Chemical formula: C₈H₉NO₂ Molecular mass: 151.163 g/mol PubChem compound: 1983
The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent, through a peripheral action by blocking pain-impulse generation.
The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation.
Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulation centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus.
Paracetamol 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 reduces fever within 30 minutes after the start of administration with a duration of the antipyretic effect of at least 6 hours.
Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulfate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.
A minor hydroxylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione may accumulate following paracetamol overdosage and cause liver damage.
Paracetamol pharmacokinetics is linear up to 2 g after single administration and after repeated administration during 24 hours. The 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 (Cmax) of paracetamol observed at the end of 15-minutes intravenous infusion of 500 mg and 1 g of Paracetamol is about 15 micrograms/mL and 30 micrograms/mL respectively.
The volume of distribution of paracetamol is approximately 1 L/kg. Paracetamol is not extensively bound to plasma proteins. Following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 micrograms/mL) were observed in the Cerebro Spinal Fluid as and from the 20th minute following infusion.
Paracetamol is metabolised mainly in the liver following 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 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.
The metabolites of paracetamol are mainly excreted in the urine. 90% of the dose administered is excreted in 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.
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 h) 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 conjugates than adults.
Table. Age related pharmacokinetic values (standardized clearance, *CLstd/Foral (l.h-1 70 kg-1), are presented below:
| Age | Weight (kg) | CLstd/Foral (l.h-1 70 kg-1) |
|---|---|---|
| 40 weeks PCA | 3.3 | 5.9 |
| 3 months PNA | 6 | 8.8 |
| 6 months PNA | 7.5 | 11.1 |
| 1 year PNA | 10 | 13.6 |
| 2 years PNA | 12 | 15.6 |
| 5 years PNA | 20 | 16.3 |
| 8 years PNA | 25 | 16.3 |
* CLstd is the population estimate for CL
In cases of severe renal impairment (creatinine clearance 10-30 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 slower in subjects with severe renal impairment than in healthy subjects. Therefore, it is recommended, when giving paracetamol to patients with severe renal impairment (creatinine clearance ≤30 mL/min), to increase the minimum interval between each administration to 6 hours.
The pharmacokinetics and the metabolism of paracetamol are not modified in elderly subjects. No dose adjustment is required in this population.
Preclinical data reveal no special hazard for humans. Studies on local tolerance of paracetamol 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.
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