Aspirin is the most widely used member of a class of drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs). Other members of this class are indomethacin and ibuprofen. These drugs produce their effects because they specifically inhibit the cyclooxygenase enzyme that is needed for prostaglandin synthesis. Through this action, the drugs inhibit inflammation but produce some unwanted side effects, including gastric bleeding, possible kidney problems, and prolonged clotting time.
It is now known that there are two isoenzyme forms (chapter 4) of cyclooxygenase. The type I isoform (COX1) is produced constitutively (that is, in a constant fashion) by cells of the stomach and kidneys and by blood platelets, which are cell fragments involved in blood clotting (see chapter 13). The type II isoform of the enzyme (COX2) is induced in a number of cells in response to cytokines involved in inflammation, and the prostaglandins produced by this isoenzyme promote the inflammatory condition.
The two isoforms of cyclooxygenase are thus quite distinct. The COX1 isoform is produced continuously by a gene on chromosome 9 and is required for the normal, physiological functioning of different organs, for platelet aggregation in blood clotting, and for the health of the gastric mucosa. The production of the COX2 isoform (by a gene on chromosome 1), is kept at a low level until it is stimulated during an inflammation. Interestingly, the ability of the glucocorticoids (such as hydrocortisone) to inhibit inflammation has been shown to be due to their ability to inhibit the COX2 isoenzyme.
When aspirin and indomethacin inhibit the COX1 isoenzyme, they reduce the synthesis of prostacyclin (PGI2) and PGE2 in the gastric mucosa. This is believed to result in the stomach irritation caused by these NSAIDs. Indeed, inhibition of the COX1 isoenzyme may cause serious gastrointestinal and renal toxicity in long-term use. This has spurred research into the development of next-generation NSAIDs that more selectively inhibit the COX2 isoenzyme. These newer COX2-selective drugs, including celecoxib and rofecoxib, (for example, Celebrex and Vioxx) thus inhibit inflammation while producing fewer negative side effects in the gastric mucosa.
There is, however, one important benefit derived from the inhibition of the type I isoenzyme by aspirin. The type I isoenzyme is the form of cyclooxygenase present in blood platelets, where it is needed for the production of thromboxane A2. Since this prostaglandin is needed for platelet aggregation, inhibition of its synthesis by aspirin reduces the ability of the blood to clot. While this can have negative consequences in some circumstances, low doses of aspirin have been shown to significantly reduce the risk of heart attacks and strokes by reducing platelet function. It should be noted that this beneficial effect is produced by lower doses of aspirin than are commonly taken to reduce inflammation.
Test Yourself Before You Continue
2. List some of the paracrine regulators produced by blood vessels and describe their actions. Also, identify specific growth factors and describe their actions.
3. Describe the chemical nature of prostaglandins. List some of the different forms of prostaglandins and describe their actions.
4. Explain the significance of the isoenzymatic forms of cyclooxygenase in the action of nonsteroidal anti-inflammatory drugs.
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