The science behind the most common medication: Acetaminophen
You know those times when you catch a cold, get a fever, or have a mild headache and just think, let me just take some panadol and everything will go away. Well, have you ever wondered how that little pill can relieve you of so much suffering? Fret no more, as this article will we discussing just exactly how something so minor can have major effects on our body.
Mechanism of action
Well, before anything, panadol is actually just a brand name while the active ingredient inside is called acetaminophen. Historically, acetaminophen was characterised as a non-steroidal anti-inflammatory (NSAIDs) due to its proposed effect of inhibiting the cyclooxygenase (COX) pathways. COX pathways are common causes of pain and inflammation when the body is damaged. In brief, COX enzymes convert arachidonic acid, a component of our cell membrane that gets released when it is damaged, into prostaglandins. These prostaglandins induce inflammation and cause pain. NSAIDs usually block one or more types of COX enzymes from performing their activity, thus reducing inflammation and pain (Ghlichloo and Gerriets, 2023). However, acetaminophen seems to not be a competing substrate for COX-1 or COX-2 enzyme, thus making the COX pathway unlikely to be the therapeutic mechanism of acetaminophen (Gerriets and Nappe, 2023).
Instead, acetaminophen seems to be first metabolized to p-aminophenol, which crosses the blood-brain barrier, and is then converted into AM404 (Högestätt et al., 2005). AM404 is widely known to be the most important mediator of acetaminophen’s analgesic property. In the brain, AM404 acts on CB1 receptors and TRPV1 receptors which helps reduce the pain sensation, not by decreasing inflammation, but by reducing the signal sent to the brain (Mallet et al., 2023). There is also a possibility that AM404 also induce analgesia via activation of those receptors in the spinal cord. Activation of these receptors could lead to downstream activation of serotonergic pathways that can also decrease pain (Ohashi and Kohno, 2020).
Together, these alternative pathways for analgesia means that acetaminophen comes with less side effects compared to NSAIDs, and in fact it is commonly indicated for patients that cannot tolerate NSAIDs.
Figure 1: Overall mechanism of action of paracetamol/acetaminophen
Conclusion
In conclusion, acetaminophen is unlike NSAIDs and the previous notion that it acts on COX pathways to reduce inflammation may not be the major way it reduces pain. On the other hand, its more potent effect on the central nervous system and its perception of pain is more likely to be the contributing factor.
Article prepared by: Jared Ong Kang Jie, R&D Director of MBIOS 2023/2024
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References
Gerriets, V. and Nappe, T.M. (2023). Acetaminophen. [online] National Library of Medicine. Available at: https://www.ncbi.nlm.nih.gov/books/NBK482369/.
Ghlichloo, I. and Gerriets, V. (2023). Nonsteroidal Anti-inflammatory Drugs (NSAIDs). [online] PubMed. Available at: https://www.ncbi.nlm.nih.gov/books/NBK547742/.
Högestätt, E.D., Jönsson, B.A.G., Ermund, A., Andersson, D.A., Björk, H., Alexander, J.P., Cravatt, B.F., Basbaum, A.I. and Zygmunt, P.M. (2005). Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System. Journal of Biological Chemistry, 280(36), pp.31405–31412. doi:https://doi.org/10.1074/jbc.m501489200.
Mallet, C., Desmeules, J., Pegahi, R. and Eschalier, A. (2023). An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact. Journal of Pain Research, Volume 16, pp.1081–1094. doi:https://doi.org/10.2147/jpr.s393809.
Ohashi, N. and Kohno, T. (2020). Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action. Frontiers in Pharmacology, [online] 11. doi:https://doi.org/10.3389/fphar.2020.580289.