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Paracetamol

Paracetamol (acetaminophen[a]) is a non-opioid analgesic and antipyretic agent used to treat fever and mild to moderate pain.[13][14][15] It is a widely used over the counter medication. Common brand names include Tylenol and Panadol.

Clinical data

N-acetyl-para-aminophenol (APAP), acetaminophen (USAN US)

63–89%[5]: 73 

negligible to 10–25% in overdose[6]

Predominantly in the liver[9]

APAP gluc, APAP sulfate, APAP GSH, APAP cys, AM404, NAPQI[7]

Pain relief onset by route:
oral – 37 minutes[8]
Intravenous – 8 minutes[8]

1.9–2.5 hours[6]

C8H9NO2

151.165 g·mol−1

1.263 g/cm3

169 °C (336 °F) [10][11]

  • 7.21 g/kg (0 °C)[12]
  • 8.21 g/kg (5 °C)[12]
  • 9.44 g/kg (10 °C)[12]
  • 10.97 g/kg (15 °C)[12]
  • 12.78 g/kg (20 °C)[12]
  • ~14 mg/ml (20 °C)

At a standard dose, paracetamol slightly decreases body temperature;[14][16][17] it is inferior to ibuprofen in that respect,[18] and the benefits of its use for fever are unclear, particularly in the context of fever of viral origins.[14][19][20] Paracetamol relieves pain in both acute mild migraine and episodic tension headache.[21][22] The aspirin/paracetamol/caffeine combination also helps with both conditions where the pain is mild and is recommended as a first-line treatment for them.[23][24] Paracetamol is effective for post-surgical pain, but it is inferior to ibuprofen.[25] The paracetamol/ibuprofen combination provides further increase in potency and is superior to either drug alone.[25][26] The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant.[15][27][28] The evidence in its favor for the use in low back pain, cancer pain, and neuropathic pain is insufficient.[15][29][27][30][31][32]


In the short term, paracetamol is safe and effective when used as directed.[33] Short term adverse effects are uncommon and similar to ibuprofen,[34] but paracetamol is typically safer than non-steroidal anti-inflammatory drugs (NSAID) for long term use.[35] Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen.[36][37] Chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding,[38] and abnormal liver function tests. The recommended maximum daily dose for an adult is three to four grams.[39][40][27] Higher doses may lead to toxicity, including liver failure.[41] Paracetamol poisoning is the foremost cause of acute liver failure in the Western world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.[42][43][44]


Paracetamol was first made in 1878 by Harmon Northrop Morse or possibly 1852 by Charles Frédéric Gerhardt.[45][46][47] It is the most commonly used medication for pain and fever in both the United States and Europe.[48] It is on the World Health Organization's List of Essential Medicines.[49] Paracetamol is available as a generic medication, with brand names including Tylenol and Panadol among others.[50] In 2021, it was the 113th most commonly prescribed medication in the United States, with more than 5 million prescriptions.[51][52]

Medical uses[edit]

Fever[edit]

Paracetamol is used for reducing fever.[13] However, there has been a lack of research on its antipyretic properties, particularly in adults, and thus its benefits are unclear.[14] As a result, it has been described as over-prescribed for this application.[14] In addition, low-quality clinical data indicates that when used for the common cold, paracetamol may relieve a stuffed or runny nose, but not other cold symptoms such as sore throat, malaise, sneezing, or cough.[53]


For patients in critical care, paracetamol decreases body temperature by only 0.2–0.3 °C more than control interventions and has no effect on their mortality.[16] It did not change the outcome in febrile patients with stroke.[54] The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported.[16] Paracetamol offered no benefit in the treatment of dengue fever and was accompanied by a higher rate of liver enzyme elevation: a sign of a potential liver damage.[55] Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection.[20]


The efficacy of paracetamol in children with fever is unclear.[56] Paracetamol should not be used solely with the aim of reducing body temperature; however, it may be considered for children with fever who appear distressed.[57] It does not prevent febrile seizures.[57][58] It appears that 0.2 °C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergency situations.[14] Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7 °C.[17] Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis[59]), including children younger than 2 years old,[60] with equivalent safety.[18] Exacerbation of asthma occurs with similar frequency for both medications.[61] Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended, however doses may be alternated if required.[57]

Pain[edit]

Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, toothache as well as pain caused by cold, flu, sprains, and dysmenorrhea.[62] It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.[15]

Interactions[edit]

Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (tmax) to paracetamol peak blood plasma concentration (Cmax), and increase Cmax. Medications slowing gastric emptying such as propantheline and morphine lengthen tmax and decrease Cmax.[110][111] The interaction with morphine may result in patients failing to achieve the therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear.[111]


There have been suspicions that cytochrome inducers may enhance the toxic pathway of paracetamol metabolism to NAPQI (see Paracetamol#Pharmacokinetics). By and large, these suspicions have not been confirmed.[111] Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for phenobarbital, primidone, isoniazid, and possibly St John's wort.[112] On the other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%.[111]


Ranitidine increased paracetamol area under the curve (AUC) 1.6-fold. AUC increases are also observed with nizatidine and cisapride. The effect is explained by these drugs inhibiting glucuronidation of paracetamol.[111]


Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation.[111] Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week.[113][114][115]

Pharmacology[edit]

Pharmacodynamics[edit]

Paracetamol appears to exert its effects through two mechanisms: the inhibition of cyclooxygenase and actions of its metabolite N-arachidonoylphenolamine (AM404).[116]


Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors.[117] Paracetamol inhibits prostaglandin synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and peroxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight.[116][117] The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the central nervous system and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding.


The second mechanism centers on the paracetamol metabolite AM404. This metabolite has been detected in the brains of animals and cerebrospinal fluid of humans taking paracetamol.[116][118] It is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase.[116] AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor.[116] This and other research indicate that cannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.[116][119]


In 2018, Suemaru et al. found that, in mice, paracetamol exerts anticonvulsant effect by activation of TRPV1 receptors[120] and decrease in neuronal excitability by hyperpolarization of neurons.[121] The exact mechanism of the anticonvulsant effect of acetaminophen is not clear. According to Suemaru et al., acetaminophen and its active metabolite AM404 show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice.[120]

Pharmacokinetics[edit]

After being taken by mouth, paracetamol is rapidly absorbed from the small intestine, while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach emptying and absorption, but the total amount absorbed stays the same.[122] In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.[6]


Paracetamol's bioavailability is dose-dependent: it increases from 63% for 500 mg dose to 89% for 1000 mg dose.[6] Its plasma terminal elimination half-life is 1.9–2.5 hours,[6] and volume of distribution is roughly 50 L.[123] Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21%.[6] The concentration in serum after a typical dose of paracetamol usually peaks below 30 μg/mL (200 μmol/L).[124] After 4 hours, the concentration is usually less than 10 μg/mL (66 μmol/L).[124]

Paracetamol is metabolized primarily in the liver, mainly by glucuronidation and sulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 2–5% of the drug is excreted unchanged in the urine.[6] Glucuronidation by UGT1A1 and UGT1A6 accounts for 50–70% of the drug metabolism. Additional 25–35% of paracetamol is converted to sulfate by sulfation enzymes SULT1A1, SULT1A3, and SULT1E1.[125]


A minor metabolic pathway (5–15%) of oxidation by cytochrome P450 enzymes, mainly by CYP2E1, forms a toxic metabolite known as NAPQI (N-acetyl-p-benzoquinone imine).[125] NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with glutathione. The non-toxic conjugate APAP-GSH is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by the large amount of formed NAPQI, and NAPQI binds to mitochondria proteins of the liver cells causing oxidative stress and toxicity.[125]


Yet another minor but important direction of metabolism is deacetylation of 1–2% of paracetamol to form p-aminophenol. p-Aminophenol is then converted in the brain by fatty acid amide hydrolase into AM404, a compound that may be partially responsible for the analgesic action of paracetamol.[123]

Society and culture[edit]

Naming[edit]

Paracetamol is the Australian Approved Name[158] and British Approved Name[159] as well as the international nonproprietary name used by the WHO and in many other countries; acetaminophen is the United States Adopted Name[159] and Japanese Accepted Name and also the name generally used in Canada,[159] Venezuela, Colombia, and Iran.[159][160] Both paracetamol and acetaminophen are contractions of para-acetylaminophenol, a chemical name for the compound. The word "acetaminophen" is a shortened form of N-acetyl aminophenol, and was coined and first marketed by McNeil Laboratories in 1955.[161] The word "paracetamol" is a shortened form of para-acetyl-amino-phenol,[162] and was coined by Frederick Stearns & Co in 1956.[163] The initialism APAP used by dispensing pharmacists in the United States comes from the alternative chemical name [N-]acetyl-para-aminophenol.[164]

Research[edit]

Claims that paracetamol is an effective analgesic medication to treat symptoms of COVID-19 was found to be unsubstantiated.[182][183][184][185]