Phenacetin

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.

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

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.

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.

Uses

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. It was also banned in India. 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. 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.

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.

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. 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. 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.

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.

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.

In popular culture

A 1974 episode of the Yorkshire Television 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.

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.

References

References

1. "Phenacetin".
2. (5 October 1983). "Drugs withdrawn from the market containing phenacetin". Department of Health and Human Services - FDA.
3. (2005). "Drug Discovery: A History". Wiley.
4. (1997). "Martha Annie Whiteley (1866-1956): Chemist and Editor". Bulletin for the History of Chemistry.
5. (1878). "Ueber eine neue Darstellungsmethode der Acetylamidophenole". [[Berichte der deutschen chemischen Gesellschaft]].
6. "Conversion of Acetaminophen into Phenacetin". [[California State University Stanislaus]].
7. ''Federal Register'' of October 5, 1983 (48 FR 45466)
8. "Drugs banned in India". Central Drugs Standard Control Organization, Dte.GHS, Ministry of Health and Family Welfare, Government of India.
9. (23 November 2006). "Cancer chemical in street cocaine". [[BBC News]].
10. (June 2000). "Anomalous refractive properties of photonic crystals". Journal of the Optical Society of America A.
11. (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.
12. (18 April 2017). "Health - Product safety - Chemical substances - Phenacetin information sheet".
13. (July 1967). "Renal papillary necrosis following phenacetin excess". Scottish Medical Journal.
14. (August 1964). "Is Phenacetin a Nephrotoxin?: A Report on Twenty-three Users of the Drug". California Medicine.
15. (2002). "Renal papillary necrosis". Toxicologic Pathology.
16. (June 2003). "Effects of phenacetin and its metabolite p-phenetidine on COX-1 and COX-2 activities and expression in vitro". Thrombosis Research.
17. (July{{ndash}}August 2007). "Howard Hughes & Pseudoaddiction". Practical Pain Management.
18. (January 9, 2018). "Taggart star's Askit questions over mother's death". BBC News.
19. (31 May 1974). "Duty of Care". [[Yorkshire Television]].
20. (1985). "Zen and the Art of Motorcycle Maintenance". Bantam.