药理学调血脂药和抗动脉粥样硬化药课件

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 AtherosclerosisAtherosclerosis Vascular endothelium modificationVascular endothelium modification inin atherosclerosisatherosclerosis Plaque formation: The fatty streakPlaque formation: The fatty streak Pathophysiology AtherosclerosisAtherosclerosis 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 1.20 1.10 1.06 1.02 1.006 0.95 510204060801000 Chylomicron Remnants VLDL IDL LDL HDL2 HDL3 Diameter (nm) Density (g/ml) Chylo- microns Lipoprotein (Sub)Classes Lp(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；非诺贝特 （二）烟酸 烟酸；阿莫替司 Treatment of Hyperlipidemia Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497. High LDL-CHigh LDL-C Therapeutic Lifestyle ChangeTherapeutic Lifestyle Change Drug TherapyDrug Therapy Therapy of Choice: StatinTherapy of Choice: Statin Alternative: Resin or niacin Statins: Mechanism of Action LDL receptor mediated hepatic uptake of LDL and VLDL remnants Serum VLDL remnants Serum LDL-C Cholesterol synthesis LDL receptor (BE receptor) synthesis Intracellular Cholesterol Apo B Apo E Apo B Systemic CirculationHepatocyte Reduce hepatic cholesterol synthesis, lowering intracellular cholesterol, which stimulates upregulation of LDL receptor and increases the uptake of non-HDL particles from the systemic circulation. LDL Serum IDL VLDLR VLDL Potential Time Course of Statin Effects * Time course established* Time course established DaysDays YearsYears LDL-C LDL-C lowered*lowered* InflammationInflammation reducedreduced VulnerableVulnerable plaquesplaques stabilizedstabilized EndothelialEndothelial functionfunction restoredrestored IschemicIschemic episodesepisodes reducedreduced CardiacCardiac eventsevents reduced*reduced* 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 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) Statin 10 mg/d20 mg/d40 mg/d80 mg/d Atorvastatin 阿伐他汀 69 (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 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 Trials Statin Adverse Events nCommon side effects Headache 头痛 Myalgia 肌痛 Fatigue 疲劳 GI intolerance Flu-like symptoms 流感样症状 nIncrease in liver enzymes（CPK） 肌酸磷酸激酶 Occurs in 0.5 to 2.5% of cases in dose-dependent manner Serious liver problems are exceedingly rare Manage by reducing statin dose or discontinue until levels return to normal nMyopathy 肌病 Occurs in 0.2 to 0.4% of patients Rare cases of rhabdomyolysis 横纹肌溶解 Reduce by nCautiously using statins in patients with impaired renal function nUsing the lowest effective dose nCautiously combining statins with fibrates nAvoiding drug interactions nCareful monitoring of symptoms Presence 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 1.1.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 Action LiverLiverCirculationCirculation HDLHDL Serum VLDL Serum VLDL results in results in reduced reduced lipolysis to LDL lipolysis to LDL Serum LDLSerum LDL VLDL Decreases hepatic production of VLDL and of Decreases hepatic production of VLDL and of apoapo B B VLDL VLDL secretionsecretion Apo BApo B HepatocyteHepatocyteSystemic CirculationSystemic Circulation Mobilization of FFAMobilization of FFA TG TG synthesissynthesis VLDL LDL 烟酸 niacin 临床应用：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 nBest agent to raise HDL-C nReduces coronary events (Coronary Drug Project) nAdverse effects Flushing, itching, headache (immediate-release, Niaspan) Hepatotoxicity, GI (sustained-release) Activation of peptic ulcer Hyperglycemia and reduced insulin sensitivity nContraindications Active liver disease or unexplained LFT elevations Peptic ulcer disease Treatment of Mixed Hyperlipidemia Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA