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Pharmacology: Pharmacokinetics: Paracetamol pharmacokinetics is linear up to 2 g after single administration and after repeated administration during 24 hours. The maximal plasma concentration (Cmax) of paracetamol is observed at the end of 15-minutes. Intravenous Infusion of 500 mg and 1 g about 15 μg/mL respectively.
Distribution: The volume of distribution of paracetamol is approximately 1 L/kg.
Paracetamol is not extensively bound to plasma proteins.
Following infusion of 1 g to plasma proteins of paracetamol (about 1.5 μg/mL) were observed in the cerebrospinal fluid at and after the 20th minute following infusion.
Metabolism: Paracetamol is metabolised mainly in the liver following the two major hepatic pathways: glucuronic acid conjugation and sulphuric acid conjugation. The latter route is rapidly saturable at doses that exceed the therapeutic doses. A small fraction (less than 4%) is metabolised by cytochrome P450 to a reactive intermediate (N-acetyl benzoquinone imine), which under normal conditions of uses, is rapidly detoxified by reduced glutathione and eliminated in the urine after conjugated with cysteine and mercapturic acid. However, during massive overdosing, 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 in 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.
Neonates, Infants and Children: The pharmacokinetics parameter 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 hr) than in adults. In neonates the plasma half-life is longer than in infants i.e. around 3.5 hours. Neonates, infants and children up to 10 years excrete significantly less glucuronide and more sulphate than adults.
Special Populations: Renal insufficiency: In case of severe renal impairment (creatinine clearance 10-30 mL/min), the elimination of paracetamol is slightly delayed, the elimination half-life ranging from 2.5-3 hours for the glucuronide and sulphate conjugates, the elimination rate is 3 times slower in subjects with severe renal impairment than in heathy subjects. Therefore when giving paracetamol to patients with severe renal impairment (creatinine clearance 30 mL/min) the minimum intervals between each administration should be increased to 6 hours.
Elderly Subjects: The pharmacokinetics and the metabolism of paracetamol is not modified in elderly subjects.
No dose adjustment is required in this population.
