Phenacetin

Overview
Phenacetin, introduced in 1887, was used principally as an analgesic, and was the first NSAID and fever reducer to go on the market. Typical doses of 300mg to 500mg a day result in an analgesic effect. Its analgesic effects are due to its actions on the sensory tracts of the spinal cord. In addition, phenacetin has a depressant action of 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), intercostal neuralgia, and some forms of ataxia.

Phenacetin, and products containing phenacetin have been shown in an animal model to be carcinogenic. 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. In addition, people with glucose-6-phosphate dehydrogenase deficiency may experience acute hemolysis 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 cascade.

Synthesis (Northern Kentucky University)

ETHER SYNTHESIS: CONVERSION OF ACETAMINOPHEN INTO PHENACETIN Required Pre-lab readings: Ege, 5th Ed., sect 13.4, pp 498-501; Morhig, Chapter 19. Techniques you must be prepared to use: reflux; extraction; rotary evaporation; recrystallization. In the reaction today you will be converting 4-acetamidophenol (Acetaminophen) into ethyl 4- acetamidophenyl ether (Phenacetin). Both compounds are ingredients in many over-the-counter analgesics. This reaction is an example of the Williamson ether synthesis. For most ether syntheses strong bases such as amide ion are necessary to generate the nucleophile.

In a 50 mL round-bottomed flask place 12 mmol of liquid ethyl iodide, 15 mL of methyl ethyl ketone (2-butanone; MEK) as solvent, Acetaminophen (1.5 g; ?? mmol.), and powered anhydrous K2CO3 (2.5 g; ?? mmol). Mechanically stir this mixture and reflux for 1 hour. After the reflux is complete cool the flask in an ice/water bath and gravity filter the contents into a separatory funnel. Use small amounts of ether to insure that you have quantitatively transferred all the organic material from the flask to the funnel. Wash the organic phase with 5% aq. NaOH (what is the purpose of this step?), then dry it (Na2SO4) and decant into a flask and remove the solvents by rotary evaporation. The product is purified by recrystallization from water. Allow the purified product to air dry.

Phenacetin was widely used until the third quarter of the twentieth century, but was then largely replaced by non-carcinogenic drugs. Some branded 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. 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.

Connection between chronic phenacetin use and renal papillary necrosis
Chronic use of phenacetin is known to lead to renal papillary necrosis. This is a condition which results in destruction of some or all of the renal papillae in the kidneys.

Use as a filler for illegal cocaine
Phenacetin is now being widely used as a cutting agent to adulterate illegally supplied cocaine due to the similar physical features of the two drugs.

Notes and references

 * Carcinogen report from the NIH
 * Safety (MSDS) data for phenacetin

Phénacétine Фенацетин 非那西丁

Fenacetyna