Source: Υπουργείο Υγείας (CY) Revision Year: 2022 Publisher: Remedica Ltd, Aharnon Str., Limassol Industrial Estate, 3056 Limassol, Cyprus
Pharmacotherapeutic group: Analgesics, Other Analgesics and Antipyretics
ATC code: N02BE01
Paracetamol is an analgesic for the treatment of mild to moderate pain and a member of the group of aniline derivatives.
Its mode of action is not well elucidated. A market cerebral and a weak peripheral inhibition of prostaglandin synthesis has been established. Furthermore, paracetamol probably activates a central mechanism preventing the transmission of pain stimuli. Paracetamol inhibits the effect of endogenous pyrogens on the hypothalamic regulation of the body temperature. Its antipyretic action is unrelated to the cause of the fever.
After rectal administration, paracetamol is absorbed almost completely from paracetamol suppositories.
Remedol 125 mg suppositories: As compared with the oral dosage form, its relative bioavailability is about 102%.
Remedol 250 mg suppositories: As compared with the oral dosage form, its relative bioavailability is about 93%.
Remedol 500 mg suppositories: As compare with the oral dosage form, its relative bioavailabily is about 89%.
Peak plasma concentrations are reached within 2 to 3 hours.
Binding to plasma proteins is of minor importance (up to 10%) and can rise after overdose with paracetamol.
Following metabolization in the liver (up to 55% conjugation to glucuronic acid, about 35% to sulphuric acid, furthermore cysteine and mercapturic acid), the pharmacologically inactive metabolites are excreted through the kidneys. Approximately 4% of paracetamol is eliminated as such.
The toxic metabolites p-aminophenol and –resulting from N-hydroxylation – N-acetyl-p-benzoquinonimine bound by glutathione and cysteine, are produced in small amounts.
The kinetics of paracetamol are linear to the dose administered. The average elimination half life is 1.5 to 2.5 hours. In general, the drug is completely excreted within 24 hours. Longer half lives are seen in the presence of impaired liver and kidney function, after overdosage and in the newborn.
The absorption and elimination of the drug are unrelated to the patient’s age. Ethnic differences are negligible.
The maximum and the average duration of the drug’s effect correlates more or less with its concentration in plasma.
The LD50 of paracetamol varies with species and the route of administration, ranging from 310 mg/kg after subcutaneous injection in the mouse to 2620 mg/kg after oral administration in the guinea-pig. The lowest lethal dose (LDLo) observed in humans in 260 mg/kg by mouth.
The lowest cumulative toxic amounts range between 1.6 g/kg after intraperitoneal injection in the rat and 136 g/kg after oral administration in the mouse. In rats receiving 1 g/kg of paracetamol daily by mouth for 3 to 12 days, the serum transaminase activity was found to rise by tenfold, and a marked reduction in glutathione levels associated with a pericentral liver necrosis was observed. Feeding of the drug in the diet of mice over prolonged period of time was shown to be fatal within 2 to 10 weeks in animals receiving the two highest concentrations, while the lower concentrations caused liver necrosis. The amounts used were about 12 to 14 times higher than the therapeutic doses of paracetamol.
The relationship between treatment with paracetamol and analgesic-induced nephropathy is the subject of some controversy. Experiments in the mouse have shown that the administration of 150 to 600 mg/kg of paracetamol causes a dose and time-related depletion of renal glutathione levels. Thus, the detoxification of reactive decomposition products of paracetamol in the kidneys might be jeopardized.
Investigations concerning reproduction toxicology have revealed that embryotoxic and fetotoxic effects are only produced by extremely large amounts of paracetamol (≥1500 mg/kg b.wt.) No teratogenic effects have been observed in humans receiving paracetamol during pregnancy. The drug does not cause gene mutations in bacteria or in mammalian cells, but in vitro may give rise to chromosome damage in mammalian cells, in concentrations similar to those producing severe toxic effects on the liver and the bone marrow. Various mechanism (inhibition of ribonucleotide reductase, increase in cytosolic and intranuclear calcium concentrations, NAPQI-induced damage to the DNA after depletion of glutathione) are being discussed. However, this effect has been caused by threshold doses far above therapeutic amounts.
No carcinogenic action of paracetamol has been observed after the administration of threshold doses producing toxic effects on the liver (300 mg/kg/day in the rat and 1000 mg/kg/day in the mouse).
Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.
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