The acetyl (CH3CO) derivative of salicylic acid has been widely used as a general purpose pain

reliever for over a hundred years. It is potent, relatively safe and inexpensive. Annual production of
aspirin is in excess of 40,000 tons worldwide.

Written records from 500 B.C. indicate that the Greek doctor Hippocrates used the bark of
the willow tree as a pain reliever for individuals suffering from rheumatism and various forms of
inflammation.’ Research showed later that the active ingredient was Salicylic acid (see formula
below).

OH

OH
Salicylic acid

By the end of the 19th century, doctors regularly prescribed salicylic acid for
the treatment of arthritic pain. However, salicylic acid is no longer used as an oral medicine, since it
is very irritating to the stomach and can Cause serious gastrointestinal bleeding. lts main use is in
topical medications to remove warts and callouses.

Acetylsalicylic acid was discovered by the German chemist Felix Hoffmann, who tried to
make a less irritating medicine for his arthritic father. In 1897 he prepared aspirin, a more potent
and less irritating anti-inflammatory agent, and just two years later Bayer & Co. began marketing it
as Aspirin. Aspirin acts by inhibiting the enzyme cyclooxygenase (COX) that directs the synthesis of a
family of cell regulators called prostaglandins (PGs). In the stomach, a particular PG (PGE-) is
beneficial because it inhibits the excessive production of hydrochloric acid (HCI) and enhances the
formation of a protective layer of mucus.

Aspirin was widely used during the flu epidemic in Europe in 1917-1918 because it
effectively lowers dangerously high fevers. Such fevers are caused by elevated levels of PGE, in the
brain which are decreased by aspirin. By the 1950s aspirin became by far the most widely used
painkiller globally. That massive usage allowed the detection of aspirin's anticlotting properties and
the realization that it could be used to lower the risk of heart attack due to the clotting of blood in
disease-narrowed arteries. Taken soon after a heart attack, aspirin may also limit the size of the
infarcted area.”

Subsequent research indicated that aspirin inhibits blood clotting at low dosages (80-90 mg
per day). During the late 1980s studies also showed that aspirin can limit brain damage due to
occlusive stroke caused by a blood clot, if taken early. The use of aspinn is contraindicated in
hemorrhagic stroke, because it may increase bleeding.°

The anticlotting action of aspirin at low doses is due to the irreversible inhibition of
cyclooxygenase in blood platelets by transfer of the acetyl group from aspirin to a critical serine
hydroxyl group at the catalytic site of the enzyme. Since mature platelets have a lifetime of only
about 2 weeks and are not able to synthesize new protein, the clotting ability of aspirin-treated
platelets is permanently blocked.