What does cox 2 do

The studies tested new uses of the drugs and have shown an increased risk for cardiovascular problems among certain groups of patients. For example, elderly patients and those who take the drugs for long periods of time tend to be more susceptible to known side effects such as gastrointestinal, kidney, and liver problems.

The most important thing to remember is that each patient should meet with his or her physician to determine the best course of action based on individual risk factors, treatment needs, and previous experience with NSAIDs.

NSAIDs non-steroidal anti-inflammatory drugs are the most frequently prescribed class of drugs for rheumatoid arthritis and osteoarthritis. Patients with arthritis experience inflammation in the joints that causes stiffness, limited range of motion, and often debilitating pain.

NSAIDs are used to inhibit the cyclooxygenase enzyme that controls inflammation. In addition to performing the anti-inflammatory function, NSAIDs also serve as an analgesic painkiller.

They also don't seem to affect platelets the way non-selective NSAIDs do, which means that COX-2 inhibitors may not increase bleeding risk as much as COX-1 inhibitors when used with blood thinners, like warfarin.

If you simply need pain relief, Tylenol acetaminophen may be considered instead. While NSAIDs and COX-2 inhibitors are both considered significant treatment options for osteoarthritis , rheumatoid arthritis, and ankylosing spondylitis, the benefits and risks must be considered for each individual.

Learn tips for managing arthrits pain, medications, and daily challenges. Prostaglandins and inflammation. Arterioscler Thromb Vasc Biol. Ghlichloo I, Gerriets V.

In: StatPearls [Internet]. Hawkey CJ. Best Pract Res Clin Gastroenterol. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol.

Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Saad J, Pellegrini MV. Brune K, Patrignani P. New insights into the use of currently available non-steroidal anti-inflammatory drugs. J Pain Res. Published Feb Zarghi A, Arfaei S. Iran J Pharm Res. Sibbald B. Rofecoxib Vioxx voluntarily withdrawn from market. Burton B. Walker C. Epidemiologic, animal, and human data indicate that NSAIDs, inhibitors of cyclooxygenase, are chemopreventive for colon cancer.

The in vivo mechanism by which COX-2 affects tumor growth has not been determined. Metabolites of arachidonic acid are critical for numerous biologic processes, including inflammation, ovulation, implantation, angiogenesis, platelet aggregation, and immunologic function.

Eicosanoids are the products of arachidonic acid metabolism, and the cyclooxygenase COX, prostaglandin H synthase, PGHS enzymes play a key role in the production of eicosanoids. Significant advances have been made in understanding the role of these enzymes in certain biologic processes.

The focus of this review will be limited to the role of cyclooxygenase in development information and cancer. Arachidonic acid is a 20 carbon unsaturated fatty acid distributed throughout the lipid bilayer of the cell, and is usually esterified at the SN-2 position of phospholipids.

Phospholipase enzymes cleave membrane bound arachidonate, thus making it available for conversion to bioactive lipids. Once liberated, the arachidonic acid can be metabolized through one of three major pathways: 1 the cyclooxygenase pathway; 2 the lipoxygenase pathway; or 3 the cytochrome P monooxygenase pathway. Additionally, free radical peroxidation can convert arachidonic acid non-enzymatically to yield isoprostanes.

The cyclooxygenase pathway, which is the focus of this study, is the most extensively studied of the major pathways. This occurs via a two-step process, in which the first step introduces two molecules of oxygen to arachidonate, forming the bicyclic peroxide intermediate, prostaglandin G 2 PGG 2.

The second step occurs in a distinct reactive site located on the other side of the molecule, and requires the diffusion of PGG 2 to this site. Though these enzymes are membrane bound, they do not contain transmembrane domains; rather, they possess four amphipathic helices juxtaposed such that they form a localized region of hydrophobicity. The hydrophobic region serves to anchor the lower portion of the enzyme in the membrane.

The cyclooxygenase active site is located in an area of hydrophobicity near the amphipathic helices. Access to this site occurs via a channel buried in the lipid bilayer. Both substrate and inhibitors use this channel to reach the active site. Cycloxygenase-1 was first purified from bovine vesicular glands in Miyamoto et al. COX-1 is constitutively expressed in many tissues including kidney, lung, stomach, duodenum, jejunum, ileum, colon, and cecum of rat, dog, Rhesus monkey, and human Kargman et al.

COX-1 activity is believed to be responsible for producing cytoprotective prostaglandins, such as prostacyclin and PGE 2 , which are thought to be critical to maintain integrity of gastric mucosa Allison et al. In , Simmons et al. In , Kujubu et al. This second isoform, now known as cyclooxygenase-2 COX-2 , shares significant sequence homology and catalytic activity with COX However, its expression pattern is markedly different. Most tissues, with the exception of the placenta, the macula densa of the kidney and brain, do not constitutively express COX-2 Harris et al.

However, a variety of extracellular and intracellular stimuli will rapidly induce COX These stimuli include lipopolysaccharide LPS Fu et al. In , Vane and colleagues first demonstrated that aspirin and indomethacin inhibited prostaglandin production by blocking cyclooxygenase enzymatic activity Vane, Since that report, it has been found that nonsteroidal anti-inflammatory drugs NSAIDs directly affect cyclooxygenase activity, either by covalently modifying the enzyme as in the case of aspirin and the selective COX-2 inhibitor APHS , or by competing with the substrate for the active site as with virtually all other NSAIDs.

Because prostaglandins participate in a number of normal physiologic functions, it is predictable that chronic blockade of cyclooxygenase leads to some undesirable side effects. Potentially life-threatening side-effects of NSAID use include gastrointestinal ulceration, bleeding and perforation. Some studies have estimated that regular users of NSAIDs have a threefold greater relative risk of developing serious gastrointestinal complications when compared to non-users Gabriel et al.

Therefore, inhibitors which could distinguish between the two cyclooxygenase isoforms might achieve analgesic and anti-inflammatory benefits without the accompanying undesirable gastrointestinal side effects. The prototypical cyclooxygenase inhibitor, aspirin, blocks cyclooxygenase enzymatic activity covalently through the acetylation of Ser in COX-1, and Ser in COX-2 Wennogle et al. This modification does not affect the peroxidase activity of the enzyme, and aspirin-acetylated COX-2, but not COX-1, can generate HETE, which is normally produced via the lipoxygenase pathway Capdevila et al.

In purified enzyme assays, both non-preferential inhibitors such as indomethacin and flurbiprofen Laneuville et al. COX-2 selectivity with these inhibitors is achieved only when COX-2 is pre-incubated with inhibitor prior to substrate addition.

The binding of the inhibitor occurs as a two step mechanism. In contrast, inhibition of COX-1 by this class of drugs is much weaker, rapidly reversible, and detectable only at low arachidonate concentrations.

Recently, a new COX-2 inhibitor has been developed Kalgutkar et al. While this level of selectivity is not as great as that of some other COX-2 inhibitors, this inhibitor offers a unique advantage in that it covalently modifies the enzyme, thus insuring complete, permanent activation of COX-2 while sparing COX-1 enzymatic function.

The pro-inflammatory role of COX-2 recently has been questioned. Using the carrageenin-induced pleurisy model, investigators have demonstrated that later-stage COX-2 generated cyclopentanone prostaglandins may actually enhance resolution of inflammation Gilroy et al.

Furthermore, investigators have found that inhibition of COX-2 in animal models for ulcer formation decreases the rate of ulcer healing Mizuno et al. These observations have clear clinical implications if they translate accurately from animal models of inflammation to inflammatory conditions in humans. Phenotypic analysis of mice in which either Cox1 Ptgs1 or cox-2 Ptgs2 has been inactivated via homologous recombination yields information about the role of cyclooxygenases in development.

Such animals were first produced and studied in Dinchuk et al. Phenotypic abnormalities, some of which were unexpected, were observed in both Cox1 and cox-2 null mice and are described below and summarized in Table 1. In , Langenbach et al. However, detailed study of the animals revealed certain phenotypic anomalies, many of which were unexpected. One expected finding in the null mice was decreased platelet aggregation in response to arachidonic acid treatment. Platelet localized COX-1 enzyme produces precursors for the synthesis of thromboxane, a potent inducer of platelet aggregation Schafer, COX-1 deficient platelets presumably cannot produce these precursors, and therefore exhibit delayed aggregation.

Also, because platelets lack nuclei, they are unable to produce COX-2 via a compensatory mechanism. Despite the decrease in platelet aggregation, the Cox1 null mice did not have any significant hemorrhagic complications. As mentioned above, COX-1 generated prostaglandins appear to be cytoprotective to the gastric mucosa. Thus, it was hypothesized that null mice might exhibit gastric pathology. Additionally, when null mice were treated with indomethacin, an NSAID known to induce ulcer formation, there was reduced ulceration when compared to wild type mice.

Western blotting revealed that COX-2 protein levels were equivalent in wild type and Cox1 null mice. Therefore, compensation by induction of COX-2 was not occurring in these tissues. The authors speculated that compensation by non-prostaglandin pathways may have been occurring. Another unexpected finding in the Cox1 null mice was a lack of significant renal pathology. COX-1 is widely expressed in the kidney, and is known to produce vasodilatory prostaglandins which are considered important for the maintenance of renal blood flow and glomerular filtration rate.

In the study by Langenbach et al. However, the lesions were of minimal severity, and did not progress, or cause appreciable alterations in kidney function Langenbach et al.

Prostaglandins play important regulatory roles in the reproductive processes of ovulation, implantation, and parturition Chakraborty et al. However, fertility, defined as the capacity to conceive, was normal in both male and female null mice. Furthermore, matings in which either parent is Cox1 heterozygous resulted in normal litter size and perinatal pup survival. These matings resulted in equal numbers of homozygous and heterozygous pups, suggesting that COX-1 production in either maternal or fetal tissue could restore perinatal survival.

Unlike human kidney development, mouse kidney development continues postnatally. Three-day-old cox-2 null mice exhibit no kidney abnormalities. However, by 6 weeks of age, striking abnormalities appear in the subcapsular nephrogenic zone, and include glomerular sclerosis and associated tubulointerstitial injury.

Compromised renal function as a result of damage to overworked immature nephrons results in increased blood urea nitrogen and serum creatinine levels.