质子泵抑制剂与抗血小板药精.ppt

质子子泵抑制抑制剂与抗血小板与抗血小板药第1页，本讲稿共19页Omeprazole 奥美拉唑奥美拉唑 1988Lansoprazole 兰索拉唑兰索拉唑 1991Pantoprazole 泮托拉唑泮托拉唑 1994Ilaprazole 艾普拉唑艾普拉唑1998Rabeprazole 雷贝拉唑雷贝拉唑 1999Esomeprazole 埃索美拉唑埃索美拉唑 2000Dexlansoprazole 右旋兰索拉唑右旋兰索拉唑 2009Proton Pump Inhibitors on Marketing解放军总医院消化病中心解放军总医院消化病中心 Great success to control Acid related diseases in the past 2 decades -NV-UGIB,Peptic Ulcer,GERD,etc.第2页，本讲稿共19页The potential benefits of antiplatelet therapy for atherosclerotic cardiovascular(CV)disease have been amply demonstrated over the past 20 years,especially thienopyridine drugs in preventing stent thrombosis.Antiplatelet agents increase the risk of bleeding associated with mucosal breaks in the upper and lower gastrointestinal(GI)tract.Rational use of thienopyridines is based on weighing their risks against their benefits.Balance between Benefits and Risks解放军总医院消化病中心解放军总医院消化病中心第3页，本讲稿共19页791 residents studied60 were prescribed clopidogrel248 were on aspirin 326 were prescribed a PPI.Among residents who were prescribed PPIs155 were prescribed omeprazole;72 pantoprazole51 rabeprazole;44 esomeprazole;15 lansoprazole.39 residents took a combination of clopidogrel and a PPI(any PPI)for a mean 203 days.9 residents took the combination of clopidogrel,aspirin and a PPI(any PPI)for a mean of 173 days.The Prevalence of Co-administrationClopidogrel and Proton Pump Inhibitors Shrestha K.et al.Qual Prim Care.2011;19(1):35-42解放军总医院消化病中心解放军总医院消化病中心第4页，本讲稿共19页Oral antiplatelet therapy may increase bleeding complications,the largest proportion due to GI hemorrhage.Gastroprotection strategies consist of use of PPIs in patients at high risk of GI bleeding.2008 Expert Consensus ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the GI Risks of Antiplatelet Therapy and NSAID Use解放军总医院消化病中心解放军总医院消化病中心第5页，本讲稿共19页2008 Expert Consensus ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the GI Risks of Antiplatelet Therapy and NSAID Use解放军总医院消化病中心解放军总医院消化病中心第6页，本讲稿共19页Many investigations of potential adverse interaction has been conducted recentlyEvidence of a possible adverse drug interaction between PPIs and thienopyridines has emergedIt has been difficult for physicians including cardiologists,gastroenterologists and all practionersHow to treat our patients with both kinds of drugs解放军总医院消化病中心解放军总医院消化病中心Potential adverse interaction 2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines JACC Vol.56,No.24,2010第7页，本讲稿共19页解放军总医院消化病中心解放军总医院消化病中心Metabolism of clopidogrel and PPI第8页，本讲稿共19页Metabolism of PPIsAll PPIs are hepatically metabolized to an extent via the cytochrome P450 mixed oxidase system.The isoenzymes CYP3A4,particularly CYP2C19 are the major isoforms that cause PPI biotransformation.The relative contribution of CYP2C19 pathway differs among drugs and has been reported to be omeprazole=esomeprazole pantoprazole lansoprazole rabeprazole in general metabolism In contrast to the situation with clopidogrel,reduced CYP2C19 function results in less inactivation of PPI and an increase in pharmacodynamic effect(greater acid inhibition).解放军总医院消化病中心解放军总医院消化病中心Metabolism of clopidogrel and PPIFock KM et al.Clin Pharmacokinet 2008;47:1-6第9页，本讲稿共19页A reduction in active metabolite levels of about 45%was found in people who received clopidogrel with omeprazole compared to those taking clopidogrel alone.The effect of clopidogrel on platelets was reduced by as much as 47%in people receiving clopidogrel and omeprazole together.解放军总医院消化病中心解放军总医院消化病中心The data from the manufacturer of clopidogrelEffect of PPI on the metabolite levels of clopidogrel 第10页，本讲稿共19页The concomitant use of omeprazole and clopidogrel should be avoided Other drugs that should be avoided in combination with clopidogrel because they may have a similar interaction include:esomeprazole,cimetidine,fluconazole,etc.解放军总医院消化病中心解放军总医院消化病中心 FDA alert in 2009 11第11页，本讲稿共19页Except cimetidineNo evidence that other drugs reduce stomach acid,H2 blockers ranitidine(Zantac)famotidine(Pepcid)nizatidine(Axid)(Tagamet and Tagamet HB-a CYP2C19 inhibitor)antacids interfere with the anti-clotting activity of clopidogrel.解放军总医院消化病中心解放军总医院消化病中心H2 receptor blockers第12页，本讲稿共19页Pantoprazole is less potent than omeprazole to inhibit CYP2C19 and does not appear to attenuate the pharmacodynamic response to clopidogrelPantoprazole had no association with recurrent MI in a large population-based,case-control study of patients receiving clopidogrel解放军总医院消化病中心解放军总医院消化病中心Alternative PPI Pantoprazole第13页，本讲稿共19页噻吩吡啶类抗血小板药包括噻吩吡啶类抗血小板药包括普拉格雷、替卡格雷普拉格雷、替卡格雷.普拉格雷（普拉格雷（prasugrelprasugrel）通过细胞色素通过细胞色素P450P450系统代谢系统代谢（包括（包括CYP3ACYP3A、CYP2B6CYP2B6、CYP2C9CYP2C9和和CYP2C19CYP2C19）活化）活化CYP2C19CYP2C19不是其主要代谢途径。不是其主要代谢途径。尚未在我国上市尚未在我国上市替卡格雷（替卡格雷（ticagrelorticagrelor）替卡格雷通过替卡格雷通过CYP3A4CYP3A4代谢代谢不受不受CYP2C19CYP2C19变异的影响变异的影响尚未在美国及我国上市尚未在美国及我国上市解放军总医院消化病中心解放军总医院消化病中心Alternative antiplatelet therapy第14页，本讲稿共19页Clopidogrel alone,aspirin alone,and their combination are all associated with increased risk of GI bleeding.Use of a PPI or histamine H2 receptor antagonist(H2RA)reduces the risk of upper GI bleeding compared with no therapy.PPIs reduce upper GI bleeding to a greater degree than do H2RAs.解放军总医院消化病中心解放军总医院消化病中心2010 Expert Consensus（1）2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines JACC Vol.56,No.24,2010第15页，本讲稿共19页Pharmacokinetic and pharmacodynamic studies,using platelet assays as surrogate endpoints,suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of clopidogrel.The strongest evidence for an interaction is between omeprazole and clopidogrel.解放军总医院消化病中心解放军总医院消化病中心2010 Expert Consensus（2）2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines JACC Vol.56,No.24,2010第16页，本讲稿共19页Platelet function testingReally reflect the clinical events?Pharmacogenomic testing CYP2C19,high costno practical and no feasibility解放军总医院消化病中心解放军总医院消化病中心Individualed TEST 第17页，本讲稿共19页Clinical observational studies:interactions yesA single randomized clinical trial(RCT):interactions No解放军总医院消化病中心解放军总医院消化病中心2010 Expert Consensus（3）2010 Expert Consensus Document on the Concomitant Use of PPIs and Thienopyridines JACC Vol.56,No.24,2010A clinically important interaction cannot be excluded,particularly in certain subgroups,such as poor metabolizers of clopidogrel.Individualized treatmentInconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs.第18页，本讲稿共19页 A physician is one who pours drugs of which he knows little into a body of which he knows less.Franois Voltaire 伏尔泰1694 1778解放军总医院消化病中心解放军总医院消化病中心第19页，本讲稿共19页