Paracetamol: Difference between revisions

{{drugbox| verifiedrevidWatchedfields = 456349142changed

| drug_name = Paracetamol (acetaminophen)

| pregnancy_US = BC

| pregnancy_category = Not tested but seems to be safe

| routes_of_administration = [[Mouth|Oral]], [[Rectal (medicine)|rectal]], [[Intravenous therapy|intravenous]]

| bioavailability = ~10063-89%<ref>{{cite isbn|978-0-9775174-5-9}}</ref>{{rp|73}}

| molecular_weight = 151.17163 g/mol

| smiles = CC(NC1=CC=C(O)Nc1ccc(cc1C=C1)=O

| melting_notes = <ref>{{cite doi|10.1021/ci0500132}}</ref><ref>{{cite web | url = http://lxsrv7.oru.edu/~alang/meltingpoints/meltingpointof.php?csid=1906 | title = melting point data for paracetamol |publisher=Lxsrv7.oru.edu | accessdate = 2011-03-19}}</ref>

Paracetamol is classified as a mild analgesic. It is commonly used for the relief of [[headache]]s and other minor aches and pains and is a major ingredient in numerous [[common cold|cold]] and [[Influenza|flu]] remedies. In combination with [[opioid analgesic]]s, 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.<ref>{{cite book|url = http://www.sign.ac.uk/pdf/SIGN106.pdf|title = Guideline 106: Control of pain in adults with cancer|author = Scottish Intercollegiate Guidelines Network (SIGN)|publisher = National Health Service (NHS)|location = Scotland|year = 2008|isbn = 978 1 905813 38 49781905813384|chapter = 6.1 and 7.1.1}}</ref> Though acetaminophenparacetamol is used to treat inflammatory pain, it is not generally classified as an [[NSAID]] because it exhibits only weak anti-inflammatory activity.

It is the active metabolite of the [[coal tar]]-derived [[phenacetin]], once popular as an analgesic and antipyretic in its own right. However, unlike phenacetin and its combinations, paracetamol is not considered [[carcinogen]]ic at therapeutic doses.<ref name=Bergman>{{cite journal |author=Bergman K, Müller L, Teigen SW |title=The genotoxicity and carcinogenicity of paracetamol: a regulatory (re)view |journal=Mutat Res |volume=349 |issue=2 |pages=263–88 |year=1996 |pmid=8600357 |doi=10.1016/0027-5107(95)00185-9}}</ref> The words ''acetaminophen'' (used in the United States,<ref name=Bradley"MacintyreRowbotham2008"/>{{cite journal |author=BradleyCanada,<ref N |titlename=BMJ should use "paracetamolMacintyreRowbotham2008" instead of "acetaminophen" in its index |journal=BMJ |volume=313 |issue=7058 |page=689 |year=1996|pmid = 8811774|pmc = 2351967}}</ref> Canada, Japan, South Korea, Hong Kong, and IranColombia)<ref name=INN2007/> and ''paracetamol'' (used elsewhere as well as in Canada) both come from a chemical name for the compound: ''para''-'''acet'''yl'''aminophen'''ol and '''''par'''a''-'''acet'''yl'''am'''inophen'''ol'''. In some contexts, such as on prescription bottles of painkillers that incorporate this medicine, it is simply abbreviated as '''APAP''', for '''a'''cetyl-'''p'''ara-'''a'''mino'''p'''henol. It is on the [[WHO Model List of Essential Medicines]], a list of the most important medication needed in a basic [[health system]].<ref>{{cite web|title=WHO Model List of Essential Medicines|url=http://apps.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1|work=World Health Organization|accessdate=22 April 2014|date=October 2013|format=PDF}}</ref>

Paracetamol is approved for reducing [[fever]] in people of all ages.<ref name=AHFS>{{cite web|title=Acetaminophen|url=http://www.drugs.com/monograph/acetaminophen.html|work=The American Society of Health-System Pharmacists|accessdate=3 April 2011}}</ref> The [[World Health Organization]] (WHO) recommends that paracetamol only be used to treat fever in children only if their temperature is greater than {{convert|38.5|°C|°F}}.<ref>{{cite news|url=http://news.bbc.co.uk/1/hi/health/7623230.stm|title=Baby paracetamol asthma concern|date=September 19, 2008|work=[[BBC News]]|accessdate=September 19, 2008}}</ref> The efficacy of paracetamol by itself in children with fevers has been questioned<ref>{{cite journal |author=Meremikwu M, Oyo-Ita A |title=Paracetamol for treating fever in children |journal=Cochrane Database Syst Rev |issue=2 |page=CD003676 |year=2002 |pmid=12076499 |doi=10.1002/14651858.CD003676 }}</ref> and a meta-analysis showed that it is less effective than [[ibuprofen]].<ref>{{cite journal |author=Perrott DA, Piira T, Goodenough B, Champion GD |title=Efficacy and safety of acetaminophen vs ibuprofen for treating children's pain or fever: a meta-analysis |journal=Arch Pediatr Adolesc Med |volume=158 |issue=6 |pages=521–6 |year=2004|pmid=15184213 |doi=10.1001/archpedi.158.6.521 |url=}}</ref>

Paracetamol is used for the relief of pains associated with many parts of the body. It has [[analgesic]] properties comparable to those of [[aspirin]], while its anti-inflammatory effects are weaker. It is better tolerated than aspirin in patients in whom excessive [[gastric acid]] secretion or prolongation of bleeding time may be a concern. Available without a prescription since 1959,<ref>{{cite itweb has|url=http://www.tylenol.com/news/about-us in|title=Our recentStory years|publisher=McNEIL-PPC, Inc. |accessdate=March 8, 2014}}</ref> it has increasinglysince become a common household drug.<ref>{{cite news|url=http://www.medicinenet.com/acetaminophen/article.htm|title=Medication and Drugs|date=1996-20101996–2010|work=MedicineNet|accessdate=April 22, 2010}}</ref>

Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the [[non-steroidal anti-inflammatory drug|NSAID]]s aspirin and ibuprofen, but ibuprofen and paracetamol have similar effects in the treatment of headache. Paracetamol can relieve pain in mild arthritis {{Citation needed|date=July 2012}}, but has no effect on the underlying inflammation, redness, and swelling of the joint.<ref>{{cite It is asweb effective as the non|url=http://www.arthritisresearchuk.org/arthritis-steroidalinformation/drugs/painkillers/paracetamol.aspx [[anti-inflammatory]]|title=Paracetamol drug (|publisher=[[NSAID]])Arthritis [[ibuprofen]]Research in relieving the pain of [[osteoarthritisUK]] of the knee. {{Citation needed|dateaccessdate=JulyOctober 16, 20122013}}</ref>

In June 2009, a [[Food and Drug Administration (United States)|U.S. Food and Drug Administration]] (FDA) advisory committee recommended that new restrictions should be placed on paracetamol usage in the United States to help protect people from the potential toxic effects. The maximum dosage at any given time would be decreased from 1000&nbsp;mg to 650&nbsp;mg, while combinations of paracetamol and [[narcotic]] [[analgesic]]s would be prohibited. Committee members were particularly concerned by the fact that the present maximum dosages of paracetamol had been shown to produce alterations in [[liver|hepatic]] function.<ref name="WebMD">{{cite web|url=http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen |title=FDA May Restrict Acetaminophen |publisher=Webmd.com |date=2009-07-01 |accessdate=2011-03-19}}</ref> On January 13, 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit the amount of paracetamol to no more than 325&nbsp;mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk forof severe liver damage.<ref name="FDA_20110113">{{Cite press release

}}</ref> Manufacturers will havehad three years to limit the amount of paracetamol in their prescription drug products to 325&nbsp;mg per dosage unit.<ref name="FDA_CDER" /><ref name="NYT_Harris" />

In November 2011, the [[Medicines and Healthcare products Regulatory Agency]] revised UK dosing of liquid paracetamol for children.<ref>[{{cite web|url=http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON134919 |title=Liquid paracetamol for children: Revised UK dosing instructions have been introduced] |publisher=Mhra.gov.uk |accessdate=2014-02-18}}</ref>

==Classification=Pregnancy===

[[Image:AM404 skel.svg|thumb|[[AM404]] &nbsp;– [[Metabolite]] of paracetamol]]

[[Image:Anandamide skeletal.svg|thumb|[[Anandamide]] &nbsp;– Endogenous [[cannabinoid]]]]

To date, the mechanism of action of paracetamol is not completely understood. The main mechanism proposed is the inhibition of [[cyclooxygenase]] (COX), and recent findings suggest that it is highly selective for [[COX-2]].<ref name="Hinz_2008">{{Cite pmid|17884974}}</ref> Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting [[thromboxane]]s.<ref name="Hinz_2008" /> While it has [[analgesic]] and [[antipyretic]] properties comparable to those of [[aspirin]] or other [[NSAID]]s, its peripheral anti-inflammatory activity is usually limited by several factors, one of which is the high level of [[peroxides]] present in [[inflammation|inflammatory]] lesions. However, in some circumstances, even peripheral anti-inflammatory activity comparable to [[NSAID]]s can be observed. An article<ref>{{cite journal|author=Andersson DA, Gentry C, Alenmyr L, Killander D, Lewis SE, Andersson A, Bucher B, Galzi J-L, Sterner O, Bevan S, Högestätt ED, Zygmunt PM|pmid=22109525|title=TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ(9)-tetrahydrocannabiorcol|journal=Nat Commun|year= 2011 |volume=2|page=551|doi= 10.1038/ncomms1559}}</ref> in Nature Communications from researchers in London, UK and Lund, Sweden in November 2011 has found a hint to the analgesic mechanism of paracetamol (acetaminophen), being that the metabolites of paracetamol e.g. [[NAPQI]], act on [[Transient receptor potential cation channel, member A1|TRPA1-receptor]]s in the spinal cord to suppress the signal transduction from the superficial layers of the dorsal horn, to alleviate pain. This conclusion has been contested in a new hypothesis paper<ref name=Claesson>{{cite web|last=Claesson|first=A|title=On the mechanism of paracetamol’s analgesic activity and a note on related NSAID pharmacology|url=http://www.slideshare.net/aclaesson/paracetamol-mechanism-on-slide-share|work=SlideShare|accessdate=1 March 2013}}</ref> on how paracetamol might act. The author concedes that [[NAPQI]] is the active metabolite but that this reactive compound should react not only with the thiol in TRPA1 but also with any other suitably available nucleophile that it happens to encounter. It is suggested that thiol groups in cysteine proteases, e.g. the proteases that take part in the processing of procytokines, such as those generating [[Interleukin_1_family|IL-1β]] and [[Interleukin-6|IL-6]], might be the targets giving rise to overall analgesic effects.

The COX family of enzymes are responsible for the metabolism of [[arachidonic acid]] to [[prostaglandin H2|prostaglandin H₂]], an unstable molecule that is, in turn, converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories such as the [[NSAID]]s block this step. Only when appropriately oxidised is the COX enzyme highly active.<ref name="pmid104998">{{cite journal |author=Ohki S, Ogino N, Yamamoto S, Hayaishi O |title=Prostaglandin hydroperoxidase, an integral part of prostaglandin endoperoxide synthetase from bovine vesicular gland microsomes |journal=J. Biol. Chem. |volume=254 |issue=3 |pages=829–36 |year=1979 |pmid=104998 |doi=}}</ref><ref name="pmid3094341">{{cite journal |author=Harvison PJ, Egan RW, Gale PH, Nelson SD |title=Acetaminophen as a cosubstrate and inhibitor of prostaglandin H synthase |journal=Adv. Exp. Med. Biol. |volume=197 |pages=739–47 |year=1986 |pmid=3094341 |doi=10.1007/978-1-4684-5134-4_68 |series=Advances in Experimental Medicine and Biology |isbn=978-1-4684-5136-8}}</ref> Paracetamol reduces the oxidizedoxidised form of the COX enzyme, preventing it from forming pro-inflammatory chemicals.<ref name="pmid16413237"/><ref name="GnGRoberts">Roberts, L.J. II. & Marrow, J.D. "Analgesic-antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout" in, "Goodman & Gilman's The Pharmacological Basis of Therapeutics 10th Edition" by Hardman, J.G. & Limbird, L.E. Published by McGraw Hill, 2001, pp.687–731 ISBN 0071354697</ref> This leads to a reduced amount of ''prostaglandin E2'' in the CNS, thus lowering the hypothalamic set-point in the thermoregulatory centre.

The exact mechanisms by which COX is inhibited in various circumstances are still a subject of discussion. Because of differences in the activity of paracetamol, aspirin, and other NSAIDs, it has been postulated that further COX variants may exist. One theory holds that paracetamol works by inhibiting the [[COX-3]] isoform - a COX-1 [[splice variant]] - of the COX family of enzymes.<ref name="Hinz_2008" /> When expressed in dogs, this enzyme shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol.<ref name="pmid12242329"/> However, some research has suggested that, in humans and mice, the COX-3 enzyme is without inflammatory action and paracetamol's blockage of it is not significant in its functioning in humans.<ref name="Hinz_2008" /><ref name="pmid15879007"/> Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that, in an inflammatory environment where the concentration of peroxides is high, the high oxidation state of paracetamol prevents its actions. This idea would mean that paracetamol has no direct effect at the site of inflammation, but instead acts in the CNS where the environment is not oxidative, to reduce temperature, etc.<ref name="pmid12242329">{{cite journal |author=Chandrasekharan NV, Dai H, Roos KL, ''et al.'' |title=COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue=21 |pages=13926–31 |year=2002 |pmid=12242329 |doi=10.1073/pnas.162468699 |pmc=129799}}</ref> The exact mechanism by which paracetamol is believed to affect COX-3 is disputed.

[[4-Aminophenol|''4''-Aminophenol]] may be obtained by the amide [[hydrolysis]] of paracetamol. ''4''-Aminophenol prepared this way, and related to the commercially available [[Metol]], has been used as a developer in photography by hobbyists.<ref>{{cite book|last=Henney|first=K|coauthorsauthor2=Dudley B|title=Handbook of Photography|publisher=Whittlesey House|year=1939|page=324}}</ref> This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, ''4''-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an [[indophenol]] dye under oxidization by air.<ref>{{cite journal

[[Image:Axelrod.jpg|thumb|[[Julius Axelrod]] ''(pictured)'' and [[Bernard Brodie (biochemist)|Bernard Brodie]] demonstrated that acetanilide and phenacetin are both metabolizedmetabolised to paracetamol, which is a better tolerated analgesic.]]

[[Acetanilide]] was the first [[aniline]] derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of [[Antifebrin]] by A. Cahn and P. Hepp in 1886.<ref>{{cite journal|last = Cahn|first = A|coauthors author2= Hepp P|title = Das Antifebrin, ein neues Fiebermittel|journal = Centralbl. Klin. Med.|year = 1886|volume = 7|pages = 561–64}}</ref> But its unacceptable toxic effects, the most alarming being [[cyanosis]] due to [[methemoglobinemia]], prompted the search for less toxic aniline derivatives.<ref name="pmid17227290" /> [[Harmon Northrop Morse]] had already synthesizedsynthesised paracetamol at [[Johns Hopkins University]] via the reduction of [[4-Nitrophenol|''p''-nitrophenol]] with [[tin]] in glacial [[acetic acid]] in 1877,<ref>{{cite journal

but it was not until 1887 that clinical pharmacologist [[Joseph von Mering]] tried paracetamol on patients.<ref name="pmid17227290" /> In 1893, von Mering published a paper reporting on the clinical results of paracetamol with [[phenacetin]], another aniline derivative.<ref>Von Mering J. (1893) Beitrage zur Kenntniss der Antipyretica. Ther Monatsch 7: 577–587.</ref> Von 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 established [[Bayer]] as a leading pharmaceutical company.<ref name=drugdiscov>{{cite book|title=Drug Discovery: A History|first=Walter|last=Sneader|publisher=Wiley|year=2005|isbn=0471899801|page=439|location=Hoboken, N.J.|url=http://books.google.com/books?id=jglFsz5EJR8C&pg=PA439}}</ref> Overshadowed in part by [[aspirin]], introduced into medicine by [[Heinrich Dreser]] in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter "headache mixtures", usually containing phenacetin, an [[aminopyrine]] derivative of aspirin, caffeine, and sometimes a [[barbiturate]].<ref name="pmid17227290" />

Von Mering's claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and paracetamol.<ref name=drugdiscov/> In 1947 [[David Lester (biochemist)|David Lester]] and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.<ref>{{cite journal|author = Lester D, Greenberg LA, Carroll RP|title = The metabolic fate of acetanilid and other aniline derivatives: II. Major metabolites of acetanilid appearing in the blood|journal = J. Pharmacol. Exp. Ther.|year = 1947|volume = 90|pages = 68–75|url = http://jpet.aspetjournals.org/cgi/reprint/90/1/68|pmid = 20241897|issue = 1}}</ref> In three papers published in the September 1948 issue of the ''[[Journal of Pharmacology and Experimental Therapeutics]]'', [[Bernard Brodie (biochemist)|Bernard Brodie]], [[Julius Axelrod]] and Frederick Flinn confirmed using more specific methods that paracetamol was the major metabolite of acetanilide in human blood, and established that it was just as efficacious an analgesic as its precursor.<ref>{{cite journal|last = Brodie|first = BB|coauthorsauthor2=Axelrod J |authorlink2= [[Julius Axelrod|Axelrod J]]|title = The estimation of acetanilide and its metabolic products, aniline, ''N''-acetyl ''p''-aminophenol and ''p''-aminophenol (free and total conjugated) in biological fluids and tissues|journal = J. Pharmacol. Exp. Ther.|year = 1948|volume = 94|issue = 1|pages = 22–28|pmid = 18885610}}</ref><ref>{{cite journal|last = Brodie|first = BB|coauthors author2= Axelrod J|title = The fate of acetanilide in man|url = http://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdf|journal = J. Pharmacol. Exp. Ther.|year = 1948|volume = 94|issue = 1|pages = 29–38|pmid = 18885611}}</ref><ref>{{cite journal|last = Flinn|first = Frederick B|coauthors author2= Brodie BB|title = The effect on the pain threshold of ''N''-acetyl ''p''-aminophenol, a product derived in the body from acetanilide|journal = J. Pharmacol. Exp. Ther.|year = 1948|volume = 94|issue = 1|pages = 76–77|pmid = 18885618}}</ref> They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, [[phenylhydroxylamine]]. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolizedmetabolised to paracetamol.<ref>{{cite journal| author= Brodie BB, Axelrod J|title=The fate of acetophenetidin (phenacetin) in man and methods for the estimation of acetophenitidin and its metabolites in biological material| journal=J Pharmacol Exp Ther|year=1949|pages=58–67|volume=94|issue=1}}</ref> This led to a "rediscovery" of paracetamol.<ref name="pmid17227290" /> It has been suggested that contamination of paracetamol with [[4-aminophenol]], the substance von Mering synthesizedsynthesised it from, may be the cause for his spurious findings.<ref name=drugdiscov/>

Paracetamol was first marketed in the United States in 19531950 byunder the name Triagesic, a combination of paracetamol, [[Sterling-Winthrop Co.aspirin]], whichand promoted[[caffeine]].<ref itname=badmed/> asReports preferablein to1951 aspirinof sincethree itusers wasstricken safewith tothe takeblood fordisease children[[agranulocytosis]] andled peopleto withits ulcers.<refremoval name=drugdiscov/>from Thethe bestmarketplace, knownand brandit todaytook forseveral paracetamolyears inuntil it became clear that the Uniteddisease States,was [[Tylenol]],unconnected.<ref name=badmed/> Paracetamol was establishedmarketed in 19551953 whenby [[McNeilSterling-Winthrop LaboratoriesCo.]] startedas sellingPanadol, paracetamolavailable asonly aby painprescription, and feverpromoted relieveras forpreferable children,to underaspirin thesince brandit namewas Tylenolsafe Children'sfor Elixir—thechildren wordand "tylenol"people waswith aulcers.<ref contractionname=badmed/><ref of ''para''-ace'''tyl'''aminoph'''enol'''.name=drugdiscov/><ref name="1955_mcneilLandauAchilladelis1999">"[http://www.chemheritage.org/EducationalServices/pharm/asp/asp08.htm{{cite Abook|last1=Landau|first1=Ralph Festival| oflast2=Achilladelis|first2=Basil Analgesics]."|last3=Scriabine| ''[first3=Alexander| title=Pharmaceutical Innovation: Revolutionizing Human Health|url=http://wwwbooks.chemheritagegoogle.orgcom/books?id=IH4lPs6S1bMC&pg=PA248| year=1999| publisher=Chemical Heritage Foundation].'|isbn=978-0-941901-21-5|pages=248–249}}</ref> In 1955, paracetamol was marketed as Children's 2001.[[Tylenol]] RetrievedElixir onby August[[McNeil 17,Laboratories]].<ref 2007name="Rapoport1991">{{cite book|last=Rapoport|first=Alan |title=Headache Relief|url=http://books.google.com/books?id=5Vilw1AgDhkC&pg=PA97|date=15 December 1991|publisher=Touchstone|isbn=978-0-671-74803-6|page=97}}</ref> In 1956, 500&nbsp;[[milligram|mg]] tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of [[Sterling Drug]] Inc. Panadol was originally available only by prescription, for the relief of 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. In 1963, paracetamol was added to the ''[[British Pharmacopoeia]]'', and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.<ref name=badmed>{{cite book|title=Bad Medicine: The Prescription Drug Industry in the Third World|author = Milton Silverman, Mia Lydecker, Philip Randolph Lee|publisher=Stanford University Press|year=1992|isbn=0804716692|pages=88–90|url=http://books.google.com/books?id=p5FdLvvYEnsC&pg=PA88}}</ref> Concerns about paracetamol's 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 commercial demise of phenacetin, blamed as the cause of [[analgesic nephropathy]] and hematological toxicity.<ref name="pmid17227290" />

Paracetamol is available in a [[Tablet (pharmacy)|tablet]], [[Capsule (pharmacy)|capsule]], liquid suspension, [[suppository]], [[intravenous]], [[intramuscular]] and [[intramuscularEffervescent]] form. The common adult dose is 500&nbsp;mg to 1000&nbsp;mg. The recommended maximum daily dose, for adults, is 4000&nbsp;mg. In recommended doses, paracetamol is generally safe for children and infants, as well as for adults,<ref>"Acetaminophen." Physicians' Desk Reference, 63rd ed. Montvale, NJ: Thomson PDR; 2009: 1915–1916.</ref> although rare cases of acute liver injury have been linked to amounts lower than 2500&nbsp;mg per day.<ref name="2009_FDA_support">"[http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM164897.pdf Acetaminophen Overdose and Liver Injury—Background and Options for Reducing Injury]", ''Charles Ganley, MD, Gerald Dal Pan, MD, Bob Rappaport, MD'', May 22, 2009, Retrieved July 8, 2010.</ref>

{{Reflist|232em}}

*{{Portal-inline|Pharmacy and Pharmacology}}

* [http://www.chemsynthesis.com/base/chemical-structure-18651.html Paracetamol at Chemsynthesis]

* [http://www.pharmwebcdc.netgov/pwmirrorniosh/pwyipcsneng/paracetamol/pharmwebpicneng1330.html Paracetamol InformationInternational Chemical Safety CentreCards]

* [http://wwwprofiles.cdcnlm.nih.gov/nioshHH/ipcsnengViews/neng1330Exhibit/narrative/amines.html Paracetamol InternationalThe ChemicalJulius SafetyAxelrod CardsPapers]

* [http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/ucm168830UCM172664.htmpdf FDA: Consumer Update "Acetaminophen and Liver Injury: Q and A for Consumers" (linkPDF)]

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