A short guide to aspirin

Aspirin

written by Mike Harrington, PhD as a supplement for my BIOL 107 course

Version 2.2 - Updated August 9, 2006

What is Aspirin?

Aspirin is the trade name of the chemical acetylsalicylic acid (ASA) shown here. Crystals of aspirin look quite dramatic under polarized light (pictures).

Where does Aspirin come from?

The history of botanical remedies for pain is a long one. Ancient Egyptians used leaves from the myrtle bush, Europeans used willow leaves, and the Native peoples of North America made pain remedies from birch bark. All of these plants have been found to contain a chemical called salicylic acid shown here:

Salicylic acid (SA) was isolated by Johann Buchner in 1828. Work progressed on its isolation and purification through the nineteenth century. SA was found to be an effective pain reliever but it caused severe irritation in the mouth and stomach. Felix Hoffmann (below), a chemist at the Bayer chemical factory solved this problem by synthesizing a derivative, ASA, that was still active but much less irritating.

In 1899 Bayer began selling ASA as the pain reliever aspirin. The name comes from a = acetyl, spir = Spiraea, a genus of plants which makes SA, and in = a common suffix for medicines. Aspirin went on to become the biggest selling drug in the world. Each year more than 100 billion aspirin tablets are consumed. Hoffmann went on to develop a medication to treat patients recovering from addiction to the painkiller morphine. His "non-addictive" substitute was marketed under the brand name heroin. It was a less successful product for Bayer.

For more information check out the Chemical Heritage Foundation's Aspirin adventures (the source of these figures), Bayer's History of Aspirin, or the History of Heroin.

What benefits does aspirin provide?

Aspirin is an extraordinarily versatile drug.

(1) Aspirin is an analgesic (anti-pain), anti-inflammatory, and antipyretic (fever-reducing) medicine that works by inhibiting the production of messengers (called prostaglandins) that act on the central nervous system. This occurs because aspirin inactivates the COX-2 enzyme necessary to make these messengers (see below).

(2) In the 1980s it was demonstrated to also act as an cardioprotector. It reduces the likely hood of heart attacks and strokes by inhibiting the aggregation of blood platelet cells. If taken during a heart attack it reduces the risk of death by 23%. It does this by inactivating an enzyme in platelets called COX-1.

(3) Recently, some studies have shown that long term use of aspirin may decrease the likely hood and slow the progression of certain cancers. However other studies have not found a connection.

For more information about what Aspirin does see the Bayer Aspirin web site or this article written by Shauna Roberts.

What negative side-effects does aspirin have?

Like any other medicine, aspirin has negative side effects in certain situations - usually with excessive doses.

(1) It may cause stomach problems and kidney problems. This is because both of these organs require COX-1 for their normal functioning (see below).

(2) It may cause metabolic acidosis - a drop in the blood pH. This occurs when an excess of aspirin, an acid, overwhelms the blood's bicarbonate buffer system.

(3) It may cause hyperpyrexia - elevated body temperatures. To explain how we need to examine how the mitochondria in our cells synthesize ATP using the process of cellular respiration. Mitochondria have a proton gradient across their inner membrane. This gradient is made by electron transport chains (ETCs) using electrons removed from organic molecules. This proton gradient powers ATP Synthases which make ATP. However, aspirin molecules can carry protons across the inner mitochondrial membrane allowing them to bypass the ATP Synthases. In this situation the ETCs and the ATP Synthases are said to be uncoupled. As the efficiency of cellular respiration decreases the amount of heat produced increases. The result is hyperprexia. This situation usually occurs when small children eat aspirin tablets thinking that they are candy.

(4) In rare cases aspirin causes Reye's syndrome if it is given to children to treat chickenpox (varicella virus infection) or the flu (influenza virus infection). It is a severe and often fatal disorder characterized by deterioration of the brain and liver. Its cause is unknown. This is why aspirin, even children's aspirin, should never be given to a child under the age of 17 unless directed to by a physician.

(5) Aspirin may also trigger an asthma attack in people with asthma. How this happens is not clear.

How does aspirin work?

Aspirin has been known to work for over a hundred years. However, it was not until 1971 that a British pharmacologist John Vane (right), discovered how it works. He was awarded the Nobel prize in 1982 for his work.

Aspirin targets a group of enzymes called Cyclooxygenases. These enzymes catalyze a key step in the synthesis of prostaglandins. Prostaglandins are hormones that carry local messages to neighbouring cells (most other hormones carry messages throughout the body). There are two cyclooxygenase genes in humans; the enzymes they make are called COX-1 and COX-2 (illustrated below).


COX-1	COX-2

Put simply, aspirin is an enzyme inhibitor. It attaches an acetyl group to the active site of COX-1 and COX-2. The acetyl group is added to serine530 in COX-1 and serine516 in COX-2. Thus aspirin is a COX-1/COX-2 irreversible inhibitor.

Protein-Serine-CH₂-OH + Aspirin --> Protein-Serine-CH₂-O-CO-CH₃

COX-1 makes prostaglandins that are necessary for the synthesis of protective gastric mucus in the stomach and for proper blood flow in the kidneys. It also makes a prostaglandin necessary for platelet cell functioning. So by inactivating this enzyme aspirin has a negative effect on the stomach and kidneys but a beneficial effect on the circulatory system.

COX-2 makes prostaglandins that are involved in inflammation, pain, and fever. By destroying this enzyme, aspirin can reduce each of these three responses within our bodies.

For more information on Cyclooxygenase including some nifty pictures.

What are COX-2 inhibitors?

From the above description it would seem that a better pain-killer than aspirin would be one that inhibited COX-2 but didn't inhibit COX-1. Indeed, drugs with these properties have been developed and are referred to as selective COX-2 inhibitors. COX-2 inhibitors such as Celebrex (celecoxib, made by Pfizer) and Vioxx (rofecoxib, made by Merck & Co.) were introduced in Canada in 1999. They decrease pain, fever, and inflammation with no negative effects on the stomach. Vioxx for example was used to treat arthritic, menstrual, and acute pain. Its world-wide sales were $2.5 billion (US) in 2003.

The COX-2 controversy began on September 30, 2004 when Merck & Co. voluntarily withdrew Vioxx from the market (see their physician notification letter). They had been testing Vioxx for anti-cancer properties in their APPROVe (Adenomatous Polyp Prevention on VIOXX) trial. Unfortunately, patients who were on Vioxx for more than 18 months began to show an increased frequency of serious cardiovascular problems. The frequency of heart attacks, strokes, and blood clots was 1.5% in patients taking Vioxx compared to 0.78% in patients taking a placebo. Although this increase is small it potentially represents a large number of people world-wide. It is not clear why Vioxx causes cardiovascular problems. It may be due to increasing the patient's blood pressure or by causing inflammation of blood vessel walls. It is also not clear if the problems with Vioxx extend to the other COX-2 inhibitors. Predictably lawyers, politicians, and conspiracy theorists are swarming all over Merck & Co..

While Vioxx is no longer made Celebrex is still available in Canada. Health Canada considers it to be no more dangerous than other pain-killers but recommends that it not be taken by heart surgery patients or people with a history of cardiovascular problems. That said there is still pressure on Pfizer to withdraw Celebrex in Canada - presumably to make it easier to sue the company for damages.