Paracetamol, known as acetaminophen in the United States, is a painkiller that is popular throughout the world because it is remarkably safe and it does not irritate the stomach. Paracetamol was first discovered to have both analgesic and antipyretic properties in the late nineteenth century. Prior to this, cinchona bark, which was also used to make the anti-malaria drug quinine, had been used to treat fevers. As cinchona became scarcer, people began to look for cheaper synthetic alternatives. Two of these alternative compounds were acetanilide and phenacetin, developed in 1886 and 1887 respectively. By this time, Harmon Northrop Morse had already synthesized acetaminophen in 1878 through the reduction of p-nitrophenol with tin in glacial acetic acid.In 1893, the white, odourless crystalline compound with a bitter taste that became known as paracetamol was discovered. Initially, paracetamol was found in the urine of patients who had taken phenacetin and in 1889 it was demonstrated that paracetamol was a urinary metabolite of acetanilide. These discoveries, however, failed to attract much attention and were largely ignored at the time.It was not until 1948, when Brodie and Axelrod established that paracetamol was a major metabolite of both acetanilide and phenacetin, that paracetamol experienced a resurgence of interest. As a derivative of p-aminophenol, paracetamol corresponds to the active principal metabolite phenacetin. It was commonly assumed at the time that their rapid conversion by the body into paracetamol was actually responsible for the therapeutic effects of both of these medicines. It was eventually ascertained that phenacetin had its own pharmacological action and was not dependent on paracetamol for its effects. Because a high proportion of phenacetin is converted into paracetamol in the liver, however, phenacetin required a large dosage to achieve any direct analgesic effect. In 1956, 500mg tablets of paracetamol went on sale in the United Kingdom and its popularity as an over-the-counter analgesic rapidly increased. This popularity was partly explained by the fact that paracetamol was proven to be easier on the stomach than some other analgesics. Paracetamol gradually became combined with both analgesics and oral decongestants.Paracetamol works as a weak prostaglandin inhibitor. It achieves this by blocking the production of prostaglandins, which are chemicals involved in the transmission of the pain message to the brain. In this regard, paracetamol is different from Aspirin and NSAIDs (non-steroidal anti-inflammatory drugs) in that it blocks the pain message at the brain and not at the source of the pain, as the others do. Structually, paracetamol is similar to aspirin. They are both recognised by the same enzyme, which is called cyclo-oxygenase (COX). Cyclo-oxygenase serves as a pain activator, amplifying the degree of pain experienced in order to let the body know that there is a problem. It is this enzyme that is responsible for the biosynthesis of prostoglandins. By reducing the amount of prostaglandin available for synthesis, paracetamol helps relieve headache pain by reducing the dilation of the blood vessels that cause the pain. Paracetamol, however, only inhibits prostaglandin biosynthesis in the central nervous system (CNS) with little or no effect on peripheral tissues.Paracetamol is used to relieve mild to moderate pain, including instances of tension headache, migraine headache, muscular aches, neuralgia, backache, joint pain, rheumatic pain, general pain, toothache, teething pain, and period pain. It is suitable for most people, including the elderly and young children, because it has very few side effects. Paracetamol is used to treat osteoarthritis, a type of non-inflammatory arthritis due to the "wear and tear" of the joints, because of its analgesic properties and its lack of gastrointestinal side effects. It can also help with the pain experienced by sufferers of arthritis.Paracetamol is an antipyretic that can reduce fever by affecting the part of the brain known as the hypothalamus that regulates the temperature of the body. This is why paracetamol is included in many cough, cold and flu medications. Specifically, paracetamol has been given to children after they have been given vaccinations in order to prevent them developing post-immunisation pyrexia, or fever.Paracetamol can be used by patients for whom NSAIDs are contraindicated, including those with asthma or peptic ulcers. Because there are few interactions with other medications, paracetamol can be taken by people with sensitivity to aspirin. Cholestyramine, which lowers high cholesterol, may reduce the rate at which paracetamol is absorbed by the gut, while Metoclopramide and Domperidone, which are used to relieve the symptoms of stomach disorders, may have the opposite effect and should be used with caution. Paracetamol has shown no propensity to be addictive, even in people who use it frequently. Long-term or regular use of paracetamol may, however, increase the anticoagulant activity of warfarin or similar anticoagulant medicines so caution may be required in these instances.Some research suggests that it may protect the arteries from the changes that lead to hardening of the arteries, which can cause strokes, heart attacks or cardiovascular disease. This is because paracetamol can inhibit the oxidation of some of the low-density lipoproteins that carry 'bad' cholesterol, counteracting the process that causes the formation of arterial plaque. There is also some evidence to suggest that paracetamol may offer some protection against ovarian cancer. Paracetamol, however, is not useful in reducing inflammation or the swelling of the skin or joints. This is because paracetamol has no clinically useful anti-inflammatory properties. The body rapidly absorbs Paracetamol, with the soluble form being absorbed even faster than the solid tablets. As the paracetamol is metabolised, the peak blood level remains less than 20mg/litre after a standard adult 1000mg dose. Blood serum levels will normally peak between half an hour to two hours after ingestion. The analgesic properties of paracetamol will last for around four hours. Paracetamol has a half-life of about two hours, after which it will rapidly be expelled from the body.Paracetamol is primarily metabolised in the liver. Paracetamol and its two primary metabolites are remarkably safe compounds. About 90% of the dose of paracetamol will be combined with glucuronide and sulphate before being excreted. Of the remaining 10%, about 5% will leave the body unchanged and the other 5% will be oxidized to benzoquinoneimine. The benzoquinoneimine is then combined with glutathione and becomes metabolised on to cysteine and mercapturate compounds before being safely excreted via the kidneys.Because they have heard that a large dose of paracetamol can damage the liver, some people mistakenly believe that a small dose of paracetamol must therefore be able to cause minor damage to the liver. Taken long-term, in proper therapeutic doses, the liver and other organs should not be harmed by paracetamol.