Sulfasalazine is a salicylate anti-inflammatory drug used to treat Crohn's disease, severe ulcerative colitis, and rheumatoid arthritis. This drug is metabolized by intestinal bacteria to mesalazine and sulfapyridine, these two compounds carry out the main pharmacological activity of sulfasalazine. The mode of action of sulfasalazine or its metabolites, 5-aminosalicylic acid, and sulfapyridine, is still under investigation but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animals. Sulfasalazine and its metabolites have been shown to inhibit leukotrienes and prostaglandins by blocking the cyclo-oxygenase and lipoxygenase pathways. The enzymes that were investigated include phospholipase A2, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX2), and arachidonate 5-lipoxygenase. The cyclooxygenase pathway begins in the cytosol with phospholipids being converted into arachidonic acid by the action of phospholipase A2. The rest of the pathway occurs on the endoplasmic reticulum membrane, where prostaglandin G/H synthase 1 & 2 convert arachidonic acid into prostaglandin H2. Prostaglandin H2 can either be converted into thromboxane A2 via thromboxane A synthase, prostacyclin/prostaglandin I2 via prostacyclin synthase, or prostaglandin E2 via prostaglandin E synthase. COX-2 is an inducible enzyme, and during inflammation, it is responsible for prostaglandin synthesis. It leads to the formation of prostaglandin E2 which is responsible for contributing to the inflammatory response by activating immune cells and for increasing pain sensation by acting on pain. Mesalazine inhibits the action of COX-1 and COX-2 on the endoplasmic reticulum membrane. This reduces the formation of prostaglandin H2 and therefore, prostaglandin E2 (PGE2). The low concentration of prostaglandin E2 attenuates the effect it has on stimulating immune cells and pain fibers, consequently reducing inflammation and pain. Fever is triggered by inflammatory and infectious diseases. Cytokines are produced in the central nervous system (CNS) during an inflammatory response. These cytokines induce COX-2 production that increases the synthesis of prostaglandin, specifically prostaglandin E2 which adjusts hypothalamic temperature control by increasing heat production. Because mesalazine decreases PGE2 in the CNS, it has an antipyretic effect. Antipyretic effects results in increased peripheral blood flow, vasodilation, and subsequent heat dissipation. Inhibitory activities on other non-arachidonic acid derivatives have also been observed, including PPAR gamma, NF-Kb, and IkappaB kinases alpha and beta.

Sulfasalazine Pathway References