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| ECHA InfoCard | 100.000.485 |
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| Formula | C10H13NO2 |
| Molar mass | 179.219 g·mol−1 |
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| 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)) |
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Phenacetin (/fɪˈnæsɪtɪn/ ⓘ;acetophenetidin,N-(4-ethoxyphenyl)acetamide[1]) is apain-relieving andfever-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 It was withdrawn from medicinal use as dangerous from the 1970s (e.g., withdrawn in Canada in 1973,[2] and by theU.S. Food and Drug Administration in 1983[3]).
Phenacetin was introduced in 1887 inElberfeld, Germany by German companyBayer, 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. Althoughparacetamol (acetaminophen) was produced earlier, a historical accident saw it ignored afterJoseph von Mering's 1893 assessment.[4]
Prior to World War One, Britain imported phenacetin from Germany.[5] During the war, a team includingJocelyn Field Thorpe andMartha Annie Whiteley developed a synthesis in Britain.[5]
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 negativeinotrope. It is anantipyretic, acting on the brain to decrease the temperature set point. It is also used to treatrheumatoid arthritis (subacute type) and intercostalneuralgia.
In vivo, one of two reactions occur. Usually phenacetin'sether is cleaved to leaveparacetamol (acetaminophen), which is the clinically relevant analgesic. A minorityof the time the acetyl group is removed from the amine, producing carcinogenicp-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.
The first synthesis was reported in 1878 byHarmon 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 theWilliamson ether synthesis:ethyl iodide,paracetamol, and anhydrouspotassium carbonate are heated in2-butanone to give the crude product, which is recrystallized from water.[7]
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) wasVincent's APC in Australia.
In the United States, theFood and Drug Administration ordered the withdrawal of drugs containing phenacetin in November 1983, due to itscarcinogenic 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 wasRoche'sSaridon, which was reformulated in 1983 to containpropyphenazone,paracetamol andcaffeine.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.
Phenacetin has been used as acutting agent to adulteratecocaine 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]
Phenacetin, and products containing phenacetin, have been shown in ananimal model to have the side effect and after-effect ofcarcinogenesis. In humans, many case reports have implicated products containing phenacetin in urothelial neoplasms, especiallyurothelial carcinoma of therenal pelvis. Phenacetin is classified by theInternational 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 withglucose-6-phosphate dehydrogenase deficiency may experience acutehemolysis, or dissolution of blood cells, while taking this drug. Acute hemolysis is possible in the case of patients who develop anIgM response to phenacetin leading to immune complexes that bind toerythrocytes in blood. The erythrocytes are then lysed when the complexes activate thecomplement system.
Chronic use of phenacetin is known to lead toanalgesic nephropathy characterized byrenal papillary necrosis.[14][15][16] This is a condition which results in destruction of some or all of therenal papillae in the kidneys. It is believed that the metabolitep-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 pioneerHoward Hughes. He had been using phenacetin extensively for the treatment ofchronic pain; it was stated during his autopsy that phenacetin use may have been the cause of hiskidney failure.[18]
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.[19]
A 1974 episode of theYorkshire Television seriesJustice, "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.[20]
In the bookZen and the Art of Motorcycle Maintenance chapter 4, "APCs for headaches" is included in a list of valuable things to take on motorcycle trips.[21]
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 producemethaemoglobinaemia. This could conceivably have been caused by the contamination of his paracetamol with the 4-aminophenol from which it was synthesised.
The phenacetin in the codeine compound produced, over time, kidney failure and death.
