非甾体类消炎药相关性胃十二指肠损害的预防与治疗.ppt
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1、非甾体类消炎药相关性胃十二指肠损害的预防与治疗,消化性溃疡出血 血小板功能不良 急性肾功能衰竭(易感者)水钠潴留致水肿 药物性肾病(止痛药相关性)过期妊娠和分娩抑制 过敏,NSAIDs 的主要副作用,NSAIDs 所致胃肠道损害,deaths,17,000,107,000,hospitalizations,1-1.5,GI ulcer complication in persons take traditional NSAIDs,greatest clinical impact,The analyses from USALaine L.Gastroenterology,2001,120:594
2、-606.,Gralnek,et al.2000;van der Molen,et al.1997;Ware&Sherbourne,1992.,0,20,40,60,80,100,Mean SF-36 score,Physicalfunctioning,Role physical,Bodily pain,General health,Mental health,Role emotional,Vitality,Socialfunctioning,NSAIDs所致GI副作用可降低患者HQL,NSAIDs 所致胃肠损害影响工作能力和日常活动13%reduced productivity at wor
3、k(n=27)26%reduced daily activities(n=61).半数以上的患者不能耐受而更换NSAIDs 种类44%的患者采用最小的NSAIDs剂量以降低GI副作用(虽然这种剂量不足以完全缓解关节炎疼痛),Knott,2000;Steinfeld et al,2002;Wahlqvist et al,2003.,NSAIDs所致GI副作用导致患者中止治疗,Hospitalisations/1000 person-years,Age(years),Gutthann SP,et al.Epidemiology,1997,8:18-24.,NSAIDs所致GI副作用增加住院率,Bi
4、daut-Russell&Gabriel,2001.,NSAIDs所致GI副作用可明显增加治疗费用,Wolfe,et al.1999,1997 US mortality data for seven selected disorders.,NSAIDs相关死亡率高,silent epidemic,NSAID胃肠道损害,总的GI损害 便秘或腹泻 胃痛消化不良或烧心 腹胀 恶心或呕吐胃肠出血或溃疡 其它,Thomas J,et al.Am J Gastroenterol,2002,97:2215-2219.,OTC NSAID(n535)No OTC NSAID(n1068),过去30天内GI损害
5、的发生率(),胃十二指肠损害的临床表现,GI损害:发生率50 消化不良(内镜阴性):15-25%,1.5-2 fold 内镜下溃疡(无症状):15-25 有症状溃疡:GU 15-31%,DU 5-8%溃疡并发症:每年 1-2%,4-fold,无症状内镜表现,Reflux esophagitis LA Grades AD.,Avidan GT,et al.2001.,C,D,NSAIDs 相关RE,NSAIDs 诱导的急性胃炎,急性粘膜糜烂和粘膜下出血服用1次小剂量NSAID也可 15-30 min上皮下出血 24 h内糜烂不伴有炎症浸润表现病变程度与消化不良不平行,NSAIDs 增加患者上腹不
6、适症状(烧心,反酸,上腹痛等),Harvey et al,2003.,NSAIDs(包括COX-2选择性制剂)六个月累计消化不良发生率约25,Acid reflux,dyspepsia,epigastric discomfort,heartburn,nausea or vomiting.,Langman et al,1999.,NSAIDs 相关溃疡,症状性溃疡每年发生率1-2%服药1周内,25-30%服药3个月内,15-30%;其中GU,10-20;DU,4-10服药6个月内,45%并发症危险性增加4倍,Laine et al.Gastroenterology.2004,127:395-40
7、2.Ofman et al.Arthritis Rheum.2003,49:508-518.,NSAID-induced GU,NSAID-induced DU,用药时间越长 NSAIDs 溃疡发生率越高,Gaithersburg,et al.FDA Arthritis Advisory Committee,2001,Cheatum,et al.1999.,消化性溃疡的发生率与NSAIDs种类相关,Patients with peptic ulcers(%),(%),NSAIDs 相关胃肠并发症,Bleeding,Obstruction,and Perforation,Capsule endo
8、scopic appearance of small bowel,Weil et al 2000,消化性溃疡出血相关危险因素,Odds ratio,0,1,2,3,4,8,Current smoking,Diabetes,Heart failure,Dyspepsia in past year,Previous peptic ulcer,Warfarin use,Oral corticosteroid use,NSAID use,5,6,7,Henry et al 1996,胃肠出血和穿孔发生与 NSAIDs 种类相关,胃肠出血和穿孔发生与 NSAIDs 剂量相关,Hawkey,et al.G
9、ut,2003,52:600-608.,与患者相关的危险因素:高龄患者65岁(75岁者为高危)有消化性溃疡或上消化道并发症病史者 Hp.感染 吸烟、饮酒 消化性不良病史 性别(男性略多于女性)药物相关危险因素:所用NSAID 副作用较明显 所用NSAID 剂量较高或同时应用两种NSAIDs NSAIDS与抗凝剂同服 NSAIDS与皮质类固醇同服,Seager&Hawkey 2001,NSAID-GI 损害相关危险因素,Hawkey&Skelly 2002,More than one risk factor,ibuprofen,800 mg three times daily,or diclof
10、enac,75 mg twice daily,celecoxib,400 mg twice daily,Patients with ulcer complications(%),2,0,1,No risk factor,n=8059,胃肠并发症发生与共存的危险因素相关,NSAID administration,Carcia Rodriguez,et al.Arch Intern Med,1998,158:33-39.,PG,Cryer B.Gastroenterol Clin North Am,2001,30:877-894.,发 病 机 制 NSAID-induced GI injury,C
11、OX途径的主要病理生理作用,NSAID,Prostaglandins,prostacyclin and thromboxane,NSAIDs 的抗炎作用机制,COX-2“Inducible”,Prostaglandins,Arachidonic Acid,CO2H,COX-1“Constitutive”,Prostaglandins,Mediate pain,inflammation,and fever,NSAIDs,Hemostasis,Protection ofgastric mucosa,Hemostasis,NSAIDs Limitations,胃酸在NSAIDs-GI损伤中起重要作用
12、,动物实验证明NSAIDs-GI损伤是pH依赖的,Elliott et al,1996.,intraduodenal indomethacin,40 mg/kg,intraduodenal saline,Wallace et al,2000.,110,Gastric blood flow(%of basal),*p0.05*p0.01,10,20,30,40,50,60,90,70,50,0,0,Time after administration(minutes),*,*,*,*,*,NSAIDs-GI损伤中粘膜血流显著降低,增加白细胞-内皮细胞间粘附,NSAIDs,中性粒细胞-内皮细胞粘附增
13、加,缺血和乏氧细胞损伤,内皮细胞和上皮细胞损伤,粘膜溃疡形成,Wallace et al,1997.,PG TNF,NEWIDEA 1,动物模型显示:选择性 NSAIDs 促进白细胞-内皮细胞间粘附,Wallace et al,2000.,升高cGMP 水平 in ASA administration,NEWIDEA 2,Herrerias JM,et al.Dig Dis Sci,2003,48:986-991.,Heat shock protein 27(HSP27),NEWIDEA 3,Ebert MP,et al.J Pathol,2005,207:177-184.,Survivin,
14、NEWIDEA 4,Chiou SK,et al.Gastroenterology,2005,128:63-73.,非选择性 NSAIDs 大多数患者每次服用可致胃粘膜糜烂 约15-30可致内镜可见的溃疡发生(通常是无症状的)COX-2 选择性 NSAIDs 消化性溃疡发生率 较非选择性制剂降低 但是存在危险因素或应用低剂量 阿司匹林者溃疡发生的危险性仍高,Hawkey Silverstein et al,2000.,Bombardier et al 2000,Perforation,obstruction,bleeding or symptomatic peptic ulcer.,罗非昔布较
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- 非甾体类 消炎药 相关性 十二指肠 损害 预防 治疗

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