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Paracetamol, also known as acetaminophen, is a long-established, non-prescription, peripherally-acting antipyretic analgesic drug. As such it is a common ingredient in over-the-counter analgesics and cold and flu remedies.

The painkilling properties of paracetamol were discovered by accident when a similar molecule (acetanilide) was added to a patient's prescription approximately 100 years ago. However, since acetanilide is toxic in moderate doses, chemists modified its structure and developed a compound that was less harmful, but which retained the analgesic properties. One of these compounds was N-acetyl-para-aminophenol, which is also known as acetaminophen in the US and paracetamol (from para-acetyl-amino-phenol) in the UK.


Acetanilide	Paracetamol	Aniline

The original compound, acetanilide, is partially converted into a mixture of paracetamol and aniline in the body. However, while paracetamol is an analgesic, aniline is toxic.

Paracetamol is one of the most commonly used drugs in the world and is manufactured in huge quantities. It was first synthesised by Morse in 1878 by the reduction of para-nitrophenol with tin in glacial acetic acid. The para-aminophenol produced by the reducing action of the tin was acetylated in situ by the acetic acid. This manufacturing procedure was subsequently simplified by using para-aminophenol as the starting material and acetylating with acetic acid. This procedure has been modified several times since.

Commercial manufacture

A number of commercial methods of manufacture are currently in use around the world. Most commonly, the starting material is phenol, which is nitrated to give a mixture of ortho- and para-nitrophenol. The para-nitrophenol is reduced to para-aminophenol and then acetylated with acetic anhydride to produce paracetamol.

The plasma half-life of paracetamol ranges from 1–4 hours. It is distributed throughout most fluids of the body and is metabolised primarily in the liver. Little unchanged drug is excreted in the urine, but most metabolic products appear in the urine within 24 hours. Compared with other minor analgesics, such as aspirin, its onset of action is generally slower, since it is only absorbed once it has left the stomach and entered the duodenum.

While the precise mode of action is paracetamol is unclear, it is thought that, like aspirin, its effect is due to inhibition of prostaglandin synthesis (How paracetamol works). Paracetamol and aspirin inhibit the same enzyme (cyclo-oxygenase) responsible for the biosynthesis of prostaglandins. By reducing the synthesis of prostaglandins, paracetamol produces analgesia by elevating the pain threshold and reduces fever by 'resetting' the hypothalamic heat-regulating centre of the brain. However, in contrast to aspirin, paracetamol is thought to act almost exclusively on the central nervous system, with little peripheral effect. This may explain why paracetamol, even in higher doses, has limited anti-inflammatory effect and is associated with fewer gastro-intestinal side effects.

Paracetamol is indicated for the relief of mild-to-moderate pain and for the reduction of fever and is a major component of many over-the-counter analgesics and cold and flu remedies. However, while its analgesic and anti-pyretic properties are comparable to those of aspirin, it does not have the same anti-inflammatory properties and is thus not routinely used in inflammatory conditions such as rheumatoid arthritis.

Warnings and contraindications on paracetamol may differ in different countries. Always read the label and leaflet appropriate to the product.

When used correctly, paracetamol is safe to take. However, its use is contraindicated in patients with a hypersensitivity to paracetamol. Paracetamol should be used with caution in patients who are renally or hepatically impaired, dependent on alcohol or malnourished.

Drug interaction warnings on paracetamol may differ in different countries. Always read the label and leaflet appropriate to the product.

It is possible that paracetamol may react with warfarin with prolonged, regular use.

Warnings on overdose may differ in different countries. Always read the label and leaflet appropriate to the product.

Although the safety of paracetamol is well established when used correctly, side effects can occur and overdosage can be extremely dangerous. Because paracetamol is extensively metabolised by the liver overdose can result in acute hepatic necrosis, although without treatment < 10% are at risk of severe liver damage. Approximately 1% will develop fulminant hepatic damage, which is usually fatal.

The reason behind the potentially fatal effects of a paracetamol overdose is the process by which it is eliminated from the body. In the first instance paracetamol is oxidised to quinone imine. This compound is extremely toxic and like other such compounds is eliminated in the liver by reaction with glutathione. If insufficient glutathione is available, the toxic quinone will not be eliminated and will react with cellular proteins and nucleic acids in the liver, eventually causing irreparable damage. Too much paracetamol effectively serves to exhaust the body's valuable glutathione reserves so that it can no longer eliminate toxic chemicals. Thus the patient suffers the symptoms of paracetamol overdose.

However, early treatment with agents that initiate glutathione synthesis, such as methionine and N-acetylcysteine, effectively boost levels of the vital glutathione in the liver to prevent liver failure and death following paracetamol overdose.

Patients who regularly consume excessive volumes of alcohol, who regularly take enzyme-inducing drugs or who have conditions causing glutathione depletion, such as malnutrition and HIV infection, are at increased risk of liver failure, following paracetamol overdose.

Warnings on hypersensitivity may differ in different countries. Always read the label and leaflet appropriate to the product.

This is a standard warning on all medicines and is designed to cover the eventuality that some patients may have a specific sensitivity to the active ingredient or to any of the other components of the medicine, such as solubilising agents, stabilisers, anti-oxidants, colourings and flavourings.

Warnings on the use of paracetamol in children may differ in different countries. Always read the label and leaflet appropriate to the product.

Paracetamol is appropriate as an antipyretic analgesic in children and there are no specific paediatric hazards. Liquid paracetamol products are particularly suitable for children, and can be given to babies to treat the raised temperatures that may follow immunization.

Warnings on paracetamol may differ in different countries. Always read the label and leaflet appropriate to the product.

There is no evidence that taking paracetamol causes asthma. One study has shown that people with severe asthma take more paracetamol than average, but this may be because they suffer from more headaches. The Committee on Safety of Medicines has reviewed this study and advised that there is no reason for advising any change in the use of paracetamol. Paracetamol is a safe and effective pain killer for many patients including asthmatics. In some rare cases, established asthmatics may be sensitive to paracetamol. In these patients, taking paracetamol may precipitate an asthma attack.

Warnings on paracetamol may differ in different countries. Always read the label and leaflet appropriate to the product.

Although paracetamol crosses the placenta the drug has been used widely as an analgesic during pregnancy and no adverse fetal events have been recorded. However, it is always wise to consult a doctor about taking any medicines.

Since paracetamol is thought to inhibit the production of prostaglandins, it is not advisable to take paracetamol during labour.

Paracetamol does appear in breast milk but has not been detected in the urine of breast-fed infants. Breast-feeding is not a contraindication to paracetamol use.

	Introduction		Uses of paracetamol
	Structure		General contraindications
	Discovery		Drug interactions
	Synthesis		Paracetamol in overdose
	Commercial manufacture		Hypersensitivity
	Chemical characteristics		Children
	Pharmacokinetics		Asthma
	Mode of action		Pregnancy, labour and breast feeding