Phenacetin: A Comprehensive Overview for Chemistry Professionals

Introduction

Phenacetin, known chemically as N-(4-ethoxyphenyl)acetamide, is a well-known pharmaceutical compound with a storied history in medicinal chemistry. Phenacetin, a painkiller, was the world's first synthetic pharmaceutical drug. It was one of the first painkillers that was not derived from opium while at the same time being absent of anti-inflammatory qualities. Phenacetin was developed in 1878 by an American chemist, Harmon Northrop Morse. It was introduced into the pharmaceutical market in 1887. However, it was withdrawn in 1983 in the United States due to unacceptable levels of interstitial nephritis in patients and potential risks of tumorigenicity. Like the United States, most Western countries did not ban phenacetin from marketing until 1983. Phenacetin is a component of APC (aspirin-phenacetin-caffeine).

Phenacetin and acetaminophen

Phenacetin (p-ethoxyacetanilide) and acetaminophen (paracetamol, p-hydroxyacetanilide) are two of the more popular analgesic antipyretics. Acetaminophen was originally introduced in 1893, whereas phenacetin was introduced as an analgesic in 1897. Phenacetin has been a commonly used drug for many years; however, acetaminophen has become a widely used drug only in the last couple of decades. While there has been a dramatic increase in acetaminophen consumption in recent years, there has been a sharp decrease in the worldwide use of phenacetin. This is primarily attributable to kidney toxicities (analgesic nephropathy) and possible tumours associated with the abuse of phenacetin. Abuse of this drug has been defined as the consumption of at least one gram per day for at least three years. Analgesic nephropathy is characterized by interstitial nephritis and progressive reduction in renal size, secondary to repeated episodes of papillary necrosis. A high incidence of tumours of the urinary tract has also been correlated with the abuse of this drug.

Genotoxicity

Phenacetin is mutagenic in Salmonella typhimurium TA100 in plate assays in the presence of liver fractions from aroclor-pretreated hamsters but not rats. Deacetylated products of the N-oxidized metabolite, N-hydroxyphenetidine, and 4-nitrosophenetole, were directly mutagenic in Salmonella TA100 and TA100 NR (nitroreductase-deficient) strains and bound covalently to nucleic acids. N-hydroxyphenacetin and N-acetoxyphenacetin are mutagenic but still require metabolic activation by liver fractions. Phenacetin is positive in micronucleus tests using CD-1 mice. Phenacetin, administered by feeding a 0.5% containing diet for 52 weeks to male Sprague–Dawley gpt delta rats, significantly increased gpt (point mutations) MFs in the target organ of carcinogenesis, kidney. In this test, both gpt MFs and Spi-deletions MF were significantly elevated also in the liver in phenacetin-treated groups of both genders.

Safety

Phenacetin is a known carcinogen and has associated adverse effects on cardiovascular, renal and urologic systems. Exposure to phenacetin is associated with nephrotoxicity, nephropathy, hemolytic anemia, methemoglobinemia, and kidney and bladder cancer.

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