非甾体类消炎药相关性胃十二指肠损害的预防与治疗

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17,000107,0001-1.5％greatestclinicalimpactTheanalysesfromUSALaineL.Gastroenterology,2001,120:594-606.Gralnek,etal.2000;vanderMolen,etal.1997;Ware&Sherbourne,1992.USpopulationn=2474asthman=110diabetesmellitusn=541NSAIDs(NASA1)n=500NSAIDs(SPACE1)n=579020406080100MeanSF-36scoreNSAIDs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%reducedproductivityatwork(n=27)–26%reduceddailyactivities(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；Steinfeldetal，2002；Wahlqvistetal，2003.NSAIDs所致GI副作用导致患者中止治疗Hospitalisations/1000person-years152025303540455055606570758085+2015105025femalenon-usersmalenon-usersfemaleusersmaleusersAge(years)GutthannSP,etal.Epidemiology,1997,8:18-24.NSAIDs所致GI副作用增加住院率CountryNaproxenDiclofenacPiroxicamUK1.40–1.441.42–1.471.84–1.93France1.361.651.67Canada1.311.22–1.671.95CountryAllNSAIDsCanada1.66(1.61–7.49)USA1.45USA2.99(non-aspirin)Bidaut-Russell&Gabriel，2001.NSAIDs所致GI副作用可明显增加治疗费用Wolfe,etal.19991997USmortalitydataforsevenselecteddisorders.NSAIDs相关死亡率高0500010,00015,00020,00025,000Numberofdeaths†‘silentepidemic’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ThomasJ,etal.AmJGastroenterol,2002,97:2215-2219.OTCNSAID（n＝535）NoOTCNSAID（n＝1068）过去30天内GI损害的发生率（％）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%,1.5-2fold内镜下溃疡(无症状):15-25％有症状溃疡:GU15-31%,DU5-8%溃疡并发症:每年1-2%,4-fold无症状内镜表现RefluxesophagitisLAGradesA–D.AvidanGT,etal.2001.ABCDNSAIDs相关RENSAIDs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－15-30min上皮下出血－24h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增加患者上腹不适症状（烧心，反酸，上腹痛等）Harveyetal，2003.n=4902Prevalence(%)heartburnacidrefluxepigastricpain01020304050NoneAspirinNSAIDsexcludingaspirinAspirin+otherNSAIDsNSAIDs(包括COX-2选择性制剂)六个月累计消化不良发生率约25％†Acidreflux,dyspepsia,epigastricdiscomfort,heartburn,nauseaorvomiting.Langmanetal,1999.non-selectiveNSAIDsn=1564CumulativeincidenceofupperGIsymptoms†over6months(%)0102030rofecoxibn=3357*p0.05*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Laineetal.Gastroenterology.2004,127:395-402.Ofmanetal.ArthritisRheum.2003,49:508-518.NSAID-inducedGUNSAID-inducedDU用药时间越长NSAIDs溃疡发生率越高Gaithersburg,etal.FDAArthritisAdvisoryCommittee,2001Cheatum,etal.1999.消化性溃疡的发生率与NSAIDs种类相关Patientswithpepticulcers(%)50010304020非诺洛芬双氯芬酸萘普生舒林酸布洛芬吲哚美辛炎痛喜康氟比洛芬依托度酸酮洛芬阿司匹林1NSAIDOtherNSAIDs(%)NSAIDs相关胃肠并发症Bleeding,Obstruction,andPerforationCapsuleendoscopicappearanceofsmallbowelWeiletal2000消化性溃疡出血相关危险因素Oddsratio012348CurrentsmokingDiabetesHeartfailureDyspepsiainpastyearPreviouspepticulcerWarfarinuseOralcorticosteroiduseNSAIDuse567Henryetal1996胃肠出血和穿孔发生与NSAIDs种类相关Estimatedrelativeriskofhaemorrhageorperforation50.00.5胃肠出血和穿孔发生与NSAIDs剂量相关Hawkey,etal.Gut,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&Hawkey2001NSAID-GI损害相关危险因素Hawkey&Skelly2002Morethanoneriskfactoribuprofen,800mgthreetimesdaily,ordiclofenac,75mgtwicedailycelecoxib,400mgtwicedailyPatientswithulcercomplications(%)201Noriskfactorn=8059胃肠并发症发生与共存的危险因素相关NSAIDadministrationCarciaRodriguez,etal.ArchInternMed,1998,158:33-39.PGCryerB.GastroenterolClinNorthAm,2001,30:877-894.发病机制NSAID-inducedGIinjury粘液碳酸氢盐屏障上皮细胞层粘膜血流供应保护性因素损伤性因素COX途径的主要病理生理作用NSAIDProstaglandins,prostacyclinandthromboxaneNSAIDs的抗炎作用机制COX-2“Inducible”ProstaglandinsArachidonicAcidCO2HCOX-1“Constitutive”ProstaglandinsMediatepain,inflammation,andfeverNSAIDsHemostasisProtectionofgastricmucosaHemostasisNSAIDsLimitationsAcidicenvironmentBicarbonatelayerIonicgradientGastricacidNSAIDsPepsinSurfaceepithelialcellsMucuslayerNeutralenvironmentMucosalbloodsupplyAlkalineenvironmentProstaglandinproductionBicarbonateproductionMucusproductionNSAIDs胃酸在NSAIDs-GI损伤中起重要作用动物实验证明NSAIDs-GI损伤是pH依赖的Elliottetal,1996.intraduodenalindomethacin,40mg/kgintraduodenalsalineTotalhaemorrhagicmucosalarea(%)GastricluminalpH02.04.05.57.012345Wallaceetal，2000.110Gastricbloodflow(%ofbasal)indomethacin,10mg/kgvehicle*p0.05**p0.0110203040506090705000Timeafteradministration(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-内皮细胞粘附增加毛细血管阻塞中心粒细胞释放蛋白酶和氧自由基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Wallaceetal,1997.PGTNFNEWIDEA1动物模型显示：选择性NSAIDs促进白细胞-内皮细胞间粘附Wallaceetal,2000.01530456002015105******Adherentleucocytes/100µmTime(minutes)*p0.05versusvehiclecelecoxib,1.0µmol/LSC-560,1.0µmol/Lcelecoxib,3.0µmol/Lindomethacin,7.0µmol/Lvehicle,1.0µmol/L升高cGMP水平inASAadministrationNEWIDEA2HerreriasJM,etal.DigDisSci,2003,48:986-991.Heatshockprotein27(HSP27)NEWIDEA3EbertMP,etal.JPathol,2005,207:177-184.SurvivinNEWIDEA4ChiouSK,etal.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&Skelly,2002;Laine,1996;Silversteinetal,2000.Bombardieretal2000†Perforation,obstruction,bleedingorsymptomaticpepticulcer.罗非昔布较萘普生上胃肠并发症发生率低naproxen,500mgtwicedailyrofecoxib,50m