Blood Substitutes

Topics: Cyclooxygenase, Non-steroidal anti-inflammatory drug, Celecoxib Pages: 6 (1951 words) Published: April 14, 2013
In September 2004, Merck (the manufacturer of Vioxx) announced a voluntary worldwide withdrawal of Vioxx because of an increased risk of heart attack and stroke. Background on PGs and COX
In general, all Nonsteroidal anti-inflammatory drugs (NSAIDs) act as cyclooxygenase inhibitor (COX), it is an enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid. The first step in the synthesis of PGs is the release of the arachidonic acid from phospholipids in the cellular membrane, this reaction is catalyzed by the enzyme phospholipase A2, then two molecules of oxygen are added to arachidonic acid by the action of COX enzyme to form prostaglandin PGG2, then by the action of peroxidase, prostaglandin PGH2 will be formed, it is an unstable intermediate from which all other PGs such as PGE2 and PGI2(prostacyclin) and also thromboxane are derived by different enzymatic reactions.Prostaglandins (PGs) have significant role in both physiologic and pathologic processes. First, Some of the important physiological roles of PGs, PGE2 and PGI2 have significant roles in gastric mucosal protection in the presence of endogenous aggressive factor such as gastric acid by mainly increasing secretion of gastric mucosa and decreasing gastric acid secretion, also PGE2 has a role in regulating the kidney function by maintaining vascular tone, blood flow, and salt and water excretion. Moreover, there are important and opposing functions of both prostacyclin PGI2 and thromboxane TXA2 in maintaining the vascular homeostasis and good cardiovascular health, in detail, TXA2 is synthesised in the platelets by the action of COX-1 during the platelet activation, it increases platelet aggregation, vasoconstriction, and smooth muscle proliferation. In contrast, PGI2 is produced in the endothelial cells by the action of COX-2; it has a potent vasodilator and inhibits platelet aggregation and smooth muscle cell proliferation. Second, pathologically, the biosynthesis of the PGs increases at inflammation sites, and then PGs will involve in the development of the inflammation signs, in detail, the main signs are redness and edema that result from increased blood flow into the inflamed tissue through the arterial dilatation and increasing microvascular permeability are caused by PGE2, also, Pain results from the action of PGE2 on peripheral sensory neurons and central sites in the spinal cord and the brain. Consequently, the inhibition of PGs production by non- specific NSAIDS will alleviate most of the pathologic effects associated with inflammation, but this also will interfere with the physiologic role of PGs. Consequently, long-term therapy with nonspecific NSAIDs is limited by their adverse effects which result from interference with the physiological roles of PGs particularly the erosion of gastric mucosal protection, to prevent this adverse effect , NSAIDS have been developed to be more selective to inhibit only one isoform of COX which is COX-2, whose expression increases during the inflammation. In detail, COX enzyme has 2 isoforms, COX-1 and COX-2; the two isoforms have similar enzymatic activity, but they are encoded by different genes, COX1 gene is expressed constitutively, so it is transcribed at constant level at most tissues, for the COX-1 enzyme, it is ubiquitous in the body and it is the main COX isoform in gastric mucosa and other important sites where PGs have important physiological roles. Regarding the COX2 gene, it is inducible gene, so the expression increases mainly in response to the inflammation , specifically, Strong COX-2 expression is observed in the synovial tissues of patients with rheumatoid arthritis (RA), however COX-2 has some physiological roles such as the production of prostacyclin in the endothelial cells by the action of COX-2 and also in the kidney tissues.
This figure summarizes the synthesis of PGs from arachidonic acid, and also the role of COX-1 and COX-2 in...
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