Парацетамол химические свойства, назначение, производство
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.]
Парацетамол препаратная продукция и сырье
сырьё
препарат