Mechanism of Action of Aspirin-Like Drugs

The Cyclooxygenase enzyme, also known as COX, is responsible for prostaglandin synthesis. There are two isoforms that were studied in this paper, COX-1 and COX-2. COX-1 is constitutively expressed; whereas, COX-2 is known as the inducible isoform. These enzymes serve a variety of functions in several vital regions of the body, but for time sake I will just discuss a few examples of their functions, and some things I found interesting.

COX-1 is known for its importance in maintaining normal physiological function in the body, and to perform the housekeeping job in synthesis of protective prostaglandins, particularly important in the stomach. PGs are cytoprotective in the sense that they work to prevent gastric erosion and ulceration. For example, in the GI tract, COX-1 activation leads to the production of prostacyclin, which reduces secretions of gastric acid and causes vasodilation at the mucosa. Furthermore, the prostanoids stimulate the secretion of viscous mucus, gastric fluid, and duodenal bicarbonate. The mucus acts as a protective barrier in combination with the alkaline environment that helps neutralize any excess acid. Also, COX-1 in platelets causes thromboxane A2 production, leading to platelet aggregation (a clotting factor.) COX-2, on the other hand, is induced by inflammatory stimuli and cytokines, and functions more in inflammation situations. It is highly expressed in human and animal colon cancer cells, and in human colorectal adenocarcinomas. The increase in PG synthesis can be controlled by nonsteroid anti-inflammatory drugs selective to the particular COX enzyme.

Nonsteroid antiinflammatory drugs (NSAIDs) are aspirin-like drugs that inhibit the activity of the COX enzyme. Since the two isoforms are found at different levels of concentration at different sites in the body, and have various functions, inhibition of them also has different effects. Different NSAIDs are selective to the different isoforms. Among other functions, COX-2 inhibitors are used as anti-inflammatory agents, and have been used in the treatment of rheumatoid arthritis and osteoarthritis. They are also show promise in the inhibition of colorectal tumor cell growth and in delaying premature labor! COX-1 inhibitors are thought to cause some side effects, including GI and renal toxicity. NSAIDs that are selective to COX-2 may have less side effects that current ones used.

The COX enzymes serve a variety of functions and are found all over the body; they are especially important in the GI tract(as discussed), kidney, brain and spinal cord. To discuss all of these in detail would take up a ton of space, but if you have any questions regarding one of these areas, do not hesitate to ask….I have read all about it! =) However, here’s a brief description of some interesting info from some areas of study.

Kidney-"Prostaglandins are important for normal kidney function in both animal models of disease states and in patients with CHF, liver cirrhosis and renal insufficiency." Thus, when NSAIDs reduce PG synthesis, it can cause problems(e.g. increased risk for renal ischemia.) Kidney cells that produce PGs contain mostly COX-1.
Brain & SC- COX-1 is abundant in the forbrain, where PGs might be involved in complex integrative functions, like control of the ANS!
Gestation/Parturition-PGs are important for inducing uterine contraction, which is why NSAIDs are used to delay labor. COX-1 in the amnion may be essential for pregnancy maintenance via PG synthesis. COX-1 and COX-2 are expressed in the uterine epithelium at different times in early pregnancy and could be important during implantation of the ovum AND significant in angiogenesis important for the placenta!