| Revision as of 13:28, 24 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 456515398 of page NAPQI for the Chem/Drugbox validation project (updated: 'CAS_number'). |
Latest revision as of 12:02, 4 January 2025 edit DMacks (talk | contribs)Edit filter managers, Autopatrolled, Administrators186,468 editsm Reverted edits by 39.124.5.202 (talk) to last version by BoghogTag: Rollback |
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{{Short description|Toxic byproduct of acetaminophen}} |
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{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}} |
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{{cs1 config|name-list-style=vanc|display-authors=6}} |
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{{Drugbox |
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{{Drugbox |
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| Verifiedfields = changed |
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| Verifiedfields = changed |
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| verifiedrevid = 412573614 |
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| verifiedrevid = 462257675 |
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| IUPAC_name = ''N''-(4-Oxo-1-cyclohexa-2,5-dienylidene)acetamide |
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| IUPAC_name = ''N''-(4-Oxo-1-cyclohexa-2,5-dienylidene)acetamide |
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| image = N-Acetyl-p-benzochinonimin.svg |
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| image = N-Acetyl-p-benzochinonimin.svg |
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| width = 200 |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = |
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| tradename = |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| IUPHAR_ligand = 6299 |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|changed|??}} |
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| CAS_number = <!-- blanked - oldvalue: 50700-49-7 --> |
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| CAS_number = 50700-49-7 |
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| PubChem = 39763 |
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| PubChem = 39763 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 36356 |
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| ChemSpiderID = 36356 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = G6S9BN13TI |
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| UNII = G6S9BN13TI |
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| ChEBI_Ref = {{ebicite|changed|EBI}} |
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| ChEBI_Ref = {{ebicite|correct|EBI}} |
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| ChEBI = 29132 |
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| ChEBI = 29132 |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL = 33232 |
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| ChEMBL = 33232 |
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| synonyms = ''N''-Acetyl-''p''-benzoquinone imine; ''N''-Acetylimidoquinone |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=8 | H=7 | N=1 | O=2 |
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| C=8 | H=7 | N=1 | O=2 |
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| smiles = CC(=O)N=c1ccc(=O)cc1 |
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| molecular_weight = 149.147 g/mol |
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| smiles = O=C\1/C=C\C(=N/C(=O)C)/C=C/1 |
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| InChI = 1/C8H7NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5H,1H3 |
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| InChIKey = URNSECGXFRDEDC-UHFFFAOYAQ |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 1S/C8H7NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5H,1H3 |
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| StdInChI = 1S/C8H7NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5H,1H3 |
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| StdInChIKey = URNSECGXFRDEDC-UHFFFAOYSA-N |
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| StdInChIKey = URNSECGXFRDEDC-UHFFFAOYSA-N |
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}} |
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}} |
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'''NAPQI''', also known as '''NAPBQI''' or '''''N''-acetyl-''p''-benzoquinone imine,''' is a toxic byproduct produced during the ] of the ] ] (acetaminophen).<ref name="met1">{{Cite web | vauthors = Mehta S |date=25 August 2012 |title=Metabolism of Paracetamol (Acetaminophen), Acetanilide and Phenacetin {{!}} Medicinal Chemistry {{!}} PharmaXChange.info |url=https://pharmaxchange.info/2012/08/metabolism-of-paracetamol-acetaminophen-acetanilide-and-phenacetin/ |url-status=live |archive-url=https://web.archive.org/web/20220511095146/https://pharmaxchange.info/2012/08/metabolism-of-paracetamol-acetaminophen-acetanilide-and-phenacetin/ |archive-date=11 May 2022 |access-date=29 August 2012 |website=pharmaxchange.info |language=}}</ref> It is normally produced only in small amounts, and then almost immediately detoxified in the liver. |
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However, under some conditions in which NAPQI is not effectively detoxified (usually in the case of ]), it causes severe damage to the liver. This becomes apparent 3–4 days after ingestion and may result in death from ] several days after the overdose. |
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== Metabolism == |
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] |
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In adults, the primary metabolic pathway for paracetamol is ].<ref name="met1"/> This yields a relatively non-toxic metabolite, which is excreted into bile and passed out of the body. A small amount of the drug is metabolized via the ] pathway (to be specific, ] and ]) into NAPQI, which is extremely toxic to liver tissue, as well as being a strong biochemical oxidizer.<ref name="met1"/> In an average adult, only a small amount (approximately 10% of a therapeutic paracetamol dose) of NAPQI is produced, which is inactivated by conjugation with ] (GSH). The amount of NAPQI produced differs in certain populations.{{Citation needed|date=April 2009}} |
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The minimum dosage at which paracetamol causes toxicity usually is 7.5 to 10g in the average person.<ref>{{Cite web|url=http://emedicine.medscape.com/article/820200-overview|title = Acetaminophen Toxicity: Practice Essentials, Background, Pathophysiology|date = 5 October 2021}}</ref> The lethal dose is usually between 10 g and 15 g.{{Citation needed|date=February 2013}} Concurrent alcohol intake lowers these thresholds significantly. Chronic alcoholics may be more susceptible to adverse effects due to reduced glutathione levels.<ref>{{Cite web |title=NIH Publications |url=http://pubs.niaaa.nih.gov/publications/arh23-1/40-54.pdf |website=pubs.niaaa.nih.gov}}</ref> Other populations may experience effects at lower or higher dosages depending on differences in P-450 enzyme activity and other factors which affect the amount of NAPQI produced. In general, however, the primary concern is accidental or intentional paracetamol overdose. |
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When a toxic dose of paracetamol is ingested, the normal glucuronide pathway is saturated and large amounts of NAPQI are produced. Liver reserves of glutathione are depleted by conjugation with this excess NAPQI. The mechanism by which toxicity results is complex, but is believed to involve reaction between unconjugated NAPQI and critical proteins as well as increased susceptibility to ] caused by the depletion of glutathione.<ref name="nih_paper">{{cite book| pmc=2836803 | pmid=20020268 | doi=10.1007/978-3-642-00663-0_12 | issue=<!-- --> | chapter=Mechanisms of acetaminophen-induced liver necrosis | year=2010 | pages=369–405 | vauthors=Hinson JA, Roberts DW, James LP| title=Adverse Drug Reactions | series=Handbook of Experimental Pharmacology | volume=196 | isbn=978-3-642-00662-3 }}</ref> |
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== Poisoning == |
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The prognosis is good for paracetamol overdoses if treatment is initiated up to 8 hours after the drug has been taken. Most hospitals stock the antidote (]), which replenishes the liver's supply of ], allowing the NAPQI to be metabolized safely.<ref name="met1"/> Without early administration of the antidote, ] follows, often in combination with kidney failure, and death generally occurs within several days. |
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=== Mechanism and antidote=== |
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NAPQI becomes toxic when GSH is depleted by an overdose of acetaminophen, Glutathione is an essential antidote to overdose. Glutathione conjugates to NAPQI and helps to detoxify it. In this capacity, it protects cellular protein thiol groups, which would otherwise become covalently modified; when all GSH has been spent, NAPQI begins to bind to certain enzymes like N-10 formyltetrahydrofolate dehydrogenase and glutamate dehydrogenase, reducing their activity and killing the cells in the process. This, along with the depletion of GSH which significantly impairs the function of mitochondria, plays a significant role in the development of paracetamol toxicity.<ref>{{cite journal | vauthors = Hinson JA, Roberts DW, James LP | title = Mechanisms of acetaminophen-induced liver necrosis | journal = Handbook of Experimental Pharmacology | issue = 196 | pages = 369–405 | date = 2010 | pmid = 20020268 | pmc = 2836803 | doi = 10.1007/978-3-642-00663-0_12 }}</ref> |
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The preferred treatment for an overdose of this painkiller is the administration of ] (either via oral or IV administration)<ref>{{cite web|url=http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20M%29/MUCOMYST.html |title=Pharmaceutical Information – MUCOMYST |publisher=RxMed |accessdate=2014-02-13}}</ref>), which is processed by cells to <small>L</small>-cysteine and used in the ''de novo'' synthesis of GSH. |
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== See also == |
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==References== |
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{{Reflist}} |
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== Further reading == |
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*{{cite journal |vauthors=Alsalim W, Fadel M |title=Towards evidence based emergency medicine: best BETs from the Manchester Royal Infirmary. Oral methionine compared with intravenous N-acetyl cysteine for paracetamol overdose |journal=Emerg Med J |volume=20 |issue=4 |pages=366–7 |date=July 2003 |pmid=12835357 |pmc=1726135 |url=|doi=10.1136/emj.20.4.366}} |
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*{{cite journal |vauthors=van de Straat R, de Vries J, Debets AJ, Vermeulen NP |title=The mechanism of prevention of paracetamol-induced hepatotoxicity by 3,5-dialkyl substitution. The roles of glutathione depletion and oxidative stress |journal=Biochem. Pharmacol. |volume=36 |issue=13 |pages=2065–70 |date=July 1987 |pmid=3606627 |doi=10.1016/0006-2952(87)90132-8}} |
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