Phenacetin

PHENACETIN (Phenacetinum) (VII), C₁₀H₁₃NO₂ (1) phenacetidine, C₆H₄OC₂H₅NHCOCH₃ (4);

colorless, lustrous crystalline leaves or crystalline powder without odor or taste; m.p. 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 on litmus. It is obtained by boiling phenacetidine with acetic anhydride. It has been manufactured in recent years in the USSR (the "Farmakon" plant in Leningrad). The therapeutic application of Phenacetin confirmed the assumption that the antipyretic action of aniline derivatives is connected with their oxidation in the body to p-aminophenol. Being p-aminophenol in which the hydrogen of the hydroxyl group 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 represented by comparing it with acetanilide (see Antifebrin). If acetylation, lowering the toxicity of aniline, gave the previously widely used antifebrin, then the introduction of the ethyl group, lowering the toxicity of p-aminophenol, increased the analgesic effect of the drug. Phenacetin is one of the most frequently used analgesics (see Analgesics, and also Narcotic substances) and antipyretics (see Antipyretics). Despite its poor solubility in water, Phenacetin is absorbed quite quickly from the digestive tract, and the reduction of the fever temperature begins already half an hour after administration. After absorption, Phenacetin undergoes decomposition, the products of which—phenacetidine and p-aminophenol—are excreted in the urine in the form of paired compounds with sulfuric or gluconic acids. The processes of decomposition and excretion of Phenacetin are completed quite quickly, and its antipyretic action usually ends after 4–6 and not more than 8 hours. This action of Phenacetin is more gentle than that of antifebrin and does not lead, in ordinary doses, to paralysis of thermoregulation. The side effect of Phenacetin is also expressed more weakly, and methemoglobinemia is observed here only with an overdose or with prolonged administration of the drug. All these advantages of Phenacetin led to the fact that it almost completely displaced the previously used antifebrin. In poisoning with Phenacetin, one must reckon not only with the damage to the blood and its consequences, but also with the direct action of Phenacetin and its decomposition products on the organs of circulation, especially the heart. Recently (Snapper) attention has been drawn to the fact that prolonged (from 1/2 to 1 year) administration of Phenacetin can lead not only to methemoglobinemia, but also to sulfhemoglobinemia, connected with the sensitization of erythrocytes to hydrogen sulfide absorbed from the large intestine. Side phenomena on the skin (exanthems, etc.) are observed with Phenacetin significantly less often, for example, with antipyrin. The average single dose is 0.3–0.5; the maximum single dose is 1.0; the maximum daily dose is 3.0. Phenacetin is prescribed in powders, pills, tablets, often in various combinations: with aspirin (aspirin), with caffeine and pyramidon (algoracin), with quinine, salicylic and citric acids (cephalodol), with veronal (veronaacetin), with codeine, etc. The therapeutic success of Phenacetin led to the synthesis of a number of drugs in which the acetyl group is replaced by residues of other acids (lactophenin, phenocold, valeridin, cryofin, pyranin, eiprin, etc.), of which, however, none has received such practical significance as Phenacetin. Recognition reactions: 1) with nitric acid—a yellow coloration of nitrophenacetin; 2) 0.2 g Phenacetin with one drop of chloroform and 3–5 cm³ of potassium hydroxide solution gives an unpleasant odor of paraethoxyphenylnitroso; 3) a solution of 0.2 g Phenacetin in 2 cm³ of concentrated hydrochloric acid after a minute of boiling gives a filtrate which, upon the addition of 6 cm³ of a 5% solution of chromic acid (or another oxidant), is colored a ruby-red color. After the administration of Phenacetin, the urine gives a dark-red coloration with ferric chloride. v. karaik. Discovery in forensic chemical cases. The internal organs are extracted with alcohol acidified with tartaric acid, proceeding as in the examination for alkaloids, using chloroform or ether extraction from an acidic solution. The residue after evaporation of the extract usually (with large amounts of Phenacetin) has a crystalline appearance. Phenacetin gives some reactions common with antifebrin: 1) indophenol reaction: the residue after evaporation of chloroform (or ether) is boiled for approximately one minute with concentrated hydrochloric acid. The liquid is diluted with water upon cooling, a drop of carbolic acid solution and several drops of calcium hypochlorite solution are added: a red-violet coloration is obtained, which changes 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°, several drops of sodium azoistite solution are added, and a layer (in a test tube) of alkaline solution of β-naphthol is added to the liquid: a red ring appears. To distinguish Phenacetin from antifebrin serve: 1) the appearance of a red coloration from several 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 release (with a sufficient amount of Phenacetin) of yellow needles of nitrophenacetin.