Antipyrine

ANTIPYRINE, Antipyrinum (from Greek anti- against and pyr-fire, heat), C₁₁H₁₂N₂O (synonyms: Pyrazolonum phenyldimethylicum, Phenyl-dimethyl-isopyrazolonum, Analgesinum, Anodynum, etc.), has two structural formulas: according to Knorr (Knorr-I) and according to Michaelis (Michaelis-II).

The chemical structures are represented in the original text as formulas for the pyrazolone ring.

The chemical structures are represented in the original text as formulas for the pyrazolone ring.

The chemical structures are represented in the original text as formulas for the pyrazolone ring.

The chemical structures are represented in the original text as formulas for the pyrazolone ring.

The chemical structures are represented in the original text as formulas for the pyrazolone ring.

The chemical structures are represented in the original text as formulas for the pyrazolone ring.

Antipyrine was obtained synthetically by Knorr in 1884 through the condensation of phenylhydrazine with acetoacetic ester and was erroneously classified by Knorr as a quinoline derivative; it was later discovered that the basis of antipyrine is a pyrazole ring, from which phenylhydrazine cannot be cleaved and cannot, as such, act on the organism. Antipyrine consists of colorless, opaque, tabular crystals with a barely perceptible odor and a faint bitter taste; it melts at 110–112°C; it is soluble in 1 part water, 1 part alcohol, 1.5 parts chloroform, and 80 parts ether. Highly diluted solutions of antipyrine produce a dark red coloration with ferric chloride, which turns yellow with sulfuric acid; a green coloration with nitrous acid; and a precipitate with tannic acid. Aqueous solutions of antipyrine have a neutral reaction. Antipyrine was introduced into therapy by Filehne. Its local action is irritating; subcutaneous injection causes abscesses and tissue necrosis; internal administration can lead to nausea, vomiting, and stomach pain. The hemostatic effect of antipyrine when applied as a solution (5–10%) to bleeding mucous membranes (nose, bladder, vagina) is explained by its locally irritating effect on blood vessels; at the site of hemorrhage cessation, the following are observed: vasoconstriction, decreased mucus secretion, and a reduction in pain sensations. The general effect of small (0.5–1.0) therapeutic doses of antipyrine on the central nervous system is expressed in a peculiar state of slight stupor, which lowers pain and reflex excitability and induces general sedation. Heartbeat increases slightly; respiration does not change; the vasomotor center is depressed, with cutaneous vessels expanding predominantly, while internal vessels remain almost unchanged. It has been pointed out that antipyrine dilates vessels not only by depressing the vasomotor center but also by acting on the vessel walls themselves. The amount of urine increases; the urine is red or reddish-brown. About 15–20 minutes after taking antipyrine, the temperature of febrile patients begins to drop, descending to normal or even lower. After remaining lowered for 2–6 hours, the temperature rises again, but with repeated use of antipyrine, the temperature drop becomes more stable (10–12 hours). Antipyrine lowers the temperature more strongly in patients with a remittent or intermittent type of fever. In septic and pyemic diseases, the temperature does not fall as sharply with antipyrine. Often, the drop in temperature from antipyrine is accompanied by increased sweating, and shivering is observed when the temperature rises. The cause of the antipyretic action of antipyrine is considered to be increased heat dissipation by the body due to the dilation of cutaneous vessels and their increased blood supply; increased sweating contributes to heat loss. Heat production in febrile patients does not change with antipyrine (Kumagawa's studies on nitrogen metabolism) or may even increase (Sudzilovsky, Maragliano), but the temperature still drops because heat dissipation exceeds heat production; such a ratio is the result of the action of antipyrine on the thermoregulatory center, which copes well with the action of antipyrine in healthy individuals: in the latter, the temperature does not drop even if much larger doses (2.0–4.0) are used than in patients, and it decreases only with large, toxic doses of antipyrine. Antipyrine is excreted from the body mostly in an unchanged form, and partly in combination with sulfuric and glucuronic acids. The side effects of antipyrine are diverse but pass quickly; the most frequent include: skin rashes—erythema, roseola, urticaria, scarlatiniform redness; profuse sweating, sometimes leading to collapse in weak, cardiac, pneumonic, and tuberculous patients; nausea, vomiting, intestinal upset; dizziness, tinnitus, visual impairment; catarrh of mucous membranes, etc. Simultaneous administration of antipyrine with calomel to a patient can cause very dangerous poisoning, as these substances react with each other in an alkaline environment, forming a toxic organometallic compound (Paderi). Therapeutic use of antipyrine: in febrile diseases as an antipyretic, analgesic, and sedative; in nervous disorders, neuralgias, headaches (migraines) as an analgesic and sedative; also for shooting pains in tabetics, labor pains, insomnia, empirically—in diabetes mellitus and diabetes insipidus, in seasickness, chorea; as a local hemostatic—for nosebleeds, bleeding during surgical procedures (lithotripsy). The maximum single dose of antipyrine is 2.0, daily—6.0. For the detection of antipyrine in forensic cases, the objects under investigation (viscera, vomit, intestinal contents, etc.) are treated with an alkaline solution and the antipyrine is extracted with chloroform; the chloroform is distilled off from the filtered extract, and pure antipyrine is isolated by repeated crystallization, which is identified by color reactions. For quantitative determination, an antipyrine solution is precipitated with a 1/20 solution of picric acid, and the excess is titrated with a 1/10 solution of sodium hydroxide (indicator—phenolphthalein).