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Phenacetin
Systematic (IUPAC) name
N-(4-Ethoxyphenyl)ethanamide
Identifiers
CAS number 62-44-2
ATC code N02BE03
PubChem 4754
DrugBank EXPT03306
Chemical data
Formula C10H13NO2 
Mol. mass 179.216 g/mol
SMILES eMolecules & PubChem
Physical data
Density 1.24 g/cm³
Melt. point 134 °C (273 °F) (decomposes)
Pharmacokinetic data
Bioavailability unknown
Protein binding unknown
Metabolism unknown
Half life unknown
Therapeutic considerations
Pregnancy cat. unknown
Legal status unknown
Routes unknown
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Phenacetin is an analgesic, once widely used; its use has declined because of its adverse effects, some of which are described in the following.

Contents

History

Phenacetin was introduced in 1887, and was used principally as an analgesic, and 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.

Known mechanism of action

Its 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.

Preparation

The first synthesis was reported in 1878 by Harmon Northrop Morse.[1]

Phenacetin may be synthesized as an example of the Williamson ether synthesis: ethyl iodide, paracetamol, and anhydrous potassium carbonate are refluxed in 2-butanone to give the crude product, which is recrystallized from water.[2]

Phenacetin from paracetamol.png

Uses

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. However the U.S. Food and Drug Administration ordered the withdrawal of drugs containing phenacetin in November 1983, owing to its carcinogenic and kidney-damaging properties (Federal Register of October 5, 1983 (48 FR 45466)). As a result some branded, 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.

Phenacetin is now being used as a cutting agent to adulterate cocaine in the UK, owing to the similar physical features of the two drugs. [3]

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 transitional cell carcinoma of the renal pelvis. 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.[4] 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.[5][6][7] This is a condition which results in destruction of some or all of the renal papillae in the kidneys.

Notes and references

  1. ^ H. N. Morse (1878). "Ueber eine neue Darstellungsmethode der Acetylamidophenole". Berichte der deutschen chemischen Gesellschaft 11 (1): 232–233. doi:10.1002/cber.18780110151. 
  2. ^ "Conversion of Acetaminophen into Phenacetin". Chemistry Department Master Experiment Archive. California State University Stanislaus. http://wwwchem.csustan.edu/archive/Phenacetin.htm. 
  3. ^ "Cancer chemical in street cocaine". BBC News. 23 November 2006. http://news.bbc.co.uk/2/hi/uk_news/6178026.stm. 
  4. ^ Dubach U, Rosner B, Stürmer T (1991). "An epidemiologic study of abuse of analgesic drugs. Effects of phenacetin and salicylate on mortality and cardiovascular morbidity (1968 to 1987)". N Engl J Med 324 (3): 155–60. PMID 1984193. 
  5. ^ Cochran A, Lawson D, Linton A (1967). "Renal papillary necrosis following phenacetin excess". Scott Med J 12 (7): 246–50. PMID 6036245. 
  6. ^ Tan G, Rabbino M, Hopper J (1964). "Is Phenacetin a Nephrotoxin? A Report on Twenty-three Users of the Drug". Calif Med 101: 73–7. PMID 14180501. 
  7. ^ Brix A (2002). "Renal papillary necrosis". Toxicol Pathol 30 (6): 672–4. doi:10.1080/01926230290166760. PMID 12512867. 

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