非甾體類消炎藥相關(guān)性胃十二指腸損害的預(yù)防與治療

非甾體類消炎藥相關(guān)性胃十二指腸損害的預(yù)防與治療消化性潰瘍出血血小板功能不良急性腎功能衰竭（易感者）水鈉潴留致水腫藥物性腎?。ㄖ雇此幭嚓P(guān)性）過期妊娠和分娩抑制過敏NSAIDs

的主要副作用NSAIDs

所致胃腸道損害deaths17,000107,000hospitalizations

1-1.5％GIulcercomplicationinpersonstaketraditionalNSAIDsgreatestclinicalimpact

TheanalysesfromUSALaineL.Gastroenterology,2001,120:594-606.Gralnek,etal.2000;vanderMolen,etal.1997;Ware&Sherbourne,1992.USpopulation

n=2474asthma

n=110diabetesmellitus

n=541NSAIDs(NASA1)

n=500NSAIDs(SPACE1)

n=579020406080100MeanSF-36scorePhysical

functioningRolephysicalBodilypainGeneralhealthMentalhealthRoleemotionalVitalitySocial

functioningNSAIDs所致GI副作用可降低患者HQLNSAIDs所致胃腸損害影響工作能力和日?；顒?3%reducedproductivityatwork(n=27)26%reduceddailyactivities(n=61).半數(shù)以上的患者不能耐受而更換NSAIDs種類44%的患者采用最小的NSAIDs劑量以降低GI副作用（雖然這種劑量不足以完全緩解關(guān)節(jié)炎疼痛）Knott，2000；Steinfeldetal，2002；Wahlqvistetal，2003.

NSAIDs所致GI副作用導(dǎo)致患者中止治療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CountryNaproxenDiclofenacPiroxicamUK1.40–1.441.42–1.471.84–1.93France1.361.651.67Canada1.311.22–1.671.95Country

AllNSAIDsCanada1.66(1.61–7.49)USA1.45USA2.99(non-aspirin)Bidaut-Russell&Gabriel，2001.NSAIDs所致GI副作用可明顯

增加治療費用Wolfe,etal.19991997USmortalitydataforsevenselecteddisorders.NSAIDs相關(guān)死亡率高NSAIDtoxicityLeukaemiaAIDSMultiplemyelomaAsthmaCervicalcancerHodgkin’sdisease0500010,00015,00020,00025,000Numberofdeaths?‘silentepidemic’NSAID胃腸道損害總的GI損害便秘或腹瀉胃痛消化不良或燒心腹脹惡心或嘔吐胃腸出血或潰瘍其它ThomasJ,etal.AmJGastroenterol,2002,97:2215-2219.OTCNSAID（n＝535）NoOTCNSAID（n＝1068）過去30天內(nèi)GI損害的發(fā)生率（％）胃十二指腸損害的臨床表現(xiàn)GI損害:發(fā)生率＞50％消化不良(內(nèi)鏡陰性):15-25%,1.5-2fold內(nèi)鏡下潰瘍(無癥狀):15-25％有癥狀潰瘍:GU15-31%,DU5-8%潰瘍并發(fā)癥:每年1-2%,4-fold

無癥狀內(nèi)鏡表現(xiàn)RefluxesophagitisLAGradesA–D.AvidanGT,etal.2001.ABCDNSAIDs相關(guān)RENSAIDs誘導(dǎo)的急性胃炎急性粘膜糜爛和粘膜下出血服用1次小劑量NSAID也可－15-30min上皮下出血－24h內(nèi)糜爛不伴有炎癥浸潤表現(xiàn)病變程度與消化不良不平行NSAIDs增加患者上腹不適癥狀

（燒心，反酸，上腹痛等）Harveyetal，2003.n=4902Prevalence(%)heartburnacidrefluxepigastricpain01020304050NoneAspirinNSAIDs

excluding

aspirinAspirin

+other

NSAIDsNSAIDs(包括COX-2選擇性制劑)

六個月累計消化不良發(fā)生率約25％?Acidreflux,dyspepsia,epigastricdiscomfort,heartburn,nauseaorvomiting.Langmanetal,1999.non-selectiveNSAIDsn=1564CumulativeincidenceofupperGIsymptoms?over6months(%)0102030rofecoxibn=3357*p<0.05*NSAIDs

相關(guān)潰瘍癥狀性潰瘍每年發(fā)生率1-2%服藥1周內(nèi),25-30%服藥3個月內(nèi),15-30%;其中GU,10-20％;DU,4-10％服藥6個月內(nèi),45%并發(fā)癥危險性增加4倍Laineetal.Gastroenterology.2004,127:395-402.Ofmanetal.ArthritisRheum.2003,49:508-518.NSAID-inducedGUNSAID-inducedDU用藥時間越長NSAIDs潰瘍發(fā)生率越高Gaithersburg,etal.FDAArthritisAdvisoryCommittee,2001

Cheatum,etal.1999.消化性潰瘍的發(fā)生率與NSAIDs種類相關(guān)Patientswithpepticulcers(%)50010304020非諾洛芬雙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相關(guān)胃腸并發(fā)癥Bleeding,Obstruction,andPerforationCapsuleendoscopic

appearanceofsmallbowelWeiletal2000消化性潰瘍出血相關(guān)危險因素Oddsratio012348CurrentsmokingDiabetesHeartfailureDyspepsiainpastyearPreviouspepticulcerWarfarinuseOralcorticosteroiduseNSAIDuse567Henryetal1996胃腸出血和穿孔發(fā)生與NSAIDs種類相關(guān)EstimatedrelativeriskofhaemorrhageorperforationAzapropazone50.00.5PiroxicamKetoprofenIndomethacinNaproxenAspirinSulindacDiflunisalDiclofenacIbuprofen胃腸出血和穿孔發(fā)生與NSAIDs劑量相關(guān)Hawkey,etal.Gut,2003,52:600-608.

與患者相關(guān)的危險因素:高齡患者>65歲(>75歲者為高危)有消化性潰瘍或上消化道并發(fā)癥病史者Hp.感染吸煙、飲酒消化性不良病史

性別（男性略多于女性）

藥物相關(guān)危險因素:

所用NSAID副作用較明顯

所用NSAID

劑量較高或同時應(yīng)用兩種NSAIDs

NSAIDS與抗凝劑同服NSAIDS與皮質(zhì)類固醇同服Seager&Hawkey2001

NSAID-GI損害相關(guān)危險因素Hawkey&Skelly2002Morethanone

riskfactoribuprofen,800mgthreetimesdaily,ordiclofenac,75mgtwicedailycelecoxib,400mgtwicedailyPatientswithulcercomplications(%)201Noriskfactorn=8059胃腸并發(fā)癥發(fā)生與共存的危險因素相關(guān)NSAIDadministration

CarciaRodriguez,etal.ArchInternMed,1998,158:33-39.PGCryerB.GastroenterolClinNorthAm,2001,30:877-894.發(fā)病機制

NSAID-inducedGIinjury粘液碳酸氫鹽屏障上皮細(xì)胞層粘膜血流供應(yīng)保護性因素?fù)p傷性因素

COX途徑的主要病理生理作用NSAIDProstaglandins,prostacyclinandthromboxaneNSAIDs

的抗炎作用機制COX-2

“Inducible”

ProstaglandinsArachidonicAcidCO2HCOX-1

“Constitutive”ProstaglandinsMediatepain,

inflammation,andfeverNSAIDsHemostasisProtectionofgastricmucosaHemostasisNSAIDsLimitationsAcidic

environmentBicarbonatelayerIonicgradientGastric

acidNSAIDsPepsinSurface

epithelialcellsMucus

layerNeutral

environmentMucosal

bloodsupplyAlkaline

environmentProstaglandin

productionBicarbonate

productionMucus

productionNSAIDs胃酸在NSAIDs-GI損傷中起重要作用動物實驗證明NSAIDs-GI損傷是pH依賴的Elliottetal,1996.intraduodenal

indomethacin,40mg/kgintraduodenalsalineTotalhaemorrhagicmucosalarea

(%)GastricluminalpH02.04.05.57.012345Wallaceetal，2000.110Gastricbloodflow(%ofbasal)indomethacin,10mg/kgvehicle*p<0.05**p<0.0110203040506090705000Timeafteradministration(minutes)*********NSAIDs-GI損傷中粘膜血流顯著降低增加白細(xì)胞-內(nèi)皮細(xì)胞間粘附NSAIDs中性粒細(xì)胞-內(nèi)皮細(xì)胞粘附增加毛細(xì)血管阻塞中心粒細(xì)胞釋放蛋白酶和氧自由基缺血和乏氧細(xì)胞損傷內(nèi)皮細(xì)胞和上皮細(xì)胞損傷粘膜潰瘍形成Wallaceetal,1997.PGTNFNEWIDEA1動物模型顯示：

選擇性NSAIDs促進白細(xì)胞-內(nèi)皮細(xì)胞間粘附Wallaceetal,2000.01530456002015105******Adherentleucocytes/100μmTime(minutes)*p<0.05versusvehiclecelecoxib,1.0μmol/LSC-560,1.0μmol/Lcelecoxib,3.0μmol/Lindomethacin,7.0μmol/Lvehicle,1.0μmol/L升高cGMP水平inASAadministration

NEWIDEA2HerreriasJM,etal.DigDisSci,2003,48:986-991.

Heatshockprotein27(HSP27)NEWIDEA3EbertMP,etal.JPathol,2005,207:177-184.

SurvivinNEWIDEA4ChiouSK,etal.Gastroenterology,2005,128:63-73.

非選擇性NSAIDs

—大多數(shù)患者每次服用可致胃粘膜糜爛

—約15-30％可致內(nèi)鏡可見的潰瘍發(fā)生（通常是無癥狀的）COX-2選擇性NSAIDs消化性潰瘍發(fā)生率

—較非選擇性制劑降低

—但是存在危險因素或應(yīng)用低劑量阿司匹林者潰瘍發(fā)生的危險性仍高Hawkey&Skelly,2002;Laine,1996;Silversteinetal,2000.Bombardieretal2000?Perforation,obstruction,bleeding

orsymptomaticpepticulcer.羅非昔布較萘普生上胃腸并發(fā)癥發(fā)生率低naproxen,500mgtwicedailyrofecoxib,50mg

oncedailyDurationoffollow-up(months)CumulativeincidenceofaconfirmedupperGIevent?(%)534201042108612n=807600.20.40.60.81羅非昔布萘普生累積發(fā)生率*n=4047n=4029*表達(dá)方法為100位患者1年內(nèi)的發(fā)生率。VIGOR=Vioxx胃腸道結(jié)果研究。P=0.03；相對危險度0.46（95%CI,0.22-0.93）。Laineetal.Gastroenterology.2003;124:288-2920.羅非昔布較少發(fā)生嚴(yán)重的下消化道事件VIGOR研究的亞組分析Simonetal,1999.?Dyspepsia,diarrhoea,

abdominalpain,

Nausea

andflatulence.COX-2選擇性制劑與非選擇性NSAIDs

非潰瘍性胃腸道副作用的發(fā)生率相當(dāng)(%)

PatientswithupperGIsymptoms?Alldosestakentwicedaily05101520253035Celecoxib,100mgn=240Celecoxib,200mgn=235Celecoxib,400mgn=217Naproxen,500mgn=225Watson,etal.ArchInternMed,2000,160:2998-3003.傳統(tǒng)NSAIDs與COX-2選擇性制劑

十二個月累計消化不良發(fā)生率無明顯差異Silversteinetal2000年發(fā)生率(6-monthdata)(%)上胃腸潰瘍并發(fā)癥有癥狀的消化性潰瘍和潰瘍并發(fā)癥Celecoxib+aspirin2.014.7NSAID+aspirin2.126.0Celecoxibalone0.44p<0.051.40p<0.05NSAIDalone1.272.91聯(lián)用阿司匹林增加塞來昔布的胃腸并發(fā)癥治療方案增加普通人群胃腸道事件的危險*?95％可信區(qū)間低劑量阿司匹林2.62.2-2.9低劑量阿司匹林＋傳統(tǒng)NSAID5.64.4-7.0*丹麥國家隊列研究?N＝27694；所有患者使用阿司匹林（100-150mg/d）Serensenetal.AmJGastroenterol.2000;95:2218-2224.阿司匹林+NSAID:一種常用的危險的聯(lián)合用藥

placebo

n=410aspirin

n=406rofecoxib+aspirin

n=399ibuprofen

n=400Cumulativeincidenceofulcers(%)***p<0.001versus

placebo+aspirin024681012141618******阿司匹林+COX-2選擇性NSAID

與傳統(tǒng)NSAID單用胃腸并發(fā)癥發(fā)生率相當(dāng)Laineetal.Gastroenterology.2004;127:395-40200.511.522.5未使用阿司匹林的人群使用阿司匹林的人群年發(fā)生率*（％）依托度酸萘普生P<0.05P=0.97(NS)*上消化道潰瘍并發(fā)癥.Weidemanetal.Gastroenterology.2004;127:1322-1328.聯(lián)用阿司匹林后選擇性與非選擇性NSAIDs

潰瘍發(fā)生率均明顯增加NSAID-GI損害的治療可以停用NSAIDs－－按一般潰瘍予常規(guī)治療－抑酸劑如H2RA、PPI－PG類似物－米索前列醇等病情需要仍需繼續(xù)服用NSAIDs：－常規(guī)劑量H2RA每天分兩次服用，療程適當(dāng)延長－PPI常規(guī)劑量或倍量（每天分2次服用）－米索前列醇無明顯優(yōu)勢且腹痛、腹瀉副反應(yīng)常見

檢測Hp－－感染者根除Hp治愈后的潰瘍，如不能停用NSAIDs－長期常規(guī)抑酸劑維持治療PPIs預(yù)防NSAIDs潰瘍作用明顯優(yōu)于H2RAYeomansetal1998gastriculcerduodenalulcerOmeprazole,20mgoncedailyRanitidine,150mgtwicedaily403020100(%)

Patientsdevelopinganulcer14.81.6*05101520安慰劑達(dá)克普隆每天30mg1年內(nèi)潰瘍復(fù)發(fā)并發(fā)癥率（%）(n=61)(n=62)Hp根治性治療后重新使用阿司匹林；隨機接受PPI/安慰劑。*P=0.008Laietal.NEnglJMed.2002;346:2033-2038.PPI可預(yù)防低劑量阿司匹林引起的復(fù)發(fā)性潰瘍PPI對奈普生引起的胃粘液分泌量下降

具有明顯的抑制作用JaworskiTetal.DigDisSci2005;50(2):357-365*P<0.001*P<0.001胃粘液分泌百分比PPI對奈普生引起的胃粘蛋白分泌量下降

具有明顯的抑制作用JaworskiTetal.DigDisSci2005;50(2):357-365*P<0.01*P<0.05胃粘蛋白分泌百分比年齡≥60歲有或者沒有潰瘍史的患者6個月后的潰瘍發(fā)生率。與安慰劑相比P<0.0001。Scheimanetal.Gastroenterology.2004;126(suppl2):A-82.高?；颊逳SAIDs潰瘍的預(yù)防n=452n=459n=467**175.24.6024681012141618出現(xiàn)潰瘍的患者數(shù)（％）安慰劑耐信20mg/d耐信40mg/dPPIs,H2RA和PG類似物用于NSAIDs相關(guān)燒心癥狀Hawkeyetal1998;Yeomansetal1998;Wilsonetal200107142128Patientswithheartburn(%)6040200misoprostol,200μgqidomeprazole,20mgqd604020007142128Durationoftreatment(days)Patientswithheartburn(%)ranitidine,150mgbidomeprazole,20mgqdDurationoftreatment(days)PPI可預(yù)防反復(fù)發(fā)生的NSAIDs潰瘍出血18.614.84.41.602468101214161820ControlControlPPIPPINonaspirinNSAIDsAspirinChanetal.NEJM2001,Laietal.NEJM2002%Hp感染的處理Hp與NSAIDs的相互作用迄今尚有爭論目前推薦:對于有高危因素(尤潰瘍病史)者常規(guī)檢測Hp，如有Hp感染宜予根除治療Hp根除后仍需常規(guī)藥物預(yù)防NSAIDs潰瘍目前尚存在爭議對使用NSAIDs而無危險因素者不推薦Hp的常規(guī)檢測Huangetal2002Hp感染與NSAIDs在潰瘍發(fā)生上具有協(xié)同作用(%)PatientswithpepticulcerNSAIDuserscontrols100804020060H.pylori-

positive

n=180H.pylori-

negative

n=205H.pylori-

positive

n=127H.pylori-

negative

n=149Chanetal2002(%)

6-monthprobabilityofulcer010203040AnyulcerComplicated

ulcers****eradicationplacebo**p<0.01

清除Hp與對預(yù)防NSAIDs潰瘍發(fā)生有益Labenzetal2002

*p<0.05

**p<0.01Patientswithpepticulcer(%)tripletherapy

+placebo

n=161tripletherapy

+PPI

n=173PPIs

n=155placebo

n***PPI治療較清除Hp對預(yù)防NSAIDs潰瘍同樣有效Ulcerpreventioninlong-termNSAIDusersGraham,etal.ArchInternMed,2002,162:169-175.

米索前列醇(Misoprostol)

10年回顧性研究：NSAIDs潰瘍平均治愈時間平均時間150100500100.075.097.590.6135.3所有患者PPIH2RB米索前列醇*所有患者平均治療時間設(shè)為100天79.0替普瑞酮A.Yanagawa,T.Endo.Inflammation&Regeneration,2001,21:149-153.對照組阿司匹林組阿司匹林＋替普瑞酮粘液量顯著減少粘液量接近正常水平abcIshihara.K.,etal.:

The71stJapaneseBiochemicalSociety(1998）黏膜保護劑改善NSAIDs引起的胃粘液量減少(鼠)預(yù)防NSAID潰瘍的推薦方案對于存在NSAID潰瘍發(fā)生高危因素的患者－選用胃腸損害副反應(yīng)較小的NSAIDs－且劑量盡量減少－并必須給予藥物預(yù)防預(yù)防藥物：－PPI常規(guī)劑量作為首選－米索前列醇0.2mgqid，也可0.4-0.6mg/d－H2RA倍量才可同時預(yù)防GU和DU對存在高危因素的患者(尤潰瘍病史)－常規(guī)檢測Hp－Hp陽性者予根除治療，之后常規(guī)藥物預(yù)防GwentPartnershipMedicines&TherapeuticsCommittee-June2005如何正確使用NSAIDs首先評估危險因素心血管危險因素（CV）胃腸道危險因素（GI）CVR-ⅠCVR-ⅡCVR-ⅢGIR-ⅠGIR-ⅡCVR-Ⅰ+GIR-Ⅰ不存在CVR或未應(yīng)用抗凝藥物(如低劑量aspirin)無/低GIR應(yīng)用傳統(tǒng)非選擇性NSAID出現(xiàn)胃腸癥狀加用對胃腸有保護作用的藥物

GwentPartnershipMedicines&TherapeuticsCommittee-June2005CVR-Ⅱ+GIR-Ⅰ存在CVR但未應(yīng)用抗凝藥物(如低劑量aspirin)無/低GIR

處理同前應(yīng)用傳統(tǒng)非選擇性NSAID出現(xiàn)胃