Paracetamol 83406 move=:edit= 224976261 2008-07-11T07:37:16Z Colonel Warden 953853 fic cite {{drugbox | | IUPAC_name = ''N''-(4-hydroxyphenyl)acetamide | image = Paracetamol-skeletal.svg | image2= Paracetamol-3D-balls.png | width = 200 | CAS_number = 103-90-2 | ATC_prefix = N02 | ATC_suffix = BE01 | PubChem = 1983 | smiles = C1=CC(=CC=C1NC(C)=O)O | DrugBank = APRD00252 | C = 8 |H = 9 |N = 1 |O = 2 | molecular_weight = 151.169 g/mol | density = 1.263 | melting_point = 169 | solubility = 0.1-0.5 g/100 mL at 22 C | bioavailability = almost 100% | metabolism = 90 to 95% [[Liver|Hepatic]] | elimination_half-life = 1–4 hours | excretion = [[Kidney|Renal]] | pregnancy_AU = A | pregnancy_US = B | pregnancy_category = safe | legal_AU = unscheduled | legal_UK = GSL | legal_US = OTC | routes_of_administration = Oral, [[rectal]], [[Intravenous therapy|intravenous]] | licence_US = ACETAMINOPHEN }}'''Paracetamol''' ([[International Nonproprietary Name|INN]]) ({{IPAEng|ˌpærəˈsiːtəmɒl, -ˈsɛtə-}}) or '''acetaminophen''' ([[United States Adopted Name|USAN]]) is a widely-used [[analgesic]] and [[antipyretic]]. Derived from [[coal tar]], it is the active metabolite of [[phenacetin]], but unlike phenacetin, paracetamol has not been shown to be [[carcinogenic]] in any way. Unlike [[aspirin]], it is not a very effective [[anti-inflammatory]] agent. It is well tolerated, lacks many of the side-effects of [[aspirin]], and is available [[over-the-counter drug|over-the-counter]], so it is commonly used for the relief of [[fever]], [[headache]]s, and other minor aches and pains. Paracetamol is also useful in the management of more severe pain, where it allows lower dosages of additional [[non-steroidal anti-inflammatory drug]]s (NSAIDs) to be used, thereby minimizing overall side-effects. It is also used in combination with [[opioid]] analgesics.<ref> ''Control of Pain in Patients with Cancer'' Sign Guidelines '''40'''Section 6 [http://www.sign.ac.uk/guidelines/fulltext/44/section6.html].</ref> It is a major ingredient in numerous [[common cold|cold]] and [[Influenza|flu]] [[List of paracetamol brand names|medications]]. It is considered safe for human use at recommended doses; however, acute [[overdose]] can cause potentially fatal [[Hepatotoxicity|liver damage]]. The risk is heightened by the use of alcohol. The number of accidental self-poisonings and [[suicide]]s from paracetamol has grown in recent years.<ref>{{citation|url=http://www.foxnews.com/story/0,2933,179845,00.html|title=Acetaminophen poisonings on the rise|publisher=Fox News|date=Dec 27, 2005}}</ref> The words ''acetaminophen'' and ''paracetamol'' come from the chemical names for the compound: ''para''-'''acet'''yl'''aminophen'''ol and '''''par'''a''-'''acet'''yl'''am'''inophen'''ol'''. (The brand name [[Tylenol]] also derives from this name: ''para''-ace'''tyl'''aminoph'''enol'''.) In some contexts, it is shortened to '''APAP''', for ''N''-'''a'''cetyl-'''p'''ara-'''a'''mino'''p'''henol. == History == In ancient and medieval times, known [[antipyretic]] agents were compounds contained in white [[willow]] bark (a family of chemicals known as [[salicin]]s, which led to the development of [[aspirin]]), and compounds contained in [[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 was also used to create the anti-[[malaria]] drug [[quinine]]. Quinine itself also has antipyretic effects. 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 = 2006-12-29 | url = http://www.didyouknow.cd/aspirin.htm}}</ref> When the cinchona tree became scarce in the 1880s, people began to look for alternatives. Two alternative antipyretic agents were developed in the 1880s: [[acetanilide]] in 1886 and [[phenacetin]] in 1887. [[Harmon Northrop Morse]] first synthesized paracetamol via the reduction of [[4-Nitrophenol|''p''-nitrophenol]] with [[tin]] in glacial [[acetic acid]] in 1878;<ref>{{cite journal | title = Ueber eine neue Darstellungsmethode der Acetylamidophenole | pages = 232–233 | author = H. N. Morse | year = 1878 | doi = 10.1002/cber.18780110151 | journal = Berichte der deutschen chemischen Gesellschaft | volume = 11 | issue = 1}}</ref> however, paracetamol was not used in medical treatment for another 15 years. In 1893, paracetamol was discovered in the urine of individuals that had taken [[phenacetin]], and was concentrated into a white, crystalline compound with a bitter taste. In 1899, paracetamol was found to be a metabolite of acetanilide. This discovery was largely ignored at the time. In 1946, the Institute for the Study of Analgesic and Sedative Drugs awarded a grant to the New York City Department of Health to study the problems associated with analgesic agents. Bernard Brodie and [[Julius Axelrod]] were assigned to investigate why non-aspirin agents were associated with the development of [[methemoglobinemia]], a condition that decreases the oxygen-carrying capacity of blood and is potentially lethal. In 1948, Brodie and Axelrod linked the use of acetanilide with methemoglobinemia and determined that the analgesic effect of acetanilide was due to its active metabolite paracetamol. They advocated the use of paracetamol, since it did not have the toxic effects of acetanilide.<ref name="Jpharmacol1948-Brodie">{{cite journal| author= Brodie BB, Axelrod J | title=The fate of acetanilide in man | journal=J Pharmacol Exp Ther | year=1948 | pages=29–38 | volume=94 | issue=1 |url=http://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdf |format=PDF}}</ref> The product was first sold in 1955 by McNeil Laboratories as a pain and fever reliever for children, under the brand name [[Tylenol|Tylenol Children's Elixir]].<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. In June 1958, a children's formulation, '''Panadol Elixir''', was released. 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. 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." == Chemistry == === Structure and reactivity === 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]]. 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]]. === Synthesis === From the starting material phenol, paracetamol can be made in the following manner: # Phenol is nitrated using sulfuric acid and [[sodium nitrate]] (as phenol is highly activated, its nitration requires very mild conditions compared to the oleum-fuming nitric acid mixture required to nitrate benzene). # The para isomer is separated from the ortho isomer by fractional distillation (there will be little of meta, as OH is o-p directing). # The 4-nitrophenol is reduced to 4-aminophenol using a reducing agent such as [[sodium borohydride]] in basic medium. # 4-aminophenol is reacted with [[acetic anhydride]] to give paracetamol. Notice that the synthesis of paracetamol lacks one very significant difficulty inherent in almost all drug syntheses: Lack of [[stereocenter]]s means there is no need to design a stereo-selective synthesis. More efficient, industrial syntheses are also available. == Available forms == [[Image:medAcetaminophen.jpg|thumb|right|Tablets are the most common form of paracetamol.]] [[Image:Panadol suppositories.jpg|thumb|right|500&nbsp;mg Panadol suppositories]] '''Panadol''', which is marketed in Europe, Africa, Asia, 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-PPC, Inc), '''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. 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 approximately 1/8&nbsp;[[grain (measure)|grain]], approximately 1/4&nbsp;[[grain (measure)|grain]], approximately 1/2&nbsp;[[grain (measure)|grain]], and approximately 1&nbsp;[[grain (measure)|grain]] of [[codeine]], respectively. A US [[grain (measure)|grain]] is 64.78971&nbsp;milligrams - this is usually rounded in manufacture down to a multiple of 5&nbsp;mg (so that a #3 contains 30 mg, and a #4 contains 60 mg, while a #1 may be 8 mg or 10 mg depending on manufacturer. 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 generics 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 [[hydrocodone|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. It is commonly administered in [[tablet]], liquid suspension, [[suppository]], [[intravenous]], or [[intramuscular]] form. The common adult dose is 500&nbsp;[[milligram|mg]] to 1000&nbsp;mg. The recommended maximum daily dose, for adults, is 4&nbsp;grams. In recommended doses, paracetamol is safe for children and infants, as well as for adults. {| class="wikitable" |- ! Brand Names<ref>{{cite book | title = Reader's Digest Guide to Drugs and Supplements | publisher = Reader's Digest Association, Inc. | date = 2002 | location = Pleasantville, New York; Montreal | isbn = 0-7621-0366-3}} </ref> |- | Aceta, Actimin, Anacin-3, Apacet, Aspirin Free Anacin, Atasol, Banesin, Dapa, Datril Extra-Strength, Feverall, Fibi, Fibi plus, Genapap, Genebs, Liquiprin, Neopap, Oraphen-PD, Panadol, Paralen, Phenaphen, Redutemp, Snaplets-FR, Suppap, Tapanol, Tylenol, Valorin, Xcel, Few Drops. |} == Mechanism of action == The mechanism by which paracetamol reduces fever and pain is still a source of debate.<ref name="AMH">[http://www.amh.net.au Australian Medicine Handbook] 2008, pg 30</ref> The reason for this confusion has largely been due to the fact that paracetamol reduces the production of [[prostaglandins]]—pro-inflammatory chemicals. [[Aspirin]] also inhibits the production of prostaglandins, but, unlike aspirin, paracetamol does not have much anti-inflammatory action. Likewise, whereas aspirin inhibits the production of the pro-clotting chemicals [[thromboxane]]s, paracetamol does not. Aspirin is known to inhibit the [[cyclooxygenase]] (COX) family of enzymes, and, because of paracetamol's partial similarity of aspirin's action, much research has focused on whether paracetamol also inhibits COX. It is now clear, however, that paracetamol acts via (at least) two pathways.<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="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="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="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> 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. The activity of the COX enzyme relies on its being in the oxidized form to be specific, tyrosine 385 must be oxidized to a radical.<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 |issue= |pages=739–47 |year=1986 |pmid=3094341 |doi=}}</ref> It has been shown that 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, p.687–731.</ref> Further research has shown that 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, similarly to 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, though it has been demonstrated that, after blocking cannabinoid receptors and hence making any action of cannabinoid reuptake irrelevant, paracetamol no longer has any analgesic effect, suggesting its pain-relieving action is indeed mediated by 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> One theory holds that paracetamol works by inhibiting the [[COX-3]] isoform of the cyclooxygenase family of enzymes. This enzyme, when expressed in dogs, shares a strong similarity to the other COX enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol.<ref>{{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}}</ref> 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 is able to block cycloxygenase as in aspirin, but that in an inflammatory environment, where the concentration of peroxides is high, the oxidation state of paracetamol is high which prevents its actions. This would mean that paracetamol has no direct effect at the site of inflammation but instead acts in the CNS to reduce temperature etc where the environment is not oxidative.<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}}</ref> The exact mechanism by which paracetamol is believed to affect COX-3 is still disputed by some research. == Metabolism == [[Image:Paracetamol metabolism.png|thumb|350px|right|The reactions involved in paracetamol metabolism.]] Paracetamol is [[drug metabolism|metabolised]] primarily in the [[liver]], where its major metabolites include inactive sulfate and [[glucuronide]] conjugates, which are excreted by the kidneys. Only a small, yet significant amount is metabolised via the hepatic [[cytochrome P450]] enzyme system (its [[CYP2E1]] and [[CYP1A2]] isoenzymes), which is responsible for the toxic effects of paracetamol due to a minor alkylating metabolite (''N''-acetyl-''p''-benzo-quinone imine, abbreviated as [[NAPQI]]).<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> There is a great deal of [[polymorphism (biology)|polymorphism]] in the P450 gene, and genetic polymorphisms in [[CYP2D6]] have been studied extensively. The population can be [[CYP2D6#Genotype/phenotype variability|divided into]] "extensive," "ultrarapid," and "[[Poor metaboliser|poor metabolizers]]" depending on their levels of CYP2D6 expression. CYP2D6 may also contribute to the formation of NAPQI, albeit to a lesser extent than other P450 isozymes, and its activity may contribute to paracetamol toxicity, in particular, in extensive and ultrarapid metabolizers 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> The metabolism of paracetamol is an excellent example of [[toxication]], because the metabolite NAPQI is primarily responsible for toxicity rather than paracetamol itself. Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance, accounting for more than 100,000 calls, as well as 56,000 emergency room visits, 2,600 hospitalizations, and 458 deaths due to acute liver failure per year.<ref name="hepatology_2004">Lee, William M. "[http://www3.interscience.wiley.com/cgi-bin/fulltext/109086434/PDFSTART Acetaminophen and the U.S. acute liver failure study group: Lowering the risks of hepatic failure]." ''Hepatology''. [[June 30]], [[2004]]. Vol. 40, Issue 1. p. 6–9. Retrieved on [[August 17]], [[2007]].</ref> A recent study of cases of acute liver failure between November 2000 and October 2004 by the [[Centers for Disease Control and Prevention]] (US) found that paracetamol was the cause of 41% of all cases in adults, and 25% of cases in children.<ref name="CDC_study_2007">Bower, W.A.; Johns, M.; Margolis, H.S.; Williams, I.T.; Bell, B.P. "[http://www.blackwell-synergy.com/doi/abs/10.1111/j.1572-0241.2007.01388.x Population-Based Surveillance for Acute Liver Failure]." ''Am. J. Gastroenterol.'' [[June 29]], [[2007]]. Retrieved on [[August 17]], [[2007]].</ref> At usual doses, the toxic metabolite NAPQI is quickly detoxified by combining irreversibly with the [[thiol|sulfhydryl groups]] of [[glutathione]] or administration of a sulfhydryl compound such as [[N-acetylcysteine]], to produce a non-toxic conjugate that is eventually excreted by the [[kidney]]s.<ref name="foye_medchem"/> Also, [[methionine]] has been recommended in some cases,<ref name="methionine">Mant, T.G.K.; Tempowski, J.H.; Volans, G.N.; Talbot, J.C.C. "[http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1442311&blobtype=pdf Adverse reactions to acetylcysteine and effects of overdose]." ''British Medical Journal.'' [[July 28]], [[1984]]. Vol. 289. pp. 217–219. Retrieved on [[August 17]], [[2007]].</ref> although recent studies show that N-acetylcysteine is a more effective antidote to paracetamol overdose.<ref name="overdose_comp">Alsalim, W.; Fadel, M. "[http://emj.bmj.com/cgi/content/abstract/20/4/366 Oral methionine compared with intravenous n-acetyl cysteine for paracetamol overdose]." ''Emerg. Med. J.'' 2003. Vol. 20. pp. 366–367. Retrieved on [[August 17]], [[2007]].</ref> ==Comparison with NSAIDs== Paracetamol, unlike other common analgesics such as [[aspirin]] and [[ibuprofen]], has relatively little [[anti-inflammatory]] activity, and 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> However, a [[randomized controlled trial]] of acute musculoskeletal pain in children found that the standard OTC dose of [[ibuprofen]] (400&nbsp;mg) gives greater relief of pain than the standard dose of paracetamol (1000 &nbsp;mg).<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> ===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. However, some studies have shown that high dose-usage (greater than {{nowrap|2000 mg per day}}) does increase the risk of upper gastrointestinal complications.<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 = 2006-12-29 | pmid= 11178116 | volume = 3 | pages = 98}}</ref> Paracetamol is safe in pregnancy, and does not affect the closure of the fetal [[ductus arteriosus]] as NSAIDs can. Unlike aspirin, it is safe in children, as paracetamol is not associated with a risk of [[Reye's syndrome]] in children with viral illnesses. Like NSAIDs and unlike [[opioid]] analgesics, paracetamol has not been found to cause euphoria or alter mood in any way. While paracetamol and NSAIDs may damage the liver, they do not pose a large risk of [[addiction]], [[Chemical dependency|dependence]], [[physiological tolerance|tolerance]], and [[withdrawal]]. Paracetamol, particularly in combination with weak [[opioid]]s, is more likely than NSAIDs to cause [[rebound headache]] (medication overuse headache), although less of a risk than [[ergotamine]] or [[triptan]]s used for [[migraine]]s.<ref>{{cite journal | author=Colás Chacartegui R, Temprano González R, Gómez Arruza C, Muñoz Cacho P, Pascual Gómez J | title=[Abuse pattern of analgesics in chronic daily headache: a study in the general population] | journal=Rev Clin Esp | volume=205 | issue=12 | pages=583–87 | year=2005 | pmid= 16527179}}</ref> A 2008 preliminary case-control study based on a parent survey presented evidence that paracetamol following [[MMR vaccine|MMR vaccination]] is apparently associated with development of [[autism]] in children aged 1–5 years. The effect seemed to appear only in children who show some post-vaccination regression together with other post-vaccination [[sequelae]] such as fever, and it was not seen with other painkillers such as ibuprofen. The effect has not been independently confirmed.<ref>{{cite journal |journal=Autism |date=2008 |volume=12 |issue=3 |pages=293–307 |title= Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey |author= Schultz ST, Klonoff-Cohen HS, Wingard DL, Akshoomoff NA, Macera CA, Ji M |doi=10.1177/1362361307089518 |pmid=18445737}}</ref> == Toxicity == Paracetamol is contained in many preparations (both [[over-the-counter drug|over-the-counter]] and [[prescription drug|prescription-only]] medications). In some animals—for example, cats—small doses are toxic. Because of the wide availability of paracetamol, there is a large potential for overdose and toxicity.<ref>{{cite journal | author = Sheen C, Dillon J, Bateman D, Simpson K, Macdonald T | title = Paracetamol toxicity: epidemiology, prevention and costs to the health-care system | journal = QJM | volume = 95 | issue = 9 | pages = 609–19 | year = 2002 | pmid = 12205339 | url=http://qjmed.oxfordjournals.org/cgi/content/full/95/9/609 | doi = 10.1093/qjmed/95.9.609}}</ref> Without timely treatment, overdose can lead to [[liver failure]] and death within days; paracetamol toxicity 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}} [11157536 Free full text]</ref> It is sometimes used in [[suicide]] attempts by those unaware of the prolonged timecourse and high morbidity (likelihood of significant illness) associated with paracetamol-induced toxicity in survivors.{{Fact|date=June 2008}} In the UK, sales of over-the-counter paracetamol are restricted to packs of 32 tablets in pharmacies, and 16 tablets in non-pharmacy outlets.<ref>[http://www.hants.gov.uk/regulatory/tradingstandards/medicines.html Limits on Sale in UK]</ref> Up to 100 tablets may be sold in a single transaction, except in pharmacies, where only 32 may be sold, with more being sold at a pharmacist's discretion. In Ireland, the limits are 24 and 12 tablets, respectively. In Australia, paracetamol tablets are available at supermarkets in small-pack sizes, whereas, with children's formulations, pack sizes greater than 48 tablets and suppositories are restricted to pharmacies.{{Fact|date=June 2008}} === Mechanism === Paracetamol is mostly converted to inactive compounds via [[Drug metabolism#Phase I vs. Phase II|Phase II metabolism]] by conjugation with [[sulfate]] and [[glucuronide]], with a small portion being oxidized via the [[Cytochrome P450 oxidase|cytochrome P450]] enzyme system. Cytochromes {{nowrap|P450 2E1}} ([[CYP2E1]]) and 3A4 ([[CYP3A4]]) convert paracetamol to a highly-reactive intermediary metabolite, N-acetyl-p-benzo-quinone imine ([[NAPQI]]).<ref name="RichardsonJA">Richardson, J.A. Management of acetaminophen and ibuprofen toxicoses in dogs and cats. ''J Vet Emerg Crit Care.'' 2000; 10: 285–291.</ref><ref name="RumbeihaWK">Rumbeiha, W.K.; Lin, Y.S.; Oehme, F.W. Comparison of N-acetylcysteine and methylene blue, alone or in combination, for treatment of acetaminophen toxicosis in cats. ''Am J Vet Res.'' 1995; 56: 1529–1533.</ref><ref name="SellonRK">Sellon, R.K. Acetaminophen. In: Peterson ME, Talcott PA, eds. Small Animal Toxicology. Toronto: WB Saunders, 2001: 388–395.</ref> Under normal conditions, NAPQI is detoxified by conjugation with [[glutathione]]. In cases of paracetamol toxicity, the sulfate and glucuronide pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI. As a result, hepatocellular supplies of glutathione become exhausted and NAPQI is free to react with cellular membrane molecules, resulting in widespread [[hepatocyte]] damage and death, leading to acute hepatic necrosis. In animal studies, hepatic glutathione must be depleted to less than 70% of normal levels before hepatotoxicity occurs.<ref name="RichardsonJA">Richardson, J.A. Management of acetaminophen and ibuprofen toxicoses in dogs and cats. ''J Vet Emerg Crit Care.'' 2000; 10: 285–291.</ref> === Toxic dose === The toxic dose of paracetamol is highly variable. In adults, single doses above 10&nbsp;grams or 200&nbsp;mg/kg, which ever is lower, have a reasonable likelihood of causing toxicity.<ref name="clintox2006-dart">{{cite journal | author=Dart RC, Erdman AR, Olson KR, Christianson G, Manoguerra AS, Chyka PA, Caravati EM, Wax PM, Keyes DC, Woolf AD, Scharman EJ, Booze LL, Troutman WG; American Association of Poison Control Centers | title=Acetaminophen poisoning: an evidence-based consensus guideline for out-of- hospital management | journal=Clin Toxicol (Phila) | year=2006 | pages=1–18 | volume=44 | issue=1 | pmid= 16496488}}</ref><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 |month=March |pmid=18312195 |doi= |url=http://www.mja.com.au/public/issues/188_05_030308/dal10916_fm.html}}</ref> Toxicity can also occur when multiple smaller doses within 24 hours exceeds these levels, or even with chronic ingestion of doses as low as 4&nbsp;g/day, and death with as little as 6&nbsp;g/day.{{Fact|date=June 2008}} In children acute doses above 200&nbsp;mg/kg could potentially cause toxicity.<ref name="clintox2004-tenenbein">{{cite journal | author = Tenenbein M | title = Acetaminophen: the 150 mg/kg myth | journal = J Toxicol Clin Toxicol | volume = 42 | issue = 2 | pages = 145–48 | year = 2004 | pmid = 15214618}}</ref> However, acute paracetamol overdose in children rarely causes illness or death, and it is very uncommon for them to have levels that require treatment, with chronic supratherapeutic doses being the major cause of toxicity in children.<ref name="DalyMJA"/> In a normal dose of 1 gram of paracetamol four times a day, one-third of patients may have an increase in their [[liver function tests]] to three times the normal value.<ref name="pmid16820551">{{cite journal |author=Watkins PB, Kaplowitz N, Slattery JT, ''et al'' |title=Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial |journal=JAMA |volume=296 |issue=1 |pages=87–93 |year=2006 |pmid=16820551 |doi=10.1001/jama.296.1.87}}</ref> However, it is unclear as to whether this leads to [[liver failure]].<ref name="pmid17723075">{{cite journal |author=Dart RC, Bailey E |title=Does therapeutic use of acetaminophen cause acute liver failure? |journal=Pharmacotherapy |volume=27 |issue=9 |pages=1219–30 |year=2007 |pmid=17723075 |doi=10.1592/phco.27.9.1219}}</ref> Since paracetamol is often included in combination with other drugs, it is important to include all sources of paracetamol when checking a person's dose for toxicity. In addition to being sold by itself, paracetamol may be included in the formulations of various analgesics and cold/flu remedies as a way to increase the pain-relieving properties of the medication, and sometimes in combination with [[opioids]] such as [[hydrocodone]] to deter people from using it recreationally or becoming addicted to the opioid substance. In fact, the human toll of paracetamol, in terms of both fatal overdoses and chronic liver toxicity, likely far exceeds the damage caused by the opioids themselves.<ref name="brecher1972-drugs">{{cite book | author = Brecher, Edward M | title = Consumers Union Report on Licit and Illicit Drugs | year = 1972 |location = Boston |publisher = Little, Brown | isbn = 0316153400}}</ref>{{page number}} === Risk factors === Chronic excessive [[alcohol consumption and health|alcohol consumption]] can [[enzyme induction and inhibition|induce]] [[CYP2E1]], thus increasing the potential toxicity of paracetamol.<ref name="Hepatology1995-Zimmerman">{{cite journal | author=Zimmerman HJ, Maddrey WC | title=Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure | journal=Hepatology | year=1995 | pages=767–73 | volume=22 | issue=3 | pmid= 7657281}}</ref> For this reason, [[analgesic]]s such as [[aspirin]] or [[ibuprofen]] are often recommended over paracetamol for relief of [[hangover]]s when other factors, such as gastric irritation, are not involved.{{Fact|date=June 2008}} [[Fasting]] is a risk factor, possibly because of depletion of hepatic glutathione reserves.<ref name="DalyMJA"/> It is well documented that concomitant use of the CYP2E1 inducer [[isoniazid]] increases the risk of hepatotoxicity, though whether 2E1 induction is related to the hepatotoxicity in this case is unclear.<ref name="AmJGastroenterol1993-Crippin">{{cite journal | author=Crippin JS | title=Acetaminophen hepatotoxicity: potentiation by isoniazid | journal=Am J Gastroenterol | year=1993 | pages=590–92 | volume=88 | issue=4 | pmid= 8470644}}</ref><ref name="Chest1994-Nolan">{{cite journal | author=Nolan CM, Sandblom RE, Thummel KE, Slattery JT, Nelson SD | title=Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis | journal=Chest | year=1994 | pages=408–11 | volume=105 | issue=2 | pmid= 7508362 | doi = 10.1378/chest.105.2.408}}</ref> Concomitant use of other drugs that induce CYP enzymes such as antiepileptics (including [[carbamazepine]], [[phenytoin]], and [[barbiturate]]s) have also been reported as risk factors.{{Fact|date=June 2008}} === Natural history === Individuals that have overdosed on paracetamol, in general, have no specific symptoms for the first 24 hours. Although [[nausea]], [[vomiting]], and [[diaphoresis]] may occur initially, these symptoms, in general, resolve after several hours. After resolution of these symptoms, individuals tend to feel better, and may believe that the worst is over. If a [[toxic]] dose was absorbed, after this brief feeling of relative [[Health|wellness]], the individual develops overt [[liver failure]]. In massive overdoses, [[coma]] and [[metabolic acidosis]] may occur prior to hepatic failure. In general, damage occurs in hepatocytes as they metabolize the paracetamol. Rarely, [[acute renal failure]] also may occur. This is usually caused by either [[hepatorenal syndrome]] or [[Multiple organ dysfunction syndrome]]. Acute renal failure may also be the primary clinical manifestation of toxicity. In these cases, it has been suggested that the toxic metabolite is produced more in the kidneys than in the liver.<ref name="clintox2001-boutis">{{cite journal | author = Boutis K, Shannon M | title = Nephrotoxicity after acute severe acetaminophen poisoning in adolescents | journal = J Toxicol Clin Toxicol | volume = 39 | issue = 5 | pages = 441–5 | year = 2001 | pmid = 11545233 | doi = 10.1081/CLT-100105413}}</ref> The prognosis of paracetamol toxicity varies depending on the dose and the appropriate treatment. In some cases, massive hepatic [[necrosis]] leads to fulminant hepatic failure with complications of bleeding, [[hypoglycemia]], [[renal failure]], [[hepatic encephalopathy]], [[cerebral edema]], [[sepsis]], multiple organ failure, and death within days. In many cases, the hepatic necrosis may run its course, hepatic function may return, and the patient may survive with liver function returning to normal in a few weeks.{{Fact|date=June 2008}} === Diagnosis === Evidence of liver toxicity may develop in one to four days, although, in severe cases, it may be evident in 12 hours. Right-upper-quadrant tenderness may be present. Laboratory studies may show evidence of massive hepatic necrosis with elevated [[aspartate transaminase|AST]], [[alanine transaminase|ALT]], [[bilirubin]], and prolonged coagulation times (in particular, elevated [[prothrombin time]]). After paracetamol overdose, when AST and ALT exceed 1000&nbsp;IU/L, paracetamol-induced hepatotoxicity can be diagnosed. However, the AST and ALT levels can exceed 10,000&nbsp;IU/L. In general, the AST is somewhat higher than the ALT in paracetamol-induced hepatotoxicity. A drug [[nomogram]] was developed in 1975, which estimated the risk of toxicity based on the serum concentration of paracetamol at a given number of hours after ingestion.<ref name="pediatrics1975-rumack">{{cite journal | author = Rumack B, Matthew H | title = Acetaminophen poisoning and toxicity | journal = Pediatrics | volume = 55 | issue = 6 | pages = 871–76 | year = 1975 | pmid = 1134886}}</ref> To determine the risk of potential hepatotoxicity, the paracetamol level is traced along the standard nomogram. A paracetamol level drawn in the first four hours after ingestion may underestimate the amount in the system because paracetamol may still be in the process of being absorbed from the gastrointestinal tract. Delay of the initial draw for the paracetamol level to account for this is not recommended, since the history in these cases is often poor and a toxic level at any time is a reason to give the antidote. === Treatment === ====Initial measures==== The initial treatment for uncomplicated paracetamol [[overdose]], similar to most other overdoses, is gastrointestinal decontamination. In addition, the [[antidote]], [[acetylcysteine]] plays an important role. Paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this time. Absorption may be somewhat slowed when it is ingested with food. There is considerable room for physician judgement regarding gastrointestinal decontamination; [[activated charcoal]] administration is the most commonly-used procedure; however, [[gastric lavage]] may also be considered if the amount ingested is potentially life threatening and the procedure can be performed within 60 minutes of ingestion.<ref name="jtoxclintox2004-vale">{{cite journal | author=Vale JA, Kulig K; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists | title=Position paper: gastric lavage | journal=J Toxicol Clin Toxicol | year=2004 | pages=933–43 | volume=42 | issue=7 | pmid=15641639 | doi=10.1081/CLT-200045006}}</ref> [[Syrup of ipecac]] has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated charcoal and oral acetylcysteine.<ref name="clintox2006-dart"/> Activated charcoal [[adsorbs]] paracetamol, reducing its gastrointestinal absorption. Administering activated charcoal also poses less risk of [[Aspiration pneumonia|aspiration]] than gastric lavage. Previous to this method, there was reluctance to give activated charcoal in paracetamol overdose, because of concern that it may also absorb acetylcysteine. Studies have shown that no more than 39% of an oral acetylcysteine is absorbed when they are administered together.<ref name="AmJEmergMed1987-ekins">{{cite journal | author = Ekins B, Ford D, Thompson M, Bridges R, Rollins D, Jenkins R | title = The effect of activated charcoal on N-acetylcysteine absorption in normal subjects | journal = Am J Emerg Med | volume = 5 | issue = 6 | pages = 483–87 | year = 1987 | pmid = 3663288 | doi = 10.1016/0735-6757(87)90166-5}}</ref> Other studies have shown that activated charcoal seems to be beneficial to the clinical outcome. It appears that the most benefit from activated charcoal is gained if it is given within two hours of ingestion.<ref name="jtoxclintox1999-buckley">{{cite journal | author=Buckley NA, Whyte IM, O'Connell DL, Dawson AH. | title=Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose | journal=J Toxicol Clin Toxicol | year=1999 | pages=753–57 | volume=37 | issue=6 | pmid=10584587 | doi=10.1081/CLT-100102452}}</ref> However, administering activated charcoal later than this can be considered in patients that may have delayed gastric emptying due to co-ingested drugs or following ingestion of sustained- or delayed-release paracetamol preparations. Activated charcoal should also be administered if co-ingested drugs warrant decontamination. There are conflicting recommendations<ref name="AmJEmergMed1987-ekins"/><ref name="AnnEmergMed1994-spiller">{{cite journal | author = Spiller H, Krenzelok E, Grande G, Safir E, Diamond J | title = A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose | journal = Ann Emerg Med | volume = 23 | issue = 3 | pages = 519–23 | year = 1994 | pmid = 8135427 | doi = 10.1016/S0196-0644(94)70071-0}}</ref> regarding whether to change the dosing of oral acetylcysteine after the administration of activated charcoal, and even whether the dosing of acetylcysteine needs to be altered at all. ====Acetylcysteine==== [[Acetylcysteine]] (also called N-Acetylcysteine or NAC) works to reduce paracetamol toxicity by supplying sulfhydryl groups (mainly in the form of [[glutathione]], of which it is a [[protein precursor|precursor]]) to react with the toxic NAPQI metabolite so that it does not damage cells and can be safely excreted. (NAC can be bought as a dietary supplement in the United States.) If the patient presents less than eight hours after paracetamol overdose, then acetylcysteine significantly reduces the risk of serious hepatotoxicity. If NAC is started more than 8 hours after ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver has already begun, and the risk of acute hepatic necrosis and death increases dramatically. Although acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48 hours after ingestion.<ref name="BMJ1991-keays">{{cite journal | author = Keays R, Harrison P, Wendon J, Forbes A, Gove C, Alexander G, Williams R | title = Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial | journal = BMJ | volume = 303 | issue = 6809 | pages = 1026–9 | year = 1991 | pmid = 1954453}}</ref> In clinical practice, if the patient presents more than eight hours after the paracetamol overdose, then activated carbon is probably not useful, and acetylcysteine is started immediately. In earlier presentations, the doctor can give carbon as soon as the patient arrives, start giving acetylcysteine, and wait for the paracetamol level from the laboratory. In United States practice, [[intravenous]] (IV) and oral administration are considered to be equally effective. However, IV is the only recommended route in Australasian and British practice. Oral acetylcysteine is given as a&nbsp;140mg/kg loading dose followed by 70&nbsp;mg/kg every four hours for 17 more doses. Oral acetylcysteine may be poorly tolerated due to its unpleasant taste, odor, and its tendency to cause nausea and vomiting. It can be diluted to a 5% solution, from its marketed 10% or 20% solutions, to improve palatability. Where oral acetylcysteine is required, the inhalation formulation of acetylcysteine (Mucomyst) is often given orally. The respiratory formulation can also be diluted and filter sterilized by a hospital pharmacist for IV use; however this is an uncommon practice. If repeat doses of carbon are indicated because of another ingested drug, then subsequent doses of carbon and acetylcysteine should be staggered every two hours. Intravenous acetylcysteine (Parvolex/Acetadote) is used as a continuous intravenous infusion over 20 hours (total dose 300&nbsp;mg/kg). Recommended administration involves infusion of a 150mg/kg loading dose over 15 minutes, followed by a 50mg/kg infusion over four hours; the last 100&nbsp;mg/kg are infused over the remaining 16 hours of the protocol. Intravenous acetylcysteine has the advantage of shortening hospital stay, increasing both doctor and patient convenience, and it allows administration of activated carbon to reduce absorption of both the paracetamol and any co-ingested drugs without concerns about interference with oral acetylcysteine.<ref name="clintox1999-buckley">{{cite journal | author = Buckley N, Whyte I, O'Connell D, Dawson A | title = Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning? | journal = J Toxicol Clin Toxicol | volume = 37 | issue = 6 | pages = 759–67 | year = 1999 | pmid= 10584588 | doi = 10.1081/CLT-100102453}}</ref> Baseline laboratory studies include [[bilirubin]], [[Aspartate transaminase|AST]], [[Alanine transaminase|ALT]], and [[prothrombin time]] (with INR). Studies are repeated at least daily. Once it has been determined that a potentially-toxic overdose has occurred, acetylcysteine is continued for the entire regimen, even after the paracetamol level becomes undetectable in the blood. If hepatic failure develops, acetylcysteine should be continued beyond the standard doses until hepatic function improves or until the patient has a liver transplant. ===Prognosis=== The mortality rate from paracetamol overdose increases two days after the ingestion, reaches a maximum on day four, and then gradually decreases. Patients with a poor prognosis are usually identified for likely liver transplantation. [[Acidemia]] is the most important single indicator of probable mortality and the need for transplantation. A mortality rate of 95% without transplant was reported in patients who had a documented [[pH]] less than 7.30. Other indicators of poor prognosis include [[renal insufficiency]], grade 3 or worse [[hepatic encephalopathy]], a markedly elevated prothrombin time, or a rise in prothrombin time from day three to day four. One study has shown that a [[factor V]] level less than 10% of normal indicated a poor prognosis (91% mortality), whereas a ratio of [[factor VIII]] to factor V of less than 30 indicated a good prognosis (100% survival).<ref name="Pereira">{{cite journal |author=Pereira LM, Langley PG, Hayllar KM, Tredger JM, Williams R |title=Coagulation factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators |journal=Gut |volume=33 |issue=1 |pages=98–102 |year=1992 |pmid=1740285 | doi = 10.1136/gut.33.1.98}} {{PMC|1373872}}</ref> ===Prevention=== Besides preventing an overdose, one way to prevent liver damage may be the use of Paradote. Paradote is a combination tablet containing 100 mg [[methionine]] and 500 mg paracetamol. Methionine is included in order to ensure that sufficient levels of [[glutathione]] in the [[liver]] are maintained in order to minimize the liver damage caused if a paracetamol overdose is taken. ==Effects on animals== Paracetamol is extremely toxic to [[cat]]s, and should not be given to them under any circumstances. Cats lack the necessary [[glucuronyl transferase]] enzymes to safely break paracetamol down and minute portions of a normal tablet for humans may prove fatal.<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}}</ref> Initial symptoms include vomiting, salivation and discolouration of the tongue and gums. After around two days, liver damage is evident, typically giving rise to [[jaundice]]. Unlike an overdose in humans, it is rarely liver damage that is 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]]. Effective treatment is occasionally possible for small doses, but must be extremely rapid. In dogs, paracetamol is a useful anti-inflammatory with a good safety record, causing a lower incidence of gastric ulceration than NSAIDs. It should be administered only on veterinary advice. 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 = 2007-01-03 | 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 = 2007-01-03 | url=http://www.noahcompendium.co.uk/Dechra/Pardale-V_Oral_Tablets/-27624.html}}</ref> Any cases of suspected ingestion in cats or overdose in dogs should be taken to a [[veterinarian]] immediately for detoxification.<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> The effects of toxicity can include liver damage, [[Hemolytic anemia|haemolytic anaemia]], oxidative damage to the red blood cells and bleeding tendencies. There are no home remedies, and the amount of irreversible liver failure is dependent on how quickly veterinary intervention begins. Treatment of paracetamol overdose by a veterinarian may involve the use of supportive fluid therapy, [[acetylcysteine]] (trade name Mucomyst), [[methionine]], or [[S-adenosyl methionine|S-adenosyl-<small>L</small>-methionine]] (SAMe) to slow liver damage and [[cimetidine]] (trade name Tagamet) to protect against gastric ulceration. Once liver damage has occurred, it cannot be reversed. <ref>{{cite web | title = Acetaminophen Toxicity in Dogs | author = Manning AM | publisher = PetPlace.com | accessdate = 2007-01-03 | url = http://www.petplace.com/dogs/acetaminophen-toxicity-in-dogs/page1.aspx}}</ref> Vitamin C can be used to aid in the conversion of methemoglobine back to hemoglobine (6 x 30mg/kg every 6 hours) Paracetamol is also lethal to snakes, and has been used in attempts to control 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> ==See also== * [[Tylenol scare]] * [[List of paracetamol brand names]] ==Notes and references== {{Reflist|2}} ==External links== *[https://online.epocrates.com/u/10a307/acetaminophen?mode=SingleMatch&src=PK Acetaminophen on Epocrates Drug Lookup] *[http://curriculum.toxicology.wikispaces.net/2.1.1.1+Acetaminophen Acetaminophen in WikiTox Toxicology Teaching] *[http://www.pharmweb.net/pwmirror/pwy/paracetamol/pharmwebpic.html Paracetamol Information Centre] **[http://www.pharmweb.net/pwmirror/pwy/paracetamol/pharmwebpic5.html History of paracetamol] *[http://www.pharmcast.com/Patents/October2000/100300OG/6126967_Acetaminophen100300.htm U.S. Patent 6,126,967] *[http://www.ch.ic.ac.uk/rzepa/mim/drugs/html/paracet_text.htm History & chemistry of paracetamol] *[http://www.lef.org/protocols/appendix/otc_toxicity_01.htm Paracetamol (Acetaminophen) and NSAID Toxicity] *[http://profiles.nlm.nih.gov/HH/Views/Exhibit/narrative/amines.html The Julius Axelrod Papers] {{analgesics}} {{featured article}} [[Category:Amides]] [[Category:Phenols]] [[Category:Analgesics]] [[Category:Antipyretics]] [[Category:World Health Organization essential medicines]] {{Link FA|fr}} {{Link FA|de}} {{Link FA|es}} {{Link FA|he}} {{Link FA|pt}} {{Link FA|vi}} [[ar:باراسيتامول]] [[bs:Paracetamol]] [[bg:Парацетамол]] [[ca:Paracetamol]] [[cs:Paralen]] [[da:Paracetamol]] [[de:Paracetamol]] [[dv:ޕެރަސެޓަމޯލް]] [[et:Paratsetamool]] [[es:Paracetamol]] [[fa:استامینوفن]] [[fr:Paracétamol]] [[id:Parasetamol]] [[it:Paracetamolo]] [[he:פרצטמול]] [[hu:Paracetamol]] [[ms:Asetaminofen]] [[nl:Paracetamol]] [[new:प्यारासिटामोल]] [[ja:アセトアミノフェン]] [[no:Paracetamol]] [[pl:Paracetamol]] [[pt:Paracetamol]] [[ro:Paracetamol]] [[ru:Парацетамол]] [[simple:Paracetamol]] [[sk:Paracetamol]] [[sl:Paracetamol]] [[fi:Parasetamoli]] [[sv:Paracetamol]] [[ta:பாராசித்தமோல்]] [[th:พาราเซตามอล]] [[vi:Paracetamol]] [[tr:Parasetamol]] [[zh:对乙酰氨基酚]]