As we have learned over the past few tutorials, traditional nonsteroidal anti-inflammatory drugs,
or NSAIDs, can inhibit both of our cyclooxygenase enzymes with roughly equal ability. These enzymes,
COX-1 and COX-2, produce prostaglandins which lead to inflammation, so their inhibition is what gives
these drugs their anti-inflammatory ability. But there are drugs that inhibit only one of these and
not the other. Cyclooxygenase-2, or COX-2, was discovered in the 1990s. While the previously
discovered COX-1 enzyme is always active in our bodies and serves a homeostatic function,
COX-2 was found to be activated specifically in response to inflammation. Because of this,
it was hypothesized that inhibition of the pro-inflammatory COX-2 was responsible for
the beneficial effects of NSAID use while the side effects are attributed to inhibition
of the homeostatic COX-1. Pharmaceutical companies looked to develop compounds that
could specifically target only one of these nearly structurally identical enzymes. In their efforts,
researchers discovered that COX-2 has a large gap in its binding site that COX-1 does not have,
which was exploited by designing compounds that are too big to fit in the active site of COX-1,
thereby leading to 100-fold selectivity for the COX-2 enzyme.
Despite the high expectations for COX-2 selective NSAIDs, these drugs have failed
to live up to the hype. Like other NSAIDs, COX-2 selective inhibitors are antipyretic,
analgesic, and anti-inflammatory. They are prescribed for some instances of osteoarthritis,
rheumatoid arthritis, and menstrual cramps. Contrary to expectations, however,
COX-2 selective drugs still showed unwanted gastric side effects, and research is ongoing
as to whether these compounds are better tolerated in patients. Unlike other NSAIDs,
COX-2 selective inhibitors actually increase blood clotting, possibly due to inhibition of COX-2
within the cells lining blood vessels which make the anti-clotting prostaglandin, PGI2.
This thrombogenic, or pro-clotting, effect carries an increased risk of heart attack and stroke.
An infamous example of this was the case of Rofecoxib, sold as Vioxx in the United States,
which was the subject of the largest drug recall in history. Vioxx was removed from circulation
in 2004 after 5 years on the market due to an increase in heart attack and stroke observed in
patients after prolonged use. At the time of its removal, it was actively prescribed to over 20
million people for pain relief, and The Lancet reported that as many as 140,000 people could
have suffered from serious coronary heart disease as a result of taking the drug in the U.S. alone.
Both the producer of Vioxx, Merck, and the Federal Drug Administration,
were heavily criticized for missing evidence of these dangers before the drug’s release.
The result of the recall cost Merck nearly 6 billion dollars, 4.8 billion of which was in
fines, and close to 1 billion in legal expenses. Currently, celecoxib, commonly known by the brand
name Celebrex, is the only COX-2 selective NSAID available in the U.S., and it carries black box
warnings for increased risk of heart attack and stroke. Other COX-2 selective compounds
are still being researched and developed in the hopes of generating a drug with increased COX-2
selectivity, but without the risk of thrombotic events. Whether additional compounds will be
approved for use within the U.S. remains to be seen. For now, the lack of decreased side effects,
increased risk of thrombotic events, and increased price of production weigh heavily
on the risk-benefit analysis physicians must make when choosing the correct NSAID for each patient.
And with that we wrap up an introduction to nonsteroidal anti-inflammatory drugs,
so let’s move on to some other categories.