Paracetamol扑热息痛Word格式.docx
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Paracetamol扑热息痛Word格式.docx
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°
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
/ˌpæ
rəˈsiːtəmɒl,ˌpæ
rəˈsɛtəmɒl/)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
(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
∙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
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
fromthe
ortho-byproduct,andreducingthe
nitrogroup
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
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