Planil 2X Gel Mechanism of Action

Pharmacology: Pharmacodynamics: Diclofenac has pharmacological actions similar to those of other prototypical non-steroidal anti-inflammatory drugs (NSAIDs). It exhibits anti-inflammatory, analgesic, and antipyretic activity.
Diclofenac inhibits the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase (COX); at least 2 isoenzymes, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), have been identified that catalyze the formation of prostaglandins in the arachidonic acid pathway.
Diclofenac, like other prototypical NSAIDs, inhibits both COX-1 and COX-2. Although the exact mechanisms have not been clearly established, NSAIDs appear to exert anti-inflammatory, analgesic, and antipyretic activity principally through inhibition of the COX-2 isoenzymes; COX-1 inhibitory presumably is responsible for the drugs' unwanted effects on GI mucosa and platelet aggregation.
Pharmacokinetics: Absorption: Diclofenac is also absorbed into systemic circulation following topical application, but plasma concentrations generally are very low compared with oral administration.
Following topical application of diclofenac sodium (1%) gel (4 g) 4 times daily, to one knee, the mean peak plasma diclofenac concentrations of 15 ng/mL occur in about 14 hours. Likewise, when gel is applied to both knees and both hands 4 times daily (48g), the mean peak plasma diclofenac concentrations of 53.8 ng/mL occur in about 10 hours.
Application of a heat patch for 15 minutes before the application of the gel did not affect systemic absorption. Moderate exercise did not affect systemic absorption of the drug.
The absorption for diclofenac, 1% and 3%, gel may take around 10 to 14 hours and approximately 5 hours, respectively.
Distribution: Diclofenac is absorbed percutaneously when applied. At therapeutic concentrations, it is more than 99% bound to plasma proteins, mainly to albumin. Diclofenac penetrates synovial fluid where concentrations may persist even when plasma concentration fall. Only small amounts are distributed into breast milk. The terminal half-life is around 1 to 2 hours.
As diclofenac accumulates in the applied area, skin, acts as reservoir, which creates a sustained release of drug into the underlying tissues. It then preferentially distributes and persists in deep inflamed sites, rather than in blood stream.
Metabolism: The exact metabolic rate of diclofenac has not been fully elucidated, but the drug is rapidly and extensively metabolized in the liver. Diclofenac is metabolized to 4'-hydroxydiclofenac, 5-hydroxydiclofenac, 3'-hydroxydiclofenac, and 4', 5-dihydroxydiclofenac via hydroxylation, glucuronidation and sulfidation.
Excretion: Its glucuronide and sulfate conjugates are excreted mainly in the urine (about 60%) but also in the bile (about 35%); less than 1% is excreted as unchanged diclofenac.