Diclofenac - Mechanism of Action

Mechanism of Action

The exact mechanism of action is not entirely known, but the primary mechanism responsible for its anti-inflammatory, antipyretic, and analgesic action is thought to be inhibition of prostaglandin synthesis by inhibition of cyclooxygenase (COX). It also appears to exhibit bacteriostatic activity by inhibiting bacterial DNA synthesis.

Inhibition of COX also decreases prostaglandins in the epithelium of the stomach, making it more sensitive to corrosion by gastric acid. This is also the main side effect of diclofenac. Diclofenac has a low to moderate preference to block the COX2-isoenzyme (approximately 10-fold) and is said to have, therefore, a somewhat lower incidence of gastrointestinal complaints than noted with indomethacin and aspirin.

The action of one single dose is much longer (6 to 8 hr) than the very short half-life of the drug indicates. This could be partly because it persists for over 11 hours in synovial fluids.

Diclofenac may also be a unique member of the NSAIDs. Some evidence indicates diclofenac inhibits the lipoxygenase pathways, thus reducing formation of the leukotrienes (also pro-inflammatory autacoids). It also may inhibit phospholipase A₂ as part of its mechanism of action. These additional actions may explain the high potency of diclofenac – it is the most potent NSAID on a broad basis.

Marked differences exist among NSAIDs in their selective inhibition of the two subtypes of cyclo-oxygenase, COX-1 and COX-2. Much pharmaceutical drug design has attempted to focus on selective COX-2 inhibition as a way to minimize the gastrointestinal side effects of NSAIDs like aspirin. In practice, use of some COX-2 inhibitors with their adverse effects has led to massive numbers of patient family lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs, such as diclofenac, have been well tolerated by most of the population.

Besides the well-known and often-cited COX-inhibition, a number of other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:

• Blockage of voltage-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation also known as phase inhibition)

• Blockage of acid-sensing ion channels (ASICs)

• Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)