Fevere Mechanism of Action

Analgesic/Anti-Pyretic (Anilide).
Pharmacology: Pharmacodynamics: Paracetamol solution for infusion provides onset of pain relief within 5 to 10 minutes after the start of administration. The peak analgesic effect is obtained in 1 hour and the duration of this effect is usually 4 to 6 hours. Paracetamol 10 mg/mL solution for infusion reduces fever within 30 minutes after the start of administration with a duration of the anti-pyretic effect of at least 6 hours.
Pharmacokinetics: Absorption: 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 is about 15 mcg/mL and 30 mcg/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 protein of Paracetamol (about 1.5 mcg/mL) were observed in the cerebrospinal fluid after the 20th minute following infusion.
Metabolism: Paracetamol is metabolized mainly in the liver following 2 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 (<4%) is metabolized by cytochrome P450 to a reactive intermediate (N-acetyl benzoquinone imine), which under normal conditions of use, is rapidly detoxified by reduced glutathione and eliminated in the urine after conjugation 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. Ninety percent (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 (t1/2) is 2.7 hours and total body clearance is 18 L/hr.
Special Population: Neonates, Infants and Children: The pharmacokinetic parameters of Paracetamol observed in infants and children are similar to those observed in adults, except for the plasma t1/2 that is slightly shorter (1.5-2 hours) than in adults. In neonates, the plasma t1/2 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 conjugates than adults.
Renal Insufficiency: In cases of severe renal impairment (creatinine clearance (CrCl) 10-30 mL/min), the elimination of Paracetamol is slightly delayed, the elimination t1/2 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 healthy subjects. Therefore, when giving Paracetamol to patients with severe renal impairment (≤CrCl 30 mL/min), the minimum interval between each administration should be increased to 6 hours.
Elderly: The pharmacokinetics and the metabolism of Paracetamol is not modified in elderly subjects. No dose adjustment is required in this population.