高度脂溶性钙离子拮抗剂

高度脂溶性钙离子拮抗剂 在高血压、动脉硬化中的应用 北京大学人民医院 孙宁玲,高血压的进展,2000全球死亡率: 高血压对其他危险因素的影响,高死亡率, 发展中地区,低死亡率 发展中地区,发达地区,高血压 (BP),吸烟,高胆固醇,低体重,性别为男性,高体重指数,少动生活方式,饮酒,室内环境污染,缺铁,0,1000,2000,3000,4000,5000,6000,7000,8000,死亡率分布 (In thousands; total 55,861,000),Adapted from Ezzati et al, Lancet, 2002.,高血压患者心血管事件危险性增高,弗明翰心脏研究 - 高血压与正常血压的心血管事件危险性 (患者年龄35-64岁，随 访36年),Risk Ratio 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0 Excess Risk 22.7 11.8 9.1 3.8 4.9 5.3 10.4 4.2,冠脉疾病,中风,外周血管疾病,心衰,Biennial Age-Adjusted Rate per 1000,Kannel WB JAMA 1996;275(24):1571-1576.,高血压及动脉硬化 参与 心血管事件的发生,高血压与动脉硬化是相联的,a,Hypertension,Other factors - hypercholesterolaemia - glucose intolerance etc.,Atherosclerosis,Coagulation factors,Clinical events of CHD - angina - infarction - sudden death,(very late stage),Relationship between hypertension, atherosclerosis and cardiovascular events,a,Hypertension,出血性卒中,Atherosclerosis,缺血性 卒中,其他致 动脉硬化因素,血栓,心绞痛/心肌梗死,a,高血压是动脉硬化的启动因素,动脉粥样硬化的进展过程与高血压有关,LDL Oxidised LDL,动脉壁损伤 细胞粘附于内皮表面,内皮功能失调 使内皮渗透性增加,生长因子 eg. PDGF, FGF, TGF-b,平滑肌细胞增殖,高血压,高血压,高血压,高血压怎样导致动脉硬化： haemodynamic factors,a,Internal Carotid,External Carotid,Flow Divider,Common Carotid Artery,Main steps in the atherosclerotic process (atherogenesis),a,平滑肌细胞增殖.,迁移至内皮下,高血压,高血压怎样导致动脉硬化: mechanical factors,a,内皮损伤,High BP,Lipids/free radicals,渗透性增加,内皮的收缩因子(内皮素)占优,Main steps in the atherosclerotic process (atherogenesis),a,(Per-) Oxidation,吞噬细胞增殖,Esterification,（脂化作用）,炎症与动脉粥样硬化形成及演变,正常 黏附 侵润 剥落,内皮细胞,平滑肌细胞,CAMs,基质,泡沫细胞,T淋巴细胞,激活的巨核细胞,组织因子 栓塞 MMPs 基质降解,高血压,L-NMMA = NG monomethyl L-arginine monoacetate. John and Schmieder. J Hypertens. 2000;18:363-374.,Gene expression,G,Endothelial Cell,L-Arginine,L-NMMA,eNOS,Ca2+ calmodulin,Acetylcholine,Substance P,Bradykinin,2-agonists,pathway,L-Arginine,NO,Soluble guanylate cyclase,cGMP,Endothelium-dependent vasodilation,Smooth Muscle Cell,Endothelium-Dependent Vasodilation: L-ArginineNitric Oxide Pathway,Endothelial injury,Removal of endothelial cells,Cytokines and growth factors,Cell adhesion molecules,Endothelial repair,Incorporation of endothelial progenitor cells,Cytokines and growth factors,Cell adhesion molecules,Adapted from Omoigui and Dzau. J Vasc Med Biol. 1991;3:382-391.,高血压是内皮功能 不良的重要原因 并导致血管组织 结构的病变,Abnormal Endothelium,Vasocon- striction,Platelet/ leukocyte adhesion,SMC migration and growth,Lipid deposition Clearance,高血压,糖尿病,Dysfunction,血脂紊乱,既往研究发现： 积极降脂治疗可以改善内皮 功能，降低预后事件,Effects of Lipid-Lowering Therapy on Endothelial Function in CHD Patients,Treasure et al. N Engl J Med. 1995;332:481-487.,Change in Diameter (%),30,20,10,0,-10,-20,-30,-40,-50,Initial,Follow-up,Placebo Group,Initial,Follow-up,Lovastatin Group,Dilation,Constriction,Acetylcholine Challenge,Effect of Aggressive Lipid Lowering on Carotid IMT in Heterozygous Familial Hypercholesterolemia: ASAP,Smilde et al. Lancet. 2001;357:577-581.,Change in IMT (mm),0.09,0.07,0.05,0.03,0.01,-0.01,-0.03,-0.05,-0.07,-0.09,0,1,2,Atorvastatin 80 mg (n=160),Years,Baseline LDL,8.33 mmol/L,Overview of Statin Trials,AF/TexCAPS 6605 -24%,4S 4444 -35%,LIPID 9014 -25%,CARE 4159 -28%,WOS 6595 -20%,Trial N LDL,% Reduction Major Coronary Events,Secondary,Primary,*P.001; P=.002 LaRosa et al. JAMA. 1999;282:2340-2346.,-38*,-25*,-25,-31*,-38*,结 论,积极的降脂治疗可以改善内皮功能 积极的降脂治疗可以改善动脉硬化及中间终点 积极降脂治疗可以改善预后终点,降压治疗是否可以改善预后？ 降压治疗是否有改善内皮功能的作用？ 什么样降压药物具有较好的抗动脉硬化效果？,问题的提出：,Reduction of events with antihypertensive therapy,a,a,20-25%,35-45%,Antihypertensive therapy,CHF,Stroke,MI,-20,-0,-40,-60,50%,2003 JNC7,钙离子在高血压及动脉硬化中的作用,a,a,Ca,+,Calciumions,1)内皮细胞(内皮素) 2) 血管平滑肌细胞 3) 巨噬/泡沫细胞 4) LDL/胆固醇代谢,钙离子拮抗剂是否能过阻断这些过程？,降压治疗（CCB）是否可以改善预后 降压治疗（CCB)是否有改善内皮功能的作用？ 什么样降压药物具有较好的抗动脉硬化效果？,回答提出的问题,CCBs 在动脉硬化中的临床试验,Jukema J, et al. Arterioscler Thromb Vasc Biol 1996;16:42530. Lichtlen P, et al. Lancet 1990;335:110913. Pitt B, et al. Circulation 2000;102:150310.,结果已经发表在11月8日的 Lancet 2003，362：1527-35. 荟萃 29个随机试验 162,341例患者 700,000余次的病人年,降压治疗试验协作研究组 （ABPL）第二轮分析,ABPL 试验（血压的差异与事件的关系） 活性药物 vs plac,mmHg 差异 ACEI / plac ( -5 / -2 ) CCB / plac ( - 8 / - 4 ),R R R R 总死亡率 0.80 0.89 CVD死亡 0.80 0.78 CVD事件 0.72 0.82 脑卒中 0.72 0.62 冠心病 0.80 0.78 心力衰竭 0.82 1.21,ABPL 试验（血压的差异与事件的关系） 活性药物 vs 活性药物,mmHg 差异 ACEI CCB ACEI D / BB (+ / 0 ) D/BB (+1/ 0 ) CCB (+1 / +1 ),R R R R R R 总死亡率 1.00 0.99 1.04 CVD死亡 1.03 1.05 1.03 CVD事件 1.02 1.04 0.97 脑卒中 1.09 0.93 1.12 冠心病 0.98 1.01 0.96 心力衰竭 1.07 1.33 0.82,卒 中 不同活性药的比较,随机治疗,ACEI vs D/BB CA vs D/BB ACEI vs CA,试验数,6 9 6,病例数,47449 68467 25767,(mmHg),0/2 0/0 1/1,0.5 1.0 2.0,RR (95% CI),1.09(1.00, 1.18 0.93(0.86, 1.01 1.12(1.01, 1.25,Relative Risk,前者更好,后者更好,第二轮分析,ABPL,降压治疗（CCB)是否可以改善预后？ 降压治疗（CCB）能够改善内皮功能 什么样降压药物具有较好的抗动脉硬化效果？,回答提出的问题,Circulating endothelial progenitor cells are derived from bone marrow,EPC: endothelial progenitor cell,EPC,Smooth muscle,Endothelium,Coronary artery,Bone marrow,EPC migration,EPC,Bone marrow,EPC incorporation,EPC: endothelial progenitor cell,心血管危险因素是与内皮原细胞数量的减少及不同有关,Endothelial progenitor cells (colony-forming units),5,0,5,10,15,Framingham risk score,0,20,40,60,30,50,70,10,20,p=0.001, r= 0.47,Hill J et al. N Engl J Med 2003,内皮功能改善与内皮源性细胞数量加有关,Endothelial progenitor cells (colony-forming units),0,2,4,6,8,Change in brachial reactivity (%),0,20,40,60,30,50,70,10,16,10,12,14,Hill J et al. N Engl J Med 2003,p=0.001, r= 0.59,EPC: endothelial progenitor cell,TREND: Endothelial Function and ACE Inhibition,*P.0003 for quinapril vs placebo. Mancini et al. Circulation. 1996;94:258-265.,P=.002 overall,Net Change (%) in Target Segment Response After 6 Months,Acetylcholine Dose (mol/L),10-6,10-4,*,Placebo,Quinapril,*,NO Production From Human Coronary Microvessels: Amlodipine and Ramiprilat,Zhang et al. Am J Cardiol. 1999;84:27L-33L.,Change in Nitrite (pmol/mg),Concentration (log),Amlodipine,*,*,*,*,*,*,*,Ramiprilat,*P.01 vs control,Brovkovych V et al. Hypertension 2001,Nifedipine preserves NO concentration stimulates NO release,Electrochemical sensor,0.01 0.1 1 10 100 1,000,240,120,40,0,80,200,160,NO release (nmol/L),Nifedipine (nmol/L),Loke et al. Hypertension. 1999;34:563-567; Zhang et al. J Pharmacol Exp Ther. 1999;288:742-751; Laufs et al. Circulation. 1998;97:1129-1135.,Postulated Effects of Different Agents on Endothelial Cell NO Production,Endothelial Cell,Statins,Kinins,Inactive peptides,CCB,eNOS,NO2,ACE,BK2,eNOS mRNA,ACEI,不同药物对内皮功能不良的治疗作用,ACE-Is,ARBs,CCBs,动脉,coronary,+,+,no data,peripheral,+,+,皮下微循环,+,+,+,肌性微循环,acetylcholine, metacholine,bradykinin,+,+,+,no data,ACE-I: angiotension-converting enzyme inhibitor, ARB: angiotensin II receptor blocker, CCB: calcium channel blocker,降压治疗（CCB)是否可以改善预后？ 降压治疗（CCB)是否有改善内皮功能的作用？ CCB具有较好的抗动脉硬化效果,回答提出的问题,ESC/ESH建议 分析心血管事件终点 既要看终末终点又要分析中间终点（替代终点）,危险因素阶段,靶器官损害阶段,临床疾病阶段,终末疾病阶段,高血压 糖尿病 其它危险因素,颈动脉中内膜增厚 冠状动脉病变 血管内皮功能紊乱 左室肥厚 蛋白尿,心绞痛 心肌梗塞 脑卒中 肾脏损害,心力衰竭 肾功能衰竭 卒中后功能障碍 死亡,中间终点,逆转中间终点的目的是减少终末终点发生,心肌梗塞或中风与颈动脉厚度的关系,内膜-中层厚度的五分位数 (combined measure of max CCA and ICA),每1000名病人 出现心梗或中风的比率-年,13.6,18.4,22.2,40.9,New England Journal of Medicine, 1999;340:14-22,7.8,SECURE: Progression Slope of Mean Maximum IMT,Progression Mean Max IMT Slope (mm/y),0.022,0.018,Placebo (n=227),Ramipril 2.5 mg/d (n=232),0.014,Ramipril 10 mg/d (n=234),37% Relative Reduction P=.028 vs Plac,Effect of Ramipril Was Significant After Adjustment for BP and Hx Hypertension,Lonn et al. Circulation. 2001;103:919-925.,PREVENT：氨氯地平 显著延缓 颈动脉粥样硬化,内膜中层厚度变化,(mm),氨氯地平 安慰剂, 0.033, 0.013,Pitt et al. Circulation. 2000.,P=0.007,INSIGHT impact on intima-media thickness,Simon A, et al. Circulation 2001;103:294954.,Follow-up (years),Change from baseline in carotid artery IMT (mm),Nifedipine GITS,0.04 0.03 0.02 0.01 0 0.01,Co-amilozide,Progression,Regression,p=0.007,p=0.001,p=0.006,Baseline 2 3 4,Verapamil in Hypertension and Atherosclerosis Study (VHAS),Correlation of rate of change in mean maximum intima-media thickness (Mmax) and initial Mmax,Modified from Zanchetti A, et al. J Hypertens 1998;16:166776.,0.06 0.04 0.02 0 0.02 0.04 0.06 0.08 0.10 0.12,Rate of Mmax change (mm/year),y = 0.037x + 0.051,y = 0.082x + 0.086,Verapamil,Chlorthalidone,0.5 1.0 1.5 2.0,Initial Mmax (mm),拉西地平与阿替洛尔比较 主要终点结果 (每年CBMmax 的进展),0.0146,0.0145,0.0057,0.0087,0,0.005,0.01,0.015,0.02,0.025,PP,PP2,人群,mm,阿替洛尔,拉西地平,-61%,-40%,p=0,0010,p=0,0073,Circulation.2002;19:2422-2427,ELSA研究,拉西地平和细胞膜和钙通道的相互作用,High lipophilicity,Extracellular,Lacidipine Ca2+,Intracellular,slow dissociation,accumulation within lipid bilayer,long duration of action,INTERACTION OF LACIDIPINE WITH THE DIHYDROPYRIDINE RECEPTORS,Lacidipine inhibits the development of atherosclerosis,LDL Oxidised LDL,动脉壁损伤后细胞粘附于内皮表面,拉西地平减少内皮功能失常和渗透性增加,拉西地平减少平滑肌细胞增殖,拉西地平减少 LDL的氧化,Growth factors eg. PDGF, FGF, TGF-b,The effect of lacidipine on endothelium-dependent vasodilatation in hypertensives,700,600,500,400,300,200,100,0,Bradykinin,Acetylcholine,*,*,Normotensives Hypertensives Lacidipine-treated hypertensives,前壁血流 增加(%),* p 0.05 * p 0.01 compared to baseline,Ghiadoni et al, 1996,拉西地平能降低TNF-a 刺激内皮细胞粘附分子的表达,Journal of Hypertension, 1999;17:1837-1841,细胞粘附分子表达的减少 (%),氨氯地平,拉西地平,乐卡地平,0,-10,-20,-30,-40,-50,-60,-70,-80,-90,拉西地平抑制平滑肌细胞增殖和胆固醇脂化,剂型 胆固醇的 dose 增殖效果 研究 脂化作用 (mm) Lacidipine 10-6 Inhibition Mason (1992) Reduction ( 95%) 1-20 Inhibition Bernini (1993) Nifedipine Reduction Etingin, Hajjar (1985), and Schmitz (1988) Increase Daugherty (1987) No effect 10-50 Inhibition Bernini (1991, 1993) Verapamil Reduction Daugherty (1987) Reduction (91%) 50 Inhibition Bernini (1993) Diltiazem Reduction Daugherty (1987),Reichardt, 1995,拉西地平治疗52周对高血压患者 血清超氧化物歧化酶 (SOD)活性的影响,Yamakado, 1994,Before lacidipine,0,1,2,4,5,3,Serum superoxide dismutase activity (U/ml),After lacidipine,*,* p 0.05,拉西地平治疗52周对高血压患者血清过氧化物酶的影响,Yamakado, 1994,Before lacidipine,0,1,2,4,5,3,Serum lipid peroxidase (nmol/ml),After lacidipine,* p 0.05,*,6,7,短效及长效CCB对血压的影响,Optimal therapeutic range,0 4 8 12 16 20 0 4 8 12 16 20 0,mmHg,-30,-20,-10,0,Day 27 Day 28,Short-acting drug,Long-acting drug,Early morning blood pressure surge,凌晨血压增高的风险,6:00,0:00,12:00,18:00,Muller et al. N Engl J Med 1985;313:13151322 Marler et al. Stroke 1989;20:473476,0,20,40,60,80,100,120,140,160,180,脑血管事件 (per 2 h),0,5,10,15,20,25,30,35,40,45,50,心肌梗死 (per h),Stroke (n=1,167),Myocardial infarction (n=2,999),Time of day,钙离子拮抗剂的T/P值,药物 T/P 值 SBP T/P值 DBP T/P 值 平均 T/P值 硝苯地平控释片 101.8 88.2 95.0 非洛地平 75 68 71.5 氨氯地平 68 67 67.5 缓释地尔硫卓 74 67 70.5,拉西地平治疗后血压峰值和谷值的变化,Peak,Systolic blood pressure (mmHg),Diastolic blood pressure (mmHg),55% 84% 98% 78%,0 -5 -10 -15 -20 -25,Placebo 1mg 2mg 4mg 6mg,63% 79% 89% 94%,0 -5 -10 -15 -20 -25,Meredith, 1997,Lacidipine 降低了高血压患者血压变异性,SBP,DBP,Variability,mmHg,Placebo Lacidipine,15 13 11 9 7 0,15,Baseline Treatment,mmHg,Palatini et al, 1991,Baseline Treatment,13,11,9,7,0,拉西地平长期治疗后 动脉顺应性明显改善,Pancera, 1989,Baseline,Compliance (dyne-1cm410-7),3,1 month,6 months,*,* p 0.005 vs baseline,2.5,2,1.5,1,0.5,0,钙拮抗剂-二氢吡啶类 适应证 禁忌证 强制性 可能的 老年人 （无） 快速心律失常 单纯收缩期高血压 充血性心力衰竭 心绞痛 周围血管病 颈动脉粥样硬化 妊娠,2003 ESC/ESH 药物的适应证/禁忌证,Investigator assessment of lacidipine efficacy,Tcherdakoff, 1995,Very good,Good,Moderate,Bad,44%,2%,All patients,43%,46%,11%,1%,42%,Patients 65 years,11%,Investigator assessment of lacidipine tolerability,Tcherdakoff, 1995,37%,All patients,58%,38%,6%,5