Paracetamol Kabi Mechanism of Action

Pharmacotherapeutic group: Other analgesics and antipyretics, anilides. ATC code: N02BE01.
Pharmacology: Pharmacodynamics: The precise analgesic and antipyretic mode of action of paracetamol has not been established. A central and peripheral effect is likely.
Paracetamol Kabi provides onset of pain relief within 5 to 10 minutes following administration. The peak analgesic effect is obtained within 1 hour and analgesia usually persists 4 to 6 hours.
Paracetamol Kabi reduces fever within 30 minutes following administration. The antipyretic effect persists for at least 6 hours.
Pharmacokinetics: Adults: Absorption: Following single and repeated administration during 24 hours paracetamol pharmacokinetics is linear up to 2 g.
Bioavailability of paracetamol following infusion of 500 mg and 1 g of paracetamol is similar to that observed following infusion of 1 g and 2 g propacetamol (corresponding to 500 mg and 1 g paracetamol), respectively.
The maximal plasma concentration (C_max) of paracetamol observed at the end of a 15-minute intravenous infusion of 500 mg and 1 g of paracetamol is about 15 μg/ml and 30 μg/ml, respectively.
Distribution: The volume of distribution of paracetamol is approximately 1 l/kg. Paracetamol is not extensively bound to plasma proteins (about 10%). Twenty minutes following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 μg/ml) were observed in the cerebrospinal fluid.
Biotransformation: Paracetamol is mainly metabolised in the liver following two major hepatic pathways: conjugation with glucuronic acid and sulphuric acid. At doses that exceed the therapeutic dose, the latter route is rapidly saturated. A small fraction (less than 4%) is metabolised by cytochrome P450 to a reactive intermediate (N-acetyl benzoquinone imine) which, with normal dosing, is rapidly detoxified by reduced glutathione and eliminated in the urine after conjugation with cysteine and mercapturic acid. However, in the event of massive overdose, the quantity of this toxic metabolite is increased.
Elimination: The metabolites of paracetamol are mainly excreted in the urine. 90% of the dose administered is excreted within 24 hours, mainly as glucuronide (60-80%) and sulphate (20-30%) conjugates. Less than 5% is eliminated unchanged. Plasma half-life is 2.7 hours and total body clearance is 18 l/h.
Newborn infants, infants and children: The pharmacokinetic parameters of paracetamol observed in infants and children are similar to those observed in adults, except for the plasma half-life that is slightly shorter (1.5 to 2 hours) than in adults. In newborn infants, the plasma half-life is longer than in infants, i.e. around 3.5 hours. Newborn infants, infants and children up to 10 years excrete significantly less glucuronide and more sulphate conjugates than adults. (See Table 1.)

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Special population: Renal insufficiency: In severe renal impairment (creatinine clearance 10-50 ml/min), the elimination of paracetamol is slightly delayed, the elimination half-life ranging from 2 to 5.3 hours. For the glucuronide and sulphate conjugates, the elimination rate is 3 times lower in subjects with severe renal impairment than in healthy subjects. Therefore, when giving paracetamol to patients with severe renal impairment (creatinine clearance 10-50 ml/min), the minimum interval between each administration should be increased to 6 hours (see Dosage & Administration).
Elderly: The pharmacokinetics and metabolism of paracetamol are not altered in elderly. No dose adjustment is required in this patient population.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans beyond the information included in other sections of the SmPC. Studies on local tolerance of paracetamol solution for infusion in rats and rabbits showed good tolerability. Absence of delayed contact hypersensitivity has been tested in guinea pigs.
Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.
Paracetamol was found to be noncarcinogenic in male rats as well as in male and female mice. Equivocal evidence of carcinogenic activity was noted for female rats based on an increased incidence of mononuclear cell leukemia.
A comparative review of the literature on paracetamol genotoxicity and carcinogenicity showed that genotoxic effects of paracetamol appear only at dosages above the recommended range resulting in severe toxic effects including pronounced liver and bone marrow toxicity. The threshold level for genotoxicity is not reached at therapeutic dosages of paracetamol.