Acetaminophen (Paracetamol)

Acetaminophen, also known as paracetamol, is mainly used to treat pain and fever. These conditions are related to an increased production of pro-inflammatory chemicals called prostaglandins.

Now, acetaminophen works by decreasing the production of prostaglandins, thereby relieving pain, and reducing fever.

In order to understand how acetaminophen works, first we need to talk briefly about inflammation, which is the body’s response to a harmful stimulus, such as infection or injury.

So, during inflammation, your immune cells use an enzyme called phospholipase A2 to take membrane phospholipids and make a 20 carbon polyunsaturated fatty acid, called arachidonic acid.

Arachidonic acid is a substrate for an enzyme called cyclooxygenase or COX.

The enzyme cyclooxygenase exists in two different isoforms: COX-1 and COX-2.

COX-1 is a constitutive enzyme, meaning that it’s always active, while on the other hand, COX-2 is an inducible enzyme, meaning that it must be turned on to function. This is usually triggered by immune cells and vascular endothelial cells during inflammation.

Both enzymes produce prostaglandin E2 (PGE2) and prostacyclin (PGI2), which cause vasodilation and attract different immune cells to the area.

They also act on neurons that detect pain, called nociceptors, and make them more sensitive to stimuli by lowering their threshold for activation.

Finally, they stimulate the hypothalamus to increase the body temperature, causing fever.

Prostaglandin E2 also has other effects like causing uterine contractions, decreasing the secretion of acid, and increasing the production of protective mucus in the stomach.

Alright, now let’s focus on acetaminophen. Acetaminophen is administered orally, rectally, or intravenously; and it works by reversibly inhibiting COX in the central nervous system, thereby decreasing production of the prostaglandins that cause fever and pain.

It’s important to note that acetaminophen is not considered a non-steroidal anti-inflammatory drug (NSAID) because it doesn't inhibit COX peripherally; so unlike NSAIDs, it doesn't have anti-inflammatory activity.

Common indications for acetaminophen include fever and mild to moderate pain, such as myalgia and headache.

Although it’s mainly used alone, it can be coadministered with other medications, such as ibuprofen or morphine to treat severe pain after operations.

Moreover, because it doesn’t affect COX in platelets and the stomach, acetaminophen is a preferred drug in the treatment of fever and pain in individuals with bleeding disorders, peptic ulcers, and individuals allergic to aspirin.

Also, it’s the first-line therapy for children with fever or pain, because aspirin can cause Reye’s syndrome, which is a life-threatening condition that can occur after a viral infection. It’s characterized by progressive encephalopathy and liver degeneration and is linked with aspirin use.

Alright, let’s move onto the metabolism of acetaminophen, which is done by hepatocytes in the liver.

Hepatocytes mainly metabolize acetaminophen by glucuronidation and sulfation to non-toxic metabolites, which are then excreted in the urine.

But, a small amount of acetaminophen is also metabolized by cytochrome P450 enzymes to a highly toxic metabolite, N-acetyl-p-benzoquinone imine or NAPQI.

Normally, this toxic metabolite is inactivated by an antioxidant called glutathione; so in therapeutic doses, acetaminophen doesn’t cause severe side effects.

But, if someone takes too much acetaminophen, the hepatocytes can’t break it all down, so more acetaminophen undergoes CYP450 metabolism, which creates more NAPQI.

Now, because there’s a limited amount of glutathione in hepatocytes, high levels of NAPQI will deplete them, leading to a build up of NAPQI. This toxic metabolite will start causing cell death and acute hepatic necrosis.

Acetaminophen toxicity is the most common cause of liver failure in the USA.

It’s important to note that it could even occur with therapeutic doses in individuals with low glutathione stores, such as infants, elderly, individuals with malnutrition, or with a genetic condition called glutathione synthesis deficiency.

On the other hand, chronic use of alcohol, or some medications like barbiturates, phenytoin, and carbamazepine, can enhance the activity of CYP450, so more NAPQI is produced.

Early symptoms of toxicity are non-specific and they include nausea, vomiting, and abdominal pain; but, as the liver injury progresses, symptoms worsen and individuals may have jaundice, coagulopathy, hepatic encephalopathy, and acute renal failure.

Treatment consists of administration of N-acetylcysteine or for short, NAC, which replenishes glutathione and prevents its depletion.

Summary

All right, as a quick recap. Acetaminophen, also known as paracetamol, is mainly used to treat mild to moderate pain and fever, but it can also be coadministered with other medications, to treat severe acute pain.

Acetaminophen is administered orally, rectally, or intravenously, and it works by reversibly inhibiting COX in the central nervous system.

Finally, acetaminophen toxicity is caused by an increased production of NAPQI, which results in hepatic necrosis and liver failure; and it’s treated by administration of N-acetylcysteine.