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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u 消化性溃疡出血消化性溃疡出血u 血小板功能不良血小板功能不良u 急性肾功能衰竭（易感者）急性肾功能衰竭（易感者）u 水钠潴留致水肿水钠潴留致水肿u 药物性肾病（止痛药相关性）药物性肾病（止痛药相关性）u 过期妊娠和分娩抑制过期妊娠和分娩抑制u 过敏过敏NSAIDs 的主要副作用的主要副作用NSAIDs 所致胃肠道损害所致胃肠道损害 deaths17,000107,000hospitalizations 1-1.5 GI ulcer complication in persons take traditional NSAIDsgreatest c
2、linical impact The analyses from USALaine L.Gastroenterology,2001,120:594-606.Gralnek,et al.2000;van der Molen,et al.1997;Ware&Sherbourne,1992.US populationn=2474asthman=110diabetes mellitusn=541NSAIDs(NASA 1)n=500NSAIDs(SPACE 1)n=579020406080100Mean SF-36 scorePhysicalfunctioningRole physicalBodily
3、 painGeneral healthMental healthRole emotionalVitalitySocialfunctioningNSAIDs所致所致GI副作用可降低患者副作用可降低患者HQLuNSAIDs 所致胃肠损害影响工作能力和日常活动所致胃肠损害影响工作能力和日常活动 13%reduced productivity at work(n=27)26%reduced daily activities(n=61).u半数以上的患者不能耐受而更换半数以上的患者不能耐受而更换NSAIDs 种类种类u44%的患者采用最小的的患者采用最小的NSAIDs剂量以降低剂量以降低GI副作用副作用
4、（虽然这种剂量不足以完全缓解关节炎疼痛）（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所致所致GI副作用导致患者中止治疗副作用导致患者中止治疗Hospitalisations/1000 person-years15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+2015105025female non-usersmale non-usersfemale usersmale usersAge(years)Gutthann SP,et al.Epid
5、emiology,1997,8:18-24.NSAIDs所致所致GI副作用增加住院率副作用增加住院率CountryNaproxenDiclofenacPiroxicamUK1.401.441.421.471.841.93France1.361.651.67Canada1.311.221.671.95CountryAll NSAIDsCanada1.66(1.617.49)USA1.45USA2.99(non-aspirin)Bidaut-Russell&Gabriel，2001.NSAIDs所致所致GI副作用可明显副作用可明显增加治疗费用增加治疗费用Wolfe,et al.19991997 U
6、S mortality data for seven selected disorders.NSAIDs相关死亡率高相关死亡率高NSAID toxicityLeukaemiaAIDSMultiple myelomaAsthmaCervical cancerHodgkins disease0500010,00015,00020,00025,000Number of deathssilent epidemicNSAIDNSAID胃肠道损害胃肠道损害 总的总的GIGI损害损害 便秘或腹泻便秘或腹泻 胃痛胃痛消化不良或烧心消化不良或烧心 腹胀腹胀 恶心或呕吐恶心或呕吐胃肠出血或溃疡胃肠出血或溃疡 其它
7、其它Thomas J,et al.Am J Gastroenterol,2002,97:2215-2219.OTC NSAID（n535）No OTC NSAID（n1068）过去过去30天内天内GI损害的发生率（）损害的发生率（）胃十二指肠损害的临床表现胃十二指肠损害的临床表现u GI损害损害:发生率发生率50u 消化不良消化不良(内镜阴性内镜阴性):15-25%,1.5-2 foldu 内镜下溃疡内镜下溃疡(无症状无症状):15-25u 有症状溃疡有症状溃疡:GU 15-31%,DU 5-8%u 溃疡并发症溃疡并发症:每年每年 1-2%,4-fold 无症状内镜表现无症状内镜表现Reflu
8、x esophagitis LA Grades AD.Avidan GT,et al.2001.ABCDNSAIDs 相关相关RENSAIDs 诱导的急性胃炎诱导的急性胃炎u急性粘膜糜烂和粘膜下出血急性粘膜糜烂和粘膜下出血u服用服用1次小剂量次小剂量NSAID也可也可 15-30 min上皮下出血上皮下出血 24 h内糜烂内糜烂u不伴有炎症浸润表现不伴有炎症浸润表现u病变程度与消化不良不平行病变程度与消化不良不平行NSAIDs 增加患者上腹不适症状增加患者上腹不适症状（烧心，反酸，上腹痛等）烧心，反酸，上腹痛等）Harvey et al，2003.n=4902Prevalence(%)hear
9、tburnacid refluxepigastric pain01020304050NoneAspirinNSAIDsexcludingaspirinAspirin+otherNSAIDsNSAIDs(包括包括COX-2选择性制剂选择性制剂)六个月累计消化不良发生率约六个月累计消化不良发生率约25Acid reflux,dyspepsia,epigastric discomfort,heartburn,nausea or vomiting.Langman et al,1999.non-selective NSAIDsn=1564Cumulative incidence of upper GI
10、symptoms over 6 months(%)0102030rofecoxibn=3357*p1 NSAIDOther NSAIDs(%)NSAIDs 相关胃肠并发症相关胃肠并发症Bleeding,Obstruction,and PerforationCapsule endoscopic appearance of small bowelWeil et al 2000消化性溃疡出血相关危险因素消化性溃疡出血相关危险因素Odds ratio012348Current smokingDiabetesHeart failureDyspepsia in past yearPrevious pept
11、ic ulcerWarfarin useOral corticosteroid useNSAID use567Henry et al 1996胃肠出血和穿孔发生与胃肠出血和穿孔发生与 NSAIDs 种类种类相关相关Estimated relative risk of haemorrhage or perforationAzapropazone50.0 0.5PiroxicamKetoprofenIndomethacinNaproxenAspirinSulindacDiflunisalDiclofenacIbuprofen胃肠胃肠出血和穿孔出血和穿孔发生与发生与 NSAIDs 剂量剂量相关相关H
12、awkey,et al.Gut,2003,52:600-608.p 与患者相关的危险因素与患者相关的危险因素:高龄患者高龄患者65岁岁(75岁者为高危岁者为高危)有消化性溃疡或上消化道并发症病史者有消化性溃疡或上消化道并发症病史者 Hp.感染感染 吸烟、饮酒吸烟、饮酒 消化性不良病史消化性不良病史 性别（男性略多于女性）性别（男性略多于女性）p 药物相关危险因素药物相关危险因素:所用所用NSAID 副作用较明显副作用较明显 所用所用NSAID 剂量较高或同时应用两种剂量较高或同时应用两种NSAIDs NSAIDS与抗凝剂同服与抗凝剂同服 NSAIDS与皮质类固醇同服与皮质类固醇同服Seager
13、&Hawkey 2001 NSAID-GI 损害相关危险因素损害相关危险因素Hawkey&Skelly 2002More than one risk factoribuprofen,800 mg three times daily,or diclofenac,75 mg twice dailycelecoxib,400 mg twice dailyPatients with ulcer complications(%)201No risk factorn=8059胃肠并发症发生与共存的胃肠并发症发生与共存的危险因素危险因素相关相关NSAID administration Carcia Rodr
14、iguez,et al.Arch Intern Med,1998,158:33-39.PGCryer B.Gastroenterol Clin North Am,2001,30:877-894.发发 病病 机机 制制 NSAID-induced GI injury粘液碳酸氢盐屏障粘液碳酸氢盐屏障上皮细胞层上皮细胞层粘膜血流供应粘膜血流供应保护性因素保护性因素损伤性因素损伤性因素 COX途径的主要病理生理作用途径的主要病理生理作用NSAIDProstaglandins,prostacyclin and thromboxaneNSAIDs 的抗炎作用机制的抗炎作用机制COX-2“Inducible
15、”ProstaglandinsArachidonic AcidCO2HCOX-1“Constitutive”ProstaglandinsMediate pain,inflammation,and feverNSAIDsHemostasisProtection ofgastric mucosaHemostasisNSAIDs LimitationsAcidicenvironmentBicarbonate layerIonic gradientGastricacidNSAIDsPepsinSurfaceepithelial cellsMucuslayerNeutralenvironmentMuco
16、salblood supplyAlkaline environmentProstaglandin productionBicarbonate productionMucus productionNSAIDs胃酸在胃酸在NSAIDs-GI损伤中起重要作用损伤中起重要作用动物实验证明动物实验证明NSAIDs-GI损伤是损伤是pH依赖的依赖的Elliott et al,1996.intraduodenal indomethacin,40 mg/kgintraduodenal salineTotal haemorrhagic mucosal area(%)Gastric luminal pH02.04.05.57.012345Wallace et al，2000.110Gastric blood flow(%of basal)indomethacin,10 mg/kgvehicle*p0.05*p0.0110203040506090705000Time after administration(minutes)*NSAIDs-GI损伤中粘膜血流显著降低损伤中粘膜血流显著降低增加白细胞增加白细胞
