Thromboxane NSAIDs’ 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... 

NSAIDs may also cause kidney diseases, hepatitis, hypersensitivity reactions, rash, and CNS complaints of drowsiness, dizziness, headaches, depression, confusion, and tinnitus. All nonselective NSAIDs inhibit COX-l-dependent thromboxane production in platelets, thereby increasing bleeding risk. NSAIDs should be avoided in late pregnancy because of the risk of premature closure of the ductus arteriosus. 

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. 

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

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-... 

B. Mechanism of Action Aspirin and other NSAIDs inhibit thromboxane synthesis by blocking the enzyme cyclooxygenase. Thromboxane is a potent stimulator of platelet aggregation. Aspirin is particularly effective because it irreversibly inactivates the enzyme. Because the platelet lacks the machinery for synthesis of new protein, inhibition by aspirin persists until new platelets are formed (several days). Other NSAIDs cause a less persistent antiplatelet effect (hours). 

The advent of COX-2-selective inhibitors has led to unexpected results. By selectively inhibiting the COX-2 isoform, COX-2-selective NSAIDs increase the risk of cardiovascular events in certain patientsP COX-2 is responsible for the production of prostacyclin, a vasodilatory and antiplatelet substance. On the other hand, COX-1 controls the production of thromboxane A2, a vasoconstrictor and platelet aggregator. Selective inhibition of COX-2 results in decreased prostacyclin levels in the face of stable thromboxane A2 levels. An imbalance in the thromboxane A2 prostacyclin ratio ensues, which creates an environment that favors thrombosis. 

NSAIDs are drugs related to acetyls alley lie acid which inhibit cyclooxygenase (COX), the enzyme in the synthesis of PGs and thromboxanes from arachidonic acid. There are two isoforms of cyclooxygenase, COX-1 and COX-2 [121].The former is constitutively expressed in blood vessels, stomach and kidney, while COX-2 is normally not present at these sites. It can,... 

Acetylsalicylic acid and related non-steroidal anti-inflammatory drugs (NSAIDs) selectively inhibit the cyclooxygenase activity of prostaglandin synthase [2] and consequently the synthesis of most eicosanoids. This explains their analgesic, antipyretic, and antirheumatic effects. Frequent side effects of NSAIDs also result from inhibition of eicosanoid synthesis. For example, they impair hemostasis because the synthesis of thromboxanes by thrombocytes is inhibited. In the stomach, NSAIDs increase HCl secretion and at the same time inhibit the formation of protective mucus. Long-term NSAID use can therefore damage the gastric mucosa. 

All NSAIDs except aspirin inhibit cyclooxygenase reversibly. Inhibition by aspirin, caused by the covalent acetylation of the enzyme, is irreversible. In platelets most NSAIDs block thromboxane synthesis more than that of prostacyclin and the overall effect is therefore inhibition of platelet aggregation. This effect is already noticeable at low doses. Because of the irreversible nature of the enzyme inhibition by aspirin and the fact that in platelets the novo enzyme synthesis is not possible the aggregation inhibitory effects of aspirin last several days. 

The NSAIDs (eg, indomethacin, ibuprofen see Chapter 36) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. Selective COX-2 inhibitors, which were developed more recently, vary—as do the older drugs—in their degree of selectivity. Indeed, there is considerable variability between (and within) individuals in the selectivity attained by the same dose of the same NSAID. Aspirin is an irreversible COX inhibitor. In platelets, which are anuclear, COX-1 (the only isoform expressed in mature platelets) cannot be restored via protein biosynthesis, resulting in extended inhibition ofTXA2 biosynthesis. 

The thromboxanes have a six-membered ring containing an ether. They are produced by platelets (also called thrombocytes) and act in the formation of blood clots and the reduction of blood flow to the site of a clot. The nonsteroidal antiinflammatory drugs (NSAIDs)— aspirin, ibuprofen, and meclofenamate, for example— were shown by John Vane to inhibit the enzyme prostaglandin H2 synthase (also called cyclooxygenase or COX), which catalyzes an early step in the pathway from arachidonate to prostaglandins and thromboxanes (Fig. 10-18 see also Box 21-2). 

T Aspirin (acetylsalicylate Fig. 21-15b) irreversibly inactivates the cyclooxygenase activity of COX by acetylating a Ser residue and blocking the enzyme s active site, thus inhibiting the synthesis of prostaglandins and thromboxanes. Ibuprofen, a widely used nonsteroidal antiinflammatory drug (NSAID Fig. 21-15c), inhibits the same enzyme. The recent discovery that there are two isozymes of COX has led to the development of more precisely targeted NSAIDs with fewer undesirable side effects (Box 21-2). 

Mechanism of NSAID Action Inhibition of Prostaglandin and Thromboxane Synthesis... 

The NSAIDs (eg, aspirin, indomethacin, ibuprofen) block both prostaglandin and thromboxane formation by inhibiting COX activity. For example, aspirin is a long-lasting inhibitor of platelet COX and of TXA2 biosynthesis because it irreversibly acetylates the enzyme. Once acetylated, platelet COX cannot be restored via protein biosynthesis because platelets lack a nucleus. 

Meloxicam is an enolcarboxamide related to piroxicam that has been shown to preferentially inhibit COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as the other coxibs. The drug is popular in Europe and many other countries for most rheumatic diseases and has recently been approved for treatment of osteoarthritis in the USA. Its efficacy in this condition and rheumatoid arthritis is comparable to that of other NSAIDs. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, it appears that even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result... 

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