View source for Phenacetin

{{Short description|Pharmaceutical drug}}
{{drugbox
| verifiedrevid = 464199717
| IUPAC_name = ''N''-(4-Ethoxyphenyl)acetamide
| image = Phenacetin skeletal.svg
| image_class = skin-invert-image
| image2 = Phenacetin molecule ball.png
| image_class2 = bg-transparent
<!--Clinical data-->
| pregnancy_category = 
| legal_status = 
| routes_of_administration = 
<!--Pharmacokinetic data-->
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 
<!--Identifiers-->
| IUPHAR_ligand = 7402
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 62-44-2
| ATC_prefix = N02
| ATC_suffix = BE03
| ATC_supplemental = 
| PubChem = 4754
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB03783
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4590
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = ER0CTH01H9
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00569
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 8050
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 16073
<!--Chemical data-->
| C=10 | H=13 | N=1 | O=2
| smiles = O=C(Nc1ccc(OCC)cc1)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C10H13NO2/c1-3-13-10-6-4-9(5-7-10)11-8(2)12/h4-7H,3H2,1-2H3,(H,11,12)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = CPJSUEIXXCENMM-UHFFFAOYSA-N
| density = 1.24
| melting_point = 134
| melting_high  = 137.5
| melting_notes = 
| solubility         = 0.766
| sol_units  = &nbsp;g/L ({{Convert|25|C|F}})
}}
'''Phenacetin''' ({{IPAc-en|f|ɪ|ˈ|n|æ|s|ɪ|t|ɪ|n|audio=LL-Q1860 (eng)-Flame, not lame-phenacetin.wav}}; '''acetophenetidin''', '''''N''-(4-ethoxyphenyl)acetamide'''<ref name=canada/>) is a [[analgesic|pain-relieving]] and [[antipyretic|fever-reducing]] drug, which was widely used following its introduction in 1887. It was withdrawn from medicinal use as dangerous from the 1970s (e.g., withdrawn in Canada in 1973,<ref>{{cite web |url=https://www.drugbank.ca/drugs/DB03783 |title=Phenacetin|website=DrugBank|access-date= 28 April 2020}}</ref> and by the [[U.S. Food and Drug Administration]] in 1983<ref>{{cite web|url=https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/UCM078577.pdf|archive-url=https://web.archive.org/web/20140930103207/https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Over-the-CounterOTCDrugs/StatusofOTCRulemakings/UCM078577.pdf|archive-date=30 September 2014|title=Drugs withdrawn from the market containing phenacetin|date=5 October 1983|publisher=Department of Health and Human Services - FDA}}</ref>).

==History==
Phenacetin was introduced in 1887 in [[Elberfeld]], Germany by German company [[Bayer]], and was used principally as an analgesic; it was one of the first synthetic fever reducers to go on the market. It is also known historically to be one of the first non-[[opioid]] analgesics without anti-inflammatory properties. Although [[paracetamol]] (acetaminophen) was produced earlier, a historical accident saw it ignored after [[Joseph von Mering]]'s 1893 assessment.<ref name=drugdiscov>{{cite book |title=Drug Discovery: A History | vauthors = Sneader W |publisher=Wiley |year=2005 |isbn=978-0471899808 |page=439 |location=Hoboken, NJ |url=https://books.google.com/books?id=jglFsz5EJR8C&pg=PA439 |url-status=live |archive-url=https://web.archive.org/web/20160818021904/https://books.google.com/books?id=jglFsz5EJR8C&pg=PA439 |archive-date=18 August 2016 |quote=The eminent clinical pharmacologist Joseph von Mering collaborated with the Bayer Company in a trial of paracetamol in 1893. He found it to be an effective antipyretic and analgesic, but claimed it had a slight tendency to produce [[methemoglobinemia|methaemoglobinaemia]].  This could conceivably have been caused by the contamination of his paracetamol with the 4-aminophenol from which it was synthesised.}}</ref>

Prior to World War One, Britain imported phenacetin from Germany.<ref name="Creese1997" />  During the war, a team including [[Jocelyn Field Thorpe]] and [[Martha Annie Whiteley]] developed a synthesis in Britain.<ref name="Creese1997">{{cite journal | vauthors = Creese MR |title=Martha Annie Whiteley (1866-1956): Chemist and Editor |journal=Bulletin for the History of Chemistry |date=1997 |volume=8 |issue=20 |pages=42–45 |doi=10.70359/bhc1997n20p042 |url=http://www.scs.illinois.edu/~mainzv/HIST/bulletin_open_access/num20/num20%20p42-45.pdf}}</ref>

==Known mechanism of action==
Phenacetin's analgesic effects are due to its actions on the sensory tracts of the spinal cord. In addition, phenacetin has a depressant action on the heart, where it acts as a negative [[inotrope]]. It is an [[antipyretic]], acting on the brain to decrease the temperature set point. It is also used to treat [[rheumatoid arthritis]] (subacute type) and intercostal [[neuralgia]].

''In vivo'', one of two reactions occur. Usually phenacetin's [[ether]] is cleaved to leave [[paracetamol]] (acetaminophen), which is the clinically relevant analgesic. A minority
of the time the acetyl group is removed from the amine, producing carcinogenic [[P-Phenetidine|''p''-phenetidine]]. This reaction is quite rare, however, as evidenced by the fact that the drug was on the market for almost 100 years before a statistical link was established, when Canada, followed by the United States, withdrew it from the market.

==Preparation==
The first synthesis was reported in 1878 by [[Harmon Northrop Morse]]. Morse's cited article describes the synthesis of paracetamol from 4-aminophenol and acetic acid.<ref>{{cite journal | title = Ueber eine neue Darstellungsmethode der Acetylamidophenole | pages = 232–233 | vauthors = Morse HN | year = 1878 | doi = 10.1002/cber.18780110151 | journal = [[Berichte der deutschen chemischen Gesellschaft]] | volume = 11 | issue = 1 | url = https://zenodo.org/record/1425148 }}</ref>

Phenacetin may be synthesized as an example of the [[Williamson ether synthesis]]: [[ethyl iodide]], [[paracetamol]], and anhydrous [[potassium carbonate]] are heated in [[2-butanone]] to give the crude product, which is recrystallized from water.<ref>{{cite web | title = Conversion of Acetaminophen into Phenacetin | publisher = [[California State University Stanislaus]] | work = Chemistry Department Master Experiment Archive | url = http://wwwchem.csustan.edu/archive/Phenacetin.htm | url-status = dead | archive-url = https://web.archive.org/web/20081202111801/http://wwwchem.csustan.edu/archive/Phenacetin.htm | archive-date = 2008-12-02 }}</ref>

==Uses==
[[File:Vicks Double-Buffered Cold Tablets.jpg|left|thumb|[[Vicks]] cold tablets, containing: [[salicylamide]], phenacetin {{Frac|2|1|2}} grs., [[pyrilamine maleate]], caffeine, [[ephedrine sulphate]], [[magnesium hydroxide]], and [[aluminum hydroxide]] complex (U.S. Pat. 2,446,981). That patent number is from 1948; these tablets would have been made shortly thereafter.]]

=== Medical ===
Phenacetin was widely used until the third quarter of the twentieth century, often in the form of an A.P.C., or "[[aspirin]]-phenacetin-[[caffeine]]" [[compound analgesic]], as a remedy for fever and pain. An early formulation (1919) was [[Vincent's APC]] in Australia.

In the United States, the [[Food and Drug Administration]] ordered the withdrawal of drugs containing phenacetin in November 1983, due to its [[carcinogen]]ic and kidney-damaging properties.<ref>''Federal Register'' of October 5, 1983 (48 FR 45466)</ref> It was also banned in India.<ref name=ban>{{cite web|url=http://cdsco.nic.in/html/drugsbanned.html|title=Drugs banned in India|publisher=Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India|access-date=2013-09-17|url-status=dead|archive-url=https://web.archive.org/web/20150221053621/http://cdsco.nic.in/html/drugsbanned.html|archive-date=2015-02-21}}</ref> As a result, some branded, and previously phenacetin-based, preparations continued to be sold, but with the phenacetin replaced by safer alternatives. A popular brand of phenacetin was [[Hoffmann-La Roche|Roche]]'s [[Saridon]], which was reformulated in 1983 to contain [[propyphenazone]], [[paracetamol]] and [[caffeine]]. [[Coricidin]] was also reformulated without phenacetin. Paracetamol is a metabolite of phenacetin with similar analgesic and antipyretic effects, but the new formulation has not been found to have phenacetin's carcinogenicity.

=== Other ===
Phenacetin has been used as a [[cutting agent]] to adulterate [[cocaine]] in the UK and Canada, due to the similar physical properties.<ref>{{cite news | publisher = [[BBC News]] | url = https://news.bbc.co.uk/1/hi/uk/6178026.stm | title = Cancer chemical in street cocaine | date=  23 November 2006}}</ref> There, it has been given the nickname "magic".

Due to its low cost, phenacetin is used for research into the physical and refractive properties of crystals. It is an ideal compound for this type of research.{{why|date=January 2021}}<ref name=canada>{{cite journal | vauthors = Gralak B, Enoch S, Tayeb G | title = Anomalous refractive properties of photonic crystals | journal =  Journal of the Optical Society of America A| volume = 17 | issue = 6 | pages = 1012–1020 | date = June 2000 | pmid = 10850471 | doi = 10.1364/JOSAA.17.001012 | citeseerx = 10.1.1.462.8012 | bibcode = 2000JOSAA..17.1012G }}</ref><ref>{{Cite journal | url=http://www.turpion.org/php/paper.phtml?journal_id=qe&paper_id=556 | doi = 10.1070/QE1995v025n12ABEH000556 | title = GdVO4as a new medium for solid-state lasers: Some optical and thermal properties of crystals doped with Cd3+, Tm3+, and Er3+ions | journal = Quantum Electronics | volume = 25 | issue = 12 | pages = 1162–1165 | year = 1995 | vauthors = Studenikin PA, Zagumennyi AI, Zavartsev YD, Popov PA, Shcherbakov IA | s2cid = 250787020 | url-access = subscription }}</ref>

In Canada, phenacetin is used as a laboratory reagent, and in a few hair dye preparations (as a stabilizer for hydrogen peroxide). While it is considered a prescription drug, no marketed drugs contain phenacetin.<ref>{{cite web |url=https://www.canada.ca/en/health-canada/services/chemical-substances/fact-sheets/chemicals-glance/phenacetin.html |title=Health - Product safety - Chemical substances - Phenacetin information sheet|website=Government of Canada - |date=18 April 2017|access-date= 29 April 2020}}</ref>

==Safety==
Phenacetin, and products containing phenacetin, have been shown in an [[animal model]] to have the side effect and after-effect of [[carcinogenesis]]. In humans, many case reports have implicated products containing phenacetin in urothelial neoplasms, especially [[urothelial carcinoma]] of the [[renal pelvis]]. Phenacetin is classified by the [[International Agency for Research on Cancer]] (IARC) as carcinogenic to humans.<ref name=canada/> In one prospective series, phenacetin was associated with an increased risk of death due to urologic or renal diseases, death due to cancers, and death due to cardiovascular diseases.<ref>{{cite journal | vauthors = Dubach UC, Rosner B, Stürmer T | title = An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987) | journal = The New England Journal of Medicine | volume = 324 | issue = 3 | pages = 155–160 | date = January 1991 | pmid = 1984193 | doi = 10.1056/NEJM199101173240304 | doi-access = free }}</ref>
In addition, people with [[glucose-6-phosphate dehydrogenase deficiency]] may experience acute [[hemolysis]], or dissolution of blood cells, while taking this drug. Acute hemolysis is possible in the case of patients who develop an [[IgM]] response to phenacetin leading to immune complexes that bind to [[erythrocytes]] in blood. The erythrocytes are then lysed when the complexes activate the [[complement system]].

Chronic use of phenacetin is known to lead to [[analgesic nephropathy]] characterized by [[renal papillary necrosis]].<ref>{{cite journal | vauthors = Cochran AJ, Lawson DH, Linton AL | title = Renal papillary necrosis following phenacetin excess | journal = Scottish Medical Journal | volume = 12 | issue = 7 | pages = 246–250 | date = July 1967 | pmid = 6036245 | doi = 10.1177/003693306701200702 | s2cid = 33774826 }}</ref><ref>{{cite journal | vauthors = Tan GH, Rabbino MD, Hopper J | title = Is Phenacetin a Nephrotoxin?: A Report on Twenty-three Users of the Drug | journal = California Medicine | volume = 101 | issue = 2 | pages = 73–77 | date = August 1964 | pmid = 14180501 | pmc = 1515485 }}</ref><ref>{{cite journal | vauthors = Brix AE | title = Renal papillary necrosis | journal = Toxicologic Pathology | volume = 30 | issue = 6 | pages = 672–674 | year = 2002 | pmid = 12512867 | doi = 10.1080/01926230290166760 | doi-access = free }}</ref> This is a condition which results in destruction of some or all of the [[renal papilla]]e in the kidneys.  It is believed that the metabolite [[p-Phenetidine|''p''-phenetidine]] is at least partly responsible for these effects.<ref name=Kankuri>{{cite journal | vauthors = Kankuri E, Solatunturi E, Vapaatalo H | title = Effects of phenacetin and its metabolite p-phenetidine on COX-1 and COX-2 activities and expression in vitro | journal = Thrombosis Research | volume = 110 | issue = 5–6 | pages = 299–303 | date = June 2003 | pmid = 14592552 | doi = 10.1016/S0049-3848(03)00416-X }}</ref>

One notable death that can possibly be attributed to the use of this drug was that of the aviation pioneer [[Howard Hughes]]. He had been using phenacetin extensively for the treatment of [[chronic pain]]; it was stated during his autopsy that phenacetin use may have been the cause of his [[kidney failure]].<ref>{{cite journal | vauthors = Tennant F |date=July{{ndash}}August 2007 |title=Howard Hughes & Pseudoaddiction |url=http://www.foresttennant.com/pdfs/HowardHughes.pdf |journal=Practical Pain Management |volume=7 |issue=6 |page=20 |access-date=2 November 2015 |quote=The phenacetin in the codeine compound produced, over time, kidney failure and death. |url-status=dead |archive-url=https://web.archive.org/web/20150924014602/http://www.foresttennant.com/pdfs/HowardHughes.pdf |archive-date=24 September 2015 }}</ref>

[[Askit Powders]], a once-popular headache cure on the UK market, have been associated with kidney failure in chronic users due to containing phenacetin until 1966, when they were reformulated to remove it.<ref>{{Cite news|url=https://www.bbc.com/news/uk-scotland-glasgow-west-42618096|title=Taggart star's Askit questions over mother's death|work=BBC News|date=January 9, 2018}}</ref>

== In popular culture ==
A 1974 episode of the [[Yorkshire Television]] series [[Justice (1971 TV series)|''Justice'']], "Duty of Care", features a court case that resulted from a woman dying of phenacetin poisoning, as a result of taking A.P.C. for five years. This explained that phenacetin caused renal papillary necrosis.<ref>{{Cite AV media |title=Duty of Care |work=[[Justice (1971 TV series)|Justice]] |date=31 May 1974 |publisher=[[Yorkshire Television]] }}</ref>

In the book ''[[Zen and the Art of Motorcycle Maintenance]]'' chapter 4, "APCs for headaches" is included in a list of valuable things to take on motorcycle trips.<ref>{{Cite book |last1=Pirsig |first1=Robert M. |date=1985 |publisher=Bantam |edition=82nd printing |title=Zen and the Art of Motorcycle Maintenance |page=35}}</ref>

== See also ==
* [[Bucetin]]

== References ==
{{Reflist}}

== External links ==
{{wiktionary}}
* [https://web.archive.org/web/20120318172218/http://ntp.niehs.nih.gov/INDEX4E62.HTM?objectid=07039573-D7A5-91CA-B2D1FF0D1100CFB8 Carcinogen report from the NIH]
* [http://www.inchem.org/documents/iarc/suppl7/analgesicmx&phenacetin.html IARC report]
* [http://physchem.ox.ac.uk/MSDS/PH/phenacetin.html Safety (MSDS) data for phenacetin] {{Webarchive|url=https://web.archive.org/web/20060924185947/http://physchem.ox.ac.uk/MSDS/PH/phenacetin.html |date=2006-09-24 }}

{{Analgesics}}
{{Prostanoidergics}}

[[Category:Analgesics]]
[[Category:Antipyretics]]
[[Category:Acetanilides]]
[[Category:Disulfiram-like drugs]]
[[Category:Withdrawn drugs]]
[[Category:1887 introductions]]
[[Category:Phenol ethers]]
[[Category:IARC Group 1 carcinogens]]