ures may be indicated by the patient's clinical condition.
Haemodialysis is of little value since mefenamic acid and its metabolites are firmly bound to plasma proteins.
5. Pharmacological properties
5.1 Pharmacodynamic properties
ANIMAL MODELS
Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID) with anti- inflammatory, analgesic and antipyretic properties.
Its anti-inflammatory effect was first established in the UV erythema model of inflammation. Further studies included inhibition of granulation tissue growth into subcutaneous cotton pellets in rats and carrageenin induced rat paw oedema tests.
Antipyretic activity was demonstrated in yeast-induced pyresis in rats. In this model its antipyretic activity was roughly equal to that of phenylbutazone and flufenamic acid, but less than that of indomethacin.
Analgesic activity was demonstrated in tests involving pain sensitivity of rats paws inflamed by brewers yeast. Mefenamic acid was less potent than flufenamic acid in this model.
Prostaglandins are implicated in a number of disease processes including inflammation, modulation of the pain response, dysmenorrhoea, menorrhagia and pyrexia.
In common with most NSAIDs mefenamic acid inhibits the action of prostaglandin synthetase (cyclo oxygenase). This results in a reduction in the rate of prostaglandin synthesis and reduced prostaglandin levels.
The anti-inflammatory activity of NSAIDs in the rat paw oedema test has been correlated with their ability to inhibit prostaglandin synthetase. When mefenamic acid is ranked in both these tests it falls between indomethacin and phenylbutazone and it is probable that inhibition of prostaglandin synthesis contributes to the pharmacological activity and clinical efficacy of mefenamic acid.
There is also considerable evidence that the fenamates inhibit the action of prostaglandins after they have been formed. They therefore both inhibit the synthesis and response to prostaglandins. This double blockade may well be important in their mode of action.
5.2 Pharmacokinetic properties
Absorption and Distribution
Mefenamic acid is absorbed from the gastro intestinal tract. Peak levels of 10 mg/l occur two hours after the administration of a 1g oral dose to adults.
Metabolism
Mefenamic acid is predominantly metabolised by cytochrome P450 enzyme CYP2C9 in the liver, first to a 3-hydroxymethyl derivative (metabolite I) and then a 3-carboxyl derivative (metabolite II). Both metabolites undergo secondary conjugation to form glucuronides.
Therefore in patients who are known or suspected to be poor CYP2C9 metabolisers based on previous history/experience with other CYP2C9 substrates, mefenamic acid should be administered with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.
Elimination
Fifty two percent of a dose is recovered from the urine, 6% as mefenamic acid, 25% as metabolite I and 21% as metabolite II. Assay of stools over a 3 day period accounted for 10-20 % of the dose chiefly as unconjugated metabolite II.
The plasma levels of unconjugated mefenamic acid decline with a half life of approximately two hours.
5.3 Preclinical safety data
Preclinical safety data does not add anything of further significance to the prescriber.
6. Pharmaceutical particulars
6.1 List of excipients
Lactose monohydrate
Sodium laurilsulfate
Gelatin
Purified water*
Erythrosine (E127)
Quinoline yellow (E104)
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