Celecoxib, a non-steroidal anti-inflammatory drug (NSAID), is a selective inhibitor of cyclooxygenase-2 (COX-2), also known as prostaglandin G/H synthase 2. Like other NSAIDs, celecoxib exerts its effects by inhibiting the synthesis of prostaglandins involved in pain, fever and inflammation. COX-2 catalyzes the conversion of arachidonic acid to prostaglandin G2 (PGE2) and PGE2 to prostaglandin H2 (PGH2). In the COX-2 catalyzed pathway, PGH2 is the precusor of prostaglandin E2 (PGE2) and I2 (PGI2). PGE2 induces pain, fever, erythema and edema. Celecoxib inhibits COX-2 via noncompetitive negative allosteric modulation by binding to the upper portion of the active site, preventing its substrate, arachidonic acid, from entering the active site. Similar to other COX-2 inhibitors, such as rofecoxib (Vioxx) and valdecoxib, celecoxib appears to exploit slight differences in the size of the COX-1 and -2 binding pockets to gain selectivity. COX-1 contains isoleucines at positions 434 and 523, whereas COX-2 has slightly smaller valines occupying these positions. Studies support the notion that the extra methylene on the isoleucine side chains in COX-1 adds enough bulk to proclude celecoxib from binding. Celecoxib (like most "coxib" NSAIDs) is approximately ten times more selective for COX-2 than COX-1. Celecoxib is used mainly to treat rheumatoid arthritis and osteoarthritis which require something more potent to reduce inflammation than a typical over-the-counter NSAID like aspirin (also known as ASA, acetylsalicylic acid). It may also be prescribed for menstrual pain; however, evidence supporting this use is poor. The analgesic, antipyretic and anti-inflammatory effects of celecoxib occur as a result of decreased prostaglandin synthesis. This figure depicts the anti-inflammatory, analgesic and antipyretic pathway of celecoxib. While not shown in detail in the figure, celecoxib may play a role in interfering with platelet aggregation. Prostaglandin synthesis varies across different tissue types. Platelets, which are anuclear cells derived from fragmentation of megakaryocytes, contain COX-1, but not COX-2. COX-1 activity in platelets is required for thromboxane A2 (TxA2)-mediated platelet aggregation: COX-1 inhibits the production of prostaglandins and the production of thromboxane A2, a platelet activator. Platelet activation and coagulation do not normally occur in intact blood vessels. After blood vessel injury, platelets adhere to the subendothelial collagen at the site of injury. Activation of collagen receptors initiates phospholipase C (PLC)-mediated signaling cascades resulting in the release of intracellular calcium from the dense tubula system. The increase in intracellular calcium activates kinases required for morphological change, transition to the procoagulant surface, secretion of granular contents, activation of glycoproteins, and the activation of phospholipase A2 (PLA2). Activation of PLA2 results in the liberation of arachidonic acid, a precursor to prostaglandin synthesis, from membrane phospholipids. The accumulation of TxA2, ADP and thrombin mediates further platelet recruitment and signal amplification. TxA2 and ADP stimulate their respective G-protein coupled receptors, thromboxane A2 receptor and P2Y purinoreceptor 12, and inhibit the production of cAMP via adenylate cyclase inhibition. This counteracts the adenylate cyclase stimulatory effects of the platelet aggregation inhibitor, PGI2, produced by neighbouring endothelial cells. Platelet adhesion, cytoskeletal remodeling, granular secretion and signal amplification are independent processes that lead to the activation of the fibrinogen receptor. Fibrinogen receptor activation exposes fibrinogen binding sites and allows platelet cross-linking and aggregation to occur. Neighbouring endothelial cells found in blood vessels express both COX-1 and COX-2. COX-2 in endothelial cells mediates the synthesis of PGI2, an effective platelet aggregation inhibitor and vasodilator, while COX-1 mediates vasoconstriction and stimulates platelet aggregation. PGI2 produced by endothelial cells encounters platelets in the blood stream and binds to the G-protein coupled prostacyclin receptor. This causes G-protein mediated activation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic AMP (cAMP). Four cAMP molecules then bind to the regulatory subunits of the inactive cAMP-dependent protein kinase holoenzyme causing dissociation of the regulatory subunits and leaving two active catalytic subunit monomers. The active subunits of cAMP-dependent protein kinase catalyze the phosphorylation of a number of proteins. Phosphorylation of inositol 1,4,5-trisphosphate receptor type 1 on the endoplasmic reticulum (ER) inhibits the release of calcium from the ER. This in turn inhibits the calcium-dependent events, including PLA2 activation, involved in platelet activation and aggregation. Inhibition of PLA2 decreases intracellular TxA2 and inhibits the platelet aggregation pathway. cAMP-dependent kinase also phosphorylates the actin-associated protein, vasodilator-stimulated phosphoprotein. Phosphorylation inhibits protein activity, which includes cytoskeleton reorganization and platelet activation. Celecoxib preferentially inhibits COX-2 with little activity against COX-1; in fact, celecoxib does not inhibit COX-1 at recommended therapeutic concentrations. COX-2 inhibition in endothelial cells decreases the production of PGI2 and the ability of these cells to inhibit platelet aggregation and stimulate vasodilation. These effects are thought to be responsible for the adverse cardiovascular effects observed with other selective COX-2 inhibitors, such as rofecoxib, which has since been withdrawn from the market. Other side effects of celecoxib include gastric effects (e.g. abdominal pain, nausea, diarrhea, gastrointestinal bleeding or perforation), anaphylaxis, kidney failure, and increased risk of adverse cardiovascular events (i.e. "heart attack" or stroke), explained by the described mechanism. Many of these risks are common to NSAIDs. Use of celecoxib is contraindicated in pregnancy and breastfeeding. Interestingly, platelet aggregation is not the only "off-target" therapeutic side effect of coxibs: celecoxib may inhibit Kv2.1 ion channels, playing a role in pain management (as well as cardiovascular and neurological function) beyond anti-inflammation. It may also bind to and inhibit endoplasmic reticulum Ca2+-ATPases to increase intracellular calcium levels in various cell lines - this modulation of calcium stores may play a role in mitochondria-mediated cytotoxicity, explaining the exploration of celecoxib as an anticancer agent (based on lipo-oxygenase inhibition in glioma cells). Celecoxib has also been shown to bind to cadherin-11 and may reduce colon and rectal polyps in people with familial adenomatous polyposis; however, more evidence is needed for clinical use. Celecoxib is often administered orally and metabolized by Cytochrome P450 liver enzymes.

Celecoxib Pathway References