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Pain relievers, to be specific, Acetaminophen or Paracetamol (N-acetyl-para-aminophenol, APAP), depending on what it is called in your location is one over the counter medication that is found in almost every household. It is majorly used for aches and pains, and in so many countries, it is used for fever without prescription. While a lot of people take Acetaminophen or Paracetamol, it is important to know if it is really safe to take, and does it have any negative side effect?


![https://commons.wikimedia.org/wiki/File:Paracetamol_acetaminophen_500_mg_pills](https://upload.wikimedia.org/wikipedia/commons/e/e5/Paracetamol_acetaminophen_500_mg_pills.jpg)

[https://commons.wikimedia.org](https://commons.wikimedia.org/wiki/File:Paracetamol_acetaminophen_500_mg_pills.jpg)</div>



Acetaminophen or Paracetamol are oral, rectally or intravenous medications, but in this case, we will be looking at orally, meaning it is taken through the oral cavity, and it goes into the stomach, through the esophagus. Just like food, medicines get digested in the stomach, and then moves into the duodenum of the small intestine, where the majority of the medication gets absorbed into the bloodstream. Different article have different timing to when medicine gets dissolved and absorbed, but it usually takes between 1 hour to 5 hours after ingestion, but from injection it goes straight into the bloodstream. Acetaminophen or Paracetamol in other to treat fever interacts with the hypothalamus in the brain, which regulates homeostasis (including temporature) in the body. For pain, according to this [article](https://academic.oup.com/cid/article/31/Supplement_5/S202/334078), Acetaminophen or Paracetamol inhibits weekly, the enzyme [cyclooxygenase](https://www.sciencedirect.com/topics/neuroscience/cyclooxygenase) (COX)-1 and (COX)-2 which produces prostaglandin which is responsible for pains and inflammation unlike Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) like Ibuprofen, but it does inhibit the (COX)-1 and (COX)-2 thereby reducing pain but not usually at the peripheral tissues.

Another [article](https://pubmed.ncbi.nlm.nih.gov/22206817/) shows that in other to eliminate pain, Acetaminophen or Paracetamol would get involved in the serotonergic system. It affects the Decending Serotonergic Inhibitory Pathway which secretes a neurotransmitter called serotonin. Since Serotonin is responsible for moods, sleep and inhibiting pain, then Acetaminophen or Paracetamol can trigger the production of Serotonin which inhibits pain.


Acetaminophen or Paracetamol when it gets into the bloodstream and is done with its action goes into the liver, and breaks down the Acetaminophen to metabolites which are then sent to the kidney to be excreted through the urinary tubule. While the Liver does a good job in breaking down Acetaminophen or Paracetamol to be excreted, too much of it can be harmful. According to [nhs.uk](https://www.nhs.uk/medicines/paracetamol-for-adults/), 4000 mg daily taken at 4 hours interval at 500 mg with 2 doses. When people take the proper dose, the liver will convert the drug to metabolites, using two enzymes family which are Sulfotranferase, and [UDP-Glucuronosyltransferase](https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/glucuronosyltransferase), and the second class is the cytochrome P450 Group. The first enzyme family breaks down Acetaminophen to metabolites which is harmless to Kidney and is excreted with urine. The remaining paracetamol will be metabolized by the [cytochrome P450 Group](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4093435/) to [N-acetyl-p-benzoquinone imine](https://pubmed.ncbi.nlm.nih.gov/4033631/) (NAPQI) which is a toxic metabolite to the liver, but it is metabolized and detoxified by an enzyme called [Hepatic Glutathione](https://www.webmd.com/vitamins/ai/ingredientmono-717/glutathione). The detoxified metabolite is then sent to the kidney and excreted. In cases of overdose, the first group of enzyme in the liver won't be able to convert the major number of Acetaminophen to the harmless metabolite, thereby leaving more to the cytochrome P450 Group to convert to the harmful/toxic metabolite. With this, more Glutathione is required to detoxify the metabolite but when it is in large quantity, the Glutathione become less capable of converting all increasing the toxic NAPQI leading to liver toxicity (hepatotoxicity/necrosis). 


#### <center>Conclusion</center>
People could either intentionally or untentionally overdose on Acetaminophen or Paracetamol, but the fact remains that, compares to  Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) like Ibuprofen, Acetaminophen is less evasive, and it becomes a harmful tablet when it is overdosed. It is also very important to not take alcohol while using any type of medications, of which Acetaminophen or Paracetamol is one.
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* [Potential Deleterious Effects of Paracetamol Dose Regime Used in Nigeria Versus That of the United States of America](https://www.researchgate.net/publication/360245532_Potential_Deleterious_Effects_of_Paracetamol_Dose_Regime_Used_in_Nigeria_Versus_That_of_the_United_States_of_America#pf8)

* [Paracetamol and pain: the kiloton problem](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451482/)

* [Paracetamol: A Review of Guideline Recommendations](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347233/)


* [How are drugs absorbed in the body? The science of medicine, explained](https://www.inverse.com/science/how-do-drugs-know-where-to-go-in-the-body)

* [Paracetamol for adults ](https://www.nhs.uk/medicines/paracetamol-for-adults/)

* [Medicines and the Digestive System](https://www.hopkinsmedicine.org/health/conditions-and-diseases/medicines-and-the-digestive-system)

* [How Does The Body Metabolize Medication?](https://ocrc.net/how-does-the-body-metabolize-medication/)

* [Loss of hypothermic and anti-pyretic action of paracetamol in cyclooxygenase - 1 ](https://repository.uel.ac.uk/download/ac3cc3e415b55ab424e8e42ec210c6618baad779e6196bc69efc3afe85df4c4a/1055138/Ayoub%20and%20Flower%202019-EJP.pdf)

* [Mechanism of Action of Acetaminophen: Is There a Cyclooxygenase 3?](https://academic.oup.com/cid/article/31/Supplement_5/S202/334078)

* [Systemic paracetamol-induced analgesic and antihyperalgesic effects through activation of descending serotonergic pathways involving spinal 5-HT₇ receptors](https://pubmed.ncbi.nlm.nih.gov/22206817/)

* [LiverTox: Clinical and Research Information on Drug-Induced Liver Injury](https://www.ncbi.nlm.nih.gov/books/NBK548162/)