Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: Acetic acid derivatives and related substances, ATC code: M01AB05

Mechanism of action:
Diclofenac sodium is a non-steroidal agent with marked analgesic/anti-inflammatory properties. It is an inhibitor of prostaglandin synthetase, (cyclo-oxygenase).
Diclofenac sodium in vitro does not suppress proteoglycan biosynthesis in cartilage at concentrations equivalent to the concentrations reached in human beings.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
After ingestion of the diclofenac slow release tablet, the active principle is slowly released into the gastrointestinal contents. Once released from the tablet, diclofenac is rapidly absorbed from the gastrointestinal tract but is subject to first-pass metabolism.
Peak plasma concentrations occur about 4.5 hours after administration of the slow release tablets when taken with a meal. Food and antacids decrease the rate but not the extent of absorption of diclofenac. The systemic availability of diclofenac from the SR formulations is on average 82% of that achieved with the same dose of enteric-coated tablets (possibly due to release rate dependent first-pass metabolism).
The active substance is 99.7% bound to plasma proteins, mainly albumin.
Diclofenac enters the synovial fluid and peak synovial fluid concentrations at steady state exceed plasma concentrations. Furthermore, elimination from the synovial fluid is slower than from plasma. Diclofenac and its metabolites cross the placenta and traces of diclofenac have been found in the milk of lactating women. The half-life for the terminal elimination phase is 3 hours. Approximately 60% of the administered dose is excreted via the kidneys in the form of metabolites and less than 1% in unchanged form. About 30% of the dose is excreted via the bile in metabolised form.
In patients with impaired renal function, accumulation of diclofenac sodium has not been reported. However, half-life of diclofenac may be prolonged in patients with severe renal impairment.
Five Diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'- hydroxy-4'-methoxy-Diclofenac. The major Diclofenac metabolite, 4'-hydroxy- Diclofenac, has very weak pharmacologic activity. The formation of 4'-hydroxy Diclofenac is primarily mediated by CYP2C9. Both Diclofenac and its oxidative metabolites undergo glucuronidation or sulfation followed by biliary excretion.
Acylglucuronidation mediated by UGT2B7 and oxidation mediated by CYP2C8 may also play a role in Diclofenac metabolism. CYP3A4 is responsible for the formation of minor metabolites, 5-hydroxy- and 3'-hydroxy-Diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxy- Diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects.