In the previous tutorial, we learned some basics regarding nonsteroidal anti-inflammatory drugs,
which apply broadly to the whole category. But we want to know some
details regarding specific NSAIDs as well, so let’s start with aspirin.
Aspirin is a member of the salicylic acid structural class of NSAIDs. Like other NSAIDs,
aspirin is commonly prescribed for its antipyretic, analgesic, and anti-inflammatory
effects. As we mentioned, there are stories dating back to ancient Greece regarding the use
of willow leaves and meadow sweet to treat fever. These plants were later found to contain salicin,
a precursor to salicylic acid, which was used to treat arthritis by the early 1800s. However,
it was not well tolerated by patients due to its unpleasant taste and strong gastric side effects.
But in 1899, a chemist named Felix Hoffman at Bayer Pharmaceuticals synthesized aspirin
from salicylic acid. The important alteration Hoffman made was the addition of an acetyl group
to salicylic acid, generating acetylsalicylic acid, which is the chemical name for aspirin. This
modification makes aspirin unlike any other NSAID because it irreversibly inhibits cyclooxygenase,
or COX, enzymes by acetylation. Other NSAIDs inhibit cyclooxygenase enzymes
by competing with the enzyme’s substrates for access to the active site. In such cases, when
the drug has been cleared from the active site, the effect of the drug ceases. Aspirin, however,
transfers its acetyl group to one of the amino acid residues in the active site of the enzyme.
To be specific, aspirin acetylates serine 529 in COX-1, and serine 516 in COX-2. These are
homologous serine residues, meaning that they are in the same relative position in the active site
and perform the same function, with the discrepancy in number being due to
the fact that the amino acid sequence of these two enzymes is slightly different.
As we can see, this oxygen atom attacks the carbonyl on aspirin
and is thereby acetylated, converting aspirin into salicylic acid in the process.
The hydroxyl group in the serine residue is critical in carrying out enzymatic function,
and its nucleophilicity is nullified once acetylated. So by altering the structure
of the active site, aspirin renders the enzyme permanently ineffective. This means that new
enzymes must be made within the body before the effect of aspirin wears off.
The irreversible inhibition of COX enzymes by aspirin makes it effective
in very low doses to prevent blood clotting. Prostaglandins produced in blood platelets
and the epithelial cells lining our blood vessels are important for blood clotting activity.
Cyclooxygenase enzymes in blood platelets generate the pro-clotting prostaglandin, TxA2,
whereas the cells in our vessels generate the anti-clotting prostaglandin, PGI2.
Importantly, platelets lack a nucleus, and therefore have no capacity to generate
new RNA transcripts for protein production, so when their COX enzymes are inhibited by aspirin,
they are prevented from generating pro-clotting prostaglandins for the lifetime of that platelet,
which is usually 8 to 9 days. Cells lining the blood vessels, however, continually generate
new COX enzymes, and thus can still generate anti-clotting prostaglandins. This shift in the
balance of pro- and anti-clotting compounds is what leads to aspirin’s blood thinning effects.
This is a cumulative effect of multiple low doses of aspirin because COX enzymes in platelets are
acetylated within the portal vein, which carries blood from the gut where aspirin is absorbed,
to the liver, where aspirin is rapidly metabolized into salicylic acid.
Perhaps most interestingly, acetylation of cyclooxygenase-2 by aspirin
leaves certain enzyme functions intact, leading to the creation of unique compounds
called aspirin-triggered lipoxins, or ATLs, such as 15-epi-lipoxin-A4. This compound is
an epimer of a lipoxin made in the body, meaning they differ in the stereochemistry of only one
chiral center. This epimer has been found to have potent anti-inflammatory effects and it
is thought that this actually increases aspirin’s anti-inflammatory activity.
The properties we’ve described make aspirin a potent and clinically important NSAID for
the treatment of not only fever and pain but also in low dose for heart disease or
patients who have had a stroke. Despite its many uses, certain patients can display a
hypersensitivity to aspirin. 10-25% of people with asthma have their symptoms worsened
by use of aspirin. Additionally, aspirin has been associated with Reye’s syndrome, which occurs
primarily in young people and is characterized by swelling of the liver and brain. Due to this
association, aspirin is not used in children, or young adults with a virus-induced fever.
However, acetaminophen, commonly known as Tylenol, has not been implicated in Reye’s syndrome and has
less significant gastric side effects, making it the drug of choice for the treatment of
fever in children and young adults. So let’s move forward and take a look at this substance next.