Feb 2, 20223 min read

Paracetamol – The History and Science of a Household Medicinal Molecule | Tawfeeq Hamayun

Paracetamol, with the chemical name acetaminophen and a molecular formula C8H9NO2, is a medication or drug that was initially synthesised by Harmon Northrop Morse in 1877 at Johns Hopkins University, through the reduction of p-nitrophenol (a phenolic compound) with tin in acetic acid. However, it was only ten years later, in 1887, when it was first trialled on humans by clinical pharmacologist Joseph von Mering who claimed in his report that paracetamol tended to produce methemoglobinemia (a condition where elevated amounts of altered iron ions in haemoglobin are found in the blood). This meant that paracetamol was discarded in favour of another drug that didn’t share these unwanted side effects. This was only disproved half a century later by David Lester and Leon Greenberg in 1947 where lab tests showed that von Merings’ findings were negligible in the amount of methaemoglobin produced and stated that paracetamol was a powerful and highly useful medication that belonged to family of drugs that have analgesic / pain relieving and antipyretic/fever relieving properties. This ‘rediscovery’ of paracetamol led to its marketisation in the United Kingdom and the United States where it has gained popularity since, as an analgesic agent with very few side effects and little interaction with other pharmaceutical agents.

Paracetamol is often used to treat aches and pain such as a headache or reduce high temperature. Like any other drug, Paracetamol comes with its side effects. These include nausea, stomach pain, loss of appetite, etc. In addition to this, some people may be allergic to the drug, causing a rash, swelling, low blood pressure and a fast heartbeat. It is absorbed within 30 minutes to 2 hours through the gastrointestinal tract after the intake, most of which is metabolised by the liver and the remaining, excreted through urine. Paracetamol is available almost everywhere and can be administered through oral, suppository and intravenous (when it is injected in the veins; for quick results) methods. Sometimes, other chemicals and active ingredients are added to paracetamol such as opiate codeine, ascorbic acid, caffeine, etc, to change its properties and enhance it to the desired effect.

The overdose of paracetamol causes liver damage, which can be fatal, with statistics showing approximately 30,000 people per year going to hospital after taking too much paracetamol or paracetamol poisoning and 150 people die of overdose paracetamol each year in the UK alone. The liver damage is not directly caused by the Paracetamol molecule, it is caused by a molecule that is the product of paracetamol when it is broken down, N-acetyl-p-benzo-quinone imine, which reacts with liver cells and kidney tubules.

Image 1

The acetaminophen molecule (labelled paracetamol) contains three functional groups (see image 1), one of which is the OH (hydroxyl group), the amide group and the aromatic group also known as the benzene ring. Acetaminophen’s site of pharmacological action is within the central nervous system. It can easily pass the blood-brain-barrier and inhibits the Cyclooxygenase pathway, which reduces the synthesis of prostaglandin which, in turn, reduces pain sensation in the nerves and increases the pain threshold. This explains its pain-relieving properties. Its analgesic properties are because Paracetamol undergoes conjugation with Arachidonic acid by fatty acid amid hydrolase enzymes, which forms AM404 in the brain and spinal cord inhibiting the Anandamide Membrane Transporter which gives it its calming property. This is also depicted in the diagram below.

Image 2

Paracetamol can also be synthesised through several different methods. The traditional methods differ. In one of the methods (Image 3), nitration of phenol with nitic acid is undergone, producing 4-nitrophenol when it undergoes hydrogenation. Whereas in another method, the nitrobenzene is reduced electrolytically which produces 4-aminophenol directly.

Paracetamol can also be synthesised by reacting 4-aminophenol with ethanoic anhydride, which forms an amide bond and ethanoic acid as by-product (Image 4). After the completion of the reaction, Paracetamol is isolated and purified.