《药理学_调血脂药和抗动脉粥样硬化药》由会员分享，可在线阅读，更多相关《药理学_调血脂药和抗动脉粥样硬化药（29页珍藏版）》请在金锄头文库上搜索。
1、调血脂药和抗动脉粥样硬化药调血脂药和抗动脉粥样硬化药Pathophysiology损损 伤伤 血脂异常血脂异常 高血压高血压 吸烟，等吸烟，等单单 核核 细细 胞胞巨巨 噬噬 细细 胞胞泡泡 沫沫 细细 胞胞血血 管管 平平 滑滑 肌肌 细细 胞胞 脂质脂质Scavenger receptorScavenger receptor 脂质脂质AtherosclerosisAtherosclerosisVascular endothelium modificationVascular endothelium modification inin atherosclerosisatheroscleros
2、isPlaque formation: The fatty streakPlaque formation: The fatty streakPathophysiologyAtherosclerosisAtherosclerosis泡沫泡沫 细胞细胞脂质脂质 条纹条纹 斑块斑块 前期前期粥样粥样 斑块斑块纤维粥纤维粥 样斑块样斑块复合复合 病变病变十年三十年四十年内皮功能障碍内皮功能障碍From plaque to thrombosis, From plaque to thrombosis, key event: key event: plaque ruptureplaque rupture第一
3、节第一节 调血脂药调血脂药胆固醇（胆固醇（Ch)Ch) 三酰甘油（三酰甘油（TGTG） 磷脂（磷脂（PLPL） 游离脂肪酸（游离脂肪酸（FFAFFA）血血 脂脂脂脂 蛋蛋 白白1.201.101.061.021.0060.95510204060801000Chylomicron RemnantsVLDLIDLLDLHDL2HDL3Diameter (nm)Density (g/ml)Chylo- micronsLipoprotein (Sub)ClassesLp(a)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 IIaIIa 透
4、明透明 易发冠心病易发冠心病 IIbIIb 透明透明 易发冠易发冠 心病心病 III III 奶油上层奶油上层 易发冠心病易发冠心病下层混浊下层混浊 IV IV 混浊混浊 易发冠心病易发冠心病 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; 示浓度降低一一. .降低降低TCTC和和LDLLDL的药物的药物二二. .降低降低TGTG及及VLDLVLDL的药物的药物三三. .降低降低LpLp(a)(a)的药物的药物（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
5、贝特 （二）烟酸烟酸；阿莫替司Treatment of HyperlipidemiaExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.High LDL-CHigh LDL-CTherapeutic Lifestyle ChangeTherapeutic Lifestyle ChangeDrug TherapyDrug TherapyTherapy of Choice: StatinTherapy of Choice:
6、StatinAlternative: Resin or niacinStatins: Mechanism of ActionLDL receptor mediated hepatic uptake of LDL and VLDL remnantsSerum VLDL remnantsSerum LDL-CCholesterol synthesis LDL receptor (BE receptor) synthesisIntracellular CholesterolApo BApo EApo BSystemic CirculationHepatocyteReduce hepatic chol
7、esterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic circulation.LDLSerum IDLVLDLRVLDLPotential Time Course of Statin Effects* Time course established* Time course establishedDaysDaysYears
8、YearsLDL-C LDL-C lowered*lowered*InflammationInflammation reducedreducedVulnerableVulnerable plaquesplaques stabilizedstabilizedEndothelialEndothelial functionfunction restoredrestoredIschemicIschemic episodesepisodes reducedreducedCardiacCardiac eventsevents reduced*reduced*调 血 脂改善血 管内皮 细胞功 能减轻 炎性
9、反应减少 缺血 发作稳定 斑块减少心 血管事 件n调血脂作用n非调脂作用改善血管内皮；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药理作用他汀类临床应用他汀类临床应用n调血脂n肾病综合征n血管形成术后再狭窄n预防心脑血管急性事件n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.Absolute reductions* (mg/dL) and (percentage reductions)Statin10 mg/d20 mg/d40 mg/d80 mg/dAtorvastatin 阿伐他汀6
10、9 (37)80 (43)91 (49)102 (55)Fluvastatin 氟伐他汀29 (15)39 (21)50 (27) 61 (33)Lovastatin 洛伐他汀39 (21)54 (29)68 (37) 83 (45)Pravastatin 普伐他汀37 (20)45 (24)53 (29) 62 (33)Simvastatin 辛伐他汀51 (27)60 (32)69 (37) 78 (42)*Standardized to LDL-C 186 mg/dL (mean concentration in trials) before treatment. Independent
11、 of pretreatment LDL-C.Maximum dose of 80 mg/d administered as two 40-mg tablets. Not FDA approved at 80 mg/d.LDL-C Lowering According to Statin and Dose: A Meta-analysis of 164 TrialsStatin Adverse EventsnCommon side effectsHeadache 头痛 Myalgia 肌痛 Fatigue 疲劳GI intolerance Flu-like symptoms 流感样症状nInc
12、rease in liver enzymes（CPK） 肌酸磷酸激酶Occurs in 0.5 to 2.5% of cases in dose-dependent mannerSerious liver problems are exceedingly rareManage by reducing statin dose or discontinue until levels return to normalnMyopathy 肌病Occurs in 0.2 to 0.4% of patientsRare cases of rhabdomyolysis 横纹肌溶解Reduce bynCaut
13、iously using statins in patients with impaired renal functionnUsing the lowest effective dosenCautiously combining statins with fibratesnAvoiding drug interactionsnCareful monitoring of symptomsPresence of muscle toxicity requires the discontinuation of the statinBile acid binding-resins胆汁酸结合树脂胆 固 醇
14、 结合剂+胆汁酸HMG-CoA还原酶胆固醇 7羟化酶胆汁酸LDL受 体1.1.减少食物脂类吸收减少食物脂类吸收2.2.阻滞胆汁酸重吸收阻滞胆汁酸重吸收3.3.肝内肝内ChCh转化为胆汁酸转化为胆汁酸4.LDL4.LDL受体受体5.5.血浆血浆LDLLDL进入肝细胞进入肝细胞6.HMG-CoA6.HMG-CoA还原酶继发活性增加还原酶继发活性增加 肠腔STATIN临床应用临床应用 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不良反应 特殊臭味,刺激性;胃肠道反应药物相互作用药物相互作用 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烯胺 考来替
15、泊考来替泊二.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)n降低cAMP水平脂肪酶活性降低TG合成不足VLDL减少LDL减少HDL分解代谢减少HDL增高n抑制血小板聚集和扩张血管Nicotinic Acid: Mechanism of ActionLiverLiverCirculationCirculationHDLHDLSerum VLDL Serum VLDL results in results in reduced reduced lipolysis to LDL lipolysis to LDL Serum LDLSerum LDLVLDLDecreases hepatic pro
