PPI质子泵抑制剂.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。,从药理学看所有的PPI都一样吗？,姚明辉,复旦大学上海医学院药理学系主任,概述,THE IMPORTANCE,OF ACID,FOOD DIGESTION,BACTERIA CONTROL,ENZYME ACTIVATION,B,12,ABSORPTION,THE PARIETAL,CELL,概述,概述,THE PARIETAL,CELL,THE DISEASES OF ACID,PEPTIC ULCER DISEASE,GASTRO-ESOPHAGEAL,REFLUX DISEASE(G E R D),HELICOBACTER PYLORI,ZOLLINGER-ELLISSON,Figure Physiological and pharmacological regulation of gastric secretions:the basis for therapy of peptic ulcer disease,.,质子泵抑制剂（PPI）共性,1.化学结构相似,2.为目前临床最常用的抗酸药(H,2,受体阻断药),3.为目前临床最有效的治疗与酸相关性疾病药物,4.作用机制相似,按化学结构分类的相似性,目前研制开发中的质子泵抑制剂(PPI)主要可分为两大类：,1.苯丙咪唑替代物(即ATP拮抗型)如奥美拉唑、兰索拉唑、泮托拉唑等，它们抑制H,+,K,+,-ATP酶活性是不可逆的，只有当新的质子泵生成并插入壁细胞膜上时，质子泵的活性才能得以恢复。,按化学结构分类的相似性,因此，尽管PPI的血浆半衰期短，其药效作用时间却较长。作用时间取决于新生质子泵再生的速度。,按化学结构分类的相似性,2.咪唑吡啶替代物(即K,+,拮抗型)如,SCH28080，通过与K竞争而抑H,+,K,+,-ATP,酶，这种抑制是可逆的，其抗分泌作用疗,效短暂。我们通常所指PPI均为苯丙咪唑,替代物，包括取代吡啶类和取代苯胺类。,作用机制相似,1.弱碱性药物。,2.前体药物(prodrugs),需在体内激活。,作用机制相似,弱碱性PPIs,聚积于胃壁细胞（壁细胞分泌小管）,亚磺酰胺或次磺酸,813半胱氨酸残,基上的巯基,H,+,，K,+,-ATP酶（亚基）,共价二硫键,使H,+,，K,+,-ATP酶失活，抑制胃酸分泌,MECHANISM OF ACTION OF PPIs,Adapted from Sachs G et al.,Annu Rev Pharmacol Toxicol,.1995;35:277-305.,cAMP,Ca,+,Acetylcholine,Histamine,Parietal,Cell,H,+,Site of Action,(proton pump),Gastrin,ECL cell,Lumen,+,+,+,K,+,ATP-,ase,+,MECHANISM OF ACTION OF PPIs,Activesulfenamide,Parietal,Cell,H,+,Canaliculus pH 4,Activation,Inhibition,PPIs,H,+,/K,+,ATPase,Protonation,Adapted from Sachs G et al.,Annu Rev Pharmacol Toxicol,.1995;35:277-305.,临床适应证相似,1.促进胃、十二指肠溃疡愈合,2.治疗胃-食道反流病(GERD),3.幽门螺杆菌,3.卓艾综合征(Zollinger-,Ellison syndrome),ARE ALL PROTON,PUMP INHIBITORS,THE SAME?,第一代PPIs局限性,药代动力学有明显个体差异,受给药时间和进餐的影响,起效较慢,不能持久抑制胃酸,明显的药物相互作用,药物相互作用,相互作用主要表现,1.细胞色素P450酶系统,奥美拉唑主要经CYP2C19和CYP3A4,代谢，可与卡马西平、安定、苯妥英、,茶碱、咖啡因、华法林及,硝苯吡啶,等,药物发生相互作用。,当奥美拉唑与克拉,霉素合用时，它们的血药浓度会上升。,药物相互作用,相互作用主要表现,兰索拉唑与CYP3A4代谢密切相关,大环内酯类抗生素-红霉素、克拉霉素,特非那定、茶碱、阿司咪唑、环孢素、,部分钙通道阻滞剂、部分3-羟基-3-甲,基戊二酰辅酶,药物相互作用,相互作用主要表现,兰索拉唑与CYP3A4代谢密切相关,H,2,受体阻滞剂、皮质激素、口服避孕药,阿司咪唑、西沙必利,药物相互作用,相互作用主要表现,2.改变体液pH,因PPI能显著升高胃内pH，有些药物的吸收可能会有所改变，如酮康唑和伊曲康唑的吸收会下降,地高辛,水平升高。长期用奥美拉唑VitB12吸收减少。,药物相互作用,相互作用主要表现,3.毒性增加,PPI+双硫仑(disulfiram,解酒药),长期用奥美拉唑高胃泌素血症（500ng/L）,新一代PPIs特性,新一代PPIs基本特性,1.可不同程度克服第一代PPIs局限性,2.新一代PPIs的代表药物为:,(1),雷贝拉唑 (Rabeprazole),(2)埃索美拉唑(Esomeprazole),R A B E P R A Z O L E,A PROTON PUMP INHIBITOR,“P A R I E T “in China and Europe,from Parietal Cell,“,A C I P H E X“in The USA,from Acid pH Elimination,雷贝拉唑基本特性,1.临床抑酸效果好；对成熟和幼稚壁细,胞均有更好的抑酸效果,2.抑酸作用起效快；,3.昼夜均可维持较高的抑酸水平；,4.疗效确切，个体差异小；,5.与其他药物之间无相互影响。,雷贝拉唑基本特性,1.作用部位药物浓度高,雷贝拉唑（RAB)与奥美拉唑(,OME,)在成熟和幼稚胃壁细胞泌酸小管中的药物浓度比较,10,pKa,-,pH-,=10,5-1,=10,4,=10000(,幼稚,RAB,),10,pKa,-,pH-,=10,4-1,=10,3,=1000(,幼稚,OME,),10,pKa,-,pH-,=10,5-3,=10,2,=100(,成熟,RAB,),10,pKa,-,pH-,=10,4-3,=10(,成熟,OME,),雷贝拉唑（RAB)与奥美拉唑(OME)在成熟和幼稚胃壁细胞泌酸小管中的药物浓度比较,由于RAB和OME的PKa不同，在幼稚和成熟壁细胞中RAB聚积均较OME高10倍,治疗比,壁细胞,成熟,幼稚,RAB：pKa=5.0,OME：pKa=4.0,雷贝拉唑基本特性,2.临床疗效好,Day 1 Antisecretory Effects of PPIs in 18 H.pylori-Negative Subjects,Median Intragastric pH,Pantoflickova D et al.,Gastroenterology,2000;118(4):A5895.,0,1,2,3,4,PAN,OME,MUPS,LAN,3.4,RAB,*,2.9,2.2,1.9,1.8,1.3,Placebo,*,P,0.05 vs.all other PPIs and placebo.,Day 1 Antisecretory Effects of PPIs in 18 H.pylori-Negative Subjects:pH Nighttime,*,P,4的百分率,雷贝拉唑和其他,P,PI,第1天的抑酸效果,在,18,例幽门螺杆菌阴性的健康志愿者中观察了服用雷贝拉唑,20mg,、,兰索拉唑,30mg,、,泮托拉唑,40mg,、,奥美拉唑,20mg,及奥美拉唑复合剂型,(MUPS)20mg,后胃内,pH,变化，结果表明，雷贝拉唑在第一个,24,小时胃内,pH,明显高于其他质子泵抑制剂,。,Pantoflickova,D.,et al.,Acid inhibition on the first day of dosing:comparison of four proton pump inhibitors.,Aliment,Pharmacol,Ther,2003.17(12):p.1507-14.,昼夜均可维持较高的抑酸水平,10mg,单次剂量的雷贝拉唑比,20mg,奥美拉唑和,40mg,泮托拉唑更多的升高夜间酸高峰时的,pH,值，并缩短夜间酸高峰的维持时间,Luo,J.Y.,et al.,Effect of a single oral dose of rabeprazole on nocturnal acid breakthrough and nocturnal alkaline amplitude.,World J Gastroenterol,2003.9(11):p.2583-6.,NEW CONCEPTS IN ACID SECRETION&SUPPRESSION,GASTRIC ATPase RECEPTORS,1000 1300 Cysteine Residues,CHANNELS OF ACID SECRETION,ACID SECRETION and SUPPRESSION,A P P,I P P,PARIETAL CELL,ATPase,1000-1300 CYSTEINE,RESIDUES,I.MODLIN,G.SACHS Acid Related Diseases ,Verlag,1998,813,822,321,892,Stimulated Acid Secretion,Basal Acid Secretion,ACID SECRETION ANDSUPPRESSION,.,Circadian,Rhythm,Stimulated Acid Secretion,4 ATPase Channels,Basal Acid Secretion,6 ATPase Channels,PPIs +,PPIs +,M M M,Gastric,pH,ACID SECRETION and SUPPRESSION,A P P,OMEPRAZOLE,LANSOPRAZOLE,PANTOPRAZOLE,RABEPRAZOLE,X X,I P P,PARIETAL CELL,ATPase,1000-1300,CYSTEINE,RESIDUES,I.MODLIN,G.SACHS Acid Related Diseases ,Verlag,1998,813,822,321,892,HELICOBACTER PYLORI,THE LATEST AND MOST EFFECTIVE TREATMENT OF H.PYLORI,Seven Day Regimen,Rabeprazole 20 mg BID,Clarithromycin 500mg BID,Amoxicillin 1000mg BID,RCA 89%Eradication in 7 days,OAC 82%Eradication in 10 days,抗幽门螺旋杆菌作用,临床上在清除幽门螺旋杆菌的三联治疗中用大剂量的雷贝拉唑比低剂量雷贝拉唑或奥美拉唑更有效。,ITT,：,intention-to-treat population,PP,：,per protocol population,Kositchaiwat,C.,et al.,Low and high doses of,rabeprazole,vs.,omeprazole,for cure of Helicobacter pylori infection.,Aliment,Pharmacol,Ther,2003.18(10):p.1017-21.,雷贝拉唑基本特性,3.个体差异小,药物相互作用较少。,CYP 2C19和CYP 3A4基因表型对PPIs代谢的影响,细胞色素的同工酶有,种之多（），其基因多态性与药物代谢及其疗效密切相关。与代谢相关的450同工酶主要为肝脏微粒体中的、4，其中,基因定位于人类号染色体上,CYP2C19对PPIs代谢的影响,CYP2C19与药物相互作用及其临床意义有关，并可用于解释不同PPI的疗效差异以及制定治疗剂量个体化方案。弱代谢型患者的疗效优于强代谢型；强代谢型患者应加大PPI剂量，以提高疗效（有人建议倍剂量）。,CYP 2C19基因表型对PPIs代谢的影响,AUC=时量曲线下面积，EM=CYP 2C19强代谢型，PM=CYP 2C19弱代谢型,Ishizaki T,Horai Y.Aliment Pharmacol Ther 1999;13(suppl 3):27-36,AUC,PM,/AUC,EM,第一代PPI对细胞色素P450同工酶系统的依赖,Healing rates of erosive reflux oesophagitis and CYP2C19 polymorphism.The healing rates were evaluated by endoscopy 4 weeks after the start of treatment in 58 of 88 patients.At 8 weeks,the healing rates in homozygous extensive metabolizers(homo-EMs),heterozygous extensive metabolizers(hetero-EMs)and poor metabolizers(PMs)were 77.4%(24/31),95.0%(38/40)and 100%(17/17),respectively,and the rate was significantly lower in homo-EMs than in hetero-EMs and PMs(77.4%vs.95.0%,P,0.05;77.4%vs.100%,P,0.05;MantelHaenszel test).,Kawamura,M.,et al.,The effects of lansoprazole on erosive reflux oesophagitis are influenced by CYP2C19 polymorphism.,Aliment Pharmacol Ther,2003.17(7):p.965-73.,P H A R M A C O D Y N A M I C S,News We Can Use,PROTON PUMP INHIBITORS,CYP 450 Liver Metabolism,2C 19,3A 4,THIOETHER,Omeprazole -Esomeprazole,Lansoprazole -Pantoprazole,RABEPRAZOLE,Slow Metabolizers Fast Metabolizers,Genetically Controlled,埃索美拉唑,奥美拉唑含有,S-,异构体和,R-,异构体，前者为埃索美拉唑,埃索美拉唑-奥美拉唑的异构体,埃索美拉唑,年以前，由于推测奥美拉唑的两种构型S(左旋体)和R(右旋体)作用机制相同，在胃壁细胞分泌小管聚集后，无论左旋体或右旋体，在酸性环境下均分解成次磺酰胺，与质子泵的巯基结合，抑制胃酸分泌；而且当时单一异构体很难制备，无法获得足以进行体内研究的数量，所以只能在体外进行试验。,埃索美拉唑,结果显示，两者生理效应相同，同时两种异构体在pH=7时及在有机溶剂中可以相互转变（也称消旋作用），因此异构体的概念在当时未被看好。,埃索美拉唑,1990年以后情况发生了改变，科学家设法通过微生物学或酶的方法合成单一异构体，并用色谱法分离奥美拉唑的对映异构体，由此得到了以克计（继之是以公斤计）的埃索美拉唑，足以进行体内试验以鉴定不同异构体的药代动力学差异。,埃索美拉唑,有趣的是，在首先进行的动物实验中，右旋体比埃索美拉唑表现出更好的生物利用度；在接下来的人体研究中，结果则恰恰相反，埃索美拉唑显示出更为优越的代谢功能。,埃索美拉唑具有更高的生物利用度,血浆浓度和时间曲线显示，埃索美拉唑的曲线下面积(AUC)大于奥美拉唑，后者又大于右旋体，而AUC是与药物吸收有关。埃索美拉唑对酸分泌的抑制作用为90.7%，奥美拉唑为64.5%，而右旋体为25.3%。研究表明，埃索美拉唑由于其代谢途径的改善（通过CYP3A4代谢增加），个体变异很小，因此其疗效具有很好的可预测性。,埃索美拉唑可使胃酸得到24小时深度抑制且酸反跳极低,治疗前胃内pH中位数,治疗前胃内pH 4时间百分比,治疗后胃内pH中位数,治疗后胃内pH 4时间百分比,埃索美拉唑 40mg bd,1.4(1.2-1.8),93.8(89.4-98),6.75*(6.3-7.1),4.3*(2.4-9.4),奥美拉唑 40mg qd,1.6(1.1-1.8),90.6(87.6-94.5),4.4(3.0-5.8),47.7(27.1-58),表中数值为中位数（四分位数）；*同40mg奥美拉唑治疗相比，p0.001；*同40mg奥美拉唑治疗相比，p4的维持时间埃索美拉唑为14个小时，雷贝拉唑为12.1小时，奥美拉唑11.8小时，兰索拉唑11.5小时，泮托拉唑10.1小时,Miner,P.,Jr.,et al.,Gastric acid control with esomeprazole,lansoprazole,omeprazole,pantoprazole,and rabeprazole:a five-way crossover study.,Am J Gastroenterol,2003.98(12):p.2616-20.,雷贝拉唑与埃索美拉唑,40mg埃索美拉唑和兰索拉唑以及20mg雷贝拉唑相比，使胃内pH4的有效率61%，而30mg兰索拉唑和20mg雷贝拉唑分别为53%和45%，埃索美拉唑的维持时间也更长。,Wilder-Smith,C.H.,et al.,Esomeprazole 40 mg Provides Improved Intragastric Acid Control as Compared with Lansoprazole 30 mg and Rabeprazole 20 mg in Healthy Volunteers.,Digestion,2003.68(4):p.184-188.,Comparison of Rabeprazole 20 mg vs Esomeprazole 20 mg on Intragastric pH,Primary objective:to compare the anti-secretory effects(Day 1 and Day 5)of 5 daily doses of rabeprazole 20 mg and esomeprazole 20 mg,Open-label,randomized,2-way crossover design in 24 healthy,H.pylori,negative adults,Two study periods were separated by a washout of at least 14 days,Subjects were dosed daily in the morning,Baisley K et al.,Am J Gastroenterology.,2001;96(suppl 1):A149.,Antisecretory Effects of Rabeprazole 20 mg vs Esomeprazole 20 mg,The correlation of these data to clinical effect has not been established.,*,P,4(%),Day 1,Day 5,The correlation of these data to clinical effect has not been established.,*ACIPHEX,was statistically significant vs esomeprazole on Days 1(,P,0.001)and Day 5(,P,3和4的时间百分比明显比埃索美啦唑高。,Warrington S，et al Aliment Pharmacol Ther.2002 Jul;16(7):1301-7.,雷贝拉唑与埃索美拉唑,在抑制幽门螺旋杆菌方面，雷贝拉唑最强（埃索美拉唑较弱）,Zhonghua Liu Xing Bing Xue Za Zhi.2003 Jun;24(6):447-8.,雷贝拉唑与埃索美拉唑,1.,雷贝拉唑对CYP2C19的依赖比埃索美,啦唑弱,2.药物相互作用少,3.CYP2C19基因的多态性对雷贝拉唑,的代谢没有显著影响，但是对埃索,美啦唑影响明显。,Thjodleifsson B,Drugs Aging.2002;19(12):911-27,Metabolic Pathways of PPIs,The thickness of arrows indicates an approximate contribution of CYP isoforms to each of the metabolic pathways.Thus,thick arrows indicate a more dominant and thin arrows a less dominant biotransformation pathway mediated via each CYP p450 isoform.,The correlation of these data to clinical effect has not been established.,Ishizaki T et al.,Aliment Pharmacol Ther,.1999;13:27-36.Product labeling of esomeprazole(Astra Zeneca).,Rabeprazole,2C19,3A4,Not,Cytochrome,Mediated,demethylated,thioether,sulfone,Omeprazole,2C19,3A4,3A4,2C19,sulfone,5-hydroxy,3-hydroxy,5-O-desmethyl,Pantoprazole,2C19,3A4,demethylated,sulfone,Lansoprazole,2C19,3A4,sulfone,hydroxy,2C19(Major),Esomeprazole,3A4(Remaining),sulfone,Hydroxy and desmethyl,Rabeprazole,Rabeprazole 主要特点,FAST RELIEF CONSISTENT RESPONSE POTENCY,HIGHEST pH Day 1,7 DAY TREATMENT OF H.PYLORI,疗效,代谢,pka,剂量,谢 谢,