A bitter pill with a fatal attraction

Painkiller turned killer?
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The Independent Online
Speaking at the British Medical Association annual clinical meeting earlier this month, Professor Sir David Carter, director of the Liver Transplant Centre at Edinburgh Royal Infirmary, called for a ban on Britain's most popular painkiller, blaming it for a significant number of patients who need transplants.

Britons buy 4 billion paracetamol tablets a year for aching heads, muscles and joints. Paracetamol is sold under many trade names such as Hedex, Panadol and Calpol (the syrup form suitable for children), and it is also added to other tablets and linctuses such as Anadin Extra, Solpadeine and Night Nurse.

Every week more than 500 people go to hospital having taken an overdose of this painkiller, on average five of them die. While most who receive medical help have taken an overdose deliberately, a few have exceeded the safe level by taking too many paracetamol-based cold remedies. Treatment consists of the antidote, N-acetylcysteine, and if this is given within 10 hours of taking an overdose they will usually come to no harm. However, for a few the antidote comes too late and, although they appear to recover, recovery is brief, because paracetamol has destroyed their liver.

Paracetamol is the generic name for N-(4-hydroxyphenyl) acetamide, which used to be called para-acetaminophenol. It is a bitter-tasting, white solid, which is not very soluble in water, and melts at 170 degrees C. The molecule consists of a benzene ring with hydroxy (OH) and acetamide (NHCOCH3) groups attached. It was first prepared in the 19th century from 4-nitrophenol, which was made from the phenol produced by Victorian gasworks. Paracetamol was originally used to make dyes and as a developer in photography. Then, in about 1950, it began to be sold as a safer alternative to aspirin, which causes stomach bleeding and ulcers in some who take it.

Paracetamol, like aspirin, acts primarily on the nervous system by blocking the enzymes needed to make prostaglandins, whose production is stimulated when the body is damaged or invaded by viruses or bacteria. It is the over-production of prostaglandins which leads to the discomforts of inflammation, pain and high temperatures. People used to use paracetamol unknowingly in the treatment of fevers 100 years ago, when the chemical acetanilide (generic name antifebrin) was given to hospital patients. This brought their temperatures down because the body's own metabolism converts it to paracetamol - although this was not realised at the time.

Paracetamol lasts in the body for about six hours, and the average person can take 24 paracetamol tablets (12 grams), at the rate of two every six hours for three days, and come to no harm. But if they take them in one go, they could die.

In his book Introduction to Toxicology (2nd edition, Taylor & Francis) Professor John Timbrell of the London School of Pharmacy explains the paracetamol mystery: "Although paracetamol's effects are beneficial, our body still treats the molecule as something to be excreted, and it does this by converting it to other molecules that are more soluble in water and filtered out by our kidneys. There are three enzymes that help remove it, and it is the one which comes into play if we take too much that causes the problem."

The body's preferred way of removing paracetamol is with an enzyme which adds a sulphate group to the molecule. Alternatively, it can use another enzyme to attack the unwanted chemical with glucuronic acid, a derivative of glucose, which has the same effect of making it more soluble. If the amount of paracetamol is low, as it is with the recommended dosage, these enzymes cope quite easily. But if we take too much then a third enzyme, a mono-oxygenase, becomes more important.

This oxidises paracetamol to a highly reactive molecule, N-acetyl-4-benzoquinone imine, which can attack the protein of the liver; but it is prevented from doing so by the natural antidote, glutathione. It is when this eventually becomes depleted that the liver is at risk, but this can be prevented by giving the patient the antidote N-acetylcysteine, which increases the liver's glutathione levels.

There is also another way of preventing damage due to overdosing: adding methionine to paracetamol tablets. This essential amino acid boosts the amount of glutathione in the liver. Pameton or Paradote tablets offer this added protection, even though they are slightly more expensive at about pounds 2 a pack of 24, compared with pounds l.50 for advertised products, and less than pounds l for own-brand varieties. Medical authorities are divided on whether such tablets are effective in preventing liver damage. Those who take paracetamol for long-term treatment should not be prescribed them because of the dangers associated with excess intake of methionine. "Packs of these brands should carry warnings against too-frequent use," says Dr Geoffrey Brandon, of the Paracetamol Information Centre, points out that a high intake of methionine has been linked to heart disease and strokes.

The author is science writer in residence at Imperial College, London.