Aspirin cyclooxygenase inhibition

The widely used platelet inhibitor aspirin or acetylsalicylic acid, by acetylating the enzyme cyclooxygenase, inhibits platelet function by preventing the formation of thromboxane A2 and the synthesis of prostaglandin I2 (PGI2) (68). Aspirin has been used in combination with other antiplatelet agents such as ticlopidine, which inhibits ADP-induced platelet aggregation (69). 

An irreversible enzyme inhibitor of clinical value is aspirin, which inhibits cyclooxygenase and dierefore prostaglandin formation (Chapter 11). 

Indomethacin, like aspirin, reversibly inhibits cyclooxygenase action by blocking formation of thromboxane A2. 

The drug acetylsalicylic acid (aspirin) irreversibly inhibits the cyclooxygenase activity, while ibuprofen inhibits the reductase activity. Both drugs treat inflammation, pain, and fever because they inhibit prostaglandin synthesis. Prostaglandins are very unstable, so they tend to act locally (otherwise a sprained ankle would cause pain throughout the body). 

Prostaglandins such as PGEj are potent vasodilators, so they increase blood flow. Local vasodilation occurs at inflammatory sites. Aspirin irreversibly inhibits cyclooxygenase. A single serine residue in the enzyme is acetylated as follows ... 

Currently, the two antiplatelet agents with proven efficacy are aspirin, which inhibits cyclooxygenase -dependent synthesis of thromboxane Aj (TXj ), and ticlopidine, wdrich blocks the ability of ADP to inhibit stimulated adenyl cyclase. Bodi of these drags have proven prophylactic uses in reducing the risk of thrombo -occlusive and thromboembolic complications for all major arterial beds in individuals with a previous history of such episodes. Controlled trials show that both aspirin and ticlopidine are indicated in the secondary prevention of stroke, myocardial induction and peripheral vascular occlusion. However, there are limitations to their efficacy. No net changes in vascular events are seen with primary prevention. Moreover, antiplatelet drugs do not alter thrombocytopenia or impairment... 

Low doses (<100 mg) of aspirin quickly inhibit cyclooxygenase in all the platelets in the circulation. Therefore, the onset of the antiplatelet effect of aspirin is less than 60 minutes. It has been reported, however, that some patients either have or develop aspirin resistance and may require higher doses to achieve the desired antiplatelet effect. Despite this, routine testing for aspirin resistance is not recommended. It was observed recently that administration of ibuprofen prior to the administration of a daily aspirin dose prohibits the aspirin from binding irreversibly to the cyclooxygenase and may decrease its antiplatelet effect. Current recommendations are to administer aspirin at least 2 hours before ibuprofen or to wait at least 4 hours after an ibuprofen dose. 

Aspirin and other nonsteroidal anti-inflammatory drugs can precipitate an attack in up to 20% of adults with asthma. The mechanism is related to cyclooxygenase inhibition, and 5-hpoxygenase inhibition can prevent the symptoms. The prevalence increases with age. The greatest frequency occurs in severe corticosteroid-dependent asthmatics in their fourth and fifth decades who also have perennial rhinitis and nasal polyposis (presence of several polyps). Other drugs that do not precipitate bronchospasm but which prevent its reversal are the 8-blocking agents. ... 

The mechanism by which cyclooxygenase inhibition produces bronchospasm in susceptible individuals is unknown. Arachidonic acid metabolism through the 5-lipoxygenase pathway may lead to the excess production of leukotrienes C4 and D4. Leukotrienes C4, D4, and E4 produce bronchospasm and promote histamine release from mast cells, whereas the administration of leukotriene receptor antagonists and 5-lipoxygenase inhibitors ablate the pulmonary and nonpuhnonary responses to aspirin in aspirin-sensitive asthmatics. The precise mechanism by which augmented leukotriene production occurs is unknown, and available hypotheses do not explain why only a small number of asthmatic patients react to aspirin and NSAIDs. 

FIGURE 33-4. Tissue distribution and actions of cyclooxygenase (COX) isoenzymes. Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin (ASA) inhibit COX-1 and COX-2 to varying degrees COX-2 inhibitors inhibit only COX-2. Broken arrow indicates inhibitory effects. 

The details of cyclooxygenase inhibition by NSAIDs were developed in Chapter 5. It should now be reiterated that only aspirin inhibits the enzyme in platelets irreversibly, even at low doses, thus preventing the production and release of TXA2 from them. Aspirin s... 

In the presence of aspirin, cyclooxygenase is irreversibly inactivated by ) acetylation. New cyclooxygenase molecules are not produced in platelets, because these cells have no nuclei and, therefore, cannot synthesize new mRNA. Thus, the inhibition of cyclooxygenase by aspirin persists for the lifespan of the platelet (7-10 days). When aspirin is taken daily at doses between 81 and 325 mg, new platelets are affected as they are generated. Higher doses do not improve efficacy but do increase side effects, such as gastrointestinal bleeding and easy bruisability. 

Aspirin Irreversibly inhibits cyclooxygenase. Thus prevents formation of thromboxane A2 and prostaglandins (which induce platelet aggregation). Reduce risk of recurrent transient ischemic attacks or stroke. Reduces risk of myocardial infarction in patients with unstable angina or prior infarction. Also used for antiinflammatory and analgesic purposes. Gl ulceration, bleeding, hemorrhage, salicylism. 

I he prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase whkh results In the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and Is used In the prevention of arterial and venous thrombosis. (From Martindale, The Extra Pharmacopoeia, 30Ch ed, pS)... 

The connection between fatty acid metabolism and SRS formation was made when it was discovered that an intact lipoxygenase reaction was essential for SRS formation [76-81]. Conversely, inhibition of lipoxygenase prevented SRS formation as determined by prevention of anaphylactic bronchoconstriction [82,83]. Further evidence for lipoxygenase involvement is provided by the enhanced antigen-induced tracheal contraction demonstrated during cyclooxygenase inhibition [84-86] as well as the finding of clinical cases with aspirin-induced asthma [87]. The observations... 

In 1 969, Dr. John Vane and his collaborators at the Royal College of Surgeons in London discovered that aspirin inhibited production of prostaglandins by injured tissue. Eventually it was shown that this happens because aspirin binds to cyclooxygenase, inhibiting the conversion of arachidonic acid to PCCj. This stops the production of prostaglandins, resulting in a reduction of... 

---