How Painkillers Work

One way to reduce pain and fever is to inhibit prostaglandin synthesis. The ancient Greeks did this by chewing on the bark of willow trees. It turns out that willow tree bark is a natural source of salicylates and these compounds inhibit the COX acivity of prostaglandin H synthase (PGHS) by modifying the enzyme to prevent arachidonate from binding to the active site.

Unfortunately, most salicylates taste horrible and cause inflammation of the mouth, throat, and stomach. Furthermore, they block the synthesis of other prostaglandins that promote blood clotting so an excess of salicylates will lead to bleeding of ulcers and other problems.

Aspirin is a modified salicylate. The active ingredient is called acetylsalicylic acid. It was introduced as a commercial drug in 1887. It doesn't taste as bad as most other salicylates and doesn't produce severe side effects.

Although it's better than natural salicylates, aspirin can cause dizziness, ringing in the ears, and bleeding or ulcers of the stomach lining. The stomach problems are caused by inhibition of a different COX activity from the one leading to prostaglandin synthesis.

There are two different forms of PGHS or COX. COX-1 is a constitutive enzyme that regulates secretion of mucin in the stomach, thus protecting the gastric wall. COX-2 is an inducible enzyme that promotes inflammation, pain, and fever. Aspirin inhibits both isozymes.

There are many other nonsteroidal anti-inflammatory drugs (NSAIDS) that inhibit COX activity. Aspirin is the only one that inhibits by covalent modification of the enzyme. The others act by competing with arachidonate for binding to the COX active site. Ibuprofen (Advil®), for example, binds rapidly, but weakly, to the active site and its inhibition is readily reversed when drug levels drop. Acetaminophen (Tylenol®) is an effective inhibitor of COX activity in intact cells.


Physicians would like to have a drug that selectively inhibits COX-2 and not COX-1. Such a compound would not cause stomach irritation. A number of specific COX-2 inhibitors have been synthesized and many are currently available for patients. These drugs, while expensive, are important for patients with arthritis who must take pain killers on a regular basis. In some cases, the new NSAIDS have been associated with increased risk of cardiovascular disease and they have been taken off the market. X-ray crystallographic studies of COX-2 and its interaction with these inhibitors have aided the search for even better replacements for aspirin without the cardiovascular side effects.

[Modified from Horton et al. Principles of Biochemistry ©Pearson Prentice Hall]