beta-阻海口

,国家卫生部 全国合理用药监测系统 孙忠实 2011,10,27,海口,药物基因组学与受体阻滞剂的安全性 Pharmacogenomics and Sefaty of beta-blockrs,WHO实况报道 第317号2011年9月,心血管病是全球范围造成死亡的最主要原因：与其 它任何原因相比，心血管病每年造成的死亡最多。2008年估计有1730万人死于心血管病，占全球死亡的30%。在这些死亡中，估计有730万死于冠心病，620万死于中风。 80%以上的心血管病死亡发生在低收入和中等收入国家，男性和女性的发生率几乎持平。到2030年，几乎有2360万人将死于心血管病，主要死于心脏病和中风。预计它们将继续成为死亡的一个主要原因。,2,WHO:The top 10 causes of deathUpdated June 2011,3,美国医疗中的不良事件, Estimated 100,000 deaths per year (in 1994; Lazarou et al 1998); 6th leading cause of death in the US; Experienced by approximately 7% of patients (2.2 million) per year; Medication-related health problems account for an estimated 3% to 7% of hospital admissions (Pirmohamed M, et al 2004); During their hospital stay, 15% of patients experienced adverse drug reactions (Davies, et al 2009); Increased patient non-compliance。,4,为什么药物疗效不一样?,5,为什么药物的无效率如此之高?,Disease Drug Class Poor/Non Responders(%)Cancer (breast, lung, brain)Various70 100DiabetesSulfonylureas25 50AsthmaBeta-2 agonist40 75OA/RANSAID, COX-220 50Duodenal UlcerProton pump20 90HypertensionThiazides50 75Beta-blockers20 30ACE inhibitors10 30Angiotensin IIs10 30HyperlipidemiaHMGCoA reductase inhibitors 30 75DepressionSRRIs20 40Tricyclics25 50MigraineSerotonin25 50BPHSteroid 5a-reductase40 100,6,7,为什么药物的无效率如此之高?,所用药物无效而浪费财力巨大Ineffective Therapies Waste Money,8,Cost of Ineffectiveness to Healthcare System$390 million $1.2 billion$345 million $575 million$2.3 billion $5.8 billion$3.8 billion $8.8 billion$560 million $1.0 billion,Major Drug Hypertension Drugs ACE Inhibitors Heart Failure Drugs Beta Blockers Anti Depressants SSRIs Cholesterol Drugs StatinsAsthma Drugs Beta-2-agonists,药物不良反应多与基因变异相关,Over 16( 60%) of the 27 drugs most frequently cited in ADRs are metabolized by at least 1 enzyme with an inherited DNA variant known to cause poor metabolism!Pharmacogenomics 2003;Lazarou et al (JAMA 1998),9,PGx个体化给药的热点:波立维,10,11,Pharmacogenomics = drug therapy + genetic diagnostic test,什么是药物基因组学?,+,Pharmacogenetics: the study of how genetic differences among individuals cause varied responses to a drug,Pharmacogenomics: Study of the effect of variation in multiple genes, or Is the Whole Genome Application of Pharmcogenetics.目前已将二者统一称为PGx.,药物基因组学与药物基因学的区别,12,Prevalence of Use in 2006 for Drugs withPharmacogenomic Biomarker Information in the Product Labeling,Pharmacotherapy 2008;28(8):992998,13,不良反应与药酶变异相关最多的药物,DrugTreatment Enzyme Genotype Frequency,Fluoxetine antidepressant CYP1A2/CYP2D6 2-6/3-10Imipramine antidepressant CYP1A2/CYP2D6 12/3-10%Isoniazid antituberculosis NAT 50-59%Metoprolol Beta-blocker CYP2D6 3-10%Naproxen NSAID CYP2C9 2-6%Phenytoin Anticonvulsant CYP1A2 12%Piroxicam NSAID CYP1A2 12%S-Ibuprofen NSAID CYP1A2 12%S-Warfarin Anticoagulant CYP2C9 2-6%Theophylline Brochodilator CYP1A2 12%,From Pharmacogenomic:Social, Ethical and Clinical Dimensions, M. Rothstein, ed.,2005 Gus Rosania,14,常用药物与相关药酶基因多态性,15,25%重要处方药是经2D6代谢,16,CYP 2D6诱导剂,DexamethasoneRifampin,17,2D6的抑制剂,18,美托洛尔说明书明确提示确有较多的药物相互作用,Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.,19,美托洛尔说明书明确提示确受到PGx的影响,Metoprolol tartrate is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of Lopressor (metoprolol tartrate) is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers.,20,药物相互作用的典型病例分析-1,52岁男性,经4位医师依据不同病情共处方8种药:对乙酰氨基酚,西咪替丁,可待因,红霉素,布洛芬,美托洛尔,帕罗西汀及替沃噻吨,其中有4种药物发生了严重DDI;因可待因为前药,经CYP2D6转化为吗啡方有镇痛作用;美托洛尔,帕罗西汀(低浓度)受CYP2D6代谢,而治疗量帕罗西汀又可抑制CYP2D6;红霉素为CYP3A4抑制剂,可增加帕罗西汀浓度,四药形成恶性循环的DDI,结果是可待因无效,血压急剧下降,减少心脏变力和变时作用,同时抑郁症恶化,成为“抑郁综合征”。,21,多用药 多考虑,22,多用药 多考虑,23,关于药酶的基因多态性,P450酶的基因多态型（Genetic polymorphism）使药物代谢存在着种族和个体差异,目前分为4种表型： 正常代谢型 (EM),又称快代谢型（Extensive Metabolizer，占75-85%）; 活性缺乏型 (PM),又称慢代谢型（Poor Metabolizer,占5-10%）;超速代谢型( UM)（Ultrarapid Metabolizer,占1-10%); 中间代谢型( IM)（Intermediate Metabolizer,占10- 15%)(此型介于EM与PM之间） 。,24,从基因型到表型（药酶）,25,A:为显性基因; a :为隐性基因,26,遗传与代谢状态,27,药物疗效和毒性差异,基因组,基因多态性,药物靶点,药物转运体,药物代谢酶,基因,基因(组)决定药物的效应,28,两类药物经酶代谢的不同结果,29,2D6的基因多态性,CYP2D6s的等位基因(125个;2008年)与功能正常功能: CYP2D 6*1、 *33、*35;降低功能: CYP2D 6*2、 *9、*10、*17、*36、*41;增强功能: CYP2D 6*1N、 *2N、 *35N,N= *1、*2、*33 、*41;(为重复序列基因多态性); 全无功能: CYP2D6*3 、* 4、 *5 、*6 、* 7、 *8、 *11 、*12 、*13、 *14 、*15 、 * 16、 * 18、 19 * 、 * 20 、 * 21 、 * 38 、 * 40 、 * 42、 *43 、* 44 、* 56、 * 62,30,31,2D6等位基因在不同人群中的分布,CYP450 allele nomenclature committee database: http:/www.imm.ki.se/cypalleles,32,药酶基因多态性与药物浓度,(PM),(IM),(EM),(UM),33,-受体阻滞剂应用广泛但风险却很大,Blockers are among the most widely prescribed of all drug classes, with more than 120 million prescriptions in the United States in 2004; Are recommended as a first-line agent for various diseases, including heart failure, hypertension, and angina, as well as after myocardial infarction. However, -blocker therapy often produces variable responses among patients. Genetic differences may contribute to this variability in responses to -blockers. Pharmacotherapy.2007;27(6):874-887,34,肾上腺素能受体阻滞剂在心血管疾病中临床应用的专家共识(2009) 中华医学会心血管病学分会和中华心血管病杂志编辑委员会,不仅高度评价了受体阻滞剂的临床地位和重要作用,更重要的是强调规范使用!为什么要强调规范使用? 认识上有误区; 使用率低; 应用不规范; 选药不当. 遗憾地是“共识”未提及药物基因组学对规范使用受体阻滞剂的重要作用,即提高疗效、减少ADR所必需!,35,抗高血压的药物基因组学的过去、现在和未来Pharmacogenomics of antihypertensive drugs: past, present and future,21世纪将更加肯定高血压药物基因组学的临床价值!(The next decade should clearly define the clinical potential for hypertension pharmacogenomics.)Pharmacogenomics (2010) 11(4), 487491,36,欧洲心脏病协会2011年会(ESC Congress 2011),大会主题是“冠状动脉疾病:从基因到预后(Coronary artery disease: From genetics to outcome )”; 充分表明医药界对基因影响药物作用个体差异的高度重视,是未来医药学重点发展方向之一。27 Aug 2011 - 31 Aug 2011 , Paris France,37,美托洛尔受药酶基因多态性的影响,The mean plasma half-life of the drug is 5.2 hours for extensive metabolizers and 21.6 hours for poor metabolizers,38,美托洛尔主经2D6代谢/比索洛尔则否,39,美托洛尔主要被2D6代谢,美托洛尔70%80%依赖2D6代谢,共有3个代谢产物:O-去甲美托洛尔依赖2D6和3A4代谢,约占全部代谢的60%; -OH美托洛尔仅依赖2D6代谢,约占全部代谢的10%; N-去烷基美托洛尔仅依赖2D6代谢,约占全部代谢的10%;,Clin Pharmacokinetics 2009;48:689723,40,美托洛尔受药酶基因多态性的影响显著,41,携带PM者美托洛尔血浓度较EM高6.2倍,IM3.9倍Metoprolol and pharmacokinetic data according to the CYP2D6 genotype(91例白人,平均剂量47,5mg,平均疗程12.6月),Pharmacogenetics 2002, 12:465472,42,Pharmacogenetics 2002, 12:465472,43,2D6基因多态性决定美托洛尔的作用,Plasma metabolic ratio of metoprolol/-OH-metoprolol: Cmax :PM:IM=3.9倍 (P 0.01) AUC: PM:EM=6.2倍(P 0.001) ADR:PM:EM=5倍为什么有些患者即使服用推荐剂量美托洛尔却发生严重心动过缓、低血压以及疲劳症?为什么同服帕罗西汀、普罗帕酮等也出现上述病症?,Pharmacogenetics 2002, 12:465472,44,2D6基因多态性对长期服用美托洛尔血浓度的影响与比索洛尔比较,共72例患者入选,其中美托洛尔俎38例;比索洛尔组40例(有6例交叉)至少用药4周;患者2D6基因多态性检测结果见下表:J Cardiovasc Pharmacol 2005;46:713720,45,72例患者2D6基因多态性的分布与分组根据有无2D6*10及其多态性,组,组,组,showed that normalized plasma concentration ofmetoprolol in patients homozygous for the reduced functionalallele was 3 times higher than in those with normal functional,46,结果:美托洛尔受2D6基因多态性影响显著,而比索洛尔则否,J Cardiovasc Pharmacol 2005;46:713720,47,结果:美托洛尔受2D6基因多态性影响显著组的血药浓度较组高3倍,Het-PM,Hom-2D6*10,Heter-2D6*10,Hom-PM,J Cardiovasc Pharmacol 2005;46:713720,EM,showed that normalized plasma concentration of metoprolol in patients homozygous for the reduced functional allele was 3 times higher than in those with normal functional,*P0.01; #PUM;浓度相差60 倍,美托洛尔血药浓度与CYP2D6基因多态性的关系,1.27,49,比索洛尔不受2D6基因多态性的影响,Heter-PM,EM,Hom-PM,Heter-2D6*10,Hom-2D6*10,J Cardiovasc Pharmacol 2005;46:713720,50,结果:美托洛尔受2D6基因多态性 影响显著,而比索洛尔则否,J Cardiovasc Pharmacol 2005;46:713720,组与组*P75:1,Bisoprolol 天生丽质,Non-ISA,CIBIS CIBISIIITIBBSDECREASE,Balance Clearance,NHI price: Concor 5mg/片3. 03.5元,HypertensionAnginaCHF,75,实施PGx指导的个体化给药的优越性,1. Shift emphasis from reaction to prevention; 2. Select optimal therapy ( trial-and-error);3. Avoid adverse drug reactions ( drug safety);4. Increase patient compliance;5. Reduce time and cost of clinical trials;6. Revive drugs that are failing in clinical trials or were withdrawn from the market;7. Reduce the overall cost of healthcare,76,77,20世纪:千人一药一量!,One drug fits all !One dose fits all !,21世纪:一人一药一量“量体裁衣”给药,78,21世纪人人持有基因身份证,79,2004年启动医师PGx的继续教育FDA September 13-14, 2004,80,药物基因组学的伟大意义,“If