Phenacetin
|
| Systematic (IUPAC) name |
| N-(4-Ethoxyphenyl)acetamide |
| Clinical data |
| Pregnancy cat. |
unknown |
| Legal status |
unknown |
| Routes |
unknown |
| Pharmacokinetic data |
| Bioavailability |
unknown |
| Protein binding |
unknown |
| Metabolism |
unknown |
| Half-life |
unknown |
| Identifiers |
| CAS number |
62-44-2 Y |
| ATC code |
N02BE03 |
| PubChem |
CID 4754 |
| DrugBank |
DB03783 |
| ChemSpider |
4590 Y |
| UNII |
ER0CTH01H9 Y |
| KEGG |
D00569 Y |
| ChEBI |
CHEBI:8050 Y |
| ChEMBL |
CHEMBL16073 Y |
| Chemical data |
| Formula |
C10H13NO2 |
| Mol. mass |
179.216 g/mol |
|
|
InChI
-
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) Y
Key:CPJSUEIXXCENMM-UHFFFAOYSA-N Y
|
| Physical data |
| Density |
1.24 g/cm³ |
| Melt. point |
134 °C (273 °F) (decomposes) |
Y (what is this?) (verify)
|
Phenacetin is an analgesic, once widely used; its use has declined because of its adverse effects.
|
Contents
- 1 History
- 2 Known mechanism of action
- 3 Preparation
- 4 Uses
- 5 Safety
- 6 Notes and references
- 7 External links
|
History
Phenacetin was introduced in 1887, 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.
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.
It is metabolised in the body to paracetamol.
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]
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 be made shortly thereafter.
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 urothelial 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.
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.[8]
Notes and references
- ^ H. N. Morse (1878). "Ueber eine neue Darstellungsmethode der Acetylamidophenole". Berichte der deutschen chemischen Gesellschaft 11 (1): 232–233. doi:10.1002/cber.18780110151.
- ^ "Conversion of Acetaminophen into Phenacetin". Chemistry Department Master Experiment Archive. California State University Stanislaus.
- ^ "Cancer chemical in street cocaine". BBC News. 23 November 2006.
- ^ 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. doi:10.1056/NEJM199101173240304. PMID 1984193.
- ^ Cochran A, Lawson D, Linton A (1967). "Renal papillary necrosis following phenacetin excess". Scott Med J 12 (7): 246–50. PMID 6036245.
- ^ Tan G, Rabbino M, Hopper J (1964). "Is Phenacetin a Nephrotoxin?: A Report on Twenty-three Users of the Drug". Calif Med 101 (2): 73–7. PMC 1515485. PMID 14180501.
- ^ Brix A (2002). "Renal papillary necrosis". Toxicol Pathol 30 (6): 672–4. doi:10.1080/01926230290166760. PMID 12512867.
- ^ Tennant, Forest. "Howard Hughes & Pseudoaddiction" Practical Pain Management (July/August 2007)
External links
- Carcinogen report from the NIH
- IARC report
- Safety (MSDS) data for phenacetin
