Pharmacology: Pharmacodynamics: Paracetamol is a centrally acting analgesic and antipyretic with minimal anti-inflammatory properties.
Analgesic: The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting prostaglandin synthesis in the central nervous system (specifically cyclooxygenase (COX)-2) 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 sensitize pain receptors to mechanical or chemical stimulation.
Antipyretic: Paracetamol acts centrally on the hypothalamic heat-regulating center to produce peripheral vasodilatation resulting in increased blood flow through the skin, sweating and heat loss. Paracetamol reduces fever by inhibiting the release of prostaglandins in the central nervous system and by inhibiting endogenous pyrogens at the hypothalamic thermoregulatory center.
Pharmacokinetics: Following oral administration paracetamot is rapidly absorbed.
Paracetamol absorption takes place mainly in the small intestine and therefore the rate of absorption is depending on the rate of gastric emptying. It has been shown that drugs which delay gastric emptying also delay the absorption of paracetamol whereas metoctopramide (a drug which increases the rate of gastric emptying) accelerates absorption of the analgesic although the total absorbed amount does not increase.
The presence of food in the stomach has also been reported to reduce the rate of absorption of paracetamol. Alterations in gastric pH have no appreciable effect on paracetamol absorption.
During absorption, the amount of paracetamol which is inactivated is negligible and it has been shown that paracetamol does not affect gastric mucosal permeability and does not produce mucosal bleeding.
Peak plasma concentrations are reached 1 hour after absorption. The plasma half-life is 1 to 3 hours. Paracetamol penetrates the brain and is present in breast milk of human.
Paracetamol is metabolized by the microsomal enzyme system of the liver. This metabolism is mainly to the glucuronide and sulphate conjugates, accounting for approximately 49% and 26% of the ingested dose respectively. About 4% is excreted as free paracetamol. Other minor pathways include the production of catechol derivatives and cysteine conjugates (via glutathione). Paracetamol excretion is rapid and occurs via the urine.