Paracetamol through the lens of ion channels

Paracetamol (also known as acetaminophen) is a familiar over-the-counter medication widely used for relieving pain and reducing fever. Interestingly, despite its widespread use, its exact mode of action is still not fully understood.

Traditionally, it was believed that paracetamol’s primary mechanism of action involved inhibiting the enzyme cyclooxygenase (COX), which is also targeted by nonsteroidal anti-inflammatory drugs (NSAIDs). However, unlike NSAIDs, paracetamol does not exhibit significant anti-inflammatory effects, indicating that alternative pathways might be involved.

Some evidence suggests that paracetamol may also act through the endocannabinoid system and/or enhance serotonergic mechanisms that inhibit pain pathways in the CNS.

Alongside these mechanisms, ion channels have emerged as crucial determinants of paracetamol’s analgesic action. Recent research highlights that ion channels such as TRPV1, TRPA1, and Kv7 are integral to the analgesic effects of paracetamol. Its metabolites, like AM404 and NAPQI, activate these channels, contributing to paracetamol’s pain-relieving effects.

While paracetamol is safe under recommended doses, excessive intake can lead to severe liver damage. Paracetamol overdose is a serious and potentially life-threatening condition and is one of the most common causes of poisoning worldwide.

The primary concern with a paracetamol overdose is the formation of a toxic metabolite called N-acetyl-p-benzoquinone imine (NAPQI). Normally, NAPQI is detoxified by glutathione in the liver, but in an overdose situation, glutathione stores are depleted, leading to NAPQI accumulation, oxidative stress, hepatocyte death, and liver failure.

Ion channels, particularly calcium-permeable channels like TRPM2 and TRPV4, have been shown to play significant roles in liver injury. TRPM2 channels are activated by reactive oxygen species (ROS), leading to increased intracellular calcium levels, which contribute to liver cell injury and death. This activation is especially relevant in conditions of oxidative stress, such as those induced by paracetamol overdose. In TRPM2 knockout mice, acetaminophen-induced liver damage was significantly diminished compared with wild-type mice.

Likewise, inhibition or genetic deletion of TRPV4 in mice reduced paracetamol-induced liver damage by attenuating oxidative stress and mitochondrial dysfunction, suggesting TRPV4 as a potential therapeutic target for paracetamol overdose-induced liver failure.

Overall, ion channels appear to significantly influence paracetamol’s action. But you have to be on your guard. At the right dosage, ion channels are your best friends in fighting pain with paracetamol. But take too much, and they turn into frenemies with your liver. Best to keep it cool and follow the guidelines!