对乙酰氨基酚

对乙酰氨基酚

对乙酰氨基酚（英文：paracetamol或acetaminophen，又称扑热息痛）是一种常用的退热和止痛药物，常用于发烧、头痛和其他轻微疼痛。它是许多感冒药和止痛药的主要成分。按标准计量服用对乙酰氨基酚是相当安全的，但是由于其疗效广泛，故意或偶然的过量服用也是常见的。对乙酰氨基酚与阿斯匹林和布洛芬等常见的止痛药不同，不含有抗炎成分，所以也就不是所谓的“非甾体抗炎药（NSAID）”。按常规计量服用对乙酰氨基酚不会刺激胃粘膜或引起肾脏或胎儿动脉导管血液疾病，而NSAID类药物可能引起此类症状与非甾体类抗炎药物相似，但是与鸦片类药物不同，对乙酰氨基酚不会使人精神愉快或是改变心情。对乙酰氨基酚和NSAID类药物不会有令人上瘾和产生依赖性的危险。对乙酰氨基酚的分子式非手性的，所以不会有旋光性。对乙酰氨基酚的两个英文名字都来自于他的化学名称“N-acetyl-para-aminophenol”（N-乙酰-对-氨基苯酚）和“para-acetyl-amino-phenol”（对乙酰氨基酚）。在某些文献中，对乙酰氨基酚被简记作“apap”。历史在古老的中世纪时期，仅有的退热药物是一种存在于柳树树皮中的物质（一类叫作水杨酸的物质，后来导致了阿司匹林的发展）和一种存在于金鸡纳树树皮里的物质。金鸡纳树皮也是用来制造抗疟疾药物奎宁的主要原料，奎宁本身也有退热的功效。直到19世纪中后期才发展出提炼分离水扬苷和水杨酸的技术。1880年代以来，随着金鸡纳树日益减少，人们开始寻找其替代品。1886年科学家发明了退热冰（乙酰苯胺），1887年又发明了非那西丁（乙酰对氨苯乙醚）。1873年，HarmonNorthropMorse首先通过对-硝基酚和冰醋酸的在锡催化下反应合成了对乙酰氨基酚，但是在二十年之内对乙酰氨基酚并没有用于医学用途。1893年，在某些服用了非那西丁的患者的尿液里发现了对乙酰氨基酚的存在，并浓缩成白色、稍有苦味的晶体。1899年对乙酰氨基酚被发现是退热冰的代谢产物，但是这些发现在当时并没有被重视。1946年美国止痛与镇静剂研究所（theInstitutefortheStudyofAnalgesicandSedativeDrugs）拨款给纽约市卫生局（NewYorkCityDepartmentofHealth）研究止痛剂的问题。伯纳德・布罗迪（BernardBrodie）和朱利叶斯・阿克塞尔罗德（JuliusAxelrod）被分配研究非阿司匹林类退热剂为何产生高铁血红蛋白症（一种非致命的血液疾病）这一副作用。1948年伯纳德和阿克塞尔罗德发现退热冰的作用归功于他的代谢产物对对乙酰氨基酚，因此他们提倡使用对乙酰氨基酚替代退热冰，因为对乙酰氨基酚类似没有退热冰的毒副作用。1955年，对乙酰氨基酚在美国境内上市销售，商品名泰诺（Tylenol）。1956年，500毫克一片的对乙酰氨基酚在英国境内上市销售，商品名必理通（Panadol）。1963年，对乙酰氨基酚列入英国药典，并因其较小的副作用和与其它药物的相互作用而流行开来。用量成年人每日推荐用量为每次500mg至1000mg，每日四次，每日最大用量4g，服用超过7.5g/日或150mg/kg体重可能导致肝中毒。在推荐剂量内，对乙酰氨基酚对于成人和幼儿都是安全的。但是因为对乙酰氨基酚用途广泛，它的效用也往往被低估。含对乙酰氨基酚的药品在许多非处方药中都有对乙酰氨基酚成分，种类超过200种，主要包括：泰诺、必理通、感冒清、白加黑、酚麻美敏胶囊、双扑伪麻片、复方对乙酰氨基酚片等。所以用量应计算所有服用的药品中的对乙酰氨基酚的用量。/*含对乙酰氨基酚的药品*/，内容扩充毒性ParacetamolhasanarrowtherapeuticindexCthetherapeuticdoseisclosetothetoxicdose.Additionally,paracetamoliscontainedinmanypreparations（bothover-the-counterandprescriptiononlymedications）.Thismeansthat,despitebeingoneofthesafestanalgesicsavailableatrecommendeddoses,thereisalargepotentialforoverdoseandtoxicity.[1]Withouttimelytreatment,paracetamoloverdosecanleadtoliverfailureanddeathwithindays.Becauseofthewideover-the-counteravailabilityofthedrug,itissometimesusedinsuicideattemptsbythoseunawareoftheprolongedtimecourseandhighmorbidityassociatedwithparacetamol-inducedtoxicity.IntheUK,salesofover-the-counterParacetamolinpharmaciesarerestrictedtopacksof32tabletspercustomerperoccasion（only16tabletsinnon-pharmacystores）.InIreland,thelimitsare24and12tabletsrespectively.毒性机理在代谢阶段，大部分扑热息痛在第二阶段代谢通过结合硫酸盐和葡萄糖苷酸失去活性,一小部分被细胞色素氧化酶P450氧化。细胞色素P4502E1（CYP2E1）把扑热息痛转化为高活性的中间代谢物,N－乙酰醌亚胺（NAPQI）。一般情况下，NAPQI通过结合谷胱甘肽被解毒。但是摄入太多扑热息痛后，硫酸盐和葡萄糖苷酸被饱和，更多的扑热息痛酒杯分流到细胞色素P450系统产生NAPQI。这样，干细胞提供的谷胱甘肽耗尽后，剩余NAPQI与细胞膜分子反应，造成大量肝细胞损伤和死亡,临床上导致急性肝脏坏死。在动物试验中发现，在发生肝脏中毒之前70%的肝脏谷胱甘肽已被耗尽。中毒剂量扑热息痛的中毒剂量存在很大变数。成年人中，单次剂量超过10g或者150mg/kg就会有高风险导致中毒[2]24小时内多次服用小计量累积到中毒剂量也会导致中毒,长期日摄入量低于4g/日也可导致中毒,日摄入剂量稍低于6g/日可导致死亡。儿童单次摄入超过200mg/kg可能导致中毒。这一水平高于成人主要由于儿童较成人有相对大的肾脏和肝脏，能够容纳更多的超剂量扑热息痛。[3]儿童中急性扑热息痛过量比慢性长期过量服用中毒有更高的致病和死亡可能。由于扑热息痛经常包含在其它复方制剂药品中，因此计算所有药品中扑热息痛剂量总和是否超标非常重要。另外在购买药物是要注意,扑热息痛可能会包含在不同阵痛药和抗感冒/流感药配方中，来加强阵痛效果。为了防止过量，应当仔细阅读药品说明书，查找配方是否含有扑热息痛，并咨询药剂师防止过量服用。导致中毒的风险因素长期过量摄入酒精（例如酗酒）可提高CYP2E1,这会潜在的提高扑热息痛的毒性。[4]由于这个原因，其它阵痛药如阿斯匹林或布洛芬有时被推荐为替代药品。禁食也是一个风险因素,可能因为禁食会导致肝脏谷胱甘肽储量严重不足。有报道指出，伴随使用CYP2E1诱导剂异烟肼（一种晶状抗菌化合物，用于治疗结核病）可提高肝中毒风险,尽管CYP2E1诱导是否造成肝脏中毒在这种情况的关系并不清楚。[5][6]同时使用含有诱导CYP酶的药物如抗癫痫药（包括立痛定,苯妥英,巴比妥酸盐等）也有报道导致中毒风险。代谢过程Individualswhohaveoverdosedonparacetamolgenerallyhavenospecificsymptomsforthefirst24hours.Althoughnausea,vomiting,anddiaphoresismayoccurinitially,thesesymptomsgenerallyresolveafterseveralhours.Afterresolutionofthesesymptoms,individualstendtofeelbetter,andmaybelievethattheworstisover.Ifatoxicdosewasabsorbed,afterthisbrieffeelingofrelativewellness,theindividualdevelopsoverthepaticfailure.Inmassiveoverdoses,comaandmetabolicacidosismayoccurpriortohepaticfailure.Damagegenerallyoccursinhepatocytesastheymetabolizetheparacetamol.Rarely,acuterenalfailurealsomayoccur.ThisisusuallycausedbyeitherhepatorenalsyndromeorMultipleorgandysfunctionsyndrome.Acuterenalfailuremayalsobetheprimaryclinicalmanifestationoftoxicity.Inthesecases,ithasbeensuggestedthatthetoxicmetaboliteisproducedmoreinthekidneysthanintheliver.[7]Theprognosisofparacetamolvariesdependingonthedoseandtheappropriatetreatment.Insomecases,massivehepaticnecrosisleadstofulminanthepaticfailurewithcomplicationsofbleeding,hypoglycemia,renalfailure,hepaticencephalopathy,cerebraledema,sepsis,multipleorganfailure,anddeathwithindays.Inmanycases,thehepaticnecrosismayrunitscourse,hepaticfunctionmayreturn,andthepatientmaysurvivewithliverfunctionreturningtonormalinafewweeks.诊断Evidenceoflivertoxicitymaydevelopin1to4days,althoughinseverecasesitmaybeevidentin12hours.Rightupperquadranttendernessmaybepresent.LaboratorystudiesmayshowevidenceofmassivehepaticnecrosiswithelevatedAST,ALT,bilirubin,andprolongedcoagulationtimes（particularly,elevatedprothrombintime）.Afterparacetamoloverdose,whenASTandALTexceed1000IU/L,paracetamol-inducedhepatotoxicitycanbediagnosed.However,theASTandALTlevelscanexceed10,000IU/L.GenerallytheASTissomewhathigherthantheALTinparacetamol-inducedhepatotoxicity.Adrugnomogramwasdevelopedin1975whichestimatedtheriskoftoxicitybasedontheserumconcentrationofparacetamolatagivennumberofhoursafteringestion.[8]Todeterminetheriskofpotentialhepatotoxicity,theparacetamollevelistracedalongthestandardnomogram.Aparacetamolleveldrawninthefirstfourhoursafteringestionmayunderestimatetheamountinthesystembecauseparacetamolmaystillbeintheprocessofbeingabsorbedfromthegastrointestinaltract.Delayoftheinitialdrawfortheparacetamolleveltoaccountforthisisnotrecommendedsincethehistoryinthesecasesisoftenpoorandatoxiclevelatanytimeisareasontogivetheantidote.TreatmentInitialmeasuresTheinitialtreatmentforuncomplicatedparacetamoloverdose,similartoanyotheroverdose,isgastrointestinaldecontamination.Inaddition,theantidote,acetylcysteineplaysanimportantrole.Paracetamolabsorptionfromthegastrointestinaltractiscompletewithin2hoursundernormalcircumstancessodecontaminationismosthelpfulifperformedwithinthistimeframe,absorptionmaybesomewhatslowedwhenitisingestedwithfood.Thereisconsiderableroomforphysicianjudgementregardinggastrointestinaldecontamination,activatedcarbonadministrationisthemostcommonlyusedprocedure,however,gastriclavagemayalsobeconsiderediftheamountingestedispotentiallylifethreateningandtheprocedurecanbeperformedwithin60minutesofingestion.[9]Syrupofipecachasnoroleinparacetamoloverdosebecausethevomitingitinducesdelaystheeffectiveadministrationofactivatedcarbonandoralacetylcysteine.Activatedcarbonadsorbsparacetamol,reducingitsgastrointestinalabsorption.Administeringactivatedcarbonalsoposeslessriskofaspirationthangastriclavage.Previouslytherewasreluctancetogiveactivatedcarboninparacetamoloverdose,becauseofconcernthatitmayalsoabsorbacetylcysteine.Studieshaveshownthatnomorethan39%ofanoralacetylcysteineisabsorbedwhentheyareadministeredtogether.[10]Otherstudieshaveshownthatactivatedcarbonseemstobebeneficialtotheclinicaloutcome.Itappearsthemostbenefitfromactivatedcarbonisgainedifitisgivenwith2hoursofingestion.[11]However,administeringactivatedcarbonlaterthanthiscanbeconsideredinpatientswhomayhavedelayedgastricemptyingduetoco-ingesteddrugsorfollowingingestionofsustainedordelayedreleaseparacetamolpreparations.Activatedcarbonshouldalsobeadministeredifco-ingesteddrugswarrantdecontamination.Thereareconflictingrecommendations[10][12]regardingwhethertochangethedosingoforalacetylcysteineaftertheadministrationofactivatedcarbon,andevenwhetherthedosingofacetylcysteineneedstobealteredatall.乙酰半胱氨酸Acetylcysteineworkstoreduceparacetamoltoxicitybysupplyingsulfhydrylgroups（mainlyintheformofglutathione,ofwhichitisaprecursor）toreactwiththetoxicNAPQImetabolitesothatitdoesnotdamagecellsandcanbesafelyexcreted.Ifthepatientpresentslessthan8hoursafterparacetamoloverdose,thenacetylcysteinesignificantlyreducestheriskofserioushepatotoxicity.IfNACisstartedmorethan8hoursafteringestion,thereisasharpdeclineinitseffectivenessbecausethecascadeoftoxiceventsintheliverhasalreadybegunandtheriskofacutehepaticnecrosisanddeathincreasesdramatically.Althoughacetylcysteineismosteffectiveifgivenearly,itstillhasbeneficialeffectsifgivenaslateas48hoursafteringestion.[13]Inclinicalpractice,ifthepatientpresentsmorethan8hoursaftertheparacetamoloverdose,thenactivatedcharcoalisprobablynotuseful,andacetylcysteineisstartedimmediately.Inearlierpresentationsthedoctorcangivecharcoalassoonasthepatientarrives,startgivingacetylcysteine,andwaitfortheparacetamollevelfromthelaboratory.InUnitedStatespractice,intravenous（IV）andoraladministrationareconsideredtobeequallyeffective.However,IVistheonlyrecommendedrouteinAustralasianandBritishpractice.Oralacetylcysteineisgivenasa140mg/kgloadingdosefollowedby70mg/kgevery4hoursfor17moredoses.Oralacetylcysteinemaybepoorlytoleratedduetoitsunpleasanttaste,odor,anditstendencytocausenauseaandvomiting.Itcanbedilutedtoa5%solution,fromitsmarketed10%or20%solutions,toimprovepalatability.Whereoralacetylcysteineisrequired,theinhalationformulationofacetylcysteine（Mucomyst）isoftengivenorally.TherespiratoryformulationcanalsobedilutedandfiltersterilizedbyahospitalpharmacistforIVuse,howeverthisisanuncommonpractice.Ifrepeatdosesofcharcoalareindicatedbecauseofanotheringesteddrug,thensubsequentdosesofcarbonandacetylcysteineshouldbestaggeredeverytwohours.Intravenousacetylcysteine（Parvolex/Acetadote）isusedasacontinuousintravenousinfusionover20hours（totaldose300mg/kg）.Recommendedadministrationinvolvesinfusionofa150mg/kgloadingdoseover15minutes,followedby50mg/kginfusionover4hours;thelast100mg/kgareinfusedovertheremaining16hoursoftheprotocol.Intravenousacetylcysteinehastheadvantageofshorteninghospitalstay,increasingbothdoctorandpatientconvenience,anditallowsadministrationofactivatedcarbontoreduceabsorptionofboththeparacetamolandanyco-ingesteddrugswithoutconcernsaboutinterferencewithoralacetylcystine.[14]Baselinelaboratorystudiesincludebilirubin,AST,ALT,andprothrombintime（withINR）.Studiesarerepeatedatleastdaily.Onceithasbeendeterminedthatapotentiallytoxicoverdosehasoccurred,acetylcysteineiscontinuedfortheentireregimen,evenaftertheparacetamollevelbecomesundetectableintheblood.Ifhepaticfailuredevelops,acetylcysteineshouldbecontinuedbeyondthestandarddosesuntilhepaticfunctionimprovesoruntilthepatienthasalivertransplant.药量预测Themortalityratefromparacetamoloverdoseincreases2daysaftertheingestion,reachesamaximumonday4,andthengraduallydecreases.Patientswithapoorprognosisareusuallyidentifiedforlikelylivertransplantation.Acidemiaisthemostimportantsingleindicatorofprobablemortalityandtheneedfortransplantation.Amortalityrateof95%withouttransplantwasreportedinpatientswhohadadocumentedpHof<7.30.Otherindicatorsofpoorprognosisincluderenalinsufficiency,grade3orworsehepaticencephalopathy,amarkedlyelevatedprothrombintime,orariseinprothrombintimefromday3today4.OnestudyhasshownthatafactorVlevellessthan10%ofnormalindicatedapoorprognosis（91%mortality）whilearatiooffactorVIIItofactorVoflessthan30indicatedagoodprognosis（100%survival）.对动物的危害扑热息痛对猫和狗有着较强的毒性,因此任何情况下都不要给药。猫缺少必要的酶来代谢扑热息痛，使药物浓度下降到安全水平，因此对人类来说微量的扑热息痛就可导致猫死亡。[15]任何情况下，如发现猫可能误食，应立即带到兽医处解毒。[16]在没有家用治疗的情况下，吞食大量扑热息痛后狗比猫有更高的成活率，而肝脏永久性损伤程度则取决于及时就医的拖延时长。跟人类情况一样,乙酰半胱氨酸（Mucomyst）和甲氰咪胺：（Tagamet）可以阻止进一步的肝脏损伤，但没有一种可以对损伤进行修复。[2]参考文献↑SheenC,DillonJ,BatemanD,SimpsonK,MacdonaldT（2002）."Paracetamoltoxicity:epidemiology,preventionandcoststothehealth-caresystem.".QJM95（9）:609-19.PMID12205339.↑DartRC,ErdmanAR,OlsonKR,ChristiansonG,ManoguerraAS,ChykaPA,CaravatiEM,WaxPM,KeyesDC,WoolfAD,ScharmanEJ,BoozeLL,TroutmanWG;美国毒品控制中心协会.（2006年）."Acetaminophenpoisoning:anevidence-basedconsensusguidelineforout-of-hospitalmanagement.".ClinToxicol（Phila）第44卷（1期）:1-18页.PMID16496488.↑TenenbeinM（2004年）."Acetaminophen:the150mg/kgmyth.".JToxicolClinToxicol第42卷（2期）:145-8页.PMID15214618.↑ZimmermanHJ,MaddreyWC（1995年）."Acetaminophen（paracetamol）hepatotoxicitywithregularintakeofalcohol:analysisofinstancesoftherapeuticmisadventure".Hepatology第22卷（3期）:767-73页.PMID7657281.↑CrippinJS（1993年）."Acetaminophenhepatotoxicity:potentiationbyisoniazid".AmJGastroenterol第88卷（4期）:590-2页.PMID8470644.↑NolanCM,SandblomRE,ThummelKE,SlatteryJT,NelsonSD（1994年）."Hepatotoxicityassociatedwithacetaminophenusageinpatientsreceivingmultipledrugtherapyfortuberculosis".Chest105卷（2期）:408-11页.PMID7508362.↑BoutisK,ShannonM（2001）."Nephrotoxicityafteracutesevereacetaminophenpoisoninginadolescents".JToxicolClinToxicol39（5）:441-5.PMID11545233.↑RumackB,MatthewH（1975）."Acetaminophenpoisoningandtoxicity".Pediatrics55（6）:871-6.PMID1134886.↑ValeJA,KuligK;AmericanAcademyofClinicalToxicology;EuropeanAssociationofPoisonsCentresandClinicalToxicologists.（2004）."Positionpaper:gastriclavage".JToxicolClinToxicol42（7）:933-43.PMID15641639.^10.010.1EkinsB,FordD,ThompsonM,BridgesR,RollinsD,JenkinsR（1987）."TheeffectofactivatedcharcoalonN-acetylcysteineabsorptioninnormalsubjects".AmJEmergMed5（6）:483-7.PMID3663288.↑BuckleyNA,WhyteIM,O’ConnellDL,DawsonAH.（1999）."ActivatedcharcoalreducestheneedforN-acetylcysteinetreatmentafteracetaminophen（paracetamol）overdose".JToxicolClinToxicol37（6）:753-7.PMID10584587.↑SpillerH,KrenzelokE,GrandeG,SafirE,DiamondJ（1994）."AprospectiveevaluationoftheeffectofactivatedcharcoalbeforeoralN-acetylcysteineinacetaminophenoverdose".AnnEmergMed23（3）:519-23.PMID8135427.↑KeaysR,HarrisonP,WendonJ,ForbesA,GoveC,AlexanderG,WilliamsR（1991）."Intravenousacetylcysteineinparacetamolinducedfulminanthepaticfailure:aprospectivecontrolledtrial".BMJ303（6809）:1026-9.PMID1954453.↑BuckleyN,WhyteI,O’ConnellD,DawsonA（1999）."OralorintravenousN-acetylcysteine:whichisthetreatmentofchoiceforacetaminophen（paracetamol）poisoning?".JToxicolClinToxicol37（6）:759-67.PMID10584588.↑AllenAL（2003年）."Thediagnosisofacetaminophentoxicosisinacat".CanVetJ第44卷（6期）:509-10页.PMID12839249.↑VillarD,BuckWB,GonzalezJM（1998年）."Ibuprofen,aspirinandacetaminophentoxicosisandtreatmentindogsandcats".VetHumToxicol第40卷（3期）:156-62页.PMID9610496.