NSAIDs or Non-Steroidal Anti Inflammatory Drugs are a group of pharmacological agents which are involved in a wide range of functions. At present, NSAIDs are being used as analgesics, antipyretic, antirheumatic, and anti-inflammatory agents. Their primary mechanism of action is the inhibition of the first step in the synthesis of prostanoids by inhibiting the cyclooxygenase enzymes. Aspirin is the prototype of NSAIDs and newer agents include Diclofenac, Naproxen, Indomethacin and Ibuprofen, amongst others. Aspirin or acetyl salicylic acid is a compound composed of the acetyl and the salicylate portions.
Both these portions of the intact aspirin molecule, as well as the active salicylate metabolite are functionally active and are involved in the analgesic, antipyretic, and anti-inflammatory effects of aspirin. Aspirin is different from other NSAIDs in that it binds irreversibly to the cyclooxygenase enzyme i. e. acetylates the active site of the enzyme, while all other NSAIDs are reversible inhibitors of this enzyme. Thus the aspirin induced suppression of thromboxane production lasts for the life of the anucleate platelet viz. approximately seven to ten days.
In addition, the salicylate portion of the aspirin molecule may competitively inhibit prostaglandin formation. It is important to note that the platelet aggregation–inhibiting effect of aspirin specifically involves its ability to act as an acetyl donor to the platelet membrane. This is in contrast to the nonacetylated salicylates, which have been shown to have no clinically significant effect on platelet aggregation. Aspirin may also inhibit formation of the platelet aggregation inhibitor prostacyclin (prostaglandin I2) in blood vessels; however, this action is reversible.
(Richard, 2000). What is the biosynthetic origin of prostanoids? Prostanoids are biologically active lipids which are involved in the body’s inflammatory response and are derived from C-20 unsaturated fatty acids (eicosanoids) (Christie, 2009). There are three main subgroups of prostanoids viz. prostaglandins, prostacyclins and thromboxanes. Under normal conditions, prostanoids are not stored within cells, but are synthesized as in response to hormonal stimuli when required.
The first step in prostanoids synthesis is the release of arachidonic acid, from the cell membrane phospholipids, by the action of the enzyme phospholipase A2. Arachidonic acid is an essential fatty acid derived from linoleic acid from the diet . This molecule cannot be synthesized de novo in animals, and is a major component of phospholipids which are important for the integrity of cellular membranes. Arachidonic acid is then acted upon by one of two isoenzymes, cyclooxygenase-1 or cyclooxygenase–2 (COX-1 and COX-2).
Cyclooxygenase catalyze the process of addition of two oxygen molecules to arachidonic acid to form a bicyclic endoperoxide and thus metabolize arachidonic acid to five primary prostanoids: PGE2, PGF2? , PGI2, TxA2, and PGD2. The function of both the cyclooxygenase isoenzymes is to catalyze the same reaction however, their site of action differs. After addition of the oxygen molecules, a further hydroperoxy group is added in position 15 of the 20 carbon chain to form prostaglandin PGG2. In the next step, the hydroperoxide is reduced by a functionally coupled peroxidase reaction to form prostaglandin PGH2 (Christie, 2009).
PGH2 is an important unstable intermediate since all other prostanoids can be derived from it by varying enzymatic reactions, for example PGE2, PGD2, LGE2, PGF2? , prostacyclins and thromboxanes. For instance, PGE2, which is the principal prostanoid found in certain renal cells is formed from PGH2 by a prostaglandin E synthase. Similarly, PGD2 is derived from PGH2 by the action of prostaglandin D synthases. Other molecules, including Levuglandins, such as LGE2, are formed from PGH2 by a non-enzymic rearrangement (Christie, 2009).
PGE and PGD are also precursors for important molecules. Both these molecules undergo spontaneous dehydration reaction to form prostaglandins A and J, respectively, by spontaneous dehydration reactions (Christie, 2009). Another important molecule, PGF2? , is synthesized by via two routes. It can either be produced directly from PGH2 or PGE2. The conversion from PGH2 occurs via the action of prostaglandin H-endoperoxide reductase, involving the use of NADPH. On the other hand the conversion from PGE2 occurs by the action of an enzyme prostaglandin E 9-ketoreductase (Christie, 2009).
Prostacyclin, which is the main prostanoid found in endothelial and smooth muscle cells and thromboxanes, which are found in platelets and lungs, are also synthesized directly from PGH. The formation of PGI2 (prostacyclin) from PGH2 is mediated via prostacyclin synthase. On the other hand, production of TXA2 from PGH2 is catalyzed by thromboxane A synthase. The prerequisite for the formation of both prostacyclin and thromboxanes is the transfer of PGH across the cell membranes since the enzymes involved in their synthesis are located on the cytosolic face of the endoplasmic reticulum (Christie, 2009).