Non-steroidal Anti-inflammatory Drug - Mechanism of Action

Mechanism of Action

Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A₂). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane (1927–2004), who received a Nobel Prize for his work (see Mechanism of action of aspirin).

COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. COX-2 was discovered in 1991 by Daniel L. Simmons at Brigham Young University. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.

When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum internal bleeding can result.

NSAIDs have been studied in various assays to understand how they affect each of these enzymes. While the assays reveal differences, unfortunately different assays provide differing ratios.,

The discovery of COX-2 led to research to development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs.

Acetaminophen is not considered an NSAID because it has little anti-inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body.

However, many aspects of the mechanism of action of NSAIDs remain unexplained, for this reason further COX pathways are hypothesized. The COX-3 pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed.

NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase.