Pharmacology: Pharmacodynamics: Mode or Mechanisms of Action: Analgesic: Inhibits prostaglandin synthesis in the central nervous system (CNS) and through a peripheral action blocking pain impulse generation.
The peripheral action is due to inhibition of prostaglandins or to inhibution of the or actions of other substances, which sensitize pain receptors to mechanical or chemical stimulation.
650 mg tab: The mechanism of action has not been fully determined.
Antipyretic: Produced antipyresis by acting centrally on the hypothalamic heat-regulating centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss.
The central action involves inhibition of prostaglandin synthesis in the hypothalamus.
Pharmacokinetics: Absorption: Rapid and almost complete following oral administration; may be decreased if taken following a high-carbohydrate meal.
500 mg tab: The rate and extent of absorption from the suppository dosage form may vary depending on the composition of the base.
Distribution: 650 mg tab: In breast milk: Peak concentrations of 10 to 15 mcg per mL (66.2 to 99.3 micromoles/L) have been measured in breast milk 1 to 2 hours following maternal ingestion of a single 650-mg dose. The half-life in breast milk is 1.35 to 3.5 hours.
Protein binding: 650 mg tab: Not significant with doses producing plasma concentrations below 60 mcg per ml (397.2 micromoles/L); may reach moderate levels with high or toxic doses.
500 mg tab & oral susp: Not significant with doses producing plasma concentrations below 60 mcg per ml; may reach moderate levels with high or toxic doses.
Metabolism: Approximately 90 to 95% of a dose is metabolised in the liver, primarily by conjugation with glucuronic acid, sulphuric acid, and cysteine. An intermediate metabolite, which may accumulate in overdosage after the primary metabolite pathways become saturated, is hepatotoxic and possibly nephrotoxic.
Half-life: 1 to 4 hours; does not change with renal failure but may be prolonged in acute overdosage, in some forms of hepatic disease, in the elderly and in the neonate, and may be some what shortened in children.
Time to peak concentration: 0.5 to 2 hours.
Peak plasma concentration: 650 mg tab: 5 to 20 mcg per ml (33.1 to 132.4 micromoles/L), with doses up to 650 mg.
500 mg tab & oral susp: 5 to 20 mcg per ml (with doses up to 6.50 mg).
Time to peak effect: 650 mg tab & oral susp: 1 to 3 hours.
Duration of action: 3 to 4 hours.
Excretion: Renal; primarily as conjugates.
500 mg & 650 mg tab: 3% of a dose may be excreted unchanged.
Oral susp: 2% of a dose may be excreted unchanged.
In dialysis: Haemodialysis: 650 mg tab: 120 ml per minute (for unmetabolized drug): metabolites are also cleared rapidly.
Haemoperfusion: 200 ml per minute.
Peritoneal dialysis: <10 ml per minute.