Phenacetin

PHENACETIN (Phenacetinum) (VII), para-acet-p-phenetidin, C₆H₄(OC₂H₅)(1)(NHCOCH₃)(4). Colorless, shiny crystalline leaflets or a crystalline powder without odor and taste; melting point 134-135°; phenacetin dissolves in 1,400 parts of cold and 80 parts of boiling water, in 16 parts of cold and 2 parts of hot alcohol with a neutral reaction to litmus.

It is obtained by boiling p-phenetidin with acetic anhydride. In recent years it has been manufactured in the USSR (the Pharmakon plant in Leningrad). The therapeutic use of phenacetin justified the assumption that the antipyretic action of aniline derivatives is associated with their oxidation in the organism to p-aminophenol.

Being a p-aminophenol in which the hydrogen of the hydroxyl is replaced by ethyl, and one of the hydrogens of the amino group by acetyl, phenacetin is ethoxyacetanilide, and its pharmacological properties can be more clearly understood when compared with acetanilide (see Antifebrin). If acetylation, by lowering the toxicity of aniline, yielded the previously widely used antifebrin, the introduction of the ethyl group, while lowering the toxicity of p-aminophenol, increased the analgesic effect of the preparation. Phenacetin is one of the most frequently used analgesics (see Analgesics, as well as Narcotics) and antipyretics (see Antipyretica). Despite its poor solubility in water, phenacetin is absorbed quite rapidly from the digestive tract, and the reduction of febrile temperature begins as early as half an hour after ingestion. After absorption, phenacetin undergoes cleavage, the products of which—phenetidin and p-aminophenol—are excreted in the urine in the form of paired compounds with sulfuric or glucuronic acids. The processes of cleavage and elimination of phenacetin are completed quite rapidly, and the antipyretic effect usually ends after 4-6 and not more than 8 hours. This action of phenacetin is gentler than that of antifebrin, not leading in ordinary doses to paralysis of thermoregulation. The side effects of phenacetin are also less pronounced, and methemoglobinemia is observed here only when doses are exceeded or during prolonged administration of the drug. All these advantages of phenacetin have led to the fact that it has almost completely supplanted the previously used antifebrin. In case of phenacetin poisoning, one must reckon not only with blood damage and its consequences, but also with the direct action of phenacetin and its decomposition products on the circulatory organs, mainly the heart. Recently (Snapper), attention was drawn to the fact that prolonged (from 1/2 to 1 year) use of phenacetin can lead not only to methemoglobinemia, but also to sulfhemoglobinemia associated with the sensitization of erythrocytes to hydrogen sulfide absorbed from the large intestines. Side effects on the skin (exanthems, etc.) are observed with phenacetin much less frequently than, for example, with antipyrine. The average single dose is 0.3-0.5; maximum single dose, 1.0; maximum daily dose, 3.0. Phenacetin is prescribed in powders, pills, tablets, often in various combinations: with aspirin (aspiphenin), with caffeine and pyramidon (algocratin), with quinine, salicylic and citric acid (kephaldol), with veronal (veronacetin), with codeine, etc. The therapeutic success of phenacetin led to the synthesis of a number of preparations in which the acetyl group is replaced by residues of other acids (lactophenin, phenocold, valeridin, cryophine, pyrantin, eypyrin, etc.), none of which, however, acquired the same practical significance as phenacetin. Identification reactions: 1) with nitric acid—yellow coloration of nitrophenacetin; 2) 0.2 g of phenacetin with 1 drop of chloroform and 3-5 cm³ of a potassium alkali solution give an unpleasant odor of p-ethoxyphenylisocyanitrile; 3) a solution of 0.2 g of phenacetin in 2 cm³ of concentrated hydrochloric acid after a minute of boiling gives a filtrate which, upon addition of 6 cm³ of a 5% chromic acid solution (or another oxidizing agent), turns ruby-red. After taking phenacetin, the urine gives a dark red coloration with ferric chloride. V. Karasik.

Detection in forensic-chemical cases. Viscera are extracted with alcohol acidified with tartaric acid, proceeding as in the investigation for alkaloids, using chloroform or ether extraction from an acid solution. The residue after evaporation of the extract usually (with large amounts of phenacetin) has a crystalline appearance. Phenacetin gives some general reactions with antifebrin: 1) indophenol reaction: the residue after evaporation of chloroform (or ether) is boiled for approximately one minute with concentrated hydrochloric acid. After cooling, the liquid is diluted with water, a drop of carbolic acid solution and a few drops of chlorinated lime solution are added: a red-violet coloration is obtained, turning to blue upon alkalization with aqueous ammonia. 2) Formation of an azo dye: the solution obtained by boiling the residue with hydrochloric acid is cooled to 0°, a few drops of sodium nitrite solution are added, and a layer of an alkaline solution of β-naphthol is poured onto the liquid in a test tube: a red ring appears. To distinguish phenacetin from antifebrin, the following serve: 1) the appearance of a red coloration from a few drops of chromic anhydride solution added to the liquid obtained by boiling the residue with concentrated hydrochloric acid (see above). 2) The appearance of a bright yellow coloration upon heating the residue with diluted nitric acid and the precipitation (with a sufficient amount of phenacetin) of yellow needles of nitrophenacetin.