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Untold story of paracetamol: Caution on self-medication

Mr. Satish Siripini, Assistant Professor, Faculty of Pharmacy

Paracetamol, also known as para-acetaminophenol, is most commonly used Over the Counter (OTC) drug, for its antipyretic and analgesic activity, whether alone or in combination with other analgesics. The market value of Paracetamol in 2021 is found to be US$ 1.56Bn, so it became very handy in public domain for self-medication due to its unreported adverse effects. The spectrum of paracetamol application expands from fever due to seasonal infections to auto immune rheumatic fevers, mild head ache to severe neuropathy. Despite of its broad therapeutic index, it is later found to be interacting with other drugs and foods with unknown mechanisms. However, these adverse drug reporting of paracetamol are not aware by the common public. This article is to review several ADR reported for paracetamol in different cases.

Paracetamol decreases prostaglandin biosynthesis by inhibiting the cyclo-oxegenase enzyme, this may cause imbalance and might increase the leukotrienes compared to Prostaglandin causing forced expiratory volume[i] showing symptoms similar to aspirin induced asthma.

The phenolic group containing Paracetamol is well absorbed orally, metabolised in liver and excreted in urine. Glucuronide (47-62%) and sulphate (25-36%) metabolites of Paracetamol has a conventional mechanism of excretion, whereas the minor metabolite(8-10%), N- acetyl P-benzoquinone-imine(NAPQ1) released along with 3 hydroxy paracetamol by Cytochrome P450 mediated oxidation, is found to cause hepatotoxicity[ii]. Depletion of hepatic glutathione (malnutrion, other factors also with large dose of paracetamol) and alcohol or drug-based enzyme induction can cause the adverse drug reactions[iii]. Alcoholics are more prone to Paracetamol induced hepatotoxicity due to its enzyme induction, whereas increased glutathione depletion and increase oxidative stress exacerbating the asthmatics. The oxidative stress on hepatic cells can also leads to many metabolic disorders on long run.

In a study conducted by Lykke Ida Kaas Oldenburg et al, 7 shown drug interaction with warfarin, 1 shown with phenytoin and 1 with valsartan showing abnormal biochemical values, ALAT/ASAT and even causing hypertension out of 104 geriatric patients[iv].  In another study it increased the BP by 4mmHg in the hypertension treated patients owing to risk of stroke and cardiac ischemia[v]. There is an evidence of increased upper GI bleeding when administered 2-3gm/day among 40-67 age group. As the PG-E2 is involved in epigenetic regulation, Paracetamol can also affect foetal development and might affect the generations.

Finally, with the above observation from various research groups conveys that the paracetamol can cause hepatotoxicity, trigger asthma, epigenetic alterations, metabolic changes, oxidative stress and many other side effects with varied factors like age, gender, and comorbidities. Hence, adverse effects unreported doesn’t mean that the drug is free of adverse effects but might be observed on chronic usage of drugs or in comorbidities. One should be cautious on self-medication of paracetamol which is handy and frequent subject of self-medication.

[i] McCrae JC, Morrison EE, MacIntyre IM, Dear JW, Webb DJ. Long-term adverse effects of paracetamol – a review. Br J Clin Pharmacol. 2018;84(10):2218-2230. doi:10.1111/bcp.13656

[ii] Kulo A, Peeters MY, Allegaert K, et al. Pharmacokinetics of paracetamol and its metabolites in women at delivery and post-partum. Br J Clin Pharmacol. 2013;75(3):850-860. doi:10.1111/j.1365-2125.2012.04402.x

[iii] Waring WS, Robinson OD, Stephen AF, Dow MA, Pettie JM. Does the patient history predict hepatotoxicity after acute paracetamol overdose?. QJM. 2008;101(2):121-125. doi:10.1093/qjmed/hcm139

[iv] Lykke Ida Kaas Oldenburg, Kim Peder Dalhoff, Luana Østerdal Sandoval, Charlotte Vermehren, “The Risk of Drug-Drug Interactions with Paracetamol in a Population of Hospitalized Geriatric Patients”, Journal of Pharmaceutics, vol. 2020, Article ID 1354209, 9 pages, 2020.

[v] Chalmers JP, West MJ, Wing LM, Bune AJ, Graham JR. Effects of indomethacin, sulindac, naproxen, aspirin, and paracetamol in treated hypertensive patients. Clin Exp Hypertens 1984; 6: 1077–1093.

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