Prostaglandin synthetase, inhibition

Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID). It exhibits anti-inflammatory, analgesic and antipyretic activities. The mechanism of action is not completely understood but may be related to prostaglandin synthetase inhibition. 

Vinci JM, Gill JR Jr, Bowden RE, et al. The kallikrein-kinin system in Bartter s syndrome andits response to prostaglandin synthetase inhibition. J Clin Invest 1987 61 1671-1682. 

Demerson, C.A. Humber, L.G. Abraham, N.A. Schilling, G. Martel, R.R. Pace-Asciak, C. Resolution of etodolac and antiinflammatory and prostaglandin synthetase inhibiting properties of the enantiomers. J.Med.Chem., 1983, 26, 1778—1780... 

Lema, W.J. etal. 1985. Prostaglandin synthetase inhibition by alkaloids of Heimia salicifolia "Journal ofEthnopharmacology 15(2) 161-167. 

Kaufman J, Hamburger R, Matheson J, Flamenbaum W. Bumetanide-induced diuresis and natriuresis effect of prostaglandin synthetase inhibition. J Clin Pharmacol (1981) 21, 663-1. 

McCarthy, J.T., Torres, V.E. and Romero, J.C., Wochos, D.N. and Velosa, J.A. (1982). Acute intrinsic renal failure induced by indomethacin Role of prostaglandin synthetase inhibition. Mayo Clin. Proc., 57, 289—96... 

Baumann J, Wurm G, Bruchhausen FV 1980 Prostaglandin synthetase inhibition by flavonoids and phenolic compounds in relation to their scavenging properties. Arch Pharm (Weinheim) 313 330-337... 

Aminophenol is a selective nephrotoxic agent and intermpts proximal tubular function (121,122). Disagreement exists concerning the nephrotoxity of the other isomers although they are not as potent as 4-aminophenol (123,124). Respiration, oxidative phosphorylation, and ATPase activity are inhibited in rat kidney mitochondria (125). The aminophenols and their derivatives are inhibitors of 5-Hpoxygenase (126) and prostaglandin synthetase... 

Hawkey, C.J. and Truelove, S.C. (1983). Inhibition of prostaglandin synthetase in human rectal mucosa. Gut 24, 213-217. 

Pharmacology The site and mechanism of the analgesic effect is unclear. APAP reduces fever by a direct action on the hypothalamic heat-regulating centers, which increases dissipation of body heat (via vasodilatation and sweating). APAP is almost as potent as aspirin in inhibiting prostaglandin synthetase in the CNS, but its peripheral inhibition of prostaglandin synthesis is minimal. 

Pharmacology Salicylates have analgesic, antipyretic, anti-inflammatory, and antirheumatic effects. Salicylates lower elevated body temperature through vasodilation of peripheral vessels, thus enhancing dissipation of excess heat. The anti-inflammatory and analgesic activity may be mediated through inhibition of the prostaglandin synthetase enzyme complex. 

III.a.4.3. Changes in renal blood flow. Blood flow through the kidney is partially controlled by the production of renal vasodilatory prostaglandins. If the synthesis of these prostaglandins is inhibited (e.g. by indomethacin), the renal excretion of lithium is reduced with a subsequent rise in serum levels. The mechanism underlying this interaction is not entirely clear, as serum lithium levels are unaffected by some potent prostaglandin synthetase inhibitors (e.g. aspirin). If an NSAID is prescribed for a patient taking lithium the serum levels should be closely monitored. 

The peripheral component of their analgesic action is due to the inhibition of prostaglandin synthetase and thereby inhibiting the synthesis of prostaglandins (PGs) which sensitise the pain receptors to mechanical and chemical stimuli. Aspirin inhibits prostaglandin synthesis and blocks the sensitization of pain mechanism. 

Apazone is an analgesic (pain reliever) not currently available in the United States. It is absorbed well through the G.l. tract and binds extensively to plasma proteins thereby extending its half-life (20-24 hours). Its mode of action is to inhibit prostaglandin synthetase. This, in turn, affects the pain centers and decreases the inflammatory response. 

Feverfew is widely consumed in England as a remedy for arthritis and migraine. Feverfew contains parthenolide, which is a member of sesquiterpene. Parthenolide inhibits the activity of prostaglandin synthetase. It also inhibits platelet aggregation and alter serotonin release (Figure 25.2). 

The ability of aspirin to diminish inflammation is apparently due to its inhibition of the synthesis of prostaglandins, a group of C-20 molecules that enhance inflammation. Aspirin alters the oxygenase activity of prostaglandin synthetase by moving the acetyl group to a terminal amine group of the enzyme. 

Another important example of the importance of chirality, related to rheumatology, is that shown by some members of the NSAID family of aryl acids. Certain molecules which inhibit prostaglandin synthetase in vitro show in vivo antiinflammatory actions. Such compounds include several families of acidic NSAIDs, particularly the aryl acids salicylates, indomethacin analogs, phenylacetic acids, fenamic acids and enolic compounds. With respect to the indomethacin analogs, an important characteristic has emerged, namely, the requirement for a sinister absolute configuration (the S form, which happens to be -t-) at the chiral centre. For these drugs the (5)-(-l-) enantiomers show dominant, if not exclusive, activity. ... 

Tolmetin Sodium, USP. Tolmetin sodium. I-methyl-5-(p-toluoyl)pyrrule-2-acetate dihydrate sodium. McN-25.<9 (Tolectin). is an arylacetic acid derivative with a pyrrole a- the aryl group. This drug is absorbed rapidly, with a lela-tivcly short plasma half-life (I hour). It is recommended for use in the management of acute and chronic RA. It shm- similar, but le.ss frequent, adverse effects with aspirin. Il doe-not potentiate coumarin-like drugs nor alter the Mood levels of sulfonylureas or insulin. Like other drugs in this class, it inhibits prostaglandin synthetase and lowers PCE blood levels. 

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