Nonsteroidal anti-inflammatory drugs, NSAIDs, are the most widely used anti-inflammatories.
NSAIDs inhibit production of prostaglandins, a group of compounds that contribute to inflammatory
response and are responsible for signs such as fever and pain.
NSAIDs are very effective, and unlike other anti-inflammatories, they have no immunosuppressive
effect.
Prostaglandins are synthesized from arachidonic acid by the action of cyclooxygenase (COX)
enzymes.
COX metabolizes arachidonic acid to prostaglandin H2, PGH2, which is then converted to different
isoforms in different tissues, where they fulfill different functions.
Physiological prostaglandins act to maintain local homeostasis such as temperature regulation,
bronchial tone, uterine tone, gastric mucosal barrier, among others.
Some prostaglandins exert opposing effects to maintain balance.
For example, platelet’s TXA2 constricts blood vessels and promotes platelet aggregation,
while endothelial PGI2 dilates blood vessels and inhibits platelet aggregation.
Together they modulate the interaction between activated platelets and blood vessel wall.
Physiological levels of prostaglandins are generally very low, but they go up drastically
immediately upon acute inflammation, with PGE2 involved in most of its cardinal signs.
There are 2 known COX enzymes: COX-1 and COX-2.
COX-1 is expressed constitutively in most cells and is the major source of physiological
prostaglandins.
COX-2 is selectively induced by inflammatory stimuli and is the predominant source of inflammatory
prostaglandins.
But COX-2 also has some physiological functions in some tissues.
NSAIDs can be classified as non-selective, meaning they inhibit both COX-1 and COX-2,
albeit with different efficiencies; and COX-2 selective.
All non-selective NSAIDs, except aspirin, act as reversible COX inhibitors.
They compete with arachidonic acid for binding to the enzyme.
Aspirin, on the other hand, covalently modifies and permanently destroys COX enzymes.
The irreversible action of aspirin is most notable in blood platelets, which cannot synthesize
new enzymes because they have no nucleus.
Once the enzyme is inactivated by aspirin, no production of TXA2, and hence no platelet
aggregation, is possible for the entire lifespan of the platelets.
This makes aspirin stand out as a potent anti-thrombotic agent.
In fact, aspirin is commonly prescribed to reduce risk of blood clot formation, as a
preventive measure for heart attacks and ischemic strokes.
For maximum effect, aspirin should not be taken together with other nonselective NSAIDs
as these will compete with aspirin for a common binding site on the platelet’s COX-1.
Being anti-thrombotic, aspirin prolongs bleeding and is therefore contra-indicated in patients
with bleeding risks or hemorrhagic disorders.
Aspirin is also linked to Reye’s syndrome.
COX-1-dependent prostaglandins suppress gastric acid secretion and help maintain gastric mucosal
barrier, providing protection to the stomach lining.
Because non-selective NSAIDs inhibit COX-1, they may cause gastric irritation, peptic
ulcer disease, and gastrointestinal bleeding.
The newer COX-2-specific NSAIDs, coxibs, are designed to reduce this gastrointestinal toxicity,
but their use is controversial, as they appear to increase cardiovascular occlusive events.
A possible explanation is that coxibs selectively inhibit COX-2-dependent PGI2, which is vasodilatory
and anti-thrombotic, while having no effect on COX-1-dependent TXA2, which is pro-thrombotic
and vasoconstrictory, and thus tipping the scales of homeostasis in favor of blood clot
formation and vasoconstriction.
Some non-selective NSAIDs also exhibit various levels of cardiovascular toxicity depending
on their COX-2 versus COX-1 inhibition ratio.
Suppression of physiological vasodilatory prostaglandins by NSAIDs may increase the
risk for hypertension, edema, and exacerbate pre-existing heart failures.
Inhibition of renal vasodilatory prostaglandins, in the context of circulatory stress, may
reduce renal blood flow and glomerular filtration rate, and ultimately cause renal ischemia
or failure.