Paracetamol扑热息痛.docx

1、Paracetamol扑热息痛ParacetamolParacetamolSystematic (IUPAC) nameN-(4-hydroxyphenyl)acetamideIdentifiersCAS number103-90-2ATC codeN02BE01PubChemCID 1983DrugBankDB00316ChemSpider1906Chemical dataFormulaC8H9NO2Mol. mass151.17 g/molSMILESeMolecules&PubChemPhysical dataDensity1.263g/cmMelt. point168C (334F)S

2、olubilityinwater12.781mg/mL (20C)Pharmacokinetic dataBioavailability100%Metabolism90 to 95%HepaticHalf-life14 hExcretionRenalTherapeutic considerationsLicence dataUS FDA:linkPregnancy cat.A(AU)B(US)safeLegal statusUnscheduled(AU)GSL(UK)OTC(US)RoutesOral,rectal,intravenous(what is this?)(verify)Parac

3、etamol(international nonproprietary name) (pronounced/prsitml, prstml/) oracetaminophen(/sitmnfn/(listen) (USAN) is a widely usedover-the-counteranalgesic(pain reliever) andantipyretic(fever reducer).It is commonly used for the relief ofheadaches, and other minor aches and pains, and is a major ingr

4、edient in numerouscoldandfluremedies. In combination withopioid analgesics, paracetamol can also be used in the management of more severe pain such as post surgical pain and providing palliative care in advanced cancer patients.2The onset of analgesia is approximately 11 minutes afteroral administra

5、tionof paracetamol,3and itshalf lifeis 14 hours.While generally safe for use at recommended doses (1,000 mg per single doseand up to4,000 mg per dayfor adults, up to2,000 mg per dayif drinking alcohol),4acuteoverdosesof paracetamol can cause potentially fatalliver damageand, in rare individuals, a n

6、ormal dose can do the same; the risk is heightened byalcohol consumption.Paracetamol toxicityis the foremost cause ofacute liver failurein theWestern world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand.5678Paracetamol is part of the class o

7、f drugs known as anilineanalgesics; it is the only such drug still in use today.9It is the active metabolite ofphenacetin, once popular as an analgesic and antipyretic in its own right, but unlike phenacetin and its combinations, paracetamol is not considered to becarcinogenicat therapeutic doses.10

8、The wordsacetaminophen(used in the United States, Canada, Hong Kong, Iran,11Colombia and other Latin American countries) andparacetamol(used elsewhere) both come from chemical names for the compound:para-acetylaminophenol andpara-acetylaminophenol. In some contexts, it is simply abbreviated asAPAP,

9、forN-acetyl-para-aminophenol.The classification of paracetamol, and the terminology used to refer to it, can cause confusion. It is often classified as a nonsteroidal anti-inflammatory drug (NSAID), but paracetamol has few anti-inflammatory effects in many tissues. However,aspirin, paracetamol and o

10、ther NSAIDs all act by the same mechanism (inhibition ofprostaglandinsynthesis) and all show varying levels of analgesic, anti-inflammatory, antipyretic and antiplatelet actions.12Contentshide 1History 2Structure and reactivity 3Synthesis 4Reactions 5Available forms 6Mechanism of action 7Metabolism

11、8Indications 9Efficacy and side effectso 9.1Efficacyo 9.2Adverse effects 10Toxicity 11Effects on animals 12References 13External linkseditHistoryAcetanilidewas the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into m

12、edical practice under the name ofAntifebrinby A. Cahn and P. Hepp in 1886.13But its unacceptable toxic effects, the most alarming beingcyanosisdue tomethemoglobinemia, prompted the search for less toxic aniline derivatives.9Harmon Northrop Morsehad already synthesized paracetamol atJohns Hopkins Uni

13、versityvia the reduction ofp-nitrophenolwithtinin glacialacetic acidin 1877,1415but it was not until 1887 that clinical pharmacologistJoseph von Meringtried paracetamol on patients.9In 1893, von Mering published a paper reporting on the clinical results of paracetamol withphenacetin, another aniline

14、 derivative.16Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin establishedBayeras a leading pharmaceutical company.17Overshadowed in part byaspirin, intro

15、duced into medicine byHeinrich Dreserin 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter headache mixtures, usually containing phenacetin, anaminopyrinederivative of aspirin, caffeine, and sometimes abarbiturate.9Von Merings claims remained essentiall

16、y unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and paracetamol.17In 1947David Lesterand Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent stu

17、dy they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.18In three papers published in the September 1948 issue of theJournal of Pharmacology and Experimental Therapeutics,Bernard Brodie,Julius Axelrodand Frederick Flinn confirmed using more specific met

18、hods that paracetamol was the major metabolite of acetanilide in human blood, and established it was just as efficacious an analgesic as its precursor.192021They also suggested that methemoglobinemia is produced in humans mainly by another metabolite,phenylhydroxylamine. A followup paper by Brodie a

19、nd Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.22This led to a rediscovery of paracetamol.9It has been suggested that contamination of paracetamol with4-aminophenol, the substance from which it was synthesized by von Mering, may be the cause for his spurious findi

20、ngs.17Bernard BrodieandJulius Axelrod(pictured)demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better tolerated analgesic.Paracetamol was first marketed in the United States in 1953 bySterling-Winthrop Co., which promoted it as preferable to aspirin since

21、 it was safe to take for children and people with ulcers.17The best known brand today for paracetamol in the United States,Tylenol, was established in 1955 whenMcNeil Laboratoriesstarted selling paracetamol as a pain and fever reliever for children, under the brand name Tylenol Childrens Elixirthe w

22、ord tylenol was a contraction ofpara-acetylaminophenol.23In 1956, 500mgtablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary ofSterling DrugInc. Panadol was originally available only by prescription, for the relief of

23、 pain and fever, and was advertised as being gentle to the stomach, since other analgesic agents of the time contained aspirin, a known stomach irritant.citation neededIn 1963, paracetamol was added to theBritish Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side

24、-effects and little interaction with other pharmaceutical agents.15Concerns about paracetamols safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercia

25、l demise of phenacetin, blamed as the cause ofanalgesic nephropathyand hematological toxicity.9The U.S.patenton paracetamol has long expired, and generic versions of the drug are widely available under theDrug Price Competition and Patent Term Restoration Actof 1984, although certain Tylenol prepara

26、tions were protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for Extended release acetaminophen particles.24editStructure and reactivityPSAof the paracetamol moleculeParacetamol consists of abenzenering core,substitutedby onehydroxylgroup and thenitrogenatom of anamideg

27、roup in thepara(1,4)pattern.25The amide group isacetamide(ethanamide). It is an extensivelyconjugated system, as thelone pairon the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, thep orbitalon thecarbonylcarbon, and the lone pair on the carbonyl oxygen are all conjugated. The presen

28、ce of two activating groups also make the benzene ring highly reactive towardelectrophilicaromatic substitution. As the substituents are ortho,para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces thebas

29、icityof the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on thephenoxideanion.editSynthesisCompared with many other drugs, paracetamol is much easier to synthesize, because it lacksstereocenters. As a result, there is no need to design a stere

30、o-selective synthesis.Industrial preparation of paracetamol usually proceeds fromnitrobenzene.26A one-step reductive acetamidation reaction can be mediated by thioacetate.27Paracetamol may be easily prepared in the laboratory bynitratingphenol withsodium nitrate, separating the desiredp-nitrophenolf

31、rom theortho- byproduct, and reducing thenitro groupwithsodium borohydride. The resultantp-aminophenolis then acetylated withacetic anhydride.28In this reaction,phenolis strongly activating, thus the reaction requires only mild conditions (cf. the nitration of benzene):editReactionsp-Aminophenolmay be obtained by the amidehydrolysisof paracetamol.p-Aminophenol prepared this way, and related to the commercially availableMetol, has been used as a