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The fall of selective COX-2 inhibitors.
Cyclooxygenase (COX) inhibitors have been long used as non-steroidal anti-inflammatory drugs (NSAIDs); these are used for the
management of differing types of pain. The Cyclooxygenase inhibitors work by inhibiting a key enzyme used in the production of
prostanoids. The suppression of prostanoid synthesis leads to three key therapeutic effects; anti-inflammatory through vasodilation
reduction, analgesic effects through decreased bradykinin and 5-hydrotryptamine release and anti-pyretic effect through limited
interleukin-1 release.
The Cyclooxygenase enzyme exists in the body in two isoform, COX-1 and COX-2. Traditional NSAIDs show very little selectivity
for either isoform, or very weakly selective one way or the other. This leads to the problems that are associated with NSAIDs. The
most common of these is gastrointestinal problems, and recently it has been shown that these are down to the inhibition of gastric
COX-1, that helps to protect the mucosa as it has inhibits the acid secretion. This gives a dose limiting toxicity and did lead to
looking to other areas that may do the same function but do not give these unwanted side effects.
This lead to COX-2 selective inhibitors being developed (Coxibs). The key difference between COX-1 and COX-2 is when they are
expressed. COX-1 is expressed at a basal level performing a ‘Housekeeping’ role as oppose to COX-2 which is induced in
inflammatory cells after injury. The first generation of Coxibs entered clinical trials in 1995 and entered the US drug market in 1998-
9 and by 2000, performed exceptionally giving sales of above $3billion.
1, 2

The continual monitoring of these new drugs looking into gastrointestinal benefits did give initial positive results over six months in
the CLASS and VIGOR trials
3
, however these did not put to bed the doubt about coxibs. The CLASS trial did not give any
significant advantage over 12 months. More worryingly, however was the VIGOR study that seemed to indicate issues with
cardiovascular side effects. These were severe enough for the US FDA to issue a warning in rofecoxib, which warned of the use to
patients with ischemic heart disease history. This study along with a series of further clinical trials did show an increase in
unfavourable cardiovascular responses.
The mechanisms behind the cardiovascular side effect are complex and indeed some reports have shown that coxibs may be
cardioprotective.
4
It is however believed that the effects occur due to the altering of both vascular tone caused by interactions with
the action of angiotensin II, a potent vasoconstrictor. The Coxibs have been shown to oppose this mode of action
5
. The other effect
that coxibs have is on cardiovascular thrombotic events, this is the key mechanism believed to be giving side effects. The coxibs
affect the prostanoids that are active in the vasculature. The key prostanoids are TXA2 and PGI2.
When COX-1 inhibitors are given TXA2 is not synthesised, the effect of this inhibition, is to reduce the vasoconstrictor and platelet
aggregator effects.
1
This comparison with PGI2 which is synthesised by COX-2, leading to vasodilation and platelet synthesis
inhibition. This means by using a COX-2 inhibitor, you lose the benefits of the PGI2 and get the effects of the TXA2, thought to be
the cause of unwanted cardiovascular side effects such as vasoconstriction and thickening of the blood. These two combined with
an altered renin release from the kidneys can lead to an increase in blood pressure and, as such, hose predisposed to cardiac
failure and myocardial infarction may have a problem whilst taking COX-2 inhibitors.
Coxibs along with traditional NSAIDs can have key effects on the renal system, this is due to the presence of both COX-1 and
COX-2, unusually for COX-2, it is detectable in normal resting kidney cells, and this leads to a number of metabolic changes that
occur when a coxib is administered. These effects may have little in the way of an effect when a patient is healthy
6
, but in patients
with pre-existing nephrotic conditions this could have a huge effect. The effects come from an inhibition of prostaglandin synthesis.
The prostaglandins have a huge effect on the workings of the kidneys. These effects include the inhibition of renin release, which
could lead to fluid retention and have further effects on the hearts activity. Another issue with those suffering with problems with the
kidneys are with the maintenance of renal blood flow and glomerular nitration, as both of these are dependent on local generation
of vasodilator prostaglandins. These effects are not limited to the coxibs, with non-selective NSAIDs inducting peripheral oedema
in up to 5% of the population
6

Overall, the coxibs were first devised to overcome the problematic side effects on the gastrointestinal tract associated with long
term non-selective NSAID use. Early papers did suggest this was the case, but later and longer trials quickly disputed this, with the
CLASS trial being one that gave initial early promise but this did not come to fruition over a longer period. The APPROVe trial gave
across the board increases in the risk of cardiovascular issues. But these are not all conclusive due to the lack of similar results in
other trials such as the PreSAP trial. I believe that further trials are needed to evaluate the use of coxibs as a last resort as for
those unable to take traditional NSAIDs, with heightened awareness of the dangers of traditional NSAIDs to the general public.



1. I. G. E. Zarraga and E. R. Schwarz, Journal of the American College of Cardiology, 2007, 49, 1-14.
2. A. Whelton and C. Hamilton, The Journal of Clinical Pharmacology, 1991, 31, 588-598.
3. C. Bombardier, L. Laine, A. Reicin, D. Shapiro, R. Burgos-Vargas, B. Davis, R. Day, M. B. Ferraz, C. J. Hawkey, M.
C. Hochberg, T. K. Kvien and T. J. Schnitzer, New England Journal of Medicine, 2000, 343, 1520-1528.
4. J. E. Dinchuk, B. D. Car, R. J. Focht, J. J. Johnston, B. D. Jaffee, M. B. Covington, N. R. Contel, V. M. Eng, R. J.
Collins, P. M. Czerniak, S. A. Gorry and J. M. Trzaskos, Nature, 1995, 378, 406-409.
5. R. C. Harris and M. D. Breyer, Clinical Journal of the American Society of Nephrology, 2006, 1, 236-245.
6. D. C. Brater, Seminars in Arthritis and Rheumatism, 2002, 32, 33-42.



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