Парацетамол

Описание

Acetaminophen differs from the nonsteroidal anti-inflammatory agents described in that it is devoid of anti-inflammatory and antirheumatic properties. It was recently shown that acetaminophen, like aspirin, inhibits cyclooxygenase action in the brain and is even stronger than aspirin. On the other hand, the mechanism of analgesic action of acetaminophen is not fully clear, since it acts poorly on peripheral cyclooxygenase.

Химические свойства

White Solid

Использование

Acetaminophen is widely used as an analgesic and fever-reducing agent. Acetaminophen is designed for moderate analgesia. It is also effective like aspirin and is used in analgesia for headaches (from weak to moderate pain), myalgia, arthralgia, chronic pain, for oncological and post-operational pain, etc.

Показания

Acetaminophen (Tylenol) is an effective antipyretic and analgesic that is well tolerated at therapeutic doses. It has only weak antiinflammatory activity; thus, it is not useful in the treatment of rheumatoid arthritis and other inflammatory conditions.

Всемирная организация здравоохранения(ВОЗ)

Paracetamol, a widely used analgesic and antipyretic is known, in case of overdose, to cause liver damage, frequently with fatal outcome. In recommended dosages this risk does not occur. Paracetamol is listed in the WHO Model List of Essential Drugs.

Общее описание

Odorless white crystalline solid. Bitter taste. pH (saturated aqueous solution) about 6.

Реакции воздуха и воды

Slightly soluble in water.

Профиль реактивности

Acetaminophen is sensitive to light. Incompatible with strong oxidizers. 

Пожароопасность

Flash point data for Acetaminophen are not available; however, Acetaminophen is probably combustible.

Биологическая активность

Cyclooxygenase inhibitor; may be selective for COX-3 (IC 50 values are 460, > 1000 and > 1000 μ M for canine COX-3, and murine COX-1 and COX-2 respectively). Widely used analgesic and antipyretic agent.

Механизм действия

The mechanism of action of paracetamol is not well understood, but it may act in a similar fashion to NSAIDs, with inhibition of cyclo-oxygenase enzymes COX-1 and COX-2 to reduce the phenoxyl radical formation required for COX-1 and 2 activity and prostaglandin synthesis. I t has selectivity for inhibition of prostaglandin synthesis with low concentrations of peroxidases and arachidonic acid, but limited effect at higher concentrations and, therefore, has limited anti-inflammatory effects. Unlike opioids, paracetamol has no well-defined endogenous binding sites. I n some circumstances, it may exhibit a preferential effect on COX-2 inhibition. There is growing evidence of a central antinociceptive effect of paracetamol. It has also been found to prevent prostaglandin production at the cellular transcriptional concentration, independent of COX activity.

Фармакокине?тика

Paracetamol is absorbed rapidly from the small intestine after oral administration; peak plasma concentrations are reached after 30–60min. It may also be given rectally and intravenously (either as paracetamol or the prodrug propacetamol). It has good oral bioavailability (70%–90%); rectal absorption is more variable (bioavailability ~50%–80%) with a longer time to reach peak plasma concentration. The plasma half-life is approximately 2–3 h.
Paracetamol is metabolised by hepatic microsomal enzymes mainly to the glucuronide, sulphate and cysteine conjugates. None of these metabolites is pharmacologically active. Aminimal amount of the metabolite N-acetyl-pamino- benzoquinone imine is normally produced by cytochrome P450– mediated hydroxylation. This reactive toxic metabolite is rendered harmless by conjugation with liver glutathione, then excreted renally as mercapturic derivatives. With larger doses of paracetamol, the rate of formation of the reactive metabolite exceeds that of glutathione conjugation, and the reactive metabolite combines with hepatocellular macromolecules, resulting in cell death and potentially fatal hepatic failure. The formation of this metabolite is increased by drugs inducing cytochrome P450 enzymes, such as barbiturates or carbamazepine.

Клиническое использование

Acetaminophen is weakly acidic (pKa = 9.51) and synthesized by the acetylation of p-aminophenol. It is weakly bound to plasma proteins (18–25%). Acetaminophen is indicated for use as an antipyretic/analgetic, particularly in those individuals displaying an allergy or sensitivity to aspirin. It does not possess anti-inflammatory activity, but it will produce analgesia in a wide variety of arthritic and musculoskeletal disorders. It is available in various formulations, including suppositories, tablets, capsules, granules, and solutions. The usual adult dose is 325 to 650 mg every 4 to 6 hours. Doses of greater than 2.6 g/day are not recommended for long-term therapy because of potential hepatotoxicity issues. Acetaminophen, unlike aspirin, is stable in aqueous solution, making liquid formulations readily available, a particular advantage in pediatric cases.

Метаболический путь

Acetaminophen (APAP) is metabolized by mice, and nine metabolites are identified in the urine. The main metabolites are APAP-glucuronide and 3-cysteinyl- APAP. Hydroquinone metabolites of S-(2,5- dihydroxyphenyl)cysteine and S-(2,5-dihydroxyphenyl)- N-acetylcysteine result from the benzoquinone metabolite of APAP.

Метаболизм

acetaminophen is undergoes rapid first-pass metabolism in the GI tract primarily by conjugation reactions, with the O-sulfate conjugate being the primary metabolite in children and the O-glucuronide being the primary metabolite in adults. A minor, but significant, product of both acetaminophen and phenacetin is the N-hydroxyamide produced by a CYP2E1 and CYP3A4.

Методы очистки

Recrystallise Paracetamol from water or EtOH. The 3,5-dinitrobenzamide complex gives orange crystals from hot H2O and has m 171.5o. [Beilstein 13 H 460, 13 I 159, 13 II 243, 13 III 1056, 13 IV 1091.]