View source for Paracetamol

{{drugbox|Watchedfields = changed
| verifiedrevid = 306792031
|
| IUPAC_name = ''N''-(4-hydroxyphenyl)acetamide
| image = Paracetamol-skeletal.svg
| image2= Paracetamol-from-xtal-3D-balls.png
| width = 200
| CASNo_Ref = {{cascite}}
| CAS_number = 103-90-2
| ChemSpiderID = 1906
| ATC_prefix = N02
| ATC_suffix = BE01
| PubChem = 1983
| smiles = C1=CC(=CC=C1NC(C)=O)O
| DrugBank = DB00316
| C = 8 |H = 9 |N = 1 |O = 2
| molecular_weight = 151.17 g/mol
| density = 1.263
| melting_point = 168
| pKa = 9.5
| solubility = 14 
| bioavailability = ~100%
| metabolism = 90 to 95% [[Liver|Hepatic]]
| elimination_half-life = 1–4 h
| excretion = [[Kidney|Renal]]
| pregnancy_AU = A
| pregnancy_US = B
| pregnancy_category = safe
| legal_AU = unscheduled
| legal_UK = GSL
| legal_US = OTC
| routes_of_administration = [[Mouth|Oral]], [[rectal]], [[Intravenous therapy|intravenous]]
| licence_US = Acetaminophen
}}
'''Paracetamol''' ([[International Nonproprietary Name|INN]]) ({{pron-en|ˌpærəˈsiːtəmɒl, ˌpærəˈsɛtəmɒl}}) or '''acetaminophen''' ({{IPA-en|əˌsiːtəˈmɪnɵfɨn||Acetaminophen.ogg}}) ([[United States Adopted Name|USAN]]) is a widely used [[over-the-counter drug|over-the-counter]] [[analgesic]] (pain reliever) and [[antipyretic]] (fever reducer).

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 in advanced cancer).<ref>[http://www.sign.ac.uk/guidelines/fulltext/106/index.html ''Control of Pain in Adults with Cancer'' Sign Guidelines '''106''' Section 6.1 and 7.1.1].</ref>

While generally safe for use at recommended doses ({{nowrap|1,000 mg per single dose}} and up to {{nowrap|4,000 mg per day}} for adults, up to {{nowrap|2,000 mg per day}} if drinking alcohol<ref>[http://www.drugs.com/acetaminophen.html Acetaminophen]</ref>), acute [[overdose]]s of paracetamol can cause potentially fatal [[Hepatotoxicity|liver damage]] and, in rare individuals, a normal dose can do the same; the risk is heightened by [[Ethanol|alcohol consumption]]. [[Paracetamol toxicity]] is the foremost cause of [[acute liver failure]] in the [[Western world]], and accounts for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand.<ref name="DalyMJA">{{cite journal |author=Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA |title=Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres |journal=Med. J. Aust. |volume=188 |issue=5 |pages=296–301 |year=2008 |pmid=18312195|url=http://www.mja.com.au/public/issues/188_05_030308/dal10916_fm.html}}</ref><ref>{{cite journal |author=Khashab M, Tector AJ, Kwo PY |title=Epidemiology of acute liver failure |journal=Curr Gastroenterol Rep |volume=9 |issue=1 |pages=66–73 |year=2007 |pmid=17335680 |doi= 10.1007/s11894-008-0023-x}}</ref><ref name=Hawkins>{{cite journal |author=Hawkins LC, Edwards JN, PI |title=Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature |journal=Drug Saf |volume=30 |issue=6 |pages=465–79 |year=2007 |pmid=17536874 |doi= 10.2165/00002018-200730060-00002|url=}}</ref><ref name=Larson/>

Paracetamol is part of the class of drugs known as "[[aniline]] analgesics"; it is the only such drug still in use today.<ref name=pmid17227290/> It is the active metabolite of [[phenacetin]], once popular as an analgesic and antipyretic in its own right, but unlike phenacetin and its combinations, paracetamol is not considered to be [[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, Canada, Hong Kong, Iran,<ref name=Bradley>{{cite journal |author=Bradley, N |title=BMJ should use "paracetamol" instead of "acetaminophen" in its index |journal=BMJ |volume=313 |issue=7058 |pages=689 |year=1996}}</ref> Colombia and other Latin American countries) and ''paracetamol'' (used elsewhere) both come from chemical names for the compound: ''para''-'''acet'''yl'''aminophen'''ol and '''''par'''a''-'''acet'''yl'''am'''inophen'''ol'''. In some contexts, it is simply abbreviated as '''APAP''', for ''N''-'''a'''cetyl-'''p'''ara-'''a'''mino'''p'''henol.

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 other NSAIDs all act by the same mechanism (inhibition of [[prostaglandin]] synthesis) and all show varying levels of analgesic, anti-inflammatory, antipyretic and antiplatelet actions.<ref>Byrant, Bronwen and Knights, Katleen. Pharmacology for Health Professionals. s.l. : Elsevier, 2007, p. 270.</ref>

==History==
<!-- Commented out for [[WP:SYNT]]; I can't find any reference to support this chain of consequences. (Xasodfuih)
In ancient and medieval times, [[antipyretic|anti-fever]] compounds came from white [[willow]] bark (a family of chemicals known as [[salicin]]s, which led to the development of [[aspirin]]), and [[cinchona]] bark.<ref name="white_willow">Gormley, James J. "[http://findarticles.com/p/articles/mi_m0FKA/is_n3_v58/ai_18169209 White willow bark is a gentle, effective pain-reliever]." ''Better Nutrition.'' March, 1996. Retrieved on August 17, 2007.</ref> Cinchona bark also gave the anti-[[malaria]] drug [[quinine]] which also [[antipyretic|reduces fever]]. Efforts to refine and isolate [[salicin]] and [[salicylic acid]] took place throughout the middle- and late-19th century, and was accomplished by [[Bayer]] chemist [[Felix Hoffmann]] (this was also done by French chemist [[Charles Frédéric Gerhardt]] 40 years earlier, but he abandoned the work after deciding it was impractical).<ref>{{cite web|title = The Aspirin story|publisher = Did You Know?|accessdate = 29 December 2006|url = http://www.didyouknow.cd/aspirin.htm}}</ref> When the [[cinchona]] tree became scarce in the 1880s, people began to look for alternatives.{{Fact|date=May 2009}} 2009}}-->

[[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 = 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 synthesized paracetamol at [[Johns Hopkins University]] via the reduction of [[4-Nitrophenol|''p''-nitrophenol]] with [[tin]] in glacial [[acetic acid]] in 1877,<ref>{{cite journal
|title = Ueber eine neue Darstellungsmethode der Acetylamidophenole
|pages = 232–233
|author = Morse HN
|year = 1878
|doi = 10.1002/cber.18780110151
|journal = [[Berichte der deutschen chemischen Gesellschaft]]
|volume = 11
|issue = 1}}</ref><ref name=badmed/>
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.}}</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/>
<!--
In 1893, paracetamol was discovered in the urine of individuals who had taken [[phenacetin]], and was concentrated into a white, crystalline compound with a bitter taste.{{Fact|date=January 2009}} In 1899, paracetamol was found to be a metabolite of [[acetanilide]].{{Fact|date=January 2009}} This discovery was largely ignored at the time.
-->

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&ndash;75|url = http://jpet.aspetjournals.org/cgi/reprint/90/1/68}}</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 it was just as efficacious an analgesic as its precursor.<ref>{{cite journal|last = Brodie|first = BB|coauthors = [[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 = Axelrod J|title = The fate of acetanilide in man|url = http://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdf |format=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 = 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 followup paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized 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 from which it was synthesized by von Mering, may be the cause for his spurious findings.<ref name=drugdiscov/>

[[Image:Axelrod.jpg|thumb|left|200px| [[Bernard Brodie (biochemist)|Bernard Brodie]] and [[Julius 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 by [[Sterling-Winthrop Co.]], which promoted it as preferable to aspirin since it was safe to take for children and people with ulcers.<ref name=drugdiscov/> The best known brand today for paracetamol in the United States, [[Tylenol]], was established in 1955 when [[McNeil Laboratories]] started selling paracetamol as a pain and fever reliever for children, under the brand name Tylenol Children's Elixir&mdash;the word "tylenol" was a contraction of ''para''-ace'''tyl'''aminoph'''enol'''.<ref name="1955_mcneil">"[http://www.chemheritage.org/EducationalServices/pharm/asp/asp08.htm A Festival of Analgesics]." ''[http://www.chemheritage.org/ Chemical Heritage Foundation].'' 2001. Retrieved on August 17, 2007.</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.{{Citation needed|date=January 2009}} 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&ndash;90}}</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/>

The U.S. [[patent]] on paracetamol has long expired, and generic versions of the drug are widely available under the [[Drug Price Competition and Patent Term Restoration Act]] of 1984, although certain Tylenol preparations were protected until 2007. U.S. patent 6,126,967 filed September 3, 1998 was granted for "Extended release acetaminophen particles".<ref>{{Ref patent |country=US |number=6126967 |status=patent|title=Extended release acetaminophen particles |gdate=October 03, 2000}}</ref>

==Structure and reactivity==
[[Image:Polar-surface-area.png|thumb|[[Polar surface area|PSA]] of the paracetamol molecule]]

Paracetamol consists of a [[benzene]] ring core, [[substituent|substituted]] by one [[hydroxyl]] group and the [[nitrogen]] atom of an [[amide]] group in the ''para'' (1,4) [[Arene substitution patterns|pattern]].<ref name="Bales">{{cite journal|last=Bales|first=JR|coauthors= Nicholson JK, Sadler PJ|title=Two-dimensional proton nuclear magnetic resonance "maps" of acetaminophen metabolites in human urine|journal=Clinical Chemistry|volume=31|issue=5|pages=757–762|url=http://www.clinchem.org/cgi/reprint/31/5/757|pmid=3987005|date= May 1, 1985 }}</ref> The amide group is [[acetamide]] (ethanamide). It is an extensively [[conjugated system]], as the [[lone pair]] on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the [[atomic orbital|p orbital]] on the [[carbonyl]] carbon, and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive toward [[electrophile|electrophilic]] aromatic 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 the [[base (chemistry)|basicity]] of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the [[phenol|phenoxide]] [[ion|anion]].
<br />
<br />

==Synthesis==
Compared with many other drugs, paracetamol is much easier to synthesize, because it lacks [[stereocenter]]s. As a result, there is no need to design a stereo-selective synthesis.

Industrial preparation of paracetamol usually proceeds from [[nitrobenzene]].<ref>{{cite book|author = Anthony S. Travis|year = 2007|chapter = Manufacture and uses of the anilines: A vast array of processes and products|editor = Zvi Rappoport|title = The chemistry of Anilines Part 1|publisher = Wiley|isbn = 978-0-470-87171-3|pages = 764}}</ref> A one-step reductive acetamidation reaction can be mediated by thioacetate.<ref>{{cite journal |author=Bhattacharya A.; Purohit V. C.; Suarez, V.; Tichkule, R; Parmer, G.; Rinaldi, F. |title=One-step reductive amidation of nitro arenes: application in the synthesis of Acetaminophen |journal=Tetrahedron Letters |volume=47 |issue=11 |pages=1861–1864 |year=2006|doi=10.1016/j.tetlet.2005.09.196}}</ref>

Paracetamol may be easily prepared in the laboratory by [[nitration|nitrating]] phenol with [[sodium nitrate]], separating the desired [[4-Nitrophenol|''p''-nitrophenol]] from the ''ortho''- byproduct, and reducing the [[nitro group]] with [[sodium borohydride]]. The resultant [[p-aminophenol|''p''-aminophenol]] is then acetylated with [[acetic anhydride]].<ref>{{cite book |author=Ellis, Frank |title=Paracetamol: a curriculum resource |publisher=Royal Society of Chemistry |location=Cambridge |year=2002 |isbn=0-85404-375-6}}</ref> In this reaction, [[phenol]] is strongly activating, thus the reaction only requires mild conditions (c.f. the nitration of benzene):
:[[Image:Synthesis of paracetamol from phenol.svg|400px]]

==Reactions==
[[p-Aminophenol|''p''-Aminophenol]] may be obtained by the amide [[hydrolysis]] of paracetamol. ''p''-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|coauthors=Dudley B|title=Handbook of Photography|publisher=Whittlesey House|year=1939|page=324}}</ref>

==Available forms==
{{multiple image
| align     = right
| direction = vertical
| width     = 200
| image1    = Tylenol rapid release pills.jpg
| alt1      = Tylenol Rapid Release Tablets
| caption1  = Tylenol Rapid Release Tablets
| image2    = Panadol.jpg
| alt2      = Panadol 500 mg tablets
| caption2  = Panadol 500 mg tablets
| image3    = Generic_paracetamol_dprk.jpg
| alt3      = Generic paracetamol from a North Korean manufacturer
| caption3  = Generic paracetamol from a North Korean manufacturer

}}
{{seealso|List of paracetamol brand names}}

Paracetamol is available in a [[tablet]], [[Capsule (pharmacy)|capsule]], liquid suspension, [[suppository]], [[intravenous]], and [[intramuscular]] 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 generally is 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>

'''[[Panadol]]''', which is marketed in Africa, Asia, Europe, Central America, and [[Australasia]], is the most widely available brand, sold in over 80 countries. In North America, paracetamol is sold in generic form (usually labeled as acetaminophen) or under a number of trade names, for instance, '''[[Tylenol]]''' ([[McNeil Laboratories|McNeil-PPC, Inc.]]), '''[[Anacin|Anacin-3]]''', '''Tempra''', and '''Datril''',. While there is brand named paracetamol available in the UK (e.g. Panadol), unbranded or generic paracetamol is more commonly sold. '''[[Acamol]]''', a brand name for paracetamol produced by [[Teva Pharmaceutical Industries]] in [[Israel]], is one of the most popular drugs in that country. In the Philippines, the largest-selling paracetamol brand is Biogesic, manufactured by the drug giant United Laboratories. Biogesic tablet sales reach nearly a billion units each year in the country alone, not including liquid suspension formats. The brand is also available in most of the ASEAN countries where the drug giant has market presence.
In Europe, the most common brands of paracetamol are '''Efferalgan''' and '''Doliprane'''. In India, the most common brand of paracetamol is '''Crocin''' manufactured by Glaxo SmithKline Asia. In Bangladesh the most popular brand is '''Napa''' manufactured by Beximco Pharma.

In some formulations, paracetamol is combined with the [[opioid]] [[codeine]], sometimes referred to as [[co-codamol]] ([[British Approved Name|BAN]]). In the United States and Canada, this is marketed under the name of Tylenol #1/2/3/4, which contain 8–10&nbsp;mg, 15&nbsp;mg, 30&nbsp;mg, and 60&nbsp;mg of [[codeine]], respectively. In the U.S., this combination is available only by prescription, while the lowest-strength preparation is over-the-counter in Canada, and, in other countries, other strengths may be available over the counter. There are generic forms of these combinations as well. In the UK and in many other countries, this combination is marketed under the names of [[Tylex]] CD and Panadeine. Other names include Captin, Disprol, Dymadon, Fensum, Hedex, Mexalen, Nofedol, Paralen, Pediapirin, Perfalgan, and Solpadeine. Paracetamol is also combined with other opioids such as [[dihydrocodeine]], referred to as [[co-dydramol]] ([[British Approved Name|BAN]]), [[oxycodone]] or [[hydrocodone]], marketed in the U.S. as [[Percocet]] and [[Vicodin]], respectively. Another very commonly used analgesic combination includes paracetamol in combination with [[propoxyphene napsylate]], sold under the brand name [[Darvocet]]. A combination of paracetamol, codeine, and the calmative [[doxylamine|doxylamine succinate]] is marketed as Syndol or Mersyndol.

Paracetamol is commonly used in multi-ingredient preparations for [[migraine]] headache, typically including [[butalbital]] and paracetamol with or without [[caffeine]], and sometimes containing codeine.

{| class="wikitable"
|-
! Brand names<ref>{{cite book
|title = Reader's Digest Guide to Drugs and Supplements
|publisher = Reader's Digest Association, Inc.
|year = 2002
|location = Pleasantville, New York; Montreal
|isbn = 0-7621-0366-3}}
</ref>
|-
| Aceta, Actimin, Anacin-3, Apacet, Aspirin Free Anacin, Atasol, Banesin, Ben-u-ron, Biogesic, Crocin, Dafalgan, Dapa, Dolo, Datril Extra-Strength, DayQuil, Depon & Depon Maximum, Feverall, Few Drops, Fibi, Fibi plus, Genapap, Genebs, Lekadol, LemSip, Liquiprin, Lupocet, Milidon, Neopap, Ny-Quil, Oraphen-PD, Panado, Panadol, Paracet, Parol, Panodil, Paratabs, Paralen, Phenaphen, Plicet, PyongSu Cetamol, Redutemp, Snaplets-FR, Suppap, Tamen, Tapanol, Tempra, Tylenol, Uphamol, Valorin, Xcel.
|}
</br>

==Mechanism of action==
{{Cleanup-section|date=January 2010}}
The main mechanism of action of paracetamol is considered to be 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> 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 high level of [[peroxides]] present in [[inflammation|inflammatory]] lesions. However, in some circumstances even peripheral anti-inflammatory activity comparable to other [[NSAID]]s can be observed.

Because of its selectivity for COX-2 it does not significantly inhibit the production of the pro-clotting [[thromboxane]]s.<ref name="Hinz_2008" />

[[Image:AM404 skel.svg|thumb|right|200px|[[AM404]]&mdash;a metabolite of paracetamol]]
[[Image:Anandamide skeletal.svg|thumb|right|200px|[[Anandamide]]&mdash;an endogenous cannabinoid]]
<!--if you know how to make stack these images better (make a vertical gallery?) please do it.-->

The COX family of enzymes are responsible for the metabolism of [[arachidonic acid]] to [[prostaglandin H2|prostaglandin H<sub>2</sub>]], an unstable molecule which is in turn converted to numerous other pro-inflammatory compounds. Classical anti-inflammatories such as the [[NSAID]]s block this step. Only when appropriately oxidized 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}}</ref>

Paracetamol reduces the oxidized 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.

Paracetamol also modulates the [[Endocannabinoid system|endogenous cannabinoid system]].<ref name="pmid15987694">{{cite journal |author=Högestätt ED, Jönsson BA, Ermund A, ''et al.'' |title=Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system |journal=J. Biol. Chem. |volume=280 |issue=36 |pages=31405–12 |year=2005 |pmid=15987694 |doi=10.1074/jbc.M501489200}}</ref> Paracetamol is metabolized to [[AM404]], a compound with several actions; most important, it inhibits the uptake of the endogenous cannabinoid/vanilloid [[anandamide]] by neurons. Anandamide uptake would result in the activation of the main pain receptor (nociceptor) of the body, the [[TRPV1]] (older name: vanilloid receptor). Furthermore, AM404 inhibits sodium channels, as do the anesthetics lidocaine and procaine.<ref name="DOI10.1007/978-0-387-74349-3_9">{{cite journal |author=Köfalvi A |title=Chapter 9: Alternative interacting sites and novel receptors for cannabinoid ligands. In: 'Cannabinoids and the Brain' Springer-Verlag |pages=131–160 |year=2008 |doi=10.1007/978-0-387-74349-3_9}}</ref> Either of these actions by themselves has been shown to reduce pain, and are a possible mechanism for paracetamol. However, it has been demonstrated that, after blocking cannabinoid receptors with synthetic antagonists, paracetamol's analgesic effects are prevented, suggesting its pain-relieving action involves activation of the endogenous cannabinoid system.<ref name="pmid16438952">{{cite journal |author=Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A |title=The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors |journal=Eur. J. Pharmacol. |volume=531 |issue=1–3 |pages=280–1 |year=2006 |pmid=16438952 |doi=10.1016/j.ejphar.2005.12.015}}</ref>

The exact mechanisms how COX is inhibited in various circumstances is still 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. A recently discovered COX-1 splice variant termed [[COX-3]] was considered to explain some of the knowledge gap, however newer findings do not support the hypothesis that it plays any significant role in the functioning of paracetamol.<ref name="Hinz_2008" />

Aspirin is known to inhibit the [[cyclooxygenase]] (COX) family of enzymes, and because paracetamol's action is partially similar to aspirin's,{{Clarify|date=January 2010}} much research has focused on whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two pathways.<ref name="pmid17227290">{{cite journal |author=Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S |title=Paracetamol: new vistas of an old drug |journal=CNS drug reviews |volume=12 |issue=3–4 |pages=250–75 |year=2006 |pmid=17227290 |doi=10.1111/j.1527-3458.2006.00250.x}}</ref><ref name="pmid16413237">{{cite journal |author=Aronoff DM, Oates JA, Boutaud O |title=New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases |journal=Clin. Pharmacol. Ther. |volume=79 |issue=1 |pages=9–19 |year=2006 |pmid=16413237 |doi=10.1016/j.clpt.2005.09.009}}</ref><ref name="pmid15879007">{{cite journal |author=Kis B, Snipes JA, Busija DW |title=Acetaminophen and the cyclooxygenase-3 puzzle: sorting out facts, fictions, and uncertainties |journal=J. Pharmacol. Exp. Ther. |volume=315 |issue=1 |pages=1–7 |year=2005 |pmid=15879007 |doi=10.1124/jpet.105.085431}}</ref><ref name="pmid15662292">{{cite journal |author=Graham GG, Scott KF |title=Mechanism of action of paracetamol |journal=American journal of therapeutics |volume=12 |issue=1 |pages=46–55 |year=2005 |pmid=15662292| doi = 10.1097/00045391-200501000-00008}}</ref>

One theory holds that paracetamol works by inhibiting the [[COX-3]] isoform of the COX family of enzymes. 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.<ref name="pmid15879007"/> Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that is in an inflammatory environment where the concentration of peroxides is high, and the high oxidation state of paracetamol prevents its actions. This 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.

==Metabolism==
[[Image:Paracetamol metabolism.svg|thumb|250px|Main pathways of paracetamol metabolism (click to enlarge). Pathways shown in blue and purple lead to non-toxic metabolites; the pathway in red leads to toxic [[NAPQI]].]]
Paracetamol is [[drug metabolism|metabolised]] primarily in the [[liver]], into non-toxic products. Three [[metabolic pathway]]s are notable:
*[[Glucuronidation]] is believed to account for 40% to two-thirds of the metabolism of paracetamol.<ref name=Goldfrank>Hendrickson, Robert G.; Kenneth E. Bizovi (2006). "[http://books.google.com/books?id=cvJuLqBxGUcC&pg=PA525 Acetaminophen]", in Nelson, Lewis H.; Flomenbaum, Neal; Goldfrank, Lewis R. ''et al.'' ''Goldfrank's toxicologic emergencies'', p. 525, New York: McGraw-Hill. Retrieved on January 18, 2009 through [[Google Book Search]].</ref>
*Sulfation (sulfate conjugation) may account for 20–40%.<ref name=Goldfrank/>
*N-hydroxylation and rearrangement, then GSH conjugation, accounts for less than 15%. The hepatic [[cytochrome P450]] enzyme system metabolizes paracetamol, forming a minor yet significant alkylating metabolite known as [[NAPQI]] (''N''-acetyl-''p''-benzo-quinone imine).<ref name="foye_medchem">Borne, Ronald F. "Nonsteroidal Anti-inflammatory Drugs" in ''Principles of Medicinal Chemistry'', Fourth Edition. Eds. Foye, William O.; Lemke, Thomas L.; Williams, David A. Published by Williams & Wilkins, 1995. p. 544–545.</ref> NAPQI is then irreversibly conjugated with the [[thiol|sulfhydryl groups]] of [[glutathione]].<ref name="foye_medchem"/>

All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the [[#Toxicity|toxic effects]] of paracetamol; this constitutes an excellent example of [[toxication]].

Production of NAPQI is due primarily to two [[isoenzyme]]s of cytochrome P450: [[CYP2E1]] and [[CYP1A2]]. The P450 gene is highly [[polymorphism (biology)|polymorphic]], however, and individual differences in paracetamol toxicity are believed to be due to a third isoenzyme, [[CYP2D6]]. Genetic polymorphisms in [[CYP2D6]] may contribute to significantly different rates of production of NAPQI. Furthermore, individuals can be classified as [[CYP2D6#Genotype/phenotype variability|"extensive", "ultrarapid", and "poor" metabolizers]] (producers of NAPQI), depending on their levels of CYP2D6 expression. Although CYP2D6 metabolises paracetamol into NAPQI to a lesser extent than other P450 enzymes, its activity may contribute to paracetamol toxicity in extensive and ultrarapid metabolisers, and when paracetamol is taken at very large doses.<ref>{{cite journal |author=Dong H, Haining RL, Thummel KE, Rettie AE, Nelson SD |title=Involvement of human cytochrome P450 2D6 in the bioactivation of acetaminophen |journal=Drug Metab Dispos |volume=28 |issue=12 |pages=1397–400 |year=2000 |pmid=11095574 |doi=}} [http://dmd.aspetjournals.org/cgi/content/full/28/12/1397 Free full text]</ref> At usual doses<!--in poor metabolizers-->, NAPQI is quickly detoxified by conjugation.<ref name="foye_medchem"/> Following overdose, and possibly also in extensive and ultrarapid metabolizers, this detoxification pathway becomes saturated and consequently NAPQI accumulates.

== Indications ==
{{Expand section|date=January 2009}}
The [[World Health Organization]] (WHO) recommends that paracetamol be given to children with fever higher 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>

Paracetamol/acetaminophen is used for the relief of fevers, aches and pains associated with many parts of the body. It has [[analgesic]] and [[antipyretic]] properties comparable to those of [[aspirin]], while its anti-inflammatory effects are weaker. It is better tolerated than [[aspirin]] in patients where excessive [[gastric acid]] secretion or prolongation of bleeding time may be a concern. Available without a prescription, it has in recent years increasingly become a common household drug.<ref>{{cite news|url=http://www.medicinenet.com/acetaminophen/article.htm|title=Medication and Drugs|date=1996-2010|work=MedicineNet|accessdate=April 22, 2010}}</ref>

Acetaminophen can relieve pain in mild arthritis but has no effect on the underlying inflammation, redness, and swelling of the joint. It is as effective as the nonsteroidal anti-inflammatory drug [[ibuprofen]] (Motrin, Advil) in relieving the pain of osteoarthritis of the knee. Unless directed by physician, acetaminophen should not be used for longer than 10 days.

==Efficacy and side effects==
Paracetamol, unlike other common analgesics such as [[aspirin]] and [[ibuprofen]], has relatively little [[anti-inflammatory]] activity, so it is ''not'' considered to be a [[non-steroidal anti-inflammatory drug]] (NSAID).

===Efficacy===
Regarding comparative [[efficacy#Pharmacology|efficacy]], studies show conflicting results when compared to [[Non-steroidal anti-inflammatory drug|NSAIDs]]. A [[randomized controlled trial]] of chronic pain from osteoarthritis in adults found similar benefit from paracetamol and [[ibuprofen]].<ref name="pmid2052056">{{cite journal |author=Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI |title=Comparison of an antiinflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee |journal=N. Engl. J. Med. |volume=325 |issue=2 |pages=87–91 |year=1991 |pmid=2052056 |doi=}}</ref>{{Verify credibility|date=January 2009}}<ref>{{doi|10.1111/j.1365-2710.2006.00754.x}}</ref>

A randomized controlled trial of acute musculoskeletal pain in children found that the standard OTC dose of [[ibuprofen]] gives greater relief of pain than the standard dose of paracetamol.<ref name="pmid17332198">{{cite journal |author=Clark E, Plint AC, Correll R, Gaboury I, Passi B |title=A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma |journal=Pediatrics |volume=119 |issue=3 |pages=460–7 |year=2007 |pmid=17332198 |doi=10.1542/peds.2006-1347}}</ref>{{Verify credibility|date=January 2009}} Another study has questioned the benefits of this drug as an antipyretic in children.<ref>{{cite journal |author=Meremikwu M, Oyo-Ita A |title=Paracetamol for treating fever in children |journal=Cochrane Database Syst Rev |issue=2 |pages=CD003676 |year=2002 |pmid=12076499 |doi=10.1002/14651858.CD003676}}</ref>

===Adverse effects===
In recommended doses, paracetamol does not irritate the lining of the stomach, affect blood [[coagulation]] as much as NSAIDs, or affect function of the [[kidney]]s.{{Citation needed|date=January 2009}} However, some studies have shown that high dose-usage (greater than {{nowrap|2,000 mg per day}}) does increase the risk of upper gastrointestinal complications such as [[Upper gastrointestinal bleeding|stomach bleeding]].<ref>{{cite journal|author= García Rodríguez LA, Hernández-Díaz S|title = The risk of upper gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs, glucocorticoids, acetaminophen, and combinations of these agents|journal = Arthritis Research and Therapy|date = December 15, 2000|doi = 10.1186/ar146|accessdate = December 29, 2006|pmid= 11178116|volume = 3|pages = 98|issue= 2|pmc= 128885}}</ref> The researchers found that heavy use of aspirin or paracetamol - defined as 300&nbsp;grams a year (1&nbsp;g per day on average) - was linked to a condition known as small, indented and calcified kidneys.<ref>{{cite news| url=http://news.bbc.co.uk/2/hi/health/3271191.stm|work=BBC News|title=Painkillers 'cause kidney damage'|date=November 23, 2003|accessdate=March 27, 2010}}</ref> Paracetamol is safe in pregnancy, and does not affect the closure of the fetal [[ductus arteriosus]] as other NSAIDs can.<ref>{{cite journal |author=Rudolph AM |title=Effects of aspirin and acetaminophen in pregnancy and in the newborn |journal=Arch. Intern. Med. |volume=141 |issue=3 Spec No |pages=358–63 |year=1981 |pmid=7469626 |doi= 10.1001/archinte.141.3.358|url=}}</ref> Unlike aspirin, it is safe in children, as paracetamol is not associated with a risk of [[Reye's syndrome]] in children with viral illnesses.<ref>{{cite journal |author=Lesko SM, Mitchell AA |title=The safety of acetaminophen and ibuprofen among children younger than two years old |journal=Pediatrics |volume=104 |issue=4 |pages=e39 |year=1999 |pmid=10506264 |doi= 10.1542/peds.104.4.e39|url=http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=10506264}}</ref>

Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood in any way.
In 2008, the largest study to date on the long term side effects of paracetamol in children was published in ''[[The Lancet]]''. Conducted on over 200,000 children in 31 countries, the study found that the use of paracetamol for fever in the first year of life was associated with an increase in the incidence of [[asthma]]tic symptoms at 6–7 years, and that paracetamol use, both in the first year of life and in children aged 6–7 years, was associated with an increased incidence of [[Allergic conjunctivitis|rhinoconjunctivitis]] and [[eczema]].<ref name=lancet08>{{cite journal|author=Beasley, Richard; Clayton, Tadd; Crane, Julian; von Mutius, Erika; Lai, Christopher; Montefort, Stephen; Stewart, Alistair|year=2008|title=Association between paracetamol use in infancy and childhood, and risk of asthma, rhino conjunctivitis, and eczema in children aged 6–7 years: analysis from Phase Three of the ISAAC programme.|journal=[[The Lancet]]|volume=372|pages=1039–1048|url=http://www.thelancet.com/journals/lancet/article/PIIS0140673608614452/abstract|accessdate=September 19, 2008|doi=10.1016/S0140-6736(08)61445-2}}</ref> The authors acknowledged that their "findings might have been due to confounding by indication", i.e. that the association may not be causal but rather due to the disease being treated with paracetamol, and emphasized that further research was needed. Furthermore a number of editorials, comments, correspondence and their replies have been published in ''The Lancet'' concerning the methodology and conclusions of this study.<ref>{{Cite doi|10.1016/S0140-6736(08)61414-2}}</ref><ref>{{Cite doi|10.1016/S0140-6736(08)61417-8}}</ref><ref>{{Cite doi|10.1016/S0140-6736(09)60032-5}}</ref><ref>{{Cite doi|10.1016/S0140-6736(09)60030-1}}</ref><ref>{{Cite doi|10.1016/S0140-6736(09)60029-5}}</ref><ref>{{Cite doi|10.1016/S0140-6736(09)60028-3}}</ref><ref>{{Cite doi|10.1016/S0140-6736(09)60031-3}}</ref> The UK regulatory body the [[Medicines and Healthcare products Regulatory Agency]], also reviewed this research and published a number of concerns over data interpretation, and offer the following advice for healthcare professionals, parents, and carers: "The results of this new study do not necessitate any change to the current guidance for use in children. Paracetamol remains a safe and appropriate choice of analgesic in children. There is insufficient evidence from this research to change guidance regarding the use of antipyretics in children."<ref>{{Cite journal|title = Paracetamol use in infancy: no strong evidence for asthma link|url = http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON030923|year = 2008|journal = Drug Safety Update|pages = 9|volume = 2|issue = 4|last1=[[Medicines and Healthcare products Regulatory Agency]]|last2=[[Commission on Human Medicines]]|accessdate=May 1, 2009}}</ref>

==Toxicity==
{{Main|Paracetamol toxicity|Analgesic nephropathy}}

Paracetamol hepatotoxicity is, by far, the most common cause of acute liver failure in both the United States and the United Kingdom.<ref name="Larson">{{cite journal |author=Larson AM, Polson J, Fontana RJ, ''et al.'' |title=Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study |journal=Hepatology |volume=42 |issue=6 |pages=1364–72 |year=2005 |pmid=16317692 |doi=10.1002/hep.20948}}</ref><ref>{{cite journal |author=Ryder SD, Beckingham IJ |title=ABC of diseases of liver, pancreas, and biliary system. Other causes of parenchymal liver disease |journal=BMJ |volume=322 |issue=7281 |pages=290–92 |year=2001 |pmid=11157536 |doi=10.1136/bmj.322.7281.290 |pmc=1119531}} [11157536 Free full text]</ref> Paracetamol overdose results in more calls to [[poison control center]]s in the US than overdose of any other pharmacological substance.<ref name="hepatology_2004">{{cite journal |author=Lee WM |title=Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure |journal=Hepatology |volume=40 |issue=1 |pages=6–9 |year=2004 |pmid=15239078 |doi=10.1002/hep.20293 |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/109086434/PDFSTART}}</ref> Signs and symptoms of paracetamol toxicity may initially be absent or vague. Untreated, overdose can lead to [[liver failure]] and death within days. Treatment is aimed at removing the paracetamol from the body and replacing glutathione. [[Activated charcoal]] can be used to decrease absorption of paracetamol if the patient presents for treatment soon after the overdose. While the antidote, [[acetylcysteine]], (also called N-acetylcysteine or NAC) acts as a precursor for glutathione, helping the body regenerate enough to prevent damage to the liver, a [[liver transplant]] is often required if damage to the liver becomes severe.<ref name="DalyMJA"/>

There are tablets available (brandname in the UK Paradote) which combine paracetamol with an antidote (methionine), to protect the liver in case of an overdose.

In June 2009, an [[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 to be consumed at any given time would be decreased from 1000&nbsp;mg to 650&nbsp;mg, while combinations of paracetamol and [[narcotic]] [[analgesics]] 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 [[hepatic]] function.<ref name="WebMD">[http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen "FDA May Restrict Acetaminophen"]</ref> The FDA has not implemented their recommendations as of March 2010.<ref>[http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm165107.htm "FDA: Drug Safety & Availability - Acetaminophen Information"]</ref>

==Effects on animals==
Paracetamol is extremely toxic to cats. Cats lack the necessary [[glucuronyl transferase]] enzymes to safely break paracetamol down, and minute portions of a tablet may prove fatal. Initial symptoms include vomiting, salivation and discolouration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, [[methaemoglobin]] formation and the production of [[Heinz bodies]] in red blood cells inhibit oxygen transport by the blood, causing [[asphyxiation]] ([[methemoglobemia]] and [[hemolytic anemia]]).<ref name="CanVetJ2003-Allen">{{cite journal|author=Allen AL|title=The diagnosis of acetaminophen toxicosis in a cat|journal=Can Vet J|year=2003|pages=509–10|volume=44|issue=6|pmid=12839249|pmc=340185}}</ref> Treatment with [[N-acetylcysteine]], [[methylene blue]] or both is sometimes effective after the ingestion of small doses of paracetamol. According to one paper female cats may have a better survival rate although sample size was small.<ref name="pmid8585668">{{cite journal |author=Rumbeiha WK, Lin YS, Oehme FW |title=Comparison of N-acetylcysteine and methylene blue, alone or in combination, for treatment of acetaminophen toxicosis in cats |journal=Am. J. Vet. Res. |volume=56 |issue=11 |pages=1529–33 |year=1995 |pmid=8585668}}</ref>

Although paracetamol is believed to have no significant anti-inflammatory activity, it has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.<ref name=smallani>{{cite book|title=Small Animal Clinical Pharmacology|first=Jill E.|last=Maddison|coauthors=Stephen W. Page, David Church|publisher=Elsevier Health Sciences|year=2002|isbn=0702025739|pages=260–261}}</ref> A paracetamol-codeine product (trade name Pardale-V)<ref>{{cite web|title = Pardale-V Tablets: Presentation|publisher = UK National Office of Animal Health Compendium of Animal Medicines |date=September 28, 2006|accessdate = 3 January 2007| url = http://www.noahcompendium.co.uk/Dechra/Pardale-V_Oral_Tablets/-27619.html}}</ref> licensed for use in dogs is available on veterinary prescription in the UK.<ref>{{cite web|title = Pardale-V Tablets: Legal Category|publisher = UK National Office of Animal Health Compendium of Animal Medicines|date = November 15, 2005 |accessdate=3 January 2007| url=http://www.noahcompendium.co.uk/Dechra/Pardale-V_Oral_Tablets/-27624.html}}</ref> It should be administered to dogs only on veterinary advice. The main effects of toxicity in dogs is liver damage.<ref name="VetHumToxicol1998-Villar">{{cite journal|author=Villar D, Buck WB, Gonzalez JM|title=Ibuprofen, aspirin and acetaminophen toxicosis and treatment in dogs and cats|journal=Vet Hum Toxicol|year=1998|pages=156–62|volume=40|issue=3|pmid= 9610496}}</ref> N-acetylcysteine treatment is efficacious in dogs when administered within a few hours of paracetamol ingestion.<ref name=smallani/>

Paracetamol is also lethal to snakes, and has been suggested as chemical control program for the [[brown tree snake]] (''Boiga irregularis'') in [[Guam]].<ref>{{cite journal |author=Johnston J, Savarie P, Primus T, Eisemann J, Hurley J, Kohler D |title=Risk assessment of an acetaminophen baiting program for chemical control of brown tree snakes on Guam: evaluation of baits, snake residues, and potential primary and secondary hazards |journal=Environ Sci Technol |volume=36 |issue=17 |pages=3827–33 |year=2002 |pmid=12322757 |doi=10.1021/es015873n}}</ref>

==References==
{{Reflist|colwidth=30em}}

==External links==
{{Portal|Pharmacy and Pharmacology}}
*[http://www.chemsynthesis.com/base/chemical-structure-18651.html Paracetamol at Chemsynthesis]
*[http://www.pharmweb.net/pwmirror/pwy/paracetamol/pharmwebpic.html Paracetamol Information Centre]
*[http://profiles.nlm.nih.gov/HH/Views/Exhibit/narrative/amines.html The Julius Axelrod Papers]
*[http://www.fda.gov/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/UnderstandingOver-the-CounterMedicines/SafeUseofOver-the-CounterPainRelieversandFeverReducers/ucm164977.htm FDA: Safe Use of Over-the-Counter Pain Relievers/Fever Reducers]
*[http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm168830.htm FDA: Consumer Update "Acetaminophen and Liver Injury: Q and A for Consumers" (link)]
*[http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM172664.pdf FDA: Consumer Update "Acetaminophen and Liver Injury: Q and A for Consumers" (PDF)]
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Acetaminophen U.S. National Library of Medicine: Drug Information Portal - Paracetamol]

{{Analgesics}}
{{Cannabinoids}}

[[Category:Phenols]]
[[Category:Acetanilides]]
[[Category:Analgesics]]
[[Category:Antipyretics]]
[[Category:World Health Organization essential medicines]]

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