Metamizole sodium

Metamizole sodium is a pyrazolone derivative with analgesic, antipyretic and slight antiinflammatory and spasmolytic properties. It has the most potent analgesic effect of all the pyrazolone derivatives. As with other analgesics, its mechanism of action has not been elucidated in detail. It includes inhibition of prostaglandin synthesis (PGE1 and PGE2) and reversible inhibition of platelet aggregation. It inhibits cyclo-oxygenase and influences the effect of arachidonic acid. Concurrently, a central active component also appears to be present.

Depression of the central pain perception through activation of neurones in the pain-inhibitory system is also postulated for the analgesic activity component.

The antipyretic effect is mediated via a central attack on the hypothalamic heat-regulating centre, supported by increased heat dissipation via the periphery. The anti-inflammatory effect of metamizole sodium derives from its anti-exudative and vasoconstrictive properties, which may result, at least in part, from inhibition of endogenous prostaglandin synthesis.

Absorption

Following oral administration, metamizole sodium is rapidly and almost completely absorbed in the gastrointestinal tract.

Biotransformation

Metamizole sodium is rapidly cleaved to 4-methylaminoantipyrine (MAA) via non-enzymatic hydrolysis. Further metabolism leads via the active 4-aminoantipyrine (AA) to 4-acetylaminoantipyrine (AAA). A further metabolic pathway leads via incomplete oxidation of MAA to 4-formylaminoantipyrine (FAA). Only 65–70% of the administered dose is recovered via these metabolites.

Distribution

Maximum plasma concentrations (relating to all metabolites) are determined after approximately 30–90 min. Following oral administration of 1 g metamizole sodium, the maximum plasma concentration (C_max) of MAA is 10.5 ± 2.8 µg/ml; following rectal administration of 1 g metamizole sodium, the corresponding figure is 6.1 ± 1.9 µg/ml. Plasma protein binding is 57.6% (MAA), 47.9% (AA), 17.8% (FAA) and 14.2% (AAA).

Elimination

The pharmacokinetic response of the metabolites appears to be dose dependent. Elimination is approximately 90% renal with the major metabolite AAA and 10% via the biliary route with a half-life of approximately 10 h. In elderly patients, the elimination half-life of MAA increases from 2.6 h (12 volunteers, 21–30 years of age) to 4.5 h (9 volunteers, 73–90 years of age).

Following intramuscular injection, the metabolites of metamizole sodium show a comparable response.

Subchronic/chronic toxicity

Subchronic and chronic toxicity studies have been conducted in various animal species. Rats received 100–900 mg metamizole sodium/kg BW per os for a period of 6 months. At the highest dose (900 mg/kg BW), an increase in reticulocytes and Ehrlich’s inner bodies was observed after 13 weeks.

Dogs received metamizole sodium at doses of 30–600 mg/kg BW for a period of 6 months. From 300 mg/kg BW, dose-dependent haemolytic anaemia and functional renal and hepatic changes were observed.

Mutagenic and carcinogenic potential

Contradictory results have been obtained for metamizole in in vitro and in vivo investigations of mutagenicity.

Long-term investigations in rats gave no indications of a tumorigenic potential. In 2 out of 3 long-term studies in the mouse, increased incidences of hepatocellular adenomas were observed at high doses.

Reproductive toxicity

Embryotoxicity studies in rats and rabbits produced no indications of any teratogenic effects.

Embryolethal effects were observed in rabbits from a daily dose of 100 mg/kg BW, which was not yet maternally toxic. In rats, embryolethal effects occurred at maternally toxic doses. Daily doses above 100 mg/kg BW in rats led to prolonged gestation and birth complications with increased mortality of the dams and offspring.

Fertility tests showed a slightly reduced gestation rate in the parent generation at a dose above 250 mg/kg BW and day. The fertility of the F₁ generation was not impaired.