Phenacetin

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Phenacetin
Phenacetin skeletal.svg
Phenacetin molecule ball.png
Clinical data
ATC code
Identifiers
  • N-(4-Ethoxyphenyl)acetamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
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UNII
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Chemical and physical data
Formula C10H13NO2
Molar mass 179.219 g·mol−1
3D model (JSmol)
Density 1.24 g/cm3
Melting point 134 to 137.5 °C (273.2 to 279.5 °F)
Solubility in water 0.766 g/L (25 °C (77 °F))
  • O=C(Nc1ccc(OCC)cc1)C
  • InChI=1S/C10H13NO2/c1-3-13-10-6-4-9(5-7-10)11-8(2)12/h4-7H,3H2,1-2H3,(H,11,12) Yes check.svgY
  • Key:CPJSUEIXXCENMM-UHFFFAOYSA-N Yes check.svgY
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Phenacetin (acetophenetidin, N-(4-ethoxyphenyl)acetamide [1] ) is a pain-relieving and 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 It was withdrawn from medicinal use as dangerous from the 1970s (e.g., withdrawn in Canada in 1973, [2] and by the U.S. Food and Drug Administration in 1983 [3] ).

Contents

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. [4]

Prior to World War One, Britain imported phenacetin from Germany. [5] During the war, a team including Jocelyn Field Thorpe and Martha Annie Whiteley developed a synthesis in Britain. [5]

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. 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. [6]

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. [7]

Uses

Vicks cold tablets, containing: salicylamide, phenacetin 2 1/2 grs., pyrilamine maleate, caffeine, ephedrine sulphate, magnesium hydroxide, aluminum hydroxide complex (U.S. Pat. 2,446,981). That patent number is from 1948; these tablets would have been made shortly thereafter. Vicks Double-Buffered Cold Tablets.jpg
Vicks cold tablets, containing: salicylamide, phenacetin 2½ grs., pyrilamine maleate, caffeine, ephedrine sulphate, magnesium hydroxide, 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 carcinogenic and kidney-damaging properties. [8] It was also banned in India. [9] 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 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. [10] 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? ] [1] [11]

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. [12]

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. [1] 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. [13] 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. [14] [15] [16] This is a condition which results in destruction of some or all of the renal papillae in the kidneys. It is believed that the metabolite p-phenetidine is at least partly responsible for these effects. [17]

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. [18]

A 1974 episode of the Yorkshire Television series Justice, "Duty of Care", featured 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. [19]

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. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Nonsteroidal anti-inflammatory drug</span> Class of therapeutic drug for relieving pain and inflammation

Non-steroidal anti-inflammatory drugs (NSAID) are members of a therapeutic drug class which reduces pain, decreases inflammation, decreases fever, and prevents blood clots. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack, and kidney disease.

An antipyretic is a substance that reduces fever. Antipyretics cause the hypothalamus to override a prostaglandin-induced increase in temperature. The body then works to lower the temperature, which results in a reduction in fever.

<span class="mw-page-title-main">Paracetamol</span> Common medication for pain and fever

Paracetamol is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain. It is a widely used over the counter medication. Common brand names include Tylenol and Panadol.

<span class="mw-page-title-main">Phenylbutazone</span> Nonsteroidal anti-inflammatory drug (NSAID)

Phenylbutazone, often referred to as "bute", is a nonsteroidal anti-inflammatory drug (NSAID) for the short-term treatment of pain and fever in animals.

<span class="mw-page-title-main">Acetanilide</span> Chemical compound

Acetanilide is an odourless solid chemical of leaf or flake-like appearance. It is also known as N-phenylacetamide, acetanil, or acetanilid, and was formerly known by the trade name Antifebrin.

<span class="mw-page-title-main">Dextropropoxyphene</span> Withdrawn opioid medication

Dextropropoxyphene is an analgesic in the opioid category, patented in 1955 and manufactured by Eli Lilly and Company. It is an optical isomer of levopropoxyphene. It is intended to treat mild pain and also has antitussive and local anaesthetic effects. The drug has been taken off the market in Europe and the US due to concerns of fatal overdoses and heart arrhythmias. It is still available in Australia, albeit with restrictions after an application by its manufacturer to review its proposed banning. Its onset of analgesia is said to be 20–30 minutes and peak effects are seen about 1.5–2.0 hours after oral administration.

Butalbital/acetaminophen, sold under the brand name Butapap among others, is a combination medication used to treat tension headaches and migraine headaches. It contains butalbital, a barbiturate and paracetamol (acetaminophen), an analgesic. Versions also containing caffeine are sold under the brand name Fioricet among others. It is taken by mouth. The combination is also sold with codeine.

Cyclooxygenase-3 (COX-3) is an enzyme that is encoded by the PTGS1 (COX1) gene, but is not functional in humans. COX-3 is the third and most recently discovered cyclooxygenase (COX3050) isozyme, while the first two to be discovered were COX-1 and COX-2. The COX-3 isozyme is encoded by the same gene as COX-1, with the difference that COX-3 retains an intron that is not retained in COX-1.

<span class="mw-page-title-main">Analgesic nephropathy</span> Medical condition

Analgesic nephropathy is injury to the kidneys caused by analgesic medications such as aspirin, bucetin, phenacetin, and paracetamol. The term usually refers to damage induced by excessive use of combinations of these medications, especially combinations that include phenacetin. It may also be used to describe kidney injury from any single analgesic medication.

Propyphenazone/paracetamol/caffeine is an analgesic combination indicated for the management of headache. It contains the analgesics propyphenazone and paracetamol and the stimulant caffeine.

<span class="mw-page-title-main">NAPQI</span> Toxic byproduct of acetaminophen

NAPQI, also known as NAPBQI or N-acetyl-p-benzoquinone imine, is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol (acetaminophen). It is normally produced only in small amounts, and then almost immediately detoxified in the liver.

Compound analgesics are those with multiple active ingredients; they include many of the stronger prescription analgesics.

<span class="mw-page-title-main">Renal papillary necrosis</span> Medical condition

Renal papillary necrosis is a form of nephropathy involving the necrosis of the renal papilla. Lesions that characterize renal papillary necrosis come from an impairment of the blood supply and from subsequent ischemic necrosis that is diffuse.

<span class="mw-page-title-main">Hydrocodone/paracetamol</span> Combination pain relief drug

Hydrocodone/paracetamol is the combination of the pain medications hydrocodone and paracetamol (acetaminophen). It is used to treat moderate to severe pain. It is taken by mouth. Recreational use is common in the United States.

<span class="mw-page-title-main">AM404</span> Active metabolite of paracetamol

AM404, also known as N-arachidonoylphenolamine, is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action and anticonvulsant effects. Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.

<span class="mw-page-title-main">Paracetamol poisoning</span> Toxicity due to paracetamol overdose

Paracetamol poisoning, also known as acetaminophen poisoning, is caused by excessive use of the medication paracetamol (acetaminophen). Most people have few or non-specific symptoms in the first 24 hours following overdose. These symptoms include feeling tired, abdominal pain, or nausea. This is typically followed by absence of symptoms for a couple of days, after which yellowish skin, blood clotting problems, and confusion occurs as a result of liver failure. Additional complications may include kidney failure, pancreatitis, low blood sugar, and lactic acidosis. If death does not occur, people tend to recover fully over a couple of weeks. Without treatment, death from toxicity occurs 4 to 18 days later.

Aspirin/paracetamol/caffeine is a combination drug for the treatment of pain, especially tension headache and migraine. It contains aspirin, a non-steroidal anti-inflammatory drug; paracetamol (acetaminophen), an analgesic; and caffeine, a stimulant.

<span class="mw-page-title-main">Benzhydrocodone</span> Chemical compound

Benzhydrocodone (INN) is an opioid prodrug of the morphinan class. Its chemical structure consists of hydrocodone coupled with benzoic acid. Benzhydrocodone itself is inactive and acts as a prodrug to hydrocodone upon cleavage of the benzoate portion of the molecule.

<i>p</i>-Phenetidine Chemical compound

p-Phenetidine (4-ethoxyaniline) is a chemical compound with the molecular formula C8H11NO. It is one of the three isomers of phenetidine. It is used as an intermediate in the synthesis of pharmaceutical drugs, dyes, and the sweetener dulcin.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

References

  1. 1 2 3 Gralak B, Enoch S, Tayeb G (June 2000). "Anomalous refractive properties of photonic crystals". Journal of the Optical Society of America A. 17 (6): 1012–1020. Bibcode:2000JOSAA..17.1012G. CiteSeerX   10.1.1.462.8012 . doi:10.1364/JOSAA.17.001012. PMID   10850471.
  2. ↑ "Phenacetin". DrugBank. Retrieved 28 April 2020.
  3. ↑ "Drugs withdrawn from the market containing phenacetin" (PDF). Department of Health and Human Services - FDA. 5 October 1983. Archived from the original (PDF) on 30 September 2014.
  4. ↑ Sneader W (2005). Drug Discovery: A History. Hoboken, NJ: Wiley. p. 439. ISBN   978-0471899808. Archived from the original on 18 August 2016. 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 methaemoglobinaemia. This could conceivably have been caused by the contamination of his paracetamol with the 4-aminophenol from which it was synthesised.
  5. 1 2 Creese MR (1997). "Martha Annie Whiteley (1866-1956): Chemist and Editor" (PDF). Bulletin for the History of Chemistry. 8: 42–45.
  6. ↑ Morse HN (1878). "Ueber eine neue Darstellungsmethode der Acetylamidophenole". Berichte der deutschen chemischen Gesellschaft . 11 (1): 232–233. doi:10.1002/cber.18780110151.
  7. ↑ "Conversion of Acetaminophen into Phenacetin". Chemistry Department Master Experiment Archive. California State University Stanislaus. Archived from the original on 2008-12-02.
  8. ↑ Federal Register of October 5, 1983 (48 FR 45466)
  9. ↑ "Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India. Archived from the original on 2015-02-21. Retrieved 2013-09-17.
  10. ↑ "Cancer chemical in street cocaine". BBC News. 23 November 2006.
  11. ↑ Studenikin PA, Zagumennyi AI, Zavartsev YD, Popov PA, Shcherbakov IA (1995). "GdVO4as a new medium for solid-state lasers: Some optical and thermal properties of crystals doped with Cd3+, Tm3+, and Er3+ions". Quantum Electronics. 25 (12): 1162–1165. doi:10.1070/QE1995v025n12ABEH000556. S2CID   250787020.
  12. ↑ "Health - Product safety - Chemical substances - Phenacetin information sheet". Government of Canada -. 18 April 2017. Retrieved 29 April 2020.
  13. ↑ Dubach UC, Rosner B, Stürmer T (January 1991). "An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987)". The New England Journal of Medicine. 324 (3): 155–160. doi: 10.1056/NEJM199101173240304 . PMID   1984193.
  14. ↑ Cochran AJ, Lawson DH, Linton AL (July 1967). "Renal papillary necrosis following phenacetin excess". Scottish Medical Journal. 12 (7): 246–250. doi:10.1177/003693306701200702. PMID   6036245. S2CID   33774826.
  15. ↑ Tan GH, Rabbino MD, Hopper J (August 1964). "Is Phenacetin a Nephrotoxin?: A Report on Twenty-three Users of the Drug". California Medicine. 101 (2): 73–77. PMC   1515485 . PMID   14180501.
  16. ↑ Brix AE (2002). "Renal papillary necrosis". Toxicologic Pathology. 30 (6): 672–674. doi: 10.1080/01926230290166760 . PMID   12512867.
  17. ↑ Kankuri E, Solatunturi E, Vapaatalo H (June 2003). "Effects of phenacetin and its metabolite p-phenetidine on COX-1 and COX-2 activities and expression in vitro". Thrombosis Research. 110 (5–6): 299–303. doi:10.1016/S0049-3848(03)00416-X. PMID   14592552.
  18. ↑ Tennant F (July–August 2007). "Howard Hughes & Pseudoaddiction" (PDF). Practical Pain Management. 7 (6): 20. Archived from the original (PDF) on 24 September 2015. Retrieved 2 November 2015. The phenacetin in the codeine compound produced, over time, kidney failure and death.
  19. ↑ "Duty of Care", Justice (1971 TV series) , Yorkshire Television, 31 May 1974
  20. ↑ Pirsig, Robert M. (1985). Zen and the Art of Motorcycle Maintenance (82nd printing ed.). Bantam. p. 35.
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