL-C,Therapeutic Lifestyle Change,Drug Therapy,Therapy of Choice:Statin,Alternative:Resin or niacin,Statins:Mechanism of Action,LDL receptormediated hepatic uptake of LDL and VLDL remnants,Serum VLDL remnants,Serum LDL-C,Choles
5、terol synthesis,LDL receptor(BE receptor)synthesis,Intracellular Cholesterol,Apo B,Apo E,Apo B,Systemic Circulation,Hepatocyte,Reduce hepatic cholesterol synthesis,lowering intracellular cholesterol,which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the
6、systemic circulation.,Serum IDL,VLDL,Potential Time Course of Statin Effects,*Time course established,Days,Years,LDL-C lowered*,Inflammationreduced,Vulnerableplaquesstabilized,Endothelialfunctionrestored,Ischemicepisodesreduced,Cardiaceventsreduced*,调血脂,改善血管内皮细胞功能,减轻炎性反应,减少缺血发作,稳定斑块,减少心血管事件,调血脂作用非调脂
7、作用 改善血管内皮；促进血管平滑肌细胞凋亡；稳定斑块；减轻血管炎性反应；抑制血小板聚集等,他汀类药理作用,他汀类临床应用,调血脂肾病综合征血管形成术后再狭窄预防心脑血管急性事件器官移植术后的排斥反应和骨质疏松症,Law MR et al.BMJ.2003;326:1423-1427.,*Standardized to LDL-C 186 mg/dL(mean concentration in trials)before treatment.Independent of pretreatment LDL-C.Maximum dose of 80 mg/d administered as two
8、40-mg tablets.Not FDA approved at 80 mg/d.,LDL-C Lowering According to Statin andDose:A Meta-analysis of 164 Trials,Statin Adverse Events,Common side effectsHeadache 头痛 Myalgia 肌痛 Fatigue 疲劳GI intolerance Flu-like symptoms 流感样症状Increase in liver enzymes（CPK）肌酸磷酸激酶Occurs in 0.5 to 2.5%of cases in dos
9、e-dependent mannerSerious liver problems are exceedingly rareManage by reducing statin dose or discontinue until levels return to normalMyopathy 肌病Occurs in 0.2 to 0.4%of patientsRare cases of rhabdomyolysis 横纹肌溶解Reduce byCautiously using statins in patients with impaired renal functionUsing the low
10、est effective doseCautiously combining statins with fibratesAvoiding drug interactionsCareful monitoring of symptomsPresence of muscle toxicity requires the discontinuation of the statin,Bile acid binding-resins 胆汁酸结合树脂,胆固醇,结合剂+胆汁酸,HMG-CoA还原酶胆固醇 7羟化酶胆汁酸,LDL,受体,1.减少食物脂类吸收2.阻滞胆汁酸重吸收3.肝内Ch转化为胆汁酸4.LDL受体
11、5.血浆LDL进入肝细胞6.HMG-CoA还原酶继发活性增加,肠腔,STATIN,临床应用a及b型高脂蛋白血症,家族性杂合子高脂蛋白血症,不良反应特殊臭味,刺激性;胃肠道反应药物相互作用避免和某些药物同时服用,影响其吸收HMG-CoA还原酶抑制药;叶酸;铁剂等 考来烯胺 考来替泊,二.降低TG和VLDL的药物,(一)贝特类吉非贝齐(gimfibrazil)非诺贝特(fenofibrate)降低LDL-C和TG;升高HDL-C 对冠心病防治的价值-尚无定论(二)烟酸类烟酸(nicotinic acid);阿昔莫司(acimox)降低cAMP水平脂肪酶活性降低 TG合成不足VLDL减少LDL减少
12、HDL分解代谢减少HDL增高抑制血小板聚集和扩张血管,Nicotinic Acid:Mechanism of Action,Liver,Circulation,HDL,Serum VLDL results in reduced lipolysis to LDL,Serum LDL,VLDL,Decreases hepatic production of VLDL and of apo B,VLDL secretion,Apo B,Hepatocyte,Systemic Circulation,Mobilization of FFA,TG synthesis,VLDL,烟酸 niacin,临床应
13、用：广谱调血脂药 b和型高脂蛋白血症最好 混合型高脂蛋白血症、高TG血症、低HDL血症、高Lp（a）血症,Clinical Features of Nicotinic Acid,Best agent to raise HDL-CReduces coronary events(Coronary Drug Project)Adverse effectsFlushing,itching,headache(immediate-release,Niaspan)Hepatotoxicity,GI(sustained-release)Activation of peptic ulcerHyperglycem
14、ia and reduced insulin sensitivityContraindicationsActive liver disease or unexplained LFT elevationsPeptic ulcer disease,Treatment of Mixed Hyperlipidemia,Expert Panel on Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults.JAMA 2001;285:2486-2497.,High LDL-C and TGs,Therapeutic L
15、ifestyle Change,Drug Therapy,Achieve the LDL-C goal,1,STEP,Achieve the non-HDL-C goalIncrease LDL-C lowering orAdd a fibrate,niacin or fish oils,2,STEP,第二节 抗氧化剂,防止氧自由基（OFR）产生和脂蛋白氧化修饰阻止AS发生和发展的重要措施普罗布考 维生素E，维生素C，辅酶Q10,第三节 多烯脂肪酸,n-3型多烯脂肪酸二十碳五烯酸和二十二碳六烯酸n-6型多烯脂肪酸 亚油酸,低分子量肝素天然类肝素酸性糖酯类,第四节 多糖类,第五节 抗AS中草药,淤阻痰阻症结,本,标,健脾养气 滋阴养血 补益肝肾,活血化瘀 消食化痰 软坚散结 通腑化浊,银杏叶 丹参 绞股蓝,
