Platelet aggregation, NSAIDs

Aspirin has been remarkably successful in the treatment of the pain and swelling of inflammatory disease and in fact, an estimated 45,000 tons of aspirin are still consumed each year. This success resulted in the syntheses of many other aspirin-like drugs , now referred to as NSAIDs. Aspirin, however, continues to have a unique use in the prevention of thrombosis. Since it produces irreversible inhibition of COX-1 by acetylation of serine at position 530 in the active site, a daily low dose of aspirin will cause a cumulative inhibition of COX-1 in platelets, in the portal circulation. A gradual inhibition of platelet aggregation occurs, reducing the possibility of occlusion of coronary or cerebral vessels by platelet thrombi. However, there are no systemic... 

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 more likely to cause GI side effects. The salicylate salts cause fewer GI side effects than aspirin and do not inhibit platelet aggregation. 

A recent trend in the pharmaceutical industry has been to harness the intrinsic tissue-protective properties of NO for improving the gastric tolerance of nonsteroidal antiinflammatory drugs (NS AIDs). This trend has led to the synthesis of hybrid, chimeric molecules containing an NSAID or aspirin moiety and a NO-donor functionality [153, 154]. One such hybrid is a NO-releasing derivative of aspirin, NCX-4016. In a doubleblind, randomized, placebo-controlled gastrointestinal safety assessment in healthy subjects, NCX-4016 (400 or 800 mg twice daily for 7 days) acted like aspirin as an inhibitor of arachidonic acid-induced platelet aggregation in vitro [155]. Whether... 

Ex vivo platelet aggregation Ilb/IIIa antagonists, NSAIDs... 

Piateiet aggregation NSAIDs can inhibit platelet aggregation the effect is quantitatively less and of shorter duration than that seen with aspirin. These agents prolong bleeding time (within normal range) in healthy subjects. 

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. 

Paracetamol, synonym acetaminophen, is world wide probably the most popular analgesic and antipyretic. Its mechanism of action is not well understood. It is not really an NSAID as it is only a very weak inhibitor of cyclo-oxygenase and has hardly any anti-inflammatory activity. For the same reason paracetamol gives only negligible gastrointestinal irritation and gives hardly any blockade of platelet aggregation. Paracetamol concentrations in plasma reach a peak in 30-60 minutes, and the half-life in plasma is about 2 hours. Almost 100% of... 

Celecoxib (Celebrex) and rofecoxib (Vioxx) are highly selective COX-2 inhibitors. Because of this, they produce less erosion of the GI mucosa and cause less inhibition of platelet aggregation than do the nonselective COX inhibitors. Short-term (6 months-to a year) clinical trials have shown that celecoxib and rofecoxib produce less GI toxicity than nonselective NSAIDs. However, serious GI bleeding and ulceration have occurred in patients taking these drugs, and long-term prospective studies of their safety have yet to be completed. Like the nonselective NSAIDs, the selective COX-2 inhibitors can produce renal side effects such as hypertension and edema. 

Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs. Probably because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9. Adverse effects are the common toxicities listed above. 

The biochemical paths and actions by which aspirin and other salicylates achieve their therapeutic effects were poorly understood until at least a partial mechanism w as proposed by Sir John Vane in 1971. Vane, who later received a Nobel Prize for his efforts (1982), found that NSAIDs, including aspirin, block the production of prostaglandins by cells and tissues. During the same time frame. Vane and other researchers also confirmed the inhibitory effects of aspirin on platelet aggregation, this caused by interference with the ability of platelets to synthesize prostaglandins, notably thromboxane A2. The complexities of the topic go well beyond the scope of this volume, but are well ventilated in the Vane (1971), the Smith-Willis (1971). and the Weissmann (1991) articles listed, See also Prostaglandins,... 

Rofecoxib, a furanose derivative, is a potent, selective COX-2 inhibitor (Table 36-1). In the USA, rofecoxib is approved for osteoarthritis and rheumatoid arthritis, and it also appears to be analgesic and antipyretic—in common with other NSAIDs. This drug does not inhibit platelet aggregation and appears to have little effect on gastric mucosal prostaglandins or lower gastrointestinal tract permeability. At high doses it is associated with occasional edema and hypertension. Other toxicities are similar to those of other coxibs. 

Valdecoxib, a diaryl-substituted isoxazole, is a new highly selective COX-2 inhibitor. Pharmacokinetic characteristics and dosage in arthritis are set forth in Table 36-1. In primary dysmenorrhea, dosage is 20 mg twice daily, and the drug is as effective as nonselective NSAIDs for this indication. Gastrointestinal and other toxicities are similar to those of the other coxibs. Valdecoxib has no effect on platelet aggregation or bleeding time. Serious reactions have been reported in sulfonamide-sensitive individuals. 

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