Paracetamol扑热息痛.docx

Paracetamol扑热息痛.docx

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Paracetamol扑热息痛

Paracetamol

Paracetamol

Systematic（IUPAC）name

N-（4-hydroxyphenyl）acetamide

Identifiers

CASnumber

103-90-2

ATCcode

N02BE01

PubChem

CID1983

DrugBank

DB00316

ChemSpider

1906

Chemicaldata

Formula

C8H9NO2 

Mol.mass

151.17g/mol

SMILES

eMolecules & PubChem

Physicaldata

Density

1.263 g/cm³

Melt.point

168 °C（334 °F）

Solubility inwater

12.78 [1] mg/mL（20 °C）

Pharmacokineticdata

Bioavailability

~100%

Metabolism

90to95% Hepatic

Half-life

1–4h

Excretion

Renal

Therapeuticconsiderations

Licencedata

USFDA:

link

Pregnancycat.

A（AU） B（US） safe

Legalstatus

Unscheduled （AU） GSL （UK） OTC（US）

Routes

Oral, rectal, intravenous

（whatisthis?

）  （verify）

Paracetamol （internationalnonproprietaryname）（pronounced /ˌpærəˈsiːtəmɒl,ˌpærəˈsɛtəmɒl/）or acetaminophen （/əˌsiːtəˈmɪnɵfɨn/  （

 listen））（USAN）isawidelyused over-the-counter analgesic （painreliever）and antipyretic （feverreducer）.

Itiscommonlyusedforthereliefof headaches,andotherminorachesandpains,andisamajoringredientinnumerous cold and flu remedies.Incombinationwith opioidanalgesics,paracetamolcanalsobeusedinthemanagementofmoreseverepainsuchaspostsurgicalpainandprovidingpalliativecareinadvancedcancerpatients.[2] Theonsetofanalgesiaisapproximately11minutesafter oraladministration ofparacetamol,[3] andits halflifeis1–4hours.

Whilegenerallysafeforuseatrecommendeddoses（1,000mgpersingledose andupto 4,000mgperday foradults,upto 2,000mgperday ifdrinkingalcohol）,[4] acute overdoses ofparacetamolcancausepotentiallyfatal liverdamage and,inrareindividuals,anormaldosecandothesame;theriskisheightenedby alcoholconsumption. Paracetamoltoxicity istheforemostcauseof acuteliverfailure inthe Westernworld,andaccountsformostdrugoverdosesintheUnitedStates,theUnitedKingdom,AustraliaandNewZealand.[5][6][7][8]

Paracetamolispartoftheclassofdrugsknownas"aniline analgesics";itistheonlysuchdrugstillinusetoday.[9] Itistheactivemetaboliteof phenacetin,oncepopularasananalgesicandantipyreticinitsownright,butunlikephenacetinanditscombinations,paracetamolisnotconsideredtobe carcinogenicattherapeuticdoses.[10] Thewords acetaminophen （usedintheUnitedStates,Canada,HongKong,Iran,[11] ColombiaandotherLatinAmericancountries）and paracetamol （usedelsewhere）bothcomefromchemicalnamesforthecompound:

 para-acetylaminophenoland para-acetylaminophenol.Insomecontexts,itissimplyabbreviatedas APAP,for N-acetyl-para-aminophenol.

Theclassificationofparacetamol,andtheterminologyusedtorefertoit,cancauseconfusion.Itisoftenclassifiedasanonsteroidalanti-inflammatorydrug（NSAID）,butparacetamolhasfewanti-inflammatoryeffectsinmanytissues.However, aspirin,paracetamolandotherNSAIDsallactbythesamemechanism（inhibitionof prostaglandin synthesis）andallshowvaryinglevelsofanalgesic,anti-inflammatory,antipyreticandantiplateletactions.[12]

Contents

 [hide]

∙1 History

∙2 Structureandreactivity

∙3 Synthesis

∙4 Reactions

∙5 Availableforms

∙6 Mechanismofaction

∙7 Metabolism

∙8 Indications

∙9 Efficacyandsideeffects

o9.1 Efficacy

o9.2 Adverseeffects

∙10 Toxicity

∙11 Effectsonanimals

∙12 References

∙13 Externallinks

[edit]History

Acetanilide wasthefirstanilinederivativeserendipitouslyfoundtopossessanalgesicaswellasantipyreticproperties,andwasquicklyintroducedintomedicalpracticeunderthenameof Antifebrin byA.CahnandP.Heppin1886.[13] Butitsunacceptabletoxiceffects,themostalarmingbeing cyanosis dueto methemoglobinemia,promptedthesearchforlesstoxicanilinederivatives.[9] HarmonNorthropMorse hadalreadysynthesizedparacetamolat JohnsHopkinsUniversity viathereductionof p-nitrophenol with tin inglacial aceticacid in1877,[14][15] butitwasnotuntil1887thatclinicalpharmacologist JosephvonMering triedparacetamolonpatients.[9] In1893,vonMeringpublishedapaperreportingontheclinicalresultsofparacetamolwith phenacetin,anotheranilinederivative.[16] VonMeringclaimedthat,unlikephenacetin,paracetamolhadaslighttendencytoproducemethemoglobinemia.Paracetamolwasthenquicklydiscardedinfavorofphenacetin.Thesalesofphenacetinestablished Bayer asaleadingpharmaceuticalcompany.[17] Overshadowedinpartbyaspirin,introducedintomedicineby HeinrichDreser in1899,phenacetinwaspopularformanydecades,particularlyinwidelyadvertisedover-the-counter"headachemixtures,"usuallycontainingphenacetin,an aminopyrine derivativeofaspirin,caffeine,andsometimesa barbiturate.[9]

VonMering'sclaimsremainedessentiallyunchallengedforhalfacentury,untiltwoteamsofresearchersfromtheUnitedStatesanalyzedthemetabolismofacetanilideandparacetamol.[17] In1947DavidLester andLeonGreenbergfoundstrongevidencethatparacetamolwasamajormetaboliteofacetanilideinhumanblood,andinasubsequentstudytheyreportedthatlargedosesofparacetamolgiventoalbinoratsdidnotcausemethemoglobinemia.[18] InthreepaperspublishedintheSeptember1948issueofthe JournalofPharmacologyandExperimentalTherapeutics, BernardBrodie, JuliusAxelrod andFrederickFlinnconfirmedusingmorespecificmethodsthatparacetamolwasthemajormetaboliteofacetanilideinhumanblood,andestablisheditwasjustasefficaciousananalgesicasitsprecursor.[19][20][21] Theyalsosuggestedthatmethemoglobinemiaisproducedinhumansmainlybyanothermetabolite, phenylhydroxylamine.AfollowuppaperbyBrodieandAxelrodin1949establishedthatphenacetinwasalsometabolizedtoparacetamol.[22] Thisledtoa"rediscovery"ofparacetamol.[9] Ithasbeensuggestedthatcontaminationofparacetamolwith 4-aminophenol,thesubstancefromwhichitwassynthesizedbyvonMering,maybethecauseforhisspuriousfindings.[17]

BernardBrodie and JuliusAxelrod（pictured） demonstratedthatacetanilideandphenacetinarebothmetabolizedtoparacetamol,whichisabettertoleratedanalgesic.

ParacetamolwasfirstmarketedintheUnitedStatesin1953by Sterling-WinthropCo.,whichpromoteditaspreferabletoaspirinsinceitwassafetotakeforchildrenandpeoplewithulcers.[17] ThebestknownbrandtodayforparacetamolintheUnitedStates, Tylenol,wasestablishedin1955when McNeilLaboratoriesstartedsellingparacetamolasapainandfeverrelieverforchildren,underthebrandnameTylenolChildren'sElixir—theword"tylenol"wasacontractionof para-acetylaminophenol.[23] In1956,500 mg tabletsofparacetamolwentonsaleintheUnitedKingdomunderthetradenamePanadol,producedbyFrederickStearns&Co,asubsidiaryof SterlingDrug Inc.Panadolwasoriginallyavailableonlybyprescription,forthereliefofpainandfever,andwasadvertisedasbeing"gentletothestomach,"sinceotheranalgesicagentsofthetimecontainedaspirin,aknownstomachirritant.[citationneeded] In1963,paracetamolwasaddedtothe BritishPharmacopoeia,andhasgainedpopularitysincethenasananalgesicagentwithfewside-effectsandlittleinteractionwithotherpharmaceuticalagents.[15] Concernsaboutparacetamol'ssafetydelayeditswidespreadacceptanceuntilthe1970s,butinthe1980sparacetamolsalesexceededthoseofaspirininmanycountries,includingtheUnitedKingdom.Thiswasaccompaniedbythecommercialdemiseofphenacetin,blamedasthecauseof analgesicnephropathy andhematologicaltoxicity.[9]

TheU.S. patent onparacetamolhaslongexpired,andgenericversionsofthedrugarewidelyavailableunderthe DrugPriceCompetitionandPatentTermRestorationAct of1984,althoughcertainTylenolpreparationswereprotecteduntil2007.U.S.patent6,126,967filedSeptember3,1998wasgrantedfor"Extendedreleaseacetaminophenparticles".[24]

[edit]Structureandreactivity

PSA oftheparacetamolmolecule

Paracetamolconsistsofa benzene ringcore, substituted byone hydroxyl groupandthe nitrogen atomofan amide groupinthe para （1,4） pattern.[25] Theamidegroupis acetamide （ethanamide）.Itisanextensively conjugatedsystem,asthe lonepair onthehydroxyloxygen,thebenzenepicloud,thenitrogenlonepair,the porbital onthe carbonyl carbon,andthelonepaironthecarbonyloxygenareallconjugated.Thepresenceoftwoactivatinggroupsalsomakethebenzeneringhighlyreactivetoward electrophilic aromaticsubstitution.Asthesubstituentsareortho,para-directingandparawithrespecttoeachother,allpositionsontheringaremoreorlessequallyactivated.Theconjugationalsogreatlyreducesthe basicity oftheoxygensandthenitrogen,whilemakingthehydroxylacidicthroughdelocalisationofchargedevelopedonthe phenoxide anion.

[edit]Synthesis

Comparedwithmanyotherdrugs,paracetamolismucheasiertosynthesize,becauseitlacks stereocenters.Asaresult,thereisnoneedtodesignastereo-selectivesynthesis.

Industrialpreparationofparacetamolusuallyproceedsfrom nitrobenzene.[26] Aone-stepreductiveacetamidationreactioncanbemediatedbythioacetate.[27]

Paracetamolmaybeeasilypreparedinthelaboratoryby nitrating phenolwith sodiumnitrate,separatingthedesired p-nitrophenol fromthe ortho-byproduct,andreducingthe nitrogroup with sodiumborohydride.Theresultant p-aminophenol isthenacetylatedwith aceticanhydride.[28] Inthisreaction, phenol isstronglyactivating,thusthereactionrequiresonlymildconditions（cf.thenitrationofbenzene）:

[edit]Reactions

p-Aminophenol maybeobtainedbytheamide hydrolysis ofparacetamol. p-Aminophenolpreparedthisway,andrelatedtothecommerciallyavailable Metol,hasbeenusedasa