Prostaglandins NSAID inhibition

NSAIDs inhibit cyclooxygenases (COX), the enzymes that catalyze the transformation of arachidonic acid (a ubiquitous cell component generated from phospholipids) to prostaglandins and thromboxanes. Two isoforms, COX-1 and COX-2, are constitutively expressed in peripheral tissues and in the central nervous... 

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. 

Lithium intoxication can be precipitated by the use of diuretics, particularly thiazides and metola-zone, and ACE inhibitors. NSAIDs can also precipitate lithium toxicity, mainly due to NSAID inhibition of prostaglandin-dependent renal excretion mechanisms. NSAIDs also impair renal function and cause sodium and water retention, effects which can predispose to interactions. Many case reports describe the antagonistic effects of NSAIDs on diuretics and antihypertensive drugs. The combination of triamterene and indomethacin appears particularly hazardous as it may result in acute renal failure. NSAIDs may also interfere with the beneficial effects of diuretics and ACE inhibitors in heart failure. It is not unusual to see patients whose heart failure has deteriorated in spite of increased doses of frusemide who are also concurrently taking an NSAID. 

TABLE 36.2 Adverse Effects of NSAIDs - Relationship to Prostaglandin Synthesis inhibition and Cyclooxygenase Isoforms... 

System Affected Adverse Effects Prostaglandin Effects Inhibited by NSAIDs COX Isoforms Involved... 

The answer is d. (Hardman, p 617. Katzung, p 318.) Most NSAIDs inhibit both cyclooxygenase I and II, resulting in decreased synthesis of prostaglandins, prostacyclins, and thromboxanes. 

Prostaglandin inhibition may result in reduced renal sodium excretion, impaired resistance to hypertensive stimuli, and reduced renal lithium excretion. Most NSAIDs inhibit platelet function may increase likelihood of bleeding due to other drugs that impair hemostasis. Most NSAIDs are highly bound to plasma proteins. 

NSAIDs inhibit prostaglandin synthesis. This can potentiate the effect of water reabsorption in the renal tubules of vasopressin. 

NSAIDs inhibit prostaglandin synthesis, leaving actions of vasoconstrictors unopposed. 

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. 

NSAIDs inhibit arachidonate cyclo-oxygenase and therefore reduce the production of prostaglandins and thromboxanes. 

NSAIDs inhibit prostaglandin synthesis, and in so doing can reduce GFR in susceptible patients, including those with cirrhosis. A number of renal complications can occur, including acute renal failure. All NSAIDs have been associated with nephrotoxicity. There is a small amount of data suggesting that renal effects are less likely to occur with sulindac, but studies relate to short-term therapy only, and there have been case reports of acute renal failure developing in high-risk patients [4,27,35]. 

A relatively simple thiazole has been shown to be a quite potent antiinfla-matory agent. Darbufelone (143), which is quite different in structure from all preceding NSAIDs inhibits both arms of the arachidonic acid cascade at the very inception of the process. This in effect shuts off production of both prostaglandins and leukotrienes. This agent is prepared in a single step by condensation of substituted benzaldehyde 141 with the enolate from thiazolone (142). ... 

NSAID-induced acute renal deterioration occurs in the setting of severe vasoconstrictive renal ischemia and can be attributed to interruption of the delicate balance between hormonally mediated pressor mechanisms and prostaglandin-associated vasodilatory effects (Figure 3). During NSAID inhibition of renal... 

NSAID-Assodated Ulcer. NSAIDs inhibit the production of prostaglandins, prostacyclins, and thromboxanes from arachidonic acid by covalently modifying the enzyme cyclooxygenase (COX) and irreversibly inhibiting the ability of arachidonic acid to bind to the active site on the enzyme. Chronic administration of NSAIDs has been linked to ulcer disease, although there is no evidence that they are the direct cause of ulcer formation. In patients already diagnosed with ulcer disease, chronic administration of NSAIDs was associated with a fourfold increase in the risk of ul-... 

NSAIDs probably rednce proteinnria throngh prostaglandin E2 inhibition, resulting in a rednction of intraglomemlar pressure, a decrease in GER, and also restoration of the barrier size-selectivity of the GBM. Indomethacin and meclofenamate are the two NSAIDs that have been evalnated the most. Their antiproteinuric effect is comparable to those attained with ACEIs, and combined treatment with an ACEI results in additional proteinnria rednction. However, adherence to a low-sodinm diet or concnrrent nse of a dinretic is needed to maximize the antiproteinuric effect. Due to their potential for nephrotoxicity, especially in patients with poor renal fnnction, long-term use of an NSAID for renoprotection is not preferred. ... 

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